The Health Consequences of Smoking A Report of the Surgeon General: 1971 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 - Price $1.75 Preface This report is a comprehensive review of more than 20 years of research into the problem of smoking and health. This re- search has been carried on under the sponsorship of many groups in this country and abroad, including governments, universities, private research institutions, voluntary health agencies, and the tobacco industry. Seven years ago, an advisory committee to the Surgeon General concluded that cigarette smoking is a serious hazard to health and is related to illness and death from lung cancer, chronic broncho- pulmonary disease, cardiovascular disease and other diseases. In the intervening years, a great deal of new research has been com- pleted. This has resulted in a growing understanding of the bio- mechanisms whereby cigarette smoking adversely affects the hu- man organism and contributes to the development of serious illness. It is encouraging that cigarette consumption in this country is declining. If this decline can be maintained, it will result in better health for our population and in fewer deaths among those of our ‘citizens who are in their most productive years of life. JESSE L. STEINFELD, M.D., Surgeon General. Acknowledgments The National Clearinghouse for Smoking and Health, Daniel Horn, Ph.D., Director, was responsible for the preparation of this report. Daniel P. Asnes, M.D., was consulting editor. Staff direc- tor for the report was David G. Cook, M.D. The professional staff has had the assistance and advice of a number of experts in the scientific and technical fields, both in and outside of the government. Their contributions are gratefully acknowledged. Special thanks are due the following: ANDERSON, WILLIAM H., M.D.—Chief, Pulmonary Disease Section, University of Louisville School of Medicine, Louisville, Ky. ANTHONISEN, NICHOLAS, R., M.D.—Ph. D.—Associate Professor, Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada. AUERBACH, OscaR, M.D.—Senior Medical Investigator, VA Hospital, East Orange, N.J. AYRES, STEPHEN M., M.D.—Director, Saint Vincent’s Hospital and Medical Center of New York, Cardiopulmonary Laboratory, New York, N.Y. Baker, CARL, M.]).— Director, National Cancer Institute, National Institutes of Health, Bethesda, Md. BELLET, SAMUEL, M.D.—Director, Division of Cardiology, Philadelphia General Hospital, Philadelphia, Pa. Binc, RicHarp J., M.D.—Professor of Medicine, California Institute of Tech- nology, Pasadena, Calif. Bock, Frep G., Ph. D.—Director, Orchard Park Laboratories, Roswell Park Memorial Institute, Orchard Park, N.Y. Boren, Hoiiis, M.D.—Professor of Medicine, Marquette School of Medicine, Wood VA Hospital, Milwaukee, Wis. BOUTWELL, RosweL. K., M.D.—Professor of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wis. Cooper, THEODORE, M.D.—IJirector, National Heart Institute, National In- stitutes of Health, Bethesda, Md. CORNFIELD, JEROME—Research Professor of Biostatistics, University of Pitts- burgh Graduate School of Public Health, Biostatistics Project, Bethesda, Md. EARL, CHRISTOPHER J., M.1).—National Hospital, London, England. EPSTEIN, FREDERICK H., M.D.—Professor of Epidemiology, University of Michigan, School of Public Health, Ann Arbor, Mich. Fark, Hans L., Ph. D).—Associate Director for Laboratory Research, National Institute of Environmental Health Sciences, Research Triangle Park, N. C. FERRIS, BENJAMIN G., JR., M.1).—Professor, Department of Physiology, Har- vard School of Public Health, Boston, Mass. Firzpatrick, Mark J., M.D., M.P.H.—Obstetrician, Perinatal Biology and In- fant Mortality, National Institute of Child Health and Human Development, National Institute of Child Health and Human Development, National In- stitutes of Health, Bethesda, Md. FRAZIER, Topp M.—Assistant Director, Harvard Center for Community Health and Medical Care, Harvard School of Public Health, Boston, Mass. GoLpsMITH, JOHN R., M.D.—Head, Environmental Epidemiology Unit, Cali- fornia State Department of Public Health, Berkeley, Calif. HANNA, MIcHaeL G., Jr., Ph. ).—Biology Division, Oak Ridge National Lab- oratory, Oak Ridge, Tenn. Hiecins, Ian T. T., M.D., M.R.C.P.—Professor, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Mich. HOFFMANN, DIETRICH, Ph. D.—Division of Environmental Toxicology, Ameri- can Health Foundation, New York, N.Y. ISRAEL, Robert A.—Director, Division of Vital Statistics, National Center for Health Statistics, U.S.P.H.S., U.S. Department of Health, Education and Welfare, Rockville, Md. KELLER, ANDREW Z., D.M.D., M.P.H.—Chief, Research in Geographic Epide- miology, Veterans Administration Central Office, Washington, D.C. KIRSNER, JOSEPH, M.D.—Professor of Medicine, University of Chicago School of Medicine, Chicago, III. Knox, Davip L., M.D.—Associate Professor, The Wilmer Ophthalmological Institute, The Johns Hopkins University School of Medicine, Baltimore, Md. KOLBYE, ALBERT C., JR., M.D., J.D.—Deputy Director, Bureau of Foods, Food and Drug Administration, U.8. Department of Health, Education and Wel- fare, Washington D.C. KoTin, Paut, M.D.—Director, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. KRUMHOLZ, RICHARD A., M.D.—Director, Institute of Respiratory Diseases, Kettering Medical Center, Kettering, Ohio. Ligpow, AVERILL A., M.D.—Professor and Chairman, Department of Path- ology, University of California at San Diego, La Jolla, Calif. LILIENFELD, ABRAHAM, M.D.—-Professor and Chairman, Department of Chronic Diseases, Johns Hopkins School of Hygiene and Public Health, Baltimore, Md. MacManon, Brian, M.D.—Professor of Epidemiology, Harvard University School of Public Health, Boston, Mass. McLean, Ross, M.D.—Medical Consultant, Regional Medical Program of Texas, Austin, Tex. MCMILLAN, GARDNER C., M.I).--Chief, Arteriosclerotic Disease Branch, Na- tional Heart and Lung Institute, National Institutes of Health, Bethesda, Md. MITCHELL, ROGER S., M.1).—Director, University of Colorado Medical Center, Webb- Waring Institute for Medical Research, Denver, Colo. MurRpPHY, EDMOND A., M.D., Sc. D.— Associate Professor of Medicine and Bio- statistics, The Johns Hopkins Hospital, Baltimore, Md. PAFFENBARGER, RALPH S., JR, M.D.—Chief, Bureau of Adult Health and Chronic Diseases, California State Department of Public Health, Berkeley, Calif, Peters, JOHN M., M.D.—Associate Professor of Occupational Medicine, Har- vard University School of Public Health, Boston, Mass . PETERSON, WILLIAM F., M.D.—Chairman, Department of Obstetrics and Gynecology, Washington Hospital Center, Washington, D.C. Petty, THoMas L., M.D.—Associate Professor of Medicine, University of Colorado Medical Center, Denver, Colo. vi SAFFIOTTI, UMBERTO, M.D.—Associate Scientific Director for Carcinogenesis Etiology, National Cancer Institute, National Institutes of Health, Beth- esda, Md. ScHUMAN, LEONARD M., M.D.—Professor and Head, Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, Minn. SHIMKIN, MICHAEL B., M.D.—Coordinator, Regional Medical Program, Uni- versity of California at San Diego, La Jolla, Calif. STAMLER, JEREMIAH, M.D.—Executive Director, Chicago Board of Health, Health Research Foundation, Chicago, IM. UnpDERWoop, Paut B., Jr., M.D— Associate Professor, Department of Ob- stetrics and Gynecology, University of South Carolina Medical School, Charleston, S.C. VAN DUUREN, BENJAMIN L., M.D.—Professor of Environmental Medicine, In- stitute of Environmental Medicine, New York University Medical Center, New York, N.Y. Victor, Maurice, M.D.—Professor of Neurology, Department of Neurology, Case Western Reserve, Cleveland, Ohio. Wynper, ERNeEST L., M.D.—President and Medical Director, American Health Foundation, New York, N.Y. The following professional staff of the National Clearinghouse for Smoking and Health contributed to the preparation of this re- port: John H. Holbrook, M.D., Richard W. White, Robert 8S. Hutch- ings, Elaine Bratic, Annabel W. Hecht, Richard H. Amacher, Donald R. Shopland and Jennie M. Jennings. Special thanks are due Nancy S. Johnston, Kathryn Carlysle, Mary E. Dement, and Mildred H. Ritchie. vii Contents Page PREFACE 2.0.0... cc nce teen eevee ili ACKNOWLEDGMENTS ....... 0... ccc cece ee eee Vv Chapter 1. Introduction .............0... 00.00.00. 0008 1 Chapter 2. Cardiovascular Diseases .................4. 15 Chapter 3. Chronic Obstructive Bronchopulmonary Disease ... 0... eects 135 Chapter 4. Cancer ....... 0.0... cc cece ec cece ever es 231 Chapter 5. Pregnancy ........... 0.00. ccc eee e ce euees 385 Chapter 6. Peptic Uleer ........ 0.0.0 cece cece ees 419 Chapter 7. Tobacco Amblyopia ..............0..000c0e 431 CHAPTER 1 General Considerations, Preparation of the Present Document, and Summary of the Report GENERAL CONSIDERATIONS The first major development in the modern history of the effects of smoking on health occurred in 1950 with the publication of four retrospective studies on smoking habits among lung cancer pa- tients and among controls (1, 4, 6, 7). At that time, the question was, “Are smokers more likely to get lung cancer than nonsmok- ers?” Although some epidemiologists were satisfied that the an- swer was in the affirmative, others turned for confirmation to prospective studies in which the smoking habits of large popula- tions were recorded and the populations followed to identify sub- sequent mortality. The first report of Hammond and Horn in 1954 (2), showed significantly elevated overall death rates for smokers as compared to nonsmokers. This elevation in death rates, almost entirely confined to those who smoked cigarettes, together with the evidence for a gradient according to the amount smoked, changed the question from one concerning only lung cancer to one concern- ing overall death rates and from one concerning smoking to one primarily concerned with cigarette smoking. In effect, the question became, “Do cigarette smokers have higher overall death rates than nonsmokers and smokers of pipes and cigars?” With the publication of the later reports of the major prospec- tive studies in the late 1950’s and early 1960’s, it became clear that cigarette smokers had higher overall death rates than nonsmokers, as well as higher death rates from a number of individual causes of death. The question then became, “Why?” When the Advisory Committee on Smoking and Health to the Surgeon General was established in 1962, it undertook the evalua- tion of the scientific evidence up to that time. The conclusion of the Committee in its 1964 Report was that: “Cigarette smoking is a health hazard of sufficient importance in the United States to war- rant appropriate remedial] action.” Not only did the Committee conclude that the evidence clearly showed that male cigarette smokers do in fact have higher death rates than nonsmokers but that the convergence of epidemiological, experimental, and path- ological evidence also clearly indicated a cause-and-effect relation- ship for several of the implicated diseases, particularly cancer of the lung and chronic bronchitis, In several other important dis- eases, the evidence on biomechanisms to explain epidemiological 3 associations was felt to be inadequate at that time to draw firm conclusions about a cause-and-effect relationship. Three and one-half years later, when The Health Consequences of Smoking: A Public Health Service Review, 1967 was published, the conclusions of the 1964 review were taken as a starting point, and the nature of the task of interpreting the scientific evidence was restated as follows: 1. How much mortality and excess disability are associated with smoking? 2. How much of this early mortality and excess disability would not have occurred if people had not taken up cigarette smoking? 3. How much of this early mortality and excess disability could be averted by the cessation or-reduction of cigarette smoking? 4, What are the biomechanisms whereby these effects take place and what are the critical factors in these mechanisms? That and subsequent reviews in 1968 and 1969 have provided some answers to these questions, particularly in summarizing the evidence for various theories as to how cigarette smoking affects the human organism to produce elevated disease and death rates. At least five different processes have been suggested whereby cigarette smokers experience higher mortality or morbidity rates than do nonsmokers. 1. Cigarette smoking initiates a disease process by producing progressive irreversible damage. In this case, the total effect would be approximately proportional to the total accumulated dosage experienced over the years. Cessation of smoking leaves impaired function which does not improve appreciably but does not continue to deteriorate from continued exposure to cigarette smoke. How- ever, such function may deteriorate through aging or through exposure to other harmful agents. It appears that such a relation- ship probably exists for chronic obstructive lung disease and pos- sibly for the development of atherosclerotic heart disease. 2. Cigarette smoking initiates a disease process with continual repair and recovery until some critical point is reached at which the process is no longer reversible. The total effect would therefore be affected to some extent by accumulated exposure but would be affected also by the level of contemporary smoking. Cessation of smoking would result in a rapid reduction of risk provided the critical level initiating an irreversible process has not been reached. The evidence supports this kind of mechanism accounting both for the high dose-response relationship in lung cancer and for the reduction in risk from lung cancer among ex-smokers. 3. Cigarette smoking promotes a disease process either by providing positive support to the development of a pathological condition or by interfering with and diminishing the normal capa- 4 bility of the organism to cope with and defend against a disease process. This may take place by promoting the development of a subclinical disease to a clinically recognizable one, by promoting a mild disease state to a more severe form, or by increasing fatality rates of severe disease states. This type of mechanism could ac- count for modestly increased mortality rates for a number of se- vere diseases for which there is no evidence that cigarette smoking itself has a role in initiating the disease. Some of the excess mor- tality from infectious respiratory disease and from coronary heart disease might take place through this kind of mechanism. 4, Cigarette smoking produces a set of temporary conditions which increase the probability that a critical event will occur with attendant disability and possibly fatal consequences. For example, there is evidence to support the theory that each cigarette can pro- duce a set of conditions which increase the probability of myocar- dial damage through increased demand for oxygen at a time when the suppy is diminished. Presumably, once the supply/demand im- balance is alleviated, the probability of myocardial damage would revert to its normal level. Cessation of smoking should have an almost immediate effect of reducing the risk sharply for morbidity or mortality produced through this mechanism. 5. Cigarette smoking may be artificially related to excess dis- ability or death by way of a close association with some other con- dition or exposure which is found at a high level in smokers, but not in nonsmokers, and is itself responsible for the disease. The one cause of death for which cigarette smokers have elevated death rates that is generally interpreted in this way is cirrhosis of the liver, Since most heavy consumers of alcoholic beverages are smok- ers, and since alcohol consumption is an important part of the process that produces cirrhosis of the liver, the high rate of cirrho- sis among cigarette smokers is discounted as resulting from this kind of artificial relationship. Some authors have proposed that there may be genetic factors that link smoking and certain diseases in this fashion. Obviously, the cessation of smoking would have no effect on morbidity or mortality from diseases which are artificially related to smoking. These different ways in which cigarette smoking can be related to elevated morbidity and mortality rates are important considera- tions in attempting to estimate the potential public health benefits of giving up smoking. For some types of relationship, there would be no benefits; for some, rather small benefits; for some, substan- tial benefits, taking place over a long period of time; and for others, substantial benefits taking place rather rapidly. During the past few years, a sharp reduction has taken place in the cigarette smoking habits of the U.S. population. The Na- 5 tional Center for Health Statistics has recently published a com- parison of smoking habits in the U.S. in 1955 and 1966 based on two large scale household surveys (5). These showed a drop in cigarette consumption in men under 55 years of age but no appre- ciable change among those 55 or over. Among women, every age group showed an increase in the eleven year period. A recent sur- vey conducted for the National Clearinghouse for Smoking and Health, based on a much smaller sample (approximately 5,000 interviews), was conducted in the Spring of 1970 (3) (table 1). Even with the smaller number of cases, it is clear that a much larger drop took place in the four years from 1966 to 1970 than in the eleven years from 1955 to 1966. The drop extended to the age group 55-64 among men, again with no appreciable drop among men over age 65. For the first time, the increase in smok- ing among women leveled off, or even dropped slightly among women under 55. The increase among women over 55 was of a lesser magnitude than previously observed. TABLE 1.--Percentage of Current Smokers of Cigarettes (regu- larly or occasionally) by sex and age. U.S. Surveys: 1955 and 1966 (CPS-Current Population Surveys) and 1970 (NCSH- Survey conducted for National Clearinghouse for Smoking & Health) .. Male Female CPS CPS NCSH CPS CPS NCSH Age 1955 1966 1970 1955 1966 1970 18-24 __-------- 53.0 48.3 *47.0 33.3 34.7 *31.1 25-384 ___------- 63.6 58.9 46.8 39.2 43.2 40.3 85-44 .___--_--- 62.1 57.0 48.6 85.4 41.1 39.0 45-54 _-_.------ 58.0 53.1 43.1 25.7 37.8 36.0 55-64 _--.--.--- 45.8 46.2 387.4 13.4 23.0 24.3 65+ -_--------- 25.8 24.6 23.7 4,7 8.1 11.8 11955 survey based on approximately 45,000 persons; 1966 survey based on approximately 35,000 persons; 1970 survey based on approximately 5,000 persons. 2 Estimated. With the massive changes in smoking behavior which have taken place among adults in the past few years, largely as an expression of the desire to protect health, changes should be ex- pected in mortality rates among those groups which have experi- enced the greatest reduction both in accumulated dosage and in concurrent dosage. An analysis of U.S. mortality rates for 1970 and the years to follow will provide a very valuable addition to the knowledge concerning the effects of smoking on death rates. PREPARATION OF THE PRESENT DOCUMENT Following the publication of Smoking and Health—Report of the Advisory Committee to the Surgeon General—in 1964, the fol- 6 lowing documents were published as reviews of the medical litera- ture concerning the health consequences of smoking, as called for by Public Law 89-92: 1. The Health Consequences of Smoking, A Public Health Serv- ice Review: 1967. 2. The Health Consequences of Smoking, 1968 Supplement to the 1967 PHS Review. 3. The Health Consequences of Smoking, 1969 Supplement to the 1967 PHS Review. These documents reviewed the medica] literature which had been published since the original Surgeon General’s Report. This format of publishing a supplement to a supplement has become unwieldy, particularly in the light of the lack of availability of the previous reviews to the general public. Therefore, when Public Law 91-222 was signed into law on April 1, 1970 calling for an eighteen month interval between the last report and the new re- port, the decision was made to review the entire field with em- phasis on the most recent additions to the literature. The National Clearinghouse for Smoking and Health has the responsibility for continuous monitoring and compilation of the medical literature on the health consequences of smoking. This is accomplished through several mechanisms: 1. A scientific review corporation is on contract to extract arti- cles on smoking and health from the medical and scientific litera- ture of the world. This organization provides a semi-weekly acces- sions list with abstracts and copies of the various articles. Trans- lations are called for as needed. Articles of pertinence are identi- fied by a series of code words and phrases. 2, The National] Library of Medicine, through the Medlars sys- tem, sends the National Clearinghouse for Smoking and Health a monthly listing of articles in the smoking and health area. These are reviewed, and pertinent articles are ordered. 3. Staff members keep up with the current contents of medical and scientific literature and identify articles of pertinence. Initia] drafts of the present review were prepared by Clearing- house staff and consultants who reviewed the previous reports and identified those articles which have been important in the develop- ment of knowledge in this field. These were abstracted and placed into tabular form, and a draft text of the report was prepared. The first drafts of the individual chapters were sent to experts for review, criticism, and comment with respect to the articles re- viewed, those articles not included, and conclusions. The drafts were then revised on the basis of these comments and rewritten until they met with general approval of the reviewers. The final 7 drafts were reviewed as a whole by the Director of the National Clearinghouse for Smoking and Health, the Director of the Na- tional Cancer Institute, the Director of the National Heart and Lung Institute, the Director of the National Institute of Environ- mental Health Sciences, and by six additional experts both within and outside of the Public Health Service. SUMMARY OF THE REPORT CARDIOVASCULAR DISEASES Coronary Heart Disease 1. Data from numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing to the development of coronary heart disease, including fatal CHD and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smoking of pipes and cigars is appreciably less than that incurred by cigarette smokers. 2. Analysis of other factors associated with CHD (high serum cholesterol, high blood pressure, and physical inactivity) show that cigarette smoking operates independently of these other fac- tors and can act jointly with certain of them to increase the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate the pathophysiological changes of pre-existing coronary heart disease and therefore contributes to sudden death from CHD. 4, Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coronary arteries. 5. The cessation of smoking is associated with the decreased risk of death from CHD. 6. Experimental studies in animals and humans suggest that cigarette smoking may contribute to the development of CHD and/ or its manifestations by one or more of the following mechanisms: a. Cigarette smoking, by contributing to the release of catecho- lamines, causes increased myocardial wall tension, contraction velocity, and heart rate, and thereby increases the work of the heart and the myocardial demand for oxygen and other nutrients. b. Among individuals with coronary atherosclerosis, cigarette smoking appears to create an imbalance between the increased needs of the myocardium and an insufficient increase in cor- onary blood flow and oxygenation. ce. Carboxyhemoglobin, formed from the inhaled carbon mon- oxide, diminishes the availability of oxygen to the myocardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxemia, thus reducing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhesive- ness which might contribute to acute thrombus formation. Summary Statement of Recent Additions to Knowledge Relating Smoking and Coronary Heart Disease.—A number of epidemi- ologic studies have provided additional evidence concerning ciga- rette smoking as a significant risk factor in the development of CHD, Experimental studies on animals have suggested that ciga- rette smoking, particularly the absorbed nicotine and carbon mon- oxide, contributes to the development of atherosclerosis. Cerebrovascular Disease 1. Data from numerous prospective studies indicate that ciga- rette smoking is associated with increased mortality from cere- brovascular disease. 2. Experimental] evidence concerning the relationship of smok- ing and cerebrovascular disease is at present insufficient to allow for conclusions concerning pathogenesis. However, some of the pathophysiological considerations discussed concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction. Nonsyphilitic Aortic Aneurysm Cigarette smoking has been observed to increase the risk of dying from nonsyphilitic aortic aneurysm. Peripheral Vascular Disease 1. Data from a number of retrospective studies have indicated that cigarette smoking is a likely risk factor in the development of peripheral vascular disease. Cigarette smoking also appears to be a factor in the aggravation of peripheral vascular disease. 2. Cigarette smoking has been observed to alter peripheral blood flow and peripheral vascular resistance. CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE 1. Cigarette smoking is the most important cause of chronic obstructive bronchopulmonary disease in the United States, Ciga- rette smoking increases the risk of dying from pulmonary emphy- sema and chronic bronchitis, Cigarette smokers show an increased prevalence of respiratory symptoms, including cough, sputum pro- 9 duction, and breathlessness, when compared with nonsmokers. Ventilatory function is decreased in smokers when compared with nonsmokers. 2. Cigarette smoking does not appear to be related to death from bronchial asthma, although it may increase the frequency and severity of asthmatic attacks in patients already suffering from this disease. 3. The risk of developing or dying from COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers, while clearly less than that among cigarette smokers. 4, Ex-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function and with a decrease in pulmonary symptom prevalence. 5. Young, relatively asymptomatic, cigarette smokers show measurably altered ventilatory function when compared with non- smokers of the same age. 6. For the bulk of the population of the United States, the im- portance of cigarette smoking as a cause of COPD is much greater than that of atmospheric pollution or occupational exposure. How- ever, exposure to excessive atmospheric pollution or dusty occu- pational materials and cigarette smoking may act jointly to pro- duce greater COPD morbidity and mortality. 7. The results of experiments in both animals and humans have demonstrated that the inhalation of cigarette smoke is associated with acute and chronic changes in ventilatory function and pul- monary histology. Cigarette smoking has been shown to alter the mechanism of pulmonary clearance and adversely affect ciliary function. 8. Pathological studies have shown that cigarette smokers who die of diseases other than COPD have histologic changes charac- teristic of COPD in the bronchial tree and pulmonary parenchyma more frequently than do nonsmokers, 9. Respiratory infections are more prevalent and severe among cigarette smokers, particularly heavy smokers, than among nonsmokers. 10. Cigarette smokers appear to develop postoperative pul- monary complications more frequently than nonsmokers. Summary Statement of Recent Additions of Knowledge Relat- ing to Chronic Obstructive Bronchopulmonary Disease.—Studies have demonstrated that cigarette smokers show increased symp- toms and pulmonary dysfunction as well as mortality from COPD when compared to nonsmokers. Investigations of alpha,-antitryp- sin deficiency in relationship to pulmonary emphysema have sug- 10 gested that cigarette smoking may act jointly with hereditary fac- tors in the pathogenesis of pulmonary emphysema. A pathological study on animals has shown that long-term inhalation of cigarette smoke produces lesions characteristic of pulmonary emphysema. CANCER Lung Cancer: 1. Epidemiological evidence derived from a number of prospec- tive and retrospective studies, coupled with experimental and pathological evidence, confirms the conclusion that cigarette smok- ing is the main cause of lung cancer in men. These studies reveal that the risk of developing lung cancer increases with the number of cigarettes smoked per day, the duration of smoking, and earlier initiation, and diminishes with cessation of smoking. 2. Cigarette smoking is a cause of lung cancer in women but accounts for a smaller proportion of the cases than in men. The mortality rates for women who smoke, although significantly higher than for female nonsmokers, are lower than for men who smoke. This difference may be at least partially attributable to differences in exposures: the use of fewer cigarettes per day, the use of filtered and low “tar” cigarettes, and lower levels of inhala- tion. Nevertheless, even when women are compared with men who apparently have similar levels of exposure to cigarette smoke, the mortality ratios appear to be lower in women. 3. The risk of developing lung cancer among pipe and/or cigar smokers is higher than for nonsmokers but significantly lower than for cigarette smokers. 4. The risk of developing lung cancer appears to be higher among smokers who smoke high “tar” cigarettes, or smoke in such a manner as to produce higher levels of ‘tar’ in the inhaled smoke, 5. Ex-cigarette smokers have significantly lower death rates for lung cancer than continuing smokers, There is evidence to support the view that cessation of smoking by large numbers of cigarette smokers would be followed by lower lung cancer death rates. 6. Increased death rates from lung cancer have been observed among urban populations when compared with populations from rural environments. The evidence concerning the role of air pollu- tion in the etiology of lung cancer is presently inconclusive. Fac- tors such as occupational and smoking habit differences may also contribute to the urban-rural difference observed. Detailed epi- demiologic surveys have shown that the urban factor exerts a small influence compared to the overriding effect of cigarette smok- ing in the development of lung cancer. W 7. Certain occupational! exposures have been found to be asso. ciated with an increased risk of dying from lung cancer. Cigarette smoking interacts with these exposures in the pathogenesis of lung cancer so as to produce very much higher lung cancer death rates in those cigarette smokers who are also exposed to such substances, 8. Experimental studies on animals utilizing skin painting, tracheal instillation or implantation, and inhalation of cigarette | smoke or its component compounds, have confirmed the presence of complete carcinogens as well as tumor initiators and promoters in tobacco smoke. Lung cancer has been found in dogs exposed to the inhalation of cigarette smoke over a period of more than 2 years. Cancer of the Larynx 1. Epidemiological, experimental, and pathological studies support the conclusion that cigarette smoking is a significant fac- tor in the causation of cancer of the larynx. The risk of develop- ing laryngeal cancer among cigarette smokers as well as pipe and/ or cigar smokers is significantly higher than among nonsmokers. The magnitude of the risk for pipe and cigar smokers is about the same order as that for cigarette smokers, or possibly slightly lower. 2. Experimental exposure to the passive inhalation of cigarette smoke has been observed to produce premalignant and malignant changes in the Jarynx of hamsters. Oral Cancer 1. Epidemiological and experimental studies contribute to the conclusion that smoking is a significant factor in the development of cancer of the oral cavity and that pipe smoking, alone or in conjunction with other forms of tobacco use, is causally related to cancer of the lip. 2. Experimental studies suggest that tobacco extracts and to- bacco smoke contain initiators and promoters of cancerous changes in the oral cavity. Cancer of the Esophagus 1. Epidemiological studies have demonstrated that cigarette smoking is associated with the development of cancer of the esoph- agus, The risk of developing esophageal cancer among pipe and/ or cigar smokers is greater than for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower. 2. Epidemiological studies have also indicated an association between esophageal cancer and alcohol consumption and that alco- hol consumption may interact with cigarette smoking. This com- 12 bination of exposures is associated with especially high rates of cancer of the esophagus. Cancer of the Urinary Bladder and Kidney 1. Epidemiological studies have demonstrated an association of cigarette smoking with cancer of the urinary bladder among men. The association of tobacco usage and cancer of the kidney is less clear-cut. 2. Clinical and pathological studies have suggested that tobacco smoking may be related to alterations in the metabolism of tryp- tophan and may in this way contribute thereby to the development of urinary tract cancer. Cancer of the Pancreas Epidemiological studies have suggested an association between cigarette smoking and cancer of the pancreas. The significance of the relationship is not clear at this time. Summary Statement of Recent Additions of Knowledge Relating Smoking and Cancer.—Epidemiological studies have confirmed that cigarette smokers incur an increased risk of dying from lung can- cer and that those smokers who switched to filter cigarettes incur a lesser risk. Pathological studies have shown that cancer of the lung and cancer of the larynx have been found in animals exposed to the long-term inhalation of cigarette smoke. SMOKING AND PREGNANCY Maternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birthweight and an increased incidence of prematurity, defined by weight alone. There is strong evidence to support the view that smoking mothers have a significantly greater number of unsuccessful pregnancies due to stillbirth and neonatal death as compared to nonsmoking mothers. There is insufficient evidence to support a comparable statement for abortions. The recently published Second Report of the 1958 British Perinatal Mortality Survey, a carefully designed and controlled prospective study involving large numbers of patients, adds further support to the conclusions. PEPTIC ULCER Cigarette smoking males have an increased prevalence of peptic ulcer disease and a greater peptic ulcer mortality ratio. These relationships are stronger for gastric ulcer than for duodenal ulcer, Smoking appears to reduce the effectiveness of standard peptic ulcer treatment and to slow the rate of ulcer healing. TOBACCO AMBLYOPIA Tobacco amblyopia is presently a rare disorder in the United States. The evidence suggests that this disorder is related to nutri- tional or idiopathic deficiencies in certain detoxification mecha- nisms, particularly in handling the cyanide component of tobacco smoke. (1) (2) (3) (4) (5) (6) (7) 14 INTRODUCTION REFERENCES Dott, R., Hit, A. B., Smoking and carcinoma of the lung. Preliminary report. British Medical Journal 2: 739-748, September 23, 1950. HaMMonbD, E, C., Horn, D. The relationship between human smoking habits and death rates. Journal of the American Medical Association 155: 1816-1828, August 7, 1954. Horn, D. Address given at National Conference on Smoking and Health, San Diego, Calif., September 9-11, 1970. 13 pp. Levin, M. L., GotpsTEIN, H., GeRHARDT, P. R. Cancer and tobacco smok- ing. A preliminary report. Journal of the American Medical Asso- ciation 143(4): 336-338, May 27, 1950. NATIONAL CENTER FOR HEALTH StTaTIsTics. Changes in cigarette smoking habits between 1955 and 1966. U.S. Department of Health, Education, and Welfare, April 1970. 33 pp. Scurek, R., BAKER, L. A., BALLARD, G. P., Dorgorr, S. Tobacco smoking as an etiologic factor in disease. I. Cancer. Cancer Research 10: 49-58, 1950. WYnDER, E. L., GRAHAM, E. A. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma. A study of six hundred and eighty four proved cases. Journal of the American Medical Association 148 (4): 329-8386, May 27, 1950. CHAPTER 2 Cardiovascular Diseases Contents Introduction 0.0.0.0. . ccc eee ees Epidemiological Studies........... 00... 000 eee eee Coronary Heart Disease Mortality ................. Coronary Heart Disease Morbidity ................. Retrospective Studies. ........0. 2... cee eee The Interaction of Cigarette Smoking and Other CHD Risk Factors ..... 0.0.0.0 0c cece eee eee eee Smoking and Serum Lipids .................-.. Smoking and Hypertension................-.4- Smoking and Physical Inactivity ............... Smoking and Obesity ............. 0.0002 ee eee Smoking and Electrocardiographic Abnormalities . Smoking and Heart Rate ................04050- The Effect of Cessation of Cigarette Smoking on Coronary Heart Disease... 0.0... cc teen eens The Constitutional Hypothesis .............0 002 eeeeee Autopsy Studies Relating Smoking, Atherosclerosis, and Sudden CHD Death .........0.. 0... ccc ee eee Experimental Studies Concerning the Relationship of Coronary Heart Disease and Smoking ................ Cardiovascular Effects of Cigarette Smoke and Nicotine 2.0.0... cee teens Coronary Blood Flow ...... 0.0... 000 0 ccc eee e eee Cardiovascular Effects of Carbon Monoxide ......... Effects of Smoking on the Formation of Atherosclerotic Lesions 0... teen eens The Effect of Smoking on Serum Lipid Levels ........ The Effect of Smoking on Thrombosis .............. Other Areas of Investigation............ 0.000000 0s Cerebrovascular Disease ......00.. 0006 cece eee eee eees Nonsyphilitic Aortic Aneurysm .......0.....0 ce eee ee ee Peripheral Arteriosclerosis ............ceceeeeveeeeees Experimental Evidence...... 00.0000 cece eee eee Thromboangiitis Obliterans.........00 0.00 e cece eee eees Summary and Conclusions ......... 0.002 e eee eee eee AT 48 52 56 56 58 59 63 65 66 66 66 67 72 73 13 74 7 Coronary Heart Disease .......................... Cerebrovascular Disease .............. 0.00.00 eeee Nonsyphilitic Aortic Aneurysm .................... Peripheral Vascular Disease ...................... References ......... 0.000000 cece cece cence eeccees FIGURES . National Cooperative Pooling Project, Inter-Society Com- mission for Heart Disease Resources ............... . Risk of coronary heart disease (12 years) according to cigarette smoking habit and presence of “predisposing factors” (men 30-59 at entry). Framingham Heart Study... cece ccc e eect eneeeeens . Estimated coronary heart disease death ratios in a 17-51 year follow-up, and frequencies of paired combinations of six high-risk characteristics in college, for all ages atdeath 0.0... ccc cee cece eeeee . Relationship between smoking status and serum choles- terol level at initial examination, and incidence of clin- ical coronary heart disease in men originally age 40-59 free of definite CHD. Peoples Gas Light and Coke Company Study, 1958-1962....................... . Average annual incidence of first myocardial infarction among men in relation to overall physical activity, class, and smoking habits (age-adjusted rates per 1,000) 22... ccc ete e eee eeees LIST OF TABLES (A indicates tables located in Appendix at end of Chapter) 1. Sudden death and acute mortality with first major coronary episodes ......... 0.0... cee eee ees 2. Coronary heart disease mortality ratios related to smoking—prospective studies .................. 3. Sudden death from coronary heart disease related to smoking... 0... ce eee eens 4. Coronary heart disease morbidity as related to SMOKing. 2... eee teens 5. Coronary heart disease morbidity as related to smok- ing—-angina pectoris—prospective studies ....... A6. Coronary heart disease morbidity and mortality— retrospective studies .......... 0.000 e eee ae A. Differences in serum lipids between smokers and non- smokers... 0. 0. ce ee eee eens 18 23 24 25 43 44 23 26 30 32 37 93 98 LIST OF TABLES (CONT.) (A indicates tables located in Appendix at end of Chapter) Page A8. Blood pressure differences between smokers and non- SMOkers . 01... eee cee een eee 103 9. Death rates from coronary heart disease, by systolic blood pressure: ILWU mortality study, 1951-1961 42 10. Death rates from coronary heart disease, by diastolic blood pressure: ILWU mortality study, 1951-1961 42 11. Death rates from coronary heart disease, among hy- pertensives and nonhypertensives: ILWU mortality study, 1951-1961......... 0000000000... 42 12. Death rates from coronary heart disease among men without abnormalities related to cardiopulmonary diseases by weight classification in 1951: ILWU mortality study, 1951-1961..................... 45 13. Death rates from coronary heart disease, by electro- cardiographic findings in 1951: ILWU mortality study, 1951-1961.........00.00 0.0... cece 45 14. 1958 status with respect to heart rate, blood pressure, cigarette smoking, and ten-year mortality rates, by cause (1,329 men originally age 40-59 and free of definite coronary heart disease) Peoples Gas Com- pany Study, 1958-1968.............0.......... 45 15. The effect of the cessation of cigarette smoking on the incidence of CHD ............. 0.0.0 cece eee 46 16. Annual probability of death from coronary heart dis- ease, in current and discontinued smokers, by age, maximum amount smoked, and age started smoking 46 A17. Incidence of new coronary heart disease by smoking category and behavior type for men 39-49 years Of ABE Lec eee eee enes 105 A18. Incidence of new coronary heart disease by smoking category and behavior type for men 50-59 years Of age 2... eee eee eee beeen eee eens 106 19. Autopsy studies of atherosclerosis ..............4. 53 A 20. Experiments concerning the effects of smoking and nicotine on animal cardiovascular function ...... 107 A 21. Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans... 1138 A 22. Experiments concerning the effect of nicotine or smoking on catecholamine levels ................ 119 A 23. Experiments concerning the atherogenic effect of nicotine administration.............-..00000005 120 LIST OF TABLES (CONT.) (A indicates tales located in Appendix at end of Chapter) 24, Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia ......... A 25. Experiments coricerning the effect of smoking and nicotine upon blood lipids (Human Studies) ...... A 25a.Experiments concerning the effect of smoking and nicotine upon blood lipids (Animal Studies)...... A 26. Experiments concerning the effect of carbon mon- oxide exposure upon blood lipids ............... A 27, Smoking and thrombosis .................0.0.00. 28. Deaths from cerebrovascular disease related to SMOKING... ee eee eens 29. Deaths from nonsyphilitic aortic aneurysm related to smoking—prospective studies .................. A 30. Experiments concerning the effect of nicotine and smoking upon the peripheral vascular system .... 20 Page 64 123 127 129 130 68 71 133 INTRODUCTION Coronary Heart Disease (CHD) cuts short the lives of many men in the Western World in their prime productive years. More Americans die from heart disease than from any other disease. In 1967, in this country, a total of 345,154 men and 227,999 women were classified as dying of arteriosclerotic heart disease (ASHD) (196), a category which consists largely of what is commonly called CHD. During the years from 1950 to 1967, the age-adjusted death rate from ASHD increased 15.1 percent (196, 197). Besides the many deaths attributed to CHD, much morbidity results from this disease. The National Health Examination Sur- vey of 1960-1962 estimated that 3.1 million American adults, ages 18 to 79, had definite CHD and 2.4 million had suspect CHD, together representing about 5 percent of the population. It was further estimated that of Americans under age 65, almost 1.8 mil- lion had definite CHD and 1.6 million had suspect CHD (195). There are several manifestations of CHD, all related in part to the basic process of severe atherosclerosis, a disease of arteries in which fatty materials (lipids) accumulate in the form of plaques in the walls of medium and large arteries. This process, as it occurs in the coronary arteries, leads to stiffening of the wall and narrow- ing of the lumen which, when severe, result in a diminution in the blood supply to the cardiac muscle. Angina pectoris, a major mani- festation of CHD, results from diminution in blood supply relative to the needs of the myocardium. If the blood supply to a portion of the myocardium is completely obstructed, due for example to the formation of a thrombus at the site of atherosclerotic narrowing, necrosis or death of a portion of heart muscle may occur. This occurrence is known as a myocardial infarction. In many cases, a disturbance of cardiac rhythm occurs at the time of thrombosis, and the patient may die immediately. It is estimated that approxi- mately 25 percent of patients suffering coronary artery occlusion die within the first three hours following the occlusion (table 1) (88). Not infrequently, sudden death occurs in patients with severe coronary atherosclerosis but without a demonstrable arterial occlu- sion, In these cases, it is thought that the meager blood flow to a portion of the myocardium becomes so diminished with respect to cardiac needs as to lead to a fatal arrhythmia, as well as to, per- haps, a myocardial infarction. 21 a CIGARETTE SMOKING(S) AT ENTRY—WITH CONTROL OF SERUM CHOLESTEROL (C) AND DIASTOLIC BLOOD PRESSURE (H)—AND TEN YEAR INCIDENCE AND MORTALITY RATES. 7,594 WHITE MALES AGE 30-59 AT ENTRY, POOLING PROJECT 171 RATE FIRST MAJOR : RATE ALL CHD DEATHS PER 1,000 CORONARY EVENT * PER 1,000 150 — oe 150— 100— 100 — 82 50— 45 20 O—a— RISK NONE s C OR H S+C OR CORH s+c C+H C+H FACTORS OF 3 ONLY ONLY $S-+H ONLY OR S+H +S NUMBER 28 97 74 167 31 82 17 50 4l 90 12 4z OF EVENTS NUMBER 1,249 2,018 1,302 1,794 384 595 1,249 2,018 1,302 1,794 384 595 National Cooperative Pooling Project; smoking status at entry and 10-year age-adjusted rates per 1,000 men for first major coronary event (incling nonfatal Ml, fatal MI, and sudden death due to CHD) and any coronary death. U.S. white males age 30-59 at entry. All rates age-adjusted by 10-year age groups to the U.S. white male population 1960. Graphs present rates for noncigarette vs. cigarette smokers at entry with simultaneous control of blood pressure and serum cho- lesterol level. For this latter analysis, the following cutting points were used: (a) Cigarette smoking S -—any use at ertry (b) Serum cholesterol c — 250 mg./dl. (c) Diastolic blood pressure H — 90 mm. Hg. SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88). Figure 1—National Cooperative Pooling Project; smoking status at entry and 10-year age-adjusted rates per 1,000 men for first major coronary event (includes nonfatal MI, fatal MI, and sudden death due to CHD) and any coronary death. U.S. white males age 30-59 at entry. All rates age-adjusted by 10 year age groups to the U.S. white male population 1960. Graphs present rates for noncigarette vs. cigarette smokers at entry with simultaneous control of blood pressure and serum cholesterol level. For this latter analysis, the following cutting points were used: (a) Cigarette smoking-——-S—any use at entry (b) Serum cholesterol_C-=250 mg./dl. (c) Diastolic blood pressure—H-=90 mm. Hg. SouRcE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88). TABLE 1.—Sudden death and acute mortality with first major coronary episodes Proportion per Author, year, Number and Number 1,000 events country, type of Data of (as calculated on reference population collection Event events the basis of age- Comment adjusted rates) Pooling 7,594 males Medical exam- Ali first major coronary Data from the Pooling Project, Council on Project, males 30-59 ination and episodes, nonfatal and fatal. 501 1,000.0 Epidemiology, American Heart Association, American years of age follow-up. Sudden death (death a national cooperative project for pooling Heart at entry. within 3 hours of onset data from the Albany civil servant, Chicago Association, Ten-year of acute illness). 123 245.5 Peoples Gas Co., Chicago Western Blectric 1970, experience. All acute deaths with Co., Framingham Community, Los Angeles U.S.A. first episodes. 165 329.3 civil servant, Minneapolis-St. Paul business (88). men, and other prospective epidemiologic studies of adult cardiovascular disease in the United States. Source: Inter-Society Commission for Heart Disease Resources (88). Representative references include: (54, 94, 148, 177) and others listed as 6a-6k in Inter-Society Commission for Heart Disease Resources report. 307* 300 ;—- CIGARETTE SMOKING: (__] None 0.200 >1 PKG./DAY 196* 2 . < e a a 123 ra ° 103* = 100 + 87 37 OBS.| 19 28 30 ae 12 EXP.! 50.8 27.3 34.4 16.8. 9.7 NONE ANY ONE ANY TWO PREDISPOSING FACTORS (CHOLESTEROL 250, HYPERTENSION, DIABETES) “SIGNIFICANTLY DIFFERENT FROM “NONSMOKER” P<.05 Figure 2—Risk of coronary heart disease (12 years) according to cigarette smoking habit and presence of “predisposing factors” (men 30-59 at entry). Framingham Heart Study. Source: Kannel, W. B., et al. (94). Numerous epidemiological studies have indicated that cigarette smokers have increased mortality ratios for CHD; that is, cigarette smokers show significantly increased death rates compared with nonsmokers (table 2). The risk incurred by cigarette smoking in- creases with increasing dosage and, as measured by mortality ratios, is more marked for men in the younger age groups, under age 60, although the absolute increment in death rates experienced by smokers over that of nonsmokers continues to increase with increasing age. Table 2 lists the mortality ratios found in the major studies. Certain of these studies, including those at Framingham, Massachusetts, the Health Insurance Plan of New York City (HIP), and at Tecumsen, Michigan, have analyzed morbidity as well as mortality from CHD and have indicated that the risk of developing fatal and nonfatal CHD is greater among cigarette smokers than among nonsmokers (tables 3 and 4). Conflicting evidence has been published concerning the relationship of ciga- rette smoking and the incidence of angina pectoris. While some 24 Cigarettes —A No sport —A Hes Ywe<2.9 A 3] No sport —B Hts | Vete<12.9 —B Height <68 —B 3 2 Lae 1.9 2 12 | 354 245 13 14 | 2a 19 : 524 386 1901 | 28] |, 66 ){ 33 an 1387 $32 3as | | 227 175 85 i es 0 0 Cigarettes —A No sport—A a —A 3 Ht. /3wh< 12.9 —B Sys. BP 1304+ —B Parent dead —B 3 , 20 2.1 ; g % Ms 1.7 [32k 17 2 1.3 | 122 : 4o || 492 53 < 1 1.0 153 1.0 | 570 76 69 ! x 391 tee 289 64 | | 1242 591 kc 978 201 1338 WwW 4 q 0 1 0 uw Cigarettes —A No sport —A Sys. BP 130+ —A a 3 Sys. BP 1304+. —B Heightc68 —B Heightc68 —B 4 a 2.4 b 131 <= 2 140 Le 132 z= 14 14 1.3 : 1.4 12 lil z 1.0 | 238 | | 201 1.0 feos] o9 we 10 [245 302 wt < 1) (334 ] | 442 | | 373 go | 41268) [477 424 | | 417 390 3 844 239 52 1023 o 0 0 oO 9 Cigarettes —A No sport —A Sys. BP 130+ —A R 3 Height <68 —B Parent dead —B Parent dead -—B 3 2 2.5 Fe a 73 wo, 2.0 1.8 69 | |2 15 96 13 | a4 183 1.4 M1 1 1.0 277 199 1.0 282 1.0 285 : 1 346 || 468 | | 394 93 wis 15 509 | | 4a7 | | 215 875 253 39 1182 237 0 0 Cigarettes —A nes tc12.9 A Height<68 —A 3 Parent dead —B Sys. BP 1304 —B Parent dead —B 3 2 18 Lg is {2 1 df 1.3 | 124 1313 : 1 149 1.0 1} 2:0 | 307 3 102 1.0 232 260] [138] | as | (a 445 502 197 482 143 a2 554 470 | | 227 1071 1119 | | 291 1253 0 Q A— A+ A— A+ A— A+ A— A+ A— A+ A— A+ B— p— B+ B+ B— B— B+ B+ B— B— B+ B+ PRESENCE (-+) OR ABSENCE (—) OF CHARACTERISTICS (A or B) Top numbers in bars are CHD decedents with paired binations of ch teristics; bottom bers, control subjects with combinations. . 354 y 175 18> oe 65 * 524 Figure 3—Estimated coronary heart disease death ratios in a 17-51 year follow-up, and frequencies of paired combinations of six high-risk charac- teristics in college, for all ages at death. Source: Paffenbarger, R. S., et al. (146). 25 TABLE 2.—Coronary heart disease mortality (Actual number of deaths CSM = Smokers Author, year, Number and Follow- Number country, type of Data up ©: Cigarettes /day reference population collection (years) deaths Hammond = 187,783 Question- 314 5,297 NS ......... 1.00 (709), and white males naire and Allsmokers .1,70 (3361) "{P<9-901) Horn, in 9 states follow-up <10 ........1.29 (192) 1958, 50-69 years of death 10-20 ....1.89 (864) U.S.A. of age. certificate. 20-40 ..... 2.20 (604) (77, 78). >40 ........2.41 (118) Doyle 2,282 males, Detailed 10 93 NS ......... 1.00 (20) etal, Fram- medical Allsmokers .2.40 (73) 1964, ingham, examina- <20 ........2.00 (17) U.S.A. 30-62 years tion and 20 ........1.70 (20) (54). of age. follow-up. 8 >20 ........38.50 (36) 1,913 males, Albany, 39-55 years of age. Doll and Approxi- Question- 10 1,376 NS ........1.00 Hill, mately naire and Allsmokers .1.35 1964, 41,000 follow-up 1-14... £1.29 Great male British of death 15-24 ....1.27 Britain physicians. certificate. >25 «1... 1. 148 (50), Strobel 3,749 male Question- 9 162 NS 1.00 and Gsell Swiss phy- naire and 1965 sicians. follow-up 1-20 .......1.48 Switzer- of death | a 1.76 land certificate. (180). Best, Approxi- Question- 6 2,000 NS ........1,00 1966 mately naire and Allsmokers .1.60 (1380) Canada 78,000 follow-up om 10 ........1.55 (387) (24). male Cana- of death 10-20 ......1.58 (766) dian certificate. 320 oo... eee 1.78 (277) veterans. Kahn U.S. male Question- 8% 10,890 NS ........1.00 (2997) 1966 veterans naire and Allsmokergs .1.74 (4150) U.S.A. 2,265,674 follow-up 1-9 ........1.89 (489) (93). person of death 10-20 ...... 1.78 (2102) years. certificate. 21-39 ......1.84 (1292) >39 Lo... 2.00 (266) Hirayama, 265,118 Trained in- 1 @l1 NS ........ 1.00 (17) 1967, Japanese terviewers 1-24 .......1.138 (69) Japan adults over and follow- 25 ow... 1.00 (5) (84). age 40, up of death certificate. Kannel 5,127 males Medical ex- 12 52 NS o.oo... 1.00 (27) et al., and females amination SM>20 ....2.20 (25) ; mt? 1968, age 30-59. and U.S.A. follow-up. (94). 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 26 ratios related to smoking—prospective studies shown in parentheses )1 NS = Nonsmokers] Cigars, pipes Age variation Comments Cigars 50-54 55~59 60-64 65-69 NS. .1,00 NS -- 1,00 (90) 1.00 (142) 1.00 (204) 1.00 (273) SM. .1.28 (420) Allsmokers .1.93 (765) 1.85 (962) 1.66 (921) 1.41 (718) Pipes <10 --1,38 (35) 1.88 (50) 1.17 (49) 1.27 (58) NS. .1,00 10-20 .......2.00 (213) 2.04 (258) 1.91 (235) 1.58 (158) SM. .1.08 (312) >20 .-2.51 (2038) 2.47 (199) 1.92 (129) 1.56 (73) Data apply only to males aged 40-49 and free of CHD at entry. NS include pipe, cigar and ex-smokers. 35-44 45-64 65-84 NS ......0.. 1.00 1.00 1.00 1-14 20.0... 3.73 1.40 1.71 15-24 2.00... 4.45 1.73 1.27 D265... 1.36 1,92 1.58 NS. .1,00 SM. .1.45 Cigars 30-49 50-69 70 and over NS. .1,00 NS .........1.00 1.00 1.00 SM. .0.98 (16) <10 ........0.97 (18) 1.56 (220) 1.71 (99) Pipes 10-20 - 1.45 (115) 1.67 (557) 1,29 (94) NS. .1,00 >20 --1.85 (65) 1.76 (184) 1.73 (28) SM..0.96 (95) Cigars NS. .1.00 3M. .1.04 (623) Pipes NS. .1.00 3M. .1.08 (886) Prelimin- ary report. * ">" values specified only for those provided by authors. 27 TABLE 2.—Coronary heart disease mortality ratios (Actual number of deaths [SM = Smokerg Author, year, Number and Follow- Number country, type of Data up © Cigarettes /day reference population collection (years) deaths Hammond 358,534 Question- 6 14,819 Males Females and males naire and NS ........ 1,00 1.00 Garfinkel, 445,875 follow-up 1-9 1.27 0.84 1969, females of death 10-19 1.60 1.22 U.S.A. age 40-79 certificate. 20-30 1.73 1.52 (76). at entry. >40 »1.77 0.61 Paffenbar- 50,000 male Baseline 17-51 1,146 NS ~+++1.00 ger and former interview matched 3M .. 1.50 (385) (P<0.01) Wing students. and exam- with 1969 ination and 2,292 U.S.A. follow-up controls (146) by death certificate, Paffenbar- 3,263 male Initial multi- 16 291 NS and <20 1.00 (137) ger et al., longshore- phasic SM >20 ....2.08 (154) (p<0.01) 1970, men 35-64 screening U.S.A, years of and follow- (144). age. up of death certificate. Taylor 2,571 male Interviews 5 46 NS ........1.00 (4) et al., railroad and regular <20 ........1.97 (20) 1970, employees follow-up >20 -. 3,60 (22) U.S.A. 40-59 years exam- (183). of age at ination. entry. Weir and 68,153 Cali- Question- 5-8 1,718 NS ......... 1.00 Dunn, fornia male naire and Allsmokers .1.60 1970, workers follow-up #10 ........1.89 U.S.A. 35-64 years of death +20 we. 1.67 (205). of age at certificate, 230 Le. 1.74 entry. Pooling 7,427 white Medical ex- 10 239 NS .... 2... 1.00 (27) Project, males amination 1G woe. 1.65 (34) American 30-59 years and 20 ........1.70 (86) Heart of age at follow-up. >20 -..3.00 (68) Associa- entry. tion, 1970, U.S.A. (88). 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 28 related to smoking—prospective studies (cont.) shown in parentheses)! NS = Nonsmokers] Cigars, pipes Age variation Comments Males tBased on 4H-49 50-59 60-69 70-79 5-9 deaths. NS . 1.00 1.00 1.00 1.00 1-9 - 1.60 1.59 1.48 1.14 10-19 .......2.59 2.13 1.82 1.41 20-30 . 8.76 2.40 1.91 1.49 >40 - 5.b1 2.79 1.79 1.47 Females NS .........1.00 1.00 1.00 1,00 1-9 ». 1.31 1.15 1.04 0.76 10-19 . 2.08 2.37 1.79 0.98 20-30 .......3.62 2,68 2.08 1.27 >40 .......48.31 3.73 $2.02 _— 3O-44 45-54 55-69 NS . 1.00 1.00 1.00 (p<0.01) SM ......... 1.80 (88) 1.60 (163) 1.20 (184) Data apply only to those free of CHD at entry. 35-44 45-54 55-64 65-69 NS includes NS ......... 1.00 1.00 1.00 1,00 pipes and x10 . 4.22 2.05 1.41 1.17 cigars. +20 . 6.14 317 1.64 1,26 SM includes +30 .....,..8.57 3.33 1.66 1.36 ex-smokers. >40 woe... 7.93 3.15 1.42 1.42 All . 6.24 2,95 1.56 1,24 1.00 (27) 1.20 (24) 29 TABLE 3,—Sudden death from coronary (Mortality ratios—actual number Author year, Number and Data Follow-up Number country, type of collection years oO. reference population deaths Pooling 7,427 white Medical 10 145 Project, males 30-59 examination American Heart years of age and Association, at entry. follow-up. 1970, U.S.A. (88). TABLE 4.—Coronary heart disease (Risk ratios—actual number of CHD {SM = Smokers NS = Nonsmokers PROSPECTIVE STUDIES Author, year, Number and Data Follaw- Number of country, type of collection up incidents Cigarettes/day reference population years Doyle 2,282 males Detailed 10 243 myo- NS ............1.00 (52) etal, Framingham, medical cardia] All smokers ... .2.36(191) 1964, 30-62 years examina- infare- <20 ... eee eee 1.98 (44) U.S.A. of age. tion and tions and 20 .. 2.05 (64) (54). 1,913 males follow-up. CHD >20 - 3.04 (83) Albany, deaths. 39-55 years of age. Stamler 1,329 CHD- Interview 4 46 CHD NS ............1,00 (2) etal., free male and examin- <10 cigarettes. 2.92 (6) 1966, employees of ation with <5 cigars....{° U.S.A. Peoples Gas clinic <5 pipes..... (177), Company follow-up. 10-19 cigarettes.3.67 (8) 40-59 years >20 cigarettes . } 3.83 (29) of age. > 5 cigars.... > 5 pipes..... Epstein, 6,565 male Initial 4 96 male, Males 1967, and female medical 92 female 40-59 U.S.A. residents examina- CHD in- NS seceee 1.00 (1) (61), of Tecumseh, tion and cluding EX ............6.53 (10) Mich. repeat deaths, Cigarettes .....5.20 (36) follow-up angina, and Females examini- myocardial NS -. 1.00 (21) tions. infarctions, EX ............0.89 (3) Cigarettes ..... 1.02 (14) 1 Unless otherwise specified, disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 30 laurt disease related to smoking of deaths shown in parentheses ) Cigarettes/day Cigars, pipes Comment Never smoked ...........1.00 (13) 1.00 (15) See_table 1 for description of LO eee e ee eee eee ee 90 (23) 1.86 (13) Pooling Project. BE ccc ccc n veneer eee AGO (50) BD eee ene ee 8,86 (44) morbidity as related to smoking manifestations shown in parentheses)! EX = Ex-smokers] PROSPECTIVE STUDIES—Continued Pipes, cigars Age variation Comments Data include CHD deaths, only on males 40-49 years of age and free of CHD on entry. NS includes pipes, cigars, and ex-smokers. NS includes ex-smokers. Includes all CHD. Males—Continued Males Reexamination 60 and over 40-59 of patients 1.00 (7} SM ....1.80(2) was spread 1,27(41) 60 and over over 114-6-year 1.96 (28) SM... .0.86(6) period, but Femates—Continued data are re- 1.00(47) ported in 1.31 (5) terms of 0.42 (2) 4-year inci- dence rates. Actual number of CHD inci- dents derived from data on incidence and total in smok- ing class, 31 TABLE 4.—Coronary heart disease (Risk ratios—actual number of CHD [SM = Smokers NS = Nonsmokerg PROSPECTIVE STUDIES Author, year, Number and Data Follow- Number of country, type of collection up incidents Cigarettes/day reference population years Jenkins, 3,182 males Initial] 4ly 104 myo- NS weeeee 1.00 (21) etal., 39-59 years medical cardial EX cece ee 2 AT (15) 1968, of age at examina~ infarctions. Current .......2.78 (68) U.S.A. entry. tion and 0-15/day ......41.39 (45) (90). follow-up S16 Lo. e ee 3.08 (59) by repeat examina- tions. Kannel, 5,127 males Medical 12 228 myo- Myocardial Infarction etal., and females examination cardial Males 1968, 30-59 years and fallow- infarc- NS ..........--1.00 (21) U.S.A. of age. up. tions. All SM ........1.51(153) (94). 380 CHD. Heavy SM ....1.85 (59) Risk of CHD (overail} Males NS ............1,00 (61) 1-10 .. 1.34 (25) 11-20 .1.80 (90) >20 ..2.41 (76) Shapiro 110,000 male Baseline med- 3 Total Males et al., and female ical inter- unspeci- NS we... 1.00 1969, enrollees view and fied. All current ....2.14 U.S.A. of Health examination cigarettes (p<(0.01) (172), Insurance and regular <20 ween ee 150 Plan of follow-up. >20 Lees 2.336 Greater >40 wee 6.36 New York (HIP) 35-64 years of age. Keys 9,186 males Interviews. 5 65 deaths. NS, EX 1970 in 5 coun- and regu- 80 myocar- (SM <20) ...1.00(305) Yugo- tries 40-59 lar follow- dial in- All current slavia years of up examina- farctions. (>20) we... 1.31(108) Finland age at entry. tion by 128 angina Italy local pectoris. Nether- physicians. 155 other lands — Greece $428 total. (111). 1Unless otherwise specified, disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exelusion of either oceasional, miscellaneous, mixed, or ex-smokers. 32 morbidity as related to smoking (cont.) manifestations shown in parentheses )+ EX = Ex-smokers] PROSPECTIVE STUDIES—Continued Pipes, cigars Age variation Comments tIncludes nen- (p<0.001) 39-49 50-59 smokers and NS......1.00 (4) 1.00 (6) ex-smokers. (p<0.001) Current 4.23(35) 2.26(33) NS includes (comparing former pipe 0-15 and 16+) and cigar smokers. Myocardial infarction—Continued Females 1.00 (31) 1.71 (23) Risk of CHD (overall) —Continued Females 1.00 (89) 0.86 (18) 1.29 (18) 0.93 (3) Females Males only Males Females Total myo- 1.00 NS 165-100 85-44 45-54 55-64 35-44 45-54 55-64 cardial in- 2.00 SM ......1.82 1.00 1.00 1.00 1.00 1.00 1.00 farction in- (p>0.01) (p<0.01) 2.47 3.06 1.69 2.25 2.87 1,80 eludes those 0.52 2.15 1.32 dead within M7 3.04 3.29 aie 125° 2.81 165 je hours. 5.92 10.09 7.69 5.30 20.25 11.79 4.07 NS include ex-smokers. Includes all CHD incidence including EKG diagnoses. Covers all countries in- vestigated except U.S.A. t Difference between total CHD and the sum of smoking groups is due to difference in figures presented by authors. 33 TABLE 4.—-Coronary heart disease (Risk ratios—actual number of CHD {SM = Smokers NS = Nonsmokerg PROSPECTIVE STUDIES Author, year, Number and Data Follow- Number of country, type of collection up incidents Cigarettes/day reference population years Taylor, 2,571 male Interviews 5 46 deaths. NS and EX ....1.00 (62) et al. railroad and regu- 33 myocar- All} current ....1.77(150) 1970 employees lar follow- dial-in- U.S.A. 40-59 up examina- farctions. (183). years of tion. 78 angina age at pectoris. entry. 55 other CHD, 212 total. Dayton 422 male U.S. Interviews upto8 27 sudden <10 .+ 1.00 (25) et al., veterans par- and routine deaths. 10-20 ~-1.04 (22) 1970, ticipating as follow-up 44 definite >20 .1.17 (18) U.S.A. controls ina examina- myocardial (48,49). clinical trial of tions, infarctions. a diet high in unsatu- rated fat. Dunn 13,148 male Data only up to14 Total un- et al., patients in on new specified. 1970 periodic health incidents U.S.A. examination extracted (55). clinics. from clinic records. Pooling 7,427 white Medical 10 538 Project, males 30-59 examination includes Never smoked ..1,00 (53} American years of and follow- fatal and <10 .-1.65 (72) Heart age at entry. up. nonfatal 20 «2.08 (205) Association myocardial >20 . 8.28 (154) 1970, infarction U.S.A. and sudden (88). death. Pauletal., 1,989 Western Screening 1963, Electric Co. examinazion Coronary US.A. male workers and cases (87) (148). participating history. NS oo... eee 23 in a prospec- 7 Lee eee 2 tive study 8-12 9 for 444 years. 13-17 6 18-22 ........, AT 23-27 3 >28 9 1Unless otherwise specified, disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 34 morbidity as related to smoking (cont.) manifestations shown in parentheses)! EX = Ex-smokers] PROSPECTIVE STUDIES—Continued Pipes, cigars Age variation Comments All CHD including EKG diagnoses. No data on NS asa separate group. 30-89 40-49 50-59 + Includes tLow NS, EX, and SM 1.00(25) =1.00(125) 1,00(157) <20 cigarettes/ tHigh day. SM 2.17(¢10) 0.90 (81) 1.41 (53) } >20 ciga- rettes/day. Includes all CHD but excludes death, No data avail- able comparing smokers and nonsmokers. 1.00 (53) 1.25 (54) Noncoronary 88 developed controls clinical (1,786) coronary 33 disease, q 47 angina 11 pectoris, 12 28 myocardial 30 infarction, ; 13 deaths CHD. (p<0.005) 35 studies have shown an increased risk of this manifestation among smokers, others have not (see table 5). From these longitudinal studies, it has become increasingly clear that cigarette smoking is one of several risk factors for CHD and that it exerts both an independent effect and an effect in conjunc- tion with the other risk factors. The basic concept may be ex- pressed as follows: The more risk factors a given individual has, the greater the chance of his developing CHD. The importance of the constellation of coronary risk factors which include cigarette smoking, high blood pressure, and high serum cholesterol in pre- dicting the risk for CHD is illustrated in figures 1 through 3. Other risk factors are included in certain of these figures and are dis- cussed below. Knowledge of the effects of cigarette smoke on the cardiovascu- lar system has developed concurrently with the knowledge derived from the epidemiological studies. Nicotine, as well as cigarette smoke, has been shown to increase heart rate, stroke volume, and blood pressure, all most probably secondary to the promotion of catecholamine release from the adrenal gland and other chromaffin tissue. This release of catecholamines is also considered to be the cause of the rise in serum free fatty acids observed upon the in- halation of cigarette smoke. Studies concerning the effect of nico- tine on cardiac rhythm have also suggested that smoking might contribute to sudden death from ventricular fibrillation. In addition, research efforts have also been directed toward the effects of smoking on blood clotting and thrombosis; since many cases of sudden death and myocardial infarction are associated with thrombosis in a diseased coronary artery branch. Cigarette smoking may be associated with increased platelet aggregation in vitro and thus might play a role in the development of such throm- bi or platelet plugs in vivo. Other mechanisms have been investigated. Because cigarette smoking has been shown in some studies to be related to the prev- alence of angina pectoris as well as to the incidence of myocardial infarction, it has been suggested that smoking enhances the de- velopment of atherosclerotic lesions. Autopsy and experimental studies have shown that cigarette smoking plays a role in athero- genesis. The administration of nicotine has been observed to in- crease the severity of cholesterol-induced atherosclerotic lesions in experimental animals. Attention is presently being given to carbon monoxide, which is present in cigarette smoke in such concentra- tions as to cause carboxyhemoglobin concentrations in the blood of smokers as high as 10 percent. Based on research in animals, it is reasonable to conclude that the atherosclerotic process may be enhanced, in part, by the relative arterial hypoxemia in cigarette 36 Ze AuLnor, year, Number and Data Follow-up Number Cigars country, type of collection years of Cigarettes/day and pipes Age variation Comments reference population incidents Doyle 2,282 males, Detailed 10 81 NS . -1.00(30) NS include ex- et al., Framingham, medical All .........-.... -1.09 (51) smokers and 1964, 30-62 years examination <20 . 1,17 (15) pipe and U.S.A. of age. and 20... .. 0.99(18) cigar (54). 1,913 males, follow-up. 8 >20 vee eee eee ee AL15 (18) smokers. Albany, 39-55 years of age. Jenkins 3,182 males Initial medical 414 29 NS ......... ..1.00 (9) NS include et al., aged 39-59 examination All current former pipe 1968, at entry. and follow- cigarettes ..1.44(16) and cigar U.S.A. up by repeat >16 .. 1.63 (14) smokers. (90). examina- tion. Kannel 5,127 males Medical 12 107 Males et al., and females examination 1S 1.00(16) U.S.A, years of age and follow- Heavy SM, >20 (94). 30-59 up. cigarettes ........2.04(17) Femates NS oo. e eee ee «1,00 (58) Cigarette SM ......0.65(16) Shapiro 110,000 male Baseline 3 Total Males Females Males Males T(p<0.01) et al., and female medical Unspec- NS wee 100 1.00 NS,..1,00 35-44 45-54 55-64 F(p<0.05) 1969, enrollees of interview ified Current SM. .$1.71 NS weeee e100 1.00 1.00 NS include U.S.A. New York City and examina. cigarettes 11,91 1.20 Current cigarettes ..3.40 1.57 2.06 ex-smokers. (172). HIP 35-64 tion and <40 steee -1.51) 1.20 <40 «22.35 1.40 1.54 years of age. regular >40 . 4.85 § . >40 . 1015 2.58 6.15 follow-up. Females NS . «1.00 1.00 1.00 Current cigarettes ..1.56 1.67 0.97 <40 os . 167 1.53 1.04 DAD cee eee ee — 4,12 _ 1 Unless otherwise specified, disparities between the total number of manifestations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. smokers caused by the increased carboxyhemoglobin level. With respect to the acute event of myocardial infarction, atten- tion has been focused on the role of nicotine. Nicotine stimulates the myocardium, increasing its oxygen demand. Other experiments have demonstrated that in the face of diminished coronary flow (due to partial occlusion from severe atherosclerosis in man or to partial mechanical obstruction in the animal), nicotine does not lead to an increase in coronary blood flow as seen in the normal individual. These effects exaggerate the oxygen deficit when the supply of oxygen has already been decreased by the presence of carboxyhemoglobin. Thus, a marked imbalance between oxygen demand (which has been increased) and oxygen supply (which has been decreased) is created by the inhalation of CO and nico- tine. This imbalance may contribute to acute coronary insufficiency and myocardial infarction. EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, both retrospective and pros- pective, have been carried out in various countries in order to iden- tify the risk factors associated with the development of coronary heart disease (CHD). Many of these studies have included smok- ing as one of the variables investigated. Tables 2 to 4 present the major findings. CORONARY HEART DISEASE MORTALITY Table 2 lists the various prospective studies concerning the rela- tion of CHD mortality and smoking. These studies demonstrate the dose-related effect of cigarette smoking on the risk of developing CHD. For example, the Dorn Study of U.S. Veterans as reported by Kahn (93) reveals progressively increasing mortality ratios, from 1.39 for those smoking 1 to 9 cigarettes per day to 2.00 for those smoking more than 39 cigarettes per day. Although the data are not detailed in the accompanying tables, several of these stud- ies have also shown that increased rates of CHD mortality are associated with increased cigarette dosage, as measured by the degree of inhalation and the age at which smoking began. Although not as striking, the data for females reveal the same trends. In most studies, the smokers’ increased risk of dying from CHD appears to be limited mainly to those who smoke cigarettes, Some studies that have investigated other forms of smoking have shown much smaller increases in risk for pipe and cigar smokers when compared to nonsmokers. However, the recent study by Shapiro, et al. (172) of a large population enrolled in the Health Insurance Plan (HIP) of New York City showed a significantly increased 38 risk for the development of myocardial infarction and rapidly fatal myocardial infarction for a group consisting of both pipe and cigar smokers. Table 3 details the findings of the American Heart Association Pooling Project on sudden death. The Pooling Project, a national cooperative project of the AHA Council on Epidemiology, is de- scribed in table 1 (88). Cigarette smokers in the 30 to 59 year age group incurred a risk of sudden death from CHD substantially greater than that of nonsmokers. Pipe and cigar smokers were observed to show a risk slightly greater than that of nonsmokers (table 3). The relative risk of CHD mortality is greatest among cigarette smokers (as well as among those with other risk factors) in the younger age groups and decreases among the elderly. In table 2, Hammond and Horn found that for those smoking more than one pack per day, the risk is 2.51 in the 50 to 54 year age group and 1.56 in the 65 to 69 year age group. Although the relative risk for CHD among smokers decreases in the older age groups, the actual number of excess deaths among smokers continues to climb since the differences in death rates between smokers and nonsmok- ers continue to rise. CORONARY HEART DISEASE MORBIDITY Tables 4 and 5 list the prospective studies carried on in a num- ber of countries to identify the risk of CHD morbidity incurred by smoking. Here, CHD morbidity includes myocardial infarction as well as angina pectoris. Certain studies, notably those of Doyle, et al. (54), Keys, et al. (111), and Taylor, et al. (182) include a number of CHD deaths in their data that could not be separated out using the information provided in their respective reports. As noted in the discussion on CHD mortality, the CHD risk ratio increases significantly as the number of cigarettes smoked per day increases. Similarly, the HIP data of Shapiro, et al. (172) show that the elevated morbidity ratios declined with increasing age as has been shown for mortality ratios. A recent monograph edited by Keys (11 1) dealt with the 5-year CHD incidence in males age 40 to 59 from seven countries. As summarized in table 4, cigarette smoking was found to be associ- ated with an increased incidence of CHD in the U.S. railroad worker population, 2,571 individuals (183). None of the differences in ratio between smokers and nonsmokers was statistically signifi- cant for the 13 other population samples which varied in size from 505 to 982 individuals, from the five other countries. (Smoking was not considered in the two Japanese populations.) When more cases 39 become available to provide greater statistical stability to the rates, this intercultural comparison should prove illuminating. The results of those studies which have separated out angina pectoris as a manifestation of CHD are presented in table 5. Doyle, et al. (54) found no relationship between this manifestation of CHD and cigarette smoking. Both Jenkins, et al. (90) and Kannel, et al. (94) observed increased risk ratios among male cigarette smokers although these differences were not statistically signifi- cant. More recently, Shapiro, et al. (172) found a significantly increased risk for angina among their male cigarette smokers as well as increasing risk ratios with increasing dosage among both males and females, particularly in the younger age groups. A variety of hypothetical explanations have been advanced to account for this seeming contradiction. Among these are the relatively small number of cases, the difficulties associated with the definitive diagnosis of the syndrome, and differences in the methods of clas- sifying those cases of angina pectoris which are followed by myo- cardial infarction. RETROSPECTIVE STUDIES Table A6 presents data from the various retrospective studies of CHD prevalence. Most of these are case-control studies and show an increased percentage of smokers among those with clinical CHD when compared with a selected control population, usually without apparent CHD, Two of these studies include data on mortality. THE INTERACTION OF CIGARETTE SMOKING AND OTHER CHD RISK FACTORS The preceding section has reviewed the epidemiologic evidence which supports the judgment that cigarette smoking is a signifi- cant risk factor in the development of CHD. Many of the studies discussed above have identified a number of biochemical, physio- logical, and environmental factors, other than cigarette smoking, which also increase the risk of developing CHD. These risk factors include elevated serum lipids (particularly serum cholesterol) and hypertension, which, with cigarette smoking, are considered to be of greatest importance. Other factors are obesity, physical inac- tivity, elevated resting heart rate, diabetes (as well as asympto- matic hyperglycemia), electrocardiographic abnormalities, and a positive family history of premature CHD (88). A number of these studies have also found that these factors, when present in the same individual, exert a combined effect on the risk of developing CHD. Figures 1 through 3 depict this inter- action of risk factors. As may be noted in Figures 1 and 2, the 40 additional factor of smoking greatly increases the risk of develop- ing CHD among those people already at high risk because of other factors. Furthermore, these studies have shown that the effect of smok- ing on the risk of developing CHD is statistically independent of the other risk factors. That is, when the effect of the other factors is statistically controlled, smoking continues to exert a significant effect on increasing the risk of developing and dying from CHD. Smoking and Serum Lipids The interaction of smoking and serum lipid levels in the develop- ment of CHD should be considered in the light of information con- cerning the relationship of smoking to serum lipid levels. Table A7 presents studies which deal with the association between smoking and lipids, notably cholesterol, triglycerides, and lipoproteins (con- cerned with lipid transport). While some of the studies have indi- cated that smokers show increased serum levels of these lipid con- stituents, others have not. The populations investigated and the methods of the various studies show significant variation. This lack of comparability makes interpretation of the findings difficult. It is clear, however, that in the presence of high serum choles- terol, cigarette smoking increases the risk of CHD. Figure 4 de- picts the data from the Chicago Peoples Gas, Light and Coke Com- pany study which show that smoking greatly increases the risk of CHD in each of the cholesterol groups. Smoking and Hypertension Some epidemiological studies have indicated that smokers tend to have lower mean systolic and/or diastolic blood pressures than nonsmokers, while other studies have not found this to be the case (table A8). Reid, et al. (155), in a study of 1,300 British and American postal workers, found that the blood pressure difference between the smoking and nonsmoking groups was eliminated after controlling for body weight. Tables 9 through 11, derived from the study by Borhani, et al. (27), demonstrate the following associations: That for both smok- ers and nonsmokers, the risk of dying from CHD increases with increasing diastolic or systolic pressure, and that the risk of mor- tality from CHD is higher among smokers than among nonsmokers in each blood pressure group. Cigarette smoking, therefore, has been shown to elevate CHD mortality independently both of its effect on blood pressure and of the effect of hypertension on CHD. Smoking and Physical Inactivity The recent study by Shapiro, et al. (772) of more than 110,000 41 TABLE 9.—Death rates from coronary heart disease, by systolic blood pressure; ILWU mortality study 1951-61 (Coronary heart disease as classified under ISC Code 420) Smokers Nonsmokers Systolic blood Person-years Death Person-years Death Age group pressure in 1951 of observation ratel of observation rate! 45-54 <130 1,877 27 2,413 8 130-149 2,066 34 2,912 17 150-169 740 95 1,177 26 >170 369 109 672 45 55-64 <130 1,067 84 1,550 26 130-149 1,380 94 2,401 325 150-169 647 93 1,558 45 >170 524 210 1,117 125 1 Rate per 10,000 person-years of observation. 2 p<0.025, 1 p<0.01 Source: Borhani, N. O., et al. (27). TABLE 10.—Death rates from coronary heart disease, by diastolic blood pressure: ILWU mortality study, 1951-61 (Coronary heart disease as classified under ISC Code 420) Smokers Nonsmokers Diastolic blood Person-years Death Person-years Death Age group pressure in 1951 of observation ratet of observation ratel AB-B4 ce ce eee <80 1,527 26 1,700 6 80-— 89 2,115 AT 2,947 17 90- 99 961 52 1,507 33 >100 448 89 1,020 20 55-64 oe ee eee <80 1,059 104 1,447 221 80- 89 1,521 59 2,704 15 90-- 99 669 194 1,521 246 >100 369 163 954 147 1 Rate per 10,000 person-years of observation. = p<0.05. 3 p<0.01. Source: Borhani, N. O., et al. (27). TABLE 11.—Death rates from coronary heart disease, among hypertensives and nonhypertensives: ILWU mortality study, 1951-61 (Coronary heart disease as classified under ISC Code 420) Smokers Nonsmokers Blood pressure Person-years Death Person-years Death Age group status 1 of observation rate? of observation rate? 45-54 ......... Hypertensives .......... 883 125 1,871 $32 Nonhypertensives ...... 4,169 29 5,303 13 55-64 ......... Hypertensives .......... 931 150 2,219 95 Nonhypertensives ...... 2,687 93 4,407 316 1 According tu the WHO recommendation, the following cut-off points are recommended for the definition of hypertension: (1) Normotension—below 140/90 mm. Hg. (2) Hypertension—systolic blood pressure 160 mm. Hg. or over, or diastolic 95 mm. Hg. or over, or both. (3) Borderline—the residual category. In this analysis, Normotensives and Borderlines were combined and the population was grcuped into ‘Nonhypertensives’ (1 and 3) and ‘Hypertensives’ (2). 2 Rate per 10,000 person-years of observation. > p<0.01. Source: Borhani, N. O., et al. (27). 42 INCIDENCE PER 1,000 MEN 80— — 80 70— — NON NON SMOKERS SMOKERS SMOKERS SMOKERS SMOKERS SMOKERS <225 225-274 2754 <225 225-274 275+ CHD 46° 1 5 2 9 16 12 N 1329* 187 235 71 336 317 151 AGE 49 49 50 51 50 49 50 SYSTOLIC 13 139 131 133 135 PRESSURE 133 8 WEIGHT 1.16 1.19 1.21 1.18 1.12 1.15 1.17 RATIO Figure 4—Relationship between smoking status and serum cholesterol level at initial examination, and incidence of clinical coronary heart disease in men originally age 40-59, free of definite CHD, and followed subsequently without systematic intervention, Peoples Gas Light and Coke Company study, 1958-1962. *For 34 men, no information on smoking status was available; one of these men had a coronary episode. Source: Stamler, J., et al. (177). persons participating in the Health Insurance Plan of New York City has further identified and elaborated upon the interaction of the various risk factors. Physical inactivity, both in employment and during leisure time, was found to be a potent risk factor for the development of CHD, particularly for rapidly fatal myocardial infarction. Figure 5 depicts the effect which smoking exerts on CHD in combination with physical inactivity. Of note, also, is the observa- tion that within each activity grouping, smoking greatly increases the risk of myocardial infarction, thus exerting an independent effect. Smoking and Obesity The analysis by Truett, et al. (190) of the risk factor data from the Framingham study revealed that weight, while a significant risk factor, had a considerably smaller effect on CHD incidence than serum cholesterol, cigarette smoking, or elevated blood pres- sure, The results concerning the interaction of smoking and obesity from the San Francisco longshoremen study are shown in table 12. 43 11.0 10.0 9.0 8.0 7.0 6.0 5.9 4.0 Rate per 1,000 (age-adjusted) 3.0 F 2.0 1.0 0.0 Not dead within 48 hrs. Dead within 48 hrs. 10.89 5.72 (57) 5.78 4.48 (166) 5.18 (46) 1.30 (1) Least More active active NONCIGARETTE SMOKERS 6.33 3.76 (47) 3.03 2.34 (118) 2.57 G)) 0.69 (33) Least More active active Note: Both for cigarette smokers and noncigarette smokers differences between rates among the least and more active men are statistically significant for total MI and rapidly fatal Mis at the 0.99 confidence level. For other Mls the difference is statistically significant only for the nonsmokers (confidence level 0.95). Figure 5—Average annual incidence of first myocardial infarction among men in relation to overall physical activity class and smoking habits (age-ad- justed rates per 1,000) (Actual number of deaths or myocardial infarctions are represented by figures in parentheses) Source: Shapiro, S., et al. (172). This table shows that cigarette smokers in the 55 to 64 year age group were observed to have higher CHD death rates than non- smokers in all weight categories. Similar findings, although not in all weight groups, were observed for the 45 to 54 year age group. Cigarette smoking is thus shown to be a CHD risk factor indepen- dent of body weight. 44 TABLE 12.—Death rates from coronary heart disease among men without abnormalities related to cardiopulmonary diseases by weight classification in 1951: ILWU mortality study, 1951-61 (Coronary heart disease as classified under ISC Code 420) Smokers Nonsmokers Weight Person-years Death Person-years Death Age group classification 2 of observation rate = of observation rate? 45-54 ......... Not overweight ........ 388 21 279 q Slightly overweight .... 962 28 1,096 0 Moderately overweight . 1,383 28 1,574 28 Markedly overweight .. 1,055 22 1,797 9 55-64 20.2... Not overweight ........ 222 43 247 0 Slightly overweight .... 536 75 605 36 Moderately overweight . 855 109 1,320 411 Markedly overweight .. 735 . 88 1,653 312 >The four classes are defined in the text. * Rate per 10,000 person-years of observation. *p20 Smoked 1-19 cigarettes/day cigarettes/day Hammond Never and Garfinkel, smoked regularly ......1.00(1,841) 1.00(1,841) Male data only 1969, Current U.S.A. cigarette smokers ....... 1.90 (1,063) 2.55 (2,822) (76). Stopped <1 year .........1.62 (29) 161 (62) V4 eee cece eee ee 122 (5TH 1.51 (154) BO cece eee cee ee ee L26 (55) 1.16 (135) LOG oe cece cee eee 0.96 (52) 1.25 (133) S20 Lee ce eee eee 1.08 (70) 1.05 (80) All ex-cigarette smokers ..1.16 (263) 1.28 (564) Total definite myocardial infarction Shapiro Never smoked 1.0.0.0... 00 eee eee eee en een etnies 1.00 etal, Current cigarette smokers ........-:ee cess ee ee eens 1.87 1969, Stopped 5 years 2... ... cece cece ee ee teen e eee 0.76 U.S.A. (172). Pooling Project, American Heart Association 1976, U.S.A. (88). Al CHD deaths Never smoked ........-..+5 1.00 (27) >, pack/day ....-----.565 1.65 (34) 1 pack/day wae eee oL.70 (86) >1 pack/day wee es 3.00 (68) Ex-smokers ween ee 0,80 (19) First major coronary event 1.00 (53) See table 4 1.65 (72) for description 2,08 (205) of Pooling 3.28 (154) Project. 1.25 (51) TaBLe 16.—Annual probability of death from coronary heart disease, in current and discontinued smokers, by age, maximum amount smoked, and age started smoking Age started smoking 15-19 20-24 Discontinued Discontinued Maximum daily Current for five or Current for five or Age number of ciga- smokers more years smokers more years rettes smoked (Probability x10 5) BB-64 oe eee 0 501 — 501 —_— 16-20 798 568 811 551 21-39 969 766 872 698 65-742 1. ee eee 0 1,015 — 1,015 — 10-20 1,502 1,169 1,478 1,213 21-39 1,710 1,334 1,573 1,098 1For age group 65-74, probabilities for discontinued smokers are for 10 or more years of dis- continuance since data for the 5-9 year discontinuance group are not given. Source: Cornfield, J., Mitchell, S. (45). Based on data derived from Kahn, H. A. (93). 46 Smoking and Electrocardiographic Abnormalities Electrocardiographic (ECG) abnormalities such as T-wave and ST-segment changes as well as a number of arrhythmias are use- ful indicators of CHD and may, therefore, be predictive of the development of clinically overt CHD manifestations. The results summarized in table 13, from the prospective study by Borhani, et al. (27), reflect the joint predictive value of smoking and ECG abnormalities on the death rate from CHD. Smoking and Heart Rate Recent analysis by Berkson, et al. (23) of the data derived from the Chicago Peoples Gas, Light and Coke Company study of middle-aged men revealed that resting heart rates of 80 or greater were associated with an increase in the risk of death from CHD. These authors found that this association was independent of the other major coronary risk factors. Table 14 presents the interaction between smoking, blood pres- sure, and elevated heart rate in increasing the risk of CHD mor- tality. This study shows that cigarette smoking increases CHD risk in the presence of elevated heart rate as well as in its absence. THE EFFECT OF CESSATION OF CIGARETTE SMOKING ON CORONARY HEART DISEASE A number of epidemiological studies have been concerned with the CHD incidence and mortality among ex-cigarette smokers as compared with current smokers (51, 76, 88, 90, 93, 172). These studies are listed in table 15. Table 16 presents the data derived by Cornfield and Mitchell (45) from the Dorn Study of U.S. Veterans (93). Ex-cigarette smokers show a reduced risk of both myocardial infarction and death from CHD relative to that of continuing ciga- rette smokers. The Pooling Project (88) and the Western Collab- orative Study Group (192) which adjusted for the other risk fac- tors of elevated serum cholesterol and blood pressure observed this relationship. Hammond and Garfinkel (76) noted that cessation of smoking is accompanied by a relative decrease in risk of death from CHD within 1 year after stopping. This decreased risk of CHD among ex-smokers further strength- ens the relationship between smoking and CHD. It must be noted, Owever, that the group of ex-smokers is composed of individuals who have stopped smoking for a variety of reasons. Those who Stop because of ‘ill health and the presence of symptoms are gen- frally at high risk and can bias the group results in one direction; 47 those healthy persons who stop as part of a general concern about their health and may adopt a number of self-protective health prac- tices are generally at low risk and can bias the group results in the other direction. Therefore, ex-smokers as a group are not fully representative of the entire population of smokers and may have limited value in predicting what would happen if large numbers of cigarette smokers stopped smoking purely for self-protection. Cer- tain incidence studies, such as the Pooling Project (88), were initi- ated with only clinically healthy individuals. The data from such studies, as well as those from the British physicians study, contain ex-smoker data less influenced by these biases. Fletcher and Horn (63) have recently presented data derived from the British physicians study of Doll and Hill. Over the past 10-15 years, cigarette smoking rates among British physicians have declined significantly in comparison with those of the general British population. The information presented by these authors concerning all cardiovascular diseases showed that for individuals between the ages of 35 and 64, the age-adjusted death rate for CHD declined by 6 percent among physicians and rose by 10 percent among the male population of England and Wales during the period from 1953-57 to 1961-65. THE CONSTITUTIONAL HYPOTHESIS The effect of smoking on the incidence of CHD has been found to be independent of the influence of the other CHD risk factors. When such risk factors as high serum cholesterol (177), increased blood pressure (27), elevated resting heart rate (23), physical in- activity (172), obesity (27), and electrocardiographic abnormali- ties (27) have been controlled, cigarette smokers still show higher rates of CHD than nonsmokers. It has been suggested by some (39, 170) that the relationship between cigarette smoking and CHD has a constitutional basis. That is people with certain constitutional make-ups are more likely to develop CHD, and the same people are more likely to smoke cigarettes. This hypothesis maintains that the relationship between cigarette smoking and CHD is thus largely fortuitous and that the significant relationships are between the genetic make-up of the individual and CHD and between the genetic make-up of the indi- vidual and his becoming a cigarette smoker. Two sets of epidemio- logic data bear on this hypothesis. It has been maintained that people with a certain temperament are more likely to smoke and also more likely to develop CHD. These characteristics have been demonstrated for those with the 48 of 1.6, while those in the second group were found to have one of approximately 1.1. The authors concluded that this difference be. tween the two groups provides better support for the importance of constitutional factors as against the importance of cigarette smoking in the development of angina pectoris. A similar study was done using the responses of 4,379 U.S. Vet- eran twin pairs (approximately 60 percent of estimated available total) who completed the mailed questionnaires (38). Cederlof, et al. found a significantly increased prevalence of chest pain and “angina pectoris” among smokers when Group A was analyzed, Analysis of the smoking-discordant matched twin pairs (Group B) revealed no association between smoking and cardiovascular symp- toms among the monozygotic pairs. The dizygotic pair data did show a slight association. The authors concluded that this lack of association among the monozygotes and its presence among the dizygotes and unmatched pairs strengthens the case for a constitu. tional hypothesis. A major problem in these studies is the small number of cases available and, therefore, the statistical instability of the results, In the Swedish study, among the 274 monozygotes, only 19 smokers and 16 nonsmokers were classified as having angina pectoris while among the 733 dizygotes, 25 smokers and 25 nonsmokers were so classified. In neither group was the difference between the prev- alence ratios found in the Group A analysis and that in the Group B analysis of statistical significance. Analysis of the data on women shows a similar lack of significance. Similar criticisms may be made of the study which utilized the U.S. Veteran Twin Registry. In that study, the authors observed that the difference in the prevalence of angina pectoris between the low-cigarette-exposure and high-cigarette-exposure dizygotic groups was not present among the monozygotes. The authors ques- tioned whether the excess morbidity associated with cigarette smoking found in the dizygotic group was causal as it was not pos- sible to reproduce the association when studying monozygotic smoking-discordant twin pairs. As noted above, the numbers in this study are also small so that the differences in rates do not approach statistical significance. Tibblin (188) has questioned the value of a mailed questionnaire to diagnose heart disease. The questionnaire as originally con- structed was used and validated by interview technique alone (157, 158). Cederlof, et al. (40) conducted a study to determine the validity of this questionnaire as a mailed instrument by personally interviewing and examining 170 of the twin pairs who had replied. Of the eight males who were diagnosed as having “angina pectoris” by the questionnaire. four were found to be free of symptoms on 50 clinical examination, while among 204 responding negatively, two were found to have angina by clinical criteria. None of the 11 women who were diagnosed as positive by questionnaire was found to be clinically affected, and of the 136 reporting as negative, three had symptoms of angina pectoris. Other major difficulties associated with these studies include the problems of using prevalence data in the investigation of a disease (CHD) from which a significant number of those affected die shortly after the onset of symptoms, the inclusion of ex-smokers in the smoking population, and the low numbers of heavy cigarette smokers in the Swedish population. In general, the problems of using twin registries to study the etiology of cardiovascular disease with mortality and morbidity ratios in the neighborhood of 2 to 1 are much more difficult than in studying the etiology of bronchopulmonary disease in which the relationships are of the order of magnitude of 4 to 1. More recently, Friberg, et al. (69) reported on mortality data from the Swedish Twin Registry. The authors suggested that part of the increased mortality observed among smokers when com- pared with nonsmokers was not due to smoking per se but to fac- tors associated with smoking. The very small numbers of total deaths presently available (47 deaths among 706 dizygotic pairs and 13 deaths among 246 monozygotic pairs) do not provide a sta- tistically stable base for deriving any conclusions at the present time. Hauge, et al. (87) have recently reported on the influence of smoking on the morbidity and mortality observed in the Danish Twin Register. Among 762 monozygotic and same-sexed dizygotic twin pairs, angina pectoris was found to be significantly more fre- quent in those cotwins with a higher consumption of tobacco than in those with a lower or no consumption. A similar tendency was observed for myocardial infarctions but was not of statistical Significance, Seltzer, who has been a proponent of the constitutional hypothe- sis, in a recent review of some of the experimental, clinical, and pathological data relating smoking and CHD, concluded that the evidence from these areas has not “reasonably substantiated” the “hypothesis” of the acute effect of cigarette smoking on the coro- nary circulation, nor has the chronic effect of cigarette smoking on the cardiovascular system been shown to be a “clear” and con- sistent one (170). His views are contrary to those of most re- searchers in this field. Although the data from the twin studies are inconclusive with regard to a role for genetic factors in heart disease, it would be Surprising if genetic factors did not play such a role. It is open to 51 question whether findings from twin studies can be used to distin- guish between the hypothesis that genetic factors govern the level of host susceptibility or resistance to the effects of an exogenous influence such as cigarette smoking and the hypothesis that genetic factors “cause” both heart disease and smoking. AUTOPSY STUDIES RELATING SMOKING, ATHEROSCLEROSIS, AND SUDDEN CHD DEATH A number of researchers have investigated the cigarette smoking habits and the cardiovascular pathology of those individuals dying suddenly from CHD and of large populations of individuals with and without histories of overt CHD. Spain and Bradess (175) recently analyzed the smoking habits of 189 individuals who died suddenly and unexpectedly, apparently from the first acute clinical episodes of CHD. The authors noted a close correlation of a history of cigarette smoking with this type of sudden death and also with shorter survival times following the acute episode. This association was strongest in those persons under 50 years of age. The authors also observed that those surviving very short pe- riods of time showed a notable lack of intracoronary artery throm- bi at autopsy and that the frequency of thrombi present increased with increasing survival time. They suggested that thrombi found at autopsy may be the result rather than the cause of certain instances of myocardial infarction, particularly of lesions showing subendocardial necrosis. This finding is of significance in the study of the effect of smoking on myocardial metabolism and oxygen supply and demand rather than on thrombus or platelet plug formation. While the autopsy study of Spain and Bradess (175) concerned sudden death among smokers, other autopsy studies from various countries have been directed towards the relationship of cigarette smoking to the presence of atherosclerotic disease in the aorta and coronary arteries. These are concerned with the long-term effects which smoking has on the cardiovascular system and are sum- marized in table 19. The studies of Auerbach, et al. (12), Avtan- dilov, et al. (12), Sackett, et al. (165), and Strong, et al. (182) found that aortic and coronary atherosclerosis were more common and more severe among smokers than among nonsmokers. Auerbach, et al. (12) noted that this relationship persisted when the cases were matched for both age and cause of death or when the follow- ing cases were excluded; men with a history of diabetes; men who had died of any type of heart disease; and men whose hearts weighed 400 grams or more. Sackett, et al. (765) found that the 52 es (Figures in parentheses are number of individuals in that smoking category)! [SM = smokers NS = nonsmokers] Author, year, Autopsy Data country, population collection Cigarettes per day Conclusions Comments reference Wilens 989 consecutive Routine clinical Severity of aortic sclerosis The authors conclude that Smoking data unavailable and Plair, male autopsies records of Above average Average Below average in 60 percent of cases, the for 120 cases. 1962, at New York previous and NS wi. ee sees 9.9(161) 60.2 29.8 degree of sclerosis at Each aorta specimen given U\S.A. City VA present <20 . 19.1(152) 63.2 17.8 autopsy was commen- an “atherosclerotic age” (214). hospitals. admissions. 20-30 .... ee eee 26.4 (288) 62.5 11.1 surate with age of patient, by comparison witha >30 coerce e F25.1(199) 61.3 $13.6 regardless of smoking standard, If ‘‘athero- habits. In the remaining sclerotic age’ was found 40 percent there is evi- to be 10 years more than dence that cigarette real age, the aorta was smoking may be asso- said to show above- ciated with an above- average sclerosis. average degree of aortic tp<(0.001 comparing 9.9 sclerosis. with 25.1 and 29.8 with 13.6. Auerbach, 1,372 autopsies Interview with Degree of coronary artery atherosclerosig (overall age- The authors conclude that et al., of male next of kin. adjusted results) the percentage of men 1965, patients in No athero- with an advanced degree of U.S.A. Orange, New sclerosis Slight Moderate Advanced coronary atherosclerosis (12). Jersey, VA NS vee ee BB (69) 57.3 21.8 15.3 was higher among ciga- hospital for Current rette smokers than among whom smoking cigarette nonsmokers and that the habit data were <20 .....,2.6(139) 30.9 37.3 29.2 percentage increased available and 20-39 ....0.8(299) 19.7 42.1 37.4 with amount of cigarette who did not >40 ......0.6(144) 18.1 35.4 45.9 smoking. This relation- have overt CHD ship persisted even at death. when cases were matched for age and cause of death. 1 Unless otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. vs TABLE 19.—Autopsy studies of atherosclerosis (cont.) (Figures in parentheses are number of individuals in that smoking category )+ [SM = smokers NS = nonsmokers] Author, year, Autopsy Data country, population collection Cigarettes per day Conclusions Comments reference Avtandilov, 259 male and Not specified, Comparative size of mean area of atherosclerotic lesions The author concludes that Causes of death 96-athero- 1965, 141 female but there were: in inner coat of coronary arteries. the worst changes were sclerotic, 102-accidental, Russia autopsies. 180 SM and Right coronary artery Left coronary artery found in the left and 202-various diseases. qs). 220 NS. SM NS SM NS right coronary arteries {T-test for significance 30-39 .. $15.5 (30) 1.8 (32) $6.3 2.2 with less severe changes of difference between 40-49 .. 23.6 (34) 11.5 (27) 15.8 4.4 in circumflex artery means is significant 50-59 .. 136.3 (39) 14.8 (39) $27.9 9.9 and aorta. at p<0.05 level. 60-69 .. $31.9 (32) 23.8 (36) $26.5 22.5 70-79... 41.9(18) 31.7 (36) 26.1 35.8 Sackett, 893 total, Patient The results concerning aortic atherosclerosis are given in The authors conclude that etal. including 433 interview on form of figure presentation of ridit-analysis. among males, “... & 1968, male and 450 admission. large increase in the ULS.A. female (white) severity of aortic athero- (165). patients autop- sclerosis occurred in the sied at Roswell Park Memorial Hospital. Represents all deaths 1956-1964 exclusive of 81 male pipe and cigar smokers and 55 incom- plete files. 1 Unless otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokera. groups using either ciga- rettes only or both ciga- rettes and alcohol as compared with the group using neither cigarettes nor alcohol... there was only a small and statistically insignificant difference between the group using cigarettes alone and the group using both cigarettes and alcohol, ...” The severity of aortic atherosclerosis increased with increasing use of cigarettes, when measured both by in- tensity and by duration of smoking. Ss TABLE 19,-Autopsy studies of atherosclerosis (cont.) (Figures in parentheses are number of individuals in that smoking category)! [SM = smokers NS = nonsmokers] Author, year, Autopsy Data country, population collection Cigarettes per day Conclusions Comments reference Viel 1,150 males Interview with The results concerning internal fibrous streaks and fatty The authors conclude that: et al., and 290 relatives. plaques in the left anterior descending coronary artery ‘‘No relationship be- 1968 females who are reported in graphic form only, An examination of tween atherosclerotic Chile died violently this data indicates that the moderate and heavy smokers lesions and the use of (200), in 1961-1964. appeared to show consistently higher percentages of tobacco was discernible.” Smoking infor- diseased areas than the nonsmokers. But the statement mation avail- of the authors implies that these differences were not able only on statistically significant when subjected to an analysis 566 males. of variance. Strong 747 males 20— Interview with Basal Group (excluding diseases related to smoking or The authors conclude that: This report concerns only etal, 64 years of next of kin CHD). Mean percentage of coronary artery internal ‘Atherosclerotic in- ages 25-64. 1969 age autopsied within 8 weeks surface involved with raised lesions (number of cases). volvement of aorta and No data on statistical U.S.A. betwen 1963— of death. White coronary arteries is significance provided. (182). 1966 at Charity 25-84 S5—-44 45-54 55-64 greatest in heavy Hospital in NS ooo eee eee ee eee 2 (5) 19(14) 20 (6) 80(11) smokers and least in New Orleans. 1-24 cigarettes/day . 9(14) 17(10) 26(16) 39 (7) nonsmokers.” >25 cigarettes/day --12 (9) 31(14) 26(25) 3920) Negro NS woe eee ee ee ees 414) 8 (8) 16011) 17(14) 1-24 cigarettes/day .... 3(39) 11(31) 14(30) 28(22) >25 cigarettes/day --17(10) 14017) 29082) 16 (11) 1Unless otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. severity of aortic atherosclerosis, as measured both by intensity and duration, increased with increasing use of cigarettes and that this dose-relationship persisted when the patients were matched for the consumption of alcohol. On the other hand, Viel, et al. (200) concluded from their study of accidental deaths in Chile that “no relationship. between atherosclerotic lesions and the use of tobacco was discernible.” Examination of the data (provided in graph form only) indicates that heavy smokers showed consistently higher percentages of diseased areas than nonsmokers, but appar- ently these differences were not statistically significant when sub- jected to an analysis of variance. Thus, in addition to the acute effects which smoking exerts on cardiovascular physiology, cigarette smoking is associated with a significant increase in atherosclerosis. EXPERIMENTAL STUDIES CONCERNING THE RELATIONSHIP OF CORONARY HEART DISEASE AND SMOKING Several areas of interest in cardiovascular pathophysiology have been investigated in the search for the mechanisms by which ciga- rette smoking contributes to cardiovascular disease, particularly coronary artery disease. Previous Public Health Service Reviews (191, 192, 198, 198) have described in detail and commented on the results of experiments by many teams of researchers. Central to the discussion which follows is a concept of cardiac physiology which provides a framework for analysis and under- standing of the varied research. That concept concerns the dynamic balance between myocardial oxygen need and supply. CARDIOVASCULAR EFFECTS OF CIGARETTE SMOKE AND NICOTINE The inhalation of tobacco smoke or the parenteral administra- tion of nicotine has been found by many researchers to be asso- ciated with a number of specific acute cardiovascular responses. These responses have been observed in human as well as animal subjects, including increased heart rate, blood pressure, cardiac output, stroke volume, velocity of contraction, myocardial contrac- tile force, myocardial oxygen consumption, arrhythmia formation, and electrocardiographic or ballistocardiographie changes (tables A20 to A22). The effect of these responses on coronary blood flow will be discussed in a following section. That the acute effects observed following the inhalation of ciga- rette smoke are due primarily to the nicotine present in the smoke may be seen in the results of a number of experiments. In humans, Irving and Yamamota (89) and Von Ahn (202) duplicated the 56 effects of cigarette smoking by the administration of nicotine intra- venously. Similar results in animals were noted by Kien and Sherrod (712). The mechanism by which cigarette smoke and hence nicotine in- duces these changes has been of interest to numerous investigators. Nicotine has long been known as a stimulator of both sympathetic and parasympathetic ganglia. Research has centered, therefore, on the function of catecholamines, mainly epinephrine and norepi- nephrine, as mediators, of these responses. Using isolated rabbit atrial myocardium, Burn and Rand (85) noted that the prior ad- ministration of reserpine to the perfusate blocked the increased rate and amplitude of contraction seen following the administra- tion of nicotine. West, et al. (208) showed that the in vivo cardiac stimulating effect of nicotine was blocked by tetraethylammonium chloride. Leaders and Long (125), Romero and Talesnik (156), and, more recently, Ross and Blesa (160) have all demonstrated this blockade in animals using agents such as pentolinium, hexa- methonium, guanethidine, and reserpine. More direct evidence of the catecholamine-releasing effect of nicotine has been found by Watts (203) and Westfall, et al. (209, 210, 211) (table A22). Among animal subjects, nicotine adminis- tration and the inhalation of the smoke of standard cigarettes caused significant increases in peripheral arterial epinephrine lev- els, while cornsilk cigarette smoke inhalation evoked no such change. In humans, cigarette smoking was found to be associated with a significant increase in urinary epinephrine excretion, The source of these nicotine-released catecholamines, particu- larly those which mediate the immediate and local cardiac re- sponses to intracoronary injections of nicotine, is felt to be the myocardial chromaffin tissue (35, 160). The more widespread effects are most probably mediated by hormones released from the adrenal gland. According to recent research of Saphir and Rapaport, catechol- amine release may not be the sole mediator of these responses (166). These investigators reported that intra-arterial injections of nicotine into the mesenteric circulation of cats were followed within 1 to 2 seconds by enhanced myocardial performance, in- creased left ventricular systolic pressure, and increased systemic resistance. Sectioning of the mesenteric afferent nerves led to a diminished response. The authors concluded that the cardiovascu- lar response to nicotine may also be neurogenic in nature. Nadeau and James (142) injected nicotine directly into the sinus node artery of dogs and noted an initial bradycardia, due probably to direct vagal stimulation, followed by tachycardia, due probably to catecholamine release. 57 That the presence of nicotine may predispose the myocardium, particularly a hypoxic or previously damaged myocardium, to ar- rhythmia formation is suggested by the research of Balazs, et al. (16), Bellet, et al. (21), and Greenspan, et al. (74). Balazs pro- duced myocardial lesions in dogs either by pretreatment with iso- proterenol or ligation of the anterior descending coronary artery. It was found that while normal animals did not develop arrhy- thmias upon challenge with small doses of intravenous nicotine, the animals with damaged myocardiums responded with increased arrhythmia formation shortly after their spontaneous arrhythmias had ceased. More recently, Bellet, et al. (20) studied the effect of cigarette smoke inhalation on the ventricular fibrillation threshold in anesthetized dogs. They observed a statistically significant de- crease in the threshold following smoke inhalation. Greenspan, et al. (74), using isolated dog right ventricular myocardium, ob- served that nicotine perfusion increased the automaticity of the Purkinje fibers system and decreased the conduction velocity. The authors consider that these two nicotine-induced effects probably predispose the myocardium to the initiation of arrhythmias. CORONARY BLOOD FLOW Studies in animals and humans (tables A20, A21) have noted alterations in coronary blood flow (CBF) following the inhalation of cigarette smoke or the administration of nicotine. Generally, exposure of the normal subject to these agents results in an in- crease in flow. Kien and Sherrod (112), Leb, et al. (126), Ross and Blesa (160), Travell, et al. (189), and West et al. (208), working with normal animals, and Bargeron, et al. (17), working with normal humans, have demonstrated this response. As with the other cardiac responses to the administration of nicotine, it has been found that the augmentation in CBF is most probably due to the release of catecholamines. Using instantaneous coronary arte- rial flow measurement in dogs, Ross and Blesa (160) were able to reproduce the effects of intracoronary nicotine with the adminis- tration of epinephrine and were able to block the response to nico- tine by pretreatment with pentolinium. The direct action of catecholamines on the coronary arteries may not, however, be solely responsible for the increase in CBF seen with cigarette smoking and intravenous nicotine administra- tion. It appears that the catecholamine-induced increase in myo- cardial work and therefore in myocardial oxygen requirement is a prerequisite for the increase in CBF. Kien and Sherrod (112), using tracheostomized dogs, found that without blood pressure and cardiac output changes CBF did not increase following either the inhalation of cigarette smoke or the administration of nicotine 58 intravenously, although CBF did increase following such changes. Recent work by Leb, et al. (126) has utilized Rb* as a radioactive marker in order to distinguish capillary flow from overall total CBF. The authors consider that this capillary flow represents that portion of CBF which is effectively involved in nutrient and oxygen exchange. The researchers observed that the increase in effective coronary flow was almost proportional to the nicotine- induced increase in myocardial oxygen consumption. However, the increase in total coronary flow which may be due to increased myocardial shunting was far in excess. Thus, the increased work evoked by the effect of nicotine on the myocardium may induce local hormonal release in the myocardium and coronary vessels leading to coronary vasodilatation and increased CBF. This homeostatic response to increased work appears to be fully effective only in the subjects with normal coronary arteries. Bellet, et al. (22), working with normal dogs and dogs that had under- gone either coronary artery ligation or artificially-induced coro- nary artery narrowing, noled that the increase in CBF following the intravenous administration of nicotine was significantly less among the animals with coronary insufficiency. Work with humans discussed above has revealed a similar increase in CBF with smok- ing in normals. Regan, et al. (154) studied seven men with EKG- proven myocardial infarction and observed that cigarette smoke evoked slight increases in myocardial oxygen consumption in only three patients and caused no overall rise in CBF. A number of other investigators have noted that patients with overt CHD do not respond to the stimulus of cigarette smoke as readily as do normals (67, 149, 164). Thus, patients with compromised coronary circulation may not be capable of increasing their coronary flow in the face of the in- creased demands of a myocardium stimulated by nicotine or ciga- rette smoke. In the normal state, the heart responds to increased oxygen demands by increasing coronary flow because even at rest oxygen extraction is almost at a maximal level. Any further in- crease in extraction may produce coronary sinus pO, values incom- patible with proper tissue oxygenation. CARDIOVASCULAR EFFECTS OF CARBON MONOXIDE Carbon monoxide (CO) is a colorless and odorless gas, low levels of which have significant effects on human and animal physi- ology which are just now beginning to be understood, According to Wynder and Hoffmann (215), it is present in cigarette smoke in concentrations of approximately 2.9 to 5.1 percent. The concen- tration of CO in smoke is subject to many factors, among them 59 the type of tobacco and the porosity of cigarette paper. The con. centration of CO in smoke has been found to increase significantly toward the last puffs of the cigarette. According to Chevalier, et al. (41 ), a concentration of approx. mately 4 percent CO in cigarette smoke will produce alveolar levels of around 0.04 percent which, equilibrated with hemoglobin, result in carboxyhemoglobin (COHb) concentrations of from 3 to 10 per. cent. A number of investigators have compared COHb levels in smokers and nonsmokers. Goldsmith and Landaw (73) reported the analysis of expired air samples obtained from 3,311 longshore. men. Using a regression analysis, they calculated the concentra. tion of COHb and found that nonsmokers showed levels of 1.2 per. cent while those smoking over 2 packs per day had levels of 6.8 percent and that smokers of lesser amounts had intermediate levels. Occupational exposure accounted for the mean nonsmokers’ level being over 1.0 percent, an unusual finding in comparison with other studies. Kjeldsen (113) interviewed and obtained blood samples from 934 CHD-free smokers and nonsmokers. The mean COHb level for 196 nonsmokers was 0.4 percent while all inhaling smokers had a mean level of 7.3 percent. All 416 cigarette smokers, regardless of inhalation or amount smoked, showed a mean level of 4.0 percent. Carbon monoxide has many varied and Significant effects on human physiology. An overall review of these effects may be found in a discussion by Lilienthal (127) or more recently in an exten- sive review by the United States Public Health Service National Air Pollution Control Administration (7 94). Apart from its effects on respiratory and circulatory function, CO has been found to affect certain central nervous system functions adversely. These effects are probably due to interference by CO with the proper oxygenation and oxidative metabolism of the tissue in question. CO interferes with oxygen transport in a variety of ways. First, the affinity of hemoglobin for CO is approximately 200 times greater than its affinity for oxygen, and thus CO can easily dis- place oxygen from hemoglobin. Second, CO shifts the oxyhemo- globin dissociation curve. By increasing the avidity with which oxygen is bound by hemoglobin, CO interferes with O, release at the tissue level. This is of greatest importance at the tissue level where the oxygen content of the capillary blood has been reduced to approximately 40 percent saturation. Here the shift can sub- stantially decrease the oxygen tension supplying the tissues. Third, and of more recent note, is the possible interference by CO with the homeostatic mechanism by which 2, 3-diphosphogly- cerate (2, 3-DPG) controls the affinity of hemoglobin for oxygen. Bunn and Jandl (34) have recently reviewed the various experi- 60 ments concerning this glycolytic intermediate. The question of whether the low levels of CO present in the blood of smokers can affect this homeostasis is presently under investigation (29, 143), and firm conclusions cannot be drawn at this time. Apart from its effect on hemoglobin affinity, CO appears to induce arterial hypoxemia, and this may act as an additional cause of tissue hypoxia. Ayres, et al. (74, 15) observed unexpectedly that exposure of individuals to CO sufficient to raise their levels of COHb to between 5 and 10 percent was associated with a signifi- cant fall in arterial pO.. Greater fall in venous pO. was noted, but this was considered secondary to increased tissue extraction. In a recent article, Brody and Coburn (30) suggested that this COHb-induced arterial hypoxemia was due to the interaction of a number of factors. These authors noted that in the presence of veno-arterial shunts or of an imbalance in the ventilation-perfu- sion ratio, the shift in the oxyhemoglobin dissociation curve in- creased the alveolar-arterial O. gradient and resulted in arterial hypoxemia. The presence of shunts as smal] as 2 percent of cardiac output as well as of approximately 10 percent COHb was found to cause an increase in the gradient. Such ventilation-perfusion (V/Q) abnormalities have recently been noted even in asymp- tomatic smokers (see Chapter on Chronic Obstructive Broncho- pulmonary Disease). The increased levels of COHb found in the blood of smokers may interact with these V/Q abnormalities to further decrease available oxygen. In normal individuals, coronary flow can increase to meet the increased oxygen demands of a stressed myocardium (as that under nicotine stimulation), while in individuals with severe CHD coronary flow cannot respond as readily. In such cases, myocardial oxygen extraction must be increased above the almost maximal extraction found at rest. Any interference with arterial oxygen levels or hemoglobin affinity could very well decrease available oxygen supplies below the level required for proper tissue func- tion. That this occurs is suggested by the experiments discussed below. Chevalier, et al. (41) exposed 10 young nonsmokers to CO con- centrations sufficient to induce COHb levels of approximately 4 percent, Taking measurements from blood specimens obtained at cardiac catheterization under resting and exercise conditions, the authors noted that the ratio of oxygen debt to oxygen uptake in- creased significantly under conditions of increased COHb. Accord- ing to the investigators this implied that the same work was being done at a greater metabolic cost. These same authors (121, 122) had previously noted similar findings among smokers and observed 61 that cessation of smoking was associated with a significant im. provement in oxygen debt accumulation. More recent work by Ayres, et al. (15) has focused on the dif. ference in response to CO exposure between 7 normals and 4 pa- tients suffering from CHD (proven arteriographically) . The induc. tion of a COHb concentration of approximately 9 percent in the normals was followed by an increase in coronary blood flow, a decrease in hemoglobin-oxygen percent extraction and no change in myocardial oxygen consumption, coronary sinus oxygen tension, and lactate and pyruvate extraction ratios. The induction of simi- lar COHb levels in the CHD patients was followed by no change in coronary blood flow, a decrease in the hemoglobin-oxygen ex- traction ratio, and no change in myocardial oxygen consumption, However, these patients did manifest a decrease in coronary sinus pO, as well as a decrease in lactate and pyruvate extraction. The latter measures indicate that the myocardium was functioning under hypoxic conditions. Because the coronary flow could not in- crease and because the myocardium could not extract O. from HbO, which was under the influence of CO, coronary sinus oxygen tension decreased to a point which could inactivate certain oxida- tive enzyme processes. Thus, the myocardial function of persons with CHD may be unable to compensate for the stresses induced by smoking. Although COHb levels resulting from the CO present in the atmosphere during pericds of high air pollution are much lower than those due to the inhalation of cigarette smoke, these concen- trations of COHb might contribute to the manifestations of CHD. Cohen, et al. (44) studied the case fatality rates for patients ad- mitted to 35 Los Angeles area hospitals with myocardial infarction in relation to atmospheric CO pollution. The authors observed an increased MI case fatality rate in areas of increased pollution, and then only during periods of relatively increased CO pollution. An area of interest which has been discussed in previous reports concerns the presence of hydrogen cyanide in tobacco smoke. According to Wynder and Hoffmann (215), the amount present ranges from 11 to 32 micrograms HCN per puff. It is known that a significant amount of this material is detoxified to thiocyanate and excreted as such in the urine or saliva. However, cyanide is a potent inhibitor of oxidative metabolism. Such inhibition of myo- cardial oxidative metabolism may be of importance when combined with the other factors mentioned above which tend to decrease the oxygen supply available and increase the need for oxygen on the part of the myocardium. 62 EFFECTS OF SMOKING ON THE FORMATION OF ATHEROSCLEROTIC LESIONS A number of autopsy studies have demonstrated a significant association between cigarette smoking and the presence of aortic and coronary artery atherosclerosis, even in men without a his- tory of clinical CHD. The possible pathophysiologic mechanisms for the atherogenic influence of cigarette smoking are discussed in this section. A number of investigators have studied the effect of nicotine administration, either subcutaneously or intravenously, upon athe- rosclerotic changes in the aorta and coronary arteries of animals (table A283). When administered alone, nicotine induces certain necrotic changes in the arterial wall. However, in combination with the administration of increased amounts of cholesterol] in the diet, nicotine aggravates either subendothelial fibrosis (75) or definite atheromatous lesions (46, 75, 80, 130, 178). Studies by Choi (42) and by Wenzel, et al. (207) did not demonstrate this synergism between cholesterol and nicotine. The other major cigarette smoke component under discussion in this chapter, carbon monoxide, has also been recently implicated in atherogenesis. Table 24 presents the studies which have related exposure to CO in combination with increased dietary cholesterol to both macroscopic and microscopic aortic and coronary athero- matosis. Astrup, et al. (10) exposed cholesterol-fed rabbits to CO continually over a period of up to 10 weeks. The experimental group showed increased aortic atheromatosis over that shown by the control group, also cholesterol-fed. Kjeldsen, et al. (114) observed that exposure of rabbits to increased oxygen concentra- tions significantly reduced the amount of cholesterol-induced atheromatosis in rabbits. Most recently, Webster, et al. (204) have extended this research to primates. These investigators found that cholesterol-fed squirrel monkeys developed significantly more coronary artery atherosclerosis when exposed intermittently to CO over a 7-month period than when exposed only to room air. Recent discussion has centered on the mechanisms whereby CO can induce these changes (9, 212). Astrup (9), referring to pre- vious experiments in humans which had shown increased vascular permeability for albumin upon chronic exposure to CO (11), con- siders it likely that this increase in permeability allows for in- creased filtration of lipoproteins into arterial walls. This, he con- siders, is a primary cause of intimal and medial lipid accumulation and, therefore, of atherosclerosis. Another point of view has been stressed by Whereat (212), who considers the filtration theory to be an inadequate hypothesis for 63 v9 TABLE 24,—Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia Author, year, Number and country, type of animal Procedure Results reference Astrup 24 female Regular diet plus 2 percent The experimental group exposed to carbon monoxide showed increased macro- and etal., albino rabbits. cholesterol: mieroscopic aortic atheromatosis over that shown by control animals. Micro- 1967 I. (12) control. scopic examination revealed intimal lipoid deposition limited in penetration by Denmark TI. (12) continual exposure to the internal elastic membrane. Coronary vessels were found to show similar (70). carbon monoxide: changes. Carboxyhemoglobin. (COHb) levels averaged 15-19 percent during the 0.017 percent for 8 weeks. first 8 weeks and 33 percent during the final 2 weeks. 0.035 percent for 2 weeks. Kjeldsen 24 castrated male Regular diet plus 2 percent The experimental group exposed to hypoxia showed increased macroscopic aortic etal, albino rabbits, cholesterol: atheromatosis over that shown by control animals. Microscopic examination re- 1968, T, (12) control. vealed more intimal and subintimal lipid deposition in the aortas of the exposed Denmark H, (12) continual exposure. rabbits than in those of the nonexposed. The total amount of cholestero! de- (117). to hypoxia: posited in the aortas of the experimental group was three times higher than in 10 percent-0, for 6 weeks. those of the control group. 9 percent 0, for 2 weeks, Kjeldsen 24 castrated male Regular diet plus 2 percent Macroscopically, the experimental group showed significantly fewer atheromatous etal. albino rabbits. cholesterol: changes. Microscopically, the experimental group showed significantly less aortic 1969, I. (12) control. intimal lipid deposition. Denmark II, (12) exposure to 28 percent (114). 0 for 10 weeks, Webster 22 female squirrel Diet containing 0.5 percent The experimental group exposed to carbon monoxide showed a greater mean per- et al., monkeys. cholesterol and 25 percent fat: centage of coronary arteries with atherosclerotic lesions and more lumen occlu- 1970, I. (10) eontrol. sion among the affected arteries. There were significantly more CO-treated U.S.A. Il. (12) experimentally exposed to monkeys than control monkeys having 35 percent or more apparent athero- (204). 200-300 p.p.m. carbon monoxide sclerotic stenosis among the affected arteries. Aortic atherosclerosis was appar- for 20 hours per week for 7 months. ently not aggravated by exposure to CO. COHb levels at the end of each exposure period averaged 16-26 percent during the final 24 weeks of the experiment. mural lipid accumulation. The author notes that when the oxida- tion of the pyridine nucleotide, nicotinamideadenine dinucleotide (NAD), is impaired, the reduced form of this nucleotide (NADH) provides an essential factor for fatty acid synthesis. Fatty acid synthesis in the aorta and heart is carried out by mitochondrial enzymes whose hydrogen donor is NADH. Substances which slow or impair the reoxidation of this compound tend to increase mito- chondrial fatty acid synthesis (and decrease fatty acid utilization) in the arterial wall. Carbon monoxide prevents this oxidation proc- ess both directly and indirectly. Indirectly, it decreases the oxygen available for diffusion into the tissue. Directly, carbon monoxide can stall the process of NADH oxidation by combining with cyto- chrome oxidase. Further research is required into this problem, particularly in view of the fact that cyanide is also a respiratory chain inhibitor and thus may also adversely affect arterial wall fat metabolism. THE EFFECT OF SMOKING ON SERUM LIPID LEVELS In the discussion concerning the epidemiological aspects of CHD, it was noted that increased serum cholesterol was a significant risk factor for the development of overt CHD. Serum triglycerides have also been related to CHD incidence. Of concern also is the immediate effect which cigarette smoking has upon blood lipid levels. The studies concerning this immediate effect are presented in tables A25 and A25a. The table is divided into a section concern- ing studies on humans (table A25) and one concerning studies utilizing animals or in vitro systems (table A 25a). Although no consistent response was noted for serum cholesterol, serum free fatty acids were found consistently to rise following smoking. As with other cardiovascular reactions to nicotine and smoking, it appears that the fatty acid response is also mediated by catechol- amine release. This relationship has been observed in a number of experiments by Kershbaum, et al. (105, 106, 108, 109, 110) and Klensch (118). That nicotine is primarily responsible for this rise May be seen by reference to the study by Kershbaum, et al. (105) in which lettuce-leaf cigarettes of minimal nicotine content had a negligible effect upon serum free fatty acids in comparison with that of regular cigarettes. ; While attention has been centered upon nicotine as the agent Inducing the immediate increase in serum lipids, recent studies have been concerned with the effect of chronic exposure to carbon monoxide on serum lipid metabolism. These studies are listed in table A26. Among rabbits fed increased amounts of cholesterol, 65 the authors observed significant increases in cholesterol and tri. glyceride concentrations in those exposed to CO versus thoge maintained in a normal atmosphere. THE EFFECT OF SMOKING ON THROMBOSIS In the study of CHD, a number of investigators have turned their attention to thrombosis because myocardia] infarction and sudden coronary death frequently result from thrombotic events, A thrombus may be of either gross or microscopic dimensions, and a minute thrombus at a strategic site may precipitate a fatal ar. rhythmia. However, thrombotic and prethrombotic states are dif. ficult to detect except when gross, and the emphasis has been pri- marily on factors which can be studied conveniently. Coagulation is now thought to have a secondary role in the consolidation of an arterial thrombus and little if any in initiating the process. The prime mechanism in thrombogenesis appears to be the reaction of the platelet. Several papers have been written about platelet re. activity in vitro but few about the effect of smoking on platelet behavior in vivo. The assay of fibrinolysis, which may also be im- portant, has received scanty treatment. The relevant studies are listed in table A27. Many of these are discussed in the 1968 sup- plement (192) and by Murphy (140). Corroborative data are stil] inconclusive as to whether smoking shortens platelet survival. OTHER AREAS OF INVESTIGATION Certain other aspects of cardiovascular pathophysiology may be of importance in the relationship of smoking to CHD. Glucose me- tabolism and insulin response, when altered, may alter myocardial response. This topic has been covered in detail in the 1968 Supple- ment to the Health Consequences of Smoking (192). Also, varia- tions in blood hemoglobin and hematocrit may adversely affect coronary blood flow. A number of studies showing a possible rela- tionship of smoking to hemoconcentration have been reviewed pre- viously (791, 192), and the reader is referred to those discussions. CEREBROVASCULAR DISEASE The term cerebrovascular disease (CVD) refers to a number of different types of vascular lesions affecting the central nervous system: subarachnoid hemorrhage, cerebral] hemorrhage, cerebral embolism, and thrombosis (ICD Codes 330 to 334), In 1967 in the United States, a total of 93,071 males and 109,113 females were listed as dying from CVD as the underlying cause (196). Epidemiological studies indicate that cigarette smoking is asso- 66 ciated with increased mortality from cerebrovascular disease, whether CVD is listed as the underlying or as a contributory cause of death. Table 28 presents the results of the seven major epidemi- ological studies. The smoking of pipes and cigars does not appear to increase significantly the risk of dying from CVD. The impor- tance of high blood pressure and diabetes as risk factors for mor- tality from CVD has recently been noted by Hammond and Gar- finkel (76). The data from their study, as presented in table 28, also indicate that the mortality ratio for cigarette smokers is greater for persons under 75 years of age than for older individuals. Many of the pathophysiologica] considerations discussed in the sections concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction. In a study reported by Kuhn (123), 20 habitual smokers re- frained from smoking for one-half day, and base line retrograde brachiocerebral angiograms were taken; they then smoked one cigarette, inhaling deeply, and had repeat angiograms. Those over 60 years of age failed to have significant acceleration of flow as demonstrated in carbon dioxide inhalation experiments. More recently, Miyazaki (132) studied the effect of smoking on the cerebral circulation of 12 moderate/heavy cigarette smokers as measured indirectly using an ultrasonic Doppler technique to record internal carotid artery flow. Measurements were made be- fore and after ordinary smoking and showed an increase in cere- bral blood flow and a decrease in cerebral vascular resistance in all subjects. No significant difference in response was observed between the 4 younger and 8 older (over 60 years of age) subjects. More research is needed to clarify the role of cigarette smoking in the acute pathogenesis of CVD manifestations. However, the chronic effect of smoking upon the cerebral circulation (particu- larly its extracranial portion) is likely to be similar to the effect of smoking upon the aortic and coronary atherosclerosis. NON-SYPHILITIC AORTIC ANEURYSM Aortic aneurysm is an uncommon but not rare cause of death. In 1967 in the United States, a total of 8,448 men and 3,173 women were listed as dying from aortic aneurysm as the underlying cause (196). Cigarette smoking appears to increase the risk of dying from this disease, perhaps by promoting the atherosclerotic proc- ess which underlies this type of aneurysm. As illustrated in table 29, the mortality ratios for cigarette smokers are high relative to other cardiovascular diseases in which smoking increases the risk, and the risk increases in proportion to the amount smoked. 67 89 TABLE 28.—Deaths from cerebrovascular disease related to smoking (Mortality ratios—actual number of deaths shown in parentheses)! (SM = smokers NS = nonsmokers] PROSPECTIVE STUDIES Number of Author, Follow- deaths due Pipes year, Number and Data up to CVD as Cigarettes per day and Age variation Comments country, type of collection years underlying cigars reference population cause Hammond 187,783 white Questionnaire 3% 1,050 NS .....,..1.00 (164) t(p<0.01). and Horn, males in9 and follow- Cigarettes 1958, states 50-69 up of death SM_......£1.30 (556) U.S.A. years of age. certificate. Other SM ..1.25 (330) (77, 78). Cigarettes only <0 ...0.., 1.24 (41) 10-20 ......1.44 (140) 20 ........1.46 (83) Doll and Approximately Questionnaire 10 605 NS .........1.00 Hil, 41,000 male and follow- ANISM ......1.05 1964, British up of death All Great physicians. certificate. cigarette 1.12 Britain 1-14 ......1.10 (50). 15-24 eee 1.09 25 14... 126 Kannel 5,127 males Medical 12 130 NS .........4.00 © (5) Data apply only etal., and females examination Heavy SM to males 30-59 1965 30-59 years and follow- (20)... .3.23 (8) years of age U.S.A. of age, up. at entry. (96), Data apply only to cerebral infarction. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 69 TABLE 28.—Deaths from cerebrovascular disease related to smoking (cont.) (Mortality ratios—actual number of deaths shown in parentheses)? [SM = smokers NS = nonsmokers] PROSPECTIVE STUDIES Number of . Author, deaths due Pipes year, Number and Data Follow- underlying Cigarettes per day and Age variation Comments country, type of collection up years to CVD as cigars reference population cause Kahn, U.S. male Questionnaire 814 2,008 NS ..1.00 (614) Pipes 1966, veterans and follow- All SM ..1.06 (82) UVS.A. 2,265,674 up of death current ....1.30(1,894) NS ..1.00(614) (93). person certificate. Current Cigars years. cigarettes ..1.52 (692) NS ..1.00(614) 1-9 --1.51 (98) SM ..1.08(135) 10-20 «1.42 (325) 21-39 1.70 (215) >39 ~1.59 (37) Hammond 358,534 males Questionnaire 6 4,099 Current tBased on only and 445,875 and follow- regular Males 5-9 deaths. Garfinkel, females 40-79 up of death cigarette 40-49 50-59 60-69 70-79 1969, years of age certificate. Never U.S.A. at entry. smoked 1.00 1.00 1.00 1.00 (76). 1-9 «2.79 1.95 1.30 0.95 10-19 .114 1.48 $1.44 0.92 20-39 .....2.21 2.03 1.62" 1.22 >40 1.2... 1.64 2.40 1,72 $0.68 Females Never smoked = 1.00 1.00 1.00 1.00 1-9 . 1.50 1.26 1.26 0.83 10-19 . 2.60 2.70 2.15 $0.57 20-39 » 2.90 2.67 1,83 1.28 >40 .....15.70 £8.52 _ — 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. oz TABLE 28.—Deatlhs from cerebrovascular disease related to smoking (cont.) (Mortality ratios—actual number of deaths shown in parentheses)! SM = Smokers. NS = Nonsmokers. PROSPECTIVE STUDIES Paffen- 3,263 male Initial multi- 16 67 NS and barger, longshoremen phasic <20 .........1.00 (42) et al. 35-64 years screening >20 .........1.15 9 (25) 1970 of age in and follow- U.S.A. 1951. up of death (144). certificate. RETROSPECTIVE STUDY Paffen- >50,000 male _—i Initial college Death Rates The 63 deaths from barger University entrance Cases (158) Controls (615) occlusive stroke and students medical ex- SM wo. ee eee ee ee ee es 45.0 31.3 (p<0.01) contributed to the Williams followed up aminations Cigarette SM >10 per day . 20.9 11.2 (p<0.01) statistical sig- 1967 to 50 years. with follow- nificance, U.S.A. up of death The 95 deaths from (145). certificate. hemorrhagic Controls— stroke showed surviving no statistica} classmates significance as age-matched. a single group. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. Z TABLE 29.—-Deaths from nonsyphilitic aortic aneurysm related to smoking—prospective studies (Mortality ratios—actual number of deaths shown in parentheses)? {SM = Smokers NS = Nonsmokers] Author, year, Number and Data Follow-up Number country, type of collection years of Cigarettes per day Pipés Cigars Comments reference population deaths Hammond 187,783 white Questionnaire 3, 68 NS ...+..1,00(25) (expected) and Horn, males in9 and follow-up SM 1, 2.72 (68) (p<0.005) 1958, states 50-69 of death U.S.A. years of age. certificate. (77,78). Kahn, U.S. male Questionnaire By 491 NS ....cee cece ee ee ee 100 (58) NS ..1.00(58) NS . .1.00(58) 1966, veterans and follow-up Current cigarettes ..5.24(284) SM ..1.138 (8) SM ..2.06(24) U.S.A. 2,265,674 of death 1-9 cigarettes/day ...2.12 (13) (98). person years. certificate. 10-20 wi. cece cece eee 5.53 (124) 21-89 2... eee eee 595 (76) 89 eee eee ee ee eee T26 (17) Hammond 358,534 males Questionnaire 6 337 NS... eee eee 100 Data apply only and 445,875 females and follow-up 1-9 wo. eee eee 2.62 to males 50-69 Garfinkel, 40~79 years of of death 10-19 .......-- 3.85 years of age. 1969, age at entry. certificate. 20-39 ..........4,54 U.S.A. >40 2.0.2.2... 8.00 (76). Weir and 68,153 California Questionnaire 5-8 51 NS ...........-1.00 SM include Dunn, male workers and follow-up All ...........-+2.64 ex-smokers, 1970, 35-64 years of of death #10 oe eee 2.44 NS include pipe U.S.A. age at entry. certificate. #20 ............2.88 and cigar (205). 2280 2. eee 2654 smokers. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. PERIPHERAL ARTERIOSCLEROSIS Peripheral arteriosclerosis represents the effects on the vaseu- lature of the extremities of the pathophysiologic processes which Produce coronary and aortic atherosclerosis. A number of studies have been concerned with smoking as a risk factor in the develop. ment of this disease. Kannel, et al. (95) observed, in the Framing. ham study, that diabetes mellitus and elevated serum cholesterol, as well as cigarette smoking, were also risk factors in the develop. ment of peripheral vascular disease. Juergens, et al. (92) reviewed the records of and contacted 478 male patients with arteriosclerosis obliterans (a severe form of peripheral arteriosclerosis), who had been patients at the Mayo Clinic between 1939 and 1948. The diagnosis of this condition was based upon certain clinical criteria: the presence of intermittent claudication, the marked diminution or absence of lower extremity arterial pulsations, and objective trophic manifestations of per- ipheral limb ischemia. Smoking information was available on 401 patients. These patients were compared with a control group of 350 Mayo Clinic patients of similar age who showed no clinical evidence of vascular disease. It was found, for males under the age of 60, that 2.5 percent of the cases and 25 percent of the con- trols were nonsmokers. However, no difference was noted between the percentages of heavy smokers in each group. The authors also implicated high blood pressure and elevated serum cholesterol as risk factors in the occurrence of this disease. Begg (19) noted similar findings in a study of 294 male patients with intermittent claudication who were patients at the Western Infirmary in Glasgow, Scotland. In comparing the smoking his- tories of 100 patients with this complaint with those of 116 healthy male controls, the author found that 1 percent of the patients and 21 percent of the controls had never smoked. A total] of 42 percent of the patients smoked more than 20 cigarettes per day while only 24 percent of the controls had a similar history of heavy smoking. The author concluded that smoking, while not a prime cause of peripheral arteria] disease, is a significant cofactor in its develop- ment in almost all cases. The author also noted obesity, high blood pressure, and elevated serum cholesterol as risk factors, Schwartz, et al. (168) compared the prevalence of risk factors in four groups of subjects: 141 cases with arteriosclerotic disease of the lower limbs, 551 cases with coronary arteriosclerosis, 58 cases with both conditions, and finally an indefinite number of control individuals who had been hospitalized for injuries. The in- vestigators reported that certain risk factors, including hyper- cholesterolemia, hypertension, and cigarette smoking, were signifi- 72 cant in both coronary and lower limb arteriosclerosis. The authors noted that the inhalation of cigarette smoke appeared to be an important risk factor for coronary arteriosclerosis up to age 55 while in arteriosclerosis of the lower extremities, inhalation ap- peared to increase the risk even in the older age groups. Widmer, et al. (213) compared 277 male patients with arterial occlusion of the limbs as demonstrated by aortography or oscillog- raphy with 2,082 men demonstrated by oscillography to be free of arterial disease. The authors found that cigarette smoking, parti- cularly heavy smoking, was significantly more frequent among the cases with arterial occlusion than among the controls. Increased beta-lipoproteins and systolic hypertension were also found to be more common among the cases. EXPERIMENTAL EVIDENCE A number of experimenters have investigated the acute effects of smoking or nicotine upon the peripheral circulatory system. These investigators, as listed in table A30, have measured effects in terms of alterations in skin temperature and blood flow as meas- ured by plethysmography, radioactive iodinated albumin clear- ance, or radiosodium clearance from the skin. The majority of these studies have shown significant decreases in peripheral blood flow and skin temperature upon smoking, particularly in persons without manifest peripheral vascular disease, The study of Freund and Ward (68) demonstrates the difference in peripheral vascular reactivity found between normals and patients with arterioscle- rotic changes in the vessels of their extremities. The work of Strémblad (181) on blockade of this response with automatic SYS- tem blockers indicates that the reactivity of these vessels is sec- ondary to the local release of catecholamines. Most probably, the degenerative changes associated with this disease create a stiffen- ing of the vessel wall and prevent rapid alteration, particularly dilatation, in response to the catecholamines liberated by smoking or nicotine. THROMBOANGIITIS OBLITERANS Thromboangiitis obliterans (Buerger’s Disease) (TAO) is an uncommon obstructive vasculitis primarily involving the arteries and veins of the extremities. Severely affected patients may even lose their limbs secondary to ischemic changes. Much discussion has centered upon the question as to whether this disease is a clin- ical and pathological entity separate from peripheral arterioscle- rosis. McKusick, et al. (128) consider it to be a distinct entity 73 while Eisen (57) concludes that TAO is the acute inflammatory phase of severe arteriosclerosis, Clinically, it has been shown that smoking aggravates this dis. ease and cessation of smoking frequently aids in complete or par. tial remission, Razdan, et al. (153) and Brown, et al. (32) found very few nonsmokers in groups of patients diagnosed as having typical TAO. A recent study from Israel (16) involved a case. control comparison of 46 patients with TAO and 32 matched con. trols. Although the controls were found to smoke less per day than the patients, this difference was not found to be statistically sig. nificant. However, 100 percent of the smoking patients and only 72 percent of the smoking controls were inhalers, a difference sig- nificant at the 0.02 level. CARDIOVASCULAR DISEASES SUMMARY AND CONCLUSIONS CORONARY HEART DISEASE 1. Data from numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing to the development of coronary heart disease including fatal CHD and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smokers of pipes and cigars is appreciably less than that by cigarette smokers. 2. Analysis of other factors associated with CHD (high serum cholesterol, high blood pressure, and physical inactivity) shows that cigarette smoking operates independently of these other fac- tors and can act jointly with certain of them to increase the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate the pathophysiological changes of pre-existing coronary heart disease and therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coro- nary arteries. 5. The cessation of smoking is associated with a decreased risk of death from CHD, 6. Experimental studies in animals and humans suggest that cigarette smoking may contribute to the development of CHD and/ or its manifestations by one or more of the following mechanisms: a. Cigarette smoking, by contributing to the release of catechol- amines, causes increased myocardial wall tension, contraction 74 velocity, and heart rate, and thereby increases the work of the heart and the myocardial demand for oxygen and other nutrients. b. Among individuals with coronary atherosclerosis, cigarette smoking appears to create an imbalance between the increased needs of the myocardium and an insufficient increase in coro- nary blood flow and oxygenation, c. Carboxyhemoglobin, formed from the inhaled carbon mon- oxide, diminishes the availability of oxygen to the myocardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxemia, thus reducing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhesive- ness which might contribute to acute thrombus formation. CEREBROVASCULAR DISEASE 1. Data from numerous prospective studies indicate that ciga- rette smoking is associated with increased mortality from cerebro- vascular disease. 2. Experimental evidence concerning the relationship of smok- ing and cerebrovascular disease is at present insufficient to allow for conclusions concerning pathogenesis. However, some of the pathophysiological considerations discussed concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction. NOoN-SYPHILITIC AORTIC ANEURYSM Cigarette smoking has been observed to increase the risk of dying from nonsyphilitic aortic aneurysm. PERIPHERAL VASCULAR DISEASE 1. Data from a number of retrospective studies have indicated that cigarette smoking is a likely risk factor in the development of peripheral vascular disease. Cigarette smoking also appears to be a factor in the aggravation of peripheral vascular disease. 2. Cigarette smoking has been observed to alter peripheral blood flow and peripheral vascular resistance. CARDIOVASCULAR REFERENCES (1) ACHESON, R. M., Jessop, W. J. E. Tobacco smoking and serum lipids in old men. British Medical Journal 2: 1108-1111, October 28, 1961. (2) Apter, I., HENSEL, QO. Intravenous injections of nicotine and their ef- fects upon the aorta of rabbits. Journal of Medical Research 15: 229-239, 1906, 75 (3) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) 76 ALLISON, R. D., RotH, G. M. Central and peripheral vascular effects during cigarette smoking. Archives of Environmental Health 19(2). 189-198, August 1969. Amprus, J. L., Minx, I. B. Effect of cigarette smoking on blood coagu. lation, Clinical Pharmacology and Therapeutics 5(4) : 428-481, 1964, Aronow, W. S., Kapitan, M. A., Jacoz, D. Tobacco: A precipitating factor in angina pectoris. Annals of Internal Medicine 69(3); 529. 536, September 1968. ARONOW, W. S., SWANSON, A. J. Non-nicotinized cigarettes and angina pectoris. Annals of Internal Medicine 70(6): 1227, June 1969, ARONow, W. S., Swanson, A. J. The effect of low-nicotine cigarettes on angina pectoris. Annals of Internal Medicine 71(3): 599-601, September 1969. ASHBY, P., Datay, A. M,, Micvar, J. H. D. Smoking and platelet stickj. ness. Lancet 2: 158-159, July 24, 1965. ASTRUP, P. Effects of hypoxia and of carbon monoxide exposures oy experimental atherosclerosis. Annals of Internal Medicine 71(2). 426-427, August 1969. AsTrupP, P., KJELDSEN, K., Wanstrup, J. Enhancing influence of carbon monoxide on the development of atheromatosis in cholesterol-fed rabbits. Journal of Atherosclerosis Research 7: 343-354, 1967. AsTRup, P., Pau, H. G. (Editors). A Comparison of Prolonged Ex. posure to Carbon Monoxide and Hypoxia in Man. Reports of a Joint Danish-Swiss Study. Scandinavian Journal of Clinical and Labora. tory Investigation 22 (Supplement 103): 1968. 71 pp. AUERBACH, O., HAMMOND, E. C., GARFINKEL, L. Smoking in relation to atherosclerosis of the coronary arteries. New England Journal of Medicine 273(15): 775-779, October 7, 1965. AVTANDILOV, G. G., Ko.enova, V. L, PONOMARENKo, O. V. Kureniye tabaka i stepen’ ateroskleroticheskogo porazheniya koronarnykh arteriy serdtsa i aorty. (Tobacco smoking and the degree of athero- sclerotic lesions of coronary arteries of the heart and aorta.) Kar- diologiya 5(1): 30-34, January-February 1965, Ayres, S. M., GIANNELLI, S., JR., ARMSTRONG, R. G. Carboxyhemoglo- bin: Hemodynamic and respiratory responses to small concentrations, Science 149: 193-194, July 9, 1965. AYRES, S. M., MUELLER, H. S., GReGory, J. J., GIANNELLI, S., JR, Penny, J. L. Systemic and myocardial hemodynamic responses to relatively small concentrations of carboxyhemoglobin (COHB). Ar. chives of Environmental Health 18(4): 699-709, April 1969. BaLazs, T., OHTAKE, S., Cummines, J. R., Nos.e, J. F. Ventricular extrasystoles induced by epinephrine, nicotine, ethanol, and vaso- pressin in dogs with myocardial lesions. Toxicology and Applied Pharmacology 15(1): 189-205, July 1969. BARGERON, L. M., Jr., EHMKE, D., GONLUBOL, F., CASTELLANOS, A,, SIEGEL, A., Bing, R. J. Effect of cigarette smoking on coronary blood flow and myocardial metabolism. Circulation 15: 251-257, February 1957. BARNETT, A. J., BOAKE, W. C, Cigarette smoking and occlusive arterial disease of the legs. Medical Journal of Australia 1: 240-242, Feb- ruary 138, 1960. Breec, T. B. Characteristics of men with intermittent claudication. Practitioner 194 (2): 202-207, February 1965. (20) (21) (22) (28) (24) (25) (26) (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) BELLET, S., FLEISCHMANN, D., RoMAN, L., DEGuzMaAN, N. The effect of cigarette smoke inhalation on the ventricular fibrillation threshold. Circulation (Supplement 8) 42(4): 1385, October 1970. BELLET, S., KERSHBAUM, A., MEapk, R. H., Jr., ScHwWarRTz, L. The ef- feet of tobacco smoke and nicotine on the normal heart and in the presence of myocardial damage produced by coronary ligation. Amer- iean Journal of the Medical Sciences 201(1): 40-51, January 1941. BELLET, S., West, J. W., MuLier, O. F., Manzoui, U. C. Effect of nicotine on the coronary blood flow and related circulatory parame- ters. Correlative study in normal dogs and dogs with coronary in- sufficiency. Circulation Research 10(1): 27-34, January 1962. BERKSON, D. M., STAMLER, J. LINDBERG, H. A., MILLER, W. A., STEVENS, E. L., SoYuGeEnic, R., Toxicu, T. J., STAMLER, R. HEART rate: An important risk factor for coronary mortality—ten-year experience of the Peoples Gas Co. Epidemiologic study (1958-68). IN: Jones, R. J. (Editor). Atherosclerosis. Proceedings of the Second Interna- tional Symposium. New York, Springer-Verlag, 1970. pp. 382-389. Best, E. W. R. A Canadian Study of Smoking and Health. Ottawa, Department of National Health and Welfare, 1966. 133 pp. BLACKBURN, H., JR., ORMA, E., HARTEL G., Punsar, 8. Tobacco smoking and blood coagulation: Acute effect on plasma Stypven time. Ameri- can Journal of the Medical Sciences 238: 448-451, October 1959. BLOMSTRAND, R., LUNDMAN, T. Serum lipids, smoking and heredity. Acta Medica Scandinavica 180(Supplement 455): 51-60, 1966. BoruHanl, N. O., HECHTER, H. H., BRESLow, L. Report of a 10-year followup study of the San Francisco longshoremen. Mortality from coronary heart disease and from all causes. Journal of Chronic Diseases 16: 1251-1266, 1963. Boyce, E., Jk, Moraes, I. B., NICHAMAN, M. Z., TALBERT, C. R., JR., Watkins, R. S. Serum beta lipoproteins and cholesterol in adult men. Relationships to smoking, age, and body weight. Geriatrics 23(12): 102-111, December 1968. BREWER, G. J., EATON, J. W., Wen, J. V., GROVER, R. F. Studies of red cell glycolysis and interactions with carbon monoxide, smoking, and altitude. Advances in Experimental Medicine and Biology 6: 95-114, 1970. Bropy, J. S., CopurN, R. F. Carbon monoxide-induced arterial hypoxe- mia. Science 164(3885): 1297-1298, June 18, 1969. BRONTE-STEWART, B. Cigarette smoking and ischaemic heart disease. British Medical Journal 1: 379-884, February 11, 1961. BRowN, H., SELLWoop, R. A., HARRISON, C. V., MARTIN, P. Throm- boangiitis obliterans. British Journal of Surgery 56 (1): 59-63, January 1969. BuECHLEY, R. W., Drakes, R. M., Brestow, L. Relationship of amount of cigarette smoking to cornary heart disease mortality rates in men. Circulation 18(6): 1085-1090, December 1958. Bunn, H. F., JaNpL, J. H. Control of hemoglobin function within the red cell. New England Journal of Medicine 282(25): 1414-1421, June 18, 1970. Burn, J. H., RaANb, M. J. Action of nicotine on the heart. British Medi- cal Journal 1: 187-139, January 18, 1958. CaGaNova, A., CAGAN, S., SIMKO, V. Lipidy krvneho sera u nefajcia- rov a fajciarov. (Blood serum lipids in nonsmokers and smokers.) Bratislavske Lekarske Listy 50(3) : 387-392, September 3, 1968. 77 (38) (39) (40) (41) (42) (43) (44) (45) (46) (47) (48) (49) (50) (52) 78 CEDERLOF, R. The Twin Method in Epidemiological Studies on Chronie Disease. Institute of Hygiene of the Karolinska Institute, Department of Environmental Hygiene of the National Institute of Public Health, Department of Sociology, University of Stockholm, Stockholm, 1966. 71 pp. CEDERLOF, R., FRiseRG, L., HRUBEC, Z. Cardiovascular and respiratory symptoms in relation to tobacco smoking. A study on American twins. Archives of Environmental Health 18(6): 934-940, June 1969, CEDERLOF, R., FRIBERG, L., JONSSON, E., Kars, L. Respiratory symptoms and “angina pectoris” in twins with reference to smoking habits. An epidemiological study with mailed questionnaire. Archives of Environmental Health 13 (6): 726-737, December 1966. CEDERLOF, R., JONSSON, E., LUNDMAN, T. On the validity of mailed questionnaires in diagnosing “angina pectoris” and “bronchitis”, Archives of Environmental Health 13(6): 738-742, December 1966, CHEvaLier, R. B., Krumuotz, R. A., Ross, J. C. Reaction of non. smokers to carbon monoxide inhalation. Cardiopulmonary responses at rest and during exercise. Journal of the American Medical Asso. ciation 198(10): 1061-1064, December 5, 1966. Cuol, Y. Y. Effect of nicotine upon cholesterol-induced atherosclerosis in rabbits. New Medical Journal 10(7): 685-693, 1967. CLARK, V. A., CHAPMAN, J. M., CouLson, A. H. Effeets of various fac- tors on systolic and diastolic blood pressure in the Los Angeles Heart Study. Journal of Chronic Diseases 20: 571-581, 1967. CoHEN, S. I., DEANE, M., GOLDSMITH, J. R. Carbon monoxide and sur- vival from myocardial infarction. Archives of Environmental Health 19(10) : 510-517, October 1969. CORNFIELD, J., MITCHELL, S. Selected risk factors in coronary disease. Possible intervention effects. Archives of Environmental Health 19(3): 382-394, September 1969. CzocHRA-LysaNowIcz, Z., GORSKI, M., Kepra, M. Wplyw nikotyny j kofeiny na rozwoj miazdzycy u krolikow. (The effect of nicotine and caffeine on the development of arteriosclerosis in rabbits.) Annales Universitatis Mariae Curie-Sklodowska; Section D: Medicina 14(20): 181-206, 1959. Dawser, T. R., KANNEL, W. B., REVOTSKIE, N., STOKEs, J., Kacan, A,, Gorpon, T. Some factors associated with the development of coronary heart disease. Six years’ followup experience in the Framingham study. American Journal of Public Health and the Nation’s Health 49(10) : 1849-1356. October 1959. Dayton, S., Pearce, M. L. Diet and atherosclerosis. Lancet 1 (7644): 473-474, February 28, 1970. Dayton, S., PEARCE, M. L., Hasuimo7o, S., Dixon, W. J., ToMIYAsu, U. A Controlled Clinical Trial of a Diet High in Unsaturated Fat in Preventing Complications of Atherosclerosis. Circulation 40(1 Sup- plement 11), July 1969. 63 pp. DoLit, R., HILt, A. B. Mortality in relation to smoking: 10 years’ ob- servations of British doctors. (Part I) British Medical Journal 1(5395) : 1399-1410, May 30, 1964. Dory, R., Hitz, A. B. Mortality in relation to smoking: 10 years’ ob- servations of British doctors. (Concluded) British Medical Journal 1 (5396): 1460-1467, June 6, 1964. (52) DORKEN, H. Die Rauchgewohnheitenbej jiingeren Herzinfarkt-Patien- (54) (55) (56) (57) (58) (59) (60) (61) (62) (63) (64) (65) (66) ten. (Smoking habits of younger patients with myocardial infare- tion.) Mitinchener medizinische Wochenschrift 109(4); 187-192 January 27, 1967. D6RKEN, H. Die Rauchgewohnheiten bei jingeren Frauen mit Herzin- farkt. (The smoking habits of younger females with myocardial in- farction.) Mtinchener medizinische Wochenschrift 109(41); 2129 2134, October 13, 1967. Dorie, J. T., Dawser, T. R., KANNEL, W. B., Krncn, S. H. Kaun, H. A. The relationship of cigarette smoking to coronary heart disease. The second report of the combined experience of the Albany, N.Y., and Framingham, Mass., studies. Journal of the American Medical Association 190(10) : 886-840, December 7, 1964. DuNN, J. P., Ipsen, J., ELsom, K. O., OHTANI, M. Risk factors in coro- nary artery disease, hypertension and diabetes. American Journal of the Medical Sciences 259(5) ; 309-822, May 1970. Epwarps, F., McKEown, T., WHITFIELD, A. G. W. Association between smoking and disease in men over sixty. Lancet 1: 196-200, January 24, 1959. EISEN, M. E. Coexistence of thromboangiitis obliterans and arterio- sclerosis: Relationship to smoking. Journal of the American Geria- trics Society 14 (8): 846-858, August 1966. ENGELBERG, H. Cigarette smoking and the in vitro thrombosis of hu- man blood. Journal of the American Medical Association 193(12): 1033-1035, September 26, 1965. ENGELBERG, H., FUTTERMAN, M. Cigarette smoking and thrombotic co- agulation of human blood. Archives of Environmental Health 14(2): 266-270, February 1967. ENGLISH, J. P., Witiius, F. A., BERKSON, J. Tobacco and coronary disease. Journal of the American Medical Association 115(16): 1327-1329, October 19, 1940. EPpsTEIN, F. H. Some uses of prospective observations in the Tecumseh Community Health Study. Proceedings of the Royal Society of Medi- cine 60(1): 4-8, January 1967. FIDANZA, F., IMBiMgBo, B., DI BENEDETTA, C. Indagine epidemiologica delle cardiopatie ischemiche nei reclusi del penitenziario di S. Stefano di Ventotene. (Epidemiological investigation of isehemic heart di- sease in prisoners of S. Stefano di Ventotene prison.) Gironale dell’ Arteriosclerosi 4: 255-267 1966. FLetcHer, C. M., Horn, 1). Smoking and health. WHO Chronicle 24(8): 345-370, August 1970. Foire, L. E., SAMANEK, M., Aviapo, D. M. Cardiopulmonary effects of tobacco and related substances. IJ. Coronary vascular effects of cigarette smoke and nicotine. Archives of Environmental Health 12(6): 712-716, June 1966. Forte, I. E, Wittiams, A. J. PoTGieTer, L., SCHMITTHENNER, J. E., HAFKENSCHIEL, J. H., RreceL, C. Coronary blood flow and cardiac oxygen metabolism during nicotine-induced increases in left ventricu- lar work. Annals of the New York Academy of Sciences 90(1): 174-185, September 27, 1960. FRANKL, W. S., FRIEDMAN, R., SoLorr, L. A. Cardiac output, blood pressure and free fatty acid responses to smoking in the nonbasal State. American Journal of the Medical Sciences 252(1): 39-44, July 1966. 79 (67) (68) (69) (70) (71) (72) (73) (74) (75) (76) (77) (78) (79) (80) (81) 80 FRANKL, W. S., WINTERS, W. L., SoLoFF, L. A. The effects of smoking on the cardiac output at rest and during exercise in patients with healed myocardial infarction. Circulation 31 (1) : 42-44, January 1965, FREUND, J., Warp, C. The acute effect of cigarette smoking on the digital circulation in health and disease. Annals of the New York Academy of Sciences 90(1): 85-101, September 27, 1960. FRIBERG, L., CEDERLOF, R., LUNDMAN, T., OLsson, H. Mortality jn smoking discordant monozygotic and dizygotic twins, A study on the Swedish Twin Registry. Archives of Environmental Health 21(4); 508-513, October 1970. FRIEDELL, M. T. Effect of cigarette smoke on the peripheral vascular system. Radioactive iodinated albumin used as indicator of volu- metric change. Journal of the American Medical Association 152 (10): 897-900, July 4, 1953. GLYNN, M. F., Musrarp, J. F., BUCHANAN, M. R., Murpuy, E. A. Cigarette smoking and platelet aggregation. Canadian Medical Asso- ciation Journal 95(11): 549-553, September 10, 1966. GorMan, J. W., LINDGREN, F. T., STRISOWER, B., DELALLA, O., GLAZER, F, TAMPLIN, A. Cigarette smoking, serum lipoproteins, and coronary heart disease. Geriatrics 10(8) ; 349-354, August 1955. GoLpsmiTH, J. R., LANDAw, S. A. Carbon monoxide and human health, Science 162(3860) : 1852-1359, December 20, 1968. GREENSPAN, K., EpmManps, R. E., KNOEBEL, S. B., Fiscn, C. Some effects of nicotine on cardiac automaticity, conduction, and inotropy. Archives of Internal Medicine 123(6): 707-712, June 1969. Groscoceat, Y., ANGUERA, G., LELLOUCH, J., Jacotor, B., BEAUMONT, J.-L., Paros, E., Manrer, E. L’intoxication chronique par la nico- tine chez le lapin nourri au cholesterol. Effets sur la paroi aortique et sur la lipidemie. (Chronic nicotine poisoning in the rabbit on a cholesterol diet. Effects on the wall of the aorta and on lipidemia.) Journal of Atherosclerosis Research 5(8): 291-301, 1965. HAMMonp, E. C., GARFINKEL, L. Coronary heart disease, stroke, and aortic aneurysm. Factors in the etiology. Archives of Environmental Health 19(2): 167-182, August 1969. Hammonp, E. C., Horn, D. Smoking and death rates—report on forty- four months of follow-up of 187,783 men. I. Total mortality. Journal of the American Medical Association 166 (10): 1159-1172, March 8, 1958. HaMmMmonb, E. C., Horn, D. Smoking and death rates—report on forty- four months of follow-up of 187,783 men. IJ. Death rates by cause. Journal of the American Medical Association 166(11): 1294-13808, March 15, 1958. Har_an, W. R., OBERMAN, A., MITCHELL, R. E., GRAyBrEL, A. Con- stitutional and environmental factors related to serum lipid and lipoprotein levels. Annals of Internal Medicine 66(3): 540-555, March 1967. Hass, G. M., LANDERHOLM, W., HEMMENS, A. Production of caleific athero-arteriosclerosis and thromboarteritis with nicotine, vitamin D, and dietary cholesterol. American Journal of Pathology 49 (4): 789-771, October 1966. Hauce, M., Harvap, B., Rei, D. D. A twin study of the influence of smoking on morbidity and mortality. Acta Geneticae Medicae et Gemellologiae 19: 335-336, 1970. (82) (83) (84) (85) (86) (87) (88) (89) (90) (91) (92) (93) (94) (95) HEYDEN-STUCKY, S., SCHIBLER-REICH, S. Kardiologische Risikofaktoren bei Schweizer Mannern. (Cardiological risk factors in Swiss men.) Schweizerische Medizinische Wochenschrift 97(1): 20-25, January 7, 1967. Hiceins, M. W., KseL_sperc, M. Characteristics of smokers and non- smokers in Tecumseh, Michigan. II. The distribution of selected physi- cal measurements and physiologic variables and the prevalence of certain diseases in smokers and nonsmokers. American Journal of Epidemiology 86(1): 60-77, July 1967. HirayaMa, T. Smoking in relation to the death rates of 265,118 men and women in Japan. National Cancer Center, Research Institute. Tokyo, September 1967. 14 pp. Hoop, B., TiBBL1N, G., WELIN, G., ORNDAHL, G., KoRSAN-BENGTSEN, K. Myocardial infarction in early age. III. Coronary risk factors and their deficient control. Acta Medica Scandinavica 185(4): 241-251, April 1969. HueEpPEeR, W. C. Experimental studies in cardiovascular pathology. VII. Chronic nicotine poisoning in rats and in dogs. A.M.A. Archives of Pathology 35: 846-856, 1943. Hyams, L., SEcI, M., ARCHER, M. Myocardial infarction in the Japan- ese. A retrospective study. American Journal of Cardiology 20(4): 549-554, October 1967. INTER-SOCIETY COMMISSION FOR HEaRT DISEASE Resources. Athero- sclerosis Study Group and Epidemiology Study Group. Primary pre- vention of the atherosclerotic diseases. Circulation 42(6) : A-54-A-95, December 1970. Trvinc, D. W., YAMAMOTO, T. Cigarette smoking and cardiac output. British Heart Journal 25: 126-132, 1963. JENKINS, C. D., ROSENMAN, R. H., ZYZANSKI, S. J. Cigarette smoking. Its relationship to coronary heart disease and related risk factors in the Western Collaborative Group Study. Circulation 38(6): 1140- 1155, December 1968. JOUVE, A., RocHu, P., AVRIL, P. Enquetes epidemiologiques sur l’athero- sclerose dans la region Provencale. (Epidemiological investigations of atherosclerosis in the Provence region.) Union Medicale du Canada 98(5): 761-766, May 1969. JUERGENS, J. L., BARKER, N. W., Hings, E. A., JR. Arteriosclerosis ob- literans: Review of 520 cases with special reference to pathogenic and prognostic factors. Circulation 21(2) : 188-195, February 1960. Kaun, H. A. The Dorn study of smoking and mortality among U.S. veterans: report on 84% years of observation. IN: Haenszel, W. (Edi- tor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S. Public Health Service, National Cancer Institute Monograph No. 19, January 1966. pp. 1-125. KANNEL, W. B., CaSTELLI, W. P., MCNAMARA, P. M. Cigarette smoking and risk of coronary heart disease. Epidemiologic clues to patho- genesis. The Framingham study. IN: Wynder, E. L., Hoffmann, D., (Editors). Toward a Less Harmful Cigarette. Bethesda, U.S. Depart- ment of Health, Education, and Welfare, Public Health Service, Na- tional Cancer Institute Monograph No. 28, June 1968. pp. 9-20. KANNEL, W. B., Dawser, T. R., SKINNER, J. J., JR., MCNamara, M., SHURTLEFF, D. Epidemiological aspects of intermittent claudication: The Framingham Study. Circulation (Supplement TH to Vols. 31 and 32): 121-122, October 1965. 81 (96) (97) (98) (99) (100) (101) (102) (103) (104) (105) (106) (107) (108) (109) (110) (111) 82 KANNEL, W. B., Dawser, T. R., CoHEN, M. E., MCNAMARA, P. M. Vas- cular disease of the brain—epidemiologic aspects. The Framingham study. American Journal of Public Health and the Nation’s Health 55(9): 1855-1366, September 1965. KARVONEN, M., ORM, E., Keys, A., FIpanza, F. BROXEK, J. Cigarette smoking, serum-cholesterol, blood-pressure, and body fatness. Obser- vations in Finland. Lancet 1: 492-494, March 7, 1959. / KastL, O, Berufliche und Umweltanalyse infarktkranker Eisenbahn- bediensteter. (Occupational and ervironmental analysis of infaret patients in railway service.) Medizinische Klinik 64 (42): 1911-1917, October 17, 1969. Kepra, M., I)Mowsk1, G. The influence of tobacco smoking on the devel- opment of atherosclerosis and on the composition of blood lipids, Polish Medical Journal 5(1): 87-43, 1966. Kepra, M., Koro.ko, A. Tobacco smoking and blood clotting. Bulletin of Polish Medical Science and History 8: 145-148, October 1965. Kepra, M., Poveszak, J., Pirera, A. Wplyw palenia tytoniu na poziom tluszezowcow krwi. (Influence of tobacco smoking on the bload lipid levels.) Polski Tygodnik Lekarski 20(39): 1452-1454, September 27, 1965. Kerrican, R., Jain, A. C., Doyte, J. T. The circulatory response to cigarette smoking at rest and after exercise. American Journal of the Medical Sciences 255(2); 118-119, February 1968. KERSHBAUM, A., BELLET, S., CAPLAN, R. F., Feiner, L. J. Effect of cigarette smoking on free fatty acids in patients with healed myo- cardial infarction. American Journal of Cardiology 10(2): 204-208, August 1962. KERSHBAUM, A., BELLET, S., DICKSTEIN, E. R., FEINBERG, L. J. Effect of cigarette smoking and nicotine on serum free fatty acids. Based on a study in the human subject and the experimental animal. Circulation Research 9(3) : 631-638, May 1961. KERSHBAUM, A., BELLET, S., HIRABAYASHI, M., FEINBERG, L. J. Regular filtertip, and modified cigarettes. Nicotine excretion, free fatty acid mobilization and catecholamine excretion. Journal of the American Medical Association 201(7) : 545-546, August 14, 1967. KERSHBAUM, A., BELLET, S., JIMENEZ, J., FEINBERG, L. J. Differences in effects of cigar and cigarette smoking on free fatty acid mobilization and catecholamine excretion. Journal of the American Medical Asso- ciation 195 (13): 1095-1098, March 28, 1966. KERSHBAUM, A., BELLET, S., KHORSANDIAN, R. Elevation of serum cho- lesterol after administration of nicotine. American Heart Journal 69 (2) : 206-210, February 1965. KERSHBAUM, A., JIMENEZ, J., BELLET, S., ZANUTTINI, D. Modification of nicotine-induced hyperlipidemia by anti-adrenergic agents. Journal of Atherosclerosis Research 6: 524-530, 1966. KERSHBAUM, A., KHORSANDIAN, R., CAPLAN, R. F., BELLET, S., FEIN- BERG, L. J. The role of catecholamines in the free fatty acid response of cigarette smoking. Circulation 28(1): 52-57, July 1968. KERSHBAUM, A., OSADA, H., ScRIABINE, A., BELLET, S., PAPPAJOHN, D. J. Influence of nicotine on the mobilization of free fatty acids from rat adipose tissue in vitro and in the isolated perfused dog limb. Cir- culation 86(4, Supplement 2): 20, October 1967. Keys, A. (Editor). Coronary Heart Disease in Seven Countries. Circu- lation 41(4, Supplement 1): 1970. 211 pp. (112) (1128) (114) (115) (116) (117) (118) (119) (120) (121) (122) (123) (124) (125) (126) (127) Kren, G. A., SHERROD, T. R. Action of nicotine and smoking on coronary circulation and myocardial oxygen utilization. Annals of the New York Academy of Sciences 90(1): 161-173, September 27, 1960. KJELDSEN, K. Smoking and Atherosclerosis. Investigations on the sig- nificance of the carbon monoxide content in tobacco smoke in athero- genesis. Copenhagen, Munksgaard, 1969. 145 pp. KJELDSEN, K., ASTRUP, P., WANSTRUP, J. Reversal of rabbit atheroma- tosis by hyperoxia. Journal of Atherosclerosis Research 10(2): 178- 178, September-October 1969. KJELDSEN, K., DAMGAARD, F. Influence of prolonged carbon monoxide exposure and altitude hypoxia on serum lipids in man. Scandinavian Journal of Clinical and Laboratory Investigation 22 (Supplementum 102) : 16-19, 1968. KJELDSEN, K., MozEs, M. Buerger’s disease in Israel. Investigations on carboxyhemoglobin and serum cholesterol levels after smoking. Acta Chirurgica Scandinavica 135(6): 495-498, 1969. KJELDSEN, K., WANSTRUP, J., ASTRUP, P. Enhancing influence of arte- rial hypoxia on the development of atheromatosis in cholesterol-fed rabbits. Journal of Atherosclerosis Research 8(5): 835-845, 1968. KiEeNscH, H. Blut-Katecholamine und -Fettsduren beim Stress durch Rauchen und durch koérperliche Arbeit. (Blood catecholamines and fatty acids under stress induced by smoke and exercise.) Zeitschrift flr Kreislaufforschung 55(10): 1035-1044, October 1966. Kontrinen, A. Cigarette smoking and serum lipids in young men. Brit- ish Medical Journal 1: 1115-1116, April 21, 1962. KONTTINEN, A., RAJASALMI, M. Effect of heavy cigarette smoking on post-prandial triglycerides, free fatty acids, and cholesterol. British Medical Journal 1(5334): 850-852, March 30, 1963. KruMHo zz, R. A., CHEVALIER, R. B., Ross, J. C. Cardiopulmonary fune- tion in young smokers. A comparison of pulmonary function measure- ments and some cardiopulmonary responses to exercise between a group of young smokers and a comparable group of nonsmokers. Annals of Internal Medicine 60(4) : 603-610, April 1964. KrRuMHOLz, R. A., CHEVALIER, R. B., Ross, J. C. Changes in cardiopul- monary functions related to abstinence from smoking. Studies in young cigarette smokers at rest and exercise at 3 and 6 weeks of abstinence. Annals of Internal Medicine 62(2): 197-207, February 1965. Kuun, R. A. Mode of action of tobacco smoke inhalation upon the cere- bral circulation. Annals of the New York Academy of Sciences 142 (Article 1): 67-71, March 15, 1967. Larson, R. K., Fukupa, P., Murray, J. F. Systemic and pulmonary vascular effects of nicotine in anesthetized dogs. American Review of Respiratory Diseases 91(4): 556-564, April 1965. LEADERS, F. E., Lona, J. P. Action of nicotine on coronary vascular re- sistance in dogs. American Journal of Physiology 203(4): 621-625, October 1962. Les, G., DERNTL, F., Rosin, E., Binc, R. J. The effect of nicotine on effective and total coronary blood flow in the anesthetized closed-chest dog. Journal of Pharmacology and Experimental Therapeutics 178 (1) : 188-144, May 1970. LILIENTHAL, J. L., JR. Carbon monoxide. Pharmacological Review 2: 324-354, 1950. 83 (128) (129) (180) (131) (132) (138) (134) (185) (136) (137) (138) (139) (140) (141) (142) (143) (144) 84 McKusick, V. A., Harris, W. S., OTTESEN, 0. E., GoopMAN, R. M. SHELLEY, W. M., BLOopWELL, R. D. Buerger’s disease: A distinet clin. ical and pathologic entity. Journal of the American Medical Associa. tion 181(1) : 5-12, July 7, 1962. MARSHALL, W. J., JR., STANLEY, FE. L., Kezp1, P. Cardiovascular effects of cold pressor tests, 40° head-uyp tilt, and smoking on smokers and nonsmokers. Diseases of the Chest 56(4); 290-296, October 1969. Mastova, K. K. The influence of nicotine on experimental atherosclero. sis. Bulletin of Experimental Biology and Medicine 41: 20-23, 1956, MILLs, C. A., Porter, M. M. Tobacco smoking and automobile-driving stress in relation to deaths from cardiac and vascular causes. Ameri. can Journal of the Medical Sciences 234 (1): 35-43, July 1957. MIYAZAKI, M. Circulatory effect of cigarette smoking, with special ref. erence to the effect on cerebral hemodynamics, Japanese Circulation Journal 33(9) : 907-912, September 1969. MobpzELEWSKI, A., MALec, A. Zachowanie sie niektorych lipidow we krwi u palaczy. (Patterns of certain blood lipids in smokers.) Wiado- mosci Lekarskie 22(8) : 229-233, February 1, 1969. Moyer, C. A., Mappocx, W. G. Peripheral vasospasm from tobaceo, A.M.A. Archives of Surgery 49(2): 277-285, February 1940. Mutcany, R., Hickey, N. J. Cigarette smoking habits of patients with coronary heart disease. British Heart Journal 28: 404-408, 1966. Mutcany, R., Hickey, N. J. The role of cigarette smoking in the cau- sation of atherosclerosis. Geriatrics 22(2): 165-174, February 1967, Muccany, R., Hickey, N. J., Maurer, B. J. Coronary heart disease in women. Study of risk factors in 100 patients less than 60 years of age. Circulation 36(4) : 577-586, October 1967. MuLInos, M. G., SHULMAN, I. The effects of cigarette smoking and deep breathing on the peripheral vascular system. Studied by five methods. American Journal of the Medical Sciences 199(5): 708-720, May 1940, Murcuison, L. E., Fyre, T. Effects of cigarette smoking on serum- lipids, blood-glucose, and platelet adhesiveness. Lancet 2(7456) : 182- 184, July 23, 1966. Murpuy, E. A. Thrombozyten, Thrombose und Gerinnung, (Thrombo- cytes, thrombosis and clotting.) IN: Schievelbein, H. (Editor). Niko- tin: Pharmakologie und Toxikologie des Tabakrauches. Stuttgart (West Germany), Georg Thieme Verlag, 1968. pp. 178-192. Mustarb, J. F., Murpuy, E. A. Effect of smoking on blood coagulation and platelet survival in man. British Medical Journal 1(5334) : 846- 849, March 30, 1963. Napeau, R. A., JAMEs, T. N. Effects of nicotine on heart rate studied by direct perfusion of sinus node. American Journal of Physiology 212 (4) : 911-916, April 1967. Osk1, F. A., Gortiies, A. J., MILLER, W. W., DELIVORIA-PAPADOPOULOS, M. The effects of deoxygenation of adult and fetal hemoglobin on the synthesis of red cell 2,3-diphosphoglycerate and its in vivo conse- quences. Journal of Clinical Investigation 49(2): 400-407, February 1970. PAFFENBARGER, R. S., JR., LAUGHLIN, M. E., Gima, A. S., Black, R. A. Work activity of longshoremen as related to death from coronary heart disease and stroke. New England Journal of Medicine 282 (20): 1109-1114, May 14, 1970. (145) PAFFENBARGER, R. S., Jr., WiLLiaMs, J. L. Chronic disease in former college students. V. Early precursors of fatal stroke. American Jour- nal of Public Health and the Nation’s Health 57(8): 1290-1299, August 1967, (146) PAFFENBARGER, R. S., JR., WrnG, A. L. Chronic disease in former college students. X. The effects of single and multiple characteristics on risk of fatal coronary heart disease. American Journal of Epidemiology 90(6) : 527-535, December 1969. (147) Pace, I. H., Lewis, L. A., Mornuppin, M. Effect of cigarette smoking on serum cholesterol and lipoprotein concentrations. Journal of the American Medical Association 171(11): 1500-1502, November 14, 1959. (148) Paut, O., Lepper, M. H., PHELAN, W. H., Duperruis, G. W., MACMIL- LAN, A., McKean, H., Park, H. A longitudinal study of coronary heart disease. Circulation 28(1): 20-31, July 1963. (149) PEeNTECcosT, B., SHILLINGFoRD, J. The acute effects of smoking on myo- cardial performance in patients with coronary arterial disease. Brit- ish Heart Journal 26: 422-429, 1964. (150) PINCHERLE, G., WricHT, H. B. Screening in the early diagnosis and prevention of cardiovascular disease. Journal of the College of Gen- eral Practitioners 13: 280-289, 1967. (151) Pozner, H., Briimoria, J. D. Effect of smoking on blood-clotting and lipid and lipoprotein levels. Lancet 1(7660) : 1318-1321, June 20, 1970. (152) Puri, P. S., ALaMy, D., Bina, R. J. Effect of nicotine on contractility of the intact heart. Journal of Clinical Pharmacology 8(5) : 295-301, September—-October 1968. (153) Razpan, A. N., SINGH, R. P., Srivastava, V. K. Thromboangiitis obli- terans. A clinical study of 125 cases. International Surgery; Bulletin 47 (2): 122-125, February 1967. (154) Recan, T. J., HELLEMS, H. K., Bina, R. J. Effect of cigarette smoking on coronary circulation and cardiac work in patients with arterio- sclerotic coronary disease. Annals of the New York Academy of Sci- ences 90(1): 186-189, September 27, 1960. (155) Rew, D. D., HoLLaNnn, W. W., Rose, G. A. An Anglo-American eardio- vascular comparison. Lancet 2(7581) : 1375-1378, December 30, 1967. (156) Romero, T., TALESNIK, J. Influence of nicotine on the coronary circula- tion of the isolated heart of the cat. Journal of Pharmacy and Phar- macology 19(5) : 322-328, 1967. (157) Rosr, G. A. The diagnosis of ischaemic heart pain and intermittent claudication in field surveys. Bulletin of the World Health Organiza- tion 27(6) : 645-658, 1962. (158) Rosr, G. A. Chest pain questionnaire. Milbank Memorial Fund Quar- terly 43(2, part 2): 32-39, April 1965. (159) Rosenman, R. H., FRIEDMAN, M., Straus, R., WuRM, M. KosiTtcuHexk, R., Haun, W., WERTHESSEN, N. T. A predictive study of coronary heart disease. The Western Collaborative Group Study. Journal of the American Medical Association 189(1) : 15-22, July 6, 1964. (160) Ross, G., BLesa, M. I. The effect of nicotine on the coronary circulation of dogs. American Heart Journal 79(1): 96-102, January 1970. (161) Roru, G. M., Scuick, R. M. The effects of smoking on the peripheral circulation. Diseases of the Chest 37(2) : 203-210, February 1960. 85 (162) (163) (164) (165) (166) (167) (168) (169) (170) (171) (172) (1738) (174) (175) 86 ROTTENSTEIN, H., PEIRCE, G., Russ, E., FELDER, D., MONTGOMERY, H. Influence of nicotine on the blood flow of resting skeletal muscle and of the digits in normal subjects. Annals of the New York Academy of Sciences 90(1): 102-118, September 27, 1960. RussEk, H. I., ZOHMAN, B. L. Relative significance of heredity, diet ang occupational stress in coronary heart disease of young adults. Baseq on an analysis of 100 patients between the ages of 25 and 40 years and a similar group of 100 normal control subjects, American Journal of the Medical Sciences 235 (3): 266-277, March 1958. Russek, H. I., ZouMAN, B. L., Dorset, V. J. Effects of tobacco and whiskey on the cardiovascular system. Journal of the American Med. ical Association 157(7) : 563-568, February 12, 1955. SACKETT, D. L., Gipson, R. W., Bross, I. D. J., PICKREN, J. W. Relation between aortic atherosclerosis and the use of cigarette and alcohol. An autopsy study. New England Journal of Medicine 279 (26) : 1413- 1420, December 26, 1968. Sapuir, R., Rapaport, E. Cardiovascular responses of the cat to mesen- teric intra-arterial administration of nicotine, cyanide and venous blood. Circulation Research 25 (6) : 713-724, December 1969. SCHIMMLER, W., NEFF, C., SCHIMERT, G. Risikofaktoren und Herzin- farkt. Eine retrospektive studie. (Risk factors and myocardial in- farct. A retrospective study.) Miinchener Medizinische Wochenschrift 110 (27) : 1585-1594, July 5, 1968. ScHwartz, D., LeLtoucn, J., ANGUERA, G., RIcHarb, J. L., BEAUMONT, J. L. Etiologie comparee de l’arteriopathie obliterante des membres inferieurs et de l’arteriopathie coronarienne. (Comparative etiology of lower limb obliterative arteriopathy and of coronary arteriopathy.) Archives des Maladies du Coeur 58: Supplement No. 3, 24-32, 1965. ScHwartTz, D., LELLoucH, J., ANGUERA, G., BEAUMONT, J. L., LENEGRE, J. Tobacco and other factors in the etiology of ischemic heart disease in man: Results of a retrospective survey. Journal of Chronic Dis. eases 19(1) : 35-55, January 1966. SELTZER, C. C. The effect of cigarette smoking on coronary heart dis- ease. Where do we stand now? Archives of Environmental Health 20(8) : 418-423, March 1970. SEN Gupta, A. N., GHosH, B. P. Observations on some cardiovascular and biochemical effects of tobacco smoking in health and in ischaemic cardiacs. Bulletin of the Institute of Post-Graduate Medical Educa- tion and Research 9(2): 45-57, April 1967. SHApIRO, S., WEINBLATT, E., FRANK, C. W., Sacer, R. V. Incidence of Coronary Heart Disease in a Population Insured for Medical Care (HIP). Myocardial infarction, angina pectoris, and possible myocar- dial infarction. American Journal of Public Health and the Nation’s Health 59(6) : Supplement to June 1969. 101 pp. SHEPHERD, J. T. Effect of cigarette-smoking on blood flow through the hand. British Medical Journal 2: 1007-1010, October 27, 1951. Socanl, R. K., Josut, K. C. Effect of cigarette and biri smoking and tobacco chewing on blood coagulation and fibrinolytic activity. Indian Heart Journal 17: 238-242, July 1965. Spain, D. M., BrapEss, V. A. Sudden death from coronary heart dis- ease. Survival time, frequency of thrombi, and cigarette smoking. Chest 58(2): 107-110, August 1970. (176) (177) (178) (179) (180) (181) (182) (183) (184) (185) (186) (187) (188) (189) (190) (191) SPAIN, D. M., NaTHAN, D. J. Smoking habits and coronary atheroscle- rotic heart disease. Journal of the American Medical Association 177 (10) : 683-688, September 9, 1961. STAMLER, J., BERKSON, D. M., LEVINSON, M., LinpBERG, H. A., MoJon- NIER, L., MILLER, W. A., HALL, Y., ANDELMAN, S. L. Coronary artery disease. Status of preventive efforts. Archives of Environmental Health 13(3): 322-335, September 1966. STEFANOVICH, V., GORE, I., KagiyaMA, G., IwaNnaGa, Y. The effect of nicotine on dietary atherogenesis in rabbits. Experimental and Molec- ular Pathology 11(1) : 71-81, August 1969. Stesra, M., Jz. Predictive significance of risk factors in exertional an- gina pectoris. Cardiologia 51(6) : 336-339, 1967. StRoBEL, M., GSELL, O. Mortalitat in Beziehung zum Tabakrauchen: 9 Jahre Beobachtungen bei Arzten in der Schweiz. (Mortality in rela- tion to tobacco smoking. Nine years of observation in Swiss doctors.) Helvetica Medica Acta 32(6): 547-592, December 1965. Strompeap, B. C. R. Effect of intra-arterially administered nicotine on the blood flow in the hand. British Medical Journal 1: 484-485, February 21, 1959. Stronc, J. P., Ricuarps, M. L., McGitt, H. C., Jk. Eocen, D. A., McMurray, M. T. On the association of cigarette smoking with coro- nary and aortic atherosclerosis. Journal of Atherosclerosis Research 10(3) : 803-317, November—December 1969. Tayior, H. L., BLACKBURN, H., Keys, A., PARLIN, R. W., VASQUEZ, C., PucHNER, T. Five-year follow-up of employees of selected U.S. rail- road companies. IN: Keys, A. (Editor). Coronary Heart Disease in Seven Countries. American Heart Association Monograph No. 29, 1970. pp. 20-39. THIENES, C. H. Chronic nicotine poisoning. Annals of the New York Academy of Sciences 90 (1) : 289-248, September 27, 1960. Tuomas, C. B. Familial and epidemiologic aspects of coronary disease and hypertension. Journal of Chronic Diseases 7(3) : 198-208, March 1958. Tuomas, C. B., Murpuy, E. A. Circulatory responses to smoking in healthy young men. Annals of the New York Academy of Sciences 90(1) : 266-276, September 27, 1960. TIBBLIN, G. High blood pressure in men aged 50. A population study of men born in 1913. Acta Medica Scandinavica (Supplementum 470) : 1-84, 1967. Trippin, G. Kommentar till en svensk tvillingundersékning. (Comment on research on twins in Sweden.) Lakartidningen 65 (47) : 4654-4655, November 20, 1968. TRAVELL, J., RINZLER, S. H., Karp, D. Cardiac effects of nicotine in the rabbit with experimental coronary atherosclerosis. Annals of the New York Academy of Sciences 90(1) : 290-301, September 27, 1960. TRUETT, J., CORNFIELD, J., KANNEL, W. A multivariate analysis of the risk of coronary heart disease in Framingham. Journal of Chronic Diseases 20: 511-524, 1967. U.S. Pustic HEALTH SERVICE. The Health Consequences of Smoking. A Public Health Service Review: 1967. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1696, 1967. 199 pp. a7 (192) (193) (194) (195) (196) (197) (198) (199) (200) (261) (202) (203) (204) (205) 86 U.S. Pupiic HEALTH Service. The Health Consequences of Smoking, 1968 Supplement to the 1967 Public Health Service Review. Washing. ton, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1696, 1968. 117 pp. U.S. Pusric HEALTH Service. The Health Consequences of Smoking, 1969 Supplement to the 1967 Public Health Service Review. Washing- ton, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1696-2, 1969. 98 pp. U.S. Pusric HEALTH SERVICE. NATIONAL AIR POLLUTION CON. TROL ADMINISTRATION. Air Quality Criteria for Carbon Mon- oxide. Washington, U.S. Department of Health, Education and Wel- fare, National Air Pollution Control Administration Publication No, AP-62, March 1970. 158 pp. U.S. Pupiic HEALTH SERvicr. NATIONAL CENTER FOR HEALTH STATISTICS. Vital and Health Statistics. Data from the National Health Survey. Coronary Heart Disease in Adults—United States— 1960-1962. Washington, U.S. Department of Health, Education and Welfare, National Center for Health Statistics Series 11, No. 10, September 1965. 46 pp. U.S. Pustic HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STATISTICS. Vital Statisties of the United States—1967, Vol. II.— Mortality, Part A. Washington, U.S. Department of Health, Educa- tion and Welfare, Public Health Service Publication, 1969. U.S. Pustic HEALTH Service. NATIONAL CENTER FOR HEALTH STATISTICS. Vital Statistics Rates in the United States 1940-1960, Washington, U.S. Department of Health, Education and Welfare, Public Health Service Publication No. 1677, 1968. 881 pp. U.S. Pupiic Heattu Service. Smoking and Health, Report of the Ad- visory Committee to the Surgeon General of the Public Health Serv- ice. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1108, 1964. 387 pp. VAN BUCHEM, F.S. P. Serum lipids, nutrition and atherosclerotic com- plications in man. Acta Medica Seandinavica 181 (4) : 403-416, April 1967. ViEL, B., Donoso, S., SaLcepo, D: Coronary atherosclerosis in persons dying violently. Archives of Internal Medicine 122(2): 97-103, Au- gust 1968. - ViLicER, U., HEYDEN-Stucky, S. Das Infarktprofil. Unterschiede zwi- schen infarktpatienten und Kontrollpersonen in der Ostschweiz. (The infarct profile. Differences between infarct patients and controls in East Switzerland.) Schweizerische Medizinische Wochenschrift 96 (23) : 748-758, June 11, 1966. Von AHN, B. Tobacco smoking, the electrocardiogram, and angina pec- toris. Annals of the New York Academy of Sciences 90(1): 190-198, September 27, 1960. Watts, D. T. The effect of nicotine and smoking on the secretion of epi- nephrine. Annals of the New York Academy of Sciences 90(1): 74- 80, September 27, 1960. Wenster, W. S., CLARKSON, T. B., LorLanb, H. B. Carbon monoxide- aggravated atherosclerosis in the squirrel monkey. Experimental and Molecular Pathology 13(1): 36-50, 1970. Weir, J. M., Dunn, J. E., Ir. Smoking and mortality: A prospective study. Cancer 25(1): 105-112, January 1970. (210) (211) (212) (213) (214) (215) WENZEL, D. G. BECKLOFF, G. L. The effect of nicotine on experimental hypercholesterolemia in the rabbit. Journal of the American Phar- maceutical Association; Scientific Edition 47(5) : 388-848, May 1958. WENZEL, D. G., TURNER, J. A., Kissi_, D. Effect of nicotine on choles- terol-induced atherosclerosis in the rabbit. Circulation Research 7: 256-261, March 1959. WEstT, J. W., GuzMAN, 8. V., BELLET, S. Cardiac effects of intracoro- nary arterial injections of nicotine. Circulation Research 6: 389-395, May 1958. WESTFALL, T. C., CrpoLLONI, P. B., EpmunpDowicz, A. C. Influence of propranolol on hemodynamic changes and plasma catecholamine levels following cigarette smoking and nicotine. Proceedings of the Society for Experimental Biology and Medicine 123: 174-179, 1966. WESTFALL, T. C., Watts, D. T. Effect of cigarette smoke on epinephrine secretion in the dog. Proceedings of the Society for Experimental Bi- ology and Medicine 112(4): 848-847, April 1963. WESTFALL, T. C., Watts, I). T. Catecholamine excretion in smokers and nonsmokers. Journal of Applied Physiology 19(1): 40-42, January 1964. Wuereat, A. F. Is atherosclerosis a disorder of intramitochondrial respiration? Annals of Internal Medicine 73(1) : 125-127, July 1970. WipM_Er, L. K., HARTMANN, G., DucHosaL, F., PLECHL, 8.-C. Risk fac- tors in arterial occlusion of the limbs. German Medical Monthly 14 (10) : 476-479, October 1969. Wiens, S. L., PLatr, C. M. Cigarette smoking and arteriosclerosis. Science 138: 975-977, November 30, 1962. Wywnoer, E. L., HOFFMANN, D. Tobacco and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York, Academic Press, 1967. 730 pp. 89 CARDIOVASCULAR APPENDIX TABLES £6 TABLE A6.—Coronary heart disease morbidity and mortality--retrospective studies (Actual number of cases shown in parentheses)? {SM = Smokers NS = Nonsmokers EX = Ex-smokers] Author, year, Numin - and Data country, f collection Cases (percent) Controls (percent) Comments reference hopu English 1,000 pintes « Case selection Age Percent Smokers Percent Smokers et al., manifest! “HD, from Mayo) 4u-49 2 79.7 (187) 61.9 (302) (p<0,001) 1940, 403: 30f age. Founda- BOBO occ eee T7382) 73.9 (371) (not significant) U.S.A. Cont: Is: 1,000 tion files. 60 or over ....... -68.8(431) 61.8 (327) (not significant) (60). male non-CHD Controls Allages ........69.8 66.3 (p<0.05) patients. same year of admis- sion age- matched. Mills and 474 white male Undefined. 40-49 50-59 60-69 YO orover 40-49 50-59 60-69 70 er over Porter, coronary deaths. (56) (135) (153) (130) (216) (188) (114) (88) 1957, Controls: 606 NS Lowe eee ee O14 6.66 18.30 33.84 19.91 24.47 35.09 54.12 U.S.A, white males. Allcigarettes .........83.93 82.23 49.02 18.44 70.83 59.94 43.86 16,47 (181). Pipes, cigars .......... 8.93 11.11 32.68 47.70 9.26 16.47 21.05 29.41 Buechley Males reporting Question- NS ............-..20.4 (23) NS. ...........42.1(51) etal., CHD to California naire and 20 2... 61.1 (69) 20 .......... 46.3 (56) 1958, Health Survey interview. 20 0... .e eee 185 (21) 20 Looe ee 11.6(14) U.S.A. with matched (38). controls from same survey (included those surviving first myocardial infarction). ¥6 TABLE A6.—Coronary heart disease morbidity and mortahty—retrospective studies (cont.) (Actual number of cases shown in parentheses) [SM = Smokers NS = Nonsmokers EX = Ex-smokers] Author, year, Number and Data country, type of collection Cases (percent) Controls (percent) Comments reference population Russek and 97 male and 3 Interviews Tobacco usage>80 cigarettes/day Patients Zohman, female coronary by 70 percent. 35 percent. included 89 1958, patients. Controls: authors. with classical U.S.A. 100 healthy controls myocardial (163). of similar age, infarction sex, occupation, and 11 with and ethnic origin. angina pectoris. Spain and 269 males identified 3,000 males NS ..............80.0 (81) 29.0 (772) Nathan, as having CHD by in New <40/day .........29.0 (78) 33.0 (870) 1961, physical examination York City >40/day . 18.0 (33) 9.0 (234) (p<0.05) U.S.A. and history. Controls: inter- EX ..............14.0 (89) 14.0 (361) (176). 2,637/3,000 males viewed and Cigar, pipe ....... 14.0 (38) 15.0 (400) identified as examined Total ..... 100.0 (269) 100.0 (2,687) not having CHD by medical group. Mulcahy and 400 mz.’ s less than Interview. Males Males Control smoking Hickey, 60 yours of age with NS oo... eee... 4.50 (18) 18.2(110) data obtained 1967 classical CHD. Data SM .............90.75 (363) 70.6 (427) from estimated Ireland compared with male EX ............. 4.758 (19) 11.2 (68) smoking habits (185, 186). population con- Total ..........100.00(400) 100.0(605) of Irish sumption figures. population of same age group. Schwartz 612 male patients Interview, Average amount 15.5 (p<0.0001) Data apply only to et al, with angina or laboratory, per day as 86.0 those under 55 1966, myocardial and cigarettes . 18.6 years of age. France infaretion. clinicalex- Al!SM ..........86.0 (169). 612 age-matched aminations. Inhalers ..........59.0 45.0 (p<<0.00001) controls. $6 (SM = Smokers (AACLUAL NUUWEF OL Cots sLUWwLL in barelibieses J+ NS = Nonsmokers EX = Ex-smokers] Author, year, Number and Data . country, type of collection Cases (percent) Controls (percent) Comments reference population Villiger and 100 cases with Hospital Malea(72) Females(28) Males(72) Females(28) These are not pure Heyden- recent myocardial history or NS see see. 6.94 71.4 $25.0 82.1 smoking classes. Stucky, infarctions. interview. Cigarettes . 0.0... cece eee eee ee 66.7 28.6 45.8 14.3 ft (p<0.01) 1966, 72 males, 28 females, 1-19 cigarettes/da. tee eee ee ee AB 10.7 23.6 10.7 Swit- 100 age-matched P20 ccc ete eee eee ns AB.6 17.9 $22.2 3.6 zer- controls (72 male Cigar, pipe . 44,4 27.8 . land industrial EX . 42 $15.3 3.6 (201). employees and 28 females in hospital for other diagnoses). Dérken, 205 males up to 44 Death cer- NS coe ee eee eee 10 (2) 18,4 (76) Ex-smokers listed 1967, years of age with tificate re- Cigarette Units under nonsmokers, Germany myocardial infarc- view. In- 1B oo... eeeeeeeees 15 (8) ~ 10.4 (43) Smoking information (52). tion or sudden terview of 10-15 .. 82.2 (62) 46.5 (192) available only on death (139 deceased, patient 20-30 . 48,5 (84) 22.5 (93) 193/205. These 66 living). Controls or kin. 35 21.8 (42) 2.2 (9) cigarette categories —Hamburg age- 100.0 (193) 100.0(413) include mixed or cigar matched citizens (only 28 were mixed (62 were mixed or smokers recalculated selected randomly. or cigar smokers) cigar smokers) as to number of ciga- rettes. No patients or controls smoked pipes exclusively. Dorken, 33 females up to Death cer- Cigarettes per day 1967, 44 years of age tificates, O ceeeeeeecaaeees 61, (2) 63.2 (84) (p<0.001) Germany with myocardial inter- WB oe eee ee ee 17.3 (23) (58). infarction or sudden views. 6-15... ee eee 48.5 (16) 16,5 (22) death. Controls—133 20-30 ............39.4 (13) 3.0 (4) females 27-44 years B85 eee eee eee GL (2) of age from clinic without CVD or lung cancer. TABLE A6.—Coronary heart disease morbidity and mortality—retrospective studies (cont.) oJ * (Actual number of cases shown in parentheses)? [SM = Smokers NS = Nonsmokers EX = Ex-smokers] Author, year, Number and Data country, type of collection Cases (percent) Controls (percent) Comments reference population Hyams 79 males surviving Interviews NS ....... eee eee 101 (8) 21.0 (33) etal., myocardial infare- by trained 1-9 cigarettes 1967, tion. 157 age- personnel, perday ........ 7.0 (5) 10,5 (13) Japan matched controls 10-15 ............25.4 (18) 33.9 (42) (87). hospitalized for non- 16-20 woo... ee 35.2 (25) 25.8 (32) CVD but include 21-34 ............22.5 (16) 17.7 (22) hypertensive disease, >35 see. 99 (7) 12.1 (15) AIL SM « -100.0 (71) 100.0(124) Mulcahy 100 female patients Hospital SM .............,63.0 (63) 45.6 (261) Smoking on controls et al., less than 60 years interviews. NS ..............33.0 (33) 45.3 (259) obtained from 1967, of age admitted to EX .............. 4.0 (4) 9.1 (52) statistics of Treland hospital with CHD. Total .....100.0(100) 100.0 (572) smoking in (187). Irish Republic. Sudden death not ineluded. Stejfa, 70 male and Direct Prevalence of risk factors Authors then followed 1967, female patients interviews. Angina patienta Control group the 70 patients for Poland with recent onset 60.0 3 years and noted (179). exertional angina 48.1{p>0.1) that smoking signifi- pectoris, 54 controls cantly influenced of same age. the incidence of coronary occlusion. Schimmler 603 males with Hospital NS oo... eee... 9.0 (44) 26.0 (187) (p<0.001) etal, healed myocardial interviews. EX ..............12,0 (59) 20.0(142) (p<0.001) 1968, infarctions. 714 male Cigar, pipe .... ..12.0 (62) 11.0 (77) Germany controls of same age <19 cigarettes ....25.0(129) 14.0(101) (p<0.001) (167). without detectable 200 6.6... 42.0(209) 29.0(207) (n<0,001) heart disease. Total .....100.0(503) 100.0(714) £6 TABLE A6, Coronary heart disease morbidity and mortalely—retrospeetive studies (cunt.) (Actual number of cases shown in parentheses) ! [SM = Smokers NS = Nonsmokers EX > Ex-smokers] Author, year, Number and Data country, type of collection Cases (percent) Controls (percent) Comments reference population Hood et al., 230 males surviving Interview (230) (855) 1969, early first myocardial and exam- Never smoked... .1.75 24.2 Sweden infarction. Controls: ination. EX before (85), 855 randomly selected infarction ......1.75 19.7 males 50 years of EX after age. infarction .....29.1 . <15 cigarettes ...28.3 27.4 15 cigarettes ...22.6 20.0 All ..............80.0 47.4 Pipe ............ 16.5 8.8 Jouve 1,229 CHD patients; Interview. 43.0 13.0(p<0.0001) etal., 802 males, 427 1969, females. Controls: France 743 individuals of (91). both sexes; age, sex, and social class matched, Kastl, 275 male railway Interview NS ..... 2.2.0... -20.0 (55) 29.8 (82) 1969, employees up to 65 and ex- 2-20 cigarettes or Germany years of age sur- amina- up to 6 cigars. ..32.0 (88) 63.3 (82) (98). viving myocardial tion. >20 cigarettes or infarction. 275 con- >6 cigars. .......48.0(132) 6.9 (19) trol employees with minor circulatory disturbances. 1 Unless otherwise specified, disparities between the total number of cases and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 86 TABLE A7.—Differences in serum lipids between smokers and nonsmokers (Actual number of individuals shown in parentheses)?! [SM = Smokers NS = Nonsmokers] Author, year, Number and country, type of Results Comments reference population Gofman 401 male Difference between SM and NS +Sf refers to Svedberg et al,, employees Ages 20-29 Ages 80-89 Ages40-59 flotation units of 1955, 20-59 years Lipid: (NS 55, SM 37) (NS 56, SM 67) (NS 17, SM 44) centrifuged lipoproteins. ULS.A., of age. TSE 0-12 « $59.9 p<0.001 +19.9 p<0.05 + 3.9 p<0.05 (72). Sf 12-20 -. + 9.4 p<0.001 + 5.4 p<0.05 — 3.5 p<0.05 Sf 20-100 + $20.0 p<0.025 + 9.1 p<0.05 + 8.5 p<0.05 Sf 100-400 - +15.8 p<0.025 412.1 p<0.05 — 4.5 p<0.05 Cholesterol ....... +212 p<0.05 + 9.0 p<0.05 — 48 p<0.05 Thomas, 521 medical Serum cholesterol mg. percent 1958, students. NS (264) SM (257) U.S.A. Observed/Expected Observed/Expected (185). <250 170/157 149/161.6 >250 Len ere ee ee ee ee nee eee 87/99.6 115/102.4 Chi Square Value = 5.2 p<<0.025 Dawber 2,253 males Serum cholesterol mg. percent The authors conclude that etal., participating 29-44 45-59 there is evidence of a 1959, in the Framingham NS oo cece cent eee e pees ence ne 216.1(149) 228.3(131) gradient of cholesterol with U.S.A. study 29-59 All cigarettes 224.8 (874) 229.5 (589) increasing amount of cigarette (47), years of age. <10 217.4 (75) 229.1 (76) smoking in younger men. 10-19 221,1(134) 230.1 (95) 20-39 225.8 (551) 227.8 (350) >40 229.0(114) 238.5 (68) Pipe and 214.9 (128) 227.1(166) Karvonen 525 males in Serum cholesterol mg. percent The authors state that no et al., various West Finland East Finland Helsinki trend was noted associating 1959, occupations 208.0(64) 226.6 (39) 235.1 (62) increasing amount smoked with Finland 20-59 years 228.7(91) 249.7(103) 257.8 (166) increasing serum cholesterol, (97). of age. although smokers and nonsmokers did have different overall levels. 66 Author, year, TABLE A7.—Differences in serum lipids between smokers and nonsmokers (cont.) Number and (Actual number of individuals shown in parentheses)! {SM = Smokers NS = Nonsmokers] country, type of Results Comments reference population Acheson 221 randomly Mean serum cholesterol Mean Beta/Alpha and Jessop, chosen pensioners mg. percent lipoprotein ratio 961 65-85 years of NS oo. Lice eee ee ee eee = 214(38) 2.0 (36) Treland age. 5 cigarettes/day tae 201(12) 2.1011) (1). 5 213 (34) 1.9(33) 20 201 (33) 1.9 (35) S80 ee eee 206 (8) 1.8 (8) Bronte- Approximately Cholesterol mg. percent Beta/ Alpha lipoprotein ratio No data given on numbers in Stewart, 600 healthy 25-389 40-55 25-39 40-55 each group. 1961, males 25-55 tA TE A E A E A E fA—African. South years of age, NS... ww... V9 197 222 246 2.89 3.34 3.75 4.59 £E—European. Africa “Heavy SM .. 186 223 204 236 3.82 4.40 4.07 5.40 (3r). Konttinen, 314 male military Serum cholesterol Serum phospholipids No serum lipid differences 1962, recruits 18-25 mg. percent mg. percent found among the various Finland years of age. NS Loic ce eee ee CIAB) cece ee eee = 208.8 218.0 smoking groups. (119). (Cigarettes per day) 1-10 (58)............. 206.8 222.3 11-19 ae (54). .....0.0..., 2181 224.7 20 eee ee eens (62)............, 202.8 210.5 Blomstrand 76 monozygotic I. Monozygotes discordant for smoking: Smokers showed slightly lower levels The authors conclude from the and Lundman, 1966, Sweden (26). twin pairs and 87 dizygotic twin pairs obtained from Swedish Twin Registry. of cholesterol, triglycerides, and phospholipids than nonsmokers. II. Dizygotes discordant for smoking: Smokers showed significantly higher levels of phospholipids. No differences for cholesterol and triglycerides. differing MZ and DZ results that constitutional factors are probably more important than smoking in determining lipid levels. 001 TABLE A7.—Differences in serum lipids between smokers and nonsmokers (cont.) (Actual number of individuals shown in parentheses)1 [SM — Smokers NS = Nonsmokers] Author, year, Number and country, type of Results Comments reference population Fidanza 111 male prisoners Serum cholesterol mg. percent No statistically significant etal., 34-69 years of Ages <39 40-49 50-59 60-69 differences found between 1966, age. BS ES 195 (12) 189 (10) 176 (7) SM and NS. Italy <20 cigarettes/day 208 (5) 201(16) 202 (13) 195 (10) (62). >20 cigarettes/day 197(5) 175 (7) 171 (7) Serum triglycerides mg. percent NS clic ccc cece cen eee eens a $4.7 719 85.0 <20 cigarettes/day 84.5 99.4 101.9 89.8 >20 cigarettes/day 91.0 86.0 65.7 Kedra and 200 clinically Serum cholesterol Phospholipids Total lipids Serum cholesterol also noted Dmowski, healthy males mg. percent mg. percent mg. percent to increase with increasing 1966, 20-50 years of NS(100) oo... ee 170.2 268.1 1,234.8 intensity and duration of Poland age. SM 100) .......00. 24a p<0.01 257 5 p>0.05 vasa P<0.01 smoking. (99), Beta-lipoproteins Total fatty acide percent of total mg. percent lipoproteina NS(100) 797.8 43.1 SM 100) ....cee eee 26094 p<0.01 woof p<0.01 Harlan 657 former naval Serum cholesterol Serum triglycerides Lipoproteins et al., aviation cadets Found to be related Found not to be related Sf 0-12 related. p<{0.05 1967, 48 years of age to cigarette smoking to cigarette smoking. Sf 20-100 unrelated. U.S.A, (average). p<0.05. Sf 100-400 unrelated. (79). Heyden- 500 plant workers Serum cholesterol Serum triglycerides No statistically significant Stucky and 30-60 years of mg. percent mg. percent difference found between Schibler- age. <10 cigarettes/day 210.0(334) 110.0 SM and NS, Reich, 1967, >10 cigarettes/day 260.0 (166) 180.0 . Switzerland (82). LOL TABLE A7.—Differences in serum lipids between smokers and nonsmokers (cont.) {Actual number of individuals shown in parentheses)?! [SM = Smokers NS = Nonsmokers] Author, year, Number and country, type of Results Comments reference population Higgins 5,030 male and Males Females and Kjelsberg, female residents NS woe ce eee tenes 209.9 (360) 210.1(1,439) 1967, of Tecumseh, Cigarette o.oo cee ea ee 212.5(1,426) 212.4 (910) ULS.A. Michigan, 16-79 (83). years of age. Pincherly 2,000 men Percentage with serum The authors noted that smokers and Wright, participating in Serum cholesterol cholesterol >270 showed significantly higher 1967, executive health mg. percent mg, percent (p<0.001) serum cholesterol England examinations NS(677) 236.2 19.0 levels than nonsmokers. (150), 28-70 years of Ex-smoker (388 } beeen eee 246.0 28.0 age. 1-19 cigarettes /day (424) 239.2 24.0 >20 cigarettes/day (511) 249.4 30.0 Van Buchem, 1967, 918 randomly chosen males 40-59 years Serum cholesterol 0-209 mg. percent 210-249 mg. percent >250 mg. percent The authors found no correlation between smoking Netherlands of age for entry NS co.cc ee eee ee ee = 12.4 (32) 14.0 (44) 14.2 (41) and serum cholesterol levels. (199). into prospective Cigarette SM 71.6 (184) 67.8 (213) 68.2(197) study. Other 16.0 (41) 18.2 (57) 17.6 (51) Boyle et al., 1,104 male factory Serum cholesterol Serum Beta-lipoprotecin Beta-lipoproteins were found 1968, employees 20-64 mg. percent mg. percent to increase with age, but U.S,A. years of age. NS oe ce ee eee 243 (519) q 0.325) smokers had higher levels <0.005 < (28). SMe cceeeceee eee eeeeees 251576) § PSPS 0.3514 P<0.001 than nonsmokers at all ages. Caganova 49 males living Serum cholesterol Scrum Beta-lipoprotein etal., in youth hostel, mg. percent mg. percent 1968, 21.6 average age. NS(384) coe eee eee eee ee 188.20) r 359.80) : . <0.001 Czechoslovakia 0S 214.20 P<0.025 4gg.4o¢ PS 9-00 (36). Beta/aipha lipoprotein ratio NS(84) oc oe ee e ee ee ee ee eee ete ees 1.16 SM(1B) oe ce ccc ce ese cee cc ee cece te teeeen tue eseeeeees 1.55 ¢ P< 0-025 zoL TaBLeE A7.—Differences in serum lipids between smokers and nonsmokers (cont.) (Actual number of individuals shown in parentheses)?! [SM = Smokers NS = Nonsmokers] Author, year, Number and country, type of Results Comments reference population Medzelewski 140 males 20-68 Serum-choleaterol NS p<0.01 Serum Beta-lipoproteins Serum free fatty acida NS p<0.01 and Malec, years of age, NS (20) p<0.01 1969, Heavy smokers Heavy smokers Heavy smokers Poland (133), Kjeldsen, 934 employees of Serum cholesterol mg. percent 1969, various firms NS (196) 0.0 en ee cn nen eee t een eens 236) p<0.01 Denmark in Copenhagen. SM (7388) 2474 (118). Pozner 64 male and Serum cholesterol Serum triglycerides Total phospholipids Significant figures refer to and Billimoria, female healthy mg. percent mg. percent mg. percent heavy smokers as compared 1970, volunteers 19-30 NS(20) wo... ee eee 176.3 68.6 193.4 with nonsmokers. England years of age. Light SM(17) «..... «172.1 68.4 188.9 (151). {Over 7.3 cigarettes/day ) Heavy SM(27)..... 200.0 p<0,05 87.6 p>0.05 215.0 p<0.001 (Over 22.5 cigarettes/day ) 1 Unless otherwise specified, disparities between the total number of cases and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. col TABLE A8.—Blood pressure differences between smokers and nonsmokers (Actual number of individuals shown in parentheses)! {SM = Smokers NS = Nonsmokers] Author, year, country, reference Number and type of population Results Comments Dawber et al., 1959, U.S.A. (47). 1,253 male and female residents of Framingham. Systolic blood pressure No association found Ages 29-44 45-59 between systolic blood NS(149) ... 6. eee : 188.8 143.0 pressure and smoking. Cigarettes(874) . : teeae .: 132.5 140.3 <10(75) 144.0 10-19 (134) 141.6 20-89 (551) 138.9 >40(114) 141.5 Pipe and cigar(128) oie ce ee ee ee tee etnies 135.0 141.9 Edwards et al., 1959, England (56). 1,737 male patients of general prac~ titioners over 60 years of age. Proportion of males with “Hypertension” (=2200/=2100 mm. Hg.) NS us... cease cence cece cee ee re eereeseeeerees 27.2 percent (151) Cigarettes 2... cect cea cre eee nee enees 20.5 percent (780) Pipe ooo cece cece eee ete eeeeesereeeess 25.9 percent (341) Karvonen et al., 1959, Finland (97). 525 males in various regions of Finland 20-59 years of age. Systolic blood pressure No data on pipe and West Fintand East Finland Helsinkt cigar smokers. No NS Loic ccc ce ee ete eens 139.2 (64) 142.6 (39) 182.8 (62) statistical significance SM wee eee eee eee nes 133,2(91) 135.4 (103) 129.8(166) noted. Diastolic blood pressure NS Loc ee ee eee eee 84.7 86.8 89.6 SM woe eee eee eee 81.9 84.1 86.8 Clark et al., 1967, U.S.A. (43). 1,859 male civil servants. Mean syatolic Mean diastolic Nonsmoker and smoker blood-pressure blood-pressure groups were of similar NS(728) oo. cece eee ett et ee eee 137.0 < 83.9) < average age. SM (407) oo cc ccc cece cece cece eens eeeeens 133.6( (P=0-05) 82.5 (p30.08) ol TABLE A8.—Blood pressure differences between smokers and nonsmokers (cont.) (Actual number of individuals shown in parentheses }1 [SM = Smokers NS = Nonsmokers] Author, year, country, Number and type Results Comments reference of population Higgins and 5,030 male and Age adjusted Age adjusted Kjelsburg, female residents mean. systolic blood pressure mean diastolic blood pressure 1967, U.S.A. of Tecumseh, Michigan, Males Females Males Females (83). 16-79 years of age. NS ........137.9 (360) 84.5 (1439) 136.6 (360) 82,1( 1439) v (p<0.001) Cigarette ...136.4(1426) 81.4 (910) 131.6 (1426) 79.0 (910) § . Reid et al., 676 male British Mean systolic blood pressure The author did note 1967, England and 625 male (adjusted for difference in weight) Mean. diastolic blood pressure SM-NS blood pressure dif- (155). American postal UK U.S.A. UK U.S.A, ferences prior to workers 40-59 NS ....... 128.2 (45) 124.8 (89) 79.3 81.0 controlling for weight, years of age. 1-14 grams 130.2 (27) 133.0 (60) 19.4 82.1 but not after such control, 15-24 grams 128.5 (232) 127.7(169) 78.5 17.3 >25 grams 127.9 (70) 128.1 (218) 97.5 771 All amounts 129.1 (519) 128.6 (447) 78.7 17.8 Tibblin, 1967, 895 males in Blood pressure 215-145/ 150-170/ Numbers in parentheses Sweden Goteborg, Sweden, 110/70 (89) 75-95 (468) 100-110 (220) >175/>115(75) represent total in blood (187). born in 1913. NS woe eee eee ee ee ee ee 18.0 23.0 25.5 34.7 pressure group. 1-14 cigarettes ...........29.2 29.2 25.5 18.7 The author noted Dl5 cigarettes ...........28.1 20.9 15.5 17.3 a stepwise decrease with Pipeandcigar ...........11.2 8.6 10.0 4.0 level of blood pressure as smoking increased. ‘Unless otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the exelusion of either occasional, miscellaneous, mixed, or ex-smokers. sol TABLE A17.—Incidence of new coronary heart disease by smoking category and behavior type for men 89-49 years of age (Numbers in parentheses are number of CHD cases in each subgroup) Smoking group Former Current and Cigarettes Behavior Never cigarette former pipe type smoked smokers and cigar only 1-15 16-25 26 and over Total Acc ee ee nee eee 15.3(5) 13.8 (7) 1.3(1) 1.6(1) 15.8(15) 14.9 (16) 9.3 (45) Boece cece eee eens 1.3(2) 5.1 (3) 2.2(2) 7.3(4) 3.1 (3) 4.9 (4) 3.3 (18) Total ...........2.--- 2.9(7) 9.1(10) 1.8(3) 4.9(5) 9.3 (18) 10.4(20) 6.2 (63) Analysis of variance table Source Sum of squares df. Mean square F P Within cells... 0... cece een eee creer ener eaten 59.471 2,245 0.026 oe oe Regression on age 0.458 1 0.458 17.296 0.001 Between smoking group: 0.504 5 0.101 3.81 0.002 Between behavior types? ..0. 00 ce cece cc tee et nee en ee 0.329 1 0.329 12.43 0.001 Interaction 2.0.6.6 ccc eee n ene e eee e cnet te 0.396 5 0.079 2.99 0.011 1 Rates are age-adjusted annual incidence per 1,000 men. ?Mean squares for “between smoking groups” and “‘between behavior types’”’ are each computed eliminating the general mean and the other main effect but ignoring interaction, thus yielding an estimate of each main ef- fect unconfounded by other significant main effects. Source: Jenkins, C. D. et al. (90). 901 TABLE A18,.—-Incidence of new coronary heart disease by smoking category and behavior type for men 50-59 years of age (Numbers in parentheses are number of CHD cases in each subgroup ) Smoking group Interaction ©0060. cece cee cee eee ee nenenees Former Current and Cigarettes Behavior Never cigarette former pipe type smcked smokers and cigar only 1-15 16-25 26 and over Total Ace eee cee veces 112.4(5) 18.6(8) 21.8 (8) 16,4(5) 21.5 (9) 30,0(14) 20.4(49) Bow. cece eee eee 10.0(4) 5.101) 8.4 (3) 4.7(1) 21.1 (7) 19,1 (5) 12.0(21) Total vio. eee 11.1(9) 14.2(9) 14.9(11) 11.5 (6) 21.3(16) 26.0(19) 16.8(70) Analysis of variance table Source Sum of squares d.f. Mean square F P Within cells 200 cece cee cease oe 63.527 911 0.070 a ae Regression on age ...00 0000.0. cc cece cece cece ence cece ‘i 0.177 1 0.177 2.54 0,111 Between smoking groups 0.522 5 0.104 1.496 0.188 Between behavior types = 0.296 1 0.296 4.24 0.040 0.129 5 0.026 0.37 0.870 1 Rates are age-adjusted annual incidence per 1,000 men. *Mean squares for “between smoking groups” and “between behavior types” are each computed eliminating the general mean and the other main effect but ignoring interaction, thus yielding an estimate of each main ef- fect unconfounded by other significant main effects. Source: Jenkins, C. D. et al. (90). 20t TABLE A20.—Experiments concerning the effects of smoking and nicotine on animal cardiovascular function Author, year, Number and Smoking Heart Blood country, type of procedure rate pressure Comments reference population Bellet 89 experiments Inhalation Definite Definite Coronary artery ligation increased the frequency etal, on dogs which of tobacco increase. increase. of nicotine-induced severe arrhythmias; these 1941, had undergone smoke in became less evident with increasing time since U.S.A. coronary chamber. ligation. (21). artery liga- Nicotine Definite Definite tion up to intravenous increase, increase, 45 days before. 0.2-1.2 mg./kg, Burn and 10 rabbits, Experimenta! Isolated atrial specimen showed increased rate and Rand, 5 eaperimental, animals pre- increased amplitude of contractions with admin- 1958, 5 control, treated with istration of nicotine proportional to pretreat- England isolated atria, intraperitoneal ment. These reactions were blocked by reserpine, (35). nicotine and and the authors consider nicotine effects to be the atria of mediated by catecholamine release from chro- both groups maffin store in myocardium. excised and perfused with nfeotine. West et al., 33 normal Coronary Definite I. Myocardial contractility increased 40-90 per- 1958, adult mongrel intra- increase cent in 15/15 animals tested accompanied by U.S.A. dogs. arterial (systolic). ST segment depression and T-wave inversion (208), nicotine: and blocked by tetraethylammonium chloride. I. 0.2-2.2 II, Coronary blood flow increased 19 percent upon ug./ke. left circumflex artery injection; coronary blood Il. 0.04-1 flow showed no change upon left anterior de- ue./ke. scending artery injection, 64 observations on 10 dogs. (Tetraethylammonium chloride blocked CBF in- crease.) The authors found no evidence of coronary vaso- constriction in these healthy animals. 80L TABLE A20.- Eaperiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) Author, year, Number and Smoking Heart Blood Cardiac Coronary country, type of procedure rate pressure output blood Comments reference population flow Forte 27 observa- Intravenous Definite No change. No significant change in either left ventricular et al., tions on 8 nicotine up initial work or myocardial oxygen extraction. 1960, dogs. to 21.5 mg. increase U.S.A. given as 5-15 then (65). ne./ke./ decrease. minute. Kien and 21 adult dogs Cigarette Definite Definite Increase Effects of cigarette smoke were duplicated by in- Sherrod, smoke under increase. increase. following travenoug nicotine and epinephrine. 1960, positive increase During cigarette smoke inhalation, it was noted ULS.A. pressure via in blood that without blood pressure or output changes, (112). tracheostomy. pressure coronary blood flow did not increase and that Nicotine 20 and cardiac while adverse EKG changes were noted they cor- ug./kg. intra- output. related more closely with decreased cardiac oxy- venously. gen utilization than with actual cardiac work. Epinephrine 5 ug./kg. intra- venously. Travel! 14 normal Intravenous Definite Nicotine-induced coronary blood flow and heart et al., rabbits and nicotine increase rate increase in the atherosclerotic animals re- 1960, 16 rabbits 0.01-0,1 mg. in normals. quired 10 times and 2 times, respectively, the U.S.A. with severe amounts required in the normal animals. (189). cholesterol- induced athero- sclerosis. 601 TABLE A20.—Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) Author, : year, Number and Smoking coutry, type of procedure Comments reference population Bellet I. 10 normal dogs Intravenous I. 125 percent The authors noted that: etal., IL. 9 dogs at nicotine, increase 1, The response of coronary blood flow to nico- 1962, varying in- 20 we./ke./ II. 82.5 percent tine resembled that of anoxemia in the pres- U.S.A, tervals fol- minute for increase ence of coronary insufficiency. (22). lowing coro- 15-20 minutes. IIT, 83.3 percent 2. The greater the induced coronary impairment nary artery increase the smaller the increment in coronary blood ligation. flow. Ill. 7 dogs with varying grades of artificially- induced coro- nary artery narrowing. Leaders 15 adult Left anterior Nicotine and norepinephrine both increased coro- and mongrel descending nary vascular resistance and myocardial contrac- Long. dogs. intracoronary tile force (the former measured by a constant- 1962, injection of volume variable-pressure system). The action of U.S.A. nicotine or nicotine was blocked by pretreatment with hex- (125). norepinephrine. amethonium, pentolinium, reserpine, or guane- thidine. Larson 13 adult Intravenous Definite Definite Systemic vascular resistance and pulmonary artery et al., mongrel nicotine, increase. increase. and left atrial pressures showed biphasic re- 1965, dogs. 0.02 mg./kg./ sponses of increase followed by decrease. U.S.A. minute for (124). 10-12 minutes. OlL TABLE A20.—Eaperiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) Author, year, Number and Smoking country, type of procedure Comments reference population Folle 7 dogs of 30 investigated ¥. Cigarette smoke inhalation I. No change in coronary vascular resistance. et al., (Remainder experienced to isolated left lower lobe Ii. 5/6 showed increase in coronary vascular resistance due, according to 1966, U. (6 Nadeau and Ja catheterization failures). S.A. 4). 26 dogs mes, 1967, U. (1 Rom Talesnik, 19 U. a Puri et 19 U. S.A. 42). 16 experiments on isolated 67, cat heart. S.A, 56). ero and 22 mongrel dogs al., 68, S.A. (152). and then blood perfused coronary arteries. Il. Cigarette smoke to rest of lung and then blood passed to general circulation. III. Nicotine perfused directly into left coronary artery. Nicotine 0.01-10.0 ug. into sinus node artery. Nicotine in varying doses in perfusate of coronary arteries. I. (14) Intravenous nicotine 50 uwe./kg./minute for 3-4 minutes II. (8) Propranolol] pretreat- ment, then 50 ng./kg./minute nicotine for 3-4 minutes the author, to general sympathetic nervous system stimulation. III. 4/5 showed increase in coronary vascular resistance. The authors con- clude that the cardiac effects of tobacco arise almost entirely from the extracardiac actions of smoking instead of the direct response of the heart. Heart rate showed initial slowing (due probably to vagal stimulation) fol- lowed by acceleration (due probably to vagal paralysis and catecholamine release). No systemic blood pressure changes noted, Over 5 ug. of nicotine was found tev produce an initial bradycardia asso- ciated with increased coronary flow, followed by prolonged tachycardia with an initial decrease in coronary blood flow followed by a prolonged increase. Pretreatment with hexamethonium or reserpine prevented both the myocardial stimulation and the increase in coronary blood flow. The authors consider the action of nicotine to be a combination of a direct vasoconstrictive effect and an indirect catecholamine-releasing vasodilating effect. I. Nicotine produced a definite increase in the force and velocity of left ventricular contraction. II. Pretreatment with propranolol produced (relative to results of Group I): (a) A further increase in left ventricular systolic pressure. (b) A decrease in velocity of shortening. (c) A significant increase in left ventricular end-diastolic pressure. The authors conclude that propranolol probably impairs the norepinephrine- like effects of nicotine on the myocardium while enhancing its peripheral vasopressor effects. LLL TABLE A20.—Experiments concerning the effects of smoking and nicotine on animal curdiovaseular function (cont.) Comments Author, year, Number and Smoking country, type of procedure reference population Balazs Beagle dogs with lesions I. Normals (3-6 per experiment); etal., induced in myocardium by (a) 4 we./kg. intravenous 1969, either: (1) Isoproterenol nicotine, (b) 40 ug./kg. U.S.A. pretreatment, or (2) intravenous nicotine. (16). ligation of the anterior Il. Experimental (3), 4 we./kg. descending coronary artery. intravenous nicotine I. (a) No evidence of arrhythmias; (b) A single or a few ectopic beats in 2/3 normal dogs. IE. Extrasystoles noted in 2/3 animals during the first day after cessation of the arrhythmia induced by the lesion alone, but not thereafter. These and nicotine-induced arrhythmias were of a short duration. Greenspan Cardiac muscle isolated from Nicotine 2~100 ug./cc. in et al., the right ventricle of 10 Tyrode’s solution perfusate. 1969, adult dogs. U.S.A. (74). Nicotine perfusion produced: (1) An inerease in myocardial contractile force apparently independent of adrenergic innervation. (2) An increased automaticity of the Purkinje fiber system apparently due to release of catecholamines from chromaffin tissue stores. (3) A decrease in conduction velocity. The authors conclude that the latter two effects probably predispose to ar- rhythmia formation. Saphir and 88 mongrel catg Nicotine 5-12 ug.; kg. injected Rapaport, intraarterially to mesenteric 1969, circulation. U.S.A. (166). I. Mesenteric injection of nicotine was followed with 1-2 seconds by: (a) Increased left ventricular systolic pressure (LVSP). (b} Increased systemic resistance. (c) Enhanced myocardial performance. II. Left ventricular injection of nicotine was followed by: (a) Increased LVSP. (b) Bradycardia. (c) Enhanced myocardial performance greater than that seen in mesenteric-injected group. IIl. Pretreatment with phenoxybenzamine diminished the increase in LVSP while propranolol pretreatment diminished the enhancement of my- ocardial performance while LVSP still showed a significant increase. IV. Mesenteric sympathetic nerve section led to a diminished response. The authors conclude that the cardiovaseular responses to nicotine may be neurogenic in nature with receptors distributed in certain abdominal arteries. ZiL TABLE A20.—E periments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) Author, year, Number and Smoking country, type of procedure Comments reference population Leb et al., 12 mongrel dogs and Nicotine 100 ug./kg. for Effective Coronary Flow (ECF) is that part of the total coronary flow 1970, CBF measured with use of 2 minute intravenously. (TCF) which is “effectively ’ involved in nutrient exchange. U.S.A, Rb* and digital counter. Nicotine injection was followed by: (126). (1) 96.6 percent increase in TCF. (2) 51.1 percent increase in ECF. (3) 73.1 percent increase in myocardial oxygen consumption and analysis revealed that capillary flow increased almost proportionately to my- ocardial oxygen consumption whereas the increase in TCF was far in excess. (4) Definite increases in cardiac output, heart rate, left ventricular work, and aortic pressure. Ross and 10 dogs undergoing Nicotine 10-100 ug. intra- Nicotine injection was followed by: Blesa, instantaneous coronary coronary injection. (1) Inereased contractile force. 1970, arterial low measurement, (2) Decreased myocardial contraction time. U.S.A. (3) Decreased time necessary to reach peak tension. (160). (4) Decreased total stroke systolic CBF, (5) Increased total stroke diastolic CBF. (6) Increased total stroke CBF. (7) Changes similar to intraarterial epinephrine. (8) Changes blocked by pentolinium pretreatment, (9) No change in heart rate or blood pressure. The authors conclude that catecholamines released from the ventricular myocardium mediated these responses to nicotine. TABLE A21.—E'xperiments concerning the effects of smoking. and nicotine on the cardiovascular system of humans A utnor, Number and Smoking Heart Blood Electrocardiogram Stroke Coronary country, type of procedure rate pressure’ ballistocardiogram volume blood Comments reference population flow Russek I. 28 healthy 1 standard and 1 I. Increase, Increase. EKG: Denicotinized ciga- etal., male smokers denicotinized I. 16/28 showed rettes evoked changes 1955, 21-60 years cigarette. significant of a lesser degree U.S.A. of age (aver- changes. in normals and CHD (164), age 42). II, No sig- subjects, but in the II. 37 male patients Il. Increase. Increase. nificant latter group there with overt changes. was no significant clinical CHD BCG: difference between 42-70 years of I... these changes. age (average II. 18/37 showed 54), 6 were significant nonsmokers. change. Bargeron 14 of 30 healthy 1 cigarette Insignificant Increase. Definite Coronary vascular et al., adult male vol- inhaled at increase. increase. resistance fell 1957, unteer smokers intervals of significantly. U.S.A. and nonsmokers 20 seconds. Myocardial 0, (17). who underwent usage underwent no successful catheterization 18--53 years of age. significant change. Pyruvate extraction fell slightly. Authors consider lack of increase in heart rate as due to baseline apprehensive tachycardia. Pil TABLE A21.—Ecperiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author, Number and Smoking Heart Blood Electrocardiogram Stroke Cardiac country, type of procedure rate pressure _ ballistocardiogram volume output Comments reference population Regan 7 males with 2 standard Definite Definite Increase. No signi- Myocardial 4 consump- et al., history of cigarettes in increase. increase, tion rose slightly in 1960, EKG-proven 25 minutes 3 out of 7. U.S.A. myocardial inhaled at The author considers (154). infarction minute that the EKG changes undergoing intervals. noted on smoking are cardiac ca- probably due less to theterization. decreased coronary blood flow than to increased workload (oxygen need) where oxygen supply does not increase. Noted no evidence of myocardial ischemia during smoking. Thomas and 113 clinically One standard Definite Definite Definite Definite Pulse pressure showed Murphy, healthy young cigarette increase. increase. increase. increase, a decrease, 1960, males, smoked at Smokers responded U.S.A own pace. slightly but signi- (186) fieantly more actively than non- smokers. BCG changes were increasingly common with increasing age, weight, and serum cholesterol. TABLE A2l.—E'xperiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author, year, Number and Smoking Heart Blood Electrocardiogram Stroke Cardiac country, type of procedure rate pressure ballistocardiogram volume output Comments reference population Von Ahn, The author Cigarette Increase. EKG: Slight ST EKG changes more 1960, reviews a smoking. segment prominent in young, Sweden series of depression clinically healthy (202). experiments and T-wave subjects than in performed flattening, older, habitual between smokers. Intra- 1944-1954. venous nicotine and smoking showed identical cardio- vascular effects. Smoking elicited angina pectoris in a number of CHD patients. Irving and 5 normal males, (a) Sham smoking. (a) No No change. (a) Nochange. No change. Cardiac output Yamamoto, 15 patients with change. measured by dye 1963, diseases not de- (b) Non-inhalation (b) No No change. (b) No change. No change. dilution technique. England fined, 19-66 years smoking. change. (89). of age, allmod- (ec) 2 standard (c) Definite Widened (c) Definite Definite erate-heavy cigarettes in increase. pulse, increase. increase. cigarette smokers, 10 minutes, pressure, (d) Nicotine 0.6 (d) Definite Definite (d) Definite Definite mg. intra- increase. increase. increase. change. venously. stl Gtk TABLE A21.—Ewperiments concerning the e ffects of smoking and nicotine on the cardiovascular system of humans (cont.) Author, year, Number and Smoking Heart Blood Electrocardiogram Stroke Cardiac Coronary country, type of procedure rate Pressure _ ballistocardiogram volume output blood Comments reference population flow i -nteeost I. 14 volunteers Single cigarette Definite Definite I, 10 27 percent tnd with clinical smoked at own increase increase percent increase, shiling- CHD, 13/14 rate in 6-7 in all in all increase, Ford, smokers, minutes. groups, groups. ted, average age biol, 39.5. ifgay, Il. 5 patients If. Inter- Interme- with angina mediate diate pectoris, all change. change. smokers, ave- rage age 43.4, ITI. 14 patients IIL. 8 per- 1 percent with history of cent increase. definite myo- decrease, cardial infarc- tion, all smok- ers average age 54.1, brankl 5 male and 3 2 standard Definite No signifi- No signifi- The author contrasts etal, female patients cigarettes in increase cant changes cant this-‘response with 1965, with healed 10 minutes at at rest at rest or changes that seen among USA. myocardial infare- rest and under and at during at rest or healthy young Car) tion 48-69 years graded exercise. exercise. exercise, during individuals. of age 2/8 non- exercise. smokers. Author, Cardiac year, Number and Smoking Heart Blood Electrocardiogram country, type of procedure rate pressure ballistocardiogram output Comments reference population Sen Gupta 6 healthy male 1 untipped Increase Increase No change. and Ghosh, nonsmokers. cigarette in in all in all 1967, 8 healthy male 5-7 minutes, groups. groups, 6/8 showed ST India smokers, changes. (i7t). 6 patients with All showed ST CHD, nonsmokers and T-wave 3 patients with changes. CHD, smokers. All showed ST 36-64 years of age. and T-wave changes. Aronow 10 male patients 1 standard high Definite Definite Product of systolic etal. with classical nicotine ciga- increase. increase. blood pressure and 1968, angina pectoris. rette in 5 heart rate showed a U\S.A. 32-59 years of age minutes. significant increase (5). on smoking while left ventricular ejection time values did not. All patients developed angina more rapidly under a constant exercise load if they had smoked before exercising. Kerrigan 24 male and 1 2 filtered ciga- Definite Definite Cardiac The increase in etal, female healthy rettes in 15 increase increase index. cardiac index, heart 1968, smokers, average minutes with under under rest Definite rate, and blood U.S.A. age, 45. measures taken rest and and exercise increase pressure during (102). & male and 2 at rest and during exercise conditions, under rest exercise with smoking female healthy exercise. conditions. and was the sum of such Zit nonsmokers, average age 33. exercise conditions. increases seen with smoking or exercise separately. Neither group showed increases in peri- pheral vascular resistance. StL TABLE A2l.—Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author, year, Number and Smoking Heart Blood Electrocardiogram Stroke Cardiac Coronary country, type of procedure rate pressure ballistocardiogram volume output blood Comments reference population flow Allison 30 healthy male 2 standard ciga- Definite Increase. Increase fol- Definite decrease in and Roth, subjects. rettes smoked increase. lowed by pulmonary blood 1969, 19-59 years of in.12-16 minute decrease volume as indicated U.S A. age. period. within 20 by impedance methods (3). minutes. of thoracic pulse volume. Aronow and 10 male patients 1 low nicotine Definite Definite All patients developed Swanson, with classical cigarette in increase. increase. angina sooner if 1969, angina pectoris. 5 minutes. they smoked before U.S.A. 32-59 years of exercising. (7), age. Aronow and 10 male patients 1 non-nicotine No change. No change. No difference noted Swanson, with classical cigarette in in time or onset 1969, angina pectoris. 5 minutes. of exercise-induced U.S.A, 32-59 years of angina between (6). age. smoking and non- smoking procedures, Marshall 42 normotensive 3/4 of onestandard Insignificant Insignificant Blood pressure response et al., healthy male cigarette. increase. increase, to cold pressor test 1969, prisoners noted to be greater in U.S.A. 18-50 years of heavy smokers. (129). age. Presyncopal reactions 13 nonsmokers. 16 moderate smokers. 13 heavy smokers, to 40 degree head-up tilt more frequent in smokers, 6Ul TABLE A22.—Experiments concerning the effect of nicotine or smoking on catecholamine levels Author, year, Number and country, type of Procedure Results reference subject Watts, 11 dogs 0.02-0.60 mg/kg. Nicotine administration was associated with significant increases in peripheral arterial 1960, nicotine intravenously. epinephrine levels. Ganglionic blocking agents prevented this effect. U.S.A. (208). Westfall 22 mongrel dogs Cigarette smoking via Regular cigarette smoke evoked a statistically significant increase in adrena] vein, and Watts, tracheal cannula; vena cava, and femoral artery levels of epinephrine. Cornsilk cigarette smoke evoked 1963, 1 cigarette/8 minutes no change. U.S.A. for 35 minutes. (210). Westfall 21 male volunteers 3 cigarettes smoked in Smoking at rate noted for 214 hours evoked a significant increase in urinary epine- and Watts, approximately 25 30 minutes. phrine, but not norepinephrine levels. 1964, years of age; U.S.A. 11 nonsmokers, (211), 10 smokers. Westfall et al., 1966, U.S.A. (209). Mongrrel dogs Standard cigarette smoke exposure via endotracheal tube. Smoke inhalation every third inspiration for 3 minutes. Smoke inhalation evoked a rise in cardiac output, stroke volume, blood pressure, and plasma catecholamine levels. Pretreatment with propranolol diminished the cardiac output and stroke volume responses but increased the blood pressure response—the latter effect due to the release of alpha-receptor activity by beta-blockade. OUL TABLE A23.--Experiments concerning the atherogenic effect of nicotine administration Author, year, country, Number and type Procedure Results reference of animal Adler et al, Rabbits Nicotine 1.5 mg. intravenously in 5 percent The authors noted an arterionecrosis of the aorta, affecting mainly the 1906, solution 6 of 7 days per week for more than inner muscular layers. Macroscopically, early changes consisted of U.S.A, 4 months. small areas of caleareous ridging and aneurysmal dilatation without (2). notable fatty degeneration or intimal discontinuity. Microscopically, early changes appeared in the muscle cells of the media, and “chalky” deposits were noted between the elastic fibers. Hueper, I. 6 mongrel dogs. Nicotine subcutaneously. Increasing dosage up I. 4/6 animals died of infection and showed marked edema and focal 1943, up to 2.5 ce. of 3 percent solution for 1 hyalinization of the media of the aorta and large elastic arteries, U.S.A. month, 2/6 animals were sacrificed and showed thickening and hyaliniza- (86). tion of the walls of the coronary arteries and edema of the media as well as endothelial proliferation of other arteries, Il. 60 rats. Increasing doses up to 1 ec. of 1 percent II. Much less aortic involvement than that found in the dogs; infre- solution for 1 month. quent arteriolar changes consisting of fibrosis and thickening of the media. Maslova, Rabbits 1. (10) Nicotine subcutaneously 1 percent I. Aortic wall-—-acute swelling of elastic fibers with focal fragmenta- 1956, solution 0.2 ce. daily for 115 days. tion and partial disintegration--no intimal fat deposits seen. USSR Coronary vessels—-thickening of the vessel wall—no fat deposits. (180). II. (14) Nicotine plus 0.2 grams cholesterol] Il. Aorta—‘massive” deposits of ‘‘cholesterol” in the intima and vasa per day. vasorum with “loosening” of the aortic wall. Coronary vessels— the larger vessels showed moderate fat deposition and the smaller vessels showed swelling of the elastica. Ill. (10) Cholesterol only. II. Aorta—isolated lipid deposition in the arch and ascending portions only. Coronary vessels—-no fat deposition. Czochra- Rabbits T, (10) 1.0 g. cholesterol/day for 100 Index of aortic lesion density (cholestero} infiltration) : Lysanowicz days, I. 2.5, et al., iL. (10) Cholesterol plus 0.0015 g. nicotine/ IL. 3.4, 1959, day intravenously. U.S.A. Il]. (4) Nicotine only. IIf. No aortic lesions noted. (46), Lat TABLE A23.—-Experiments concerning the atherogente effect of nicotine administration (cont.) Author, year, country, reference Wenzel et al., Number and type Procedure of animal Rabbits i. (12) Control untreated. Results General findings: Marked aortic pathologic invelvement was noted in all cholesterol-treated groups: however, no difference was noted between Group Il and Groups TV., V., and VI. Cardiac histopathology: I. No change. li, Advanced atherosclerotic changes in the subendocardial vessels. HI, Thickening and fibrosis of coronary artery small branches. IV.-VI. More severe changes with greater fatty metamorphosis and actual early myocardial necrosis, but no dose-dependent ef- fects observed. 1959, HI. (12) Control diet plus 1 percent U.S.A. cholesterol and 5 percent cottonseed (127). vil added, Ill. (12) Contre! diet plus oral nicotine 2.28 mg./ke./day. IV. (12) Regimen II plus oral nicotine 2.28 mg./ke./day. V. (12) Regimen IT plus oral nicotine 1.42 mg./kg./day. VI. (12) Regimen IT plus oral nicotine 0.57 mg./kg./day. Thienes Newborn rats and Nicotine subcutaneously up to 5 mg./kg. 1960, mice. twice daily by the end of 1 month. U.S.A. Animals autopsied at | year. (184) Grosgogeat Male rabbits TI. (10) Nicotine subcutaneously 0.75 et al., me./day. 1965, (10) Controls—saline injected. France Sacrificed at from 20-120 days. (75). Il. (27) Same as Group I. (27) Controls—saline injected. Sacrificed at 90 days. III. (66) Nicotine subcutaneously 0.8-1.5 meg./day. Sacrificed at 30 days, IV. (24) Nicotine subcutaneously 0.75 mg./day. (24) Controls—saline injected. One-half of each group ate cholesterol- enriched diet (0.5--1.0 percent choles- terol added). Sacrificed at 60 days. No arterial pathology noted. Medial degeneration seen more frequently in controls. Suggests that older animals be used. Significant differences in aortic subendothelial fibrosis between control and experimental groups noted only in II] and IV. In group IV, the nicotine-treated group showed more severe changes. (aay TABLE A23.—Experiments concerning the atherogenic effect of nicotine administration (cont.) Author, year, country, Number and type Procedure Results reference of animal] Hass et al., Male rabbits Nicotine Diet Vitamin D 1966, I. (8) Control Control Control I. Infrequent medial calcific disease without lipid localization. ULS.A. II. (7) Control Cholesterol! Control HII. No medial calcific disease but frequent intimal atheroma formation. (80). HI. (14) Nicotine Control Control II. Rare caleifie medial degeneration: no intimal atheromatous disease, IV. (15) Nicotine Cholesterol Control IV, The largest number of atheromatous lesions. V. (9) Control Cholesterol Vitamin D V. No medial calcific disease. VI, (14) Nicotine Cholesterol Vitamin D VI. Consistent medial calcific disease. (Sacrificed at various times) Control—no treatment. Nicotine—subcutaneous injections in oil— increasing amounts 2 times per week, Vitamin D—subcutaneous injections up to 6-8 x 1 1U. Cholesterol—-250-500 mg. cholesterol] added per 100 g. diet. Choi, Albino rabbits I. Nicotine 1-5 mg./kg./day intraperi- I. Increasing nicotine dosages were associated with decreased atheroma 1967, toneally. formation (findings not Statistically significant). Korea Cholesterol 1 g./day (in varying Il. Nicotine alone produced no atheroma formation but was associated (42). eombinations with controls). with the presence of aortic medial calcification and endothelial] IT. Nicotine alone. hyperplasia. II. Cholesterol alone. (Sacrificed at 60 days) ITI. Cholesterol alone was associated with a definite increase in atheroma formation. Stefanovich Female albing I. (10) Diet supple- Percent of aortic In both stock and cholesterol-fed animals, nicotine was also noted to etal, rabbits. mented with 2.0 surface involved increase aortic triglyceride content and to decrease aortic free cho- 1969, percent choles- with lesterol content. U.S.A. terol. Nicotine in- atherosclerosis (178). tramuscularly I. 9.4 2.78 mg./kg,/day, II. 5.7 5/7 days. Ill. 0.1 Il. (10) Cholesterol Tv. only. III. (10) Nicotine only. IV. (10) Control. zl TABLE A25.—Experiments concerning the effect of smoking and nicotine upon blood lipids (Human Studies) Author, year, Number and Smoking Plasma free Serum Serum country, type of procedure fatty acids cholesterol triglycerides Other Comments reference population Page 13 male and 2 nonfiltered No change. Serum lipoproteins et al., 7 female cigarettes No change (10 subjects). 1959, laboratory in 10 minutes U.S.A. workers and blood (147). 17-51 years levels of age. measured over 30- minute period. Kershbaum 31 male I. 17 subjects Mean rise No change. No change. The authors consider the in- et al., patients or smoked 2 T, 351 pEq./L. crease among controls to be 1961, staff 16-72 non-filter II. 9.8 wEq./L. due to fasting. U.S.A. years of age, cigarettes III. 272-2,304 (104). 7 normals, in 10 BEQ./L. 7 CHD, minutes. 17 other II. 9 controls. medical ITIL. 5 subjects diagnoses. smoked 6 cigarettes in 40 minutes. Kershbaum I. 17 male I, IL, 11, Mean rise No difference found between re- et al,, patients 2 non-filter I. 858 wEq./L. sults following inhalation or 1962, with healed cigarettes in Il. 320 wEq./L. noninhalation. U.S.A. myocardial 10 minutes. I. 292 wEa./L. Statistically significant difference (108). infarctions. IV. No smoking. IV. 20 wEaq./L. found between increases in Tf. 16 non-CHD patients. III. 10 normals. IV. 13 normals. Groups II and III and Group I. Pol TABLE A25. Author, year, country, reference Kershbaum etal, 1968, ULS.A. (f09), Konttinen and Rajasalmi, 1963, Finland C120). Kedra etal, 1965, Poland (107), Number and type of population 11 normal} patients. 40 healthy moderate smokers 19- 20 years of age, 37 male and 5 female medical students 22-23 years of age. Eeperiments concerning the effect of smoking and nicotine upon blood lipids (cont.) (Human Studies) Smoking procedure 9 standard cigarettes in 3 hours. Samples at 10, 20, and 40 minutes of smoking period, Fed at fat meal and then 20 were allowed to smoke cigarettes of known-nicotine content over 6 hour period (approximately 283 cigarettes consumed). 3 cigarettes smoked in rapid suecession and samples taken at 10 and 30 minutes. [ISM — Smokers Plasma free fatty acids Definite increase at start of smoking period. NS—definite increase at 6 hours. 5SM-—-definite increase at 6 hours. No change. Serum cholesterol No change in either group. No change. NS = Nonsmokers] Serum triglycerides Other 3 patients with trime- thaphan camphor- sulfonate (Arfonad) pretreatment and 8 formerly adrenalecto- mized patients showed either minimal or no elevation. NS-.-definite increase at 2 hours. SM—slight increase at 2 hours. Beta-lipoproteins defi- nite increase. Comments Both free and total urinary catecholamines increased with smoking and the author considers them as mediators of the FFA increase. SZ TABLE A25,.—Baperiments concerning the effect of smoking and nicotine upon blood lipids (econt.) {Human Studies) Author, year, Number and Smoking Plasma free Serum Serum country, type of procedure fatty acids cholesterol triglycerides Other Comments reference population Frankl 5 male and 1 2 standard No change. Subjects were in nonfasting, etal, female cigarettes nonbasal state. 1966, healthy inhaled in U.S.A. smokers 10 minutes. (66). 24-29 years of age. Kershbaum 43 normal male I. Terminal I. Indefinite Cigar smoking in 11 subjects etal. heavy cigarette segment of increase. showed an intermediate in- 1966, or cigar cigar in 20 Il. Definite crease in the excretion of ULS.A. smokers, minutes—-15 increase. urinary catecholamines as (106). 21 46 years subjects. Ill. Increase with compared to that with ciga- of age. Il. 3 cigarettes inhalation rette smoking. in 20 minutes greater than 15 subjects with non- Cineluding 6 inhalation from group I). in every Ill. Cigarette subject, inhalation or noninhalation 6 subjects, Klensch, 56 observations 1 standard Definite Indefinite increase in venous 1966, on student cigarette increase. epinephrine levels. Germany smokers 20-24 in 4 minutes. (118). years of age. FFA measured at 16~25 minutes. 9eL TABLE A25.—Experiments concerning the effect of smoking and nicotine upon blood lipids (cont.) {Human Studies) Author, year, Number and Smoking Plasma free Serum Serum country, type of procedure fatty acids cholesterol _ triglycerides Comments reference population Murchison 8 male and 4 2 cigarettes I. Definite No change. No change, Both regular and sham smokers and female mod- in 15 minutes. increase. showed significant increases Fyfe, erate smokers I. Lit-ciga- II. No change. No change. No change, in concentration of serum 1966, with various rettes. oleic acid and significant Scotland diseases 37— II. Unlit-ciga- decreases in concentration o: (139), 67 years of rettes,. serum palmitic acid. . age. Kershbaum 6 normal et al., heavy 1967, cigarette U.S.A. smokers (105). 28-45 years of age. Various types of cigarettes of known nicotine content. Regular cigarettes, filter cigarettes, charcoal-filter cigarettes, pipe tobacco plus cigarettes all showed similar increase in FFA. Lettuce leaf cigarettes had negligible effect. Both catecholamine and nicotine excretion rates showed responses to the various ciga- rettes similar to that of the FFA response. 2éL TABLE A25a.—Experiments concerning the effect of smoking and nicotine upon blood lipids (Animal Studies) ANIMAL AND IN VITRO STUDIES Author, Number year, and Smoking Plasma free Serum Serum ' country, type of procedure fatty acids cholesterol triglycerides Other reference population Comments Wenzeland 48 male J. Untreated control— Group II and IV Beckloff, New 12 subjects. showed an im- 1958, Zealand Il. Regular diet plus mediate in- U.S.A. white 0.1 percent cholesterol— crease in plasma (206). rabbits. 12 subjects. cholestero} and Ill. Regular diet plus 2.28 phospholipids me./kg./day nicotine with a level- in water—12 subjects. with a leveling IV. Diet plus— : of response (a) 0.1 percent cholesterol at 4 weeks. (b) 2.28 mg./kg./day ‘Group 1V showed nicotine in water— a further in- 12 subjects. crease at 8-12 week period. . The authors consider an el- evated cholesterol/ phos- pholipid ratio to bea notable indication of atherogenic susceptibility. The concomitant increase in phospholipids with the cholesterol may negate the importance of nico- tine-induced hypercho- lesterolemia as an atherogenic stimulus. Kershbaum 5 mongrel Intravenous infusion of 20 : Definite increase in etal., dogs. mg./kg. nicotine 13/15 observations, 1961, in 20 minutes. TSA, th). Kev hbaum 20 adult TI. 9 received IM nicotine J. Significant increase No change ead, mongrel daily for 6 weeks; in 8/9 dogs. in any Tb, dogs. up to 1 mg./kg. Il. No change. group. USA, II. 5 placebo injection. Ill. No change. (107). IIT. 6 control. 8zL TABLE A25a.— Experiments concerning the effect of smoking and nicotine upon blood lipids (cont.) Author, Number (Animal! Studies) ANIMAL AND IN VITRO STUDIES year, and Smoking country, type of procedure Other Comments reference population Kershbaum 28 adult Intravenous infusion of nicotine. The authors report on the etal, mongrel results of the use of ne- 1966, dogs. thalide (a Beta-adrener- U.S.A. gic blocker), phenoxy- (108). benzamine, and chlor- promazine to block the FFA response to nicotine. Only nethalide was suc- cessful and this consti- tutes an indication that nicotine stimulates Beta- adrenergic receptors to release catecholamines which, in turn, stimulate the release of FFA. Kershbaum Sprague- Nicotine perfusion. Although nicotine perfusion etal., Dawley was not associated with 1967, rat FFA release from fat tis- U.S.A. fat-pad sue, epinephrine did (t10). tissue. produce a significant in- crease in FFA release. The authors conclude that the sympathetic nervous system mediates the FFA response to nicotine in the intact animal. ot. TABLE A26. Experiments concerning the effect af carrion monoride exposure upon blood lipids Author, year, Number and country, type of Smoking procedure Results reference population Kjeldsen & male students 2 Five daily one-half hour ex posures No significant changes in total fatty acids, phospholipids, or triglycerides. and years of age. to 0.5 percent CO for 8-10 days. Cholesterol showed a significant inerease only during the last 3 days of Damgaard Overall mean COHb result: +g exposure. 1968, was 12.5 percent. Denmark (115). Kjeldsen, 72 female albino rabbits: J. 12 control and 12 exposed L. Serum cholesterol concentrations cca riidly aud then remained slightly 1969, I. Regular diet, 24 to gradually increasing CO above control vaiues far the d-week period, Denmark subjects. concentrations (0.015-0.40 Tl. At 35 days, the serim cholesterat eoencentration in the exposed group was Cty. VI. Regular diet plus percent) over a 4-week 21, times that ti tue coutrol preup. Ill. Serum cholestero) eonesutrations among those exposed were significantly Kjeldsen, 1960, Denmark Cita). period. 2 percent choles- 12 control and 12 exposed to terol, 24 subjects. If. Hi. Resulay diet plus 0.020 percent CO for 35 days. % percent choles- Ill. 12 control and 12 exposed to to 0.020 percent CO for 7 weeks, then 0.036 percent CO for 3 weeks, terol, 24 suigects. 12 control and 12 maintained at 10 pereent oxygen levels for 6 weeks, then 9 percent for 2 weeks. 24 castrated male albino rabbits. Regular diet plus 2 percent cholesterol. higher than those in ihe control group for 5 weeks of the 10-week period. Serum cholesterol and triglyceride concentrations rose to significantly higher levels during 3 of the 8 weeks. No changes noted in serum phospholipids. O€L TABLE A27.—Smoking and thrombosis Author, Whole Partial Recalcified year, Number and Experi- blood Pro- thrombo- plasma Platelet Platelet Platelet Platelet country, type of mental clotting thrombin plastin clotting adhesive- count survival turnover Other Comments reference population conditions ! time time time time ness Black- 16 adult 12 individuals Plasma burn schizo- smoked 2 atypven et al., phrenic high- time 1959, patients, 8 nicotine (—) U.S.A. university standard (25), students, all brand smokers. cigarettes. Mustard 7 white males Compared Platelet and with either after clumping Murphy, CVDor periods of time 1983, COPD, all abstinence (—) (—) C) (—-) (-) (+) (+) (+) U.S.A, heavy or econtinua- decrease — inerease (141). smokers $5- tion of 72 years of smoking. age, Ambrus 20 healthy Deep inhala- Thromhoplastin 2 students and male non- tion of one generation became ill. Mink, smoking nonfiltered (—) (-) (-) (+) (-) tine Results 1964, medical cigarette. increase f--) reflect U.S.A. students <30 data on 18. (4). years of age. Ashby 27 male 13 controls Increase of etal, medical measured at subjects 1965, students and 2 separate greater Tyeland hospital times 14 than that (8). staff subjects (4-) of controls members. measured increase at p<0.01. before and after smoking 2 cigarettes in 20 minutes, 1EL Author, Whole Partial Recalcified year, Number and Experi- blood Pro- thrombo- plasma Platelet Platelet Platelet Platelet country, type of mental clotting thrombin plastin elotting adhesive- count survival turnover Other Comments reference population conditions } time time time time ness _ ae Sogani 11 observations Smoked 2 cig- Fibrinolysis Biri-- and on male arettes or (+) tobaceo Joshi, smokers all] 2 biris or decrease wrapped in 1965, regular chewed f (~—) (-—) t--} (+) tobacco India tobacco betel nut inerease leaf. (174). users. quid in 20 minutes, Engel- 40 male and 2 cigarettes Chandler berg, 20 female in 20 (in vitro) 1965, hospital pa- minutes. thrombosis ULS.A. tients, all time (58), smokers 17- + 68 years of decrease uge. Kedra 39 male and 5 cigarettes Thrombin and 11 female in 1 hour. time Korolko, smokers and {+) (—) (++) (+) 1965, 24 male and decrease decrease decrease Poland 26 female (100). nonsmokers 18-25 years of age. Murchi- 8 males and 2 cigarettes +t Smoking both son 4 female in 15 lit and unlit and patients minutes. cigarettes Fyfe, with lit or unlit (Tt) (+) caused a rise 1966, various cigarettes. increase in platelet Scotland diseases, all adhesiveness (139). heavy which the smokers 37- authors 67 years correlated of age. with rise in plasma non- esterified fatty acids. zEL TABLE A27.—Smoking and thrombosis (cont.) Author, year, Number and Experi- Platelet Platelet eountry, type of mental adhesive- count Other Comments reference population conditions? ness Glynn 20 male and 3 cigarettes Platelet Smokers found etal, 17 female in 30 serotinin to havea 1966, smokers and minutes. 9) {(—) greater Canada 9 male and Platelet tendency for (71). 21 female adenosine platelet nonsmokers nucleotide aggregation 17-76 years (—) than non- of age. smokers. Engelberg $4 male and 1 cigarette Thrombus No relation and 53 female in 5 minutes. formation found with Futter- patients and time increase in man, medical (+) free fatty 1967, house staff. decrease acids. U.S.A. (59). Murphy, Literature Platelet 196%, review with adherence to U.S.A, summary of (+) (+) vascular (140). data and conclusions. Symbols: -- ~ No effect, * .. Questionable effect. increase increase endothelium (+) increase Fibrinolysis (+) decrease Thrombus formation time (+) decrease 1 Results, +- = Definite effect. unless otherwise stated, measured before and after smoking procedure noted. specific coagulation test as TABLE A30.—Ewperiments concerning the effect of nicotine and smoking upon the peripheral vascular system Author, year country, reference Moyer and Maddock, 1940, U.S.A. (2384). 20 subjects (including heavy smokers) were studied for the effects of the following procedures on skin temperature: the inhalation of a lit cigarette, inhalation through an empty paper tube, or the ad- ministration of 1 mg. nicotine intravenously. All subjects responded with decreased cutaneous temperature following the smoking and nicotine procedures, No changes were noted following sham smoking. Mulinos and Shulman, 1940, U.S.A. (188). A number of experimental groups, each consisting of 6-17 persons, were studied for the effects of deep breathing and cigarette smoking on skin temperature and digit or limb plethysmography. The au- thors concluded that deep breathing alone could account for the changes in temperature and blood flow noted upon smoking and noted that denicotinized cigarettes evoked the same or greater vasoconstriction as that noted following the smoking of a standard cigarette. Shepherd, 1951, Treland (1273). 50 young male smokers were studied with plethysmography before and after the normal and rapid inhalation of a standard cigarette. The author noted that rapid inhalation was associated with a pro- longed decrease in extremity blood flow while a more natural rate of inhalation was followed by a momentary decrease in flow. The author considered the former reaction to represent the pharmacolo~- gic effect of the smoke and the latter tu represent the physiologic response to deep breathing, as the natural inhalation of an unlit cigarette produced the same transient decrease in flow as did the natural inhalation of the lit cigarette. Friedell, 1953, USA. (70). 52 male and 48 female young smokers and nonsmokers were studied for the effects of smoking on hand blood volume as measured by the use of radioactive iodinated albumin. The inhalation of un- filtered cigarettes was associated with an average decrease in hand blood volume of 19 percent in men and 33 percent in women; while filtered cigarettes showed respective decreases of 11 percent and 21 percent. Strémblad, 1959, Sweden (181). 11 male and female subjects (smokers and nonsmokers) were studied for the effect of the intra-arterial administration of nicotine (bra- chial artery) on blood flow to the hand as measured by venous occlusion plethysmography. Increasing doses of nicotine were asso- ciated with increasing numbers of individuals manifesting vagso- constriction. The vasoconstrictive effects of nicotine were abolished by the prior administration of either hexamethonium or pentolinium. Barnett and Boake 1960 Australia (18). © male patients with intermittent claudication (7 were heavy smokers) were studied for the effect of smoking on blood flow to the leg as measured by venous occlusion Pplethysmography. Smoking an un- filtered cigarette was found not to produce any consistent changes in blood flow to the calf or foot of the affected leg, Freund and Ward, 1960, U.S.A. (68). 15 male prison inmates (less than 35 years of age) and 14 male patients with peripheral vascular disease (approximately 65 years of age) were studied for the effect of smoking on digital circulation as measured by skin temperature, plethysmography, and radiosodium clearance from the skin. Smoking was found to adversely affect the first and third measures in a significant manner (while plethys- mographic values were variable) only in the healthy prisoners and not at all in the patient group. Roth and Schick, 1960, U.S.A, (161). 100 normal individuals underwent 425 experimental procedures con- cerning the effect of smoking on the peripheral circulation. Smok- ing was found to be associated with a decrease in extremity skin temperature. 133 TaBLe A30.—Experiments concerning the effect of nicotine and smoking upon the peripheral vascular system (cont.) Author, year, country, reference Rottenstein et al., 8 males (18-21 years of age) were studied for the effect of ‘intras 1960, U.S.A. (162). venous nicotine on extremity temperature and blood flow. Intra. venous nicotine was found to evoke a decrease in skin temperature while increasing muscle blood flow. The former effect began sooner and lasted longer than the latter. Allison and Roth, 30 healthy ind:viduals (19-59 years of age) were studied for the effect 1969, U.S.A. (8). of smoking two cigarettes on extremity pulse volumes and skin temperature. Smoking was found to be associated with a 2-6 per. cent decrease in skin temperature and a 45-50 percent decrease in blood pulse volumes to segments of the finger, calf, and toe, 134 CHAPTER 3 Chronic Obstructive Bronchopulmonary Disease Contents Introduction. .......0 0.00. ce eee eee Epidemiological Studies... 1.2.2.0... cece ee eee COPD Mortality... 2.0.0.0... 00. cc ee eee COPD Morbidity.......... 0.0.0... 02. e eee ee eee Ventilatory Function. .......... 0.2.0.0. eee eee eee Genetic Factors... 0.0.0... ce eee ees Alpha,-antitrypsin 2.2.0.0... ee eee Air Pollution........0.. 00.000 cc cece eens Occupational Hazards.......... 0... c cee ee Cadmium ........ 0... eee eens Pathological Studies .......0. 20.0.0. ec ee Experimental Studies Animal Studies ....... 0... 00. ee tees Studies in Humans ........... 0.0 cece eee eee ees Studies Concerning Pulmonary Clearance Overall Clearance Ciliary Function Phagocytosis... . 0... ccc eee ees Studies Concerning the Surfactant System Other Respiratory Disorders .......... 00.002 e eee eee Infectious Respiratory Diseases Postoperative Complications Summary and Conclusions References FIGURES 1. Percent of lung sections with Grade IV or V fibrosis ... 2. Percent of lung sections with Grade II or III emphysema LIST OF TABLES (A indicates tables located in appendix at end of chapter) 1. Chronic obstructive bronchopulmonary disease mor- tality ratios Page 139 141 141 145 146 148 150 152 153 154 154 158 158 163 164 164 164 165 172 172 172 174 175 176 161 162 142 137 A2 A3. Ad, A10. 11. 12, Al3. Al4, Al5, Al6. A17. 138 LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) . Smoking and chronic obstructive pulmonary disease symptoms—percent prevalence................. Smoking and ventilatory function ................ Glossary of terms used in tables and text on smoking and ventilatory function......................, Cessation of smoking and human pulmonary function . Epidemiological studies concerning the relationship of air pollution, social class, and smoking to chronic obstructive bronchopulmonary disease (COPD)... . Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary disease........... Studies concerning the relation of human pulmonary histology and smoking ..................00.-.. Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheobronchial tree and pulmonary parenchyma of animals .............. Experiments concerning the effect of the chronic in- halation of NO. upon the tracheobronchial tree and pulmonary parenchyma of animals ............. Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function. . Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance....... Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function ......... Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tension .... Studies concerning the relationship of smoking to in- fectious respiratory disease in humans .......... Complications developing in the postoperative period in patients undergoing abdominal operations .... Arterial oxygen saturation before and after operation 230 230 INTRODUCTION Chronic obstructive bronchopulmonary disease (COPD) is char- acterized by chronic obstruction to airflow within the lungs. The term COPD refers to three common respiratory ailments; namely, chronic bronchitis, pulmonary emphysema, and reversible obstruc- tive lung disease (bronchial asthma) .* Chronic bronchitis has been defined as the chronic or recurrent excessive mucus secretion of the bronchial tree. It is characterized by cough with the production of sputum on most days for at least three months in the year during at least two consecutive years (217). Pulmonary emphysema is that anatomically defined condition of the jung characterized by an abnormal, permanent increase in the size of the distal air spaces (beyond the terminal bronchiole) ac- companied by destructive changes (217). Patients can suffer from both of these conditions simultaneously. The symptoms as well as the abnormalities in pulmonary function observed in the presence of the two ailments may be quite similar. Patients with chronic bronchitis suffer from productive cough with or without dyspnea (breathlessness both at rest or on exertion) while pulmonary emphysema is characterized mainly by dyspnea. COPD comprises a spectrum of clinical manifestations; thus, it is frequently difficult to determine whether a particular patient is suffering from one of the two specified diseases alone or which one predominates when both are thought to be present. COPD is responsible for significant mortality in the United States. In 1967, a total of 21,507 men and 3,885 women were re- corded as dying from chronic bronchitis and emphysema (221). This figure does not include a sizable number of individuals for whom COPD was a contributory cause of death. During the past two decades, a major increase has taken place in the mortality from COPD in the United States. In 1949, the death rate from COPD was 2.1 per 100,000 resident population, while in 1960 it was 6.0 (222), and in 1967, 12.9 (221). Although * Because mortality from bronchial asthma does not appear to be related to cigarette smoking, the term COPD will be used henceforth to refer only to chronic bronchitis and pulmonary emphysema. Exacerbation of pre-existing bronchial asthma has been observed among cigarette smokers, Further elaboration of this question may be found in a previous Public Health Service Review (223). 139 much of this rise is probab.y due to changes in certification and recording methods as well as to an increased interest on the part of the medical community, an appreciable proportion is also gen- erally accepted as reflecting a real increase in disease. Similar jn. creases over the past 20 to 30 years have also been observed in Canada (7) and in Israel (54). The lack of a similar increase in Great Britain, a country with an extremely high rate of COPD may be the result of a number of factors including improved therapy and decreased air pollution. Moreover, it is also likely that the diagnosis of COPD has been made more commonly and ac. curately in Great Britain for a longer time than in the United States, or elsewhere. Furthermore, the British definitions of bron. chitis and emphysema have (cliffered in the past from those used in the United States. The mortality from and prevalence of COPD is probably under. estimated. In a study of death certificates, Moriyama, et al. (170) reported that COPD is often omitted as a contributing cause of death. In a study of more than 350 autopsies, Mitchell, et al. (169) noted that the disease often goes unreported and that emphysema was occasionally found unassociated with severe clinical airway obstruction. Hepper, et al. (110) observed that ventilatory test re- sults were abnormal in 10 percent of 714 patients in whom no symptoms, signs, or past history of pulmonary disease were noted. They concluded that severe degrees of ventilatory impairment may be undetected by history and physical examination alone. Boushy, et al. (40) evaluated clinica] symptoms, physiologic measurements of airway obstruction, and morphologic bronchial and parenchymal changes in 90 males with bronchogenic carcinoma. The authors found that when either clinical, physiologic, or pathologic evidence of COPD was used alone, one-third to one-fourth of the patients were considered normal, but when all three criteria were used to- gether, only one patient was free of COPD. The importance of COPD as a contributing cause of mortality is now beginning to be more fully recognized. Clinicians have long observed that the majority of their patients suffering from COPD were cigarette smokers (1, 150). Epidemio- logical studies have validated this impression by indicating that cigarette smokers are at a much greater risk of developing or dying from this disease and that the risk increases with increased dosage of cigarette smoke, reaching in the smoker of two packs or more a day a level as high as 18 times that of the nonsmokers (132). The salutary effect of giving up smoking has also been borne out by clinical observation and epidemiological studies. In a number of studies, smokers were found to suffer more fre- quently than nonsmokers from pulmonary symptoms including 140 cough, cough with production of phlegm, and dyspnea. By a variety of pulmonary function tests, smokers were shown to have dimin- ished function as compared to nonsmokers and also to have a steeper slope of the expected decline of function with age. Tests of ventilation/perfusion relationships in the lung have revealed ab- normal function in smokers. Autopsy studies have indicated that smokers dying of causes other than COPD have significantly more changes characteristic of emphysema than nonsmokers. Several recent studies have validated the clinical impression that among patients who undergo surgery, cigarette smokers run a greater risk of developing complications in the post-operative period than nonsmokers, Abundant experimental evidence of the role of smoking in bronchopulmonary disease has been obtained from experiments employing animals and tissue and cell cultures. Recent work has demonstrated, in dogs trained to inhale cigarette smoke through a tracheostoma, that emphysema, pulmonary fibrosis, and other path- ologic changes in the pulmonary parenchyma and bronchi develop and that these changes are proportional to the total dosage of cig- arette smoke inhaled. In vivo and in vitro studies have shown that whole cigarette smoke, or certain fractions thereof, inhibit ciliary activity of the bronchial epithelium, adversely affect the mucous sheath, and inhibit the phagocytic activity of the pulmonary alveolar macrophage. These abnormalities lead to retarded clear- ance of inhaled foreign matter including infectious agents from the lungs, thus predisposing the individual to respiratory infec- tions. Evidence also exists that pulmonary surfactant may be ad- versely affected by cigarette smoke. The convergence of these lines of evidence, which will be de- scribed in more detail in the body of this chapter, leads to the judgment that cigarette smoking is the most important cause of COPD in man. EPIDEMIOLOGICAL STUDIES COPD MORTALITY Numerous epidemiological studies, based on a variety of pop- ulations and carried on in a number of countries, have investi- gated the association between cigarette smoking and COPD. They have shown a greatly increased mortality and morbidity from COPD among smokers as compared to nonsmokers. Results from the major prospective studies relating smoking and COPD mortal- ity are presented in table 1. The majority of the studies separate 141 cre TABLD 1.—Chronic obstructive bronchopulmonary disease mortality ratios (Actual number of deaths shown in parentheses)! SM = Smokers. NS = Nonsmokers PROSPECTIVE STUDIES so Number and Data Follow-up Number Cigarettes/day Chronic country, type of collection years of deaths pipes, cigars bronchitis Emphysema Other reference population Hammond 187,783 white Questionnaire 314 338 Cigarettes and males in 9 and follow-up SM ......308 NS .......1.00 (30) Horn, states 50-69 of death NS ...... 30° <10 ......1.67 (10) 1958, years of age. certificate, 10-20 .....3.00 (57) U.S.A, >20 22... 3.64 (40) C108). All ,....,.2.85 (281) Pipes NS ......1.00 (30) SM ...... 1.77 (23) Cigars NS ......1.00 (80) SM ......1.29 (18) Doll and Approximately Questionnaire 10 292 Cigarettes Cigarettes Hill 41,000 male and follow-up Chronic NS ......1,00 NS ..... 1.00 1964 British of death bronchitis 1-14 .....6.80 1-14... .0,65 Great physicians. certificate. 111 15-24 ...12.80 15-24 ..1,08 Britain Other 25... 21.20 >25 ....0.63 (70). 181 All ..... 11.60 AH ..... 0.81 Pipes and Pipes and Cigars Cigars SM _......3.00 SM ..... 0.78 eri TABLE 1.—Chronic obstructive bronchopulmonary disease mortality ratios (cont.) (Actual number of deaths shown in parentheses)! SM = Smokers. NS = Nonsmokers Author, year, Number and Data Follow-up Number Cigarettes/day Chronic country, type of collection years of deaths pipes, cigars bronchitis Emphysema Other reference population PROSPECTIVE STUDIES Best, Approximately Questionnaire 6 124 Cigarettes Cigarcttes 1966, 78,000 male and follow-up NS. ......1.00 NS ....... 1.00 Canada Canadian of death <10 i... 7.02(17)} <10 =... 4.81 (9) (80). veterans. certificate. 10-20 ...13.65(49) 10-20 .....6.12(21) 200... 14.63 (12) >20 = ......6.93 (7) All ..... 11.42 (78) AH ......... 5.85 (37) Pipes Pipes SM .......2.11 (5) SM. ........ 0.75 (2) Cigars Cigars SM _......3.57 (1) SM .......3.83 (1) Hammond, 440,558 males Interviews by 4 389 Males 1966, 562,671 ACS volun- SM ...... 369 NS... 1.00 (20) U.S.A. females teers. NS ......20 SM (age (108). 35-84 years 45-64). .6.55(194) of age in SM (age 25 states. 65-79) .11.41(175) Kahn, U.S. male Questionnaire Bl, Bronchitis NS. ......1.00 (81) Current ciga- Current ciga- 1966, veterans ‘and SM ....... 64 AIlSM ...6.49(348) rettes only rettea only U.S.A. 2,265,674 follow-up NS .......138 Current ciga- NS. ......1.00(13) NS) .......1,00 (18) (182). person years. of death Emphysema rettes .10.08(229) 1-9 ...... 3.63 (5) 1-9 ....... 5.83 (10) certificate. SM ......284 Pipes 10-20 ....4.51(22) 10-20 ....14.04 (93) NS .......18 SM. ......2.36 (9) 21-389 ....4.57(12) 21-39 ....17.04 (62) Cigars 239 ww, 8.31 (4) 239... 25.34 (17) SM. ......0.79 (5) All ......4.49(43) All ....,.14.17(186) byl TABLE 1.—Chronic obstructive bronchopulmonary disease mortality ratios (cont.) (Actual number of deaths shown in parentheses)} SM = Smokers. NS = Nonsmokers Author, year, Number and Data Follow-up Number Cigarettes/day Chronic country, type of collection years of deaths pipes, cigars bronchitis Emphysema Other reference population PROSPECTIVE STUDY Weirand 68,153 males Questionnaire 5-8 58 Cigarettes Dunn, in various and NS. ...... 71.00 1970, occupations follow-up #10)... 8.18 U\S.A. in California. of death #20) —«..., 11.80 (225). certificate. 380 0... 20.86 AH ...... 12.33 RETROSPECTIVE STUDY Wicken, 1,189 males. Personal inter- 1,188 obtained Cigarettes 1966, view with retrospec- only North- relatives of tively. NS ......1.00(124) ern individuals SM ....1,064 1-10 ..... 2.95 (245) Treland listed on NS ..... 124 11-22) ....3.48(300) (227). death 23... 4.44 (168) register. Mixed SM ...,.. 1.55 (62) Pipes or cigars SM ......1.84(289) 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. ?.NS includes pipe and cigar smokers; SM includes ex-smokers. the findings for chronic bronchitis and emphysema. Such specific grouping of the mortality data should be viewed with some reser- vations in the light of the difficulties mentioned above in dis- tinguishing the two diseases clinically. The dose relationship of increased mortality ratios with increased consumption of cigarettes is indicated by the results of all the studies which present rates for different levels of smoking. Kahn (132), for instance, noted that those smoking only 1 to 9 cigarettes per day incurred an emphysema mortality ratio of 5.53 while those smoking over 39 per day incurred one of 25.34. Pipe and cigar smokers were found in some studies to have slightly elevated mor- tality ratios in comparison with nonsmokers although other studies did not show this. The risk of dving from COPD among cigar and pipe smokers appears to be much less than that incurred by cigarette smokers but may be somewhat greater than that among nonsmokers (table 1). The effect of stopping smoking on COPD mortality is reflected in the results of Doll and Hill (70, 71) in their study of British physi- cians. They found that during the years immediately following cessation of smoking, mortality ratios remained elevated and did not begin to decline below the level of continuing smokers until nearly a decade later. This delay in response is probably due to two factors: the presence in the ex-smokers’ group of many who quit for reasons of il] health and the long-term effects of cigarette smoke on the respiratory tree, some of which are irreversible. Kahn (132) also noted that the age-specific mortality ratios for ex-smokers were lower than those for continuing smokers of cor- responding amounts of cigarettes. A better estimate of the potential effect of stopping smoking on COPD mortality can be gained by studying the death rates in a population in which a high proportion of smokers have stopped smoking to protect their health rather than as a response to ill health. Among doctors age 35-64 in England and Wales, many of whom have stopped smoking cigarettes, there was a 24 percent reduction in bronchitis mortality between 1953-57 and 1961-65, as compared with a reduction of only 4 percent in all men of the same age in England and Wales, among whom there was no reduc- tion of cigarette smoking. (84). COPD MoRBIDITY Many investigators have studied the prevalence of bronchopul- monary symptoms (including those of chronic nonspecific respira- tory disease) among smokers and nonsmokers. These studies are outlined in table A2. Their results indicate that the cigarette 145 smoker is much more likely to suffer from respiratory symptoms such as cough, sputum prcduction, and dyspnea than is the non- smoker. Such symptoms, particularly cough and sputum produc- tion, increase with increasing dosage of cigarette smoke. Table A2 also shows that pipe and cigar smokers experience COPD symptoms more frequently than nonsmokers although not to the degree found in cigarette smokers. These morbidity findings are similar to the mortality findings presented above. Similarly, cessation of cigarette smoking has been shown to be associated with a decrease in symptom prevalence. Mitchell, et al. (168) studied 60 patients who succeeded in stopping smoking and 84 continuing smokers, Among the ex-smokers, more than 70 per- cent reported improvement in their cough while less than 5 percent of the continuing smokers did so. Wynder, et al. (237) followed 224 ex-smokers of cigarettes and noted that 77 percent reported cessation of persistent cough and an additiona] 17 percent reported definite improvement. Hammond (102) reported similar results concerning cough and shortness of breath in a study of a large group of ex-smokers. VENTILATORY FUNCTION Another type of quantification of the effects of smoking on the bronchopulmonary system has been obtained by those groups of investigators who have studied pulmonary function in various groups. Results are presented in table A3, and a glossary of the terms used in the various tests is presented in table Ad. The pa- rameters investigated have included maximal breathing capacity (maximal voluntary ventilation), expiratory flow rates, forced expiratory volume, and vita] capacity. Although certain of these parameters appear to be more sensitive measures of pulmonary dysfunction than others, the overwhelming majority of these stud- ies have shown diminished function among smokers. An increase in the expected age-diminution rate in smokers has been observed in those studies which employed either repeated examinations or examinations at many different age levels. Higgins, et al. (117) conducted a nine-year follow-up examination of 385 male residents of a British industrial town who were age 55-64 at the beginning of the study. Among the survivors who were tested initially and nine years later, the average clecline in FEV,,-; was smallest in non- smokers, slightly greater in ex-smokers, and greatest in smokers. As with COPD mortality and symptom prevalence, the impairment of pulmonary function shows a dose-relationship with increasing amounts of cigarettes smoked, 146 The data contained in table A3 provide two different kinds of information. The majority of the studies were conducted on un- selected populations, which probably include a number of individ- uals with clinically manifest COPD. Therefore, these studies re- flect the prevalence of COPD-related dysfunction (as determined by pulmonary function tests) in relation to smoking. However, some studies of younger individuals have revealed that pulmonary function tests are abnormal in clinically asymptomatic smokers. Krumholz, et al. (140) and Rankin, et al. (189) have shown that pulmonary diffusing capacity is impaired in young asymptomatic smokers when compared with age-matched nonsmokers. Similar impairment in other pulmonary function tests was noted by Peters and Ferris (182, 183) in an asymptomatic college-age group and by Zwi, et al. (241) and Krumholz, et al. (140, 142) in groups of young asymptomatic physicians and medical students. Several investigators have employed tests which measure the relationship of ventilation and perfusion (V/Q relationships) in the various pulmonary segments. These tests are predicated on observations that some segments of the lung may be relatively under or overperfused and that, likewise, segments may be under or overventilated. Anthonisen, et al. (70) investigated pulmonary function in 10 male smokers with clinically mild chronic bronchitis, all of whom had smoked cigarettes for at least 20 years. Regional pulmonary function was studied using radioactive xenon. Despite the fact that overall pulmonary function was nearly normal in sev- eral patients, all had depressed V/Q ratios in some lung regions with the basal areas being those most commonly affected. The au- thors suggested that significant disease in the peripheral airways may exist in patients whose chronic bronchitis is clinically mild and who show no present impairment of ventilatory capacity. The radioactive xenon test may reveal severe compromise of local gas exchange when usual studies of ventilatory capacity do not reveal any impairment. Similar results concerning peripheral airway ob- struction in bronchitic patients with normal, or only minimally in- creased pulmonary resistance, have been observed by Woolcock, et al. (234). These authors also noted that their patients demon- strated frequency-dependent compliance which was unaffected by the administration of bronchodilator aerosols. Strieder, et al. (214) have recently investigated the mechanism of postural hypoxemia in 24 asymptomatic smokers and non- smokers. They found that standard ventilatory tests and lung vol- umes were normal in both the smoking and nonsmoking groups. However, the arterial pO? measured in the supine position was significantly lower among the smokers and alveolar-arterial oxygen gradients, while breathing room air, were larger in smokers than in 147 nonsmokers (more so in the supine than in the erect position). The increase in alveolar-arterial O, gradients was greater for heavy than for light smokers. The authors concluded that maldistribution of ventilation and perfusion accounted for the observed hypoxemia. They also felt that this mild diffuse airway disease among asympto- matic smokers is physiologically significant mainly because of in. volvement of small bronchi, as expressed by maldistribution unac- companied by gross airway obstruction. A similar ventilatory distribution abnormality among smokers has also been observed by Ross, et al. (198) with the mere severe alterations found in the long-term srnokers. Although of concern in the consideration of COPD, such dis. turbances of the V/Q relationship may also have adverse effects upon cardiac function depending upon the level of hypoxemia (219), The discussion in the section on Coronary Heart Disease noted that carbon monoxide has adverse effects on both oxygen transport and alveolar-arteria] exchange as well as on oxygen debt developed with exercise (50). Further research is needed on the joint effect of these pulmonary and carbon monoxide induced hypoxemic influences. A number of other studies have provided further evidence con- cerning the adverse effect of smoking on ventilatory function. Table 5 presents those experiments which dea] with the effect of cessation of smoking on pulmonary function. Among the param- eters which have been noted to improve after stopping smoking are: diffusing capacity, compliance, resistance, maximal breathing capacity, and forced expiratory volumes. These parameters showed improvement within 3 to 4 weeks after cessation of smoking. GENETIC FACTORS Recent interest has been shown in the possible contribution of genetic factors to the pathogenesis of COPD. Earlier studies (127, 147) had noted the existence of kindreds with high incidences of chronic bronchitis, emphysema, or both diseases. In addition to the presence of genetic susceptibility, Larson, et al. (147) also observed that all but one of the 11 symptomatic individuals in their two kindreds were smokers. They postulated that the susceptibility of some smokers to develop emphysema may be, at least partially, genetically detemined. More recently, Larson, et al. (148) studied 156 relatives of COPD patients and 86 control individuals. The subjects underwent pul- monary function testing, incliding forced expiratory volume and residual volume total lung capacity measurements. The authors observed that pulmonary function abnormalities were most prev- alent among the relatives who smoked and least prevalent among 148 6rL TABLE 5.—Cessation of smoking and human pulmonary function’ Author, year, Number and country, type of Results Comments reference population Krumholz 10 physicians Following 3 wecka abstinence Following 6 weeks abstincnce (6 subjects only)t + All subjects were >5 pack et al., 25-33 years Lung volumes—no significant change. Lung volumes: per year smokers. 1965, of age. Peak expiratory flow rate—increase Inspiratory reserve volume—increase (p<0.05). U.S.A. (p<00.01). Functional residual capacity—increase (p<0.05). (141). Maximal breathing capacity—increase (p<0.02). Mean diffusing capacity: Mean diffusing capacity—no change. Resting—inerease (p<0.02) Exercise—no change. Compliance—-increased in 6/8 tested. Compliance—continued to show increase. Wilhelmsen, 16 smokers. Value prior to cessation Value after cessation Significance Mean duration of the non- 1967, (43,7 mean Vital capacity ........4.50 4.57 Not significant. smoking period was 40 U.S.A. age). FEV, ween eee 888 3.52 p<0.05. days. (230). FEV, )/FVC wees 15,0 76.8 Not significant. PEFR ooo. cece eee ee 6.97 7.45 Not significant. MEFR 50%... «10... 8.81 3.93 Not significant. MEFR 25% Cw... we ee SD 1,50 p<0.05. Inspiratory resistance .2.07 1.43 p<0.025, Expiratory resistance .2.80 2.04 p<0.02, Compliance ..........000- No change Peterson 12 smokers After 1 month ecssation After 18 months cessation etal, studied at MBC increase (p<0.001). Increase (p<0.01). 1968, various FEV, increase (p40 cigarettes/day ............ 2.8 Megahed 50 male patients Mucous gland hypertrophy et al., with chronic Percent 1967, bronchitis under- NS oo. ec ee cence ee 29 (2/7) Egypt going bronchial SM oe, 17 (3/43) (P<0.02) (163), biopsy and lavage. 2G TABLE 8.—Studies concerning the relation of human pulmonary histology and smoking (cont.) (Actual number of deaths shown in parentheses) SM — Smokers. NS = Nonsmokers Author, year, Number and country, type of Results Comments reference population Auerbach 562 males au- Degrce of tracheal and bronchial arteriolar thickening etal, topsied at East (by percentage of smokers) 1968, Orange VA 0.0-0.4 0.5--0.9 10-14 1.5-1.9 2.04 U.S.A. Hospital. Never smoked (122) 21... . cece ee ee eee 46.1 39.3 13.3 1.3 aan (14). <20 cigarettes/day (120) 11.7 22.0 33.5 28.4 4.4 20-49 cigarettes/day (254) .. 50 8.6 37.4 40.9 8.1 >40 cigarettes/day (66) ..... 1.38 1.4 31.5 45.3 20.5 ' Numerous experiments detailing changes in bronchial epithelium are detailed tabularly in the Cancer chapter. EXPERIMENTAL STUDIES ANIMAL STUDIES A number of investigators have studied the effect of the inhalg. tion of cigarette smoke on the macroscopic and microscopic struc. COPD, i.e., bronchitis, parenchymal] disruption, alveolar septa] rupture, alveolar space dilatation, and the loss of cilia and ciliated cells in the bronchial] mucosa, The investigations of Auerbach and his coworkers (15, 16, 88) have demonstrated by the use of both light and electron microscopy that dogs who inhale cigarette smoke through tracheostomas de. velop progressively more severe lesions of the bronchi and paren. chyma with increased exposure to cigarette smoke. In electron microscopic studies of specimens taken from the lungs of dogs thus exposed to cigarette smoke, the following changes were observed: In 5 dogs sacrificed after only 44 days of smoking exposure, there was a proliferation of goblet cells as well as a partial loss of cilia in the lining cells, and in 5 dogs sacrificed after 420 days or more of exposure, the number of cell layers in the bronchial] epithelium was found to be twice that of the nonsmoking dogs. Goblet cells and ciliated columnar cells were no longer present; instead, the surface was lined with columnar and cuboidal cells with stubby projections in place of cilia. Mitotic figures were frequently observed in the basal cells. These findings may be relevant to carcinogenesis as well as to the development of COPD. In a long-term experiment, carried out by the same group, dogs were exposed to varying doses of cigarette smoke. Details of the experimental procedure have been outlined in the section on Pul- monary Carcinogenesis. The animals were separated into non- smoker, filter-tip cigarette, nonfilter-light, and nonfilter-heavy ex- posure groups. The dogs were “smoked” for 875 days, or approxi- mately 29 months, The animals which died during the experiment and the animals sacrificed after day 875 were examined for pul- monary parenchymal changes as well as for bronchial epithelial alterations. As seen in figures 1 and 2, dose-related pathological changes, including fibrosis and emphysema, were found in the lung parenchyma of the exposed dogs. These changes were similar to those seen in the lungs of humans with COPD. 158 6cL TABLE 9.—Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheo-bronchial tree and pulmonary parenchyma of animals’ {Actual number of animals shown in parentheses) Author, A. Type of year, Animal exposure country, and B. Duration Results reference strain C. Material Leuchten- 603 CF, A, Inhalation, Number of mice showing specified changes berger, female mice. B. Up to 8 ciga- Number Number et al, rettes/day for Months of of No Mild Severe bronchitis 1960, up to 2 years. exposure cigarettes mice change bronchitis with atypism U.S.A, C. Cigarette smoke. 0 0 150 146 2 2 (no atypism) (152). 1-3 100-200 36 20 9 7 4-8 250-500 36 19 10 7 9-23 600-1600 34 19 7 8 1-23 25-1526 151 RR 33 30 Holland 60 rabbits. A. Inhalation. Cytology of tracheobronchial mucosa etal., B. Up to 20 ciga- Generalized Generalized 1968, rettes/day for Normal Focal hyperplaasis hyperplasia emphysema (123). 2-5. Controls 2... ese e eee eee eee ee ees (30) 21/30 6/30 3/30 1/30 C. ‘Normal ciga- Exposed (30) 7/30 10/30 9/30 11/30 rette smoke’’, Hernandez Adult Grey- A. Inhalation. Mean Mean et al., hound B. Twice daily/ Number of number of parenchymal Groups 1966 dogs. 5 per week, sections months disruption/dog compared P-value U.S.A. C. Cigarette I. Controls ............. (€8)112 we 0.7150 I-IIl insignificant (f11). smoke, Il. Allexposed ........... (15) 205 10.50 0.9583 II-I insignificant HII. Exposed 1l year ...... (8) 107 14.74 1.2350 iv-I p <0,02 OL TABLE 9,—Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheo-bronchial parenchyma of animals* (cont.) (Actual number of animals shown in parentheses) tree and pulmonary Author, A. Type of year, Animal exposure country, and B. Duration Results reference strain C. Material Auerbach Beagle dogs. A. Active inhalation Controls ....(10)—No evidence of pulmonary fibrosis or septal rupture. etal., via tracheostomy. Exposed ....(10)—Early (sacrificed) : 1967, B. Up to 12 cigarettes 1. Alveolar space dilatation. U.S.A. per day for up 2. Pad-like attachments to alveolar septa. (15, 16). to 423 days. Medium exposure: Septal wall thickening. C. Cigarette smoke. Latest exposure: 1. Focal subpleural pulmonary fibrosis. 2. Ruptured alveolar septa. 3. Granulomata. Frasca Beagle dogs. A, Active inhalation Electron microscopic results: etal., via tracheostomy. After 44 days — Increased number of goblet cells. 1968, B. Up to 12 cigarettes Decreased number of cilia on surface lining cells. U.S.A. per day for up After 420 days— Increased number of epithelial cell layers. (88). to 423 days. Loss of ciliated columnar cells. C. Cigarette smoke. Frequent interruptions in basement membrane. 1 Numerous experiments detailing changes in bronchial epithelium are detailed tabularly in the Cancer Chapter. 100 91.7 an i. z Q 5 w 60-— 7) Go z Ss _ a ms ° ke 407— z rT] o x ta 5 a 20 12.9 a 5.7 0.0 # : GROUP N: GROUP F: GROUP L: GROUP H: NONSMOKING FILTER-TIP NO FILTER NO FILTER (4% as many cigarettes) as Group H Ficure 1.—Percent of lung sections with grade IV or V fibrosis. Sources: Hammond, et al. (104). Several investigative groups have exposed rodents to various ambient concentrations of nitrogen dioxide over prolonged periods of time. This gas is found in cigarette smoke and in some indus- trially polluted air. The results of these studies are outlined in table A10. It is clear that chronic exposure to low levels of NO, is capable of inducing lesions in the bronchial tree although the rela- tionship between these changes, cigarette smoking, and the devel- opment of COPD remains to be determined. Rosenkrantz, et al. (196, 197) have recently undertaken experi- ments dealing with pulmonary cellular metabolism. They exposed Swiss albino mice to cigarette smoke or its vapor phase for varying lengths of time. On autopsy, animals exposed to cigarette smoke showed elevations in the levels of lung DNA, lactate, and glycogen which the authors conclude reflect hyperplasia and macrophage infiltration. Similarly, a dose-related increase in lung hydroxypro- line was observed. This was considered to be due to increased fi- broblastic collagen synthesis. 100 98.8 60F 40 PERCENT OF LUNG SECTIONS 24.3 GROUP N: GROUP F: GROUP L: GROUP H: NONSMOKING FILTER-TIP NO FILTER NO FILTER (A as many cigarettes) as Group H FIGURE 2.—Percent of lung sections with grade II or III emphysema. Sources Hammond, et al. (104). Aviado and coworkers have performed a series of experiments on live animals and in heart-lung preparations to study the effect of cigarette smoke on pulmonary physiology and structure (18, 19, 20, 21, 22, 179, 180, 199, 200, 201, 202). The authors observed that cigarette smoke causes acute bronchoconstriction both by the re- lease of histamine and the stimulation of parasympathetic nerve pathways in the lung. Bronchial arterial injections of nicotine were found to cause reactions similar to those observed after cigarette smoke inhalation. The bronchoconstriction was usually followed by bronchodilatation which the authors attributed to sympathetic stimulation. As mentioned in the Chapter on Cardiovascular Dis- eases, nicotine has been shown to induce the release of catechola- mines. Experiments by Aviado and coworkers as well as other authors (66, 99) using guinea pigs showed that exposure to cigarette smoke was associated with increased bronchopulmonary resistance and decreased pulmonary compliance. The authors related these changes to the bronchoconstriction of terminal ventilatory units. 162 Similar experiments in dogs showed that the increase in resistance following either cigarette smoke exposure or intravenous nicotine could be blocked by pretreatment with atropine. As a parasympa- thetic blocker, atropine would decrease the acute bronchoconstric- tive phase. Most recently, Aviado and his colleagues (20, 130) have at- tempted to induce physiologic and anatomic changes similar to those found in the lungs of patients with emphysema. They ex- posed male rats to cigarette smoke, the introduction of the enzyme papain, as well as to partial tracheal ligation. In 10 rats exposed to cigarette smoke twice daily for 30 minutes over a period of 10 weeks, no changes in pulmonary compliance or resistance were noted, Also, no abnormal histological changes were observed in the group exposed only to cigarette smoke. However, animals who underwent tracheal ligation as well as smoke exposure showed in- creased numbers of enlarged air spaces and increased pulmonary resistance when compared with animals who underwent only tracheal ligation. STUDIES IN HUMANS The acute effects of cigarette smoke inhalation on bronchopul- monary function in man have been investigated by a number of workers. The results of these studies are presented in table 11. The majority of studies, particularly the more recent ones, found that the inhalation of cigarette smoke is associated with an acute in- crease in pulmonary resistance and a decrease in pulmonary com- plianee. Chapman (48) also observed decreases in pulmonary dif- fusing capacity and arterial O. tension. Chiang and Wang (51) noted changes in nitrogen washout time and alveolar dilution fac- tor, alterations which reflect impaired alveolar ventilation and gas mixing. James (131) examined the effect of prior smoking on the mul- tiple breath nitrogen washout test in 41 pneumoconiotic miners and 5 normal young males. Prior smoking of a cigarette in the subject’s normal manner was found to adversely affect the indices of dis- tribution in 20 percent of the miners and in all of the 5 normals who smoked within one hour of testing. The author suggests that smoking be prohibited prior to any series of pulmonary function studies. Anderson and Williams (9) studied the acute effect of cigarette smoke inhalation upon the ventilation-perfusion (V/Q) measure- ments in the lung in normals and in patients with COPD. Cigarette smoking was observed to cause acute changes in the V/Q measure- ments, and the COPD patients were found to be particularly liable to these changes. 163 Finally, Robertson, et al. (194) studied the effect of unfiltered © and filtered cigarette smoke and cigar smoke upon bronchial] re- activity in 19 of the most reactive persons in a group of 91 heavy smokers. They observed that bronchial reactivity was significantly reduced by increasing che retention efficiency of the filter and that reactivity to inhaled cigar tobacco was no less than that to cigarette smoke. They concluded that differences in inhalation account for the difference in COPD prevalence observed between cigarette and cigar smokers, STUDIES CONCERNING PULMONARY CLEARANCE Overall Clearance The ability of the lung to rid itself of inhaled particles that can- not be easily exhaled is dependent upon a number of physiologic mechanisms including ciliary activity, the mucous sheath, and the pulmonary alveolar macrophage. Studies concerning the effect of human cigarette smoking and the exposure of animals to cigarette smoke on this clearance system are presented in table A13. LaBelle, et al. (145) and Bair and Dilley (23) observed no change in clear- ance following the exposure of rats, rabbits, or dogs to cigarette smoke. The latter authors noted, however, that normal clearance rates obtained prior to smoking were too low to reflect any sig- nificant change except complete cessation. Albert, et al. (2) exposed donkeys to cigarette smoke via nasal catheter and observed impairment of clearance times. Holma (125) obtained similar results in rabbits. In a related study, Albert, et al. (2) studied the bronchial clear- ance times of 9 nonsmokers and 14 cigarette smokers in a total pop- ulation of 36 subjects. The rates of bronchial clearance were slower on the average in the cigarette smokers when compared with the nonsmokers, although a wide variation was present in each group. In relation to their study mentioned above, they also noted that the shape of the whole lung clearance curves seen in smokers (with markedly prolonged 50 percent clearance times) was similar to that developed in the donkey following acute exposures to sulfur dioxide or cigarette smoke. ~ Ciliary Function Numerous experiments have shown that cigarette smoke or cer- tain constituents of cigarette smoke adversely affect and can even bring about a cessation of ciliary activity in respiratory epithelium in vivo and in vitro in cultures of ciliated microorganisms. The re- sults of a number of these experiments are presented in table 12. 164 Ciliary activity has been shown to be affected by particulate matter as well as by the gas phase components of cigarette smoke. The rel- ative importance of these two large classes of components of smoke in producing ciliastasis is presently a matter of some discussion. Dalhamn and Rylander (63, 64) consider the particulate phase to be of greater importance while Battista and Kensler (28, 29) con- clude that gas phase components are more important in the induc- tion of ciliastasis. Studies investigating the effect of cigarette smoke on the morphology of the tracheobronchial tree in animals have noted a decrease or absence in the number of cilia in smoke-exposed ani- mals. Recently, Kennedy and Elliot (734) studied the effect of the direct exposure of cigarette smoke upon the electron microscopic structure of protozoan mitochondria. After 42 minutes of exposure to mainstream smoke, they noted destruction of the internal mem- brane structure of the mitochondria. Thus, cigarette smoke has been shown to be toxic to ciliary func- tion by pathological (including electron microscopic) and physio- logical methods. , Phagocytosis The effect of cigarette smoke upon pulmonary alveolar phago- cytosis, one part of the clearance mechanism, has been studied by several authors. Masin and Masin (162) observed increased varia- tion in the size of lipid inclusions in sputum macrophages obtained from smokers as compared to those obtained from nonsmokers. They attributed these differences to a combined effect of irritation of the alveolar lining, increased turnover of alveolar cells, and in- creased injury to the macrophages. Green and Carolin (96) noted that cigarette smoke inhibited the ability of rabbit alveolar macro- phages to clear cultures of S. aureus. This effect was noticeably reduced by filtration. Similarly, Yeager (239) exposed rabbit alveolar macrophages which had been induced by M. bovis to cigar- ette smoke and observed a dose-dependent decrease in protein syn- thesis. This alteration occurred at smoke solution concentrations that did not affect cell viability. The alteration was only partly re- versible and was due mainly to gas phase components, Myrvik and Evans (175) observed similar protein synthesis alterations in macrophages exposed to NO. Roque and Pickren (195) obtained alveolar macrophages at thoracotomy from 17 smokers and 4 nonsmokers, They found a decrease in the activity of oxidoreductases and hydrolases in the macrophages of smokers. The reduction in the enzymatic activity was directly proportional to the amount of stored fluorescent ma- terial present in the macrophages. This material was thought to 165 99L TABLE 11.—Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function A. Method ? B. Material 1 C. Duration of smoking Results Comments A. Pulmonary function. B. 3 cigarettes. C. 30 minutes, Vital capacity (VC) T. 10/91 decrease. I. No significant change. Maximal breathing capacity 9/91 patients showed 10/91 decrease. VC increase due to No significant change. clearance of secre- tions, All mild or moderate smokers. Author, year, Number and country, type of reference population Bickerman I. 66 male and and 25 female Barach, patients 1954, with chronic U.S.A. nontuberculous (81). respiratory diseases (average age 50). II. 20 male and 7 female normal sub- jects (average age 20). Eich, I. 31 patients with et al., obstructive 1957, pulinonary U.S.A, emphysema. (76). Il. 14 normal subjects, IIL. 5 patients with respiratory complaints. All habitual smokers. A. Esophageal balloon technique to measure pulmonary compliance and resistance. B. 1 cigarette. C. Undefined. Mean airway resistance I. Statistically significant increase. II. No change. Ill. No change, Mean airway compliance No change. No change. No change, 291 TABLE 11.—Experiments concerning the acute effect of cigarctte smoke inhalation on human pulmonary function (cont.) Author, A. Method 2 year, Number and B. Material * country, type of C, Duration of Results Comments reference population smoking Attinger [. 20 normal A. Esophagal balloon I. No change. No change. etal. subjects technique to measure 1958, (10 Sm, pulmonary compliance U.S.A. 10 NS). and resistance. (18). II. 34 patients with B. 1-4 cigarettes. Ii, Expiratory resistance rose No change. various diseases; C. 10 minute interval significantly only among 9 rheumatic heart between patients with diseases, 8 pul- cigarettes. emphysema. monary emphy- sema, 7 asthma, 5 pulmonary fibrosis, 5 undefined. Motley and 125 males and A. Pulmonary 41 smokers Pulmonary compliance Various groups of Kuzman, 16 females function. (8 normals, normals and cardio- 1958, (24-70 years of B. 2 cigarettes. 33 patients Significant decrease after pulmonary patients U.S.A. age—normals C. Undefined. with cardio- smoking. showed little or no (174). and patients). pulmonary change in arterial disease). pd, during exercise and at rest follow- ing cigarette smoke inhalation. Nade}l and I. 22 patients with A. Body plethy- Airway conductance/thoracie gas volume Nicotine bitartrate Comroe, cardiopulmonary smography. I. 18/22 significant decrease (inhibited by pretreatment aerosol evoked no 1961, disease—all B. 15 puffs. with isoproterenol aerosol), change. U.S.A. smokers. C. 5 minutes. Il. 31/36 significant decrease (inhibited by pretreatment with (176). II, 36 normals (21 isoprotereno] aerosol). smokers, 15 nonsmokers). 89k TABLE 11.—Eaperiments concerning the acute effect of cigaretie smoke inhalation on human pulmonary function (cont.) Author, A. Method 1 year, Number and B. Material? country, type of C, Duration of Results Comments reference population smoking Simonssgon, I. 9 male and 7 A. Pulmonary Mean PEV,, Mean FEV, 4 No significant changes 1962, female normals function. (immediately after) (45 minutes later) observed in FEV/FVC. Sweden, (most smokers). B,. 1-2 cigarettes. I. Significant decrease. No significant decrease. (207), IT. 15 male and 1 C. 5-6 minutes II. Significant decrease. Significant decrease. female pulmonary per cigarette. disease patients (most smokers). Zamel I. 6 male and 6 A. Body plethy- Airway resistance et al., female nonsmokers. smography. I. Significant increase. 1963, II. 6 male and 6 B. 1 cigarette. II. Significant increase, England, female smokers C. Undefined. (240). (18-32 years of age.) Chapman, I, 12 normal A. Pulmonary funetion I. All showed a decrease in diffusing capacity. 1965, volunteers Arterial blood II. 4/6—significant decrease in arterial 04 tension. Treland (all smokers). studies. No change in vital capacity or FEV. (48). II. 6 patients with B. 1 cigarette. chronic non- C. Undefined. specific lung disease. McDermott I, 32 normals. A. Body plethy- Mean airway resistance Light smokers showed and II. 28 with chronic smography, I, Significant increase, greater changes than Collins, bronchitis B. Cigarette. IL. Significant inerease. heavy smokers. 1965, (All ciga- C. Undefined. Wales rette smokers (160), 35-60 years of age.) 691 TABLE 11.—Ewperiments concerning the acute effect of cigarctte smoke inhalation on human pulmonary funetion (cont.) Author, A. Method! year, Number and B. Material + country, type of C, Duration of Results Comments reference population smoking Miller and 10 normal A. Esophageal balloon Dynamic Inapiratory and Sproule, cigarette technique. FEV 4.5 compliance expiratory resistance 1966, smokers B. 1 cigarette. No significant Significant Significant ULS.A. (40 years C. One inhalation change decrease. increase (166). of age). every 30-60 seconds. Sterling, 11 normal] adults A. Body plethy- Airway resistance 1967, (8 smokers, smography. Significant increase (Return England 3 nonsmokers). B. 15 inhalations. to normal in 30 minutes) . (213). Cc. 5 minutes. Chiang and 7 male normal A. Pulmonary function Nitrogen washout Lung clearance Alveolar dilution All lung volumes, Wang, nonsmokers Nitrogen washout. time index factor except for residual 1970, (18-43 years B. 2 cigarettes. Significant Significant Significant volume showed no Formosa of age). C. Undefined. increase. increase. decrease. significant change. (51). No significant change in any of the flow rates. Guyatt 710 subjects; A. Body plethy- Bronchoconstriction On the average, non- et al., 508 smoked smography. Significant increase with smoking. smokers and ex-smokers 1970, between meas- B. 1 cigarette. showed bronchodilation England ures 202 C. Undefined. and smokers showed (100). did not smoke. bronchoconstriction. 1 All the experiments listed concern studies of pulmonary function be- fore and after smoking the epecified number of cigarettes (unless other- wise specified). The authors postulate that the result among nonsmokers is due to the release of adrenal hormones in these sub- jects. ozt TABLE 12.—Eaperiments concerning the effect of cigarette smoke on human and animal pulmonary clearance Author, year, country, Subjects Method Results Comments reference Laurenzi Swiss-Webster Mice exposed to Significant increase in S. aureus retention in mice exposed to: etal, male mice. aerosol of S. aureus (a) hypoxia—retention ratio 2.5 (10 percent 0,4). 1963, and sacrificed at (b) cigarette smoke—retention ratio 4.5. U.S.A. intervals following (149). exposure to various stimuli. LaBelle Albino female Silver iodide or 17-30 hours of exposure to cigarette smoke caused no change in pulmonary etal, rabbits. colloidal gold clearance as compared with controls breathing room air. 1966, intratracheally, U.S.A. (145). Bair and Sprague-Dawley Radivactive aerosol. Acute exposure to cigarette smoke had no gross effect on clearance. Chronic Dilley, female rats, exposure to cigarette smoke (up to 18-20 cigarettes/7 hour day/5 day week 1967, male beagle dogs. Radioactive aerosol. for up to 420 days) had no observable effects. The authors noted, however, U.S.A, that normal clearance rates were too low to reflect anything but complete (28). cessation. 50 percent 90 percent ¢ Approximate values. clearance clearance None of 9 nonsmokers Albert 36 subjects Radioactive tagged Number of — Average time time had 50 percent times etal., undergoing 117 Fe0, particles subjects age (minutes) (minutes) over 200 minutes or 1969, experiments. measured with Nonsmokers ................ 9 28 88 357 90 percent times over U.S.A. Scintillation Allsmokers ...............,. 14 33 172 496 600 minutes while (2). counter. 20-29 cigarettes/day ......... 7 29 191 T6519 6/14 smokers exceeded 30-40 cigarettes/day 7 386 153 474 both these limits. Uranium miners ............. 3 52 310 580 Cigar and pipe smokers ..... 4 46 87 375 Emphysema patients ......... 2 66 330 575 LZL TABLE 12.—Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance (cont.) Author, year, country, Subjects Method Results Comments reference Albert Donkeys exposed Radioactive tagged Average Trachael transit Those donkeys exposed et al., to cigarette Fe0, particles number time to the greatest 1969, smoke by nasal measured with cigarettes in Percent clearance Halftime clearance amount of smoke U.S.A. catheter. Scintillation 2-hour period Control Cigarette Control Cigarette Control Cigarette showed residual (3). counter. 18-24 58 69 1.2 1.9 0.6 1.2 impairment of 36 58 64 1.0 3.4 0.4 5.8 clearance for at least 2 months after acute exposure. Holma, Rabbits Cr*t monodisperse Exposure to fresh cigarette smoke (1.5 cc. puffs, 40 puffs/8 minutes) caused 1969, (anesthetized). polystyrene a “significant” increase in lung retention 10 minutes following cessation of U.S.A. aerosol. exposure. (125). originate in tobaceo smoke. The authors suggested that the tobaeeo smoke may have induced abnormalities in the mitochondria of the macrophage. In a study of pulmonary macrophages harvested by endobronchial lavage from smokers and nonsmokers, Pratt, et aj, (187) observed that the macrophages of smokers contained an ab- normal pigment. These studies indicate that the function of pulmonary clearance carried on by the macrophage and ciliary systems is adversely af. fected by cigarette smoke. STUDIES CONCERNING THE SURFACTANT SYSTEM The surfactant system of the lung consists of various biologically active compounds such as phospholipids and mucopolysaccharides which are present in the alveolar lining. Norma] pulmonary fune- tion is influenced and partly determined by the integrity of this system (203). The purpose of the surfactant system is to main- tain the proper amount of surface tension in the alveoli so that the expansion and contraction of the alveoli are facilitated, Studies concerning the effect of cigarette smoke upon the sur- factant system and the surface tension of the pulmonary alveoli are presented in table Al4. Exposure of rat and dog lung extracts to cigarette smoke has been found to induce a notable decrease in the maxima] surface tension demonstrated by the extracts (94, 165, 224). Cook and Webb (57) observed that surfactant activity was diminished in smokers and in patients with pulmonary disease when compared with healthy nonsmokers. Scarpelli (203) in a recent review, concluded that the lowering of maximal surface tension by cigarette smoke has been demon- strated reasonably well. The relationship of these findings to the pathogenesis of emphysema is unclear at this time. OTHER RESPIRATORY DISORDERS INFECTIOUS RESPIRATORY DISEASES Several studies have examined the question of whether ciga- rette smokers are at an increased risk of developing infectious res- piratory and bronchopulmonary disease. Table A15 presents a summary of these studies. Lowe (157) observed an excess of smokers among 705 tuberculosis patients, but Brown and Campbell (43) in a similar study found that the difference was not present when the cases and controls were matched for alcohol intake. More recent studies have been concerned with the frequency of upper respiratory infections among groups of smokers and nonsmokers. A number of investigators (108, 181, 183) have reported increased 172 sates of respiratory illnesses among smokers. Finklea, et al. (838) studied a male college population (prospectively) during the 1968-69 influenza epidemic. They found that smokers of all amounts xxperienced more clinical illness than did nonsmokers and that this -elation was dose-dependent. Similarly, smokers required more bed rest than nonsmokers. A survey conducted by the National Center for Health Statistics (220), involving approximately 134,000 persons, showed that male cigarette smokers reported 54 percent more cases of acute bron- chitis than males who had never smoked cigarettes, while female smokers reported 74 percent more acute bronchitis than did females who had never smoked. Male cigarette smokers reported 22 percent more eases of influenza than did males who had never smoked cigar- ettes, while the female smokers reported an excess of 9 percent. Experimental evidence in support of this relationship has been noted by Spurgash, et al. (211). Mice were challenged with Klebsiella pneumoniae or Diplococcus pneumoniae before or after a single exposure to cigarette smoke. They observed that those ani- mals exposed to smoke exhibited a decrease in resistance to respira- tory infection, as shown by an increase in mortality and a decrease in survival time. Preexposure to cigarette smoke was found to have no significant effect on resistance of mice to influenza infection initiated by aerosol exposure. However, exposure of infected mice to smoke resulted in significantly higher mortality, thus suggest- ing that cigarette smoke can aggravate an existing respiratory viral infection. In the light of the experimental evidence presented above con- cerning the effect of cigarette smoke on pulmonary clearance, phagocytosis, and ciliary function, it seems reasonable to conclude that such changes in tracheobronchial physiologic function would predispose a person to respiratory infections or aggravate already existing ones. Further evidence is derived from the work of Henry, et al. (109) and Ehrlich, et al. (75). These investigators exposed squirrel monkeys to atmospheres containing 10 and 5 p.p.m. of nitrogen dioxide. They observed that this exposure increased the suscepti- bility of the animals to airborne Klebsiella pneumoniae as demon- strated by increased mortality and reduced lung clearance of viable bacteria. Infectious challenge with influenza virus 24 hours before exposure to 10 p.p.m. was fatal to all monkeys within three days. Infected controls showed symptoms of viral infection but did not succumb to the infection. The extent to which the various oxides of nitrogen present in cigarette smoke contribute to the increased sus- ceptibility to respiratory disease noted in smokers is presently undefined. 173 POSTOPERATIVE COMPLICATIONS Several studies have been published which examine the questions of whether smokers run an increased risk of developing postopera. tive pulmonary complications over nonsmokers undergoing similar operations. Morton (173) reported on a study of more than 1,100 patients undergoing abdominal operations in which he found that cigarette and mixed smokers were significantly more likely to develop bron. chitis, bronchopneumonia, or atelectasis during the postoperative period than nonsmokers (table A16). Wiklander and Norlin (229) examined the incidence of post. operative complications in 200 patients undergoing laparotomy in the winter months when it was expected that pulmonary compli. cations would be at their maximum. These authors found no sig- nificant differences between the frequency of complications jn smokers and nonsmokers. No information about the definition of a smoker and no data on dosage of tobacco smoke were reported, Piper (186) observed the prevalence of postoperative pulmonary complications in 150 patients undergoing laparotomy. Of the total] sample, 66.7 percent developed pulmonary complications during the first postoperative week, All patients considered in the statis- tical analysis as having pulmonary complications had radiographic evidence of disease. Of the cigarette smokers, 73.5 percent had complications as compared to 55.5 percent of the nonsmokers, When the smokers were divided according to dosage, heavy smok- ers being those consuming more than 10 cigarettes per day for the previous six months, 55 percent of light smokers and 88 percent of heavy smokers were considered to have postoperative compli- cations. Piper also reported that stopping smoking for up to four days preoperatively had no apparent effect on the incidence of complications, Wightman (228) reported on the incidence of postoperative pul- monary complications in 455 patients undergoing abdominal oper- ations and in 330 patients undergoing other operations. Of the cigarette smokers, 14.8 percent developed complications as com- pared to 6.3 percent of the nonsmokers. The substantial difference between these figures and those of Piper (186) is due to the latter’s use of radiographic criteria alone. Wightman utilized only clinical criteria. Morton (172) has recently reported a study of postoperative hypoxemia in 10 patients, 5 of whom were cigarette smokers, Four of the smokers had chronic bronchitis. He found that the smokers had a more pronounced decrease in arterial oxygen saturation, per- sisting into the second postoperative day (table A17). 174 In summary, the majority of studies so far reported indicate that cigarette smokers run a higher risk of developing postopera- tive pulmonary complications than do nonsmokers, corroborating a long-held clinical impression. The risk of developing such com- plications appears to increase with increasing dosage of cigarette smoke. SUMMARY AND CONCLUSIONS 1. Cigarette smoking is the most important cause of chronic ob- structive bronchopulmonary disease in the United States. Ciga- rette smoking increases the risk of dying from pulmonary emphy- sema and chronic bronchitis. Cigarette smokers show an increased prevalence of respiratory symptoms, including cough, sputum pro- duction, and breathlessness, when compared with nonsmokers. Ventilatory function is decreased in smokers when compared with nonsmokers. 2. Cigarette smoking does not appear to be related to death from bronchial asthma although it may increase the frequency and se- verity of asthmatic attacks in patients already suffering from this disease. 3. The risk of developing or dying from COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers while clearly less than that among cigarette smokers. 4. Ex-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function and with a decrease in pulmonary symptom prevalence. 5. Young, relatively asymptomatic, cigarette smokers show measurably altered ventilatory function when compared with non- smokers of the same age. 6. For the bulk of the population of the United States, the im- portance of cigarette smoking as a cause of COPD is much greater than that of atmospheric pollution or occupational exposure. How- ever, exposure to excessive atmospheric pollution or dusty occupa- tional materials, and cigarette smoking may act jointly to produce greater COPD morbidity and mortality. 7. The results of experiments in both animals and humans have demonstrated that the inhalation of cigarette smoke is associated with acute and chronic changes in ventilatory function and pul- monary histology. Cigarette smoking has been shown to alter the mechanism of pulmonary clearance and adversely affect ciliary function. 8. Pathological studies have shown that cigarette smokers who die of diseases other than COPD have histologic changes charac- 75 teristic of COPD in the bronchial tree and pulmonary parenchyma more frequently than do nonsmokers. 9. Respiratory infections are more prevalent and severe among cigarette smokers, particularly heavy smokers, than among nonsmokers, 10. Cigarette smokers appear to develop postoperative pulmo- nary complications more frequently than nonsmokers. CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE REFERENCES (1) ABpoTT, 0. A., Hopkins, W. A., VAN FLeit, W. E., RoBINson, J. §. A new approach to pulmonary emphysema, Thorax 8: 116-132, 1953, (2) ALBERT, R. E., LIPPMANN, M., BRISCOE, W. The characteristics of bron- chial clearance in humans and the effects of cigarette smoking, Archives of Environmental Health 18(5): 738-755, May 1969. (3) ALBERT, R. E,, SPIEGELMAN, J. R., SHATSKY, S., LIPPMANN, M. The effect of acute exposure to cigarette smoke on bronchial clearance in the miniature donkey. Archives of Environmental Health 18(1): 30-41, January 1969. (4) ANDERSON, A. E., JR, FURLANETO, J. A.. FOoRAKER, A. G. Bronchopul- monary derangements in nonsmokers. American Review of Respira- tory Diseases 101(4): 518-527, April 1970, (5) ANDERSON, A. E., JR., HERNANDEZ, J. A., ECKERT, P., FoRAKER, A. G. Emphysema in lung macrosections correlated with smoking habits, Science 144 (3621) : 1025-1026, May 22, 1964, (6) ANDERSON, A. E., JR., HERNANDEZ, J. A., HoLMEs, W. L., FoRAKER, A. G. Pulmonary emphysema. Prevalence, severity, and anatomical patterns in macrosections, with respect to smoking habits. Archives of Environ- mental Health 12(5) : 569-577, May 1966. (7) ANDERSON, D. O. Observations on the classification and distribution of pulmonary emphysema in Canada. Canadian Medical Association Journal 89: 709-716, October 5, 1963. (8) ANDERSON, D. O., Ferris, B. G., JR., ZICKMANTEL, R. The Chilliwack Respiratory Survey, 1963. Part IV. The effect of tobacco smoking on the prevalence of respiratory disease. Canadian Medical Association Journal 92(20) : 1066-1076, May 15, 1965. (9) ANDERSON, W. H., WitiraMs, J. B. Effects of cigarette smoke on dis- tribution of pulmonary perfusion. In: Current Research in Chronic Respiratory Diseases. Proceedings of the 11th Aspen Emphysema Conference, Aspen, Colo. U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1879, 1969. pp. 75-79. (10) ANTHONISEN, N. R,, Bass, H., ORIOL, A., Pace, R. E. G., Batgs, D. V. Regional lung function in patients with chronic bronchitis. Clinical Science 35: 495-511, December 1968. (11) AsHForD, J. R., Brown, S., DUFFIELD, D. P., Smiry, C.S., Fay, J. W. J. The relation between smoking habits and physique, respiratory symp- toms, ventilatory function, and radiological pneumoconiosis amongst coal workers at three Scottish collieries. British Journal of Preventive and Social Medicine 15: 106-117, 1961. 176 (12) (18) (14) (15) (16) (17) (18) (19) (20) (21) (22) (28) (24) ASHLEY, I), J. B. Environmental factors in the aetiology of lung cancer and bronchitis. British Journal of Preventive and Social Medicine 28 (4): 258-262, November 1969. ATTINGER, EX. O., GOLDSTEIN, M. M., SEGAL, M. S. Effects of smoking upon the mechanics of breathing. I. In normal subjects. American Review of Tuberculosis and Pulmonary Diseases 77(1): 1-16, January 1958. AUERBACH, O., HAMMOND, FE. C., GARFINKEL, L., Thickening of walls of arterioles and small arteries in relation to age and smoking habits. New England Journal of Medicine 278(18): 980-984, May 2, 1968. AUERBACH, O., HAMMOND, E. C., KIRMAN, D., GARFINKEL, L. Emphysema produced in dogs by cigarette smoking. Journal of the American Medical Association 199 (4) : 241-246, January 23, 1967. AUERBACH, O,, HAMMOND, E. C., KIRMAN, D., GARFINKEL, L. Emphysema produced in dogs by cigarette smoking. In: Hanna, M. G., Jr., Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 875-387. AUERBACH, O., Stout, A. P., HAMMOND, E. C., GARFINKEL, L. Smoking habits and age in relation to pulmonary changes. Rupture of alveolar septums, fibrosis and thickening of walls of small arteries and arterioles, New England Journal of Medicine 269(20): 1045-1054, November 14, 19638. Aviapo, D. M., Carritto, L. R. Hormones and pulmonary effects of tobacco. I. Corticosteroids and their antiasthmatic action. Archives of Environmental Health 18(6) : 925-933, June 1969. Aviabo, D. M., PALECEK, F. Pulmonary effects of tobacco and related substances. I. Pulmonary compliance and resistance in the anesthetized dog. Archives of Environmental Health 15(2) : 187-198, August 1967. Aviabo, D. M., SADAVONGVIVAD, C., CARRILLO, L. R. Cigarette smoke and pulmonary emphysema. Influence of bronchodilators and biogenic amines in experimental induction in rats. Archives of Environmental Health 20(4) : 483-487, April 1970. Aviabo, D. M., SAMANEK, M. Bronchopulmonary effects of tobacco and related substances. I. Bronchoconstriction and bronchodilatation: In- fluence of lung denervation. Archives of Environmental Health 11 (2): 141-151, August 1965. Aviabo, 1). M., SAMANEK, M., Foiie, L. E. Cardiopulmonary effects of tobacco and related substances. I. The release of histamine during inhalation of cigarette smoke and anoxemia in the heart-lung and intact dog preparation. Archives of Environmental Health 12(6): 705-724, June 1966. Bair, W. J., DILtey, J. V. Pulmonary clearance of *9FE,0, and °CR,O, in rats and dogs exposed to cigarette smoke. In: Davies, C. N. (Edi- tor). Inhaled Particles and Vapors. II. Proceedings of an International Symposium. Cambridge, September 28 to October 1, 1965, Oxford, Pergamon Press, 1967. pp. 251-271 BaLcHuUM, O. J., FELTON, J. S., JAMISON, J. N., GAINES, R. S., CLARKE, D. R., Owan, D., THe INDUSTRIAL HEALTH COMMITTEE, THE TUBERCU- LOSIS AND HEALTH ASSOCIATION OF Los ANGELES CouNTY. A Survey for chronic respiratory disease in an industrial city. Preliminary re- sults. American Review of Respiratory Diseases 86(5) :675-685, November 1962. 177 (25) (26) (27) (28) (29) (30) (31) (32) (33) (36) (37) (38) (39) (40) 178 BALLENGER, J. J. Experimental effect of cigarette smoke on human respiratory cilia. New England Journal of Medicine 263 (17): 832-835, October 27, 1960. BaLLENGER, J. J., Dawson, F. W., DERUYTER, M. G., Harding, H. B. Effects of nicotine on ciliary activity in vitro. Annals of Otology, Rhinology and Laryngology 74(2): 3808-311, June 1965. Bates, D. V., Gorpon, C. A., PAu, G. I., Pace, R. E. G., SNIDAL, D, P,, Wootr, C. R. Chronie bronchitis. Report on the third and fourth Stages of the coordinated study of chronic bronchitis in the Department of Veterans Affairs, Canada. Medical Services Journal, Canada 22(1): 1-59, January 1966. Battista, S. P., KENSLER, C. J. Use of the nonimmersed in vitro chicken tracheal preparation for the study of ciliary transport activity, Cigarette smoke and related components. Archives of Environmental Health 20(3) : 318-825, March 1970. Battista, S. P., KEnsLER, C. J. Mucus production and ciliary transport activity. In vivo studies using the chicken. Archives of Environmental} Health 20(3) : 826-338, March 1970. Best, E. W. R. A Canadian Study of Smoking and Health. Ottawa, Department of National Health and Welfare, 1966. 137 pp. BICKERMAN, H. A., Baracu, A. L. The effect of cigarette smoking on ventilatory function in patients with bronchial asthma and obstructive pulmonary emphysema. Journal of Laboratory and Clinical Medicine 43 (3) : 455-462, March 1954. Brair, W. H., Henry, M. C., EXRLICH, R. Chronic toxicity of nitrogen dioxide. IT. Effect on histopathology of lung tissue. Archives of En- vironmental Health 18(2) : 186-192, February 1969, Boake, W. C. A Study of illness in a group of Cleveland families. XVIIL Tobacco smoking and respiratory infections. New England Journal of Medicine 259 (26) : 1245-1249, December 25, 1958. BONNELL, J. A. Emphysema and proteinuria in men casting copper- cadmium alloys. British Journal of Industrial Medicine 12: 181-195, July 1955. BONNELL, J. A., KAZANTZIS, G., KING, E. A follow-up study of men ex- posed to cadmium oxide fume. British Journal of Industrial Medicine 16: 185-147, 1959. Boucot, K. R., Cooper, D. A., Welss, W. Smoking and the health of older men. I. Smoking and chronic cough. Archives of Environmental Health 4(1) : 59-72, January 1962. Bounvys, A. Perers, J. M. Control of environmental lung disease. New England Journal of Medicine 283 (11) : 573-582, September 10, 1970, Bouuuys, A., SCHILLING, R. S. F., VAN DE WOESTIJNE, K. P. Cigarette smoking, occupational dust exposure, and ventilatory capacity. Ar- chives of Environmental Health 19(6) : 793-797, December 1969. Bounvys, A., WoLrson, R. L., HORNER, D. W., BRAIN, J. D., ZUSKIN, E. Byssinosis in cotton textile workers. Respiratory survey of a mill with rapid labor turnover. Annals of Internal Medicine 71(2); 257-269, August 1969. Bousny, S. F., HELGASON, A. H., Biruie, D. M., Gyorky, F. G. Clinical physiologic, and morphologic examination of the lung in patients with bronchogenic carcinoma and the relation of the findings to postopera- tive deaths. American Review of Respiratory Diseases 101 (5): 685- 695, May 1970. (41) (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) (58) (54) (55) (56) (57) Bower, G. Respiratory symptoms and ventilatory function in 172 adults employed in a bank. American Review of Respiratory Diseases 83: 684-689, 1961. BRINKMAN, G. L., Coates, E. O., JR. The prevalence of chronic bronchitis in an industrial population. American Review of Respiratory Diseases 86: 47-54, 1962. Brown, K. E., CAMPBELL, A. H. Tobacco, alcohol and tuberculosis. British Journal of Diseases of the Chest 55(3): 150-158, 1961. CaRSON, S., GOLDHAMER, R., CARPENTER, R. Responses of ciliated epithelium to irritants. Mucus transport in the respiratory tract. American Review of Respiratory Diseases 93 (3, Part 2): 86-92, March 1966. CEDERLOF, R. Friperc, L., HRuBEcC, Z. Cardiovascular and respiratory symptoms in relation to tobacco smoking. Archives of Environmental Health 18(6) : 934-940, June 1969. CEDERLOF, R., FRIBERG, L., Jonsson, E., Kars, L. Respiratory symptoms and “angina pectoris” in twins with reference to smoking habits, An epidemiological study with mailed questionnaire. Archives of Environ- mental Health 13 (6) : 726-737, December 1966. CHANG, S. C. Microscopie properties of whole mounts and sections of human bronchial epithelium of smokers and nonsmokers. Cancer 10 (6) : 1246-1262, November—December 1957. CHAPMAN, T. T. The acute effect of cigarette smoking on pulmonary function. Journal of the Irish Medical Association 56 (333): 72-74, March 1965. CuesTEr, E. H., GIttesriz, D. G., Krause, F. D. The prevalence of chronic obstructive pulmonary disease in chlorine gas workers. Amer- ican Review of Respiratory Diseases 99(3) : 365-373, March 1969. CHEVALIER, R. B., KRUMHOLZ, R. A., Ross, J. C. Reaction of nonsmokers to carbon monoxide inhalation. Cardiopulmonary responses at rest and during exercise. Journal of the American Medical Association 198(10) : 1061-1064, December 5, 1966. CHIANG, S. T., WaNG., B. C. Acute effects of cigarette smoking on pul- monary function. American Review of Respiratory Diseases 101 (6): 860-868, June 1970. CHIvers, C. P. Respiratory function and disease among workers in alka- line dusts. British Journal of Industrial Medicine 16: 51-60, 1959. Coates, E. O., JR. Bowsr, G. C., REINSTEIN, N. Chronic respiratory disease in postal employees. Epidemiologic survey of a group em- ployed in one building. Journal of the American Medical Association 191(3) : 161-166, January 18, 1965. CouHEN, J. Chronic bronchitis and emphysema. Observations on trends and distribution according to death certificate data, Israel 1960 to 1964. Israel Journal of Medical Sciences 3(6): 885-889, November-— December 1967. COLLEGE OF GENERAL PRACTITIONERS. Chronic bronchitis in Great Brit- ain. A national survey carried out by the respiratory diseases study group of the College of General Practitioners. British Medical Journal 2: 973-979, October 14, 1961. ComroE, J. H., JR., Forster, R. E., II, DuBors, A. B., BRIscor, W. A., CARLSEN, E. The Lung. Clinical Physiology and Pulmonary Function Tests. Chicago, Year Book Medical Publishers, Inc., 1963. 390 pp. Coox, W. A., WEBB, W. R. Surfactant in chronic smokers. Annals of Thoracic Surgery 2(3) : 327-333, May 1966. 179 (58) (59) (60) (61) (62) (63) (64) (65) (66) (67) (68) (69) (70) (71) (72) (73) (74) (75) 180 Cootey, J. R. T., Ret, D. D. Urban and social origins of childhood bron- chitis in England and Wales. British Medical Journal 2(5708) : 213- 217, April 25, 1970. DALHAMN, T. The effect of cigarette smoke on ciliary activity in the upper respiratory tract. A.M.A. Archives of Otolaryngology 70: 166- 168, 1959. DaLuamn, T. Effect of cigarette smoke on ciliary activity. American Review of Respiratory Diseases 93(3) : 108-114, March 1966. DALHAMN, T., RYLANDER, R. Ciliastatic action of smoke from filter- tipped and non-tipped cigarettes. Nature 201(4917): 401-402, Janu- ary 25, 1964, DALHAMN, T., RYLANDER, R. Ciliastatic action of cigarette smoke. Vary- ing exposure times. Archives of Otolaryngology 81(4) : 379-382, April 1965. DALHAMN, T., RYLANDER, R. Tar content and ciliotoxicity of cigarette smoke. Acta Pharmacologica et Toxicologica 25(3) : 369-372, 1967. DaALHAMN, T., RYLANDER, R. Ciliotoxicity of cigarette smoke and its volatile components. American Review of Respiratory Diseases 98(3): 509-511, September 1968. DALHAMN, T., RYLANDER, R. Ciliotoxicity of cigar and cigarette smoke. Archives of Environmental Health 20(2): 252-253, February 1970. Davis, T. R. A., Battista, S. P., KENSLER, C. J. Mechanism of respira- tory effects during exposure of guinea pigs to irritants. Archives of Environmental Health 15(4) : 412-419, October 1967. DEANE, M., GoLpsmiITH, J. R., Tuma, D. Respiratory conditions in out- side workers. Report on outside plant telephone workers in San Fran- cisco and Los Angeles. Archives of Environmental Health 10(2): 323-831, February 1965. DENSEN, P. M., JONES, E. W., Bass, H. E., BReveR, J. A survey of respi- ratory disease among New York City postal and transit workers. 1. Prevalence of symptoms. Environmental Research 1: 262-286, 1967. DENSEN, P. M., Jones, E. W., Bass, H. E., Brevgr, J., REED, E. A survey of respiratory disease among New York City postal and transit work- ers. 2. Ventilatory function test results. Environmental Research 2(4): 277-296, July 1969. Dott, R., Hirt, A. B. Mortality in relation to smoking: Ten years’ observations of British doctors, (Part I) British Medical Journal 1(5395) : 1899-1410, May 30, 1964. Dori, R., Hur, A. B. Mortality in relation to smoking: Ten years’ observations of British doctors. (Concluded) British Medical Journal 1(5396) : 1460-1467, June 6, 1964. Dow ine, H. F., Jackson, G. G., INouyE. T. Transmission of the experi- mental common cold in volunteers. IT. The effect of certain host factors upon susceptibility. Journal of Laboratory and Clinical Medicine 50(4) : 516-525, October 1957. EDELMAN, N. H,. MITTMAN, C., Norris, A. H., Coen, B. H., SHock, N. W. The effects of cigarette smoking upon spirometric performance of community dwelling men. American Review of Respiratory Diseases 94(3) : 421-429, September 1966. Epwarps, F., McKEown, T., WHITFIELD, A. G. W. Association between smoking and disease in men over sixty. Lancet 1: 196-200, January 24, 1959. EHRLICH, R., HENRY, M. C., FENTERs, J. Influence of nitrogen dioxide on resistance to respiratory infections. In: Hanna, M. G., Jr., Nette- (76) (77) (78) (79) (80) (81) (82) (88) (84) (85) (86) (87) (88) (89) (90) (91) sheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Pro- ceedings of a Biology Division, Oak Ridge National Laboratory Con- ference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 248-257. E1cu, R. H., GILBERT, R., AUCHINCLOSS, J. H., Jr. The acute effects of smoking on the mechanics of respiration in chronic obstructive pul- monary emphysema. American Review of Tuberculosis 76: 22-32, 1957. Etwoop, P. C., PEMBERTON, J., MERRETT, J. D., Carey, G. C. R., Mcautay, I. R. Byssinosis and other respiratory symptoms in flax workers in Northern Ireland. British Journal of Industrial Medicine 22:27-387, 1965. ERIKsson, S. Studies in Alpha,-antitrypsin Deficiency. Acta Medica Scandinavica 177 (Supplementum 482): 1965. 85 pp. Fak, G. A., Briscoe, W. A. Chronic obstructive pulmonary disease and heterozygous alpha,-antitrypsin deficiency. Annals of Internal Medi- cine 72(4) : 595-596, April 1970. Fark, H. L., TREMER, H. M., Kotin, P. Effect of cigarette smoke and its constituents on ciliated mucus-secreting epithelium. Journal of the National Cancer Institute 23(5): 999-1012, November 1959. Ferris, B. G., JR., ANDERSON, D. O. The prevalence of chronic respiratory disease in a New Hampshire town. American Review of Respiratory Diseases 86(2): 165-177, August 1962. Ferris, B. G., JR., ANDERSON, D. O., Burcess, W. A. Prevalence of respiratory disease in a flax mill in the United States. British Journal -of Industrial Medicine 19: 180-185, 1962. FINKLzEA, J. F., SANDIFER, S. H., SMrrH, D. D. Cigarette smoking and epidemic influenza. American Journal of Epidemiology 90(5): 390— 399, November 1969. FLetTcuer, C. M., Horn, D. Smoking and health. WHO Chronicle 24(8) : 345-870, August 1970. FLETCHER, C. M., TINKER, C. M. Chronic bronchitis. A further study of simple diagnostic methods in a working population. British Medical Journal 1; 1491-1498, May 27, 1961. Frick, A. L., Paton, R. R. Obstructive emphysema in cigarette smokers. A.M.A. Archives of Internal Medicine 104: 518-526, 1959. FRANKLIN, W., LOWELL, F, C. Unrecognized airway obstruction associ- ated with smoking. A probable forerunner of obstructive pulmonary emphysema. Annals of Internal Medicine 54 (3) :379-386, March 1961. Frasca, J. M., AUERBACH, O., PARKS, V. R., JAMIESON, J. D. Electron microscopic observations of the bronchial epithelium of dogs. II. Smok- ing dogs. Experimental and Molecular Pathology 9(3) : 880-399. December 1968. FREEMAN, G., CRANE, S. C. STEPHENS, R. J., Furiosi, N. J. Pathogenesis of the nitrogen dioxide-induced lesion in the rat lung: A review and presentation of new observations. American Review of Respiratory Diseases 98(3) : 429-448, September 1968. FREEMAN, G., Haybon, G. B. Emphysema after low-level exposure to NO,. Archives of Environmental Health 8(1) : 125-128, January 1964. FREEMAN, G., STEPHENS, R. J., CRANE, S. C., Furiosi, N. J. Lesion of the lung in rats continuously exposed to two parts per million of nitrogen dioxide. Archives of Environmental Health 17(2): 181-192, August 1968. 181 (92) FREoUR, P., Coupray, P., ROUSSEL, A., SERISE, A. Les bronchites chronj. ques et l’insuffisance respiratorie dans Vagglomeration de Bordeaux. (Chronic bronchitis and respiratory insufficiency in Bordeaux). Journal de Medecine de Bordeaux 143 (2): 1865-1879, December 1966. (98) GANDEVIA, B. A productive cough upon request as an index of chronic bronchitis: The effects of age, sex, smoking habit, and environment upon prevalence in Australian general practice. Medical Journal of Australia 1(1): 16-20, January 4, 1969, (94) GIAMMoNa, S. T, Effects of cigarette smoke and plant smoke on pulmo. nary surfactant. American Review of Respiratory Diseases 96(8): 589-541, September 1967. (95) GoLpsmitTH, J. R., Hecuter, H. H., PERKINs, N. M, Borwani, N, 0. Pulmonary function and respiratory findings among longshoremen, American Review of Respiratory Diseases 86(6) 3867-874, Decembe;: 1962, (96) GREEN, G. M., Caroin, D. The depressant effect of cigarette smoke on the in vitro antibacterial activity of alveolar macrophages. New Eng- land Journal of Medicine 276 (8): 421-427, February 23, 1967, (97) GREENBERG, M., Ming, J. F., Wart, A. Survey of workers €xposed to dusts containing derivatives of Bacillus subtilis, British Medical Journal 2: 629-633, June 13, 1970. (98) GUENTER, C. A., WELCH, M. H., RUSSELL, T. R., Hybe, R. M., HAMMar- STEN, J. F. The pattern of lung disease associated with alpha-1 anti- trypsin deficiency. Archives of Internal Medicine 122(3) : 254-257, September 1968. (99) GUILLERM, R., SAINDELLE, A., Fatot, P., Hee, J. Action de la fumee de (100) Guyart, A. R., Berry, G., ALPERS, J. H., BRAMLEY, A. c., FLETCHER, Cc. M. Relationship of airway conductance and its immediate change on smoking to smoking habits and symptoms of chronic bronchitis. Amer- ican Review of Respiratory Diseases 101(1): 44-54, January 1970, (101) HAMMaRSTEN, J, F., WEtcH, M. H., RICHARDSON, R. H., PATTERSON, C. D., GUENTER, C. A. Familial alpha,-antitrypsin deficiency and pul- monary emphysema. Transactions of the American Clinical and Clima- tological Association 80(1): 7-14, 1968. (702) HammMonp, E. C. Evidence on the effects of giving up cigarette smoking, American Journal of Public Health and the Nation’s Health 55(5): 682-691, May 1965. (103) HAMMOND, E. C. Smoking in relation to the death rates of 1 million men and women. In: Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases, Bethesda, U.S. Public Health Service, National Cancer Institute Monograph No. 19, January 1966, pp. 127-204, (104) Hammonn, E. C., AUERBACH, O., KIRMaN, D., GARF'NKEL, L. Effects of cigarette smoking on dogs. I. Design of experiment, mortality, and findings in lung parenchyma. Archives of Environmental Health 21(6) : 740-753, December 1970. (105) Hammonp, E. C., Horn, D. Smoking and death rates—report on forty- four months of follow-up of 187,783 men. II. Death rates by cause. 182 (106) (107) (108) (109) (110) (111) (112) (113) (114) (115) (116) (117) (118) (119) Journal of the American Medical Association 166(11): 1294-1308, March 15, 1958. Haypon, G. B., Davipson, J. T., LILLINGTON, G. A., WASSERMAN, K. Nitrogen dioxide-induced emphysema in rabbits. American Review of Respiratory Diseases 95(5) : 797-805, May 1967. HAYDON, G. B., FREEMAN, G., Furtost, N. J. Covert pathogenesis of NO, induced emphysema in the rat. Archives of Environmental Health 11(6) : 776-783, December 1965. Haynes, W. F., JR., KrsTutovic, V.J., BELL, A. L. L., JR. Smoking habit and incidence of respiratory tract infections in a group of adolescent males. American Review of Respiratory Diseases 93(5): 130-735, May 1966. HENRY, M. C., FInDiay, J., SPANGLER, J., EHRLICH, R. Chronic toxicity of NO, in squirrel monkeys. III. Effect on resistance to bacterial and viral infection. Archives of Environmental Health 20(5): 566-570, May 1970. HEpPer, N. G., Hyatt, R. E., Fowrer, W. S. Detection of chronic obstructive lung disease. An evaluation of the medical history and physical examination. Archives of Environmental Health 19(6) : 806- 813, December 1969, HERNANDEZ, J. A., ANDERSON, A. E,, JR, HOLMES, W. L., Foraker, A. G. Pulmonary parenchymal defects in dogs following prolonged cigarette smoke exposure. American Review of Respiratory Diseases 93(1) : 78- 83, January 1966. Higgins, I. T. T. Respiratory symptoms, bronchitis and ventilatory capacity in random sample of an agricultural population. British Medical Journal 2: 1198-1208, November 23, 1957. Hiceins, I. T. T. Tobaeco smoking, respiratory symptoms, and ventila- tory capacity. Studies in random samples of the population, British Medical Journal 1: 325-329, February 7, 1959. Hicerns, I. T. T., Cocuran, J. B. Respiratory symptoms, bronchitis and disability in a random sample of an agricultural community in Dumfriesshire. Tubercle 39: 296-301, 1958. Hicerns, I. T. T., Cocurane, A. L. Chronic respiratory disease in a random sample of men and women in the Rhondda Fach in 1958. British Journal of Industrial Medicine 18: 93-102, 1961. Hicerns, I. T. T.. Cocorane, A. L., Gitson, J. C., Woop, C. H. Popula- tion studies of chronic respiratory disease. A comparison of miners, foundryworkers, and others in Staveley, Derbyshire. British Journal of Industrial Medicine 16: 255-268, 1959. Hicerns, I. T. T., Gitson, J. C., Ferris, B. G., JR., Waters, M. E., CAMPBELL, H., Hiccins, M. W. Chronic respiratory disease in an industrial town: A nine-year follow-up study. Preliminary report. American Journal of Public Health and the Nation’s Health 58 (9): 1667-1676, September 1968. Hicerns, I. T. T., Hiceins, M. W., Locksuin, M. D., CANALE, N. Chronic respiratory disease in mining communities in Marion County, West Virginia. British Journal of Industrial Medicine 25(3): 165-175, July 1968. Hiceins, I. T. T., OLpHaM, P. D., CocHrane, A. L., GiLson, J. C. Res- piratory symptoms and pulmonary disability in an industrial town. Survey of a random sample of the population. British Medical Journal 2: 904-909, October 20, 1956. 183 (120) (121) (122) (128) (124) (125) (126) (127) (128) (129) (130) (131) (132) (132) (134) (135) 184 HILDING, A. C. On cigarette smoking, bronchial carcinoma and ciliary action. IT. Experimental study on the filtering action of cow’s lungs, the deposition of tar in the bronchial tree and removal by ciliary action. New England Journal of Medicine 254 (25): 1155-1160, June 21, 1956. HOLLAND, W. W., ELLioTT, A. Cigarette smoking, respiratory symptoms and anti-smoking propaganda. An experiment. Lancet 1(7532) : 41-43, January 6, 1968. HOLLAND, W. W., Han, T., BENNETT, A. E., Eviorr, A. Indications for measures to be taken in childhood to prevent chronic respiratory disease. Milbank, Memorial Fund Quarterly 47 (3, part 2): 215-227, July 1969. HOoLuanp, R. H., KozLowski, E. J., Booker, L. The effect of cigarette smoke on the respiratory system of the rabbit. A final report. Cancer 16(5): 612-615, May 1963. HOLLAND, W. W., Rew, D. D. The urban factor in chronic bronchitis, Lancet 1(7383): 445-448, February 27, 1965. Homa, B. The acute effect of cigarette smoke on the initial course of lung clearance in rabbits. Archives of Environmental Health 18(2): 171-173, February 1969. Hunt, E. Prevalence of Respiratory Symptoms, Chronic Bronchitis and Pulmonary Emphysema in a Finnish Rural Population. Field survey of age group 40-64 in the Harjavalta area. Acta Tuberculosea et Pneumologica Scandinavica (Supplementum 61): 1965. 111 pp. Hurst, A. Familial emphysema. American Review of Respiratory Dis. eases 80: 179-180, 1959. Hyatt, R. E., Kistin, A. D., Manan, T. K. Respiratory disease in Southern West Virginia coal miners. American Review of Respiratory Diseases 89(3) : 387-401, March 1964. Ibr, G., SUNTZEFF, V., Cowpry, E. V. A comparison of the histopathology of tracheal and bronchial epithelium of smokers and nonsmokers. Cancer 12(3) : 473-484, May—June, 1959. Ito, H., Aviano, D. M. Pulmonary emphysema and cigarette smoke. Experimental induction and use of bronchodilators in rats. Archives of Environmental Health 16(6) : 865-870, June 1968, JAMES, R. H. Prior smoking as a determinant of the distribution of pulmonary ventilation. American Review of Respiratory Diseases 101(1): 105-107, January 1970. KAHN, H. A. The Dorn study of smoking and mortality among U.S. veterans: Report on 8% years of observation. In: Haenzel, W. (Edi- tor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S. Public Health Service, National Cancer Institute Monograph No. 19, January 1966, pp. 1-125, KAaMINSKI, E, J., FANCHER, O. E., CALANDRA, J. C. In vivo studies of the ciliastatic effects of tobacco smoke, Absorption of ciliastatic compo- nents by wet surfaces. Archives of Environmental Health 16(2) : 188- 193, February 1968. KENNEDY, J. R., ELLiorT, A. M. Cigarette smoke: The effect of residue on mitochondrial structure. Science 168 (38935) : 1097-1098, May 29, 1970. KENSLER, C. J., Battista, S. P. Chemical and physical factors affecting mammalian ciliary activity. American Review of Respiratory Diseases 93(8, Part 2): 98-102, March 1966. (186) (187) (188) (139) (140) (141) (142) (143) (144) (145) (146) (147) (148) (149) (150) (151) (152) KLEINERMAN, J. Effects of NO, in hamsters: Autoradiographic and electron microscopic aspects. In: Hanna, M. G., Jr., Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlin- burg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 271-281. Korpik, P., BULBRING, E., BURN, J. H. Ciliary movement and acetyl- choline, British Journal of Pharmacology and Chemotherapy 7: 67-— 79, 1952. KRAHL, V. E., BULMASH, M. H. Studies on living ciliated epithelium. American Review of Respiratory Diseases 99(5) : 711-718, May 1969. Krucer, A. P., SMITH, R. F. Effects of gaseous ions on tracheal ciliary rate. Proceedings of the Society for Experimental Biology and Medi- cine 98: 412-414, 1958. KRUMHO1LZ, R. A., CHEVALIER, R. B., Ross, J. C. Cardiopulmonary func- tion in young smokers. A comparison of pulmonary function measure- ments and some cardiopulmonary responses to exercise between a group of young smokers and a comparable group of nonsmokers. Annals of Internal Medicine 60(4): 603-610, April 1964. KTUMHOLz, R. A., CHEVALIER, R. B., Ross, J. C. Changes in cardiopul- monary functions related to abstinence from smoking. Studies in young cigarette smokers at rest and exercise at 3 and 6 weeks of ab- stinence. Annals of Internal Medicine 62(2) :197~207, February 1965. KRUMHOLZ, R. A., CHEVALIER, R. B., Ross, J. C. A comparison of pul- monary compliance in young smokers and nonsmokers. American Review of Respiratory Diseases 92(1): 102-107, July 1965. KuEPPERS, F. Identification of the heterozygous state for the alpha,-anti- trypsin deficiency gene in man. Biochemical Genetics 3(3) : 283-288, 1969, KueEpPeERS, F., FALLAT, R., Larson, R. K. Obstructive lung disease and alpha,-antitrypsin deficiency gene heterozygosity. Science 165 (3896) : 899-901, August 29, 1969. LABELLE, C. W., BEvILAcQuA, D. M., BRIEGER, H. The influence of ciga- rette smoke on lung clearance. An experimental approach. Archives of Environmental Health 12(5): 588-596, May 1966. LAMBERT, P. M., Rem, D. D. Smoking, air pollution, and bronchitis in Britain. Lancet 1(7652) : 853-857, April 25, 1970. Larson, R. K., BARMAN, M. L. The familial occurrence of chronic ob- structive pulmonary disease. Annals of Internal Medicine 63(6): 1001-1008, December 1965. Larson, R. K., BARMAN, M. L., KUEPPERS, F., FUDENBERG, H. H. Genetic and environmental determinants of chronic obstructive pulmonary disease. Annals of Internal Medicine 72(5) : 627-632, May 1970. LAURENZI, G. A., GUARNERI, J. J., ENDRiGA, R. B., CAREY, J. P. Clear- ance of bacteria by the lower respiratory tract. Science 142: 1572— 1573, December 20, 1963. LEESE, W. L. B. An investigation into bronchitis. Lancet 2: 762-765, October 138, 1956. LEFCOE, N. M., Wonnacott, T. H. The prevalence of chronic respiratory disease in the male physicians of London, Ontario. Canadian Medical Association Journal 102(9): 381-385, February 28, 1970. LEUCHTENBERGER, C., LEUCHTENBERGER, R., ZEBRUN, W., SHAFFER, P. A correlated histological, cytological, and cytochemical study of the tracheobronchial tree and lungs of mice exposed to cigarette smoke. 185 (158) (154) (155) (156) (157) (158) (159) (160) (161) (162) (163) (164) (165) (166) (167) (168) 186 II. Varying responses of major bronchi to cigarette smoke, absence of bronchogenic carcinoma after prolonged exposure, and disappearance of bronchial lesions after cessation of exposure. Cancer 18(4) : 724_ 732, July-August 1960. Lewis, G. P., Lye, H., MILLER, S. Association between elevated hepatic water-soluble protein-bound cadmium levels and chronic bronchitis and/or emphysema. Lancet 2(7634) : 1830-1333, December 20, 1969. LIEBERMAN, J. Heterozygous and homozygous alpha, -antitrypsin defi- ciency in patients with pulmonary emphysema. New England Journal of Medicine 281 (6): 279-284, August 7, 1969. LIEBERMAN, J., Mitrman, C., SCHNEIDER, A. S. Sereening for homo- zygous and heterozygous alpha,-antitrypsin deficiency. Protein elec- trophoresis on cellulose acetate membranes. Journal of the American Medical Association 210 (11) : 2055-2060, December 15, 1969, LIEBESCHUETZ, H. J. Respiratory signs and symptoms in young soldiers and their relationship to smoking. Journal of the Royal Army Medical Corps 105: 76-81, 1959. Lowe, C. R. An association between smoking and respiratory tubercu- losis. British Medical Journal 2: 1081-1086, November 10, 1956. Lowe, C. R. Chronic bronchitis and occupation. Joint meeting No. 1. Section of Occupational Medicine with Section of Epidemiology and Preventive Medicine. Proceedings of the Royal Society of Medicine 61(1) : 98-102, January 1968. LUNDMAN, T. Smoking in Relation to Coronary Heart Disease and Lung Function in Twins, A Co-twin Study. Acta Medica Scandinavica 180 (Supplement 455) : 1966. 75 pp. McDermott, M., CoLiins, M. M. Acute effects of smoking on lung air- ways resistance in normal and bronchitic subjects. Thorax 20: 562- 569, 1965. Martt, J. M. Pulmonary diffusing capacity in cigarette smokers, An- nals of Internal Medicine 56(1): 89-45, January 1962. MasIN, F., MASIN, M. Frequencies of alveolar cells in concentrated sputum specimens related to cytologic classes. Acta Cytologica 10(5) : 362-367, September—-October 1966. MEGAHED, G. E., SENNA, G. A., Erssa, M. H., SALeu, S. Z., Essa, H. A. Smoking versus infection as the aetiology of bronchial mucous gland hypertrophy in chronic bronchitis. Thorax 22(8) : 271-278, May 1967. MENDENHALL, W. L., SHREEVE, K. E. The effect of cigarette smoke on the tracheal cilia. (Abstract) 28th Annual Meeting, April 21-24, 1937, Memphis, Tennessee. The Scientific Proceedings of the American So- ciety for Pharmacology and Experimental Therapeutics, Inc. Journal of Pharmacology and Experimental Therapeutics 60: 111-112, 1937. MILLER, D., BoNDURANT, 8. Effects of cigarette smoke on the surface characteristics of lung extracts. American Review of Respiratory Diseases 85(5) : 692-696, May 1962. MILieER, J. M., SPROULE, B. J. Acute effects of inhalation of cigarette smoke on mechanical properties of the lungs. American Review of Respiratory Diseases 94(5) : 721-726, November 1966. Mts, C. A. Tobacco smoking: Some hints of its biologic hazards. Ohio State Medical Journal 46(12): 1165-1170, December 1950. MITCHELL, R. S., Wess, N. C., Fittey, G. F. Chronic obstructive bron- chopulmonary disease. III. Factors influencing prognosis. American Review of Respiratory Diseases 89(6) : 878-896, June 1964. (169) (170) (171) (172) (173) (174) (175) (176) (177) (178) (179) (180) (181) (182) (183) (184) (185) MITCHELL, R. S., SILVERS, G. W., Dart, G. A., Petty, T. L., VINCENT, T. N., RYAN, S. F., Fitey, G. F. Clinical and morphologic correla- tions in chronic airway obstruction. American Review of Respiratory Diseases 97(1): 54-61, January 1968. MortyaMa, I. M., DawseEr, T. R., KANNEL, W. B. Evaluation of diag- nostic information supporting medical certification of deaths from cardiovascular disease. In: Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S. Public Health Service, National Cancer Institute Mon- ograph No. 19, January 1966. pp. 405-419. Mork, T. A Comparative Study of Respiratory Disease in England and Wales and Norway. Acta Medica Scandinavica 172 (Supplementum 384), 1962. 100 pp. Morton, A. Postoperative hypoxaemia. Medical Journal of Australia 2(7): 341-342, August 16, 1969. Morton, H. J. V. Tobacco smoking and pulmonary complications after operation. Lancet 1: 368-370, March 18, 1944. Mot ey, H. L., KuZMAN, W. J. Cigarette smoke. Its effect on pulmonary function measurements. California Medicine 88(3): 211-220, March 1958. Myrvik, Q. N., Evans, D. G. Metabolic and immunologic activities of alveolar macrophages. Archives of Environmental Health 14(1): 92- 96, January 1967. NADEL, J. A., CoMRok, J. H., JR. Acute effects of inhalation of cigarette smoke on airway conductance. Journal of Applied Physiology 16: 713- 716, 1961. NANDI, M., Jick, H., SLONE, D., SHAPIRO, 8., LEwis, G. P. Cadmium con- tent of cigarettes. Lancet 2(7634) : 1829-1330, December 20, 1969. OSWALD, N. C., MEDVEL, V. C. Chronic bronchitis; the effect of cigarette- smoking. Lancet 2: 843-844, October 22, 1955. Pacecek, F., Aviapo, D. M. Pulmonary effects of tobacco and related sub- stances. II. Comparative effects of cigarette smoke, nicotine, and his- tamine on the anesthetized cat. Archives of Environmental Health 15 (2): 194-208, August 1967. PaLeEceK, F., Oskoul, M., AviaDo, D. M. Pulmonary effects of tobacca and related substances. III. Inhibition of synthesis of histamine in various species. Archives of Environmental Health 15(2): 204-2138, August 1967. PaRNELL, J. L., ANDERSON, D. O., KINNIs, C. Cigarette smoking and respiratory infections in a class of student nurses. New England Journal of Medicine 274(8) : 979-984, May 5, 1966. Peters, J. M., Ferris, B. G., JR. Smoking, pulmonary functions and respiratory symptoms in a college-age group. American Review of Respiratory Diseases 95(5) : 774-782, May 1967. Peters, J. M., FERRIS, B. G., JR. Smoking and morbidity in a college-age group. American Review of Respiratory Diseases 95(5): 783-789, May 1967. PETERSON, D. I., LONERGAN, L. H., HARDINGE, M. G. Smoking and pul- monary function. Archives of Environmental Health 16(2): 215-218, February 1968. Puitiirs, A. M., PHILLIPS, R. W., THOMPSON, J. L. Chronic cough. Analysis of etiologic factors in a survey of 1,274 men. Annals of In- ternal Medicine 45(2) ; 216-231, August 1956. 187 (186) (187) (188) (189) (196) (191) (192) (193) (194) (195) (196) (197) (2068) Piper, D. W. Respiratory complications in the postoperative period, Scottish Medical Journal 3(5) : 193-198, May 1958. Pratt, S. A., FINLEY, T. N., Smiru, M. H., LapMan, A. J. A comparison of alveolar macrophages and pulmonary surfactant(?) obtained from the lungs of human smokers and nonsmokers by endobronchial lavage. Anatomical Record 163(4): 497-508, April 1969. RaKIETEN, N., RAKIETEN, M. L.., FELDMAN, D., BOYKIN, M. J., JR. Mam- malian ciliated respiratory epithelium. Studies with particular refer- ence to effects of menthol, nicotine, and smoke of mentholated and nonmentholated cigarettes. A.M.A. Archives of Otolaryngology 56: 494-508, 1942. RANKIN, J., GEE., J. B., CHosy, L. W. The influence of age and smoking on pulmonary diffusing capacity in healthy subjects. Medicina Thora- calis 22(3): 366-3874, 1965. RANKIN, J. G., HALE, G. S., WILKINSON, P., O’Day, D. M., SANTAMARIA, J.N., Baparczy, G. Relationship between smoking and pulmonary dis- ease in alcoholism. Medical Journal of Australia 1(14): 730-733, April 5, 1969 Reap, J., SELBy, T. Tobacco smoking and ventilatory function of the lungs. British Medical Journal 2: 1104-1108, October 28, 1961. REVOTSKIE, N., KANNEL, W., GoLDsMITH, J. R., Dawer, T. R. Pul- monary function in a community sample. American Review of Respi- ratory Diseases 86(6) : 907-911, December 1962. RIMINGTON, J. Chronic bronchitis, smoking and social class. A study among working people in the towns of Mid and East Cheshire. British Journal of Diseases of the Chest 63(4): 193-205, 1969. ROBERTSON, D. G., WARRELL, D. A., NEwToN-Howes, J. S., FLETCHER, C. M. Bronchial reactivity to cigarette and cigar smoke. British Med- ical Journal 3(5665) : 269-271, August 2, 1969. Rogue, A. L., PICKREN, J. W. Enzymatic changes in fluorescent alveolar macrophages of the lungs of cigarette smokers. Acta Cytologica 12 (6) : 420-429, November—December 1968. ROSENKRANTZ, H., Esper, H. J., Spracue, R. Lung hydroxyproline lev- els in mice exposed to cigarette smoke. Life Sciences 8(11, Part 1): 571-576, June 1, 1969. ROSENKRANTZ, H., SPRAGUE, R. Biochemical screen to investigate whole smoke and vapor phase effects in mice. Archives of Environmental Health 18(6): 917-924, June 1969. ves. J. C.. LEY, G. D., KRuMHoLz, R. A., RaHBaRI, H. A technique for evaiuation of gas mixing in the lung: Studies in cigarette smokers and nonsmokers. American Review of Respiratory Diseases 95(3): MS Aviabo, D, M. Bronchopulmonary effects of tobacco and sated substances. IT. Bronchial arterial injections of nicotine and ne. Archives of Environmental Health 11(2): 152-159, Au- reiated substances. IV. Bronchial vascular and bronchomotor re- sponses; their suggested defense function. Archives of Environmental et ~ 11(2): 167-176, August 1965. &, M., Avrapo, D. M. Cardiopulmonary effects of tobacco and x} substances. III. Pulmonary vascular effects of cigarette smoke catine, Archives of Environmental Health 12(6): 717-724, June (202) (203) (204) (205) (206) (207) (208) (209) (210) (211) (212) (213) (214) (275) (216) (217) (218) SAMANEK, M., Avrapo, D. M., PESKIN, G. W. Bronchopulmonary effects of tobacco and related substances. I1I. Axon reflexes elicited from the visceral pleura. Archives of Environmental Health 11(2): 160-166, August 1965. SCARPELLI, E. M. The Surfactant System of the Lung. Philadelphia, Lea & Febiger, 1968. 269 pp. SCHOETTLIN, C. E. The health effect of air pollution on elderly males. American Review of Respiratory Diseases 86(6): 878-897, December 1962. SHauH, J. R., WARAWADEKAR, M. S., DESHMUKH, P. A., PHUTANE, P. N. Institutional survey of pulmonary tuberculosis with special reference to smoking habits. Indian Journal of Medical Sciences 13(5): 381- 392, May 1959. SHort, J. J., JOHNSON, H. J., Ley, H. A., Jr. The effects of tobaceo smoking on health. A study of 2,081 medical records. Journal of Laboratory and Clinical Medicine 24: 586-589, 1939. SIMONSSON, B. Effect of cigarette smoking on the foreed expiratory flow rate. American Review of Respiratory Diseases 85: 584-539, 1962. SLUIS-CREMER, G. K., SICHEL, H. 8. Ventilatory functions in males in a Wit-watersrand town. Comparison between smokers and nonsmokers. American Review of Respiratory Diseases 98(2): 229-239, August 1968. SLUIS-CREMER, G. K., WALTERS, L. G., SICHEL, H. S. Chronic bronchitis in miners and nonminers: An epidemiological survey of a community in the gold-mining area in the Transvaal. British Journal of Indus- rial Medicine 24(1) : 1-12, January 1967. Situ, J. P., SmitH, J. C., McCarr, A. J. Chronie poisoning from ead- mium fume. Journal of Pathology and Bacteriology 80: 287-296, 1960. SpurGasuH, A., EHRLICH, R., PETZOLD, R. Effect of cigarette smoke on resistance to respiratory infection. Archives of Environmental Health 16(3) : 885-391, March 1968. STANESCU, D. C., TrecuLescu, D. B., Pacuraru, R., GavriLcescu, N. Chronic effect of smoking upon pulmonary distribution of ventilation in healthy males. Respiration 25(6) : 497-504, 1968. STERLING, G. M. Mechanism of bronchoconstriction caused by cigarette smoking. British Medical Journal 3: 275-277, July 29, 1967. STRIEDER, D. J., MurRpHY, R., Kazemi, H. Mechanism of postural hy- poxemia in asymptomatic smokers. American Review of Respiratory Diseases 99(5): 760-766, May 1969. TALAMO, R. C., ALLEN, J. D., KAHAN, M. G., AUSTEN, K. F. Hereditary alpha,-antitrypsin deficiency. New England Journal of Medicine 278 (7) : 845-3851, February 15, 1968. TaRKOFF, M. P., KUEPPERS, F., MILLER, W. F. Pulmonary emphysema and alpha,-antitrypsin deficiency. American Journal of Medicine 45 (2) : 220-228, August 1968. THURLBECK, W. M., HENDERSON, J. A., FRASER, R. G., Bates, 1). Chronic obstructive lung disease. A comparison between clin : genologic, functional and morphologic criteria in chronic bronc : emphysema, asthma and bronchiectasis. Medicine 49(2): 81-145, March 1970. ToKuHATA, G. K., DESSAUER, P., PENDERGRASS, E. P., HanrMan. T.. Dicon, E., MILcer, W. Pneumoconiosis among anthracite coa: ? in Pennsylvania. American Journal of Public Health and the Nation: Health 60(3): 441-451, March 1970. (219) (220) (221) (222) (228) (224) (225) (226) (227) (228) (229) (280) (281) (232) (238) (234) 190 U.S. Pusiic HEALTH SERVICE. The Health Consequences of Smoking. 1968 Supplement to the 1967 Public Health Review. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1696, 1968. 117 pp. U.S. PuBLic HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STATISTICS. Cigarette smoking and health characteristics, United States, July 1964—June 1965, Washington, U.S. Department of Health, Education, and Welfare, Vital and Health Statistics Series 10, No. 34, Public Health Service Publication No. 1000, May 1967. 64 pp. U.S. PUBLIC HEALTH SERVICE, NATIONAL CENTER FOR HEALTH STATISTICS. Vital Statistics of the United States—1967. Vol. II—Mortality, Part A. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication, 1969. U.S. PuBLic HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STATISTICS. Vital Statistics Rates in the United States 1940-1960. Washington, U.S. Department of Health, Education and Welfare, Public Health Service Publication No. 1677, 1968. 881 pp. U.S. PuBLic HEALTH SERVICE. Smoking and Health. Report of the Ad- visory Committee to the Surgeon General of the Public Health Serv- ice. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1103, 1964. 387 pp. Wess, W. R., Coox, W. A., LANius, J. W., SHaw, R. R. Cigarette smoke and surfactant. American Review of Respiratory Diseases 95(2): 244-247, February 1967. Weir, J. M., Dunn, J. E., Jn. Smoking and mortality: A prospective study. Cancer 25(1): 105-112, January 1970. WE LcH, M. H., REINECKE, M. E., HAMMARSTEN, J. F., GUENTER, C. A. Antitrypsin deficiency in pulmonary disease: The significance of in- termediate levels. Annals of Internal Medicine 71(8) : 588-542, Sep- tember 1969. WickKen, A. J. Environmental and personal factors in lung cancer and bronchitis mortality in Northern Ireland, 1960-62. Tobacco Research Coucil, Research Paper No. 9, 1966. 84 pp. WIGHTMAN, J. A. K. A prospective survey of the incidence of postopera- tive pulmonary complications. British Journal of Surgery 55(2): 85- 91, February 1968. WIKLANDER, O., NorLIN, U. Effect of physiotherapy on post-operative pulmonary complications: A clinical and roentgenographic study of 200 cases. Acta Chirurgica Scandinavica 112: 246-254, 1957. WILHELMSEN, L. Effects on bronchopulmonary symptoms, ventilation, lung mechanics of abstinence from tobacco smoking. Scandinavian Journal of Respiratory Diseases 48(3/4) : 407-414, 1967. WILHELMSEN, L., OHRA, I, TIBBLIN, G. Decrease in ventilatory capacity between ages of 50 and 54 in representative sample of Swedish men. British Medical Journal 3 (5670) : 553-556, September 6, 1969. Wison, R. H., Meapor, R. S., Jay, B. E., Hiccins, E. The pulmonary pathologic physiology of persons who smoke cigarettes. New England Journal of Medicine 262(19) : 956-961, May 12, 1960. WINKELSTEIN, W., KANTOR, S. Respiratory symptoms and air pollution in an urban population of Northeastern United States. Archives of Environmental Health 18(5) : 760-777, May 1969. Wootcock, A. J., VINCENT, N. J., MACKLEM, P. T. Frequency depend- ence of compliance as a test for obstruction in the small airways. Journal of Clinical Investigation 48: 1097-1105, 1969. (235) (236) (237) (238) (239) (240) (241) Wynoper, E. L., GoopmMan, I). A., HOFFMANN, D. Ciliatoxic components in cigarette smoke. II. Carboxylic acids and aldehydes. Cancer 18 (4): 505-509, April 1965. WYNDER, E. L., Kaiser, H. E., GoopMaN, D. A., HOFFMANN, D. A method for determining ciliastatic components in cigarette smoke, Cancer 16 (9) : 1222-1225, September 1963. Wynpber, FE. L., KAUFMAN, P. L., Lesser, R. L. A short-term follow-up study on ex-cigarette smokers. With special emphasis on persistent cough and weight gain. American Review of Respiratory Diseases 96(4) : 645-655, October 1967. WYnNDER, E. L., LEMON, F. R., MANTEL, N. Epidemiology of persistent cough. American Review of Respiratory Diseases 91(5): 679-700, May 1965. YEAGER, H., Jr. Alveolar cells: Depressant effect of cigarette smoke on protein synthesis. Proceedings of the Society for Experimental Bi- ology and Medicine 131(1): 247-250, May 1969. ZAMEL, N., YousseFr, H. H., Prime, F. J. Airway resistance and peak expiratory flow-rate in smokers and nonsmokers. Lancet 1: 1237-1238, June 8, 1963. Zwi, S., GOLDMAN, H. I., Levin, A. Cigarette smoking and pulmonary function in healthy young adults. American Review of Respiratory Dis- eases 89(1): 73-81, January 1964. 191 BRONCHOPULMON=RY APPENDIX TABLED TABLE A2.—Smoking and chronic obstructive pulmonary disease symptoms'—percent prevalence (Numbers in parentheses represent total number of individuals in particular smoking group) EX = Ex-smokers. Number and type of population Other Comments 2,031 male and female insurance policy holders. NS.........10.9 SM .........18.0 Chest illnesses as repre- sented by frequent colds. 8,602 male and 2,242 female clerical workers 40-65 years of age. Chronic Bronchitis Chronie Males bronchitis NS .......15.8 (474) defined by SM .......18.4 (1,940) habitual Females cough and NS .......12.1 (619) sputum SM .......18.8 (579) production. 1,274 male factory workers without overt pulmonary disease or heart failure. SM = Smokers. NS = Nonsmokers. Breathlessness Cough Sputum production or dyspnea NS....... 1.6 (496) SM ....... 6.4(1,293) NS....... 2.0 (451) SM .......51.0 (823) 301 male and 280 female rural dwellers 25-74 years of age, Cough and sputum Males Males NS .......0. 7.1 (28) NS.......... SM .........538.9 (222) SM.......... Females Females NS......... 4.5 (176) NS.......... SM .........17.2 (98) SM.......... Chronic Bronchitig Males NS 3.6 SM ....... 9.9 Females NS 3.4 SM 8.6 Sé6L 961 TABLE A2.—Snoking and chronic obstructive pulmonary, disease symptoms'—percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference population Higgins 94 males and Females Males Males Chronte bronchitis and 92 females Cough and sputum NS. 33.3 NS..... 0.0 Males Cochran, randomly chosen NS ......--- (6) SM. .....29.3 SM..... 16.0 NS ....... 0.0 1958, (members of an $ ..24.0 (75) Females Females SM ....... 6.7 England agricultural .. Bl (64) NS ..... 02... 45.3 NS ..... 10.9 Females (114). community.) . 3.0 (20) SM............20.0 SM..... 10.0 NS ....... 0.0 SM . 6.0 Edwards 1,737 male out- Chronic bronchitis etal., patients on NS .......16.6 (151) 1959, lists of Cigarettes 29.7 (T79) England general prac- 1-9 .. 23.4 (235) (74). titioners >60 10-19 - 81.2 (369) years of age. >20 - 338.7 (175) Pipe 18.5 (840) Flick 222 male NS .......10,0 (51) NS.........25.0 (49) NS..... 30.0 (47) and patients not SM .......55.0 (157) SM.........65.0 (156) SM. - 60.0(188) Paton, suffering from 1959, overt cardio- U\S.A. pulmonary (86). disease, 20-90 years of age. Higgins 776 males in Cough and sputum Chronic bronchitis et al., various SM......... 71 (85) NS............ 94 NS..... Td SM ...... 14.3 1959, occupations NS .........36.9 (575) SM.......,.....24.9 SM..... 20.2 NS 3.5 England 25-64 years (116). of age. Zé6l TaBLe A2.—Smoking and chronic obstructive pulmonary disease symptoms'—percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference population Higgins, 393 males in Cough and sputum Chronic bronchitis Chronic 1959, various NS ........ 6.1 (33) NS.......... 18.2 NS.......... 3.0 NS ...... 6.0 bronchitis England occupations 1-14 g./day 9.7 (173) 1-14 ¢./day 30.1 1-14g./day 23.7 1-14 ¢./day 13.9 defined as (113). 55-64 years DIB ow... 42.3 (142) 1B... 888 DIB LL... 28.9 1B... 17.6 persistent of age. sputum and at least 1 chest illness in past 3 years. Tobacco gram equivalents are: 1 cigarette = 1lgram, leigar = 2-5 grams, 1 pipe = 10-25 grams. Liebeschuetz,147 male NS....... 0.0 (52) 1959, soldiers SM....... 18.0 (88) England 20-30 years (156). of age. Ashford 4,014 male Respiratory symptoma Respiratory etal., coal workers. NS wees 103 (677) symptoms— 1961, EX ......19.5 (123) “bronchitis England Cigarettes 21.1 (1,504) and/or {ift). Pipe only 35.1 (202) asthma’’. No Cigarettes dose rela- and pipe 37.1 (90) tionship ANISM ...21.7 (3,214) found. 86L TABLE A2.—Smoking and chronic obstructive pulmonary disease symptoms'—percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference population Bower, 95 male and NS........ 4.1 (49) NS ........ 20.4 NS ...... 34.7 Chest illness— 1961, 77 female SM........27.6 (76) SM ........ 34.2 SM ...... 38.2 chest colds U.S.A. bank employees Pipe, cigar (18) Pipe, cigar 15.4 Pipe, cigar during each (Al). 40-70 years 53.9 of last 2 of age. winters. Fletcher and 363 male London NS ........ .. (80) NS voces cee 8.7 NS ....... eee ee NS...... 4.3 Tinker, transport 1-14 g./day 15.5 (156) 1-14g./day ..29.9 1-14 g./day .. 8.2 1-14 g./day 1961, employees >15 woes 27,3 (116) DIB wee. ae. 36,9 D>1B ......... 8.6 8.2 England 40-50 years >15 2... 10.7 (85). of age. Read 170 male and Males and 132 female NS........ 4.4 Selby, individuals SM ........28.1 1961, interviewed EX ........21.2 Australia in an out- Females (191). patient NS........ 49 elinic (not SM ........18,6 all patients). Balchum 1,451 male NS ........10.2 (253) NS .......... 11.0 NS... eee ee 9.8 etal. light SM ....... .23.3(1,198) SM... - 80.4 SM ........0. 14,5 1962, industry <1 pack- <1 pack- <1 pack-year .10.0 U.S.A. employees in (257) year . 12.0 1- 9 ........12.0 (24). California, (263) 1- 9 .....,.,18.0 10-19 ........11.0 0 (303) 10-19 ......0e 82.0 20-29 ........ 18.0 20-29 ..... 21.0 (236) 20-29 ++ 84,0 30-39 ........ 21.0 30-39 28.0 (144) 30-39 . . 40.0 40-49 13.0 40-49 39.0 (92) 40-49 ........ 37.0 50-59 .......- 38.0 50-59 ..... 34.0 (29) 50-59 «45.0 >60 29.0 >60 -50.0 (24) >60 .-62.0 66t TABLE A2.—Smoking and chronic obstructive pulmonary disease symptoms'—percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. Author, NS = Nonsmokers. EX = Ex-smokers. year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference population Boucot 6,137 males NS wo... eee 18.0 (806) et al., 1962, enrolling SM ........31,5 (5,381) U.S.A. in pulmonary (86). neoplasm project. Ferris 90 male and Chronic Nonspecific et al, 71 female Respiratory Disease 1962, flax mill- Males Females U.S.A. workers. NS ..15,0(20) 10.0(60) (82). EX ..12.5(16) 1-20 .27.8(22) .. >20 53.1(382) 60.0 (4) Ferris 542 male and Chronic bronchitis Age-specific and 625 female Males rates. Anderson, residents of NS .......18.8 (126) 1962, New Hampshire EX ....... 11.9 (17) U.S.A. town chosen Cigarettes 40.3 (340) (81). by random 1-10 ....,29.8 sampling of 11-20 ..... 34.2 census. 21-30 .....42.3 31-40 .... 61.1 D>41 .....,75.8 Females NS ....... 94 (878) EX .......10.8 (87) Cigarettes 19.8 (208) 1-10 .....13.1 11-20 ..... 22.2 21-30 31-40 27.3 D>41 ow... 002 Tapie A2.—Smoking and chronic obstructive pulmonary disease symptoms'—percent pre valenec (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference population Goldsmith 3,381 active Respiratory etal., or retired conditions 1962, longshoremen. NS .-.. 81.4 (744) U.S.A. Moderate/ heavy (95). smokers 43.0 (1,238) Coates 1,342 male and Cough and chronic phlegm Current etal., 242 female NS. .....11.2 (747) NS ...14.7 NS ...... 4.0 smoking 1965, Detroit post 1-14 ...12.7 (266) (not sig.) 1-14 .28.2(p<0.001) 1-14 5.3(not sig.) data. U.S.A. office 15-24 ...27.6 (402) (p<{0.001) 15-24 .30.7 (p<0.001) 15-24 ....17.2(p<0.001) (53). employees. >25 . 36.4 (170) (p<0.001) >25). 34,1 (p<0.001) S25... 25.3 (p<0,001) Deane 508 tele- Persistent cough, NS includes et al., phone phlegm, dyspnea ex-smokers, 1965, company NS ....... 4.5 (200) pipe, and U.S.A. workers. Current cigarette cigar (67), smokers 15.9 (308) smokers. Huhti, 653 male and Males Chronic bronchitis Ex-smokers 1965, 823 female NS NS ........-5 15.6 Males represent Finland residents of EX. EX ..........24.8 NS wees BT those who (126). a Finnish 1-14 ........ 25.0 EX .......16.3 have communal 15-24 ........ 26.2 1-14 .....38.0 stopped region, >25 ve eee ee B18 15-24 . 41.4 smoking 40-64 years Females >25 «2... 40.0 for more of age. NS oe 29.2 Females than 1 EX .... . 388.3 NS ...... 4.5 month. 1-14 . 14.3 EX ......13.3 Dyspnea 15-24 21.0.2. 14.0 1-14 .....10.4 Grade II >25 vhs 15-25) 57.0 only. Dep gt 10% TABLE A2.—Smoking and chronic obstructive pulmonary disease syniptoms'—percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Other Comments reference population Wynder 315 male New York City et al., patients in NS........14.0 (44) 1965 New York City Pipe, cigar 33.0 (64) U.S.A. and 315 male Cigarettes: (288). patients in 1-10 ...45,.0 (44) California. 10-20 ...46.0 (88) >20 ....67.0 (85) California NS wo... 22.0 (69) Pipe, cigar 30.0 (32) Cigarettes: 1-10 ...45.0 (54) 10-20 ...74.0 (91) >20 = ....74.0 (69) Freour 1,055 randomly Clinical signs of et al., chosen males in bronchitis and 1966 Bordeaux 30-70 respiratory France years of age. insufficiency (92). NS ...... 25.4 (45) SM ......54.4 (478) Haynes, 179 male Average number of Heavy et al., preparatory severe respiratory smoker— 1966 school illnesses per 10 more than U.S.A. students students (adjusted 10 ciga- (108). 14-19 years for age) rettes of age. NS) ....... 0.36 per day. All smokers 2.30 Heavy SM 3.34 20z TABLE A2.—Smoking and chronic obstructive pulmonary disease symptoms'—percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference population Densen 5,313 male Postai Postal Postal Dyspnea et al., and 7,291 NS ....... 7.0 (903) 13.1 19.8 represented 1967, female postal Pipe, cigar 12.4 (628) 17.4 24.8 by Grade IT U.S.A. and transit Cigarettes only. (68). workers. only ....27,0(2,687) 28.9 317 Transit Transit Transit NS ....... 6.4(1,012) 9.6 11.7 Pipe, cigar 10.5 (765) 14.1 14.2 Cigarettes only ....23.5(3,746) 23.7 21.9 Higgins 926 white NS ....... 15.4 (162) NS ........... 811 NS ........... 5.0 etal., male resi- SM .......47.2 (518) SM ...........46.2 SM ........... 10.7 1968, dents of EX ....... 19.3 (144) EX .........., 28.5 EX ...........16.8 U\S.A. Marion (118). County, West Virginia, 26-69 years of age. Holland 9,786 male Malea Females Males Females and and female NS ....... 3.8 (1,900) 3.2 (3,137) 2.4 2.1 Elliott, school SM ....... 6.3 (1,098) 6.3 (554) 6.1 8.3 1968, children, EX ....... 2.9(1,782) 4.3(1,151) 3.9 42 England
  • 20 ..... 20,6 Females NS ...... 3.4(12,861) EX ...... 38 (959) Pipe .... 0.0 Cigarettes (8,985) 1-9 1... BI 10-19... 10.6 D>20 oo. eee 18.5 Wilhelmsen 313 males Chronic bronchitis et al., 50-54 years NS ...... 1.0 (88) 1969, of age randomly EX 2.2... 3.0 (67) Sweden sampled from 1-14 grams/ (281). population day ... 5.0 (94) of Goteborg. D165 1... 17.0 (64) $02 TABLE A2.—Smoking and chronic obstructive pubnonary disease symptoms'—percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS -= Nonsmokers. EX = Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference pepulation Lambert 9,975 male Persistent cough and phlegm and and female Males Reid, responders dlge Age Age Age 1970, to a postal 85 45 45-55 55-65 65-69 England survey NS « 1(227) 6 (200) 11(171) T (61) (146). (4,688 males KX . 7(803) 11(358) 15 (335) 18(148) and 5,287 <20 ....15 (521) 22 (488) 30(490) 37 (189) females 20 ». 23 (191) 28 (204) 32 (149) 38 (37) 35-69 years >20 --27(148) 28 (136) 42(121) 25 (12) of age). Females NS . 8(500) 4(637) 5 (925) 6 (21) EX ..... 3(127) 8(128) 7 (94) 7 (Al) <20 . 9(602) 13 (472) 16 (306) 11 (65) 20 .16 (128) 27 (122) 31 (77) 14. (7) 20 . 23 (22) 26 (39) 43 (7) (1) Lefcoe 310 male Age-standardized rates Excluded from and physicians of chronic reapiratory ex-smokers Wonnacott, in London disease are those 1970, and Ontario, NS .......... 1.0 (88) cigarette Canada 25-74 years EX «. 5.0 (61) smokers who (151). of age. SM 34.0 (101) now smoke Pipe, cigar ..12,0 (388) pipes or cigars. ‘Data collected by either direct interview, questionnaire, review of medical records and/or medical examination. soz TABLE A2a.—Smoking and chronic obstructive pulmonary disease symptoms'—percent prevalence (Numbers in parentheses represent total number of individuals in particuar smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, year, Number and country, type of Cough Bronchitis Comments reference popuation Cederlof 9,319 twin Observed/ Observed Explanation of analyses for All ex-smokers included et al., pairs expected Hypermorbidity expected Hypermorbidity respiratory symptom with smokers. 1966, registered Group A: cases ratio cases ratio prevalence: MZ—monozygotic Sweden in Sweden Males ........393/151.9 2.6 157/50.8 3.1 Group A analysis—using each pairs (46). of 12,889 Females 186/ 49.4 2.8 43/11.2 3.8 firstborn twin as one group DZ—dizygotic pairs available. Group B SM/NS: in an unmatched relationship Author concludes that MZ Males .... 14.6/7,.7 1.9 6.6/ 1.1 6.0 (274) to each secondborn twin, since hypermorbidity Females ... 13.6/7.6 1.8 3.0/ 2.3 1.33 (264) Group B analysis—using each for smoking persists DZ Males .... 12.8/5.5 2.25 4.5/ 1.8 2.54 (733) twin set as matched pair. in smoking-discordant Females ... 14.5/5.7 2.57 5.5/ 1.8 3.0 (653) All comparisons in Groups A MZ population, a and B are between smoking- easual relationship of discordant pairs. smoking and broncho- pulmonary symptoms is supported. Cederlof 4,379 twin Prevalence of respiratory symptoms No ex-smokers included et al., pairs (all Group A: in Group B analysis. 1969, U.S. veterans) NS » AD 4.3 1.6 Group A-—as above. The authors conclude U\S.A. in U.S. 1-10 peeeeee OF 6.4 2.7 Group B—as above. that the data indicate (45). National 11-380 pee ee ee LSB 15.3 8.0 a strong probability Academy of 31 ee bene eee ebad 27.7 16.8 of a causal connection Sciences Twin Pipe, cigar ............. 7.1 TA 2.7 with smoking. Even Registry (of Group B: NS SM NS SM these symptoms, 9,000 avial- MZ oo ce eee ee 2.4 5.4 18 4.8 however, seem to be able). DZ 9.8 1.6 9.1 influenced by genetic ' Data collected by either direct interview, questionnaire, review of medical records and/or medical examination. factors. 90% TABLE A3.—Smoking and ventilatory function (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers, EX = Ex-smokers. Author, year, Number and country, type of MBC EFR FEV ve Miscellaneous Comments reference population Chivers, 463 male Height-in-inches ¢Mean EFR 1959, employees Cigarettes/day: 64"" 66" 68"" 70"" in liters England of alkaline 0-5 peeeee $97 (28) 91 (35) 108 (81) 101 (21) per minute. (52). industry 6~20 - 89(50) 8&8 (75) 101 (112) 109 (75) Regression plant. >20 . 63 (6) 88.5 (9) 92.5 (9) 113(12) analysis of data revealed & significant re- lationship between smoking and de- creasing function. Higgins 773 males 25-34 55-64 FEV 9.45 expressed et al., in various NS 145 (56) 10% (29) as mean indirect 1959, occupations BX 148 (81) 89 (62) MBC. England (25-34 and 1-14 grams (116). 55-64 years -140(193) 87(157) of age). >>15 grams -133 (89) 80(136) Wilson 28 male RV/TLC etal., residents of NS..... 5.59 (14) NS 211 1960 Dallas, SM ..... 34.44 (14)SM ....... 227.01 U.S.A. Texas, (232). former rural dwellers; matched for body surface, age, and height. 202% TABLE A3.—Smoking and ventilatory function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers, EX = Ex-smokers. Author, year, Number and country, type of MBC EFR FEV ve Miscellaneous Comments reference population Ashford 4,014 male FEV, 9 Data represent etal., coal workers Age: NS SM results after 1961, at 3 Scottish <21-30 4.09(103) 3.96(280) correction for Scotland collieries. 21-30 .3.86(182) 3.77(555) sitting height. (11). 31-40 .3.44(188) 3.88(777) SM includes pipe 41-50 .3.04(110) 2.96 (755) smoker. 51-60 .2.71(102) 2.56(610) Data on ex-smoker >60 ...2.38 (42) 2.21(287) not included. FEV, found significant; lower for SM than NS. Fletcher 363 male Mean peak EFR and London NS ......-. 570 (30) Tinker, transport I-14 grams 537 (156) 1961, employees, >15 grams 628 (116) England EX ........ 555 (61) (85). Franklin 213 male FEV, 9 FEVo 9, FEVo.s9 Heavy smoker and factory He . 0.75 0.75 | represents an Lowell, workers favy 2,670 3,011 2,710 Light .. 3,703 (59) amount equal 1961, 40-60 years Light 12,489 72,656 72,284 Heavy 13,578 (104) to or more U,S.A. of age. than 30 pack (87). years. 802 TABLE A3.—Smoking and ventilatory function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group ) NS = Nonsmokers. SM = Smokers, EX = Ex-smokers. Author, year, Number and country, type of MBC EFR FEV vc Miscellaneous Comments reference population Balchum 1,451 male MMEFR Data for: MMEFR etal., employees NS ....... 15.6 (88) 7.8(19) given as pereent 1962, in Pack/year: of individuals U.S.A. California <1 ..... 15.0 (257) 8.0 with a value of (24). light indus- 1-9 .... 10.0 (263) 6.0 <500 L/M; try. 10-19 ... 10,0 (303) 12.0 FEV, 5 20-29 ... 19.0 (236) 24.0 given as percent 30-39 ... 33.0 (144) 26.0 of individuals 40-49 ... 38.0 (92) 40.0 with value of 50-59 ... 55.0 (29) 45.0 <70 percent >60 ..... 71.0 (24) 62.0 of expected. Goldsmith 3,311 active MEFR FEV, 4 Authors concluded etal., or retired NS ........ 313.63 (250) 2.99 that cigarette 1962, longshore- Pipe, cigar 299.26(125) 2.80 smoke was found U.S.A. men. EX ....... 295.23(102) 2.84 to have a slight (95). Cigarettes/day: effect on =20..... 309.73 (144) 2.89 pulmonary 20-40 ... 303.44(346) 2.91 function. 240 ..... 307.63 (57) 2.90 Martt, 73 healthy D,co Smokers defined 1962, medical per- u as those smoking U.S.A. sonnel with- NS 2 33.10(30) >20 cigarettes/ (161) out signifi- SM <6 years 728.40 (8) oy for varyi . B-l0 years ...°28.20(10) CY *OP Varying cant age 10 years ...524.90(25) Petiods. difference between smokers and nonsmokers. 60% TABLE A3.—Smoking and ventilatory function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers, EX = Ex-smokers. Author, year, Number and country, type of MBC EFR FEV vc Miscellaneous Comments reference population Revotskie 1,130 male FEV 0 Data presented et al., and 1,818 Males Females in terms of 1962, female NS .....0.98 (55) 0.98(255) ratio of U.S.A. residents in Cigarettes/day: observed to (192). Framing- 1-10 .0.97 (90) 0.99 (92) predicted ham par- 10-29 .0.91(163) 0.93 (157) values. ticipating >30 ..0.90 (81) 0.91 (22) in the pro- spective study. Krumholz 18 physicians MEFR Mean D, etal., 24-87 years NS ...eeae 580 (9) NS SM 1964, of age. SM ........ 1590 (9) Rest .......ee 36 231 U.S.A. Exercise: (149). 2minutes . .50 S41 4minutes . .50 143 3 minutes post exercise 39 135 Zwi 20 medical MMEFR Authors found etal, studentsor NS . 187 (10) 4.34 5.77 a significant difference 1964, graduate SM ...1193 (10) 15.09 15.58 between SM and UOS.A. physicians. NS for RV/TLC, (241). compliance, and non- elastic resistance. Coates 1,342 male FEV, 14 Timed VC! FEV, ,/VC et al., and 242 Age: NS 25 cig/day NS >285/day NS >25/day 1965, female post 40-44 12,99(186) 2.85 (69) 3.89 3.85 30.77 0.74 U.S.A. office 45-49 52.95(170) 2.64 (42) 3.92 3.83 30.74 0.70 (53). employees 50-54 12.75(116) 2.62 (22) 3.71 3.74 20.74 0.70 >40 years 55-59 12.64 (64) 2.44 (18) 3.54 3.61 50.74 0.68 of age. 60-64 12.85 (53) 2.80 (8) 3.30 3.83 10,72 0.70 "aBB Jo “HOO Foz SIB94 89-07 PezIeITOD uaaq aswasip aaBy san[ea Tq 4x04 “1Bak youd 96°F 5 -eiidsa1 Jo “(egr) ] uBy} Ja}8a18 3e9 oe 410381] ‘wsn 30 sayous-xe pus OUn}Oa SZ eA Lee Ag qsud ‘9961 srayours teZ1o pus 4710747P TTS" *"* SN g90T gH (49) LIITr** WS a 4noqyTH “Te 42 adidsepnpurgn /7q 1g lags (89) T@IT ** SN saree gaz EWE *ALOISIY IBBA YIV g UBY} tayBIIs 10 0} [ends WAM Sr0'0s ‘WS asoy} ele stayoug 2-01 | ay “sUuBIDISAUd ‘Gr) “quatayip AyUwa Dag /aounmyduey ayenpylzs v sa “Yrusis ousem (OT)LLT0e OWS 20 syuepnys . 2961 Bdnoi8 ZAof waIe (OT) THZOT SN [sotpaut “Ts 7 aoBjans Apoq usa aounydumos Alpuouwjng aeurg2 = zoyuniy “qUBOYUsIS A[[@o14819848 7OU St puaty ft “sdnoiz ; 2 288 79-09 ‘6h-Sb . 92°F . 80's | (98) BIg bend teen eens 92 sop yueoyyUBys a he id {ee (1) 86F LU etery ugg eee Pe-9r“pusyurg St ABP /S3< eae OnTr PLS Lvs (LL) Ter (BOE) BTQ ttt py Uy UuOoLser PUB GN Uaamyeq + ABD /893}91BFIC) [Bani & Jo sUatayid $ 6r's I9'F S8°S 688 (08) sor (TFT) Tgg otc “ss Xa squepisar *“(98T) “papnyaur 8T’s or avs 9P's (604) OIF (BBE) G9G ttt eee SN ayeuay Pas[urd jou slayours saypway «sappy sao eaj0W sappma gy aa]0 2g pus 9961 TeS1D pus adig FOA p90s09 Yaga +addd areur gag nyny uwonjurndod aouedayor S}USUIIOD, SNOOUB_LIOSI AL OA AGI qd oaN pu P camoy *“Axyunoo ‘1oqyny “sdayqows-xq = YY (dnoiz Zuryows zenozaud Ul S[ENPLAIpUL Jo JaquINU [8207 JUasaIdaI SasaqjUusrEd Ul slaquin yy) (7409) uorvjounf Asozopjzuaa pun Suryomsg—ey Aavy ‘saayomg = WS “SI@HOUSUON = SN . 210 LLe TABLE A3.—Smoking and ventilatory funetion (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers, EX = Ex-smokers. Author, year, Number and country, type of MBC EFR FEV ve Miscellaneous Comments reference population Edelman 410 male FEV, 4 Vital capacity Ex-smokers of etal., community NS ........ 164 (152) 7.89 2.83 4.93 cigarettes only. 1966, dwellers Current Difference signifi- U.S.A. 20-103 cigarette cant between NS (78). years of smokers. .5161(118) 7.86 52.64 34.74 and current age. EX seveees 157 (98) 8.09 2.80 4.17 cigarette smokers Pipe, cigar .. 167 (47) 8.20 2.91 5.08 at p<0.01. Peters 124 male MEFR FEV, 4 FEV, /VCe Heavy smoker refers and college age NS ........ 210.28 (41) 4.68 287.5 to greater than Ferris, students, Moderate 10.06 (54) 4.59 85.3 or equal to + 1967, Heavy 9.64 (29) 4.43 83.9 pack years. U.S.A. EX ....... 9.48 (10) 4.74 83.2 Moderate smoker (182). includes pipe and cigar smokers, Difference between NS and heavy smoker is significant. Higgins 926 white FEV, 5 et al., male NS ........ 3.64(160) 1968, residents EX ........, 3.25(148) U.S.A. of Marion Cigarette SM 3.48(611) (118). County, 1-14 .. 3.67 (88) West 15-24 ....... 8.57(278) Virginia, D>25 we... eee. 8.30(150) 20-69 years of age. Le TABLE A3.—Smoking and ventilatory function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers, EX = Ex-smokers. Author, year, Number and country, type of MBC EFR FEV vc Miscellaneous Comments reference population Sluis- 5383 white 35-44 45-54 >55 FEV 5.4 1 cigarette = Cremer male NS ........ 553 (106) 527 (101) 444 (27) B5-44 45-54 >bS 1 gram. and factory Grams/day: 3.70 3.22 2.76 1 ounce tobacco = Sichel, workers 1-14, 557 (26) 519 (17) 410 (7) 3.64 3.31 2.24 26 grams. 1968, over 35 15-24 532 (94) 446 (35) 401(13) 3.66 2.94 2.28 leigar=2to5 South years of 25 1528 (66) 494 (31) 1380(10) 3.54 3.05 12.12 grams. Africa age. t Derived slopes (208). found signifi- eantly different from 0. Stanescu 87 male bus FEV, 4 Nitrogen gradient et al, drivers; Younger Older Younger Older Younger Older 1968, 27 aged NS ..... 4,470(14) 3,310 (40) 5,125 4,290 1,53 2.49 Rumania 20-25, 60 SM... .. -4,500(13) 13,200 (20) 15,285 14,290 1Y.47 53.77 (212). aged 40-60, all without respiratory symptoms. Densen 5,287 male FEV 14 FEV expressed as et al., postal and Postal standardized for 1969, 7,213 male White Non-white specified postal U.S.A transit NS ....... 3.29 (685) 3.05 (204) and transit (69) workers in All cigarette cece cece eter eae ee vanes 8.11 (2,340) 2.94 (768) workers at age New York <25 grams/day ..... 0. cee cee cee ce eee 3.14 (1,292) 2.95 (599) 45 and at sitting City. 2225 grams/day 3.06 (1,038) 2.93 (161) height of 35 Transit inches. White Non-white Includes mixed NS occ cece eee e tee teen ene eee 3.39 (620) 3.08 (298) smokers. All cigarette 3.11 (2,941) 2,99(1,041) <25 grams/day 3.15 (1,929) 3.00 (891) 2225 grams/day ............0..000ee-eeee+ 8.02(1,011) 2.95 (149) £k@ TABLE A3.—Smoking and ventilatory function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) EX = Ex-smokers. NS = Nonsmokers. SM = Smokers, Author, year, Number and country, type of MBC EFR FEV vc Miscellaneous Comments reference population Rankin 60 male FEV, FEV expressed as et al., and 10 NS wee es 497.5 (12) percent of 1969, female SM . 78.4 (58) predicted value Australia patients for age, sex, (190). with chronic and height. alcoholism 26-66 years of age. Wilhelmsen 313 male PEFR FEV, ve 1963 values only. etal., residents NS Lecce cee ee ee ee eens 525 (88) 3.77 4.83 1969, of Géteburg DD, Ca 539 (67) 3.69 4.77 Sweden 50-54 years 1-14 grams/day ..........-.0065 521(94) 3,62 4.83 (231). of age. S15 grams/day ............0065 492 (64) 3.39 4.56 Lefcoe 310 male MMFR FEV 1.9 MMFR has been and physicians NS ....... 4.09 (88) 3.39 standardized for Wonna- of London, Cigarette age and height. cott, Ontario. smokers. 3.64(101) 3.11 1970, EX ....... 3.99 (61) 3.38 Canada Pipe, cigar 4.17 (33) 3.17 (151). Pyle TABLE A3.—Smoking and ventilatory function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers, EX = Ex-smokers. Author, year, country, FEV Miscellaneous Comments reference Lundman, 37 MZ and FEV 9 N, washout gradient MZ = monozygotic. 1966, 62 DZ twin os 7 ss : DZ = dizygotic. Sweden pairs selected Significant differences Significant differences The author concludes that the degree of ventilation as measured by N : between smoking discordant between smoking dis- . : : 2 (159). from Swedish : . . . washout was correlated with cigarette consumption, The FEV : : twin pairs found for: cordant twin pairs se 2-0 Twin-Pair . was significantly lower for smokers and there was a correlation Registry. 1. Group A MZ males found for: with cigarette consumption. . and females. Group B DZ males. 2. Group B DZ males. 3. Group A DZ males. Explanation of analyses for respiratory symptom prevalence: Group A analysis—using each firstborn twin as one group in an unmatched relationship to each secondborn twin. Group B analysis—using each twin set as matched pair. All comparisons in Group A and B are between smoking-discor- dant pairs. 1 Not significant (difference or trend). 2 p<0.05 3 p<0.01 4 p<0.005 5 p<0.001 a 4 TaBLE A4.—Glossary of terms used in tables and text on smoking and ventilatory function Symbo} Term Volume or rate Definition MBC......... Maximal breathing LiterS. 0. cc eee eee eee The maximal volume of gas that can be breathed in one minute. capacity. MVV......... Maximal voluntary ventilation. EFR......... Expiratory flow rate............ Liters/minute.... 2.0... 00sec eee Rate of flow for a specified portion of a forced expiration (MMEFR—rate PEFR .. Peak expiratory flow rate. of flow measured for middle half of FVC). MEFR........ Maximal expiratory flow rate. MMEFR...... Maximal] midexpiratory flow rate, FEV ......... Forced expiratory Liters... ee eee eee Volume expired within a specified time interval. (FEV, ,—volume expired volume. in first second of expiration.) VG... eee Vital capacity........ 0. eee Liters. ... 00. cee ee ee eee Maximal volume of a gas that can be expelled from the lungs by forceful FVG......... Forced vital capacity. effort following a maximal expiration. FEV /VC. ... Foreed expiratory Percent... .... cece eee e eens Volume of forced expiration (in time specified) related to vital capacity, volume/vital capacity. dD, wee nutes Pulmonary diffusing ml/min/mmHg The ability of a chosen gas to pass from the alveolus to within the pulmonary ; capacity. eapillary. N, washout... Nitrogen washout Exponential The stepwise pulmonary alveolar clearance of a gas. (Slope of curve depends gradient. curve. upon the uniformity and adequacy of ventilation of all parts of the lung.) It may be done as a single--or multiple—breath procedure. Compliance....... - Liters/CMH,0. paveteueuees Volume change of the lung produced by a unit pressure change. RV.. . Residual volume..........-6.. 045 Liters... 0... ccc ee ce ce eee Volume of gas remaining in the lungs at the end of a maximal expiration. TLC......... Total lung capacity..........0.. Liters... 0.0. cee eee ee ee Volume of gas contained in the lungs at the end of a maximal inspiration. FRC .Functional residual Liters... cee ccc eae Volume of gas remaining in the lungs at the resting expiratory level. capacity. Aleveolar volume. ............. Liters. 0... eee eee eee ene eee Volume of gas contained in pulmonary alveoli. SOURCE: Comroe, J. et al. (56) TABLE A6,—Epidemiological studies concerning the relationship of air pollution, social class, and sinoking to chronic obstructive bronchopulmonary disease (COPD) Author, year, Number and type country, of population Results reference Higgins, 301 males and Male data only (170): oo 1957, 280 females (a) The frequency of recurrent chest illnesses was high England living in 2 er in the more polluted region but the prevalence of (112). separate other respiratory symptoms and mean valueg were districts. similar. (45-64 years (b) Significant difference observed in COPD mortality of age.) rate. College of 787 males and (a) Male urban inhabitants manifested almost twice the General 782 females prevalence of chronic bronchitis as rural males: this Practi- 45-64 years of difference could not be explained on the basis of tioners, age from smoking habits. 1961, medical doctors’ (b) No significant urban/rural differences noted for England case lists. PEFR! (55). (c) No significant urban/rural differences noted for COPD symptoms among females. Ferris and Anderson, 1962, U.S.A. (81). 1,219 males and females living in 3 different areas of a New Hampshire town, Following adjustment for differences in smoking habits, no significant differences in chronic bronchitis were observed among the 3 pollution areas. Mork, 1962, U.S.A. (171). 339 male trapsport employees from London and Norway. The excess prevalence of serious respiratory symptoms (dy. spnea, wheezing) and PEFR dysfunction among London Transport employees was only partly eliminated after standardization for smoking, and the author suggests that this is due to differences in air pollution levels, Schoettlin, 1962, US.A. (204). 2,622 males 45-75 years of age. (a) No positive correlation found between chronic respira. tory illness and city size. (b) A positive correlation was found between chronic res. piratory illness and cigarette smoking (particularly du- ration}. Anderson et al., 1965, Canada (8). Holland and Reid, 1965, England (124). Bates 778 residents of Berlin, N.H., and 918 residents of Chilliwack, Canada. 676 male transport employees in Londen and rural England. 216 hospitalized veterans from various areas of Canada (all standardized for age, tobacco consumption, and eecupation) . Berlin, New Hampshire, has higher SO, and particulate air pollution levels and the higher respiratory disease preva- lence rates among its residents were not accounted for by age differences, but were aceounted for after stan- dardization for smoking habits (except that PEFR and FEV, 4 dysfunction was more prevalent in New Hamp- shire, and the authors suggest that this difference re flects air pollution differences). (a) London employees manifested a greater prevalence of COPD symptoms and PEFR dysfunction than did the rural employees. {b) Smoking habit differences alone were not sufficient to explain this difference in COPD manifestations. {c) Both groups manifested pulmonary dysfunction cor- related with tobacco consumption. Winnipeg (cleanest of all areas in 50, and industrial dustfall}) residents manifested decreased prevalence of chest ilnesses, less severe grades of dyspnea, and less sputum volume produced when compared to residents of all uther areas. 216 Tas_e A6.—Epidemiological studies concerning the relationship of air pollution, social class, and smoking to chronic obstructive bronchopulmonary disease (COPD) (cont.) Author, year, Number and country, type of Results reference population Ashley, Standardized Positive correlations: 1969, mortality (a) Smoke concentration and bronchitis mortality. England ratios for (by) SO, and smoke concentration and bronchitis mor- (12). males (1958-63) tality and social class. for 53 boroughs (c) Pollution and social class. with air pollution indexes. Holland 10,971 children Factors affecting prevalence of respiratory symptoms: etal, over 11 years of (a) Smoking—highly significant association. 1963, age in 4 areas. (b) Area of residence (pollution)—-significant association England except for periods of cough and phlegm lasting more (122). than 3 weeks. Winkelstein and Kantor, 1969, U.S.A. (288), 842 females over 25 years of age in various regions of Buffalo. {c) Social class, age, sex—-no association noted. (a) The increased prevalence of respiratory symptoms could not be explained by social class differences. (b) No overail association noted between productive cough and air pollution. Cooley and Reid, 1970, England (58). 10,887 children 6-10 years of age from con- trasting urban and rural areas. Ilinesses considered included chronic cough, past bronchitis, blocked nose, (a) Every geographic area showed a clear gradient of in- creasing illness prevalence with decreasing social class. (b) Social classes I, II, and III showed no urban/rural gradient while ITV and V showed a clear excess in fre- quency of chest illnesses among urban residents over rural residents. Lambert and Reid, 1970, England (146). 9,975 males and females responding to questionnaire survey. fa) The trend of increasing prevalence of bronchitic symp- toms from rural to urban respondents was not negated by adjustment for smoking differences. (b) After adjustment for age and smoking habits, male respondents manifested a clear correlation of persistent cough and phlegm prevalence with increasing air pollu- tion. Correlation was not as striking in females. (c) Although the proportionate rise in symptom preva- lence increased with air pollution similarly in each smok- ing group, the absolute differences in morbidity risk in- ereased with increased cigarette consumption, suggesting synergistic influences of cigarette smoking and air pollu- tion. {d) In the absence of cigarette smoking, the correlation between the prevalence of persistent cough and phlegm and air pollution was slight. 1 See Glossary of Terms: Bronchopulmonary table A4. 217 TaBLeE A7.—Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary disease Author, year, Number and country, type of Results reference population Higgins 185 males Miners showed increased symptom prevalence (breathless- et al. (84 nonminers, ness, cough, sputum). 1956, 101 miners) Miners showed increased prevalence of chronic bronchitis, - England without pneumo- Miners showed decreased MBC. (119). coniosis. Differences in smoking between the two groups did not ac- count for above differences. Phillips 1,274 males None of the industrial environments were associated with etal. factory employees an increased prevalence of chronic cough. 1956, (coke and Cigarette smoking and age were directly correlated with U.S.A. electrolytic increased prevalence of chronic cough. (185). process}. Higgins 325 males 25-34 Miners as compared to workers in non-dusty occupations: etal, years of age and 25-34 years of age—significantly increased prevalence of 1959, 401 males 55-64 chronic bronchitis and MBC abnormalities. England years of age in 55-64 years of age—less significantly increased prevalence (116). various occupa- of chronic bronchitis and MBC abnormalities than in tions. 25-34 years of age group, No smoking information available. Chivers, 463 males in No significant differences in PEFR?! between dusty and 1959, non-dusty and non-dusty groups. England dusty occupations Cigarette smoking (especially in those >40 years of age) (52). (lime and soda was associated with decreased PEFR values. ash exposure). Higgins 300 male miners Miners showed increased prevalence of symptoms and de and and 300 male creased MBC values which remained even after standard- Cochrane, nonminers 35-64 ization for smoking habits. 1961, years of age. Total dust exposure was not directly correlated with these England findings. (115). Wives of miners showed similar symptom and test changes as compared with wives of nonminers. Brinkman 1,317 males 40-65 Increased silica exposure was associated with an increased and years of age prevalence of chronic bronchitis. Coates, with various Highest prevalence of chronie bronchitis was noted in the 1962, silica exposure non-exposed group; and this group was noted to have U.S.A. histories. the highest number of smokers and highest consumption. (42). Hyatt 267 male miners Increased history of underground work was associated with etal., and ex-miners an increased bronchopulmonary symptom prevalence and 1964, 45-55 years decreased pulmonary function values. U.S.A, of age. The impairment of pulmonary function associated with (128). underground work was separate from effect of smoking; but smoking and underground work did show additive effects. Elwood 2,528 male and Preparing room workers who manifested byssinosis symp- etal., female flax toms also showed an increased prevalence of chronic 1965, workers over 35 bronchitis independent of age or smoking when compared Ireland years of age. with non-preparing room workers. (77). Female workers manifested a signiticant association be- tween byssinosis symptoms and smoking while male work- ers did not. Sluis-Cremer et al., 1967, South Africa (209). 218 827 miners and nonminers over 35 years of age, Those smokers exposed to gold mine dust manifested more symptoms of COPD! than did non-dust exposed smokers, while prevalence of symptoms, among nonsmokers, was similar for the two groups, TaBLE A7.—Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary disease (cont.) Author, year, Number and country, type of reference population Results 827 miners and nonminers over 35 years of age. Sluis-Cremer etal., 1967, South Africa (209). (cont.) The dose relationship of cigarettes and COPD?! symptoms was much more noticeable among those exposed to dust. The authors stressed the synergistic actions of cigarette smoking and dust exposure. Those exposed to dust manifested a significantly greater prevalence of byssinosis symptoms than nonexposed, Smokers manifested a significantly greater prevalence of byssinosis symptoms than nonsmokers. No significant differences in Monday morning FEV? values were observed between smokers and nonsmokers. Prevalence of byssinosis symptoms did not show any re- lationship to length of employment. Hemp workers (especially the older ones) were noted to have different smoking habits from control group—fewer heavy smokers, more light smokers, more ex-smokers due to doctor’s orders. Aged 20-49 — a. No difference in FEV, values . between controls and hemp workers in any smok- ing category. b. No difference in FEV, values between men in different smoking categories. Aged 50-69-41. Hemp workers manifested decreased FEV 1.) values in all smoking groups except for heaviest smokers. Ex-smok- ers had lowest FEV 1. values. b. Those smoking most had lower FEV, values as compared with light and non- smokers. The authors conclude that: There appears to be no synergism between smoking and hemp exposure as to effect on FEV, although the selection process whereby those with symptoms have a greater tendency to stop smoking may obscure such a relationship. Chlorine-exposed group manifested no difference in symp- toms and a decreased MBC value when compared with non-exposed group, Smokers in chlorine-exposed group had significantly de- ereased MBC and FEV values as compared with non- smokers in non-exposed group. Sensitized group manifested lower FEV, ,/FVC1 values as compared with nonsensitized group even after smok- ing habits were controlled for. Bouhuys 455 male cotton et al., textile workers 1969, (214 exposed to U.S.A. dust in carding (39). and spinning rooms, 241 not exposed). Bouhuys 216 male hemp etal, workers and 247 1969, workers in other U.S.A. industries in (88). same region, 20-69 years of age. Chester 189 male chlorine etal., plant workers 1969, (55 with history U.S.A. of severe ex- (49). posure). Greenberg 121 workers in et al., washing powder 1970, factory (48 found England to be sensitized (97). to product, 73 not). Tokuhata 801 male miners et al., 1970, ULS.A. (218). Increased mine exposure was associated with residual vol- ume and FEV abnormalities even after adjustments for age and smoking. A systematic exposure-impairment relationship was noted only among smokers while relatively few nonsmokers shuwed COPD impairment, Smoking miners manifested more X-ray alterations and COPD symptoms than nonsmokers, regardless of num- ber of years of underground exposure. 1 See Glossary of Terms in Bronchopulmonary table Aé4. 219 TaBLE A10.—Experiments concerning the effect of the chronic inhalation of NO, upon the tracheobronchial tree and pulmonary parenchyma of animals Author, year, country, Animal Results reference Freeman Sprague-Dawley 25 p.p.m.: and rats. (a) after 37-41 days-—-moderate hypertrophy and hyper. Haydon, plasia uf bronchial and bronchiolar epithelium. 1964 (b) after 146-157 days—(1} Advanced hypertrophy and U.S.A. hyperplasia of bronchial and (90). bronchiolar epithelium, (2) Increased lung volume. (3) Proliferation of connective tissue. Haydon Sprague-Dawley 12.5 p.p.m. to death: et al., rats. (a) Hypertrophy and occasional metaplasia of bronchial 1965 and bronchiolar epithelium. U.S.A. (b) Increase in number of actively secreting goblet cells. (107). Haydon Albino rabbits. 8-12 p.p.m. for 4 months: et al., (a) Abnormal dilatation of peripheral air spaces. 1967 (b) Decreased density of alveolar walls, U\S.A. (¢) Hypertrophy and hyperplasia of bronchial epithelium (106). (especially terminal bronchiolar). (d) Increase in size of alveolar ducts. (e) Increased elastic tissue staining. (f) Increased alveolar size. Freeman Sprague-Dawley 0.8 p.p.m.-2 p.p.m, for entire lifespan: et al., rats. (a) Alveolar distention. 1968, (b) Reduction in number of cilia. U.S.A. (ce) Epithelial inactivity (‘‘dormancy”). (91). Freeman Sprague-Dawley 18 p.p.m. et al., rats. (a) 5 days—terminal bronchiolar epithelial hypertrophy. 1968, (b) 4 weeks—(1) Widespread bronchiolar epithelial hy- U.S.A. pertrophy. {89), (2) Non-necrotizing emphysema. Blair Female Swiss 0.5 p.p.m.: etal, Albino mice. (a) 6 hours/day for 3 months—pneumonitis. 1969, (b) 24 hours/day for 3 months—(1) Respiratory bronchi- ULS.A. olar obstruction. (32). (2) Alveolar expansion and bronchiolar inflammation con- sistent with early focal emphysema. Kleinerman, Male Syrian Golden 100 p.p.m. for 513 hours: 1970, hamsters. (a) thymidine autoradiography—intense burst of prolif. U.S.A. eration of epithelium returning to normal in 4 days (186). (more persistent distally). 220 (b) electron microscope-(1} Decreased number of se- cretory cells + secretory granules, (2) Increased number of lyso- somal structures. (3) No change in number of ciliated cells. TABLE A18.—Experiments concerning the effect of cigarette smoke or tts constituents upon ciliary function Author, year, country, System Method ! Results reference Mendenhall /7 vitro: Cigarette smoke Controls—ciliary activity depressed approxi- and Calf trachea. by direct appli- mately 4 percent. Shreeve, eation or in Experimental—ciliary activity depressed ap- 1937, solution. proximately 40 percent. U.S.A. (164). Rakieten In vitro: I, Nicotine in J. Ciliary activity depressed only upon ex- etal. {a) rabbit Locke-Ringers posure to 100 mg. percent solution. 1942, and rat solution. Il. Ciliary activity depressed after 15-20 min- USA. trachael Il. Cigarette smoke utes exposure depending on concentration (188). rings. in solution. of smoke in solution. (b) human nasal mucous membrane Kordik In vitro: Nicotine in Locke’s Nicotine at 10—° g./ce had no effect on ciliary etal. Rabbit solution. activity. 1952, trachea England (187), Hilding, In vitro: Cigarette smoke All tracheas showed depressed or absent ciliary 1956, Cow trachea (direct activity. U.S.A. exposure}. (120). Krueger In vivo: Cigarette smoke. Cigarette smoke decreased ciliary activity by and Rabbit approximately 200 beats/minute. Smith, trachea 1958, ULS.A. (139). Dalhamn, Tn vivo: Cigarette smoke. I. 7/10 showed cessation of ciliary activity 1959, I. Rat after one exposure. Sweden trachea II. 6/10 showed cessation of ciliary activity (59). In vitro: after one exposure. Il. Rabbit TIl. 6/7 showed cessation of ciliary activity trachea after one cigarette exposure. Ili. Human ciliated mucosa Falk In vitro: Cigarette smoke. Decreased ciliary activity noted on exposure to et al, Rat and rabbit cigarette smoke: 1959 tracheal (a) Repetitive exposure was associated with U.S.A, epithelium. persistence of response over longer periods (80). of time. (b) ‘‘Tar’-rich cigarette was more inhibitory than ‘‘tar’’-poor. {c)} Filtered smoke was less inhibitory than unfiltered. Ballenger, Jn vitro: Cigarette smoke Ciliary activity was fully inhibited within 5-28 1960, Human in solution. minutes of exposure depending upon concen- U.S.A, bronchial tration of smoke in solution. (25). and tracheal epithelium obtained during anesthesia. 221 TABLE A13.—Eaperiments concerning the effect of cigarette smoke or its constituents upon ciliary function (cont.) Author, year, country, System Method 2 Results reference Wynder In vivo: Cigarette smoke; Unfiltered cigarette smoke—ciliastasis by 2nd. et al., Fresh water and its fractions 5th puff, 1963, mussel in solution. Acid (phenolic) fraction solution—immediate U.S.A. ciliated ciliastasis. (286). epithelium. Whole extract fraction solution—no ciliastasis, Neutral fraction solution—no ciliastasis. 1 percent phenol solution—immediate ciliasta- sis. Dalhamn In vivo: Cigarette smoke. Unfiltered cigarettes—ciliastasis in 3/5 cats and Cat trachea. after 5 cigarettes. Rylander, Filtered cigarettes—no ciliastasis after 8 ciga- 1964, rettes (5 cats). Sweden Controls—no ciliastasis (5 cats). (61), Ballenger Invitro: Nicotine in solution. Initial stimulation of activity followed by de et al., Human celine and complete ciliastasis after 12-24 1965, ciliated hours of exposure. U.S.A. tracheal (26). epithelium obtained during. anesthesia. Dalhamn in vive: Cigarette smoke. The longer the time interval between expo- and Cat trachea. sures, the more puffs were required to cause Rylander, ciliastasis, 1965, Sweden (62). Wynder In vivo: Various compounds Formic, acetic, propionic, benzoic acids all etal, Fresh water in solution. more ciliatoxic than phenol. 1965, mussel Oxalie acid less ciliatoxie than phenol. U.S.A. ciliated Formaldehyde, acrolein more ciliatoxic than (285). epithelium phenol. Carson In vivo: Cigarette smoke. Percent decrease in ciliary activity etal., Cat trachea. Control . 0... ec ee cece eee eens 0 1966, Unfiltered smoke ...........-.: eee cece eee 5B U'S.A. Cellulose acetate filter .......... 45 (44). Carbon cellulose acetate filter 30 Dalhamn, In vivo: Cigarette smoke. Mean number of puffs required to produce 1966, Cat trachea. ciliastisis Sweden No filter 0... cc eee ee eee eee eee 91 (60). Charcoal filter ........ 0... cece cece eee eee 170 Commercial cellulose acetate filter ........ 194 Charcoal and acetate filter .............. 512 Cambridge filter 2.0.00... . cc ccc eee eee 600 Kensler In vivo: Cigarette smoke Rabbit trachea—Total smoke condensate of 3 and Rabbit and components cigarettes, gas phase condensate of 7 ciga- Battista, trachea, in Tyrode’s rettes caused similar ciliastasis. 1966, eattrachea, solution. Other species—All found sensitive to ciliastatic U.S.A. dog trachea, components of cigarette smoke. Bulk of ac- (185). monkey tivity noted in gas phase (HCH, formalde- trachea, hyde, acrolein). rat trachea. TaBLe A13.—Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function (cont.) Author, year, country, System Method 1 Results reference Dalhamn In vivo: Cellulose acetate- Increased amounts of tar were associated with and Cat trachea. filter cigarettes decreased number of puffs required to inhibit Rylander, with varying ciliary activity. 1967, amounts of Sweden “tar” but simi- (63). lar gas phases. Dalhamn In vivo: Unfiltered and Whole smoke found to be markedly more toxic and Cat trachea. Cambridge-filter to ciliary activity than volatile (gas) phase Rylander, cigarettes. at lower dosages (puff volume). This differ- 1968, ence diminishes with increasing puff volume. Sweden (64). Kaminski In vivo: Whole and filtered Wet chamber adsorption significantly reduced et al., Cat trachea. cigarette smoke the ciliastatic activity of whole smoke, but 1968, exposed or unex- did not affect the ciliastatic activity of smoke U.S.A, posed to ‘‘wet previously filtered by Cambridge or charcoal (188). chamber” made filters. to stimulate oral mucosa and saliva. Krahl In vivo: Cigarette smoke Significant ciliastasis, reversible. and Common dissolved in Bulmash, mollusk sea water. 1969, ciliated U.S.A. epithelium. (188). Battista In vitro: Cigarette smoke The authors observed that: and Chicken or HCN in (1) The more diluted smoke required more Kensler, tracheal Tyrode’s puffs to cause ciliastasis. 1970, epithelium. solution, (2) Activated charcoal filtered smoke was U.S.A. less ciliastatic than cellulose acetate filtered (28). smoke and also contained less HCN and acrolein, (3) HCN alone was ciliastatic but recovery was more rapid than after cigarette smoke alone. They conclude that the gas phase components are more related to ciliastasis (as particulate matter is not significantly decreased by char- coal filtration while HCN and acrolein are). Battista In vivo: Cigarette smoke. The authors observed that: and Hen trachea. (1} Whole smoke acutely depressed ciliary Kensler, activity in 4-6 puffs. 1970, (2) Gas phase was only slightly less depres- U.S.A. sant than whole smoke. (29). (3) Chronic exposure (1 cigarette/day for 32 days) to smoke resulted in no apparent permanent defect in ciliary activity (al- though mucous production was signifi- cantly increased). 223 TABLE A1l3.—Experiments concerning the effect of cigarette smoke or its constituents upon cittary function (cont.) Author, year, country, System Method 1 Results reference Dalhamn In vivo: Unfiltered cigarette Average number of puffa required to arrest and Cat trachea. and cigar smoke. ciliary activity Rylander, Cigarette smoke ....... 13 1970, Cigar smoke ......... “rap (@<0.01) Sweden The authors note that cigar smoke is of a (65). different pH and that it contains more igo- prene, acetone, toluene, and acetonitrile, Kennedy In vivo: Mainstream Electron microscopic observations: and Protozoan cigarette smoke, (1) After 7 minutes exposure—alteration of Elliott, (ciliated). mitochondrial structure. 1970, (2) After 42 minutes exposure—destruction U.S.A. of internal mitochondrial membrane struc- (194). ture, (3) Gas phase alone, while ciliatoxic, did cause mitochondrial swelling but no dis- ruption of membrane structure. +Unless otherwise stated, method entailed the direct observation of ciliary activity using markers. 224 St TABLE Al4.-Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tension Author, year, country, System Method Results reference Miller and Rat lung extracts Cigarette smoke: (1) Exposure to cigarette smoke was associated with decreased surface tension in lung extract. Bondurant, (1) Applied to (2) Surface tension of rats (lung extracts) exposed to’ cigarette smoke was decreased 1962, extract. as compared with those not exposed. U.S.A. (2) Exposure (165) of rats. Cook 40 subjects undergoing Surface tension and Webb bronchoscopy: values of surfactant 1966, 14 normal 20 100 Stability index (reflects + Values significantly U.S.A. 7 nonsmokers with percent percent surfactant activity) different from (57) pulmonary disease area area values of normals 19 smokers with and Normal .....-+-5- 6.5 60.0 1.61 at p<0.02 level. without pulmonary Pulmonary disease. patients .....- 717.0 $50.0 1.00 Chronic smokers .. 15.7 51.0 1.04 Giammona In vitro: Exposed to In vitro: 1967, Surfactant material cigarette Exposure to cigarette smoke was associated with a significant decrease in maximal surface U.S.A. induced from dogs smoke for tension. (94) and rats. 3 hours/day In vivo: In vivo: for up to Dogs and cats (exposed for 1 week)—no significant change. Dogs, cats, and 3 weeks. Guinea pigs (exposed for 3 weeks)~-significant decrease in maximal] surface tension. guinea pigs. Webb, Bronchial Direct Surface tension valucs of surfactant et al. washing, exposure to 20 percent 100 percent 1967, from cigarette smoke. Number areca arca Stability index U.S.A. dog lungs. Control .......- 11 U1 : 60.7 1.60 (224) Smoke 10 is.74 (P<0.002 weet (p<0.002) 0.84 92% TaBLE A15.—Studies concerning the relationship of smoking to infectious respiratory disease in humans (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokers Author, year, Number and Data country, type of collection Results Comments reference population Mills, 118 male and Hospital Cases Controls The author stated that 1950, female patients Interview. Mean age 49.6 49.6 there was a U.S.A. with pneumonia NS ccc cece cece ese eae 15.25 25.21 significant difference (167). and 472 healthy Cigarettes only 63.56 62.33 in tobacco usage individuals from Mixed 21.19 22.46 between the “random” sample. two groups. Lowe, 520 male and Interview by Males Females Cigarette smokers 1956, 185 female trained Cases Controls Cases Controls include pipe smokers. England tuberculosis social NS cece cece renee eee eee 2.5 8.1 37.8 61.4 The author noted a (157). patients and 419 worker. Cigarettes/day: 1-9 ...... 9.2 12.9 20.5 25.7 significant deficiency male and 249 W019 eee eee 38.1 35.6 30.8 20.5 of non- and light female control 20-29 oo eee eee eee 29.4 27.4 smokers and an outpatients. 80-39 cee eee eee eee 11.3 9.3 11.4 2.4 excess of heavy oo | 9.4 6.7 smokers among the cases Dowling, Individuals Interview and Exposed to placebo Exposed to infectious agent No statistically etal, exposed to medical Percent Percent significant 1957, “infectious examination. developing developing differences U.S.A. cold agent” Number “cold” Number “cold” noted. (72). and placebo. NS wee ccc eee cee eee 111 10 328 34 SM woe ccc ee eee eves 18 14 249 35 LEZ TaBLE A15.—Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.) (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokers Author, year, Number and Data country, type of collection Results Comments reference population Boake, Parents of Interview Number of No statistically 1958, 59 families. Person- reapiratory Illnesses/ significant U.S.A. years ilineasea person-years differences (38). NS cece eee eee enes (24) 120 624 5.2 noted. Cigarettes/day: 1-10 ......... (19) 99 529 5.3 U2-20 Lecce eee eee eee (25) 108 486 4.5 S20 cece eee cnn eee (19) 99 424 4.3 Pipe, cigar ...-.....ees renee (14) 12 304 4.2 Shah Tuberculosis Survey, X-ray, Tuberculous Normal or + Numbers in et al, institute and by X-ray . nontuberculous parentheses 1959, employees. interview. NS coe e cece ccc ee eee ee t10 (19.7) 178 (168.3) represent figures India SM owe ee eee eee 86 (26.3) 215 (224.7) “expected” by use of (205). 2x2 contingency table. Tuberculous employees were found to have significantly fewer nonsmokers and more smokers. 8zz TABLE A15.—Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.) (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokers Author, year, Number and country, type of Data reference population collection Results Comments Brown 306 male and Interview Smoking habits prior to diagnosis Data presented only et al., female Tuberculous patients Controls on Queensland 1961, tuberculosis (percent) (percent) sample. Australia elinie NS coc cee eee cee nee . 9.1 19.9 The authors noted (4). patients, Cigarettes/day: 10.5 15.4 that the 221 male and 10-19 84.3 19.5 significant difference female 20-29 26.3 25.8 between the outpatients. 30-39 1.2 5.4 patients and >40 Lo. 6.2 9.1 controls was not Pipes 5.9 4.6 present when the groups were matched for alcohol intake. Haynes 191 male Interview Average number of respiratory illnesses/10 students etal, prep school (adjuated for age) 1966, students. All severe lower U.S.A. All All severe or combined (108). respiratory respiratory respiratory episodes episodes episodes NS (99) ci cec cece cence eee 11,1 1.6 0.36 SM (92) cee eee eee eee 20.2 6.7 3.34 Parnell 47 smoking- Interview Median number of illnesses/student The authors noted et al., nonsmoker pairs and health All All that these 1966 of student nurses service respiratory other differences were Canada matched for age records. diseasest illnesses statistically (181). and parents’ NS (47) 2.08 2.99 significant. occupational SM (47) 2.54 5.00 ¢ Particularly class. tracheitis, bronchitis, and pneumonia. 672 Tapie Al5.—Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.) (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokers Author, year, Number and Data country, type of collection Results Comments reference population Peters 1,496 Harvard Medical history, Number of visits to student health unit for respiratory illness/ student t p<0.001. et al., and chart review, (common. colds, pharyngitis, bronchitis, laryngitis, 1967, 370 Radcliffe and pneumonia—not allergic rhinitis) U.S.A. students. questionnaire. Harvard Radcliffe (183). DS 1.44 (771) 1.44 (193) SM nce eee eee eee $2.27 (725) 2.27 (177) <2 years smoked .......- 2.00 BHA eee tenes 2.30 DB eee eee eee 2.50 Finklea 1,811 male Questionnaire Heavy smokers—21 percent more clinical illnesses than nonsmokers; The authors also et al., college prior to 20 percent more requiring bed rest than nonsmokers noted that: 1969 students. A,/HK/68 ” Light smokers—10 percent more clinical illnesses than nonsmokers; (a) Smokers U.S.A. epidemic and 7 percent more requiring bed rest than nonsmokers. exhibited (83). follow-up on serologic morbidity. evidence of increased subclinical A,/HK/68 infection. (b) There was no difference in the vaccination status between smokers and nonsmokers. TABLE A16.—Complications developing in the postoperative period in patients undergoing abdominal operations Men over 20 Percent Percent broncho- Percent Group Cases chest Percent pneumonia total clear bronchitis and complication atelectasis rate Smokers .............-.+.-.- 800 41,7 53.0 5.3 58.3 Light Smokers .............. 180 68.4 27.7 3.9 31.6 Nonsmokers ................ 66 92.5 6.0 1.5 1.5 Women over 20 Smokers ............0 0005: 23 89.1 43.5 17.4 60.9 Light Smokers ............. 62 WS 20.9 1.6 22.5 Nonsmokers ..........-.00005 518 88.8 8.1 3.1 112 Source: Morton, H. J. V. (173) TABLE A17.—Arterial oxygen saturation before and after operation Arterial oxygen saturation (percentage) Case Before Group number operation Day 1 Day 2 Day 3 1 94 93 94 2 94 93 94 Nonsmokers 2... 0.0.00 cece eee eee 3 96 93 94 4 95 90 94 5 94 90 93 6 95 91 89 91 7 92 89 81 89 Smokers . 1.2.00... 0. cee eee eee 8 91 89 85 89 9 93 91 88 92 10 30 87 88 92 Source: Morton, A. (172). 230 CHAPTER 4 Cancer Contents Introduction ..... 0.0 ce ce eee eee teens Lung Cancer Nickel Chromium Pathological Studies Tracheobronchial Implantation and Instillation ........... 0.0 c eevee Inhalation .. 0.0... cee eee Reduction in Tumorigenicity .............. Summary and Conclusions ....... 00.052. e eee eens Cancer of the Larynx Pathological Study Oral Cancer Epidemiological Studies ... 0.0.0... c eee ee ee ee eee Prospective Studies 00... 0... cee eee ee eee eee Retrospective Studies ........ 0... cee eee ees Lung Cancer Trends in Other Countries ............ Histology of Lung Tumors .......... 00.002 eee eee ee Lung Cancer Relationships in Women ............-. Lung Cancer, the Urban Factor, and Air Pollution.... Lung Cancer and Occupational Hazards ............ Uranium Mining ........... 2.00 ee ee Other Occupations... 0.0.0... 02. AsbestoS. 2... ccc eee eee AYSCNIC. 2 eee enn eee Pulmonary Carcinogenesis ....... 0... ee ee eee General Aspects of Carcinogenesis ............. Polynuclear Aromatic Hydrocarbons ....... Nitrosamine Compounds................5- Pesticides and Fungicides................-. Radioactive Isotopes ...........0000e sere Inhibitors of Ciliary Movement ........... Experimental Studies ...............0 eee eee Skin Painting and Subcutaneous Injection... Tissue and Organ Culture .............4. Epidemiological Studies ...... 0.0... ec eee eee eee Experimental Study .. 02.6... 0c cece eee ees Summary and Conclusions .......... 2. eee eee eee Epidemiological Studies ...... 0.0... eee eee ee ee eee Experimental Studies ......... 00.50 e eee eee eee eee Summary and Conclusions ..... 6.0.52. eee eee eee Cancer of the Esophagus ................000ccceeeeeue Epidemiological Studies ...................00 0000, Pathological Study ........0. 000... cee cee cee eeee Experimental Studies ....... 0000.0 0c. e cece ce eee Summary and-Conclusions .............0....00000, Cancer of the Urinary Bladder and Kidney .............. Epidemiological Studies (Bladder) ................. Epidemiological Studies (Kidney) ................. Experimental Studies ........00.0. 0.0... 0c cece eee Summary and Conclusions .........0..... 00000000, Cancer of the Pancreas ..... 0.00. cece cece cee ccceee Summary and Conclusions .............. 000.00 ceee References ......... 00.0 ccc eve ec cece ev cece ee ncnnnces FIGURES 1. Lung cancer, Finland and Norway ................... 2. Percent of smoking dogs with tumors ................ 3. Percent of lung lobes with tumors in smoking dogs ..... 4. Effects of chronic cigarette smoke inhalation on the A3. Ad, 10. 234 hamster larynx ....... 0.0000. cc cee cece ce eeeee LIST OF TABLES Lung cancer mortality ratios ................004, Lung cancer mortality ratios for males by duration of cigarette smoking .............. 0.00.00 ceeeee Outline of methods used in retrospective studies of smoking in relation to lung cancer ............. Group characteristics in retrospective studies on lung cancer and tobacco use ...............00.00 ce Annual means of total lung cancer mortality and sex ratios for selected periods in Finland and Norway Epidemiologic and pathologic investigations concern- ing smoking and histology of lung cancer ....... Grouping of pulmonary carcinomas .............. Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking CaleQOry . 6. ke cee ce cece nuevas Epidemiologic investigations concerning the relation- ship of lung cancer to smoking, air pollution, and urban or rural residence ...................04, Pathologic and cytologic findings in the tracheo- bronchial tree of smokers and nonsmokers ...... Page 289 289 292 292 293 293 293 296 296 299 299 299 299 245 274 274 284 241 244 323 329 246 247 334 250 2538 259 Al4, Al5, Al6. 17. 18. 19, 20. A21, A22, A23, A24, 20. 26. 27, A28. A28a, LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) Identified or suspected tumorigenetic agents in cigarette smoke .........0. 0. ccc eee eee eee Autopsy studies concerning the presence of radio- activity in the lungs of smokers .:............. Experiments concerning the effects of the skin paint- ing or subcutaneous injection of cigarette smoke condensate or its constituents upon animals ..... Experiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures .. Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constitu- ents into the tracheobronchial tree of animals .... Experiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals .................. Data on pedigreed male beagle dogs of groups F, L, H, hand N .... ec eens Summary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H, h and N Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found .... Laryngeal cancer mortality ratios — prospective studies 2.0... ccc ene ee eens Outline of retrospective studies of tobacco use and cancer of the larynx .....0...... 0.0 cece cece eee Summary of results of retrospective studies of tobacco use and cancer of the larynx ...............005- Number and percent distribution by relative fre- quency of atypical] nuclei among true vocal cord cells, of men classified by smoking category ..... Number and percent distribution, by highest num- ber of cell rows in the basal layer of the true vocal cord, of men classified by smoking category .... Deposition of }#C-labeled smoke particles in particu- lar regions of the respiratory tract ............ Classification of the five registered stages of epithe- lial changes at the larynx .............. 0.2.0.4. Oral cancer mortality ratios—prospective studies. . Outline of retrospective studies of tobacco use and cancer of the oral cavity ............. 05. eee Summary of results of retrospective studies of smok- ing by type and oral cancer of the detailed sites. . Page 265 335 337 343 346 349 270 271 272 278 354 358 359 360 282 283 286 361 368 235 LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) Page 429. Experimental studies concerning oral carcino- WENESIS oo eee eee 371 30. Esophageal cancer mortality ratios—prospective studies occ eee een eens 290 A381. Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus ...... 375 A3la. Summary of results of retrospective studies of to- bacco use and cancer of the esophagus ......... 378 A382. Atypical nuclei in basal cells of epithelium of esoph- agus of males, by smoking habits and age ...... 379 A33. Atypical nuclei in basal cells of epithelium of esoph- agus of males, by amount of smoking and age .... 386 34, Kidney and urinary bladder cancer—prospective studies 2... ec ee eee eee 294 A35. Summary of methods used in retrospective studies of smoking and cancer of the bladder ............ 381 A35a. Summary of results of retrospective studies of smok- ing and cancer of the bladder ..........-...... 383 26. Pancreatic cancer mortality ratios—prospective StUdIeES oe eee eee ee eee 298 236 INTRODUCTION During the early vears of this century, a number of pathologists and clinicians reported a dramatic increase in the incidence of lung cancer, Autopsy studies and studies of lung cancer death rates re- vealed a significant increase beginning prior to World War I and continuing during the ensuing years. This epidemic of lung cancer continues to the present day, with nearly 60,000 deaths expected from this disease in the United States during 1970. Beginning in the 1920’s, a number of reports appeared which suggested a relationship between lung cancer and tobacco smoking (4, 203, 278). Since that time, many clinical and epidemiological studies have been published which confirm this relationship. The 1964 Report (291) contains a thorough review and analysis of the data available at that time as well as an excellent discussion of the considerations necessary for their evaluation. Major epidemiological studies have demonstrated that smokers have greatly increased risks of dying from lung cancer compared to nonsmokers. An increased risk of lung cancer has been found for every type of smoking habit investigated, but two character- istics of the risk are particularly evident: The risk is much greater for cigarette smokers than for smokers of pipes and cigars, and among cigarette smokers a dose relationship exists. That is, the more one smokes, as measured by total pack-years of smoking, present level of smoking, degree of inhalation, or age at start of smoking, the greater is the risk. It has also been shown that the risk of lung cancer among ex-smokers decreases with time almost to the level of nonsmokers; the time required is dependent on the degree of exposure prior to cessation. Pathologists have found that the squamous cell or epidermoid form of lung cancer is the most prevalent one in cigarette smoking populations and that this form accounts for a major portion of the rise in lung cancer deaths (75.4). Such studies have also indi- cated a lower prevalence among smokers for oat-cell and adeno- carcinomas of the lung than for the squamous form, but in most studies a higher frequency of these tumors is found among smokers than among nonsmokers. Smoking has been implicated in the development of other types of cancer in humans. Among these is cancer of the larynx. A num- 237 ber of epidemiological studies have demonstrated increased mor- tality rates for laryngeal cancer in smokers, particularly cigarette smokers, compared with nonsmokers. Autopsy studies have re. vealed that a clear dose-relationship exists between smoking and the development of cellular changes in the larynx, including carei- noma in situ. Cancers of the mouth and oropharynx have been found to be more common among users of all types of tobacco than among abstainers. Although smoking is a definite risk factor in the de- velopment of malignant lesions of the oral cavity and pharynx, its relative contribution in conjunction with other factors such as poor nutrition and alcohol consumption has not been fully clarified, Similarly, although smokers are more likely to develop carci. noma of the esophagus than nonsmokers, the relative additional] contribution of smoking in conjunction with nutritional factors and alcohol consumption requires clarification. Smokers have been found to be more at risk for the development of cancer of the urinary bladder than are nonsmokers, and there is evidence to suggest that some smoking-induced abnormal meta- bolic product or abnormal concentration of a metabolic product may be responsible for this increased risk. In addition, cancer of the kidney is apparently more common in smokers than in non- smokers, but the epidemiologic evidence for this relationship is not as definite as for bladder cancer. Epidemiological studies have indicated an association between smoking and cancer of the pancreas. The significance of this rela- tionship is unclear at this time. Experimental studies have demonstrated the carcinogenicity of the condensate of tobacco smoke, or “tar.” This material, when painted on the skin of animals, leads to the development of squam- ous cell tumors of the skin. Researchers have shown that this condensate contains substances known as carcinogens, capable of inducing cancers. Among these carcinogens are several chemicals which have been identified as tumor initiators, that is, compounds which initiate changes in target cells and also tumor promoters, or compounds which promote the neoplastic development of initi- ated cells. Other, as yet unidentified, factors are presumably also involved because the sum of the carcinogenic effects of the known agents does not equa] that of cigarette smoke condensate. Numerous experiments have been performed in which whole cigarette smoke, filtered smoke, or certain constituents of smoke, such as the “tar,” are administered by varying methods to animals or to tissue and cell cultures in order to investigate the neoplastic- inducing properties of cigarette smoke, Particular difficulty has been encountered in experiments which have attempted to deliver 238 whole cigarette smoke to the larynx and into the lungs of experi- mental animals. This has resulted in the use of other methods such as the implanting of pellets containing suspected carcinogens and the instilling into the trachea of suspected carcinogens as such, or adsorbed onto fine inert particulate matter as a carrier. The dif- ficulty with the inhalation studies has been twofold. First, the animals, particularly the smaller species such as the rat, frequently die from the acute toxic effects of the nicotine and carbon monoxide in the tobacco smoke. Second, the upper respiratory tract of experi- mental animals, particularly the nose, is much different from anal- ogous human structures, resulting in a more efficient filtration of smoke in the upper respiratory tract. Nevertheless, in rodents and canines, progressive changes apparently indicative of ultimate neo- plastic transformation have been identified in the respiratory tract. Recently, two studies in different species and in different target organs have been reported concerning the development of early in- vasive cancer following the prolonged inhalation of cigarette smoke. Auerbach and his coworkers (11) trained dogs to inhale cigarette smoke through a tracheostoma. After approximately 29 months of daily exposure, these investigators found a number of cancers of the lung. Dontenwill (76) in the second of these two studies, exposed ham- sters to the passive inhalation of cigarette smoke over varying and prolonged periods of time. He observed the development of pre- malignant changes and, ultimately, invasive squamous cell cancer of the larynx. LUNG CANCER Cancer of the lung in the United States accounted for 45,383 deaths among males and 9,024 deaths among females in 1967 (289). It is presently estimated that approximately 60,000 people will die of lung cancer during 1970. The alarming epidemic of lung cancer is a relatively recent phenomenon. Death rates for lung cancer (ICD Codes 162, 163) rose from 5.6 (per 100,000 resident population per year) in 1939 to 27.5 in 1967 (289, 290). This rapid increase followed the in- creased use of cigarettes among the United States population. The increase has occurred principally among males, although more re- cently females have shown a similar rising pattern. The converging evidence for the conclusion that cigarette smok- ing is the major cause of lung cancer is derived from varied types of research including epidemiological, pathological, and laboratory investigations. 239 EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, both retrospective and pros- pective, have been carried out in different parts of the world to investigate the relationship between smoking and cancer of the lung. These studies are outlined in tables 1, 2, A3, and A4. Prospective Studies The major prospective studies concerning the relationship of smoking and lung cancer are presented in table 1. In all, these investigations have studied more than a million persons from a number of different populations for up to 10 years. These studies show increased lung cancer mortality ratios for cigarette smokers of all amounts ranging from 7.61 to 14.20 among male smokers as compared to nonsmoking males. The one major prospective study of female cigarette smokers reveals an overall mortality ratio of 2.20 (118). Also uniformly present in these studies is a dose-related increase in the mortality from lung cancer with increasing amounts of cigar- ettes smoked per day. Other measures of exposure show similar trends. Hammond (118) reported increased mortality ratios asso- ciated with increased inhalation (table 1) as well as with increased duration of smoking (table 2). .. Ex-smokers show significantly lower lung cancer death rates than continuing smokers. In their study of more than 40,000 British physicians, Doll and Hill (74, 75) noted a decrease in lung cancer mortality rates with increasing time since smoking stopped (table 1). During the past 20 years, half of all the physicians in Britain who used to smoke cigarettes have stopped smoking. While the death rates from lung cancer rose by 7 percent among all men from England and Wales during the period from 1953-57 through 1961- 65, the rates for male doctors of the same ages fell by 38 percent (96). Pipe and cigar smokers have been shown in the prospective stud- ies to have lung cancer mortality rates higher than those of non- smokers, although these are generally substantially lower than those of cigarette smokers (table 1). Retrospective Studies More than 30 retrospective (case-control) studies have been re- ported concerning the relationship of smoking and lung cancer. These studies are outlined in tables A3 and A4. Table A4 presents the percent of nonsmokers and of heavy smokers among both cases and controls as well as the relative risk ratios for all smokers. 240 Lez TABLE 1.—Lung cuncer mortality ratios (Actual number of deaths shown in parentheses)? SM = Smokers. NS = Nonsmokers. Prospective studies Author, Number year, and type collection Follow- Number Regular cigarette Pipe country, of Data up 0 smoking only cigar Inhalation Exsmokers Comments reference population years deaths (cigarettes/day) Hammond 187,783 Question- Bla 448 Pipe No data Bronchogenic 341/448 and white naire and SM . 443 NS ..... 1,00 (15) NS . 1.00 (15) (acluding adenocarcinoma) deaths with Horn, males interview. NS. 15 <10 . 8.00 (24) SM . 2.57 (18) Never smoked .......-- 1.00 microscopic 1958, in 9 ...10.50 (84) Cigar Previously <1 pack/day proof. In- U\S.A. States .. 23.40(117) NS ... 1.00 (15) Continuing weve ee 16.94 cludes those (120). ages ... 410.73 (397) SM ... 1.00 (7) Duration >10 years .. 1.51 smokers who Previously >1 pack/day also smoked Continuing .....-.-++: 46.21 pipes and Duration] 10 years ..17.79 without microscopic proof. Dolland Approxi- Question- 10 212 NS ....-- 1.00 (3) Pipe and Cigar No data Cigarette amokers Hill, mately naire and SM . 209 1-14 . 814 (22) NS.... 1.00 (3) NS coc cc cece cee ee cease 100 (3) 1964, 41,000 followup NS. 8 15-24 ...19.86 (53) Grams/day Continuing .....---+-- 18.29 (124) Great male of death >>25 | 82.48 (57) 1-14... 6.00 (12) Duration 20 years . 2.71 (2) Best, Approxi- Question- 6 3381 NS ..... 1.00 (7) Pipe No data { Refers 1966, mately naire and TSM . 324 <10 ....10.00 (67) NS ....1.00 (7) NS ..cccceee ce eeeee es 1,00 (7) to cure 1966, 78,000 followup NS. 7 10-20 ...16.41(204) 5M ... .4.35 (18) Ex-smokers 0: rent Canada male of death 20.0 ....17,81 (63) Cigar cigarettes only ...... 6.06 (18) cigarette (21). Canadian certificate. All ..... 14.20(245) NS ....1.00 (7) smokers veterans. SM ....2.94 (2) only. cre TABLE 1.—Lung cancer mortality ratios (cont.) (Actual number of deaths shown in Parentheses )1 SM = Smokers. NS = Nonsmokers. Prospective studies Author, Number year, and type Data Follow- Number Regular cigarette Pipe country, of collection up 0: smoking only cigar Inhalation Exsmokers Comments reference population years deaths (cigarettes/day ) Kahn U.S. male — Question- 8% 1,256 Pipe (Dorn), veterans naire and SM .1,178 NS ..... 1.00 (78) NS ....1.00 (78) No data 1966, 2,265,674 followup NS. 78 1-9 .... 5.49 (45) SM ....1.84 (17) NS ............ 1.00 (78) U.S.A, person of death 10-20 ... 9.91(303) Cigar Number of cigarettes/day: (189), years. certificate. 21-39 ...17.41(315) NS ....1.00 (78) 1-9 «ee. 0.95 (4) >39 ....23.93 (82) SM ....1.59 (6) 10-20 ......... 8.48 (39) All .....12.14(749) Pipe and cigar 21-39 ........, 9.83 (57) NS ....1.00 (78) >39 wo... 8.24 (19) SM ....1.66 (20) Hammond, 440,558 Interviews 4 Males Current cigarettes Pipe Males ICD code 1966, males by ACS 1,159 only NS ....1.00 (49) NS ........ 1.00 (49) 162 only, U.S.A. 562,671 volunteers. SM .1,116 Males SM ....2.24 (21) Slight ...... 8.42 (120) (118), females NS. 49 NS ..... 1.00 (49) Cigar Moderate ...11.45(311) 35-84 Females 1-9 .... 4.60 (26) NS ....1.00 (49) Deep ....... 14.31(141) years of 183 10-19 ... 7.48 (82) SM ....1.85 (22) Females age in 25 SM. 81 20-39 ... 18.14(881) Pipe and cigar NS ........ 1.00 (102) States, NS . 102 >40 ....16.61 (82) NS ....1,00 (49) Slight ....,. 1.78 (25) All ..... 9.20(719) SM ....0.90 (11) Moderate Females Deep i + 3.70 (45) NS ..... 1.00(102) 1-19 .... 1.06 (20) >20 .... 4.76 (50) AN ..... 2.20 (81) TABLE 1.—Lung cancer mortality ratios (cont.) (Actual number of deaths shown in parentheses)! SM = Smokers. NS = Nonsmokers. Prospective studies ere Author, Number Follow- year, and type Data up Number Regular cigarette country, of collection years of smoking only Exsmokers Comments reference population deaths (cigarettes/day ) Buell 69,868 Question- 3 304 NS .... 1.00 etal. American naire and <20 .... 2.80 1967, Legion- followup 20 ... 3.50 U,S.A. naires of death >20 .... 4.90 (49). 35-75 certificate. years of age and older. Hirayama, 265,118 Trained 1% 48 NS ..... 1.00 (3) Preliminary 1967, male and PHS SM. 40 1-24 .. 2.69 (29) report. Japan female nurse >25 . 5.68 (5) (125). adults interview 40 years and fol- ofageand lowup of older. death certificate. Weir and 68,153 Question- 5-8 368 NS -» 1.00 NS include Dunn, males in naire and +10 .... 3,72 pipe and 1970, various followup #20 ». 9.05 cigar U.S.A. occupa- of death >30 . 9.56 smokers (806). tions in certificate. All ..... 7.61 SM include California. ex-smokers. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or examokers, TABLE 2.—Lung cancer mortality ratios for males by duration of cigarette smoking (Actual number of deaths are shown in parentheses) Age began cigarette smoking 35-54 55-69 70-84 35-84 25 or older .........--, 2.77 (5) 3.39 (12) 3.38 (3) 3.21 (20) 20-24 cece eee eee 5.83 (31) 11.11 (72) 12.11 (7) 9.72(110) TB-19 eee eee 8.71 (112) 13.06 (176) 19.37 (27) 12.81(315) IB eee cee ee eee 12.80 (35) 15.81 (57) 16.76 (9) 15.10(101) Source: Hammond,E. C. (118). These smoker-nonsmoker risk ratios range from 1.2 to 36.0 for males and from 0.2 to 5.3 for females. Although not presented in tabular form, the data concerning lung cancer and pipe or cigar smoking are similar to those found by the prospective studies mentioned above. However, a study by Abelin and Gsell (1) conducted on a rural Swiss population noted that an increased risk of lung cancer was present among heavy cigar and pipe smokers (as well as cigarette smokers) to a greater degree than previously reported. The authors suggest that their findings might be due to differences in either the amount smoked or the car- cinogenicity of Swiss and German cigars. The difference might also be explained by the greater use and more frequent inhalation of small cigars in Switzerland as compared to other countries where large cigars are more commonly smoked but rarely inhaled. Kreyberg (154), in a review of 887 cases of lung cancer in Norway, noted that pipe smokers showed an increased risk of lung cancer, although this risk was substantially lower than that for cigarette smokers. LUNG CANCER TRENDS IN OTHER COUNTRIES Several studies of particular interest are those in which the changing mortality from lung cancer has been investigated in countries in which cigarette smoking has become popular and wide- spread only in recent years. In those countries where accurate statistics for lung cancer mortality are available for both the pre- smoking and post-smoking periods, long-term trends can be studied in some detail. Two such studies have dealt with lung cancer mortality trends in Iceland. Dungal (83) noted in 1950 that lung cancer was a rare disease in Iceland and felt that this rarity could be explained by the relatively late onset of heavy tobacco smoking in the Icelandic population when compared to that of Great Britain and Finland. He observed that the annual per capita consumption of tobacco did not reach one pound in Iceland until 1945, while Great Britain and Finland passed that amount before 1920. In 1967, Thorarinsson, et al. (276) noted a sharp rise in the incidence of lung cancer in Ice- 244 60— SS Finiand Cy 50— 2 a BE Norway 40— 30— 8 20— 2 8 - to o é oe) 2 _/ LJ = 10 £ - © g e+ * B z ¢ 6— < 4— 3— 2— 1934-36 1939-41 1944-46 1949-51 1954-56 1959-61 1963-64 Calendar Years Ficure 1.—Lung cancer, Finland and Norway. Source: Kreyberg, L. (154). land after 1950 and found a correlation between that increase and the increasing sale of cigarettes in that country. Kreyberg (154) analyzed the lung cancer death rates of both Norway and Finland in relation to the use of tobacco in those two Countries over the past 100 years. Figure 1 shows the substantial difference in lung cancer mortality between the two countries. Kreyberg observed that cigarettes came into use in Norway in 1886 while the Finnish population (more closely allied to Russia socio- economically) was consuming more than 100 million cigarettes per year during the decade of the 1880's, Cigarettes remained scarce in Norway until after World War I, and this 30-year lag in consump- 245 TABLE 5.—Annual means of total lung cancer mortality and sex ratios for selected periods in Finland and Norway Finland Norway Year ——______ Males Females Males Females 1936-38 6... eee 192 33 34 30 Sex ratio ................ §.8:1 11:1 1968-65 6 eee 1,319 121 355 79 Sex ratio ................, 10.9:1 45:1 Source: Kreyberg, L. (154). tion behind that of Finland is reflected in a similar lag in total lung cancer mortality and sex ratios (table 5). HISTOLOGY oF LUNG TUMoRS A number of investigators have focused their interest upon the relationship of cigarette smoking to the varied histology of lung tumors. The major histological types of lung cancer include squa- mous cell (epidermoid) carcinoma, small and large cell anaplastic carcinomas, adenocarcinoma (including bronchiolar and alveolar types), and undifferentiated carcinoma (153). A review of these studies (table 6) indicates a closer relationship between cigarette smoking and epidermoid carcinoma than between cigarette smok- ing and adenocarcinoma (42, 113). The work of Kreyberg (153) in Norway, over the past 20 years, provides evidence of a specific histologic relationship. This inves- tigator noted that a clearer association is obtained if the various types of pulmonary carcinomas are grouped. Table A7 presents his groupings of the specific histologic types. Using this classification as a basis for analysis of lung cancer sex-ratios in N orway, Kreyberg has observed that Group I carcinomas are significantly more frequent among males while Group II carcinomas show an approximately equal] distribution among males and females. The author considers the recent rise in lung cancer in Norway to be a reflection of the increased prevalence of Group I carcinomas. Table 8 presents a summary of Kreyberg’s investigation concerning 793 male and female cases of lung cancer. Among both males and fe- males, the risk ratio among smokers is substantially higher for Group I types than for those of Group II. However, adenocarcinoma among males shows a risk ratio of 2.9, signifying a relationship with smoking. Kreyberg attributes the lower rates noted among females to their significantly lower consumption of tobacco in all forms. 246 Lez TaBLE 6.—Epidemiologic and pathologic investigations concerning smoking and the histology of lung cancer" (Actual number of cases shown in parentheses) Author, Number of year, persons and country, case selection Results Comments reference method Wynder 644 autopsies on Percent cases by histologic type and smoking history The percentage of chain and males with All lung cancers other than smokers in the general Graham, confirmed adenocarcinoma (605) Adenocarcinoma (89) population (7.6) was 1950, lung cancer. Nonsmokers 6... ee eee eee 1.3 10.3 significantly less than U.S.A. Light cigarette smokers ............0065 2.3 U4 among the patients with (816). Moderate 0... eee ee eee eee 10.1 15.4 adenocarcinoma. The Heavy oo e eee tee eter e eee 35.2 38.5 authors refrained from Excessive (occ ce cece eee eens 30.9 10.3 making any definite Chain 6 cece eee 20.3 18.7 conclusions due to the insufficient number of cases. Doll 916 male and 79 Percent patients with lung cancer by average amount smoked daily over 10 years No statistically and female cases Males significant difference Hill, with histologically Oat-cell or was found between 1952, confirmed Epidermoid (475) anaplastic (80%) Adenocarcinoma ($3) the amounts smoked by England lung cancer. Nonsmokers........ 0.2 (1) 0.7 (2) 6.1 (2) the patients in the (78). Smokers: different histological <5 cigarettes/day .. 2.9 (14) 3.9 (12) 6.1 (2) groups. Number of 35.6 (169) 36.3(110) 21.2 (7) proven adenocarcinomas W-25 cee eae 36.8 (175) 34.7(105) 48.5 (16) too small for ZB eee ee 24.4(116) 24.4 (74) 18.2 (6) conclusions. Females Oat-cell or Epidermoid (18) anaplastic (38) Adenocarcinoma (10) Males—105 unclassified Nonsmokers ......... 61.1 (11) $1.6(12) 50.0 (5) tumors. Smokers: Females-—13 unclassified <5 cigarettes/day .. 5.6 (1) 15.8 (6) 20.0 (2) tumors. 5-14 2 eee eee 22.2 (4) 23.7 (9) 10.0 (1) 15-25 wee eee ee eee 5.6 (1) 18.4 (7) see DOB eee ce eee eee 5.6 (1) 10.5 (4) 20.0 (2) 8re TABLE 6, E'pidemiologic and pathologic investigations concerning smoking and the histology of lung cancer’ (cont.) (Actual number of cases shown in parentheses) Author, Number of year, country, case seieelion Results Comments reference method Breslow 493 male and 25 Percent of patients with specific lung cancera by tobacco usage during the 20 years prior to study Nonsmokers include pipe et al., female cases and cigar smokers only. 1954, with histologically All lung cancers other than The authors conclude U.S.A. proven lung adenocarcinoma Adenocarcinoma Controls that cigarette smoking (42). cancer. (472) (518) appears to affect the 518 age and Nonsmokers oo... cece eee eas 5.9 24.4 development of sex-matched Cigarette smokers .............. 000000, 94.1 75.6 epithelial carcinoma controls. more than that of adenocarcinoma. Schwartz 430 male and Percent of smokers by histologic type and smoking history et al., female cases 1957, with histologically Epidermoid Anaplastic Unknown type Cylindrical + Difference France confirmed lung Cases .............. 96.0 97.0 100.0 significant (247). cancer. 4 matched Controls oo... 6... 29.0T 83.0T 96.0 at p<<0.05 level. control froups. Haenszel 158 female Relative risk for specified tumors (smokers/nonsmokers) 134 cases with final et.al., cases of histological 1958, lung cancer. Group I (Kreyberg) Adenocarcinoma determination. U.S.A. Adjusted for age and occupation. ............. 3.0t 1.19 + Difference from (118). unity significant at p=0.01. Haenszel 2,191 male Standardized mortality ratios Cases obtained from a and cases of 10 percent sample of Shimkin, lung cancer Epidermoid and undifferentiated lung cancer deaths in 1962, with adequate carcinomas Adenocarcinoma yg a. during 1958, U.S.A. histologic data. White males total ........ 00. ccc ccc cee ene 100 100 The authors noted an (112). Never smoked 6 18 absence of important Ex-smokers 34 46 differentials by <1 pack/day 123 116 histologic type. >1 pack/day ... 499 467 TABLE 6. pide miologic and pathologic investigations concerning smoking and the histology of lung cancer’ (cont.) (Actual number of cases shown in parentheses) Author, year, country, reference Cohen and Hossain, 1966, U.S.A. (58). Ashley and Davies, 1967, England (6). Ormos et al. 1969, Hungary (204). Number of persons and case selection method 417 male and female cases of lung cancer with histologic diagnosis 1439-63 at one hospital. Results Comments Percent cases by histologic type wid smoking history (number of smokers} 442 male and female cases of histologically diagnosed lung cancer, 113 male and female cases of histologically proven Jung vaAncer With adequate smoking information. Squamous Undifferentiated Adenocarcinoma Alveolar Nonsmokers ......... 1.0 (3) 10.0 (17) 23.0 (8) 20.0(1) Smokers... ..0...005 89.0 (183) 90.0(145) 60.0(20) Pereent eases by histologic type and smoking history Undifferentiated Squamous Adenocarcinom Nonsmokers ...........-- 2.8 (4) 2.5 (6) 3.4 (2) Pipe cece eee 9.9 (14) 9.9 (24) 1.7 (i) Cigarette 00.0... eee eee 87.3 (124) 87.6(211) 94.9(56) S10 day 2... ee eee ee 14.1 (20) 22.4 (54) 22.0(13) 10-20 .. 33.8 (48) 41.5(109) 33.9 (20) 21 30 12.0 (17) 21.6 (52) 16.9(10) 31-40 14.1 (20) 12.9 (31) 6.5 (5) 0 7.1 (10) 6.2 (15) 5.1 (3) The authors also noted that: 1. Adenocarcinomas were 215.8 times more common in women Only 1 percent of Kreyberg Group I eases were nonsmokers. ws The authors noted that cigarette smoking appears to be as strongly related to adcnocareinoma as to the other 2 lypes. Ashley’s data on tetal number of cigarette smokers are inconsistent with his breakdown of smokers into groups based on number of cigarettes smoked per day. Percent cases by histologic type and smoking history Croup land large ecll carcinomas 36.0 (9) 64.0(16) Group I 21.0(18) 79.0(68) Nonsmokers Smokers The author noted that the small number of eases allows for no definite conclusions. 6r7 Data obtained from patient. interview and other sources. Osz TABLE 8.—Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking category (Smokers constituted 85 percent of populations studied) Smoking category Expected Risk number ratio Sex and type of tumor Smoking Non- among among Total all methods smokers smokers } smokers Males Epidermoid carcinoma ........0. 0... cece eee e ence c ee aeeaens 434 431 3 17.0 25.4 Small cell anaplastic carcinoma ............. 00.0 ceec ence ccucceeus 117 116 1 5.7 20.4 Adenocarcinoma 0.1.0... ieee cee ene ee tence ence eenenenes 88 83 5 28.3 29 Bronchiolol-alveolar carcinoma ...... doe snes see an sees Carcinoid .................005 46 39 q 39.7 1.0 Bronchial gland tumor 0 685 669 16 90.7 TA Females Epidermoid carcinoma ............. 0.0 cc ccc ccc ccc cucceesetueeuge 12 9 3 15 12.0 Small cell anaplastic carcinoma ............. 0.0 cceceeees 8 5 3 15 6.6 Adenocarcinoma . 16... ccc cence teen neces 56 14 42 10.5 1.3 Bronchiololealveolar carcinoma 2.0.0.0... 0.0000 c ce cece cece cee ues — tae see an eee Carcinoid «1.0... cece cee cee teen cere crv breetnvenaenas 32 q 25 6.3 Ll Bronchial gland tumor ........... 0.0 .c ccc cccccaccecescescucee . 6 108 35 73 18.3 1.9 1+ Number that would be expected if incidence rate among smokers were Source: Kreyberg, L. (154) equal to that of nonsmokers. LUNG CANCER RELATIONSHIPS IN WOMEN Lung cancer death rates for women are presently much lower than the corresponding rates for men. In addition, it has been ob- served that among certain strains of mice exposed to carcinogenic agents, the male animals show a greater tendency to develop lung tumors than do the females (200, 307) although there are strains for which this is apparently not so. The extent of the influence of endocrine factors in the sex variation in the incidence of lung tumors is unknown. As of 1967 in the United States, women accounted for only about one-sixth of the total deaths from lung cancer (289). However, the lung cancer death rate in women has risen by over 400 percent in the past 40 years. From 1950 to 1967 alone, the rate per 100,000 population doubled, increasing from 4.5 to 8.9 (289, 290). A number of retrospective studies concerning lung cancer and cigarette smoking among women have found that the difference in the prevalence of lung cancer between males and females is ac- counted for principally by those tumors classified as Kreyberg’s Group I (154, 311). These, as was noted above, are the tumors, par- ticularly in males, which show the closest relationship with smok- ing. Haenszel, et al. (113), in a study of 158 women with lung cancer, observed that the sex differential for lung cancer death rates diminishes, but does not fully disappear when only non- smokers are considered. Hammond (118) found that the death rate for lung cancer in nonsmoking males was somewhat higher than for nonsmoking fe- males. However, the difference in male-female rates was much greater when smokers were compared. It appears that a substantial part of the difference in death rates between male smokers and fe- male smokers can be explained mainly by differences in their smok- ing habits. These differences in smoking habits between males and females are of two types. First, overall consumption among females is still significantly lower than that among males. In 1966 (281), 30 per- cent of males reported that they had never smoked while for fe- males the corresponding figure was 59 percent. This study also noted that nearly three times as many males as females reported consuming more than 20 cigarettes per day. Second, it has been shown that women smoke differently than men (303) : They begin smoking later than men (114) and do not smoke cigarettes as close to the end, where proportionally more nicotine and “tar” are in- haled. Women smoke more filter-tip and “low tar and nicotine” Cigarettes than men. Furthermore, cigarette smoking still tends to be heavily concentrated among women under the age at which lung cancer is most likely to occur. 251 Finally, analysis of the ratio of male and female lung cancer death rates (283, 284, 285, 286, 287, 288, 289, 290) reveals that since 1960 this ratio has shown a steady decline, reflecting the greater relative rise in mortality from lung cancer in the female population. LUNG CANCER, THE URBAN FACTOR, AND AIR POLLUTION A number of studies have been concerned with the relative influ- ences of smoking, urban residence, and air pollution in the etiology of lung cancer. Table 9 lists studies performed in the United States, Great Britain, and Japan which have dealt with this question. Kotin and Falk (749, 150) and more recently the Royal College of Physi- cians (228) have reviewed the literature concerning the influence of atmospheric and environmental factors in the pathogenesis of lung cancer. The studies listed in table 9 show a number of important trends. Lung cancer death rates are found to be higher among urban popu- lations than among rural populations. It is not known to what ex- tent this urban factor in the etiology of lung cancer is due to differences in the levels of air pollution. Other factors associated with urban residence which may influence the etiology of lung cancer are: differences in smoking habits between the two popula- tions, occupational differences, and possible differences in the re- porting of lung cancer deaths (228). The studies also uniformly show that within each urban/rural grouping, lung cancer death rates increase with increased smoking. Whether air pollution acts with cigarette smoking to influence lung cancer death rates in a combined manner is presently unclear (112, 126, 264, 265), and the evidence concerning a separate role of air pollution in the etiology of lung cancer is still inconclusive (228). The recent report of the Royal College of Physicians on air pollu- tion and health (228) concluded that “the study of time trends in the death rates of lung cancer in urban areas demonstrates the overwhelming effect of cigarette smoking on the distribution of the disease. Indeed, only the detailed surveys that have taken individual smoking histories into account have sueceeded in separating the relatively very smal] influence of the ‘urban factor’ on the over- riding effect of cigarette smoking in the development of cancer of the lung.” 252 €sz@ TABLE 9.—Epidemiologic investigations concerning the relationship of lung cancer to smoking, air pollution, and urban or rural residence (Actual number of deaths shown in parentheses) Author, Population year, studied and Country, method of Results Comments reference data collection Doll, Estimated death rates Lung cancer mortality (1950) per 1,000 Authors noted that 1953, from lung cancer Males Females Nonemokers estimates are based on England in English London Other urban Rural London Other urban Rural All areas very few deaths. (70). population and Age: among nonsmokers 25-44 10, 0.126 0.095 0.070 0.028 0.028 0.012 0.020 obtained from 45-64 ...... 1.572 1.264 0.851 0.194 0.152 0.120 0 090 general register. 65-74 oo, 3.124 2.006 1.164 0.440 0.326 0.288 1219 Stocks and Death rates in Male lung cancer death rates 1952-64 (per 100,000) ages 54-74 The authors noted the Campbell, England and —— upward gradient among 1955, Northern Wales. Rural (68) Mixed (118) Urban (539) nonsmokers, pipe England Review of patient Nonsmokers ....... 0.00.0 ce cece eee neveuaue 14 . 131 smokers and light (265). chart or interview Pipe .......... 0.00. cece eee n nee unneeues Al 25 143 cigarette smokers and the with kin or Cigarettes: Light .....0.0.0 000.0000. c cece eee 87 153 297 lack of a similar physicians. Moderate 183 132 287 gradient among Heavy oo cee eee teen eee eee cee 363 303 394 moderate and heavy cigarette smokers. Hammond 187,783 white males Age standardized death rates due to bronchogenic carcinoma (males) Data excluded and Horn, in 9 states, - adenocarcinoma. when 1958, Questionnaire Suburb City of City of standardized for age and U.S.A, and interview. Rural or town 10,900-50,000 >50,000 smoking, rural rate was (120). Nonsmokers ............. tee 4.7 (2) 9.3 (3) 14.7 (4) still noted to be 25 Cigarette smokers 65.2 (52) 71.7 (67) 90.9 (59) 85.2 (83) percent less than urban. sz TABLE 9.—Epidemiologic investigations concerning the relationship of lung cancer to smoking, air pollution, and urban or rural residence (cont.) (Actual number of deaths shown in parentheses) Author, et aon Country, snethed ot Results Comments reference data collection Haenszel 10 percent of all Age- and smoking-standardized lung cancer mortality ratios Standardized Mortality et al., white male lung (epidermoid and undifferentiated carcinomas only) Ratio = 100 for U.S. 1962, cancer deaths in , White males age 35 and U.S.A. U.S.A. for 1958 Metropolitan countica Nonmetropolitan counties over in 1958, The authors (112). for whom next of 750,000 2... 119 2,500-50,000 ...... 90 also noted “... joint kin or physicians 10,000-50,000 ......... 151 Rural nonfarm ....74 effects of residence and supplied smoking 2,600-10,000 ........... 99 Farm ............ 57 smoking histories in the data. 2,191 cases schedule of lung-cancer with adequate rates far greater than information. those expected on the assumption of additivity of the separate effects...” Doll 41,000 male British Standardized death rates for lung cancer The authors noted that and Hill, physicians. rural mortality data 1964, Questionnaire and Conurbation(49) Large Towns (84) Small Towns (32) Rural (18) were affected by a England follow-up of death Nonsmokers ........,. 0.03 0.00 0.11 0.12 significant number of (74). certificate. Cigarette smokers: city residents SO 0.48 0.32 0.87 0.52 retiring to the country. 15-24 ll, 1.31 1.88 1.06 1.15 25 eee 1.90 4.43 2.20 1.17 Wicken, 1,908 male and Lung cancer death rate per 100,000—age- and smoking-standardized Total number of deaths 1966, female lung cancer noted under method of Northern deaths over 35 Inner Outer Belfast Urban Small data collection include Treland years of age from Belfast Belfast Environs Areas Towns Rural 954 controls. ($08). register. Personal Males ....... 157 (241) 139 (157) 135 (45) 118 (185) 137 (26) 47(149) interviews with Females ..... 22 (38) 17 (24) 12 (6) 23 (35) 22 (5) 12 (43) kin or physicians, Sst TABLE 9.--E'pidemiologic investigations concerning the relationship of lung cancer to smoking, air pollution, and urban or rural residence (cont.) (Actual number of deaths shown in parentheses) Author, Population year, studied and Country, method of Results Comments reference data collection Buell 304 lung cancer Age-adjusted lung cancer death rates per 100,000 man years and mortality ratios The authors noted the lack etal., deaths among of death-rate difference 1967, American San Francisco/ All other between Los Angeles and U.S.A. Legionnaires Los Angeles San Diego California counties San Francisco regions (49). aged 25 and over. Rate Ratio Rate Ratio Rate Ratio and concluded that Questionnaires to Nonsmokers” ................ 28.1 2.5 43.9 3.9 11.2 1.0 photochemical smog is next of kin. Smokers: not related to <1 pack/day ...........--- 63.6 5.7 771 6.9 61.02 5.4 lung cancer. +1 126.0 11.3 134.5 12.0 124.9 11.2 i 241.3 21.6 226.0 20.2 137.5 12.3 Hitosugi, 185 male and Lung cancer death rate per 100,000 The authors postulated a 1968, female lung cancer slight synergistic Japan deaths and 4,191 Pollution region effect between smoking (126). matched controls Males Low Intermediate High and air pollution. aged 35-74. Data Nonsmokerg oo. ce eee ene ee eeee 11.5 3.8 4.9 from Smokers: questionnaires 1-14 cigarettes/day ..............ecee cesses 10.6 14.2 23.5 and interviews. DIB ccc cece cece nent et ennee eet enenenes 21.3 18.6 314 Females Nonsmokers 0... eee eee eree 4.6 6.9 3.8 Smokers: 1-14 cigarettes/day 1.0.0.0... cece ee eee eee eee 19.7 16.5 15.3 DIB cece e nce eee enn eee eeee 12.4 20.5 17.1 Age- and smoking-adjusted lung cancer death rate per 100,000 Low Intermediate High Males 20... 2. ccc cee ee teens seve eevee 16.1 22.4 28.4 Females .... ccc cece ec eee cere eee eet eennee 16 11.6 8.7 LUNG CANCER AND OCCUPATIONAL HAZARDS Uranium Mining The excess risk for the development of lung cancer among uran- ium and fluorspar miners has been known for more than 30 years, In a recent review, Bair (17) noted that radon and radon-decay products are the only inhaled radionuclides to be epidemiologically related to lung cancer. Lundin, et al. (178), in a continuation of the work initiated by Wagoner, et al. (299, 800, 301), have re. cently reported on a 17-year follow-up of 3,414 white underground uranium miners. The authors estimated that smoking uranium miners experienced an excess of lung cancer ten times greater than did nonsmoking miners. Saccomanno (231), in recent testimony, analyzed the data of the United States Public Health Service (USPHS) Study Group as presented by Lundin, et al. (178) above. He reported that cigar- ette smoking uranium miners incurred lung cancer rates four times greater than those of other cigarette smokers. Of the 62 lung cancer deaths in this population, 60 occurred in smokers. He also observed that among 100,000 uranium miners 700 lung cancer deaths per year would be expected to occur among cigarette smokers compared with only 4 among nonsmokers. Other Occupations Nelson (199) has recently reviewed certain environmental and occupational hazards as they relate to inhalation carcinogenesis. He observed that cancer of the respiratory tract has been linked epidemiologically and, in some cases, experimentally with occupa- tional exposure to the following materials: chromium, nickel, arsenic, and asbestos. Doll (72) and Goldblatt (100), in earlier reviews, also noted an association with coal, natural gas, and graphite exposures. Nickel Morgan (194) noted that much of the nasal and lung cancer at- tributed to nickel exposure may have been due to arsenical impuri- ties found in processed nickel prior to 1925. Doll (69) found that the number of excess deaths among nickel workers under 50 years of age had declined following the change in nickel manufacturing processes. The experiments of Hueper (134) and Sunderman, et al. ( 267, 268, 269) have shown that both guinea pigs and rats develop lung cancer following chronic exposure to nickel carbony! or nickel dust. Sunderman and Sunderman (270) also reported that ciga- rette smoke contains nickel and that this concentration of nickel 256 may be capable of inhibiting the induction of lung aryl hydroxylase, an enzyme which is able to detoxify aromatic hydrocarbons includ- ing known carcinogens such as benzo[a]pyrene. Asbestos In 1955, Doll (71) found that lung cancer was a definite hazard among asbestos workers. In a more recent study, Selikoff, et al. (251, 252) examined the relationship of smoking and asbestos ex- posure to lung cancer. These authors followed 370 people who had been asbestos workers during the years 1942-1962. Over a 5-year follow-up period, 94 deaths occurred in this group, of which 24 were due to bronchogenic carcinoma, The authors noted that according to data obtained from Hammond (118), only 3.16 deaths from lung cancer would have been expected among smokers, and calculated a 7.6 to 1.00 mortality ratio due to asbestos exposure. None of the 87 nonsmokers or pipe and cigar smokers died of lung cancer. When the expected number of nonsmoker deaths (0.26) is compared with the actua] number (24) which occurred among the smoking asbes- tos workers, an extremely high mortality ratio of 92 to 1 is obtained, thus reflecting the possible interaction of asbestos exposure and cigarette smoking. Exposure of mice (179) and rats (106) to asbestos dust or the intratrachea] injection of chrysotile asbestos dust has resulted in the production of significant numbers of primary pulmonary car- cinomas. Miller, et al, (184) exposed hamsters to intractracheal injections of benzo[a]pyrene. These authors observed that the addi- tion of the chrysotile variety of asbestos to the injections appeared to promote benzo[a]pyrene carcinogenesis in the respiratory tract, as determined by the time of appearance and yields of papillomas and carcinomas. Arsenic A recent epidemiologic study by Lee and Fraumeni (163) has indicated an excess of lung cancer deaths among smelter workers exposed to arsenic for more than one year. Cigarette smoking was not taken into account in their computations. Experimental work on the induction of cancer in animals using arsenic has yielded either negative or inconclusive results (133, 135). Chromium Exposure to industrial bichromate compounds has been associ- ated with an excess of lung cancer deaths (22,255). Laskin, et al. (159) have recently reported that intrabronchial pellet implanta- 257 tion of various chromium compounds in rats is associated with the development of squamous cell carcinomas and adenocarcinomas. However, Nettesheim, et al. (200) exposed mice to chromium oxide dust and observed that it had no discernible effect on lung tumor incidence. PATHOLOGICAL STUDIES Investigators who have conducted detailed autopsy studies on patients who died of lung cancer have reported the increased pres- ence, when compared to noncancer patients, of bronchial epithelia] changes which they considered to be precursors of bronchogenic carcinoma (7, 8, 23, 51,.104, 208, 220, 279, 309). Such changes include squamous metaplasia, atypical squamous metaplasia (with acanthosis, dyskeratosis, and numerous mitotic figures), and car- cinoma in situ. Carnes (51) noted that carcinoma in situ was pres- ent in 119 cases of lung caneer but not in any of the 119 controls who were matched for age, sex, and race. Autopsy studies comparing the frequency of these cancer- related changes in the lungs of smokers and nonsmokers are pre- sented in table 10. Virtually all the studies noted an increased prevalence of these epithelial alterations among smokers as com- pared with nonsmokers. Definite dosage-dependent relationships were evident in the results of many of the reports. Also, Auerbach, et al. (14) observed that the number of cells with atypical nuclei decreases progressively in the bronchial mucosa of ex-cigarette smokers, depending upon the number of years between cessation of smoking and death, although it usually remains above that found in nonsmokers. The cytologic studies included in this table (182, 198, 222) all noted an increased percentage of sputum specimens showing meta- plasia among smokers as compared with nonsmokers. PULMONARY CARCINOGENESIS General Aspects of Carcinogenesis Agents found in cigarette smoke which have been identified as, or are suspected of being carcinogenic, are listed in table 11. The list includes certain compounds which most probably contribute to the pathogenesis of the various cancers discussed in the other sec- tions of this chapter. Many other agents have been identified in tobacco and tobacco smoke. At the present time, they do not appear to bear a direct relationship to carcinogenesis. Stedman (262) and Wynder and Hoffmann (319) provide detailed listings and discus- sions concerning these materials. 258 687% TABLE 10.—Pathologic and cytologic findings in the tracheo- (Actual number of cases shown in parentheses ) bronchial tree of smokers and nonsmokers Author, Number of year, cases and country, method of Results Comments reference selection Chang, 105 males and Percent of cases with bronchial basal cell hyperactivity Smokers included 1957, females 40-86 Nonamokerg . 6.0.0.0... eee eee eee ce cece ence cece sees. 23.5 (34) pipe and cigar U.S.A. years of age. Smokers... eee eee cece e cece entre seein see e 43.7 (71) smokers. and Heavy smokers . 2.0.0.0... 00... ccceceueeee beeen ee teen eae ee ee 61.3 (81) t p0.01 in com. Korea parison with (85). nonsmokers. Hamilton Selected Percent of casea with: No lung cancer etal, autopsy Basal cell Squamous Transitional patients included. 1957, material. Number Age range hyperplasia metaplasia metaplasia USA. = ss Smokers ............,.., 15 39-77 86.6 20.6 (117), Nlonsmokers ............. 20 28-83 40.0 15.0 Sanderud, 100 males Percent of cases with bronchial squamous epithelial metaplasia Nonsmokers in- 1958, autopsied at Nonsmokers . 0.1.0... eee ccc ceeceee sen eec cece ese n. 54.0 (39) clude those Norway Gade Institute a ee eee 80.5 (20) smoking less (240). on whom All cigarette 2.0... ceec cree eee ee eee. 79.0 (88) than or equal to smoking data Cigarettes per day: 5 grams per day. was available. a 70.0 (23) W025 eee ence cence neti ee eee. 90.0 (10) 25.1... peseevayee eee ee ane nes eee eee teenies beeneeee 100.0 (5) Knudtson, 100 persons Percent of cases with: Atypical Age, occupation, 1960, 23-85 years No. of No Bagal cell Squamous proliferative and site of U.S.A, of age Pereons change hyperplasia metaplasia metaplasia residence were (147). autopsied at Nonsmokers ............. (21) 47.6 28.6 14,3 found to have no Seattle appreciable Veterans 17.8 11.1 11 effect. Hospital on 18.2 18.2 64.5 whom 20.4 29.5 29.5 smoking = > 21 ws... eee (9) Wi 33.3 44.4 data was bee cece eee (6) oe 100.0 available. 09% TABLE 10.—Pathologic and cytologic findings in the tracheo-bronchial tree of smokers and nonsmokers (cont.) (Actual number of cases shown in parentheses) Author, Number of year, eases and country, method of Results Comments reference selection Auerbach 339 persons Number of Percent sections Percent sections The authors noted a et al., 22-88 years Number sections with cilia absent with some dose-response re- 1961, of age of of bronchial and entirely atypical cells lation of smoking U.S.A. autopsied at persons epithelium atypical cells and cilia absent to: (12). East Orange Nonsmokers: a. loss of cilia, Veterans <40 years of age ................. 8 883 0.3 b. increase in Hospital 40-59 cece cece eens 11 560 oe number of (excludes 60-69 ee cece eee 28 1,463 0.1 atypical lung Ea 18 918 0.5 cells, cancer). Smokers <1 pack/day: ¢. carcinoma <40 years of age ...............,. 14 727 0.1 4.7 in situ. 40-59 ce cee ee ene 24 1,240 1.0 16.9 Average number of 60-69 ec cee cee eeeee 35 1,772 0.5 10.8 sections per case PTO cence eee ee eee 22 1,101 0.6 9.4 equaled 62.3, Smokers >1 pack/day: <40 years of age ........-........ 17 880 1.5 12.5 CS 63 3,027 4.5 17.4 Sr 84 4,186 6.9 20.5 PTO cee eee ete tenes 15 156 9.8 23.7 Cross 140 persons Percent sections showing changes in bronchial epithelium (number of sections) ¢ The authors noted etal, autopsied at Squamous Atypical Carcinoma that the differ- 1961, Towa City Normal Hyperplasia metaplasia metaplasia Carcinoma ence between U.S.A. Veterans Nonsmokers (31) «ees. 61(562) 36 (137) 8 (33) #15 (58) smokers and non- (64). Hospital Smokers (109) ............. 440570) 43 (562) 16 (197) 20 (263) smokers was on whom statistically smoking significant. data was available. 97 TABLE 10.—Pathologic and cytologic findings in the tracheo-bronchial tree of smokers and nonsmokers (cont.) (Actual number of cases shown in parentheses) Author, Number of year, cases and country, method of Results Comments reference selection Auerbach 72 autopsied Number of Percent sections Percent sections Percent sections Each ex-smoker et al., former ciga- sections of with cilia absent with some atypi- with 50 percent matched with a 1962, rette smokers bronchial and entirely cal cells and atypical cells current smoker U.S.A. who had been Number epithelium atypical cella cilia abaent andcilia present plus never-smoker (14). smoking for Nonsmokers ..... 12 3,156 0.0 01 0.5 for age, occupa-~ 2210 years BEx-smokers ...... 92 3,436 0.2 0.9 2.5 tion, and resi- and had Current smokers 72 3,587 8.0 19.0 80.8 dence. There wags ceased an average of ==5 years ago. 50.3 sections per subject and none had less than 18 sections. c97 TABLE 10.-—Pathologic and cytologic findings in the tracheo-bronchial tree of smokers and nonsmokers (cont.) (Actual number of cases shown in parentheses) Author, Number of year, cases and country, method of Results Comments reference selection Auerbach 456 male and Percent sec- Percent sec- Percent sec- Major findings etal, 302 female Number of tions with tions with tions with 50 noted: 1962, smokers and nections of cilia absent some atypi- percent atypical Urban nonsmokers U\S.A. nonsmokers bronchial and entirely eal cella and cells and showed more (18). autopsied and Number epithelium atypical cells cilia absent cilia present lesion than rural. matched for Males: Both lesions and age, occu- Nonsmokers ........... 47 2,346 os 0.1 0.7 atypical nuclei pation, and Cigarette smokers ...... 75 3,393 6.9 21.2 78.5 were much less residence. Females: frequent in non- Nonsmokers ........... a7 2,879 . 0.1 0.5 smokers and less Cigarette smokers ...... 16 3,507 2.5 13,3 62.6 frequent in pipe Males: and cigar smokers Nonsmokers ........... 35 1,706 . 0.2 0.5 than in cigarette Cigar smokers ......... 35 1,733 0.3 10.0 10.7 smokers, Cigarette smokers ...... 35 1,526 12.8 27.3 83.1 57.1% of cases had 50-55 sections 31.5% of cases had 40-49 sections 7.8% of cases had 30-39 sections 4.6% of cases had 16-29 sections Robbins, 103 students Percent in each cytologic class Smokers defined as 1966, 17-24 years Slightly Moderately Strongly those having con- U.S.A. of age who Normal atypical atypical atypical sumed 210 ciga- (222). underwent Nonsmokers (45) ...... 00... .000 cee 86.7 4.4 8.9 oe rettes a day for aerosol Smokers (58) oo... cece ees ee eee es 55.2 32.8 10.8 1.7 = 1 year. sputum induction. 69% TABLE 10.—-Pathologic and cytologic findings in the tracheo-bronchial tree of smokers and nonsmokers (cont.) (Actual number of cases shown in parentheses) Author, Number of year, cases and country, method of Results Comments reference selection Maltoni 1,000 healthy Number Percent showing mctaplasia et al., males who Nonsmokers 2.0.0.0... cece ccc cence cece ecee seen euneuseeenyenes 294 41,16 1968, underwent Smokers: Italy sputum 1-10 cigarettes/day 189 47.09 (182). induction. 11-20 385 51.43 21-30 93 61.29 >30 39 69.23 Nasiell, 50 nonsmoking Sputum cytologic changes Percent with t Regarded by 1968, outpatients, Percent Percent with atypical author as “real Sweden 398 smokers Number Males Mean age metaplasia metaplasiat premalignant (198). participating Nonsmokers ............. 50 42 57.1 18 4 change.” in general Smokers ................ 398 713 45.6 62 27 health exam- ination who underwent sputum induction. Spain 157 males and Number Percent with metaplasia The authors found et al., 78 females Males: - no evidence of 1970, autopsied fol- Nonsmokers 36 50.0 carcinoma in situ U.S.A. lowing sudden Ex-smokers 21 57.7 or preneoplastic (258). or accidental 1 = pack 68 713.6 whom smok- Females: ing data were Nonsmokers 34 84.1 available (ex- 1 pack ooo cece cece eevee eee cane ene eteenes 18 33,3 smokers ex- D1 pack oo... cece ee ene bebe e nent veenees 26 46.1 cluded from female data). In order to facilitate understanding of the relationships of the various compounds to one another, the third column presents the presently understood relative importance of each of the various groups of compounds. These compounds have been tested only in animals or tissue cultures, and it should be stressed that the rela- tive importance of one compound may not be the same in man as it is in animals. Table 11 is divided into two major sections. The first section details those compounds which are considered to be or are suspected of being cancer initiators. These are compounds which induce irreversible changes in responsive cells. In the second section are listed those compounds which are considered to be or are suspected of being tumor promoters. These compounds promote the malig- nant reproduction of cells in which neoplastic changes have been initiated. A number of these initiators may also act as complete carcinogens in their own right. The evidence concerning the two stage initiation-promotion mechanism is still rather limited for respiratory tract carcinogenesis. The polynuclear aromatic hydrocarbons (PAH) listed are pres- ently considered to play a very significant role in pulmonary car- cinogenesis due to tobacco smoking. These compounds act as tumor initiators or complete carcinogens. The particular role of these agents in environmental and occupational carcinogenesis has been reviewed by Falk, et al. (92). That such hydrocarbons are pro- duced from tobacco during human smoking has been shown by Kiryu and Kuratsune (146). These authors reported the presence of benzfaJanthracene, chrysene, benzo[a]pyrene, and _ benzo- [b]fluoranthene in the “tar” produced by norma] smoking and measured in either filters or stubs. Two hydrocarbons which have frequently appeared in the litera- ture on experimental tobacco carcinogenesis may not actually be present in tobacco smoke, They have been used as representatives of carcinogenic PAH, a class which includes many constituents that have been identified in cigarette smoke condensate. They are 7,12-dimethy!benzlajanthracene and 3-methylcholanthrene and have been frequently used as tumor initiators or complete carcino- gens, particularly in skin painting and tracheal implantation experiments. The nitrosamine compounds listed are potent carcinogens affect- ing many organ systems, including the respiratory tract (188, 189). Magee and Barnes (181) have presented a detailed account of experiments in this area. Nitrosamines have been identified in trace amounts in tobacco ‘‘tar” and the conditions required for their formation (the presence of secondary amines and nitric oxide) are 264 TABLE 11.—-Identified or suspected tumorigenic agents in cigarette smoke* Estimated concentra- tion in 100 Presently understood relative Components cigarettes importance in experimental (85 mm. tobacco carcinogenesis non filter) I. Complete carcinogens and tumor initiators: Polynuclear aromatie hydrocarbons ........- 10-30 ug Tumor initiators. 1. Benzo(a)pyrene .. 6.00... . eee eee 3.9 2. Dibenz(a,hjanthracene ........-.---5 0.4 3. Benzo(b)fluoranthene ...........-... 0.3 4, Benzo(j)fluoranthene .........-.--65 0.6 6. Dibenzo(a,i) pyrene ......-..0- eee eee Trace 6. Benz(a)anthracene .......-.--.--+-5- 0.3 7. Chrysene 0.0.0... eee eect 2.0 8. Indeno(1,2,8-ced) pyrene .......-+--45- 0.5 9. Benzo(e)phenanthrene” ...........-+ Trace 10. Methylbenzo (a) pyrenes 0.1 11, Methylchrysenes ........6.. 0.2000 ee 2.0 N-heterocyclic hydrocarbons 1-2 Tumor initiators. 1. Dibenz(a,h) acridine 0.01 2. Dibenz (a,j) acridine 1.0 3, 7H-dibenzo (c,g) carbazole 0.07 N-nitrosamines? ........0. 000 cee eee eee 1-10 Suspected carcinogens of possible importance (presence in fresh smoke possible}. 1. DimethyInitrosamine ...........-+5-5 0.4 2.Diethylnitrosamine ......... Trace 3. Methyl-n-butylnitrosamine Trace 4. Nitrosopyrrolidine ............ 0.4 5. Nitrosopiperidine ............-.-++5) Trace Epoxides, peroxy compounds, and lactones: 1. Epoxides ........ 0062 e cee eee No data Certain of these compounds are 2. Peroxides 2.0... 6. e eee eee eens Present known carcinogens; presence in 8. Lactones 2.0.2.0 0 eee eee eee sees smoke condensate not established. a. q-Levantenolide 20.0 b. p-Levantenolide naa 2.0 N-alkyl-heterocyclics: 1. I-methylindole ........ 6.00... e eee Present Possible initiator. Pesticides and fungicides :3 No essential contribution suspected. L. TDE oo. cee en tee 10-100 2 10-100 3. 10-190 4 10-106 Beta-naphthylamine .......62 0.6.2 serene 2-3 Suspected bladder carcinogen; of doubtful significance at reported levels. Polonium 210 2.66... ee ees 1-50 Of some importance only in the pieocuries ease of relatively high concen- tration, but not important at reported levels. Nickel compounds ........- +--+ eeeee rere Present Suspected carcinogens of some importance. 265 TABLE 11.—Identified or suspected tumorigenic agents in cigarette smoke? (cont.) Estimated concentra- tion in 100 Presently understood relative Components cigarettes importance in experimental (85 mm. tobacco carcinogenesis nonfilter) Il. Tumor promoting agents: Neutral promoters (polymers) Nodata Of possible importance. (unknown structures.) Volatile phenols 2.0.0... eee eee 20-30 mg. Of possible importance. 1. Phenol 2. Cresol Nonvolatile fatty acids .................... 20-100 mg. Of minor importance. 1. Stearic acid 2. Oleic acid N-alkyl heterocyclics: Of possible importance. 1.9-methylearbazole ................... Present 1 Modified and expanded from ($19, 320) with reference to (52, 60, 89, 111, 129, 202, 262, 293, 294, 295). * Has not been tested as an initiator, but is a known complete carcinogen. 3 See Neurath, (202). 4 See (111, 128). found in tobacco smoke (38). However, nitrosamines may be arti- facts dependent on the method of smoke collection (201). Neurath (202) considers the nitrosamines listed in table 11 as being present in fresh cigarette smoke (253, 254). However, con- clusive confirmation of their presence in fresh smoke is not available (38, 138, 155, 319). Certain of the pesticides and fungicides presently in use on tobacco have been found to be carcinogenic (91, 273, 280). A num- ber of these, such as DDT, are now being phased out of regular domestic use. The compounds listed have been shown to be present in trace amounts in mainstream tobacco smoke (111,128). A recent, extensive review by Guthrie (111) provides more detailed informa- tion concerning these agents, Radioactive isotopes can be found in tobacco and tobacco smoke (105). Potassium-40, while present in tobacco leaf, is not trans- mitted in any substantial amount to mainstream smoke (230). Polonium-210 (Po.,,), however, is transmitted into the mainstream smoke (94, 123, 142, 145, 215, 217). A number of autopsy studies (table A12) have shown that the bronchial epithelium of smokers contains significantly more Po.,, than that of nonsmokers, Little, et al. (172, 173, 174) have also noted that the concentration of polonium was markedly higher at sites of bronchial bifurcation. These authors stress the importance of this finding for pulmonary carcinogenesis by noting that bronchogenic carcinomas are fre- 266 quently located at bifurcations and that the polonium levels which they found in those regions probably have biologic significance (216). Other investigators (123, 217) have not observed this excess at bifurcations, and in a recent discussion Wynder and Hoff- mann (320) concluded that it appears unlikely that Po.,, in the amounts present in cigarette smoke plavs a role in tobacco car- cinogenesis. Although not listed as a separate group, there are a number of agents in cigarette smoke which are potent inhibitors of ciliary movement. Their importance in carcinogenesis derives from the Increased amount of time which they afford the known carcinogens to be present on the surface of the bronchial epithelium, These inhibitors include volatile aldehydes, hydrogen cyanide, nitrogen oxides, volatile phenols, and certain volatile acids such as formic and acetic (729). Experimental Studies In some respects, the animal and tissue culture studies detailed below apply to neoplastic transformations, not only in the lung but in other tissues in which tobacco smoke, particularly cigarette smoke, is believed to play a role, These general experiments will be presented here, however, with the experiments which bear on lung tissue directly. Skin Painting and Subcutaneous Injection Numerous animal studies on rats, mice, and rabbits, have been performed utilizing known carcinogens, whole tobacco “tar,” and various tobacco condensate subfractions, or compounds known to be present in tobacco smoke. These experiments involve the single or repeated painting of shaved or unshaved animal skin. A selected number of these studies is presented in table A13. Numerous other studies, performed prior to and following 1953, are reviewed by Wynder and Hoffmann (319). The skin painting method is still considered to be a valid pro- cedure for the identification of agents suspected of participating in pulmonary carcinogenesis, as well as for the quantification of the reduction in tumorgenicity of specific agents. Tissue and Organ Culture The exposure of tissue and organ cultures to cigarette smoke, its condensates, or its constituent compounds has been shown to sig- nificantly alter patterns of cell growth and reproduction. Table A1l4 presents an outline of these experiments. Once again, less severe effects have been noted when filtered smoke was used (165). 267 Tracheobronchial Implantation and Instillation More complex experiments concerning the carcinogenicity of cigarette and tobacco smoke are represented by those which involve the direct implantation, instillation, or fixation of suspected ma- terials into the tracheobronchial tree of animals. Certain of these experiments are outlined in table A15, Recent reviews by Saffiotti (233, 234) Laskin, et al. (159), and Montesano, et al. (189) as well as that by Wynder and Hoffmann (319) provide more detailed and extensive accounts of these experiments. Of note among the results outlined in this table are the following: The enhanced carcinogenicity found when benzo[a]pyrene (B[a]P) is combined with a carrier such as hematite dust (235), and the definite increase in bronchial epithelial preneoplastic and neo- plastic changes among dogs treated with smoke condensate as com- pared with those undergoing only physical bronchial stimulation (224). Inhalation Various species, including mice, rats, hamsters, and dogs, have been exposed to cigarette smoke or aerosols of its constituents. These inhalation experiments are outlined in table A16. It must be noted that the majority of the studies listed involve the passive inhalation of the material presented usually in a chamber. Active inhalation experiments, exemplified by the work of Rockey and Speer (223) and Auerbach and his colleagues (11, 119) involved animals which were trained to inhale voluntarily, thus more closely simulating human smoking. Results of note among these experiments include the following: Mihlbock (195) observed that cigarette smoke inhalation en- hances the already substantial rate of spontaneous alveolar cell carcinoma formation in hybrid mice, and various investigators in- duced adenomas in experimental animals (108, 168, 206). Harris and Negroni (121) found that exposure to cigarette smoke achieved some enhancement of adenocarcinoma formation in mice but did not observe proven squamous cell carcinoma. Some of their mice had also been exposed to Swine influenza virus aerosol. In a related study, Boren (32) exposed hamsters to cigarette smoke at set inter- vals over a 48-hour period. The author observed alterations in pul- monary cell kinetics (the pattern of DNA synthesis) as demon- strated by H*-thymidine autoradiography. The pattern of the label- ing response to cigarette smoke was significantly different from that of the response to high oxygen concentrations. Auerbach, et al. (11) have reported the development of early 268 invasive squamous cell bronchogenic carcinoma in dogs following a period of direct inhalation of cigarette smoke. These investiga- tors trained beagle dogs to inhale cigarette smoke through a tracheostoma (350) and divided the animals into groups according to dosage as detailed in table 17. A number of dogs died during the course of the experiment which ran for 875 days, or approximately 29 months. The causes of death are listed in table 18. All of the remaining dogs, with the exception of group “h” (high exposure, heavy weight), were sacrificed shortly after day 875; the survivors among the heavier dogs are continuing to smoke. Examination of the respiratory tree of the animals revealed a number of tumors (table 19). Most of these were similar to the type of tumor which in man is referred to as bronchiolo-alveolar, This tumor arises in the bronchiolar and alveolar epithelium and tends to be multicentric. Two striking characteristics of these bronchiolo- alveolar tumors were the existence of a histologic spectrum (from a tumor resembling the benign condition of adenosis to frankly malignant tumors with invasion of the pleura and surrounding parenchyma) and the marked tendency to squamous change, Inva- sive bronchiolo-alveolar tumors were found in 12 dogs in the group which had been exposed to the largest dosage of cigarette smoke. Several had tumors of more than one category. Ten of these dogs had invasive bronchiolo-alveolar tumors which did not extend into the pleura, one dog had an invasive bronchiolo-alveolar tumor which extended to the pleura, and four had invasive bronchiolo- alveolar tumors extending into the pleura beyond the pleural- pulmonary junctions. In addition, two bronchogenic squamous cell carcinomas were found in this group (table 19). The dosage de- pendence of tumor formation is shown in figures 2 and 3. Major findings of the study were twofold. First, that smoking filter-tip cigarettes was less harmful, both in terms of pulmonary parenchymal damage and lung tumors, than smoking identical cigarettes without filters. This supports the generally held view that total particulate matter is a meaningful indicator of the car- cinogenic potential of a cigarette. Second, lung cancer of two types found in man was produced by the inhalation of cigarette smoke. Two of the dogs were found to have early invasive squamous cell carcinoma of the bronchus, and both belonged to the high-dosage group. These carcinomas were indistinguishable from early invasive Squamous cell carcinomas found in the bronchial tubes of human beings who smoke cigarettes. The majority of tumors found in the dogs were of a bronchiolo-alveolar type, which although not as common as squamous cell cancer in man, is not rare in humans. This type is often included in the category of adenocarcinoma. A number of studies have shown an excess of these tumors among 269 022 TABLE 17.—Data on pedigr ced male beagle dogs of groups F, L, H,h,andN (Some of the figures apply only to dogs surviving 875 days or longer) Number of dogs on day No. 57) 00... eee Weight at start (day No. 1) mean weight (pounds) ... Cigarettes per dog in 875 days 20... eee eee Mean number of cigarettes per day wo... ee eee Equivalent number of civarettes per day for 150 pound man Type of cigarettes:2 Milligrams of tar per cigarette 2.00, Milligrams of nicotine per cigarette ........0.......... Total dosage in 875 days: Grams of tar per Le No No No Filter filter filter filter Nonsmokers group group group group group F L H h N 12 12 24 38 8 25.0 25.1 25.0 31.9 30.7 6,143 3,103 6,129 6,129 none 7.02 3.54 7.0 7.0 42.1 21.2 42.0 32.9 — 17.8 34.8 34.8 34.8 —_— 117 1.85 1.85 1.85 — 109.3 103.5 207.8 207.8 — 7.19 5.56 11.12 11.12 — 4.37 4.12 8.31 6.51 —— 0.29 0.22 0.44 0.35 — Source: Adapted from Hammond, E. C. et al. (119). 1 The smoking dogs were divided into groups F, L, H, and h on day No. 57. ? Dogs of groups L, H, and h smoked filter-tip cigarettes during a training period at the start of the experiment, but smoked nonfilter cigarettes thereafter. TABLE 18.—Summary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H,h, and N (Each death classified according to most severe condition—some dogs died of a combination of causes listed ) ZZ Filter No No No tip filter filter filter Nonsmokers Principal cause of death Group Group Group Group Total F L H h Pulmonary emphysema and fibrosig ............-....00-- — — 2 _- 2 Cor pulmonale (pulmonary emphysema and fibrosis with right heart enlargement) — — 3 5 8 Pulmonary infarction ............... 1 1 2 5 9 Bronchopneumonia ...............05- ~ — 3 1 4 Aspiration of food .............- Sees etevesstesuesescres 1 1 —_ 2 Uncertain 2... cece eee n nee ene neeneee — — 2 1 3 Number of deaths ©. 0.0.0.0... cece cece eee eee eee 2 2 12 12 28 Number surviving 875 days ....... 2.0... c cece eee eens 10 10 12 26 66 Total number of dogs 0.0.2... cece cece tee teen nee 12 12 24 38 94 Source: Hammond, E. C. et al. (119). cLz TABLE 19.—Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found Number Age at Early squamous Group Day of 0. death Lobes with bronchiolo-alveolar tumors cell bronchial death cigarettes (years) Non-invasive Invasive carcinoma Group N (nonsmokers) oN 904a — 5.1 LA _ — N 904b — 4.9 RA — — Group F (filter-tip) 0.0.0... 0.0.00. ee eee ee F 878a 6,161 5.1 LA — — F 879a 6,170 4.7 LA — —_ F 885a 6,224 5.2 LA — ~ F 890a 6,269 5.4 LA — — Group L (no filter) oo... eee eee L 347 1,055 3.8 LA, LC — _ L 812 2,847 5.1 RA _ a L 876a 3,103 5.1 LA, RA — _ L 877a 8,107 6.2 LA, LC — _— L 882a 3,127 5.2 LA, LD — —_ L 896a 3,183 5.3 LA, RD _ _ L 899a 3,195 5.4 LA —_ — Group H (no filter) . 20.00.0000... ce eee H 185 518 2.5 RC — —_ H 259 1,343 3.3 LA, RA, RD a =_ EH 563 3,404 47 LD, RA —_— _ H 716 4,689 5.0 . LA a H 753 5,030 3.8 RI LA, RA, RD _ H 760 5,088 4.2 LA — — H 858 5,970 5.3 LA — — H 876a 6,129 49 LA, LD, RA _ H 877a 6,138 5,4 ae LA LABB H 8788 6,147 5.3 RA LA _— H 882a 6,183 5.4 LA —_— _ H 883a 6,192 AT RA, RD, RI LA _ H 885a 6,210 5.0 LA, RA LMB H 889a 6,246 5.0 . LA _ H 890a 6,255 4.9 LA — _— H 892a 6,273 5.7 LC, RA — — H 892b 6,273 5.3 . LA, RA —_ H 897a 6,318 5.2 RA _ _ H 897b 6,318 4.5 LC LA _— £27 TABLE 19.—Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found (cont.) Number Age at Early squamous Group Day of of death Lobes with bronchiolo-alveolar tumors cell bronchial death cigarettes (years) Non-invasive Invasive carcinoma Group h (no filter) .h 606 3,769 46 LA —— — h 626 3,928 4.4 os LA, RI _ h 649 4,143 5.0 RI LA, RA — h 794 5,400 5.1 LA, RA — -- LA, left apical lobe; LC, left cardiac; LD left diaphragmatic; RA, right apical; RC, right cardiac; RI, right intermediate; RD, right diaphragmatic; LABB, left apical branch bronchus; LMB, left main bronchus. For smoking dogs, the day of death indicates the number of days since “ start of smoking. The letter sacrificed after day #875. Source: Auerbach, O. et al. (11). 'a’’ or “b” follows the day of death of dogs ——___ 79.2 80 F o o 50 a wu ° L kK z 8 & 40h wl 33.3 20 0 eee GROUP N: GROUP F: GROUP L: GROUP H: NONSMOKING FILTER-TIP NO FILTER NO FILTER (% as many cigarettes) as Group H TUMORS 2 4 7 19 DOGS 8 12 Tz 24 FIGURE 2.—Percent of smoking dogs with tumors. SourcE: Adapted from Auerbach, O., et al. (11). 60 + wo L a o ° 4 40 wu ° 5 S a o 20.8 ti a 20 - 14.3 4.8 3.6 an 0 q GROUP N: GROUP F: GROUP L: GROUP H: NONSMOKERS FILTER-TiP NO FILTER NO FILTER (% as many cigarettes) as Group H TUMORS 2 4 42 35 LOBES 56 84 84 168 FIGURE 3.—Percent of lung lobes with tumors in smoking dogs. Source: Adapted from Auerbach, O., et al. (11). 274 cigarette smokers (6, 42, 112), but the magnitude of this relation- ship is not as great as that with squamous cell cancer in man. Reduction in Tumorigenicity The importance of reducing total particulate matter in cigarette smoke is reflected in the dose-dependent results of the Auerbach- Hammond study. A major objective of experimental tobacco car- cinogenesis must be the reduction in the tumorigenicity of cigarette smoke and other tobacco products. In a recent article (320), Wynder and Hoffmann have reviewed the various methods applied to achieve this goal. Among these methods are the modification of the tobacco itself, the modification of the conditions of tobacco pyrolysis, the use of additives, and the use of filters. The use of filters should produce a reduction of particulate matter as well as of gas phase components. Bross (44) studied 974 cases of lung cancer at Roswell Park Memoria] Institute and concluded that smokers who switched to filter cigarettes showed a decreased risk of developing lung cancer. However, even after switching, heavy smokers were still found to have a mortality risk five times that of nonsmokers. More recently, Wynder, et al. (324) reported on an interview study of 350 patients with histologically confirmed lung cancer and 552 age and sex-matched controls. They found that subjects who had switched from nonfilter to filter cigarettes ten or more years prior to the study incurred a lower relative risk of lung cancer at all consumption levels than that incurred by those who continued to smoke nonfilter cigarettes. The authors suggest that this difference in relative risk may be due to the lower “tar” content in filter cigarette smoke. Prospective studies concerning the effects of filter cigarette smoking are presently being conducted. Apart from variations in “tar” exposure due to filtration, it appears that different patterns of smoking result in the inhalation of varied amounts of “tar.” Graham, et al. (103) simulated dif- ferent inhalation patterns with the use of an analytic smoking ma- chine. He found that smoking a given number of puffs over a long period of time results in greater “tar” retrieval than smoking them over a short period. Also, he observed that taking most of the puffs at the end of the cigarette results in the highest retrieval while taking most at the beginning results in the smallest retrieval. Complementing these observations is the same author’s case/con- trol study (102) of 183 men with lung cancer and 161 men with diseases not related to tobacco smoking. He found that the lung cancer patients had significantly greater high “tar” yield cigarette smoking patterns than the controls. The risk of lung cancer was found to increase with the increase in mean number of puffs per 275 cigarette, the average length of time taken to smoke a cigarette (except in the highest number of puffs category), and the taking of more puffs at the end of the cigarette. These findings, and those of the study of Auerbach, et al. (11), add further support to the dose-response relationship between lung cancer and total cigarette smoke condensate exposure. SUMMARY AND CONCLUSIONS 1. Epidemiological evidence derived from a number of prospec- tive and retrospective studies coupled with experimental and path- ological evidence confirm the conclusion that cigarette smoking is the main cause of lung cancer in men. These studies reveal that the risk of developing lung cancer increases with the number of cigar- ettes smoked per day, the duration of smoking, and earlier initia- tion, and diminishes with cessation of smoking. 2. Cigarette smoking is a cause of lung cancer in women but accounts for a smaller proportion of cases than in men. The mor- tality rates for women who smoke, although significantly higher than for female nonsmokers, are lower than for men who smoke. This difference may be at least partially attributed to difference in exposure; such as, the use of fewer cigarettes per day, the use of filtered and low “tar” cigarettes, and lower levels of inhalation. Nevertheless, even when women are compared with men who ap- parently have similar levels of exposure to cigarette smoke, the mortality ratios appear to be lower in women. 3. The risk of developing lung cancer among pipe and/or cigar smokers is higher than for nonsmokers but significantly lower than for cigarette smokers. 4, The risk of developing lung cancer appears to be higher among smokers who smoke high “tar” cigarettes or smoke in such a man- ner as to produce higher levels of “tar” in the inhaled smoke, 5. Ex-cigarette smokers have significantly lower death rates for lung cancer than continuing smokers, There is evidence to support the view that cessation of smoking by large numbers of cigarette smokers would be followed by lower lung cancer death rates. 6. Increased death rates from lung cancer have been observed among urban populations when compared with populations from rural environments. The evidence concerning the role of air pollu- tion in the etiology of lung cancer is presently inconclusive. Factors such as occupational and smoking habit differences may also con- tribute to the urban-rural difference observed. Detailed epidemio- logic surveys have shown that the urban factor exerts a small influence compared to the overriding effect of cigarette smoking in the development of lung cancer. 276 7. Certain occupational exposures have been found to be asso- ciated with an increased risk of dying from lung cancer, Cigarette smoking interacts with these exposures in the pathogenesis of lung cancer so as to produce very much higher lung cancer death rates in those cigarette smokers who are also exposed to such substances. &. Experimental studies on animals utilizing skin painting, tracheal instillation or implantation, and inhalation of cigarette smoke or its component compounds, have confirmed the presence of complete carcinogens as well as tumor initiators and promoters in tobacco smoke. Lung cancer has been found in dogs exposed to the inhalation of cigarette smoke over a period of more than two years. CANCER OF THE LARYNX Cancer of the larynx is a disease which predominantly affects males in the 55 to 70 year age group. In 1967, a total of 2,468 males and 329 females died of laryngeal cancer in the United States. With the development and application of more effective therapy during the past 30 years, the death rate for cancer of the larynx appears to be dropping slightly (282, 289); however, the incidence con- tinues to rise. Figures from the Connecticut Cancer Registry (88) show that the age-adjusted incidence per 100,000 population of cancer of the larynx for males rose from 3.0 in 1950 to 5.6 in 1961. EPIDEMIOLOGICAL STUDIES A number of epidemiological studies have investigated the rela- tionship between smoking habits and the development of cancer of the larynx. The major prospective studies, as outlined in table 20, show that smokers of cigarettes run an approximately six-to- tenfold risk of dying from this form of cancer as compared to non- smokers. Smokers of pipes and cigars incur a three-to-sevenfold risk. The retrospective studies listed in table A21 uniformly show fewer nonsmokers and more smokers among cases with cancer of the larynx than among matched controls. Table A22 summarizes the relative risk ratios derived from the retrospective studies. The wide variation is due to a number of factors, including type of popu- lation and interview technique. But, in general, the magnitude of most of these ratios is of the same order as in the prospective studies. Wynder, et al. (372) have distinguished between cancer of the intrinsic and extrinsic larynx. Tumors arising on the vocal cords are classified as intrinsic and constitute approximately 70 percent of the lesions. The extrinsic larynx is composed of those sections of the larynx excluding the vocal cords and may also be referred to as 277 82% TABLE 20.—Laryngeal cancer mortality ratios (Actual number of deaths shown in parentheses)! SM = Smokers. NS = Nonsmokers. Prospective studies Number Author, of year, Number and Data Follow- laryngeal Cigarettes/day Pipes, cigars Comments country, type of collection up cancer reference population years deaths Hammond 187,783 white Questionnaire 3% 24 Cigarette smokers 17/24. Cigar Data referring to mortality and males 50-69 and follow- SM ..24 3/24 ratio included cancer of Horn, years of age up of death NS .. 0 Mixed esophagus and mouth. 1958, in 9 states. certificate. 4/24 U.S.A. (120). Doll and Approximately Questionnaire 10 16 All smokers by amount Pipe and cigart + Includes data on ex- Hill, 41,000 male and follow- SM ..16 in grama NS .... 1.00 smokers of pipes and cigars. 1964, British up of death NS ..0 NS ool ce eee eee ne SM .... 5.00 No NS died of laryngeo- Great physicians. certificate. 1-14) ww we ee ee. (1.00 tracheal cancer, therefore Britain 15-24 - 1.00 1-14 gram SM set as 1.00 (74). 45) 7.50 standard. Data combine laryngeal and tracheal carcinoma. Kahn U.S. male Questionnaire 8 54 NS ..... ee... ee 1.00 (3) Pipe Refers to current cigarette (Dorn), veterans, and follow- SM ..51 1-9 wo... eee 3.27 (1) NS .... 1.00 (3) smokers only. 1966, 2,265,674 up of death NS .. 3 10-20 ............ 8.45(10) SM ....10.33 (6) U.S.A. person years, certificate. 21-39) ....,.......18.62(11) Pipe and cigar (189). >: 18.85 (3) NS .... 1.00 (3) Al voc. eee ee ee. 9.695 (25) SM .... 7.28(11) Hammond, 440,558 males Interviews 4 57 NS) .............. 1.00 (8) Pipe and cigar Male data only. 1966, 562,671 fe- by ACS SM ..54 SM (age 45-64) .. 6.09(82) NS .... 1,00 (3) Pipe and cigar data refer to U.S.A. males 35-84 volunteers. NS .. 3 SM (age 65-79) .. 8.99(18) SM .... 3.87 (4) males 55-84 years of age. (118), years of age in 25 states. 6L£0 TABLE 20.—Laryngeal cancer mortality ratios (cont.) (Actual number of deaths shown in parentheses)! SM — Smokers. NS = Nonsmokers. Prospective studies Number Author, ° year, Number and Data Follow- laryngeal Cigarettes/day Pipes, cigars Comments country, type of collection up cancer reference population years deaths Weir and 68,153 males Questionnaire 5-8 11 NS wee e cece ee ee OO No nonsmokers died of Dunn, in various and follow- SM ..11 EIQ Lee ee 1,00 laryngeal carcinoma, 1970, occupations up of death NS .. 0 *20 Lo. ee. 599 therefore +10 smoker set U.S.A. in California. certificate. B80 Lee. 584 as 1.00 standard, (806). NS includes pipe and cigar smokers. SM includes ex-smokers. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. the hypopharynx. These authors noted that the percentage of heavy smokers among the patients with cancer of both the extrinsic and intrinsic larynx was significantly greater than that among controls, However, it is of interest that the excess risk of laryngeal cancer among cigar and pipe smokers in this study could be attributed to the extrinsic laryngeal group. As in studies of oral cancer, it appears that alcohol consumption should also be taken into account in studies of laryngeal cancer. Wynder, et al. (372) reported a significantly increased risk of extrinsic cancer among those with alcohol intake above 7 ounces of whiskey per day. With less than this amount, no increased risk was evident. Schwartz, et al. (248), noted no effect in relation to aleohol intake. Further research into the interaction of these two variables is necessary. PATHOLOGICAL STUDY Auerbach, et al. (9) studied histological changes in the larynges of 942 men, age 21 to 95, who were autopsied at a single hospital between 1964 and 1967. Cases of primary cancer of the larynx were excluded from the study. Smoking histories for all cases were obtained from family members of the deceased by trained inter- viewers. The randomized histological sections were graded by one observer. Tables A23 and A24 summarize the findings in the true vocal cord, Of the men who never smoked, 75 percent had no cells with atypical nuclei, only 4.5 percent had sections with areas con- taining 60 to 69 percent of cells with atypical nuclei, and none had a higher percentage. The 116 ex-smokers had laryngeal histology similar to that of the nonsmokers, as far as atypical nuclei were concerned. However, disintegrating nuclei were found in 40.5 per- cent of the ex-cigarette smokers and in only 0.4 percent of the remaining cases. Only one of the 9 cigar and or pipe smokers had no atypical cells. Three had carcinoma in situ, and one case had a section showing early invasive primary carcinoma, The highest percentage of atypical cells was found among the cigarette smokers. The proportion of cases with a high degree of cellular change increased with increased daily smoking. None of the pack-or-more-a-day smokers was free of atypical nuclei in the laryngeal epithelium. Of those who smoked two or more packs per day, 85 percent had lesions with 60 percent or more atypical cells as compared to 1 percent of the nonsmokers. Between 10 and 18 percent of the cigarette smokers had areas of carcinoma in situ, and 1 of the 641 cases showed early microscopic invasion. The thickness of the basal level of the true vocal cord was also directly related to the amount smoked. 280 EXPERIMENTAL STUDY Dontenwill (76) has recently reported the development of an effective and practicable method hy which small rodents (ham- sters, rats, mice) can be exposed to long-term passive inhalation of cigarette smoke in a manner which circumvents the fatal effects of acute toxicity which ruined earlier attempts but allows for a dosage of smoke great enough to induce the development of chronic patho- logical changes. The Svrian Golden hamster was found to be the most suitable species for such inhalation experiments for several reasons: its resistance to pulmonary infections, its resistance to the effects of nicotine as compared to that of rats or certain strains of mice, and, especially, its susceptibility to develop tracheobronchial cancers after treatment with carcinogens, in contrast to its almost total freedom from the spontaneous development of these tumors. Dontenwill demonstrated that the concentration of deposited cigarette smoke was greatest in the hamster’s larvnx as compared to the other portions of the exposed respiratory tract (table 25), and that the larvngeal epithelium was the tissue which underwent the greatest smoke-induced histological changes. In studying the changes in the larynx, the author differentiated five stages of epithelial change, using as his reference the Atlas of Tumor Pathology of the Armed Forces Institute of Pathology (5). Table 26, quoted by Dontenwill, describes the five types of change. They range from benign, such as epithelial hyperplasia, to pre- malignant, exemplified by pseudoepitheliomatous leukoplakia. The results of the inhalation experiment are presented in figure 4 in which a dosage-related increase in the severity of the epithelial changes is represented in graphic form. The author also reported, and depicted with photomicrographs, the finding of an early inva- sive squamous cell carcinoma. This form of cancer is the predomi- nant type involving the human larynx. SUMMARY AND CONCLUSIONS 1. Epidemiological, experimental, and pathological studies sup- port the conclusion that cigarette smoking is a significant factor in the causation of cancer of the larynx. The risk of developing larvngeal cancer among cigarette smokers as well as pipe and/or cigar smokers is significantly higher than among nonsmokers. The magnitude of the risk for pipe and cigar smokers is about the same order as that for cigarette smokers, or possibly slightly lower. 2. Experimental exposure to the passive inhalation of cigarette smoke has been observed to produce premalignant and malignant changes in the larynx of hamsters. 281 TABLE 25.—Deposition of "C-labeled smoke particles in particular regions of the respiratory tract me TT Traced Traced Estimated Deposition Proportional deposition radio- radio- of area of the in relation Organ activity Organ activity Particles respiratory to the (nCi) (mCi) (%) tract Proportional area a Tt Tr ee Head and palate . +. 6.11 Head, palate 5.5 BT .4 Tongue ........... 0.41 Oral cavity 1.6 10.0 in total. Larynx ........... 039 0,1-0.3 X561~187 Trachea ........., 0.26 7.6 (traced) SLT 0.6 X62.3 Lungs tees ee eee. 6.95 1000 X1 Total ......, 14,12 "14.7 100.0 We a a | Cigarettes labeled with MC -1-n-hexadecan: data represent mean values from 10 animals, calculated from surface distribution in the head. ? The value of 14.7 contains 0.58 nanocuries as estimated from quantity of deposition in the nontraced oral cavity regions fcaleulated as to Proportional area). Sounce: Dontenwill, W, (76). 282 £82 TABLE 26.—Classification of the five registered stages of epithelial cha Acanthosis (thicken- Hy perkeratosis Stage ing of stratum increased spinosum multi- eornification cellular layer) (stratum corneum) 1. Pachydermia (epithelial hyperplasia) ........--..++-- + + 2. Leucoplakia 26... cc et eee + 4. 8. Verrucous Jeucoplakia 2.0.0... 0.00: ete eee eee eee + 4 4, Papillomatous Jeucuplakia 2.06.0... ee eee + t 5. Pseudoepitheliomatous leucoplakia 2.2.12... 2 000s + + Symbols: + = negative; {= minimal; + = weak; ++ = medium; +++ = strong. 2 From Atlas of Tumor Pathology of the Armed Forces Institute of Pathology. Source: Adapted from Dontenwill, W. (76). Parakeratosis (in- complete cornifica- tion of nuclei in the stratum corneum) t nges at the laryna’,” Dyskeratosis (pre- mature atypical cornification changes in the Mitosis nucleus prolifera- tion of the basal TOTAL 146 34 35 8 6 10 7 11 4 5 17 4 5 e ° aces |e oe . jeoe ce 5 * ee ee io . es 4 oe ° ° je ° ee 3 > eeoee ie esas ie joo e oO Oo 2 a e a jeocesles e oe ee . zl ° e ee oe e je ° 6 retetetel e é eeee 2 4 6 8 10 12 14 16 18 20 22—>28 SMOKE EXPOSURE, months e =ONE ANIMAL @ =ANIMAL LIVING ©=LARYNX CANNIBALIZED FIGURE 4,—Effects of chronic cigarette smoke inhalation on the hamster larynx. Review of the results of the inhalation experiments: number of smoke-ex- posed animals with and without changes in the larynx, duration of smoke exposure, and number of animals still alive. Source: Dontenwill, W. (76). ORAL CANCER The cancers included in this category are those of the lips, tongue, floor of the mouth, hard and soft palate, gingiva, alveolar mucosa, buccal mucosa, and oropharyns. It is estimated that 15,000 of these cancers will be diagnosed in the United States in 1970, accounting for about 2.5 percent of the estimated 600,000 malignant neo- plasms reported (289). A variety of histological types of malig- nant neoplasms can affect these tissues, but squamous cell car- cinoma is by far the predominant type, accounting for about 90 percent of the cancers. The incidence of and mortality from coral cancers has remained steady over the past 20 to 30 years. The Connecticut Cancer Reg- istry (88), which is a fairly reliable index of incidence, noted that the incidence among males remained between 15.8 and 16.3 per 100,000 population during the years from 1950-1961, Examination of mortality rates over the past 20 to 30 years (282, 289) reveals a similar constancy. The apparent lack of change in mortality from oral cancer in 284 contrast to the sharp increase that took place in lung cancer rates in those years is probably due to several of the following factors. First, pipe and cigar smoking are both significantly related to can- cer of the oral cavity, and the increase in cigarette smoking among men, noted between 1920 and 1955, has been, to a large degree, accompanied by corresponding reductions in the use of pipes and cigars. Second, aside from the various changes which the Interna- tional Classification of Diseases (ICD) had undergone during that period, the diseases discussed above are recorded in ICD Codes 140-148 which include some neoplasms not found to be related to the use of tobacco. The various sites of cancer themselves do not contribute equally to the overall rate and are subject to widely dif- ferent cure rates, so that their contributions to the total incidence rate is different from their contribution to the overall mortality rate from oral cancer. Although more than 20,000 cancers of the oral cavity were estimated as newly diagnosed in 1967, the total number of individuals recorded as dving from oral cancer during that year was only 6,718 (289). Oral cancer occurs predominantly in people of the middle and older age groups. More than 90 percent of all oral cancers occur in persons over age 45, with the average age at time of diagnosis approximating 60, Although the majority of oral cancers occur in men, there is recent evidence that the ratio of males affected to females affected is decreasing (257). EPIDEMIOLOGICAL STUDIES The use of tobacco in various forms has been associated with the development of cancer of the ora! cavity and pharynx. The studies in this area of concern are truly international, many having been carried out in Asian re tions as well as in the West. The major prospect: c epidemiological studies have found in- creased rates of these sureers for cigarette smokers as well as for pipe and cigar smokers (see table 27). Pipe smoking, per se, has long been recognized as a cause of lip cancer (2917). The methodol- ogy and results of the numerous retrospective studies are sum- marized in tables AZS and A28a. These studies almost uniformly show significant relationships between the various forms of tobacco use and «veces of fe oral cavity and pharynx. tudies str Asics oe’ ons have examined the prevalence or inci- dence of premahignanh: cnange, such as oral leukoplakia, as well as that of cancer of the oral cavity. In many of these studies, forms of tobacco use not prevalent in Western countries have been investi- gated, including reverse smoking (in which the lighted end of the Cigarette is kept in the mouth close to the palate) and the chewing 285 987 TABLE 27.—Oral cancer mortality ratios—prospective studies (Actual number of deaths shown in parentheses) SM= Smokers, NS = Nonsmokers. Author year, Number and Data Follow- Number country, type of collection up years oO Cigarettes Pipes, cigars Comments reference population deaths Hammond 187,783 white Questionnaire Bu, 56 20/56 Pipe Mixed Data referring to mortality and males in 9 and follow-up TSM ...51 5/56 21/56 ratio do not include cancer of Horn, States 50-69 of death NS .3 Cigar larynx and esophagus, 1958, years of age. certificate. 5/56 + Excludes two occasional ULS.A. only smokers. (120). Doll and Approximately Questionnaire 10 19 All amokers by amount Pipe and cigar No NS died of oral cancer, Hill, 41,000 male and follow-up SM ...19 in grams NS. ....... 1,00 therefore 1-14 gram 1964, British of death NS . 0 NS . -—_ oo SM... 1.00 smoker set as 1.00 Great physicians. certificate. 1-4 .» 1,00 standard. Britain 15-24 ». 0.25 (74). 25 . 5.25 Kahn U.S. male Questionnaire 814 61 NS ...........2-- 1.00011) Pipe Data do not include pharynx. (Dorn), veterans, and follow-up SM ..50 {Cigs/day 1-9 .. 0.86 (1) NS { Refers to current cigarette 1966, 2,265,674 of death NS. ..11 10-20 .. 2.93(18) SM smokers only. U.S.A. person years. certificate. 21-39 « 1.34(20) (139). >39 5.73 (3) NS 1.00(11) All . 4.09(37) SM . . 4.11 (9) Hammond, 44,554 males Interviews by 4 95 NS .............. 1.00 (7) t Pipe and/or tT Male data only. Pipe and 1966, 562,071 females ACS volunteers SM ..88 SM (age 45-64) ... 9.90(63) cigar. cigar data refer to males U.S.A. 35-1 years of NS . 7 SM (age 65-79) . 2.93(25) NS ....... 1.00 (7) 55-84 years of age. (118). age in 25 States. SM ....... 4.94(15) Weir and 68,154 rales Questionnaire 5-8 19 NS .. 1.00 SM includes ex-smokers. Dunn, in various and follow-up +10 . 8.69 NS includes pipe and 1970, occupations of death H20 Le eee eee 1.17 cigar smokers. U.S.A. in California. certificate. >30 «. 5.62 (306). All - 2.76 of ‘‘pan” or “Nass,” which are mixtures of tobacco with either betel nut or lime ash, and other ingredients (241, 255, 256). Snuff dipping, a habit in which snuff is placed in the gum and retained there for prolonged periods, has also been associated with the development of oral cancer (193, 210), as has the chewing of tobacco (124, 193, 241, 298). The risk of developing a second primary mouth or throat eancer, after the recognition of the first primary cancer, has been found to be greater in continuing smokers than in those who quit smok- ing. All of the patients studied by Moore (190) were asymptomatic for at least three years following the treatment of the first cancer. Of the 117 patients with adequate smoking histories, only 4 of 43 (9 percent) who quit smoking developed a new primary cancer. On the other hand, 27 of 74 (36 percent) who continued to smoke developed a second primary cancer, However, a study by Castigliano (53) of patients treated for oral cancer did not show a greater risk of a second primary among continuing smokers. In this study, 5 of 26 (19 percent) of those patients who did not quit smoking developed a second primary cancer as compared to 9 of 51 (18 percent) of those who did quit. The rate of quitting smoking in the two studies is markedly dif- ferent (36 percent in the Moore study and 62 percent in the Casti- gliano study). From the data presented in the two papers, it is not possible to evaluate the other significant ways in which the pop- ulations may have differed. Keller (140) studied 408 males with histologically confirmed squamous cell cancer of the mouth or pharynx. This author dealt with the question of recurrent tumors in a somewhat different manner. The patients were observed for the development of a sec- ond or third primary cancer at an anatomically discrete site of the mouth and pharynx within a median period of three years after the first cancer. He found that a second or third cancer (termed a coexisting cancer) developed in 28 of the 408 cases. Among these 28 cases with 33 coexisting neoplasms, 21.7 percent were heavy smokers, but among their matched controls, there were no heavy smokers. Coexisting cancers were most commonly found on the soft palate, an anatomical site that is in direct contact with the main- stream of tobacco smoke, More recently, Wynder, et al. ($175) studied 63 male and 23 female patients with multiple primary cancers of the mouth and pharynx. They observed that heavy smoking prior to the develop- ment of the oral cancer was associated with a greater likelihood of developing a second primary. Also, continued smoking after the first primary was found to have a significant association with the occurrence of a second primary. 287 With or without smoking, use of aleohol appears to contribute to the development of oral cancer (124, 140, 188, 297, 322). In a study of male veterans, Keller (740) found that heavy smoking and heavy drinking were associated with cancer of the mouth and pharynx. No studies are presently available which determine the relative contributions and possible interactions of heavy smoking, heavy drinking, and concurrent nutritional deficiencies in the etiol- ogy of these cancers. EXPERIMENTAL STUDIES In 1964, the Advisory Committee to the Surgeon General on Smoking and Health (291) reported that cigarette smoke and ciga- rette smoke condensates had failed to produce cancer when applied to the oral cavity of mice and rabbits or to the palate of hamsters and that the oral mucosa appears to be resistant in general to can- cer induction even when highly active carcinogens such as benzo- [a]pyrene are applied. Some of the difficulties in experimental de- sign were attributed to the fact that mechanical factors, such as secretion of saliva, interfere with the retention of applied carcino- genic agents on the tissues of the oral cavity and pharynx. Positive results with certain carcinogens have, however, been obtained in the hamster cheek pouch, but it has also been pointed out that the cheek pouch lacks salivary glands and that its structure and fune- tion differ from those of the oral mucosa. The majority of these studies are outlined in table A29, Although cigarette smoke condensate acts as a complete carcino- gen on mouse skin, the work of several authors (319) supports the concept that cigarette smoke contains cancer promoters that may be of special importance, particularly in oral carcinogenesis. Elzay (90) has reported that whole cigarette smoke is a promoting agent for the hamster cheek pouch. More importantly, regarding the chewing of tobacco, Bock, et al. (27.30), Van Duuren, et al. (294), and Wynder and Hoffmann (321) have shown that unburned to- bacco products contain tumor promoters that might contribute to the promoting activity of the smoke. Roth, et al. (226, 227) have shown that the dye-binding capacity of the DNA of oral epithelial cells is significantly enhanced in cigarette smokers in contrast to nonsmokers, probably reflecting an increase in the DNA content of oral epithelial cells in smokers. Smokers had values of dye-binding capacity intermediate between nonsmokers and 21 patients with proven oral cancer. Those smok- ers who refrained from smoking for up to six months showed a significant decrease toward more normal values. 288 SUMMARY AND CONCLUSIONS 1. Epidemiological and experimental studies contribute to the conclusion that smoking is a significant factor in the development of cancer of the oral cavity and that pipe smoking, alone or in conjunction with other forms of tobacco use, is causally related to cancer of the lip. 2. Experimental studies suggest that tobacco extracts and tobacco smoke contain initiators and promoters of cancerous changes in the oral cavity. CANCER OF THE ESOPHAGUS Esophageal cancer accounted for 4,306 deaths among American males in 1967 and 1,321 deaths among females. The death rate from esophageal cancer has remained relatively constant since 1949, EPIDEMIOLOGICAL STUDIES The major prospective epidemiologica] studies (table 30) have indicated a significant relationship between smoking and esopha- geal cancer. Overall mortality ratios for male cigarette smokers range from 1.74 to 6.17. There are insufficient data concerning females for establishing firm conclusions. A number of retrospective studies concerning the relationship of smoking and esophageal cancer are outlined in table A351 and A3la, Smokers incur risk ratios ranging from 1.3 to 6.6 when compared with nonsmokers. As in studies of oral cancer, the effect of alcohol consumption must be taken into account in studies of esophageal cancer. Because a relationship between alcohol consumption and tobacco use is known to exist, Wynder and Bross (310) analyzed the association between tobacco consumption and esophageal cancer after adjust- ing for alcohol intake. They found that in the absence of alcohol consumption, there was no association between the use of tobacco and esophageal cancer but that in the presence of alcohol consump- tion, an increasing relative risk with increasing number of ciga- rettes smoked was apparent, as well as an association between cigar and pipe smoking and esophageal cancer. More recently, Takano, et al. (272), in a retrospective study of 200 patients with esophageal carcinoma, found an increased risk With smoking which was magnified by increased alcoho] consump- tion. Martinez (783) analyzed the association of tobacco usage and esophageal cancer after controlling for age, sex, and alcohol consumption. Increasing relative risks with increasing tobacco use 289 062 TABLE 30.—Esophageal cancer mortality ratios—prospective studies SM = Smokers. (Actual number of deaths shown in parentheses)! NS = Nonsmokers. Author, Number of year, Number and Data Follow- esophageal country, type of collection up years cancer Cigarettes/day Pipes, cigars Comments reference population deaths Hammond 187,783 white Questionnaire 3% 34 Cigarette smokers Pipe Mixed Data referring to and males in 9 and follow-up NS ... 1 15/33. 2/38 cigarette mortality ratios Horn, States 50-69 of death SM . 38 Cigar smokers included cancer 1958, years of age. certificate. 2/388 13/33 of mouth ULS.A. and larynx. (120). Doll and Approximately Questionnaire 10 29 All smokers by amount {Pipe and cigar tIncludes ex- Hill, 41,000 male and follow-up in grama NS .... 1.00 smokers of pipe 1964, British of death NS. ...... 1.00 SM .... 2.00 and cigars. Great physicians. certificate. 1-14 .... 2.00 Britain 15-24 .... 3.50 (74). 25 ...... 5.00 All ...... 3,00 Kahn U.S. male Questionnaire 814 111 NS ...... 1.00(11) Pipe f Refers to (Dorn), veterans and follow-up NS... 11 t1-9 -. 1.76 (2) 1.99 (3) cigarette 1966, 2,265,674 of death SM_...100 10-19 .... 4.71(18) Cigar smoking U.S.A. person years. certificate. 20-39... .11.50(24) 5.33 (12) only. (139). D250 we. 7.65 (3) All ...... 6.17(47) Hammond, 440,558 males Interviews by 4 46 NS ...... 1.00 (6) Pipe and Cigar 1966, 562,671 females ACS volunteers. NS... 6 SM (age NS .... 1.00 U.S.A. 35-84 years of SM . 40 45-64) . 4.17(32) SM .... 3.97(14) (118). age in 25 States. SM (age 65-79) . 1.74 (8) TABLE 30.—Esophageal cancer mortality ratios—prospective studies (cont.) (Actual number of deaths shown in parentheses) SM= Smokers, NS = Nonsmokers. Author year, Number and Data Follow- country, type of collection up years Comments reference population Hirayama, 265,118 male Trained PHS 14 SM . 21 NS. ...... 1,00 (p<0.01) Refers to all 1967, and female nurse inter- SM ...... 2.47(21) forms of Japan adults 40 view and smoking. (125). years of age follow-up and older. of death certificate. Weir and 68,153 males Questionnaire 5-8 32 NS 1.00 NS includes pipe Dunn, in various and follow-up +10 1.27 and cigar 1970, occupations of death +20 ...... 1.69 smokers. U.S.A. in California. certificate. >30 1.82 (906). All v2.0... 1.82 L6z 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. were noted. The consumption of very hot beverages was also found to be related to the development of esophageal cancer. PATHOLOGICAL STUDY Autopsy studies of smokers as compared with nonsmokers, spe- cifically observing the pathological changes in esophageal tissue, have been performed by Auerbach, et al. (15). A microscopic study was made of 12,598 sections of esophageal autopsy tissue from 1,268 men who died from causes other than esophageal cancer. The findings were strikingly similar to the abnormalities generally ac- cepted as representing premalignant tissue changes in the respira- tory tract epithelium. Esophageal epithelial cells with atypical nuclei (having an irregular distribution of chromatin) were found far more frequently in cigarette smokers than in nonsmokers. Basal cell hyperplasia and hyperactive glands were also found more fre- quently in cigarette smokers than in nonsmokers. An increase in frequency with amount of cigarette smoking was noted for both epithelial cells with atypical nuclei and basal cell hyperplasia. Tables A32 and A33 summarize these findings. EXPERIMENTAL STUDIES Kuratsune, et al. (156) investigated the possibility that the car- cinogens known to be present in tobacco smoke could penetrate the esophageal epithelium more readily if dissolved in aqueous ethanol. Mice were exposed to several compounds by esophageal intubation. Tissues were then removed and studied by fluorescence microscopy. Deeper penetration and a different distribution were found when B[a]P was dissolved in aqueous ethanol as compared to B[a]P in olive oil. It was also found that benzo[a]anthracene and fluoran- thene dissolved in ethanol solution or aqueous caffeine solution could penetrate the epithelium of the esophagus. Horie, et al. (132) reported on the development of 10 papillomas and one squamous cell carcinoma of the esophagus in a group of 63 mice periodically forced to drink a solution of benzo|a]pyrene dissolved in diluted ethanol. Twenty-six papillomas and one squam- ous cell carcinoma also developed in a group of 63 mice to which 4-nitroquinoline 1-oxide was administered in the same way. None of the 67 control animals given only diluted ethanol developed neoplasms. Several other authors have reported nitrosamine-induced esopha- geal cancer in experimental animals (56, 79, 80, 81). As noted above, the presence of nitrosamines in cigarette smoke is still a subject of debate. : 292 SUMMARY AND CONCLUSIONS 1. Epidemiological studies have demonstrated that cigarette smoking is associated with the development of cancer of the esopha- gus. The risk of developing esophageal cancer among pipe and/or cigar smokers is greater than that for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower. 2. Epidemiological studies have also indicated an association be- tween esophageal cancer and alcohol consumption and tthat aleohol consumption may interact with cigarette smoking. This combina- tion of exposures is associated with especially high rates of cancer of the esophagus. CANCER OF THE URINARY BLADDER AND KIDNEY EPIDEMIOLOGICAL STUDIES ( BLADDER ) Cancer of the urinary bladder accounted for 6,019 deaths among American males and 2,743 deaths among American females in 1967 (289). Incidence rates have increased from 1949 to 1962 (88), but the death rates from bladder cancer have remained relatively stable during that period. Improvements in early diagnosis and therapy may have masked the increasing incidence of this disease. A number of epidemiological studies have indicated that smokers have an increased risk of contracting or of dying from bladder cancer (see tables 34 and A35). Certain of these studies include kidney cancer mortality in the results. The major prospective stud- ies, with the exception of that of British physicians, have shown bladder cancer mortality ratios among cigarette smokers ranging from 1.40 to 2.89. Smokers of more than 1 pack per day were shown to incur ratios of 3.42 to 5.41. The study by Doll and Hill (74, 75) of British physicians, on the other hand, reports death rates for smokers to be lower than those of nonsmokers based on 38 bladder cancer deaths. The mortality ratios for pipe or cigar smokers are substantially lower than those among cigarette smokers. Pipe smokers were shown by both Hammond and Horn (120) and Kahn (139) to incur ratios approximating 1.20, Retrospective studies (table A35a) have also shown an increased proportion of smokers among bladder cancer patients when com- pared with matched controls. Relative risk ratios for bladder can- cer among smokers range from 1.0 to 7.3 among all smokers and up to 10.8 among heavy smokers of al] types. 293 ¥6t TABLE 34.—Kidney and urinary bladder cancer—prospective studies—Mortality ratios (Actual number of deaths shown in parentheses)1} NS = Nonsmokers. SM = Smokers. year, Number and Data Follow- Number country, type of collection up years o: Cigarette/day Pipe, cigar Kidney Bladder Comments reference population deaths Hammond 187,783 white Questionnaire 8% 287 NS .... 1.00(38) Pipe Data include patients and males in 9 and <10 .. 2.00(14) NS ...1.00(38) dying of prostatic Horn, States. interview. SM .249 10-20 .. 2.00(42) SM ...1.17(21) carcinoma. 1958, NS .. 38 >20 . 8.42(41) Cigar Data refer to U.S.A. NS ...1.00(38) microscopically (120). 5SM_ ...1.06(19) proven carcinomas. Doll and Approximately Questionnaire 10 38 NS ...1.00 AU SM by Hill, 41,000 male and follow- SM ...0.41 amount in grams 1964, British up of death NS. ...1.00 Great physicians. certificate. 1-14 ..0.59 Britain 15-24 ..0.65 (74). >25 ...0.76 All ....0.71 Best, Approximately Questionnaire 10 114 NS. .... 1.00 Pipe Refers to 1966, 78,000 male and follow- <10 =... 1.88(29) NS ...1.00 genitourinary Canada Canadian up of death 10-20 ., 1.44(57) SM ...0.56(10) cancers as a (21). veterans. certificate. >20 .. 21.43 (15) Cigar group. All » 1.40(10) NS ...1.00 SM ...1.16 (3) Hammond, 440,558 males Interviews by 4 Bladder Cigarettes Cigarettes Male data only. 1966, 562,671 ACS 138 NS... eee 1.00 (22) 1.00(23) Bladder includes U.S.A. females volunteers. SM. .115 SM (age 45-64) ., .1.42 (54) 2.00 (59) other urinary (118). 35-84 years NS .. 23 SM (age 65-79) =... .1.57 (28) 2.96 (56) tract cancers. of age in 25 Kidney States. 104 SM. 82 NS .. 22 TABLE 84.—Kidney and urinary bladder cancer—prospective studies—Mortality ratios (cont.) (Actual number of deaths shown in parentheses)! SM = Smokers. NS = Nonsmokers. Author, $6 year, Number and Data Follow- Number country, type of collection up years 0 Cigarette/day Pipe, cigar Kidney Bladder Comments reference population deaths Kahn U.S. male Questionnaire 814 Bladder NS . -1.00(39) 1.00(52) Bladder includes (Dorn), veterans and follow- 224 Pipe . 1.32 (6) 1.20 (8) other urinary 1966, 2,265,674 up of death SM .172 Cigar a -.0.77 (6) 0.94(10) tract cancers. U.S.A, person certificate. NS .. 52 Cigarettes/day: (139). years, Kidney 1-9 0.97 (4) 1.10 (6) 141 WO-19 eee 1.84 (21) 1.93 (37) SM ..102 20-39 .. 1,68 (16) 3.20 (34) NS .. 39 >39 » 2.75 (5) 2.52 (5) All 1.45 (46) 2.15 (82) Hirayama, 265,118 male Trained PHS 1, SM 6 NS - 1.00 Bladder cancer only. 1967, and female nurse inter- SM_....10.00 (6) Refers to all Japan adults 40 view and forms of smoking. (125). years of age follow-up and older. of death certificate. Weir and 68,153 males Questionnaire 5-8 Bladder NS ...1.00 NS ...1.00 SM include ex- Dunn, in various end follow- 27 110 =. .0.86 +10 ...1.52 smokers. 1970, occupations up of death Kidney 20 =. .3.30 +20 ...2.81 NS include pipe U.S.A, in California. certificate. 27 >>30 =. .2.57 30 ...5.41 and cigar (306). All ...2.46 All ....2.89 smokers. ‘Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. EPIDEMIOLOGICAL STUDIES (KIDNEY) A total of 5,894 Americans died of cancer of the kidney during 1967. A relationship between smoking and this type of cancer has been suggested by several epidemiological studies, The three major studies which separately examine the relationship of kidney cancer to smoking (table 34), namely those of Hammond (118), Kahn (139), and Weir and Dunn (306), have shown mortality ratios for all cigarette smokers to range from 1.42 to 2.46. Retrospective studies by Bennington, et al. (18, 19) have indicated a significant association between all forms of smoking and renal adenoma and adenocarcinoma. EXPERIMENTAL STUDIES Numerous experiments have been undertaken by many investi- gators to elucidate the relationship of tobacco smoking to bladder carcinogenesis. The two areas of major concern have centered upon the presence of a known bladder carcinogen, beta naphthylamine, in cigarette smoke and the presence of abnormal tryptophan me- tabolism in patients with bladder cancer. By virtue of data gathered concerning industrial exposure of workers, beta naphthylamine has long been known as a bladder carcinogen. Complementing such data was the work of Hueper, et al. (136) who subjected mongrel dogs to daily subcutaneous injec- tions and oral administration of commercial beta naphthylamine. Thirteen of the 16 animals developed bladder papillomas and car- cinomas of the bladder. Saffiotti, et al. (236) fed hamsters a diet containing up to 1.0 percent beta naphthylamine and observed that 18 of 39 animals developed bladder tumors, almost all typical tran- sitional cell carcinomas. More recently, Conzelman, et al. (59) ad- ministered beta naphthylamine to 24 rhesus monkeys for more than 30 months. Transitional cell carcinomas of the urinary blad- der were induced in 9 of the animals, and a dose-response relation- ship was apparent. Pailer, et al. (207) and Miller and Stedman (185) failed to find this amine in cigarette smoke. However, more recently, Hoffmann, et al. (127) identified it in cigarette smoke. The authors, noting the minute quantity present in each cigarette (2.2 x 10-‘g), hesi- tated to attach a biological significance to the finding. Of more recent interest have been the metabolites of tryptophan present in certain patients with bladder cancer. A number of nor- mal and abnormal metabolites of tryptophan have been found to be carcinogenic when tested by implantation in the bladders of mice. These include 3-hydroxykynurenine (OHKy), 3-hydroxyanthranilic 296 acid (OHA), 3-hydroxy-2-amino-acetophenone (all orthoamino- phenols), the 8-methy] ether of xanthurenic acid (CHXa), xanthu- renic acid (Xa), L-kynurenine (Ky), quinaldic acid, and 3-meth- oxyanthranilic acid (3CHOA) (2, 36, 37, 39, 47, 48). OHKy and OHA are frequently present in human urine, as is kynurenic acid (KyA). Certain investigators have concentrated their attention on the presence of abnormal tryptophan metabolites and increased amounts of normal tryptophan metabolites in the urine of patients with bladder cancer as compared with selected controls (1, 40, 46, 97, 148, 214, 243, 329). These authors have observed the increased excretion of Ky, KyA, OHKy, anthranilic acid, OHA, and acetylky- nurenine in such patients. Yoshida, et al. (329), in a recent study concerning the relationship between tryptophan metabolism and heterotopic recurrences of human urinary bladder tumors, reported that those patients with recurrences showed abnormal metabolite excretion more often than those without recurrences. The relationship of smoking to these biochemical findings is presently uncertain. Kerr, et al. (743), in 30 experiments on 3 smokers and 3 nonsmokers who were given large doses of trypto- phan, found that smoking increased the urinary excretion of OHKy and OHA and decreased that of N’methylnicotinamide (an end product of tryptophan metabolism). Kerr concluded that smoking interferes with the normal metabolism of tryptophan. Recently, Brown, et al. (45) studied 15 adults under smoking and abstinence conditions and found that except for the basal excretion of acetylky- nurenine, tryptophan metabolite excretion did not change with smoking or cessation. The authors also compared 13 nonsmokers and 17 regular cigarette smokers under basal and tryptophan- loaded conditions. No differences were observed in the excretion of the measured tryptophan metabolites. However, due to its instabil- ity, OHA was not measured. The authors concluded that the rela- tionship of smoking to urinary bladder cancer was probably not via its effect on the kynurenine pathway of tryptophan metabolism. Another experimental approach to the relationship of smoking and urinary bladder cancer is reflected in the work of Schlegel, et al. (244, 245). The authors observed an elevated concentration of certain ortho-aminophenols in the urine of bladder cancer patients and cigarette smokers, when compared with nonsmokers (244). More recently (245), the same group compared the chemilumines- cence of the urines of smokers, nonsmokers, and bladder tumor patients. They noted that nonsmokers showed the lowest level of luminescence (which they relate to the presence of aromatic hydro- carbons) and the bladder tumor patients the highest level. The normal cigarette smokers’ level was found to be intermediate. 297 862% TABLE 36.—Pancreatic cancer mortality ratios—prospective studies (Actual number of deaths shown in parentheses)? NS = Nonsmokers. SM = Smokers. Author, Number and Data Follow-up Number . Comments country, type of collection years of deaths Cigarettes Pipes, cigars reference population Best, Approximately Questionnaire 6 SM . 85 Current (cigarettes only) Pipes 1966, 78,000 male and follow-up NS ..... 1.00 NS ..1.00 Canada Canadian of death <10 . 1.40 (5) SM ..2.60 (6) (21). veterans. certificate. 10-20 . 1.96 (16) Cigars >20 - 2.37 (7) NS ..1.00 SM ..2.63 (1) Hammond 440,558 males Interviews by 4 262 NS... 1.00 (29) Male data only. 1966 562,671 females ACS SM +233 5M (age ULS.A. 35-84 years volunteers, NS . 29 45-64) 2.69(158) (118). of age in 25 SM (age States. 65-79) 2.17 (75) Kahn | US. male Questionnaire 8, 344. NS ..... 1.00 (88) Pipes tT Refers to current smokers (Dorn) veterans, and follow-up SM .. 256 1-9 . O87 (8) NS ..1.00(88) of all types. 1966 2,265,674 of death NS . 88 10-20 - 1.93 (65) SM ..0.74 (8) USA. person years. certificate. 21-39 - 2.18 (48) Cigars (139). >39 - 187 (7) NS ..1.00(88) All ...., 1.84(125) SM_ . .1.52 (27) Both NS ..1.00(88) SM_. .0.93(13) Hirayama, 265,118 male Trained PHS 14 SM .14 =+NS ...., 1.00 lipco 01) ~~ 1967, and female nurse inter- SM 15.56 (1406 ‘ Japan adults 40 view and (125). years of age follow-up of and older. deathcertificate. Weir and 68,153 males Questionnaire 5-8 SM . 71 NS ..... 1.00 SM includes ex-smokers. Dunn, in various and follow-up +10 .. 2,94 NS includes pipe and cigar 1970, occupations of death +20 .. 2.45 smokers. U.S.A. in California. certificate. >30 . 1.44 (306). All ..... 2.43 ' Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the ex- phates nh tat At present, no definite conclusions can be drawn concerning the interrelationships of bladder cancer, abnormal tryptophan metab- olism, and tobacco smoking. Further study is required in this and the other areas of bladder cancer pathophysiology. SUMMARY AND CONELUSIONS 1. Epidemiological studies have demonstrated an association of cigarette smoking with cancer of the urinary bladder among men. The association of tobacce usage and cancer of the kidney is less clear-cut. 2. Clinical and pathological studies have suggested that tobacco smoking may be related to alterations in the metabolism of trypto- phan and may in this way contribute to the development of urinary tract cancer. CANCER OF THE PANCREAS Several prospective epidemiologic studies have suggested a rela- tionship between cigarette smoking and cancer of the pancreas (table 36), A retrospective study of 465 cases of pancreatic cancer by Ishii, et al. (137) has shown a dose-related increased risk of pancreatic cancer in association with smoking. Analysis of dietary data revealed that the relative risk for pancreatic cancer from smoking was considerably greater than from dietary factors. No experimental studies relating to this question have been reported. SUMMARY AND CONCLUSIONS Epidemiological studies have suggested an association between cigarette smoking and cancer of the pancreas. The significance of the relationship is not clear at this time. REFERENCES (1) ABELIN, T., GSELL, O. T. Relative risk of pulmonary cancer in cigar and Pipe smokers. Cancer 20(8): 1288-1296, August 1967. (2) ALIFANO, A., Papa, S., TANCREDI, F., Exicio, M. A., QUA LIARIELLO, E. Tryptophan-nicotinic acid metabolism in patients with tumours of the bladder and kidney. British Journal of Cancer 18: 386-389, 1964. (3) ANTHONY, H. M., THoMas, G. M. Bladder tumours and smoking. Interna- tional Journal of Cancer 5(2) : 266-272, March 15, 1970. (4) ARKIN, A., WaGNER, 1). H. Primary carcinoma of the lung. A diagnostic study of one hundred and thirty-five cases in 4 years. Journal of the American Medical Association 106(8) : 587-591, February 22, 1986. 299 (3) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) 300 ASH, J. E., Beck, M. R,, WILKES, J. D. Tumors of the upper respiratory tract and ear. IN: Atlas of Tumor Pathology. Section IV—Fascicles 12 and 13. Washington, Armed Forces Institute of Pathology, 1964. ASHLEY, D, J. B., Davirs, H. D. Cancer of the lung. Histology and bio. logical behavior. Cancer 20(2): 165-174, February 1967. AUERBACH, O. The pathology of carcinoma of the bronchus. New York State Journal of Medicine 49: 900-907, April 15, 1949, AUERBACH, O., GERE, J. B., PAWLowsKI, J. M., MUEHsaM, G. E., SMOLIN, H. J., Stour, A. P. Carcinoma-in-situ and early invasive carcinoma occurring in the tracheobronchial trees in cases of bronchial carci- noma. Journal of Thoracic Surgery 34(3): 298-309, Septemher 1957, AUERBACH, O., HAMMOND, E. C., GARFINKEL, L. Histologic changes in the larynx in relation to smoking habits. Cancer 25(1): 92-104, January 1970. AUERBACH, O., HAamMmMonp, E. C., KIRMAN, D., GARFINKEL, L., Stout, A. P. Histologic changes in bronchial tubes of cigarette-smoking dogs. Cancer 20(12): 2055-2066, December 1967. AUERBACH, O., HAMMOND, E. C., Kirman, D., GARFINKEL, L. Effects of cigarette smoking on dogs. IT. Pulmonary neoplasms. Archives of En- vironmental Health 21(6) : 754-768, December 1970. AUERBACH, O., Stout, A. P., HaAmmMonn, E.C., GARFINKEL, L. Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. New England Journal of Medicine 265(6): 253-267, August 10, 1961. AUERBACH, O., Stout, A. P., HAMMOND, E. C., GARFINKEL, L, Changes in bronchial epithelium in relation to sex, age, residence, smoking and pneumonia. New England Journal of Medicine 267(8) ; 111-119, July 19, 1962, AUERBACH, O., Stout, A. P., HaMMonpD, E. C., GARFINKEL, L. Bronchial epithelium in former smokers. New England Journal of Medicine 267(3): 119-125, July 19, 1962. AUERBACH, O., Stout, A. P., HAMMOND, E. C., GARFINKEL, L. Histologic changes in esophagus in relation to smoking habits. Archives of En- vironmental Health 11 (1) : 4-15, July 1965. Awa, A., OHNUKI, Y., Pomerat, C. M. Some comparative effects of smoked paper, tobacco and cigarettes on chromosomes in vitro. Texas Reports on Biology and Medicine 19: 518-528, 1961. Bair, W. J. Inhalation of radionuclides and carcinogenesis. IN: Hanna, M. G., JR., Nettesheim, P., Gilbert, J.R. (Editors). Inhalation Carcin- ogenesis. Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970, pp. 77-101. BENNINGTON, J. L., FERGUSON, B. R., CAMPBELL, P. B. Epidemiologic studies of carcinoma of the kidney. II. Association of renal adenoma with smoking. Cancer 22(4) : 821-823, October 1968. BENNINGTON, J. L., LAUBSCHER, F. A, Epidemiologic studies on car- cinoma of the kidney. I. Association of renal adenocarcinoma with smoking. Cancer 21(6): 1069-1071, June 1968, BERWALD, Y., SACHS, L. In vitro transformation of normal cells to tumor cells by carcinogenic hydrocarbons, Journal of the National Cancer Institute 34(4): 641-658, October 1965, Best, E. W. R. A Canadian Study of Smoking and Health. Ottawa, De- partment of National Health and Welfare, 1966, 137 pp. (22) (23) (24) (25) (26) (30) (31) (32) (83) (24) (35) BIDSTRUP, P. L., CASE, R. A. M. Carcinoma of the lung in workmen in the bichromates-producing industry in Great Britain. British Journal of Industrial Medicine 13: 260-264, 1956. Back, H., ACKERMAN, L. V. The importance of epidermoid carcinoma im situ in the histogenesis of carcinoma of the lung. Annals of Surgery 136(1): 44-55, July 1952. BLACKLOCK, J. W. S. The production of lung tumours in rats by 3:4 benzpyrene, methylcholanthrene and the condensate from cigarette smoke. British Journal of Cancer 11(2): 181-191, 1957. BLACKLOCK, J. W. S. An experimental study of the pathological effects of cigarette condensate in the lungs with special reference to carcino- genesis. British Journal of Cancer 15(4): 745-762, December 1961. BLUMLEIN, H. Zur kausalen Pathogenese des Larynxkarzinoms unter Berticksichtigung des Tabakrauchens. (Causal pathogenesis of laryngeal carcinoma with respect to tobacco smoking.) Archiv fiir Hygiene und Bakteriologie Miinchen 139: 349-404, 1955. Bock, F. G. The nature of tumor-promoting agents in tobacco products. Cancer Research 28(11) : 2363-2368, November 1968. Bock, F. G., Moore, G. E. Carcinogenic activity of cigarette-smoke condensate. I. Effect of trauma and remote X irradiation. Journal of the National Cancer Institute 22(2): 401-411, February 1959. Bock, F. G., Moors, G. E., CLarx, P. C. Carcinogenic activity of cigar- ette smoke condensates. III. Biological activity of refined tar from several types of cigarettes. Journal of the National Cancer Institute 34(4) : 481-493, April 1965, Bock, F. G., Moore, G. E., Croucn, S. K. Tumor-producing activity of extracts of unburned tobacco. Science 145 (3684) : 831-833, August 21, 1964. Bock, F. G., Moore, G. E., Down, J. E., CLarK, P. C, Carcinogenic activ- ity of cigarette smoke condensate. Biological activity of refined tar from certain brands of cigarettes. Journal of the American Medical Association 181(8): 668-673, August 25, 1962. Boren, H. G. Pulmonary cell kinetics after exposure to cigarette smoke. IN: Hanna, M.G., Jr., Nettesheim, P., Gilbert, J. R. (Editors). Inhala- ation Carcinogenesis. Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 229-241. BORENFREUND, E., KRIM, M., SANDERS, F. K., STERNBERG, S. S., BENDICH, A, Malignant conversion of cells in vitro by carcinogens and viruses. Proceedings of the National Academy of Sciences of the United States of America 56: 672-679, 1966. BorIsyuk, Y. P. Rak legkikh u krys, vyzvannyy intratrakheal’nym vvedeniyem prodoktov kureniya. (Cancer of the lung in rats induced by intratracheal intubation of tobacco smoke products.) Voprosy Onkologii 15(6): 49-53, June 1969. Boucuarp, J., May, R. M. L’effet des goudrons de tabac sur les greffes sours-capsulaires de poumon chez la souris. (The effect of tobacco tars on sub-capsular implants of the lung in mice.) Archives d’Anatomie Microscopique et de Morphologie Experimentale 49 (3) : 307-832, 1960. 301 302 (36) BoyLtanp, E. The Biochemistry of Bladder Cancer. Sprinefiel C. C. Thomas, 1963. 95 pp. (37) BoyLanp, E., Bussy, E. R., DuKgs, C. E., GROVER, P. L., MANs Further experiments on implantation of materials into the u bladder of mice. British Journal of Cancer 18(8) : 575-581, Sep: 1964. (38) BoyLanp, E., Roe, F. J. C. Carcinogenic nitrosamines which » present in cigarette smoke. IN: Severi, L, (Editor). Lung Tun Animals. Perugia, Division of Cancer Research, University of Px June 1966. pp. 667-676. (39) BoyLanp, E., WATSON, G. 3-hydroxyanthranilic acid, a carcinoge duced by endogenous metabolism. Nature 177(4514): 837-838 5, 1956. (40) BoyLanp, E., Wi.iiams, D. C. The metabolism of tryptophan. : metabolism of tryptophan in patients suffering from the cancer bladder. Biochemical Journal 64: 5078-582, 1956. (41) BRapsHaw, E., SCHONLAND, M. Oesophageal and lung cancer in African males in relation to certain socio-economic factors. An ysis of 484 interviews. British Journal of Cancer 23 (2): 27, June 1969. (42) BREsLow, L., Hoactin, L., RASMUSSEN, G., ABRAMS, H. K. Occup: _ and cigarette smoking as factors in lung cancer. American Jour Public Health and the Nation’s Health 44(2): 171-181, February (43) Bropers, A. C. Squamous-cell epithelioma of the lip. A study o hundred and thirty-seven cases. Journal of the American M Association 74(10): 656-664, March 6, 1920. (44) Bross, I. D. J. Effect of filter cigarettes on the risk of lung cancer Wynder, E. L., Hoffmann, D, (Editors). Toward a Less Ha Cigarette. Bethesda, Md., U.S. Public Health Service, National C Institute Monograph No. 28, June 1968. pp. 35-40. (45) Brown, R. R., Price, J. M., Burney, S. W., FRIEDELL, G. H. La effect of smoking on the excretion of tryptophan metabolites by Cancer Research 30(3) : 611-614, March 1970. (46) Brown, R.R., Price, J. M., SaTTER, E. J., Wear, J. B. The metaboli: tryptophan in patients with bladder cancer. Acta Unio Internatio Contra Cancrum 16: 299-303, 1960. (47) Bryan, G. T. Role of tryptophan metabolites in urinary bladder ca American Industrial Hygiene Association Journal 380(1): 2 January—February 1969, (48) BrYAn, G. T., Brown, R. R., Price, J. M. Mouse bladder carcinogen of certain tryptophan metabolites and other aromatie nitrogen pounds suspended in cholesterol. Cancer Research 24(4): 596- May 1964. (49) BUELL, P. E., DuNN, J. E., BREsLow, L. Cancer of the lung and Angeles-type air pollution. Prospective study. Cancer 20(12): 2 2147, December 1967. (50) CAHAN, W. G., Kirman, D. An effective system and procedure , cigarette smoking by dogs. Journal of Surgical Research 8(12):. 575, December 1968. (51) CaRNEs, W. H. The respiratory epithelium of patients with lung car IN: The Morphological Precursors of Cancer. Proceedings of International Conference held at the University of Perugia, June 1 (52) (58) (54) (55) (58) (59) (60) (01) (62) A publication of the Division of Cancer Research, University of Perugia, Italy. pp. 625-634, CARUGNO, N., Ross, S. Evaluation of polynuclear hydrocarbons in cigarette smoke by glass capillary columns. Journal of Gas Chroma- tography 5(2) : 103-106, February 1967. CASTIGLIANO, S. G. Influence of continued smoking on the incidence of second primary cancers involving mouth, pharynx, and larynx. Journal of the American Dental Association 77(3) : 580-585, September 1968. CHAN, P. C., SANDERS, F, K., WYnNDER, E. L. Effect of 3,4-benzo (a) pyrene on mouse lung primordia in vitro. Nature 228 (5208) : 847-848, August 23, 1969, CHANG, S. C. Microscopic properties of whole mounts and sections of human bronchial epithelium of smokers and non-smokers. Cancer 10(6) : 1246-1261, December 1957, Capp, N. K., Craig, A. W. Carcinogenic effects of diethylnitrosamine in RF mice. Journal of the National Cancer Institute 39(5) : 903-916, November 1967. Coss, B. G., ANSELI, J. S. Cigarette smoking and cancer of the bladder. Journal of the Ameriean Medical Association 193(5): 329-332, August 2, 1965. COHEN, S., Hossain, S. Primary carcinoma of the lung. A review of 417 histologically proved cases. Diseases of the Chest 49(1): 67-74, January 1966 CONZELMAN, G. M., JR., MOULTON, J. E., FLANpers, L. E., III, SPRINGER, K., Crout, D. W. Induction of transitional cell carcinomas of the uri- nary bladder in monkeys fed 2-naphthylamine. Journal of the National Cancer Institute 42 (5) : 825-836, May 1969. Cook, J. W. Tobacco Smoke and Lung Cancer. London, The Royal Insti- tute of Chemistry, Lecture Series No. 5, 1961. 18 pp. CORNFIELD, J. A method of estimating comparative rates from clinical data. Applications to cancer of the lung, breast, and cervix. Journal of the National Cancer Institute 11: 1269-1275, 1951. Crocker, T. T. Effect of benzo(a)pyrene on hamster, rat, dog, and monkey respiratory epithelia in organ culture. IN: Hanna, M. G., JR, Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomie Energy Commission Symposium Series 18, April 1970. pp. 483-443. CROCKER, T. T., NIELSEN, B. L., LASNITZKI, I. Carcinogenic hydrocar- bons. Effects on suckling rat trachea in organ culture. Archives of Environmental Health 10(2): 240-250, February 1965. Cross, K. R., Waxz, D. V., PALMER, G. K., WARNER, E. D. A study of the tracheobronchial epithelium and changes related to smoking. Journal of the Iowa Medical Society 51(8): 187-140, March 1961. Davies, R. F., Day, T. D. A study of the comparative carcinogenicity of cigarette and cigar smoke condensate on mouse skin. British Journal of Cancer 23(2) : 363-368, June 1969. DEELEY, T. J., CoHEN, S. L. The relationship between cancer of the bladder and smoking. IN: Bladder Cancer. Chapter 18, Proceedings of the 5th Inter-American Conference on Toxicology and occupational medicine, the University of Miami, School of Medicine, Coral Gables, Fla., 1966. pp. 163-169. 303 (67) (68) (69) (70) (72) (72) (73) (74) (75) (76) (77) (78) (79) (80) (81) (82) 304 DELLa Porta, G., Kors, L., SHUBIK, P. Induction of tracheobronchial] carcinomas in the Syrian golden hamster. Cancer Research 18: 599. 597, June 1958, D1amonnD, L. The effect of carcinogenic hydrocarbons on rodent and pri- mate cells in vitro. Journal of Cellular and Comparative Physiology 66: 183-195, 1965. Dox, R. Cancer of the lung and nose in nickel workers. British Journal] of Industrial Medicine 15 (4) : 217-223, October 1958. Dott, R. Mortality from lung cancer among nonsmokers. British Journal of Cancer 7: 303-312, 1953. Doit, R. Mortality from lung cancer in asbestos workers. British Jour- nal of Industrial Medicine 12(1): 81-86, January 1955. Dox, R. Occupational lung cancer: A review. British Journal of Indus- trial Medicine 16: 181-190. 1959. Dox, R., Hi, A. B. A study of the aetiology of carcinoma of the lung. British Medical Journal 2: 1271-1286, December 13, 1952, Dot, R., Hii, A. B. Mortality in relation to smoking: Ten years’ obser- vations of British doctors. (Part 1) British Medical Journal 1 (5395) : 1399-1410, May 30, 1964. Dot, R., Hitt, A. B. Mortality in relation to smoking: Ten years’ obser- vations of British doctors. (Concluded) British Medical Journal 1(5396) : 1460-1467, June 6, 1964. DONTENWILL, W. Experimental investigations on the effect of cigarette smoke inhalation on small laboratory animals. IN: Hanna, M. G., Jr., Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis, Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 389-412. DONTENWILL, W., WIEBECKE, B. Tracheal and pulmonary alterations following the inhalation of cigarette smoke by the golden hamster. IN: Severi, L. (Editor), Lung Tumors in Animals. Perugia, Italy, Divi- sion of Cancer Research, University of Perugia, June 1966. pp. 519- 526. . DRUCKREY, H. Experimental investigations on the possible carcinogenic effects of tobacco smoking. Acta Medica Scandinavica 170 (Supple- ment 369) : 24-42, 1961. Druckrey, H., LANDScHUTz, C., PREUSSMANN, R. Oesophagus-carcinome nach Inhalation von Methyl-butyl-nitrosamin (MBNA) an Ratten. (Carcinomas of the oesophagus, induced by inhalation of methyl-butyl- nitrosamine (MBNA) in rats.) Zeitschrift fiir Krebsforschung 71 (2) : 135-139, July 1968. DruckreEy, H., PREUSSMANN, R., BiuM, G., IVANKOoVIC, S., AFKHAM, J. Erzeugung von Karzinomen der Spelseréhre durch unsymmetrische Nitrosamine. (Esophageal carcinomas induced by asymmetric nitro- samines.) Naturwissenschaften 50(3) : 100-101, 1963, DruckrEy, H., PREUSSMANN, R., IvANKovIC, S., SCHMAHL, D. Organo- trope carcinogene Wirkungen bei 65 verschiedenen N-nitroso-Verbin- dugen an BI)-Rattan. (Organotropic carcinogenic effects of 65 different N-nitroso compounds of Bl)-rats). Zeitschrift fiir Krebsforschung 69 (2) :103-201, March 22, 1967. , Druckrey, H., ScHIpBacH, A. Quantitative Untersuchungen zur Bedeutung des Benzpyrens fiir die carcinogene Wirkung von Taba- krauch. (Quantitative studies on the significance of benzopyrene for (83) (84) (85) (86) (87) (88) (89) (90) (91) (92) (93) (98) the carcinogenic effect of tobacco smoke.) Zeitschrift fir Krebsfor- schung 65: 465~470, 1963. Duncar., N. Lung carcinoma in Iceland. Lancet 2(6624): 245-247, August 12, 1950. DunuaM, L. J., HERROLD, K. M. Failure to produce tumors in the ham- ster cheek pouch by exposure to ingredients of betel-quid; histopatho- logic changes in the pouch and other organs by exposure to known carcinogens. Journal of the National Cancer Institute 29(6): 1047- 1067, December 1962. DUNHAM, L. J., Rabson, A. S., STEWaRT, H. L., FRANK, A. S., YouNG, J. L., JR. Rates, interview, and pathology study of cancer of the uri- nary bladder in New Orleans, Louisiana. Journal of the National Cancer Institute 41(3): 683-709, September 1968. DuTTA-cHOUDHURI, R., Roy, H., SEN Gupta, B. K. Cancer of the larynx and hypopharynx. A clinicopathological study with special reference to aetiology. Journal of the Indian Medical Association 32(9): 852- 362, May 1, 1959. EBENIUS, B. Cancer of the lip. A clinical study of 778 cases with particu- lar regard to predisposing factors and radium therapy. Acta Radio- logica (Supplement 48): 1-232, 1943. EISENBERG, H., CAMPBELL, P. C., FLANNERY, J. T. Cancer in Connecticut. Incidence characteristics 1935-1962, Hartford, Connecticut State De- partment of Health, 1967. 97 pp. ELMENHOorST, H., ReEcKzEH, G. Aromatische Kohlenwasserstoffe im Tabakrauch. (Aromatic hydrocarbons in tobacco smoke.) Beitrage zur Tabakforschung 2(5): 180-204, May 1964. Evzay, R. P. Effect of alcohol and cigarette smoke as promoting agents in hamster pouch carcinogenesis. Journal of Dental Research 48 (6, Part 2): 1200-1205, November—December 1969. EPSTEIN, S. S., ANDREA, J., JAFFEE, H., JosHt, S., Fak, H., MANTEL, N. Carcinogenicity of the herbicide maleic hydrazide. Nature 215 (5108): 1388-1390, September 28, 1967. ESSENBERG, J. M. Cigarette smoke and the incidence of primary neo- plasm of the lung in the albino mouse. Science 116: 561-562, November 21, 1952. Fak, H. L., Kortin, P., MEHLER, A. Polycyclic hydrocarbons as carcin- ogens in man. Archives of Environmental Health 8(5): 721-730, May 1964, Ferri, E. S., BaRaTta, E. J. Polonium-210 in tobacco, cigarette smoke and selected human organs. Public Health Reports 81(2): 121-127, February 1966. Ferri, E. S., Baratta, E. J. Polonium-210 in tobaeco products and hu- man tissues. Radiological Health Data and Reports 7(9}: 485-488, September 1966. FLETCHER, C. M., Horn, D. Smoking and health. WHO Chronicle 24 (8): 345-370, August 1970. FRIEDELL, G. H., BURNEY, S. W., BELL, J. R., Soto, E. Pathology as re- lated to tryptophan metabolite excretion, occupational history, and smoking habits in patients with bladder cancer. Journal of the Na- tional Cancer Institute 48 (1) : 303-306, July 1969. GELFAND, M., GRAHAM, A. J. P., LIGHTMAN, S. Carcinoma of bronchus and the smoking habit in Rhodesian Africans. British Medical Journal 3 (5616) : 468-469, August 24, 1968. 305 (99) (100) (101) (102) (103) (104) (105) (106) 107) (108) (109) (110) (111) (112) (113) (114) (115) (116) 306 GELLHORN, A. The cocarcinogenic activity of cigarette tobacco tar. Can- cer Research 18(6): 510-517, June 1958 GOLDBLATT, M. W. Occupational carcinogenesis. British Medical Bulletin 14(2): 136-140, 1958. GRAHAM, E. A.. CRONINGER, A. B., WYNDER, E. L, Experimental produc- tion of carcinoma with cigarette tar. IV, Successful experiments with rabbits. Cancer Research 17(11): 1058--1066, lecember 1957, GRAHAM, S. Cancer of lung related to smoking behavior. Cancer 21 (8) 528-530, March 1968 GRAHAM, S., Croucn, S., LEVIN, M. L., Bock, F. G. Variations in amounts of tobacco tar retrieved from selected models of smoking be- havior simulated by smoking machine. Cancer Research 23(7): 1025-. 1030, August 1963. Gray, S. H., Corponnter, J. Early carcinoma of the lung. A. M. A. Archives of Surgery 19: 1618-1626, 1929 GreGorY, L. P. Polonium-210 in leaf tobacco from four countries. Science 150: 74-76, October 1, 1965. Gross, P., DE TREVILLE, T. P., Torker, E. B., KASCHAK, M., BABYAK, M. A. I:xperimental asbestosis. The development of lung cancer in rats with pulmonary deposits of chrysotile asbestos dust. Archives of En- vironmental Health 15(3) : 343-3855, September 1967. GSELL, O, Carcinome bronchique et tabac. (Bronchial carcinoma and tobacco.) Medecine et Hygeine 12(279): 429-431, December 1, 1954. GUERIN, M. Tumeurs pulmonaires et cancer buccal chez le rat soumis a Pinhalation de fumee de sigarette. (Pulmonary tumors and oral can- cers in rats subjected to inhalation of cigarette smoke.) Bulletin de Association Francaise pour l’Etude du Cancer 46(2) ; 295-309, 1959. GUERIN, M. Cuzin, J.-L. Action carcinogene du goudron de fumee de cigarette sur la peau de souris. (Carcinogenie action of tar from cigarette smoke on mouse skin.) Bulletin de Association Francaise pour I’Etude du Cancer 44(3): 387-408, 1957 GuIMARD, J. Alterations cellulaires provoquees in vitro, sur des fibro- blastes quiescents et en mitose, par des goudrons entiers de tabac (Cellular changes induced in vitro in quiescent fibroblasts and those in mitosis by nonfractional tobacco tar.) Archives des Sciences Physiologiques 20(2): 153-167, 1966. GuTHRIE, F. ©. The nature and significance of pesticide residues on tobacco and in tobacco smoke. Beitrage zur Tabakforschung 4(6): 229-246, November 1968. HAENSZEL, W., LOVELAND, I). B., SIRKEN, M. G. Lung-cancer mortality as related to residence and smoking histories. I. White males. Journal of the National Cancer Institute 28(4) : 947-1001, April 1962. HAENSZEL, W., SHIMKIN, M. B. A retrospective study of lung cancer in women. Journal of the National Cancer Institute 21(5): 825-842, November 1958. HAENSZEL, W., SHIMKIN, M, B., MILter, H. P. Tobacco smoking patterns in the United States. Public Health Monograph No. 45, May 1956. 111 pp. HAENSZEL, W., TARUBER, K. FE. Lung-cancer mortality as related to residence and smoking histories. II. White females. Journal of the National Cancer Institute 32(4): 803-838, April 1964. HAMER, I)., WoopHousE, D. L. Biological tests for carcinogenic action of tar from cigarette smoke. British Journal of Cancer 10: 49-58, 1956. (117) HAMILTON, J. 1)., Sepp, A., Brown, T. C., MacDonatp, F. W. Morpho- . logical changes in smokers’ lungs. Canadian Medical Association Journal 77(3): 177-182, August 1, 1957. (118) HaMMonpD, E. C. Smoking in relation to the death rates of 1 million men and women. IN: Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. Bethesda, Md., U.S. Public Health Service, National Cancer Institute Monograph, No. 19, January 1966. pp. 127-204. . (119) HAMMOND,E. C., AUERBACH, O., KIRMAN, D., GARFINKEL, L. Effects of cigarette smoking on dogs. J. Design of experiment, mortality and findings in lung parenchyma. Archives of Environmental Health 21(6): 740-758, December 1970. (120) HAMMOND, E. C., Horn, I)? Smoking and death rates—report on forty- four months of follow-up of 187,783 men. II. Death rates by cause. Journal of the American Medical Association 166(11): 1294-13808, March 15, 1958. (121) Harris, R. J. C., NEGRONI, G. Production of lung carcinomas in C57BL mice exposed to a cigarette smoke and air mixture. British Medical Journal 4(5580) : 687-641, December 16, 1967. (122) Herroip, K. M., DuNHAM, L. J. Induction of carcinoma and papilloma of the tracheobronchial mucosa of the Syrian hamster by intratracheal instillation of benzo(a)pyrene. Journal of the National Cancer Insti- tute 28(2): 467-491, February 1962. (122) Hitz, C. R. Polonium-210 in man. Nature 208(5009) : 4238-428, October 30, 1965. (124) HirayaMa, T. An epidemiological study of oral and pharyngeal cancer in Central and Southeast Asia. Bulletin of the World Health Organ- ization 34(1): 41-69, 1966. (125) Hirayama, T. Smoking in relation to the death raes of 265,118 men and women in Japan. Tokyo, National Cancer Center, Research Institute, Epidemiology Division, September 1967. 14 pp. (126) Hrrosuci, M. Epidemiological study of lung cancer with special refer- ence to the effect of air pollution and smoking habit. Bulletin of the Institute of Public Health 17(8) : 237-256, September 1968. (127) HOFFMANN, I)., Masupa, Y., WYNDER, E. L. Alpha-naphthylamine and beta naphthylamine in cigarette smoke. Nature 221(5177): 254-256, January 18, 1969. (128) HOFFMANN, D., RATHKAMP, G. Chemical studies on tobacco smoke. V. Quantitative determination of chlorinated hydrocarbon insecticides in cigarette tobacco and its smoke. Beitrage zur Tabakforschung 4(5): 201-214, July 1968. (129) HorrMann, D., WyNpeErR, E. L. Chamber development and aerosol dis- persion. IN: Hanna, M. G., Jr., Nettesheim, P., Gilbert, J.R. (Editors). Inhalation Carcinogenesis. Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, Octo- ber 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 173-191. (180) Horsti, L. R., ERMALA, P. Papillary carcinoma of the bladder in mice, obtained after peroral administration of tobacco tar. Cancer 8(4): 679-682, July-August 1955. (131) Homsurcer, F., TREGER, A., Baker, J. R. Mouse-skin painting with smoke condensates from cigarettes made of pipe, cigar, and cigarette 307 (132) (133) (134) (185) (136) (187) (138) (139) (140) (141) (142) (143) (144) (145) 308 tobaccos. Journal of the National Cancer Institute 31(6): 1445-1459, December 1963. Horik, A., KOHCHI, S., KURATSUNE, M. Carcinogenesis in the esophagus. IJ. Experimental production of esophageal cancer by administration of ethanolic solution uf carcinogens. Gann 56(5): 429-441, Oetoher 1965, Hvurper, W. ©. Experimental studies in metal cancerigenesis. VJ. Tissue reactions in rats and rabbits after parenteral introduction of suspen- sions of arsenic, beryllium, or asbestos in lanolin. Journal of the National Cancer Institute 15(1): 118-129, August 1954. HueEper, W. C, Experimental studies in metal cancerigenesis. TX. Pul- monary lesions in guinea pigs and rats exposed to prolonged inhala- tion of powdered metallic nickel. A.M.A. Archives of Pathology 65: 600-607, June 1958. HUuEPperR, W. C., PAYNE, W. W. Experimental studies in metal ecarcino- genesis. Chromium, nickel, iron, arsenic. Archives of Environmental! Health 5(5): 445-462, November 1962. HUEPER, W. C., WILEY, F. H., Wore, H. D., Ranta, K. E., LEMING, M. F., BLoop, F. R. Experimental production of bladder tumors in dogs by administration of beta-naphthylamine. Journal of Industrial Hy- giene and Toxicology 20(1): 46-84, January 1938. Iso, K., NAKAMURA, K., OZAKI, H., YAMADA, N., TAKEUCHI, T. Suizo- gan no ekigaku ni okeru mondaiten. (Some aspects of the epidemiology of cancer of the pancreas.) Nippon Rinske 26(8) : 1839-1842, August 1968. JOHNSON, D. E., MILLAR. J. D., RHOADES, J. W. Nitrosamines in tobacco smoke. IN: Wynder, FE. L., Hoffmann, D. (Editors). Toward a Less Harmful Cigarette. Bethesda, Md., U.S. Department of Health, Edu- cation, and Welfare, Public Health Service, National Cancer Institute Monograph 28, June 1968. pp. 181-189. Kaun, H. A. The Dorn study of smoking and mortality among U.S. vet- erans: Report on 815 years of observation. IN: Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. Bethesda, Md., U.S. Public Health Service, National Cancer Institute Monograph No. 19, January 1966. pp. 1-125. KELLER, A. Z. Cirrhosis of the liver, aleoholism and heavy smoking asso- ciated with cancer of the mouth and pharynx. Cancer 20(6): 1015- 1022, June 1967. KELLER, A. Z. Cellular types, survival, race, nativity, occupations, habits and associated diseases in the pathogenesis of lip cancers. American Journal of Epidemiology 91(5) : 486-499, May 1970. KELLey, T. F. Polonium—210 content of mainstream cigarette smoke. Science 149 (3683) : 587-538, July 30, 1965. Kers, W. K., BARKIN, M., LeEvERS, P. E., Woo, S. K.-C., Menczyk, Z. The effect of cigarette smoking on bladder carcinogens in man, Canadian Medical Association Journal 93(1): 1-7, July 5, 1965. Kipa, H., OMoro, T., SAKAMOTO, K., Momosk, 8. Fukuoka ken hokubu ni okeru boko shuyo no ekigaku to tokel. (Statistics and epidemiology of urinary bladder tumors in northern Fukuoka, Japan.) Hifu to Hinyo 30(5) : 888-889, October 1968. KILIBARDA, M., PETROVIC, D., PANOov, 1)., DauRic, D. Contamination with polonium-210, uranium and radium-226 due to smoking. Health Phy- sics 12: 1808, December 1966. (149) (150) (151) (152) (157) (158) (159) (160) (161) (162) (163) (164) Kiryu, 8., KURATSUNE, M. Polyeyclic aromatic hydrocarbons in the ciga- rette tar produced by human smoking. Gann 57: 317-822, August 1966. KNUDTSON, K. P. The pathologic effects of smoking tobacco on the tra- chea and bronchial mucosa. American Journal of Clinical Pathology 33 (4): 310-817, April 1960, KOcHEN, W., Hocusere, K. Untersuchugen tiber den Trypthophan-Stoff- wechsel beim Blasen-Carcinom. (Studies about the tryptophan metab- olism in the carcinoma of bladder.) Zeitschrift fiir Krebsforschung 73(3) : 251-264, January 29, 1970. KoTIn, P., Fack, H. L. Atmospheric factors in pathogenesis of lung can- cer. Advances in Cancer Research 7: 475-514, 1963. Kortin, P., Fark, H. L. Polluted urban air and related environmental factors in the pathogenesis of pulmonary cancer. Diseases of the Chest 45 (3): 236-246, March 1964. Kou.umigs, M. Smoking and pulmonary carcinoma. Acta Radiologica 39: 255-260, 1953. KRESHOVER, S. J. The effect of tobacco on epithelial tissues of mice. Journal of the American Dental] Association 45 (6) : 528-540, Novem- ber 1952. KREYBERG, L. Histological Lung Cancer Types. A Morphological and Bio- logical Correlation. Acta Pathologica et Microbiologica Scandinavica (Supplementum 157): 1962. 92 pp. KREYBERG, L. Aetiology of Lung Cancer. A Morphological Epidemiologi- cal and Experimental Analysis. Oslo, Universitetsforlaget, 1969. 99 pp. KuHn, H. Tobacco alkaloids and their pyrolysis products in the smoke. IN: Von Euler, U.S. (Editor). Tobacco Alkaloids and Related Com- pounds. New York, Macmillan, 1965, pp. 37-61. KURATSUNE, M., KoHCHI, S., Horie, A. Carcinogenesis in the esophagus. I, Penetration of benzo(a)pyrene and other hydrocarbons into the esophageal mucosa. Gann 56(2): 177-187, 1965. KUSCHNER, M. The J. Burns Amberson Lecture. The causes of lung can- cer, American Review of Respiratory Diseases 98(4): 5738-590, Octo- ber 1968. LANcasTER, H. O. Cancer statistics in Australia. Part II. Respiratory system. Medical Journal of Australia 1: 1006-1011, June 30, 1962. LASKIN, S., KUSCHNER, M., Drew, R. T. Studies in pulmonary carcino- genesis. IN: Hanna, M.G., Jr., Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, Octo- ber 8-11, 1968. U.S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 321-351. LaASNITZKI, I. The effect of a hydrocarbon-enriched fraction from ciga- rette smoke on mouse tracheas grown in vitro. British Journal of Cancer 22(1) : 105-109, March 1968. LaSNITZzKI, I. The effect of a hydvocarbon-enriched fraction of cigarette smoke condensate on human fetal lung grown in vitro. Cancer Research 28 (3) :516—-513, March 1968, LEDERMANN, 8. Cancers, tabac, vin et alcool. (Cancers, tobacco, wine and alcohol.) Concours Medical 1: 1107, 1109-1111, 1118-1114, 1955. Ler, A. M., FRAUMENI, J. F., JR. Arsenic and respiratory cancer in man: An occupational study. Journal of the National Cancer Institute 42 (6) ; 1045-1052, June 1969. LEUCHTENBERGER, C., LEUCHTENBERGER, R. The role of influenza virus in the development of malignant transformation in vitro and in the res- 309 (165) (166) (167) (168) (169) (170) (171) (172) (173) (174) (175) (176) (177) 310 piratory tract of mice, with and without exposure to cigarette smoke. Rivista di Biologia 59: 445-463, 1966. LEUCHTENBERGER, C., LEUCHTENBERGER, R, Cytologic and cytochemical effects on primary mouse kidney tissue and lung organ cultures after exposure to whole, fresh smoke and its gas phase from unfiltered, char- coal-filtered, and cigar tobacco cigarettes. Cancer Research 29(4): 862-872, April 1969. LEUCHTENBERGER, C., LEUCHTENBERGER, R., DooLin, P. F. A correlated histological, cytological, and cytochemical study of the tracheobron- chial tree and lungs of mice exposed to cigarette smoke. I. Bronchitis with atypical epithelial changes in mice exposed to cigarette smoke. Cancer 2(3) : 490-506, May-June 1958. LEUCHTENBERGER, C., LEUCHTENBERGER, R., ZEBRUN, W., SHAFFER, P. A correlated histological, cytological, and cytochemical study of the tracheobronchial tree and lungs of mice exposed to cigarette smoke. II. Varying vesponses of major bronchi to cigarette smoke, absence of bronchogenic carcinoma after prolonged exposure, and disappearance of bronchial lesions after cessation of exposure. Cancer 13(4): 721- 732, July-August 1960. LEUCHTENBERGER, R., LEUCHTENBERGER, C., ZEBRUN, W., SHAFFER, P. A correlated histological, cytological, and cytochemical study of the tracheobronchial tree and lungs of mice exposed to cigarette smoke. III. Unaltered incidence of grossly visible adenomatous lung tumors in female CF, mice after prolonged exposure to cigarette smoke. Can- cer 13(5): 956-958, September—October 1960. LeEvIN, M. L., GOLDSTEIN, H., GERHARDT, P. R. Cancer and tobacco smok- ing. A preliminary report. Journal of the American Medical Associa- tion 143 (4) : 386-338, May 27, 1950. LIicKINT, F. Der Tabakrauch als Ursache des Lungenkrebses. Spezieller Teil IV. Atiologie und Prophylaxe des Lungenkrebses. (Tobacco smoke as cause of lung cancer. Special Section IV. IN: Etiology and Prophylaxis of Lung Cancer.) Dresden, Theodor Steinkopff, 1953. pp. 66-141, LILIENFELD, A. M., Levin, M. L., Moore, G. E. The association of smok- ing with cancer of the urinary bladder in humans, A.M.A. Archives of Internal Medicine 98: 129-135, 1956. LITTLE, J. B., Raprorp, E. P., JR. Polonium-210 in bronchial epithelium of cigarette smokers. Science 155 (3762) : 606-607, February 3, 1967. LITTLE, J. B., RADFORD, E. P., JR., McComss, H. L., Hunt, V. R. Polo- nium-210 in lungs and soft tissues of cigarette smokers. Radiation Research 22: 209, 1964. LITTLE, J. B., RADFORD, E. P., JR., McComss, H. L., Hunt, V. R. Distribu- tion of Polonium-210 in pulmonary tissues of cigarette smokers. New England Journal of Medicine 273 (25) : 1348-1851, December 16, 1965. Locxwoop, K. On the etiology of bladder tumors in Kobenhavn- Frederiksberg. An inquiry of 369 patients and 369 controls. Acta Pathologica et Microbiologica Scandinavica 51(Supplementum 145) : 1961. 166 pp. LomsBarD, H. L., SNEGIREFF, L. S. An epidemiological study of lung cancer. Cancer 12(2): 406-413, March-April 1959. LORENZ, E., STEWART, H. L., DANIEL, J. H., NELSON, C. V. The effects of breathing tobacco smoke on strain A mice. Cancer Research 3: 123, 1943. (178) (179) (180) (181) (182) (188) (184) (185) (186) (187) (188) (189) (190) (191) (192) (193) LuNDIN, F. E., JR., Ltoyp, J. W., SMITH, E. M., ARCHER, V. E., HoLapay, D. A. Mortality of uranium miners in relation to radiation exposure, hard-rock mining and cigarette smoking—1950 through September 1967, Health Physics 16(5) : 571-578, May 1969. Lyncu, K. M., Mciver, F. A., Cain, J. R. Pulmonary tumors in mice exposed to asbestos dust. A.M.A. Archives of Industrial Health 15: 207-214, March 1957. McConneELt, R. B., Gorvon, K. C. T., JONES, T. Occupational and per- sonal factors in the aetiology of carcinoma of the lung. Lancet 2: 651-656, October 4, 1952. MAGEE, P. N., Barnes, J. M. Carcinogenic nitroso compounds. Advances in Cancer Research 10: 163-246, 1967. MALTONI, C., Carrerti, D., CANEPARI, C., GHETTI, G. Incidenza della metaplasia squamosa dell’epitelio respiratorio in rapporto al fumo di sigaretta. Studio citologico su 1000 individui di sesso maschile ap- parentemente sani. (Incidence of squamous metaplasia of the respira- tory epithelium in relation to cigarette smoking. Cytological study on 1000 apparently healthy male individuals.) Cancro 21 (4): 349-856, 1968. MARTINEZ, I. Factors associated with cancer of the esophagus, mouth, and pharynx in Puerto Rico. Journal of the National Cancer Institute 42 (6): 1069-1094, June 1969. MILteRr, L., SMITH, W. E., BERLINER, S. W. Tests for effect of asbestos on benzo(a)pyrene carcinogenesis in the respiratory tract. Annals of the New York Academy of Sciences 132(Article 1) : 489-500, Decem- ber 31, 1965. MILLER, R. L., STEDMAN, R. L. Essential absence of beta-naphthylamine in cigarette smoke condensate. Tobacco 165 (8) : 32, August 25, 1967. Miits, C. A., Porter, M. M. Tobacco smoking habits and cancer of the mouth and respiratory system. Cancer Research 10: 539-542, 1950. MILs, C. A., PorTER, M. M. Tobacco smoking, motor exhaust fumes, and general air pollution in relation to lung cancer incidence. Cancer Re- search 17: 981-990, 1957. MONTESANO, R., SaFFIOTTI, U. Careinogenic response of the hamster respiratory tract to single subcutaneous administrations of diethyl- nitrosamine at birth. Journal of the National Cancer Institute 44(2): 413-417, February 1970. MONTESANO, R., SAFFIOTTI, U., SHUBIK, P. The role of topical and sys- temic factors in experimental respiratory carcinogenesis. IN: Hanna, M. G., Jv., Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Car- cinogenesis. Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970, pp. 3538-371. Mookrg, C. Multiple mouth-throat cancer. American Journal of Surgery 110 (4) : 534-536, October 1965. Moore, C., CHRISTOPHERSON, W. M. The effect of cigarette-smoke con- densate on hamster tissues. Exteriorized oral pouch and skin. A.M.A. Archives of Surgery 84(4) : 425-431, April 1962. Moore, C., Mitier, A. J. Effect of cigarette tar on the hamster pouch, A.M.A. Archives of Surgery 76(5): 786-793, May 1958. Moore, G. E., BisseNcER, L. L., PRoEHL, E. C. Intraoral cancer and the use of chewing tobacco. Journal of the American Geriatrics Society 1: 497-506, 1953. (194) (195) (196) (197) (198) (199) (200) (201) (202) (203) (204) (205) (206) (207) 312 Morcan, J. G. Some observations on the incidence of respiratory cancer in nickel workers. British Journal of Industrial Medicine 15: 224-234, 1958. MUHLBOCK, O. Carcinogene Werking van Sigarettenrook bij Muizen. (Carcinogenic action of cigarette smoke in mice). Nederlands Tijdschrift voor Geneeskunde 99 (31) : 2276-2278, July 30, 1955, MULLER, F. H. Tabakmissbrauch und Lungencarcinom. (Tobacco misuse and lung carcinoma). Zeitschrift fiir Krebsforschung 49 (1): 57~85, 1939. Munoz, N., Correa, P., Bock, F. G. Comparative carcinogenic effect of two types of tobacco. Cancer 21(3) : 376-389, March 1968. NASIELL, M. The Epithelial Picture in the Bronchial Mucosa in Chronic Inflammatory and Neoplastic Lung Disease and its Relation to Smok- ing. A comparative histologic and sputum-cytologie study. Stockholm, Cytology Laboratory, Department of Pathology at Sabbatsberg Hos- pital, Karolinska Institutet, 1968. 72 pp. NELson, N. Inhalation carcinogenesis in man: Environmental and occu- pational hazards. IN: Hanna, M. G., Jr., Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Proceedings of a Biology Divi- sion, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, October 8-11, 1969. U. S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 3-12. NETTESHEIM, P., HANNA, M. G., JR., DoHerry, D. G., NEWELL, R. F., HELLMAN, A. Effects of chronic exposure to artificial smog and chrom- ium oxide dust on the incidence of lung tumors in mice. IN: Hanna, M. G., Jr., Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carecin- ogenesis. Proceedings of a Biology Division, Oak Ridge Nationa] Laboratory Conference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series No. 18, April 1970, pp. 305-320. NEvURATH, G. Zur Frage des Vorkommens von N-Nitroso-Verbindungen im Tabakrauch. (Occurrence of n-Nitroso compounds in tobacco smoke.) Experientia 23(5): 400-404, 1967. NEURATH, G. Stickstoffverbindungen des Tabakrauches. (Nitrogen com- pounds in tobacco smoke.) Arzneimittel-Forschung 19(7) : 1093-1106, July 1969. OCHSNER, A., DE BAKEY, M. Primary pulmonary malignancy. Treatment by total pneumonectomy. Analysis of 79 collected cases and presenta- tion of 7 personal cases. Surgery, Gynecology and Obstetrics 68: 435~ 451, 1939. OrMos, J., KARACSONYI, G., BILICZKI, F., SZONYI, F. Lung cancer in the Hungarian plain. Neoplasma 16(6) ; 667-675, 1969. Orr, J, W., WoopHousE, D. L., HAMER, I)., MARCHANT, J., HOWELL, J. S. Cigarette tobacco tars. British Empire Cancer Campaign Annual Re- port 383: 288-239, 1955. OTTo, H. Experimentelle Untersuchungen an Mausen mit passiver Zigarettenrauchbeatmung. (Experimental investigations on mice through passive inhalation of cigarette smoke.) Frankfurter Zeitsch- rift fur Pathologie 73: 10-238, 1963. PalLer, M., Hupscu, W. J., Kuyn, H. Untersuchung der aliphatischen und aromatischen primdren und sekundéren Amine des Zigaretten- rauches mit Hilfe der Gaschromatographie und Massenspektrometric. (Study of the aliphatic and aromatic primary and secondary amines of cigarette smoke by gas chromatography and mass spectrometry.) (208) (209) (210) (212) (212) (213) (214) (215) (216) (217) (218) (219) (220) Fachliche Mitteilungen der Oesterreichischen Tabakregie No. 7: 109- 118, April 1967. PAPANICOLAOU, G. N., Koprowska, I. Carcinoma-in-situ of the right lower bronchus: A case report. Cancer 4(1): 141-146, January 1951. Passey, R. D., Roz, E. M. F., MIDDLETON, F. C., BERGEL, F., EVERETT, J. L., Lewis, G. E., Martin, J. B., BoyLanp, E., Sims, P. Cigarette smoking and cancer. British Empire Cancer Campaign Annual Report 32: 60-62, 1954, Peacock, E. E., Jr, GREENBERG, B. G., BRAWLEY, B. W. The effect of snuff and tobacco on the production of oral carcinoma: An experimen- tal and epidemiological study. Annals of Surgery 151(4): 542-550, April 1960. PERNU, J. An epidemiological study on cancer of the digestive organs and respiratory system. A study based on 7,078 cases. Annales Medicinae Internae Fenniae 49 (Supplement 33): 1960, 117 pp. Potter, E. A., TULLY, M. R. The statistical approach to the cancer prob- lem in Massachusetts. American Journal of Public Health and the Nation’s Health 35: 485-490, May 1945, PROTZEL, M., GIARDINA, A. C., ALBANO, E. H. The effect of liver imbal- ance on the development of oral tumors in mice following the applica- tion of benzpyrene or tobacco tar. Oral Surgery, Oral Medicine and Oral Pathology 18(5) : 622-635, November 1964. QUAGLIARIELLO, E., TANCREDI, F., FEDELE, L., SACCONE, C. Tryptophan- nicotinic acid metabolism in patients with tumours of the bladder. Changes in the excretory products after treatment with nicotinamide and vitamin B,. British Journal of Cancer 15: 867-372, 1961. RADFORD, E. P., JR., Hunt, V. R. Polonium-210: 4 volatile radio-element in cigarettes. Science 143 (3603) : 247-249, January 17, 1964. Raprorp, E. P., Hunt, V. R., Littie, J. B. Carcinogenicity of tobacco- smoke constituents. Science 165 (3890) : 312, July 18, 1969. RaJEWSKY, B., STAHLHOFEN, W. Polonium-210 activity in the lungs of cigarette smokers. Nature 209 (5030) : 1812-1313, March 26, 1966. Ranpic, K. Untersuchungen zur Atiologie des Bronchialkarzinoms. (Investigations on the etiology of bronchial carcinoma.) Offentliche Gesundeheitsdienst 16(9): 305-318, December 1954. Reppy, D. G., ANGULI, V. C. Experimental production of cancer with betel nut, tobacco and slaked lime mixture. Journal of the Indian Medical Association 49(7) : 315-518, October 1, 1967. REINGOLD, I. M.. OTTOMAN, RL E KONWALER, B. E. Bronchogenie car- cinoma: A study of 60 necropsies. American Journal of Clinical Path- ology 20; 515-525, 1950. Riepon, R. H. Effect of tobacco condensate on respiratory tract of white Pekin ducks. A.M.A. Archives of Pathology 69(1): 55-63, January 1960. Ropsins, W. T. Bronchial epithelium in smoking and nonsmoking col- lege students. Journal of the American College Health Association 14(4) : 265-266, April 1066. Rockey, E, E., Speer, F. 1). The iil effects of cigarette smoking in dogs. International Surgery 46(6) : 520-530, December 1966. Rockey, FE. E., Speer, F. D., THompPsoN, S. A., AHN, K. J., Hirose, T. Experimental study on effect of cigarette smoke condensate on bron- chial mucosa. Journal of the American Medical Association 182 (11): 1094-1098, December 15, 1962. 313 (225) (226) (227) (228) (229) (230) (231) (282) (233) (234) (235) (236) (287) (288) (239) 314 Roe, F. J. C. Role of 3,4-benzopyvene in carcinogenesis by tobacco smoke condensate. Nature 194 (4833) : 1089-1090, June 16, 1962. Roru, D., FREDRICKSON, I). T., OPPENHEIM, A., LONDON, M. Bioassay of the effects of smoking on IYNA content of human respiratory epi- thelium. Cancer 21(6): 1182-1136, June 1968. RotH, D., OPPENHEIM, A., Freprickson, D. T. DNA-dependent dye binding by oral epithelium. Its relation to smoking habits. Archives of Environmental Health 17(1): 59-61, July 1968. ROYAL COLLEGE OF PHYSICIANS. Air pollution and Health. Summary and Report on Air Pollution and Its Effect on Health. By the Committee of the Royal College of Physicians of London on Smoking and Atmos- pheric Pollution. Pitman Medical and Scientific Publishing Co., Ltd., London, 1970. 80 pp. ROZENBILDS, J. G, Carcinoma of the larynx and hypopharynx in South Australia 1952-1966. Medical Journal of Australia 2(6): 244-249, August 5, 1967. RUNECKLES, V. C. Natural radioactivity in tobacco and tobacco smoke. Nature 191 (4786) : 322-825, July 22, 1961. SACCOMANNO, G. Radiation exposure of uranium miners. U.S. Congress. Radiation Standards for Uranium Mining. Hearings before the Sub- committee on Research, Development, and Radiation of the Joint Committee On Atomic Energy, Congress of the United States. 91st Congress, 1st Session, March 17, and 18, 1969. pp. 301-315. SapDOoWSKY, D. A., GILLIAM, A. G., CORNFIELD, J. The statistical associa- tion between smoking and carcinoma of the lung. Journal of the Na- tional Cancer Institute 18: 1287-1258, 1953. SAFFIOTTI, U. Experimental respiratory tract carcinogenesis. Progress in Experimental Tumor Research i1: 302-333, 1969. SAFFIOTTI, U. Experimental respiratory tract carcinogenesis and its relation to inhalation exposures. IN: Hanna, M. G., Jr., Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Proceedings of a Biology J)ivision, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomie Energy Com- mission Symposium Series 18, April 1970. pp. 27-54. SaFrFiorti, U., Ceris, F., Kors, L. H. A method for the experimental induction of bronchogenic carcinoma. Cancer Research 28(1): 104- 124, January 1968. SAFFIOTTI, U., CEriIs, F., MONTESANO, R., SELLAKUMAR, A. R. Induction of bladder cancer in hamsters fed aromatic amines. Chapter 10, IN: DEICHMANN, W. B., LAMPE, K. L. (Editors). Bladder Cancer. Proceed- ings of the 5th Inter-American Conference on Toxicology and Occupa- tional Medicine. Coral Gables, University of Miami, School of Medi- cine, 1967. pp. 129-135. : SaFFioTtTl, U., Ceris, F., SHuBIK, P. Histopathology and histogenesis of lung cancer induced in hamsters by carcinogens carried by dust par- ticles. In: Severi, L. (Editor). Lung Tumors in Animals. Perugia, Division of Cancer Research, University of Perugia, June 1966. pp. 537-546. Sat.ey, J. J. Experimental carcinogenesis in the cheek pouch of the Syrian hamster. Journal of Dental Research 33(2): 253-262, April 1954. SALLEY, J. J. Smoking and oral cancer. Journal of Dental Research 42 (Supplement to No. 1): 328-339, 1963. (240) SANDERUD, K. Squamous metaplasia of the respiratory tract epithelium: An autopsy study of 214 cases. 2. Relation to tobacco smoking, occupa- tion, and residence. Acta Pathologica et Microbiologica Scandinavica 43(1): 47-61, 1958. (241) SANGHVI, L. D., RAo, K. C. M., KHANOLKAR, V. R. Smoking and chewing of tobacco in relation to cancer of the upper alimentary tract. British Medical Journal t: 1111-1114, May 7, 1955. (242) SCHARIRE, E., SCHONIGER, F. Lungenkrebs und Tabakverbrauch. (Lung cancer and smoking.) Zeitschrift fir Krebsforschung 54: 261-269, 1943. (243) SCHLEGEL, J. U., PIPKIN, G., BANowsky, L. Urine composition in the etiology of bladder tumor formation. Journal of Urology 97(8) : 479- 481, March 1967. (244) SCHLEGEL, J. U., Pipkin, G. E., NisHimurA, R., DUKE, G. A. Studies in the etiology and prevention of bladder carcinoma. Journal of Urology 101(3) : 317-324, March 1969. (245) SCHLEGEL, J. U., Pipkin, G. E., SHuLTz, G. N. The aetiology of bladder tumours. British Journal of Urology 41(6) : 718-723, December 1969. (246) SCHREK, R., BAKER, L. A., BALLARD, G. P., DoLGoFF, S. Tobacco smoking as an etiologic factor in disease. I. Cancer. Cancer Research 10: 49-58, 1950. (247) ScHwartz, L., DENorx, P.-F. L’enquette francaise sur Vétiologie du can- cer broncho-pulmonaire. Role du tabac. (French investigation on the etiology of bronchopulmonary cancer. Role of tobacco.) Semaine des Hopitaux de Paris 38 (62/7): 3630-3643, October 30, 1957. (248) SCHWARTZ, D. DENOIX, P.-F., ANGUERA, G. Recherche des localisations du cancer associees aux facteurs tabac et alcool chez homme. (Re- search on the localizations of cancer associates with tobacco and alco- holic factors in man.) Bulletin de l’Association Francaise pour l’Etude du Cancer 44: 336-861, 1957. (249) ScHwartz, D., FLAMANT, R., LELLoucH, J., DENorx, P.-F. Results of a French survey on the role of tobacco, particularly inhalation, in dif- ferent cancer sites. Journal of the National Cancer Institute 26 (5): 1085-1108, May 1961. (250) Sea, M., FukusHIMA, I., FusIsaku, S., Kurinara, M., Saito, S., ASANO, K., Kamor, M. An epidemiological study on cancer in Japan. The report of the Committee for Epidemiological study on Cancer, Spon- sored by the Ministry of Welfare and Public Health. Gann 48 (Sup- plement) : April 1957. 63 pp. (251) SELIKoFF, I. J. BapER, R. A., Baber, M. E., Cure, J., HAMMOND, E. C. Asbestosis and neoplasia. American Journal of Medicine 42(4): 487- 496, April 1967. (252) SELIKorF, I. J.. HAMMOND, E. C., CHuRG, J. Asbestos exposure, smoking, and neoplasia. Journal of the American Medical Association 204(2): 106-112, April 8, 1968. (253) SERFONTEIN, W. J., HuRTER, P. Nitrosamines as environmental earcino- gens. II. Evidence for the presence of nitrosamines in tobacco smoke condensate, Cancer Research 26(4, Part 1): 575-579, April 1966. (254) SERFONTEIN, W. J., Smit, J. H. Evidence for the occurrence of N-nitros- amines in tobacco. Nature 214 (5084) : 169-170, April 8, 1967. (255) SHANTA, V., KRISHNAMURTHI, S. Further studies in aetiology of car- cinomas of the upper alimentary tract. British Journal of Cancer 17(1): 8-23, March 1963. 315 (257) (258) (259) (260) (261) (262) (263) (264) (265) (266) (267) (268) (269) (270) (271) (272) 316 SHANTA, V., KRISHNAMURTHI, S. Further studies in etiology of car. cinomas of the upper alimentary tract. Acta; Unio Internationaljs contra Cancrum 20: 586-594, 1964. SILVERMAN, S., JR., GALANTE, M. Oral Cancer. University of California, San Francisco Medical Center, January 1970. 56 pp. SPAIN, D. M., BRADESS, V. A., TARTER, R., MATERO, A. Metaplasia of bronchial epithelium. Effect of age, sex, and smoking. Journal of the American Medical Association 211(8) : 1831-1334, February 23, 1970. STASZEWSKI, J. Palenie a rak wargi, jamy ustnej, migdalkow i krtani, (Tobacco smoking and its relation to cancer of the mouth, tonsils and larynx.) Nowotwory 10(2): 121-132, 1960. STASZEWSKI, J. Palenie tytoniu a rak przelyku i zoladka oraz choroba wrzodowa. (Smoking and its relation to carcinoma of the upper diges- tive tract (esophagus and stomach) and to peptic ulcer.) Polski Tygodnik Lekarski 16(16): 287-292, May 4, 1960. STASZEWSKI, J. Smoking and cancer of the urinary bladder in males in Poland. British Journal of Cancer 20(1): 32-85, March 1966. STEDMAN, R. L. The chemical composition of tobacco and tobacco smoke. Chemical Reviews 68(2) : 153-207, April 1968. Stocks, P. Cancer incidence in North Wales and Liverpool region in relation to habits and environment. British Empire Cancer Campaign Annual Report 35 (Supplement to Part 2): 66-95, 1957. Stocks, P. Recent epidemiological studies of lung cancer mortality, cigarette smoking and air pollution, with discussion of a new hypothe- sis of causation. British Journal of Cancer 20(4) : 595-628, December 1966. Stocks, P., CAMPBELL, J. M. Lung cancer death rates among non- smokers and pipe and cigarette smokers. British Medical Journal 2: 923-929, October 15, 1955. Sucrura, K. Experimental production of carcinoma in mice with cigar- ette smoke tar. Gann 47(2) : 243-244, June 1956. SUNDERMAN, F. W., DONNELLY, A. J. Studies of nickel carcinogenesis metastasizing pulmonary tumors in rats induced by the inhalation of nickel carbonyl. American Journal of Pathology 46(6): 1027-1041, June 1965. SUNDERMAN, F. W., DONNELLY, A. J., WEST, B., Kincaip, J. F. Nickel poisoning. IX. Carcinogenesis in rats exposed to nickel carbony]. A.M.A. Archives of Industrial Health 20(1): 36-41, July 1959. SUNDERMAN, F, W., Kincalp, J. F., DONNELLY, A. J., WEST, B. Nickel poisoning. IV. Chronic exposure of rats to nickel carbonyl. A report after one year of observation. A.M.A. Archives of Industrial Health 16(6) : 480-485, December 1957. SUNDERMAN, F., W., SUNDERMAN, F. W., JR. Nickel poisoning. XI. Impli- cation of nickel as a pulmonary carcinogen in tobacco smoke. American Journal of Clinical Pathology 35(3) : 203-209, March 1961. Svopopa, V. An analysis of some possible epidemiological factors in- volved in carcinoma of the larynx. Neoplasma 15 (6): 677-684, 1968. TAKANO, K., OsocosH1, K., KamMimuRa, N., Kanpa, K., Kane, K., KAMIYAMA, R., SAKAMOTO, K., SaTo, H., SHIRAI, Y., SEI, M., TANABE, T., Hortno, M., Minami, Y., Morosi, H., Morita, R., OrrHata, H., HirayaMa, T. Shokudogan no ekigaku, toku ni atsui inshokubutsu, inshu, kitsuen narabi ni eiyo ketsubo ni tsuite. (Epidemiology of can- cer of the esophagus, with particular reference to the effect of hot food and drink, drinking, smoking, and nutritional deficiencies.) Nip- pon Rinsho 26(8) : 1823-1828, August 1968. (272) TARJAN, R., KEMENY, T. Multigeneration studies on DDT in mice, Food and Cosmetic Toxicology 7: 215-222, 1969. (274) TERRACOL, J., CALVET, J., MARQUES, P., Cott, J. Le tabac et le cancer du larynx. (Tobacco and cancer of the larynx.) Vie Medicale 48: 1149-1150, August 1967. (275) Tuayer, P. S., KENstEr, C. J. Cigarette smoke: Charcoal filters reduce components that inhibit growth of cultured human cells. Science 146 (3644): 642-644, October 30, 1964, / (276) THORARINSSON, H., HALLGRIMSSON, J., BJARNASON, O., PETERSEN, G. Carcinoma of the lung in Iveland. Diseases of the Chest 52(6): 754- 759, December 1967. (277) Tipton, PD. L., Crocker, T. T. Duration of bronchial squamous meta- plasia produced in dogs by cigarette smoke condensate. Journal of the National Cancer Institute $5(3);: 487-495, September 1964. (278) TyYLecoTE, F, E. Cancer of the lung. Lancet 2: 256-257, July 30, 1927. (279) UMIkER, W., Srorey, C. Bronchogenic carcinoma-in-situ. Report of a case with positive biopsy, cytological examination, and lobectomy. Cancer 5(2) : 369-374, March 1952, (280) U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Report of the Secretary’s Commission on Pesticides and Their Relationship to Environmental Health. Washington, U.S. Department of Health, Edu- cation, and Welfare, December 1969. 677 pp. (281) U.S. Pustic HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STaTIs- TIcs. Changes in cigarette smoking habits between 1955 and 1966. Washington, U.S. Department of Health, Education, and Welfare, Vital and Health Statistics Series 10, Number 59, Public Health Serv- ice Publication No, 1600, April 1970. 33 pp. (282) U.S. Pusiic HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STATIS- Tics. Mortality from diseases associated with smoking: United States, 1950-64. Washington, U.S. Department of Health, Education, and Welfare, Vital and Health Statistics Series 20, No. 4, Public Health Service Publication No. 1000, Octobér 1966. 45 pp. (283) U.S. Pupric HEALTH SERVICE. NaTiONAL CENTER FOR HEALTH STATIS- Tics. Vital Statistics of the United States—1961. Vol. II—Mortality, Part A. Washington, U.S. Department of Health, Education, and Wel- fare, Public Health Service Publication, 1964. (284) U.S. Pustic HEALTH Service. NATIONAL CENTER FoR HEALTH STAaTIS- Tics. Vital Statistics of the United States—1962. Vol. II-——-Mortality, Part A. Washington, U.S. Department of Health, Education, and Wel- fare, Public Health Service Publication, 1964. (285) U.S. Puptic HEALTH SERVICE, NATIONAL CENTER FOR HEALTH STATIS- Tics. Vital Statistics of the United States—1963. Vol. II—Mortality, Part A. Washington, U.S. Department of Health, Education, and Wel- fare, Public Health Service Publication, 1965. (286) U.S. Pusptic HEALTH SERVICE, NATIONAL CENTER FOR HEALTH STATIS- Tics. Vital Statistics of the United States—1964. Vol. II—Mortality, Part A. Washington, U.S. Department of Health, Education, and Wel- fare, Public Health Service Publication, 1966. (287) U.S. Puplic HEALTH SERVICE, NATIONAL CENTER FOR HEALTH STATIS- TICS. Vital Statistics of the United States—1965. Vol. Ii—Mortality, 317 (288) (289) (290) (291) (292) (293) (294) (295) (296) (297) (298) (299) (300) (301) 318 Part A. Washington, U.S. Department of Health, Education, and Wel. fare, Public Health Service Publication, 1967. U.S. PuBltic HEALTH SERVICE. NATIONAL CENTER FOR HEALTH Statis- TIcs. Vital Statistics of the United States—1966. Vol. 1Il—Mortality, Part A. Washington, U.S. Department of Health, Education, and Wel- fare, Public Health Service Publication, 1968. U.S. PusLic HEALTH SERVICE. NATIONAL CENTER FOR HEALTH Starts. Tics. Vital Statistics of the United States—1967. Vol. II—Mortality, Part A. Washington, U.S. Department of Health, Education, and Wel- fare, Public Health Service Publication, 1969. U.S. PuBLic HEALTH SERVICE. NATIONAL CENTER FOR HEALTH Sratis- Tics. Vital Statistics Rates in the United States 1940-1960. Wash- ington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1677, 1968. 881 pp. U.S. PuBLic HEALTH SERVICE. Smoking and Health. Report of the Ad- visory Committee to the Surgeon General of the Public Health Service. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1103, 1964. 387 pp. VALKo, P. Koureni a vyskyt zhoubnych novotvaru hrtanu. (Smoking and occurrence of malignant tumors of the larynx.) Ceskoslovenska Otolaryngologie 1: 102-105, 1952. VAN DuUuREN, B. L. Tobacco carcinogenesis. Cancer Research 28(11): 2357-2362, November 1968. VAN DUUREN, B. L., Stvak, A., LANGSETH, L., GOLDSCHMIDT, B. M., SEGAL, A. Initiators and promoters in tobacco: carcinogenesis. IN: Wynder, E. L., Hoffmann, D. (Editors). Toward a Less Harmful Cigarette. Bethesda, U.S. Public Health Service, National Cancer In- stitute Monograph No. 28, June 1968. pp. 173-180. Van Duuren, B. L., Sivak, A., GOLDSCHMIDT, B. M., Katz C.,, MELCHIONNE, 8S. Initiating activity of aromatic hydrocarbons in two- stage carcinogenesis. Journal of the National Cancer Institute 44 (5): 1167-1178, May 1970. VAN DUUREN, B. L., Sivak, A., SEGAL, A., ORRIS, L., LANGSETH, L. The tumor-promoting agents of tobacco leaf and tobacco smoke condensate. ~ Journal of the National Cancer Institute 37 (4): 519-526, October 1966, VINCENT, R. G., MARCHETTA, F. The relationship of the use of tobacco and alcohol to cancer of the oral cavity, pharynx or larynx. American Journal of Surgery 106(3) : 501-505. September 1968 . VOGLER, W. R., Lioyb, J. W., MILMorE, B. K. A retrospective study of etiological factors in cancer of the mouth, pharynx, and larynx. Can- cer 15(2) : 246-258, March-April 1962. WaAGONER, J. K., ARCHER, V. E., CaRROLL, B. E., HoLapay, I). A., Law- RENCE, P. A. Cancer mortality patterns among U.S. uranium miners and millers, 1950 through 1962, Journal of the National Cancer Insti- tute 82(4): 787-801, April 1964. : Waconer, J. kK., ARCHER, V. E., LunpINn, F. F., Jr., Horapay, D. A., Lioyp, J. W. Radiation as the cause of lung cancer among uranium miners. New England Journal of Medicine 273 (4): 181-188, July 22, 1965. WAGONER, J. K., MILLER, R. W., LUNDIN, F. E., JR., FRAUMENI, J. F., JR, Hais, M. E. Unusual cancer mortality among a group of underground metal miners. New England Journal of Medicine 269(6): 284-289, August 8, 1963. (302) (303) (304) (305) (306) (307) (308) (309) (310) (311) (312) (313) (814) (815) (316) ($17) (818) (819) (320) Wau, P. N., Keuar, U., Laniri, B. Factors influencing oral and oro- pharyngeal eancers in India. British Journal of Cancer 19(4): 642- 660, December 1965. WalIncrow, S. M., Horn, D., Ikarp, F. F. Dosage patterns of cigarette smoking in American adults. American Journal of Public Health and the Nation’s Health 58(1) : 54-70, January 1968. WASSINK, W. F. Ontstaansvoorwaarden voor longkanker. (Conditions for the origin of lung cancer.) Nederlands Tijdschrift voor Genees- kunde 92 (46) : 3732-8747, November 13, 1948. Watson, W. L., Contre, A. J. Smoking and lung cancer. Cancer 7(2): 245-249, March 1954. Weir, J. M., DUNN, J. E., Jn. Smoking and mortality: A prospective study. Cancer 25(1) : 105-112, January 1970. WEISBURGER, J. H., WEISBURGER, E. K. Tests for chemical carcinogens. IN: Busch, H. (Editor). Methods in Cancer Research. New York, Academic Press, 1967. pp. 307-898. WICKEN, A. J. Environmental and Personal Factors in Lung Cancer and Bronchitis Mortality in Northern Ireland, 1960-62. London, Tobacco Research Council, Research Paper No. 9, 1966. 84 pp. WILLIAMS, M. J. Extensive carcinoma-in-situ in the bronchial mucosa associated with two invasive bronchogenic carcinomas. Report of case. Cancer 5(4): 740-747, July 1952. Wywnoper, E. L., Bross, I. J. A study of etiological factors in cancer of the esophagus. Cancer 14(2) : 389-418, March-April 1961. WYNDER, E. L., Bross, I. J., CORNFIELD, J.. O7DONNELL, W. E, Lung can- cer in women. A study of environmental factors. New England Jour- nal of Medicine 255 (24) : 1111-1121, December 13, 1956. WYNDER, E. L., Bross, I. J., Day, E. A study of environmental factors in eancer of the larynx. Cancer 9(1) :86-110, January-February 1956, WyYwNDER, E. L., Bross, I. J. FELDMAN, R. M. A study of the etiological factors in cancer of the mouth. Cancer 10(6) : 1800-1328, November- December 1957. WYNDER, E. L., CORNFIELD, J. Cancer of the lung in physicians. New England Journal of Medicine 248(11) : 441-444, March 12, 1953. Wynober, E. L., Dopo, H., BLocu, D. A., GANTT, R. C., Moore, O. S. Epidemiologic investigation of multiple primary cancer of the upper alimentary and respiratory tracts. Cancer 24(4): 730-739, October 1969. Wywnper, E. L., GRAHAM, E. A. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma. A study of six hundred and eighty- four proved cases. Journal of the American Medical Association 143 (4) : 329-336, May 27, 1950. Wynper, E. L., GRAHAM, E. A., CRONINGER, A. B. Experimental produc- tion of carcinoma with cigarette tar. Cancer Research 13: 855-864, 1953. WYNDER, E. L., GRAHAM, E. A., CRONINGER, A. B. Experimental produc- tion of carcinoma with cigarette tar. H. Test with different mouse strains. Cancer Research 15: 445-448, 1955. WYwnober, E. L., HOFFMANN, D. Tobacco and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York, Academic Press, 1967, 730 pp. WYNDER, E. L., HOFFMANN, L. Experimental tobacco carcinogenesis. Science 162(3856) : 862-871, November 22, 1968. 319 (821) WyYNber, E. L., HorrFMANN, D. A study of tobacco carcinogenesis, xX Tumor promoting activity. Cancer 24(2): 289-3801, August 1969, , (322) WYNDER, E. L., HULTBERG, S., JACOBSSON, F., Bross, I. J. Environmental factors in cancer of the upper alimentary tract. A Swedish study with special reference to Plummer-Vinson ( Paterson-Kelly) syndrome. Cancer 10(8): 470-487, May-June 1957. (323) Wynver, E. L., Kopr, P., ZiecLer, H. A study of tobacco carcinogenesis, If. Dose-response studies. Cancer 10(6): 1193-1200, November-De. cember 1957. (324) Wynoer, E. L., Mausucu, K., BEATTIE, E. J., JR. The epidemiology of lung cancer. Recent trends. Journal of the American Medical Associa. tion 213(13) : 2221-2228, September 28, 1970. ($25) WyYNbER, E. L., NAVARRETE, A., AROSTEGUI, G. E., LLaMBEs, J. L, Study of environmental factors in cancer of the respiratory tract in Cuba. Journal of the National Cancer Institute 20 (4): 665-678, April 1958, (826) WyNobeERr, E. L., ONDERDONK, J., MANTEL, N. An epidemiological investi- gation of cancer of the bladder. Cancer 16(11) : 1888-1407, November 1963. (327) Wynoer, E. L., Tacucut, K. T., BADEN, V., HOFFMANN, D. Tobacco car- cinogenesis. IX. Effect of cigarette smoke on respiratory tract of mice after passive inhalation. Cancer 21(1): 134-158, January 1968. (328) Wynoper, E. L., WRIGHT, G. A study of tobacco carcinogenesis. I, The primary fractions. Cancer 10(2): 255-271, March-April 1957. (329) YosHpa, O., BROWN, R. R., BRYAN, G. T. Relationship between trypto- phan metabolism and heterotopic recurrences of human urinary blad- der tumors. Cancer 25 (4) : 773-780, April 1970. (330) Yosuipa, O., MiyaKawa, M., Harapa, T., OKapA, K. Bokogan no ekigaku ni okeru mondaiten. (Some aspects of the epidemiology of urinary bladder cancer.) Nippon Rinsho 26(8): 1850-1854, August 1968. 320 CANCER APPENDIX TABLES ete TABLE A3.—Outline of methods used in retrospective studies of smoking in relation to lung cancer Author, year, country, reference Sex of cases Number of persons and method of selection Cases Controls Collection of data Miilier 1939, Germany (196). M 86 lung cancer decedents 86 healthy men of the same age Cases: Questionnaire sent to relatives of de- ceased. Controls: Not stated. Schairer and Schéniger, 1943, Germany (242), M 93 cancer decedents autopsied {average age 53.9). 270 men aged 53 and 54 Cases: Questionnaire sent to next of kin. Controls: Questionnaire sent to 700. Potter and Tully, 1945, U.S.A. (212). 43 male patients over 40 years of age. 1,847 patients of same group with diagnoses other than cancer. Cases and controls interviewed in clinics. Wassink, 1948, Nether- lands (304). M 134 male clinic patients with lung cancer. 100 normal men of same age groups as cases. Cases: Interviewed in clinic. Controls: Not stated. Schrek et al., 1950, U.S.A. (246). 82 male lung cancer cases among 5,003 patients recorded, 1941- 48, 522 miscellaneous tumors other than lung, larynx, pharynx, or Hip. Smoking habits recorded during routine hos- pital interview. Mills and Porter, 1950, U.S.A. (186). 444 respiratory cancer decedents. 430 sample of residents matched by age in Columbus, Ohio, from census tracts strati- fied by degree of air pollution. Cases: Relatives queried by mail question- naire or personal visit. Controls: House-to-house interviews. vee TABLE A3.—-Outline of methods used in retr ospective studies of smoking in relation to lung cancer (cont.) Author, year, Sex of Number of persons and method of selection country, cases Collection of data reference Cases Controls Levin et al., M 236 cancer hospital patients with 481 patients in same hospital with nonma- Cases and Controls: Routine clinical history 1950, diagnosed lung cancer. lignant diagnoses. taken before diagnosis. U.S.A. (169). - _ i — Wynder and M.-F 605 hospital and private lung 780 patients of several hospitals with diag- Nearly all data by personal interview; a few Graham, cancer patients in many cities. noses other than lung cancer. cases by questionnaire; a few from inti- 1950, mate acquaintances. Some interviews with U.S.A. knowledge or presumption of diagnosis, (816). some with none. 595 diagnosed by tissue examination, nine by sputum, and one by pleural fluid examination. McConnell M-F 100 lung cancer patients, un- 200 inpatients of same hospitals, matched by Personal interviews by the authors of both et al., 1952, selected, in 3 hospitals in Liv- age and sex, without cancer. cases and controls. England, erpool area. (180). Doll and M-F 1,465 patients with lung cancer 1,465 patients in same hospitals, matched by Personal interviews of cases and controls by Hill, in hospitals of several cities. sex and age group; some with cancer of almoners. 1952, other sites, some without cancer. Great Britain (78). Sadowsky M 477 patients with lung cancer 615 patients in same hospitals with illnesses Personal questioning by trained interviewers. et al., in hospitals in 4 states. other than cancer. 1953, U.S.A. (232). sve TABLE A3.—Outline of methods used in retrospective studies of smoking in relation to lung cancer (cont.) a Collection of data Mail questionnaire to estates of decedents. Cases and controls questioned about smoking habits when taking case histories. 351 di- agnoses confirmed histologically; 494 diag- noses confirmed by clinical, X-ray, and operative data. Personal interviews by staff members of co- operating hospitals and clinics. Cases and controls questioned by trained interviewers, each matched pair by the same person. The 769 consecutive patients of case and control groups were questioned by the same trained interviewer. Control group includes patients with oral and esophageal cancer and bronchitis. Author, year, Sex of Number of persons and method of selection country, cases reference Cases Controls Wynder and M 63 physicians reported in AMA 133 physicians of same group dying of can- Cornfield, Journal as dying of cancer of cer of certain other sites. 1953, the lung. U.S.A. (314). Koulumies, M--F 812 lung cancer patients diag- 300 male outpatients of same hospital over 1953, nosed at one hospital. 40 years of age. Finland (151), Lickint, M-F 246 lung cancer patients in a 2,002 sample of persons without cancer liv- 1953, number of hospitals and clinics. ing in the same area and of the same sex Germany and age range as cases. (170). Breslow M-F 518 lung cancer patients in 11 518 patients admitted to same hospitals about et al., California hospitals. the same time, for conditions other than 1954, cancer or chest disease, matched for race, U.S.A. sex, and age group. (42). Watson and M-F 801 patients at Memorial Hospi- 468 patients of same clinic during same Conte, tal with lung cancer. period with diagnoses other than lung 1954, cancer. ULS.A. (805). Gsell, M 135 men with diagnosis of bron- 135 similar hospital patients with diagnoses 1954, chial carcinoma. other than lung cancer, and of the same Switzerland age. (107). Personal interviews, all by the same person. 9ZE TaBlE A8.—Outline of methods used in retrospective studies of smoking in relation to lung cancer (eunt.) Author, year, Sex of Number of persons and method of selection country, cases - - Collection of data reference Cases Controls Randig, M-F 448 lung cancer patients in a 512 patients with other diagnoses, matched Controls were interviewed at about the same 1954, number of West Berlin hospi- for age. time as the cases, each case-control pair Germany tals. by the same physician. (218). Wynder et al., F 105 patients with lung cancer in 1,304 patients at Memoria] Center with tu- Cases: Personal interview or questionnaire 1956, several New York City hospi- mors of sites other than respiratory or mailed to close relatives or friends. U.S.A. tals. upper alimentary. Controls: Personal interview. (311). Segi et al., M-F 207 patients with lung cancer in 5,636 patients free of cancer in 420 local Cases and controls by personal interview 1957, 33 hospitals in all parts of health centers, selected to approximate using long questionnaire on occupational Japan the country. the sex and age distributions of cases. and medical history and living habits. (250), Mills and M--F 578 residents of defined areas 3,310 population sample approximately pro- Cases: From death certificates, hospital rec- Porter, dying of respiratory cancer. portional to cases as regards areas of resi- ords, and close relatives or friends. 1957, dence, and 10 years or more in the area, Controls: Personal home visits or telephone U.S.A. calls, usually interviewing housewife. (187). Stocks, M-F 2,356 patients suffering from or 0,362 unselected patients of the same area Cases: Histories taken at the hospital from 1957, dying with lung cancer within admitted for conditions other than cancer. relatives by health visitors. England certain areas. Controls: Personal interview in hospital. (263). Schwartz and M 602 patients with bronchopul- 1,204 patients (3 groups) in same hospitals Personal interviews in the hospital; cases Denoix, monary cancer in hospitals. with other cancer, with nonmalignant ill- and controls at about the same time by 1957, ness, and accident cases, matched by age the same interviewer. France group. (247). LTE TABLE A3.—Outline of methods used in retrospective studies of smoking in relation to lung cancer (cont.) Author, year, Sex of country, cases reference Number of persons and method of selection Cases Controls Collection of data Haenszel and F Shimkin, 1958, U.S.A. (113). 158 lung cancer patients avail- able for interview in 29 hos- pitals. 339 patients in same hospital and service at same time, next older and next younger than each case. Personal interviews by resident, medical so- cial worker, or clinic secretary. Lombard and M Snegireff, 1959, U.S.A. (176). 500 men dying of lung cancer, microscopically confirmed. 4,238 controls in 7 groups including volun- teers, hospital and clinic patients, random population sample, and house-to-house sur- vey samples. Personal interviews by trained workers. Pernu, M-F 1960, Finland (277). 1,606 respiratory cancer patients in 4 hospitals and from cancer registry. 1,773 cancer-free persons recruited by Parish Sisters of 2 institutes in all parts of the country. Cases: From case histories or mailed ques- tionnaires. Controls: Questionnaires distributed by Par- ish Sisters. Haenszel M etal., 1962, U.S.A. (112). 2,191 sample of 10 percent of white male lung cancer deaths in the U.S.A. in 1958. 31,516 random sample from Current Popu- lation Survey. Cases: By mail from certifying physicians and family informants. Controls: Personal interview by census enu- merators. Lancaster, M 1962, Australia (158). 238 hospital patients with lung cancer. 476 in 2 groups, 1 with other cancer, 1 with some other disease, matched by sex and age. Personal interviews of both cases and con- trols in hospitals. Haenszel and F Taeuber, 1964, U.S.A. (115). 749 sample of 10 percent of white female lung cancer deaths in the U.S.A. in 1958 and 1959. 34,339 random sample from Current Popula- tion Survey used to estimate population base. Cases: Ry mail from certifying physicians and family informants. Controls: Personal interview by census enu- merators. 8ze TABLE A3.—Outline of methods used in retrospective studies of smoking in relation to lung cancer (cont.) Author, year, Sex of Number of persons and method of selection country, cases Collection of data reference Cases Controls Wicken, M-F 954 patients with primary lung 954 age and sex-matched controls from same Interviews with relatives. 1966, cancer. locale and deceased from nonrespiratory Northern diseases. Treland (308). Gelfand et al., M 1968, 32 patients with bronchogenic cancer. 32 age and sex-matched patients Hospitalization interviews. Rhodesia (98), Hitosugi, M-F 185 patients with lung cancer 491 persons sex-matched from similar air- Cases: Hospital interviews. 1968, pollution regions. Controls: Interviews by trained public health Japan nurses. (126), Bradshaw and M Schonland, 1969, South Africa (Natal) (41). 45 Zulu patients with lung can- eer. 341 Zulu patients without lung cancer. Interviewed by trained African social worker. Ormos et al., M-F 1969, Hungary (204). 118 patients with lung cancer. 3,089 control persons without data on health history. Cases: Data derived from case histories and interviews with relatives. Controls: Interviews with a random sample of train passengers. Wynder, et al., M-F 1970 U.S.A. (324). 240 patients with Kreyberg Type I lung cancer. 480 age and sex-matched patients Hospitalization interview. 6ZE TABLE A4.—Group characteristics in retrospective studies on lung cancer and tobacco use SM = Smokers. NS = Nonsmokers. —— _ _—_— _ reece Males Females Author, Cases Controls Cases Controls year, a Relative _—— “————— Relative Comments reference Percent Percent Percent Percent risk Percent Percent Percent Percent risk non- heavy non- heavy ratio non- heavy non- heavy ratio Number smokers smokers! Number smokers smokers! SM:NS?. Number smokers smokers! Number smokers smokers! SM:NS2 — ee Or Miiller, 86 3.5 65.1 86 16.3 36.0 95.4 (4) (4) (4) (4) (4) (4) a 1939 (196). — 7 ee oo eee Schairer and 93 3.2 31.2 270 15.9 9.3 55.7 (4) (4) (4) (4) (4) (4) ++. 16 female Schéniger, cases not 1943 (242). analyzed. So eee Se Potter and 43 7.0 30.2 2,804 26.0 23.0 34,1 (4) () (4) (4) (4) (4) tae Tully, 1945 (212). — a 192 AGB Wassink, 134 4.8 54.8 100 19.2 19.2 4.7 {*) (4) (4) {4) (4) (4) -+. Percentages 1948 (204). estimated from chart. ST a Be EEE Schrek et al., 82 14.6 18.3 522 23.9 9.2 1.8 (4) @) (4) (4) (4) (4) tee 1950 (246). ———_._ ~ — OT Mills and 444 7.2 ee 430 30.5 see 5.7 (4) (4) (4) a) (4) (*) see Porter, 1950 (186), Levin et al., 236 15.3 vee 481 21.7 wee 1.5 (*) (*) (4) (*) (*) (4) -+. Quantity 1950 (171). smoked not considered. — ‘780.~«ABSSSC*S dg tered Wynder and 605 1.3 51.2 780 14.6 19.1 13.0 40 57.5 25.0 552 79.6 1.2 2.9 Graham, 1950 (816). a Oce TABLE A4.—Group characteristics in retrospective studies on lung cancer and tobacco use (cont.) SM = Smokers. NS = Nonsmokers. Males Females Author, Cases Controls Cases Controls ; year, “ — Relative Relative Comments reference Percent Pereent Percent Percent risk Percent Percent Percent Percent risk non- heavy non- heavy ratio non- heavy non- heavy ratio Number smokers smokers! Number smokers smokers! SM:NS2 Number smokers smokers' Number smokers smokers! SM:NS? McConnell 93 54 38.5 186 6.5 23.2 1.2 7 BT. 14 78.6 wee 2.8 etal, 1952 (180). Doll and Hill, 1,357 0.5 25.1 1,357 45 13.4 9.4 108 37.0 11.1 108 54.6 0.9 2.1 Percentage 1952 (78). “heavy” smokers understated. Sadowsky 477 3k tee 615 13.2 3.9 (4) (4) (*) @) (*) (4) ... Gradient etal, with amount 1953 (232). smoked. Wynder and 63 41 67.6 133 20.6 29.3 36,1 (*) () (@) QO) (4) @) Cornfield, 1953 (814). Koulumies R12 0.6 58.9 300 18.0 25.0 36.0 (4) (4) (4) 1958 (152). Lickint 224 1.8 35.8 1,000 16.0 4.8 310.4 22 64.0 4.5 1,002 90.4 0.1 5.3 _ 1953 (170). Breslow et al., 493 3.7 TA. 518 10.8 42.7 3.2 1954 (42). Watson and 265 1.9 71.7 287 9.7 51.6 35.6 36 58.3 2.8 181 82.0 11 3.3 Conte, 1954 (305). Gsell, 135 0.7 68.1 135 16.0 14.0 326.8 (*) @) (4) (@) Q) @) 1954 (107). TABLE A4,—Group characteristics in retrospective studies on lun SM = Smokers. NS = Nonsmokers. g cancer and tobacco use (cont.) Males Females Author, Cases Controls Cases Controls year, Relative — Relative Comments reference Percent Percent Percent Percent risk Percent Percent Percent Percent risk Num- non- heavy non- heavy ratio Num- non- heavy non- heavy ratio ber smokers smokers! Number smokers smokers? SM: NS? ber smokers smokers! Number smokers smokers' SM:NS? Randig, 415 1.2 34.2 381 6.8 17.9 35.1 33 51.5 3.0 131 70.3 0 2.2 1954 (218). Wynder etal. (*) (4) (*) (4) (4) (4) 105 56.2 16.2 1,304 66.0 3.4 1.4 1956 (3112). Segi et al., 166 2,124 oe Quantities 1957 (250). smoked stated as averages only. Differences are statistically significant. Mills and 484 8.4 26.0 1,588 27.6 5.3 42 94 83.0 4.3 1,722 73.3 0.5 0.6 Percent “heavy” Porter, smokers under- 1957 stated. Only (187), 506¢ survey yesponse among female cases. Stocks, 2,101 1.9 28.2 5,960 8.7 22.3 49 255 57.6 17.2 3,402 68.6 10.7 1.6 1957 (262). Schwartz and 602 1.0 58.2 1,204 9.5 36.2 10.4 (4) (4) () (4) (@) (4) Denoix, 1957 (247). Haenszel and (*) @) (*) (‘) (4) (*) 158 51.9 14.6 339 69.6 8.2 2.5 Shimkin, 1958 (113). zee TABLE A4.—Group characteristics in retrospective studies on lung cancer and tobacco use (cont.) SM = Smokers. NS = Nonsmokers. Males Females Author, Cases Controls Cases Controls year, oa Relative Relative Comments reference Pereent Percent Percent Percent risk Percent Percent Percent Percent risk Num- non- heavy non- heavy ratio non- heavy non- heavy ratio ber smokers smokers' Number smokers smokers! SM:NS? Number smokers smokers! Number smokers smokers! SM:NS? Lombard and 500 1.6 sae 4,238 11.0 tee U9 (4) (4) (@) {4) @) (4) ... Authors’ Snegireff, calculations for 1959 (176). heavy smoking based on lifetime number of packs of cigarettes. Pernu, 1,477 6.6 34.5 713 37.2 20.8 8.4 129 $5.3 26.4 1,060 91.6 ; 0.7 1.9 Quantities 1960 (211). given only in grams per day. Haenszel 2,191 3.4 41.9 (*) 16.2 12.0 5.2 (4) (@) {*) (4) (4) (*4) .«» Population et al., sample of 1962 (1122). 31,516 used as base. Not a case- control study. Lancaster, 238 2.5 86.1 476 20.1 71.2 9.8 (4) @) () (*) «) ) 1962 (158). Haenszel and @) (4) (4) (*) (4) () see 749 60.9 11.5 (4) 67.3 2.5 1.3 Population Taeuber, sample of 1964 (115). 34,339 used as base. Not a case-control! study. a @ w TABLE A4.—Group characteristies in retrospective stuslies on lung cancer and tobacco use (cont.) SM = Smokers. NS = Nonsmokers. Males Females Author, Cases Controls Cases Controls year, Relative Relative Comments reference Percent Percent Percent Percent risk Percent Percent Percent Percent risk um- non- heavy non- heavy ratio non- heavy non- heavy ratio ber smokers smokers! Number smokers smokerst SM:NS? Number smokers smokers! Number smokers smokerst SM:NS? Wicken, 803 4.0 40.0 803 14.0 22.0 3.9 151 58.0 29.0 151 80.0 17.0 2.9 Heavy smokers— 1966 (308). greater than 23 a day. Gelfand et al., 32 6.3 ves 32 63.0 ee 525.3 () (4) (4) () () (4) 1968 (98). Hitosugi, 124 5.6 67.8 1,889 13.2 55.0 2.6 61 54.1 6.6 2,352 80.5 2.9 2.3 Air pollution 1968 (125). found to have no effect on lung cancer rates of non- smokers. Heavy smokers—great- er than 15 a day. Bradshaw and 45 0.0 wae 341 31.7 a tae (4) (4) @) (4) Q) (4) Schonland, 1969 (41). Ormos et al., 94 15 58.5 1,811 42.9 38.9 9.3 24 95.8 0.0 1,278 81.7 9.7 0.2 Heavy smokers— 1969 (204). greater than 15 a day. Wynderetal., 210 1.4 67.5 420 21.0 40.9 320.8 30 16.7 44.0 182 57.6 23.3 6.78 Heavy 1970 (3384). smokers~— greater than 20a day. 1 For this table, heavy smokers are defined as those smoking 20 or more 3 Based upon fewer than 5 case nonsmokers. cigarettes per day, unless otherwise stated. * Does not apply. = Computed according to method of Cornfield, J. (61). TABLE A7.—Grouping of pulmonary carcinomas Group I: A. Epidermoid carcinoma. B. Small cell anaplastic carcinoma (‘‘oat-cell”’ earcinoma). Group H: A. Adenocarcinoma. B. Bronchiolo-alveolar cell carcinoma. C. Carcinoid tumor. D. Mucous gland tumor. Extra (not included in I and II): A. Large cell undifferentiated carcinoma. B. Combined epidermoid und adenocarcinoma. Unsuitable for diagnosis. Source: Kreyberg, L. (1532). 334 see TABLE Al2.—Autopsy studies concerning the presence of radioactivity in the lungs of smokers NS = Nonsmokers. SM = Smokers. Author, year, Number country, of Results Comments reference cases Little et al., Po!” levels in various tisanes (pe/g tissue) Vertebral bodies, renal 1964, Peribronchia! Bronchial cortex, spleen, and UNS.A. (178). lymph nodeg Lung (average) epithelium urinary bladder showed NS wool. 5 0.011 0.001-2 negligible no differences. SM oo... eae 12 0.011 0.008 0.028-1.25 Hill, 1965, Mean Po? levels in various tissues (pe/kg tissue) The authors found no ULS.A. (128). Bronchial tree Alveolae Total lung Liver Kidney excessive concentrations NS wo. eee e eee eee 6 3.1 3.4 3.2 14.8 15.0 at bronchial bifurca- SM ow. eee. 4 7.3 9.9 2.6 20.0 20.5 tions. Little et al., Po’ levels in various epithelial tissue regions of lung (ne/g)t The authors noted con- 1965, Site: siderable interpersonal UVS.A. (174). NS 2... eee eee 8 Mainstem bronchus ..........000 0.00 .. ccc eeeece cece cess <0.2- 1.7 variation but did find a SM... 28 Lobar bronchus . 2.6.0... cece cee ee ss etee cece <0.2~ 1.0 trend relationship be- Basal segmental bronchus ...........0.000.. cece cece cues <0.2- 2.6 tween increased daily Upper segmental bifurcation ............... see ee eee eces LOS 7.8 consumption and in- Lower segmental bifurcation .......... 0.00.0... ccc e eee <0.5-13.9 creased Po”? levels in lung parenchyma. No such relationship was noted for age of indi- vidual at death or for total pack-years. tSmokers only, 9€e TABLE Al2.—Autopsy studies concerning the presence of radioactivity in the lungs of smokers (cont.) NS = Nonsmokers. SM = Smokers. Author, year, Number country, of Results Comments reference cases Ferri and Mean Po” levels in various tissues (pe/g wet tissue) Baratta, Lung Liver Kidney 1966, NS oe. eee 10 0.031 0.1038 0.080 U.S.A. (95). SM oo... cee ee aes 14 0.065 0.125 0.070 Rajewsky and Mean Po* levels in various tissues (pe/g) t Data not given. Smokers Stahlhofen, Lung parenchyma Bronchial tree Bronchial bifurcation were considered those 1966, NS o.. eee eee t 0.0025 0.0020 0.0012 using more than 1 pack Germany (217). SM . 12 0.0078 0.0077 0.0047 a day. The authors noted that their figures were con- siderably smaller than those of Little et al. (178, 174) and also disagreed with their data on bifurcation. Little and Mean Po*'? levels in various epithelial tissues (pc/g wet tissue) Radford, SM . 25 Bronchial wall and submucosa 1967, Bronchial] epithelium: U.S.A. (172). Pipe weve Z Trachea... 6. cee cee ce eee tenet e ete te eeetnneens Ex-cigarette ...... 1 Lobar bronchi ........0 00... cee ee ee eee Never ..........05 8 Segmental bifurcation ...........02.. 0000008 Lee TABLE A13,—Experiments concerning the e fects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals Author, A. Method, year, Animal B. Frequency and/ country, and or duration, Results Comments reference strain C. Material Wynder CAF, mice A. Painting shaved skin. Pereent animals with: t Number in paren- et al., B. 3/week for 2 years. Treatment: Papillomast Cancert thesis represents 1953, C. Whole cigarette smoke “Tar” alone wees 59.0(81) 44.0(81) total in that U.S.A. condensate in acetone. “Tar’’ and croton oil 42.0(31) 9.7(31) experimental group. (317). Croton oil once/week. Acetone alone ............ 00000000. (30) (30) Skin-painting Acetone and croton oil (14) (14) experiments prior to 1953 are fully detailed in tab- ular form in this article. Passey 5 different A. Painting unshaven No malignant tumore noted in either group. etal., mouse skin. Papilloma noted on one animal (in whole ‘tar’ group) which later regressed. 1955, strains B. 2/week for 9 England (101). months. (209). C. Whole “tar” or neutral fraction. Orr et al., Mice of 2 A. Painting skin. Number animals with: 1955, strains. B. 1 or 2/week for Treatment: Papillomas England 18 months. Benzpyrene 1/week followed 4/30 at 18 months (separate group received only (205). C. 20 percent cigarette by ‘‘tar’’ 2/week. benzpyrene and showed no tumors). “tar” in acetone, “Tar” alone ............00. 0/50 at 18 months. 0.3 percent benzpyrene. see TaBLeE A18.—Experiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.) Author, Animal A. Method, year, and B. Frequency and/ country, strain or duration, Results Comments reference C. Material Wynder Mice of 4 A. Painting shaved skin. Strain Papillomas Carcinomas No tumors noted with etal., separate B. 3/week for 80 days. CBTIBL 2... ee cee cee eee eens 10/89 2/89 acetone alone. 1955, strains. C. Whole condensate Swiss .... 00... ccc ce eee cee cee tetera 22/86 12/86 Stresses U.S.A. in acetone. differences in (318). susceptibility of strain. Hamer and Outbred A. Painting unshaved Treatment: Papillomaa Woodhouse, albino skin. “Tar” 2/week ..... 0.0. ee ee 1/50 1956, strain B. Varied for 18 months. “Tar” and croton oil 1/week. ........ 2/30 U.S.A. mice. C. Whole “‘tar’’/acetone, B(a)P 3 times then “tar” 2/week ..... 4/30 (116). benzpyrene [B(a)P], Bla)P 3 times ........ 00. cee eee 0/30 croton oil. Sugiura, Rockland A. Painting unshaved Papillomas Carcinomas 1956, Swiss skin. 16/44 12/44 (only 44/60 U.S.A. albino B. 3/week for 2 years. lived from (266). mice (60). C. Whole “‘tar’’. 365-696 days). Graham Albino New A. Painting shaved skin. Treatment: Papillomas Carcinomas The authors review et al., Zealand B. 3/week for 6 years. Condensate ..........-.. 0.0002 ee eee 41/41 5/41 previous experiments 1957, rabbits. C. Whole condensate. Condensate and croton oil 1/week. 10/10 2/10 with rabbits in U.S.A. Croton oi] and acetone 1/week. 0/3 0/3 tabular form. (101). Acetone 1/week 2.0... ..... 000. e cee 0/7 0/7 Guerin and Mice A. Painting neck skin. Original number Survivors Papillomas Sarcomas ft Control group. Cuzin, (Pasteur 3B. 2/week for >1 year. TCO.112 6 eee eee eee 51 0/51 0/51 t+ Experimental group. 1957, strain.) C. Whole condensate. FE. 672 ool eee eee 220 10/220 5/220 U.S.A 6ee& TABLE A13.—Experiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.) Author, Animal A. Method, year, and B. Frequency and/ country, strain or duration, Results Comments reference Cc. Material Wynder Swiss mice A. Painting skin. Percent Percent etal., B. Varied for 12 Treatment: Number papillomas carcinomas 1957, months. B/hweek oo... cece eee eee eee 50 12.0 8.0 U.S.A. C. Whole condensate B/week so. cee cece eee 50 38.0 16.0 (828). in acetone. Q/week oo. cc cece ete eee 40 10.0 3.0 U/week 26... eee eee 40 6.0 Wynder and CAF, or A. Painting shaved skin. Percent Percent Swiss mice noted Wright, Swiss B. 8/week for lifespan. Treatment CAF: Number papillomas carcinomas to be more sus- 1957, mice. C. Whole ‘‘tar” or nicotine Whole ‘tar’ ........ 06... eee 30 53.0 27.0 ceptible. U.S.A. free ‘‘tar”’ derived Nicotine free “tar” .......... 40 73.0 25.0 Majority of carcino- ($28). from pipe and Cigarette “tar” ...........00- 30 30.0 30.0 gens noted to be cigarette tobacco. Pipe “tar? 0.0... cece eee 30 60.0 20.0 in neutral fraction Treatment Swiss: of condensate. Whole ‘tar’ .........-....00. 30 53.0 10.0 Nicotine free “tar” ........... 40 43.0 20.0 Cigarette “tar” .............. 30 63.0 33.0 Pipe “tar”? oo... cece eee eee 30 63.0 50.0 Gellhorn, Paris RII A. Painting shaved skin. Treatment: Papillomas Carcinomas 1958, mice B. Varied for 1-2 years. Benzpyrene (twice only) ............ 20/529 5/529 U.S.A. C. ‘Tar’ in acetone, Croton oi] (5/6 week) ..............4. 4/26 0/26 (99). pbenzpyrene, “Tar”? (5/6 week) .......... 0.20 cee 3/659 2/559 eroton oil. Acetone (5/6 week) ..............-. 0/30 0/30 “Tar” and croton oil (5/6 week) 10/175 0/175 Bock and Swiss A. Painting skin. Percent Moore, female B. 5/week for lifespan. Group: Number living at 6 months Skin tumors at 64 weeks 1959, mice C. Whole condensate Painted wo... ccc cece cece eee 49 13.0 U.S.A. irradiation. Painted and irradiated ......... 65 44.0 (28). Irradiated ........ 00 ce cee eee 36 Ove subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.) TABLE A13.—-Hxperiments concerning the effects of the skin painting or Author, Animal A. Method, year, and B. Frequency and/ country, strain or duration, Results Comments reference C. Material Druckrey, Rats A. Subcutaneous Group: Sarcomas ¢ Control group. 1961, injection, tc. 1/75 t Experimental group. Germany B. 1/week for 60 weeks. TE lo eee ee ee 15/75 (78), €. Smoke condensate in tricaprylin and alcohol. Bock et al., ICR Swiss A. Painting shaved skin. Surviving Pereent Percent Skin 1962, mice B. 10/week for 1 year. Treatment: at £8 weeks Skin cancer neoplasia U.S.A, C. Cigarette “tar”. Standard cigarette 24/30 25.0 54.0 (31). Standard cigarette 21/30 5.0 57.0 Standard cigarette 18/30 33.0 44.0 Standard cigarette 13/30 23.0 62.0 Filter cigarette ..... 30/30 7.0 27.0 Filter cigarette 30/30 3.0 23.0 Acetone only 66/66 Control ...........202 0000200 65/65 Roe, Albino mice A. Painting shaved skin. Treatment: Survivors Percent skin tumors Author concluded 1962, B. 3/week for 84 weeks. “Tar” and 0.025 mg. B(a)P ..... 26 12.0 that cigarette U.S.A. C. Whole smoke ‘‘tar” “Tar” and 0.06 mg. B(a)P ...... 15 27.0 smoke contains (225). with added B(a)P “Tar” and 0.25 mg. B(a)P...... 15 13.0 cocarcinogens. in acetone. “Tar” and 1.25mg.Bla)P ...... 14 64.0 B(a)P 1.25 mg. ........... 0.00.0. 14 Druckrey and Rats A. Subcutaneous Treatment (BP mg./weck): Sarcomas Schildbach, injection. 30 .. 25/30 1963, BR. 1/week for 700 days. 10... 14/40 Germany C. Benzpyrene in 3... &/50 (82). tricaprylin. — (solv 2/75 TABLE A13.—Eaperiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.) Author, A. Method, year, Animal B. Frequency and/ country, and or duration, Results Comments reference strain C. Material Homburger CAF, mice A. Painting shaved skin. Com plei¢ Percent Percent etal. B. 2-3/week for 2 years. Condensate: autopsics Papillomas Carcinomas 1963, C. Various tobaeco Pipe tobacco ................, 77 35.0 15.0 U.S.A. condensates in Cigar tobacco ................ 84 27.5 15.0 (181). acetone. Cigarette tobacco ............. 82 27.0 15.0 Benzpyrene .................. 54 10.0 20.0 Acetone only ................. 62 Bock et al., Swiss ICR A. Painting clipped skin. Percent Percent 1965, mice B. 10/week for 11 weeks. Percent concentration of tar surviving Percent cancer and U.S.A, C. Various smoke (type cigarette) : tl weeks cancer papilloma (29), condensates in 9.2 (standard) .............., 96.0 30.0 67.0 acetone, 8.3 (standard) -. 93.0 27.0 67.0 7.9 (English standard) 90.0 24.0 58.0 8.7 (king) .........,.., tee 100.0 28.0 69.0 4.0 (filter) 22... 98.0 9.0 36.0 4.4 (filter) 22... 100.0 10.0 41.0 2.5 (filter) 22... el, 97.0 4.0 16.0 Acetone control .............. 94.0 Untreated control ..........., 100.0 Cumulative number of mice with + 7,12-dimethyl- Lve Van Duuren Swiss ICR/ A. Painting shaved skin. etal, Ha mice B. Initiating agent once— Initiator Promoter Papillomaa Carcinomas benz (a) anthracene. 1966, Promoter 3/week for DMBA ...Ether tobacco leaf extract 4/20 0/20 ULS.A. 12-14 months. (0 Ether tobacco leaf extract . 0/20 0/20 (296). C. DMBAT, tobacco DMBA .. Choloroform tubacco leaf extract ...... 1/20 0/20 extracts ciga- OL... Choloroform tobacco leaf extract 2.2... 0/20 0/20 rette “tar”. DMBA ...Cigarette “tar” 11/20 4/20 O ....... Cigarette “tar” 0/20 0/20 O ....... Acetone 0/20 0/20 ove TABLE A13.—Experiments concerning the effects of the skin painting or subcutancous injection of cigarette smoke condensate or its constituents upon animals (cont.) Author, A. Method year, Animal B. Frequency and/ country, and or duration, Results Comments reference strain C. Material Munozetal., Swiss ICR/ A. Painting shaved skin. Dark tobacco “tar” At risk Tumors Carcinomas The authors noted 1968, 4a mice B. Varied. 4.0 percent ...........0.0 00005 81 50 17 a shortened latent U.S.A. C. ‘'Tar” from dark 8.0 percent .........-......--- 71 46 16 period for dark and (Colombian) and Light tobacco tar: tebacce. Colombia light (U.S.A.) 4.0 percent ..............0-005 95 26 6 (197). tobaccos. 8.0 percent oe 938 54 20 Acetone . 0... ieee cece eens 91 0 0 Davies and Albino A. Painting shaved skin. Percent of carcinoma-bearing animals at 116 weeka The authors concluded Day, mice B. Varied regimen. Treatment: (actual number of animals in parentheses) that the lack of 1969, C. Cigarette and 300 mg. 150 mg. 75mg. 37.5 mg. difference in re- Great cigar condensate. Standard cigarette ........ 20.1(29) 13.2 (19) 0.7 (1) . sults from the first Britain Cigar oo... cee eee oe 27.1(39) 11.1(16) 2.1(3) and third groups (65). Cigar tobacco cigarette 18.9(10) . .. under treatment suggests that the increased tumori- genicity of cigar tobacco is due to physical processing factors. eve TABLE A14.—Experiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures Author, year, country, reference Bouchard and May, 1960, France (85). Awa etal., 1961, Japan (16). Thayer and Kensler, 1964, U.S.A. (275). Berwald and Sachs, 1965, Israel (20). Tissue or organ culture Mouse lung. Human fetal lung. KB mammalian tumor cells. SWR mice and golden hamster embryos. Results Material/delivery Increased number of mitotic abnormalities in the treated cultures; particularly in Tobacco smoke condensate perfusion for 24 hours the first 5-10 days after grafting. and subsequent grafting under renal capsule of mice. Paper smoke induced the most severe changes, consisting of cytoplasmic vacu- Direct exposure to smoke from: olization and nuclear pyknosis. Also noted were a decrease in the mitotic index a. Whole cigarettes. and an increase in abnormal divisions, more so with paper. smoke than with b. Tobacco alone. ec. Paper alone. the other two. Significant growth inhibition was shown in unfiltered smoke. Cytotoxic compo- Cigarette smoke condensate applica- nents were noted in both the gas and particulate phases. tion; filtered and unfiltered cigarettes. Benzo(s) pyrene caused increased cell transformation as manifested by: Direct application of benzo(a)pyrene a. Hereditary random growth pattern. b. Progressive growth as tumors after subcutaneous injection into adults. (B(a)P]. ec. Ability to grow continuously in culture. Application of Treated cultures revealed cellular metaplasia, basal cell hyperplasia, increased mitotic rate, and increased H*-thymidine incorporation proportional to the con- Crocker et al., Suckling rat trachea in organ culture. B(a) P in acetone. centration of material and duration of application. Inhibition of cell growth. 1965, ULS.A. (63). Diamond, 1965, U.S.A. (68). Various con- tinuous cell strains (mammalian). Application of B(a) Pin either dimethylsulfoxide (DMSO) or paraffin. yre TABLE Al4.—E'xperiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures (cont.) Author, year, country, reference Tissue or organ culture Material/delivery Results Borenfreund et al, 1966, U.S.A. (38). Guimard, 1966, France (110). Lasnitzki, 1068, England (160). Hamster Jung tissue. Chicken embryo muscular explants. Mice neonatal trachea. Application of B(a)P in either DMSO or dimethyl- formamide. Application of tobacco extract. Application of a hy- drocarbun-enriched fraction of whole smoke condensate. a. Increased appearance of new small chromosomes and telocentric chromosomes. b. Increased ability to grow in hamster cheek pouch and there become spindle- cell sarcomas. Increased mitotic activity and increased incidence of anomalous mitoses. . Increased basal cell hyperplasia and pleomorphism of newly formed cells. . Increased epithelial mitosis. on Lasnitzki, Human fetal lung Application of a hy- a. Cellular enlargement and promotion of growth of new bronchi. 1968, in organ culture. drocarbon-enriched b. Increased mitoses, bronchial epithelial hyperplasia, and squamous metaplasia. England (161). fraction of whole c. Inhibition of stromal growth. smuke condensate. Chan et al., Mouse lung Application of a. Cellular disorganization. 1969, bud embryonic B(a)P in DMSO. b. Cellular pyknosis; nuclear shape and size irregularities. U.S.A. (54). cultures. c. Increased epithelial mitotic rate and decreased mesenchymal mitotic rate in those cultures exposed to B(a)P versus those exposed to pyrene or DMSO. Leuchtenberger Mouse lung Exposure to fresh smoke: and and kidney a. Unfiltered. a. Decreased RNA production, pyknosis, and death of cells. Leuchtenberger, tissue and b. Activated b. Similar results, but changes were of minimal severity. 1969, organ cultures. charcoal filter. Switzerland (165), ec. Cigarette or cigar tobacco, c. Similar effects as group a., but less severe. SVE TABLE Al4.—Experiments concerning the effect of cigarette smoke or its constituents on tissue and Author, year, Tissue or country, organ culture Material/delivery Results reference Crocker, Various organ Application of Squamous metaplasia; frequent pleomorphic cells; 1970, cultures: B(a)P in serum. (inhibited by Vitamin A). U.S.A. (62). a. Whole suck- ling hamster tracheas. b. Whole bron- chia] tubes from late fetal dogs and monkeys. organ cultures (cont.) dedifferentiation of epithelium OPE TaBLe Al5.—Eaxperiments concerning the effect of the instillation or implantation of cigarette smoke or its constituents into the tracheobronchial tree of animals Author, A. Method year, Animal B. Frequency and/ country, and or duration Results reference strain ©. Material Blacklock, CR white A. Injection into 3,4-benzpyrene: Number with tumors/number exposed 1957, rats. lung parenchyma a. 3 mg. in olive oil 5/6 sarcoma. Great by thoracotomy. b. 3 mg. in olive oil with dead Tb bacilli 2/4 sarcoma, 4/8 squamous cell carcinoma. Britain B. Once. c. 5.75 mg. in cholesterol pellet 1/8 squamous cell carcinoma. 124). C. 3,4-benzpyrene Cigarette “‘tar’’: in olive oil, a. In olive oil 0/10. with dead Tb b. In olive oil with dead Tb bacilli 1/8 sarcoma, 1/8 squamous cell carcinoma. bacilli or in Controls: cholesterol, a. 0.15 cc. olive oil 0/4. cigarette “tar’’. b. 0.15 ce. olive oil with dead Tb bacilli 0/4 ec. Cholesterol pellets 0/4. Della Porta Syrian golden A. Direct tracheal Number of etal., hamsters. instilllation. hamsters with 1958, B. Weekly up to Survivors at 20 tracheobronchial U.S.A. 45 weeks. weeks/original carcinomas (67). C. 1 percent 7,12-dime- Material: Weeks number exposed at death thylbenz(a)anthra- a. DMBA 50 pe-/ week 45 10/20 2 cene (DMBA), b. “Tar” 200 pe-/week oe 32 11/21 — cigarette “‘tar’’ c. DMBA 50 pe./week wena 12 9/20 — concentrate. then “‘tar’’ 200. pe-/ week ..........4- 30 — — d. DMBA 100 ,2./week .... 17 7/20 4 e. DMBA 100 pe./week } and “tar" 500 b 20 9/20 3 pe./week ves fesse sseee ef} Rigdon, White Pekin A. Intratracheal No neoplastic changes noted in either the experimental or control groups. 1960, ducks. injection. U.S.A. Controls: 99 B. Daily for 721 days. (221). Experimental C. Tobaeco condensate group: 52 in liquid petrolatum. Lve TABLE Al5.— FE xperiments concerning the effect of the instillation or implantation of cigarette smoke or its constituents into the tracheobronchial tree of animals (cont.) Author, A. Method year, Animal B. Frequency and/ country, and or duration Results reference strain C. Material Blacklock, CB white rats. A. Inoculation at Number Percent with 1961, thoracotomy. of rate malignant tumors Great B. Once and sacrificed Controls oo... 0. eee eee ee cence ace ecuee 275 1.5 (1 carcinoma, 3 sarcomas). Britain at 1 week-2 years. Cigarette condensate . 72 11.1 (6 carcinomas, 2 sarcomas). (25). C. Cigarette tobacco Bucerin alone 0.2... eee ee cece 44 2.3 (1 sarcoma). smoke condensate in eucerin. Herroldand = Syrian golden A. Intratracheal Number of Number with Number of tracheo- Dunham, hamsters. inoculation. Material: hamsters tumors bronchial tumors 1962, B. 0.5 cc./week for B(a) in Tween60 ... 6 3 5 (3 papillomas, 2 carcinomas). U.S.A. 5/6 months. B(a)P in Tween60! 6 3 9 (4 papillomas, 5 carcinomas). (122). C. Benzo(a) pyrene Tween60 6 0 _— in Tween60 B(a)P in olive oil 6 0 — or olive oil, Olive oil ........... 6 0 —- Rockey et al., Dogs. A. Bronchial inoculation Squamous 1962, or stimulation, Pre- metaplasia U.S.A. B. 3-5 times/week Number Invasive Carcinoma- cancerous with atypical inflam- (224). for up to 5 Procedure: of dogs carcinoma in sity changes changea mation years. Controls ........ 27 — — 6 24 C. Cigarette smoke Manipulation of condensate. bronchus ..... 25 — — _ 9G 25 Smoke condensate 130 1 3 25 98 128 Tipton and Mongrel dogs. A. Bronchial Rapid induction of squamous metaplasia in condensate-exposed animals. No tabular Crocker, Control group and inoculation. data is presented. 1964, experimental B. Daily for 8 days. U.S.A. group—19. C. Cigarette smokc (277). condensate. TABLE A15.—Experiments concerning the effect of the instillation or implantation of a & cigarette smoke or its constituents into the tracheobronchial tree of animals (cont.) Author, A. Method year, Animal B. Frequency and/ country, and or duration Results reference strain C. Material Saffiotti et al, Syrian golden A. Intratracheal Percent tumor- 1966, hamsters. inoculation. Number of bearing of Total Total number U.S.A. B. Weekly for 15 weeks. Number autopsied: tumor-bearing survivors at number of respiratory (287). C. B(a)P (3 meg.) animals 15 weeks of tumors tract cancers attached to fine Male ............... 15 100.0 24 18 hematite dust. Female 11 100.0 17 16 Kuschner, Hamsters. A. Wire mesh pellet Number of Number of 1968, implantation survivors/original animals with ULS.A. into bronchus. Implant: number in group lung cancer (157). B. Lifetime. Wire mesh only 34/35 — C. Bla)P, MCA ............. 88/91 43 methyleholan- Bay P cece ec ce teen eee ee 89/91 57 threne (MCA). Saffiotti et al., Syrian golden A. Intratracheal Number of 1968, hamsters. inoculation. hamsters with U.S.A. B. Weekly for 15 Number autopsied respiratory (235), weeks. Tnoculate: tract tumora C. B(a)P attached Control Phebe este te a eres esse eeeuee 176 —_ to a fine B(a)Pin hematite 2.0.0.0... 0c cece eee eee ae 55 35 hematite dust. Hematite only 0.0... . ce eee 41 —_ Borisyuk, Wistar rats. A. Intratracheal Number final/ Duration of 1969, intubation. initial inoculation Russia B. Monthly up to Inoculate: (months) (84). 10 months. Controls 2... ee cect eee eens 11/20 12 C. Cigarette ‘tar’. Unfractionated ‘‘tar’’ 24/200 10 Denicotinized ‘‘tar’ ..... 9/45 8 (1/9 metaplasia) Neutral ‘‘tar’’ fraction 14/100 8 (2/14 carcinomas, This group also reccived one injection of urethane intraperitonealls 1/14 papillary adenoma). 6re TABLE Al6.--E'xperiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (Figures in parentheses represent total number survivors in specific group) Author, year, Animal A. Type of exposure country, and B. Duration Results Comments reference strain C. Material Lorenz et al., Strain A mice: A. Chamber. E. No increase in tumor formation over that noted in controls. This strain of mice does 1943, TC. 97. B. Up to 693 hours. have a hereditary U.S.A. (177). TE. OT. C. Cigarette smoke. tendency to tumor formation. tC. Control. 0.01 level, Miihlbock, Hybrid (020 x A. Chamber. Percent with alveolar earcinomas No other type of 1955, DBA) mice: B. 2 hours per day for C. 31.0 lung tumors were Netherlands C. 32. up to 684 days. E. 79.0 found. (195). E, 29. C. Cigarette smoke. Leuchtenberger CF, albino mice: A. Chamber. 23 of the experimental mice showed: et al., C. and E. 275. B. To & cigarettes 15 basal cell hyperplasia. 1958, per day from 14 atypical basal cell hyperplasia. U.S.A. (166). 11-201 days. 7 dysplasia. C. Cigarette smoke. 2 squamous cel] metaplasia. Guerin, IC and Wistar A. Chamber. Percentage of rats with pulmonary tumors 1949, strain rats. B. 45 minutes C. 2.4 percent of 39 survivors. France (108). Cc. 40. per day from E. 5.1 percent of 68 survivors. E. 100. 2-6 months. C. Cigarette smoke. Ose TABLE Al6.--Experiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivors in specific group) Author, year, Animal A. Type of exposure country, and B. Duration Results Comments reference strain Cc. Material Leuchtenberger Female CF, mice: A. Chamber. Number with et. al., C. 243. B. 14-6 cigarettes severe bronchitis; 1960, E. 360. per day for 1 Exposure peribronchitis; U.S.A. (167). month to 2 years. Number Number of length atypical epithe- C. Cigarette smoke. of mice cigarettes (months) lial proliferation 151 we. 25-1,526 1-23 30 150... 0 0 2 36 ...... 100- 200 1-3 7 36 wo... 250- 500 4-8 7 34 ...... 600-1,600 9-23 8 51 100- 400 3-6 4 63 100- 400 3- 6 17 Leuchtenberger Female CF, mice: A. Chamber. Number Percent of mice Presence of tumors et al., Cc. 166. B. 4-8 cigarettes of mice Exposure with pulmonary showed an age- 1960, E. 281. per day for examined (days) adenomatous tumors relationship U.S.A. (168). 17-600 days. BL cece ee ee eee 0 56 independent of C. Cigarette smoke. Ch 17- 99 41 smoking exposure. 85 eee ee ee eee © 100-199 37 Bl wee eee ecco aes 200-600 66 Otto, 1963, Albino mice. A. Chamber. Number Exposure Number with Germany Cc. 60. B. Approximately of mice None. lung tumore (206). E. 189. 12 cigarettes per examined Varying 3 pulmonary adenomas. day for varying Cc. 60 up to 24 21 pulmonary adenomas. intervals. E. 189 months. 2 epithelial carcinomas. C. Cigarette smoke. ise TABLE A1l6.—Experiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivors in specific group) Author, year, Animal A. Type of exposure country, and B. Duration Results Comments reference strain C. Material Dontenwill and Golden hamsters, A. Chamber. Number of Daily MET des — desquama- Wiebecke, Cc. — B. Up to 4 cigarettes animale average Histologic tive metaplasia. 1966, E. 320 per day for up dead at exposure findings in MET bronch = bron- Germany to 2 years. 540 days (cigarettea) dead animals chia! papillary (77). C. Cigarette smoke. 40 tees 1 8/ 40 MET des metaplasia. 40) oe. aes eae 2 8/ 40 MET des PAP trach = tracheal 80 1-2 44/ 80 MET des (3 MET papillomata or bronch, 2 PAP trach) intense tracheal 148 1-4 67/143 MET des (13 MET metaplasia. bronch, 8 PAP trach) Leuchtenberger CF, mice. A. Chamber. Marked tEpithelial tissues and B. Up to 1,000 hours. transgression of these animals Leuchten- C. Cigarette smoke, Marked squamous Marked of lung showed an increased berger 1966, exposure to in- cell metaplasia dysplasia parenchyma frequency of cellular Switzerland fluenza virus (percent) (percent) (percent) atypism. The (164). (PR8). Controls (100): authors concluded Male — _ — that PR8 influenza Female ..... — — — virus may act as a Smoke exposed (59) : cofactor in malig- Male —_ 6.0 3.0 nant transformation. Female . —_ — _ Virus exposed (59): Male 11.0 21.0 13.0 Female ..... _ — 5.0 Smoke and virus exposed (68): Male ....... 9.0 43.0 t18.0 Female ..... 29.0 54.0 $33.0 tse TaBL_e Al6. Eaperiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivors in specific group) Author, year, Animal A. Type of exposure country, and B. Duration Results Comments reference strain >. Material Rockey and Mongrel dogs: ‘A. Tracheal fenestra- Squamous tCarcinoma in aitu Speer, CG. 1. tion (10). Hyperplasia metapla- noted in 5 separate 1966, E. 19. Nostril inhala- with sia with Pre- Carci- sites in this U.S.A. (228). tion (9). Inflam- atypical atypical cancerous noma animal. BR. Tracheal fenestra- mation features features changes in situ tion—284 treat- Controls (1!) . 9 1 1 0 0 ment days. Tracheal Nostril inhalation— fenestra- 180 treatment tion (10)... 10 5 6 1 #1 days. Nostril in- C. Cigarette smoke. halation (9) . 6 0 0 0 0 Auerbach Beagle dogs: A. Tracheostoma. Controls, experimental: etal, C. 10 (2 with B. Up to 12 No histologic change in bronchial] epithelium: 1967, tracheostoma). cigarettes per @. 1 animal died at 24 days and no histologic change noted. U.S.A, (10). E. 10. day for up b. 5 animals sacrificed at 421 days and nuclear atypism to 421 days. noted in all. C. Cigarette smoke. c. 2 animals died at 229 and 278 days and nuclear atypism was noted but of lesser severity than in those sacrificed at 421 days. Harris and C57BL mice: A. Chamber. Number of This strain of mice Negroni, Cc. 200. RB. Smoke—12 ciga- Treatment Number lung carcinomas is noted for its 1967, E. 1,437. rettes per 20 Controls .. 00.0... . eee eee 200 0 lack of spontaneous England mice for 12 Influenza aerosol alone ..... 682 15 lung tumor formation. (i121). minutes every Benzpyrene aerosol Animals exposed to other day for (4 exposures) .......040- 200 2 cigarette smoke lifetime. Smoking 200 8 (all adeno- showed no hyper- C. Cigarette smoke, carcinomas) plastic epithelial influenza virus Influenza and benzpyrene 200 3 changes such as aerosol, benz- Influenza and smoking ..... 155 3 those noted by pyrene aerosol, Leuchtenberger. ese Author, year, country, reference Wynder et al., 1968, U.S.A. (327). TABLE Al6.—Hxperiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivors in specific group) Animal and strain Male C57BL6 mice: C. and K.— more than 40. A. Type of exposure B. Duration C. Material A. Chamber. B. Up to 315 cigarettes. C. Cigarette smoke, nitrogen dioxide, volatile acids and aldehydes found in ciga- rette smoke, swine influenza Conclusions: ¢ No squamous cell respiratory cancer noted. This is attributed Results Comments tResults not provided in tabular form. to the limitation of inhalation time (CO and nicotine acute effects) and to the anatomically and physiologically intricate nasal passage defense system. Exposure to cigarette smoke, NO,, or volatile acide and alde- hydes leads to reactive hyperplasia and metaplasia, both of which were noted to be reversible. Swine influenza virus exposure produced hyperplastic and metaplastic effects which could not be enhanced by subse- quent exposure to cigarette smoke. virus. Laskin et al., Rats: A. Chamber, Squamous cell 1970, C. 45. B. 1 hour per day Exposure Number carcinomag UAS.A. (159). E. 3. for up to Atmosphere controls 3 0/ 3 690 days. Atmosphere plus benzo (a) - C. Benzo (a) pyrene pyrene exposure 21 2/21 aerosol, so, SO, controls 3 0/3 atmosphere so, plus benzo (a)- (3.5 p.p.m.}. pyrene exposure ........ 21 5/21 Hammond Reagle dogs. See text See text. et al., 1970, U.S.A. (119). ySEe TABLE A21.—Outline of retrospective studies of tobacco use and cancer of the larynx Author, year, Cases Controls country, - Collection of data reference Sex Number Method of selection Number Method of selection Schrek et al., M. 73 Referrals from V.A. hospitals in ‘‘entire 522 From same set of referrals, patients Random sample of 5,003 1950, midwest” to V.A. Cancer Center, Hines, with tumors other than lip, lung, lar- admissions; question- U.S.A. (246). Illinois, during 1942-44; patients with larynx-pharynx tumors clinically or his- tologically diagnosed: ynx-pharynx: naires from Hines re- ferrals for 1942-44; records invluded Percent Percent smoking history. Nonsmokers - 13.7 Nonsmokers ........-00 00005 23.9 Cigarettes . 79.5 Cigarettes 2... ... eset eee eeee 59.2 Cigars 3.7 Cigars Pipes 6.8 Pipes Valko, M-F 226 Clinic patients with cancer of the larynx: 108 Clinic patients of same age group with Medical history and ques- 1952, other diagnoses: tionnaire in clinic. Czechoslovakia Percent Percent (292). Nonsmokers .........-00+05- 1.5 Nonsmokers ........-.----+% 22.2 Cigarettes ........ sees 83.2 Cigars 2.2.2 ee ce eee -. 44 Pipes... cece eee eee 10.6 Sadowsky et al., M. 273 White male admissions to hospitals in 615 From same set of admissions, patients Sample of 2,605 out of 1953, New York City, Missouri, New Orleans, with illnesses other than cancer: 2,847 interviews (in- U.S.A. (282). Chicago; patients with diagnosed laryn- cluding smoking his- geal tumors, 1938-43: Percent Nonsmokers .......-+-+-eeee+ 4.0 Cigarettes only ............-. 60.1 Cigarsonly ............2005. 2.2 Pipe only Some combination Percent Nonsmokers ........-+ ... 13.2 Cigarettes only §3.3 Cigars only . . 3.4 Pipe only .......... seeee TH Some combination .......... 28.1 tory) by trained lay interviewers. Sse TABLE A21.—QOutline of retrospective studies of tobacco use and cancer of the larynx ( cont.) Author, year, Cases Controls country, Collection of data reference Sex Number Method of selection Number Method of selection Blimlein, M. 241 Clinic patients with cancer of larynx: 200 Patients with no laryngeal disease: Personal history taken in 1955, Percent Percent clinic. Patients and Germany Nonsmokers 0.8 Nonsmokers ...... . 18.0 controls over 40 years (26). Heavy smokers -- 19.3 Heavy smokers : .» 4.3 of age. Inhalers - 95.0 Inhalers .................... 17.0 Wynder et al., M. 209 White male inpatients Memorial Cancer 209 Patients with other than epidermoid Trained lay interviewers. 1956, Research Center during 1952 to 1954, cancer, individually matched controls ULS.A. (912). with benign or malignant epidermoid in same institutions: tumors of larynx: Percent Percent Nonsmokers ..............., 0.5 Nonsmokers ................ 10.5 Cigarettes Cigarettes 73.7 Cigars Cigars ........ 10.1 Pipes ............ Pipes ......,.. 3.8 Cigars/pipes Cigars/pipes ........... 1.9 Wynder et al., M. 132 Laryngeal cancer patients at Tata Mem- 132 Controls individually matched ag for Interviews for smoking 1956, orial Hospital, 1952-54: U.S.A. data above: and medical histories, India (S12). Percent Percent Nonsmokers ................ 13.6 Nonsmokers ................ 30.3 Bidis 22... 0. eee ee 78.8 Bidis ..0. 0... eee eee 62.1 Cigarettes ..0.........0...., 5.3 Cigarettes vee eee eee 4B Hookah ................0.0.., 1.5 Hookah .................... 0.8 Chilum ..................4.. 0.8 Chilum oo... 2.3 Schwartz et al., M. 121 Patients hospitalized from 1954 through 242 Same time and sources; patients hospital- Cases and controls indi- 1957, 1956 with laryngeal cancer, in Paris ized for non-cancerous conditions or vidually matched within France (248). and other large cities: trauma: institutions; each mem- Percent Percent ber of a set questioned Smokers ................00.. 96 Smokers (p<0.05) 6.00.00... 84 by the same trained lay Inhalers .................,.0, 58 Inhalers (p<0.05) 47 interviewer. Roll their own cigarettes .... 44 Roll their own cigarettes .... 31] 9SE TABLE A21.—-Outline of retrospective studies of tobacce use and cancer of the larynx (cont.) Author, year, Cases Controls eountry, Collection of data reference Sex Number Method of selection Number Method of selection Wynder et al., M. 60 Patients at Radiumhemmet with squam- 271 Patients from same source and time, By trained lay inter- 1957, ous-cell cancer of larynx, from 1952 with cancer other than squamous-cell viewers in hospital. Sweden (322). through 1955: of larynx: Percent Percent Nonsmokers ......: ++ ee reeee 5 Nonsmokers ........+.+ 0005 24 Cigarettes... 0. eee eee eee AT Cigarettes 2.0... 2. cece eee 36 Cigars 2.0.2... 2 cece ee eee eee FT Cigars... 6. cece eee eee 9 Pipes ....... 15 Pipes oo. cece ee eee eee eee 16 Mixed 17 Mixed 13 Wynder et al., M. 142 Clinic patients in Havana during 1956-57, 220 Same source and time; apparently pa- Interview of patients 1958, F. 32 with histologically diagnosed epider- 214 tients with cancers other than larynx, in clinic. Cuba (825). moid cancer of larynx. lung, or oral cavity, matched for age: Percent Percent Male Female Male Female Nonsmokers ......... 1 13 Nonsmokers .......- 16 66 Cigarettes ........... 62 72 Cigarettes 45 27 Cigars ............006 20 6 Cigars 22 6 Pipes .......-.....0.- 1 ae Pipes ....... 1 Mixed .......-.-...+. 16 9 Mixed ............0. 16 Dutta-Choudhuri M-F 582 Patients in Calcutta cancer hospital dur- 288 Not specified Tobacco histories ob- et al., ing 1950-54, with laryngeal tumor diag- tained during 1951-54, 1959, nosed and confirmed by biopsy or smear: apparently by inter- India (86). Percent Percent viewer. Nonusers ........2. 0-0-0005 14.1 Nonusers .... 22. ccc ecco 41.7 Cigarettes or bidi ........... 77.8 Cigarettes or bidi ........... 52.1 Chew 0... eee e eee eee 3.1 Chew 3.8 Both oo. cc eee eee cee eee 5.0 Both 2.4 LGE TABLE A21.—Outline of retrospective studies of tobacco use and cancer of the larynx (cont.) Author, year, Cases Controls country, Collection of data reference Sex Number Method of selection Number Method of selection Staszewski, M. 207 Patients admitted to chronic disease hos- 912 Patients admitted during 1957 and 1958 Author interviewed pa- 1960, F 13 pital during 1957 and 1958 with histo- 1,813 to ehronic disease center for cancer- tients suspected of lung Poland (259). logically confirmed squamous-cell car- ous and noncancerous conditions pre- cancer for smoking cinoma of the larynx: sumably not related to tobacco con- history and background. sumption: Percent Percent Nonsmokers ................ 0.5 Nonsmokers ................ 17.3 Cigarettes only . 87.9 Cigarettes only ............, 60.5 Pipes and/or cigars .......... 1.9 Pipes and/or cigars . 11.1 “Heavy smokers” . 88.4 “Heavy smokers” ........... 49.0 Inhalers ..0... 2... eee, 96.1 Inhalers ..... 0.0... cee es 66.8 Female smokers ............. 30.8 Female smokers ............ 8.4 Rozenbilds, M. 191 Patients admitted to 3 major hospitals No controls. Patient interviews. 1967, F, 21 with cancer of larynx and hypopharynx: Australia Percent (229). Nonsmokers ................. 8 Smokers .............02.00.08 92 Heavy smokers .............. 30 Terraco] et al., M. 961 Private service and clinic patients of ENT No controls. Patient interviews. 1967, hospital: France Percent (274). Nonsmokers 12.1 Smokers .....0.......000000, 87.9 Svoboda, M. 205 Patients admitted to a regional hospital 320 Male controls Cases: patient interviews. 1968, F. 10 over a period of 6 years all confirmed Controls: not stated. Czechoslovakia histologically: Percent (271). Percent Nonsmokers ..............0. 22.0 Nonsmokers ................ 2.93 Cigarettes (approximately) . 71.0 Cigarettes ....... 0.00. cae 94.63 Pipes (approximately) ...... 7.0 Pipes ...... cee eee e ee eee 2.44 TABLE A22.—Summary of results of retrospective studies of tobacco use and cancer of the larynx (Figures in parentheses represent ratios based on less than 5 case nonsmokers. } Relative risk ratio} ali Investigator reference smokers to nonsmokers Schrek et al., U.S.A. (246) 00 ee et eee tet nees 2.0 Valko, Czechoslavakia (292) ........, Veen eee eee ene erences 3.5 Sadowsky etal., U.S.A. (282) ooo te eee eens 3.7 Blimlein, Germany (26) ........... 27.5 Wynder et al., U.S.A. (372) 23.6 Wynder et al., India (312) bees beeen ee tees 3.1 Schwartz et al., France (248) 00. eee tt eee eae 4.6 Wynder et al., Sweden ($22) 0. c eee e eee 6.0 Wynder et al., Cuba (325) 0... cc ee ee ee eee eee nee (18.9) (males only) Dutta-Choudhuri et al., India (86) 00... ee ree 4.3 Stazewski, Poland (259) 0.00... cc ce tree eens (40.0) (males only} Svoboda, Czechoslavakia (271) 2.00... cee ce ee ee eee 8.3 1 Computed according to method of Cornfield, J. (67). 358 6S TABLE A23.—Number and percent distribution by relative frequency of atypical nuclei among true vocal cord cells, of men classified by smoking category (100 percent atypical cells defined as carcinoma) Current cigarette smokers Percent Never smoked Ex-cigarette Cigar/pipe Less than 1 1-2 packs 2 or more atypical nuclei regularly smokers smokers pack a day a day packs a day Num- — Per- Num- Per- Num-_ Per- Num- Per- Num- Per- Num- Per- ber cent ber cent "ber cent ber cent ber cent ber cent Total oo. eee eee 88 100.0 116 100.0 94 100.0 125 100.0 329 100.0 190 100.0 None oo... 0. ccc ccc eee eee eens 66 75.0 86 TA 1 1.1 1 8 0 _ 0 _ Less than 50 8 9.1 14 12.1 4 43 25 20.0 4 1.2 0 _ 50-59 10 11.4 13 11.2 50. 53.0 54 43.2 87 26.4 29 15.3 60-69 4 4.5 1 9 23 24.5 21 16.8 116 35.3 16 39.4 70-79 0 _ 2 1.7 9 9.6 9 7.2 44 13.4 38 20.0 80-89 0 _ 0 —_ 2 2.1 2 1.6 19 5.8 11 5.8 90-99 0 _ 0 _ 1 11 0 — 5 1.5 0 _ 100: Carcinoma in situ ..........000. 0 — 0 — 3 3.2 13 16.4 52 15.8 35 18.4 Invasive carcinoma ............ 0 - 0 ~ 1 1.1 0 — 2 6 2 11 Source: Auerbach, O. et al. (9). O9e TABLE A24.—-Number and percent distribution, by highest number of cell rows in the basal layer of the true vocal cord, of men classified by smoking category Current cigarette smokers Number of Never smoked Ex-cigarette Cigar/pipe Less than 1 1-2 packs 2 or more cell rows regularly smokers smokers pack a day a day packs a day Num- Per- Num- Per- Num- Per- Num- Per- Num-_ Per- Num- Per- ber cent ber cent ber cent ber cent ber cent ber cent i 0) 0 88 100.0 116 100.0 94 100.0 125 100.0 329 100.0 190 100.0 Less than 5 cell rows ......0----0-5 30 34.1 7 6.0 4 4.3 3 2.4 1 0.3 0 a BecellrowS 0.2... cee eee ee eee eee 29 33.0 27 23.3 20 21.8 27 21.6 38 11.6 20 10.5 6 cell OWS . 2.0... ee cee ee eee 8 9.1 15 12.9 15 6.0 25 20.0 51 15.4 24 12.6 Teel] rows 00... .e cece eee eee ry 6 6.8 12 10.3 18 19.1 12 9.6 38 11.6 19 10.0 Beell rows .... 6. eee eee eee 8 9.1 14 12.3 9 9.6 13 10.4 30 9.1 23 12.1 9 cell rOWS 2... ce eee ee eee eee 1 11 7 6.0 q 7.4 6 4.8 26 1.9 14 TA 10 or more cell rows .....-.-..2-0 0505 6 6.8 34 29.4 2t 22.3 39 31.2 145 44.1 90 AT.4 Source: Auerbach, O. et al. (9). L9E TABLE A28.—Outline of retrospective studies Author, of tobacco use and cancer of the oral cavity (Data obtained from patient interview and other sources) year, Cases Controls country, ~ Comments reference Sex Number Method of selection Number Method of selection Borders, M. 526 Series of clinic patients with epithelioma 500 Series of clinic patients without epithe- 1920, F. W of the lip: lioma of the lip: ULS.A. (43). Percent Percent Tobacco users 80.5 Tobacco users .............. 78.6 Smokers Smokers Cigarettes Cigarettes Chewers Chewers .... Pipes ..........., Pipes Cigars... 2... ee eevee Cigars .......... : Ebenius, M. 439 Clinic patients with cancer of the lip: 300 Not defined. t Estimate of prevalence 1943, F. 33 of use, Sweden (87). Percent Percent Male Female Male Female Tobacco users - 19.7 —_— Tobacco users . 68.7 —_— Tobacco users Tobacco users ........ — 1-2 (all pipes) oo 57.6 Pipes .......00..0.... 22.9 Pipes tee eeeeee 61.8 — Chew or use snuff ..... 60.7 — Chew or use snuff .... 47.4 — Cigars and cigarettes .. 32.5 —_— Cigars and cigarettes .. 12.9 —_ Levin et al., M. 143 Cancer Institute patients with cancer of 51 Cancer Institute patients with non-can- 1950, the lip: cer diseases of same site: U.S.A. (169). Percent Percent Smokers 2.0.0.0 ....00.0.000, 84.5 Smokers ...........0.0...., 74.0 Cigarettes 2.0.00... 0... ca 45.3 Cigarettes .........00.0...0.. 43.0 Pipes ....... 0.00 cece eee eee 48.1 Pipes ....... 0.0.0... ce eae 30.7 Cigars 2.0.0.0... eee 26.5 Cigars oo... eee eee 34.9 o9€ TABLE A28.—Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Data obtained from patient interview and other sources) Author, year, Cases Controls country, Comments reference Sex Number Method of selection Number Method of selection Mills and Porter, M. 124 Deaths from cancer of oral cavity in Cin- 145 Sample of population of Columbus, Ohio, 1950, cinnati and Detroit, 1940-45 and 1942- in same proportion of color, sex, and U.S.A. (186). 46 respectively: age as in cases: Percent Percent Cigarettes only ...........-.. 35.5 Cigarettes only ............. 32.4 Pipes, cigars, or Pipes, cigars, or combinations - 54.8 combinations - 29.7 Moore et al., M. 112 Patients over 50 years old since 1951 with 38 Patients of same age groups with be- 1953, cancer of oral cavity: nign oral lesions or benign surgical U.S.A. (198). conditions: Percent Percent Chewers oo... ccc cece ee eee 58.0 Chewers ...... eee eee cece 31.6 Pipes... 0... cece ee eee 42.0 Pipes .. 0... eee cee eee eee 47.4 Cigars and cigarettes seeeee 88.4 Cigars and cigarettes . 52.6 Sadowsky et al., M. 1,136 Hospital patients with lip, oral, and phar- 615 Patients with illness other than cancer: 1953, yngeal cancer, 1938-43: Percent U.S.A. (282). Percent Cigarettes only . 63.3 Cigarettes only 42.3 Cigars only ..............05. 3.4 Cigarsonly .... 02... cee eee 4.0 Pipes only .............0.002 7.0 Pipesonly .........-.0 ee eee 17.8 Mixed ....... 0.00 ccc ce eee ee 23.1 Mixed 2... . cece cece ee eee eee 28.2 Sanghvi et al., M. 657 Hospital patients with cancer of oral cavi- 288 Hospital patients with diseases other Smoking is of bidis among 1955, F. 81 ty and pharynx: 112 than cancer: both cases and controls. India (2417). Percent Pereent Male Female Male Female Smoke andchew..... 38.8 3.7 Smoke and chew . 24.0 —_ Smoke only .......... 46.7 6.2 Smoke only .......... 50.0 6.3 Chew only ........... 11.7 64.2 Chew only ............ 8.7 23.2 Neither .............. 2.7 25.9 Neither 17.3 70.5 e9€ TABLE A28.—Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Data obtained from patient interview and other sources ) Author, year, Cases Controls country, - -— Comments reference Sex Number Method of selection Number Method of selection Ledermann, M. 240 Patients with cancer of oral cavity and 62 Patients with cancer of skin, bone, and Differences between cases 1955, pharynx: muscle: and controls for both France (162). Percent Percent high and low alcohol in- Nonsmokers ............ 4.6 Nonsmokers ................ 17.2 take are insignificant >>20 cigarettes per day ....... 23.4 >20 cigarettes per day . 18.6 when smoking is con- trolled. Wynder et al., M. 543 Patients with cancer of ora) cavity: 207 Patients with cancer of other sites and 1957, F. 116 232 benign diseases: U.S.A. (818). Percent Percent Male Female Male Female Nonsmokers 3 47 Nonsmokers 10 70 Cigars ............... 20 — Cigars 13 _ Pipes .............6.. 1t — Pipes 6 — Mixed ............... 8 — Mixed 8 _ Chew ................ 17 — Chew ...... 8 _ Cigarettes 57 53 Cigarettes 63 30 >35 cigarettes >35 cigarettes per day : 29 _— per day : 17 — >16 cigarettes >16 cigarettes perday ............ —_ 34 per day 11 Schwartz et al., M. 3382 Hospital patients with cancer of oral cav- 608 Hospital patients with non-cancer ill- 1957, ity and pharynx: ness and accident cases, matched by France (248). age: Percent Percent Nonsmokers 16.4 Nonsmokers .............4.. 23.4 Cigarettes only . 62.7 Cigarettes only . 58.2 weet eee eres esssuae 3.3 Pipes only .................. 3.0 Pipes only v9E TanLe A28.—Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Data obtained from patient interview and other sources) Author, year, Cases Controls country, - - Comments reference Sex Number Method of selection Number Method of selection Wynder et al., M. 178 Hospital clinic patients with cancer of 220 Patients in same clinics with non-malig- 1957, : F. 34 oral cavity and pharynx: . 214 nant conditions, matched by sex and Cuba (825). age: Percent Percent Male Female Male Female Nonsmokers ........- 4 24 Nonsmokers ......-..- 16 66 Cigarettes Cigarettes predominantly ..... 45 62 predominantly ...... 45 27 Cigars predominantly . 33 12 Cigars predominantly . 22 6 Wynder et al., M. 115 Male patients with cancer of oral cavity 115 Male patients in same hospital with can- Alcohol data significant 1957, and pharynx: cer of sites other than oral, pharynx, only for hypopharynx. Sweden (822). larynx, lung, esophagus, breast: Percent Pércent Cigarettes Cigarettes 2.0.0... ce eee eee 36 Cigars Cigars 2... ee ec ee eee 9 Pipes Pipes 2... cece e eee ences 16 Mixed Mixed 0.0... ccc cece eee cee ee 13 Peacock et al., M. 25 Hospital patients with oral cancer: 74 Patients in same hospital without oral 1960, F. 20 72 cancer and 117 male and 100 female U.S.A. (210). out-patients, randomly selected. Percent $2.6 percent of first group, and 43.3 per- Chewed or used snuff over 20 eent of second group chewed or used years (all patients) ........ 55.6 snuff over 20 years. Staszewski, M. 383 Male patients with oral cancer: 912 Male patients with other cancerous and 1960, Percent non-cancerous conditions: Poland (259). Nonsmokers ........-.00006- 5.7 Percent “Heavy” smoking index 72.8 Nonsmokers ........+.000005 17.3 Cigarettes only 92.3 “Heavy” smoking index ..... 49.0 Pipes and/or cigars .......... 12.8 Cigarettes only ......0..065. 60.5 Pipes and/orcigars ........- 11.1 S9E TABLE A28.—Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Data cbtained from patient interview and other sources) Author, year, Cases Controls country, a Comments reference Sex Number Method of selection Number Method of selection Vogler et al., M. 188 Clinic patients with cancer of lip and oral 521 Patients of same clinic with other can- t Due to varying tabular 1962, F. 92 eavity: 1,064 cer or non-malignant conditions: treatment of data, per- ULS.A. (298). Percent centages of tobacco Male Female users are not all based Chewers ............. $32.9 — Percent on the same number of Excessive chewers .... 22.9 — Male Female cases. Snuff dippers ........0 — 72.0 Snuff dippers ......... tee t6.1 Excessive snuff dippers ............ _— 41.3 Tobacco users ........ 90.0 90.0 Tobacco users ........ 56.0 56.0 Vincent and M. 66 Successive patients with lesions of buccal 100 Successive patients attending gastroin- Male patients used con- Marchetta, F. 16 eavity and oropharynx: 50 testinal clinic, age-matched: siderably more alcohol 1963, Percent than male controls. ULS.A. (297). Oral Oro- Data refers to all forms Males: Cavity pharynx Percent of smoking expressed Nonsmokers ......... 3.0 — 27.0 as cigarette equivalents. <20 cigarettes Cigarette equivalents: perday ............ 18.8 15.1 24.0 l cigar = 5 cigarettes >20 cigarettes lpipe = 2 cigarettes perday ............ 78.7 84.9 49.0 t BN=Betel nut. Females: Nonsmokers ......... 55.5 28.6 82.0 <20 cigarettes perday ............0— -— 8.0 >20 cigarettes perday ............ 44.5 W104 10.0 99€ TaBLE A28.—Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Data obtained from patient interview and other sources) Author, year, Cases Controls country, Comments reference Sex Number Method of selection Number Method of selection Shanta and M. 552 Patients with oral and pharyngeal cancer 300 Controls residing in Krishnamurthi, =F. 206 (unsure of confirmation) : 100 game area matched 1964, Percent for age, sex, and India (256). Buccal Anterior Posterior class: Males: Lip mucosa tongue tongue Pharynz Males No tobacco habit ....- _— 2.0 1.2 2.0 5.3 39.1 Smokers ......--+-- 50.0 45.7 66.6 75.0 12.8 52.7 Number of cases (12) (293) (69) (48) (180) (300) Females: Femalea No tobacco habit .... 14.3 11.0 33.3 —_ 40.0 88.8 Smokers ......----- _ 4.7 5.5 _ 8.8 _ Number of cases .... (7) (152) (18) (4) (25) (100) Wahi et al., M. 589 Patients with oral and pharyngeal car- 589 Patients matched for age, sex, religion, 1965, F. 232 cinoma: 232 and social class. India (802). Percent Percent Nonsmokers ....+ +--+ -- ee 0e+ 9.62 66.5 Smokers ....---. cess eer renee 17.05 21.2 Chewers (Betel nut) ....----+ 35.44 5.9 Both ....... 0 cc eee cee eee eens 37.88 6.4 Hirayama, M. 369 Patients with oral and pharyngeal carci- 277 Patients with other (unspecified) dis- Found only a suggestive 1966, F. 176 noma: 163 eases: association between Central and Percent Percent alcohol-drinking and South East Male Female Male Female ora) cancer in non- Asia (124). Nonusers ....--2-0005 1.6 2.5 17.0 33.0 chewers only. Smokers .....-..---+5 17.1 2.6 23.8 1.2 + BN-Betel nut. Smokers, TBN and tobacco chewers . 46.7 6.6 24.9 1.8 L£9€ TABLE A28.—Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Data obtained from patient interview and other sources) Author, year, Cazes Controls country, Comments reference Sex Number Method of selection Number Method of selection Keller, M. 408 Patients with squamous cell carcinoma of 408 Next male patient admitted to same hos- Excessive alcohol con- 1967, oral cavity and oropharynx confirmed pital within 5 year age range. sumption noted for U.S.A. (140). histologically. Three New York City VA cases involving floor, Hospitals 1953-68: mesopharynx, and Percent Percent tongue. Nonuserg ................... 6.1 14.2 Findings indicate the Cigarettes .........000.0...., 68.6 56.4(p<0.0001) association of heavy Pipeonly ......... Se ceeeees 4.0 2.9 drinking with cancer Cigaronly ..............00,. 6.9 6.1 independent of the amount of tobacco used. Martinez, M. Patients with epidermoid carcinoma of 345 115 male and 38 female hospita] or clinic Cases found to consume 1969, F, 38 oral cavity and pharynx: 14 patients without cancer; 330 male and more alcoholic bever- Puerto Rico 76 female residents of same region, ages than controls. (188). age and sex matched. Percent Percent Nonsmokers .....,.......... 13.7 19.2 Heavy tobacco users ......... 24.8 12.2 (p<0.0001) Keller, M. 304 Patients with primary basal or squamous 304 Patients from same hospital matched for 1970, cell carcinoma of Jip: age and race. U.S.A. (141). Percent Percent Nonamokers ...... bee eevee 7.8 16.6 (p<0.001) Cigarettes only ........... «+. 60.2 52.8 Pipeonly . 6.0 3.4 Pipe, other . 6.8 0.4 (p<0.01) 99e TABLE A28a.—Summary of results of retrospective studies of smoking by type and oral cancer of detailed sites Author reference Tobacco chewing Betel nut chewing Miscellaneous Broders (48).......Li Ebenius (87). 2.0.0.0... ce eee eee Mills and Porter (186) ce bcd kk ube ben ene nee eee EEE eRe bee Edn een EEE ee eR AEE EOE REE EEE Ee Ee Fee ee eee nee wee eveueeeeesss.-Pipes and cigars combined—oral (+). Moore et al. (193) Lip, mouth (+) bese see ae sees Snuff—iip, mouth (+). Sadowsky etal. (232) pharynx (—)..... Cigarettes Pipes and cigars Bidis only cece e ee wee eet eee ete ee teens Lip (4). 2.2... 65 cece eee eee Lip (—). ce. cc ee eee eee Lip (4). 0.000006 wee eee cee eee Se ee een et ee eee ee Lip (4A) cee cee ene Lip, see eee Lip, mouth (—). mouth (—) cen ee ee eter eee ene Lip, tongue, other oral (-+) Sanghvi et al. (241) cece nee eens If smokers and chewers—base of tongue, hypopharynx (+). Lederman (162)... Wynder et al. (313) Female (+).... . Gingiva, lip (*)..... Schwartz et al. (248) we ee Oral (PB) occ cece ee ce eet ee ete tence teenies ce eet e et ae eee ene ttee Each site except tongue (+).... Pharynx (+). ......6-.. Oral (—) 2. ce ccc ee ee tees 69€£ TABLE A28a.— Summary of results of retrospective studies of smoking by type and oral cancer of detailed sites (cont.) — - -— _ - pe Author Cigarettes Pipes Pipes and Cigars Tobacco Betel nut . reference Cigarettes and cigars Bidis only other forms only chewing chewing Miscellaneous Wynder et al. a Oraland ec cce cece ee eee (825) pharynx, pharynx, Male (—) Male (+), Female (-++) Female (+) Wynder et al. Pharymx (+), eee cece cee ccevinetrsrreeveeerepee, Tongue, eee eee cece eee Pipes and cigars (322) other sites (—). gingiva, combined— pharynx (+), tongue (+). Peacock et al. (210) Staszewski (259).. Vogler et al. (298) Vincent and Marchetta (297) Shanta and Krishnamurthi (256 STAD OPAL ee ttt trrren vtttetrnn tien nin rn TT cavity (-+)..... Oral (TY eee... Snuff—oral (-4)1 Pipes and cigars combined—lip, oral cavity (*). -eAll forms com- bined (+), Female (+) Snuff—lip and buceal cavity in hoth cases. TO elec tet er tvntene ley All forms combined— oral (+), pharynx (+). Bee eee cence ree Cesc ve eee eeeee, Lip, All smoking types buccal —pharynx (+), mucosa (+).. post tongue (+). All forms com- bined—lip, oral cavity, pharynx (+). Ooze TABLE A28a.—Summary of results of retrospective studies of smoking by type and oral cancer of detailed sites (cont.) Author Cigarettes Pipes Pipes and Cigars Tobacco Betel nut reference Cigarettes and cigars Bidis only other forms only chewing chewing Miscellaneous Wahi et al. Anterior ec cee en enn e beet ae Cb be ebb c ccc an ene nent atnbnnnee Anterior All forms com- (802) tongue and tongue and bined—all buccal buceal sites (+). mucosa, mucosa, Males (+) Males (+) Hirayama (124)... 0.00. ee cece tee eee eee eee AN sites (—) occ cece ace Allsites (—)... Allsites (—)................. All forms com- bined—base of tongue (+), oropharynx (++). Smoking only combined —buccal mucosa (+). Keller (140)....... Allsites (4) 0.000 (0c cee cee cee eee Allsites (—). 0... ccc ce eee eee Allsites (—-) 0... eee ee cee eee All types smoking combined, heavy —floor of mouth and tongue (+). Martinez (183).....Oral cavity, Pe ee Ee ee Cente ee EEE EE CCE E ERD EEE Ue eee bee nnn s ues ee ete eeeeeereeeeaaetecenee All types of pharynx (-+-) smoking, heavy, eombined—oral cavity (+), pharynx (+). Keller (447) ....... Lip (—) occ ec enn cee eee ee eee teen necenes Trip (4+)... Lip (—). 00. cece ce cece eee enee All types of smoking com- bined—lip (+). ' Only in individuals of low economic status and over 60 years old. Symbols: (+) = significant association. (—) = association absent or not significant. (*) 2 association of doubtful significance. Ze TABLE A29.—Experimental studies concerning oral carcinogenesis Author, A. Method. year, Animal B. Frequency and/ country, and or duration. Results reference strain C. Material. Kreshover, 78 Swiss and A. Painting of lower No macroscopic or microscopic changes in controls or experimental animals. 1952, C57 mice. lip mucocutaneous U.S.A. region. (152). B. 10 times in 76 days. C. Cigarette smoke ‘concentrate’. Salley, 36 Syrian A. Painting of cheek Number of Number with ‘Number with 1954, hamsters. pouch. Treatment: survivors benign tumors carcinoma U.S.A. B. 3 per week for 16 Acetone solvent 5 1 2 (238). weeks. Benzene solvent 4 — —- C. Benz(a) pyrene in acetone or benzene. Holsti and 60 Albino mice A. Painting of lips No oral or labial changes seen in controls or experimental animals. Ermala, (40 controls). and oral cavity. 1955, B. 140 times in 12 Finland months. (190). C. Tobacco “‘tar”’. Moore and 80 Syrian A. Material soaked onto Inflammation Miller, Golden hamsters. wad and secured Original Surviving Number and basal cell 1958, in cheek pouch. Treatment: number over 1 year tumors hyperplasia U.S.A. B. Wads replaced 8 Controls oo... ee eee ee 30 23 we 4 (192). times in 2 years. Smoke condensate 80 55 we 32 C. Smoke condensate Benz (a) pyrene 20 16 .s 9 Benz (a) pyrene. Guerin, Strain IC and A. Chamber inhalation Original Buccal 1959, strain W rat. of tobacco smoke. number Survivora tumors France B. Daily (2). Controls .........5-- 40 39 0/39 (108). C. Up to 5% months. Experimental ....... 100 68 5/68 (3/6 definite epithelioma) ZLE TABLE A29.—KHxperimental studies concerning oral carcinogenesis (cont.) Author, A. Method. year, Animal B. Frequency and/ country, and or duration. Results reference strain C. Material. Peacock et al., 124 Syrian A. Packing of cheek No tumors noted in any of the 42 animals surviving over 1 year. 1960, Golden hamsters. pouch, U-S.A. B. 1 year. (210). Cc. Snuff, Tobacco, Bland material. Dunham and Syrian Golden A. Packing of cheek Hyperplasia Malignant Herrold, hamsters. pouch. Original and/or in- pouch 1962, B. Normal lifespan or Treatment: number Survivors flammation tumore U.S.A. 5-30 months. Betel quid Pies vee eres waa 375 90% over Ll year 19 — (84). C. Betel quid ingredients DMBAand MCA ............. 71 56/71 over 5-30 months — 23/56 7-12 dimethylbenz(a)- anthracene (DMBA), Methylcholanthrene (MCA) in beeswax pellets. Moore and Albino hamster A. Painting oral mucosa. Animals with Christo- exteriorized B. 3 per week for 683 Treatment: lesions (time) pherson, oral pouch, days. Controls... ec ce teen cece ee neeee Q-18 (at 392 days). 1962, C. Cigarette smoke Smoke condensate .....0..0... 000 ce cece cee eves 0/20 (at 387 days) (10 showed hyper- U.S.A. condensate. keratosis). (191), DMBA in 0.50% DMBA 200. cc cen ee cee cee teese pens 14/21 microscopic cancers (at 90 days) petrolatum. (invasive squamous cancer originating in the skin at the edge of the pouch). Salley, CAF, strain A. Ultraviolet light Treatment: Number Duration Tumors 1963, mice. exposure to and Ultraviolet light and weeks U.S.A. painting of lips. cigarette smoke .................... 40 94 — (289). B. 3 per week for 98 B(a)P and UV light ......0.0.0....... 40 48 — weeks, UV light ...... oe 40 94 —_ C. B(a)P in acetone Bla)P wool cee ee 40 45 —_ Cigarette smoke UV light. 74 TABLE A29.—Experimental studies concerning oral carcinogenesis (cont.) Author, A. Method. year, Animal B. Frequency and/ country, and or duration. Results reference strain C. Material. Hamsters A. Application to Original cheek pouch. Treatment: Number Survivors Duration Lesions B. See results. Cigarettes 5 per week vee 70 5B 64 — C. See results. DMBA once .................. 13 6 128 2 hyperplasia Croton oi! 8 per week . 10 10 30 _ DMBA once and cigarettes 5 per week ........0........ 30 28 81 12 hyperplasia 4 dyskeratosis 1 carcinoma DMBA once then croton oil 5 per week ..............,.. 29 27 81 7 hyperplasia 6 dyskeratosis 3 carcinoma Bock et al., ICR Swiss A. Painting mouse Number tumors/ 1964, mice. skin. number mice U.S.A. B. See results 36 weeks. Tobacco equivalent with tumors (30). C. Various extracts of Treatment: (cigarettes/daily) (amall papillomas) unburned tobacco DMBA. DMBA once then: Acetone benzene extract .... Concentrated Ba(OH), extract ....... Diluted Ba(OH), extract... . eee eee DMBA only ........,....... Acetone benzene extract .................. Concentracted Ba(OH) 2 extract Diluted Ba(OH) 2 extract ...0....00...00..0 0000000. None ......0.....0.00.0.0..0¢ Ce eee eee 2.5 0.5 0.5 2.5 0.5 0.5 16/7 18/8 6/2 ve TABLE A29.—Experimental studies concerning oral carcinogenesis (cont.) Author, A. Method. year, Animal B. Frequency and/ country, and or duration. Results reference strain C. Material. Protzel et al., Swiss Webster mice A. Swabbing of labial Original Percent at 18 months with 1964, with some having mucosa. number Papillomas Cancer ULS.A. liver damage in- B. Up to 13 months. Alcohol and ccl, treated .............. 40 74 46 (213). duced either by C. B(a)P in acetone. Alcohol treated ............0.000000005 40 84 50 CC14 or ethyl cc, treated 2.0... .. cece eee 40 90 40 alcohol. No toxin ......... cece ee ee cee 40 42 15 Reddy and Swiss female A. Intravaginal Original Anguli, mice. instillation. number Survivors Lesions 1967, B. Daily for 324~380 60 40 3/40 raised papillomatous India days. malignant growths (219), C. “Pan” mixture of 4/40 possible carcinoma- areca nuts, lime, in situ, and chewing tobacco. Elzay, Syrian Golden A. Application to Percent Percent 1969, hamsters. cheek pouch. Original Mortality Number with with U.S.A. B. Daily for 200 days. Treatment: number rate animals tumors cancer (90). C. See results. DMBA Alcohol Smoke 29 41.0 17 100.0 50.0 DMBA Aleohol ........ 29 66.0 10 60.0 40.0 DMBA sees Smoke 29 42.0 14 100.0 70.0 DMBA oo ........ eee ee 29 48.0 16 100.0 38.0 Alcohol Smoke 29 42.0 14 — _ Smoke 29 42.0 14 — — SLE TABLE A31.—Summary of methods used in retrospectvie studies of tobacco use and cancer of the esophagus Author, year, Cases Controls country, reference Sex Number Method of selection Number Method of selection Collection of data Sadowsky et al., M, 104 White patients admitted during 1938-43 to 615 White patients with illnesses other than Obtained by 4 specially 1953, selected hospitals in New York City, cancer admitted to same group of hos- trained lay interviewers. U.S.A. (282). Missouri, New Orleans, and Chicago. pitals during same period. 242 records out of a total of 2,847 excluded be- cause of incomplete or questionable smoking histories. Sanghvi et al., M. 93 Consecutive clinic admissions to Tata me- 288 Consecutive clinic admissions of patients By means of ‘‘detailed 1955, morial Hospital, Bombay. without cancer. questionary.”” No other India (241). 107 Consecutive admissions of patients with details given. eancers other than intraoral or eso- phagus. Wynder et al., M. 39 Patients admitted to Radiumhemmet, 115 Patients admitted to same hospital with 1957, F. 35 Stockholm, during 1952-55. 156 cancer of skin, head and neck region Sweden ($22). other than squamous cell cancer, leu- kemia, colon, and other sites. No matching. Staszewski, M. 24 Patients admitted to Oncological Institute 912 Other patients sent to Institute with No details given on 1960, during 1957-59. symptoms probably not etiologically method of data collec- Poland (260). connected either with smoking or with diseases of esophagus, stomach or du- odenum. tion. No age adjust- ment or matching. Av- erage age of cancer patients, 60.5; controls, 53. 9LE TABLE A31.--Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus (cont.) Auer Cases Controls country, + reference Sex Number Method of selection Number Method of selection Collection of data Schwartz et al., M.- 362 Admissions to hospitals in Paris and a 362 Healthy individuals admitted to same hos- Interviewed by team of 1961, few large provincial cities since 1954. pital because of work or traffie acci- specially trained inter- France (249). dents—matched by 5 year age group viewers who interviewed and time of admission. the largest proportion possible of all cancer patients. Cases and matched controls inter- viewed by same person Wynder and M. 150 Cancer patients seen in Memorial Hospi- 150 Patients seen in same hospitals during Data collected by trained Bross, tal, New York City, and Kingsbridge same time period with other tumors. interviewers. 1961, and Brooklyn VA _ Hospitals during 64%-malignant tumor; 36%-benign con- U.S.A. (810). 1950-59 (86% white). ditions. Matched by age with cancer patients. FR, 37 Same hospitals and same time period as 37 Same as with regard to male controls. male patients (86% white). 43% had malignant and 57% benign tumors. Wynder and M. 67 Admitted to Tata Memorial Hospital Bom- 134 Patients with other forms of cancer ex- Interviewed by one per- Bross, F. 27 bay. cept for oral cavity and lungs; as well son. 1961, as various benign diseases. 10% of male and 4% of India (810). female cancer cases histologically confirmed. Takano et al., M. 167 Patients with esophageal cancer. 167 Patients with cancerous and non-can- Interviews at various 1968, F. 33 33 cerous diseases of non-digestive organs, hospitals. Cases and Japan (272). controls age-matched. ZLE TABLE A31.—Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus (econt.) Author, year, Cases Controls country, al - reference Sex Number Method of selection Number Method of selection Collection of data Bradshaw and M. 98 Patients with esophageal cancer. 341 Patients with non-malignant disease. Hospital interviews by Schonland, trained African social 1969, workers. South Africa (41). Martinez, M. 120 Patients with confirmed epidermoid eso- 360 120 male, 59 female patients in same hos- Interviews by trained 1969, F, 59 phageal cancer diagnosed in 1966. VW pital with non-cancerous diagnoses. Puerto Rico personnel, 240 male, 118 female members from same (188). community. BLE TABLE A3la—Summary of results of retrospective studies of tobacco use and cancer of the esophagus Relative risk ratio. Author, Percent inhalers All smokers to year, Percent nonsmokers Percent heavy smokers among smokers nonsmokers country, Cases Controls All Heavy reference Cases Controls Cases Controls smokers smokers Sadowsky et al., 1953, 3.8 13.2 — _ — _ ~ 4.0 — U.S.A. (282). Sangvhi et al, 5.5 17.3 Average number of —- — 3.6 — 1955, bidis smoked India (241). 15.3 14.1 Wynder et al., M 13.0 24.0 1957, F (about) 85.0 (about) 92.0 — _ _ _ 2.1 — Sweden (322). —_ _ _ _— 2.0 _ Staszewski, _ 18.0 95.8 59.0 87.5 80.0 —_ _ i960, Poland (260). Schwartz et al., 3.0 17.0 Total amount amoked 39.0 38.0 6.6 —_ 1961, daily (cigarettes) France (249). 16.8 16.0 Wynder and Bross, American males 5.0 15.0 48.0 33.0 — _— 3.4 44 1961, U.S.A. and American females 41.0 78.0 27.0 16.0 — —_ 5.1 3.2 India (310). Indian males 13.0 28.0 — _ —_ —_ 2.6 _ Indian females 78.0 94.0 oo — _ _ 4.5 _ Takano et al., 17.0 23.0 — — — — 1.3 —_— 1963, Japan (272). Bradshaw and Schonland, 15.3 31.7 31.6 5.9 _— —_— 2.6 11.1 1969, South Africa (41). Martinez, 1969, 14.0 23.5 17.9 8.6 —_— — 1.8 3.5 Puerto Rico (183). 6Z€ TABLE A32,.—Atypical nuclei in basal cells of epithelium of esophagus of males, by smoking habits and age Never smoked Current regularly Cigarettes Ex-cigarettes Pipe, cigar Other Atypical nuclei Num- Per- Num- Per- Num- Per- Num- Per- Num- Per- ber cent ber cent ber cent ber cent ber cent . Allmen: Number men ...................... 91 _ 779 _ 181 ~ 89 _— 62 _ Total sections! 2.0... eee eee, 787 100.0 6,752 100.0 1,586 100.0 766 100.0 522 100.0 No atypical nuclei ................, 733 93.1 167 2.5 770 48.5 53 6.9 195 37.4 Some but <60 percent atypical ..... 52 6.6 5,389 79.8 165 48.3 688 89.8 37 60.7 60 percent or more atypical ........ 2 0.3 1,196 17.7 51 3.2 25 3.3 10 19 . Men under age 50: Numbermen ..............0.....0. 26 _— 236 _ 28 —_ 9 _ 7 —_ Total sections ...................., 223 100.0 2,059 100.0 258 100.6 V7 100.0 53 100.0 No atypical nuclei ................. 190 85.2 V1 3.4 56 21.7 1 1.3 4 5 Some but <60 percent atypical ...., 33 14.8 1,853 90.0 195 75.6 V4 96.1 46 86.8 60 percent or more atypical ......... —_— —_— 135 6.6 7 2.7 2 2.6 3 5.7 . Men aged 50-69: Numbermen ................. 0.005 44 —_ 445 cod 109 7 38 — 31 a Total sections os 379 100.0 3,853 100.0 953 100.0 310 100.0 256 100.0 No atypical nuclei 373 98.4 83 2.2 461 48.4 37 11.9 74 28.9 Some but <60 percent atypical 4 li 2,915 75.6 452 ATA 261 84.2 178 69.5 60 percent or more atypical 2 0.5 855 22.2 40 4.2 12 3.9 4 1.6 - Men aged 70 or older: Number men....... 21 —_— 98 _— 44 —_— 42 —_— 24 _ Total sections ..... : 185 100.0 840 100.0 375 100.0 379 100.0 213 100.0 No atypical nuclei 170 91.9 13 1.5 253 67.4 15 4.0 117 54.9 Some but <60 percent atypical 15 8.1 621 74.0 118 31.5 353 93.1 93 43.7 60 percent or more atypical _ _— 206 24.5 4 Ll MW 2.9 3 1.4 ‘Sections with some epithelium present. Source: Auerbach, O. et al. (15). ose TABLE A33.—Atypical nuclei in basal cells of cpithelium of esophagus of males, by anoint of smoking and age Current cigarette smokers Never smoked regularly <1 pack 1-2 packs >2 packs Cells with atypical nuelet ee RR TTT ee Number Percent Number Percent Number Pervent Number Percent . Allages . 91 see 179 413 _— 187 _ Total sections! 20... eee ee ete T87 100.0 1,544 100.0 3,629 100.0 1,579 100.0 No atypical nuclei... --. eee ee 733 93.1 89 5.8 39 1.1 139 2.5 Some but <60 percent atypical ....- 52 6.6 1,341 86.8 2,957 81.5 1,091 69.1 60 percent or more atypical .......- 2 0.3 114 TA 633 17.4 449 28.4 . Men under age 50: Number men 2.0... 0. eee eee 26 a 9 —_— 132 _— 55 - Total sections! 0.2... -. 6 ee eee eee 223 100.0 433 100.0 1,169 100.0 AST 100.0 No atypical nuclei ....---. eee ee ee 190 85.2 48 111 21 1.8 2 0.4 Some but <{60 percent atypical... 33 14.8 382 88.2 1,089 93.2 382 83.6 60 percent or more atypical .....--- tae wae 3 0.7 59 5.0 73 16.0 . Men aged 50-69: Number men... ee eee eee 44 ee 92 _ 240 a 113 —_ Total sections ! pee eee ee eee 379 100.0 789 100.0 2,116 100.0 948 100.0 No atypieal nuclei... 6.0. eee eee 3738 98.4 30 38 18 30.9 35 387 Some but <60 pereent atypical 4 lat 694 87.9 1,607 15.9 614 64.8 60 percent or more atypical 2 0.5 65 8.3 491 23.2 299 31.5 . Meu aged 70 or older: Number men... - eee eee eee 21 a 3s 41 _ 19 —_ Total sections! 0... ee ee eee eee 185 100.0 322 100.0 344 100.0 174 100.0 No atypical nuclei... 6. eee eee 170 91.9 11 3.4 —_ ~~ 2 12 Some but <60 percent atypical ....- 15 &.1 265 82.5 261 75.9 95 54.7 60 percent or more atypical .....--- a tae 46 14.3 Ks 24.1 q7 44.2 1 Sections with some epithelium present. Souree: Auerbach, O. et al. (15) l8¢e TABLE A35.—Summary of methods used in retr ospective studies of smoking and cancer of the bladder Author, year, Cases Controls country, — Te = reference Sex Number Method of selection Number Method of selection Lilienfeld et al., M. 321 Admissions to Roswell Park Memorial Institute. 337, No disease patients. 1956, 1945-55 over 45 years of age. U.S.A. (171). F. 116 Same as males ........00..000.00..000000000., 109 Benign bladder conditions. 317 No disease patients. Schwartz et al., M. 214 Admissions to hospitals in Paris and a few 214 Healthy individuals admitted to same hospital 1961, large provincial cities since 1954, because of work or traffic accident, matched France (249). by 5 year age group. Lockwood, M. 282 All bladder tumors reported to Danish Cancer 282 A. From election rolls matched with cases ac- 1961, F. 87 Register during 1942-56 and living at time RT cording to sex, age, marital status, occupa- Denmark (175). of interview in Copenhagen and Fredericks- tion, and residence. burg. (Includes bladder papillomas). B. Another control group obtained from sam- ple of Danish Morbidity Survey (1952, 1953, and 1954) compared with respect to smok- ing histories. Wynder, M. 200 First phase: 200 1963, F. 50 Admission to several hospitals in New 50 Admission to same hospitals (excluded cancer U.S.A. (826). York City during January 1957-Decem- of respiratory system, upper alimentary tract, ber 1960. myocardial infarction) matched by sex and Second phase: age. M. 100 Admission to same hospitals during 1961. 100 Same as above. F, 20 20 Cobb and Ansell, M. 136 Patients admitted to VA Hospital in Seattle 342 120 patients with eancer of sigmoid colon, 222 1965, U.S.A. (57). 1951-61. patients with non-neoplastic pulmonary dis- ease. zee TABLE A36.—Summary of methods used in retrospective studies of smoking and cancer of the bladder (cont.) Author, year, Cases Controls country, - ~ reference Sex Number Method of selection Number Method of selection Staszewski, M. 159 Patients with histologically confirmed bladder 750 Undefined source age-matched. 1966, carcinoma. Poland (261). Deeley and Cohen, M. 127 Patients with histologically confirmed bladder 127 Patients in same hospital with non-cancerous 1966, carcinoma. or pulmonary disease matched for age. England (66). Yoshida et al., M. 163 Patients with bladder cancer, 163 “Comparison cases.” 1968, F. 29 59 Japan ($30). Kida et a)., M. 88 Admissions to 15 hospitals in North Fukuoka 88 Selected from patients hospitalized in same re- 1968, F. 26 prefecture. 26 region for non-urinary ailments and age- Japan (144). matched Dunham et al., M. 334 Admissions to New Orleans hospitals with his- 350 Admissions to same hospitals with non-neoplas- 1968, F. 159 tologic diagnosis of bladder carcinoma. 177 tic diseases and diseases unrelated to geni- U.S.A. (85). tourinary tract. Anthony and Thomas, M. 381 Patients with papilloma and cancer of bladder 275 Surgical patients without cancer previously in- 1970, England (3). at Leeds betweeen 1958-67. terviewed for lung cancer study. ese TABLE A35a.—Summary of results of retrospective studies of Percent cigarettes smoking and cancer of the bladder Relative risk ratio: Author, Percent nonsmokers Percent heavy smokers smoked All smokers to nonsmokers year, — - country, All Heavy Cigarette Comments reference Sex Cases Controls Cases Controls Cases Contrels smokers smokers smokers Lilienfeld et al., M. 15.0 29.0 61.0 44.0 2.3 wee 2.9 Cigarette and other. 1956, F 87.0 83.0 1.4 U.S.A. (172). Schwartz et al., M 11.0 20.0 83.0 70.0 2 2.2 Cigarette only. 1961, France (249). Lockwood, M. 9:0 13.4 30.0 15.0 30.0 15.0 1.6 3.0 3.0 Cigarettes main mode of 1961, F. 56.0 66.0 4.0 4.0 1.5 1.2 smoking. Denmark (175). Wonder et al., M. 7.0 18.0 47.0 23.0 85.0 63.0 29 5.2 3.8 Phases A and B com- 1963, F, 61.0 86.0 6.0 3.9 tee wee bined. U.S.A. (826). Cobb and Ansell, M. 4.6 25.8 79.4 43.3 7.3 10.3 1965, ULS.A. (87). Staszewski, M. 6.7 16.0 85.7 65.7 87.1 72.2 24 3.1 2.9 Cigarettes only. 1966, Poland (261). Decley and Cohen, M. 2.4 TA 3.1 1966, England (66). bee TABLE A35a.—Summary of results of retrospective studies of smoking and cancer of the bladder (cont.) Percent cigarettes Relative risk ratio: Author, Percent nonsmokers Percent heavy smokers smoked All smokers to nonsmokers year, : - country, All Heavy Cigarette Comments reference Sex Cases Contrlos Cases Controls Cases Controls smokers smokers smokers Yoshida et al., M &.0 22.7 43.4 33.0 mo _ 3.4 3.7 _ 1968, F. 62.1 86.4 _ _ _ _ _ —_ _ Japan (330). Kida et al., M. 11.0 11.0 32.0 29.0 _ — 1.0 —_ _ 1968, F. 16.0 21.0 —_ _— _ —_ 1.4 _ —_ Japan (144). Dunham et al., M. 8.6 14.5 _ _ 49.4 45.4 1.8 _ 1.8 Cigarettes only. 1968, F. 62.2 61.5 _ _— 32.0 28.2 1.0 _ 11 U.S.A, (85). Anthony and F. 6.3 6.3 —_ —_ 36.5 29.1 1.0 _ 1.3 Cigarettes only. Thomas, More than 15 a day. 1970, England (3). CHAPTER 5 Pregnancy Contents Introduction 20... 0... cece eee eee eens Effect on birthweight ........ 00.00.0000 0c cece ccc eae Effect on outcome of pregnancy ................. 0000 0c Experimental studies ......0.0 0.000.000 ccc eee neces Summary ... cece ce eter een ene nens References 0.0.0... ccc cece eee ete nee e venus LIST OF TABLES 1. Summary of methods used in study of smoking and human PrEQNANCY 22... ee eee 2. Maternal smoking and infant weight ................ . Maternal smoking and prematurity ................0. 4, Comparison of abortion, stillbirth, and neonatal death in smoking and nonsmoking mothers ................00. Human experimental] data on smoking and pregnancy .. 6. Animal experimental data on the effect of smoking and nicotine on pregnancy ....... 0.0... c cece cece eves ae oO Page 389 389 390 407 415 415 391 397 400 405 408 411 INTRODUCTION In recent years, there has been increased research on environ- mental factors which may adversely affect the unborn child. The potential effect of maternal smoking on the fetus has been of par- ticular interest because of the large number of pregnant women who smoke and because smoking is an environmental influence which could be controlled. Based on 1970 surveys of smoking habits in representative samples of the U.S. population, it is estimated that one-third of American women in the child-bearing age group of 15 to 44 years are cigarette smokers. What propor- tion of these give up smoking or cut down substantially on their smoking during pregnancy is not known. EFFECT ON BIRTHWEIGHT Epidemiological and experimental studies have supported the view that maternal smoking during pregnancy exerts a retarding influence on fetal growth (tables 2, 6). Analvsis of over 100,000 births shows that the infants of mothers who smoke during preg- nancy have a mean birthweight of 6.1 ounces less than the infants born to nonsmoking mothers (table 2). Several studies have docu- mented that this effect is independent of other factors known to exert a negative influence on infant birthweight, such as elevated maternal] blood pressure and small maternal size (1, 36, 39). The reduction in infant birthweight is greater among heavy smoking mothers than light smoking mothers (12, 21, 23,80, 41,50, 58), and has been found in pregnancies terminating in each trimester (22, 16, 28, 40, 51,54). In a study of more than 48,000 women, Under- wood, et al. (51) demonstrated that infants born to women who smoked during part of their pregnancy were significantly smaller than infants born to nonsmokers, and that infants born to women who smoked throughout their pregnancy were significantly smaller than the infants born to women who smoked during part of their pregnancy. Russell, et al. (39) have presented evidence that al- though infants born to smoking mothers weighed less than those of nonsmoking mothers, they grew more rapidly during the first six months of life. At one year of age, children born to smoking mothers weighed nearly the same as those born to nonsmoking mothers. They concluded that smoking exerts a retarding influence 389 on fetal growth and that after delivery this is largely compensated for by a period of more rapid growth. As documented in more than 15 prospective and retrospective studies, smoking mothers have significantly more infants who are premature, as defined by weight alone (<2,500) grams, than do non- smoking mothers (table 3). Buncher (4) studied the mean dura- tion of pregnancy in smokers and nonsmokers in a survey which included 49,897 live births. He found that women smoking 20 cigarettes a day had a mean length of gestation which was approxi- mately one day shorter than that of nonsmoking women. He calcu- lated that this shortening cf gestation is enough to account for only 10 percent of the known reduction in birthweight that is associated with maternal smoking. EFFECT ON OUTCOME OF PREGNANCY Some controversy has surrounded the question of whether ma- ternal smoking during pregnancy is associated with an increased risk of spontaneous abortion, stillbirth, and neonatal death. Table 4 summarizes the studies which have dealt with this question, Some of the studies did not demonstrate such an increased risk (7, 34, 50, 51), while others did (12, 23, 33, 58). Many of these reports (7, 23, 83, 34, 41, 49, 58) were based on retrospective studies and included women delivering their infants in hospitals and infants whose names appeared on listings of newborn children (table 1). As Russell, et al. (39) have pointed out, such studies may be sub- ject to selective bias since they tend to underrepresent women who have aborted. These retrospective studies also did not systemat- ically control for maternal social class, parity, and maternal age, all of which are related to the outcome of pregnancy and also are related to smoking in some populations. In a prospective study of more than 2,000 pregnant women, Russell, et al. (39) have demon- strated a significantly higher percentage of unsuccessful pregnan- cies (that is, abortion, stillbirth, or neonatal death) among women who smoked during their pregnancy than among those who did not. He interpreted his findings to mean that 20 percent of “. .. un- successful pregnancies in women who smoke regularly would have been successful if the mother had not been a regular smoker” (38). The Second Report of the 1958 British Perinatal Mortality Sur- vey published in 1969 is one of the largest prospective studies to deal with this question (5). It included 98 percent of the total births registered during one week in March 1958 throughout England, Seotland, and Wales. In this study, a large amount of obstetric and sociobiologic information was obtained on 17,000 singleton births. This study reported that “the mortality in babies of smokers was significantly higher than in those of nonsmokers.” The increase in 390 16€ TABLE 1.—Summary of methods used in study of smoking and human pregnancy Author, year, Retrospective Number country, or ° Data collection Case selection Comments reference prospective persons Simpson, R. 7,499 Questionnaire was filled out 48 hours Multiple births excluded. The county hospital population 1957, after delivery for all patients at was different, with 50.6 per- U.S.A. (44). San Bernardino County Hospital cent of the births being for 3 years. Same form used for “Mexican’’. 2 years at St. Bernardines Hos- pital and Loma Linda Hospital. Lowe, R. 2,042 Questionnaire was filled out for every Non-Europeans and women with Social workers performed 1959, woman delivering at one of six twin births were excluded. interviews. England (28). Birmingham hospitals over a 5- month period. Frazier et al., P. 2,736 (a) Interview. All Negro women seen at Baltimore Nonsmokers include occasional 1961, (b) Prenatal clinic history. Maternity Interviewing Service in smokers. U.S.A, (12). (¢c) Birth and stillbirth certificates. 1959 who were scheduled for de- livery at Baltimore City Hospital and who received prenatal care in elinic of Baltimore City Health Department. Herriot et al., R. 2,745 Questionnaire filled out for Aber- 1962, deen city residents who were de- Scotland (16). livered in Aberdeen City Hospital over a l-year period. Savel and R, 1,415 1,500 consecutive patients admitted Included were private and ward pa- Women were considered Roth, to Newark Beth Israel Hospital tients, Negro and white patients, smokers even if they smoked 1962, were interviewed. primigravidas, and multiparas; only 1 cigarette per day. U.S.A. (41). Cesarean sections, elective indue- tions, and multiple pregnancies were excluded. c6E Author, TABLE 1.—Summary of methods used in study of smoking and human pregnancy (cont.) year, Retrospective Number country, or of Data collection Case selection Comments reference prospective persons Yerushalmy, P. 982 Form questionnaire. Pregnancies terminating in abortion 1962, were excluded. U.S.A. (53). Murdoch, R. 500 Personal interview by author. All mothers delivering at Nebraska 1963, Methodist Hospital from Septem- U.S.A. (80). ber 1962 to January 1963. O’Lane, R. 1,031 Standard U.S. Naval Obstetrical Code 1,031 Caucasian women who had “Smokers” defined as those iyo, Sheet was used with supplemental single pregnancies delivered va- smoking regularly each day. U.S.A. (93). questions. Additional information ginally over a 6-month period. was obtained from prenatal his- tory. Zabriskie, R. 2,000 History was obtained during the Twin deliveries were omitted. 1963, postpartum period from 2,000 con- U.S.A. (58), secutive births over a 6-month period. Yerushalmy, BP, 6,800 Personal interview. All women were members of Kaiser 5,381 whites 1,419 Negroes. 1964, Foundation Health Plan. Only U.S.A. (54). pregnancies terminating in single, live births included. All races ex- cept whites and Negroes were ex- cluded. MacMahon et al., R. 12,192 Mail questionnaire. Mothers of single, white, legitimate Birthweight based on birth 1965, U.S.A. (24). live births. Mothers were residents of Massachusetts and delivered in May or June of 1963. certificate. c6e TABLE 1.—Summary of methods used in study of smoking and human pregnancy (cont.) Author, year, Retrospective Wumber country, or of Data collection Case selection Comments reference prospective persons McDonald and P, 177 Interview. White, unmarried primigravidas re- Lanford, ceiving obstetric care over a 2- 1965, year period. U.S.A. (26). Peterson et al., R. 7,740 Cooperative study involving 17 hos- Includes only those multiparas whose 1965, pitals in 18 states, using U.S. Air prior infants weighed ‘>2,500 U.S.A. (34). Force obstetrical code. grams (Caucasians). All preg- nancies with any complication were excluded. Cesarean sections and induced delivery were ex- cluded. Robinson, P. 1,614 Interview. Regular attendees at prenatal clinic. 46.8 percent of women smoked 1965, cheroots. Burma ($7). Underwood et al., R. 4,440 Interview by obstetrical resident. Puerperal women from Roper Hos- Women from Roper Hospital 1965, Data was obtained on 16,158 preg- pital and Medical College Hospi- were of above average eco- U.S.A. (50). nancies from the 4,440 women. tal. Only infants weighing >1,000 nomic status. Women from grams were included. Medical College Hospital in- cluded Negro and white patients. Downing and R. 5,659 Review of clinic records from 1952 Six-year total of obstetrical patients Chapman, to 1958. at clinic. 1966, ULS.A. (7). P6e TABLE 1.—Summary of methods used in study of smoking and human pregnancy (cont.) Author, year, Retrospective Number eountry, or of Data collection Case selection Comments reference prospective persons Ravenholt et al., kh. 2,028 Epidemiologic questionnaire. Much Study population was identified by 95.4 percent of mothers were 1966, data collected over telephone. Ad- the listing of newborn infants in white. U.S.A. (35). ditional data obtained from birth a Seattle newspaper during May, certificates. June, and July of 1964. Twins were excluded. Reinke and R. 3,156 Registration data of prenatal clinic. Negro women who delivered single, Henderson live infants from 1962-64. 1966, U.S.A. (96). Kizer, 2,095 Interview. Patients receiving care at ‘‘concep- 1967, cion palacias’’ in Caracas. Venezuela (19). Underwood et al., Pr. 48,505 Code sheets submitted from 44 world- Women with single pregnancies de- 1967, wide naval installations. Code livered of infants weighing more U.S.A. (51). sheets were completed by the at- than 500 grams between July 1, tending physician upon the mo- 1963, and June 30, 1965. ther’s admission to the labor room. Duffus and R. 2,648 Antenatalclinic records. All ‘‘booked’” married city primi- The number of cigarettes MacGillivray, gravidae attending the antenatal smoked was not considered. 1968, clinics during 1960, 1964, and Seotland, (8). 1965. Mulcahy and R. 3,681 Hospital record review. Mothers admitted to the Coombe Knaggs, 1968, Ireland (28). Hospital from April 1963 to Oc- tober 1964. S6E TABLE 1.—Summary of methods used in study of smoking and human pregnancy (cont.) Author, year, Retrospective country, reference Russell et al., 1968, England (89). or prospective P. Number of persons 2,110 Data collection Data collected by Senior research midwives over a 4- to 5-year period. Case selection Women attending the two main ma- ternity units in Sheffield, who “comprised a reasonably repre- sentative sample.” Multiple preg- nancies were omitted. Comments Included some threatened abor- tions and some with “bad” obstetrical histories. Tokuhata, 1968, U.S.A. (49). 2,016 Personal interview or mail question- naire of surviving family members. Women selected from Memphis and Shelby County death registry who died of cancer of genitalia or breast since 1950 and who had been married. Control group taken from same registry. They died of causes other than cancer and were matched for race, age at death, and year of death. Buncher, 1969, ULS.A. (4). 49,897 Data obtained from U.S. Navy ob- stetrical study from 1963 to 1965. Smoking data obtained by physician at the time of mother's admission to labor room. Women with single pregnancies de- livered of infants weighing more than 500 grams between July 1, 1963, and June 30, 1965. Includes cases reported by Underwood et al. (47) in 1967. Butler and Alberman, 1969, Great Britain (5). 17,000 The British Perinatal Mortality Sur- vey of 1958 when a large amount of obstetric and sociobiclogic in- formation was obtained from birth attendants, records, and at inter- view with the mothers. 98 percent of the total births reg- istered during 1 week in March 1958 throughout England, Scot- land, and Wales. Another 7,000 perinatal deaths were surveyed by identical methods over a 8-month period. Terris and Gold, 197 Public Health Nurse interviewed each mother on first or second post- partum day. Premature Negro ward births (<2,500 grams) with no known cause of prematurity. Controls were matched by sex, birth order of infant, age, and marital status of the mother. 96£ TABLE 1.—Summary of methods used in study of smoking and human pregnancy (cont.) Author, year, Retrospective Number country, or of Data collection Case selection Comments reference prospective persons Mulcahy et al., P. 100 Interview by physician. 100 mothers of term infants who 1970, were free from all significant medi- Treland (29), ical and obstetrical complications. All were between 20 and 30 years of age and were Para III or less. All had norma! deliveries. Half were smokers of 10 or more ciga- rettes per day. L6E TABLE 2.—Maternal smoking and infant weight (Numbers in parentheses indicate absolute number of infants in respective groups) Infant weight Difference in mean weight of infant of smoker Comments Author, reference Nonsmoker Smoker versus nonsmoker Lowe (239) <10 cigarettes >10 cigarettes Effect on infant weight was independent per day per day of maternal age, parity, or complica- Male .. 7,43 Ibs. (607) 7.18 (187) 7.05 (165) tions of pregnancy. Female ...... 7.23 Ibs. (539) 6.74 (163) 6.67 (147) Total - 7.33 Ibs. (1,146) 6.98 (350) 6.87 (312) 170 g. (6 oz.) Frazier 3,080 g. (1,717) 2,924 ge. (1,019) 156g. (5.5 02.) Nonsmokers include occasional smokers. etal., (12). Herriot No data ............... (1,478) No data (1,272) 160g. (5.6 0z.) Effect on infant weight was independ- etal, ent of maternal age, parity, height, (16). or social class. Savel and White ........ 3,874 g¢. (383) 3,141 g. (428) 2332. (8.2 02.) Cigarettes Roth Negro 3,173 g (364) 3,031 g. (240) 142g. (5.0 02.) per day Infant weight (41). White smokers: 1-10) ............. 8,210. (161) 11-20 ............. 3,198 g. (184) 20 2... eee... 8,010 2. (83) Negro smokers: 1-10 ............. 8,042 g. (169) 11-20 -. 8,012 g. (57) >26 . 2,968 g. (14) Murdoch 7 Ibs. 7.5 oz. (242) 6 Ibs. 15 oz. (258) 8.5 oz. Cigarettes (30). per day Infant weight 1-10) ............ 7 Ibs. 202. 11-20) ............ 6 Ibs. 11 oz. 2000. ........... 6 Ibs. 10 02. 240 oo... ....... 6 Ibs. 8 oz. O’Lane 2,978 g. (566) 2,938 g. (465) 40g. (1.4 02.) (33), 86E TABLE 2.—Maternal smoking and infant weight (cont.) (Numbers in parentheses indicate absolute number of infants in respective groups) Infant weight Difference in mean weight. Author, of infant of smoker Comments reference Nonsmoker Smoker versus nonsmoker Zabriskie 3,820 ¢. (1,048) 3,091 g. (957) 229g. (8.1 02.) Cigarettes (58). per day Infant weight Ee | 3,205 g. (260) 10-20 ............. 8,090 g. (395) 20-30 1.00.22... 2,970 g¢. (264) >30 «1.2.2... 83,1908. (38) MacMahon Male ........ 124.0 0z. (8,053) 116.38 oz. (3,178) 7.7 oz. Cigarettes Infant weight et al., Female ...... 119.9 0z. (2,906) 111.9 oz. (3,011) 8.0 oz. per day (ounces) (24). Male Female 40 . 118.2 (66) 111.7 (49) McDonald Light smoker Heavy amoker No significant difference be- and 111.68 oz. (87) 110.83 oz. (42) 109.38 oz. (48) tween mean birthweights. Lanford (26). Underwood Cigarettes et al., Group: per day For >20 cigarettes per day Patients were divided into 8 groups: (50). ) 8,522 g. (2,406) <10 ........... 8,849 ge. 353 g. (12.5 0z.) (p<0.001) I....Private patients of above av- 10-20 ........... 3,236 g. ¢ (1,720) erage economic status. 200 ee eee ee 3,169 gr. Tl ....... 3,304 g. (557) <0 ........... 8,171 g. 212g. (7.50z.) (p<0.001) Il....White patients of average 10-20 ........... 8,146 g¢. (660) economic ,status. 20... 8,092 g. Ill ....... 3,126 g. (7,775) <10 «02.0.2... 2,988 g. 115g. (4.102.) (p<0.001) III,...Negro patients of low eco- 10-20 ........08. 2,965 g. £ (3,040) nomic status. 200 ........... 8,011 g. + Total for all smokers in each group. Ravenholt Male ......... 7.80 Ibs. (171) 7.21 Ibs. $(167) .59 Ibs. (9.4 02.) t+ Smoked >4,000 cigarettes during preg- et al., Female ...... 7.50 Ibs. (150) 7.05 Ibs. (171) .45 lbs. (7.2 02.) nancy. (35). 66€ TABLE 2.—Maternal smoking and infant weight (cont.) (Numbers in parentheses indicate absolute number of infants in respective groups) Infant weight Difference in mean weight Author, of infant of smoker Comments reference Nonsmoker Smoker versus nonsmoker Reinke and 8,135 g. (1,542) 2,987 g. (1,614) 148g. (5.2 02.) (p<0.001) a Henderson (86). Kizer (19). Data not available Data not available 97g. (3.4 02.) Total number of patients—2,095. Underwood Cigarettes etal., per day (51). 3,395 g. (24,865) 1-10 -. 3,286 g. (7,609) 109g. (3.8 oz.) 11-30 -. 8,196 g, (14,450) 199g. (7.002.) >30 . 8,182 g. (1,570) 213 ¢. (7.5 02.) Mulcahy 113.3 oz. Cigarettes and per day Knagegs 1- 4 seeees 111.4 02. 1.9 oz. (28). 5-9 Loe... 102.3 oz. 11.0 oz. 10-14 2... 102.0 oz. 11.3 oz. 15-19 wo... 102.9 oz. 10.4 oz. >20 - 102.4 oz, 10.9 oz. Russell BP The effect of maternal smoking on fetal et al., <140/ 90 117.2 J oz. (984) 107.2 + 1.0 oz. (496) 10.0 oz. weight was independent of maternal (89). 140/ 90 114.2 + 1.2 oz. (340) 108.9 + 2.4 oz. (117) 5.3 oz. parity, age, height, educational level, >150/100 99.8 + 2.6 oz. (188) 90.8 + 5.8 oz. (35) 8.5 oz. attitude to pregnancy or work during pregnancy, father's social class, con- sort’s social class, and sex of the child or premature delivery. Butler and 3,375 g@. (11,145) 3,205 g. (4,660) 170g. (6 072.) Reduction of mean birthweight of babies Alberman born to smokers was independent of (5). unduly high proportion of babies born preterm, and maternal! factors includ- ing social class and maternal height. Mulcahy 3.83 kg. (50) 3.43 kg. (50) 396 g. (14 oz.) et al., (29). oor TABLE 3.—Maternal smoking and prematurity (cont.) (Figures in parentheses are the absolute number of premature births) Premature by Author, — Percent of premature infants Mean duration of pregnancy reference Duration of — Comments Weight gestation Nonsmokers Smokers Nonsmokers Smokers Simpson <2,500 g. Name of hospital: Number and percent of (44). County .......... 7.77 (144) 11.48 (96) premature infants: Loma Linda ..... 6.16 (86) 12.13 (49) Nonsmokers .... 6.39 (328) St. Bernardines .. 5.21 (98) 10.50 (119) Cigarettes per day: 1-5 ....... 7.06 (47) 6-10 .....-11.18 (89) W1-15 0... 10.86 (31) 16-20 ......18.6 9 (77) 21-30 ......25.0 (11) >380 ....... 33.3 (9) Lowe <(260 days 6.4 (57) 10.6 (58) 279.9 days 278.5, days At each week of gestation, the (23). mean birthweight was lower in babies of smokers. Frazier <2,500 g. 11.2 (175) 18.6 (179) 88.7 weeks 38.4 weeks Infants of smokers weighed less et al., than infants of nonsmokers (12). for a wide range of preg- nancy duration. Herriot No data No data Social class: 2,745 patients in the study. etal., landIE ......... 4.0 4.8 At each week of gestation, the (16). TH oo... eee eee OB 6.8 mean birthweight was lower IVandV ........ 6.3 12.6 in babies of smokers. Savel and 36 weeks White .............8. 2.6 (10) 4.9 (21) White .39.8 39.4 Roth Negro ...........2-. 18.7 (50) 11.3 (27) Negro .38.8 38.8 4t). - aad #<(2,500 g. White . 18 (T) 3.7 (16) t+ Premature by weight but ma- Negro ..........-0005 3.6 (13) 8.3 (20) ture by date (>87 weeks). lov Premature by TABLE 3.—Maternal smoking and prematurity (Figures in parentheses are the absolute number of premature births) Author, —————— Percent of premature infants Mean duration of pregnancy reference Duration of a Comments Weight gestation Nonsmokers Smokers Nonsmokers Smokers Yerushalmy <514 lbs. 5.9 (36) 8.1 (30) (54). Murdoch <2,500 g. 3.3 (8) 13.6 (35) (30). O’Lane <2,500 g. 5.1 (29) 11.8 (55) (33). Zabriskie <2,500 ge. 3.83 (40) 9.93 (95) Cigarettes (58). per day: Prematurity <10 ........ 6.54 (260) 10-20 - 9.11 (395) 20-30 ......14.39 (264) >30 ........10.53 (38) Yerushalmy <5 Ibs. $ oz. White .. 3a (112) 6.4 (188) (p<0.01) Infants of smoking mothers (54). Negro . 49 (46) 18.4 (64) weighed less than infants of nonsmoking mothers in each gestational age. <(37 weeks White pee cease T5.9 (188) 6.5 (140) + Difference between smokers and Negro .. 13.4 (125) 16.7 (80) nonsmokers not significant. McDonald <2,500 g. Cigarettes per day and 4.6 (4) <10 48 (2) Lanford >10 8.3 (A) (26). Peterson <2,500 g. Cigarettes per day Overall incidence of prematurity etal, 2.5 (111) 1-10 3.0 (35) in smokers vs. nonsmokers (34). 11-20 4.8 (80) significant at p<0.001. (16) >20 3.4 cor TABLE 3.—Maternal smoking and prematurity (cont.) (Figures in parentheses are the absolute number of premature births) Premature by Author, Percent of premature infants Mean duration of pregnancy reference Duration of Comments Weight gestation Nonsmokers Smokers Nonsmokers Smokers Peterson <87 weeks Cigarettes per day et al., 1.3 (58) 1-10 1.4 (16) (contd.) 11-20 2.3 (38) (34). >20 2.4 (11) Robinson <2,500 g. 16.5 (152) 31.0 (181) (37). Underwood <2,500 g. Cigarettes per day Percentages and absolute num- etal., Group: ber of premature births are (50). I 4.5 (108) <10 4.2 based on 16,158 pregnancies 10-20 5.9 recorded in 4,440 women. <20 7.2 Group I. Smokers vs. non- u 71.5 (42) <10 12.6 smokers p<0.025. 10-20 12.8 Group II., III. Smokers vs. >20 15.9 nonsmokers p<0.001. TIT 9.9 (770) <10 14.1 10-20 14.8 >20 10.2 Downing No data No data 2.2 (66) 3.3 (88) and Chapman (7). Reinke and <2,500¢. 10.6 (163) 16.7 (270) 37.7 weeks 37.67 weeks p<0.001 Henderson <35 weeks 20.8 (313) 22.8 (368) p>0.05 (86). TABLE 3.—Maternal smoking and prematurity (cont.) (Figures in parentheses are the absolute number of premature births) Premature by £0p Author, a Percent of premature infants Mean duration of pregnancy reference Duration of Comments Weight gestation Nonsmokers Smokers Underwood = <2,500 g. Cigarettes per day Prematurity by birth weight rose et al., 5.7 (1,417) 1-10 7.6 (671) directly to a significant degree (51). 11-30 9.4 (1,358) (p<0.01) with each smoking >30 11.2 (176) category. <86 weeks 5.8 (1,442) 1-10 6.9 (525) Data suggested that smoking in 11-30 7.5 (1,084) any trimester decreased birth >30 7.5 (118) weight. Buncher 1 Smokes 20 cigarettes per day. (4). Female 39.69 weeks Butler and <2,500 g. 5.4 (602) 9.8 (433) Alberman (5). Terris A significant (p<0.01) difference and was found between percent of Gold mothers who smoked and (47). those who had premature deliveries and the control group. mortality rate was found for both stillbirths and neonatal deaths, and was somewhat greater for stillbirths but not significantly so (see Butler, tabie 4). The authors state that “...the differences between mortality rates in babies of smokers and nonsmokers prac- tically disappear when they are compared within groups of similar birthweights ... It therefore seems reasonable to conclude that the increased mortality found in babies of mothers who smoke is ac- counted for by the overall excess of low birthweight babies in this group...” with their attendant high risks. In 1964, Yerushalmy (54) reported on a group of 6,800 women whose pregnancies terminated in single, live births, excluding still- births and abortions. The study was prospective and was controlled for maternal age and parity. He noted that neonatal mortality in infants born to smoking mothers and weighing less than 2,500 grams was significantly less than that of small infants born to nonsmoking mothers. He referred to these small infants of smoking mothers as being “apparently healthier” than those infants weigh- ing less than 2,500 grams who were born to nonsmoking mothers. As this report showed, when compared to infants weighing more than 2,500 grams, a small (<2,500 grams) infant faces a greatly increased risk of neonatal mortality, whether it is born to a smok- ing mother or to a nonsmoking mother (54). The neonatal death rate for the small infants of smoking mothers was less than that for small infants of nonsmoking mothers, but neither group can be considered “healthy,” having sharply elevated death rates. The overall neonatal mortality for babies born to white smoking mothers was 12 percent higher than that for babies born to non- smoking mothers. This is not significantly greater than the neo- natal mortality of infants born to nonsmoking mothers. On the other hand it is also not significantly different from the 31 percent excess mortality reported by Butler, et al. (5), which is statistically significant. Interpretation of the neonatal mortality among the infants weighing less than 2,500 grams in the Yerushalmy study is dif- ficult. By considering only live births, the series may have included a higher proportion of infants whose smaller birthweight was pri- marily due to a modest growth retarding influence of maternal smoking and not to other more serious congenital defects and intra- uterine influences. Butler, et al. (5) have shown that smoking mothers have significantly more stillbirths than nonsmoking mothers, and Russell, et al. (29) have found this to be true for both stillbirths and abortions. For reasons which aren’t clear, smoking mothers have been found to have a reduced incidence of preeclamptic toxemia as com- pared to nonsmoking mothers (51). However, given the presence of 404 TABLE 4.—Comparison of abortion, stillbirth, and neonatal death in smoking and nonsmoking mothers NS = Nonsmokers SM = Smokers Sov Numbers Kates/1,Uuu total births Neonatal Neonatal Comments Author, Total births Abortions Stillbirths deaths deaths reference NS SM NS SM NS SM NS NS SM Lowe 1,155 668 t47 t Includes first-day (23). deaths. Frazier 1,717 1,019 fll F16 40 23.3 27.5 t “Fetal death”. et al., (12). Savel White and 383 428 2 3 4 10.4 47 Roth Negro (41). 364 240 8 4 5 13.7 12.5 O’Lane 1,027 887 91 112 (93). Zabriskie 2,850 2,769 250 348 (58). Yerushalmy White {54). 3,218 2,163 40 12.4 13.9 Negro 939 480 22 23,4 22.9 Peterson 4,455 3,285 4.0 0.9 etal. (34). 90P TABLE 4.—-Comparison of abortion, stillbirth, and neonatal death in smoking and nonsmoking mothers (cont.) NS = Nonsmokers SM = Smokers Numbers Rates/1,000 total births Neonatal Neonatal Comments Author, Total births Abortions Stillbirths deaths Abortions Stillbirths deaths reference NS SM NS SM NS SM NS SM NS SM NS SM NS SM Downing 3,029 2,630 126 107 $3820 t29 41.6 40.7 $10.6 t11.0 ¢ Stillbirth plus and neonatal death. Chapman (7). Tnderwond 24 ROR 23,620 8.4 8.7 T1230 F121 } Excludes perinatal et al., deaths in premature (51). infants (p>0.05). Russell TBP: t Includes abortion, etal., <140/90 984 496 727) $32 127 65 stillbirth, and ($9). ==140/90 340 117 $14 t8 41 68 neonatal death. >140/90 188 35 t20) «tit 145 314 { Blood pressure. Tokutata White Data based on use of (49). 2,555 743 $246) «$112 +96 151 cigarettes only. Nonwhite t Includes stillbirths 1,285 350 174 tée4 fl4i 183 and miscarriages. Butler 11,145 4,660 215 129 146 80 19.3 27.6 13.1 17.2 and Alberman (5). Source: Modified and expanded from Butler and Alberman (5). preeclampsia, smoking appears to increase the risk to the fetus be- cause of low birthweight and increased perinatal mortality (8). In a case-control study of sudden, unexpected death in infancy, Steele, et al. (46) observed that the percentage of smokers among mothers of cases of sudden, unexpected death, 61.2 percent, was significantly greater than the percentage among mothers of con- trols, 39.5 percent. The possible teratogenic effect of maternal smoking has not been adequately evaluated. Although it does not appear to be a major factor, there have been too few studies to determine whether ma- ternal smoking is a significant teratogenic risk (5, 23, 28, 50). Concern has been expressed about the possible long-term effects on the children of women who smoke during pregnancy. Butler (6) recently reported the results of a follow-up at age seven of the babies studied in the British Perinata] study of 1958. He found that the children of the mothers who were “heavy” smokers during pregnancy showed significantly decreased height, retardation of reading ability, and lower ratings on “social adjustment” than the children of nonsmoking mothers. The differences were independent of such factors as social class, age of mother, and parity. EXPERIMENTAL STUDIES In the past decade, research on the effect of smoking on pregnancy has increased. Summaries of human and animal experimental data in this area of study are found in tables 5 and 6. Elevated carbon monoxide levels have been found in maternal and fetal blood in women who smoke. Carbon monoxide is an inhibitor of carbonic anhydrase and as might be expected the activity of this enzyme is decreased in the cord blood of infants whose mothers smoke. The significance of elevated fetal carbon monoxide is not clear; how- ever, in an extensive monograph on this subject, Longo, (22) has concluded that “...the decreased availability of oxygen resulting from elevated (fetal) carboxyhemoglobin levels is probably in- jurious to fetal tissues.” Other changes noted in the infants of smoking mothers have included a mild metabolic acidosis and a higher mean hematocrit (56). Two studies (9, 52) have shown that placentas of women who smoke have a significantly greater ability to hydroxylate benzo[a]pyrene than the placentas from nonsmok- ers. Such findings suggest the possibility of fetal exposure to car- cinogens; however, the significance of these findings is presently speculative. Early animal studies (10, 42) showed that rats and rabbits ex- posed to nicotine or cigarette smoke have smaller offspring and more unsuccessful pregnancies than control animals. Recent radio- 407 80 TABLE 5.—Human experimental data on smoking and pregnancy Author, year, country, Design of study Results Comments reference Sontag and Fetal heart rate before and after smoking was Average fetal heart rate before smoking was 144.0. Wallace, studied 81 times in 5 patients. The average fetal heart rate for the eighth to the 1935, twelfth minute after starting to smoke was 149.0. ULS.A. (45). Hadden et al., Carbon monoxide levels were measured in 50 (a) Carbon monoxide levels were significantly 1961, smokers and nonsmokers in a prenatal clinic. (p<0.01) higher in smokers than in nonsmokers. U.S.A. (14). Twenty-six paired maternal and umbilical vein (8) Carbon monoxide concentrations in paired cord blood specimens were obtained at parturition and tested for CO levels. and maternal blood specimens were approximately equal, e) Oo; carrying capacity jin enrd and maternal blood was reduced in smokers compared to non- smokers. Heron, 1962, New Zealand (15). 58 pregnant smoking women were studied during labor to determine the effect which smoking might have on the ‘grading’ of the infant at birth. CO levels were measured in both mother and fetus. (a) CO levels in maternal and fetal blood were higher in patients who smoked. (b) Respirations in infants of mothers who smoked took longer to be established and peripheral cy- anosis was more common. A control group who had never smoked was compared with the survey group. Kumar and Zourlas, 1963, U.S.A. (20). The in vivo effects of cigarette smoking on uterine activity were studied in 17 pregnant gravidas near term and not in Jabor. The in vitro effect of nicotine on human pregnant and nonpreg- nant myometria] strips was studied. (a) In more than half (10/17), a definite increment in uterine activity was noticed during cigarette smoking. (b) Ne oxytocie effect of nicotine on myometrial strips was noted. Young and Pugh 1963, England (55). Blood CO levels were studied in 19 full-term par- turient women, 16 of whom had normal deliv- eries, Six of these smoked 10 to 20 cigarettes a day. Maternal blood was analyzed 15 to 30 minutes prior to delivery. Fetal blood was taken from the placental end of the umbilical vein. CO content of umbilical vein blood at normal deliv- eries was .52 and .36 volumes percent in infants of mothers who smoked and motherg who did not smoke, as compared with .33 and .28 volumes percent, respectively, in the maternal venous blood. Blood CO levels were also studied in non- smoking male labo- ratory workerg in London and in males in Antarctica. 607 Author, year, country, reference Mantell, 1964, New Zealand (25). Scoppetta, 1968, Italy (43). Younoszai et al., 1968, Canada (56). Engel et al., 1969, ULS.A. (9). TABLE 5.—Human experimental data on smoking and pregnancy (cont.) Design of study Cord bloods from 50 smokers and 50 nonsmokers were analyzed for carbonic anhydrase activity. CO concentrations were measured in the venous blocd of 46 pregnant women, including smokers and nonsmokers. Funicular venous blood was analyzed at the time of delivery. 32 women with normal pregnancies were studied of whom 16 smoked >20 cigarettes a day. Both groups of women had normal deliveries and healthy infants. Biochemical changes in the first 48 hours of life were studied in the infants. 37 experiments were performed on Placental blood samples obtained from 15 pregnancies to deter- mine relative affinity of human fetal Hb for CO and O,- Results A decrease in carbonic anhydrase activity in the cord bloods of infants whose mothers smoked was noted, CO levels were higher in smokers than in non- smokers. CO concentrations were approximately the same in maternal and funicular venous blood. (a) Mean CO saturation of Hb in the venous blood of the cigarette smoking mothers at the time of delivery was 8.3 percent and in the nonsmoking mothers 1.2 percent. The corresponding mean um- bilical vein blood levels were 7.3 percent and .7 percent, (6) The blood Ph, pCo,, and bicarbonate and lac- tate values in both groups of infants were within normal limits. (ce) The infants of smoking mothers showed a higher mean hematvcrit and mild metabolic acid- Osis. Human placental blood has a lower relative affinity for CO than adult bloed. It was calculated that the affinity constant of fetal Hb was approximately 20 percent less than that of Hb A. Comments Carbon monoxide is an inhibitor of carbonic anhydrase. Oly TABLE 5.—Human experimental data on smoking and pregnancy (cont.) Author, year, country, reference Design of study Results Comments Nebert et al.. 1969, U.S.A. (81), Aryl hydrocarbon hydroxylase activity was de- termined in the placentas obtained from 97 women at the time of childbirth; 46 of the women smoked between 20 and 40 cigarettes per day during pregnancy and 51 women were non- smokers. Significantly higher (p<0.001) levels of aryl hydro- carbon hydroxylase were found in women with a history of cigarette smoking. Welch et al., 1969, U.S.A. (52). Benzpyrene hydroxylase and aminoazo dye: N-demethylase activity was measured in 17 hu- man placentas obtained after childbirth from smokers and in 17 human placentas obtained from nonsmokers. Enzymes were found in the placentas from all 17 smokers. No detectable activity was observed in the placentas of nonsmokers. Ly TABLE 6.—Animal experimental data on the effect of smoking and nicotine on pregnancy Author, year, country, reference Animal Design of study Results Comments Essenberg et al., 1940, U.S.A. (10). Albino rat. 393 ‘‘young”’ from pregnant rats exposed to tobacco smoke and 113 young from preg- nant rats which received parenteral nico- tine were studied. The young of treated mothers were under- weight; the young from nicotine injected mothers were more underweight than those from smoked mothers. Increased fetal wast- age and neonata)] deaths were observed in treated animals as compared to controls. 113 “young” served as controls. Schoeneck, 1941, U.S.A. (42). Rabbit. Smoke from one cigarette was blown into the nostril of healthy does by means of a catheter each day. The does were ‘‘smoked” daily throughout pregnancy and lactation. 170 young from 28 litters of 7 “smoked” dees were studied. The offspring were not subjected to smoking at any time. (a) Offspring from “‘smoked’’ female rabbits were smaller at birth than controls (17 percent). (6) The stillbirth rate was 10 times as great in the “smoked” group. (c) The mortality rate was greater in the offspring of the ‘‘smoked’’ does. Litters from the pre- vious generation served as controls. Nishimura and Nakai, 1958, Japan (82). Mouse. 230 pregnant mice were injected, parenter- ally, with nicotine. Animals were sacrificed at term and mid-pregnancy to investigate the state of the pregnancy and the develop- ment of the offspring. Nicotine had a lethal effect upon mice em- bryos and also had a teratogenic effect on their skeletal systems. 225 full-term fetuses removed from 29 untreated mice were used as controls. Gatling, 1964, U.S.A. (18). Chick embryo. Chicken embryos were treated with doses of nicotine varying from 12 pe. to 1,000 pe. The effects of phenothiazines, corticoste- roids, and catecholamines were also studied. Nicotine induced cephalic hematoma forma- tion and central nervous system depression. aly Author, year, country, reference Becker and King, 1966, U.S.A. (2). Animal Design of study 100 primipara pregnant rats received a sin- gle heavy subcutaneous injection of nico- tine on the 21st day of pregnancy, one day prior to expected term delivery. Fetal wastage, weight of newborns, neonatal deaths, and pregnant animals’ responses were noted. Results {a) Mortality was greater among pregnant rats than among controls. {b) Pregnant rats showed more marked hy- perventilation and less body temperature depression than controls. (c) Delivery was delayed 2 to 4 days. (d) The young weighed less than normal and survived ‘‘poorly’’ during the first 48 hours of life TABLE 6.—Animal experimental data on the effect of smoking and nicotine on pregnancy (cont.) Comments 100 nonpregnant rats served as controls. King and Becker, 1966, US.A. (127). Pregnant and nonpregnant rats were in- jected subcutaneously with heavy doses of a 2 percent solution of pure nicotine for the purpose of determining the LD 0 for females of this strain (Osborne-Mendel). The LD,, for neonates of this strain was also determined within 6 to 24 hours of norma] birth. Osborne-Mendel rats LD, 9: mg./kg. Pregnant adults ................ 27.4 Nonpregnant females .......... 33.5 Neonates 2.0.0... -.. 0.0 c eee eee ee 14.55 Pregnant rats tended to die significantly later than nonpregnant rats, but their tolerance for nicotine was less. Mosier and Armstrong, 1967, U.S.A. (27). Alternate pregnant rats received oral nico tine in the dosage of either .05 mg./g. or 10 mg./g. of food. On the 20th day, the rats were killed and the fetuses were re- moved. (a) On higher nicotine intake, there was lowering of food intake. (6) There was no change in fetal weight or length on either concentration. (c) There appeared to be no effect on the number of live and “absorbing’’ fetuses. El TABLE 6.—Animal experimental data on the effect of smoking and nicotine on pregnancy (cont.) Author, year, country, reference Animal Design of study Results Comments Becker et al., Rat. 1968, U.S.A. (8). Controlled populations of pregnant rats were injected twice daily with doses of nicotine varying from .5 mg./kg. to 5 mg./kg. Ef- fects on pregnant rats and newborn were studied. (a) With the lower dosage of nicotine, the birthweights, survival, and developmental status did not differ from controls. (6) With thhe higher dosage, pregnant rats consumed less food and gained less weight than control mothers. Delivery dates were prolonged 2 to 4 days or more. Young were underweight and fetal in appearance. There were no abortions and no premature young. Contro] rats were in- jected with saline. Tialve et al., Mouse. 1968, Sweden (48). The passage of 'C-nicotine and its metabo- lites from the mother into the fetuses was studied. (a) Nicotine and its metabolites accumulated in the placenta and passed into the fetus. (6) The metabolites present in the fetus originated from the mother. (c) The passage of nicotine into the fetus was the same during the last four days of pregnancy. Fabro and Rabbit. Sieber, 1969, U.S.A. (11). (1-methyl-C)-caffeine and G-(°H)-nicotine were given to 6-day pregnant rabbits. The dose for nicotine was 50 ps-/ke., intra- venous, producing plasma levels similar to those attained in man by cigarette smok- ing (.06-.09 pe-/mi.). (a) One hour after (°H)-nicotine treatment, a high level of radioactivity compared with that in maternal plasma was found in uterine secretion (ratio = 10.8). (6) Unchanged radioactive nicotine and some of its metabolites were present in the pre- implantation blastocyst (blastocyst/plasma ratio = 3). Radioactivity in uterine secretion was not found in nonpregnant con- trols. ble Author, year, country, reference Welch et al., 1969, U.S.A. (52). Younoszai etal, 1969, Canada (57). Design of study Rats which were pregnant for 18 days were given 40 mg./kg. of 3,4-benzpyrene; 1,2- benzanthracene; 1,2,5,6-dibenzanthracene; chrysene; 3,4-benzofluorene; anthracene; pyrene; fluoranthene; perylene; or phen- anthrene orally, and BP-hydroxylase ac- tivity in the placenta was measured 24 hours later. Pregnant rats were exposed to smoke from regular tobacco cigarettes, non-nicotine cig- arettes made with lettuce leaves, and non- nicotine cigarettes (lettuce leaves) to which 15 mg. of nicotine was added. The rats were forced to inhale cigarette smoke by placing their cages in a smoking chamber. CO levels were maintained between 2 and & percent by exposing the animals to smoke 5 times a day at 2-hour intervals. Other groups of rats were fed restricted diets, receiving from 55 to 80 percent of the food consumed by control rats. Results All compounds tested stimulated: BP-hydroxylase activity in the placenta. 1,2-benzanthracene was the most active in- ducer of BP-hydroxylase. (a) Fetuses of all smoked rats were growth retarded compared to control animals, those exposed to tobacco smoke (cigarette) being most severely affected. (b) The amount of food consumed by rats exposed tu cigarette smoke was reduced. (c) There was a significant direct relation between fetal body weight and the average amount of food eaten during pregnancy. (d) Fetal weight was reduced in prpportion to the decrease in maternal food intake in the two groups of rats exposed to the let- tuce leaf cigarette smoke. In rats exposed to tobacco cigarettes, fetal weight was re- duced more than expected from the de- crease in maternal food intake. TABLE 6.—Animal experimental data on the effect of smoking and nicotine on pregnancy (cont.) Comments Placenta from control rats possessed very low BP-hydroxylase activity. Control rats were handled in the same way except that they were not ex- posed to cigarette smoke. Canada (51). Kirschbaum et al., 1970, U.S.A. (18). Intravenous injection of fresh solutions of nicotine, and simulated smoking of ciga- rettes, were carried out upon pregnant ewes. Cardiovascular functions, including gaseous exchange and blood flow of both the ewes and their fetuses were studied for acute effects. No significant changes were observed as a result of either nicotine administration or smoke inhalation. Eath experiment in- eluded a control period during which attainment of a steady state was the aim. isotope studies in mice (48) have indicated that nicotine and its metabolites accumulate in the placenta and are passed into the fetus. Many of the experimental studies were designed to determine the pathophysiology of the effect of maternal smoking on the fetus. The experimental conditions in the several studies varied greatly as did the results. No unified concept of the effect of maternal smoking on fetal growth or on the outcome of pregnancy can be derived from the presently available research. SUMMARY Maternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birthweight and an increased incidence of prematurity, defined by weight alone. There is strong evidence to support the view that smoking mothers have a significantly greater number of unsuccessful pregnancies due to stillbirth and neonatal death as compared to nonsmoking mothers. There is insufficient evidence to support a comparable statement for abortions. The recently published Second Report of the 1958 British Perinatal Mortality Survey, a carefully designed and controlled prospective study involving large numbers of pa- tients, adds further support to these conclusions. REFERENCES (1) ABERNATHY, J. R., GREENBERG, B. G., WELLS, H. B., FRAZIER, T. M. Smoking as an independent variable in a multiple regression analysis upon birth weight and gestation. American Journal of Public Health and the Nation’s Health 56(4) : 626-633, April 1966. (2) Becker, R. F., KING, J. E. Studies on nicotine absorption during preg- nancy. II. The effects of acute heavy doses on mother and neonates. American Journal of Obstetrics and Gynecology 95(3) : 515-522, June 15, 1966. (8) Becker, R. F., Lirtie, C. R. D., Kine, J. E. Experimental studies on nicotine absorption in rats during pregnancy. III. Effect of sub- cutaneous injection of small chronic doses upon mother, fetus, and neonate. American Journal of Obstetrics and Gynecology 100(7): 957-968, April 1, 1968. (4) Buncuer, C. R. Cigarette smoking and duration of pregnancy. American Journal of Obstetrics and Gynecology 103(7) : 942-946, April 1, 1969. (5) Butier, N. R., ALBERMAN, E. D. (Editors). The effects of smoking in pregnancy. Chapter 5. IN: Perinatal Problems. Edinburgh, E. & S. Livingstone, Ltd., 1969. pp. 72-84. (6) BuTLER, N. R. A national long term study of perinatal hazards. Pre- sented at the Sixth World Congress of Gynaecology and Obstetrics, New York, April 12-18, 1970, 11 pp. (7) Downina, G. C., CHapMan, W. E. Smoking and pregnancy. A statistical study of 5,659 patients. California Medicine 104 (3) : 187, March 1966, 415 (8) (9) (10) (11) (12) (18) (14) (15) (16) (17) (78) (19) (20) (21) (22) (22) (24) (25) 416 Durrus, G. M., MacGmtiivray, I. The incidence of pre-eclamptic toxaemia in smokers and nonsmokers. Lancet 1(7550) : 994-995, May 11, 1968. ENGEL, R. R., RopKEy, F. L., O’NEaL, J. D., CoLiison, H. A. Relative affinity of human fetal hemoglobin for carbon monoxide and oxygen. Blood 33(1): 37-45, January 1969. ESSENBERG, J. M., SCHWIND, J. V., Patras, A. R. The effects of nicotine and cigarette smoke on pregnant female albino rats and their off— springs. Journal of Laboratory and Clinical Medicine 25: 708-717, 1940. Fasro, S., SIEBER, S. M. Caffeine and nicotine penetrate the pre-implan- tation blastocyst. Nature 223 (5204): 410-411, July 26, 1969. FRAZIER, T. M., Davis, G. H., GOLDSTEIN, H., GOLDBERG, I. D. Cigarette smoking and prematurity: A prospective study. American Journal of Obstetrics and Gynecology 81(5) : 988-996, May 1961, GATLING, R. R. Effect of nicotine on chick embryo. Archives of Pathology 78(6) : 652-657, December 1964. Happon, W., Jz., NESBITT, R. E. L., Garcia, R. Smoking and pregnancy: Carbon monoxide in blood during gestation and at term. Obstetrics and Gynecology 18(3) : 262-267, September 1961. HERON, H. J. The effects of smoking during pregnancy: A review with a preview. New Zealand Medical Journal 61:545-548, November 1962. HergIoTT, A., BILLEWIcz, W. Z., HyTTen, F. E. Cigarette smoking in pregnancy. Lancet 1: 771-773, April 14, 1962. KING, J. E., BECKER, R. F. Studies on nicotine absorption during preg- nancy. I. LD.,: for pregnant and nonpregnant rats. American Journal of Obstetrics and Gynecology 95 (4): 508-514, June 15, 1966. KirscuBauM, T. H., Divts, P. V., JR., BRINKMAN, C. R., III. Some acute effects of smoking in sheep and their fetuses. Obstetrics and Gynecol- ogy 35(4): 527-536, April 1970. Kizer, S. Influencia del habito de fumar sobre el embarazo, parto y recien nacido. (Effect of the smoking habit on pregnancy, delivery, and the newborn.) Revista de Obstetricia y Ginecologia de Venezuela 27(4): 595-648, 1967. Kumar, D., Zourvas, P. A. Studies on human premature births. II, Jn vivo effect of smoking and in vitro effect of nicotine on human uterine contractility. American Journal of Obstetrics and Gynecology 87(3): 413-417, October 1, 1963. Lasz.o, V. A dohanyzas karos hatasai a gestatios folyamatokra, (The deleterious effects of smoking on the sequences of gestation.) Magyar Noorvosok Lapja 32(2): 168-167, March 1969, Lonco, L. D. Carbon monoxide in the pregnant mother and fetus, and its exchange across the placenta. Annals of the New York Academy of Sciences 174(1): 313-341, October 5, 1970. Lowe, C. R. Effect of mothers’ smoking habits on birth weight of their children. British Medical Journal] 2: 673-676, October 10, 1959. MACMAHnown, B., ALPERT, M., Sarper, E. J. Infant weight and parental smoking habits. American Journal of Epidemiology 82(3): 247-261, November 1963. MANTELL, C. D. Smoking in pregnancy: The role played by carbonic anhydrase. New Zealand Medical Journal 63: 601-603, September 1964. (26) (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) (43) McDona cp, R. L., LANFORD, C. F. Effects of smoking on selected clinical obstetric factors. Obstetrics and Gynecology 26 (4) : 470-475, October 1965. Mosier, H. D., Jr., ARMSTRONG, M. K. Effect of maternal nicotine intake on fetal weight and length in rats. Proceedings of the Society for Experimental Biology and Medicine 124 (4): 1135-1137, April 1967. Muccany, R., Knaces, J. F. Effect of age, parity, and cigarette smoking on outcome of pregnancy. American Journal of Obstetrics and Gyne- cology 101(6) : 844-849, July 15, 1968, MuLcany, R., Murpuy, J., Martin, F. Placental changes and maternal weight in smoking and nonsmoking mothers. American Journal of Ob- stetrics and Gynecology 106 (5) : 703-704, March 1, 1970, Murbocu, D. E. Birth weight and smoking. Nebraska State Medical Journal 48(11): 604-606, November 1968. NeBert, D. W., Winker, J., GELBOIN, H. V. Aryl hydrocarbon hydro- xylase activity in human placenta from cigarette smoking and non- smoking women. Cancer Research 29(10) : 17638-1769, October 1969. NIsHimura, H., Nakal, K. Developmental anomalies in offspring of pregnant mice treated with nicotine. Science 127 (8308) : 877-878, April 18, 1958. O’LANE, J. M. Some fetal effects of maternal cigarette smoking. Obstet- rics and Gynecology 22(2): 181-184, August 1963. PETERSON, W. F’., MorESE, K. N., KALTREIDER, D. F. Smoking and pre- maturity. A preliminary report based on study of 7,740 Caucasians. Obstetrics and Gynecology 26(6) : 775-779, December 1965. RAVENHOLT, R. T., LEVINSKI, M. J., NELLIST, D. J., TAKENAGA, M. Effects of smoking upon reproduction. American Journal of Obstetrics and Gynecology 96 (2): 267-281, September 15, 1966. REINKE, W. A., HENDERSON, M. Smoking and prematurity in the pres- ence of other variables. Archives of Environmental Health 12(5): 600-606, May 1966. RosBINsoN, P. ’Yshwn nshym Bwrmmywt vamn hhrywn whshp’tw ’1 h’m h’wbr whylwd. (Smoking by Burmese women during pregnancy and its influence on the mother, the fetus and the newborn.) Harefuah 69(2): 37-89, 1965. RUSSELL, C. S. Another hazard of smoking. New Scientist 41(631) : 64— 65, January 9, 1969. RUSSELL, C. S., TAYLor, R., Law, C. E. Smoking in pregnancy, maternal blood pressure, pregnancy outcome, baby weight and growth, and other related factors, A prospective study. British Journal of Preven- tive and Social Medicine 22(3) : 119-126, July 1968. RUSSELL, C. S., Taytor, R., Mappison, R. N. Some effects of smoking in pregnancy. Journal of Obstetrics and Gynecology of the British Com- monwealth 73: 742-746, October 1966. SAVEL, L. E., Rotu, E. Effects of smoking in pregnancy: A continuing retrospective study. Obstetrics and Gynecology 20(3): 313-316, September 1962. SCHOENECK, F. J. Cigarette smoking in pregnancy. New York State Journal of Medicine 41: 1945-1948, October 1, 1941. Scopretta, V. Sul contenuto di ossido di carbonio nel sangue circolante di gestanti fumatrici. (Carbon monoxide content in the blood circu- 417 (44) (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56) (57) (58) 418 lating in pregnant smckers.) Archivio di Ostetricia e Ginecologia 73 (3): 869-375, May-June 1968. SIMPson, W. J. A preliminary report on cigarette smoking and the incidence of prematurity. American Journal of Obstetrics and Gyne- cology 73(4): 808-815, April 1957. Sontac, L. W., WALLACE, R. F. The effect of cigarette smoking during pregnancy upon the fetal heart rate. American Journal of Obstetrics and Gynecology 29: 77-83, 1935. STEELE, R., LaNGworru, J. T. The relationship of antenatal and post- natal factors to sudden unexpected death in infancy. Canadian Medi- eal Association Journal 94: 1165-1171, May 28, 1966. TERRIS, M., GoLp, E. M. Ar epidemiologic study of prematurity. I. Rela- tion to smoking, heart volume, employment, and physique. American Journal of Obstetrics and Gynecology 103(8) : 358-370, February 1, 1969. TJALVE, H., Hansson, E., SCHMITERLOW, C. G. Passage of ?‘C-nicotine and its metabolites into mice foetuses and placentae. Acta Pharma- cologica et Toxicologica 26(6) : 539-555, 1968. TokunaTa, G. K. Smoking in relation to infertility and fetal loss. Archives of Environmental Health 17(3): 853-359, September 1968. UNDERWOOD, P. B., HESTER, L. L., LaFirteE, T., JR., GREGG, K. V. The relationship of smoking to the outcome of pregnancy. American Journal of Obstetrics and Gynecology 91(2): 270-276, January 15, 1965. UNDERWoop, P. B., Kesimr, K. F., O’LANE, J. M., CALLAGAN, D. A. Parental smoking empirically related to pregnancy outcome. Obstet- rics and Gynecology 29(1): 1-8, January 1967. WELCH, R. M., HARRISON, Y. E., GomMI, B. W., Poppers, P. J., FINSTER, M., Connery, A. H. Stimulatory effect of cigarette smoking on the hydroxylation of 3,4-benzpyrene and the N-demethylation of 3-methyl- 4-monomethylaminoazobenzene by enzymes in human placenta. Clini- cal Pharmacology and Therapeutics 10(1): 100-109, January- February 1969. YERUSHALMY, J. Statistical considerations and evaluation of epidemio- logical evidence. IN: James, G., Rosenthal, T. (Editors). Tobaeco and Health. Springfield, Charles C. Thomas, 1962. pp. 208-230. YERUSHALMY, J. Mother’s cigarette smoking and survival of infant. American Journal of Obstetrics and Gynecology 88(4): 505-518, February 15, 1964. Young, J. M., Pucu, L. G. C. E. The carbon monoxide content of foetal and maternal blood. Journal of Obstetrics and Gynecology of the British Commonwealth 7( (4): 681-684, 1963. Younoszal, M. K., Kacic, A., HAWorTH, J. C. Cigarette smoking during pregnancy: The effect upon the hematocrit and acid-base balance of the newborn infant. Canadian Medical Association Journal 99(5): 197-200, August 3, 1968. Younoszal, M. K., PEtoso, J., HAworru, J. C. Fetal growth retardation in rats exposed to cigarette smoke during pregnancy. American Jour- nal of Obstetrics and Gynecology 104(8) : 1207-1213, August 15, 1969. ZABRISKIE, J. R. Effect of cigarette smoking during pregnancy. Study of 2,000 cases. Obstetrics and Gynecology 21(4): 405-411, April 1963. CHAPTER 6 Peptic Ulcer Contents Page Summary 1.6... 0. ce eee cette etter nens 423 References 2.0.0... ccc ccc ccc eee een ene ne eeae 429 LIST OF TABLES . Smoking and peptic ulcer disease mortality ........... 424 . Summary of results of retrospective and cross sectional studies of peptic ulcer and smoking .................. 425 . Methods used in retrospective and cross sectional studies of peptic ulcer and smoking ................. 0.0000 427 421 PEPTIC ULCER It has been estimated that 10 to 12 percent of all people will suf- fer from peptic ulcer disease at some time in their lives (17). In the U.S.A. in 1967, there were 5,323 deaths from gastric ulcer and 4,502 deaths from duodenal ulcer (22). Several studies have docu- mented an association between smoking and peptic ulcer disease, which is stronger for gastric ulcer than for duodenal ulcer. Prospective studies indicate that male cigarette smokers have increased peptic ulcer mortality ratios (see table 1). Although a trend toward increased mortality from gastric ulcer is seen in cigar and/or pipe smokers, the data do not allow significant conclusions to be drawn. Similarly, no firm conclusions can be drawn about female smokers, Retrospective studies have consistently shown smaller numbers of nonsmokers in the peptic ulcer groups than in matched control populations (tables 2 and 3), Cigarette smoking has been shown to reduce the efficacy of antacid therapy in documented peptic disease (3) and to slow peptic uleer healing (7). One study indicated that smokers who had undergone surgical treatment for their peptic disease had more major complications, including recurrence of peptic disease, than nonsmokers (14). Numerous studies in both animals and man have been performed to investigate the effect of smoking or the administration of nico- tine on the gastrointestinal tract. Studies of gastric secretion and motility in normal controls and in patients with peptic ulcer dis- ease as well as in experimental animals have produced conflicting results (4, 16, 18, 19, 20). SUMMARY Cigarette smoking males have an increased prevalence of peptic ulcer disease and a greater peptic ulcer mortality ratio. These rela- tionships are stronger for gastric ulcer than for duodenal ulcer. Smoking appears to reduce the effectiveness of standard peptic ulcer treatment and to slow the rate of ulcer healing. 423 ver TABLE 1.—Smoking and peptic ulcer disease mortality (Numbers in parentheses represent actual number of deaths) SM = Smokers NS = Nonsmokers G = Gastric D = Duodenal Author, Mortality ratios year, Number and Data Actual country, type of collection deaths Cigarettes/day Pipe Cigar Comments reference population SM NS Gastric Duodenal Gastric Duodenal Gastric Duodenal Doll and 41,000 male Questionnaire 54 tPeptic Pipe/cigar t+ Total number of Hill, British and follow-up NS 1.00 4.00 deaths were too 1964, physicians. of death All cigarette 7.00 small to allow Great certificate. 1-14 gs. per day 2.33 separate examin- Britain 15-24 10.33 ations. (5, 6). >25 7.33 Hammond; 440,658 Interviews by G-83 ..11 NS .......... 1.00 (11) 1.00 (22) 1988, males 35- ACS volunteers D-93 ..22 SM (awe 45-64) 2.95) ... 2.86)... U.S.A. 84 years of SM (age 65-79) 4.06( ‘°°’ 1.50¢°"°? (11). age in 25 States. Kahn, U.S. male Questionnaire G-78 ...... 12 NS ...........0. 1.00(12) 1.00(25) 1.00(12) 1.00(25) 1.00(12) 1.00(25) 1966, veterans and follow-up D-119 -25 SM 2.84 (4) 1.59 (5) 2.90 (7) 1.58 (8) U.S.A. 2,265,674 of death All cigarette . 4.18(389) 2.98 (57) (12). person years. certificate. 5: rr 3.95 (5) 2.30 (6) 10-20 .......... 2.77(18) 2.74(26) 21-39 .- 5.45(15) 3.98 (22) >39 ». 11.57 (6) 2.89 (3) Weir and 68,153 males Questionnaire 44 NS oo. 1.00 No deaths from Dunn, in various and follow-up All cigarette a 0.53 gastric ulcer oc- 1970, occupations of death 10 woe ee eee 1.00 0.40 curred in non- U.S.A. in California. certificate. #20 1.67 0.59 smokers and risk (28). 230 2.38 0.32 of those smoking £10/day was set at 1.00. NS in- cluded pipe, cigar, and ex-smokers. Sty TABLE 2.—Methods used in retrospective and cross sectional studies of peptie uleer and smoking Author, year, Controls country, Cases Comments reference Sex Number Method of selection Number Method of selection Barnett, M 66 Gastric. Patients admitted between 1913 and 500 Selected at random from the gen- 1. Retrospective review 1927, 178 Duodenal 1926. Only cases with complete eral admissions-males, 20-60 years records at Peter Bent U.S.A. (2). smoking history selected. of age. Brigham Hospital. 2. Uleer diagnosis prob- ably well established. Trowell, M 50 Duodenal Not stated 400 Selected at random from wards of 1. Interviewed by inves- 1934, a general hospital. tigator. England 2. Uleer diagnosis con- (21). firmed by X-ray and/or surgery. Allibone and MandF 107 Consecutive admissions to hospital 107 Matched by age, sex, and time of Patients and controls in- Flint, of patients with gastric and du- admission from acute general sur- terviewed by same 1958, odenal hemorrhage or perforation. gical emergency admissions. observer. England (2). Doll et al., MandF 327 Gastric. Ulcer patients in Doll and Hill Lung 1,143 Patients with non-ulcer diseases. 1. Same interviewers and 1958, 338 Duodenal. Cancer Study plus additional pa- Each case matched with 2 con- questionnaire in cases England tients in Central Middlesex Hospi- trol patients of same sex, 5-year and controls. (7). tal. age group, and same type of 2. Ulcer diagnosis prob- Place of residence. Male patients matched by social class. ably well established, Edwards et al., 1959, England (8). M 1,737 Men aged 60 and over on 11 General Practioners’ lists were examined and interviewed by these practi- tioners. Represents about 84 per- cent of all such men on_ these lists. (9 percent non-response due to death and/or untraced.) Of 143 considered to have a peptic ulcer, 53 were confirmed by X-ray. 9otH TABLE 2. Methods used in retrospective and cross sectional studies of peptic ulcer and smoking (cont.) Author, year, Controls country, Sex Number Method of selection Comments reference Number Method of selection Kasanen and M 43 Gastric. Successive male admissions with pep- 100 Successive men treated at medical A special questionnaire Forsstrém, 57 Duodenal. tic ulcer treated at medical clinic clinic who had no gastrointestinal was used for the 1966, or outpatient department of Uni- symptoms or signs of CHD. interview. Finland versity Hospital. Only patients (13). under 65 years of age or those who had been working were in- cluded. Gillies and Mand F 100 Gastric. Patients with peptic uleer were se- 150 Matched by age and sex from the Diagnosis well established Skyring, 60 Duodenal. lected from hospital admissions in same ward at the same time and with X-ray, gastros- 1968, 1967. with absence of signs or symp- copy, or surgery. 1968, toms or past history of upper Australia gastrointestinal disease. (9). Gillies and MandF 10 Gastric. 1,405 workers from a broadcasting 100 Two contro] groups: All information obtained Skyring, 48 Duodenal. company, a manufacturing com- 1. 100 peptic ulcer patients pre- by question card. All 1969, 18 Uncertain pany, and a bus company were viously reported by authors. ulcers were proved by Australia location. interviewed for a history of pep- 1,829 2. 1,829 workers without ulcer. X-ray or surgery. (10). tic ulcer. Monson, MandF 52 Gastric. 643 physicians from Massachusetts 625 Controls were physicians without Diagnosis established by 1970, 452 Duodenal. who responded affirmatively to a ulcer disease who were matched X-ray or surgery except ULS.A, (15). 139 Not questionnaire sent to them in 1967 to ulcer patients by year of birth. for 46 “clinica]” cases. specified. asking how many had had a pep- tic ucer. Ltr TABLE 3.—Summary of results of retrospective and cross sectional studies of peptic ulcer and smoking Author, year, Percent nonsmoker Amount of tobacco used country, reference Cases Controls Cases Controls Barnett, Total .......... 18.0 25.0 1927, Gastric ........ 15.0 U.S.A. Duodenal ...... 20.0 (2). Trowell, Duodenal ...... 8.0 17.0 Average number: 1934, Cigarettes .. 12.0 perday..........11.1 per day England Pipe ....... 1.6 ounces per week.. 2.15 ounces per week (21). Allibone and 38.0 54.0 Flint, 1958, England (1). Doll et al., Gastric: Gastric: Percent amoking >>25 cigarettes per day 1958, Males ..... 1.3 47 Males ...... 10.6 11.3 England Females ... 51.1 66.8 Females .... 1.1 11 (7). Duodenal: Duodenal: Males ..... 2.1 5.8 Males ...... 10.2 12.7 Females ... 53.7 62.0 Females .... 1.9 1.9 Edwards Percent of peptic ulcer by etal, smoking category 1959, Never smoked ...........-¢2005- 6.0 England Formerly smoked .......--+025. 6.9 (8). Cigarettes: 1-9 perday .............. 9.4 10-19 perday .............. 9.8 >>20 per day ............4.- 12.0 Pipe oo. c cee cece eee e reece 6.5 Pipe and cigarettes 8.5 St TABLE 3.—Summary of results of retrospective and cross sectional studies of peptic ulcer and smoking (cont.) Author, year, Percent nonsmoker Amount of tobacco used country, — reference Cases Controls Cases Controls Kasanen “Peptic” . 10.0 40.0 Cigarettes per day: and <10 ......., 10.0 7.0 Forsstr5m, 10-20 ...... 19.0 17.0 1966, 20 we... eee 42.0 26.0 Finland 20 2... 19.0 10.0 {78). Gillies and Gastric -». 18.0 44.0 Mean number cigarettes per day: Skyring, Duodenal - 62.0 71.0 Gastric .... 23.3 17.1 1968, Duodenal .. 23.2 23.0 Australia Duration of smoking (years) : (9). Gastric .... 30.2 28.0 Duodenal .. 24.2 28.2 Gillies and Gastric +. 179 55.6 Skyring, Duodenal - 36.6 1969, Australia (20). Monson, Duodenal - 82.1 46.7 Percent smoking >20 1970, Gastric ........ 19.2 cigarettes per day U.S.A. Not Specified . 43.2 Age: Gastric Duodenal (15). P| 38.8 27.3 30.1 30 oo... eee 45.7 43.0 47.1 45 Lo... 60.2 49.5 46.9 60 ......... B41 40.4 44.0 REFERENCES (1) ALLIBONE, A., FLINT, F. J. Bronchitis, aspirin, smoking, and other fac- tors in the aetiology of peptic ulcer. Lancet 2: 179-182, July 26, 1958. (2) BARNETT, C. W. Tobacco smoking as a factor in the production of peptic ulcer and gastric neurosis. Boston Medical and Surgical Journal 197 (12) : 457-459, September 22, 1927. (3) BATTERMAN, R. C, EHRENFELD, I. The influence of smoking upon the management of the peptic ulcer patient. Gastroenterology 12 (4) : 575- 585, April 1949. (4) Cooper, P., Knicut, J. B., JR. Effect of cigarette smoking on gastric secretions of patients with duodenal ulcer. New England. Journal of Medicine 255(1): 17-21, July 5, 1956. (5) Dot, R., Hz, A. B. Mortality in relation to smoking: 10 years’ obser- vations of British doctors. Part I. British Medical Journal 1(5395): 1399-1410, May 30, 1964. (6) Dox, R., Hitt, A. B. Mortality in relation to smoking: 10 years’ obser- vations of British doctors. (concluded). British Medical Journal 1(5396) : 1460-1467, June 6, 1964. , ; (7) Dott, R., Jones, F, A., Pycott, F. Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet 1: 657-662, March 29, 1958. (8) Epwarps, F., McKeown, T., WHITFIELD, A. G. W. Association between smoking and disease in men over sixty. Lancet 1: 196-201, January 24, 1959. . (9) GiLiies, M., SKyRING, A. Gastric ulcer, duodenal ulcer and gastric car- cinoma: A case-control study of certain social and environmental fac- tors. Medical Journal of Australia 2(25): 1182-1136, December 21, 1968. (10) Gries, M. A., SkyRING, A. Gastric and duodenal ulcer. The association between aspirin ingestion, smoking and family history of ulcer, Medi- cal Journal of Australia 2(6) ; 280-285, August 9, 1969. (11) Hammonp, E. C. Smoking in relation to the death rates of 1 million men and women. IN: Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S. Public Health Service, National Cancer Institute Monograph No. 19, January 1966. pp. 127-204. (12) Kaun, H. A. The Dorn study of smoking and mortality among US. veterans: Report on 8% years of observation. IN: Haenszel, W. (Edi- tor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S. Public Health Service, National Cancer Institute Monograph No. 19, January 1966. pp. 1-125. (18) Kasanen, A., Forsstrom, J. Social stress and living habits in the etiology of peptic ulcer. Annales Medicinae Internal Fenniae 55(1): 13-22, 1966. (14) Murty, W. F., Jk., Rousse.ot, L. M., DELANy, G. J. Smoking and its relation to nutritional status of patients following gastrectomy; 2 five-year follow-up survey of 171 patients. Annals of Surgery 150(1): 76-84, July 1959. (15) Monson, R. R. Cigarette smoking and body form in peptic ulcer. Gastro- enterology 58(3) : 387-344, March 1970. 429 (16) Packarp, R. S. Smoking and the alimentary tract: A review. Gut 1: 171-174, 1960. (17) Parmer, W. L. Peptic ulcer. Chapter 32. IN: Paulson, M. (Editor). Gastroenterologic Medicine. Philadelphia, Lea & Febiger, 1969, pp. 710-757, (18) ScHNeEDorRF, J. G., Ivy, A. C. The effect of tobacco smoking on the alimentary tract. An experimental study of man and animals. Journal of the American Medical Association 112(10): 898-904, March 11, 1939, (19) STEIGMANN, F., DoLEHIDE, R. H., KAMINSKI, L. Effects of tobacco smok- ing on gastric acidity and motility of hospital controls and patients with peptic ulcer. American Journal of Gastroenterology 22: 399-409, 1954, (20) THompson, J. H. Effects of nicotine and tobacco smoke on gastric secre- tion in rats with gastric fistulas. American Journal of Digestive Diseases 15(3) : 209-217, March 1970. (21) TROWELL, O. A. The relation of tobacco smoking to the incidence of chronic duodenal ulcer. Lancet 1: 808-809, April 14, 1934. (22) U.S. Pupitic HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STATIS- Tics. Vital Statistics of the United States—-1967. Vol. JI—Mortality, Part A. Washington, U.S. Department of Health, Education and Wel- fare, Public Health Service Publication, 1969. (23) Wet, J. M., DunN, J. E., JR. Smoking and mortality: A prospective study. Cancer 25(1) : 105-112, January 1970. 430 CHAPTER 7 Tobacco Amblyopia Contents Page Summary and conclusions .............. 00 eee eee eee 436 References 2.0.0... ccc eee ee eee neces 436 433 ToBacco AMBLYOPIA Tobacco amblyopia (tobacco-alcohol amblyopia) is that syn- drome of visual failure occurring in association with the use of tobacco, with or without the concurrent use of alcohol, and with or without concurrent nutritional deficits. The disease has a subacute onset, leading to a loss of visual acuity and color perception (72). It is characterized by centrocecal scotomas which are bilateral but not necessarily symmetrical and which have sloping diffuse edges and by the presence of nuclei of denser visual loss within the large scotomas (22, 23). Such visual impairment is not unique to tobacco amblyopia, as it is also seen in neurodegenerative disorders, such as Leber’s hereditary optic atrophy (7, 25). Clinical information on tobacco amblyopia has appeared in nu- merous articles throughout the past century. This information has been reviewed by Silvette, et al. (17) and, more recently, by Dunphy (5). Pure tobacco amblyopia (TA), that is amblyopia unassociated with excessive alcohol intake or the exposure to other toxins, is rarely seen in the United States today (12). Walsh, et al. (23) have observed that when TA is found it is usually present in association with nutritional or idiopathic vitamin deficiencies. Victor (22) recently observed that the type of visual defect seen in tobacco amblyopia may be found in clinical circumstances in which tobacco is clearly not a causative factor. He questions whether TA is distinguishable from other forms of amblyopia. The prevalence of this disorder has been variously estimated in the past at from 0.5 to 1.5 percent of all eye clinic patients (20, 23). However, currently in the United States, it appears to be a rare condition. Silvette, et al. (17) have observed that the incidence of tobacco amblyopia appears to have decreased substantially during the past decades. Other authors (3, 15) have also commented on this trend. Although reference has been made to the increased fre- quency of certain types of tobacco usage in patients with this dis- order, adequate population studies with proper controls have yet to be performed. The association of this disorder with the use of tobacco is strengthened by the frequent clinical observations of improvement following the cessation of smoking although improve- ment has been noted by some to occur without cessation. Research into the pathogenesis of tobacco amblyopia has cen- 435 tered upon the interrelationships of cyanide metabolism, vitamin B,., and other vitamin deficiencies. Three reviews of this material have recently appeared (1, 12, 22). Numerous studies reviewed in these articles suggest that tobacco amblyopia may result from the incomplete detoxification of the cyanide present in tobacco smoke. This failure of detoxification may stem from or be intensified by inadequate dietary intake of necessary nutritional factors. This may be the reason for the association of this disorder with exces- sive alcohol intake and with its related nutritional deficits (2, 4, 6, 8,9, 10,11, 18, 14,16, 18, 19, 21, 24, 26, 27,28). SUMMARY AND CONCLUSIONS Tobacco amblyopia is presently a rare disorder in the United States. The evidence suggests that this disorder is related to nutri- tional or idiopathic deficiencies in certain detoxification mechan- isms, particularly in handling the cyanide component of tobacco smoke. REFERENCES (1) CANADIAN MEDICAL ASSOCIATION JOURNAL. Tobacco amblyopia. (Edi- torial) Canadian Medical Association Journal 102(4) : 420, February 28, 1970. (2) CHISHOLM, I. A., BRONTE-STEWART, J., FouLps, W. S. Hydroxocobalamin versus cyanocobalamin in the treatment of tobacco amblyopia. Lancet 2(7513): 450-451, August 26, 1967. ($) Darsy, P. W., Witson, J. Cyanide, smoking, and tobacco amblyopia. Observations on the cyanide content of tobacco smoke. British Journal of Ophthalmology 51(5) : 336-338, May 1967. (4) DreyFrus, P. M. Blood transketolase levels in tobacco-alcohol amblyopia Archives of Ophthalmology 74(5) : 617-620, November 1965. (5) Dunpuy, E. B. Alcohol and tobacco amblyopia: A historical survey. American Journal of Ophthalmology 68(4): 569-578, October 1969. (6) FouLps, W. 8., BRONTE-STEWwarT, J. M., CHISHOLM, I. A. Serum thio- cyanate concentrations in tobacco amblyopia. Nature 218 (5141) : 586, May 11, 1968. (7) Foutps, W. 8., Cant, J. S., CHisHotM, I. A., BRoNTE-STEWaRT, J., WILson, J. Hydroxocobalamin in the treatment of Leber’s hereditary optic atrophy. Lancet 1(7548): 896-897, April 27, 1968. (8) Foutps, W. S., CHISHOLM, I. A., BRONTE-STEWaRT, J., WILSON, T. M. Vitamin B,, absorption in tobacco amblyopia. British Journal of Ophthalmology 538 (6) : 393-397, June 1969. (9) Fourps, W. S., CHISHOLM, I. A., BRONTE-STEWART, J., WILSON, T. M. The optic neuropathy of pernicious anemia. Archives of Ophthalmol- ogy 82(4): 427-432, October 1969. (10) FREEMAN, A. G., HEATON, J. M. The aetiology of retrobulbar neuritis in Addisonian pernicious anaemia. Lancet 1(7183): 908-911, April 29, 1961. 436 (11) Heaton, J. M., McCormick, A. J. A., FREEMAN, A. G. Tobacco amblyo- pia: A clinical manifestation of vitamin-B,, deficiency. Lancet 2(7041): 286-290, August 9, 1958. (12) Knox, D. L. Neuro-ophthalmology. Archives of Ophthalmology 83(1): 103-127, January 1970. (18) Linpstranp, K., WILSON, J.. MATTHEWS, D. M. Chromatography and microbiological assay of vitamin B,, in smokers. British Medical Journal 2 (5520): 988-990, October 22, 1966. (14) LINNELL, J. C., SMitH, A. D. M., Smitu, C. L., WILSON, J.. MATTHEWS, D, M. Effects of smoking on metabolism and excretion of vitamin B,,. British Medical Journal 2(5599) : 215-216, April 27, 1968. (15) ScHEpPeENs, C. L. Is tobacco amblyopia a deficiency disease- Transactions of the Ophthalmological Society of the United Kingdom 66: 309-331, 1946. (16) SCHIEVELBEIN, H., WERLE, E., SCHULZ, E. K., BAUMEISTER, R. The influ- ence of tobacco smoke and nicotine on thiocyanate metabolism. Naunyn-Schmiedebergs Archiv fiir Pharmakologie und Experimentelle Pathologie 262(38) : 358-365, February 5, 1969. (17) Sirvette, H., Haac, H. B., Larson, P. S. Tobacco amblyopia. The evolu- tion and natural history of a “tobaccogenic” disease. American Journal of Ophthalmology 50(1): 71-100, January 1960. (18) SmitrH, A. D. M. Retrobulbar neuritis in Addisonian pernicious anae- mia. (Letter) Lancet 1(7184): 1001-1002, May 6, 1961. (19) Smiru, A. D. M., Duckett, 8. Cyanide, vitamine B,,, experimental demyelination and tobacco amblyopia. British Journal of Experimen- tal Pathology 46(6) : 615-622, December 1965. (20) Traquair, H. M. Toxic amblyopia, including retrobulbar neuritis. Trans- actions of the Ophthalmological Society of the United Kingdom 50: 851-385, 1930. (21) Victor, M. Tobacco-alcohol amblyopia. A critique of current concepts of this disorder, with special reference to the role of nutritional deficiency in its causation. Archives of Ophthalmology 70(3) : 318-318, Septem- ber 1963. (22) Victor, M. Tobacco amblyopia, cyanide poisoning and vitamin B,, de- ficiency. A critique of current concepts. Chapter 3. IN: Smith, J. L. (Editor) Neuro-Ophthlamology. Symposium of the University of Miami and the Bascom Palmer Eye Institute. Hallandale, Florida, Huffman Publishing Co., 1970. pp. 33-48. (23) Wa.sH, F. B., Hoyt, W. F. (Editors) Neurotoxic substances affecting the visual and ocular motor systems, Chapter 15: IN: Clinical Neuro- Ophthalmology, Volume 3, 3rd Edition. Baltimore, The Williams & Wilkins Company, 1969. pp. 26138-2616. (24) WATSON-WILLIAMS, E. J., BortromMLey, A. C., AINLEY, R. G., PHILLIPS, C. I. Absorption of vitamin B,, in tobacco amblyopia. British Journal of Ophthalmology 53(8) : 549-552, August 1969. (25) Wiison, J. Leber’s hereditary optic atrophy: A possible defect of cya- nide metabolism. Clinical Science 29(3): 505-515, December 1965. (26) Witson, J., MaTrHEews, D. M. Metabolic inter-relationships between cyanide, thiocyanate and vitamin B,, in smokers and nonsmokers. Clinical Science 31(1): 1-7, January 1966. 437 (27) Woxes, F., Picarp, C. W. The role of vitamin B,, in human nutrition. Clinical Nutrition 3(5) : 383-390, September—October 1955. (28) WyYNorr, E. L., HOFFMANN, D. Certain constituents of tobacco products. Chapter 8. K. Vapor phase of tobacco smoke. IN: Wynder, E. L., Hoffmann, I). (Editors). Tobacco and Tobacco Smoke. Studies in Ex- perimental Carcinogenesis. New York, Academic Press, 1967. pp. 451-453. 438 Index Abortions smoking effects on, 13 Abortions, spontaneous comparison of stillbirth and neonatal death with, in smoking and nonsmok- ing mothers, 390, 405-406 Acidosis metabolic, smoking mother effects on in- fant, 407 Adenocarcinoma prevalence in male and female smokers and nonsmokers, 250 relationship of cigarette smoking to, 246-249, 296 Adenoma papillary, induction in rats by exposure to cigarette tars, 348 pulmonary, induction in mice by ciga- rette smoke inhalation, 349 renal, relationship of smoking to, 296 Adrenal gland catecholamine release from, nicotine effects on, 36 Advisory Committee on Smoking and Health oo and conclusions of study Y> report on cigarette smoke and conden- sates effects on oral cavity of animals, 288 Age atypical nuclei in esophageal epithelium arranged by smoking and, 379-380 current cigarette smokers by sex and, 6 effects on CHD, 27, 39 AHA see American Heart Association Air pollution as cause of COPD, 152, 216-217 effect on COPD development, 175 relationship of lung neoplasms, smoking and place of residence, 252-255 role in etiology of lung cancer, 11, 276 Alcohol effect of consumption on esophageal neoplasms in smokers, 289, 293 effect of consumption on laryngeal neo- plasms among tobacco users, 280 effect of consumption on tobacco am- blyopia 435-436 effect of heavy consumption and heavy smoking on oral neoplasms, 288 ethanol, penetrability of dissolved benzo(a)pyrene in mice esophageal epi- thelium, 293 telationship of smoking and, in human tuberculosis, 172 Alcoholism patients with, smoking and ventilatory function in, 213 Ambly opia characterization of, 435 development from cyanide component of tobacco smoke, 14 incidence of, 435 American Heart Association pooling project on CHD, 23, 28, 30, 39 Aminoazo dyes activity in placenta of smoking mothers, 410 Angina pectoris cause of, 21 incidence with cigarette smoking, 24, 37 in Danish twins, smokers vs. nonsmok- ers, 51 in twins, constitutional factors, 50-51 prospective studies of, CHD morbidity relation to smoking 37, 39 Animals see also specific animals e.g., cats, dogs, rabbits, etc. atherosclerotic lesion development in, smoking enhancement, 36 noms induction in, from arsenic, 57 cigarette smoke effect on pulmonary physiology and structure in, 162 development of lesions from cigarette smoke inhalation, 11 effects of nicotine on cardiovascular system of, 57, 107-112 esophageal neoplasms in, induction by nitrosamines, 292 respiratory tract of, neoplastic changes following cigarette smoke inhalation, 238-239 skin of, carcinogenicity of tobacco tars, 238, 267 tests of, with smoke carcinogens, 12 ventilatory function change from smok- ing, 10 Anti-trypsin, alpha, COPD predisposition from genetic ab- sence of, 150 determination using immunoelectro- phoresis, 151 relationship in pulmonary emphysema, 10-11 Anthranilic acid, 3-hydroxy- urinary excretion of, smoking effects on, 296 Aorta aneurysms of, cigarette smoking effect on, 9,67, 71, 75 atherosclerosis in, long term smoking effects, 52-56 Areca nut see Betel nut Aromatic compounds carcinogenic properties in cigarette 439 smoke from, 264, 265 detection in urine using chemilumi- nescence technique, 297 stimulation of placental BP-hydroxylase activity in pregnant rats by, 414 Arrhythmia formation in nicotine stimulated dam- aged myocardium, 58 Arsenic lung neoplasm mortality in smelter workers exposed to, 257 respiratory tract carcinoma in workers exposed to, 256, 257 Arteries aneurysm in aortic, cigarette smoking ef- fects on, 9, 67, 71,75 atherosclerotic, increased by cigarette smoking, 8, 63 flow of carotid, cigarette smoking effects on, 67 hypoxemia, development from cigarette smoking, 9 occlusions of, cigarette smoking effects on, 73 walls of, mechanism of lipoprotein infil- tration, 63 walls of nicotine-induced necrosis, 63 Arteriosclerosis see also Thromboangiitis obliterans in aorta and coronary arteries, cigarette smoking effects on, 45, 52-56 cigarette smoking effects on, 8 development by increased carboxyhemo- globin formation, 9 development of, carbon monoxide ef- fects on, 63 development of, effects of nicotine on, 38 lesion development in, smoking enhance- ment, 36 peripheral, cigarette smoking effects on, 72-73 Arteriosclerotic heart disease (ASHD) see Coronary disease Asbestos workers see Occupations ASHD see Coronary disease Asia see also specific countries of Asia Central and Southeast, relationship of tobacco use and neoplasms of oral cav- ity, 366 Asthma bronchial, cigarette smoking effects on, 10,175 Atherosclerosis see Arteriosclerosis Atropine effects on bronchoconstriction in dogs, 163 Australia COPD morbidity in smokers in, 203 laryngeal neoplasms in, relationship to tobacco use, 357 lung neoplasm in, retrospective studies of, 327 peptic ulcer in, methods for retrospec- tive and cross-section studies of smoking and, 426, 428 440 Bacteria effect of cigarette smoke j macrophages on, 165 On action of pneumonia, mice resistance cigarette inhalation, 173 Bank employees see Occupations Benz(e)acephenanthrylene carcinogenic properties in smoke from, 264, 265 Benz(a)anthracene coholic solution of, penetrabil mice esophageal epithelium, oY of Benz(a)anthracene, 7,12-dimethyl carcinoma induction in hamsters follow ing instillation of, 346 , skin painting with, papilloma and carci. noma induction in mice by, 341 Benzo(b)fluoranthene see Benz(e)acephenanthrylene Benzo(/)fluoroanthene carcinogenic properties in ci smoke from, 265 P *Barette Benzo(c)phenanthrene carcinogenic properties in cigarette smoke from, 265 Benzo(rst)pentaphene carcinogenic properties in cigarette smoke from, 265 3,4-Benzopyrene see Benzo(a)pyrene Benzo(a)pyrene ability of smoking mothers to hydroxy). ate, 407 alcoholic solution of, penetration of mice esophageal epithelium, 292 carcinogenicity of, in relation to asbestos in hamsters, 257 carcinogenic properties in cigarette smoke from, 264, 265 detoxification by lung aryl hydroxylase, 257 effects of instillation or implantation in animal tracheobronchial tree, 346-347 effects on animal tissue and organ cul- tures in, 343-345 effects with influenza virus on cigarette inhalation by mice, 352 sarcoma induction in rats following in- stillation of, 346 skin painting with, papilloma induction in mice by, 337-338 Benzo(a)pyrene, 1-methyl- carcinogenic properties in cigarette smoke from, 265 Betel nut chewers of, relationship with oral cavity neoplasms, 366, 369-370 Birth weight see Neonate Blacks maternal smoking and infant weight, 397 maternal smoking and prematurity, 400-401 Bladder neoplasms frequency in smokers vs. nonsmokers, 238, 293-295 methods of retrospective studies of smoking and, 293, 381-384 presence of tryptophan metabolites in following Cigarette urine of patients with, 296-297 relationship of cigarette smoking to, 299 uray, cigarette smoking relationship, 1 U.S. mortality in 1967, 294 Blood see also specific components of blood, e.g., cholesterol, lipids, platelets carboxyhemoglobin formation in, from smoking, 60, 75 clotting, cigarette smoking effects on, 9, Blood circulation, coronary alteration following cigarette smoke in- halation, 58 effect of variations in hemoglobin and hematocrit, 66 Blood pressure diastolic, cigarette smoking effects, 8, 23 diastolic, in smokers with CHD, 21-22, 24,42 high, risk factor in arteriosclerosis ob- literans, 72 high, risk in mortality from CVD, 67 hypertensive vs. non-hypertensive, mor- tality rates of CHD in, 42 nicotine effects on, 36 relationship of smoking and CHD, 43, 47 smokers vs. nonsmokers, 41, 42, 103-104 systolic, mortality from elevated, with CHD, 42 BP-hydroxylase see under Enzymes Bradycardia / development in dogs given nicotine, 57 British Perinatal Mortality Survey results of, 390 Bronchitis, chronic cigarette smoking cause and effect rela- tionship, 3,9 definition, 139 mortality in cigarette smokers, 175 mortality rates in 1967, 139 smokers vs. nonsmokers, 195-205 Bronchogenic carcinoma see Carcinoma, bronchogenic Bronchopneumonia development in dogs following cigarette smoke inhalation, 271 Bronchopulmonary disease, chronic ob- structive see also Asthma, bronchitis, emphysema, respiratory diseases air pollution relationship in, 152, 216-217 characterization of, 139 cigarette smoking effects on develop- ment, 4, 9-11, 175 effect of smoking cessation on develop- ment, 10 genetic factors in pathogenesis of, 148, 150-152, 205 increased prevalence of heterozygotes in, 151-152 mortality in pipe, cigar, and cigarette smokers, 175 mortality rates from, 139-145 smoking effects on ventilation-perfusion measurements in, 163 Buerger’s disease see Thromboangiitis obliterans Burma methods used in smoking study and human pregnancy, 393 Butylamine, N-methyl-nitroso suspected carcinogenic properties in ciga- rette smoke from, 265 Cadmium in cigarette smoke, relation to emphy- sema pathogenesis, 154 Calves see Cattle Canada COPD morbidity of smokers in, 204 human experimental data on smoking and pregnancy, 409 infectious respiratory disease in, relation- ship to smoking, 228 kidney and bladder neoplasms in smok- ers in, 294 mortality rates from COPD, 139-141, 145 mortality ratios from COPD, 143 mortality ratios in smokers and non- smokers from pancreatic neoplasms, 298 thrombosis in, smoking relationship, 132 veterans of, lung neoplasm mortality ratios in smokers and nonsmokers, 241 Carbazole, 9-methyl- possible importance in tobacco carcino- genesis, 266 Carbon-14 labeled smoke particulate deposition in hamster respiratory tract, 281-282 Carbonic anhydrase see Enzymes Carbon monoxide in cigarette smoke, formation of car- boxyhemoglobin, 8-9 : effects on cholesterol-fed rabbits, 65-66 effects on human physiology, 60-62 levels in cigarette smoke, 59 levels in fetal blood of smoking mothers, 407-410 Carboxyhemoglobin effects of elevated, on fetal tissues, 407 formation in blood of smokers, 60, 75 formation from CO in cigarette smoke, 8-9 Carcinogens action on oral cavity, effect of saliva, 288 listing of, in cigarette smoke, 265-266 in smoke, effect on oral cavity, 12 Carcinoid prevalence in male and female smokers and nonsmokers, 250 Carcinoma . . formation following animal skin painting with smoke condensates, 337-342 induction in rats exposed to cigarette tars, 348 undifferential, relationship to cigarette smoking, 248-249 Carcinoma, alveolar induction in mice by cigarette smoke in- halation, 349 441 Carcinoma, anaplastic prevalence in male and female smokers and nonsmokers, 250 Carcinoma, bronchogenic development in dogs following cigarette smoke inhalation, 269, 272-273 mortality from, relationships to smok- ing, air pollution and residence, 253 mortality in smokers vs. nonsmokers as- bestos workers, 257 Carcinoma, epidermoid mortality from, relationship to smoking, air pollution and residence, 254 prevalence in male and female smokers and nonsmokers, 250 relationship of cigarette smoking to, ~ 246-249 Carcinoma, epithelial induction in mice by cigarette smoke in- halation, 350 Carcinoma, oat cell relationship of cigarette smoking to, 247 Carcinoma, squamous cell development in mice drinking alcoholic benzo(a)pyrene, 292 in oral cavity, relationship to tobacco use, 366-367 Carcinoma, tracheobronchial induction in hamsters by cigarette smoke instillation, 346-347 Cardiovascular diseases see also Coronary disease atherosclerotic, cigarette smoking rela- tionship, 4 Cardiovascular system nicotine and cigarette smoke effects on, 56-58, 107-118 Catecholamines adrenal gland release, effect of nicotine on, 36 effect on blood flow in coronary arte- ries, 58 release by cigarette smoking, 8 telease in animals by nicotine, 57, 119 Cats cardiovascular function in, smoking and nicotine effects on, 110, 111 ciliary function in, effect of cigarette smoke on, 222-224 lungs of, cigarette smoke effect on sur- factant activity, 225 Cattle ciliary function in, effect of cigarette smoke on, 221 CBF see Blood circulation coronary Central nervous system effects of carbon monoxide in smoke on, Cerebrovascular disease definition of, 66 mortality from, effects of cigarette smoking on, 9 mortality rates from, smokers vs. non- smokers, 66-70 Cessation of smoking effect on COPD development in British physicians, 142 effect on COPD morbidity in smokers vs. nonsmokers, 146 effect on development of COPD, 140 442 effect on mortality from COPD from, 175 improvements in respiratory system, 148, 149 relation to incidence and mortality from CHD, 32, 46-48, 106 CHD see Coronary disease Chemiluminescence see Luminescence Chewing see Betel nut and tobacco Chickens ciliary function in, effect of cigarette smoke on, 223 embryos of, effect of cigarette smoke on, 344 embryo of, nicotine effects on CNS, 411 Chile atherosclerosis autopsy studies in, 55 atherosclerosis in, no smoking effect found, 56 Cholesterol rabbits fed, carbon monoxide effects on, 65-66 serum, cigarette smoking relationship with, 8 serum, control in coronary disease, 21-22 serum, relationship of cigarette smoking to levels of, 41, 43 serum, relationship of elevated with ciga- rette smoking in peripheral vascular disease, 72 serum, in smokers vs. nonsmokers, 41, 98-102 serum, in smokers with CHD, 23-24, 43 synergistic relationship of carbon mon- oxide in coronary atheromatosis, 63 Chromium respiratory tract carcinoma in workers exposed to, 256 Chromium compounds lung neoplasm mortality from, 257-258 Chronic obstructive pulmonary disease see Bronchopulmonary disease, chronic obstructive Chrysene carcinogenic properties in cigarette smoke from, 265 Chrysene, 1-methyl- carcinogenic properties in cigarette smoke from, 265 Cigarette filters advantages in reduction of particulates, 269, 275 reduction of lung neoplasms from, 13 Cigarette smoke alteration of coronary biood flow, 58 bronchogenic carcinoma induction in dogs inhaling, 269, 270 cadmium levels in, 154 carbon monoxide levels in, 59 carcinogenicity of components to ani- mals, 12,277 a of death in dogs from inhalation, 71 ciliary movement inhibition, 267 effect on tissue and organ cultures, 267, 343-345 effect of nickel on induction of lung aryl hydroxylase, 256-257 high tar, risks in, 11 inhalation by dogs, lung neoplasm devel- opment, 268-269, 272-274 inhalation effects on animal respiratory tract, 268-269, 349-353 inhalation effects on hamster larynx, 281, 284 listing of identified or suspected tumori- genic agents, 264-267 2-naphthylamine identified in, 265 neoplastic changes in animals inhaling, 238-239 tobacco amblyopia relationship to cyan- ide metabolism in, 435-436 Cigarette smoke condensates carcinogenic effect on animal oral cav- ities, 288 carcinogenic properties on animal skin, 337-342 effects of instillation or implantation in animal tracheobronchial tree, 346-348 effects on tissue and organ cultures, 343-344 painting skin of animals with, 337-342 Cigarette smokers arterial occlusions in, 73 atherosclerosis in aortic and coronary ar teries, 52-56 atypical nuclei in male esophageal epi- thelium, 379-380 bladder neoplasms in, 293-295 cell rows and atypical cells in vocal cords of, 280, 359-360 cessation effects on COPD morbidity, 146, 197, 199, 203-204 cessation lowers lung neoplasm rate in, 11 changes in ventilatory function and pul- monary histology, 175 CHD in AHA pooling project, 28, 30, 39 CHD risk by, 23-25 comparative risk for lung neoplasms, 237 decline in British physicians, 48 development of altered ventilatory func- tion in young, 10 development of esophageal neoplasms, 12, 293 development of laryngeal neoplasms, 12 development of oral neoplasms, 12 development of second primary oral neo- plasms in continuing, 287 effect of filters on emphysema develop- ment, 162 effects of inhalation on bronchial reacti- vity, 164 effect on cardiovascular system, 56-58, 107-118 effects on uterine activity in gravidic women, 408 esophageal neoplasm mortality ratios in, 290-291 etiological cause of lung neoplasms, 239 histology and smoking relationship of lung neoplasms in 246-249 infant birth weight, 397-399 inhalation effects on human pulmonary function, 163, 166-169 kidney neoplasms in, 294-296 laryngeal neoplasm 354-357 lung neoplasm mortality in, 240, 243-244 mortality from cerebrovascular disease, 67-70 mortality rates affected by sex, 3 mortality ratios from COPD, 142-144 mortality ratios from pancreatic neo- plasms in, 298 mortality ratios from peptic ulcers in, 424 peptic ulcer in, smoke effects on antacid therapy, 423 percentage of women of child-bearing age, 389 possible processes for increased mortal- ity in, 4-5 postoperative pulmonary complications in, 174, 230 pulmonary surfactant activity in, 172, 225 relationship of asbestos in lung neoplasm mortality, 257 relationship in coronary and lower limb arteriosclerosis, 72 relationship of former to lung neoplasm development, 276 relationship to infectious respiratory dis- ease, 172, 226-229 relationship to laryngeal neoplasm devel- opment in, 281 relationship to lip or oral cavity neo- plasms, 361-370 relationship to lung neoplasms, 275 relationship with bladder neoplasms in men, 299 relationship with dust on COPD develop- ment, 153 with peptic ulcer, 427 tisk in CHD, 8 tisk of COPD in, 140 survey by age and sex, 6 survey of U.S., 6 Cigarettes development of esophageal neoplasms by, 12, 293 tar levels of, relationship to lung neo- plasm development, 276 Cigar smokers atypical nuclei in male esophageal epi- thelium, 379 bladders neoplasms in, 293-294 cell rows and atypical cells in vocal cords of, 280, 359-360 COPD morbidity in, 146, 197-198, 201-202, 204-205 effects of smoke on bronchial reactivity, 164 esophageal neoplasm mortality ratios in, 290 kidney neoplasms in, 294-295 lack of risk in CVD, 67 laryngeal neoplasm induction in, 12, 354-357 lung neoplasm incidence in rural Switzer- land, 244 lung neoplasm mortality in, 11, 240-243 mortality ratios from COPD in, 142-143, 145 induction in, 443 my ocardial infarction in, 32, 38-39 relationship to infectious respiratory dis- ease, 227 relationship of laryngeal neoplasms de- velopment in, 281 relationship of neoplasms of oral cavity with, 12, 361-365, 367-371 mortality ratios from pancreatic neo- plasms in, 298 mortality ratios from peptic ulcer in, 424 risk of CHD, 8 risk of COPD, 10 risk of lung neoplasm development, 276 Ciliary activity see Respiratory system Circulation see Blood circulation Cirrhoses see Liver Civil servants see Government employees under Occu- pations Coal miners see Occupations Congressional legislation see Laws Connecticut Cancer Registry figures on age-adjusted larynx neoplasm incidence, 277 figures on incidence of oral neoplasms, 284 Constitutional hy pothesis relationship to CHD and smoking, 48-49, 105-106 COPD see Bronchopulmonary disease, chronic obstructive Cornsilk smoking, lack of arterial epinephrine level increase, 57 Coronary blood flow seé Blood circulation, coronary Coronary disease see also Angina pectoris age- adjusted rates in smokers, 23 arteriosclerotic, mortality rates in US., atherosclerosis in, effects of smoking on, 4,63 blood pressure of smokers vs. nonsmok- ers, 43,47 carbon dioxide effects on oxygen uptake in, 62 cigarette smoking relationship, 5 death ratios of paired combinations of high risk, 25 first, mortality rates in smokers vs. non- smokers, 24, 26-29 incidence and mortality rates in former smokers, 46, 47-48 infarction in NYC pipe and cigar smok- ers, 32, 38-39 infarction relationship to physical activ- ity, smokers vs. nonsmokers, 44 in smokers with predisposing factors, 24 morbidity relationship of smoking to, 32-35, 37, 39, 93-97 mortality and morbidity retrospective studies, 40, 93-97 444 mortality from, relationship to electro- cardiographic findings, 42 mortality in obese vs. non-obese, 45 mortality rates in, hypertensives vs. non- hypertensives, 42 mortality rates in, smokers vs. non- smokers, 21-22 mortality rates in, with increased carbon monoxide, 62 mortality rates of paired combinations of high risk, 25 mortality rates of cigarette smokers from, AHA pooling project, 28, 30, 39 mortality rates of U.S. veterans, 26, 38 myocardial infarction in Danish twins, 31 nicotine effect on coronary blood flow in, 58 relation of triglycerides to, 65 telationship of blood presure and smok- ing, 45, 47 relationship of heart rate and smoking, 45,47 relationship of physical activity and smoking 41, 43, 44 relationship to constitutional makeup and smoking, 48-49, 105-106 relationship to ECG abnormalities and smoking, 45, 47 relationship to obesity and smoking, 4345 tisk factors, 23-24, 40-41 smokers age effects on development, 27, 39 smoking risk factor, 8 sudden mortality in, smoking effects on, 2 Coronary heart disease See Coronary disease Cows see Cattle Cresol suspected carcinogenic agent of cigarette smoke, 266 Cuba laryngeal neoplasms in, relationship to tobacco use, 356 relationship of tobacco use and neo- plasms of oral cavity, 364 D see Cerebrovascular disease Cyanides metabolism of, pathogenesis of tobacco amblyopia relationship to, 435-436 in tobacco amblyopia etiology, 14 Czechoslovakia jaryngeal neoplasms in, relationship to tobacco use, 354, 357 serum lipid difference in smokers vs. nonsmokers in, 101 Death rates see Mortality rates Denmark atherogenic effect of carbon monoxide and hypoxia, 64 bladder neoplasms in, methods and re- sults in retrospective studies of smok- ing and, 381, 383 carbon monoxide effects on human biood lipids in, 129 carbon monoxide effects on rabbit blood lipids in, 129 serum lipid differences in smokers vs. nonsmokers in, 102 twins in, angina pectoris in smokers vs. nonsmokers, 51 Deoxyribonucleic acid content increase in smokers oral epi- thelial cells, 288 levels in mice lung exposed to cigarette smoke, 161 Diabetes effect on CHD in smokers, 24 tisk in mortality from CVD, 67 Diabetes mellitus relationship with cigarette smoking in peripheral vascular disease, 72 Dibenz(¢,h acridine carcinogenic properties in cigarette smoke from, 265 Dibenz(a,j)acridine carcinogenic properties in cigarette smoke from, 265 7H-Dibenzo(c,g)carbazole carcinogenic properties in cigarette smoke from, 265 Dibenzo(a,i)pyrene see Benzo(rst)pentaphene Diethylnitrosamine suspected carcinogenic properties in ciga- rette smoke from, 265 7,12-Dimethy]-benz(a)anthracene see Benz(a)anthracene, 7,12-dimethy!- Dimethylnitrosamine suspected carcinogenic properties in ciga- rette smoke from, 265 2,3-Diphosphogly cerate effects of carbon monoxide on, 60-61 DNA see Deoxyribonucleic acid Dogs atherogenic effects of nicotine in, 120 bladder neoplasms in, fed 2-naphthyl- amine, 296 bradycardia and tachycardia in, follow- ing nicotine injection, 57-58 bronchogenic carcinoma induction in, te cigarette smoke inhalation, 269, 70 cigarette smoke instillation or implanta- tion effects on tracheobronchial tree of, 268, 347 death in, causes from cigarette smoke in- halation, 271 effect of cigarette smoke on pulmonary clearance in, 164, 170 fetal bronchial tubes of, effect of ciga- rette smoke on, 345 lungs of, cigarette smoke effects on sur- factant activity, 172, 225 lung neoplasms following cigarette smoke inhalation, 239, 277 lung neoplasms in, types and lobes where found, 269, 272-273 myocardium of, nicotine effects on, 58 neoplasm development in smoking, per- centages of, 274 pulmonary histological changes in ciga- rette smoke inhaling, 158, 159-160 respiratory tract of, cigarette smoke in- halation effects on, 268, 352, 353 smoke induced bronchoconstriction in, atropine effects, 163 smoking and nicotine effects on blood lipids in, 127-128 smoking and nicotine effects on cardio- vascular function in, 107-112 smoking and nicotine effects on cate- cholamine levels in, 119 Donkeys effect of cigarette smoke on pulmonary clearance in, 164, 171 Ducks cigarette smoke instillation or implanta- tion effects on tracheobronchial tree of, 346 Duodenal ulcer see Peptic ulcer Dusts COPD development from, 153, 218 Egypt relation of human pulmonary histology and smoking, 163 Electrocardiograph findings on, CHD mortality relationship to, 42 reading abnormalities, relationship to smoking and CHD, 45, 47 Electrophoresis use in determining serum levelof alpha,- antitrypsin, 151 Emphysema alpha,-antitrypsin absence type genetic factors, 150 cigarette smoking effects on, 9 development in dogs following cigarette smoke inhalation, 271 development of, relation of cadmium in smoke to, 154 grade II or III, smokers vs. nonsmokers, 162 mechanism inalphayantitrypsin absence type of, 151 mortality from, effect of cigarette smok- ing on, 175 mortality rates from, in 1967, 139 pulmonary, definition, 139 Employment see Occupations England see United Kingdom Enzymes see also Papain activity of, effect of smoking, 165 ary! hydrocarbon hydroxylase activity in placentas at childbirth, 410 aryl hydroxylase, effect of nickel in ciga- rette smoke on induction of , 257 benzo(a)pyrene hydroxylase, activity in placentas of smoking mothers, 410 carbonic anhydrase, carbon monoxide inhibition in fetal cord blood of smok- ing mothers, 407 carbonic anhydrase, decrease in activity in fetal cord blood in smoking mothers, 409 Epidermoid carcinoma see Carcinoma, epidermoid 445 Epinephrine levels in arteries, cigarette smoking ef- fects on, 57 Epitheliomas lip, relationship of tobacco use with, 361 Epoxides : suspected carcinogenic agents in ciga- rette smoke, 265 Esophageal neoplasms frequency in smokers vs. nonsmokers, 12, 238 induction in animals by nitrosamine, 292 methods and results of retrospective studies of tobacco use, 289, 375-378 mortality rates in U.S. for 1967, 289 relationship to smoking, 293 Esophagus basal cells of epithelium of, atypical nuclei in male smokers 292, 379-380 Ethanol see Alcohol Ex-smokers see Smokers (former) Factory workers see plant workers under Occupations Fatty acids blood, effect of smoking on levels of, 65 Jevels in smokers vs. nonsmokers, 102 rise in blood serum after smoking, 36 suspected carcinogenic agents of ciga- rette smoke, 266 Fetus heart beats in, increase in smoking mothers, 408 tissues of, effects of elevated carboxy- hemoglobin on, 407 Fibrosis in lung, smokers vs. nonsmokers, 161 Fibrillation ventricular, death from, 36 Filters see Cigarette filters Finland blood pressure differences in smokers vs. nonsmokers in, 103 COPD morbidity in smokers of, 200 lung neoplasms in, restrospective smok- ing study of methods in, 325, 327 lung neoplasm mortality in, relationship to tobacco use, 245-246 peptic ulcer in, methods and results for retrospective and cross section studies of smoking and, 426, 428 serum lipid differences in smokers vs. nonsmokers of, 98, 99 smoking and nicotine effects on human blood lipids in, 124 Fluoranthene alcoholic solution of, penetrability of esophageal epithelium, 292 Flax mill workers see Occupations Former smokers see Smokers (former) Formosa acute effect of cigarette smoke on human pulmonary function in, 169 France bladder neoplasms in, methods and re- 446 sults in retrospective studies of smok- ing and, 381-383 CHD mortality and morbidity in, 94, 97 COPD mortality of smokers in, 201 cigarette smoke effects on animal lung tissue in, 343 cigarette smoke effects on chicken em- bryos in, 344 cigarette smoke inhalation effects on rat respiratory tract, 349 esophageal neoplasms in, retrospective studies of tobacco use with, 378 laryngeal neoplasms in, relationship to tobacco use, 355, 357 lung neoplasms in, retrospective smoking study of methods in, 326 relationship of tobacco use and neo- plasms of oral cavity, 363 Framingham Heart Study morbidity ratios in CHD, 24 Fungicides concentration in cigarette smoke, 265, 266 Gastric ulcer see Peptic ulcer Genetics factors of, cigarette smoking relation- ship, 5 factors of, in COPD pathogenesis, 148, 150-152, 205 twin-studies, effects of smoking, 49-52, 99 Germany a morbidity and mortality in, 95-96, cigarette smoke inhalation effects on ani- mal respiratory tract in, 350 laryngeal neoplasms in, relationship to tobacco use, 355 lung neoplasms in, retrospective smoking study of methods in, 323, 325, 326 polonium-210 levels in lungs of smokers in, 336 smoking and nicotine effects on human blood lipids, 125 Glossary of terms used in smoking and ventilatory function, 215 Glucose metabolism and insulin response, altera- tion effects on myocardial response, 66 Glycogen levels in mice lung exposed to cigarette smoke, 161 Government employees see Occupations Graphite respiratory tract carcinoma in workers exposed to, 256 Great Britain see United Kingdom Guanethidine blockage of nicotine cardiac stimulation by, 57 Guinea pigs lung neoplasm development following chronic nickel carbonyl! or dust inhala- tion, 256 lungs of, cigarette smoke effects on sur- factant activity, 225 respiratory changes in, exposed to ciga- rette smoke, 162 Hamsters benzo(a)pyrene inhalation by, effect of asbestos dust on carcinoma induction, 257 bladder neoplasms in, fed 2-naphthyl- amine, 296 cigarette smoke instillation or implanta- tion effects on tracheobronchial tree of, 268, 346-348 laryngeal malignancies in, following smoke inhalation, 12 laryngeal neoplasms following cigarette smoke inhalation, 239 larynx of, effect of cigarette smoke in- halation on, 281, 284 lung and embryos, effects of cigarette smoke tars on, 343-344 pulmonary changes from chronic nitro- gen dioxide inhalation, 220 respiratory tract of, C-14 labeled particu- lates deposition in, 281-282 respiratory tract of, cigarette smoke in- halation effects on, 268, 351 Health Insurance Plan (NYC) myocardial infarction in pire and cigar smokers under, 32, 38-3 Heart see also Arrhythmia, brachycardia, myo- cardium and tachycardia cardiac thythm of, effect of nicotine on, 6 fetal, increased rate by maternal smok- ing, 408 myocardium of, nicotine effects on oxy- gen demand, 38 myocardium of, cigarette smoking effect on, 5,8 rate, relationship to smoking and CHD, Heart disease see Cardiovascular diseases and coronary disease Heights decreased, in children of smoking mothers, 407 Hematite dust respiratory tract neoplasms in hamsters exposed to, 348 Hematocrit ni smoking mother effects on, 407, 40 variations in, effect on coronary blood flow, 66 Hemoglobin see also Carboxyhemoglobin affinity for oxygen, CO effects on 2 ,3-di- phosphoglycerate control of, 60-61 variations in, effect on coronary blood flow, 66 Hens see Chickens Heterocyclic compounds carcinogenic properties in cigarette smoke, 264, 265 Hexamethonium blockage of nicotine cardiac stimulation by, 57 HIP of NYC see Health Insurance Plan (NYC) Hookahs smokers of, laryngeal neoplasm induc- tion in, 355 Hungary retrospective smoking study of methods for lung neoplasms in, 328 Hydrocarbons see Aromatic compounds heterocyclic compounds Hydrogen cyanide in cigarette smoke, effects on body oxi- dative metabolism, 62 3-Hydroxyanthranilic acid see Anthranilic acid, 3-hydroxy- 3-Hydroxykynurenine excretion of, smoking effects on, 296 Hydroxyproline level in mice lung exposed to cigarette smoke, 161 Hypertension see Blood pressure Hypoxemia : arterial, carbon dioxide effects on, 61, 18 Hypoxia aortic atheromatosis development in rabbits exposed to, 64 postoperative, development in smokers, 174, 230 postural, mechanism in asymptomatic smokers vs. nonsmokers, 147 Iceland lung neoplasms in, relationship to tobac- co smoking, 244 Indeno(1 ,2 ,3,-cd)pyrene carcinogenic properties in cigarette smoke from, 265 India esophageal neoplasms in, retrospective studies of tobacco use with, 378 laryngeal neoplasms in, relationship to tobacco use, 355, 356 relationship of smoking to tuberculosis in, 227 relationship of tobacco use and neo- plasms of oral cavity in, 362, 366 smoking and nicotine effects on human cardiovascular system, 117 smoking relationship to thrombosis in, 131 Indole, 1-methyl- possible initiator in tobacco carcinogene- sis, 265 Industrial workers see plant workers under Occupations Industrial hazards effect of dust on COPD development, 175 effects on COPD development in smok- ers, 153-154, 218-219 Infant see also Neonate sudden death in, relation of smoking and nonsmoking mothers, 407 Influenza virus effect on dogs inhaling cigarette smoke, 351 447 resistance of mice following cigarette smoke inhalation, 173 Inhalation studies see under Cigarette smoke Ireland acute effect of cigarette smoke on human pulmonary function, 168 CHD mortality and morbidity in smok- ers and nonsmokers in, 94 CHD mortality and morbidity in, 96 lung neoplasms in, retrospective smoking study of methods in, 328 maternal smoking and infant weight, 399 methods used in smoking study and human pregnancy , 394, 396 northern, mortality rates from COPD, 144 occupational exposure and smoking rela- tionships to COPD in, 218 relationship of lung neoplasms to smok- ing, air pollution and residence in, 254 serum lipid differences in smokers vs. nonsmokers in, 99 smoking and nicotine effects on human peripheral vascular system, 133 smoking relationship to thrombosis in, 130 Israel cigarette smoke effects on animal em- bryos in, 343 mortality rates from COPD in, increase, 140 Italy human experimental data on smoking and pregnancy, 409 serum lipid differences in smokers vs. nonsmokers in, 100 tracheobronchial tree changes in smokers and nonsmokers in, 263 Japan bladder neoplasms in, methods and re- sults in retrospective studies of smok- ing and, 382, 384 CHD mortality and morbidity in, 96 cigarette smoke effects on human fetal lung tissue in, 343 esophageal neoplasms in retrospective studies of tobacco use in, 378 kidney and bladder neoplasms of smok- ers in, 295 lung neoplasms in, retrospective smoking study of methods in, 326, 328 lung neoplasm mortality of smokers and nonsmokers in, 243 mortality ratios from esophageal neo- plasms in, 291 mortality ratios from pancreatic neo- plasms in cigarette smokers in, 298 relationships of lung neoplasms to smok- ing, air pollution, and residence in, 255 Kidney neoplasms mortality rates in U.S. for 1967, 296 relationship of tobacco use, 13, 299 in smokers and nonsmokers, 238, 294-295 Korea relation of human pulmonary histology and smoking in, 255 448 tracheobronchial tree changes in smokers and nonsmokers of, 259 Lactones suspected carcinogenic agents in ciga- rette smoke, 265 Laparotomy postoperative pulmonary complications following, in smokers vs. nonsmokers, 174 Laryngeal neoplasms development in hamsters following ciga- rette smoke inhalation, 239 development in smokers, 12, 281 mortality in smokers vs. nonsmokers, 237-238 mortality ratios from, 277-279 relationship to tobacco use and develop- ment of, 354-357 telative risk ratios from tobacco use, 277, 358 US. mortality in 1967, 277 Larynx epithelial changes in, classification of, 281, 283 hamster, C-14 labeled particulate deposi- tion in, 281-282 Laws PL 89-92, requirements for smoking haz- ards literature review, 7 PL 91-222, requirements for smoking hazards review, 7 Lip neoplasms relationship of tobacco use, 361, 362, 365, 367 relationship to pipe smoking, 289 Lipids blood effect of smoking on levels of, 65-66, 123-128 serum, differences in smokers vs. non- smokers, 41, 98-102 Lipoproteins infiltration in arterial walls, carbon mon- oxide effects on, 63 in smokers vs. nonsmokers, 99-102 Liver cirrhosis smokers, 5 Longshoremen see Occupations Luminescence techniques of, use in determining aro- matic hydrocarbon in urine, 297 Lung diseases see Bronchopulmonary diseases, adeno- carcinoma, carcinoma, tuberculosis Lungs fibroses in, smokers vs. nonsmokers, 161 hamster, C-14 labeled particulates depo- sition in, 281-282 human, effects of cigarette smoke on tis- sue from, 343-345 Lung neoplasms, air pollution role in etiology of, 11 cause and effect relationship of smoking, 276 cigarette smoking risks, 11 development in dogs following cigarette smoke inhalation, 239 effect of sex on development, 11 of, rates among cigarette environmental and atmospheric factors of, 252-255 groupings, 246-334 group characteristics of tobacco use in smokers and nonsmokers, 240, 244, 329-333 histology and smoking relationships, 246-249 mortality expected in U.S. in 1970, 237, 3 mortality from chromium compounds, 257-258 mortality in cigarette smokers by dura- tion, 240, 244 mortality in smelter workers exposed to arsenic, 257 mortality in smokers and nonsmokers, 240-243 mortality, in smokers in Norway and Finland, 245-246 occupational exposure effects on patho- genesis of, 12 prevalence in males and females by tumor type, 246, 250 reduction in number using filter-type cigarettes, 275 relationship of asbestos and smoking to, 57 relationship of female smoking, 246, 251 relationship of smoking to, 237 retrospective study methods for smoking relationships, 240, 323-328 smoking cause and effect relationship, 3 smoking habit study of patients with, 3 types implicated in smoking, 237 US. mortality rates for 1939 vs. 1967, Macrophages effect of cigarette smoke of action on staphylococcus, 165 Mammals see also specific mammals cells of, effect of cigarette smoke tars on, 343 Medical students see Occupations Methylbenzo(a)pyrene see Benzo(a)pyrene, 1-methyl- 9-Methyl carbazole see Carbazole, 9-methyl- Methylchrysenes see Chrysene, 1-methyl- Methyl-indole see Indole, 1-methyl- Methyl-n-butyinitrosamine e Butylamine, n-methyl-nitroso- N -Methylnicotinamide see Pyridinium compounds, 3-carba- moy)l-1-methy]- Mice bladder neoplasms in, induction by tryptophan metabolites, 296 rte lethal effects of nicotine on, 1 esophageal epithelium of, alcoholic benzo(a)pyrene penetrability of, 292 esophageal epithelium of, oil desolved benzo(a)pyrene penetrability of, 292 lungs of, effects of cigarette smoke on, 343, 344 lung neoplasm incidence in, from chrom- ium oxide dust exposure, 258 pulmonary carcinoma induction in, following asbestos dust inhalation, 257 pulmonary changes from chronic nitro- gen oxide inhalation, 161, 220 pulmonary changes in cigarette smoke inhaling, 159 pulmonary clearance in, cigarette smoke effects on, 170 resistance to pneumonia bacteria follow- ing cigarette inhalation, 173 respiratory tract of, cigarette smoke in- halation effect on, 268-269, 349-353 skin painting of, smoke condensates ef- fects on, 267, 337-342 Miscarriages see Abortion, spontaneous Mollusks ciliary function in, effect of cigarette smoke on, 223 Monkeys atherogenic effects of carbon monoxide and hypoxia, 64 ciliary function in, effect of cigarette smoke on, 222 fetal bronchial tubes of, effects of ciga- rette smoke on, 345 Rhesus, development of bladder neo- plasms from 2-naphthylamine, 296 squirrel, nitrogen oxide effects on resis- tance to pneumococcus, 173 Morbidity ratio CHD in smokers with predisposing fac- tors, 24 CHD in smokers vs. nonsmokers, 21-22, 24, 30-35 CHD, relation to smoking, 32-35, 37, 39 CHD, retrospective studies, 40, 93-97 in Danish twins, smoking effects on, 49-51 development of COPD in smokers vs. nonsmokers, 145, 195-205 Mortality rates from bladder neoplasms in U.S. for 1967, 293 from bronchopulmonary disease, 141-145 cerebrovascular disease, smokers vs. non- smokers, 66-67, 68-70 CHD, paired combinations of high risk characteristics in, 25 CHD, retrospective studies, 40, 93-97 CHD in smokers vs. nonsmokers, 24, 26-29 CHD in USS., 21 in Danish twins, smoking effects on, 51 from esophageal neoplasms in U.S. in 1967, 289 from kidney neoplasms in U.S, for 1967, 296 from lung neoplasms for 1939 vs. 1967 inUS., from lung neoplasms expected in 1970, 237, 239 from lung neoplasms in smelter workers exposed to arsenic, 257 from oral neoplasms in 1967, 285 449 from peptic ulcer in U.S. in 1967, 423 in former smokers, relation to CHD, 46, 47-48 in Swedish twins, smokers vs. non- smokers, 51 smokers vs. nonsmokers, 3 USS. male veterans from CHD, 26, 38 Mortality ratios CHD with high risk characteristics, esti- mated, 25 from esophageal neoplasms, prospective and retrospective studies, 289-291 from laryngeal neoplasm, 277-279 from lung neoplasms in smokers in Nor- way and Finland, 246 from lung neoplasms, in males by ciga- rette smoking duration, 240, 244 from pancreatic neoplasms in smokers and nonsmokers, 298-299 from peptic ulcer in smokers and non- smokers, 424 smokers vs. nonsmokers, from lung neo- plasms, 240-243 Mouth neoplasms frequency in smokers and nonsmokers, 8° smoking induced, 12 Mucopolysaccharides — as surfactants in lung tissue, 17 Mussels ciliary function in, effects of cigarette smoke on, 221, 222 Myocardium effects of hydrogen cyanide in smoke on, 62 oxygen consumption in nicotine stimu- lated, 59 oxygen requirements for, nicotine ef- fects, 58 2-Naphthylamine development of bladder carcinomas and papillomas in dogs, hamsters and mon- keys given, 296 suspected bladder carcinogen in tobacco smoke, 265 National Center for Health Statistics survey of U.S. smoking habits by, 54 survey on relationship of smoking and incidence of respiratory disease, 173 . National Clearinghouse for Smoking and Health responsibilities, 7 1970 survey of smoking, 6 National Cooperative Pooling Project mortality statistics from coronary dis- ease, 21-22 National Library of Medicine assistance in literature review on smok- ing, 7 Nawarai gas respifatory tract carcinoma in workers exposed to, 256 Negroes see Bracks Neonate see also Fetus, pregnancy, prematurity birth weight, effect of maternal smoking on, 389, 397-399 450 death, comparison of stillbirth and abor- tions in smoking and nonsmoking mothers, 395, 405-406 death, differences of birth weight and, in smoking and nonsmoking mothers, 404 death, smoking mothers effects on 415 tats, LDsg nicotine determination, 412 Neoplasms see also specific neoplasms, adenocarci- noma, carcinoma, lung neoplasms, etc. adenomatous, induction in mice by ciga- rette smoke inhalation, 350 bladder, in smokers and nonsmokers, 293-295, 381-384 bladder, methods of retrospective studies of smoking and, 293, 381-384 bladder, relationship of tobacco usage to, 299 bladder, relationship to cigarette smok- ing, 13, 299 bladder, U.S. mortality in 1967, 293 development in smoking dogs, percent- ages of, 274 esophageal, frequency in smokers and nonsmokers, 12, 238 esophageal, methods and results of retro- spective studies of tobacco use in, 289, 375-378 esophageal, mortality ratios, 289-291 esophageal, mortality rates for U.S. in 1967, 289 esophageal, relationship to smoking, 293 kidney, mortality rates in U.S. for 1967, 296 kidney, relationship to tobacco use, 13, 299 kidney, in smokers and nonsmokers, 238, 294-295 laryngeal, 12, 237-239, 281 laryngeal, relationship of tobacco use and development of , 354-357 laryngeal, relative risk ratios from tobac- co use, 277, 358 laryngeal, U.S. mortality in 1967, 277 lip, relationship to smoking, 289 lip, relationship to tobacco use, 361, 362, 365, 367 mammalian, cigarette smoke effect on, 343 oral cavity, relationship of tobacco use, 285, 361-367 oral cavity, relationship to smoking, 289 pancreas, relationship to smoking, 298-299 Netherlands cigarette smoke inhalation effects on mice respiratory tract in, 349 jung neoplasms in, retrospective smoking study of methods for, 323 serum lipid difference, in smokers vs. nonsmokers of, 101 New York City myocardial infarctions in cigar and pipe smokers in, 32, 38-39 New Zealand human experimental data on smoking and pregnancy, 408-409 Nickel compounds suspected carcinogenic agents in ciga- tette smoke, 265 Nickel workers see Occupations Nicotine atherogenic effects of 120-122 effect on blood lipids, 123-128 effect on blood pressure, 36 effects on cardiac rhythm of heart, 36 effects on cardiovascular system, 56-58, 107-118 effects on catecholamine release from adrenals, 36,119 effects on heart rate, 36 effects on myocardium oxygen demand, 38 effects on myometrial strips in gravidic women, 408 effects on peripheral vascular system, 72, 75, 133-134 effects on pregnancy, 411-414 induction of necrosis in arterial walls, 63 neurogenic effects of, 57 Nitrogen dioxide pulmonary changes in rodents chron- ically inhaling, 161, 220 Nitrogen oxide effects on resistance of squirrel monkeys to pneumococcus, 173 4-Nitroquinoline 1-oxide alcoholic solution of, development of papillomas in mice drinking, 292 N-Nitrosamines carcinogenicity in cigarettes smoke, 264-266 esophageal neoplasms induced in animals by, 292 Nitrosopiperidine see Piperidine, nitroso- Nitrosopyrrolidine gee Pyrrolidine, nitroso- N methylnicotinamide urinary excretion of, smoking effects on, 2 Nonsmokers see also Smokers vs. nonsmokers carboxyhemoglobin effects on oxygen uptake, 61 Norway lung neoplasms in, for pipe smokers, 244 lung neoplasm mortality in, relationship to tobacco use, 245-246 tracheobronchial tree changes in smokers and nonsmokers of, 259 Oat cell carcinoma see Carcinoma, oat cell Obesity relationship to CHD mortality, 43 relationship to smoking and CHD, 43-45 relationship with smoking in peripheral arteriosclerosis, 72 Occupations see also Industrial hazards asbestos workers, respiratory tract carci- noma, 256 asbestos workers, lung neoplasm mortal- ity in smoking, 257 bank employees, smoking and COPD, 198 coal miners, impaired pulmonary func- tion in smoking, 163 coal miners, respiratory tract carcinoma, 256 coal miners, smoking and COPD, 153, 197, 218-219 coal miners, smoking and ventilatory function, 207 flax mill workers, smoking and COPD, 199 government employees, blood pressure differences in smokers vs. nonsmokers, 99 longshoremen, mortality from smoking- related cerebrovascular disease, 70 longshoremen, mortality rates from CHD in, 28 longshoremen, smoking and COPD, 200 longshoremen, smoking and ventilatory function, 208 medical students, serum lipid differences in smokers vs. nonsmokers, 98 medical students, smoking and nicotine effects on blood lipid levels, 124 medical students, smoking and thrombo- sis relationships, 130 medical students, smoking and ventila- tory function, 209-210 nickel workers, lung neoplasms in, 256 physicians, bladder and kidney neo- plasms in smoking, 293, 294 physicians, cessation of smoking effect on COPD, 142 physicians, COPD mortality rates, 149 physicians, decline in cigarette smoking rates, 48 physicians, mortality from smoking- related cerebrovascular disease, 68 physicians, mortality rates from CHD, 6 physicians, mortality ratios from esopha- geal neoplasms, 290 physicians, mortality ratios from peptic ulcer in smoking and nonsmoking, 424 physicians, pulmonary function follow- ing cessation of smoking, 149 physicians, smoking and ventilatory function, 209-210, 213 plant workers, occupational exposure and smoking relationships to COPD, 153, 218, 219 plant workers, smoking and COPD, 198 plant workers, smoking and ventilatory function, 206-208 post office workers, blood pressure dif- ferences in smokers vs. nonsmokers, 104 post office workers, smokers and ventila- tory function, 209 post office workers, smoking and COPD, 200, 202 prisoners, serum lipid differences in smokers vs. nonsmokers, 100 prisoners, smoking and nicotine effects on peripheral vascular system, 133 railroad employees, coronary heart dis- ease, morbidity in smoking, 34 railroad employees, mortality and mor- bidity from CHD, 97 railroad employees, mortality rates from CHD, 28 smelter workers, lung neoplasm mortal- 451 ity from arsenic exposure, 257 soldiers, smoking and COPD, 197 steel workers, COPD development from dust exposure, 153 students, carbon monoxide effects on blood lipids, 129 students, infectious respiratory disease in smokers vs. nonsmokers, 228-229 students, mortality from smoking-related cerebrovascular disease, 68 students, mortality rates from CHD, 28 students, smoking and COPD, 201 students, smoking and nicotine effects on blood lipid level, 125 students, smoking and thrombosis rela- tionships, 130 students, smoking and ventilatory func- tion, 211 telephone company employees smoking and COPD, 200 textile workers, occupational exposure and smoking relationship to COPD, 218-219 transportation employees, smoking and COPD, 198, 202 transportation workers, air pollution re- lationship to COPD, 216 transportation workers, smoking and ventilatory function, 207, 212 utility company employees, CHD mor- bidity in smoking, 30 uranium miners, lung neoplasms in smokers and nonsmokers, 256 veterans, bladder and kidney neoplasms in smoking, 294-295 veterans, COPD mortality rates, 143 veterans, CHD morbidity in smoking, 32 veterans, effects of smoking on twin, 50 veterans, lung neoplasm mortality in smoker and nonsmoker, 241-243 veterans, mortality rates from CHD, 26, 38 veterans, mortality from smoking-related cerebrovascular disease, 69 veterans, mortality ratios from esopha- geal neoplasms, 290 veterans, mortality ratios from peptic ulcer in smokers vs. nonsmokers, 424 Oleic acid suspected carcinogenic agent in cigarette smoke, 266 Olive oil penetrability of benzo(a)pyrene in mice esophageal epithelium, 292 Oral cavity neoplasms estimated incidence in US. for 1970, 284 mortality from in 1967, 285 relationship of tobacco use, 285, 289, 361-367 Organs cultures of, cigarette smoke effects on cell growth and reproduction, 267, 343-345 Oropharynx neoplasms frequency in smokers and nonsmokers, 238 Oxygen see also Hypoxemia myocardial consumption of, following 452 nicotine stimulation, 58, 75 transport in body, carbon monoxide effects, 60, 75 uptake in nonsmokers with specific car- boxyhemoglobin levels, 61, 75 Palate hamster, C-14 labeled smoke particulates deposition in, 281-282 Pancreatic neoplasms relationship to smoking, 13, 238 relationship of smoking to mortality from, 298-299 Papain pulmonary effects on rats exposed to cigarette smoke with, 163 Papillomas development in mice drinking alcoholic benzopyrene, 292 formation following skin painting with smoke tars, 337-339, 341 induction in hamsters exposed to ben- zo(a)pyrene, 346-347 Pentolinium blockage of nicotine cardiac stimulation by, 57 Peoples Gas Light and Coke Co. study of CHD, serum cholesterol and smoking relationships, 43 Peptic ulcer antacid efficacy and healing of, effects of cigarette smoking on, 423 development in smokers, 13 mortality from, in U.S. in 1967, 423 mortality ratios from, in smokers and nonsmokers, 424 retrospective and cross section study methods for smoking relationship to, 425-427 Peroxides suspected carcinogenic agent in cigarette smoke, 265 Personality characteristics relationship to CHD and smoking, 48-49, 105-106 Pesticides content in cigarette smoke, 265, 266 Phagocytosis puimonary alveolar, in smokers vs. non- smokers, 165 Pharyngeal neoplasms Trequency in smokers vs. nonsmokers, 8 relationship to tobacco use, 362-364, 66 Phenol suspected carcinogenic agent of cigarette smoke, 266 Phospholipids function as surfactants in lung tissuc, 172 smokers vs. nonsmokers, 99-100, 102 Physical activity relationship to CHD and smoking, 41, 43,44 relationship to myocardial infarction, smokers vs. nonsmokers, 44 Physicians see Occupations Piperidine, nitroso- suspected carcinogenic properties in ciga- rette smoke from, 265 Pipe smokers atypical nuclei in male esophageal epi- thelium, 379 bladder neoplasms in, 293-294 cell rows and atypical cells in vocal cords of, 280, 359-360 COPD morbidity in, 146, 197-198, 201-205 development of chronic bronchopulmo- nary disease, 10 development of esophageal neoplasms, 13, 293 development of lung cancer, 11 development of oral neoplasms, 12 esophageal neoplasm mortality ratios, 0 kidney neoplasms in, 294-295 lack of risk in CVD, 67 laryngeal neoplasms induction, 12, 354-357 lung neoplasm incidence in Norway, 244 lung neoplasm incidence in rural Switzer- land, 244 lung neoplasm mortality in, 324-327 mortality rates from COPD, 142-143, 145 mortality ratios from pancreatic neo- plasms, 298 mortality ratios from peptic ulcer, 424 myocardial infarction in, 32, 38-39 peptic ulcer in, 427 relationship to infectious respiratory dis- ease, 227 relationship to laryngeal neoplasm devel- opment, 281 relationship to lip neoplasms, 289 relationship to oral cavity neoplasms, 361-364, 367 tisk of CHD, 8 a on lung neoplasm development, 6 Placenta ability to hydroxylate benzo(a)pyrene in smoking mothers, 407 Platelets adhesiveness of increased, from cigarette smoking, 9 aggregation of, cigarette smoking effects on, 36 blood, effect of smoking, 66, 75 Poland bladder neoplasms in, methods and re- sults in retrospective studies of smok- ing and, 382, 383 CHD mortality and morbidity in, 96 esophageal neoplasms in, retrospective studies of tobacco use with, 378 laryngeal neoplasms in, relationship to tobacco use, 357 relationship of tobacco use and neo- plasms of oral cavity in, 364 serum lipid differences in smokers vs. nonsmokers in, 100, 102 smoking and nicotine effects on human blood levels in, 124 smoking relationships to thrombosis in, 1 Pollution see Air pollution Polonium-210 suspected carcinogenic agent in cigarette smoke, 265-267, 335-336 Post office workers see Occupations Postoperative pulmonary complications see Respiratory system Potassium-40 present in tobacco leaf, 266 Pregnancy see also Abortion (spontaneous), pla- centa, stillbirth, neonate human, methods used in smoking study of , 391-396 maternal smoking during, effect on fetal growth and weight, 389, 397-399 maternal smoking during, effects on fetal growth, 13,415 nicotine effects on myometrial strips in, 408 unsuccessful, smoking effects on, 13 Prematurity maternal smoking and, 390, 400-403 Prisoners see Occupations Proteins see Lipoproteins Protozoae ciliary function in, effect of cigarette smoke on, 165, 224 Public Health Service review of medical literature on smoking hazards, 7 1967 study of, starting point for new studies, 4 Public laws see Laws Puerto Rico esophageal neoplasms in, retrospective studies of tobacco use with, 378 relationship of tobacco use and neo- plasms of oral cavity in, 367 Pulmonary system see Respiratory system Pyrrolidine, nitroso- suspected carcinogenic properties in ciga- rette smoke from, 265 Rabbits atherogenic effects of carbon monoxide and hypoxia, 64 atherogenic effects of nicotine, 120-122 blood lipids in, smoking and nicotine effects on 127 cardiovascular function in, smoking and nicotine effects, 108, 109 ciliary function in, cigarette smoke ef- fect on, 221-222 cholesterol fed, carbon monoxide effects on, 65-66 offspring of, nicotine and smoke effects on birth weight, 407 offspring, smoking effects on stillbirth and mortality, 411 pregnant, tritium-labeled nicotine effects in, 413 pulmonary changes in cigarette smoking, 159 pulmonary clearance in, cigarette smoke effect on, 164, 170, 171 453 skin painting, smoke condensate effects on, 267, 338 Railroad employees see Occupations Rats atherogenic effects of nicotine in, 120, 121 blood lipids in, nicotine and smoke ef- fects, 128 ciliary function in, cigarette smoke on, 221, 222 LDs9 nicotine determination in female, 412 lung neoplasms, from intrabronchial im- planting of chromium compounds, 258 lung neoplasms, from nickel carbonyl and dust inhalation, 256 lungs, cigarette smoke effects on surfac- tant activity, 172, 225 offspring, nicotine and smoke effects on birth weight, 407 pregnant, aromatic compound stimula- tion of placental BP-hydroxylase activ- ity, 414 pregnant, fetal wastage and neonate death in nicotine and smoking, 411 pulmonary carcinoma induction follow- ing asbestos dust inhalation, 257 pulmonary changes from chronic nitro- gen dioxide inhalation, 161, 220 respiratory tract of, cigarette smoke in- halation effects, 268, 349, 353 skin painting, smoke condensates effects, 267, 340 trachea of, cigarette smoke effects, 343 tracheal ligation of, cigarette smoke and papain effects on, 163 tracheobronchial tree of, cigarette smoke effects on, 268, 346-349 Reading ability in children of smoking mothers, 407 Reserpine nicotine cardiac stimulation blockage by, 57 Respiratory system see also Bronchopulmonary disease, larynx, lungs, trachea acute effect of cigarette smoke on human pulmonary function, 163, 166-169 animal, cigarette smoke instillation or implantation effects on, 268, 346-348 animal, effect of cigarette smoke inhala- tion on, 268-269, 349-353 effect of cigarette and cigar smoke on bronchial reactivity, 164 effect of cigarette smoke on human cili- ary function, 165, 221-224 effect of cigarette smoke on human pul- monary clearance, 164, 170 glossary of terms used in testing, 215 histological changes in smokers, 154-157 improvements in function following smoking cessation, 148, 149 pathological changes in cigarette smokers, 175 postoperative complication in, of smok- ers vs. nonsmokers, 174-176, 230 pulmonary alveolar phagocytosis in smokers vs. nonsmokers, 165 454 pulmonary infarction in dogs inhaling cigarette smoke, 271 surface tension of, effect of cigarette smoke on, 172, 225 surfactant activity of, in smokers vs. nonsmokers, 172, 225 surfactants in, definition, 172 tests of function of, in smokers, 146-147, 206-214 Respiratory tract diseases see also Asthma, bronchitis, broncho- pulmonary disease, emphysema, pneu- monia, tuberculosis infectious, smoking effects on, 172 226-229 infections, prevalency among smokers, 10, 176 pathological and cytological changes in, of smokers vs. nonsmokers, 258-263 ventilatory function in, smokers vs. non- smokers, 175 Rhodesia retrospective smoking study of methods for lung neoplasms in, 328 Rubidium-84 tracing capillary flow in coronary blood flow, 59 Rural populations, lung neoplasms in, suspected etiology of increased, 276 Rural residences lung neoplasm incidence in, in Switzer- land, 244 relationships of lung neoplasm to smok- ing, air pollution, and, 252-255 Russia atherogenic effects of nicotine on rabbits in, 120 atherosclerosis autopsy studies in, 54 cigarette tar effects on rat tracheobron- chial tree in, 348 Saccharides see Mucopolysaccharides Saliva interference in action of carcinogens on oral cavity, 288 Sarcoma formation following animal skin painting with smoke condensates, 338, 340 induction in rats by cigarette smoke in- jection, 346-347 Scotland see United Kingdom Sex ages of cigarette smokers by, 6 effect of, in alpha-antitrypsin deficiency emphysema, 151 effect of, on laryngeal neoplasm inci- dence development, 277 effect of, in mortality in cigarette smokers, 276 effect of, in lung neoplasms and tobacco use, 244, 329-333 lung cancer mortality by, 252 lung neoplasm development by, 11 mortality rates of cigarette smokers by, ratios of, in lung neoplasm mortality in Norway and Finland, 245-246 Sheep . pregnant, nicotine injection and smoke inhalation effects on, 414 Smelter workers see Occupations Smokers (former) . see also Cessation of smoking atypical nuclei in male esophageal epi- thelium in, 379-380 CHD mortality probability in, 46 incidence of CHD and mortality in, 46-48 lung neoplasm mortality ratios in, 241-242 lung neoplasms in, lowered rates, 11 mortality rates from COPD, 175 ie rates from ling neoplasms, Smokers vs. nonsmokers see also Nonsmokers bladder neoplasms in, 293-295, 381-384 cell rows and atypical cells in vocal cord of, 280, 359-360 CHD mortality in, 21-22 comparison of abortions, stillbirth and neonatal death in, 390. 405-406 development of COPD in, 141, 145, 195-205 differences in emphysema types in, 154, 156 effect of cigarette smoke on post-opera- tive pulmonary complications, 175 ad of sex on mortality from CHD, 28-31 esophageal epithelial cells with atypical nuclei in, 252 esophageal neoplasm mortality ratios in, 290-291 —— of tryptophan metabolites in, 7 : frequency of esophageal neoplasms in, 238 frequency of kidney neoplasms in, 238 frequency of mouth and pharyngeal neo- plasms in, 238 frequency of urinary bladder neoplasms in, 238 group characteristics in lung neoplasms and smoking in, 240, 244, 329-333 laryngeal neoplasms in, relationship to tobacco use, 354-357 lung fibrosis development in, 161 lung neoplasm mortality ratios in, 240-243 lung neoplasm mortality in uranium miners, 256 morbidity ratios from CHD, 24 mortality from cerebrovascular disease, 67-70 mortality from CHD, 24, 26-29 mortality from CHD in Swedish twins, 1 mortality from laryngeal neoplasms in, 237-238 mortality rates, 3 mortality ratios of COPD in, 142-144 mortality ratio from laryngeal neo- plasms, 278-279 mortality ratios from pancreatic neo- plasms in, 298 myocardial infarction relationships to physical activity, 44 pathological and cytological changes in respiratory tract of, 258-263 peptic ulcer in, correlated amounts of tobacco use, 427-428 postoperative hypoxemia in, 174, 230 postural hypoxemia mechanism in asymptomatic, 147 postoperative pulmonary complications in, 174-175, 230 . pulmonary alveolar phagocytosis in, 165 relation between CHD and serum choles- terol level, 43 relationship to infectious respiratory dis- ease, 172, 226-229 serum lipids in, 41, 98-102 surfactant activity in lungs of, 172, 225 type of lung neoplasms in male and fe- male, 250 - Snuff dippers of, relationship to neoplasms of oral cavity, 287, 361, 364-365 Social adjustments in children of smoking mothers, 407 Socioeconomic relationships in COPD, 152-153, 216-217 Soldiers see Occupations South Africa . esophageal neoplasms in, retrospective studies of tobacco use, 378 occupational exposure and ‘smoking rela- tionship to COPD in, 219 retrospective study of methods for lung neoplasms in, 328 serum lipid differences in smokers vs. nonsmokers in, 99 Spontaneous abortions see Abortions, spontaneous Squamous cell carcinoma see Carcinoma, epidermoid Steel workers see Occupations Stearic acid suspected carcinogenic agent of cigarette smoke, 266 Stillbirths abortions and neonatal death and, in smoking and nonsmoking mothers, 390, 405-406 effects of maternal smoking, 415 Students see Occupations Sugars see Glucose, mucopolysaccharides Surface tension see Respiratory system Surfactants see Respiratory system Sweden acute effects of cigarette smoke on human pulmonary. function, 168 blood pressure differences in smokers vs. nonsmokers in, 104 CHD mortality and morbidity in, 97 COPD morbidity in smokers in, 203, 205 effect of cigarette smoke on animals cili- ary function in, 221-224 esophageal neoplasms in, retrospective 455 studies of tobacco use with, 378 genetic studies of twins in, smoking ef- fects on, 50,99 laryngeal neoplasms in,relationship to tobacco use, 356 relationship of tobacco use and lip neo- plasms in, 361 relationship of tobacco use and neo- plasms of oral cavity, 364 serum lipid differences in smokers vs. nonsmokers of, 99 smoking and nicotine effects on human cardiovascular system, 115 smoking and nicotine effects on human peripheral vascular system, 133 tracheobronchial tree changes in smokers and nonsmokers in, 263 Switzerland CHD morbidity and mortality in, smokers vs. nonsmokers, 95 cigarette smoke effects on mice lung and kidney tissue in, 344 cigarette smoke inhalation effects on mice respiratory tract, 351 lung neoplasm incidence in cigar and pipe smokers of rural, 244 retrospective smoking study of methods for lung neoplasms in, 325 serum lipid differences in smokers vs. nonsmokers of, 100 Tachycardia development in dogs induced by nico- tine, 57 TAO see Thromboangiitis obliterans Tars, tobacco carcinogenicity on animal skin, 238 carcinogenic properties from cigarette smoke, 11, 264, 265 content in cigarettes, relationship to lung neoplasm development, 275, 276 sarcoma induction in rats following in- stillation, 346 skin painting with, carcinoma induction from, 337-342 Telephone company employees see Occupations Teratogenesis maternal smoking implications in, 407 in mice embryos, nicotine effects on, 4il Tetraethylammonium chloride blockage of nicotine cardiac stimulation by, 57 Textile workers see Occupations Thromboangiitis obliterans definition, 73 remission of, cessation of smoking ef- fects, 74 Thrombosis smoking effects on, 66, 130-132 Tissues cultures of, cigarette smoke effects on cell growth and reproduction, 267, 343-345 hypoxia of, carbon monoxide effects on, 61 Tobacco see also ali forms, e.g. Cigarettes, etc. 456 chewing of, relationship to lip and osaj cavity neoplasms, 36 1-363, 365-366 leaves, presence of potassium 40 in 266 Tobacco amblyopia , see Amblyopia Tobacco tars see Tars, tobacco Tongue hamster, C-14 labeled particulate depo- sition in, 281-282 Toxemia preeclamptic, incidence in smoking and nonsmoking mothers, 404, 407 Trachea hamster, C-14 labeled particulate depo. sition in, 281-282 Transportation employees see Occupations Triglycerides CHD incidence relationship to, 65 smokers vs. nonsmokers, 99-100, 102 Trypsin see Anti-trypsin, alpha, Tryptophan metabolism alterations by smoking, 297 alteration in urinary tract neoplasms by smoking, 13 carcinogenicity in mice bladders, 296 relation of excretion in smokers and nonsmokers, 297 Tuberculosis relationship of smokers vs. nonsmokers to, 172, 226-228 Tumorigenic agents see Carcinogens Twins angina pectoris development in, smoking effects on, 50-51 genetic studies of smoking effects on, 49-52 smoking effects on mortality and mor- bidity in, 51 Ulcers see Peptic ulcers United Kingdom bladder neoplasms in, methods in retro- spective studies of smoking and. 382-384 blood pressure differences in smokers vs. nonsmokers in, 103, 104 British Perinatal Mortality Survey of, 390, 395, 404, 415 cigarette smoke effects on human fetal lung and mice trachea, 344 cigarette smoke effects on human pul- monary function, 168, 169 cigarette smoke effects on mice respira- tory tract, 352 cigarette smoke implantation effects on rat tracheobronchial tree in, 346-347 comparison of abortions, stillbirths and neonatal deaths in smoking and non- smoking mothers, 406 COPD morbidity in smokers in, 195-197, 203, 204 effect of cigarette smoke on animal cili- ary function in, 221 human experimental data on smoking and pregnancy, 408 kidney and bladder neoplasms in smokers in, 294 lung cancer mortality in males in Eng- land and Wales, 240 maternal smoking and infant weight in, 397, 399 methods used in smoking study and human pregnancy, 391, 394-395 mortality from cerebrovascular disease telated to smoking in, 68 mortality rates from COPD in, lack of increase, 140 mortality ratios from esophageal neo- plasms in, 290 mortality ratios from laryngeal neo- plasms in, 278 mortality ratios from peptic ulcer in smokers and nonsmokers in, 424 occupational exposure and smoking rela- tionships to COPD in 218-219 peptic ulcer in, methods and results of retrospective and cross section studies of smoking and, 425-428 physicians in, decline in cigarette smok- ing rates, 48 physicians in, mortality from lung neo- plasms in smokers and nonsmokers, 41 pulmonary function in, cigarette smoke effects on, 168 relationships of lung neoplasms to smok- ing, air pollution, and residence in, 253-254 relationship of smoking tuberculosis in, 226 retrospective smoking study of methods for lung neoplasms in, 324, 326 serum lipid differences in smokers vs. nonsmokers in, 101, 102 smoking and nicotine effects on animal cardiovascular function in, 107 smoking and nicotine effects on human blood lipids in, 126 smoking and nicotine effects on human cardiovascular system in, 115 smoking relationships to thrombosis in, 131 United States acute effect of cigarette smoke on human pulmonary function in, 166-167, 169 atherosclerosis autopsy studies in, 53- 55 bladder neoplasms in, methods and re- sults in retrospective studies of smok- ing and, 381-384 blood pressure differences in smokers vs. nonsmokers in, 103-104 CHD mortality and morbidity in smokers vs. nonsmokers in, 30-35, 37, 93-94 comparison of abortions, stillbirth and neonatal death in smoking and non- smoking mothers, 405-406 cigarette smoke effects on animal tissues in, 343-345 cigarette smoke effects pulmonary sur- factants and surface tension, 172, 225 cigarette smoke implantation effects on animals tracheobronchial tree, 346-348 cigarette smoke inhalation effects on ani- mal respiratory tracts, 349-350, 352, 354 COPD morbidity in smokers in, 195, 196, 198-200, 201-202, 205 effects of cigarette smoke on animal cili- ary function in, 221-224 esophageal neoplasms in, retrospective studies of tobacco use, 378 esophageal neoplasm mortality in, in 1967, 289 human experimental data on smoking and pregnancy in, 408410 human pulmonary function following cessation of smoking in, 149 kidney and bladder neoplasms in smokers in, 293-295 jaryngeal neoplasm incidence in 1967, 277 laryngeal neoplasm in, relationships to tobacco use, 278-279, 354-355 lung neoplasm mortality in smokers and nonsmokers in, 240-243 maternal smoking and infant weight, 397-399 methods used in smoking study and human pregnancy, 391-395 mortality from aortic aneurysm related to smoking in, 71 mortality from cerebrovascular disease related to smoking, 68-70 mortality from lung neoplasms expected in 1970, 237, 239 mortality rates for bladder neoplasms in 1967, 293 mortality rates for COPD, increase of 139-140 mortality rates for kidney neoplasms in 1967, 296 mortality rates for lung neoplasms in 1939 vs. 1967, 239 mortality ratios for COPD, 142-145 mortality ratios for esophageal neo- plasms in, 290-294 mortality ratios for laryngeal neoplasms, 278-279 mortality ratios for pancreatic neoplasms in smokers and nonsmokers in, 298 mortality ratios for peptic ulcer in smokers and nonsmokers in, 424 occupational exposure and smoking rela- tionships to COPD in, 218-219 oral neoplasm incidence in, estimated for 1970, 284 peptic ulcer mortality in 1967 in, 423 peptic ulcer in, methods and results for Tetrospective and cross section studies of smoking and, 425, 426-428 polonium-210 levels in lungs of smokers in, 335-336 populations of, COPD development in, 10 relationship of human pulmonary histol- ogy and smoking in, 155-157 relationship of tobacco use and lip neo- plasms, 361-365, 367 relationship of tobacco use and neo- plasms of oral cavity, 361-365, 367 relationship of lung neoplasm to smok- ing, ait pollution, and residence in, 253-254 457 relationship of smoking to infectious res- piratory disease in, 227-229 retrospective smoking study methods for lung neoplasms in, 323-328 serum lipid differences in smokers vs. nonsmokers in, 98, 100, 101 smoking relationship to thrombosis in, 130, 131 smoking and nicotine effects on animal cardiovascular function in, 107-112 smoking and nicotine effects on human blood lipids, 123-126 smoking or nicotine effects on human catecholamine levels, 119 smoking and nicotine effects on human cardiovascular system, 113-114, 116, 117-119 smoking and nicotine effects on human peripheral vascular system, 133-134 surveys of cigarette smoking in, 6 tracheobronchial tree changes in smokers and nonsmokers in, 259-263 Uranium miners see Occupations Urban environment contribution to lung cancer mortality, 11 relationship of lung neoplasms, smoking, air pollution to, 252-255 Urban populations lung neoplasms in, suspected etiology of increased, 276 Urinary bladder see Bladder 438 Uterus cigarette smoking effects on gravidic, 408 Utility Company employees see Occupations Vascular system see also Blood circulation, cardiovascular system, cerebrovascular system, throm- boangiitis obliterans peripheral, smoking and nicotine effect on, 9, 72-73, 75, 133-134 Venezuela maternal smoking and infant weight in, 50 methods used in smoking study and human pregnancy, 445 Ventricular fibrillation death from, nicotine effects on, 36 Ventilatory function tests see Respiratory system Veterans see Occupations Virus influenza, cigarette smoke effects on re- sistance of mice with, 173 influenza, nitrogen oxide effects on squirrel monkey resistance to, 173 Vitamin deficiency relationship to tobacco amblyopia Xenon radioactive, regional pulmonary function using, 147 wy U.S. GOVERNMENT PRINTING OFFICE: 1971 O0—420-719