‘The Health Consequences of SMOKING U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service Health Services and Mental Health Administration The Health Consequences of Smoking January 1973 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. 20102 Price $1.85 domestic postpaid or $1.50 GPO Bookstore Stock Number 1723-00064 Preface This report is the seventh in a series issued by the Public Health Service reviewing and assessing the scientific evidence linking ciga- rette smoking to disease and premature death. The current report reiterates, strengthens, and extends the findings in earlier reports that cigarette smoking is a major health problem in the United States, The evidence has broadened dramatically in recent years. A Public Health Service assessment of evidence available in 1959 was largely focused on the relationship of cigarette smoking and lung cancer. The first formal report on this subject in 1964 found that cigarette smoking was not. only a major cause of lung cancer and chronic bronchitis, but was associated with illness and death from chronic bronchopulmonary disease, cardiovascular disease, and other diseases. The 1973 report confirms all these relationships and adds new evidence in other areas as well. The evidence in the chapter on preg- nancy strongly indicates a causal relationship between cigarette smoking during pregnancy and lower infant birth weight and a strong, probably causal, association between cigarette smoking and higher late fetal and neonatal mortality. Also reported is the convergence of other evidence which suggests that cigarette smoking during pregnancy interacts with other risk factors to increase the risk of an unfavorable outcome of pregnancy for certain women more than others. For the first time in this series of reports, a separate chapter is devoted to pipe and cigar smoking and the health hazards involved. Included is an assessment of the health implications of the new small “gars which look like cigarettes. A final chapter, new to the reports, concerns cigarette smoking and *xereise performance. A review of a number of fitness tests comparing “mokers to nonsmokers indicates that cigarette smoking impairs exer- “Ise performance for many types of athletic events and activities in- volving maximal work capacity. The interrelationships of smoking and health are no less complex today than they were reported to be in the 1964 report. But since that time we have greatly broadened our knowledge and understanding “f the problem. The current report symbolizes this progress. VUbees. te ab nue . Meruin K. Du Vat, M.D., Assistant Secretary for Health. Decewper 13, 1972. iii Table of Contents Page PREFACE.___._-_-.-_---_---- == eee ili TABLE OF CONTENTS... ____-----2-- ee v PREPARATION OF THE REPORT AND ACKNOWL- EDGMENTS._.___--__._- 2-2 ee vii Chapter 1. Cardiovascular Diseases________._______._____. xii Chapter 2. Nonneoplastic Bronchopulmonary Diseases. -___-___ 33 Chapter 3. Cancer________._-_._____-----_---_--- eee 65 Chapter 4. Pregnancy.______.._______._.----_-___-----_- 99 Chapter 5. Peptic Ulcer Disease. .___..._.____-_.__._____- 153 Chapter 6. Pipe and Cigar Smoking. _____._..-_.____.-___. 167 Chapter 7. Exercise Performance._______..________...___-- 239 INDEX Preparation of the Report and Acknowledgments “Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service,” subsequently referred to as the “Surgeon General’s Report,” was published in 1964. The National Clearinghouse for Smoking and Health, established in 1965, has the responsibility for the continuous monitoring, compilation, and review of the world’s medical literature which bears upon the health consequences of smoking. As called for by Public Law 89-92, the following three reviews of the medical literature on the health conse- quences of smoking, which had come to the attention of the Clearing- house since the original “Surgeon General’s Report,” were sent to the Congress: 1. “The Health Consequences of Smoking, A Public Health Service Review : 1967” (submitted July 1967). 2. “The Health Consequences of Smoking, 1968 Supplement to the 1967 PHS Review” (submitted July 1968). 3. “The Health Consequences of Smoking, 1969 Supplement to the 1967 PHS Review” (submitted July 1969). Public Law 91-222 was signed into Jaw on April 1, 1970, and called for an 18-month interval between the 1969 supplement and the next report. During this period, a comprehensive review of all of the medi- cal literature available to the Clearinghouse relating to the health consequences of smoking was undertaken, with an emphasis upon the Most recent additions to the literature. The product of this review was: “The Health Consequences of Smoking, A Report of the Surgeon General: 1971,” submitted to the Congress in January of 1971. Sub- sequently, a review of the medical literature in the field, which had ‘ome to the attention of the Clearinghouse since the publication of the 1971 report, was published as, “The Health Consequences of Smoking, . at of the Surgeon General: 1972,” submitted in January of N72. vii Every report published since the original “Surgeon General’s Re- port” has contained a review of the medical literature relevant to the association between smoking and cardiovascular disease, nonneoplastic bronchopulmonary disease, and cancer. Several of the reports in- cluded reviews of the relationship between smoking and peptic ulcer disease (1967, 1971, 1972) and cigarette smoking and pregnancy (1967, 1969, 1971, 1972). Other topics relating to the use of tobacco have received special emphasis in single reports: 1. Tobacco Amblyopia (1971 Report). 2. Allergy (1972 Report). 3. Public Exposure to Air Pollution From Tobacco Smoke (1972 Report). 4. Harmful Constituents of Cigarette Smoke (1972 Report). 5. Noncancerous Oral Disease (1969 Report). The present document, “The Health Consequences of Smoking: 1973,” includes reviews of the relationships between smoking and cardiovascular disease, bronchopulmonary disease, cancer, and peptic ulcer disease which are based upon medical literature which has become available to the Clearinghouse since the publication of the 1972 report. It also includes special reviews of the health consequences of pipe and cigar smoking and of the relationship between cigarette smoking and the outcomes of pregnancy. The material in these two latter chapters-reflects a comprehensive review of the pertinent world medical literature which has come to the attention of the Clearing- house since the publication of the original “Surgeon General’s Re- port,” including material which has become available since the 1972 report. The final chapter in this year’s report is a review of the rela- tionship between.smoking and exercise performance, an area not covered previously in any report. ‘With the exception of “Chapter 4, Pregnancy,” each chapter is orga- nized in a similar fashion. The introduction to each chapter is a sum- mary of the work reviewed in previous reports. The summary of each chapter encompasses only the work which has most recently become available to the Clearinghouse. The pregnancy chapter is organized into separate sections according to several different outcomes of preg- nancy. Each section includes a brief review of previously reported work and contains its own separate summary, in place of an overall summary for the entire chapter. viii The preparation of this report was accomplished in the following fashion : 1. The continuous monitoring and compilation of the medical liter- ature on the health consequences of smoking was accomplished through several mechanisms. (a) An information science corporation is on contract to extract articles on smoking and health from the medical literature of the world. This organization provides a semimonthly ac- cessions list with abstracts and copies of the various articles. Translations are called for as needed. Articles are classified according to subject and filed by a series of code words and phrases. (6) The National Library of Medicine, through the Medlars system, sends the National Clearinghouse for Smoking and Health a monthly listing of articles in the smoking and health area. These are reviewed, and articles not identified by the information science corporation are ordered. (c) Staff members review current medical literature and identify pertinent articles. bo - The first drafts of the individual chapters were sent to reviewers for criticism and comment with respect to the articles reviewed, articles not included, and conclusions. The drafts were then re- vised until they met with the general approval of the reviewers. The final drafts were reviewed as a whole by the Director of the National Clearinghouse for Smoking and Health, the Director of the National Cancer Institute, the Director of the National Heart and Lung Institute, the Director of the National Institute of Environmental Health Sciences, the Surgeon General, and by additional experts both within and outside of the Public Health Service. Acknowledgments The National Clearinghouse for Smoking and Health, Daniel Horn, Ph. D., Director, was responsible for the preparation of this report. Mesdlical Staff Director -for the report was Elvin E. Adams, M.D., Assistant Medical Staff Director was H. Stephen Williams, M.D. con- sulting editors were Daniel P. Asnes. M.D., David G. Cook, M.D., and ohn H. Holbrook, 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 the Government. Their contributions are gratefully acknowledged. Special thanks are due the following: ANDERSON, WILLIAM H., M.D.—Chief, Pulmonary Section, School of Medicine, University of Louisville, Louisville, Ky. AUERBACH, O8caR, M.D.—Senior Medical Investigator, Veterans Administration Hospital, East Orange, N.J. Ayres, STEPHEN M., M.D.—-Director, Cardiopulmonary Laboratory, Saint Vincent’s Hospital and Medical Center of New York, New York, N.Y. Bock, Frep G., Ph. D.—Director, Orchard Park Laboratories, Roswell Park Memorial Institute, Orchard Park, N.Y. Boren, Hoiiis G., M.D.—Medical Investigator, Veterans Administration Hos- pital, Tampa, Fla. BovuTWELL, RoswEtt K., M.D.—Professor of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wis. Bross, Inwin, M.D.—Director of Biostatistics, Roswell Park Memorial Institute, Buffalo, N.Y. Cooper, THEODORE, M.D.—Direetor, National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. EPSTEIN, FREDERICK H., M.D.—Director and Professor of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Mich. Fak, Hans L., Ph. D.—Associate Director for Program, National Institute of Environmental Health Sciences, Research Triangle Park, N.C. Ferris, BENJAMIN G., Jr., M.D.—Professor of Environmental Health and Safety, School of Public Health, Harvard University, Boston, Mass. Frazier, Topp M.—Assistant Director, Harvard Center for Community Health and Medical Care, School of Public Health, Harvard University, Boston, Mass. F RESTON, JAMES, M.D.—Agsociate Professor of Medicine, Head, Division of Gastroenterology, University of Utah Medical School, Salt Lake City, Utah. GoLpsMITH, JoHN R., M.D.—Head, Environmental Epidemiology Unit, Bureau of Occupational Health and Environmental Epidemiology, California State De- partment of Public Health, Berkeley, Calif. : Gort, Gio Batta, M.D.—Associate Scientific Director for Program, Division of Cancer Cause and Prevention, National Cancer Institute, Bethesda, Md. Hieotns, Ian T. T., M.D.—Professor of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Mich.. HorrMANN, Dietricu, Ph. D.—Chief, Division of Environmental Carcinogenesis, American Health Foundation, New York, N.Y. KELLER, ANDREW Z., D.M.D.—Chief, Research in Geographic Epidemiology, Vet- erans Administration Central Office, Washington, D KIRSNER, JOSEPH B., M.D., Ph. D.—Chief of Staff and Deputy Dean for Medical Affairs, The Pritzker School of Medicine, University of Chicago Hospitals and Clinics, Chicago, IIL. Ko.sye, ALBert C., Jr., M.D. J.D.—Deputy Director, Bureau of Foods, Food and Drug Administration, U.S. Department of Health, Education, and Welfare, Washington, D.C. Krum Hoiz, Ricwarp A., M.D.—Medical Director, Institute of Respiratory Dis- eases, Kettering Medical Center, Kettering, Ohio. ; LILIENFELD, ABRAHAM, M.D.—Professor and Chairman, Department of Epidem- iology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Md. McLean, Ross, M.D.=~Professor of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, N.C. McMILLAN, GARDNER C., M.D.—Chief, Arteriosclerotic Disease Branch, National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. MacMauon, Brian, M.D.—Professor of Epidemiology, School of Public Health, Harvard University, Boston, Mass. MEYER, Mary B., M.S.—Assistant Professor of Epidemiology, The Johns Hopkins University, Baltimore, Md. MITCHELL, Roger 8., M.D.—Chief of Staff, Veterans Administration Hospital, Denver, Colo. MurpHy, EpMonp A., M.D., Sc. D.—Associate Professor of Medicine and Bio- statistics, The Johns Hopkins Hospital, Baltimore, Md. NETTESHEIM, PauL, M.D.—Group Leader, Respiratory Carcinogenesis, Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tenn. PAFFENBARGER, RALPH §., Jr., M.D.—Chief Epidemiology Section, Bureau of Adult Health and Chronic Diseases, California State Department of Public Health, Berkeley. Calif. Pererson, WILLIAM F., M.D.—Chairman, Department of Obstetrics and Gyne- cology, Washington Hospital Center, Washington, D.C. Perry, THoMas L., M.D.—Associate Professor of Medicine and Head, Division of Pulmonary Diseases, University of Colorado Medical Center, Denver, Colo. Ratt, Davip P., M.D.—Director, National Institute of Environmental Health Sciences, Research Triangle Park, N.C. RauscHer, Frank J., M.D.—Director, National Cancer Institute, National Insti- tutes of Health, Bethesda, Md. REINKE, WILLIAM A. Ph. D.—Professor, Department of International Health, The Johns Hopkins University, Baltimore, Md. Renzertt, Arritio D., IJr., M.D.—Professor of Medicine, Pulmonary Disease Division, University of Utah Medical Center. Salt Lake City, Utah. Rosins, Morton—Chief of Study, Design, and Analysis Staff, Regional Medical Programs Service, Health Services and Mental Health Administration, Rock- ville, Md. SAFFIOTTI, UMBERTO, M.D.—-Associate Scientific Director for Carcinogenesis, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Md. Scuuman, LEonarp M., M.D.—Professor and Head, Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minn. SHIMKIN, MICHAEL B., M.D.—Professor of Community Medicine and Oncology and Coordinator, Regional Medical Program, University of California at San Diego, La Jolla, Calif. STAMLER, JEREMIAH, M.D.—Professor and Chairman, Department of Community . Health and Preventive Medicine, Northwestern University, Chicago, Ill. Vay Dovren, BENJAMIN L., M.D.—Professor of Environmental Medicine, Insti- tute of Environmental Medicine, New York University Medical Center, New York, N.Y, VYNDER, Eenest L., M.D.—President, American Health Foundation, New York, N.Y, _ The following additional staff members of the National Clearinghouse for “oking and Health contributed to the preparation of this report: Richard H. Amacher, Marjorie L. Brigham, Emil Corwin, Lillian Davis, Gertrude P. Herrin, Robert g, Hutchings, Jennie M. Jennings, Nancy S. Johnston, Dan Nemzer, mn Ritchie, James A. Robertson. Donald R. Shopland, and Kathleen H. “mith. CHAPTER 1 Cardiovascular Diseases Contents Introduction________.-.._.._-2- 22 eee Coronary Heart Disease Epidemiological Studies Smoking and Certain Risk Factors Blood Lipids_-__.____.__._._____----- 22 eee Electrocardiogram Experimental Studies Smoking and Thrombosis Cerebrovascular Disease___.______.__._._.--_-_----------- Peripheral Vascular Disease_.__.__._._.-__--___--___--__-- Summary of Recent Cardiovascular Findings References List of Figures Figure 1—Age-adjusted incidence rates of CHD by body weight and cigarette smoking (white males)_.._._._._____- Figure 2.—Age-adjusted incidence rates of CHD comparing farmers who smoke cigarettes with nonsmoking farmers___- Figure 3.—Standardized mortality ratios for arteriosclerotic heart disease for males and females by age at initiation of Cigarette smoking (Prospective study 1966-1970). ___.___- Figure 4.—The effect of cigarette smoke inhalation on the ven- tricular fibrillation threshold (VFT) of normal dogs and dogs ne experimentally produced acute myocardial infarction MI Figure 5.—Effects of smoking five consecutive cigarettes on _Plasma nicotine concentration..........---.------------- ‘eure 6.—Relative risk of developing arteriosclerosis oblit- _frans (ASO) for males by amount of cigarettes smoked - - - Figure 7.—Relative risk of developing arteriosclerosis oblit- ‘tans (ASO) for females by amount of cigarettes smoked __. 13 15 17 19 19 19 23 24 14 16 20 21 Introduction In the United States, coronary heart disease (CHD) is the leading cause of death and is the largest contributor to excess deaths among cigarette smokers. The following is a brief summary of the major relationship between smoking and cardiovascular diseases as outlined in previous reports of the health consequences of smoking (62, 63, 64,65, 66, 67). Many prospective and retrospective epidemiological studies have identified cigarette smoking, elevated serum cholesterol, and high blood pressure as major risk factors for the development of coronary heart disease. Cigarette smoking acts independently of and synergis- tically with the other CHD risk factors to greatly increase the risk of developing coronary heart disease. The risk of developing CHD for pipe and cigar smokers is much less than it is for cigarette smokers, but more than it is for nonsmokers. In the United States, cigarette smoking can be considered the major cause of cor pulmonale since it is the most important cause of chronic nonneoplastic bronchopulmonary disease. Autopsy studies have demonstrated that aortic and coronary athero- sclerosis are more common and severe, and myocardial arteriole wall thickness is greater, in cigarette smokers than in nonsmokers. Those who stop smoking cigarettes experience a decreased risk of death from coronary heart disease compared to that of continuing smokers. Experimental studies in humans and animals suggest that cigarette smoking may contribute to the development of CHD through the action of several independent or complementary mechanisms: The formation of significant levels of carboxyhemoglobin, the release of catecholamines, inadequate myocardial oxygenation which may result from a number of mechanisms, and an increase in platelet adhesiveness which may contribute to acute thrombus formation. There is evidence that cigarette smoking may accelerate the pathophysiological changes of preexisting coronary heart disease and therefore contributes to ~udden death from CHD. Recently published epidemiological, autopsy, and experimental in- ‘estigations have added to the understanding of the association be- tween smoking and cardiovascular diseases. 495-028 O—73-—-2 Coronary Heart Disease Epidemiological Studies Smoxine aNp Certain Risk Factors A prospective epidemiological study of the factors asscciated with cardiovascular diseases was conducted among the 4,847 white and 2,484 black men and women of Evans County, Ga. (23). The investigation was initiated with a private census and preliminary examinations beginning in 1960. Followup examinations were conducted after 7 years. Cassel (73) reported that high blood pressure, elevated serum cholesterol, and cigarette smoking were major risk factors for the development of coronary heart disease. Increased body weight, an elevated hematocrit, and ECG abnormalities were additional factors that were associated with elevated CHD rates. A significant finding of this study was the very low prevalence and incidence of coronary heart disease (myocardial infarction and angina pectoris) in black men. The age-adjusted prevalence rates among black men were only half those of white men. The study showed that blacks were affected by the various risk factors for CHD in a similar fashion to whites but at a lower level of disease. This appeared to be true for any level of any risk factor or any combination of risk factors. Greater physical activity of blacks as compared to whites appeared to account for part of the observed dif- ference in rates. In this study, subjects were classified on the basis of their smoking history at enrollment and both current smokers and exsmokers were considered smokers. Both black and white male smokers had a higher incidence of CHD than did nonsmokers, but white males had a higher incidence than blacks whether they were smokers or not. The age- adjusted incidence rate for white nonsmokers was 52.7 per thousand compared to 9.8 per thousand for black nonsmokers. White smokers had an incidence of 101, whereas the rate in black smokers was only 32.5. The prevalence of CHD increased with the number of cigarettes smoked per day in both groups. The combined effect of body weight and cigarette smoking on the incidence of CHD was also examined (20). The “Quetelet index” * was used to determine relative weight. The risk of developing CHD did not change with increases in relative weight among nonsmokers, but smokers experienced a substantial risk of developing CHD with increases in weight (fig. 1). The relationship of smoking to occupation and CHD was examined (14). Farmers who performed sustained physical activity had lower rates of CHD than nonfarmers. Figure 2 shows that, while smoking increased the risk of CHD in both farmers and nonfarmers, farmers had lower rates than nonfarmers whether or not they smoked. welght " Quetelet index = height? 100. Figure 1.—Age-adjusted incidence rates of CHD by * body weight and ' cigarette smoking (white males). 160 — 150 150 + Nonsmoker y 140 + * Smok y 130 } moker 120 fF 110 + 100 F Y 90 | 90 *Rate 8OF 80 51 | Vl / /; 3 8 * Distribution Lower third Middle third Upper third by weight (lean) (obese) Number 90 183 99 161 127 119 Cases 5 15 3 14 16 9 1 Smokers excluding ex-smokers. 287 months follow-up period. + Based on Quetelet index. SOURCE: Heyden, S., et al. (26). Figure 2.—Age-adjusted incidence rates of CHD comparing farmers who smoke cigarettes with nonsmoking farmers. 200 Farmers VW. Nonfarmers 158.2 150 } 98.3 100 | 93.7 Rate per y 1,000 59.6 males 50 | YY, Uj , Y, L. Cases... . (8) (9) (ll) (39) Nonsmokers Smokers and Ex-smokers SOURCE: Cassel, J. C., et al. (14). Hirayama (27) reported 5-year followup data on smoking in rela- tion to death rates from a large prospective epidemiological study of 265,118 men and women in Japan. This investigation was the first of its kind to be conducted in an Asian population. During the followup Period, 11,858 deaths occurred during 1,269,382 person years of obser- vation. Male and female cigarette smokers experienced higher mor- tality rates from arteriosclerotic heart disease than did nonsmokers. Among cigarette smokers, the mortality ratios for arteriosclerotic heart. disease were 1.56 (P<0.001) for men and 1.44 (P<0.05) for women. Dose-response relationships were found for both men and women as 'easured by the number of cigarettes smoked per day and age at initia- hon of smoking (fig. 3). Figure 3.—-Standardized mortality ratios for arteriosclerotic heart disease for males and females by age at initiation of cigarette smoking (Prospec- tive study 1966-1970). 2.00 - 1.52 1.50 4 GY Mortality Y; ratio 1.00 1.00 - 7, 0.50 + o00 LI Age at start Non- >24 20-24 <20 of smoking smoker SS: SS SOURCE: Hirayama, T. (27). Gordon, et al. (22, 57), in a further analysis of the F ramingham data, considered both by univariate and multivariate analysis the rela- tion of certain key characteristics to the development of coronary heart disease. The characteristics were : High blood pressure, elevated serum cholesterol, cigarette smoking, left ventricular hypertrophy diagnosed by electrocardiogram, and glucose intolerance. Cigarette smoking emerged as one of the important risk factors for the development of coronary heart disease. There was a strong association between ciga- rette smoking and CHD other than angina pectoris, particularly among young male and female smokers. The relative role of cigarette smoking as a risk factor was emphasized by multivariate analysis. Cigarette smoking was not as strongly related to CHD in women as it was in men. This may have been in part due to the fact that there are fewer heavy smokers among women, and women tend to inhale smoke less than men. Kagan, et al. (.3/) reported preliminary findings from the Honolulu Heart Study. The effect of migration on dietary patterns and the inci- dence of cardiovascular diseases in a cohort of men of Japanese ances- try born between 1900 and 1919, who were residents of Oahu in 1965, was examined in this prospective study. During the 2 years of fol- lowup, 101 men developed CHD in the population of 8,006 men ini- tially examined. A significant relationship to CHD was found for the following risk factors: Cigarette smoking, elevated systolic and dia- stolic blood pressure, increased serum cholesterol, triglycerides or uric acid, and various measures of obesity. Using data from the International Cooperative Study on Cardio- vascular Epidemiology, Keys, et al. (34) calculate the probabilities for men aged 40 to 59 to develop coronary heart disease in 5 years. The authors noted “* * * that the relative CHD risk of different men within a given population is well predicted from the results of the multivariate analysis of the experience of men in other far-distant populations differing in socioeconomic circumstances, language, and ethnic background.” Although the CHD incidence rate of European men was about half that of the Americans, the fact still remained that investigation of the four variables (cigarette smoking, age, systolic blood pressure, and cholesterol) was sufficient to identify men whose likelihood of dying of CHD or having a definite myo- cardial infarction within 5 years was greatly above the average. Punsar (51) reported 10-year followup data on the cohort of men in Finland who were part of the seven-country study of coronary heart disease, confirming that cigarette smoking was a major risk factor for CHD. The authors reported a 1.7-fold increase in CHD mortality among cigarette smokers. They estimated that 1,700 excess CHD deaths occur each year among cigarette smoking men in Finland. Kozarevic, et al. (38) reported the results of the initial prevalence survey and the 2-year incidence data from the Yugoslavian study of cardiovascular disease. A total of 11,121 men between the ages of 35 and 62 were examined in the towns of Tuzla and Remetinec. Criteria for the diagnosis of CHD were based on objective electro- cardiographic findings of myocardial infarction, left bundle branch block, or sudden death. A very low prevalence of myocardial infarc- hon was initially found, and only 36 new cases of CHD developed over the 2-year period. The subjects who developed CHD smoked "igarettes at about the same level as the total study population. The annual average incidence rate of acute coronary heart disease was ‘bout 1.6 per 1,000 among both the smokers and nonsmokers. The CHD ineldence rates found in this Yugoslavian study are appreciably below those found in the United States. . Comstock (16) examined the association between water hardness, “arlous other environmental factors including cigarette smoking, and death from CHD. A total of 189 deaths from CHD occurred in the a en of Washington County, Md., in the 3-year period follow- me a in 1963. For each case, two controls were randomly selected a ie census lists and matched for race, sex, and year of birth. The pe risk of CHD for all smokers was 1.5 compared to nonsmokers <0.05). This relative risk among cigarette smokers was dose- related; persons smoking more than two packs a day had the highest risk of CHD. No significant association was found between CHD and water hardness. Casciu, et al. (2), reported the prevalence of cardiovascular disease among 4,668 miners on Sardinia. Smoking and drinking habits, blood pressure, and heart rates were recorded. Smokers had higher rates of CHD than nonsmokers, and a dose-response was noted with the number of cigarettes smoked per day. The prevalence of myocardial! in- farction was 0.9 percent for nonsmokers, 1.62 percent for smokers of 10 or less cigarettes, 2.34 percent for smokers of 11 to 20 cigarettes, 9.9 percent for smokers of 20 or more cigarettes a day, and 1.42 percent for cigar or pipe smokers. When cigarette smokers were grouped by alcohol consumption, no significant difference was found in the prev- alence of myocardial infarction between drinkers and nondrinkers, Kornitzer, et al. (35, 36, 37) examined the prevalence of CHD in 566 male bank employees aged 40 to 59 in Brussels. They determined an individual’s smoking history, blood lipids, ECG, peak flow rates, relative weight, skinfold thickness, and blood pressure. The preva- lence of possible CHD as determined by ECG and CHD history was 7.1 percent in nonsmokers, 11.6 percent in cigarette smokers who in- haled, 6.9 percent in cigarette smokers who did not inhale, 10.6 percent in smokers of pipes and cigars, and 15.5 percent in the ex-smokers, Among the various risk factors examined, the strongest association was found for elevations in the serum cholesterol and the other blood lipids examined. Weaker associations were found for increased rela- tive weight, high blood pressure, and tobacco use. Agnese, et al. (2) examined 265 patients in Italy aged 20 to 65 years who had myocardial ischemia. Patients were matched with an equal number of controls by age. A number of risk factors for CHD were measured in both groups. Cigarette smoking and elevated serum cholesterol were identified as major risk factors for CHD, particularly for individuals under the age of 50. Boudik (20) found the prevalence of myocardial infarction to be significantly (P<0.001) higher in cigarette smokers than in non- smokers in a population of 8.292 Czechoslovakian men between the ages of 52 and 67. Storch, et al. (60). Estandia Cano, et al. (17), and Jakuszewska (30), in studies in Germany, Mexico, and Poland of CHD in individ- uals under the age of 40, reported that cigarette smoking was the dominant factor in the development of CHD in these patients. Golovchiner (27) found cigarette smoking to be a significant factor in the development of myocardial infarction in a study of 530 patients with CHD in Leningrad hospitals. Three studies without control groups from New Zealand (59), Nepal (47), and India (58) reviewed the prevalence of various risk factors, including cigarette smoking in populations with documented CHD. Bioop Lirms In most of the following studies where the effect of cigarette smok- ing on blood lipids was examined, there was no control for dietary factors that may independently affect serum lipid levels. Schwartz, et al. (56) examined serum lipids in relation to smoking habits and relative weight in 7,972 male employees of the Parisian Civil Service in the city of Paris. Cigarette smoking was associated with a slight but significant (P<0.001) increase in serum cholesterol. The authors found a positive correlation between increased relative weight and srum cholesterol levels, and a negative correlation between rela- tive weight and smoking habits. These factors would operate in such a way as to reduce the apparent effect of cigarette smoking on the cholesterol levels. After controlling for relative weight, however, the investigators found a significant (P<0.001) positive relationship be- tween smoking and serum cholesterol. In a study of various factors in relation to the mean serum choles- terol. Pincherle (48) examined the following parameters: blood pres- sure, height, weight, and skinfold thickness, X-ray findings of the thest and abdomen, the electrocardiogram, and smoking history; 1.000 British business executives between the ages of 25 and 65 were examined. A significant association was found between elevated serum rholesterol, obesity, elevated systolic blood pressure, inadequate exer- “ise, radiographic evidence of arterial calcification of the iliac arteries, anl certain other factors. The increase observed in mean serum choles- terol _ increasing number of cigarettes smoked was not statistically “ynificant, tomslo (53) studied the distribution of serum lipids in 324 Nor- “eghin military recruits. Cigarette smokers had a small but insignifi- “Ant Increase in serum triglycerides. No elevation was found for serum cholesterol. The subjects were young, and most smokers had only ‘uoked for a few years. te Burney and Enslein (//) investigated changes in clinical laboratory ek as related to aging and smoking in a 5-year study of 502 healthy ‘le veterans. It was found that five variables were needed to predict {f¢-related changes in those over 50. These were: fasting blood glu- cose, 2-hour post-glucose blood sugar, total serum protein, hemoglobin, and cholesterol esters. No significant differences in the laboratory data between smoking and nonsmoking subgroups were found. Vlaicu, et al. (70) examined the interaction of cigarette smoking with blood pressure and serum lipids in 100 patients with angina pec- toris who were between the ages of 40 and 59. Half the patients were smokers using more than 25 cigarettes a day. The smokers had lower serum lipids and lower blood pressure than the 50 nonsmoking pa- tients with angina pectoris. Miturzynska-Stryjecka, et al. (43) found that cigarette smoking immediately following a fatty meal did not significantly alter the serum free fatty acid, esterified fatty acid, cholesterol, or plasma tur- bidity levels over control values. Ciampolini, et al. (16) examined the effects of cigarette smoking on blood lipid values in 10 healthy volunteers between the ages of 20 and 40. Cigarette smoking resulted in a prompt rise in free fatty acids and a delayed rise in serum triglycerides. The relationship between cigarette smoking and changes in various serum lipid levels has not been clearly determined. Studies in this area continue to present conflicting results. ELECTROCARDIOGRAM Wysokinski (76) examined the effect of smoking on certain param- eters of cardiovascular function in 100 healthy nonsmokers and 100 healthy smokers who were military recruits 19 to 25 years of age in Poland. Significant prolongation of the QRS interval (P<0.001), flat- tening of the T wave, and ST segment depression following exercise were seen more frequently in the smokers than in the nonsmokers. Van Buchem, et al. (69) examined the occurrence and significance of extrasystoles and conduction disorders in 760 healthy Dutch men between the ages of 40 and 67 who were followed for 7 years. The pres- ence of extrasystoles was not correlated with cigarette smoking or ele- vated serum cholesterol and was not associated with the development of CHD over the 7-year period. Kattus, et al. (33) tested 314 healthy males 23 to 82 years of age for ischemic ST segment depression on the ECG during or after submaxi- mal exercise. The abnormal ST segment depression identified in 30 subjects was correlated significantly with elevated serum cholesterol, abnormal resting ECG, and a history of cardiac symptoms but not with smoking, high blood pressure, physical inactivity, or family his- tory of coronary disease. 12 Van Buchem, et al. (68) found no significant association between cigarette smoking and ischemic ST segment depression on ECG in 120 apparently healthy men who demonstrated this abnormality among a population of 760 men 50 to 70 years of age. Experimental Studies CIGARETTE SMOKE Studies in Man Summers, et al. (67) examined the effect of cigarette smoking on cardiac lactate metabolism in 15 patients with severe angina pectoris who had at least 75 percent obstruction in each of two or three major coronary vessels, All patients had been long-term cigarette smokers. Cigarette smoking produced increases in heart rate, systolic aortic pressure, the systolic ejection period per minute, and the tension-time index per minute, but lactate production was not induced by smoking in any patient who did not also have lactate production in the control state. In three patients with lactate abnormalities prior to smoking, inhalation of cigarette smoke sustained and slightly aggravated this condition. Studies in Animals The effect of inhalation of cigarette smoke on ventricular fibrillation threshold (VFT) in normal dogs and dogs with experimentally pro- tliced acute myocardial infarction was studied by Bellet, et al. (6). Mongrel dogs weighing 25 to 30 kilograms were anesthetized with sodium pentobarbital, and respiration was maintained using a Harvard ventilator attached to an endotracheal tube. In one group the electrical mpulses used to precipitate ventricular fibrillation were delivered through the chest wall, and in another group the impulses were deliv- ‘red directly to the heart through electrodes implanted in the myo- “ardium. The experimental group of dogs were exposed to the smoke of three cigarettes over a 10-minute period. Each cigarette contained “pproximately 2 mg. of nicotine. With acute myocardial infarction, the VFT was significantly (P<0.001) decreased, but in both the normal and myocardial infarction groups cigarette smoking resulted in a de- ‘Tease in VFT that averaged 30 to 40 percent of the control value ‘fig. 4). These findings are of interest in view of the increased inci- dence of sudden death observed among coronary patients who are heavy cigarette smokers (65). 13 Figure 4.—The effect of cigarette smoke inhalation on the ventricular fibrillation threshold (VFT) of normal dogs and dogs with experimentally pro. duced acute myocardial infarction (AMI). 0.87 le 0.7 b= *e Contro} (normal) C 0.6 + s i * Vv i *e . mal) Watt-sec. 0.8 ey. smoking (NOT ase 0.4 b Pee eo, Control (AMI) 0.3 - “tee, wee smoking (AM!) 0 15 30 45 60 75 90 Time in minutes following cigarette smoking SOURCE: Bellet, S., et al. (6). The effects of passively inhaled cigarette smoke on several measures of cardiovascular function in treadmill-exercised dogs were examined by Reece and Ball (52). The experimental dogs were trained on the treadmill for approximately 1 year before exposure to cigarette smoke began. Each dog was passively exposed to the smoke of 36 cigarettes over a 3-hour period 5 days a week in a 2.2 m.? chamber ventilated at the rate of seven exchanges per hour. The dogs were exposed to this cigarette smoke and were continued on their exercise program for an additional year. Exposure to cigarette smoke was associated with cadiac enlargement, ST segment depression, and an increase in post- exercise serum lactate concentrations. 14 NICOTINE Studies in Man Isaac and Rand (28) have recently described a method for the assay of plasma nicotine. An alkali flame ionization detector was used with a yas-liquid chromatograph. The test is sensitive to 1 ng./ml. of nicotine ina 2.5 ml. sample; 30 minutes elapsed between end of one cigarette ind start of next. Blood samples were taken before smoking and at 5, 10,and 30 minutes after the last puff of each cigarette. Plasma nicotine levels increased rapidly during cigarette smoking (fig. 5). The post- amoking decay curve consisted of two components: an initial rapid phase which may be due to the uptake of nicotine from the blood by various tissues, and a slower phase which may represent metabolism and excretion of nicotine. Some accumulation of plasma nicotine oc- curred during a day of smoking, but the background level never ap- proached the peaks attained during and immediately following active cigarette smoking. The rate of elimination was rapid enough to prevent any appreciable accumulation of nicotine from 1 day to the next. The development of sensitive tests of plasma nicotine levels will allow a greater understanding of various dynamics of smoking. Inhalation patterns can be objectively measured, and the role of nicotine in habituation to cigarettes can be evaluated. 15 Figure 5.—€ffects of smoking five consecutive cigarettes on plasma nicoting concentration. 60 + 50 F Plasma nicotine 40 F (ng./ml.) 30 + 20 b 10 F 0 Le i 1 iL A L l i Smoking period... . a a = Ww i 1 i 1 1 0 1 2 3 4 5 Time (hours) SOURCE: Isaac, P. F., Rand, M. J. (28). Studies in Animals The effect. of nicotine on regional blood flow in the canine heart. was. examined by Mathes and Rival (47). The effects of nicotine were ¢xamined in normal hearts and after partial coronary artery occlusion. Under normal circumstances, as well as after infusion of nicotine in normal hearts, the subendocardial portion of the myocardium hada 9.5-percent greater capillary flow than the subepicardial fraction. Partial ligation of the coronary arteries resulted in a 22.8-percent reduction in left ventricular blood flow; however, the subendocardial portion remained &.6 percent higher than in the epicardium. After 16 coronary artery ligation, an infusion of nicotine resulted in a signifi- cant (P<0.001) reduction in the capillary flow of the inner portion of the myocardium relative to the outer part. Bhagat, et al. (7) examined the effect of cigarette smoking on the cardiovascular system of dogs, various pharmacological agents; e.g., tyramine hydrochloride, propranolol, and chlorisondamine, were used to modify the evoked response to tobacco smoke in order to clarify the mechanisms producing the observed effects. The authors concluded that the more important actions of nicotine include a stimulation of sympa- thetic ganglia and the adrenal medulla and the release of catechola- mines from sympathetic nerve endings and chromaffin tissue. Bing, Hellberg, and associates (8, 25) studied the microcirculation of the left atrium of anesthetized cats by direct visualization using high-speed cinematography. Nicotine injections produced a slight but insignificant increase in red cell velocity in the capillary circulation during both systole and diastole. The effects of nicotine on the biosynthesis of various lipid fractions in the aorta of dogs were studied by Kupke (40). After nicotine admin- istration, significant reduction occurred in the formation of free (**C)- sterols, while elevated levels of unesterified fatty acids were formed in the media and intima of these in vitro specimens. The author suggested that nicotine may impair oxidative enzyme systems possibly by damag- ing the mitochondrial structures, thereby leading to lipid accumulation in the aorta. , Schievelbein and Eberhardt (54) reviewed the cardiovascular actions of nicotine and smoking. Carson Monoxipt Studies in Man Numerous articles have recently been published on the various effects of carbon monoxide on man and animals and are of particular interest lecause of the relatively high levels of carbon monoxide found in the main and sidestream smoke of cigarettes. Only those articles are dis- cussed here which contain data on the cardiovascular effects of carbon monoxide. ‘\ronow and Rokaw (3) examined the effects of smoking-induced ‘arboxyhemoglobin levels on angina pectoris in 10 patients with CHD. ‘he time to the onset of angina after smoking a nonnicotine cigarette Vas measured: Each patient had smoked more than a pack of ciga- rettes a day for at least 19 years and had a classical history of exer- tional dyspnea. Smoking nonnicotine cigarettes failed to result in an “levation of the blood pressure or the heart. rate: however, there was a 17 significant (P<0.01) increase in COHb levels to about 8 percent. This resulted in a significant decrease in exercise performance compared ty the nonsmoking state (P<0.01). This confirms that carbon monoxid can compromise oxygen delivery independently of the effect of nicotine, Maximal oxygen consumption under conditions of carbon monoxide intoxication were studied in human volunteers by several authors (49, 71, 72). COHb levels of 15 or 20 percent resulted in a proportionate reduction in maximal O, consumption. The volunteers responded to the decrease in oxygen-carrying capacity of the blood with a tachycardia and relative hyperventilation during moderate exercise. Carbon mon. oxide produces a limitation of an individual’s maximal oxygen con. sumption by decreasing the availability of oxygen supplied under con. ditions of increased oxygen demand. Heistad and Wheeler (24) reported that the hypoxia induced by carbon monoxide inhalation caused an inhibition of reflex vasocon. strictor responses despite the presence of normal arterial oxygen tension. Studies in Animals The effects of carbon monoxide on coronary hemodynamics and lef, ventricular function in six unanesthetized dogs were studied by Adams, et al. (7). The animals reacted to a 5-percent carboxyhemoglobin level with a 14-percent increase in coronary blood flow. Twenty percent COHb resulted in a 57-percent increase in coronary flow and slight increases in heart rate and stroke volume. Birnstingl, et al. (9) exposed young adult rabbits to 400 p.p.m. C0 for periods that varied from 6 to 14 hours. The mean COHb level after a series of 22 exposures was 17 percent. A qualitative increase in plate let stickiness, as measured by the bead-column method, developed dur. ing the 24-hour period following CO exposure. The authors observed that this “* * * provides a possible mechanism for intimal deposition and a further link in the association between habitual smoking and peripheral vascular disease.” Astrup () found the cholesterol level in the aorta of rabbits exposed to a low level of carbon monoxide for 10 weeks to be, on the average, 2.5 times higher than in the control rabbits Both the experimental and control groups were maintained on a high- cholesterol diet. Gibbons and Mitropoulos (20) reported that CO inhibited cho- lesterol biosynthesis with accumulation of lanosterol and 24,25-diby- drolanosterol in an in vitro system of rat liver homogenates exposed to a 90-percent CO atmosphere. It was felt that CO may have in fluenced an early step in the oxidative elimination of the 14o-methyl group of lanosterol. f 18 SMOKING AND THROMBOSIS Previous reports of the Surgeon General on smoking and health (62, 63, 64, 65,66) have reviewed the effects of smoking on thrombosis. Recent reviews and studies have not thus far yielded a unifying con- cept of the effect of smoking on thrombosis (4, 18, 19, 32, 45). Cerebrovascular Disease Paffenbarger and Wing (46) examined several precursors of non- fatal stroke in 102 patients with this disease in a population of 10,327 men who had attended Harvard University between the years of 1916 and 1940 and also returned a self-administered questionnaire in 1966. Examination of university medical records of these former students revealed four characteristics present in youth that predis- posed those individuals who were more likely to experience a nonfatal stroke in later life. These factors were: cigarette smoking, elevated blood pressure, increased weight for height, and short body stature. The age and interval-adjusted incidence rates per 1,000 were 10.1 for nonsmokers, 15.3 for smokers of one to nine cigarettes, and 17.9 for smokers of 10 or more cigarettes a day. The relative morbidity ratios for the four factors cited above increased from 1.1 for patients with only one risk factor to 1.7 for those with any two risk factors, and to 4.2 for patients with any three or four risk factors. Miyazaki (44) studied blood flow in the internal carotid artery using ultra sound techniques. Internal carotid blood flow was ex- amined under a variety of experimental conditions. Inhalation of “igarette smoke in three individuals aged 27, 67, and 69 resulted in an increased blood flow due to decreased vascular resistance. This effect lasted for 10 to 20 minutes following smoking. Peripheral Vascular Disease The association between cigarette smoking and arteriosclerosis obliterans (ASO) was investigated by Weiss (73). Patients were con- “ilered to have ASO if both the dorsalis pedis and posterior tibial imlses were absent in one lower extremity and the examining physician nade a diagnosis of ASO. Patients were asked the age of initiation f smoking; the daily number of cigarettes smoked; the amounts “hoked at ages 30, 50, and 70; the age at which they stopped smoking; 495-028 073-8 19 and, for males, whether they smoked cigars or a pipe, A total of 214 male cases, 206 male controls, 390 female cases, and 913 female controls were studied. The control group was composed of patients with peripheral vascular problems other than ASO but who had dorsalis pedis pulses present on initial examination. In each age and sex group, cigarette smoking was more prevalent among cases than controls. In both sexes, risks were high for smokers of less than one pack a day, and increased with the amount smoked (figs. 6 and 7). It was esti- mated that 70 percent of nondiabetic ASO in the United States is related to the use of cigarettes. Diabetes mellitus is a major risk factor for the development of ASO; however, cigarette smoking appeared to act independently of diabetes. Figure 6.—Relative risk of developing arteriosclerosis obliterans (ASO) for males by amount of cigarettes smoked. 15.0 t Males 10.0 }+ 9.1 a r 7 $ r 3 r 6.4 ), a 7 5.0 + 4.4 V); Y; 1.0 /) UY “| VA Z| Z LZ 0.0 Cases 18 21 33 69 Controls 53 15 26 37 Amount Non- <1 pack 1 pack >1 pack smoked smoker day day day SOURCE: Weiss, N. S. (73). 20 Figure 7.—Relative risk of developing arteriosclerosis obliterans (ASO) for females by amount of cigarettes smoked. Females : 15.6 15.0 - ° 5 T Relative risk 5.0F 1.0 1.0 F 0.0L | Z 1 A_ Cases 79 50 60 41 Controls 429 83 69 33 Amount Non- <1 pack 1 pack >1 pack smoked smoker day day day SOURCE: Weiss, N. S. (73). Preuss, et al. (50) examined the relationship between several factors including cigarette smoking, blood pressure, weight, and history of _ diabetes and the development of occlusive disease of the peripheral arteries in a population of 300 patients in Germany. Group I consisted of 150 patients with a mean age of 59 years who had intermittent claudication. Most of these patients were ambulatory. The 150 patients in group II had a mean age of 60 years and had far advanced periph- eral arteriosclerosis with ischemic pain at rest or evidence of gangrene. There was no control group of patients free of vascular disease. There Were few nonsmokers in either group of patients, but the group with 2) the more severe disease had a higher average daily consumption of cigarettes than did group I. The influence of cigarette smoking on late occlusion of aortofemoral bypass grafts was examined by Wray, et al. (75). A series of 100 patients who had aortic reconstruction for aneurysmal or aortoiliac occlusive disease between 1965 and 1968 were studied. Of the patients who had bypass grafts for occlusive disease, 30 patients smoked ciga- rettes and 16 did not. Late occlusions from thrombosis occurred in nine patients, each of whom was smoking more than a pack of cigarettes a day at the time the thrombosis occurred (P<0.5). The authors recom- mend cessation of cigarette smoking to all patients undergoing vascu- lar reconstruction. Schmauss and Arlt (55), Wilbert (74), and Kradjian, et al. (39) reported a greater than 93 percent prevalence of cigarette smoking in three separate series of patients with severe peripheral vascular disease. Isacsson (29) performed venous occlusion plethysmography in 684 men aged 55 in Malmé, Sweden. In addition to a detailed smoking history, a number of other factors were studied, including blood pres. sure, pulse, height, weight, ECG, heart volume, and blood lipids. The plethysmograms were taken on both legs simultaneously with the patient in the recumbent position. Measurements were taken at rest and during reactive hyperemia produced by obstructing arterial inflow to the legs for 3 minutes with a blood pressure cuff applied to the thigh. Smokers had a significantly lower mean flow capacity (MFC) than did nonsmokers. The MFC in the legs was reduced in direct proportion to . the amount of tobacco consumed per day regardless of the mode of smoking. The MFC was significantly lower with inhalation. (P<0.001) and with increasing amount smoked (P<0.001). Matsubara and Sano (42) studied the effect of cigarette smoking on human precapillary sphincters of the leg using a pressure plethysmo- graph applied to the calf. Precapillary sphincter tone was estimated using the capillary filtration coefficient, which is the product of “fune- tional capillary service area” and the filtration constant of the capillary wall. Four healthy male subjects were tested. All were regular smokers of cigarettes who had not smoked for the previous 24 hours. When cigarette smoke was inhaled deeply at 30-second intervals over a 12- to 15-minute period, there was a 19-percent decrease in the capillary filtration coefficient. indicating closure of precapillary sphincters. Cigarette smoking also resulted in a 31-percent decrease in calf blood flow, indicating some degree of constriction of the arterioles in the leg. The pressure volume curves of the venous system were not affected by cigarette smoking. Heistad and Wheeler (24) examined the effect of carbon monoxide on vascular resistance and reflex vasoconstriction in the forearms of 12 22 healthy men 19 to 23 years old. After control measurements were taken, the subjects were exposed to enough carbon monoxide to produce car- boxyhemoglobin levels of 18 to 20 or 25 percent. Carbon monoxide did not cause a change in alveolar PO, or PCO,. The arterial oxygen satu- ration was less than 75 percent, but this decrease did not result in altered resting arterial pressure nor was there much evidence of sympathetic stimulation. Carbon monoxide hypoxia did result in a significant decrease in vascular resistance in the resting forearm (P<0.05). Carbon monoxide exposure also resulted in a significant depression of the vasoconstrictor responses of the forearm following the application of negative pressure to the lower body (P<0.001) and of ice on the forehead. It appears that the hypoxia induced by carbon monoxide causes an inhibition of reflex of vasconstrictor responses despite the presence of normal arterial oxygen tension. Summary of Recent Cardiovascular Findings In addition to the summary presented in the introduction to this chapter based on previous reports of the health consequences of smok- ing, the following statements are made to emphasize the recent develop- ments in the field : 1. Recently conducted epidemiological studies from several coun- tries continue to confirm that cigarette smoking is one of the major risk factors contributing to the development of coronary heart disease. 2. Epidemiological evidence suggests that black men in the rural South respond to the same risk factors for coronary heart disease, including cigarette smoking, as white men do but apparently at lower disease rates, which appears to be in part due to differences in physical activity. - Data from several epidemiological and experimental studies sug- gest that cigarette smoking is a major risk factor in the develop- ment of peripheral vascular disease. This may in part be due to the decreased blood flow in arterioles and capillaries associated with cigarette smoking. Smoking may complicate the surgical inter- vention in this disease by contributing to late occlusion of the treated vessel. - A laboratory test has been developed which accurately measures nicotine levels in blood. This test will be useful in understanding Nicotine metabolism and can be used as an objective measure of Cigarette smoke inhalation. 23 rv wv wie Wa v Cardiovascular References (1) Apams, J. D., Ertcxson, H. H., Stone, H. L. The effects of carbon monoxide on coronary hemodynamics and left ventricular function in the conscious dog. In: Proceedings of the 1st Annual Conference on Environmental Toxicology, September 9-11, 1970. Aerospace Medical Research Labora- tory, Wright-Patterson Air Force Base, Ohio, AMRI-TR-70-102, Decem- ber 1970, pp. 107-110. (2) Acnesx, G., Canepa, R., La Rocca, M. Eta e valore di aleuni indici per la discriminazione fra soggetti normali ed ischemici. (Age and value of several indices for discrimination in normal and ischemic subjects.) Giornale di Igiene e Medicina Preventiva 11(3) : 140-151, July—Septem- ber 1970. (8) Aronow, W. S., Roxaw, S. N. Carboxyhemoglobin caused by smoking non- nicotine cigarettes. Effects in angina pectoris. Circulation 44(5) : 782- ___. 188, November 1971. CW ArrHes, F. G>An epidemiologic survey of hospitalized cases of venous een thrombosis and pulmonary embolism in young women. Milbank Memorial Fund Quarterly 50(1, Part 2) : 233-243, January 1972. (5) Astrrup, P. Rékning och koronarsjiikdom (11): Karbeskadigende virkning af CO og hypoxi. (Smoking and coronary disease (11) : Vascular damag- ing effect of CO and hypoxia.) Lakartidningen 67 (3) : 44-49, Jan. 14, 1970. (6) Brtiet, S., DeGuzman, N. T., Kostis, J. B., Roman, L., FLEISCHMANN, D. The effect of inhalation of cigarette smoke on ventricular fibrillation threshold in normal dogs and dogs with acute myocardial infarction. American Heart Journal 83(1) : 67-76 January 1972. (7) Buasat, B. Ruegt, A., Rao, P., Rana, M. W., Hueues, M. J. Effect of cigarette smoke on the cardiovascular system in dogs. Proceedings of the Society for Experimental Biology and Medicine 137(3) : 969-972, July 1971. (8) Brine, R. J., WAYLAND, H., Rickagt, A., HELLBERG, K. Studies on the coronary microcirculation by direct visualization. Giornale Italiano di Cardiologia 1: 401-408, September—October 1971. (9) Birnstinet, M. A., Brarnson, K., CHAKRABARTI, B. K. The effect of short- term exposure to carbon monoxide on platelet stickiness. British Journal of Surgery 58(11) : 837-839, November 1971. (10) Bovpix, F. Srdecni infarkt a koureni. (Myocardial infarction and smok- a ~-—. ing.) Casopis Lekaru Ceskych 110(26) : 614-620, July 25, 1971. f ( 11) Burney; 8. W., Enxsiemn, K. Investigation of changes in clinical laboratory . EY, tests related to aging and smoking. Aging and Human Development 3(1) : 95-101, February 1972. (12) Cascrv, G., Marraccini, L., Zeppa, S., Carta, G. FULGILESU, G. Sulla frequenza delle cardiovasculopatie tra gli operai dell’ industria estrattiva della sardegna. Nota II: Incidenza in rapporto all’abitudine al fumo e allalcool. (On the incidence of cardiovascular disease among the workers of the mining industry of Sardinia. Second communication : Incidence in relation to habitual smoking and consumption of alcohol.) Rassegna - Medica Sarda 71 (Supplement 1) : 191-200, 1968. { (18) Casse, J. C. Summary of major findings of the Evans County cardio- 24 vascular studies. Archives of Internal Medicine 128(6) : 887-889, De- eember 1971. (14) Onsent, J. C., Hrypen, S., Barrer, A. G., Kapitan, B. H., Tyrower, H. A., ~ Cornont, J. C., Hames, C. G. Oecupation and physical activity and coro- nary heart disease. Archives of Internal Medicine 128(6) : 920-928, De- cember 1971. (15) CIAMPOLINI, E., Drineoii, R., Ravarou1, P. Azione del fumo di sigarette su alcuni parametri del ricambio lipidico. (Action of cigarette smoking on several parameters of lipid metabolism.) Atti dell’Accademia dei Fisiocritici in Siena ; Sesione Medico-Fisica 17 : 474-480, 1968. (16y Comstock, G. W. Fatal arteriosclerotic heart disease, water hardness at “frome, and socioeconomic characteristics. American Journal of Epidemi- ology 94(1) : 1-10, July 1971. (17) Esranpra Cano, A., EsQuiven Avita, J.. Mato CaMacno, R., FEpRez Sanranper, S., Leon Montanez, E. Infarto juvenil del miocardio. (Myo- cardial infarction in the younger age groups.) Archivos del Instituto de Cardiologia de Mexico 41(2) : 187-150, March—April 1971. (18) Faccuini, G., SEMERARO, S., D1 Brass, G., TABARRONI, F., Spaanoro, D., AuTorE, A., Bonavira, E. Modificazioni nel soggetto anziano della reattivita al fumo di sigaretta: Ricerche sull’equilibrio emocoagulativo e fibrinolitico e sul circolo periferico. (Modifications of the reactivity to cigarette smoke in old subjects: Research on the hemocoagulative and fibrinolytic equilibrium and on the peripheral circulation.) Giornale di Gerontologia 19(10) : 779-784, 1972. (19) FEINLEIB, M/ Venous thrombosis in relation to cigarette smoking, physical activity, “and seasonal factors. Milbank Memorial Fund Quarterly 50(1, Part 2) : 123-141, January 1972. (20) Gisnons, G. F., Mrrropou.os, K. A. Inhibition of cholesterol biosynthesis by carbon monoxide: Accumulation of lanosterol and 24,25-dihydrolano- sterol. Biochemical Journal 127(1) : 315-317, March 1972. (21) Goroveniner, I. Y. Nekotoryye sotsial’nyye faktory zabolevayemosti infark- tom miodarda. (Some social factors in the incidence of myocardial in- farct.) Zdravookhranenie Rossiiskoi Federatsii 15(9) : 12-14, 1971. (22) Gorpon, T., Sortie, P., KANNEL, W. B. Section 27. Coronary heart disease, atherothrombotic brain infarction, intermittent claudication—a multi- variate analysis of some factors related to their incidence: The Fram- ipgham Study, 16-year follow up. In: Kannel, W. B., Gordon, T. (Editors). The Framingham Study. An Epidemiological Jaivestigation “of of Cardio; lar Disease. May 1971, 42 pp. ‘23) Hames, C. G. Introduction. (Evans County Cardiovascular and Cerebro- vascular Epidemiologic Study.) Archives of Internal Medicine 128(6) : 883-886, December 1971. 124) Hetstap, D. D., WHEELER, R. C. Effect of carbon monoxide on reflex vaso- constriction in man. Journal of Applied Physiology 32(1) : 7-11, January 1972. 125) HELLBerc, K., WAYLAND, H., Rickart, A. L., Brno, R. J. Studies on the coronary microcirculation by direct. visualization. American Journal of ony ee etialegy 29: 598-597, May 1972. 28) Heypen, §}, CASSEL, J. C., BarTEL, A., TYROLER, H. A., Hames, C. G., Cor- NONI, J. C. Body weight and cirgarette smoking as risk factors. Archives ( ~ | f internal Medicine 128(6) : 915-919, December 1971, ‘. wo Hirayama, T. Smoking in relation to the death rates of 265,118 men and Women in Japan. A report of five years of followup. Presented at the American Cancer Society’s Fourteenth Science Writers’ Seminar, Clear- water Beach, Florida, March 27, 1972, 15 pp. 25 (28) Isaac, P. F., Ranp, M. J. Cigarette smoking and plasma levels of nicotine, Nature 236 (5345) : 308-310, April 7, 1972. (29) Isacsson, S. O. Venous occlusion plethysmography in 55-year-old men. A population study in Malmé, Sweden. Acta Medica Scandinavica (Supple. ment 537) : 1972, 62 pp. (30) JaKuszewska, R. Zawal serca u osob mlodych. (Myocardial infarction in young subjects.) Wiadomosci Lekarskie 22(19): 1740-1752, October 1, 1969. (37) Kagan, A., Ruoap, G. G., ZEEGEN, P. D., NICHAMAN, M. Z. Coronary heart disease among men of Japanese ancestry in Hawaii. The Honolulu Heart Study. Israel Journal of Medical Sciences 7(12) : 1573-1577, December 1971. (82) Karrert, A. Tobacco and diabetic angiopathy. Acta Diametologica Latina 8(Supplement 1) : 429-433, September 1971. (83) Kartrus, A. A., JoRGeENgEN, C. R., Wornen, R. B., ALvaro, A. B. ST-segment depression with near-maximal exercise in detection of preclinical cor- ___.-Qpary heart disease. Circulation 44(4) : 585-595, October 1971. GH Keys, A, ARAVANIS, C., BLACKBURN, H., VAN BucHeM, F. S. P., Buzrna, R., DsorbJevic, B. 8., Fipanza, F., Karvonen, M. J., MENoTTI, A., Puppu, V., Tartor, H. L. Probability of middle-aged men developing coronary heart disease in five years. Circulation 45(4) : 815-828, April 1972. (35) KogNiTzer, M., DEMEESTER, M., Detcourt, R., BERNARD, R. Cardiopathies ischémiques dans une population d’employés de Bruxelles. Etude de la prévalence des cardiopathies ischemiques en fonction de la classe socio- économique. (Ischemic heart disease in a Brussels bank clerk population. Study of the prevalence of ischemic heart diseases as a function of socio- economic class.) Revue d’Epidemiologie, Medecine Sociale et Sante Pub- lique 19(7) : 599-612, October-November 1971. (36) Kornitzer, M., DEMEESTFR, M., Detcourr, R., Goossens, A., BERNARD, R. Enquéte cardio-vasculaire prospective dans une population sélectionnée. Resultats de l’'enquéte initiale. (Prospective cardiovascular studies in a selected population. Results of the initial study.) Acta Cardiologica 26; 285-343, 1971. (37) Kornirzer, M., DEMEESTER, M., DeNoLin, H. Enquéte dans une population demployes. Relation des habitudes tabagiques avec d’autres parametres. (Investigation of a white-collar population. Relation of tobacco habits to other parameters.) Bruxelles Medical 51(10) : 687-691, October 1971. (38) KozarEvIc, D., Pirc, B., Dawser, T. R., KAnn, H. A., ZUKEL, W. J. Prev- alence and incidence of voronary disease in a population study. The Yugoslavia Cardiovascular Disease Study. Journal of Chronic Diseases 24(7/8) : 495-505, September 1971. (39) Krapgian, R., Bow ies, L. T., Epwarps, W. S. Peripheral arterial disease in Ceylon. Surgery 69(4) : 523-523, April 1971. (40) Kupke, I. R. Biosynthesis of lipids in perfused dog aorta and coronary artery. IJ. Incorporation of (2—“C) acetate into lipids of two aortic layers and of the coronary artery under the influence of nicotine. Journal of Molecular and Cellular Cardiology 4(1) : 27-38, February 1972. (41) Martues, P., Rivat, J. The effect of nicotine on regional blood flow in the canine heart. Proceedings of the Society for Experimental Biology and Medicine 138(1) : 361-364, October 1971. (42) MATSUBARA, L., Sano, T. Effect of cigarette smoking on human precapillary ee shineters, British Journal of Pharmacology 45(1): 18-20, May 1972. (43) MITURZYNSKA-STRYJECKA, H., WIDOMSKA-CZEKAJSKA, T., RUPNIEWSKA, Z. M. Wplyw palenia papierosow na lipemie po posilku tluszezowym. (The 26 effect of acute experiment of cigarette smoking on lipaemia following fat meal.) Polski Tugodnik Lekarski 25(7) : 251-253, February 16, 1970. (44) MryazakI, M. Studies on cerebral circulation by the ultrasonic Doppler 49) 34) oD wy technique—with special reference to clinical application of the technique. In: Meyer, J. 8., Schade, J. P. (Editors). Progress in Brain Research, Volume 35. Cerebral Blood Flow, Amsterdam, Netherlands, Elsevier Pub- lishing Co., 1972, pp. 1-28. Orxtova, N. P. Some parallels between the blood coagulation activity and the condition of adrenergic and cholinergic system of the organism. Terapev- ticheskii Arkhiv 43 : 58-62, February 1971. PAFFENBARGER, R. S., Jr., Wine, A. L. Chronic disease in former college students. XI. Early precursors of nonfatal stroke, American Journal of Epidemiology 94(6) : 524-530, December 1971. Panpey, M. R. Myocardial infarction in Nepal. Indian Heart Journal) 22(2) : 73-82, April 1970. PINCHERLE, G. Factors affecting the mean serum cholesterol. Journal of Chronic Diseases 24(5) : 289-297, August 1971. Pirnay, F.. Dugarpin, J.. DEROGANNE, R. Petit, J. M. Muscular exercise during intoxication by carbon monoxide. Journal of Applied Physiology 81(4) : 573-575, October 1971. Preuss, E.-G., EpER, H. WELLER, P. Risikofaktoren bei peripheren arteriel- len Verschlusskrankheiten unterschieldlichen Schweregrades. (Risk fac- tors in occlusive diseases of the peripheral arteries, of varying severity.) Zeitschrift fiir die gesamte innere Medizin und Ihre Grenzgebiete 25(10) : 464468, May 15, 1970. Punsar, 8S. Tupakointi ja sepelvaltimotauti. (Cigarette smoking and cor- onary heart disease.) Suomen Laakarilehti 26(1/2) : 27-32, January 9, 1971. Reece, W. O., Baui, R. A. Inhaled cigarette smoke and treadmill-exercised dogs. Archives of Environmental Health 24(4): 262-270, April 1972. Romsto, I. Distribution of serum lipids in Norwegian recruits. Acta Medica Scandinavica 190(5) : 401-406, November 1971. SCHIEVELBEIN, H., EBERHARDT, R. Cardiovascular actions of nicotine and smoking. Journal of the National Cancer Institute 48(6) : 1785-1794, June 1972. Scumauss, A. K., ARLT, E. Morphologische Befunde, postoperative Kompli- kationen, Letalitiit und Liegedauer uach Amputation wegen Durchblut- ungsstérungen. (Morphological findings, postoperative complications, mortality and duration of bed rest following amputations occasioned by disorders of the peripheral circulation.) Zeitschrift ftir Arztliche Fort- bildung 64(2) : 84-87, January 15, 1970. Scuwartz, D., Ricuarp, J. L., LenLoucn, J., CLaupe, J. R. Serum lipids, smoking and body build. Study of 7.972 actively employed males. Revue Europeenne @’Etudes Cliniques et Biologiques 16: 529-536, 1971. SHURTLEFF, D. Section 26. Sume characteristics related to the incidence of cardiovascular disease and death: Framingham Study, 16-year followup. nt: Kannel, W. B., Gordon, T. (Editors). The Framingham Study. An Epidemiological Investigation of Cardiovascular Disease, U.S. Depart- ment of Health, Education. and Welfare, Public Health Service, National Institutes of Health, Washington. D.C., December 1970, 35 pp. SINGH, A. P., SinGH. S. P. Coronary heart disease—some epidemiological, clinical, and electrocardiographic observations, Journal of the Associa- tion of Physicians of India 19(9) : 629-635, September 1971. 27 (359) (60) (61) (62) (63) (635) (66) (67) (68) 28 Satyrm, A. J.. Apey, H.. Lancrey. R. B. An epidemiological survey of ischaemic heart. disease. New Zealand Medical Journal 71 (456) : 284-288 May 1970. Storcu, H., ENGELMANN, L.. KouHLer, H. Der Herzinfarkt im jtingerey Legensalter. (Myocardial infarct in young people.) Deutsche Gesund. heitswesen 26(34) : 1593-1600, August 1971. Summers, D. N., RicuMonp, S., WECHSLER, B. M. Cigarette smoke: Effects on lactate extraction in the presence of severe coronary atherosclerosis, American Heart Journal 82(4): 458467, October 1971. U.S. Pusric HeattH Service. The Health Consequences of Smoking. 4 Public Health Service Review : 1967. U.S, Department of Health, Educa. tion, and Welfare. Washington, Public Health Service Publication No, 1696, Revised January 1968, 227 pp. U.S. Pustrc HEALTH Service. The Health Consequences of Smoking. 1968 Supplement to the 1967 Public Health Service Review. U.S. Department of Health, Education, and Welfare. Washington, Public Health Service Publication 1696, 1968, 117 pp. U.S. Pustic HEALTH SERvicE. The Health Consequences of Smoking. 1969 Supplement to the 1967 Public Health Service Review. U.S, Department of Health, Education, and Welfare. Washington, Public Health Service Publication 1696-2, 1969, 98 pp. U.S. PuBLic HEALTH Service. The Health Consequences of Smoking. 4 Report of the Surgeon General : 1971. U.S. Department of Health, Educa- tion, and Welfare. Washington, DHEW Publication No. (HSM) 71-7513, 1971, 458 pp. U.S. Postrc HEaLTH Service. The Health Consequences of Smoking. A Report of the Surgeon General: 1972. U.S. Department of Health, Educa- tion, and Welfare. Washington, DHEW Publication No. (HSM) 72-6516, 1972, 158 pp. U.S. Pustic HEALTH SERVICE, Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washing. ton, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1103. 1964, 387 pp. Van BUCHEM, F. S, P., Drion, E., Wicsout, M., BosscHIETER, BE. Het véorkomen en de betekenis van een depressie van het ST-segment in het elektrocardiogram bij mannen zonder andere verschijnselen. Een 7-jarige longitudinale studie (II). (The occurrence and the significance of a depression of the ST segment in the ECG of men free from other symp- toms. A longitudinal study of 7 years (II).) Nederiands Tijdschrift voor Geneeskunde 114(8) : 320-332, February 21, 1970. 69) Van BucHemM, F. S. P., Daron, E.. WicBovt, M., BosscHIeTer, E., Frima, J. R. Het voorkomen en ae betekenis van extrasystolen en geleidingsstoornissen. Een 7-jarige longitudinale studie (I). (The occurrence and significance of extrasystoles and conduction disorders. A longitudinal study over 7 years (I).) Nederlands Tijdschrift voor Geneeskunde 114(7) : 281-286, February 14, 1970. 1790) Viatcu, R., Macavel, E., Patiu, 1. Studiu transversal (‘‘cross-sectional” ) al presiunii arteriale si al lipidelor serice la coronarieni fumatori si nefumatori. (Cross-sectional study of arterial pressure and serum lipids in coronary smokers and nonsmokers.) Medicina Interna 23(8) : 925-930, August 1971. 71) Voarn, J. A., Greser, M. A. Effect of carbon monoxide on oxygen transport during exercise. Journal of Applied Physiology 32(2) : 234-239, February 1972. '72) Voce. J. A.. GLEsER, M. A., WHEELER, R. C., WHitrex, B. K. Carbon mon- oxide and physical work capacity. Archives of Environmental Health nee March 1972. .'13) Weiss, N. S. Gigarette smoking and arteriosclerosis obliterans: An epi- demiologic approach. American Journal of Epidemiology 95(1) : 17-25, January 1972. ‘74) Winert, L. Nikotinkonsum und arterielle Verschlusskrankheit. (Nicotine consumption and arterial occlusive disease.) Medizinische Klinik 66(36) : 1190-1192, September 3, 1971. 15) Wray, R., DeParma, R. G.. Hupay. (. H. Late occlusion of aortofemoral bypass grafts: Influence of cigarette smoking. Surgery 10(6) : 969-973, December 1971. 16) WYSsOKINSKI, Z. Effects of tobacco smoking on certain parameters reflecting the condition of the circulatory system at rest and during exercise. Polish Medical Science and History Bulletin 14(2): 73-76, April 1971. 29 CHAPTER 2 Nonneoplastic Bronchopulmonary Diseases Contents Introduction.._________...------------------------------ Epidemiological Studies COPD Mortality and Morbidity_..__...-..------------- Filter Cigarettes_____.-.-..---------------------- Pulmonary Function___..____-_____-___-_________-- Occupational Hazards Byssinosis___________.-------------------------- Exposure to Asbestos___.._____------------------ Exposure to Coal Dust___._.._-__---------------- Miscellaneous Exposures. __._._.----------------- Air Pollution.....-.__.------------------------------ Autopsy Studies.........________.__---_---_-----_-- eee Experimental and Histopathological Studies Mstopathological Studies__......---------------------- Pulmonary Function. _..-..-------------------------- Pulmonary Clearance._.-_.--------------------------- Phagocytosis. .._.....-.-__-------------------------- Bacterial and Mycological Studies_.._._..----.--------- The Surfactant System__._....------------------------ “ummary of Recent Nonneoplastic Bronchopulmonary Find- Ngs.. oo eee ee eee References List of Figures Figure 1.—Age-standardized percentage of chronic sputum production in males by amount smoked and type of _Rarette. ee == -- ure 2..-Age-standardized percentage distribution of whole lung sections of males with moderate to far-advanced emphy- _ ema (score 3-9) by smoking category..__________-------- ‘Sure 3.—Prevalence of emphysema in adult males at autopsy hy smoking category._.___._.-_---.------------------ 39 41 41 43 44 45 48 50 51 53 54 55 55 56 38 47 48 33 List of Tables Pa, Table 1.—Percent prevalence of byssinosis for men by index of * severity and smoking habits (numbers in parenthesis indicate number of cases in exposure risk group)____.___________- 40 Table 2.—Degrees of emphysema in current smokers and in nonsmokers according to age groups_.____.________._____ 46 34 Introduction The term chronic obstructive bronchopulmonary disease (COPD), as used within this report, refers to chronic bronchitis and pulmonary emphysema. The following is a brief summary of the major relation- ships between smoking and nonneoplastic bronchopulmonary disease which have been presented in previous reports of the health conse- quences of smoking (91, 92, 93, 94,95, 96). Epidemiological and clinical studies have established cigarette smoking as the most. important cause of COPD in the United States. Cigarette smokers have higher death rates from pulmonary em- physema and chronic bronchitis and more frequently have impaired pulmonary function and symptoms of pulmonary disease than non- smokers. Respiratory infections are more prevalent and more severe among cigarette smokers, particularly heavy smokers, than among nonsmokers. Cigarette smokers appear to develop postoperative pul- monary complications more frequently than nonsmokers. The risk of developing or dying from COPD among pipe or cigar smokers is higher than that of nonsmokers, but it is clearly lower than that among cigarette smokers. Ex-smokers have lower death rates from COPD than do continuing smokers. Cessation of smoking is associated with improved ventilatory function and decreased pulmonary symptom prevalence. Young cigarette smokers of high school age have impaired ventilatory function compared to nonsmoking peers. For most of the United States population, cigarette smoking is a much greater factor in the development of COPD than air pollution or occupational exposure. Cigarette smoking may, however, act con- jointly with atmospheric pollution or occupational exposure to pro- duce greater mortality and morbidity from COPD than would occur from one exposure factor alone. A genetic error, homozygous alpha,-antitrypsin deficiency, present in approximately 1 in 3,600 people in the United States, has been as- sociated with the early development of severe panacinar emphysema. Available evidence does not permit a firm conclusion about the nature of the interaction between smoking and this condition. Autopsy studies have demonstrated that smokers who die of diseases other than COPD have histologic changes characteristic of COPD more frequently than do nonsmokers. 35 495-028 O—73—_-4 Experiments in both animals and humans have demonstrated that the inhalation of cigarette smoke is associated with acute and chronie changes in ventilatory function and pulmonary histology. Cigarette smoking exerts an adverse effect on the pulmonary clearance mech. anisms including ciliary and macrophage function. The effect of cigarette smoking on nonneoplastic bronchopulmonary disease has been examined in detail in a number of recently published epidemiological, pathological, and experimental studies. COPD Mortality and Morbidity Reid (70) reported that age-adjusted mortality rates from chronic nonspecific lung disease (ICD 502, 526, 527) among British citizens varied with migration patterns. British males living in the United Kingdom had a death rate of 125 per 100,000, whereas migrants to the United States experienced a mortality rate of only 24 per 100,000, which is similar to the mortality rate from chronic nonspecific Jung disease found in the U.S. population. The possibility that this varia- tion was due to significant differences in diagnostic criteria was in part ruled out by the finding that standardized morbidity surveys of both populations demonstrated differences in morbidity rates that were similar to the observed differences in mortality rates. The prev- alence of respiratory symptoms increased in proportion to the num- ber of cigarettes smoked per day. Cigarette smoking and air pollu- tion were identified as the major factors contributing to the real excess in bronchitis morbidity experienced by the British in the United Kingdom. Freour and Coudray (23) investigated the prevalence of respiratory symptoms and chronic bronchitis among a random sample of 4.000 men and women between the ages of 30 and 70 who were residents of Bor- eaux, France. A standardized questionnaire was administered and measurements of pulmonary function taken. The prevalence of chronic bronchitis increased with age and cigarette smoking. In each age cate- gory, smokers had more chronic bronchitis than did nonsmokers. The greater the number of cigarettes smoked per day and the greater the lifetime number of cigarettes smoked, the higher was the prevalence of chronie bronchitis. Coudray, et al. (73), ina study of 1,357 women in the Bordeaux Study. reported a prevalence of morning cough of 1.12 percent among nonsmoking women and 8.91 percent among women who smoked. Racoveanu. et al. (44) studied the prevalence of chronic bronchitis in 300 residents of a mountainous region and a low-lying delta area in 36 Romania. Both areas were free of air pollution. The prevalence of chronic bronchitis was higher in the mountains than in the lowlands, and although a definite association between chronic bronchitis and smoking was found in both areas, smoking patterns could not com- pletely account for the differences observed. Several papers have been recently published (24, 25. 26. 37, 55. 100) comparing respiratory symptoms. such as cough and sputum produc- tion, among smokers and nonsmokers in different populations. In each study, respiratory symptoms and disease were more common among cigarette smokers than nonsmokers. Most of these studies (24, 26, 37, 100) demonstrated a dose-response relationship between smoking and symptoms for the amount smoked as measured by the number of ciga- rettes smoked per day, the lifetime number of cigarettes, or the degree of inhalation. The spontaneous development of a pneumothorax with the resultant collapse of a lung is often produced by rupture of an emphysematous bleb on the pleural surface. Fournier and Zivy (2/) reviewed 61 cases of spontaneous pneumothorax. The smoking habits of these patients were compared with those of matched controls. Spontaneous pneumo- thorax after the age of 25, was strongly associated with cigarette smoking. Zivy (/0Z) further characterized 40 of these cases. Fiiter C1iGARETTES The effect of smoking plain and filtered cigarettes on the prevalence of sputum production was examined by Rimington (72). A total of 10,414 volunteers aged 40 and older were studied by questionnaire and chest X-ray. Of this group, 3,045 smoked filter cigarettes and 2.393 smoked nonfilter cigarettes. The rate of persistent daily sputum pro- duction was 31.9 percent in filter cigarette smokers and 37.2 per- cent in smokers of nonfilter cigarettes. The difference is significant (P<0.001). Although there was an increase in sputum production with the amount smoked in both groups, the difference between filter and nonfilter smokers was maintained irrespective of the amount smoked (fig. 1). The author observed, “While there is no doubt that smokers of any type of cigarette are liable to develop chronic bronchi- tic symptoms such as persistent phlegm, it seems likely that those plain cigarette smokers who are unable to stop smoking cigarettes would suffer less if they smoked filter brands of comparable size.” The effect. of smoking modified cigarettes on respiratory symptoms and ventilatory capacity was examined by Freedman, et al. (22). Six hundred men between the ages of 25 and 54 who smoked at least 10 cigarettes a day and had symptoms of chronic bronchitis were divided into three equal groups matched by age, pulmonary function, cigarette consumption, and cough frequency. The individuals were provided 37 Figure 1.—Age-standardized percentage of chronic sputum production in Males by amount smoked and type of cigarette. 60 CJ Filter cigarette smokers 504 y Non-filter cigarette smokers 41.6 401 32.5 28.2 Percentage w ° 19.7 Xs“: RUN E RQNE 0 Number of volunteers 4,976 382 259 1,095 878 1,568 1,256 Number with sputum 836 97 75 304 304 571 513 * Non- <10 10-19 >19 smokers cigarettes/day cigarettes/day cigarettes/day 7 (Includes ex-smokers and non-cigarette smokers. SOURCE: Rimington, J. (71). with test cigarettes “A,” “B,” or “C.” All the test cigarettes contained 1.65 mg. of nicotine. “A” delivered 22 mg. of tar, and “B” and “C” 17 mg. of tar. In addition, “C” had approximately a 50 percent reduc- tion in the vapor phase constituents. Those provided with cigarette “C” increased the average number of cigarettes smoked by about 10 per- cent, where consumption eventually leveled off. After 4 months, men smoking cigarette “C” began to have lower average cough frequency scores than the others. Significant changes did not. occur in sputum production or pulmonary function. The authors observed that, “* * * modification of the composition of cigarettes and their filters can re- duce smokers’ cough, an important and early symptom of bronchitis.” PctmMonary Funcrion Results of studies of pulmonary function and smoking from several countries, including India (65), Turkey (2), Germany (7, 34, 38), and Great Britian (42) indicate that cigarette smokers have diminished average pulmonary function compared to nonsmokers. The various measures of pulmonary function used included vital capacity, expira- tory reserve volume. residual] volume, residual functional capacity, maximum voluntary ventilation, forced expiratory volume in 1 second, and peak expiratory flow rate. 38 Other studies in which both pulmonary function and respiratory symptoms are considered (27, 30, 36, 43, 59. 69) have again confirmed that smoking is associated with an increase in pulmonary symptoms and a decrease in pulmonary function. Ex-smokers experience a decrease in the prevalence of respiratory symptoms and an improvement in pulmonary function compared to continuing smokers. These effects have been noted in several recent studies (36, 37, 43). Ulmer (87) conducted a survey of respiratory symptoms in a ran- dom sample of 2,444 individuals between the ages of 10 and 70 years in Duisburg, Germany. The prevalence of chronic bronchitis as measured by cough and/or sputum production in the morning or throughout the day increased with advancing age and with increasing cigarette con- sumption (P<0.001). Latimer, et al. (48) studied the ventilatory patterns and pulmonary complications of 46 patients following elective upper abdominal sur- gery. Factors that favored the development of postoperative macro- atelectasis included smoking, obesity, and prolonged anesthesia. Teculescu and Stanescu (84) examined several measures of pulmo- nary function in 44 asymptomatic young men between the ages of 18 and 29 in Romania. No significant differences were found between the smokers and nonsmokers. This may have been due to the selection of asymptomatic subjects for examination and relatively insensitive meas- ures of early airway obstruction. Occupational Hazards ByssINnosis Byssinosis is a respiratory disease found in cotton, flax, and hemp workers. The earliest manifestations of this disease are shortness of breath, cough, and chest tightness. Initially, symptoms oceur only pon reexposure to cotton dust at the beginning of the work week. In more advanced form, byssinosis is associated with permanent and occasionally severe airway obstruction, which may force the worker to change his occupation (37). Abnormalities in pulmonary function tests reflect the severity of the symptoms; however, chest films of workers with byssinosis reveal no characteristic findings. McKerrow tnd Schilling (54) first suggested that, byssinosis may occur more Irequently among smokers than nonsmokers. Several relatively recent ‘tudies have clarified the relationship bet ween smoking and byssinosis. Bouhuys, et al. (8) found 61 cases of byssinosis in 214 male workers 'n the carding and spinning rooms of a cotton mill. The prevalence of 39 byssinosis symptons was higher among cigarette smokers than jn nonsmokers (P<0.025). Szymezykiewiez, et al. (82) found a higher prevalence of chronic nonspecific pulmonary symptoms among smokers than nonsmokerg ina study of 3,167 cotton mill workers in Poland. An examination of 500 cotton textile workers by Schrag and Gullett (75) disclosed 63 individuals with byssinosis; 57 percent (36 workers) of those with byssinosis smoked more than a pack of cigarettes a day, whereas only 34 percent (152 workers) of those without byssinosis smoked this amount ( P<0.001). Merchant, et al. (58) conducted a study of byssinosis in a yam mill in North Carolina; 25 employees with byssinosis were identified in a population of 441 workers. A scale of 0 to 3 (based on 5 weighted questions concerning cough, breathlessness, and chest tightness on Monday mornings) was used to indicate the degree of severity of byssinosis among the working population. The effect of cigarette smoking on this byssinosis index is apparent (table 1). Among the employees with high exposure to cotton dust, no nonsmokers had a byssinosis index rating over 1, but nearly 18 percent of those currently smoking had ratings of 2 or 3. The effect of smoking alone on the byssinosis index is significant (P<0.01). Also, the interaction between current smoking and current exposure-risk on the byssinosis index is highly significant (P<0.005). Women in this study were exposed to lower levels of respirable cotton dust, and among them no age, smok- ing, or exposure-risk effects were demonstrated. Smoking among males also had a significant effect on the bronchitis index (P<0.002), Spirometry results on 134 males and 100 females were categorized by sex, age, and smoking history. Among men, the greatest impairment TaBLe 1.—Percent prevalence of byssinosis For men by index of severity and smoking habits (numbers in parentheses indicate number of cases mm exposure-risk group) Percentage of subject Index rating — (see text) Never smoked Current smokers Ex-smokers 7 (23) (85) (21) Severe... 2. 3 0 14 3 Moderate_____ 2 0 4 o Mild. 2-222. 1 22 26 29 None__.__-_2._ 0 78 57 62 Total. ---2 2. 100 100 100 Source: Merchant, J. A., et al. (68). 40 was observed among the smokers who worked in the high exposure- risk areas. The mean FEV, for 66 men in this category was only 76 percent of predicted, and their FVC was 90 percent of predicted. Nonsmoking men in both the high- and low-exposure areas had better pulmonary function than their smoking coworkers. Exposure TO ASBESTOS Langlands, et al. (45) surveyed respiratory symptoms, pulmonary function, and radiological findings among 252 asbestos insulation workers in Belfast, Ireland. Respiratory symptoms of cough, sputum production, and wheezing were much more frequent in smokers, Of the tests for pulmonary function, the peak flow rate and forced expiratory volume at 1 second were most. impaired in cigarette smokers. Although little difference was reported in the X-ray findings of smokers and ° nonsmokers, smokers of more than 25 cigarettes a day had a 20-percent reduction in pulmonary function as measured by these tests. Lung function and pulmonary symptoms in 1,015 chrysotile asbestos mine and mill workers in Quebec were studied by Becklake, et al. (6) and McDonald, et al. (53). An analysis of respiratory symptoms indi- cated that. shortness of breath was more closely related to dust ex- posure than to smoking. However, cough, wheezing, and sputum production were much more frequent in smokers than nonsmokers. Pulmonary function was assessed by measuring lung volumes, flow rates, and diffusing capacity. The best pulmonary function was found in nonsmokers with low dust exposure while smokers with high dust exposure had lower pulmonary function values. In a survey of 201 asbestos workers, Regan, et al. (67) investigated the relative power of 16 clinical, radiological, and pulmonary function variables including smoking for differentiating between asbestosis and chronic obstructive airway disease. Cigarette smoking was not a char- acteristic that could be used to separate these conditions. Exposure to Coat Dust The spectrum of pulmonary reactions to coal dust was reviewed in a volume edited by Key, et al. (40). Hunter (33) noted that coal miners who smoked experienced a higher prevalence of respiratory symptoms (cough, sputum production, breathlessness, and wheezing) and de- veloped them earlier than nonsmoking miners. Their pulmonary func- tion tests also tended to show greater impairment. than those of nonsmokers, Lainhart and Morgan (44) reported that coal miners had an increase in persistent productive cough with increasing years of €xposure to coal dust. This effect was magnified by cigarette smok- Ng independent of age or years of underground work. In an autopsy 41 study, Naeye (62) observed more right ventricular hypertrophy and q higher emphysema index in smoking miners than in nonsmoking min. ers. In commenting on the etiology of pulmonary reactions in coal min. ers. Lee (49) felt that smoking in coal miners probably facilitated the development of bronchitis and emphysema, rather than participating in the genesis of the characteristic lesion of coal workers’ pneumo. coniosis. The prevalence of chronic bronchitis in 3,012 ex-coal miners and 9,361 nonminers of similar age and social class was examined by Lowe and Khosla (6/). All were employed at the time of the investigation in two steel works in South Wales. The ex-miners had substantially more chronic bronchitis and more impaired ventilatory capacity than the nonminers irrespective of age and smoking habits. The prevalence of chronic bronchitis was 24.9 percent in smoking ex-miners and 12.9 percent in nonsmoking ex-miners. The prevalence was 18.6 percent and 7.7 percent in smoking and nonsmoking nonminers, respectively. In this study, smoking appeared to be a more important factor for the development of chronic bronchitis than coal mining or age. Haber, et al. (29) studied cigarette smoking, dust inhalation, and sputum production as factors in the etiology of chronic bronchitis among 479 coal miners and 166 farmers in Hungary. In both the miners and the farmers, there was a significantly higher proportion of chronic bronchitis cases among smokers than among nonsmokers, and the proportion of bronchitics increased with the number of cigarettes smoked. Cigarette smoking was found to be a more im- portant factor in the etiology of bronchitis than dust inhalation. Lapp, et al. (46) examined changes in several measures of ventila- tory capacity in 93 coal miners and 42 nonminers before and after a work shift. Following the shift. small but significant decreases in ventilatory capacity occurred among the miners (P<0.05). while significant increases in ventilatory capacity occurred among the non- miners (P<0.05). Decreases in pulmonary function tests were related to the dust exposure of the miners: however. the greatest decreases in pulmonary function occurred among the smokers. Seaton, et al. (76) examined several measures of pulmonary fune- tion in 214 coal workers who had radiologic evidence of CWP with lung opacities that ranged in size from less than 1.5 mm. to 3 mm. in diameter. They found no significant difference in pulmonary function between the 102 smokers and 112 nonsmokers with coal workers pneumoconiosis, Similar results were reported by Lyons, et al. (82). Hyperinflation of the lungs in coal miners was studied by Morgan, et al. (67). Residual volumes, total ling capacities. and chest X-rays of 1.455 working Pennsylvania coal miners were examined. The rela- tionship between radiographic evidence of coal workers’ pheumoconi- osis and lung volumes was investigated. The residual volume in- 42 creased with radiographic category, obstruction to air flow, and cigarette smoking. Each of these factors had a separate and additive effect that resulted in an increased residual volume. Ulmer (86) examined a random sample of the working population in the Ruhr area of West Germany. Measurements were made of the total lung capacity, airway resistance, and arterial oxygen satura- tion, All coal miners had larger total lung capacities than workers without dust exposure. Smokers had significantly larger volumes than nonsmokers (P<0.05). Lapp, et al. (47) examined pulmonary hemodynamics in 47 asymp- tomatic coal miners. They were divided into two groups depending upon the absence or presence of airway obstruction. Pulmonary hyper- tension was more frequent in the group with obstruction. The group of 23 men (mean age 51 years) without airway obstruction. had an average cigarette consumption of 17 pack-years per miner, whereas the group of 24 men (mean age 56 years) with airway obstruction averaged 31 pack-years per miner. From the work of several investigators it can be concluded that. cigarette smoking is an important factor in the development of re- spiratory disease other than pneumoconiosis, among coal miners (29. 40, 46, 47, 51, 61, 86). There is no consensus in recent publications on what role cigarette smoking may play in the development of coal workers’ pneumoconiosis (40, 61, 76). MIsceELLANEOoUs Exposures The effect of cigarette smoking on pulmonary function in jet fighter pilots and crew members was examined by Browning (9). At high altitudes, 100-percent oxygen is delivered under low pressure to the aircrew members in order to maintain adequate blood oxygen levels. The vital capacity was acutely compromised in flight on the 100-per- cent oxygen mixture. This was especially true under high G (gravity) conditions. Smokers had a significant inflight volume loss that was three and one-half times that noted among the nonsmokers under these conditions (P<0.05). Recovery of normal vital capacity follow- ing flight was also delayed in the smokers. Gregory (28) reviewed 340 cases of chonic bronchitis that occurred among the employees of the Sheffield steelworks in England. Smoking Was associated with a high prevalence of chronic bronchitis, but of particular interest was the effect of cigarette smoking on disability. The interval between the onset of chronic bronchitis and disability from this disease was significantly less (P<0.02) for those smoking More than 20 cigarettes a day than for nonsmokers and for those smoking less than this amount (P<0.02). Batawi (5) examined the prevalence of several discases including 43 respiratory illnesses in 4,643 employees in Egypt, comprising a 5.8 percent sample of 92,000 employees in 17 major industries. Respira- tory illnesses occurred more frequently in all segments of the cotton industry, as well as leather, printing, and glass industries; 40 percent of all employees were smokers, and they experienced higher rates of respiratory symptoms and illnesses than nonsmokers. Smokers with occupational exposure to dust were particularly affected. The effect of cigarette smoking and occupational exposure to dust on the prevalence of chronic bronchitis was examined by Golli (25) in Romania. There were 2,942 individuals examined of whom 142 were employed in dusty occupations. Chronic bronchitis was present in 24.6 percent of the 457 smokers and 4.4 percent of the 2,343 nonsmokers (P<0.001). Increasing age, cigarette smoking, and occupational ex- posure to dust each independently contributed to an increased prev- alence of chronic bronchitis, Recent studies in metal casting, plaster, coke, baking, agricultural, and chemical industries have documented a higher incidence of respir- atory symptoms and/or diminished pulmonary function among ciga- rette smoking workers than nonsmoking workers (42, 64, 89, 97, 99). Aw Pollution Reichel and Ulmer (68, 88) examined the effect of air pollution on the prevalence of respiratory disease among 8,162 men and women in West Germany. The three areas chosen for study had widely different atmospheric levels of sulphur oxides and particulate matter. The fre- quencies of cough and sputum production were the same within the nonsmoking groups in all three areas. No differences were found in pulmonary function or arterial blood gases between subjects of the three districts. Smokers in each area had a higher prevalence of res- piratory symptoms than nonsmokers. The authors concluded, “There is no doubt that the influence of air pollution is less important than that of age, sex, and smoking habits.” Tsunetoshi, et al. (85) examined the prevalence of chronic bron- chitis in Osaka, Japan. The independent contributions of age, smoking habits, and air pollution were examined. In male cigarette smokers using more than a pack a day, chronic bronchitis was three to four times more prevalent then in nonsmokers. In female smokers using half a pack or more a day, chronic bronchitis was five to six times more prevalent than in nonsmokers. The standardized prevalence of chronic bronchitis increased with the degree of air pollution, particu- larly sulphur dioxide pollution, but not with increasing levels of suspended particulate matter. 44 The Federal Aviation Administration, Department of Transporta- tion, and the National Institute for Occupational! Safety and Health jointly conducted a study of the levels of certain combustion byprod- ucts of tobacco on military and civilian aircraft. produced by pas- sengers’ smoking and also asked the passengers for their subjective reaction to tobacco smoke ((/). Levels of carbon monoxide, particu- late matter, polycyclic hydrocarbons, ammonia, and ozone were meas- ured on 20 military and eight domestic flights. On all aircraft the measured level of each substance was much lower than recommended occupational and environmental air quality standards. This was prob- ably the result. of the efficient ventilation systems required on all air- vraft (20 exchanges of cabin air each hour). More than 60 percent of the passengers reported that they were lothered by tobacco smoke and suggested that corrective action such as segregation of smokers and nonsmokers be taken. More than 70 per- rent of the nonsmokers who had a history of respiratory conditions were annoyed by tobacco smoke. The discomfort attributed to tobacco smoke in spite of the efficient ventilation system might have reflected crowded seating conditions or drying of the respiratory membranes which results from the very low humidity found on most aircraft. Autopsy Studies Auerbach, et al. (4) studied the relationship between age, smoking habits, and emphysematous changes in whole lung sections obtained at autopsy from 1,443 males and 388 females. A total of 7,324 sections Imm. thick were graded on a scale of 0 to 9 according to the severity of ‘mphysema. No distinction was made between centrilobular and pan- lobular emphysema. The men were classified by age, type of smoking (pipe, cigar, or cigarette), and amount of cigarette smoking. Smoking habits were ascertained by interviews with relatives. Within each of the six smoking categories, the mean degree of emphysema increased with age. Adjusting the data for age revealed that the mean degree of *mphysema was lowest among men who never smoked, was higher in Pipe or cigar smokers, and highest among regular cigarette smokers. A dose-response relationship was found for the number of cigarettes smoked per day and the severity of emphysema. Table 2 and figure 2 show these relationships. Fingerland, et al. (79) investigated the prevalence of various patho- logical conditions including emphysema and chronie bronchitis in an Mutopsy population comprising all persons over the age of 20 who “ane to autopsy over a 2-year period at the Institute of Pathological Anatomy in Czechoslovakia: 765 males and 573 females were included 45 in the study. Smoking histories were obtained from patients before death, medical records, or relatives. The smokers were divided into three groups based upon the number of cigarettes smoked during their lifetime; 26 percent of the male nonsmokers showed some evidence of emphysema, whereas 70 percent of male smokers of more than 500,000 lifetime cigarettes showed these changes (fig. 3). Similar relationships were demonstrated for chronic bronchitis. TABLE 2.—Degrees of emphysema in current! smokers and in nonsmokers according to age groups Subjects Current Packages smoked per day Age group and degree of who never pipeor emphysema (see text) smoked cigar 2 regularly <60: 0 to 0.75_________. 53 18 12 3 2 0 1 to 1.75._-_ 22 222. 2 ll 4 9 24 5 2 to 2.75. Le. 0 1 2 17 130 56 3 to 3.75_._____- 2. 0 1 5 12 50 38 4 to 4.75___ 0 0 0 8 7 5 to 6.75_________- 0 0 0 0 4 5 7 to 9.00__.______. 0 0 0 0 3 1 Totals____..____ 55 31 23 45 221 112 Mean._____--.-___- . 10 . 83 1, 29 2. 37 2. 56 2. 86 SD___.-2 eee . 04 .13 . 26 . 16 . 07 . 10 60 to 69: 0 to 0.75__ 2-22. 35 17 4 0 0 0 lto 1.75___._____. 1 8 1 0 4 1 2 to 2.75... 8 2 3 4 5 37 23 3 to 3.75__ 2 2 2 2 9 42 24 4to 4.75. 2-2 0 0 1 3 Il 9 5 to 6.75 2222 0 0 0 1 8 1 7 to 9.00__._._.. LL 0 0 0 1 5 4 Totals... 22 40 30 12 19 107 62 Mean___.__..____- . 39 . 95 1. 90 3. 59 3. 39 3. 37 SD_____.. 22 Le 13 . 16 . 34 35 ~15 . 20 70 or older: 0 to 0.75_ 22 ee 68 2) 2 0 0 0 lto 1.75 2.2 4 28 10 8 2 2 2 to 2.75.22 222228. 5 22 13 23 40 9 3 to 3.75__. Le. 4 8 5 10 38 18 4 to 4.75__. 2. 0 2 1 7 11 7 3 to 6.75_._ 22k 0 1 0 2 9 3 7 to 9.00__.._ 2-2 0 0 0 1 12 3 Totals... _ 2 LL 81 82 31 51 112 44 Mean___..________ , 50 1. 66 2.15 2, 98 3. 68 3. 91 SD___.. 22 eee . 39 -11 17 . 20 17 27 ! Subjects who smoked regularly up to time of terminal illness. Source: Auerbach, O., et al. (4). 46 Figure 2.—Age-standardized percentage distribution of whole lung sections of males with moderate to far-advanced emphysema (score 3-9) by smoking category. 60 51.9 50} i) 40} 7 36.8 YY) e w : Z 8 30 iY) Y : Z iY, a 20 4+ G V7 104 7.5 Vi V7 2.9 g Y) 0 VA) LZ. Number 6 14 64 323 of Never Pipe Cigarette smokers caseS smoked or <1 pack/day >1 pack/day regularly cigars SOURCE: Auerbach, Q., et al. (4). Mitchell, et al. (60) conducted a study to determine the accuracy of the recorded cause of death on death certificates of adults; 578 autopsies were performed on patients 40 years of age and older at two large hospitals in Colorado. In addition, 409 patients with COPD were enrolled in an emphysema registry. Autopsies were performed on the 56 patients who died during the study period. Death certificates were obtained from the State Health Department, and the recorded cause of death was compared with the autopsy findings. In 211 of the 634 autopsies performed, the cause of death was found to be COPD; how- ever, in only 160 of these cases (76 percent) was COPD listed as the cause of death on the death certificate; 3 percent of death certificates ‘Incorrectly listed emphysema as a cause of death when this was not Supported by autopsy evidence. The authors concluded their study by Suggesting “* * * that national statistics, which are based on non- autopsy confirmed diagnoses, might understate deaths from chronic bronchitis and ‘emphysema.’ ” 47 Figure 3.—Prevalence of emphysema in adult males at autopsy by SMOking - A +. Uagy mY AY IBOO Ay AAA AY smokers <200,000 200,000-500,000 >500,000 smokers SOURCE: Fingerland, A., et al. (19), Experimental and Histopathological Studies Histopathological Studies Studies in Man Naeye and Dellinger (63) examined the small pulmonary arteries of 126 male cigarette smokers and 67 nonsmokers for quantitative changes in collagen, elastic tissue, and circularly and longitudinally oriented smooth muscle. They found a progressive increase in collagen 48 and longitudinally oriented smooth muscle fibers and a progressive decrease in circularly oriented muscle fibers with age. These changes were more advanced at each age in smokers than in nonsmokers (P<0.01). Sobonya and Kleinerman (78) quantified the smooth muscle and mucous glands in the bronchi of 13 male cigarette smokers and 11 male nonsmokers from Ohio who were 18 to 46 years old and had died of nonrespiratory causes. The smokers averaged 24 pack-years of ex- posure. Although the smokers had a history of more respiratory symptoms and colds than the nonsmokers, no difference was found in the percentages of smooth muscle or bronchial glands between smokers and nonsmokers. Five of the 13 smokers showed evidence of squamous metaplasia. Ellefsen and Tos (/7) determined the goblet cell density in tracheal biopsies from 50 patients with respiratory symptoms or disease. Goblet cell density increased with symptoms of tracheobronchitis and history of exposure to dust. A slight increase was also noted in mean goblet cell density with increasing consumption of cigarettes from 136 in symptomatic nonsmokers to 154 in smokers of more than a pack a day. Studies in Animals Syzganov, et al. (81) exposed 55 dogs to cigarette smoke inhaled through tracheostomas for periods of up to a year or longer. An addi- tional 15 dogs served as nonsmoking controls. The smoking animals developed bronchitis, bronchopneumonia, interstitial pneumonia, and hyperplasia of the bronchial epithelium. Later histologic changes in- cluded squamous metaplasia and papilloma formation not found in controls. The effect of sulphur dioxide (SO.) and cigarette smoke on the mucous glands of rats and the bronchial glands of lambs was studied by Mawdesley-Thomas, et. al. (57). There was a slight increase in the goblet cell count of rats with the inhalation of SO, and cigarette smoke. Exposure of lambs to cigarette smoke inhaled through a tracheostoma resulted in hypertrophy of the bronchial glands. Jones, et al. (39) found that the addition of phenyl methyloxadiazole (PMO) to tobacco protects rats against some of the adverse effects of *xposure to cigarette smoke. Two groups of 15 Sprague-Dawley rats vere exposed to 25 cigarettes a day. 4 days a week for 6 weeks. The Froup exposed to cigarettes containing PMO showed less immediate distress after exposure and had a lower tracheal goblet. cell count, less thickening of the tracheal epithelium, and fewer cells in mitosis than those exposed to the regular cigarettes. The response of the rat lung to low levels of nitrogen dioxide (NQ,), “constituent of cigarette smoke, was studied by Stephens. Evans, and 49 their associates (78, 80). Young male rats were continuously exposed to NO, at concentrations of 2 p.p.m. and 17 p.p.m. for 1 year. Animals were sacrificed after a short exposure and also at regular intervals over the 12-month period. At the level of 17 p.p.m., destructive changes occurred in the respiratory epithelium within + hours. These changes included cell hypertrophy, loss of cilia, and increased mitotic activity, After 24 hours of exposure at this level some repair began, but cuboidal] cells replaced the normal] respiratory epithelium. At 2 p.p.m. the acute damage was less severe, and complete recovery occurred over a period of several weeks, Sherwin, et al. (77) studied the effect of low doses of NO, on the alveolar wall cells of the guinea pig. They found that continuous exposure of 2 p.p.m. NO, produced a significant increase (P<0.05) in the lactate dehydrogenase (LIDH) index of the lower lobes of the lung, suggesting that the ultrathin type 1 (LDH positive) alveolar wall cells were being replaced by relatively thick type 2 cells resulting in a physiologically significant blood-gas barrier. Pulmonary Function Ingram and O’Cain (35) studied dynamic compliance in nine smok- ers and nine nonsmokers under the age of 80 who were in good health. Both groups were identical with respect to airway resistances. lung volumes. maximal expiratory flow rates, and static compliance values, Dynamic compliance fell more rapidly in the smokers than in the non- smokers above a frequency of 0 breaths a minute. The difference was statistically significant (P<0.0001). Isoproterenol] produced no sig- nificant increase in dynamic compliance in either the smokers or the nonsmokers, In six of the smokers who stopped smoking. the dynamic complhance curves gradually approached the values of the nonsmokers over an 8-week period. Changes over this relatively long period of time indicate that the decrease in dynamic compliance observed in smokers was more likely caused by inflammatory changes or some other mecha- nism rather than muscular constriction in the bronchioles, The authors concluded that peripheral airway abnormalities are regularly present in young asymptomatic smokers. The effect of cigarette smoking on pulmonary diffusing capacity was studied by Van Ganse, et al. (98). Diffusing capacity is dependent upon: A membrane component, which is the resistance offered by the lung tissues. and the volume of blood in the lung capillaries, Studies were conducted on 142 randomly selected residents of Berlin, NIL, over the age of 25. In both men and women, there was a decrease in diffusing capacity for carbon monoxide with an increase in age and 50 with increases in cigarette smoking. Ex-cigarette smokers tended to have results similar to those of nonsmokers. The authors found that the mebrane component did not show any consistent change with in- creased current cigarette smoking. whereas the volume of blood in the lung capillaries decreased markedly with increased cigarette consump- tion, and slightly with age. The value of this vascular component in male nonsmokers was 75.5. This decreased to 49.1 in males who smoked 25 or more cigarettes a day (P<0.01). The figures for women were 77.2 and 50.7 for nonsmokers and smokers. respectively (P<0.05). Acetaldehyde is found in cigarette smoke and is a known ciliatoxic agent. The single-breath retention of acetaldehyde vapor by the respi- ratory tract of human subjects was measured by Egle (16) who found a direct relationship between the volume inhaled and the percent taken up. Up to 90 percent of the inhaled acetaldehyde was removed in a single breath. Staneseu (79) studied the single-breath oxygen test in 38 male smokers and 68 male nonsmokers who were in excellent health, A sig- nificant difference (P<0.001) in the slope of the nitrogen gradient between smokers and nonsmokers was found. Teculescu (83) performed single-breath determinations of total lung capacity in 89 males aged 19 through 67 who had normal chest X-rays and no history of respiratory disease. No significant differences were found with age or smoking habits. Pulmonary Clearance Studies in Man Tracheobronchial clearance rates were studied in nine pairs of mono- “ygotic and nine pairs of dizygotic twins by Camner. et al. (72). A test ‘ctosol of radioactively tagged teflon particles 6 to 7 microns in diam- ‘ter was inhaled and external measurements of radioactivity in the hings were made. The clearance patterns within pairs of monozygotic ‘wins were similar, more so than clearance patterns within pairs of dizygotic twins, indicating that tracheobronchial clearance rates may 'o some extent be constitutionally determined. Only one individual had heen a regular cigarette smoker. Camner and Philipson (2) also studied tracheobronchial clearance Smoking-discordant twins, using the same techniques as in the pre- ‘lous study: 10 pairs of monozygotic twins discordant with regard to “garette smoking were studied. All the smokers had used 10 to 20 “Mtrettes a day for more than 20 years. Tracheobronchial clearance “ls. on the average. significantly (P<0.02) slower in the smokers 495-028 O—TH- 51 than in the nonsmokers. Although the basic rate of mucociliary trans. port may be constitutionally determined, it is evident that cigarette. smoking decreases the effectiveness of this physiologic mechanism. The regional deposition of inhaled aerosols in man was studied by Lippmann, et al. (50), who used a monodisperse ferric oxide aerosol] tagged with a radioisotope. Particles were deposited in the pharynx, trachea. bronchi, and alveoli. Measurements were made in 65 adults including 14 nonsmokers, 29 current cigarette smokers. six elderly bronchitic patients, and one young asthmatic. Larger particles were deposited in the upper airways by turbulent precipitation with only the smal] particles of one to five micron size reaching the lower air. ways. The cigarette smokers, bronchitics, and the asthmatic had 4 higher proportion of particles deposited in the tracheobronchial area than nonsmokers. As a result, fewer particles reached the alveoli in these patients. These findings may be the result of a decrease in the diameter of the small bronchioles due to inflammation, mucus, or bronchoconstriction. Albert, et al. (3) studied the effects of cigarette smoking on the kinetics of bronchial clearance in a group of volunteers most of whom also participated in the previous study. A two-phase clearance pattern was described for many subjects. The first, a short, rapid clearance phase, was completed within a few hours and probably represented clearance of the upper airways. The second phase varied in duration from a few hours to 1 day and represented clearance of particles deposited in the distal portions of the bronchial tree. The average clearance time was 126 minutes in 18 nonsmokers, 170 minutes in 19 of the smokers, and 238 minutes in the six patients with bronchitis, most of whom had been heavy cigarette smokers for many years. Much vari- ation in clearance rates was found among smokers. Cigarette smoking resulted in diminished pulmonary clearance in the upper airways first, As a result, mucus cleared from the lower airways accumulated in the larger airways where stasis occurred. In severe cases, stasis was more generalized throughout the bronchial tree. Sanchis, et al. (74) also studied lung clearance mechanisms in nine adult females who had smoked more than 15 cigarettes a day for more than 5 years and who had no evidence of bronchitis or respiratory disease. A group of nonsmoking females matched for age served as controls. A heterodisperse aerosol of I* tagged human albumin was inhaled by the volunteers. and measurements of radioactivity were made over three crescentic areas of the right lung which corresponded to large ciliated airways, intermediate bronchi, and nonciliated periph- era] airways and alveoli, Cigarette smokers exhibited a slowing of the rapid clearance phase of the large ciliated airways and also a relative acceleration in the second clearance phase resulting in an accumula- tion of activity at the hilar area. Comparing the clearance among 52 smokers and nonsmokers, the authors found that the nonsmokers re- tained twice as much activity in the lung at the end of 24 hours as did the smokers. This finding resulted from the deposition of much more of the aerosol distal to the ciliated airways in nonsmokers than in smokers suggesting that seemingly healthy smokers may have obstruc- tion of the small airways. Camner, et al. (77) examined the short-term effects of heavy cigar- ette smoking on mucocilary transport using the same methods as in his previous studies (10, /2). The subjects were 13 men aged 27 to 38 who had been habitual smokers for several years. Baseline clearance rates were measured after refraining from cigarette smoking for 1 hour. The subjects then repeated the test but were instructed to “chain smoke” by inhaling the smoke as deeply and as frequently as possible, but without coughing. Subjects smoked much more intensely than under normal circumstances. The speed of mucocilary transport was sig- nificantly higher during intensive cigarette smoking than when they were not smoking (P<0.01). These results differ from the results of other investigators. The effect of the deep regular inhalation patterns used during the period of heavy smoking on clearance rates remains uncertain. Studies in Animals Rylander (73) studied the effect of cigarette smoke on the clearance of radioactively tagged particles and viable bacteria in the lungs of 114 experimental and control guinea pigs. The clearance of particles neasures mucus transport whereas the clearance of viable bacteria is a partial indicator of phagocytic activity. Inhalation of smoke from “igarettes with varying levels of “tar” resulted in similar decreases in both the mechanical and bactericidal clearance. In each case, the me- rhanical clearance appeared to be affected earlier than the bactericidal “learance. When phenylmethyloxadiazole (PMO) was added to the tobacco, neither the mechanical nor bactericidal clearance was affected by cigarette smoke. Dalhamn and Rylander (74) also reported that phenylvinyloxadia- zole (PVO) and phenylmethyloxadiazole (PMO), when added to 'obacco, were effective in reducing the ciliotoxic effects of cigarette “noke in in vivo cat trachea preparations. Phagocytosis Rylander (72) studied the effect of acute and chronic exposure to ‘“2rette smoke on the number of alveolar macrophages in the guinea Ne. Acute exposure to the smoke of five or more cigarettes. resulted in 53 a significant (P<0.05) reduction in the number of alveolar macro. phages. With more prolonged exposure to cigarette smoke, an increase occurred in the number of alveolar macrophages over control values, The effect of nitrogen dioxide (NO.), a compound found in cigar. ette smoke, on alveolar macrophages in rabbits was studied by Acton and Myrvik (/). Phagocytic activity and virus-induced resistance to rabbitpox virus were suppressed by exposure to 15 p-p.m. of NO, over a 3-hour period. Bacterial and Mycological Studies The prevalence of fungi in the throat was examined by Martin, et al, (56) in a population of 365 male and 103 female European patients in South Africa who were hospitalized for a variety of conditions. Throat swabs were taken shortly after admission and plated on appropriate culture media. The yeasts isolated were Rhodotorula mucilaginosa, Torulopsis glabrata, and seven species of Candida. A seasonal varia- tion in prevalence was noted with a decline in the winter and with peaks in the spring and summer. Smokers of more than 30 cigarettes 4 day had a higher prevalence of pharyngeal fungi than nonsmokers or those smoking less than this amount. No effect of age or disease category on the prevalence of pharyngeal fungi was found. The bacterial flora in respiratory tree secretions obtained at bron- choscopy from 207 patients with chronic lung disease and 48 controls were characterized by Dobisova, et al. in a study from Germany (18). No relationship was found between smoking or severity of respiratory symptoms and the composition of the bacterial flora. They also reported that smokers comprised 84.6 percent of those with chronic cough but only 58.3 percent of the controls. The effects of nitrogen dioxide and cigarette smoke. on the retention of inhaled bacteria were investigated by Henry, et al. (32). Male golden hamsters were exposed to an aerosol of Klebsiella pneumoniae follow- ing exposure to NO. and/or cigarette smoke. A control group was ex- posed to the pathogen without pretreatment. Acute exposure to either NO, or cigarette smoke resulted in an increased mortality and de- creased survival time from Klebsiella infections. Exposure to both NO. and cigarette smoke reduced the rate of clearance of viable bacteria from the lungs to a greater extent than exposure to either substance alone. The increase in lethal effects of Klebsiella exposure may have resulted from inhibition of the mucociliary transport system or redue- tion of phagocytic capacity of the alveolar macrophages. 54 The Surfactant System Finley and Ladman (20) measured pulmonary surfactant in ciga- rette smokers and nonsmokers. The surfactant was recovered after en- dobronchial lavage. The lipid content of surfactant in smokers and nonsmokers was qualitatively similar; however smokers had on the average only 14.3 percent of the surfactant levels found in nonsmokers. Their levels of surfactant returned promptly to levels found in non- smokers following cessation of smoking. Cigarette smoking may re- duce the quantity of surface active material lining the alveolar walls through either decreased production, an increased removal, or a dilu- tion with mucus from the airways. Summary of Recent Nonneoplastic Bronchopulmonary Findings In addition to the summary presented in the introduction of this chapter, based on previous reports of the health consequences of smok- ing, the following statements are made to emphasize the recent develop- ments in the field : 1. Epidemiological and clinical studies from several countries con- firm that cigarette smoking by both men and women is associated with an increased prevalence of respiratory symptoms and de- creased pulmonary function compared to nonsmokers. 2. The regular use of filter cigarettes is associated with less cough and sputum production compared with the regular use of non- filter cigarettes. - Cigarette smoking in combination with certain occupational ex- posures is associated with a higher prevalence of respiratory symptoms and COPD than is observed with either cigarette smoking or occupational exposure alone. Byssinosis is found more frequently in cotton mill employees who smoke cigarettes than in nonsmoking workers. - Recent autopsy studies confirm that pulmonary emphysema is much more frequent and severe in cigarette smokers than in honsmokers. Several recent investigations have confirmed that cigarette smok- Ing exerts adverse effects on pulmonary clearance and macro- Phage function. 55 Bronchopulmonary References (1) Acron, J. D., Myrvix, Q. N. Nitrogen dioxide effects on alveolar macro- phages. Archives of Environmental Health 24(1) : 48-52, January 1972. (2) Axatn, N., Ozaiiniir, H. Smoking and lung function measurements. Acta Medica Turcica 8(1) : 34-44, 1971. (3) ALBERT, R. E., LippMANN, M., PETERSON, H. T., Jr. The effects of cigarette smoking on the kinetics of bronchial clearance in humans and donkeys, In: Walton, W. H. (Editor), Inhaled Particles III. Proceedings of an International Symposium organized by the British Occupational Hygiene Society, London, Sept. 14-23, 1970. Surrey, England, Unwin Brothers, Ltd.; Tbe Gresham Press, 1970, pp. 165-182. (4) AUERBACH,’O., HamMonp, F. C., GARFINKEL, L., BENANTE, GC. Relation of “~~ Smoking and age to emphysema. Whole-lung section study. New England Journal of Medicine 286 (16) : 853-857, Apr. 20, 1972. (5) Batawi, M. A. Ev. Health problems of industrial workers in Egypt. In- dustrial Medicine and Surgery 41(2): 18-23, February 1972. (6) BrEcKLAKE, M. R., FouRNIER-MASSEY, G., Rossiter, C. E., McDona.p, J. C. Lung function in chrysotile asbestos mine and mill workers of Quebec. Archives of Environmental Health 24(6) : 401-409, June 1972. (7) BLoumxkeE, M., Depner, R., Grunrzic, A., KoscHorreck, B., STELZER, O. Uber Unterschiede in der Herz-Lungenfunktion und Befindlichkeit bei Minnern mit verschiedenen Rauchgewohnheiter. (On differences in the heart-and-lung function and feeling healthy in men with different smok- ing habits.) Zeitschrift ftir Praventivmedizin 14(4) : 235-242, July— August 1969. (8) Bounvuys, A., Wotrson, 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, Au- gust 1969. (9) Browntne, W. H. Deleterious effects of cigarette smoking and 100 percent oxygen on aircrew members in high-performance aircraft. Aerospace Medicine 41(1) : 39-42, January 1970. (10) CaMNer, P., PuHitipson, K. Tracheobronchial clearance in smoking-discord- ant twins. Archives of Environmental Health 25(1) : 60-68, July 1972. (17) CaMNER, P., Purzipson, K., ARvIpssoN, T. Cigarette smoking in man. Short- term effect on mucociliary transport. Archives of Environmental Health 23 (6) : 421-426, December 1971. (12) Camwner, P., PHIuipson, K., Friserc, L. Tracheobronchial clearance in twins. Archives of Environmental Health 24(2) : 82-87, February 1972. (13) Coupray, P., SERISE, M., Freour, P. Récherche epidemiologique sur les bronchites chroniques et les insuffisances respiratoires. étude de pre valence dans un echantillon de femmes de 30 4 70 ans. (Epidemiologic study of chronic bronchitis and respiratory insufficiency. Prevalence in a sample of women 30 to 70 years of age.) Révue de Tuberculose et de Pneumologie 33(6) : 769-780, September—October 1969. (14) DaLHamn, T., RyLanper, R. Reduction of cigarette smoke ciliotoxicity by certain tobacco additives. American Review of Respiratory Disease 103 (6) : 855-857, June 1971. (15) Dozrsova, M., Tryxa, L., Frser, F., TOMANEK, A. Abhangigkeit der mikro- biellen Flora im Bronchialbaum von der Bronchialsekretion und den hustensymptomen bei chronisch Lungenkranken. (Dependence of the bronchial secretion and cough symptoms on the microbial flora in the 56 bronchial tree of chronic lung disease patients.) Praxis der Pneumologie 25 (5) : 249-254, May 1971. (16) Eetr, J. L. Single-breath retention of acetaldehyde in man. Archives of Environmental Health 23(6) : 427-433, December 1971. (17) Evtersen, P., Tos, M. Goblet cells in the human trachea. Quantitative studies of a pathological biopsy material. Archives of Otolaryngology 95 (6) : 547-555, June 1972. (18) Evans, M. J.. Srepuens, R. J., Capra, L. J., FREEMAN, G. Cell renewal in the lungs of rats exposed to low levels of NOs Archives of Environ- wee mental-Health 24(3) : 180-188, March 1972. \419) Fincertanp, AX, Husax. T.. Benpiova. J. Contribution to the investiga- tion of the effect of cigarette smoking. Sbornik Vedeckych Praci Le- karske Fakulty Karlovy University v Hradci Kralove 14(2) : 221-234, 1971. (20) Frntey, T. N., LapMan, A. J. Low yield of pulmonary surfactant in ciga- rette smokers. New England Journal of Medicine 286(5): 223-227, Feb. 3, 1972. (21) Fournier, E., Zivy, P. Poumon et tabae. (Lung and tobacco.) Poumon et le Coeur 26(9) : 1109-1125, 1970. (22) FREEDMAN, S., Fiercuer, C. M., FIeLp, G. B. Effects of smoking modified cigarettes on respiratory symptoms and ventilatory capacity. Journal of the National Cancer Institute 48(6) : 1805-1810, June 1972. (23) FRreour, P., Coupray, P. Le probleme des bronchites chroniques a Bordeaux et en Gironde. Etudes epidemiologiques. (The problem of chronic bron- chitis at Bordeaux and at Gironde. Epidemiological studies.) Bordeaux Medical 3(%): 1745-1779, July-August 1970. ‘24) Gotti, V. Etude epidemiologique des bronchopathies non specifiques. (Epidemiological study of nonspecific bronchopathies.) Bronches 20(5) : 313-330, September—October 1970. (25) Gotu, V., L’Influence de l’'usage du tabac et de l’emoussiérage sur la fréquence des bronchites chroniques. (The effect of the use of tobacco and the inhalation of dust on the frequency of chronic bronchitis.) La Presse Médicale 78: 1542-1548, July 28-Aug. 1, 1970. 26) Goxxt, V., STEFANIN, E., Stan, R.. TurNnEscu, B. Etude sur la prevalence actuelle de la bronchite chronique dans une population urbaine. (Study of current prevalence of chronic bronchitis in an urban population.) Acta Tuberculosea et Pneumologica Belgica 60(5) : 714-725, September— October 1969. Gracayx, J., BuxatsKa, Z. Przewlekle zapalenie oskrzeli i ocena wydolnosci oddechowej u ozdrowiencow z gruzlicy. (Chronic bronchitis and assessment of respiratory function in convalescents after tuber- culosis.) Gruzlica i Choroby Plue 39(7) : 610-615, July 1971. Grecory, J. A study of 340 cases of chronic bronchitis. Archives of En- vironmental Health 22(4) : 428-489, April 1971. Haszer, J., HorvatH, R., Kisuinp! Kiss, K., PAL, I., Simon, Z., Ziporics, H. A dohanyzas es felso leguti hurut koroki szerepe a Peesi szenbanyaszok kronikus bronchitiseben. (Smoking and upper airway catarrh as factors causing ¢hronie bronchitis in coal miners from the city of Pees.) Orvosi Hetilap 112(23) : 1344-1348, June 6, 1971. HacERup, L., Larsen, M. Tobaksrygning og respiratoriske symptomer i en Dansk population. Fra 50 ars undersogelsen i Glostrup. (Tobacco smok- ing and respiratory symptoms in a Danish population. From a 50-year study in Glostrup.) Ugeskrift for Laeger 133(27): 1802-1306. July 9. 1971, My 57 (31) Harers, T. R., MERCHANT, J. A.. KILBURN, K. H., Hamiuton, J. D. Byssino- sis and respiratory diseases of cotton mill workers. Journal of Occupa- tional Medicine 14 (3) : 199-206, March 1972. ($2) Henry, M. C., SPANGLER, J., Finpuay, J., EHRiicu, R. Effects of nitrogen dioxide and tobacco smoke on retention of inhaled bacteria. In: Wal- ton, W. H. (Editor). Inhaled Particles IfI. Proceedings of an Inter- national Symposium organized by the British Occupational Hygiene Society, London, Sept. 14-23, 1970. Surrey, England, Unwin Brothers, Ltd., The Gresham Press, 1970, pp. 527-533. (33) Hunter, M. B. Symptomatology. In: Key, M. M., Kerr, L. E., Bundy, M. (Editors). Pulmonary Reactions to Coal Dust. A Review of U.S. Experi- ence, New York, Academic Press, 1971, pp. 57-69. (384) Hirreman, T., OswaLp, P., Lope, H., Hucxaur, H. Veranderungen der Lungenfunktion Jugendlicher als Folge langjihrigen Zigarettenrau- chens, (Changes in pulmonary function of young people as a result of cigarette smoking over many years.) Deutsche Medizinische Wochen- +. Schrift 96(46) : 1791-1793, Nov. 12, 1971. £ (35) INGRAM, R. H., Ir., O'Carn, C. F Frequency dependence of compliance in Se apparently healthy smokers versus nonsmokers. Bulletin de Physio- Pathologie Respiration 7: 195-212, January-February 1971. (36) Jancix, E. Pneumopathies chroniques non specifiques: Enquate epidemio- logique & Brno. Rapport prelminaire. (Chronic nonspecific lung diseases : Epidemiological investigation; at Brno. Preliminary report.) Bronches 19(2) : 185-199, March-April 1969. (37) Jancrk, E. Quelques données et correlations provenant d’une étude epi- demilogique sur Vincidence des symptomes caracteristiques des maladies respiratoires chroniques non specifiques. (Some facts and correlations from an epidemiologic study on the incidence of symptoms character- istic to chronic nonspecfic lung diseases.) Revue de Tuberculose et de Pneumologie 34(5) : 749-752, July-August 1970, (38) Jancix, E., JANciIK-Max, M. Chronische unspezifische Lungenerkrankun- gen. (Chronic nonspecific lung diseases.) Praxis der Pneumologie vere- inigt mit “Der Tuberkulosearzt” 26(2) : 69-81, February 1972. (39) Jones, R., Boipuc, P., Rew, L. Protection of rat bronchial epithelium against tobacco smoke. British Medical Journal 2(5806) : 142-144, Apr. 15, 1972. (40) Key, M. M., Kerr, L. E., Bunpy, M. (Editors). Pulmonary Reactions to Coal Dust. A Review of U.S. Experience. Environmental Science Series. New York, Academic Press. 1971, 215 pp. (41) Kuosta, T. Indices of ventilatory measurements, British Journal of Pre- ventive and Social Medicine 20(4) : 203-209, November 1971, (42) KircHKNoprF, M., Sovaco, M. Az idiilt hérghurut elofordulasa az Ozdi kohaszati tizemek finomhengermiii dolgozoi kireben. (The incidence rate of chronic bronchitis among the precision calendering workers at the foundry of Ozd.) Orvosi Hetilap 110(44) : 2584-2526, Nov. 2, 1969. (43) Kornitzer, M., DEMEESTER, M. La symptomatologie respiratoire en epi- demiologio. Resultats de l'enqfete effectuée dans une banque Bruxelloise. (Respiratory symptomatology in epidemiology. Results from a survey effected in a bank in Brussels.) Acta Tuberculosea et Pneumologica Belgica 61(5/6) : 481-506, September—December 1970. (44) Larnuarr, W. S., Morcan, W. K. C. Extent and distribution of respira- tory effects. In: Key, M. M., Kerr, L. E., Bundy. M. (Editors). Pulmonary Reactions to Coal Dust. A Review of U.S. Experience. New York, Aca- demic Press, 1971, pp. 29-56. 58 (46) (48) (51) (52) (53) LANGLANDS, J. H. M.. Wattace, W. F. M., Simpson, M. J. C. Insulation workers in Belfast. 2. Morbidity in men still at work. British Journal of Industrial Medicine 28(3) : 217-225, July 1971. Lapp, N. L., HanKinson, J. L., Burcess, D. B., O'Brien, R. Changes in ventilatory function in coal miners after a work shift. Archives of En- vironmental Health 24(3) : 204-208, March 1972. Lapp, N. L., SEATON, A., KAPLAN, K. C., HuNSAKER, M. R., Morcan, W. K. C. Pulmonary hemodynamics in symptomatic coal miners. American Re- view of Respiratory Disease 104(3) : 418-426, September 1971. Latimer, R. G., Dickman, M.. Day, W. C.. Gunn, M. L., Script, C. D. Ventilatory patterns and pulmonary complications after upper abdomi- nal surgery determined by preoperative and postoperative computerized spirometry and blood gas analysis. American Journal of Surgery 122(5) : 622-632. November 1971. Leg, D. H. K. Etiology. In: Key, M. M., Kerr. L. E., Bundy. M. (Editors). Pulmonary Reactions to Coal Dust. A Review of U.S. Experience. New York, Academic Press, 1971, pp. 189-195. LrppMany, M., ALBERT, R. E.. Pererson, H. T., Jr. The regional deposition of inhaled aerosols in man. In: Walton, W. H. (Editor). Inhaled Par- ticles III. Proceedings of an International Symposium organized by the British Occupational Hygiene Society, London, Sept. 14-28. 1970. Surrey, England. Unwin Brothers, Ltd., The Gresham Press, 1970, pp. 105-122. Lowe, C. R., Knosra, T. Chronic bronchitis in ex-coal miners working in the steel industry. British Journal of Industrial Medicine 29(1) : 45-49, 1972. Lyons, J. P., Ryver, R.. CampBetL, H., Goucu, J. Pulmonary disability in coal workers’ pneumoconiosis. British Medical Journal 1(5802) : 713— 716, Mar, 18, 1972. McDona.p, J. C., BECKLAKE, M. R., Fournier-Massey, G.. Rossiter. C. E. Respiratory symptoms in chrysolite asbestos mine and mill workers of Quebec. Archives of Environmental Health 24(5) : 358-363, May 1972. McKerrow, C. B., Scuitting, R. S. F. A pilot enquiry into byssinosis in two cotton mills in the United States. Journal of the American Medical Association 177 (12) : 850-853, Sept. 23, 1961. Manu, P., Dumitru, M., Guisr, O., Comanescu, (. Cercetari epidemio- logice privind bronsita cronica la un lot din populatia generala a orasului Bucuresti. (Epidemiological studies on chronic bronchitis in a sample of the general population of Bucharest.) Medicina Interna 22(9): 1123— 1134. September 1970. MARTIN, P., KANAREK. D.. Zwt. S., Born, A. V.. Koornuyor, H. J. The inci- dence of fungi in the throat. Mycopathologia et Mycologia Applicata 45 (2) : 165-187, Oct. 13, 1971. MawbpesLey-THomas, L. E.. HEALEY, P., Barry, D. H. Experimental bron- chitis in animals due to sulphur dioxide and cigarette smoke. An auto- mated quantitative study. In: Walton, W. H. (Editor). Inhaled Particles TI. Proceedings of an International Symposium organized by the British Occupational Hygiene Society. London, Sept. 14-28, 1970. Surrey, Eng- land, Unwin Brothers, Ltd., The Gresham Press, 1970. pp. 509-526. Mercuant. J. A. Kinpurx, K. H., O’Fanton, W. M., Hamivtron, J. D., Lumspen. J. C. Byssinosis and chronie bronchitis among cotton textile workers. Annats of Internal Medicine 76(3) : 423-483, March 1972. Miter, G. J., Asucrorr. M. T. A community survey of respiratory disease among East Indian and African adults in Guayana, Thorax 26(3) : 331- 338. May 1971. 59 (60) x (63) (64) (85) (66) (67) (68) (69) 60 MITCHELL, R. S.. MAIsEL. J. C., Dart, G. A.. Sinvers, G. W. The accuracy of the death certificate in reporting cause of death in adults, with special reference to chronic bronchitis and emphysema. American Review of Respiratory Disease 104 (6) : &44-850, December 1971. Morcan, W. K. (C., Bureress. D. B., Lapp, N. L.. Seaton, A.. ReEcer, R. B, Hyperinflation of the lungs in coal miners. Thorax 26(5) : 585-590, September 1971. Narre. R. L. Structural features in Appalachian coal workers. In: Key, M. M., Kerr, L. E.. Bundy. M. (Editors). Pulmonary Reactions to Coa] Dust. A Review of U.S. Experience. New York, Academic Press. 1971, -bp, 93-110. NakEye, R. L., DELLINGER, W, S. Pulmonary arterial changes with age and smoking. Archives of Pathology 92(4): 284-288, October 1971, OwsINSKI, J.. Janus, T., Mystik, M. Wystepowanie przewleklych nies- woistych chorob ukladu oddechowego (p.n.ch.1.o.) wsrod pracownikow zakladu przemyslu gipsowego “Dolina Nidy” w Gackach. (Occurrence of chronic unspecific diseases of the respiratory system among workers in the plaster works at “Dolina Nidy" in Gacki.) Przeglad Lekarski 28 (7): 476-480, 1971. Panne, R. S.. Marwaua. R. K.. PATEL, N. M. Smoking and lung funetion, Indian Practitioner 4(7) : 353-857, July 1971. RACOVEANU, C., MANICATIDE, M.. NICOLAESCU, V. Cercetari epidemiologice asupra bronsitei cronice in duoa zone fara poluare atmosferica indus- triala. (Epidemiological study of chronic bronchitis in two regions with- out industrial air pollution.) Studii si Cercetari de Medicina Interna 12(4) : 359-367, 1971. REGAN, G. M., Taga, B.. Warorp, J., THomsonx. M. IL. The relative impor- tance of clinical, radiological, and pulmonary function variables in eval- uating asbestosis and chronic obstructive airway disease in asbestos workers. Clinical Science 41: 569-582. 1971. REICHEL, G. Effect of air pollution on the prevalence of respiratory dis- eases in West Germany. Jn: Englund, H. M. Beery, W. T. (Editors). Proceedings of The Second International Clean Air Congress, Washing- ton, D.C.. Dec. 6-11, 1970. Academie Press, New York, 1971. pp. 186-191. REICHEL, G., ULMER, W. T., [KONOMIDES, S. Z. Einfliisse der Raucherge- wohnheiten auf die Hitfigkeit unspezifischer Atemwegserkrankungen, TIT. Mitteilung. (Influence of smoking habits on the incidence of non- specific respiratory diseases. IIT. (Communication.) Internationales Archiv fiir Arbeitsmedizin 27 (1/2) ; 49-72, Oct. 30, 1970. Rei, D. D. Bronchitis among the British. Israel Journal of Medical Sciences 7(12) : 1569-1572, December 1971. RIMINGTON, J. Phlegm and filters. British Medical Journal 2(5808): 262~264, Apr. 29, 1972. Ryvanner, R. Free lung cell studies in cigarette smoke inhalation ex- periments. Scandinavian Journal of Respiratory Diseases 52(2): 121- 128, 1971. RYLANDER. R. Lung clearance of particles and bacteria. Effects of cigarette smoke exposure. Archives of Environmental Health 23 (5) : 321-326, November 1971, SANCHIS, J.. DoLovicy, M.. CHALMERS, R., Newnousk. M. T. Regional distribution and lung clearance mechanisms in smokers and non- smokers, Zr: Walton, W. H. (Editor). Inhaled Particles ILI. Proceedings of an International Symposium organized by the British Occupational Hygiene Society, London, Sept. 14~23, 1970. Surrey, England, Unwin Brothers, Ltd., The Gresham Press, 1970. pp. 183-191. (75) Scurae, P. E., Guuiett, A. D. Byssinosis in cotton textile mills. American Review of Respiratory Disease 101(4) : 497-508, April 1970. (76) Seaton, A., Lapp, N. L., Morean, W. K. C. Relationship of pulmonary impairment in simple coal workers’ pneumoconiosis to type of radio- graphic opacity. British Journal of Industrial Medicine 29(1): 50-55, 1972. (77) SHERWIN, R. P., Dissie, J., WEINER, J. Alveolar wall cells of the guinea pig. Increase in response to 2 p.p.m. nitrogen dioxide. Archives of En- vironmental Health 24(1): 48-47, January 1972. (78) Soponya, R. E., KLEINERMAN, J. Morphometric studies of bronchi in young smokers. American Review of Respiratory Disease 105(5): 768-775, May 1972. STanescu, D. C. Age and smoking dependency of the single-breath oxygen ” test in healthy subjects. Pneumonvlogie 147(1) : 46-51, 1972. (80) SrepHens, R. J., FREEMAN, G., Evans, M. J. Early response of lungs to low levels of nitrogen dioxide. Archives of Environmental Health 24(3) : 160-179, March 1972. (81) Syzeanov, A. N., Gotovin, Y. A., TrorrsKaya, Y. G. O vliyanii tabachnogo dyma pri kurenii na organy dykhaniya v eksperimente. (Experiments on the influence of tobacco smoke on the respiratory organs during smoking.) Eksperimental’naia Khirurgiia i Anesteziologiia 16(6): 23-26, 1971. (82) SzyMczyKiewicz, K. E., Kunsk1, H., Gieiec, L. Clinical evaluation of the respiratory system in cotton workers. Bulletin of Polish Medical Science and History 13(3) : 110-114, July 1970. (83) TecuLescu, D. B. Validity, variability, and reproducibility of single- breath total lung capacity determination in normal subjects. Bulletin de Physio-Pathologie Respiratoire 7(3) : 645-658, May-June 1971. (84) TEcULEscU, D., Sranescu, D. Ventilatia si mixica pulmonara la barbati tineri sanatosi, fumatori si nefumatori. (Pulmonary ventilation and distribution in young healthy males, smokers and nonsmokers.) Studdi si Cercetari de Medicina Interna 5(11) : 419-428, 1970. (85) TsunetTosui, Y., Suimizu, T., TAKAHASHI, H., IcHinosawa, A., Uspa, M., NakayYaMa, N., YamMacaTa, Y., OHSHINO, A. Epidemiological study of chronic bronchitis with special reference to effect of air pollution. Internationales Archiv fur Arbeitsmedizin 29(1) : 1~27, 1971. (86) Umer, W. T. Emphysema of the lung: Clinical and experimental investi- gations of its pathogenesis. Geriaterics: 25(5): 164-165, 168-169, -- May 1970. (87) Tater,’ W. T. Lung function studies in epidemiologic investigations of respiratory diseases. Bulletin de Physio-Pathologie Respiratoire 6: 605-616, 1970. (88) Utser, W. T., REICHEL, G. Zur Epidemiologie der chronischen Bronchitis und deren Zusammenhang mit der Luftverschmutzung. (A contribution to the epidemology of chronic bronchitis and to its relation to air pollution.) Deutsche Medizinseche Wochenschrift 95(51) : 2549-2554, Dec. 18, 1970. (89) ULRicu, L., Matix, E. Chronie bronchitis in agricultural and chemical workers. Arhiv za Higijenu Rada i Toksikologiju 21(1) : 35-47, 1970. (90) U.S. DEPARTMENT oF TRANSPORTATION, FEDERAL AVIATION ADMINISTRATION, U.S, DepaARTMENT oF HeaitH. EptcaTion, AND WELFARE, NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND Heattu. Health Aspects of I ~ S im 61 (91) (92) (93) (94) (95) (96) (97) (98) (99) (700) (TAT) 62 Smoking in Transport Aircraft. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration, National Institute for Occupational Safety and Health, Rockville, Md., AD-736097, December 1971, 85 pp. U.S. Pusiic HEALTH SERVICE. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. Wash- ington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No, 1108, 1964, 387 pp. U.S. PuBLic HEALTH SERVICE. The Health Consequences of Smoking, A Public Health Service Review: 1967, U.S. Department of Health, Edu- cation, and Welfare. Washington, Public Health Service Publication No. 1696, Revised Janua ry 1968, 227 np. U.S. Pupiic HEALTH SERVIcE, The Health Consequences of Smoking, 1968 Supplement to the 1967 Public Health Service Review. U.S. Department of Health, Education, and Welfare. Washington, Publie Health Service Publication 1696, 1968, 117 pp. U.S. Pustic HEALTH SERvice, The Health Consequences of Smoking. 1969 Supplement to the 1967 Public Health Service Review. U.S. Department of Health, Edueation, and Welfare. Washington, Public Health Service Publication 1696-2, 1969, 98 pp. U.S. Purric HEALTH Servicr. The Health Consequences of Smoking. A Report of the Surgeon General: 1971, U.S. Department of Health, Edu- cation, and Welfare. Washington, DHEW Publication No, (HSM) 71- 7513, 1971, 458 pp. U.S. Pusric HEALTH SERVicE. The Health Consequences of Smoking. A Report of the Surgeon General: 1972. U.S, Department. of Health, Edu- eation, and Welfare. Washington, DHEW Publication No. (HSM) 72- 6516, 1972, 158 pp. Varic, F., STAHULIAK, 1, B. Kronicni bronhitis u pekara. (Chronic bron- chitis in bakers. ) Lijecnicki Vjesnik 93( T) : 739-748, 1971. Van GANSE, W. F., Ferris, B. G., Jr., Cotes, J. E, Cigarette smoking and pulmonary diffusing capacity (transfer factor). American Review of Respiratory Disease 105(1) : 30-41, January 1972, WALKER, D. D., ARCHIBALD, R. M., ATTFIELD, M. D. Bronchitis in men elmployed in the coke industry. British Journal of Industrial Medicine 28(4) : 358-363, October 1971. YoxoyaMa, K., SERA, Y,, KONISHIIKE, T., MarTsuMoro, T., NAGOSHI, S., ABAHI, T., SaKal, M., Hrwapa, K. Mansei kikanshien no ekigakuteki kenkyu. (Epidemiological survey of chronic bronchitis. ) Iryvo 24(2): 105-114, February 1970. Zivy, P. Le pneumothorax spontane des fumeurs, Le poumon tabagique, Tabagisme alvéolaire et troubles métaboliques. (Spontaneous pneumo- thorax of smokers: tobacco lung: alveolar nicotinism and metabolic disorders.) Revue de Tuberculose et de Pneumologie 34(1): 125-158, 1970. CHAPTER 3 Cancer Contents Introduction.-__... === eee Lung Cancer__--.-____-----2--- eee eee Epidemiological Studies Ez-Smokers._-_..--.------------------------ Uranium Mining and Exposure to Radioactivity Arr Pollution Asbestos_._._-____.---__-2 eee Autopsy and Cytological Studies Oral Cancer______....-_-__-_- eee Cancer of the Esophagus Cancer of the Larynx._.________. 2. Cancer of the Pancreas.__.._._.-.__..-.222 ee Cancer of the Kidney and Urinary Bladder Experimental Carcinogenesis_._._..._......_-___----.---_- Respiratory Tract Carcinogenesis Experiments in Mice__.__---------.------------- ee Aryl Hydrocarbon Hydroxylase (AHH)__.........------- Cell and Tissue Culture Studies_...._..........-------- Binding of Polycyclic Hydrocarbons to DNA and RNA__-- N-Nitrosamines in Tobacco Smoke____-.-- eee Summary of Recent Cancer Findings References List of Figures Figure 1.—Standardized lung cancer mortality ratios of Japanese by number of cigarettes smoked (1966-70) ______. Figure 2.—Lung cancer mortality ratios of Japanese by age at initiation of cigarette smoking (1966-70)__.._.._._...__- Figure 3.—The survival of ex-smokers and continuing smokers who were treated for a primary cancer of the oral cavity, pharynx, or larynx Page 67 68 68 71 72 72 73 73 74 76 76 77 77 78 78 80 82 84 86 87 88 88 69 69 75 65 List of Tables Table 1.—Age-standardized lung cancer death rates of British physicians and the population of England and Wales at various time periods._..-------..e Table 2.—N-dimethylnitrosamine (DMNA) content of con- densates obtained from several tobaccos grown in both “high” and “low” nitrogen soils..-_.-.-.-8 66 Page 70 Introduction This introduction is a brief summary of the major relationships between smoking and cancer which have been established in previous reports on the health consequences of smoking (9/, 92, 93, 94, 95, 96). Cigarette smoking has been clearly identified as the major cause of lung cancer in the United States. This conclusion is based on detailed epidemiological, clinical, autopsy, and experimental data which have accumulated over a period of more than 20 years. For both men and women, the risk of developing lung cancer is directly related to total exposure to cigarette smoke as measured by the number of cigarettes smoked per day, the total lifetime number of cigarettes smoked, the duration of smoking in years, the age at initiation of smoking, the depth of inhalation of tobacco smoke, and the “tar” and nicotine levels in the cigarettes smoked. Lung cancer death rates, however, are lower for women than they are for men, a finding due, in part, to a difference in exposure. Women smokers use fewer cigarettes a day, choose filtered cigarettes with lower “tar” and nicotine values, and also tend to inhale less. However, even when women experience comparable levels of ex- posure to cigarette smoke as men, their mortality rates for lung cancer still remain somewhat lower. Those who stop smoking experience a decline in the risk of develop- ing lung cancer relative to continuing smokers. The air pollution commonly found in an urban setting appears to result in elevated lung cancer death rates; however, this effect is relatively small compared to the overriding effect of cigarette smoking. Certain occupational exposures have been found to be associated with an increased risk of dying from lung cancer. Cigarette smoking interacts with many of these exposures to produce much higher death rates from lung cancer than would result from one exposure alone. Interacting exposure factors may be experienced simultaneously or at different times. The uranium mining and asbestos industries are exam- ples of occupations in which this interaction occurs. The bronchial epithelium of smokers often shows premalignant changes including squamous metaplasia, atypical squamous metaplasia, and carcinoma in situ. Pipe and/or cigar smokers experience a risk of developing lung cancer that is higher than the risk of nonsmokers; however, it remains 67 495-028 O-—73—_6 significantly lower than the risk of cigarette smokers. A more complete discussion of the risks from pipe and cigar smoking is found in another chapter of this report. Epidemiological, experimental, and autopsy data have demonstrated that cigarette smoking is a significant factor in the development of cancer of the larynx, oral cavity, esophagus, and urinary bladder, B-naphthylamine, a carcinogen known to cause cancer of the urinary bladder in humans, has been identified in cigarette smoke. There is also an association between cigarette smoking and cancer of the pancreas, Experimental studies with animals in which cigarette smoke or one of its constituent compounds is administered in a variety of assays have confirmed the presence of complete carcinogens, cocarcinogens such as tumor initiators and tumor promoters, and tumor accelerators in cigarette smoke. Recently, additional epidemiological, autopsy, and experimental studies have added to our understanding of these relationships. Lung Cancer Epidemiological Studies An ongoing prospective epidemiological study conducted in J apan provides a unique opportunity to examine the relationship of cigarette smoking to death rates in a population with genetic, dietary, and other cultural differences from previously examined Western popula- tions. Hirayama (37) has now reported S-year followup data on 265,118 men and women aged 40 years and older. This represented 91 to 99 percent of the total population in the area of the 29 health districts where the study was conducted. A total of 11,858 deaths occurred dur- ing the 5-year period which included a total of 1,269,382 person-years of observation. Both men and women who smoked cigarettes experi- enced higher death rates from lung cancer than nonsmokers. Among smokers, the lung cancer mort ality ratio was 3.85 for men and 2.44 for women as compared to nonsmokers (P<0.001). Dose-response relation- ships were demonstrated for the number of cigarettes smoked per day and the age at initiation of smoking (figs. 1 and 2). These mortality ratios are considerably lower than those reported for the United States, Canada, and Great Britain, and may reflect a lower average number of cigarettes smoked a day, an older age at initiation of smoking, or re- duced inhalation of cigarette smoke among the Japanese, In spite of these differences. the overall results of this study, including the dose- response relationships, are similar to the results of all the other niajor 68 epidemiological investigations. Thus, the reliability and accuracy of the methods of population selection and analysis used in previous studies based on population samples, and the conclusion that cigarette smok- ing is the major cause of lung cancer are again confirmed. Figure 1.—-Standardized lung cancer mortality ratios of Japanese by number of cigarettes smoked (1966—1970). 9.0 8.0} 7.0} 6.0 + 5.0 + “i a > ww w an 4.0 3.0 } Mortality ratio 2.0 1.0} 1.0 ol [1 Non- 1-14 15-24 smoker cigarettes per day smoker SOURCE: Hirayama, T. (37). OOOAT! U Z ZL) NON AS V ht pb R Figure 2.—Lung cancer mortality ratios of Japanese by age at initiation of cigarette smoking (1966—1970). 9.0 8.0 + 7.0 } & 60} 5.4 £ 5.0 | YY 2 oO 4.0 4 eT 3.2 iY) ° = 3.0} g iY 4 2.0 + “ i) iY 1.0 1.0 + iY) iY) iY 0 tA LZ Ld 4 Non- >25 <24 <19 smoker Age at initiation of smoking SOURCE: Hirayama, T. (37). 69 ye y bet TABLE 1.—Age-standardized lung cancer death rates of British physicians and the population of England and Wales at various time periods Lung cancer standardized death rate Per 1,000 men per year in— Doctors England and Wales Years... 22 1953-57 1957-61 1961-65 1954-57 1958-61 1962-65 Death rate per 1,000_.________.._____ 1.10 0.85 0.83 1.49 1.71 1. 88 Source: Doll, R., Pike, M. C. (82). Kennedy (45) studied primary lung cancer in 29 men and 11 women diagnosed before the age of 40 and found a strong association between cigarette smoking and the development of this disease. Boucot, et al. (72) further characterized the 121 cases of lung cancer detected in the population of the Philadelphia pulmonary neoplasm research project. The risk of developing lung cancer in- creased with age, was higher in nonwhites than in whites, and increased sharply with increased cigarette consumption. The relationship between cigarette smoking and lung cancer was investigated in a retrospective study by Ferrara (25) in La Plata, Argentina. The smoking habits of 144 lung cancer patients were con- trasted with those of 386 controls, A dose-response relationship was found between cigarette usage measured by the number of cigarettes smoked per day and the duration of smoking and the risk of developing lung cancer. A high incidence of lung cancer is reported from the island of Jersey in the Channel Isles compared to England and Wales. The island has no heavy industry and only minimal levels of air pollution. Cragg (16) studied 144 patients who developed lung cancer on J ersey during a 4-year study period. Only three nonsmokers were found among the 113 patients for whom histories were available. Fingerland, et al. (26) determined the prevalence of lung cancer and certain other diseases in an autopsy series of 1,338 adults in Czechoslovakia. Some 198 cases of primary lung cancer were identified. In the autopsy population, 1.4 percent of the nonsmokers, 14.1 percent of those smoking less than- 0,000 lifetime cigarettes, and 33.3 percent of those smoking more than 500,000 lifetime cigarettes had lung cancer. ‘Et a Rickard and Sampson (77 ) studied 94 Negro patients with lung cancer in Washington, D.C., and found that 57 (92 percent) of 63 patients whose smoking history was available were regular smokers. Epidemiological studies conducted in Italy (10), Sweden (48), Poland (46), Russia (42), Cuba (73), Mexico (13), and the Nether- lands (98) demonstrate an association between cigarette smoking and lung cancer. 70 Berg, et al. (5) examined the incidence of recurrent primary cancers following initial primary cancers of the respiratory and upper di- gestive systems in New York. During 23,802 man-years of observation in 9,415 patients with an initial squamous cell cancer, 518 second cancers developed at other sites. Patients whose first primary cancer was in the lung had an observed to expected relative risk ratio of 5.7 (P<0.05) for subsequent cancers of the respiratory or upper GI system. Patients with the first cancer in the oral cavity or larynx frequently developed a second cancer in the lung. Medical records confirmed long smoking histories among almost all of these patients who developed second cancers. Cancer of the lung, oral cavity, larynx, and esophagus were reported by Schmidt and De Lint (79) to be common causes of death among 6,578 men and women who had received treatment for alcoholism in Toronto. The authors attributed this finding to the strong associa- tion that exists between alcohol and tobacco use and not to the effect of alcohol alone, Carcinoma of the trachea is a relatively rare condition with only about 400 cases having been reported in the literature, In a study of 41 patients with carcinoma of the trachea, Hajdu, et al. (37) found an apparent association between cigarette smoking and the development of epidermoid cancers of this structure. An association between cigarette smoking and the development of bronchiolo-alveolar carcinoma in 74 patients was described by Delarue, etal. (78). E-x-smokers Those who stop smoking experience a decline in the risk of develop- ing lung cancer relative to continuing smokers. Doll and Pike (22 vonducted a study of the smoking habits and causes of death of 40,000 British physicians. Smoking habits were surveyed in 1941, 1957, and 1966. During the study period, more than 3,500 physicians became ex- smokers. The age-standardized percentage of ex-smokers among phy- Siclans 35 to 64 years of age rose from 18.1 percent in 1951 to 26.5 per- cent in 1957 and 29.5 percent in 1966. Concurrently, the percentage of physicians smoking cigarettes fell from 44.1 percent to 22.0 percent, while over the same period estimates of the per capita cigarette con- sumption for the adult male population in the United Kingdom sug- zested a slight increase in cigarette consumption. Over this 15-year period, the mortality from lung cancer among physicians dropped con- siderably while lung cancer death rates among the male population in England and Wales increased to some extent (table 1). Although cer- 7) tain limitations apply to the interpretations derived from secular data, analysis of the study design and the magnitude of the results indi- cate that this study constitutes important evidence of some of the bene- fits that result from the cessation of cigarette smoking. Uranium Mining and Ex posure to Radioactivit g P Epidemiological evidence supported by autopsy studies has estab. lished that airborne radiation. particularly in synergistic combination with cigarette smoking, is the major cause of the excess of respiratory cancers among uranium miners, Lundin, et al. (53) considered quantitative and temporal aspects of radon daughter exposure and respiratory cancer in a report from the Epidemiological Study of United States Uranium Miners. They ob- served a statistically significant excess of respiratory cancer among white uranium miners at each cumulative radiation exposure category down to and including 120-359 WLM (working level months). The authors noted that although cigarette smoking alone entailed a risk of the development of cancer of the respiratory tract in miners just as it does in nonminers, cigarette smoking in combination with radon daughter exposure appeared to result in an even preater risk. Several authors (30, 44, 63, 84, /04) continue to report the presence of polonium-210 or one of the thorium isotopes in tobacco leaf, tobacco smoke, or the lungs of smokers, Air Pollution Data standardized for cigarette smoking indicate the existence of an urban factor in the development of lung cancer: it is likely that air pol- lution, frequently part of the city environment, is a component of the urban factor. The National Academy of Sciences published a review (67) of the biological effects of atmospheric pollution by particulate polycyelie organic matter. Detailed epidemiological, experimental, physical, and chemical data were reviewed. It was concluded that air pollution, as commonly found in urban settings, was found to be associated with in- creased lung cancer mortality in cities, An examination of the data presented, however, indicates that cigarette smoking is, in most cases, the overriding factor in the development of lung cancer. Polycyclic hydrocarbons and related compounds which are known to cause cancer of the lung and other organs in experimental animals were found to 72 be present in relatively high concentrations in cigarette smoke, in large quantities in the air of industries in which workers have high-lung cancer rates, and also in the air of urban communities. Sterling and Pollack (86) reviewed the effects of air pollution on death rates from lung cancer. They suggested that particles resulting from the combustion of organic fuels may be more strongly related to the incidence of lung cancer in the population than cigarette smoking. The cumulated epidemiological data regarding cigarette smoking and lung cancer were not. considered by the authors in this report. Asbestos Cigarette smoking asbestos workers have markedly elevated lung cancer death rates compared to nonsmoking asbestos workers. Berry (6) examined the combined effect of asbestos exposure and smoking on mortality from lung cancer among 1,300 male and 480 female asbestos factory workers over a 10-year period. There was no significant in- crease in lung cancer mortality among smoking or nonsmoking workers with a low-to-moderate exposure to asbestos. However, among smokers who had heavy exposure to asbestos, 32 lung cancer deaths occurred among 663 men (9.9 expected), and there were 18 deaths among 292 women (1.4 expected). This contirms the greatly increased risk of de- veloping lung cancer among asbestos workers who smoke cigarettes. Autopsy and Cytological Studies The respiratory tract of cigarette smokers examined at autopsy fre- quently demonstrates epithelial changes considered to be precursors of bronchogenic carcinoma. Such changes include squamous metaplasia, atypical squamous metaplasia, and carcinoma in situ. Herrold (35) studied histologic types of primary lung cancer in U.S. veterans who were subjects of the Dorn study. Of a total of 2,241 white male vet- erans who died of lung cancer over an 8-year period, histologic mate- rial was available for review in 1477 patients. Histologic types were grouped according to the Kreyberg classification of Groups I and II tumors. Group I tumors, epidermoid and oat-cell carcinomas. were present in 27.3 percent of the 55 nonsmokers and were present in 57.8 percent of the 472 “current smokers of cigarettes only.” The difference Was statistically significant (P<0.001). confirming the strong associa- tion between cigarette smoking and Kreyberg Group I tumors. 73 Auerbach et al. (2) examined epithelial changes in the bronchial tree of 456 men and 802 women who had died of a cancer other than lung cancer. There were 72 ex-smokers among the men, all of whom had smoked for 10 years or more but had quit smoking for at least 5 years prior to death. Atypical cells were present in 93.2 percent of the current smokers, 6.0 percent. of the ex-smokers, and 1.2 percent of the non. smokers. Areas of epithelium composed entirely of atypical cells devoid of cilia were found in the bronchial tree of 8 percent of the current smokers, 0.2 percent of the ex-smokers, and none of the nonsmokers, Unusual cells with disintegrating or fading nuclei were found exclu- sively in 15 percent of the ex-smokers, The prevalence of atypical cells (hyperplastic and metaplastic) in the sputum of 122 male and 128 female workers was examined by Rob- bins (72). These smokers, all under the age of 19, were matched with a control group drawn from a population of college students. Atypical cells were found in 14 percent of the smokers and 5 percent of the non- smokers. Oral Cancer Data from the large Japanese prospective study by Hirayama (37) indicate that mortality rates from cancer of the oral cavity among males are higher in smokers than nonsmokers. A dose-response rela- tionship was demonstrated for the age at initiation of smoking. The standardized mortality ratio among cigarette smokers was 10.0 for men (P<0.001) and 1.22 for women compared to nonsmokers. These ratios are not stable due to the few deaths that occurred from ora] can- cer in this study. Certain relationships between cigarette smoking and cancer of the oral cavity, pharynx, and larynx were investigated by Moore (59). Over a 15-year period, 1,000 patients with invasive squamous carci- noma at these sites were treated in Kentueky. Of these patients, 203 had a history of cigarette smoking and had had no recurrence of cancer for a period of 3 years or more. This group was further divided on the basis of current smoking habits. Of the 122 who continued to smoke, 48 (40 percent) eventually developed a second cancer at these sites, whereas only five (6 percent) of the 81 who stopped smoking de- veloped a second malignancy. This sixfold difference is statistically significant (P<0.001). The survival curves for these two groups are presented in figure 3. 74 Figure 3.—The survival of ex-smokers and continuing smokers who were treated for a primary cancer of the oral cavity, pharynx, or larynx. 100 90 80 70 60 50 Surviving (%) 40 30 F @~-——-6 Ex-smokers > o——e Continuing Smokers 20 + 10 Ff 0 A A r i 4 4 A. sh A 3 4 5 6 7 8 9 10 11 12 13 Follow-Up (yr) SOURCE: Moore, C. (59). Martinez (57) studied the relationship between smoking in various forms and cancer of the oral cavity in a retrospective study of 153 patients with this disease. Dose-response relationships were demon- strated for the amount smoked; the amount of alcohol consumed, and the development of cancer of the oral cavity. Tyldesley (90) examined the prevalence of leukoplakia among 402 English coal miners of whom 280 smoked and chewed tobacco. Tobacco chewing was commonly found to be a substitute for smoking in under- ground conditions where smoking was impossible. Leukoplakia was found in 3.6 percent of the chewers. whereas no leukoplakia was found among the nonchewers. Nelson and Ship (62) determined the relative influence of eight variable factors on the development of oral cancer in relation to age it the onset of disease in a population of 191 patients with a confirmed diagnosis of a primary squamous cell carcinoma of the oral cavity. The factors considered included age, sex, race, consumption of alco- hol and tobacco, certain systemic diseases. and oral trauma. The prevalence of heavy tobacco use was more common among the younger Patients. While 91 percent of the cancer patients under the age of 45 smoked more than 20 cigarettes a day. only 59 percent of the patients over 65 smoked this heavily. 75 Reverse smoking is a common practice in some parts of India, whereby the lighted end of a homemade cigar is held inside the mouth, Pindborg, et al. (64) conducted an epidemiological survey of 10,169 villagers in the Srikakulam district of south India and found that 43.8 percent of those interviewed practiced reverse smoking. Leuko. plakia was found in 8.8 percent of reverse smokers compared to 01 percent in nonsmokers. The 10 patients found to have oral cancer were all reverse smokers. Reddy, et al. (68) found that reverse smokin was practiced by 73 of 100 patients with oral cancer. Reddy, et al, (66, 67) reported characteristic histologic findings of the oral cavity in biopsies obtained from reverse smokers. In two other studies fron, India, changes in the ultrastructure of the oral mucosa of chewerg (54) and smokers (65) are described. Cancer of the Esophagus In the Japanese prospective study, Hirayama (37) reported that male smokers had a mortality ratio for cancer of the esophagus of 2.24 compared to nonsmokers (P< 0.001). Martinez (57) studied the relationship between smoking in various forms and the development of cancer of the esophagus in a retrospective study of 179 patients, Dose-response relationships were demonstrated for the amount smoked and alcohol consumption and the development of cancer of the esophagus. Cancer of the Larynx The mortality ratios for cancer of the larynx in the large Japanese prospective study were reported by Hirayama (37) to be 11.0 for male cigarette smokers and 9.0 for female cigarette smokers compared to nonsmokers (P<0.001). Stell (85) conducted a retrospective study of 190 patients with carcinoma of the larynx. Only 13 percent of the patients were non- smokers or ex-smokers compared with 41 percent of the controls. The relative risk ratio for heavy cigarette smokers was 3.48 compared to nonsmokers. The relative risk was 1.34 for smokers of pipes and cigars, Moore (59) reported the occurrence of second primary cancers in 203 smokers who had been surgically treated for cancer of the oral cavity, pharynx. or larynx. without recurrence for a period of 8 years. 76 Within an average followup period of 7 years, 40 percent of the 122 patients who continued to smoke developed second primary cancers of the upper respiratory or digestive tract, but only 6 percent of the patients who stopped smoking developed second cancers. A total of 50 patients with cancer of the larynx underwent laryngectomy. Of the 16 who continued to smoke. three developed a second cancer, whereas none of the 34 ex-smokers without a larynx developed a second primary malignancy. Cancer of the Pancreas Hirayama (37) reported a significant association between cigarette smoking and the development of cancer of the pancreas. The mortality ratios were 2.05 (P<0.001) for men and 1.9 (P<0.05) for women. Krain (47) reviewed a number of environmental factors that may be associated with the 15 percent annual increase in the death rate from cancer of the pancreas found in the United States. The strongest associations appeared to be with cigarette smoking and certain occupational exposures. Cancer of the Kidney and Urinary Bladder Hirayama (37) reported a mortality ratio of 2.71 for cancer of the kidney and bladder in women who smoke cigarettes (P<0.001). The mortality ratio of 1.07 for men who smoked. compared to non- smokers was not significant ; however, the few deaths from this cancer among men in the Japanese study did not allow conclusions to be drawn. Hoover and Cole (89) examined the strength of the association between cigarette smoking and the development of bladder cancer in successive birth cohorts of men and women in the United States, Denmark, England, and Wales. Increasing rates of bladder cancer were observed in populations characterized by an increase in cigarette smoking among successive birth cohorts. The association was con- sistent in both men and women, and was also consistent for different nationalities and urban and rural groups. These findings suggest a causal role for cigarette smoking in the development of bladder cancer. In a retrospective study from Germany. Fischer (27) examined the smoking habits of 162 men with bladder cancer and a control group of 198 men who had benign prostatic hypertrophy. The relative risk 77 ratio was 6.4 for smokers of fewer than 15 cigarettes a day, and 27.5 for smokers using more than this amount. Only 3 percent of the mep with bladder cancer were nonsmokers. Xipell (03) studied renal nodules in 250 patients in Australia who came to autopsy. Benign adenomas were the most common lesions and were found in 22 percent of the patients. The remaining nodules were cysts, thrombosed veins, abscesses, granulomas, and metastatic lesions. A statistically significant difference between the smoking habits of those with adenomas and those with the miscellaneous lesions was reported (P<0.012), All the adenomas were found in smokers, Cole, et. al. (74) conducted a retrospective study of 461 persons with transitional or squamous cell carcinoma of the lower urinary tract. After the data were controlled for cigarette smoking, occupa- tional exposure appeared to contribute to 18 percent of the lower urinary tract cancer among men aged 20 to 89 compared to the 39 percent attributed to cigarette smoking in men in a previous report (14). Werf-Messing and Kaalen (100) examined the association of occupational exposure and smoking in the development of bladder cancer in 846 males in the Netherlands who had this disease. The smoking habits of cancer and control patients in each group were nearly identical; however, patients with bladder cancer had a longer exposure to hazardous working conditions than did controls. Experimental Carcinogenesis Experimental studies, mainly in animals, have added to an under. standing of many of the processes involved in tobacco carcinogenesis, Possible mechanisms of chemical carcinogenesis were reviewed by Miller and Miller (58), Ryser (76). and Leone (41). Electron spin resonance studies of carcinogenesis were reviewed by Swartz (87), Franke (28) discussed the posible role of hydrophobic interactions of polycyclie aromatic hydrocarbons with protein in chemical car- cinogenesis. Chemical carcinogenesis in Syrian hamsters was reviewed by Shubik (82) and Homburger (38). Respiratory Tract Carcinogenesis Epidemiological, clinical, and autopsy data from studies of humans have established cigarette smoking as the major cause of lung eancer in the United States. One of the reasons it has not been possible to 78 characterize fully the mechanisms responsible for this causal relation- ship is the lack of an ideal animal model in which to study respiratory tract carcinogenesis in the laboratory. Exposing animals to cigarette smoke in a closed chamber does not replicate the kinds of exposure smoking humans receive, although some recently developed smoking chambers provide conditions similar to the exposure experienced by human smokers. Many animals are obligatory nose breathers and, in them, a large portion of the particulate phase of cigarette smoke may be removed by turbulent precipitation in the nasal passages or larynx before reaching the sites in the lung most commonly exposed m humans. Auerbach, et al. (3) first demonstrated that malignant ling tumors could be produced in smoking dogs who were taught to smoke through a tracheostoma. Several investigators have recently examined respiratory tract carcinogenesis in animals using intra- tracheal instilations of chemical carcinogens found in cigarette smoke, including benzo(a)pyrene and (H-dibenz(d.g) carbazole. Tumors resulting from this type of treatment are frequently similar to lung tumors found in humans (24 32. 33. 36.77. SO), Harris, et al. (33) examined the acute ultrastructural effects of benzo(a)pyrene carried on ferric oxide particles on the tracheo- bronchial epithelium of the Syrian Golden hamster. Test substances were administered by intratracheal instillation. Ferric oxide alone resulted in some focal replacement of columnar epithelium with polygonal basal cells. This effect was reversed by termination of the treatment. After treatment with benzo(a)pyrene and ferric oxide. focal replacement of the columnar cells with pleomorphic cells oc- curred. These pleomorphic cells had the ultrastructural features of atypical squamous cells and were similar to the hyperplastic epithelial cells described in the bronchi of smoking dogs and the neoplastic “quamous cells found in human bronchogenic carcinoma, Tn an extension of this study, Harris, et al. (32) reported that. vita- min A deficiency or the application of benzo(a)pyrene-ferric oxide through intratracheal instillation resulted in squamous metaplasia of the trachea, Both lesions appeared to be morphologically similar by light microscopy, but at the ultrastructural level significant differ- neces were observed. Squamous metaplasia induced by benzo(a) py- tene-ferric oxide was characterized by defects in the basement membrane, enlarged nuclei with cytoplasmic invaginations, and Pleomorphie nucleoli not seen following vitamin A deficiency. Sellakumar and Shubik (80) treated Golden Syrian hamsters with weekly intratracheal instillations of TH-dibenz(c.g)carbazole (7H- DBC) suspended with equal amounts of ferric oxide in a saline solu- tion. One group of 35 hamsters was treated with 45 mg. of the ‘arcinogen and a second group was treated with 15 mg. More than So percent. of the animals in each group developed respiratory tract 79 tumors. Most of the tumors occurred in the major airways and were squamous cell carcinomas. Adenocarcinomas and anaplastic carcino nas were found less frequently. Saffiotti, et al. (77) examined the carcinogenic effects of benzo (a) pyrene prepared as a suspension of fine crystalline particles at. tached to ferric oxide in a physiologic saline solution and adminis. tered by intratracheal applications to Syrian Golden hamsters, Vari- ous concentrations of benzo(a)pyrene and ferric oxide were used in single and multiple applications. A single administration of 37.5 mg, of benzo(2)pyrene with 12.5 mg. of ferric oxide resulted in five bronchogenic carcinomas and five histologically benign respiratory tumors in a total of 61 hamsters. Following multiple administrations, bronchogenic carcinomas including anaplastic and squamous cell types were induced in all dosage groups and a positive dose-response rela. tionship was demonstrated. Feron (24) studied respiratory tract tumors in Syrian Golden hamsters following tracheal instillations of furfural and/or benzo(a) pyrene. Of the 62 hamsters. 41 developed respiratory tract tumors of which squamous cell carcinoma of the trachea was the most frequent type observed. Furfural ir. combination with benzo(a) pyrene resulted in a higher yield of tumors than was seen with benzo(a)pyrene alone. Furfural alone possessed no carcinogenic activit y. Shabad (87) and one of his collaborators, Yanysheva, produced benign and malignant epidermoid lung tumors in rats following single and multiple administrations of benzo(a)pyrene by intra- tracheal instillation. Dose-response relationships were demonstrated. Experiments in Mice Cigarette smoke condensate (CSC), various fractions of CSC, and many chenucal compounds identified in CSC have been tested for tumorigenic activity in mice by a variety of methods, including skin painting and suveutaneons injections. Complete carcinogens and in- complete carcinogens, which include tumor initiators, tumor _pro- moters, and tumor accelerators have been described. Several recent studies have been conducted using mice as the experimental animal which examine further the mechanisms involved in tobacco carcino- genesis. Lee and O'Neill (50) measured the effect of duration and dosage of benzo(a)pyrene applications on the rate of development of benign and malignant skin tumors in mice. The incidence rate for tumor formation was directly proportional to both time and dose. These data conformed quite closely to postulated mathematical models of the rate of tumor development. 80 Davies and Whitehead (17) studied the-effect of altering the “tar” and nicotine ratio of cigarettes on experimental carcinogenesis. No significant difference in tumor yield was found between condensates obtained from the smoke of cigarettes containing 16.6 mg. “tar” and 1.79 mg. nicotine and other cigarettes containing 10.0 mg. “tar” and 1,94 mg. nicotine. Several studies by Bock, et al. (7, 8, 9) have examined the tumor promoting activity of a number of fractions of cigarette smoke con- densate (CSC). A number of subfractions of the neutral fraction of CSC were tested for tumor promoting activity in mice pretreated with 7,12-dimethylbenz(a)anthracene as a tumor initiator (8). The most polar subfractions and the fraction containing venzo(a) pyrene were the most active tumor promoting fractions. In another study (9), the weak acid fraction of CSC was found to be a very weak complete carcinogen which probably acts primarily as a tumor pro- moting agent. The promoting activity depended primarily on the nonvolatile constituents of this fraction. More recently, Bock, et al. (7) reviewed the tumor promoting effects of CSC and extracts of tobacco leaves. A combination of two subfractions of the tobacco ex- tracts, as well as five major fractions of CSC, were found to have tumor promoting activity. The fraction containing the polynuclear aromatic hydrocarbons was found to be a complete carcinogen. Two subfractions were found to be strongly synergistic in their tumor pro- moting activity when applied simultaneously to mouse skin. Lazar, et al. (49) found that hydroquinone applied to mouse skin in conjunction with the active fractions of CSC accelerated the early histologic changes that result from the application of “tar” or its fractions. Van Duuren, et al. (97) have suggested that “cocarcinogenesis” be differentiated from “tumor promotion” defining “cocarcinogenesis” as the production of malignant tumors by two or more agents applied simultaneously or alternately in single or repeated doses to mouse skin and “tumor promotion” as a single treatment with one agent followed by single or repeated treatment with a second agent. Using these definitions, the authors found several tumor promoting agents to possess cocarcinogenic activity. Roe, et al. (74) studied mechanisms of mouse skin carcinogenesis using benzo(a)pyrene and a neutral fraction of OSC applied singly or in various combinations with each other. Skin tumor incidence rates Increased with the dose of applied material for both the neutral frae- tion and benzo(a)pyrene. Mixtures of the neutral fraction with benzo- (a)pyrene did not act independently in the production of malignant skin tumors but synergistically, suggesting that some of the eompo- nents of the neutral fraction act as cocarcinogens rather than as com- plete carcinogens. 81 Schmahl (78) found a direct relationship between the dosage and duration of subcutaneous injections of tobacco smoke condensates and the development of sarcomas in rats. Maenza, et al. (56) studied the effects of a combination of nickel subsulfide (Ni,S.) and benzo(a)pyrene on sarcoma induction in rats, The interval between administration of the carcinogen and the de. velopment of sarcomas was significantly shorter (P<0.001) in male Fischer rats given injections of a combination of 10 mg. of Ni,S. and 5 mg. of benzo(a)pyrene than in rats given either ingredient alone. There appeared to be a synergistic interaction between nickel com- pounds and the polycyclic aromatic hydrocarbons. Healey, et al. (34) added further refinements to a technique for measuring the nonspecific esterase activity of mouse skin following applications of various chemical compounds. With few exceptions, changes in esterase activity reflected the known tumor producing activity of a number of polycyclic hydrocarbons and_ tobacec condensates. Sydnor, et al. (89) examined the effect of an aqueous extract of cigarette smoke condensate on benzo(a)pyrene-induced sarcoma in female Sprague-Dawley rats. Benzo(a)pyrene was injected subcu- taneously in various concentrations of 12.5 pg. to 400 zg. per dose dis- solved in sesame oil. Injections were given on alternate days fo 30 doses. The mean tumor induction time was accelerated in five of seven groups given the aqueous extract of CSC in their drinking water. Animals given any benzo(a)pyrene eventually developed sar- comas at the site of injection. Dose-response relationships were demon- strated for the concentration of benzo(a)pyrene administered. It appeared that aqueous extracts of CSC contained one or more com- ponents which functioned as cocarcinogens. Aryl Hydrocarbon Hydronylase (AHH) Certain of the chemical compounds found in the gas and particulate phase of cigarette smoke are absorbed through the lung or oral cavity into the general circulation. Possibly through such absorption some chemical carcinogens are carried to target organs not directly exposed to cigarette smoke. Some of these chemical compounds are probably excreted unchanged while others are metabolized to various degrees by enzyme systems present in the liver and many other tissnes. The microsomal mixed-function oxidases are kev enzyme systems for the metabolism of a wide variety of chemical compounds including the 82 chemical carcinogens found in cigarette smoke. Aryl hydrocarbon hydroxylase (AHH) is a part of the cytochrome P-450 containing microsomal enzyme system that is present in several tissues of humans and many animal species. The activity of this enzyme system is in- duced following exposure to the appropriate chemical stimulus. The hydroxylation of polycyclic hydrocarbons results in the detoxification of some and the activation of others to reactive carcinogenic forms. An understanding of the role of AHH in the metabolism of chemical carcinogens in man may help clarify some of the mechanisms involved in tobacco carcinogenesis. Recently, several studies examined AHH activity in animals and man. Studies in Animals Sydnor, et al. (88) found that an aqueous extract of CSC adminis- tered in the drinking water of rats potentiated benzo(a)pyrene- induced AHH activity in the liver. The liver AHH activity was slightly increased by the aqueous extract of OSC alone. Rondia and Gielen (75) reported that rats exposed to various levels of carbon monoxide developed a decrease in AHH activity in liver homogenates. The reduction in AHH activity developed after 120 hours exposure to levels of carbon monoxide which produced carboxy- hemoglobin levels below 15 percent. Welch, et al. (99) reported that the administration of benzo(a)- pyrene to pregnant rats resulted in an increase of the in vitro AHH activity of maternal liver, placenta, and fetal liver. A twentyfold higher dose of benzo(a) pyrene was necessary for stimulation of AHH activity in fetal liver than in the placenta or maternal liver. Studies in Man Levin, et al. (52) studied the induction of AHH activity in human skin. Human foreskin obtained from circumcised children was main- tained in tissue culture medium. Exposure to 10 2/M. of benzo(a) py- rene for 16 hours led to a twofold to fivefold increase in the activity of AHH in the exposed skin over control values. Whitlock, et al. (701) reported the presence of AHH in human lymphocytes. The AHH activity of lymphocytes compared to rat liver or hamster embryo cells is relatively low. Treatment with pokeweed mitogen alone increased AHH activity about twofold. However, a threefold to eightfold greater AHH activity was found in cells treated with the mitogen and benz(a)anthracene than in resting cells. 83 495-028 O-—72——7 Cell and Tissue Culture Studies In studies of tobacco carcinogenesis, cigarette smoke condensate (CSC), subfractions of CSC, and individual chemical compounds found in CSC have been administered to a variety of animals using several routes of administration. Tests on living animals are frequently complicated and time consuming. Cell and tissue culture systems offer an alternate tool for the study of carcinogenesis which, in some in- stances, is relatively more rapid than animal testing. Specific enzyme systems and other cellular functions can often be studied in greater detail using these systems, Cells obtained from a variety of tissues and animals can be grown or maintained in culture bottles when nourished with an appropriate nutritive medium in a supportive atmosphere, When these cultures are exposed to various chemical compounds, changes can occur which may range from minor morphologic varia- tions to malignant transformation or cell death. Toxic effects on cell cultures must be differentiated from malignant transformation. Sey- eral studies have recently examined the effect of cigarette smoke condensate or individual polycyclic hydrocarbons found in CSC on various cell and tissue culture systems. Benedict, et al. (4) studied polycyclic hydrocarbon produced cyto- toxicity, malignant transformation, and chromosome deformity in a variety of cell lines derived from rats, hamsters, and human tumor cells. The cytotoxic effect of benzo(a)pyrene was found to be related to the aryl hydrocarbon hydroxylase activity (AHH) of the given cell culture. Benzo(a)pyrene was cytotoxic to fetal rat hepatocytes, but this effect was probably related to the action of the hydroxvlated metabolite, 3-hydroxybenzo(a) pyrene, since the cytotoxicity was blocked when the AHH system was overloaded with phenobarbital. Cell strains not possessing AHH activity showed no cytotoxic effects from benzo(a)pyrene alone: however, in the presence of fetal rat hepatocytes possessing AHH activity. enough benzo(a)pyrene metabo- lites were secreted into the medium to induce cytotoxic effects in the normally resistent cell lines. In hamster secondary cultures, at the chromosome level cytotoxicity was associated with chromatid breaks, whereas malignant transformation was more closely related to aneuploidy. Diamond (79) studied the metabolism of benzo( a) pyrene and 7.12- dimethylbenz(a)anthracene (DMB.A) in mouse, hamster, rat, monkey, and human cell cultures. Metabolism of hydrocarbons to “alkali solu- ble” and “water soluble” derivatives was measured. The results sug- gested that the parent compounds were first metabolized to “alkali extractable” derivatives and then to “water soluble” derivatives, All the cell cultures tested which were sensitive to the growth-inhibitory effects of benzo(a)pyrene or DMBA were able to metabolize these 84 carcinogenic hydrocarbons to “water soluble” derivatives. The data are consistent with the hypothesis that metabolism of the carcinogen isrequired for growth-inhibitory or cytotoxic effects. Several authors have examined malignant transformation in cell cultures. Inui and Takayama (4/) cultured hamster lung fibroblasts and then exposed them to crude cigarette “tar” for a period of 3 hours. Between 2 to 48 hours following this exposure, toxic effects of the “tar”, including cell necrosis, swelling, vacuolization, and disintegra- tion of cytoplasm were observed. The death of 40 to 70 percent of the cells within 72 hours was followed hy the appearance of trans- formed cells which grew at rapid rates. These transformed cells pro- duced malignant tumors when inoculated in the cheek pouch of ham- sters. Control] cell lines produced no changes when inoculated in a similar fashion. In a similar study by Di Paolo, et al. (2/), transformation of pri- mary hamster cell cultures was induced by benzo(a) pyrene. 3-methyl- cholanthrene, or 7,12-dimethylbenz(a)anthracene. Transformed cell limes were established and subsequently inoculated in hamsters pro- ducing malignant tumors at various sites. Characteristic chromosomal changes in the transformed cells were also described. An increase in proliferation and tumor production rate of L-Strain cells produced by treatment with cigarette “tar” was studied by Inui and Takayama (40). L-Strain cell cultures not exposed to “tar” did not produce tumors when inoculated in C3H mice. After an exposure to low concentrations of cigarette “tar” significant changes occurred in the cultures characterized by enlarged cells with vacuolated cytoplasm, giant cell formation, and accelerated growth rates. These transformed cells produced tumors in 70 percent of injected C3H mice. Nagata (60) treated cell cultures obtained from kidneys of new- born mice with 20-methylcholanthrene in various concentrations. Con- trol cultures could not be maintained for long; however, the treated cells formed two permanent cell lines which had a transformed mor- phology and altered karyotypes. Epithelial carcinomas were produced after the subcutaneous injection of these transformed cells into un- conditioned newborn mice. Freeman, et al. (29) isolated hamster-specific C-type RNA viruses from tumors induced by cell cultures transformed by chemical car- “mogens. Cell cultures were prepared from early passage hamster embryo cells and treated for 7 days with 3-methylcholanthrene or cer- tain fractions of cigarette smoke condensate. Following treatment, morphologically transformed cell lines were isolated and maintained. Subsequent inoculation in newborn hamsters produced malignant tumors at the site of inoculation. New cell lines were established from Soine of the resulting tumors. No infectious viruses were isolated from vell lines prior to inoculation ; however, C-type RNA viruses were iso- 85 lated from tumors and from cell lines derived from tumors. The ay. thors concluded that the chemical treatment and activation of viruses appeared to be related events. Sivak and Van Duuren (83) developed a cell culture system that responded with characteristic changes in cell morphology to the appli- cation of various fractions of tobacco leaf extracts. Certain dose. response characteristics were demonstrated, suggesting a mechanism whereby various tobacco fractions might. be rapidly screened for tumor-promoting activity. Dietz and Flaxman (20) studied the toxicity of aromatic hydro. carbons on normal human epidermal cells in vitro. Pieces of adult human abdominal skin were maintained in tissue culture medium and exposed to 3-methylcholanthrene and benzo(a)pyrene at a concentra- tion of 1 »g./ml. for a period of + days. The cultures were then kept for an additional 3 months following exposure. No malignant transforma. tion occurred; however, giant cells and a more disorderly pattern of growth were observed in the treated cultures weeks earlier than similar changes in control cultures, Binding of Polycyclie Hydrocarbons to DNA and RNA There is evidence that some chemical carcinogens including certain of the polyeyclic hydrocarbons found in cigarette smoke condensate are active because of the reaction of the carcinogen or a reactive me. tabolite with cellular macromolecules, Duncan, et al. (23) studied a series of radioactive polycyclic hydrocarbons with respect to their metabolism and tendency to bind with cellular DNA and RNA in monolayer cultures of primary mouse embryo cells. All the tested hydrocarbons were metabolized to “water soluble” metabolites at approximately equal rates. A “binding index” was calculated to de- termine the binding of various hydrocarbons to cellular DNA and RNA. The group of hydrocarbons with a high “binding index” con- sisted of potent carcinogens, while another group with much lower values for the “binding index” were with but one exception non- carcinogens. Carlassare, et al. (7/2) studied the in vivo binding of benzo( a) pyrene to DNA. Benzo(a) pyrene-“H was fed to male and female NCL mice which were sacrificed after 15 hours. The DNA was extracted and purified from the skin, spleen, and liver. The binding of benzo(a)py- rene was greatest. in the liver and somewhat less in the spleen and ekin, It was caleulated that the average molecular weight of DNA was 6 million and that 1 molecule of benzo(a)pyrene was bound to every 46.8 molecules of DN A in the liver, suggesting covalent binding of henzo(a) pyrene to DNA. 86 Alexandrov and Vendrely (1) found that cigarette smoke conden- sate, the hexane-extracted fraction of CSC, and benzo(a)pyrene all inhibited RN A synthesis in mouse skin. N-Nitrosamines in Tobacco Smoke The largest number of chemical carcinogens which have been iden- tified in cigarette smoke condensate are polycyclic hydrocarbons. N-nitrosamine compounds known for many years to be potent. car- cinogens have produced malignant tumors in a number of organ sys- tems of a wide variety of animals. These compounds were recently identified in cigarette smoke. Only recently has an association been found between exposure to N-nitrosamines and malignant tumors in humans (65). N-nitrosamines are formed chemically by a reaction of NO and NO: or nitrites with secondary amines. The chemical pre- cursors of the N-nitrosamines have been identified in cigarette smoke condensate (CSC) by a number of investigators. These studies were reviewed by Wynder and Hoffmann (102). More recently, Rhoades and Johnson (69) developed a method for the determination of N-nitrosa- mines in tobacco smoke condensate using gas chromotography. Two N-nitrosamines were found in CSC: one was identified as N-dimethyl- nitrosamine (DMNA) and the other was believed to be N-methy}- ethylnitrosamine (MENA) (43, 70). The concentration of DMNA per cigarette in nanograms was determined in condensates from ex- perimental cigarettes made -from single tobacco varieties rather than a tobacco blend. Each tobacco tested was grown in both a low- and high-nitrogen soil. High-nitrogen soil conditions resulted in a considerable increase in nitrosamines. A popular brand of nonfilter cigarettes was also tested. These results are presented in table 2. TaBLE 2.—N-dimethylnitrosamine (DMNA) content of condensates obtained from several tobaccos grown in both “high” and ‘low’ nitro- gen sorls DMNA (nano- Tobacco type Soil nitrogen grams per cigarette) Robinson_____.____________... Low nitrogen__.__._..-___.___. 0 Catterton_.........__...____..-__ do.__- 2 eee 5 Burley... 2222.88. do.._- 2 eee 3 Robinson_.____._____________- High nitrogen_._..______..___- 27 Catterton....._____..__....__.._._- do... eee 60 Burley eee eee eee do___. 2 ee 140 U.S. nonfilter.. 222-2222 8 Source: Johnson, D. E., Rhoades, J. W. (48). 87 Summary of Recent Cancer Findings In addition to the summary presented in the introduction of this chapter, based on previous reports of the health consequences of smok. ing, the following statements are made to emphasize the recent devel. opments in the field: 1. Recent epidemiological and autopsy studies from several coun- tries confirm that cigarette smoking is the major cause of lung cancer, -Continued cigarette smoking by patients following successful surgical removal of a cancer of the oral cavity, pharynx, or larynx without tumor recurrence for a period of 3 years is asso- clated with a significant increase (P< 0.001) in the risk of devel- oping a second primary cancer of the upper respiratory or diges- tive tract compared to similar patients who discontinue smoking at the time of their surgery. . The intratracheal administration of certain polycyclic hydrocar- bons found in cigarette smoke condensate results in the forma- tion of anaplastic and squamous cell cancers of the lung and re- spiratory tract in hamsters and rats, Many of these tumors are histologically similar to the Iung cancers fonnd most frequently in cigarette smokers. » The application of cigarette smoke condensate or polycyclic hy- drocarbons to various cell cultures often results in transformation to cells with a more rapid and disorderly growth pattern. Trans- formed cell lines frequently produce benign or malignant tumors when transplanted to experimental animals. . N-nitrosamines have been identified in cigarette smoke. These compounds are known to be potent cancer causing chemicals for a variety of animals. They appear to be formed in higher concen- trations from tobaccos raised under high-nitrogen soil conditions. Cancer References (1) ALEXANpDROV, K., VENDERLY, C. Action de condensats de fumée du tabac sur la synthese de RNA dans la peau des souris. (Action of tobacco smoke condensate on the synthesis of RNA in mouse skin.) Chemico- Biological Interactions 4(3) : 155-161, February 1972, (2) AUERBACH, O., Hamsonn, E. C., GARFINKEL, L. Epithelial changes in ex- cigarette smokers, Cancer Cytology 11(1) : 5-12, 1971. (3) AUERBACH, O., HamMonn, E. C., KirmMayn, D., GarFInKkeL, L. Effects of cigarette smoking on dogs. II. Pulmonary neoplasms. Archives of Ep- vironmental Health 21(6) : 754-768, December 1970. (4) Benepict, W. F., Green, J. E., Nepert, D. W. Polcyclic hydrocarbon- produced toxicity, transformation, and chromosomal aberrations as a function of aryl hydrocarbon hydroxylase activity in cell cultures. International Journal of Cancer 9(2) : 435-451, Mar. 5, 1972. (5) Bere, J. W., ScHorrenretp, D., Rirrer, F. Incidence of multiple primary cancers. ITI. Cancers of the respiratory and upper digestive system as multiple primary cancers. Journal of the National Cancer Institute 44(2) : 263-274, February 1970. (6) Berry, G., NEwHousE, M. L., Turox, M. Combined effect of asbestos exposure and smoking on mortality from lung cancer in factory workers. Lancet 2(7775) : 476-479, Sept. 2, 1972. (7) Bock, F. G. Tumor promoters in tobacco and cigarette-smoke condensate. Journal of the National Cancer Institute 48(6) : 1849-1853, June 1972. (8) Bock, F. G., Swain, A. P., Stepan, R. L, Composition studies on tobacco. XLI. Carcinogenesis assay of subfractions of the neutral fraction of cigarette smoke condensate. Journal of the National Cancer Institute 44(6) : 13805-1310, June 1970. (9) Bock, F. G., Swatn, A. P., STEDMAN, R. L. Composition studies on tobacco. XLIV. Tumor promoting activity of subfractions of the weak acid fraction of cigarette smoke condensate. Journal of the National Cancer Institute 47(2) : 429-436, August 1971. (10) BorTecHELLI, R., DELNERI, E., MOSANGHINI, O. Rapporti tra carcinoma broncopolmonare primitivo e fumo di tabacco, (Relationship between primary bronchopulmonary carcinoma and tobacco smoking.) Minerva _Medica Giuliana 9(6) : 289-291, November—December 1969. (11) Boucor, K_R., Weiss, W., SEIDMAN, H., CARNAHAN, W. J., Cooper, D. A. “Fire -Philadelphia pulmonary neoplasm research project: Basic risk factors of lung cancer in older men. American Journal of Epidemiology 95(1): 4-16, January 1972. (12) CarLassarg, F., ANTONELLO, C., BaccrcHetTti, F., MALFer, P. On the binding of benz(a)pyrene to DNA “in vivo”. Zeitschrift fiir Natur- forschung 27(2) : 200-202, February 1972. (13) Carrapa Bravo, T., NuNEz JARQUIN, E. El diagnostico roentgenologico de las neoplasias bronchopulmonares primarias. (Reoentgenological diagnosis of primary bronchoplumonary neoplasms.) Revista Mexicana de Radiologia 25(5) : 185-196, September-—October 1971. (14) Coxe, P., Hoover, R., FRrepery, G. H. Occupation and cancer of the lower -—Urinary tract. Cancer 29(5) : 1250-1260, May 1972. {15) Coxg, ,P., Monson, R. R., HANING, H., FRiepett, G. H. Smoking and cancer of the lower urinary tract. New England Journal of Medicine 284 (3): 129-134, Jan. 21, 1971. (16) Crace, J. Lung cancer in Jersey : Its incidence and associated biochem- istry. British Journal of Clinical Practice 25(8) : 360-365, August 1971. (17) Davies, R. F., WHITEHEAD, J. K. A study of the effects of altering the tar/nicotine ratio in experimental tobacco carcinogenesis. British Journal of Cancer 24(1) : 191-194, March 1970. (18) DeLarug, N. C., ANDERSON, W., SANDERS, D., Starr, J. Bronchioloalveolar carcinoma. A reappraisal after 24 years. Cancer 29(1): 90-97, Janu- ary 1972. (19) Diamonp, L. Metabolism of polyeyclic hydrocarbons in mammalian cell cultures. International Journal of Cancer 8(3): 451-462, Nov. 15, 1971. {20) Dietz, M. H., Fraxman, B. A. Toxicity of aromatic hydrocarbons on normal human epidermal cells in vitro. Cancer Research 31(9): 1206-1208, September 1971. 89 (21) (22) (23) (24) (25) (26) C. (27) (28) (29) (30) (31) (32) (33) (34 (35) 90 DrPaoto, J. A., NELSon, R. L., Donovan, P. J. Morphological, oncogenic, and karyological characteristics of Syrian hamster embryo cells trans. formed in vitro by carcinogenic polycyclic hydrocarbons. Cancer Re. search 31(8) : 1118-1127, August 1971. Dott, R.; PIKE, M. C. Trends in mortality amoung British doctors in re. lation to their smoking habits. Journal of the Royal College of Physicians 6(2) : 216-222, January 1972. Duncan, M., Brooxes, P., Dippte, A. Metabolism and binding to cellular macromolecules of a series of hydrocarbons by mouse embyro cells in culture. International Journal of Cancer 4(6) : 813-819, Nov. 15, 1969. Feron, V. J. Respiratory tract tumors in hamsters after intratrachea] instillations of benzo(a)pyrene alone and with furfural. Cancer Research 32(1) : 28-36, January 1972. Ferrara, F. A. Ecological analysis of lung cancer in the city of La Plata, In: Englund, H. M., Berry, W. T (Editors.) Proceedings of the Second International Clean Air Congress, Washington, D.C., Dec. 6-11, 1970, New York, Academic Press, 1971, pp. 244-247. FINGERLAND) A., Husak, T., BenpLova, J. Contribution to the investigation 0 é effect of cigarette smoking. Sbornik Vedeckych Praci Lekarske Fakulty Karlovy University v Hradci Kralove 14(2) : 221-234, 1971. Fiscuer, G. Rauchgewohnheiten und Blasentumoren. Eine klinische Un- tersuchung. (Smoking habits and bladder tumors. A clinical study.) Zeitschrift fur Urologie und Nephrologie 64(4) : 271-274, April 1971. FrANKE, R. The possible role of hydrophobic interactions of polycyclic aromatic hydrocarbons with protein in chemical carcinogenesis. Molecu- lar Pharmacology 5(6) : 640-657, November 1969. FREEMAN, A. E., KELLoFF, G. J.. GILpen, R. V., LANE, W. T, Swaln, A. P, Hvrsner, R. J. Activation and isolation of hamster-specific C-type RNA viruses from tumors induced by cell cultures transformed by chemical carcinogens. Proceedings of the National Academy of Sciences (USA) 68(10) : 2386-2390, October 1971. Furnica, G., Toaper, M. Continutul de 2!°Po in diferite sorturi de tigari. (Po”° content in different cigarette blends.) Igiena 18(8): 469-474, August 1969. Haspu, 8. L., Huvos, A. G., Goopner, J. T., Foorg, F. W., Ir., BEATTIE, E. J., Jr. Carcinoma of the trachea. Clinicopathologic study of 41 cases. Cancer 25(6) : 1448-1456, June 1970. Harris, C. C., Sporn, M. B., KatFMAN, D. G., Sxriru, J. M., JACKSON, F. E., Sarriorri, U. Histogenesis of squamous metaplasia in the hamster tra- cheal epithelium caused by vitamin A deficiency or benzo (a) py rene-ferric oxide. Journal of the National Cancer Institute 48(3) : 7438-747, March 1972. Harris, C. C., Sporx. M. B., KaAvurMAN, D. G., Smitn, J. M., BAKER, M. S., SaFFroTT, U. Acnte ultrastructural effects of lhenzo(a)pyrene and ferric oxide on the hamster tracheobronchial epithelium. Cancer Research 31(12) : 1977-1981, December 1971. HEAcey, P., Mawpesiey-Tromas, 1. E., Barry, D. H. The effect of some polyeyclic hydrocarbons and tobacco condensates on nonspecific esterase activity in sebaceous glands of mouse skin. Journal of Pathology 105 (2): 147-152, October 1971. HeRKotp, K. McI). Survey of histologic types of primary lung cancer in U.S. veterans. Pathology Annual 7: 45-79, 1972. (36) Hirao, F., Fustsawa, T., Tsupura, E., Yamamura, Y. Experimental eancer of the lung in rabbits induced by chemical carcinogens. Cancer Me Researeh 32 (6) : 1209-1213, June 1972. (87) HIRAYAMA, 'T. Smoking in relation to the death rates of 265,118 men and =women in Japan. A report of 5 years of followup. Presented at the American Cancer Society’s Fourteenth Science Writers’ Seminar, Clear- water Beach, Fla., Mar. 27, 1972, 15 pp. (38) Hompurcer, F. Chemical carcinogenesis in Syrian hamsters. In: Hom- burger, F. (Editor). Progress in Experimental Tumor Research. Path- _olo the Syrian Hamster. Vol. 16, Basel, S. Karger, 1972, pp. 152-175. (39) Hoover, R,°CoLtn, P. Population trends in cigarette smoking and bladder \ . a ‘-=""—@anecer. American Journal of Epidemiology 94(5) : 409-418, November 1971. (40) InuI, N., Takayama, 8S. Acceleration of proliferation and tumor produc- tion of rate of L-strain cells by treatment with cigarette tar. Gann 62(4) : 315-320, August 1971. (41) Inui, N., Takayama, 8. Effect of cigarette tar upon tissue culture cells. Neoplastic transformation of hamster lung cells by tobacco tar in tissue culture. British Journal of Cancer 25(3): 574-583, September 1971. (42) IvakuHno, G. I. O roli kureniya v zabolevayemosti rakom legkogo. (Role of smoking in the incidence of lung cancer.) Vrachebnoe Delo 9: 99-101, 1971. (43) Jounson, D. E., Raoapes, J. W. N-nitrosamines in smoke condensate from several varieties of tobacco. Journal of the National Cancer Institute 48(6) : 1845-1847, June 1972. (44) Joyer, G. The thorium-series in cigarettes and in lungs of smokers. Experi- entia 27(1) : 85-89, Jan. 15, 1971. (45) KENNEpy, A, ‘Lung cancer in young adults. British Journal of Diseases of the Chest 66(2) : 147-154, April 1972. (46) Koszarowsk1, T. O raku pluca-po 25 latach. (Lung cancer in the course of 25 years.) Polski Tygodnik Lekarski 26(47): 1805-1807, Nov. 22, 1971. (47) Kratn, L. S. Crossing of the mortality curves for stomach and pancreatic carcinoma. International Surgery 57(4) : 307-310, April 1972. (48) Larsson, S. Aldersspecifik incidens av primar lungcancer i sverige. Trenden under perioden 1959-66. (Age specific incidence of lung cancer in Sweden. The trend during the period 1959-66.) Lakartidningen 68(38) : 4229- 4236, Sept. 15, 1971. (49) Lazar, P., Izarp, C., Morée-Testa, J.. CHovurourtnxov, I. Interaction entre l’hydroquinone et le condesat de fumée de cigarette dans les tests cutanés a court terme du pouvoir carcinogéne. (Interaction between hydroquinone and cigarette smoke condensate in short-term skin tests of carcinogenic activity.) Comptes Rendus Hebdomadaires des Seances de Academie des Sciences ; D : Sciences Naturelles 274 : 496-499, Jan. 17, 1972. (50) Lez, P. N., O'NEILL, J. A. The effect both of time and dose applied on tu- mour incidence rate in benzopyrene skin painting experiments. British Journal of Cancer 25(4) : 759-770, December 1971. {57) Leone, G. Importanza dei fattori ambientali nella patogenesi dei tumori dell’ uomo. Ruolo del fumo di sigaretta. (Importance of environmental factors in the pathogenesis of tumors in man. The role of cigarette smoking.) Minerva Medica 62(49) : 2461-2480, June 20, 1971. 91 (52) Levin, W., Connery, A. H., Atvares, A. P., MerKATz, L., Kappas, A. Induc. tion of benzo(a)pyrene hydroxylase in human skin. Science 176 (4033) - 419-420, Apr. 28, 1972. (04) LuNbin, F. E., Jr, Waconer. J. K., Ancuer, V. E. Radon daughter expo- sure and respiratory cancer quantitative and temporal aspects. Nationa] Institute for Occupational Safety and Health, National Institute of En. viromental Health Sciences, Joint Monograph No. 1, 1971, 177 pp. (34) Lutira, U. K., Woops, D. A.. Want, P. N., Gupra, M. Ultrastrueture of human oral mucosa after prolonged exposure to tobacco. Indian Journal of Medical Researeh 59(1) : 157-162, Jan. 1, 1971. (35) MCGLAsHAN, NJ D. Warrrrs. CL. McLeax, A. E. M. Nitrosamines jn African aleoholic spirits and oesophageal cancer. Lancet 2: 1017, Nov. 9, 1968, (36) Maenza, R. M., PrapHan, A. M., SUNDERMAN, F. W., Jr. Rapid induction of sarcomas in rats by combination of nickel sulfide and 3,4-benzpyrene. Cancer Research 31(12): 2067-2071. December 1971. (57) Martinez, I, Retrospective and prospective study of carcinoma of the esophagus, mouth, and pharynx in Puerto Rieo. Boletin de la Asociacion Medica de Puerto Rico 62(6) : 170-178, June 1970. (38) Mitcer, J. A. Mincer, E. C. Chemical carcinogenesis: Mechanisms and approaches to its control, ( Editorial.) Journal of the National Cancer . Institute 47 (3) : v-xiv, September 1971. (59) Moor aC, Cigarette smoking and cancer of the mouth, pharynx, and larynx. ———& continuing study. Journal of the American Medical Association 218 (4) 2 533-558, Oct. 25, 1971. (66) Nacata, T. Malignant transformation of mouse kidney cells in vitro br 20-methylcholanthrene. Medical Journal of Shinshu University 15(3): 131-151, October 1970. (61) NATIONAL ACADEMY OF SCIENCES. Particulate Polyeyelic Organic Matter. Biologie Effects of Atmospheric Pollutants. Committee on Biologic Ef- fects of Atmospheric Pollutants, Division of Medical Sciences, National Research Council. Washington, 1972. 361 pp. (62) Netson, J. F.. Sip. [. [. Intraoral carcinoma : Predisposing factors and their frequency of incidence as related to age at onset. Journal of the American Dental Association 82(3): 564-568, March 1971. (63) NiKkotova, M. Ye. Radioaktivnyy faktor tabachnogo dyma. (Radioactive factors in tobacco smoke.) Gigiena i Sanitariia 35(8) : 89-93. August 1970. (44) Prxvpore, J. J. Mera, Fos. Guerra, PLC, Darrary, D. K., Siri, C. J. Reverse smoking in Andhra Pradesh, India: A study of palatal lesions among 10,160 villagers. British Journal of Cancer 25/1): 10-20, March 1971. (65) DEackova, A. Mepak. HL. Meyer, J.. Warernotse, J. P. Ultrastructure of surfice cells of the oral mucosa, Folia Morphotogica 19(2) : 165-170, 1971. oy Reppy, CR. ROM. Kaweswarn V2 R Rami, (.. Reppy, 2. G. Histo pathological study of stomatitis nicotina. British Journal of Cancer 2513) 1 403-410, September 1971, (079 Reopy, CR. ROM. Rage. M. VON. Rawere, C.. Reppy. P. G. Changes in the ducts of the glands of the hard palate in reverse smokers. Cancer 3001) 2231-238, Tuly 1972. cas) Reopy, (RR. M. Sexitar, (.. Rast, M.V.S.. Reppy, 8S. S., Kaseswart, V. R. Relation of reverse smoking to carcinoma of the hard palate. In- dian Journal of Cancer 814) : 2683-26x, December 1971. 92 (69) (76) (71) (72) (73) (76) (77) (78) BY (80) (81) (82) (83) RuoaveEs, J. W., Jounson, D. E. Method for the determination of N-nitro- samines in tobaco smoke condensate. Journal of the National Cancer Institute 48 (6) : 1841-1843, June 1972. : RuHoADES, J. W., JOHNSON, D. E. N-dimethylnitrosamine in tobacco smoke condensate. Nature 236 (53845) : 307-30, Apr. 7, 1972. Rickarp, ¥Y. D., Sampson, C. C. Incidence of bronchogenic carcinoma in Negroes. Statistical analysis of 94 cases. Journal of the National Med- ical Association 63 (1) : 10-12, January 1971. Rossins, W. T. Bronchial epithelium in cigarette smoking college students. Journal of the American College Health Association 20(3) : 208-211, February 1972. RopRicvez Rivera, L., ACHON PoLtHamus, M., Ropricurz Sitva, H., De La Paz, E., PrraA De La Veca, H., DurANnp OCHAMENDI, R., SOLLET © GuILaRTE, R. Habito de fumar y diagnostico al alta. Estudio de 453 easos. (Analysis of the smoking habit in discharged patients. Study of 453 cases.) Revista Cubana de Medicina 8(6) ; 561-567, Dec. 31, 1969. Ror, F. J. C., PETo, R., KEARNS, F., BrsHop, D, The mechanism of carcino- genesis by the neutral fraction of cigarette smoke condensate. British Journal of Cancer 24(4) : 788-S06. December 1970. Ronpia, D. J., GIELEN, J. Influence in vivo de l’oxyde de carbone a faible eoncentration sur l'activite de la benzopyrenehydroxylase et de la choles- terol-7a-hydroxylase hepatique du rat. (In vivo influence of carbon mon- oxide at low concentrations on the activity of rat liver benzo(a)pyrene- hydroxylase and cholesterol-7a-hydroxylase.) Jn: Englund, H. M., Beery, W. T.. (Editors.) Proceedings of the Second International Clear Air Congress, Washington, D.C., Dec. 6-11, 1970. New York, Academic Press, 1971, pp. 234-237. Ryser, H. J.-P. Chemical carcinogenesis. New England Journal of Medi- eine 285 (18) : 721-734, Sept. 23, 1971. Sarriorri, U., Monresano, R., SELLAKUMAR, A. R., Ceris, F., KAUFMAN, D. G. Respiratory tract carcinogenesis in hamsters induced by different numbers of administrations of benzo(a)pyrene and ferric oxide. Cancer Research 32(5) : 1073-1081, May 1972. ScHMAHL, D, Quantitative Versuche an Ratten iiber die carcinogene Wirksamkeit von Tabakrauchkondensaten. (Quantitative investigations of carcinogenic effects of tobacco smoke condensates in rats.) Zeit- sehrift fiir Krebsforschung und Klinische Onkologie 76(4) : 320-324, 1 ana W., De Lint, J. Causes of death of alcoholics. Quarterly Journal udies on Alcohol 33(1) : 171-185, March 1972. SELLAKUMAR, A., SHUBIK, P. Carcinogenicity of TH-dibenzo (c,g) carbazole in the respiratory tract of hamsters. Journal of the National Cancer In- stitute 48(6) : 1641-1646, June 1972. SHaBab, L. M. Dose response studies in experimentally induced lung tu- mours. Environmental Research 4(4) : 305-315, October 1971. SHUBIK, P. The use of the Syrian Golden hamster in chronic toxicity test- ing. In: Homburger, F, (Editor). Progress in Experimental Tumor Re- search. Pathology of the Syrian Hamster, Volume 16, Basel, 8. Karger, 1972, pp. 176-184. Sivaxk, A., VAN Duuren, B. L. A cell culture system for the assessment of tumer-promoting activity. Journal of the National Cancer Institute 44 (5) : 1091-1097, May 1970. 93 (84) Sotnicka, H., Biscnor, R. Obsah 2“Pb a 2“Po y nekterych druzich Cesk: slovenskych cigaret. (The assay of “Pb and “°Po in a group of Czech: slovakian cigarettes.) Casopis Lekaru Ceskych 109(28) : 654, July 197: (85) Stecr, P.M, Smoking and laryngeal cancer, Lancet 1(7751) : 617-61: Mar. 18, 1972. moe . (86) Sterrine, T. D., Portack, S. V. The incidence of lung cancer in the U.§ since 1935 in relation to the etiology of the disease. American Journal Public Health 62(2) :152-15x, February 1972. (87) Swartz, H. M. Electron spin resonance studies of carcinogenesis. In Klein, G., Weinhouse, S. (Editors), Advances in Cancer Research, Vo! ume 15, New York. Academic Press, 1972, pp. 227-252. (S83) Sypnor, K. LL, ALLEN, C., FLeEsHeEr, J. W. Potentiation of benzo(a)pyrene induced liver enzyme activity in Sprague-Dawley female rats by aqueou extract of cigarette smoke condensate. Journal of the National Cance Institute 48(4) : 911-919, April 1972. (89) Sypnor, K. L., ALLEN, C., Hiucins, B. Effect of an aqueous extract of ciga rette smoke condensate on benzo(a)pyrene-iuduced sarcoma and bods weight in the rat. Journal of the National Cancer Institute 48(4) : 893- 909. April 1972. (90) Tyipesrey, W. R. Tobacco chewing in English coal miners. A preliminary report, British Journal of Oral Surgery 9( 1) : 21-28, July 1971. (9f) U.S. Pusric Heattn Service, The Health Consequences of Smoking. A Public Health Service Review : 1967. U.S. Department of Health, Educa- uon, and Welfare. Washington, Public Health Service Publication No. 1606, Revised January 1968, 227 pp. (92) U.S. Peptic HEALTH SERVICE. The Health Consequences of Smoking. 1968 Supplement to the 1067 Public Health Service Review. U.S. Department of Health, Education, and Welfare. Washington, Publie Health Service Publication 1696, 1968, 117 pp. ) U.S. Pcsiic Hearty Service. The Health Consequences of Smoking. 1969 Supplement to the 1967 Publie Health Service Review. U.S. Department of Health, Education, and Welfare. Washington, Publie Health Service Publication 1696-2, 1969, 98 pp. (94) U.S. Pesnre Hractinc Service. The Health Consequences of Smoking. A Report of the Surgeon General: 1971. U.S. Department of Health, Educa- tion, and Welfare. Washington, DHEW Publication No, (HSM) 71- 7513, 1971, 458 pp. (95) TOS. Poetic Aearre SERvVIce. The Health Consequences of Smoking. A Repert of the Surgeon General: 1972. 1.8. Department of Health, Education, and Welfare. Washington. DHEW Publication No. CHISM) 72-6516, 1972, 158 pp. P49) TOS. Ponte Hrartra Service. Smoking and Health. Report of the Advi- sory Committee to the Surgeon General of the Publie Health Service. Washington, U.S. Department of Health, Education. and Welfare, Pub- lie Flealth Service Publieation No, 1108. 1964. 887 pp. (97) Vaw~ Devren. B. L.. Brazes, T.. Gorpscusimt, B. M., Karz, C., MFLCHIoNNE, S. Stvak. Al Coearcinogenesis studies on mouse skin and inhibition of tumor induction. Journal of the National Cancer Institute 4605) > 1089- 1044, May 1971. (92) War ALM Vp, Lenne, R. VAN ner. Cara rookgewoonten en bronchus eareinnam, (Chronic nonspecific lung disease. smoking and lung cancer.) Jaarhoek Kankeronderzoek en Kankerhestrijding 19: 87-96, 1969, ~ 94 99) WeELcH, R. M., Goma, B., ALVARES, A. P., Connery, A. H. Effect of enzyme induction on the metabolism of benzo(a)pyrene and 3-methy]-4-mono- methylaminoazobenzene in the pregnant and fetal rat. Cancer Research 82(5) : 973-978, May 1972. 00) Werr-MEssinc, B. vAN DER, Kaaten, J. G. A. H. Beroepen en rook- gewoonten van Rotiersdamse blaascarcinoom-patienten. (Occupations and smoking habits of bladder carcinoma patients in Rotterdam.) Jaarboek Kankeronderzoek en Kankerkestrijdig 19: 77-85, 1969. $91) WuirtLock, J. P., Jr., Cooper, H. L., Geiporn, H. V. Aryl hydrocarbon (benzopyrene) hydroxylase is stimulated in human lymphocytes by mitogens and benz(a)anthracene. Science 177 (4049) : 618-619. Aug. 18, 1972, 32) Wynoer, E. L., Horrmann, D. Tobacco and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York, Academic Press, 1967, 730 pp. 13) XIPELL, J. M. The incidence of benign renal nodules. (A cliniocopathologic study.) Journal of Urology 106(4) : 503-506, October 1971. 14) ZIsLeTRa, V. L. J. Roken, longkanker en radioactief Po?” (Smoking, lung cancer, and radioactive polonium-210.) Tijdschrift voor Sociale Genee- skunde 47 (28) : (75-779, Nov. 14, 1969. 95 CHAPTER 4 Pregnancy Contents Introduction Smoking and Birth Weight Epidemiological Studies Cigarette Smoking and the Low-Birth-Weight Infant. Evidence for a Causal Association Between Cigarette Smoking and Small-for-Dates Infants__._________ Evidence for an Indirect Association Between Ciga- rette Smoking and Small-for-Dates Infants Experimental Studies Studies in Animals Tobacco Smoke Nicotine Polycyclic Hydrocarbons Studies in Humans Carbon Monoxide._.________.______________- Polycyclic Hydrocarbons___.____.-_______ 8. Vitamin B,. and Cyanide Detoxification Vitamin C Liming of the Influence of Cigarette Smoking on Birth Weight._....----2--- 2 woe ee eee eee Site of Action at the Tissue and Cellular Level Significance of the Association Birth Weight Summary Cigarette Smoking and Fetal and Infant Mortality Introduction Spontaneous Abortion Summary Stillbirth 495-028 O—73—_8 Page 103 105 106 110 114 115 116 117 118 119 119 119 119 120 121 121 122 123 123 124 124 125 99 Cigarette Smoking and Infant Mortality—Con. Late Fetal and Neonatal Deaths Epidemiological Studies_.....-----.-0.. Comparisons of the Mortality Risks of Low- Birth-Weight Infants Born to Smokers and Nonsmokers Analysis of Previously Reported Studies________ Factors Which Influence Perinatal Mortality Other Than Smoking Experimental Studies Studies in Animals Evidence for a Clinical Effect Upon the Off- spring Lactation Summary Preeclampsia 100 Page 126 126 126 128 130 131 132 133 133 134 135 135 136 137 138 138 138 138 138 139 139 139 139 139 140 140 141 141 142 142 142 List of Figures Figure 1.—Mean birth weight for week of gestation according to maternal smoking habit: control week singletons__.______ Figure 2.—Percentage distribution by birth weight of infants of mothers who did not smoke during pregnancy and of those who smoked 1 pack of cigarettes or more per day... Figure 3.—Percentage of pregnancies with infant weighing less than 2,500 grams, by cigarette smoking categorv__..______- Figure +.—-Average birth weight by maternal smoking habit (a) before current pregnancy and (b) during current preg- nancy Figure 5.—Percent of low birth weight white infants by smok- ing status of their mothers_.-----------.-.. Figure 6.—Neonatal mortality rates among single white births in hospitals (by detailed birth weight and specified gestation groups: United States).00 Figure 7.-Perinatal mortality rate per 1,000 total births by cigarette smoking category List of Tables Table 1.—Infant birth weight by maternal and paternal smok- ing habits.-_- 22-08 Table 2.—Effect of carbon monoxide exposure of pregnant rabbits on birth weight.--.-0.---0 0 Table 3.—Comparison of the perinatal mortality for infants weighing less than 2,500 grams, of smokers and nonsmokers. Table 4.—Effect of carbon monoxide exposure of pregnant rab- bits on birth weight and neonatal mortality_..---.2 22288, Table 5.—Proportion of male infants delivered to smoking and nonsmoking mothers_-._-...2- 22-8 Table 6.—Relative risk of congenital malformation for infants of cigarette smokers and nonsmokers, comparing available studies with regard to study design, study population, sample size, number of infants with malformations, and definition of malformation Page 104 110 113 128 129 111 117 127 133 136 137 101 Introduction Cigarette smoking is a common habit among women of child-bearing age in the United States. In 1970, approximately one-third of Amer- ican women of child-bearing age were cigarette smokers. The percent- age of U.S. women who smoked throughout pregnancy is not definitely known, but is presumably lower, probably in the neighborhood of 20 to 25 percent. With a large fetal population at potential. but prevent- able, risk, the relationship between cigarette smoking and the out- come of pregnancy has been the focus of considerable and continuing research. Every investigator who has examined the relationship has confirmed that the infants of women who smoke during pregnancy have a lower average birth weight than the infants of women who do not smoke during pregnancy. Much evidence indicates that cigarette smoking during pregnancy causes this reduction in infant birth weight. Several investigators have demonstrated that the fetal and neonatal niortality rate 1s significantly higher for the infants of smokers than for the infants of nonsmokers: other investigators have not found higher mor- tality for smokers’ infants. Studies of the association bet ween maternal cigarette smoking and congenital malformations have produced con- flicting results, The following is a review of work previously reported and recent studies which bear on the relationships between cigarette smoking and different outcomes of pregnancy. In addition, the chapter includes a review of the relationship between cigarette smoking and lactation. Smoking and Birth Weight Epidemiological Studies Cigarette SmoKixne anp THE Low-Brrtu-Weient INrant In 1957, Simpson (99), using a retrospective study desion. deter- juined that among 7.499 women in San Bernardino County. Calif.. the delivery of infants weighing less than 2.500 grams was nearly twice as 103 frequent among cigarette smokers as among nonsmokers. Subsequently, Lowe (46) studied 2,042 women in Birmingham, England, and dem- onstrated in his retrospective study that the infants of smoking mothers were delivered only slightly earlier (1.4 days on the average) than those of nonsmokers. He further noted that for gestations of 260 days and over, the infants of smokers were consistently lighter in weight during each week of gestation than those of the nonsmokers, This finding has been confirmed since, and figure 1 from the British Perinatal Mortality Study (73) provides illustration of this relationship. Given the nearly constant disparity present between the birth weights of the infants of smokers and nonsmokers for gestations of 260 days and over, but absent prior to that time, and given the similar birth weights of infants of nonsmokers and of women who gave up smoking early in pregnancy and did not begin to smoke again, Lowe inferred that the influence of smoking upon birth weight might lie mainly in the later months of pregnancy. He emphasized the tentative nature of this conclusion, since the number of infants with a gestation of less than 260 days and the number of women who gave up smoking early in the pregnancy and did not begin to smoke again were both small. Figure 1.—Mean birth weight for week of gestation according to maternal smok- ing habit: control week singletons.’ ; 3650 » _—* eer 3400 o oT” n gS) Non: or 3150 s 3 smokers -7 4 ha = 105 ee s oo P 7 ~ = 4 2D Smokers 4 2900 & oi & $ ” $ 3 95 Le | 2650 § = " = 85 F + 2400 75 be . F ‘ n . 2150 36 37 38 39 40 41 42 43+ Gestation in completed weeks *This term refers to singleton births in England, Scotiand, and Wales occurring during the week of March 3-9, 1958, which are included in the Perinatal Mortality Survey. These comprise 97 percent of ali births notified in England and Wales or registered in Scotland during this week. SOURCE: Butler, N. R., Alberman, E. D. (13). 104 Lowe found that the infants whose mothers smoked throughout pregnancy weighed, on the average, 170 grams less than those whose mothers did not smoke. In addition, he noted that the entire distribu- tion of weights of infants of smokers was shifted to the left (toward lower weights) relative to that for the infants of nonsmokers. This finding, too, has been confirmed by other investigators, Figure 2 offers an illustration fron: MacMahon, et al. (49). Given that the infants of smokers and nonsmokers differed only slightly with respect to the duration of gestation. Lowe concluded that the lower birth weight of smokers’ infants must be attributed to a direct retardation of fetal growth. In other words, on the basis of his data, the infants of smokers were small-for-dates rather than truly premature. Many investigators have subsequently confirmed this point (12, 14, “5, 35,09, 78, 85, 113). Buncher (12), in a study of 49,897 births among U.S. naval wives, in the same population studied by Underwood, et al. (100), found that the infants of smokers were, on the average, de- livered only 1 day earlier than those of nonsmokers. This finding accounted for only 10 percent of the discrepancy in birth weight be- tween the two groups of infants. The remainder of the studies resulted in the detection of either similar variations in gestational length or no average difference. In a recent study, Mulcahy and Murphy (56), Figure 2.—Percentage distribution by birth weight of infants of mothers who did not smoke during pregnancy and of those who smoked 1 pack of cigarettes or more per day. INFANT WEIGHT AND PARENTAL SMOKING HABITS i ee ee — ¥ 10 —~ Nonsmokers aati Smokers ip é Percent 4 5 6 7 8 9 10 11 BIRTH WEIGHT (SCALE IN POUNDS; INTERVALS OF 4 02Z.) SOURCE: MacMahon, et al. (49). 105 in a sample of 5,099 Irish mothers, concluded that although the babies born to cigarette smokers were delivered slightly earlier than those of nonsmokers, independent of age and parity, the direct effect of smoking in retarding fetal growth was more significant. The following points, based upon the results from many different studies, can be made about the relationship between cigarette smoking during pregnancy and lower infant birth weight: 1. Women who smoke cigarettes during pregnancy have a higher proportion of low-birth-weight infants than do nonsmokers. This excess of low-birth-weight infants among cigarette smokers pre- dominantly consists of infants who are small-for-gestational age rather than gestationally premature. 2. The entire distribution of birth weights of the infants of ciga- rette smokers is shifted toward lower weights compared to the birth weights of the infants of nonsmokers, 3. The birth weights of the infants of cigarette smokers are con- sistently lighter than those of the infants of nonsmokers when the birth weights of the two sets of infants are compared within groups of similar gestational age beyond the 36th week of gestation. The results of the studies which have been considered so far identify a relationship between cigarette smoking and lower infant birth weight and illustrate some aspects of that relationship, but do not indicate whether the association is causal or indirect. The succeeding two sections of this chapter contain evaluations of the available evi- dence which bears upon the nature of the association between cigar- ette smoking during pregnancy and the incidence of small-for-dates infants. Eviwence For a Cavsan Association BeTwren CIGARETTE SMOKING AND SMALL-FoR-Dates INFANTS Evidence previously reviewed in the 1971 and 1972 reports on the health consequences of smoking (/02, 102) suggests that cigarette smoking is causally associated with the delivery of small-for-dates infants. The following is a summary of this evidence: 1. The results from all 80 studies in which the relationship between smoking and birth weight was examined have demonstrated a strong association between maternal cigarette smoking and delivery of low- birth-weight infants. On the average. the smoker has nearly twice the risk of delivering a low-birth-weight infant as that of a nonsmoker 106 (3, 13, 17, 20, 25, 29, 35, 42, 43, 46, 47, 49, 57, 58, 59, 65, 70, 72, 73, 77,78, 80, 83, 85, 90,95, 99, 100, 113,118). 2. The strong association between cigarette smoking and the de- livery of small-for-dates infants first demonstrated with results from studies of retrospective design (3, 13, 17, 35, 46, 47, 49, 57, 58, 59, 65, 70,72, 73, 77, 80, 85, 90, 95, 99, 100, 118) has been repeatedly confirmed subsequently by data from studies of prospective design (20, 25, 29, 42, 43,78, 83,113). 3. A strong dose-response relationship has been established between cigarette smoking and the incidence of low-birth-weight infants (25, 43, 46, 49, 100, 113). 4. When a variety of known or suspected factors which also exert an influence upon birth weight have been controlled for, cigarette smok- ing has always been shown to be independently related to low birth weight (1, 13, 25, 43, 46,73, 78,83). 0. The association has been demonstrated in many different coun- tries, among different races and cultures, and in different geographical settings (13, 17,25, 29, 36, 42. 43,59, 73, 78, 80, 113). 6. Previous smoking does not appear to influence birth weight if the mother gives up the habit prior to the start of her pregnancy (25. 46,49, 113). 7. The infants of smokers experience an accelerated growth rate during the first 6 months after delivery, compared to infants of nonsmokers. This finding is compatible with viewing birth as the re- moval of the smoker's infant from a toxic influence (83). 8. Data from experiments in animals have documented that ex- posure to tobacco smoke or some of its ingredients results in the delivery of low-birth-weight offspring (7, 8, 9, 23, 40, 87, 117). Several recently published studies have provided additional sup- porting evidence for a causal relationship between cigarette smoking and small-for-dates infants. The Ontario Perinatal Mortality Study (66) was conducted among 10 teaching hospitals during 1960 and 1961. The authors of this retrospective study of 50,267 births demon- strated a significant excess of infants weighing less than 2,500 grams among cigarette smokers as compared with nonsmokers (P<0.001). Smoking was significantly dose-related to the percentage of preg- nancies terminating in the delivery of a low-birth-weight infant (fig. 3). Niswander and Gordon (63) have recently reported data from the Collaborative Perinatal Study of the National Institute of Neuro- logical Diseases and Stroke. In this prospective study of 39,200 preg- nancies, which were nearly equally divided among black and white Women, the authors found a significant dose-related excess of low- birth-weight infants among smokers of both groups, compared to nonsmokers of the same race. 107 Figure 3.—Percentage of pregnancies with infant weighing less than 2,500 grams, by cigarette smoking category. -_ nD ° 12.0 F 11.0 F 10.0 fF 9.0 F @ Oo “I N U; 2 7.0 fF YY) Vz 2 6.0 + Z V7 3.0 | Y “7 V2 2.0 + Y Y V2 0.0 LZ Y) LZ Nonsmoker <1 pack =1 pack per day per day Number of infants weighing <2,500 grams: 1,322 1,186 793 Total births: 28,358 15,328 6,581 (P <0.001) SOURCE: Ontario Department of Health (66). 108 Rantakallio (76) carried out a prospective study of 11,905 single births in Finland. Cigarette smoking mothers had significantly more infants weighing less than 2,500 grams than did nonsmokers (P<0.00L). Rush and Kass (82), in a prospective study of 1,040 pregnancies in Boston, Massachusetts; Domagala. ct al. (19), in a retrospective study of 1,832 pregnancies in Poland; and Mukherjee and Mukherjee (54), in a retrospective study of 2,886 pregnancies in India, each found a significantly higher incidence of low-birth-weight infants among cigarette smokers, Butler, et al. (25) have further analyzed the British Perinatal Mor- tality Study data. Analysis of the 16,994 questionnaires revealed that 40.8 percent of the women were cigarette smokers before pregnancy, After the fourth month, this percentage hal decreased to 27.4 per- cent. Given the large number of women in the study, and the sig- nificant changes in smoking behavior which occurred, Butler, et al. found it possible to consider the effect of a change in smoking be- havior on birth weight between the beginning of the pregnancy and the fourth month (after which smoking behavior was reportedly stable), The authors stated, “If smoking itself (rather than the type of woman who smokes) has a deleterious effect on the fetus, it would be reasonable to expect the mothers who gave up smoking during pregnancy to show differences in the birth weight and peri- natal mortality of their offspring compared with those who continued tosmoke.” Their results are presented in figure 4. The birth weights by smoking categories were estimated by using a main effect model without mediating variables, However, the anthors reported that when the mediating variables (social class, maternal age, parity, maternal height, sex of infant, gestational age, and perinatal mortality) were allowed for, the results of the analysis were very similar. The effect of cigarette smoking before pregnancy was insignificant compared to that of smoking regularly after the fourth month of gestation. The authors concluded, “The finding that a change in maternal smoking habits during pregnancy had the effect of putting the baby into a birth weight and perinatal mortality category associated with the new smoking habits points toward some kind of cause-effect. relationship. *** This finding is further strengthened by the birth weight analysis which shows that the diminution in birth weight of the offspring of smoking mothers persists and is indeed little changed when allowance 7 been made for a number of other social and obstetric mediating actors.” 109 Figure 4.—Average birth weight by maternal smoking habit (a) before Current Pregnancy and (b) during current pregnancy. Number of Cigarettes /day in current pregnancy, after the fourth month 3,400 F of gestation NN 3 ” £ £3,300 } £ 2 1-4 = t 6B 3,200+ oo 2 2 3,100 + lL 1 ] l 0 1-4 5-9 10-19 20-30 Total Number of cigarettes /day before current pregnancy pis 1,67] SOURCE: Adapted from Butler, et al. (15). EvinEncE ror AN INpIRECT AssocraTion Between CIGARETTE SMOKING AND SMALL-For-Datzs Inrants Yerushalmy (1/3, 114, 115 ) has suggested that smoking is an index to a particular type of reproductive outcome and thus does not play a causal role in the production of small-for-dates infants. He has de- veloped several lines of support for this hypothesis, from an analysis of data from the prospective investigation of 13,083 mothers in the Oakland Child Health and Development Study. He has emphasized that ineffective randomization and the phenomenon of self-selection complicate the development of appropriate inferences with regard to causality. Such difficulties do not prevent the identification of causal associations, but they demand careful and critical analysis of the data. Yerushalmy has questioned the causal nature of the relation- ship between cigarette smoking and small-for-dates infants because of: (a) The relationship between the smoking habit of the father and low birth weight of the infant, (b) behavioral differences between smokers and nonsmokers, and (c) comparison of the birth weights 110 of a woman’s infants born during the periods when she smoked ciga- rettes and when she did not. Yerushalmy (//4) has stated that the smoking habit of the father could not reasonably be related to the birth weight of the infant. From preliminary data derived from the study, however, he determined that there was an increased incidence of low-birth-weight infants when the fathers smoked and, moreover, there was an apparent dose- tesponse relationship as found for maternal smoking. However, he noted that only when both the husband and the wife smoked was the incidence of low-birth-weight babies increased. He felt that these findings supported the conclusion that smoking was a marker of types of individuals and not a eausal factor for low birth weight. Other investigators have since examined this relationship (49, 100), but none has confirmed an independent association for paternal smoking. The association hetween paternal smoking and birth weight appears to be an indirect one. Paternal and maternal smoking be- havior are highly correlated and maternal smoking is strongly related to infant birth weight. Underwood. et al. (707) studied 48.505 women, their husbands* smoking behavior, and the relation with birth weight (table 1). If the mother was a nonsmoker. then the father's smoking had no influence on the birth weight of the infant. Tape 1.—Jnfant birth weight by maternal and paternal smoking habits Fathers (nonsmoking mothers) Cigarettes per day rans! ‘Birthweight (grams) _ Number -- Sse Number 9 ---—- -—--—--~-—~-~ Meu Ditferepce Mean Difference? None_- 24, 865 3,595 0 9, 547 3, 396 0 Ito 10-02 7,609 3, 286 109° 3,493 3, 389 7 M to 380.0222 14,450 3,196 199 10,403 3, 891 5 ?30. 1, 570 3, 182 213 1, 330 3, 393 3 ee ' Nonstnoker niinus smoker. a - Source: Underwood, et al. (199), Yerushalmy (7/5) pointed out that other investigators had found marked differences between smokers and nonsmokers. In his own ‘tudy, he found that nonsmokers sed contraceptives significantly More frequently than did smokers. Moreover, a significantly higher Proportion of smokers drank coffee, beer, ail whiskey. However, he id not adjust for these variables in his analysis of the association het ween cigarette smoking and Jower infant birth weight. Other in- “estigators have also found differences between smokers and non- “Hokers, For example, Frazier. et al, (25) found significant differences n the distribution of parity, work history, education, and psycho- WY somatic complaint score between smokers and nonsmokers. However, when smokers were compared with nonsmokers of the same parity, education, work history, and psychosomatic complaint score, cigarette smokers still had a significantly higher proportion of small infants than did nonsmokers, As previously mentioned, whenever other factors known or suspected to influence birth weight have been controlled, cigarette smoking has always been demonstrated to have an inde. pendent and significant effect. Ounsted (69) offered evidence that the best predictor of the birth weight of a mother’s future offspring was the birth weight of her previous children. Herriott, et al. (35) found prematurity rates for previous pregnancies among smokers to be markedly higher than among nonsmokers, independent of parity, height, and social class, Evidently a woman whose previous infants have been small tends to continue to have relatively smaller than average infants in subsequent pregnancies. The question is, will those infants be even smaller than expected if she smokes? Goldstein, et al. (28), in a comprehensive review, proposed a research design in which a woman would serve as her own control to compare outcomes of pregnancies during which she smoked with those during which she did not with consideration of the effect of parity on the outcome. Yerushalmy (2/2) has recently tested this type of research design, using data from his Oakland Growth Study. With information on the age at which a woman began to smoke cigarettes, her smoking status during the pregnancy actually studied, her prior reproductive experience, and the outcome of her present pregnancy, the author compared the outcomes of pregnancy during periods of smoking and nonsmoking using the woman as her own control. As the author noted, “If smoking causes the increase in low-birth-weight infants, then the incidence of low birth weight for infants born to smoking mothers during the period before they acquired the smoking habit, should be relatively low. If, on the other hand, the high incidence of low birth weight is due to the smoker, then it should be high for infants of future smokers also when they were born before their mothers started to smoke.” Yerushalmy then proceeded to compare the reproductive experiences of four groups of women: (a) Those who smoked in none of their pregnancies, (b) those who smoked in all of their pregnancies, (c) those who were smoking now but previously had not smoked during some pregnancies (future smokers), and (d) those who were ex- smokers now but had previously smoked during some pregnancies. These outcomes are shown in figure 5. The incidence of low-birth- weight infants in the pregnancies of the future smokers, before they started to smoke, was similar to that for women who smoked in every pregnancy, which was significantly higher than that of infants from 112 mothers who had never smoked. He also noted that ex-smokers, during the period before they quit, gave birth to relatively few low-birth- weight infants; the incidence was significantly lower than for mothers who smoked during all of their pregnancies. He concluded that the findings cannot be easily reconciled with a cause-effect basis for smok- ingand birth weight. He said, “Rather the evidence appears to support the hypothesis that the higher incidence of low-birth-weight infants is due to the smoker. not the smoking.” There are several considerations which limit the interpretations which can be drawn from this study. The information on smoking lehavior of the women during past pregnancies was apparently de- rived from the woman's age when she began to smoke, her smoking behavior early in the study pregnancy, and the age at which she had her prior pregnancies. Thus, if the woman reported that. she began wnoking at a certain age, and that she was still smoking at the time of the study, it was apparently inferred that she had smoked during all of her pregnancies. Since no questions were specifically asked about actual smoking behavior during each previous pregnancy, it is possible that the woman indeed had not smoked during every pregnancy or that the amount. or way she smoked had differed from current smoking Figure 5.——Percent of low birth weight white infants by smoking status of their mothers. Gravidas’ smoking habits Percent low birth weight infants in previous pregnancies Nonsmoker * (during all pregnancies) 5.3 2,529 Nonsmoker * (future smoker) ss S—i«d 210 Smoker 8, }** 2,076 (during all pregnancies) 8.9 , Smoker “" (future ex-smoker) | 651 2 4 6 8 10 Percent Difference is statistically significant (P <0.01). Difference is Statistically significant (P <0.02). SOURCE: Adapted from Yerushalmy, J. (112). habits. This would be important to know given the strong dose. response relationship which has been established between cigarette smoking and low birth weight, and would tend to make the reproduc. tive outcomes for ex-smokers similar to those of nonsmokers, and different from those of women who smoked in all pregnancies. For ex-smokers, the age at which smoking began was not elicited, Hence, some of the infants of ex-smokers may have been born before their mothers acquired the smoking habit. This would also tend to make the reproductive experiences of ex-smokers more like those of nonsmokers and different from those of women who smoked in al] pregnancies. No direct adjustment for age, parity, and other variables was reported, although Yerushalmy stated that the study population was limited to the births that occurred to women at age 25 years or legs, He noted that, “In order to adjust for parity, the same comparisons were performed for firstborn infants only. The numbers were reduced considerably, but the same tendencies as found above were noted.” However, no data were presented. Primiparous births and births in teenagers are strongly associated with the delivery of low-birth-weight infants. If the pregnancies which occurred among future smokers included a predominance of very young women and primiparous births, the reproductive experiences of future smokers would tend to be similar to those of women who smoked during all pregnancies, and different from those of nonsmokers. In the absence of more precise information on actual smoking behavior during pregnancy and more rigorous adjustment for maternal age, this study does not provide a critical test of the hypothesis that it is the smoking during pregnancy which is responsible for the high proportion of small-for-dates in. fants born to women who smoke. Experimental Studies Srupres 1y ANIMALS ‘Tobacco Smoke Several investigators have demonstrated that exposure of pregnant rats or rabbits to tobacco smoke leads to a reduction of birth weight in the offspring, as compared to controls (23, 87, 117). Younoszai, et al. (117) reported data from studies in rats which indicated that some agent present in cigarette smoke other than nicotine was responsible for the reduction in birth weight observed. The authors suggested that carbon monoxide might also not be responsible for the retardation of V4 fetal growth; however, the evidence presented was inadequate to support a firm conclusion. Haworth and Ford (33) recently extended the experiments of Younoszai. A group of pregnant rats was exposed to cigarette tobacco smoke for 6 to 8 minutes, five times a day, from days 3 to 20 of ges- tation. These rats were compared with another group whose food intake was restricted to the amount actually consumed by the tobacco- exposed rats, and both were compared to a well-fed control group. The animals in both experiments were killed on the 2ist day of gestation, and weights of the entire body, the liver, and the kidney of each fetus were recorded. The total average fetal weight of the group exposed to tobacco smoke was significantly lower than that of both the food-restricted and control groups. The fetal weights of the latter two groups were quite similar. Protein and DNA analyses were performed separately on the entire forebrains and hindbrains of the fetuses and on the entire carcass. Both DNA and protein were sig- ulficantly and proportionately reduced in the carcass and hindbrains uf the animals exposed to tobacco smoke. This implies that cell number was reduced and cell size was normal, and suggests that the exposure to tobacco smoke either inhibited cellular proliferation or accelerated cellular destruction. Nicotine Several workers have demonstrated that chronic injections of large loses of nicotine into pregnant rats resulted in a reduction of birth weight of the offspring (7, 8, 9, 23, 40). Other investigators have de- 'ermined that tritium-labelled nicotine injected into pregnant rabbits ind C-labelled nicotine injected into pregnant mice crossed the placenta to the developing embryo and fetus (89, 98). Kirschbaum, ttal. (47) found no significant acute effects of small doses of nicotine, ‘hjected intravenously into near-term sheep, on blood gas composition, pH, blood pressure, or heart rate in either the ewes or their fetuses. The authors concluded that the influence of maternal smoking upon the fetus must result from chronic effects or through the effects of ‘ther variables which they did not study. _ Recently, Suzuki, et al. (94) evaluated the short-term effects of in- lected nicotine on the cardiovascular performance, acid-base status, ‘nd oxygenation of pregnant female Rhesus monkeys and their infants “Wing the second half of gestation using the mothers as their own “ntrols, Nicotine was administered either as a single intravenous dos . . . . 8e of 0.5 to 1.0 mg. or as a continuous infusion of 100 yug./kg. over 495-028 O—73 9 115 a 20-minute period. The injection of nicotine in the larger, single dose into the mother produced a rise in maternal blood pressure and a fall in maternal heart rate, and an immediate fall in both fetal blood pressure and fetal heart rate followed by persistent hypotension and tachycardia in the fetus. Subsequent to the injection of 1.0 mg./kg. of nicotine into pregnant monkeys, in a single dose, significant changes in the arterial blood of the older fetuses included a fall in pH, a rise in base deficit, and a fall in oxygen tension. Carbon dioxide tension remained unchanged. Nicotine injected directly into the fetus prompted an immediate rise in fetal blood pressure and a fall in fetal heart rate. These responses were similar to those previously seen in the mothers following a direct injection of nicotine. The changes were more prominent in older rather than in younger fetuses. The authors sum- marized their findings by stating that: (a) fetuses in different ges- tational stages are differentially responsive to a given dose of nico- tine, probably because of the different stages of development of the autonomic nervous system; (b) diminished intervillous space per- fusion resulting from vasoconstriction in the uterine circulation ap- pears to be mainly responsible for the fetal asphyxia following the injection into the mother, because fetal hypotension and bradycardia were not preceded by the transient hypertension seen following the direct administration of nicotine to the fetus; (c) the differences be- tween the results obtained by Kirschbaum and by Suzuki, et al. may reflect either the considerable dosage differences or species differences; and (d) the doses which the authors employed were much larger than those which a human mother would absorb from usual cigarette smok- ing, but that differences in tolerance to nicotine between the Rhesus monkey and humans would imply that the dosages were, in fact, com- parable and that, “Hence, it can be envisaged that the concentration of nicotine which could be reached in the organism of a smoking mother would reduce oxygen availability to the fetus.” Carbon Monoxide Longo (45) has reviewed the work of several investigators which has demonstrated the transplacental passage of carbon monoxide from mother to fetus in animals. A recent study which related CO to birth weight was published by Astrup (?). He found that continuous ex- posure throughout gestation of pregnant rabbits to different levels of ambient carbon monoxide resulted in a statistically significant dose- related reduction in birth weight (table 2). The actual significance level was not reported. 116 TABLE 2.—Fiffect of carbon monoxide exposure of pregnant rabbits on birth weight Group 1, Group 2, Group 3, 0 percent 8tol0 percent 16 to 18 percent COHb COHb COHDb Number of pregnant rabbits.._.______ 17 14 17 Total number of babies__-_-__...____ 116 81 123 Average weight of babies in grams_____ 53. 7 51.0 44.7 Source: Astrup, P. (2). Polycyclic Hydrocarbons Polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene (BAP) are constituents of cigarette smoke which have been impli- cated in the generation of cancers in many animal species (1/7). No studies presently available relate benzo(a)pyrene to a reduction in birth weight of exposed offspring. Evidence suggests, however, that BAP does reach and cross the placenta. Aryl hydrocarbon hydroxylase (AHH) is a part of the cytochrome P-450- containing microsomal enzyme system, present in many tissues of different species. This enzyme system is induced to hydroxylate polycyclic aromatic hydro- carbons after exposure of cells to PAH. Several investigators have utilized the inducibility of the enzyme system to demonstrate indirectly that benzo(a)pyrene and other polycyclic hydrocarbons reach the placenta and fetus. Welch, et al. (108) extended this work by administering the poly- cyclic hydrocarbon, 3-methylcholanthrene (8-MC), to rats during late gestation. The metabolism of benzo(a)pyrene was studied in vivo (us- ing tritium-labelled benzo(a)pyrene) and in vitro. AHH activity was increased in fetal livers to adult levels by pretreatment with 3-MC Since a relatively high dose of polyeyelic hydrocarbon was required to stimulate enzyme activity in the fetus, compared to the dose which stimulated placental enzyme activity, the authors suggested that the placenta may protect the fetus from exposure to polycyclic hydro- carbons. However, immaturity of the fetal enzyme system might also account for its apparent relative insensitivity to polyevelic hydro- carbons. Therefore, an exposure of the fetus to levels of poly- cyclic hydrocarbon similar to those experienced by the mother cannot be ruled out by the available data. Schlede and Merker (86) have studied the effect of benzo(a)pyrene administration on aryl hydrocarbon hydroxylase activity in the mater- nal liver, placenta, and fetus of the rat during the latter half of gestation. The pregnant animals were treated with large oral doses of benzo(a)pyrene 24 hours prior to sacrifice. Control rats had no detectable levels of aryl hydrocarbon hydroxylase in their placentas, Treatment. with benzo(a)pyrene resulted in barely detectable placental levels on gestation day 13, but steadily rising values until day 15, and then constant levels thereafter. No activity was detected in the fetuses of untreated controls. In the treated animals, the fetal enzyme activity rose steadily from the 13th to the 18th day of gestation. The authors concluded that the stimulatory effect of benzo(a)pyrene treatment on aryl hydrocarbon hydroxylase activity in the fetus demonstrates that benzo (a) pyrene readily crosses the rat placenta. STwDIEs In Hvuasrans Carbon Monoxide Smokers and their newborn infants have significantly elevated levels of carbon monoxide as compared with nonsmokers and their infants (31, 34, 88, 116). Recently, Baribaud, et al. (5) studied 50 nonsmokers and 27 cigarette smokers and their newborns. All smokers inhaled. The authors found that the mean level of CO content in the blood of non- smokers was 0.211 volumes percent compared with 0.672 volumes per- cent in the blood of smokers. The values for blood samples from the umbilical cords of their newborns were 0.352 and 0.949 volumes per- cent, respectively. Moreover, a definite dose relationship was found bet ween CO levels and number of cigarettes smoked. Younoszai, et al. (776) found, in addition to elevated carboxyhemo- globin levels among the infants of smoking mothers, significant elevation of mean capillary hemotocrits and signifieant reduction of standard bicarbonate levels, as compared to the infants of nonsmoking mothers. Since no evidence for nicotine effects upon blood glucose, serum FFA levels, or urinary catecholamines, or for hypoxia was present, they concluded that the higher hematocrit levels in the infants of smoking mothers may have represented a compensatory response to the decreased oxygen-carrying capacity of the blood due to the presence of carboxyhemoglobin., Longo (45) pointed out that a level of 9 percent carboxyhemoglobin in the fetus is the equivalent of a 41 percent decrease in fetal blood flow or fetal hemoglobin concentration. In reviewing the studies of CO levels in human mothers and their newborns, he made the follow- 118 ing comments: “These samples were obtained at the time of vaginal delivery or Cesarean section and may not accurately reflect the normal values of (COHb)y for several reasons. The number of cigarettes smoked by the mothers during labor may be less than their normal consumption and was not specified in these studies. The blood sam- ples were collected at varying time periods following the cessation of smoking. In addition, many of the samples were probably taken early in the day before COHb levels had built up to the levels reached after prolonged periods of smoking. Thus actual levels of (COHb) x and (COHb)» may be higher than the reported values.” Polycyclic Hydrocarbons The results of several studies concur that cigarette smoking is strongly associated with the induction of aryl hydrocarbon hydrox- ylase in the human placenta (18, 38, 61, 99, 109). This finding imphes that benzo(a)pyrene or other polycyclic hydrocarbons reach the placenta. To date, evidence to support the passage of polycyclic hydro- carbons through the placenta to the human fetus has not been published. Vitamin B,, and Cyanide Detoxification McGarry and Andrews (48) determined serum vitamin B,, levels in 826 women at their first prenatal clinic visit, They found that the serum levels for smokers were significantly lower than for nonsmokers. After adjustment for gestational age, parity, social class, hemoglobin level, hypertension, and maternal weight, smokers still had signifi- cantly lower levels of B,>. They also found a direct, statistically sig- nificant dose-response relationship between cigarettes smoked and serum vitamin B,, level. They again confirmed the relationship be- tween smoking and low birth weight. The authors suggested that the lowered vitamin B,, levels reflect a disorder of cyanide detoxification. Cyanide is a demonstrable ingredient in cigarette smoke (39, 60, 62, 54,68,74,91). Vitamin C Venulet (105, 106, 107) has demonstrated that the vitamin C level is significantly lower in the serum of women who smoke cigarettes during pregnancy, compared to values for their nonsmoking counter- parts. Possible Mechanisms The following mechanisms have been proposed for the production of low birth weight and other unfavorable outcomes of pregnancy following exposure to cigarette smoke: 1. A direct toxic influence of constituents of cigarette smoke upon the fetus (2, 45, 50, 51, 117). 2. Decreased placental perfusion (94). - Decreased maternal appetite and diminished maternal Weight gain with secondary effects upon the fetus (6, 33, 36, 65, 75, 99. 117). . A direct effect upon the placenta (36, 57, 65, 110). . An oxytocic effect on uterine activity (44). - A disturbance of vitamin B,, metabolism ( 48). . A disturbance of vitamin C metabolism (105, 106, 107). oo ID oR Of the potential mechanisms, available evidence suggests that neither decreased maternal appetite and decreased maternal weight gain nor a direct effect upon the placenta are responsible for a sig. nificant reduction in birth weight. Existing evidence does not permit firm conclusions concerning the relative significance of the remaining mechanisms. Timing of the Influence of Cigarette Smoking on Birth Weight Several investigators have published results which bear on the time period during which exposure to cigarette smoke most affects fetal growth. Lowe (46) and Zabriskie (778) have offered evidence which suggests that cigarette smoking influences fetal growth most during the second half of pregnancy. Butler, et al. (15) found that the birth weights of infants of women who did not smoke after the fourth month of pregnancy were essentially the same as those of the infants of nonsmokers. This implies that the influence is most probably exerted after the fourth month of pregnancy. Herriott, et al. (35), however, found that women in lower socioeconomic classes who gave up smoking early in pregnancy tended to have intermediate weight babies as com- pared with nonsmokers and persistent smokers, but his numbers of women were small and the results were not statistically significant. Underwood, et al. (00) found that cigarette smoking in any single trimester was associated with a lower birth weight of the infant, although the difference between the birth weights of infants of women who smoked only during a single trimester and infants of non- smokers was not statistically significant because of small numbers. Several investigators have detected a nearly constant difference be- tween the birth weights of the infants of smokers and nonsmokers. delivered during the last month of pregnancy. following gestations of comparable length [fig. 1, (77)]. Although this observation is 120 compatible with the suggestion that the influence of cigarette smoking upon the fetus occurs prior to the last month of pregnancy, it is based upon data derived from cross-sectional rather than longitudinal studies. The results of many human epidemiological studies suggest that maternal smoking prior to pregnancy does not influence fetal weight gain (15, 25, 46, 49, 113). Site of Action at the Tissue and Cellular Level The use of labelled nicotine (98) and the preparations of autoradio- grams have permitted the localization of nicotine within the tissues of the fetus and mother. Tjalve, et al. (98) found high levels of nico- tine in the respiratory tract, adrenal, kidney, and intestine of 16- to 18- day mice fetuses. The use of other labelled constituents during various parts of gestation might further the understanding of how certain ingredients in cigarette smoke produce an impact upon birth weight. Haworth and Ford (33) have reported data which suggest that the reduction of birth weight of rat fetuses caused by the action of the ingredient (s) of tobacco smoke results from a reduction in cell number, but not in cell size. Significance of the Association Among all women in the United States, cigarette smokers are nearly twice as likely to deliver low-birth-weight infants as are non- smokers. Assuming that 20 percent of pregnant women in the United States smoked cigarettes through the entire pregnancy (extrapolated from data on changes in smoking behavior during pregnancy collected for the British Perinatal Mortality Study), taking into account the apparently different risks of delivering a small-for-dates infant for Caucasian and non-Caucasian women who smoke during pregnancy, and considering the number of infants with a birth weight less than 2,500 grams born to Caucasian and non-Caucasian women, an excess of nearly 43,000 occurred in the 286,000 low-birth-weight infants among the 3,500,000 infants born in the United States in 1968, because of the increased risk among women who smoke of having small-for- dates infants. Since neonatal mortality is higher for low-birth-weigth infants. with gestational age held constant, the excess of small-for-dates infants ‘mong smoking mothers would imply a significant excess mortality risk as well. 121 Birth Weight Summary A causal association between cigarette smoking and fetal growth retardation is supported by the following evidence: 1. 7. 122 The results of all 42 studies in which the relationship between smoking and birth weight was examined have demonstrated a strong association between cigarette smoking and delivery of small-for-dates infants. On the average, the smoker has nearly twice the risk of delivering a low-birth-weight infant as that of a nonsmoker. . This association has been confirmed by both retrospective and prospective study designs. . A strong dose-response relationship has been established between cigarette smoking and the incidence of low-birth-weight infants, Available evidence suggests that the effect of smoking upon fetal growth reflects the number of cigarettes smoked daily during a pregnancy, and not the cumulative effect of cigarette smoking which occurred before the pregnancy began. - When a variety of known or suspected factors which also exert an influence upon birth weight have been controlled for, cigarette smoking has consistently been shown to be independently related to low birth weight. . The association has been found in many different countries, among different populations, and in a variety of geographical settings. - New evidence suggests that if a woman gives up smoking by the fourth month of pregnancy, her risk of delivering a low-birth- weight infant is similar to that of a nonsmoker. The infants of smokers experience a transient acceleration of growth rate during the first 6 months after delivery, compared to infants of nonsmokers. This finding is compatible with viewing birth as the removal of the smoker’s infant from a toxic influence. . The results of experiments in animals have shown that exposure to tobacco smoke or some of its ingredients results in the delivery of low-birth-weight offspring. New evidence demonstrates that chronic exposure of rabbits to carbon monoxide during gestation results in a dose-related reduction in the birth weight of their offspring. . Data from studies in humans have demonstrated that smokers’ fetuses are exposed directly to agents within tobacco smoke, such as carbon monoxide, at levels comparable to those which have been shown to produce low-birth-weight offspring in animals. Cigarette Smoking and Fetal and Infant Mortality Introduction Several previous studies of the relationship between cigarette smok- ing and higher fetal and infant mortality among the infants of smokers have been reviewed in the 1971 and 1972 reports on the health con- sequences of smoking (101, 102). In many of these studies, the authors combined two or more categories of fetal and infant mortality. Differ- ent mortality outcomes, such as spontaneous abortion, stillbirth, and neonatal death, are influenced by different sets of factors. Among other factors, the frequency of abortion is influenced by congenital infections, hormonal deficiencies, and cervical incompetency. In addi- tion to other factors, the frequency of stillbirth is influenced by pre- mature separation of the placenta, uterine inertia, and dystocia. Along with other factors, the frequency of neonatal death is influenced by gestational maturity, birth injuries, and delivery room and nursery care, Separate analysis of the relationship of cigarette smoking to tach different mortality outcome, with control of the unique set of factors which influences it, may facilitate understanding of the relationship. Spontaneous Abortion Previous epidemiological and experimental studies of the relation- ship between spontaneous abortion and cigarette smoking reviewed in the 1971 and 1972 reports on the health consequences of smoking (101, 102) form the basis of the following statements: The results of several studies, both retrospective and prospective, have demonstrated a statistically significant association between ma- ternal cigarette smoking and spontaneous abortion (43, 65. 70, 99, 118). Data from some of these studies have documented a strong dose- response relationship between the number of cigarettes smoked and the incidence of spontaneous abortions (70, 99, 118). In general, vari- ables other than cigarette smoking (e.g., maternal age, parity, health, desire for the pregnancy, and use of medication), which may influence the incidence of spontaneous abortions, have not been controlled. The Tesults of the one study, in which adjustment for the woman’s desire for the pregnancy was performed, indicated that after such adjust- ment cigarette smoking during the pregnancy retained an association ith spontaneous abortion of borderline significance (43). The time Period during which cigarette smoking might exert an influence on the incidence of spontaneous abortions has not been determined. Abor- 123 tions have been produced in animals only with large doses of Nicotine (23, 96, 104) ; the relevance of these studies for humans is uncertain Spontaneous Aportion SumMMARY Although several investigators have found a significantly higher dose-related incidence of spontaneous abortion among cigarette smokers as compared to nonsmokers, the lack of control of significant variables other than cigarette smoking does not permit a firm con. clusion to be drawn about the nature of the relationship. Stillbirth Epidemiological studies of the association between cigarette smok.- ing and stillbirth previously reviewed in the 1971 and 1972 reports on the health consequences of smoking (101, 102) form the basis for the following statements : In one group of retrospective and prospective studies, a higher still. birth rate was found for the infants of smokers as compared to those of nonsmokers (14, 25, 43). In another group of retrospective and prospective studies, no significant difference was detected in the still- birth rate among the infants of smokers and nonsmokers (16, 20, 85,99, 100). Differences in study size, numbers of cigarettes smoked, or the presence or absence of control of variables, such as age and parity, which may influence stillbirth rates, were probably not sufficient to explain the differences in results obtained. Several recent epidemiological studies have added to our under- standing of the relationship between cigarette smoking and stillbirth. Niswander and Gordon (63) have reported data from 39,215 preg- nancies followed prospectively and collected between 1959 and 1966 at 12 university hospitals in the United States. A random sample of women who presented to hospital prenatal clinics were enrolled in the study. The authors reported no increase in stillbirths among white smokers as compared with white nonsmokers. A higher incidence of stillbirths was found among black women who smoked than among nonsmoking black women. and a dose-response relationship with cigarettes smoked was suggested, although the findings did not attain statistical significance. The results were not adjusted for other vari- ables, Rush and Kass (82) found, in a prospective study of 3,296 pregnancies at Boston City Hospital, a nonsignificant increase in 124 stillbirths among white women who smoked, but a statistically signifi- cant increase in stillbirths among black women who smoked (P<0.02). These findings are consistent with those previously outlined by Frazier, et al. (25) and Underwood, et al. (99). Rumeau-Roquette (87), in a prospective study of 4,824 pregnancies in Paris, demonstrated that the risk of stillbirth was significantly higher for cigarette smokers than for nonsmokers (P<0.001). The authors also presented evidence that a woman with either a previous stillbirth or at least one prior infant weighing less than 2,500 grams at birth was significantly more likely to have a future stillborn infant than a woman without such an obstetrical history. After previous obstetrical history was controlled, smokers still retained a statistically significant increased risk of subsequent stillbirth as compared to non- smokers (P<0.01). Of further interest. was the finding that among women who previously had delivered only living infants, weighing over 2,500 grams, cigarette smoking had no influence on the stillbirth rate. Previous experimental studies were reviewed in the 1971 and 1972 reports on the health consequences of smoking (/0/, 102). The authors demonstrated that exposure of pregnant rabbits to tobacco smoke and pregnant rats te large doses of injected nicotine resulted in a signifi- cant increase in stillbirths (7, 8, 23, 87). STILLBIRTH SUMMARY 1. The results of recent studies suggest that cigarette smoking is most strongly associated with a higher stillbirth rate among women who possess less favorable socioeconomic surroundings or an unfavorable previous obstetrical history. In the United States, black women have higher stillbirth rates than white women. The finding that cigarette smoking is associated with an even greater difference between the stillbirth rates of the two groups merits special attention. These findings may provide at least a partial explanation for the lack of a significant difference in stillbirth rates between smokers and nonsmokers, which some investigators have found. 2. The results of experiments in animals demonstrate that exposure to tobacco smoke and some of its ingredients, such as nicotine, can result in a significant increase in stillbirth rate. Late Fetal and Neonatal Deaths Considerable variation has occurred in the definition of the study population among the studies in which the relationship of cigarette smoking to fetal mortality (other than abortion) and early infant mortality was examined. The most commonly identified study popula. tions have been perinatal deaths, neonatal deaths, and late fetal plus neonatal deaths, Perinatal deaths are a combination of late fetal deaths (Le., stillborn infants) and deaths occurring within the first week of life. Neonatal deaths include all deaths of liveborn infants within the first 28 days of life. EPIDEMIOLOGICAL STUDIES Most of the earlier epidemiological studies of the association between cigarette smoking and late fetal plus neonatal mortality were reviewed in the 1971 and 1972 reports on the health consequences of smoking (101, 102). A review of previously unreported studies (67, 76), as well as reexamination of previously cited studies, forms the basis of the following statements: The results of several prospective and retrospective studies indicate a statistically significant higher late fetal and/or neonatal mortality for the infants of smokers compared to those of nonsmokers (14,17, 45, 43). The results of other prospective and retrospective studies iden- tified no significant difference in the mortality rates between the in- fants of smokers and nonsmokers (20, 65. 72. 85, 100, 115). If mortality rates were compared for those infants of smokers and nonsmokers weighing less than 2.500 grams. the infants of nonsmokers apparently had a considerably higher risk than did those of smokers. The results of recent studies, coupled with a critical review of the design and analysis of previous studies, and a reexamination of exist- ing data, may provide at least a partial explanation of discrepancies between the results of previous studies. Comparisons of the Mortality Risks of Low-Birth-Weight Infants Born to Smokers and Nonsmokers The perinatal mortality risk for infants weighing less than 2.500 grams appears to be lower for those infants born to women who smoke during pregnancy than for those born to nonsmokers (table 126 3). However, available evidence shows that cigarette smokers’ infants tend to be small-for-gestational age rather than gestationally pre- mature, Hence, within a given birth weight group, the infants of smokers are, on the average, gestationally more mature than those of nonsmokers. Data collected by the National Center for Health Sta- tistics (703) demonstrate that within a given birth weight group, the more gestationally mature an infant, the lower is its mortality risk (fig. 6). Thus, the difference in perinatal mortality risks experienced hy the infants of cigarette smokers and nonsmokers, within comparable birth weight classes, reflects the facts that the two sets of infants are not of the same average gestational age, and that gestational age is a major factor influencing late fetal and neonatal mortality. An accu- rate estimate of comparative mortality risks for the infants of cig- arette smokers and nonsmokers requires adjustment for gestational age, For infants of comparable gestational age, lower birth weight is as- sociated with higher mortality (fig. 6). Since infants of cigarette smokers have, on the average, lower birth weights than the infants of nonsmokers, within groups of comparable gestational age, cigarette smokers’ infants should experience higher mortality rates than non- smokers’ infants of similar gestational ages. In a recent review, Meyer and Comstock (51) provided a more extensixe discussion of these points, TABLE 3.—Comparison of the perinatal mortality for infants weighing less than 2,500 grams, of smokers and nonsmokers Perinatal mortality rate (deaths per 1,000 live births) Authcr, reference me Smokers Nonsmokers Underwood, et al. (100)............ 187 269 Ontario Department of Health (67)_22 2 232 300 Kullander and Kallen (43)... 129 139 Rantakallio (76)... 288 344 erushalmy ! (112): Black women_._-___--._-.-..-8 114 202 White women__.__..... 114 218 Butler and Alberman (14)._............ 269 284 ' Reported neonatal mortality rates only. 127 Figure 6.—Neonatal mortality rates among single white births in hospitals by detailed birth weight and specified gestation groups: United States), JANUARY 1 TO MARCH 31, 1950 400 ~ ~\ 200 \ © 28-31 weeks * NG » er £ 100 * \ £ 80 *, 32-35 \ a + weeks ® % 2 60 * ” * Oo * So * o 40 * -t *~ 3 *, a * 37 weeks and over 2 “e co 3 x 20 * * 3 * * + * * *% 10 * +. * . “eae, "a 4 4. L 1 1 1 do ho dg do ho A es ow in on no Of HO o8 on oN on AH YN RO ow aoe HN NN NN NN NM oon BIRTH WEIGHT (in grams) SOURCE: U.S. Public Heaith Service, National Center for Health Statistics (103). Recent Studies The Ontario Perinatal Mortality Study (66, 67) was conducted among 10 teaching hospitals during 1960 and 1961. In this retrospee- tive study of 51.490 pregnancies, a statistically significant increase in the perinatal mortality rate was demonstrated for smokers’ in- fants as compared with those of nonsmokers; the infants of smokers experienced an overall relative risk of 1.27 (P<0.001). Moreover, the investigators found a statistically significant dose-response relationship between the amount of cigarettes smoked and the perinatal mortality rate (P<0.001) (fig. 7). 128 Figure 7.—Perinatal mortality rate per 1,000 total births by cigarette smoking category. 2 t 40 F 2a ‘s 3 33.4 ° 8 307 27.7 ZZ 5 23.2 CL) Qa g CL) C4) 8 oy L CL) CA) 2 Ld CO) § CL CL) ° E CZ) CL) 5 10+ Z 4 ZA a £ 0 LZ Zo Nonsmoker <1 pack of 21 pack of cigarettes cigarettes per day per day Number of perinatal deaths: 659 425 220 Total births: 28,358 15,328 6,581 (P <0.001) SOURCE: Ontario Department of Health (66). Recently Butler, et al. (75) further analyzed the British Perinatal Mortality Study. They found a highly significant association between maternal smoking after the fourth month of pregnancy and both late fetal and neonatal deaths. Infants of smokers had an increase in the late fetal mortality rate of 30 percent, and an increase in the neo- natal mortality rate of 26 percent, compared to the infants of non- ‘mokers. The overall mortality ratio of late fetal plus neonatal deaths Vas 1.28 (P< 0.001). Given the large number of women in the study, ‘nd the significant changes in smoking behavior which occurred, they found it possible to consider the effect of a change in smoking 129 behavior between the beginning of pregnancy and the fourth month on late fetal and neonatal mortality. A statistically significant and dose-related increase in mortality occurred among the infants ot mothers who continued to smoke after the fourth month of pregnancy, as compared with the infants of nonsmokers and those of women who smoked prior to the pregnancy but gave up smoking by the fourt), month of gestation. Niswander and Gordon (63) reported data from the prospective Collaborative Perinatal Study of the National Institute of Neurologi. cal Disease and Stroke. The 39,215 pregnancies registered at 12 unj. versity hospitals in the United States were almost equally divided between black and white women. They found a nonsignificant INCrease in perinatal mortality among the infants of white smokers as compared to those of white nonsmokers; the overall mortality ratio was 1.13 (P>0.1). The infants of black smokers, however, had a significantly higher mortality risk than did those of black nonsmokers; the mor- tality ratio was 1.18 (P<0.02). Moreover, a definite dose-response re. lationship between cigarettes smoked by pregnant mothers anq mortality risk was shown for black infants. Black women were noted to smoke significantly fewer cigarettes, on the average, than white women. Rush and Kass (82) found, in a prospective study of 3.276 preg- nancies followed at Boston City Hospital, a nonsignificant increase in late fetal plus neonatal mortality rate among the infants of white women who smoked as compared to those of white nonsmokers, How- ever, the infants of black women who smoked had a statistically sig- nificant increase in mortality rate compared to the infants of black nonsmokers (P<0.01). The overall] mortality ratio for black women who smoked was 1.86. The difference in frequency of stillbirth among the infants of smokers and nonsmokers was the primary factor which contributed to the significance of the difference in mortality rates, Analysis of Previously Reported Studies Previously reported studies can be divided into two groups: A group in which the late fetal plus neonatal mortality rates for infants born to cigarette smokers were significantly higher than those for the infants born to nonsmokers, and a group in which no significant differences were detected in the mortality rates for the infants born to smokers and nonsmokers. The results of several studies (74. 17, 25. 42, 43, 55, 84, 92) yielded mortality ratios ranging from 1.38 to 1.78 The results of other studies (20, 65. 76. 85, 100, 115) yielded mortality ratios ranging from 1.01 to 1.06, Both groups contained retrospective and prospective studies of comparable size. The two groups did differ 130 significantly, however, with regard to control of variables other than vigarette smoking which influence perinatal mortality. Factors Which Influence Perinatal Mortality Other Than Smoking Butler and Alberman (73), on data from the British Perinatal Mortality Study, employed a logit transformation analysis of variance, and demonstrated that maternal height, age, parity, social class, and ~vere preeclampsia all had a significant independent effect on late fetal and neonatal mortality. Rumeau-Roquette (87) provided evi- dence that a previous stillbirth or low-birth-weight infant significantly increased the risk of a future stillbirth. Meyer and Comstock (5/) provided examples of how the differential distribution of smoking and other factors which are related to perinatal mortality, in a population of women, can bias data (e.g., black women have higher perinatal nortality rates than do white women, but black women smoke less than white women do. Hence. nonsmokers will tend to include more ‘lack women, and smokers more white women. This will tend to reduce any differences between the groups in mortality rates.) Meyer and Comstock concluded, “Comparisons of mortality rates of smokers’ and nonsmokers’ babies should be made within subgroups according 'o parity, socioeconomic status, and other appropriate risk factors, and not separated by birth weight.” In three of the studies in which a significantly higher mortality risk was demonstrated for the infants of smokers, adjustment for other variables was performed. The results indicated that, after such ad- justment, a significant independent association between cigarette smoking and infant mortality persisted (13 and 15, 17, 8&1). Of the studies which revealed no significant increase in mortality risks for smokers’ infants, one (115) controlled for race alone. Hence, at. least part of the discrepancy in results between the two groups of studies may be explained by a lack of control of variables other than smoking. Another possible, at least partial, explanation of the discrepancy in results obtained by the two sets of studies is that cigarette smoke may be more harmful to the fetuses of certain women than others. Several] developing lines of evidence suggest that this may be the case: I. Cigarette smoking and socioeconomic background. Butler, et al. (25) noted that when data from the British Perinatal Mortality Study are grouped by social class of the mother’s husband, the late fetal plus neonatal mortality ratio for infants of smokers and tonsmokers in the upper social classes I and IT is 1.10; the mortality ratio for the entire sample was 1.28. Rush and Kass (82) reviewed the British Perinatal Mortality Study, along with several other studies, and noted that all have shown the strongest association between excess Infant mortality and cigarette smoking among the infants of those 495-028 O—73—_10 131 mothers with lower Socioeconomic status, Comstock and Lundin (16 found excess mortality among smokers’ infants almost entirely cop. fined to those whose fathers had a grammar school education or legs, Several of the studies which revealed no significant, difference in mor. tality among the infants of smokers and nonsmokers were conducteg in predominately middle class populations (29, 100,115). 2. Cigarette smoking and previous obstetrical experience, Peterson, et al. (72) had rigid criteria for entry into his study population of 7,740 women. He included only those women who pre. viously had healthy infants with a birth weight greater than 2509 grams. He found a significant decrease in birth weight among smokers’ with increased risk of a future stillbirth, 3. Cigarette smoking and genetic differences, duce enhanced risk (82, 99, 115). Available evidence Suggests that. if those women, who are already likely to have small infants for reasons other than smoking, smoke during pregnancy, their infants will be most unfavorably affected This means that the women in the United States whose infants will be most affected by cigarette smoking are those who have an unfavor- able socioeconomic situation, have a history of previously unsuccessft] pregnancies, and are black. ExprertMenrar STuprIEs Studies in Animals Studies previously reviewed in the 1971 and 1979 reports on the health consequences of smoking (107, 102) demonstrate that exposure of rabbits and rats to tobacco smoke and to injections of large doses of nicotine resulted in significantly increased late fetal and neonatal mortality. Astrup (2) has recently studied the effect of continuous exposure of pregnant rabbits to carbon monoxide on stillbirth rates, He found a Significantly higher, dose-related incidence of stillbirths and deaths within the first 94 hours of life among the offspring of the experimental rabbits (table 4). 132 TaBLe 4.—E fect of carbon monoride exposure of pregnant rabbits on birth weight and neonatal mortality Group 1, Group 2, Group 3, 0 percent 8tol0 percent 16 to 18 percent COHDb COHb COHb Number of pregnant rabbits.___________ 17 14 17 Total number of babies... 116 81 123 Stillborn and babies died within first 24 hours___ 2-2 ry 28 344 (P<0.001) 1] percent. “10 percent. 436 percent. Source: Astrup, P. (2). Studies in Humans Some investigators have examined the causes of death among the infants of smokers as compared with those of nonsmokers. Comstock, etal. (77) found that infants of smokers died more frequently of as- phyxia, atelectasis, and immaturity. Kullander and Kallen (43) found ubruptio placentae significantly increased as a cause of death among smokers’ infants. Butler and Alberman (74) found little difference in the death rates for the infants of smokers and nonsmokers from iso- immunization and malformations, but higher rates were found for ‘mokers’ infants in the groups in which death occurred before or dur- ing labor, or in which death resulted from massive pulmonary hemor- thage, or pulmonary infection. As the authors noted, “The latter three ‘re conditions known to be associated with small-for-dates babies.” They pointed out that distribution of causes of death in the smoking Troup could be accounted for almost entirely by the excess of low-birth- weight babies. This su pports the conclusion that the mechanism which iflects birth weight also influences mortality. SIGNIFICANCE OF THE ASSOCIATION The following calculation is offered to give some idea of the order of Magnitude of increased late fetal and neonatal mortality associated “ith cigarette smoking during pregnancy. If women who smoked dur- 133 ing pregnancy in the United States had an elevation in risk of 28 per. cent for late fetal and neonatal mortality, as demonstrated by Butler, etal. (75) for Britain, Scotland, and Wales, and if 20 percent of pregnant women smoked throughout the pregnancy,’ the higher ris, of stillbirth and neonatal death for the infants of mothers who smoke cigarettes during pregnancy would account for approximately 4,600 of the 87,263 stillbirth and neonatal deaths in the United States in 196g Late Ferau anp NEONATAL DeatH Summary A strong, probably causal association between cigarette smoking and higher late fetal and infant mortality among smokers’ infants is supported by the following evidence: 1. Twelve retrospective and prospective studies have revealed a sta. tistically significant relationship between cigarette smoking and an elevated mortality risk among the infants of smokers. In three of these studies, of sufficient size to permit adjustment. for other risk factors, a highly significant independent association between smokng and mortality was established. Part of the discrepancy in results between these studies and those in which a significant association between smoking and infant mortality was not dem. onstrated may be explained by a lack of adjustment for risk fac- tors other than smoking. 2. Evidence is converging to suggest that cigarette smoking may be more harmful to the infants of some women than others; this may also, in part, explain the discrepancies between the results of the studies in which a significantly higher mortality risk was shown for the infants of smokers compared to those of nonsmokers and the results of those studies in which significant differences in mortality risk were not found. 3. Within groups of similar birth weight, the infants of nonsmokers appear to have a higher mortality risk than do the infants of ciga- rette smokers. This results from the fact that the infants of non- smokers within such similar birth weight groups are on the average gestationally less mature than the infants of cigarette smokers. Available evidence indicates that within groups of sim- iar gestational age, infants of lower birth weight experience a higher mortality risk. Since the infants of cigarette smokers are + Based on extrapolation of data on smoking behavior change during pregnancy from the British Perinatal Mortality Study. which probably yields a conservative estimate. 134 small-for-gestational age, one should expect that if the infants of cigarette smokers and nonsmokers are compared within similar gestational age classes, the infants of cigarette smokers would have the higher mortality rate. . The results of recent studies have documented a statistically sig- nificant dose-response relationship between the number or amount of cigarettes smoked and late fetal and neonatal mortality. . New data suggest that if a woman gives up smoking by the fourth month of pregnancy, she will have the same risk of incurring a fetal or neonatal loss as a nonsmoker. . Available evidence strongly supports cigarette smoking as one cause of fetal growth retardation. The causes of excess deaths among the infants of smokers are those associated with small- for-dates babies. - Data from experiments in animals have demonstrated that expo- sure to tobacco smoke or some of its ingredients, such as nicotine or carbon monoxide, results in a significant increase in late fetal and or neonatal deaths. - The results of studies in humans have shown that the fetus of a smoking mother may be directly exposed to agents such as carbon monoxide within tobacco smoke, at levels comparable to those which have been shown to produce stillbirth in experimental animals, Sex Ratio Although a number of small studies have found a slight, usually statistically nonsignificant, increase in the proportion of female infants born to smokers, the three largest studies of Underwood, ct al. (48,505 Pregnancies), Butler (15,791 pregnancies), and MacMahon (12,155 pregnancies) have found similar infant sex ratios among both smok- ing and nonsmoking mothers, with the expected slight excess of males among each (table). Summary Available evidence strongly indicates that maternal cigarette smok- ing does not influence the sex ratio of newborn infants. 135 TABLE 5.—Proportion of male infants delivered to smoking and non. smoking mothers Proportion of male infants Statistical Author, reference Pregnancies ———-_~_____. significance Smokers Non- smokers Underwood, et al. (100)_.. .____________ 48, 505 . 518 -519 None. Butler and Alberman (14)___.__________ 15, 791 . 518 . 516 Do. MacMahon, et al. (49)_____..__________ 12, 155 . 913 . 512 Do. Kullander and Kallen (43)____________. 6, 363 . 515 . s0L Do. Reinke and Henderson !(78)___.________ 3, 156 . 498 - 517 Do. Frazier, et al.! (25)... 2 2,915 . 472 . 505 Do. (P>0.05) Kizer (42)_._-.. 2222 2, 095 . 502 . 493 None. Herriott, et al. (88)_.-22 2-2 2, 745 . 492 517 Do. Ravenholt, et al (77)_-....-___-_________ 2, 052 - 501 . 533° P<0.05 Lowe (46)_____-__-- ee 2, 042 . 532 . 529 None. Russell, et al. (88).__-..___ 2-8. 2, 002 . 613 . 012 Do. ' Black women. Congenital Malformations Previous epidemiological studies which examined the relationship between cigarette smoking and congenital malformations were te- viewed in the 1971 and 1972 reports on the health consequences of smoking (101, 102). Recently, the authors of the Ontario Perinatal Mortality Study (66, 67), a retrospective study of 51,490 births, re- ported no difference in malformation rate for the infants of smokers and nonsmokers. The various studies of the association between ciga- rette smoking and congenital malformation have differed significantly with regard to study design. the type of population sampled. sample size and number of infants with malformations, the definition of mal- formation, and results (table 6). Previous experimental work was reviewed in the 1971 and 1972 reports on the health consequences of smoking (/0/, 102). The chick embryo has been employed in recent studies. The direct application of nicotine to the embryo results in cephalic hematomas (26). malforma- tions of the cervical vertebrae (93), and anomalies of the heart (27), depending upon dose of nicotine and period of incubation in which exposure occurs. Anomalies of the limbs of chicken embryos can also be induced by exposure of the egg to high levels of carbon monox- ide (4). TABLE 6.—Helative risk of congenital malformation for infants of cigarette smokers and nonsmokers, comparing available studies with regard to study design, study population, sample size, number of infants with malformations, and definition of malformation Infants Relative Author, Study design Study population Sample with risk Definition of reference size malfor- SM/NS malformations mations Lowe (46). ....... Retrospective. Stillborn plus 24-hour 2, 042 23 1.36 Major. deaths. Comstock, etal. _.._- do._....... Neonatal deaths..__.._ 236 37 -31 Major, cause of (17). death. Yerushalmy (172). Prospective... Infants less than 695 59 57 Major. 2,500 g. Ontario Depart- —- Retrospective. Stillborn plus Ist- 51, 490 1, 744 97 ment of Health week deaths plus 6), surviving infants. Butlerand Al- LL _. do._....... Stillborn plus neo- 7, 123 1, 382 1.19 Major, cause of berman (/4). natal deaths. death. (a) Stillborn plus neo- 137 43 1.25 natal deaths Kullander and Prospective. __ plus ainder Major and minor Kallen (43). er deaths to age malformations. (b) Surviving infants 4, 903 700 1.06 to age 1. (a) 1 Stillborn plus 17, 418 86 £55 (4). neonatal deaths t and deaths to Fedrick, et al. Retrospective. age 7,1 sur- (4), vivors 2 to age (b) Neonatal deaths t 7, 822 204 1.07 (). (3-month study). ' Autopsy-proven congenital cardiac malformation. * Clinically determined congenital heart disease. Congenital Malformation Sum mary Given the considerable variation in study design, study population, Sample size, number of affected infants, definition of malformation, and results, no conclusions can be drawn about any relationship between maternal cigarette smoking the present time. and congenital malformation at 137 Lactation Introduction The following section is a review of available evidence which bears upon any interaction between cigarette smoking and lactation. Empha. sis is placed upon the relationship of cigarette smoking to the quantity of milk produced, to the presence of constituents of cigarette smoke within the milk, and to effects upon the nursing infant mediated through changes in either the quantity of milk available or the sub. stances within the milk. Epidemiological Studies Underwood, et al. (99), in a study of 2,000 women from various social and economic strata, observed a definite but statistically insig- nificant trend toward more frequent inadequacy of breast milk pro- duction among those smoking mothers who attempted to nurse compared to nonsmokers. Mills (52), in a study of 520 women, found that among women who indicated either a desire to nurse or no desire to nurse yet continued to nurse beyond 10 days, and who had delivered their first live-born infant, the average pericd of nursing for mothers who smoked was significautly shorter than for nonsmokers. Moreover, among the 24 mothers who had given up smoking during at least the final 3 months of their pregnancies, the average length of nursing was identical to that of the nonsmokers. There was no significant difference between smokers and nonsmokers with regard to complete inability to nurse their offspring. This study is difficult to interpret because the author did not determine the reason(s) for the discontinuation of nursing among the women. Experimental Studies Stvupres 1x ANIMALS Nicotine Influence on the Lactation Process Blake and Sawver (77) studied the influence of subcutaneously injected nicotine (4 mg. total over a 5-minute period) upon lactation in the rat. They found that nicotine inhibited the suckling-induced 138 rise in prolactin. No effect of injected nicotine was demonstrated for oxytocin secretion since milk release was not blocked. Wilson (770) examined the effects of nicotine supplied through drinking water (0.5, 1.0. and 2.0 mg. daily) on the weight gain of nursing rats. Apparently. the nicotine had been available throughout gestation as well. because the author commented on a reduction in litter size among the experimental groups. more or less proportionate to the dose of nicotine; hence, a prenatal effect could not have been dis- tinguished from a postnatal one. Average birth weight was similar for experimental and control groups. No difference in weight gain was seen for any of the groups. The lack of impact on birth weight suggests that dose was lower than that used in other studies. Presence of Nicotine in the Milk Hatcher and Crosby (32), using a frog bioassay, reported traces of nicotine in cow’s milk 24 hours after the intramuscular injection of 0 mg./kg. and 5 hours after the injection of 0.5 mg./kg. Evidence for an Effect Upon the Nursing Offspring Hatcher and Crosby (32). found that 0.5 mng./kg. nicotine injected into nursing cats had no apparent harmful effect upon the kittens. Apparently 4.0 mg./kg. suppressed lactation. Kittens fed the milk from the cow which had been injected with 5.0 mg./kg. nicotine were also apparently unaffected. Nitrosamines Mohr (53) found that diethylnitrosamine and dibuty]nitrosamine, when administered to lactating hamsters, were associated with the development of typical tracheal papillary tumors in the young, sug- gesting passage of these compounds in‘the milk. Although diethyl- Nitrosamine and dibutylnitrosamine have not been identified in ciga- rette smoke, many N-nitrosamines are potent carcinogens, and some of them are present in cigarette smoke (37, 79). Stupres 1x Humans Nicotine and/or Tobacco Smoke Influence on the Lactation Process Emanuel (22) noted no reduction in milk production among 10 wet hurses who were encouraged to smoke seven to 15 cigarettes daily; 139 Some were observed to inhale the smoke. Hatcher and Crosby (32) noted that after a mother smoked seven cigarettes within 2 hours, it was difficult to obtain a specimen of breast milk. Perlman, et al. (71) found that of 55 women smokers with an adequate milk supply at the beginning of his study, 11 (20 percent) of the women had an Inade- quate supply at the time of discharge from the hospital. No relation. ship was reported between the number of cigarettes smoked and the likelihood of developing an inadequate milk supply. The authors’ im- pression was that there was no greater proportion with an inadequate milk supply among smokers than among nonsmokers, but no cor. roborating data were supplied. Presence of Nicotine in the Milk Hatcher and Crosby (32) found, using a frog bioassay, that the milk of a woman collected after she had smoked seven cigarettes in 9 hours contained approximately 0.6 mg./liter nicotine. Emanuel (22), using a leech bioassay, studied excretion of nicotine in the milk of wet nurses who were encouraged to smoke for the experiment. After the subjects had smoked six to 15 cigarettes over a 1- to 2-hour period, the author found nicotine in their milk 4 to 5 hours after smoking, with a maximum concentration of 0,03 mg./liter. Bisdom (70) demonstrated nicotine in the milk of a mother who smoked 20 cigarettes a day, Thompson (97) found approximately 0.1 mg./liter of nicotine in the milk of a mother who smoked nine cigarettes a day (plus three pipe- fuls). Perlman, et al. (71), using a Daphnia bioassay, demonstrated nicotine in the milk of all women who smoked in their study. Moreover, they found a direct dose-relationship between concentration of nicotine and the number of cigarettes smoked. No comment is made by the authors on the possible inaccuracy introduced by examining only the residual milk following nursing, but it is well known that the composi- tion of the fore milk and hind milk is different and perhaps the concentration of nicotine also differs. Evidence for a Clinical Effect Upon the Offspring Emanuel (22) noted that among the infants in his study, loose stools were observed only in the one whose wet nurse had smoked 20 ciga- rettes in the previous 4 hours. Bisdom (20) observed a case of “nico- tine poisoning” in a 6-week-old infant whose mother smoked 20 ciga- rettes a day. The symptoms included: restlessness, vomiting, diarrhea. and tachycardia. Nicotine was demonstrated in the milk, and the symptoms abated when smoking was stopped. Greiner (30) also de- scribed a case of possible nicotine poisoning in a 3-week-old nursling 140 whose mother smoked 35 to 40 cigarettes a day. The symptoms included vomiting and loose stools. Following the curtailment of smoking, the symptoms gradually abated over a 3-day period. Perlman, et al. (77) noted no effect of smoking on the weight gain of the infants of the smokers in their study. Furthermore, no untoward symptoms were observed. They therefore doubted an effect of smoking on lactation. They noted that the dose received by the infants was beneath the toxic level as computed from adult experience, and this accorded with their clinical observations. The fact that they admitted to the study only women with an apparently adequate milk supply may have affected their results. The authors suggested that perhaps the lack of effect of smoking upon lactation might represent the development of tolerance to nicotine, as both the mother and the offspring had been exposed throughout the pregnancy. VITAMIN C Venulet (105, 106, 107), in a series of studies, demonstrated that the level of vitamin C was reduced in the milk of smoking mothers as compared with nonsmokers. The clinical significance of this observa- tion has not been evaluated. Lactation Summary 1. The two pertinent epidemiological studies suggest. a possible in- fluence of smoking upon the adequacy of milk supply However, with only limited numbers of women and without control of other potentially significant variables, no conclusions can be drawn. 2. Studies in rats have demonstrated that nicotine can interfere with suckling-induced rise in prolactin. The relevance for humans is uncertain. 3. Evidence exists that nicotine passes into breast milk. No clear evidence for an acute effect upon the nursing infant is available. Potential chronic effects haye not been studied. 4. New evidence from experiments with mice suggests that. nitros- amines, known carcinogens, pass through the milk to suckling young. 141 Preeclampsia Previous epidemiological studies of the relationship between cig arette smoking and preeclampsia were reviewed in the 1971 and 1979 reports on the health consequences of smoking ( 101, 102) and form the basis of the following statements: The results of several large prospective and retrospective Studies indicate a statistically significant lower incidence of Preeclampsia among smoking women (14, 43, 100). The results of one large retro. Spective study demonstrated a significant inverse relationship between the incidence of preeclampsia and the number of cigarettes smoked (100). When other risk factors, such as parity, social class, maternal weight before the pregnancy, and maternal] weight gain during the Scotland (14, 41, 46, 83), The United States (100, 118), Venezuelg (42), and Sweden (43). If a maternal smoker does develop preeclamp. sia, however, available data suggest that her infant has a higher mor. tality risk than does the infant of a nonsmoker with preeclampsia (21, 83), Summary 1. Available evidence indicates that maternal] cigarette smoker have a significantly lower risk of developing preeclampsia as compared to nonsmokers, 2. Ifa woman who smokes cigarettes during pregnancy does develop preeclampsia, her infant has-a higher mortality risk than the infant of a nonsmoker with preeclampsia. Pregnancy References (1) ABERNATHY, J. R., GREENBERG, B. G., WELLs, H. B., Frazier, T ¥ Smoking as an independent variable in a multiple regression analrsis upon birth weight and gestation. American Journal of Public Health an: the Nation’s Health 56 (4): 626-633, April 1966. (2) AsTrRup, P. Pathologische Wirkungen missiger Kohlenmonoxid-Konzer. trationen. (Pathological effects of moderate carbon monoxide concentr: tions. ) Staub-Reinhaltung der Luft 32(4) - 146-150, 1972. . (3) Barey, R. R. The effect of maternal smoking on the infant birth weigh New Zealand Medical Journal 71 (456) : 293-294, May 1970. 142 4) ws (6) 7 (8 oS 10 Ht) 112) 13 119) Baker, F. D., Tumasonis, C. F. Carbon monoxide and avian embryo- genesis. Archives of Environmental Health 24(1) : 53-61, January 1972. Baripaud, L., Yacous, M., Faure, J., Manas, Y., Cau, G. L’oxyacar- bonémie de l'enfant né de mere fumeuse. (Presence of carbon monoxide in the blood of a child born of a smoking mother.) Medecine Legale et Dommage Corporel 3(3): 272-274, July-August-September 1970. Bea, V. A. Nutritional studies during pregnancy. Journal of the Ameri- can Dietetic Association 58(4): 321-326, April 1971. Becker, R. F., Kine, 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. Becker, R. F., Lirtie, C. R. D., Kine, J. E. Experimental studies on nicotine absorption in rats during pregnancy. IIT. Effect of subcutaneous injection of small chronic doses upon mother, fetus, and neonate. Ameri- can Journal of Obstetrics and Gynecology 100(7) : 957-968, Apr. 1, 1968. Becker, R. F., Martin, J. C. Vital effects of chronic nicotine absorption and chronic hypoxic stress during pregnancy and the nursing period. American Journal of Obstetrics and Gynecology 110(4) : 522-533, June 15, 1971. Bispom, C. J. W. Alcohol and nicotine poisoning in infants (sucklings), Maandschrift voor Kindergeneeskunde 6: 332-341, 1937. Brake, C. A., Sawyer, ©. H. Nicotine blocks the suckling-induced rise in circulating prolactin in lactating rats. Science 177(4049) : 619-621, Aug. 18, 1972. Buncuer, C. R. Cigarette smoking and duration of pregnancy. American Journal of Obstetrics and Gynecology 103(7) : 942-946, Apr. 1, 1969. BuTLer, N. R., ALBERMAN, E. D. (Editors), Perinatal Problems. The Sec- ond Report of the 1958 British Perinatal Mortality Survey. London, E. and 8. Livingstone, Ltd., 1969, 395 pp. Butter, N. R., ALBERMAN, E. D. (Editors). The effects of smoking in nregnancy, Chapter 5. In: Perinatal Problems. Edinburgh, E. and S. Livingstone, Ltd., 1969, pp. 72-84. Butter, N. R., GOLDSTEIN, H., Ross, E. M, Cigarette smoking in preg- hancy: Its influence on birth weight and perinatal mortality. British Medical Journal 2: 127-130, Apr. 15, 1972. Comstock, G. W., Lunoin, F. E., Jr. Parental smoking and perinatal mortality. American Journal of Obstetrics and Gyncology 98(5) : T08- 718, July 1, 1967. Comstock, G. W., Snag, F. K., Meyer, M. B., AxBEy, H. Low-birth weight and neonatal mortality rate related to maternal smoking and socio- economic status. American Journal of Obstetrics and Gynecology 111(1) : 53-59, Sept. 1, 1971. Conney, A. H., WetcH, R., KuntzMan, R., Cuane, R., Jaconson, M., MUNROFAURE, A. D., PEck, A. W., Byer, A., PoLaNnp, A., Poppers, P. J., FINsSTerR, M., Wotrr, J. A. Effects of environmental chemicals on the Metabolism of drugs, carcinogens, and normal body constituents in man. Annals of the New York Academy of Sciences 179: 155-172, July 6, 1971. DoMaeara, J., DomMacata, L. Zachowanie sie wagi urodzeniowej oraz czestose wystepowania wezesniactwa I wad wrodzonych u noworodkow kobiet palacych tyton. (Birth weight and incidence of prematurity and congenital anomalies in newborns of mothers smoking tobacco.) Pedi- atria Polska T. 47(6) :735-738, 1972. 143 (26) Downine, G. C., CHapMan, W. E. Smoking and pregnancy. A Statistica, study of 5,659 patients. California Medicine 104(3): 187, March 1968, (21) Durrus, G. M., MacGuiuivray, I. The incidence of preeclamptie toxaemig in smokers and nonsmokers. Lancet 1(7550) : 994-995, May Hi, 1968 (22) Exanuer, W. Uber das Vorkommen von Nicotin in der Frauenmile), nach Zigarettengenuss. (On the presence of nicotine in breast milk fo). lowing the use of cigarettes.) Zeitschrift fiir Kinderheilkunde 52: 47. 46, 1931. (23) Essenperc, J. M., Scuwinp, J. V., Patras, A. R. The effects of nicotine and cigarette smoke on pregnant female albino rats and their offspringy Journal of Laboratory and Clinical Medicine 25: 708-717, 1940. (24) Feprick, J.. ALBERMAN, E. D., GotpsteIn, H. Possible teratogenic effect of cigarette smoking. Nature 231: 529-580, June 25, 1971. (25) Frazier, T. M., Davis, G. H. Gotpsrern, H., Goupsrre, I. D. Cigarette smoking and prematurity: A prospective study. American Journal of Obstetrics and Gynecology 81(5) : 988-996, May 1961. (26) GaTLine, R. R. Effect of nicotine on chick embryo. Archives of Pathology 78: 652-657, December 1964. (27) Giant, S. H. Nicotine and cardiogenesis. An experimental study. Patho}. ogia et Microbiologia 37(5) : 883-392, 1971. (28) Gotpstrrn, H., Goupserc, I. D., Frazier, T. M., Davis, G. E. Cigarette smoking and prematurity. Journal of the American Osteopathic Aggy. ciation 64: 541-549, January 1965. (29) Govsarp, J., Errenng, C., Evranp, F. Caracteristiques maternelles et Doids de naissance. (Maternal characteristics and birth weight.) Revue dy Praticien 19(28, Supplement) : 54, 59-62, 65, Nov. 1, 1969. (36) Grerner, I. Nikotinvergiftung, beobachtet bei einem Saugling. (Nicotine poisoning observed in a breast feeding infant.) Jahrbuch fiir Kinder. heilkunde 146: 131-132, 1936. (31) Happon, W., Jr., Nespit, R. E. L., Garcra, R. Smoking and pregnancy Carbon monoxide in blood during gestation and at term. Obstetrics and Gynecology 18(3) : 262-267, September 1961. (32) Hatcner, R. A., Crospy, H. The elimination of nicotin in the milk. Journal of Pharmaceutical and Experimental Therapy 32(1): 1-6, 1927. (33) Hawortu, J. C., Forp, J. D. Comparison of the effects of maternal under. nutrition and exposure to cigarette smoke on the cellular growth of the rat fetus. American Journal of Obstetrics and Gynecology 112(5) : 633. 656, Mar. 1, 1972. (34) Heron, H. J. The effects of smoking during pregnancy: A review with: preview. New Zealand Medical Journal 61: 545-548, November 1962. (35) Herriorr, A., BILLewicz, W. Z., Hytren, F. E. Cigarette smoking in preg. nancy. Lancet 1: 771-773, Apr. 14, 1962. (36) Jarviney, P. A., OSTERLUND, K. Effect of smoking during pregnancy or. the fetus, placenta and delivery. Annales Paediatriae Fenniae 9: 18-24. 1963. (37) Jounson, D. E., RHoapes, J, W. N-nitrosamines in smoke condensat: from several varieties of tobacco. Journal of the National Cancer I: stitute 48(6) : 1845-1847, June 1972. (38) JvcHav, M. R. Human placental hydroxylation of 3,4-benzpyrene during early gestation and at term. Toxicology and Applied Pharmacolog: 18(3) : 665-675, March 1971. (39) Kerry, C. H., Tesu, P. G. Measurement of the total smoke issuing fres a burning cigarette. Tohacco 160(15) : 26-29, Apr. 9, 1965. 144 (49 149) (50) (51) (52) 56) 37) (38) (59 Kine, J. E., Becker, R. F. Studies on nicotine absorption during pregnancy. I. LDso for pregnant and nonpregnant rats. American Journal of Ob- stetrics and Gynecology 95(4): 508-514, June 15, 1966. KirascuBzaum, T. H., Dirts, P. V., Jr, BRINKMAN, C. R., III. Some acute effects of smoking in sheep and their fetuses. Obstetrics and Gynecology 35(4) : 527-536, April 1970. Kizer, 8. 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): 595-643, 1967. KULLANDER, S., KALLEN, B. A prospective study of smoking and pregnancy. Acta Obstetricia et Gynecologica Scandinavica 50(1) : 88-04, 1971. Kumar, D., Zourtas, P. A. Studies on human premature births. II. In vivo effect of smoking and in vitro effect of nicotine on human uterine contractility. American Journal of Obstetrics and Gynecology 87(3): 413-417, Oct. 1, 1963. 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, Oct. 5, 1970. Lowe, C. R. Effect of mothers’ smoking habits on birth weight of their children, British Medical Journal 2: 673-676, Oct. 10, 1959. McDonaup, R. L., Lanrorp, C. F. Effects of smoking on selected clinical obstetric factors. Obstetrics and Gynecology 26(4) : 470-475, October 1965. McGarry, J. M., ANDREWs, J. Smoking in pregnancy and vitamin Buy metabolism. British Medical Journal 2: 74-77, Apr. 8, 1972. MacManon, B., ALPERT, M., Satper, E. J. Infant weight and parental smoking habits. American Journal of Epidemiology 82(3) : 247-261, November 1965. MAanTELL, C. D. Smoking in pregnancy : The role played by carbonic anhy- drase. New Zealand Medical Journal 638: 601-603, September 1964. Meyer, M. B., Comstock, G. W. Maternal cigarette smoking and perinatal mortality. American Journal of Epidemiology 96(1): 1-10, July 1972. Mitts, C. A. Tobacco smoking: Some hints of its biologic hazards. Ohio State Medical Journal 46(12) : 1165-1170, December 1950. Mogg, U., ALTHOFF, J. Carcinogenic activity of aliphatic nitrosamines via the mother’s milk in the offspring of Syrian Golden hamsters. Proceed- ings of the Society for Experimental Biology and Medicine 186(3) : 1007-1009, March 1971. MUKHERJEE, S., MUKHERJEE, E. N. A study of premature births. Indian Journal of Pediatrics 38(285) : 389-392, October 1971. Mutcany, R., Kwaces, J. F. Effect of age, parity, and cigarette smoking on outcome of pregancy. American Journal of Obstetrics and Gynecology 101(6) : 844-849, July 15, 1968. Murcany, R., Mureuy, J. Maternal smoking and the timing of delivery. Journal of the Irish Medical Association 65(7) : 175-177. Apr. 1. 1972. Mvtcany, R., Morpuy, J., Martin, F. Placental changes and maternal weight in smoking and nonsmoking mothers. American Journal of Ob- stetrics and Gynecology 106(5) : 703-704, Mar. 1, 1970. Muorpocn, D. E. Birth weight and smoking. Nebraska State Medical Jour- nal 48(11) : 604-606, November 1963. Murpnty, J. F., Mutcany, R. The effect of age, parity, and cigarette smok- ing on baby weight. American Journal of Obstetrics and Gynecology 111(1) : 22-25, Sept. 1, 1971. 145 (60) Natt, J. F. Complexed cyanide in collected cigarette smoke. Abstracts of 20th Tobacco Chemists’ Research Conference, Nov. 1-3, 1966, Winston. Salem, N.C., 1966, pp. 26-27. (61) NeEBErt, D. W., Winker, J., GeLporn, H. V. Aryl hydrocarbon hydroxylase activity in human placenta from cigarette smoking and nonsmoking women. Cancer Research 29(10) : 1763-1769, October 1969. (62) Newsome, J. R., Norman, V., Kerry, C. H. Vapor phase analysis of tobac. co smoke. Tobacco Science 9: 102-110, July 28, 1965. (63) Niswanpber, K. R., Gorpon, M. Section 1. Demographic characteristics Cigarette smoking. In: The Women and Their Pregnancies. The Col. laborative Perinatal Study of the National Institute of Neurological Dig. eases and Stroke. Philadelphia, W. B. Saunders Co., 1972, pp. 72-89. (64) Norman V., Newsome, J. R., Kerry, C. H. Smoking machines for the analysis of the vapor phase of cigarette smoke. Tobacco Science 12. 216-221, 1968. . (65) O’LaNe, J. M. Some fetal effects of maternal cigarette smoking. Obstetrics and Gynecology 22(2) : 181-184, August 1963. (66) ONTARIO DepaRTMENT oF HEALTH. Second Report of the Perinatal] Mor. tality Study in Ten University Teaching Hospitals. Toronto, Canada, Ontario Department of Health, Ontario Perinatal Mortality Study Com. mittee, vol. 1. 1967, 275 pp. (67) ONTARIO DEPARTMENT OF HEALTH. Supplement to the Second Report of the Perinatal Mortality Study in Ten University Teaching Hospitals. Toron. to, Canada, Ontario Department of Health, Ontario Perinatal Mortality Study Committee, vol. IT, 1967, pp. 95-275. (68) Osnorne, J. S., ADAMEK, S., Hopgs, M. E. Some components of gas phase of cigarette smoke. Analytical Chemistry 28(2) : 211-215, February 1956 (69) OUNSTED. M. Maternal constraint of foetal growth in man. Develc pmenta! Medicine and Child Neurology 7: 479-491, October 1965. (70) PaLMcREN, B., WALLANDER, B. Cigarettriékning och abort. Konsekutiy Pros. pektiv undersékning av 4312 graviditeter. (Cigarette smoking and abor. tion. Consecutive prospective study of 4,312 pregnancies.) Likartti¢. ningen 68(22): 2611-2616, May 26, 1971. (71) PertMan, H. H., DANNENBERG, A. M., SoKOLOFF, N. The excretion of nicotine in breast milk and urine from cigarette smoking. Journal of the Americar Medical Association 120(13) : 10038-1009, Nov. 28, 1942. (72) Prrerson, W. F., Moress, K. N., KatTreiper, 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. (73) PEtersson, F. Medicinska skadeverkningar av roékning. Rékning och by. nekologisk-obstetriska tillstand. (Harmful clinical effects of smoking Smoking and gynecological-obstetrical condition.) Social-Medicinsk Tidskrift 2 (Special No.) : 78-82, February 1971. (74) Puivippr, R. J., Hopss. M. E. Some components of the gas phase «f cigarette smoke. Analytical Chemistry 28(12): 2002-2005, Decenitw: 1956. (75) Primrose. T.. Hicerns, A. A study in human antepartum nutritior Journal of Reproductive Medicine 7(6) : 257-264, December 1971. (76) RanTaKaLiio, P. Groups at Risk in Low Birth Weight Infants and Perins tal Mortality. A prospective study of the biological characteristics and socioeconomic circumstances of mothers in 12,000 deliveries in Nert!. Finland 1966. A discriminant function analysis. Acta Paediatric: Scandinavica (Supplement 193) : 1969, 71 pp. 146 vn 7 7) 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, Sept. 15, 1966. (78) REINKE, W. A., HENDERSON, M. Smoking and prematurity in the presence of other variables Archives of Environmental Health 12(5): 600-606, May 1966. (79) Ruoapes, J. W., Jounson, D. E. Method for the determination of N-nitro- sSamines in tobacce-smoke coudensate, Journal of the National Cancer Institute 48(6) ; 1841-1843, June 1972, (84) Ropinson, P.-‘Yshwn nshym Bwrinmywt yzmn bbhrywn whshp'tw ‘] h’m I’whr whylwd. (Smoking by Burmese women during pregnancy and its influence on the mother, the fetus and the newborn.) Harefuah 60 (2) : 87-39, 1965. (81) RUMEAU-ROUQUETTE. C., Govsarp, J., KAaMINSKI, M., Scuwartz, D. Mortalite perinatale en relation avec les antecedents obstetricaux et Vusage du tabae, (Perinatal mortality in relation te obstetric antecedents and tobaceo usage.) Paper presented at the Third European Congress of Perinatal Medicine, Lausanne, Apr. 14-22, 1972, 8 pp. (82) Rusu, D., Kass, BE, H. Maternal smoking: A reassessment of the associa- tion with perinatal mortality. American Journal of Epidemiology 96(3) : 183-196, September 1972. (83) Russet, C. S.. Taytor, R.. Law. C. FE. Smoking in pregnancy, maternal blood pressure, pregnancy outcome, baby weight and growth, and other related factors, A prospective study. British Journal of Preventive and Social Medicine 22 (3) - 119-126, July 1968. 'S4) Russett, C. S., TAyor, R., Mappisox, R. N. Some effects of smoking in pregnancy. Journal of Obstetries and Gynecology of the British Common- Wealth 73 : 742-746, October 1966. (85) Saver, L. E,, Rotu, E. Effects of smoking in pregnancy: A continuing retrospective study. Obstetrics and Gynecology 20(3) : 818-316, Septem- ber 1962. (86) SCHLEDE, E., MERKER, H.-J. Effect of benzo(a)pyrene treatment on the benzo(a)pyrene hydroxylase activity in maternal liver, placenta, and fetus of the rat during day 13 to day 18 of gestation. Naunyn-Schmiede- berg's Archives of Pharmacology 272(1) : 89-100, Dee. 21, 1971. (a?) ScHOENECK, F. J. Cigarette snioking in pregnancy. New York State Journal of Medicine 41: 1945-1948, Oct. 1, 1941. (88) ScoprpeTTA, V. Sul contenuto di ossido di carbonio nel sangue circolante di gestauti fumatrici. (Carbon monoxide content in the blood circulating in pregnant smokers.) Archivio di Ostetricia e Ginecologia 73(3) : 369- 375, May—June 1968. (89) SIEBER, S. M.. Farro, &. Identification of drugs in the preimplantation blastocyst and in the plasma, uterine secretion and urine of the pregnant rabbit. Journal of Pharmacology and Experimental Therapeutics 176(1) : 65-75, 1971. '10) Stupsox, 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. ny Spears, A. W., RottH. W. E. A combined approach to the quantitative analysis of the violatile components of cigarette smoke. Paper presented at the 18th Tobacco Chemists Research Conference, Raleigh, N.C, 1964, 495-028 0.—73-———11 147 (92) SreeLe, R., Lancwortn, J. T. The relationship of antenatal and post. natal factors to sudden unexpected death in infancy. Canadian Medical Association Journal 94; 1165-1171, May 28, 1966. (93) StrupeL, G. Action tératogene du sulfate de nicotine sur Vembryon de poulet. (Teratogenic action of nicotine sulphate on chick embryo, ) Comptes Rendus Hehdomadaires des Seances de !Acadamie des Sciences: T): Sciences Naturelles 272 (4) : 673-676, Jan. 25, 1971. (94) SuzuxKr, K., Horicucnt, T.. Comas-Urrutia, A. C., MUELLER-HEUBACH, E., Morisuima, H. O., Apamsons, K, Pharmacologic effects of nicotine upon the fetus and mother in the Rhesus monkey, American Journal] of Obstetrics and Gynecology 111(8) : 1092-1101, Dee. 15, 1971. (95) Terris, M., Gorn, FE. M. An epidemiologic study of prematurity, T. Relation to smoking, heart volume, employment, and physique. American Journal of Obstetrics and Gynecology 103 (3) : 358-370, Feb. 1, 1969. (96) TuiENes, C. H. Lomparp, C. F., Frerpine, F. J., Lesser, A. J., Evrey. HoRN, M. J, Alterations in reproductive functions of white rats asso- ciated with daily exposure to nicotine, Journal of Pharmacology and Experimental Therapeutics 87: 1-10, 1946. (97) THompson, W. B. Nicotine in breast milk. American Journal of Obstetrics and Gynecology 26 : 662-667, 1933. (98) TIALVE, H., Hansson, E., SCHMITERLOW, C. G. Passage of “C-nicotine and its metabolites into mice foetuses and placentae. Acta Pharmacologica et Toxicologica 26(6) : 589-555, 1968. (99) UNDERWoop, P. B.. Hester, L. L., LAFITTE, T., Jr., Greco, K. V. The relation. ship of smoking to the outcome of pregnancy, American Journal of Obstetrics and Gynecology 91(2) : 270-276, Jan. 15, 1965. (1090) UNbDERWoop, P. B., Krsier, K. F., O’LANE, J. M., CaLiacan, D. A. Parental smoking empirically related to pregnancy outcome. Obstetrics and Gynecology 29(1) : 1-8, January 1967. (701) U.S. Pusric Hearty Service. The Health Consequences of Smoking. A Report of the Surgeon General: 1971. Washington, U.S. Department of Health, Education, and Welfare, DHEW Publication No. (HSM) 71-7513, 1971, 458 pp. (102) U.S. Pupric HeaitH Service. The Hea!th Consequences of Smoking, A Report of the Surgeon General: 1972. Washington, U.S. Department of Health, Education, and Welfare, DHEW Publication No. (ASM) 72-7516, 1972, 158 pp. (103) U.S. Pusric HeartH Service. NatIONAL CENTER FOR HEALTH STATISTICS, Weight at birth and survival of the newborn—United States, early 1950. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1000, Series 21, No, 3, July 1965, 33 pp. (104) Vara, P., Kinnunex, O. The effect of nicotine on the female rabbit and developing foetus. An experimental study. Annals Medicinae Experi- mentalis et Biologica Fenniae 29 : 202-231, 1951, (105) Venutet, F. Nastepstwa niedoboru witaminy ¢ u palaczy. (Consequences of vitamin C deficiency in smokers.) Polskie Archiwum Medycyns Wewnetrznej 26 : 393-402, 1956. (106) VENULET, F., Lausz, HW. Ubytek witaminy c w narzadach zab poddanrch dzialaniu dymu tytoniowego. (Influence of tobacco smoke on ascorbic acid content in mothers’ milk.) Acta Physiologica Polonica 4(4) :351- 356, 1954. (107) Venuter, F., Danysz, A. Wplyw palenia tytoniu na poziom witaminy ¢ mleku Kobiecym. (The influence of tobacco smoking on the level cf vitamin C in human milk.) Pediatria Polska 30(9) : 811-817, 1955. 148 (108) 1109) 10) (111) (712) (173) tty) ' HLS) WIG) '117}) (118) WELCH, R. M., Goauy, B., ALVARES. A. P., Connxey, A. H. Effect of enzyme induction on the metabolism of benzo(a)pyrene and 3-methyl-4- monomethylaminoazobenzene in the pregnant and fetal rat. Cancer Re- search 82(5) : 973-978, May 1972 WELCH, R. M., Harrison, Y, E., Gomur, B. W., Poppers, P. J., FINSTER, M., Conney, A. H, Stimulatory effect of cigarette smoking on the hydroxyla- tion of 3.4-benzpyrene and the N-demethylation of 3-methyl-4-mono- methylaminoazohenzene by enzymes in human placenta. Clinical Phar- macology and Therapeutics 10(1) : 100-109, January-February 1969, Witson, E. W. The effect of smoking in preguaney on the placental coeffi- cient, New Zealand Medical Journal 74(475) : 8384-885, 1979, Wynprr, E. L., Horrmany, D. Tobacco and Tohaceo Smoke. Studies in Experimental Carcinogenesis. New York, Academie Press, 1967, 730 pp. YERUSHALMY. J. Infants with low-birth weight born before their mothers started to smoke cigarettes. Alerican Journal of Obstetrics and Gyne- cology 112(2) : 277-Ps4. Jan. 15, 1972. YERUSHALMY, J. Mother's cigarette smoking and survival of infant. Ameri- can Journal of Obstetrics and Gynecology S8(4): 505-518, Feb. 15, 1964, YERUSHALMY, J, Statistical considerations and evaluation of epidemiologi- cal evidence. In: James, G., Rosenthal, T. (Editors). Tobaceo and Health. Springfield, Charles C. Thomas, 1962, pp. 208-230, YERUSHALMY, J. The relationship of parents’ cigarette smoking to outcome of pregnancy—implications as to the problem of inferring causation from observed associations, American Journal of Epidemiology 93 (6) : 443- 456, June 1971, Younoszal, M. K., Kacic, A.. Hawortn, 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, Aug. 3, 1968. Younoszal, M, K., PEtoso, J.. Haworrn, J. C, Fetal growth retardation in rats exposed to cigarette smoke during pregnancy. American Journal of Obstetrics and Gynecology 104(8) : 1207-1213, Aug. 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. 149 CHAPTER 5 Peptic Ulcer Disease Contents Page Iroduction..-. 2 eee 155 Epidemiological and Clinical Studies... 155 Experimental Studies Gastric Seeretion-.- 2 157 Pancreatic Secretion... 159 summary of Recent Peptic Ulcer Disease Findings. .________ 162 References. — es 163 List of Figures Figure 1.—Gastric ulcer mortality ratios of Japanese (men and “omen combined) by age at initiation of cigarette smoking (1966-70) = eee 156 Figure 2.—Effect. of cigarette smoking on volume of secretin- stimulated pancreatic secretion in humans.......... 160 Figure 3.—Effect of cigarette smoking on secretin-stimulated pancreatic bicarbonate output in humans__-.-- 161 Introduction Previous epidemiological and experimental studies of the relation- ship between cigarette smoking and peptic ulcer disease were reviewed in the 1971 and 1972 reports on the health consequences of smoking (17, 78) and form the basis of the following summary : The results of epidemiological studies indicate that cigarette smok- ing males have an increased prevalence of peptic ulcer disease and a greater mortality from peptic ulcer as compared to nonsmoking males. Among males, the association between cigarette smoking and peptic ulcer disease is stronger for gastric than for duodenal ulcer, but sig- nificant for both. For males, cigarette smoking appears to reduce the effectiveness of standard peptic ulcer treatment and to slow the rate of peptic ulcer healing. The relationship between cigarette smoking and the prevalence of and mortality from peptic ulcer disease is less clear for females than for males. Experimental studies of the effect of cigarette smoking in man, and of the effect of injection and infusion of nicotine in animals, on gastric secretion and motility have produced conflicting results. In dogs, an infusion of nicotine has been found to inhibit. pancreatic and hepatic bicarbonate secretion, thus demonstrating a possible link between cigarette smoking and duodenal ulcer. Recently, additional epidemiological, clinical, autopsy, and experi- mental studies have confirmed the association between cigarette smok- ing and gastric ulcer mortality and have clarified a mechanism through which cigarette smoking might be linked to duodenal ulcer. Epidemiological and Clinical Studies Previous studies of the relationship between peptic ulcer disease and “ivarette smoking have been conducted in predominantly white, West- *'n populations. A large prospective epidemiological study is currently being conducted in Japan. From this study, Hirayama (6) reported Year followup data on 265,118 men and women, aged 40 years and older, representing 91 to 99 percent of the total population in the area of the 29 health districts in which the study was conducted. Both male 155 and female cigarette smokers experienced higher death rates from gastrie leer as compared with nonsmokers. The mortality ratio for cigarette smokers was 181 for males (P<0.001) and 2.15 for females (P<0.05). The mortality ratio for smokers (males and females con. bined) was dose-dependent as measured by age at initiation of smoking (tig. 1). The results of this study, in the context of the genetic and cu). tural differences between Japanese and Western populations, provide a significant confirmation of the association between cigarette smoking and eastrie ulcer mortality. Figure 1.—Gastric ulcer mortality ratios of Japanese (men and women combined) by age at initiation of cigarette smoking (1966-1970). 5.00 ——_, 4.00 + 2 ge 3.00 2.67 £ g iY) GS 2.00 F = 1.59 a “i 1.00 } 2°00 CL “i Z 0 Lo GY VI V4 Nonsmoker >25 <24 <19 Age at initiation of cigarette smoking (years) SOURCE: Hirayama, T. (6). 156 Alp, et al. (7) conducted a retrospective survey of 638 patients, admitted to two Australian teaching hospitals between 1954 and 1963, with chronic gastric ulcer confirmed by roent genographie, endoscopic, or surgical examination. The findings in the patients were compared with information available about the South Australian population obtained at census in 1954 and 1961, and with a control group of 233 subjects matched for age and sex with the ulcer patients. Cigarette use, a family history of peptic ulcer, domestic stress, and aspirin and alcohol intake occurred significantly more frequently among ulcer patients. Alp, et al. (2) found that after surgical treatment, recurrence of the ulcer was significantly more likely to recur among those patients who continued to smoke, drink, and use aspirin (P<0.001). Fingerland, et al. (5) compared the autopsy findings from 765 males with their smoking history. The autopsies were performed without selection during 1965 and 1966 at the University of Hradec Kralové, Czechoslovakia. Peptic ulcer was significantly more frequent among male ex-smokers and male lifelong smokers than among male non- smokers (P<0.02). Among males, a dose-response relationship was found between estimated total cigarette consumption and the presence of peptic ulcer at autopsy. Cooper and Tolins (4) reported results from a retrospective study of the relationship between cigarette smoking and postoperative com- plications among 2,988 males, admitted to 19 Veterans Administration hospitals, for the surgical treatment of duodenal ulcer. Smoking his- tory was obtained for 1,441 of the men, and of these 273 were non- smokers, 1,018 smoked cigarettes only, and 93 smoked cigarettes plus a pipe and/or cigars. The authors found no evidence of an association between either the number of cigarettes smoked per day, or the number of years of cigarette smoking, and postoperative complications, opera- tive mortality, or length of hospital stay. They emphasized that their results must be viewed with considerable caution and listed several potential sources of bias. In addition, they noted, “* * * that these results apply only to the immediate postoperative findings and do not apply to the long-range effects of smoking upon the patient after Surgery for duodenal ulcer disease.” Experimental Studies Gastric Secretion Strupres 1s Humans Morales, et al. (10, 11) studied the effect of cigarette smoking on £astric secretion in a group of 312 patients. The patients included 138 157 with duodenal ulcer, 93 with gastric ulcer, and 81 with other gastro. intestinal disorders, who served as controls. Cigarette smoking was significantly more frequent among the patients with peptic ulcer than among the controls. The chronic effect of smoking on gastric secretion was quite variable, Male smokers among the controls and in the group with duodena] ulcers had a significantly increased baseline acid output as compared with nonsmokers in the same groups (P<0.05). After a subcutaneous injection of histamine, only the group of male smokers with gastric ulcers had a significant increase in acid output over the values obtained for nonsmokers in the same group (P<0.05). Among the smokers in the control group, the relationship between gastric acid output and the number of cigarettes smoked daily was dose dependent. No such rela- tionship was obtained for either of the two groups with peptic ulcers, In these experiments, the acute effect of smoking on gastric secre- tion was slight. In one set of experiments, a group of eight smokers served as its own control. The smoking of two cigarettes prior to collection of gastric juice had no significant effect on acid output as compared to baseline values. After smoking two cigarettes and also receiving a subcutaneous injection of histamine, the patients experi- enced no significant change in gastric acid output as compared to baseline values; 21 male patients, including members from the groups with ulcers and controls, smoked one cigarette 1 hour after an intra- venous infusion of histamine. A transient depression of gastric acid output was noted as compared with the yalues obtained from nine patients who did not smoke. Stepies iw ANTrALs Konturek. et al. (8) studied the effect of intravenous infusion of nicotine on the formation of acute, experimental duodenal ulcers in cats. The authors infused nicotine intravenously in doses comparable to the smoking of four, eight. and 16 cigarettes per hour into cats in whom near maximal gastric acid output had been stimulated with intravenous pentagastrin. The investigators found that nicotine in the two lower doses had no effect upon the gastric acid output stimulated by pentagastrin, but that the highest dose produced a significant de- crease in response, due to a fall in both volume and acid concentration. Nicotine alone failed to alter a negligible basal gastric secretion. In control animals (pentagastrin alone), duodenal ulcers were found in eight of 10 animals. Nicotine at the two lower doses, in combination with pentagastrin, produced ulcers in all 26 animals, At the inter- mediate dose of nicotine, the mean ulcer area was twice that found in 158 the control group. At the highest dose of nicotine. peptic ulcers ap- peared in only two of six animals and the area of ulcer was reduced compared to controls. Shaikh, et al. (74) studied the acute and chronic effects of sub- cutaneously injected nicotine on gastric secretion in rats. Under basal conditions, the volume of gastric secretion was initially depressed, then stimulated, and depressed again as the dose of nicotine was increased. Acid output was decreased over the entire range of nicotine dosage. Pepsin output reflected a similar triphasic response to in- creasing nicotine doses as did gastric secretory volume. In the absence of nicotine, pentagastrin stimulated gastric volume, acid, and pepsin output. The injection of micotine. in increasing doses, administered simultaneously with pentagastrin. resulted in a gradual decrease in response for all parameters. Volume of gastric juice, acid output, and pepsin output were all increased significantly by chronic exposure to nicotine alone. Based on an average smoking dose of nicotine, the dose of nicotine employed in the chronic experiments corresponded to the smoking of three to five cigarettes per day. Thompson, et al. (76) extended the study of rats described above by studying the effects of chronic nicotine injections in vagotomized rats and rats with discrete lesions in the hypothalanius, In sham- operated animals, chronic nicotine injections significantly increased baseline volunie of gastric juice, acid output, and pepsin output. Fol- lowing vagotomy, the nicotine response was completely suppressed. Caudal hypothalamic lesions did not influence the response to nicotine in the presence of intact vagus nerves. Anterior hypothalamic lesions, Tanging from the anterior hypothalamic area to the ventromedial hypothalamus, blocked the nicotine-induced gastric secretory stimula- tion in the presence of intact vagi. The authors concluded that chronic nicotine-induced gastric secretory stimulation is mediated via anterior hypothalamic activation and intact vagus nerves. The importance of local effects remained uncertain. Panereatic Secretion Stupres in Humans Bynum, et al. (3) studied the effect of cigarette smoking upon pan- creatic secretion in 23 healthy young males and females, Five control male nonsmokers were compared with seven male and two female light Smokers (less than one pack of cigarettes per day for less than 3 years) and eight male and one female heavy smokers (more than one pack of 159 cigarettes per day for more than 3 years). Pancreatic secretion Was measured by the double secretin test, using Boots secretin. The exper. ment was divided into two parts for the smokers: A basal collection period and an experimental period during which the subjects smoked seven nonfiltered cigarettes at the rate of four per hour. Light smokers had basal values for pancreatic secretory volume and bicarbonate oyt. put in response to secretin which were not significantly different from controls, After the subjects had smoked, significant depression of both pancreatic volume and_ bicarbonate output was noted (P<.001), Heavy smokers had basal values that were significantly less than in the control subjects (P<0.01). Smoking, however, did not further depress the response to secretin (figs. 2 and 3). Solomon and Jacobsen (15) reviewed some possible mechanisms whereby the increased prevalence and mortality from duodenal ulcer among cigarette smokers might be produced. They concluded that evidence from studies in animals, coupled with the findings of Bynum, et al. (3), supported the hypothesis that the mechanism active in humans involves impaired neutralization of acid secondary to the inhibition of pancreatic bicarbonate secretion. Figure 2.—Effect of cigarette smoking on volume of secretin-stimulated Pancre- atic secretion in humans. 3.0 2.9 2.4 Mean volume 2.5 of 1.97 2.0 pancreatic 2.0 fluid in 1.5? milliliters 1.5 per kilogram body weight 1.9 0.5 Oo i J mw 2 g 2 2 = a a oa a cE 285 85 8 Gj 8&5 6 0 ar “a+ vo -« G > < = ~ s g wd aj xr Ir ‘Significantly different from nonsmoking test within group of light smokers (P <0.001) 3 Significantly different from nonsmoking controls (P <0.01). SOURCE: Bynum, et al. (3). 160 Figure 3.—Effect of cigarette smoking on secretin-stimulated pancreatic bicar- bonate output in humans. 12 11.5 10 8.4 8.1 Mean hourly 8 7.1? output of ia ald 6 5.5? milliequiva- 4 lents per hour 2 0 4 se fs Bs Fo BS 5 & 5 wt £ 5 835 $&§ 3835 #6 S E Ew E> E> 6 Oo z = 3 S z Pm CD ? as °s —_ aad r zr ' Significantly different from nonsmoking test within group of light smokers (P <0.001). Significantly different from nonsmoking controis (P <0.01). SOURCE: Bynum, et al. (3). STuDIEs In ANIMALS Konturek, et al. (7) extended his research on the mechanism of nicotine-induced inhibition of pancreatic secretion in the dog, using the design previously employed (9). Infused secretin alone led to a sustained increase in pancreatic bicarbonate output. Intravenous nico- tine, at all four doses of infused secretin, produced a significant in- hibition of pancreatic volume and bicarbonate output (P<0.05). Infused nicotine appeared to inhibit competitively the effect of secre- tin on pancreatic secretion of fluid and bicarbonate. Topical (intraduo- denal) nicotine failed to affect significantly the response to infused secretin, Stimulation of endogenous secretin by an acid infusion into the duodenum produced the expected pancreatic secretory response. Nicotine either applied to the duodenal mucosa or injected intra- venously significantly inhibited the pancreatic secretory response to endogenous secretin. Nicotine had no significant effect on total pancrea- tie protein output. Nicotine did not alter the cholecystokinin-induced stimulation of pancreatic secretion. The authors concluded that nico- tine may inhibit pancreatic secretion of fluid and bicarbonate both 161 by a direct effect on pancreatic secretory mechanisms, acting as a com- petitive inhibitor of secretin, and by a secondary effect on the duodena] mucosa. depressing the endogenous release of secretin by acid. Robert (/2) studied the potentiation of active duodenal ulcers by nicotine administration in the rat. Subcutaneous infusion of pentagas. trin and carbachol resulted in the dose-dependent formation of duo. denal ulcers within 24 hours. Nicotine alone produced no ulcers, Increasing doses of subcutaneously infused nicotine, in combination with the other two agents, resulted ina steadily increasing dose-related incidence and severity of the duodenal ulcers. Robert noted that Konturek, et al. (9) found that nicotine inhibited pancreatic and biliary bicarbonate secretion in dogs, and that Thompson, et al. (16) found that acute doses of nicotine in rats either depressed or did not alter gastric secretion, He concluded that the most probable mechanism by which nicotine potentiated acute duodenal ulcer formation in the rat was via a suppression of pancreatic secretion. Robert, et al. (13) further tested this hypothesis by infusing acid via the esophagus of rats in doses found to cause duodenal ulcers in one-third of the experimental animals. One group of rats also received a subcutaneous infusion of nicotine. Another received nicotine, but only water was infused via the esophagus; 31 percent of the animals receiving acid but no nicotine had duodenal ulcers; 93 percent of the nicotine-acid group had duodenal ulcers, while none of the nicotine. water group had ulcers. The ulcers in the nicotine-acid group were more numerous, extensive, and deeper than those in the animals which received actd alone. Summary of Recent Peptic Uleer Disease Findings Tn addition to the findings relating cigarette smoking to peptic ulcer disease, summarized in previous reports on the health consequences of smoking (7, 28) and cited in the introduction to this chapter, recent stiulies have contributed further to our understanding of the USssochit or: L. The finding of a significant dose-related excess mortality from gastric ulcers among both male and female Japanese cigarette smokers, in a large prospective study, and in the context of the genetic and cultural differences between the Japanese and pre- viously investigated Western populations, confirms and extends the association between cigarette smoking and gastric ulcer inortality. 162 bo (3) 4 ~~ on (6) (8) (9) (10) (12) . Data from experiments in several different animal species sug- gest that nicotine potentiates acute duodgnal ulcer formation by means of inhibition of pancreatic bicarbonate output. . Cigarette smoking has been demonstrated to inhibit pancreatic bicarbonate secretion in healthy young men and women. Peptic Ulcer Disease References ALP, M. H., Hisxop, I. G., Grant, A. K. Gastrie ulcer in South Australia, 1954-63. 1. Epidemiological factors, Medical Journal of Australia 2(24) : 1128-1132, Dec. 12, 1970. ALP, M. H., Hisxop, I. G., Grant, A. K, Gastric ulcer in South Australia, 1954-638. 2. Symptomatology and response to treatment. Medical Journal of Australia 1(7) ; 372-374, Feb. 13, 1971. Bynum, T. E.,, Sotomon, T. E., JoHNson, L. R., Jacopson, E, D. Inhibition of pancreatic secretion in muan by cigarette smoking. Gut 13(5): 361-365, May 1972, Cooper, P., ToLrns, 8, H. Relationship between smoking history and compli- cations immediately following surgery for duodenal ulcer. Mount Sinai Journal of Medicine 39(3) > 287-292, May-June 1972. ) FINGERLAND, A., Husak, T., BENbDLova, J, Contribution to the investigation of the effect of cigarette smoking. Sbornik Vedeckych Praci Lekarske Fakulty Karlovy University v Hradci Kralové 14(2) : 221-234, 1971, Hirayama, T. Smoking in relation to the death rates of 265,118 men and women in Japan. A report of 5 years of followup. Presented at the Amer- ican Cancer Society’s 14th Science Writers’ Seminar, Clearwater Beach, Fla., Mar, 27, 1972, 15 pp. Konturek, 8. J., Date, J., Jaconson, EB. D., Jounson, L. R. Mechanisms of nicotine-induced inhibition of pancreatic secretion of bicarbonate in the dog. Gastroenterology 62(3) : 425-429, 1972. Kontrurek, S. J., RavEck1, T., THor, P., DEMBINSKI, A., JAcoBson, E. D. Effects of nicotine on gastric secretion and ulcer formation in cats. Pro- ceedings of the Society for Experimental Biology and Medicine 138 (2): 674-671, November 1971. Konturek, 8. J., SoLomon, T. E., McCreteut, W. G., JoHNSoN, L. R,, Jacosson, E. D. Etiects of nicotine on gastrointestinal secretions. Gastro- enterology 60(6) : 1098-1105, June 1971. Mopars, A., Sitva, S., ALCALDE, J., WaISSBLUTH, J., Ramos, J., Bey, H,, Sanz, R. Cigarrillo y secrecion gustrica. I. Analisis de la secreci6n gdstrica en pacientes digestivos fumadores y no fumadores. (Cigarettes and gastric secretion, I. Analysis of gastric seeretion in smoking and non- smoking ulcer patients.) Revista Medica de Chile 99(4}) > 271-274, April 1971. Moraes, A,, SILVA, S., Osorio, G., ALCALDE, J., WalsssLutu, J. Cigarrillo y secrecion gastrica. II. Efecto del cigarrillo sobre la secrecién gastrica. (Cigarettes and gastric secretion, IL. Effect of cigarettes on gastric secre- tion.) Revista Medica de Chile 99 (4) : 275-279, April 1971. 495-025 O-—73 12 163 (72) Rogert, A. Potentiation, by nicotine, of duodenal ulcers in the rat. Pro. ceedings of the Society for Experimental Biology and Medicine 139(1): 319-322, January 1972. (13) Rosert, A., Stowr, D. F., NeEzaMis, J. E. Possible relationship between smoking and peptic ulcer. Nature 238 (5320) : 497-498, Oct. 15, 1971. (14) Suarixu, M. 1. Tuompson, J. H., Aures, D. Acute and chronic effects of nicotine on rat gastric secretion. Proceedings of the Western Pharma- cology Society 13: 178-184, 1970. (15) SoLomon, T. E., Jacopson, E. D. Cigarette smoking and duodenal-uleer dis. ease. New England Journal of Medicine 286 (22) : 1212-1213, June 1, 1972, (16) Tiiompson, J. H., Grorce, R., ANGULO, M. Some effects of nicotine on gastric secretion in rats. Proceedings of the Western Pharmacology Society 14: 173-177, 1971. (77) U.S. Pusric Hearty Service, The Health Consequences of Smoking. A Re port of the Surgeon General : 1971. U.S. Department of Health, Education, and Welfare. Washington, DHEW Publication No. (HSM) 71-7513, 1971, 458 pp. (178) U.S. Pustic HEaLrH SERVICE, The Health Consequences of Smoking. A Report of the Surgeon General : 1972. U.S, Department of Health, Eduea- tion, and Welfare. Washington, DHEW Publication No. (HSM) 72-6516, 1972, 158 pp. 164 CHAPTER 6 Pipes and Cigars Contents Introduction.....--------- The Prevalence of Pipe, Cigar, and Cigarette Usage__.._..___ The Definition and Processing of Cigars, Cigarettes, and Pipe Tobaccos..-_--.-- 2-2 Chemical Analysis of Cigar Smoke Mortality Overall Mortality_.-....... 22222 Mortality and Dose-Response Relationships Amount Smoked Inhalation._.________-_ ee Specific Causes of Mortality Caneer__.___-. 2. Cancer of the Lip Oral Cancer_____-.___ eee Cancer of the Larynx.____._-___._._____________.. Cancer of the Esophagus Lung Caneer_.__.__- 2-2 Tumorigenic Activity Experimental Studies Chronic Obstructive Pulmonary Disease (COPD) Gastrointestinal Disorders Little Cigars Conclusions References List of Figures Figure 1.—Inhalation among pipe smokers by age___________ Figure 2.—Inhalation among cigar smokers by age—Ham- mond... -- 222-28 Figure 3.—Depth of inhalation among cigarette smokers by age—Hammond_.____-___._-_-2.--.-__ Figure 4.—Percent distribution of 130 brands of cigarettes and 25 brands of little cigars by tar content Page 171 173 175 177 179 180 183 189 189 190 191 193 197 203 210 210 215 216 222 222 229 230 Figure 5.—-Percent distribution of 130 brands of cigarettes and 25 brands of little cigars by nicotine content List of Tables Table 1.—Percent distribution of U.S. males aged 21 and older by type of tobacco used for the years 1964, 1966, and 1970__ Table 2.—Percent distribution of U.S. males by type of tobacco used and age for 1970___2.--2 02 Table 3.—Percent distribution of British males aged 25 and older by type of tobacco used for the years 1965, 1968, and 1971 - Table 4.—Amounts of several components of 1 gram of par- ticulate material from mainstream smoke of tobacco prod- ucts. Table 5.—-A comparison of several chemical compounds found in the mainstream smoke of cigars, pipes, and cigarettes____ Table 6.—-Mortality ratios for total deaths by type of smoking (males only) -. 2-22-22. Table 7.—Mortality ratios for total deaths of cigar and pipe smokers by amount smoked—Hammond and Horn________ Table 8.—Mortality ratios for total deaths of cigar and pipe smokers by amount smoked—Best.......__...-6--. Table 9.—Mortality ratios for total deaths of cigar and pipe smokers by age and amount smoked—Kahn_____________. Table 10.—Mortality ratios for total deaths of cigar and pipe smokers by amount smoked—Hammond______.___._____. Table 11.—The extent of inhaling pipes, cigars, and cigarettes by British males aged 16 and over in 1968 and 1971______. Table 12.—Inhalation among cigar, pipe, and cigarette smokers by age—Doll and Hill.---2222-2 - Table 13.—Mortality ratios for total deaths of cigar and pipe smokers by age and inhalation—Hammond___...__._____. Table 14.—Percentage of British male cigar smokers who re- ported inhaling a lot or a fair amount by type of product smoked. _- 22-8 Table 15.—Percentage of individuals reporting inhalation of “almost every puff’ of tobacco smoke by current and pre- vious tobacco usage and tvpe of tobacco used___. Table 16.— Percentage of British males who reported inhaling a lot or fair amount of cigar smoke by current and previous tobacco usage and type of tobacco previously smoked (1968) - 168 Page 226 173 174 174 178 180 18} 181 188 188 Table 17.—Extent of reported inhalation of cigar smoke by British male cigar smokers who were ex-cigarette smokers in 1968, analyzed by extent of reported inhalation of cigarette smoke when previously smoking cigarettes__......._._____. Table 18.—Mortality ratios for total cancer deaths in cigar and pipe smokers. A summary of prospective epidemiological studies. - 22 Table 19.—Relative risk of lip cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies.__.___---2 2 Table 20.—Mortality ratios for oral cancer in cigar and pipe smokers. A summary of prospective epidemiological studies __ Table 21.—Relative risk of oral cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A sum- mary of retrospective studies.__.____.________._...____. Table 22.—Mortality ratios for cancer of the larynx in cigar and pipe smokers. A summary of prospective epidemiological studies... Table 23.—Relative risk of cancer of the larynx for men, com- paring cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies....._____.....______. Table 24.—Mortality ratios for cancer of the esophagus in cigar and pipe smokers. A summary of prospective epidemio- logical studies.--__._--_. 2-28 Table 25.—Relative risk of cancer of the esophagus for men, comparing cigar, pipe, and cigarette smokers with non- smokers. A summary of retrospective studies......___..___. Table 26.—Mortality ratios for lung cancer deaths in male cigar and pipe smokers. A summary of prospective studies____ Table 27.—Lung cancer death rates for cigar and pipe smokers by amount smoked—Doll and Hill___........... Table 28.—Iung cancer mortality ratios for cigar and pipe smokers by amount smoked—Kahn._______...__..._____. Table 29.—Relative risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies....___.___....__._____. Table 30.—Changes in bronchial epithelium of male cigar, pipe, and cigarette smokers as compared to nonsmokers____ Table 31.—Tumorigenic activity of cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals__ Table 32.—Mortality ratios for cardiovascular deaths in male cigar and pipe smokers. A summary of prospective epi- demiological studies Page 189 189 192 193 194 196 198 200 201 204 204 205 206 209 213 216 169 Table 33.—Mortality ratios for chronic obstructive pulmonary deaths in male cigar and pipe smokers. A summary of pros- pective epidemiological studies......-.2.------ Table 34.—Prevalence of respiratory symptoms and illness by type of smoking_..---- 222 Table 35.—Pulmonary function values for cigar and pipe smokers as compared to nonsmokers..._..________._.____ Table 36.—Mortality ratios for peptic ulcer disease in male cigar and pipe smokers. Summary of prospective studies___ Table 37.—Shipment of small and large cigars destined for domestic consumption (1970, 1971, 1972)__-__. Table 38.—Selected compounds in mainstream smoke________ Table 39.—The pH of the mainstream smoke of selected tobacco products 170 Pag Introduction This chapter is a review of the epidemiological, pathological, and experimental data on the health consequences of smoking cigars and pipes, alone, together, and in various combinations with cigarettes. Previous reviews on the health consequences of smoking have dealt primarily with cigarette smoking. Although some of the material on pipes and cigars presented in this chapter has been presented in previ- ous reports of the Surgeon General, this is the first attempt to summa- nize what is known about the health effects of pipe and cigar smoking. Since the use of pipes and cigars is limited almost exclusively to men inthe United States, only data on men are included in this review, The influence of pipe and cigar smoking on health is determined by examining the overall and specific mortality and morbidity ex- Perienced by users of these forms of tobacco compared to nonsmokers. Epidemilogical evidence Suggests that individuals who limit their smoking to only pipes or cigars have overal] mortality rates that are slightly higher than nonsmokers. For certain specific causes of death, however, Pipe and cigar smokers experience mortality rates that are *S great as or exceed those experienced by cigarette smokers, This analysis becomes more complex when combinations of smoking forms ire examined, The overall mortality rates of those who smoke pipes, ‘gars, or both in combination with cigarettes appear to be inter- mediate between the high mortality rates of cigarette smokers and the lower rates of those who smoke only pipes or cigars. This might Seem to suggest that smoking pipes or cigars in combination with ciga- rettes diminishes the harmful effects of cigarette smoking. However, ‘nanalysis of mortality associated with smoking combinations of ciga- rettes, pipes, and cigars should be standardized for the level of con- sumption of each of the products smoked in terms of the amount ‘moked, duration of smoking, and the depth and degree of inhalation. or example, cigar smokers who also smoke a pack of cigarettes a day might be expected to have mortality rates somewhat higher than those tho smoke only cigarettes at the level of a pack a day, assuming that th groups smoke their cigarettes in the same way. Mixed smokers ho inhale pipe or cigar smoke in a manner similar to the way they ‘noke cigarettes might be expected to have higher mortality rates ‘han mixed smokers who do not inhale their cigars and pipes and also wl 171 resist inhaling their cigarettes, Unfortunately, little of the publisheq material on mixed cigarette, pipe, and cigar smoking contains these types of analyses or controls. A paradox seems to exist between the mortality rates of ex-smokers of pipes and cigars and ex-smokers of cigarettes, Ex-cigarette smokers experience a relative decline in overall and certain specific causes of mortality following cessation. This decline is important but indirect evidence that cigarette smoking is a major cause of the elevated mor. tality rates experienced by current cigarette smokers. In contrast to this finding, several prospective epidemiological investigations, Hammond and Horn (40), Best (9), Kahn (40), and Hammond (38), have reported higher death rates for ex-pipe and ex-cigar smokers than for current pipe and cigar smokers. This phenomenon was ana- lyzed by Hammond and Garfinkel (39). The development of ill health often results in a cigarette smoker giving up the habit, reducing his daily tobacco consumption, switching to pipes or cigars, or choosing a cigarette low in tar and nicotine. In many instances, a smoking. related disease is the cause of ill health, Thus, the group of ex-smokers includes some people who.are ill from smoking-related diseases, and death rates are high among persons in ill health. As a result, ex-cigarette smokers initially have higher overall and specific mortality rates than continuing cigarette smokers, but be- cause of the relative decrease in mortality that occurs in those who quit smoking for reasons other than ill health, and because of the dwindling number of ill ex-smokers, a relative decrease in mortality is observed (within a few years) following cessation of cigarette smoking. The beneficial effects of cessation would be obvious sooner were it not for the high mortality rates of those who quit smoking for reasons of illness. A similar principle operates for ex-pipe and ex- cigar smokers, but because of the lower initial risk of smoking these forms and therefore the smaller margin of benefit following cessation, the effect produced by the ill ex-smokers creates a larger and more persistent impact on the mortality rates than is seen in cigarette smoking. For the above reasons a bias is introduced into the mortality rates of current smokers and ex-smokers of pipes and cigars, so that a more accurate picture of mortality might be obtained by combining the ex-smokers with the current smokers and looking at the resultant mortality experience. Because of a lack of data that would allow a precise analysis of mortality among ex-pipe and ex-cigar smokers, a detailed analysis of these groups could not be undertaken in this review. For each specific cause of death, tables have been prepared which summarize the mortality and relative risk ratios reported in the major 172 prospective and retrospective studies which contained information about pipe and cigar smokers. The smoking categories used include: cigar only, pipe only, total pipe and cigar, cigarette only, and mixed. The total pipe and cigar category includes: those who smoke pipes only, cigars only, and pipes and cigars. The mixed category includes: those who smoke cigarettes and cigars; cigarettes and pipes; and cigarettes, pipes, and cigars. Mortality and relative risk ratios were calculated relative to nonsmokers, The Prevalence of Pipe, Cigar, and Cigarette Usage The prevalence of pipe, cigar, and cigarette smoking in the United States was estimated by the National Clearinghouse for Smoking and Health from population surveys conducted in 1964, 1966, and 1970 (98, 99, 100). In each survey, about 2,500 interviews were conducted ona national probability sample stratified by type of population and geographic area. The use of these products among adults aged 21 and older is summarized in tables 1 and 2. The prevalence of pipe, cigar, and cigarette smoking in Great Britain for the years 1965, 1968, and 1971 is presented in table 3. Taste 1.—Percent distribution of U.S. male smokers aged 21 and older by type of tobacco used for the years 1964, 1966, and 1970 Forms used 1964 1966 1970 (percent) (percent) (percent) 1. Cigar only... 2-22-28 6.8 5.5 5. 6 2, Pipe only____.-_.______.. 1.7 3.0 3.6 3. Pipe and cigar__..._...-__...... 3.9 4.9 4.4 4. Cigarette only.....-.__-______.___...___. 28. 6 31.2 25. 9 5. Cigarette and cigar_...____....._._______ 11.3 9.9 6. 6 6. Cigarette and pipe.._...._._.__.....___. 5.3 4.9 5.3 7. Cigarette, pipe, and cigar_____--_-2_2 7.7 6. 3 4.6 8 Nonsmoker_....._._.._._.__........_._. 34. 7 34. 3 44.0 Total__. 22 100. 0 100. 0 100. 0 Number of persons in sample_____._________ 2, 389 2, 679 2, 861 Total pipe users (2+3+6+7)............._- 18.7 19.2 17.9 Total cigar users (1+34+5+7)_........_.._ 29. 9 26.7 21.2 Total cigarette users (4454647)... 52.9 52.4 42. 3 Source: U.S. Department of Health, Education, and Welfare (98, 99, 100). 173 TABLE 2.—Percent distribution of U.S. male s co used and age for 1970 Forms used Age groups 21 to 34 35 to 44 45 to 54 mokers by type of tobae. 55 to 64 65 to 75 1, Cigar only___._.._2 888. 3.7 6.5 4,7 6.7 93 2. Pipe only____-----2 4.3 3.5 3.0 3. 2 3.6 3. Pipe and cigar_._.._._.___. 3.8 3.3 5. 2 4. 4 6.9 4. Cigarette only__.__. 28. 8 29. 0 27. 1 24, 3 13.6 5. Cigarette and cigar__________ 6. 8 10. 4 5. 5 5. 2 49 6. Cigarette and pipe..________ 6.6 4.4 5.6 4.0 3 § 7. Cigarette, pipe, and cigar. ___ 5. 8 4.8 5.0 4.0 Ls & Nonsmoker_.__-._-.--- 40, 2 38. 1 43.9 48. 2 37,9 ee Total. 2-22 100.0 100.0 100.0 100.0 100. 9 ns Number of persons in sample___ 1, 009 528 523 405 388 Total pipe users...._--_________ 20. 5 16. 0 18. 8 15. 6 15.7 Total cigar users_.____________ 20. 1 25. 0 20. 4 20. 3 21.6 Total cigarette users__________ 48.1 48. 6 43. 3 37.5 23. 6 Souree: U.S. Department of Health, Education, and Welfare (100). TaBLe 3.—-Percent distribution of British male smokers aged 25 ani) older by type of tobacco used for the years 1965, 1968, and 1971 Forms used 1965 1968 1971 1. Cigars only._...222 2-8 1.9 2.8 3.3 2. Pipe only_.-__-.2 8 5. 1 5. 6 5.9 3. Cigarettes only._--_22 288 46. 8 45. 7 40.8 4. Cigarettes and pipe._.....---.. 8.0 7.0 6.1 5. Mixed smokers... 7.5 9. 1 & 4 6. Nonsmokers.-_.-_..--_. 68. 30. 7 29.9 35. 4 a Total. 22. 100. 0 100. 0 100. 0 Number of persons in sample.___.__..______ 3, 576 3, 566 3, 594 Total pipe users... 13.9 14.3 13.3 Total cigar-_____=8 ee 9. 0 11.7 11.3 Total cigarette._.-.---- 67.6 67.6 61. 6 Source: Todd, G. F. (94). 174 The Definition and Processing of Cigars, Cigarettes, and Pipe Tobaccos Cigareties The U.S. Government has defined tobacco products for tax pur- poses. Cigarettes are defined as “( 1) Any roll of tobacco wrapped in paper or in any substance not containing tobacco, and (2) any roll of tobacco wrapped in any substance containing tobacco which, because of its appearance, the type of tobacco used in the filler, or its packaging ind labeling, is likely to be offered to, or purchased by, consumers as a cigarette described in subparagraph (1).” Cigarettes are further classified by size, but virtually all cigarettes sold in the United States are “small cigarettes” which by definition weigh “not more than 3 pounds per thousand” which is not more than 1.361 grams per cigarette (96). American brands of cigarettes contain blends of different grades of Virginia, Burley, Maryland, and oriental tobaccos. Several varieties of cigarette tobaccos are flue-cured. In this process, tobacco leaves are ‘ured in closed barns where the temperature is progressively raised over a period of several days. This results in “color setting,” fixing, ind drying of the leaf. The most conspicuous change is the conversion of starch into simpler sugars and suppression of oxidative reactions. Flue-cured tobaccos produce an acidic smoke of light aroma (35, 112). Cigars Cigars have been defined for tax purposes as: “Any roll of tobacco ‘rapped in leaf tobacco or in any substance containing tobacco (other than any roll of tobacco which is a cigarette within the meaning of ‘ubparagraph (2) of the definition for cigarette)” (772). In order to clarify the meaning of “substance containing tobacco” the Treasury lepartment has stated that, “The wrapper must (1) contain a signifi- “ant proportion of natural tobacco; (2) be within the range of colors Normally found in natural leaf tobacco; (3) have some of the other tharacteristics of the tobaccos from which produced; e.g., nicotine “ontent, pH, taste. and aroma: and (4) not be so changed in the constitution process that it loses all the tobacco characteristics” 2). Further, “To be a cigar, the filler must be substantially of ‘obaccos unlike those in ordinary cigarettes and must not have any added flavoring which would cause the product to have the taste or ‘toma generally attributed to cigarettes. The fact that a product does 75 not resemble a cigarette (such as many large cigars do not) and has q distinctive cigar taste and aroma is of considerable significance in making this determination” (702). Cigars are also classified by size. “Small cigars” weigh not More than 8 pounds per thousand and “large cigars” weigh more than 3 pounds per thousand. “Large cigars” are further divided into seven classes for tax purposes based on the retail price intended by the manufacturer for such cigars (96). Cigars are made of filler, binder. and wrapper tobaccos. Most cigar tobaccos are air-cured and then fermented. More recently, reconsti- tuted cigar tobaccos have been used as wrapper, binder, or both. Cigars are either hand-rolled or machine made. Some brands of smal] cigars are manufactured on regular cigarette making machines. The aging and fermentation processes used in cigar tobacco production produce chemical catalytic, enzymatic, or bacterial transformations as eyj- denced by increased temperature, oxygen utilization, and carbon dioxide generation within fermenting cigar tobaccos. In this complex process, up to 20 percent of the dry weight of the leaf is lost through decreases in the concentration of the most readily fermentable ma- terials such as carbohydrates, proteins, and alkaloids. The flavor and aroma of cigar tobaccos are in large measure the results of precisely controlled treatment during the fermentation process (35, 36, 112), ‘ Pipe Tobaccos The definition of pipe tobacco used by the U.S. Government was repealed in 1966 and there is no Federal tax on pipe tobaccos. The most popular pipe tobaccos are made of Burley; however. many pipe tobaccos are blends of different types of tobacco. A few contain a significant proportion of midrib parts that are crushed between rollers. “Saucing” material, or casings containing licorice, sweetening agents, sugars, and other flavoring materials are added to improve the flavor. aroma. and smoke taste. These additives modify the characteristics of smoke components (772). Conclusion Because of the unique enring and processing methods used in the production of cigar and pipe tobaccos. significant physical and chemi- cal differences exist between pipe and cigar tobaceos and those used in 176 cigarettes. The extent to which these changes may alter the health consequences of smoking pipes and cigars can best be estimated by an analysis of the potentially harmful chemical constitutents found in the smoke of these tobaccos. the tumorigenic activity of smoke conden- sates In experimental animals, and a review of the epidemiological data which has accumulated on the health effects of pipe and cigar smoking. Chemical Analysis of Cigar Smoke Only a few studies have been conducted that compare the chemical constituents of cigar smoke with those found in cigarette smoke. Hoffmann, et al. (43) compared the yields of several chemical com- ponents in the smoke from a plain 85 mm. cigarette, two types of cigars, and a pipe. The particulate matter. nicotine. benzo(a)pyrene, and phenols were determined quantitatively in the smoke of these tobacco products. One cigar tested was a 135-mm,-long, 7.8-g., U.S.- made cigar. The other was a handmade Havana cigar 147 mm. long weighing 8.6 g. The relative content of nicotine in the particulate matter produced by the cigars was similar to that of the cigarette tars. The benzo(a)pyrene and phenol concentrations in the cigar condensate was two to three times greater than in cigarette “tar” (table 4). Kuhn (58) compared the alkaloid and phenol content in conden- sates from an 80-mm. Bright-blend cigarette sold commercially in Austria with that obtained’ from 103-mm. cigars. These were tested TaBLe 4.—Amounts of several components of 1 g. of particulate material Jrom mainstream smoke of tobacco products Tobacco product ! Standard 85 mm. 85 mm. Compound US. Havana pipe Cigarette plain U.S. plain U.S. cigar A cigar B tobacco tobacco cigarette —_cigarette (b) in pipe in pipe (a) (b) Nicotine (mg.)__ 2-2 46. 2 63. 6 56. 1 61.0 65. 9 77.4 Benzo(a)pyrene (ug.).___ 3.9 3.6 6.0 3.6 1.2 1.3 Phenol (mg.).....______- 8,2 6.7 15.0 7.3 2.9 4.1 9-Cresol (mg.)___-._____- 1.6 1.7 1.9 1.4 6 .8 m+ p-Cresol (mg.)___. 2 4.8 3. 8 5. 6 3.4 1.4 1.9 ™+p-Ethylphenol (mg.)_- L4 1.5 Li 1.3 .7 .7 ' Smoking conditions: (a) 1 puff per minute, duration 2 see., puff volume 35 ml. (b) 2 puffs per minute, duration 2 sec., puff volume 35 ml. Source: Hoffmann, et al. (43). 177 with and without the use of a cellulose acetate filter. The concentra. tions of total alkaloids and phenol in the cigar smoke condensate Were essentially the same as in the cigarette condensate, but pyridine Values were about 214 times higher in the cigar condensate. Campbell and Lindsey (77) measured the polycyclic hydrocarbon, levels in the smoke of a small popular-type cigar 8.8 em. long, weighi 1.9 g. Significant quantities of anthracene, pyrene, fluoranthene, and benzo(a) pyrene were detected in the unsmoked cigar tobacco, in cop. centrations much greater than those found in Virginia cigarettes hy of the same order as those found in some pipe tobaccos. The smoking process contributed considerably to the hydrocarbon content of the smoke. Table 5 compares the concentrations in the mainstream smoke of cigarettes, cigars, and pipes of four hydrocarbons frequently found in condensates. The authors reported that the mainstream smoke from a popular brand of small cigar contained the polycyclic aromatic hydrocarbons; acenaphthylene, phenanthrene, anthracene, pyrene, fluoranthene, and benzo (a) pyrene. The concentrations of these hydro. carbons in the mainstream smoke were greater than those found in Virginia cigarette smoke, Osman, et al. (69) analyzed the volatile phenol content. of Cigar smoke collected from a 7-g. American-made cigar with domestic filler. After quantitative analysis of phenol. cresols, xylenols, and meta and para ethy] phenol, the authors concluded that the levels of these com. pounds were generally similar to those reported for cigarette smoke. Osman and Barson (68) also analyzed cigar smoke for benzene, toluene, ethyl benzene, m-, p-, and o-xylene, m- and p-ethyltoluene, 1,2,4-trimethylbenzene, and dipentene, and generally found levels within the range of those previously reported for cigarette condensates, In summary, available evidence suggests that cigar smoke contains many of the same chemical] constituents, including nicotine and other alkaloids. phenols, and polycyclic aromatic hydrocarbons as are found TABLE 5.—A comparison of several chemical compounds found in the mainstream smoke of cigars, pipes, and cigarettes I Compound oo Cigars Pipes 1 Cigarettes an Acenaphthylene.--. 982228 1.6 29. 1 5.4 Anthracene_--.---2 88 11.9 110.0 10.9 Pyrene._--- 22-22. 17.6 75.5 12.5 3,4-benzpyrene___ 22. 3. 4 8.5 4 ! This is a light pipe tobacco. Source: Campbell, J. M., Lindsey, A.J. (17). 178 in cigarette smoke. Most of these compounds are found in concentra- tions which equal or exceed levels found in cigarette “tar.” A more complete picture of the carcinogenic potential of cigar “tars” is ob- tained from experimental data in animals. Mortality Overall Mortality Several large prospective studies have examined the health conse- quences of various forms of smoking. The results of these investiga- tions have been reviewed in previous reports of the Surgeon General in which the major emphasis has been on cigarette smoking and its effect on overall and specific mortality and morbidity. The following pages present a current review of the health consequences of smoking pipes and cigars. Data from the prospective investigations of Dunn, et al. (37), Buell, et al. (26), Hirayama (42), and Weir and Dunn (105) are not cited, because in these studies a separate category for pipe and cigar smokers was not established. The smoking habits and mortality experience of 187,783 white men between the ages of 50 and 69 who were followed for 44 months were reported by Hammond and Horn (41). The overall mortality rates of men who smoked pipes or cigars were slightly higher than the rates of men who never smoked. The overall mortality rate of cigar smokers was slightly higher than that of pipe smokers. In a study of 41,000 British physicians, Doll and Hill (26, 27) re- ported the overall mortality of pipe and cigar smokers as being only 1 percent greater than that among nonsmokers. Best (9), in a study of 78,000 Canadian veterans, reported overall mortality rates of Pipe and cigar smokers slightly above those of nonsmokers. Kahn (50) exam- ined the death rates and smoking habits of more than 293,000 U.S. veterans and Hammond (38) examined the smoking habits of and mortality rates experienced by 440,559 men. In these studies, pipe smokers experienced mortality rates similar to those of men who never smoked regularly, whereas cigar smokers had death rates somewhat higher than men who never smoked regularly. Table 6 summarizes the results of these five studies. Thus, data from the major prospective epidemiological studies demonstrate that the use of pipes and cigars results in a small but defi- nite increase in overall mortality. Cigar smokers have somewhat higher death rates than pipe smokers, and mixed smokers who use cigarettes in addition to pipes and cigars appear to experience an inter- mediate level of mortality that approaches the mortality experience of cigarette smokers, 495-028 O—73-—___13 179 TABLE 6.—Mortality ratios for total deaths by type of smoking (males only) Smoking type Author, reference Non- Cigar Pipe Cigar Cigarette Cigarette Mixed Cigaretts smoker only only and and cigar and pipe (cigarette only pipe and other) Hammond and Horn? (40)_._ 1.00 1.22 1.12 1.10 1. 36 1. 50 1. 43 1. 68 Doll and Hill (26). 100 _--- Lt) LOL LL. LL 1.11 1, 28 Best (9)________ 1.00 1.06 1.05 .98 1, 22 1. 26 1.13 54 Kahn (60)_____. 1.00 1.10 107 1.08 ___... _..___. 1. 1 1. 84 Hammond ? (38) _ ee 1.00 1.25 1.19 101 _...-8 _. 1 1. 57 1. 86 1 Only mortality ratios for ages 50 to 69 are presented. ? Only mortality ratios for ages 54 to 64 are presented. Mortality and Dose-Response Relationships A consistent association exists between overall mortality and the total dose of smoke a cigarette smoker receives. The methods most frequently used to measure dosage of tobacco products are: Amount smoked, degree of inhalation, duration of smoking experience, age at initiation, and the amount of tar in a given tobacco product. For cigarette smokers, the higher the dose as measured by any of these parameters, the greater the mortality. The significance of the smal] increase in overall mortality that occurs for the entire group of pipe and cigar smokers can be analyzed by examining the mortality of subgroups defined by similar measures of dosage as used in the study of cigarette smokers. Amount SMOKED Hammond and Horn (40) reported an increase in the overall mor- tality of pipe and cigar smokers with an increase in the amount smoked. Individuals who smoked more than four cigars a day or more than 10 pipefuls a day had death rates significantly higher than men who never smoked (P<0.05 for cigar smokers and P<0.05 for pipe smokers) (table 7). Cigar and pipe users who smoked less than this amount experienced an overall mortality similar to men who never 180 smoked. The study of Canadian veterans (9) also contained evidence of a dose-response in mortality by amount smoked for cigar smokers. No dose-response relationship was observed among pipe smokers (table 8). Kahn (50) reported a consistent increase in overall mortality with an increase in the amount smoked for both pipe and cigar smokers (table 9). Hammond (38) found no consistent relationship between overall mortality and the number of elgars or pipefuls smoked (table 10). TaBLE 7.—Mortality ratios Jor total deaths of cigar and pipe smokers by amount smoked— Hammond and Horn Number of deaths Amount smoked oo Observed Expected Mortality ratio Nonsmoker_._-__-_...---__- 1, 664 1, 664 1. 00 Cigar only: Total... 2-2 653 598 1. 09 1 to 4 cigars___._-8 ee 410 400 1. 03 >4 cigars-_______88e 229 185 1, 24 Pipe only: Total_ 22-22 609 560 1. 09 1 to 10 pipefuls___.-.-2 8 391 374 1.05 > 10 pipefuls------ 22 204 172 1.19 Source: Hammond, E. C., Horn, D. (40). TaBLe 8.—Mortality ratios for total deaths of cigar and pipe smokers by amount smoked—Best Number of deaths Amount smoked Observed Expected Mortality ratio Nonsmoker..-.------ 2-22 2-2 1. 00 Cigar only: Total___.-_2- 2. 90 82. 07 1.10 1 to 2 cigars.__._- 64 56. 05 1.14 3 to 10 cigars._______.__- 23 19. 40 1.19 > 10 cigars__..-_-__-____ 8 1 1. 59 . 63 Pipe only: Total. 2-8 eee 570 566. 99 1. 00 1 to 10 pipefuls_..-- 222 374 370. 09 101 10 to 20 pipefuls...--_..- 141 140. 84 1. 00 1. 00 > 20 pipefuls....-2_2 36 35. 90 Source: Best, E. W. R. (9). 181 The above evidence suggests that a dose-response relationship may exist between the number of cigars and pipefuls smoked and overall] mortality. However, because of the high-mortality rate of ex-smokers of cigars and pipes, it is difficult to interpret the data presented with- out including this group with the continuing smokers. Without data which examines patterns of both daily rate of smoking and inhalation at various age levels, no firm conclusions can be drawn as to the nature of this dosage relationship. TaBLEe 9.—Mortality ratios for total deaths of cigar and pipe smokers by age and amount smoked—Kahn Mortality ratio, age Amount smoked 55 to 64 65 to 74 Nonsmoker_______.-__--.2 2 2-2-2 eee 1. 00 1. 00 Cigar only: Total___------ 22 --eeeeee 1.01 1. 08 1 to 4 cigars per day.____..._--_____________. . 89 1. 00 5 to 8 cigars per day_____...___ 2-2 1.14 1. 23 >8 cigars per day_____..__. lee 1. 65 1. 28 Pipe only: Total. _.-.-----2 2-2 eee 1. 08 1. 06 1 to 4 pipefuls per day_____.______-__________. 1. 16 .91 5 to 19 pipefuls per day____..____._.______._- 1. 04 1.10 >19 pipefuls per day._____.____-.-- eee ee 1. 18 Source: Kahn, H. A. (56). TaBLE 10.—Mortality ratios for total deaths of cigar and pipe smokers by amount smoked—Hammond Amount smoked Mortality Amount smoked Mortality tatio ratio Nonsmoker.____..___._____- 1. 00| Current pipe smokers: Current cigar smokers: Total___-.2 22 ee 1. 04 Total___ 2-2 ee 1. 09 1 to 9 pipefuls per day____- 1. 08 1 to 4 cigars per day_______ 1. 03 >9 pipefuls per day______- . 92 >4 cigars per day.____.___ 1.18 Source: Hammond, E. C, ($8). 182 INHALATION Inhalation of tobacco smoke directly exposes the bronchi and the lungs to smoke and results in the absorption of the soluble constituents of the gas and particulate phases. Without inhalation tobacco smoke only reaches the oral cavity and the upper digestive and respiratory tracts and does not reach the lungs where further direct effects and systemic absorption of various chemical compounds can occur. Although the smoker has some voluntary control over the inhalation of smoke, the physical and chemical properties of tobacco smoke to a degree determine its acceptability and “inhalability.” The condensate of pipe and cigar smoke is generally found to be alkaline when the pH is measured by suspending a Cambridge filter in CO,-free water. Cigarette condensate is slightly acidic as measured by this method. Since alkaline smoke is more irritating to the respira- tory tract, it has been assumed that the more alkaline smoke of pipes and cigars was in part responsible for the lower levels of inhalation reported by pipe and cigar smokers. Brunnemann and Hoffmann (15) have analyzed the pH of whole, mainstream smoke of cigarettes and cigars on a puff-by-puff basis using a pH electrode suspended in main- stream smoke. Smoke from several U.S. brands of cigarettes was found to be acidic throughout the entire length of the cigarette. Of interest was the finding that cigar smoke also had an acidic pH for the first two-thirds of the cigar and became alkaline only in the last 20 to 40 percent of the puffs from the cigar. Available epidemiological evidence indicates that most cigar smokers do not inhale the smoke and most cigarette smokers do. The fact that smoke from the first half or more of a cigar is acidic, near the range of pH values commonly found in Cigarette smoke, and becomes alkaline only toward the end of the cigar might suggest that the pH of the smoke of a tobacco product May not be the only factor that influences inhalation patterns. Per- haps “tar” and nicotine levels as well as the concentration of other “irritating” chemicals also affect the degree to which a tobacco smoke will be inhaled. Nicotine is rapidly absorbed into the blood stream from the lungs *hen tobacco smoke is inhaled. The amount of nicotine absorbed from the lungs is primarily a function of the nicotine concentration in the smoke and the depth of inhalation. Some nicotine may also be ab- Sorbed through the mucous membranes of the mouth. This is more likely to occur under alkaline conditions when nicotine is unprotonated (3, 15, 79). This suggests that cigar smokers may be able to absorb Some nicotine through the oral cavity without having to inhale, par- ticularly during the time that the smoke from the cigar is alkaline. 183 With the development of sensitive measures of serum nicotine level, (48) the extent to which nicotine is absorbed through the membraneg of the mouth in pipe and cigar smokers can be more accurately determined. , Inhalation patterns of smokers were determined in several of the large prospective and some of the retrospective epidemiological studies, Inhalation was usually determined by the administration of a ques. tionnaire that required a subjective evaluation of one’s own patterns of inhalation. Although the accuracy of these questionnaires has not been confirmed by an objective measure of inhalation, such as carboxy. hemoglobin or serum nicotine levels, their reliability is supported by mortality data which demonstrate higher overall and specific death rates with self-reported increases in the depth of inhalation. Doll and Hill (26) and Hammond (38) presented information on inhalation patterns of pipe, cigar, and cigarette smokers (figs. 1, 2, 3, and table 12). Some 80 to 90 percent of cigarette smokers reported inhaling, with the majority of individuals inhaling moderately or deeply, whereas most pipe and cigar smokers denied inhaling at all, Pipe smokers reported slightly more inhalation than cigar smokers, For each type of smoking, less inhalation was reported by older smokers. This change may represent less awareness of inhalation, differences in smoking habits of successive cohorts of smokers, or it may reflect the operation of selective factors which favor survival of noninhalers. The Tobacco Research Council of the United Kingdom has, since 1957, periodically reported the use of tobacco products by the British, Figure 1.—Inhalation among pipe smokers by age. No inhalation Some inhalation 34.8 31.2 26.2 23.9 25.5 Age 40 50 60 70 80 SOURCE: Hammond, E. C. (38). 184 Figure 2.—Inhalation among cigar smokers by age—-Hammond. No inhalation Phataton 26.4 22.9 17.1 13.7 18.5 4 1 A ‘ 4 Age 40 50 60 70 80 SOURCE: Hammond, E. C. (38). Figure 3.—Depth of inhalation among cigarette smokers by age.—Hammond. None Slight inhalation Moderate inhalation __ Deep inhalation 12.1 9.2 4 4. L 4 Age 40 50 60 70 80 SOURCE; Hammond, E. C. (38). Recent reports edited by Todd have contained data on the inhalation pattern of cigar, pipe, and cigarette smokers (92, 93, 94). Table 11 shows that most cigarette smokers inhale a “lot” of “fair amount” whereas most pipe and cigar smokers do not inhale at all or “just a little.” Little change is observed in the inhalation patterns of a given product since 1968. Best (9) reported inhalation data among male cigarette smokers by smoking intensity and age group, but did not report the inhalation 185 patterns of pipe and cigar smokers, The overall mortality rates of current pipe smokers who inhaled at least slightly were reported by Hammond (38) as being somewhat higher than for men who never smoked regularly. The overall mortality rates of current cigar smokers who reported inhaling at least slightly were appreciably higher than for men who never smoked regularly (table 13). Available evidence indicates that cigarette smokers inhale smoke to a greater degree than smokers of cigars or pipes. Once a smoker has learned to inhale cigarettes, however, there appears to be a tendency to also inhale the smoke of other tobacco products. For cigars, this is evidently true whether one smokes both cigarettes and cigars or switches from cigarettes to cigars (tables 14, 15, 16). Bross and Tidings (74) examined the inhalation patterns of smokers of large cigars, cigarettes, and those who switched from one tobacco product to another (table 15). Nearly 75 percent of those who were currently smoking only cigarettes reported inhaling “almost every puff” and only 7 percent never inhaled. The opposite was true for per- sons who had always smoked only cigars among whom 4 percent re- Tape 11.—The extent of inhaling pipes, cigars, and cigarettes by British males aged 16 and over in 1968 and 1971 Tobacco product Cigars Pipes Cigarettes Amount of inhalation a 1968 1971 1968 1971 1968 1971 Inhale a lot___-__-------------.---- 23 19 8 8 47 47 Inhale a fair amount___.__-_--_.---- 16 19 10 8 31 30 Inhale just a little.___.._------.---- 27 27 24 26 13 15 Do not inhale at all_._____..--_----- 34 35 59 58 9 8 Total___..__-._----_--------- 100 ©100 100 100 =§=100 100 Source: Todd, G. F. (98, 94). TasLe 12.—IJnhalation among cigar, pipe, and cigarette smokers by age-—Doll and Hill Percentage of inhalers, age Smoking type 25to34 35to44 45to54 S5to064 65 to 74 >74 Cigar and pipe__.------------- 12.00 10.00 7.00 5.00 4.00 4. 00 Mixed (cigarette and other)..... 74.00 60.00 47.00 36. 00 30.00 26. 00 Cigarette only_--_------------ 90.00 85.00 75.00 66.00 58.00 41.00 Source: Doll, R., Hill, A. B. (#6). 186 ported inhaling almost every puff and 89 percent said they never inhaled. Cigar smokers who also smoked cigarettes reported inter- mediate levels of inhalation between the cigar only and cigarette only categories. Inhalation patterns were similar whether the individual continued to smoke both products, stopped smoking cigarettes but continued smoking cigars, or stopped smoking cigarettes and switched to cigars. In all three groups, about 20 percent reported inhaling “almost every puff.” This suggests that once an individual’s inhalation patterns are established on cigarettes, he may be more likely to inhale cigar smoke if he switches to cigars, or uses both cigars and cigarettes, than the cigar smoker who has not smoked cigarettes. Todd (93) reported similar data for a sample of smokers in the United Kingdom (table 16). The prevalence of inhaling a “lot” or “fair amount” of smoke was highest among cigarette smokers who were currently smoking cigarettes (77 percent) and lowest among current, cigar smokers who had previously smoked only cigars or pipes (18 percent). Individuals who switched from cigarettes to cigars main- TaBLe 13.—Mortality ratios for total deaths of cigar and pipe smokers by age and inhalation—Hammond Mortality ratio, age Inhalation 45 to 64 65 to 84 Nonsmoker________.__...--2---__--_.--- ee 1. 00 1. 00 Cigar only: Total__ 2222-2 ee 1. 09 98 No inhalation____....-_.2---__-e 1. 02 91 Some inhalation._..____..--__..__.__-. 1. 28 1. 37 Pipe only: Total. 2-2-2 eee 1. 04 95 No inhalation___..__._.._-__-.2_-o._ . 98 87 Some inhalation.....__...___________........ 1. 21 111 Source: Hammond, E. C. (38). TABLE 14.—Percentage of British male cigar smokers who reported inhaling a lot or a fair amount by type of product smoked 1968 1971 Type of product — Number of Percent Numberof Percent individuals individuals Cigars only__.......___.-.-.-8- 706 =—-:23.0 111 27.0 Cigars and cigarettes... -________ 1, 193 42.0 277 44.0 Cigars and pipes....--.____..__...__- 596 = 35.0 109 32.0 Cigars, cigarettes, and pipes._________ 26 52. 0 15 32.0 Source: Todd, G. F, (98, 94). 187 tained somewhat higher levels of cigar smoke inhalation than those cigar smokers who had never smoked cigarettes (30 percent). Todd (93) examined further the relationship between the inhalation of cigarette and cigar smoke. In general, cigarette smokers who switched to cigars were much less likely to report inhaling cigar smoke than cigarette smoke; however, those who in the past reported inhaling cigarette smoke a “lot” or “fair amount” were much more likely to report inhaling cigar smoke to the same degree than those ex. cigarette smokers who in the past did not inhale the smoke of their cigarettes (table 17). TaBLe 15.—Percentage of individuals reporting inhalation of “almost every puff” of tobacco smoke by current and previous tobacco usage and type of tobacco used Confidence Type of tobacco smoked Number Percen- limits of Type inhaled tage _ Current usage Previous usage patients inhaled Lower Upper Cigarettes only._._ Cigarettes only_... 2,359 Cigarette... 74.8 73.1 76.6 Cigars only. _-_--- Cigars only_____-- 649 Cigars_____ 45 3.0 60 Cigarettes and Cigarettes and 520 _____ do_____ 20.4 10.5 280 cigars. cigars. Cigars_____-_---- Cigarettes and 93 ____- do____- 183 9.0 30.0 cigars. None_____----_-- Cigarettes and 186 ____- do____- 21.5 17.8 242 cigars. Cigars....------- Cigarettes only---- 64 ..__- do_____ 17.2 16.0 280 Source: Bross, I. D.J., Tidings, J. (74). Tas ie 16.—Percentage of British males who reported inhaling a lot or fair amount of cigar smoke by current and previous tobacco usage and type of tobacco previously smoked (1968) Type of tobacco smoked Number of Percentage individuals Type inhaled inhaled Current usage Prev.ous usage Cigarettes only_.._-.__ Cigarettes only______ 2,586 Cigarette._.__ 77,7 Cigars only._...-.---- Nonsmoker-___----. 306 Cigars. .____- 18.0 Cigars only_.-.__------ Cigarettes only_.-.--- 321 ____- do_____-- 30. 0 Source: Todd, Q. F. (94). Taste 17.—Eztent of reported inhalation of cigar smoke by British male cigar smokers who were ex-cigarette smokers in 1968, analyzed by extent of reported inhalation of cigarette smoke when previously smoking cigarettes Extent of inhaling cigarettes Extent of inhaling cigars Inhale a lot Inhale a little or fair amount or not at all Percent Percent Inhale a lot or fair amount__._.______._..._______ 44.0 5. 0 Inhale a little or not at all.------ 56. 0 95. 0 a Total... 2222 ee. 100. 0 100. 0 wee Sample size______-- 222 244 56 Source: Todd, G. F. (93). Specifie Causes of M ortality Cancer Several prospective epidemiological studies have shown a signifi- cantly higher overall cancer mortality among pipe and cigar smokers compared to the cancer mortality of nonsmokers (table 18), Pipe and cigar smokers have much higher rates of cancer at certain Sites than at others. The upper airway and upper digestive tracts appear to be the most likely target organs. The relationship of pipe and cigar smoking to the development of specific cancers is detailed in the following sections. TABLE 18.—Mortality ratios for total cancer deaths in cigar and pipe smokers. A summary of prospective epidemiological studies Type of smoking Author, reference Nonsmoker Cigar only Pipe only Total pipe Cigarette and cigar only Hammond and Horn (40)____ 1. 00 1. 34 1.44 _oll 1. 97 Best (9)....-.-. 1. 00 1.13 1.38 _______. 2. 06 Hammond (88).____..._____ 100 2-0.) LL 1.21 1. 76 ahn (60)__.- 1. 00 1. 22 1. 25 1. 25 2.21 Cancer of the Lip Approximately 1,500 new cases of cancer of the lip are reported each year. Because of the possibility of early detection and surgical accessibility of cancers in this area, there are less than 200 deaths from cancer of the lip each year in the United States, Some of the earliest scientific investigations exploring the association between tobacco use and disease examined the smoking patterns of individuals with cancer of the lip. Broders (13) in 1920 examined the smoking habits of patients jp a retrospective study of 526 cases of epithelioma of the lip and 500 controls. Of the cancer cases, 59 percent smoked pipes, whereas this was true for only 28 percent of the controls. No association was found between cigar or cigarette smoking and cancer of the lip. In a restrospective study of 439 clinic patients with cancer of the lip and 300 controls conducted in Sweden, Ebenius (32) reported a significant association between pipe smoking and cancer of the lip. A total of 61.8 percent of the lip cancer cases smoked pipes, while only 22.9 percent of the controls smoked pipes. No association was found between the use of cigarettes, cigars, or chewing tobacco and cancer of the lip. In other retrospective studies, Levin, et al. (60) reviewed a series of 143 cases of cancer of the lip, and Sadowsky, et al. (77) reviewed 571 cases of cancer of the lip. In both studies, a strong association was found between pipe smoking and cancer of the lip. No significant association was found between the use of tobacco in other forms and cancer at this site. In a study of environmental factors in cancer of the upper alimen- tary tract, Wynder, et al. (173) found an association between Pipe smoking, cigarette smoking, and cancer of the lip. There were only 15 cases of cancer of the lip in this study. Staszewski (87) examined the smoking habits of 394 men with carcinoma or precancerous lesions of the lips. An association was found between the smoking of pipes and cigars and cancer of the lip, but this was only of doubtful significance. A significant association was found between the use of cigarettes and cancer of the lip. Keller (51) conducted a study of lip cancers in which he considered a number of factors including histologic types, survival, race, occupa- tions, habits, and associated diseases, A total of 304 patients with primary basal cell or squamous cell carcinoma of the lip and 304 controls from the same hospital matched for age and race were con- sidered in this series. A significant association was found between smoking in all forms and combinations and carcinoma of the hip. It was also found that increasing age and outdoor occupations with exposure to the sun were equally significant factors in the etiology of lip cancer. 190 In summary, it appears that there are several factors involved in the etiology of cancer of the lip. Among the various forms of tobacco use, pipe smoking either alone or in combination with other forms of smoking seems to be a cause of cancer of the lip. Table 19 summarizes the results of these retrospective studies. Oral Cancer The lips, oral cavity, and pharynx are the first tissues exposed to tobacco smoke drawn in through the mouth. Variations in inhalation during the smoking of various tobacco products result in different pat- terns of distribution of smoke throughout the respiratory tree. How- ever, the oral cavity and adjacent tissues are the sites most consistently exposed to tobacco smoke. For this reason, differences in inhalation should result in less variation in exposure to tobacco smoke for these sites than for the lower trachea and the lung. The inherent carcinogen- icity of pipe, cigar, and cigarette smoke is most reliably compared at those tissue sites where dosage and exposure to tobacco smoke are most nearly equal. Data from the epidemiological studies suggest that little difference exists between the smoking of cigarettes, pipes, or cigars and the risk of developing oral cancer. Hammond and Horn (40) examined the association between smok- ing in various forms and cancer of the combined sites of lip, mouth, pharynx, larynx, and esophagus. The mortality ratios were 5.00 for cigar smokers, 3.50 for pipe smokers, and 5.06 for cigarette smokers compared to nonsmokers. All the deaths from cancer of the hp, oral cav- ity, and pharynx reported by Doll and Hill (26) occurred in smokers. The death rates from cancer at these sites were 0.04 per 1,000 for pipe and cigar smokers, 0.10 per 1,000 for mixed smokers, and 0.05 per 1,000 for cigarette smokers. A fairly detailed analysis of oral cancer was pre- sented by Kahn (50) who differentiated between cancer of the oral cavity and cancer of the pharynx. The mortality ratios for oral cancers Were 1.00 for those who never smoked, 3.89 for all pipe and cigar smokers, and 4.09 for cigarette smokers. A further breakdown of the pipe and cigar smokers demonstrated a mortality ratio of 4.11 for cigar smokers, 3.12 for pipe smokers, and 4.20 for smokers of pipes and cigars. For cancer of the pharynx, the mortality ratios were 1.00 for those who never smoked, 3.06 for all pipe and cigar smokers, and 12.5 for cigarette smokers. No deaths occurred among those who smoked only cigars. The mortality ratio was 1.98 for pipe smokers and 7.76 for smokers of pipes and cigars. Hammond (38) combined cancers of the lip, oral cavity, and pharynx. The pipe and cigar smokers had a mortality ratio of 4.94 and the cigarette smokers a mortality ratio of 9.90 compared to nonsmokers. 191 TéL TABLE 19.—Relative risk of lip cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies Relative risk ratio and percentage of cases and controls by type of smoking Author, reference Number ~- —-- —— ere Nonsmoker Cigar only Pipe only Total pipe Cigarette Mixed and cigar only Broders (13): Relative risk..-..-_ | 1.0 0. 8 4.3 LL 0 LLL Cases. 537 Percent cases___________ 7 19 410 lle Lo elle Controls_..-. 222-8 500 Percent controls_________ 4 16 6 LLL 2600 LLL Ebenius (32): Relative risk___..-- 208. 1.0 7 4.1 050 222 eee Le Cases__. 2 ee el eee _... 439 Percent cases. .___._____ 49 6 41 re Controls—9 2.2 300 Percent controls__.______ 65 12 13 10, LLL wee Levin, et al. (60) Relative risk... 1.0 19g 2.9 -oeeee 14 oo Cases... 22s 143 Percent cases... | 15 27 48 LL 45 LLL Controls... 554 Percent controls_________ 22 20 2400 LL 46 lll Sadowsky, et al. (77) Relative risk... __ 1.0 11 4.3 2.6 14 0. 4 Cases___ 571 Percent cases.____..____ 8 18 6 44 22 Controls___ 615 Percent controls.________ 13 3 7 4 53 19 Wynder,! et al. (113) Relative risk__..._._____ 0 8 18 21222 LLL L0 2.2 Cases... 2, 14 Percent cases_______.___ 0 7 2900 LLL 36 29 Controls___. 222-2 115 Percent controls_________ 24 9 WL 36 13 Staszewski (87): Relative risk_.._________ |S | 2.1 24 2-1 Cases____. 394 Percent cases__..________ Gwenn Lee 12 73 2 Controls_._.-- 2-2. 912 Percent controls.________ 1 ll 61 _-L LLL. Keller: (61): Relative risk_...__..._._ 1.0 14 4.0 2.6 Cases___ 2. wae nee eee 301 Percent cases___-_ ______ 7 2 6 l 60 6 Controls___-..-2 2 265 Percent controls_________ 17 4 3 0 53 0 ) Percentage based on less than 20 patients. Ratios: relative to cigarette smokers. These studies are summarized in table 20. They demonstrate that smokers experience a large and significant risk of developing cancer of the oral cavity compared to nonsmokers. This risk seems to be about the same for all smokers whether an individual uses a Pipe, cigar, or cigarette, A number of retrospective studies have examined the relationship between smoking in various forms and cancer of the oral cavity. The results of these studies are presented in table 21. Some of the variations in relative risk of developing oral cancer observed in the retrospective studies is probably due to the lack of a uniform definition of oral cancer by anatomical site and the various means used in selecting and defin- ing cases and controls. It appears, however, that a significant risk of developing oral cancer exists for smokers compared to nonsmokers and this risk is similar for smokers of pipes, cigars, and cigarettes. Several epidemiological investigations have demonstrated an asso- ciation between the combined use of alcohol and tobacco and the development of oral cancer. A few of these studies (52, 62, 63, 109) contain data on pipe and cigar smokers. Heavy smoking and heavy drinking are associated with higher rates of oral cancer than are seen with either habit alone. TaBLE 20.—Mortality ratios for oral cancer in cigar and pipe smokers. A summary of prospective epidemiological studies Smoking type Author, reference — Pipe Total pipe Cigarette Mixed Non- Cigar smoker only only and cigar only Hammond and Horn!(40)_ 1. 00 5. 00 3.50 _______- 5.06 ___._ _- Doll and Hill? (26,27)... 0.00 _.__..... ______ 0. 80 1. 00 2. 00 Hammond ($8) _.- 1.00 -2---222 LL LLL 4. 94 39.90 .._-____ Kahn (60): Oral +.. 22-2 1. 00 4.11 3.12 3. 89 4.09 _.._____ Pharynx____.___ 1.00 .. 2 LLL 1. 98 8.06 12.54 __..____ ' Combines data for oral, larynx, and esophagus. ? Ratios: relative to cigarette smokers. 5 Mortality ratios for ages 45 to 64 only are presented. ‘ Excludes pharynx. Cancer of the Larynx The larynx is situated at the upper end of the trachea. Because of Its proximity to the oral cavity, the larynx probably has a similar *xposure to smoke drawn through the mouth as the buccal cavity and pharynx. Tobacco smoke that is not inhaled may still reach as far as the larynx and upper trachea. Pipe and cigar smokers develop cancer of the larynx at rates comparable to those of cigarette smokers. These 193 vél TaBLY 21.—Relative risk of oral cancer for men, comparing cigar, pipe, and cigarette smokers uith nonsmokers. A summary of retrospective studies Relative risk ratio and percentage of cases and controls by type of smoking Author, reference Number — Nonsmoker Cigaronly Pipeonly Total pipe Cigarette Mixed and cigar only Mills and Porter (64): Relative risk_....._---._- 10-22-22. ee Lee 7.0 4,1 0.00 2 L- Cases________. eee 124 Percent cases.__.._.____- WW Lee eee Lee 55 386 Lee Controls_.......-.--__-_- 185 Percent controls.__._._._- 38 _8 le Lee 30 820 ee Sadowsky, et ai. (77): Relative risk._._._-___-_- 1.0 2.0 4.4 20. 1.4 21 Cases.___ 2 eee 1,136 Percent cases_._.. 2... 8 4 1B Lee 42 28 Controls_._______________ 615 Percent controls.._.._.._- 13 3 T woe ee 53 23 Schwartz, et al. (83): Relative risk_.-._....___. 10 --.-.___. L6 _L 222 Le 15 _..2L LL. Cases__._..-_ 22 332 Percent cases__.___.____- WLLL ne 63 LLL ele Controls.........--.--_-- 608 Percent controls..________ 23 77 re 58 LL. ee Wynder, et al. (109): Relative risk___..-.-____- 1.0 3. 6 6.1 ____---_- 3.0 3.3 Cases_______.__-_--._-__ 543 Percent cases________.__- 3 20 Wo LeeLee 57 8 Controls_____._._._----.- 207 +Percent controls___._.____ 10 13 6 _LLLLLlee 63 8 Wynder, et al. (113): Relative risk_--__.._-__--- 1.0 1.7 a 1.2 1.4 Cases_..- 115 Percent cases___.._______ 23 13 W220 LLL 37 16 Controls__._..._..2-_---- 115 Percent controls..___..___ 26 9 WG LLL 36 13 Sét a © on oS we % ° hy as | me nn Wynder, et al. (116): Cases__._-___- 178 Percent cases____________ Controls_..---2. 8 220 =Percent controls__._.____. Pernu (73): Relative risk_.___________ Cases_____-_ ee 1,400 Percent cases____________ Controls___.-- = 713 Percent controls__.._____. Staszewski (87): Relative risk__.._________ Cases... 383 Percent cases____________ Controls_...-__-. ee 912 Percent controls_.__._____ Keller (62): Relative risk....___._____ Cases... 408 Percent cases____________ Controls._.0.222 408 Percent controls..________ Martinez (62): Relative risk...---- Cases___.. 2 170 Percent cases____.________ Controls_..--- 510 Percent controls_.._______ Martinez! (63): Relative risk..._________. Cases. _ 22 346 Percent cases___________. Controls___...--2 2. 346 Percent controls__________ 1.0 12 22 50 72 61 69 39 44 34 36 an ' This study combines data for oral cancer and cancer of the esophagus. rates are several times the rates of nonsmokers. The similarity of the mortality ratios of cancer of the larynx for smoking in various forms suggests that the carcinogenic potentials of the smoke from cigars, pipes. and cigarettes are quite alike at this site. Several of the prospective epidemiological studies include data on deaths from cancer of the larynx for pipe and cigar smokers as well as for cigarette smokers. Hammond and Horn (40) combined data for cancer of the larynx with cancer of the esophagus and oral cavity. The mortality ratios compared to nonsmokers were 5.00 for cigar smokers, 3.50 for pipe smokers, and 5.06 for cigarette smokers. There were no deaths from carcinoma of larynx among nonsmokers in the study of British physicians by Doll and Hill (26); however, the death rate for cancer of the larynx among pipe and cigar smokers was 0.10 per 1,000 while the death rate for cigarette smokers was 0.05 per 1,000. Kahn (50) reported mortality ratios for cancer of the larynx of 10.33 for cigar smokers, 9.44 for pipe and cigar smokers, 7.28 for all pipe and cigar categories combined, and 9.95 for cigarette smokers. No deaths from cancer of the larynx occurred in pipe smokers. Hammond (38) reported a mortality ratio of 3.387 for all pipe and cigar smokers and a mortality ratio of 6.09 for cigarette smokers in the age category 45 to 64, These studies are summarized in table 29. Several retrospective studies have examined the smoking habits of patients with cancer of the larynx and appropriately matched controls. The small number of pipe and cigar smokers in each study results in relative risk ratios that are quite unstable; however, it appears that pipe and cigar smokers experience a risk of developing cancer of the larynx that is similar to the risk observed among cigarette smokers (table 18). TaBLE 22.—Mortality ratios for cancer of the larynz in cigar and pipe smokers. A summary of prospective epidemiological studies Smoking type Author, reference _ Non- Cigar only Pipe only Total pipe Cigarette Mixed smoker and cigar only Hammond and Horn! (40)_----------------- 1. 00 5. 00 3.50 __------ 5.06 __.----- Doll and Hill? (26, 27)__. 0.00 22-22-20 Loe e-e 2. 00 1. 00 0. 60 Hammond (38)_..-..2-.- 1.00 _------2 LL eee 3.387 36.09 _.-____- Kahn (50)_...-.----.--- 100 10.388 _.___- 7. 28 9.95 __...--- ! Combines data for oral, larynx, and esop 1agus. ? Ratios: relative to cigarette smokers. 3 Only mortality ratios for ages 45 to 64 are presented. 196 Wynder, et al. (108, 113) distinguished between intrinsic and ex- trinsic larynx cancers. For smokers the relative risk of developing cancer of the intrinsic larynx was similar to the relative risk of lung cancer whereas the relative risk of developing extrinsic larynx cancer was more like the relative risk of cancer of the upper digestive tract. Histologic changes of the larynx in relation to smoking in various forms were described by Auerbach, et al. (5). Microscopic sections of the larynx fron: 942 subjects were examined for the presence of atypical nuclei and proliferation of cell rows. Sections were taken from four separate areas of the larynx in each case. Among those who smoked cigars and pipes but not cigarettes. only 1 percent had no atypical cells and more than 75 percent of the subjects had lesions with 50 to 69 percent atypical cells. Four of the cigar and pipe smokers had carcinoma in situ and in one of these four cases early invasion was seen in three of the sections. Of those who never smoked regu- larly, 75 percent had no atypical cells. The cigar and pipe smokers had a similar percentage of cells with atypical nuclei as cigarette smokers who smoked one to two packs per day. With respect to the prolifera- tion of cell rows in the basal layer of the true vocal cord, the least proportion of cases with eight or more cell rows was found in men who never smoked, and the greatest. proportion was found in heavy cigarette smokers. Pipe and cigar smokers had a distribution of cell rows that was comparable to that of cigarette smokers who consumed about a pack a day. Several retrospective studies have reported an association between the combined use of tobacco and alcohol and cancer of the larynx. A study by Wynder, et al. (108) included some information on pipe and cigar smoking in relation to drinking habits and the development. of cancer of the larynx, but because of the limited number of pipe and cigar smoking subjects this relationship could not be adequately determined. Cancer of the Esophagus The esophagus is not directly exposed to tobacco smoke drawn into the mouth; however, the esophagus does have contact with that portion of tobacco smoke that is condensed on the mucous membranes of the mouth and pharynx and then swallowed. The esophagus is also ex- posed to a portion of tobacco smoke that is deposited in the mucus cleared from the lung by the ciliary mechanism or by coughing. Varia- tions in inhalation of a tobacco product may not appreciably alter the &xposure the esophagus receives from smoke dissolved in mucus and saliva. This suggestion receives support from the prospective and retrospective epidemiological studies which demonstrate similar mor- tality rates for cancer of the esophagus in smokers of cigars, pipes, and cigarettes. 197 861 TaBLe 23.—Relative risk of cancer of the larynx for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies Relative risk ratio and percentage of cases and controls by type of smoking Author, reference Number —— - Nonsmoker Cigaronly Pipeonly Total pipe Cigarette Mixed and cigar only Schrek, et al. (81): Relative risk___.________ 1.0 0 Lhd ill 7 Cases___..22 2-2-8 ee 73 Percent cases ___ 14 0 TO lee 8000 LL Controls__.-. 222-222 ee §22 Percent controls___._____ 24 10 Wo LLL 59° Le Sadowsky, et al. (77): Relative risk.___.__ _____ 1.0 2.2 2.3 2-22 Le 3.7 4,1 Cases___..-_ eee. 273 Percent cases_.____..___ 4 2 5 LLL 60 29 Controls... 615 Percent controls__._______ 13 3 , 53 23 Wynder, et al. (108): Relative risk__....______ 1.0 15.5 27.7 11.1 24.6 .-- 2 2 Cases___2 ee 209 Percent cases.____..____ .5 8 5 1 86 LLL. Controls... 2-8. 209 Percent controls_________ 11 10 4 2 74 ok Wynder, et al. (113) Relative risk.._.________ 1.0 9.7 4.5 _-__ Le 6.3 6.3 Cases_.._.2 2-2-8. 60 Percent cases____._____- 5 17 1 Lele 47 17 Controls.._..___-. 22-8. 271 Percent controls__.______ 24 9 WL le 36 13 Wynder, et al. (116): Relative risk. ..__..___. 1.0 14.5 16.0 _--- LL. 22. 0 16. 0 Cases____ 08 142 Percent cases__.________ 1 20 Lo wlll 62 16 Controls_.... 222 220 Percent controls_________ 16 22 To Loe 45 16 661 Pernu (73): Cases___-__ ee 546 Controls._...-222 22 713 Staszewski (87): Cases... eee 207 Controls... 2-2 912 Svoboda (90): Cases___.-.22 22 205 Controls... 22 2-22. 320 Stell (88): 78 50 50. 2 61 95 71 79 50 In the prospective epidemiological studies, cigar, pipe, and cigarette smokers all had similar mortality ratios from cancer of the esophagus, Hammond and Horn (40) combined the categories of carcinoma of the esophagus, larynx, pharynx, oral cavity, and lip and described mortality ratios of 5.00 for cigar smokers, 3.50 for pipe smokers, and 5.06 for cigarette smokers. Doll and Hill (26) reported an esophageal cancer mortality ratio of 2.0 for pipe and cigar smokers, 4.8 for mixed smokers, and 1.5 for cigarette smokers. Kahn (50) reported the fol- lowing mortality ratios for srnoking in various forms compared to non- smokers: cigar only, 5.33; pipe only, 1.99; pipe and cigar, 4.17; all pipes and cigars combined, 4.05; and cigarettes only, 6.17. The results of these prospective studies are summarized in table 24, Several retrospective investigations have also examined the associa- tion between smoking in various forms and cancer of the esophagus. These studies have been summarized in table 25. The evidence sug- gests that cigar, pipe, and cigarette smokers develop cancer of the esophagus at rates substantially higher than those seen in nonsmokers, and that little difference exists between these rates observed in smokers of pipes and cigars and cigarettes. Histologic changes in the esophagus in relation to smoking in vari- ous forms were investigated by Auerbach, et al. (7), who looked for atypical nuclei, disintegrating nuclei, hyperplasia, and hyperactive esophageal glands. A total of 12.598 sections were made from tissues obtained from 1,268 subjects. For each of the parameters investigated, pipe and cigar smokers demonstrated significantly more abnormal histologic changes than nonsmokers; however, these changes were not as severe or as frequent as those seen in cigarette smokers. Several retrospective studies conducted in the United States and other countries have examined the synergistic roles of tobacco use and heavy alcohol intake on the development of cancer of the esophagus. Four of these investigations contain data on Pipe and cigar smoking (12. 62, 63, 107). It appears that smoking in any form in combination with heavy drinking results in especially high rates of cancer of the esophagus. TaBLe 24.—Mortality ratios for cancer of the esophagus in cigar and pipe smokers. A summary of prospective epidemiological studies Smoking type Author, reference Non- Cigar Pipe Total Cigarette omy smoker only pipe and only Mixed cigar Hammond and Horn! (40) 1. 00 5. 00 3.50 222 Le 5. 06 __-__._-- Doll and Hill (26, 27)___. 1.00 _-.-- 222 LLL. 2. 00 1. 50 4, 80 Hammond (88)._________ 1.00 _-.-_-.-. LLL. 3.97 44.17 _______. Kahn (60)______._______ 1. 00 5. 33 1.99 4.05 6.17 ..L_L-- ' Combines data for oral, larynx, and esophagus. 2 Mortality ratio for ages 45 to 64. 200 Loz TaBiE 25.—Relative risk of cancer of the esophagus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies Relative risk ratio and percentage of cases and controls by type of smoking Author, reference Number Nonsmoker Cigaronly Pipeonly Total pipe Cigarette Mixed and cigar only Sadowsky, et al. (77): Relative risk......._._-- 1.0 4.8 3.8 5. 1 3.8 3.3 Cases._....----------------- 104 Percent cases____-__-_-- 4 5 8 6 60 18 Controls__.....__-.-..-.----- 615 Percent controls________- 13 3 7 4 53 19 Wynder, et al. (113): Relative risk._.._._.___- 1.0 3.1 2.1 -.---..-- 2.6 4 Cases___._.----------------.- 39 Percent cases___.....-_. 13 15 WW Ltt. 51 3 Controls___..._._--..-------.- 115 Percent controls__.__.--_- 24 9 160 LL eee 36 13 Pernu (73): Relative risk_....__..._- 10 _--.-- -- 3.0 .-.------ 2.7 5.9 Cases____._._------.-------- 202 Percent cases___..-.---- VW LL tee e-- 7 --------- , 59 18 Controls_.._...2.22-22 2 Lae 713 Percent controls._____--- 39) LLL § _Loeteeee 50 7 Schwartz, et al. (84): Relative risk_.....__.._. 10 _..-.-L_. 2.6 _.....--- 1.7 8.6 Cases___._._.--------------- 249 Percent cases. _.......-- 2 Jollee 2 Loewe eee &8 7 Controls_____._._---------.-- 249 Percent controls_____.__- | 7 Lee ee eee 67 7 Wynder and Bross (107): _ Relative risk.....------- 1.0 3. 6 9. 0 6. 0 28 3.7 Cases_.....-.-.-----.-------- 150 Percent cases.__..-.-..- 5 19 9 4 51 11 Controls___-_.__.-.---------- 150 Percent controls______~_-- : 15 16 3 2 55 9 c0z TABLE 25-—Kelative risk of cancer of the esophagus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies.—Continued Relative risk ratio and percentage of cases and controls by type of smoking Author reference Number Nonsmoker Cigaronly Pipeonly Total pipe Cigarette Mixed and cigar only Bradshaw and Schonland (12): Relative risk... ___ | i | 4.8 _____L__ 2.3 1 LLL Cases____--- we ene eee eee 117 Percent cases_..____.___ 1 Leelee 4.00 Lee 638 Le Controls__......- 222-2 366 Percent controls_._.____. 8200 LL 1% LLL 58 Lee Martinez (62): Relative risk__._..-._..- 1.0 2.0 --.----- 0 22 lle 1.5 2. 2 Cases_.._ 2-2-2 eee 120 Percent cases____.______ 8 9 Lele eee Lee 31 43 Controls.____._....-- 22 2 -_- 360 Percent controls________- 14 8 Llu eee ee LL _e 34 34 Martinez ! (63): Relative risk_..________- 1.0 2.0 28 1. 1.7 2.5 Cases_....-...-------------- 346 Percent cases__._.___._- 21 10 WH Lee 34 34 Controls_____..---.--------- 346 Percent controls_.______- 22 9 Lo Lele eee 36 25 ! This study combines data for oral cancer and cancer of the esophagus. Lung Cancer Abundant evidence has accumulated from epidemiological, experi- mental, and autopsy studies establishing that cigarette smoking is the major cause of lung cancer. Several prospective epidemiological studies have demonstrated higher lung cancer mortality ratios for pipe and cigar smokers than for nonsmokers, but the risk of developing lung cancer for pipe and cigar smokers is less than for cigarette smokers. Table 26 presents a summary of these prospective studies. Dose- response relationships such as those that helped demonstrate the nature of the association between cigarette use and lung cancer could not be as thoroughly studied for pipe and cigar smokers because of the rela- tively few smokers in these categories. Although the number of deaths were few, Doll and Hill (26) reported increased death rates from lung cancer for pipe and cigar smokers with increasing tobacco consump- tion (table 27). Kahn (80) also demonstrated a dose-response relation- ship for lung cancer by the amount smoked (table 28). A few of the retrospective studies contained enough smokers to allow an examination of dose-response relationships for pipe and cigar smok- ing and lung cancer (/, 61, 74, 77). An increased risk of developing lung cancer was demonstrated with the increased use of pipes and cigars as measured by amount smoked and inhalation. The retrospec- tive investigation of Abelin and Gsell (7) is of particular interest. The smoking habits of 118 male patients with cancer of the lung from a tural area of Switzerland were compared with those reported in a sur- vey of all male inhabitants of a town in the same region. About 20 percent of the population of this area were regular cigar smokers, the most popular cigar being the Stiimpen, a small Swiss-made machine- manufactured cigar cut at both ends with an average weight of 4.5 g. In this investigation, cigar smokers experienced a risk of developing lung cancer that was similar to the risk of cigarette smokers. A dose- response relationship was demonstrated for inhalation and amount smoked. These data suggest that the heavy smoking of certain cigars may result in a risk of lung cancer that is similar to that experienced by cigarette smokers. Several pathologists have reported histologic changes in the bronchial epithelium in relation to smoking in various forms. Knudt- son (57) examined the bronchial mucosa of 150 lungs removed at au- ‘opsy and correlated the histologic changes noted with the history of smoking, age, occupation, and residence. Specimens obtained from the six cigar and pipe smokers demonstrated basal cell hyperplasia; however, there was no squamous or atypical proliferative metaplasia as 1s frequently seen in the heavy cigarette smokers. Sanderud (78) examined histologic sections from the bronchial tree of 100 male autopsy cases for the presence of squamous epithelial 203 metaplasia. In this study, 39 percent of the population were non- smokers, 20 percent were pipe smokers, and 38 percent smoked cig. arettes. A total of 80 percent of the pipe smokers and cigarette smokers demonstrated squamous metaplasia of the bronchial tree, whereas only 54 percent of the nonsmokers had this abnormality. Auerbach, et al. (6) examined 36,340 histologic sections obtained from 1,522 white adults for various epithelial lesions including: presence or absence of ciliated cells, thickness or number of cell rows, atypical nuclei, and the proportion of cells of various types. The pathologic findings in the bronchial epithelium of pipe and cigar smokers are compared to those found in nonsmokers and cigarette smokers (table 25). Pipe and cigar smokers had abnormalities that were intermediate between those of nonsmokers and cigarette smokers, although cigar smokers had pathologic changes that in some categories approached the changes seen in cigarette smokers. TapLE 26.—Mortality ratios for lung cancer deaths in male cigar and pipe smokers. A summary of prospective studies Type of smoking Author, reference Non- Ci Pipe ‘Total pipe Cigarette Mixed — smoker only, only and cfgar enly * Hammond and Horn (40)- _—:1. 00 3. 35 8.50 _------- 23. 12 19. 71 Doll and Hill (26, 27)---- 1.00 -------- ------ 6.14 13.29 7. 43 Best (9)_.-_.----------- 1. 00 2.9 4.35 ._------ 14,91 _____... Hammond (98)_--------- 1. 00 1. 85 2. 24 1.97 9. 20 7. 39 Kahn (60)_.------------ 1. 00 1. 59 1. 84 1.67 12.14 -_--___- TaBLE 27.—Lung cancer death rates for cigar and pipe smokers by amount smoked—Doll and Hull Smoking type Death rate per 100 Number of deaths Nonsmoker_-__.---------------------------- 0. 07 3 Cigar and pipe: 1 to 14 g. per day__-_------------------- . 42 12 15 to 24 g. per day._...----------------- . 45 6 >24 g. per day__--.-------------------- . 96 3 Cigarette only_.---------------------------- . 96 143 Source: Doll, R., Hill, A. B. (£6). 204 TABLE 28.—Lung cancer mortality ratios for cigar and pipe smokers by amount smoked—Kahn Smoking type Mortality ratio Number of deaths Nonsmoker_____.-.-.-.._--__-_-_-_-_-_------ 1. 00 78 Cigar smokers: <5 cigars per day_______._._-__--------- 114 12 5 to 8 cigars per day_______-_.-------.--- 2. 64 11 >8 cigars per day._.___-...-___._-_-___- 2. 07 2 Pipe smokers: <5 pipefuls per day____.-._._-.-_._-___- 77 2 5 to 19 pipefuls per day_.__.-.._..-_-_.-- 2. 20 12 >19 pipefuls per day. ..--.----------.-.- 2. 47 3 Cigar and pipe: 8 or less cigars, 19 or less pipefuls__ _ ___-_-- 1. 62 18 >8 cigars, >19 pipefuls.........-______-_. 2. 19 2 Source: Kahn, H. A. (50). 205 90% TABLE 29.-—Relative risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A sum- mary of retrospective studies Relative risk ratio and percentage of cases and controls by type of smoking Author, reference , Number Nonsmoker Cigaronly Pipeonly Total pipe Cigarette Mixed and cigar only Levin, et al. (60): Relative risk... - 1.0 0.7 0.8 -2--2 8. 21 2 1-ooe Cases___. 2-2 236 =©Percent cases___________ 15 11 140 Lele 66 _Lw Le Controls____..-. 2.222222. 481 Percent controls_________ 22 23 25 Loe 44 Le Schrek, et al. (81): Relative risk_..._.______ 1.0 .6 27 Lele 17 2 ie. Cases_____-- 222-8 82 Percent cases._..__.____ 15 4 5 LLL 6h LLL ieee Controls. __ 2.222222 ee 522 Percent controls_________ 22 23 Wo LL eeee 59 Lie Wynder and Graham (111) Relative risk__....-_.___ 10 5.1 3.6 Llu. 15.7 .22 Lee Cases.__. 2-2-2 605 Percent cases_____._____ 1 4 4 Lillie 91 Le Controls... 222-22. 780 Percent controls______.__ 15 8 W200 Leelee 65 LLL Doll and Hill (26): Relative risk_.-._...____ 10 222 lle 61 22 Le 9.6 _.- 2. LLL Cases__----.2. 2222-2 _ ee 1,357 Percent cases_._____.___ 5 Lee nel 4 Lille 740 Le Controls____.-..-.2- 2-2 eee 1,357 Percent controls._____.__ 5 Leanne nee 7 wont a lene 69 Lele Koulumies (56): Relative risk____________ L0 _- 2 LLL. 9.6 22-2 Le 29.3 --. 2 LL Cases__._ 22 812 Percent cases___________ 6 _---- Le 2 Leet i Controls__. 2-2 2-8. 300 ~=Percent controls_________ 18 LLL. 6 Lule lle 7 eee Sadowsky, et al. (77): Relative risk_..______._- 1.0 2.4 14 -12. lle 3.7 5.6 Cases. ..-__-_- 22-22 477 =‘ Percent cases___________ 4 2 3 Lele 57 31 Controls_.-..- 2. ee 615 Percent controls_________ 13 3 (re 53 19 £07 Wynder and Cornfield (110): Mills and Porter (66): Cases_.__.-. 2222 eee Controls___...----- 2-2-2 ee 1, 588 Schwartz and Denoix (82): Lombard and Snegireff (61): 484 2,101 Controls___---_--.--------_.-- 5, 960 1.0 2. 5 4.0 4 13 6 21 27 8 1.0 5.3 5.0 1 21 11 6 19 11 1.0 -- 222-2. Leelee To teeee eee 2 ae eee 3100 Leelee Lene 10 --------- 22 eee ne 280 Lee ene 1.0 --.------ 4.7 ) ene 6 VW Ll 14 10 ----- 2 Le 3. 1 2 2 --.e-e 9 9 _LLL-Leee 13 10 2-2 eee lle. 2 penne eee oon WO Lee eee L eee 10 --------- 4.2 To Looe en--- 4 39 eile 5 807% TaBLE 29.—Relative risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A sum- mary of retrospective studies—Continued Relative risk ratio and percentage of cases and controls by type of smoking Author, reference Number Nonsmoker Cigaronly Pipeonly Total pipe Cigarette Mixed and cigar only Wicken (106): Relative risk_......._-_- a 2.2 4.3 4.2 Cases_______- eee 803 Percent cases________-_- 40 lle eee Lele 10 78 7 Controls...._.-.._...--.------- 803 Percent controls__.___-_- 140° _Llee eee Lee 16 64 6 Abelin and Gsell (1): Relative risk_._..__-_--- 1.0 30. 7 21.8 39. 9 31.0 24.7 Cases__.--_._-_-_------------- 118 Percent cases___._.----- 2 28 7 58 25 24 Controls...._..__._....-------- 524 Percent controls. ___----- 35 19 6 31 7 10 Wynder, et al. (116): Relative risk__..__.--_-- 10 _-.------ ---.---- 2.0 12.4 ___ LL. Cases_.._-.._----------------- 210 Percent cases. _-_------- 8 _Leee---- o-e eee 5 92 _____ue. Controls____..__..----_.------- 420 Percent controls.__------ 210 lve eee Lone 15 47 60% TaBLE 30.—Changes in bronchial epithelium of male cigar, pipe, and cigarette smokers as compared to nonsmokers Percent sections Percent 3 plus Percent Percent Group Number of Sections with with epithelial cell rows With atypical cells Total hyperplasia and subjects epithelium lesions e present sections goblet cells in glands Ist set (none vs. pipe vs. cigarette—matched on 1:1 basis): Nonsmoker.._....-.._-_.__-.---_---___- 20 985 21.7 11.2 2. 6 1, 031 10. 3 Pipe only__-._--.---. 2 e eee 20 924 65. 5 38. 1 37.0 979 35. 9 Cigarette only... 2.22 eee 20 914 96. 8 88. 6 95. 2 982 72.1 2d set (none vs. pipe vs. cigarette—matched on frequency basis) : Nonsmoker___.-.___.-__--____-___--- oe. 25 1, 246 22.9 13.4 7 1,277 11.5 Pipe only___-_. 2.222 eee 25 1, 164 68. 7 38. 7 38. 2 1, 247 37.9 Cigarette only... 22-2222. 25 1, 126 96. 3 88. 7 89. 5 1, 237 75.5 3d set (none vs. cigar vs. cigarette) : Nonsmoker..______.-_.--_.----_.-_____ 35 1, 706 27. 4 12.7 8 1, 748 15. 3 Cigar only._._.-_--2 22-2 ee 35 1, 733 90. 8 40. 0 73. 6 1, 828 52. 5 Cigarette only__ 22-22 35 1, 526 99. 0 92. 7 97.8 1, 693 80. 2 Source: Auerbach et al. (6). Tumorigenic Activity The tumorigenic activity of tobacco smoke can be modified in both a quantitative and qualitative sense. Physical or chemical changes in tobacco that result in a reduction of total particulate matter upon combusion of a given quantity of tobacco may result in a reduction of carcinogenic potential. Such factors as tobacco selection, treatment, _ blending, cut, and additives may quantitatively alter tar production. Wrapper porosity and filtration may also affect tar production. Quantitative changes in the tumorigenic activity of tobacco tar on a gram-for-gram basis can be produced by the selection and treatment of tobacco, the use of additives or tobacco sheets, or adjustments in the cut and packing density. Combustion temperature can also produce quantitative changes in the particulate matter of tobacco smoke. Although high-temperature burning produces less particulate matter in the smoke, it appears that tumorigenic components occur in higher concentration when tobacco is pyrolized at temperatures higher than 700° centigrade (34). Cigars, pipes, and cigarettes are similar in that they are smoked ~ orally and have a common site of introduction to the body. The tissues of the mouth, larynx, pharynx, and esophagus appear to receive ap- proximately equal exposure to the smoke of these products. Inhalation causes smoke to be drawn deeply into the lungs and also allows for . systemic absorption of certain constituents of tobacco smoke which then can be carried further to other organs. Pipe tobacco and cigars vary from cigarettes in a number of charac- teristics that can produce both quantitative and qualitative changes in the total particulate matter produced by their combustion. Experi- mental evidence suggests that although there is some difference in the amount and quality of tar produced by cigars, this cannot account for the reduced mortality observed in cigar smokers compared to cigarette smokers. Experimental Studies Several experimental investigations have been conducted to examine the relative tumorigenic activity of tobacco smoke condensates obtained from cigarettes, cigars, and pipes. Most. of these studies were standard. ized in an attempt to make the results of the cigar and pipe experiments more directly comparable with the cigarette data and most used the shaved skin of mice for the application of tar. Tars from cigars, pipes. and cigarettes were usually applied on an equal weight basis so that qualitative differences in the tars could be determined. In several ex- periments. the nicotine was extracted from the pipe and cigar conden- sates in an attempt to reduce the acute toxic effects that resulted in animals from the high concentrations of nicotine frequently found in these products. 210 Wynder and Wright (117) examined the differences in tumorigenic activity of pipe and cigarette condensates. Tars were obtained by the smoking of a popular brand of king-size cigarettes and the same ciga- rette tobacco smoked in 12 standard-grade briar bow] pipes. Both the cigarettes and pipes were puffed three times a minute with a 2-second puff and a 35-ml. volume. Both the cigarettes and pipes attained similar maximum combustion zone temperatures; however, the use of cigarette tobacco in the pipe resulted in a combustion chamber temperature that averaged about 150° centigrade higher than temperatures achieved when pipe tobacco was used. Chemical fractionation was accomplished and equal concentrations of the neutral fraction were applied in three weekly applications to the shaved skin of CAF, and Swiss mice. The results indicate that neutral tar obtained from cigarette tobacco smoked in pipes is more active than that obtained in the usual manner from cigarettes, About twice as many cancers were obtained in both the CAF, and the Swiss mice, and the latent period was about 2 months shorter. Extending these data, Croninger. et al. (20) examined the biologic activity of tars obtained from cigars. pipes, and cigarettes. Each form of tobacco was smoked as it was manufactured in a manner to simulate human smoking or to maintain tobacco combustion. The whole tar was applied in dilutions of one-to-one and one-to-two with acetone to the shaved backs of female CAF, and female Swiss mice using three applications each week for the life-span of the animal. The nicotine was extracted from the pipe and cigar condensates to reduce the acute toxicity of the solutions. The Swiss mice. pipe. cigar. and cigarette tars produced both benign and malignant tumors. The incidence rates of malignant tumors given as percents were: 44, 41, and 37. respectively. These results suggested a somewhat higher degree of carcinogenic activity for cigar and pipe tars than for cigarette tar. Similar results were reported by Kensler (52) who applied conden- sates obtained from cigars and cigarettes to the shaved skin of mice. The incidence of papillomas produced by cigar smoke concentrate was no different from that of the cigarette smoke condensate. Similarly, there was no difference between ci gar and cigarette smoke condensates when carcinoma incidences were compared, Homburger, ct al. (45) prepared tars from cigar, pipe, and cigarette tobaccos that were smoked in the form of cigarettes. In this way, all tobaccos were smoked in an identical manner and uniform combustion temperatures were achieved. Because of this standardization, differ- *nees in tumor yield could be attributed to tobacco blend and not the Manner in which the tars were prepared. The whole tars were diluted one-to-one with acetone and applied to the shaved skin of CAF, mice three times a week for the lifespan of the test animal. Skin cancers Were produced more quickly with pipe and cigar smoke condensates than with cigarette smoke condensates, This suggests that the smoking 15 495-028 O—73 213 of pipe and cigar tobaccos in the form of cigarettes does not alter the condensates to any significant degree. Davies and Day (22) prepared tars from small cigars especially manufactured from a composite blend of cigar tobacco representing small cigar brands smoked in the United Kingdom, cigarettes espe- cially manufactured from the same tobacco used for the cigars de- scribed above, and plain cigarettes especially manufactured from a composite blend of flue-cured tobacco representing the major plain cigarette brands smoked in the United Kingdom. The whole tar was diluted to four concentration levels and applied to the shaved backs of female albino mice for their lifespan using four dosing regimens, A statistically significant increase in mouse skin carcinogenicity was shown with the cigar smoke condensate compared with the tars obtained from either flue-cured or cigar tobacco cigarettes. These results are consistent with those of the previously reported investigations. The effect of curing on carcinogenicity was examined by Roe, et al. (76). Bright tobacco grown in Mexico was either flue-cured or air- cured and bulk fermented. Both fiue-cured and air-cured tobaccos were made into cigarettes standardized for draw resistance and were smoked under similar conditions. Condensates from these cigarettes were ap- plied to mouse skin three times each week in an acetone solution. The development of skin tumors was higher in mice treated with the flue- cured condensate than in mice treated with the air-cured condensate (P<0.01). The difference may have been due to the use of equal weights of condensate rather than the use of extracts from an equal number of cigarettes. The air-cured cigarettes produced a greater weight of condensate than did the flue-cured cigarettes. A chemical analysis of the two tobaccos and two condensates revealed only small differences in composition. Evidently air curing of Bright tobacco in the method used is not associated with a loss of reducing sugars. A more detailed analysis of these experimental studies is presented in table 31. These experimental data suggest that cigar and pipe tobacco con- densates have a carcinogenic potential that is comparable to cigarette condensates. This is supported by human epidemiological data for those sites exposed equally to the smoke of cigars, pipes. and cigarettes. The partially alkaline smoke derived from pipes and cigars is gen- erally not inhaled, and as a result there appears to be a lower level of exposure of the lungs and other systems to the harmful properties of pipe and cigar smoke than occurs with cigarette smoking. It is antic- ipated that modifications in pipe tobacco or cigars which would result in a product that was more readily inhalable would eventually result in elevated mortality from cancer of the lung, bronchitis and emphy- sema, arteriosclerotie cardiovascular diseases, and the other condi- tions which have been clearly associated with cigarette smoking. 212 £12 TABLE 31.—Tumorigenic activity of cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals [Key: A=Method. B=Frequency. C=Duration. D=Material.] Percent Author, reference Animal Activity Treatment Number a Papillomas Carcinomas Wynder and CAF, and A. Painting shaved skin. CAF;: Wright Swiss mice. B. 3 times a week. Pipe (cigarette tobacco)_____. 30 60 20 (117). C. Lifespan (24 months). Cigarette... 222 30 30 3 D. Neutral fraction tar from Swiss: cigarettes and cigarette Pipe (cigarette tobacco) ______ 30 63 50 tobacco smoked in pipes. Cigarette... 30 63 33 Croninger, et Female Swiss A. Painting shaved skin. Cigar, nicotine free (1:1)_._____ 46 65 41 al. (20). mice. B. 3 times a week. Pipe, nicotine free (1:1).__.____ 45 71 44 C. Lifespan. Cigar (1:2)-._- 22228 78 33 18 D, Whole tar diluted in Pipe, nicotine free (1:2)___.____ 89 30 16 acetone. Cigarette (1:1)_._-____.. Ll. 86 47 37 Acetone controls. _.__________. 23 0 0 Kensler (6%)__. Swiss mice_____. A. Painting shaved skin. Cigar tar (J) 100 mg. per week_. 100 42 41 B. 3 times a week. Cigarette tar (G) 100 mg. per 100 40 28 C. Lifespan. week. D. Whole tar diluted in Cigarette tar (E) 100 mg. per 100 34 34 acetone. week, Fle TaBLE 31.—Tumorigenic activity of cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals—Continued [Key: A=Method. B= Frequency. C=Duration. D=Material.] Percent Author, reference Animal Activity Treatment Number ———-—-——--—----—-- Papillomas Carcinomas Homburger, et CAF, mice------ A. Painting shaved skin. Cigar tobacco cigarettes ! 65 mg. 100 37.5 19 al. (48). B. 2 to 3 times a week. per week. C. Lifespan (2 years). Pipe tobacco cigarettes | 64 mg. 100 23 20 D. Whole tar diluted 50 per- per week. cent in acetone. Cigarettes | 62 mg. per week- --- 100 15 23 Acetone controls___~---------- 100 0 0 Davies and Female albino A. Painting shaved skin. Cigars, small 83 mm. long 150 144 44 27 Day (22). mice. B. Varied. per week. C. 116 weeks. Cigar tobacco cigarettes 150 72 32 14 D. Whole tar in 150 mg. per week. acetone. Cigarettes 150 per week_------- 144 28 13 Roe, et al. Female Swiss A. Painting shaved skin. Flue-cured Bright tobacco 180 400 52 30 (76). mice. B. 3 times a week. mg. per week. C. Lifespan. Air-cured Bright tobacco 180 400 68 23 D. Whole tar diluted in mg. per week. acetone. Acetone controls 0.75 cc. per 400 L.3 0.5 weck. 1 Cigar, pipe, and cigarette tobacco smoked as cigarettes at similar combustion temperatures. CARDIOVASCULAR DISEASES The majority of deaths in the United States each year are due to cardiovascular diseases. Cigarette smoking has been identified as a major risk factor for the development of coronary heart disease (CHD). However, pipe and cigar smokers experience only a small increase in mortality from coronary heart disease above the rates of nonsmokers. Cigarette smokers have higher death rates from cerebro- vascular disease than nonsmokers, whereas pipe and cigar smokers have cerebrovascular death rates that are only slightly above the rates of nonsmokers. Table 32 summarizes the major prospective epidemiologi- cal investigations that examined the association of smoking in various forms and total cardiovascular diseases, coronary heart. disease. and cerebrovascular disease. Doll and Hill. (28), Best (9), and Kahn (50) examined dose-response relationships for pipe and cigar smokers and- reported a slight increase in mortality from coronary heart disease with an increase in the number of cigars or pipefuls smoked. Other prospective epidemiological studies have also examined the relationship of smoking in various forms to coronary heart disease and related risk factors. Jenkins, et al. (49) in the Western Collaborative Group Study of coronary heart disease, reported an incidence of coro- nary heart disease in men aged 50 to 59 who were pipe and cigar smok- ers that was intermediate between the rates seen in cigarette smokers and nonsmokers. No increase in incidence of coronary heart disease was seen among the pipe and cigar smokers in the younger age groups. Shapiro, et al. (85), in a study of the health insurance plan (HIP) population, reported incidence rates for myocardial infarction, angina pectoris, and possible MI, in pipe and cigar smokers that. were similar to the incidence rates seen in cigarette smokers. These rates were con- siderably higher than those of nonsmokers. Data from the pooling project (47) suggested that the incidence of CHD deaths, sudden death, and the first major coronary event in pipe and cigar smokers was intermediate between the incidence experienced by cigarette smok- ers and nonsmokers. In contrast to these. studies, Doyle, et al. (30) reported no increase in CHD deaths, myocardial infarction, or angina pectoris in pipe and cigar smokers over the rates of nonsmokers in the Framingham study. The retrospective studies of Mills and Porter (64), Villiger and Heyden-Stucky (104), Schimmler, et al. (80), and Hood, et al. (46) contained data suggesting that pipe and cigar smokers experience mortality rates from coronary heart disease that are essentially similar to those experienced by cigarette smokers. The retrospective study of Spain and Nathan (86) reported lower rates of coronary heart, dis- ease in all smoking categories than were found in nonsmokers. Van Buchem (103) and Dawber, et al. (23) examined serum choles- terol levels in groups of individuals classified according to smoking 215 habits. In these two studies, pipe and cigar smokers had serum choles. terol levels that were nearly identical with the levels found in nonsmokers. Tibblin (97) and Dawber, et al. (23) investigated the effect of smok- ing on blood pressure. The proportion of smokers decreased in groups with higher blood pressures, although this was not as dramatic for pipe and cigar smokers as it was for cigarette smokers. In an experimental study using anesthetized dogs, Kershbaum and Bellet (54, 55) examined the effects of inhaled and noninhaled ciga- rette, cigar. and pipe smoke on serum free fatty acid levels and urinary catecholamine and nicotine excretion. In this study, inhalation of to- bacco smoke from all these sources resulted in similar increases in serum free fatty acids and in catecholamine and nicotine excretion. TABLE 32.—Mortality ratios for cardiovascular deaths in male cigar and pipe smokers. A summary of prospective epidemiological studies Type of smoking Author, reference Category Non- Cigar Pi Total Ciga- smoker only only pipe and rette only Mixed cigar Hammond and Cardiovascular 1.00 1.26 1.07 _____- 1.57 __LL_. Horn (40). total. Coronary._-_------- 1.00 1.28 1.03 ___.-- 1.70 _____. Cerebrovascular. - . _- 1.00 1.31 1.23 _____. 1.30 __L__. Doll and Hill Cardiovascular 1.00 _.--. _-_--- 0.99 1.26 1.13 (26, 27). total. Coronary___..------ 1.09 _---. ------ .94 1.23 118 Cerebrovascular -___- 1,00 __--. -___-- -95 1.18 97 Best (9)_..-_-_- Cardiovascular 1.00 1.14 .95 _____. 1.52 __ LL. total. Coronary__.-------- 1.00 .99 1.00 _-___- 1.60 _____- Cerebrovascular. ____ 1.00 1.28 .85 _____- .88 _____- Hammond ! Cardiovascular 1.00 __... _--__- 1.06 1.90 _____. (38). total. Coronary.._-------- 1.00 1.385 1.19 _____- 1.84 1.58 Cerebrovascular-___- 1.00 ____-_ ___-_- 1.09 1,41 1. 40 Kahn (50)______ Cardiovascular 1.00 1.05 106 1.05 1.75 _____. total. Coronary. ._-------- 1.00 1.04 1.08 1.05 1.74 _____- Cerebrovascular... - 1.00 1.08 1.09 1.06 1.52 _____- 1 Mortality ratios for ages 55 to 64 only are presented . Curoxtc OsstrectTive PutMonary Disease (COPD) Chronic bronchitis and pulmonary emphysema account for most of the morbidity and mortality from chronic respiratory disease in the United States. Cigarette smokers have higher death rates from these 216 diseases and have more pulmonary symptoms and impaired pul- monary function than nonsmokers. Cigarette smokers also have more frequent and more severe respiratory infections than nonsmokers. The relationship between smoking pipes and cigars and these diseases is summarized in this chapter. The major prospective epidemiological studies are summarized in table 33. In a retrospective study of 1,189 males and matched controls in Northern Ireland, Wicken (706) investigated smoking in various forms and mortality from bronchitis. The relative risk ratios com- pared to nonsmokers for mortality from chronic bronchitis were 1.98 for all smokers, 1.55 for pipe and cigar smokers, 2.25 for cigarette smokers, and 1.49 for mixed smokers. From a review of these prospective and retrospective studies, it appears that pipe and cigar smokers experience mortality rates from bronchitis and emphysema that are higher than the rates of non- smokers. Although these morality rates approach those of cigarette smokers, in most instances they are intermediate between the rates of cigarette smokers and nonsmokers. Pipe and cigar smokers have significantly more respiratory symp- toms and illnesses than nonsmokers. Those studies which contain data on pipe and cigar smoking as related to respiratory symptoms are summarized in table 34. Only a few studies have examined pulmonary function in pipe and cigar smokers. There appears to be little difference in pulmonary funce- tion values for pipe and cigar smokers as compared to nonsmokers (table 35). Naeye (67) conducted an autopsy study on 322 Appalachian coal workers who were classified according to the type of coal mined and tobacco usage. Emphysema was slightly greater in cigarette smokers, as were anatomic evidences of chronic bronchitis and bronchiolitis. Those changes found in pipe and cigar smokers were intermediate between those of cigarette smoking miners and nonsmoking miners. Changes in pulmonary histology in relation to smoking habits and age were examined by Auerbach, et al. (8). Fibrosis, alveolar rupture, thickening of the walls of small arteries, and thickening of the walls of the pulmonary arterioles were found to be highly related to the smoking habits of the 1,340 male subjects examined. The 91 pipe and cigar smokers over the age of 60 were found to have somewhat more alveolar rupture than the men of the same age distribution who never smoked regularly. However, pipe and cigar smokers as a group had far less rupture than cigarette smokers, The same relations as described above were found for fibrosis, thickening of the walls of the arterioles and small arteries, and padlike attachments to the alveolar septums. Tobacco smoke has been shown experimentally to have a ciliostatic ‘flect on the respiratory epithelium. The interval between puffs, the 217 amount of volatile and particulate compounds in the smoke, and the exposure volume have been shown to influence the toxic effect of tobacco smoke. Dalhamn and Rylander (2/7) exposed the upper trachea of anesthetized cats to the smoke of cigarettes and cigars, observing the effect on ciliary activity through an incident-light microscope. A chemical analysis of the gas and particulate phases revealed that the cigar smoke was more alkaline and, in general, contained higher concentrations of isoprene, acetone, acetonitrile, toluene, and total particulate matter compared to cigarette smoke. The average number of puffs required to arrest ciliary activity was found to be 73 for the cigarette smoke and 114 for the cigar smoke. The difference is statisti- cally significant (P <0.01). Of the two smokes, the smoke with the highest concentration of volatile compounds was found to be the least ciliostatic. This suggests that the degree of ciliotoxicity of a smoke is not necessarily correlated to the level of one or several of the substances found in the smoke. Passey, et al. (70. 71, 72) studied the effect of smoke from flue-cured cigarette tobacco cigarettes and air-cured cigar tobacco cigarettes on the respiratory system of rats. In two separate but similar experi- ments, a total of 48 animals were exposed to English cigarette tobacco smoke, 48 were exposed to air-cured cigar tobacco smoke, and 12 were exposed to an air-cured Burley tobacco smoke. The rats in groups were exposed to the specific smoke in a smoke-filled cabinet. Animals ex- posed to the smoke from air-cured tobaccos remained healthy through- out. the experiments, even at high levels of smoke exposure. The three deaths that occurred within this group were from nonrespiratory causes. In both experiments, the rats exposed to cigarette tobacco smoke began to die within 1 or 2 months, and in each experiment most of the animals died within a week or two of the first deaths. At autopsy the rats exposed to flue-cured tobacco smoke on gross examination were found to have greatly enlarged lungs, the trachea was often full of mucus, and there was evidence of pneumonia. On microscopic examina- tion it was found that the trachea and bronchi contained purulent cellular exudates. evidence of metaplastic changes, an absence of cilia, and goblet cell hpyerplasia. Typically. the cause of death was a lobar or bronchopneumonia. The author concluded that, “the smokes of flue- cured tobaccos are more dangerous to man and to animals than those of air-cured tobaccos.” 218 Unfortunately, few details were published concerning the method used to expose the animals to the different types of smoke. The fre- quency and duration of exposure were not specified, and the extent of actual inhalation of smoke by the different groups of rats was either not determined or not reported. It is also difficult to determine the effect of smoke exposure on the frequency and severity of respiratory infections when animals are exposed to smoke in groups where common exposure occurs. The rat strain used was not identified, but it was noted that animals appeared to suffer from an endemic rat bron- chiectasis. It is not known to what extent epidemics of respiratory infections occurred among these animals. Because of these difficulties, no firm conclusion can be drawn concerning the effect of smoking flue- cured or air-cured tobaccos on the incidence of respiratory infections in rats. TABLE 33.—Mortality ratios for chronic obstructive pulmonary deaths in male cigar and pipe smokers. A summary of prospective epidemio- logical studies Type of smoking Author, reference Category Non- Cigar Tipe Tota) Ciga- smoker only only pipe and rette only Mixed cigar Hammond and COPD total_.______ 1.00 129 1.77 _____ 2.85 ._____ Horn (40). Emphysema_____--. _.-. ----- ----- @- ee ee. Bronchitis_---..-..-. 222 2222. Lee. Lee ee. Doll and Hili COPD total___-...2 2-22 ©, lee ee ee. (26, 27). Emphysema___-.--. _... _-.-. 222-2 ___-. __ ee Bronchitis__________ 1.00 _---. _L_Le 4.00 7.00 6.67 Best (9)________ COPD total__...2-. _22. eee Lee Le. Emphysema__-_.____ 1.00 3.33 .75 _____ 5.85 _.-2_ Bronchitis__________ 1.00 3.57 2.11 _.___ 11.42 ___Lo. Hammond (38)... COPD total..___.-. ___. __._. ©... 22. 2 Emphysema. .______ 1.00 __-... LL. 1.37 16.55 ._____ Bronchitis-...-...-. ~22. 2-2. ole. Lee Kahn (60) ______ COPD total________ 100 .79 2.36 .99 10.08 ______ Emphysema_._-______ 100 1.24 2.13 1.31 14.17 _____. Bronchitis__________ 1.00 1.17 1.28 1.17 4.49 ______ ! Only mortality ratios for ages 55 to 64 are presented. 495-028 O—73—_16 219 TasLe 34.—Prevalence of respiratory symptoms and illness by type of smoking Percent prevalence Author, reference Number and type of Tiness population Non- Total Ciga- smoker pipe and rette Mixed cigar only Boake (10)... Parents of 59 Cough_____.------ 32 32 48 ______ families. Sputum 24 15 20 _____. production. Chest illness_._._- 5 4 5 Lule. Edwards, et 1,737 male Chronie bronchitis_ 17 119 31 14 al. (38). outpatients. Ashford, et 4,014 male Bronchitis_______- 10 «135 21 37 al. (4). workers in 3. Pneumoconiosis....60 11 134 14 2 Scottish collieries. Bower (11)... 95 male bank Cough..._._-_---- 0 0 29 _____. employees. Sputum 8 15 33 __o production. Wheeze___._-_-_.-- 8 31 33 _____. Chest illness____-_- 15 54 40 __L__. Wynder, etal. 315 male pa- Cough (New 14 33 56 51 (114). tients in York). New York Cough 22 30 67 66 and 315 male (California). patients in Influenza (New il 21 24 _____. California. York). Influenza 28 24 31 _.__L. (California). Chest illness 9 10 12 _.LLL. (New York). Chest illness 7 6 V1 LLL. (California). Densen, et al. 5,287 male Persistent cough- - 7 ll 25 __.--- (24). postal and Persistent 11 16 26 _____- 7,213 male sputum transit production. workers in Dyspnea__._.----- 16 19 26 ____-- New York Wheeze....-.----- 14 21 32 ____-- City. Chest illness__- ~~ - 13 16 18 ___.-- Cederlof, et 4,379 twin pairs, Cough_.--------- 4 7 17 ___--- al. (18). all U.S. Prolonged cough. -- 2 4 11 ___.-- veterans. Bronchitis -—.------ 2 3 10 __.--- Rimington 41,729 male Chronic bronchitis - 5 19 17 __---- (76). volunteers. 220 TaBLE 34.—Prevalence of respiratory symptoms and illness by type of smoking—Continued Percent prevalence Author, reference Number and type of Illness population Non- Total Ciga- smoker pipe and rette Mixed cigar only Comstock, et 670 male tele- Persistent cough._ 10 16 41.2 LL. al. (19). phone Persistent 13 20 42 _____. employees. sputum. Dyspnea________. 33 39 44 _____. Chest illness in 14 18 20 _____. past 3 years. Lefeoe and 310 male phy- Chronic respira- 9 18 44 Wonnacott sicians in tory disease. (69). London, Chronic bronchitis. 1 12 34 _____. Ontario. Obstructive lung 1 3 4 LLL disease. Asthma__________ 7 3 6 _-___. Rhonchi_________. 0 3 9 LLL 1 Figures for pipe only. TaBLE 35.—Pulmonary function values for cigar and pipe smokers as compared to nonsmokers Type of smoking Author, reference Number and type Function of population Non- Total pipe Cigarette Mixed smoker and cigar only Ashford, et 4,014 male FEV, ,9_--.__- 3.39 12.59 3.14 2.62 al. (4). workers in 3 Scottish collieries. Goldsmith, 3,311 active Puffmeter____ 313.63 299.26 303.44 __.___ et al. (37). or retired FEV} .9---.__- 2. 99 2. 80 2.91 ______ longshore- TVC_._______ 3. 87 3. 68 3.88 ______ men. Comstock, 670 male FEV; .9-.---_- 3, 12 3. 26 2.82 _ 2. et al. (19). telephone employees. Lefeoe and 310 male FEV, 9_.-____ 3. 39 3.17 3.11 22. Wonnacott physicians MMFR liters 4.09 4.17 3. 64 ___2__ (69). in London, per second. Ontario. ' Figures for pipe only. 221 GASTROINTESTINAL DISORDERS Cigarette smokers have an increased prevalence of peptic ulcer disease and a greater peptic ulcer mortality ratio than is found in nonsmokers. These relationships are stronger for gastric ulcer than for duodenal ulcer. Cigarette smoking appears to reduce the effective- ness of standard peptic ulcer treatment regimens and slows the rate of ulcer healing. Cigar and pipe smokers experience higher death rates from peptic ulcer disease than nonsmokers. These rates are higher for gastric ulcers than for duodenal ulcers but are somewhat less than those rates experienced by cigarette smokers. Table 31 presents the mortality ratios for ulcer disease in cigar and pipe smokers as reported in the prospective epidemiological studies. Retrospective or cross-sectional studies by Trowell (95), Allibone and Flint (2), Doll, et al. (29), and Edwards, et al. (33) contain data on ulcer disease in pipe smokers as well as cigarette smokers. No association was found between pipe smoking and ulcer disease in these investigations. TaBLE 36.—Mortality ratios for peptic ulcer disease in male cigar and pipe smokers. Summary of prospective studies Type of smoking Author, reference Tliness Total Ciga- Non- Cigar Pipe pipe rette Mixed smoker only only and only cigar Hammond and Duodenal ulcer_.-.-- 1.00 0,25 1. 67 _----- 2.16 _._..- Horn (40). Doll and Hill Gastric ulcer__------ 1.00 _...- ----- 4.00 7.00 5.30 (86, 27). Hammond (38)__ Gastric ulcer_-_----- 1.00 _-.-- ----- 2.04 2.95 .-_-_- Duodenal ulcer_-_..- 1.00 ----- ----- .92 2.86 __---- - Kahn (50)_----- Gastric ulcer__..--.. 1.00 2.90 2.84 2.48 4.13 -__-_- Duodenal ulcer--_---- 1.00 1.58 1.59 1.39 2.98 _-_.-- Little Cigars In the past year, several new brands of little cigars (weighing 3 pounds or less per 1,000) have appeared on the national market. These cigarette-sized products are manufactured, packaged, advertised, and sold in a manner similar to cigarettes. Little cigars enjoy several legal advantages over cigarettes: They have access to television advertising; they are taxed by the Federal Government and by most States, at much lower rates than cigarettes, resulting in a significant price advantage; - 222 and they do not carry the warning label required on cigarette pack- ages and in cigarette advertising. A market appears to be developing for these products, as there has recently been a sharp increase in the shipment of little cigars destined for domestic consumption (table 37). It is important to estimate the potential public health impact of these little cigars. An adequate epidemiological evaluation of the ef- fect of little cigar smoking on health could take 10 or 15 years and is probably an impractical consideration ; however, a review of the epide- miological, autopsy, and experimental data concerning the health con- sequences of cigarette, pipe, and cigar smoking summarized in this and previous reports is helpful in considering the potential impact on health of smoking little cigars. An analysis of the chemical constit- uents suggests that both cigarettes and cigars contain similar com- pounds in similar concentrations. Two exceptions are reducing sugars, which are not found in quantity in the fermented tobaccos commonly used in cigars, and the pH of the inhaled smoke. The pH of the smoke from U.S. commercial cigarettes is below 6.2 from the first to the last puff, whereas the smoke from the last half of a cigar may reach as high as pH 8 to 9. With increasing pH, nicotine is increasingly present in the smoke as the free base. Skin painting experiments in mice indicate that tumor yields with cigar or pipe “tars” are nearly identical with those obtained with cigarettes “tars”. In addition, the epidemiological data suggest that depth of inhalation probably accounts for the fact that cigarettes are so much more harmful than cigars and pipes in con- tributing to the development of lung cancer, coronary heart disease, and nonneoplastic respiratory disease. For such diseases as cancer of the oral cavity, larynx, and esophagus, where smoke from cigars, pipes, and cigarettes is available to the target organ at comparable levels, the mortality ratios are very similar for all three forms of tobacco use. Several factors, including “tar,” nicotine, and the pH of the smoke, probably operate to influence inhalation patterns of smokers. The relative contribution of individual factors to the inhalability of a tobacco product has not been determined. Smoking those brands of little cigars which can be inhaled by a significant portion of the population in a manner similar to the pres- ent use of cigarettes would probably result in an increased risk of de- veloping those pulmonary and cardiovascular diseases which have been associated with cigarette smoking. On the other hand, smoking those little cigars which are used like most large cigars whereby the smoke is rarely inhaled would probably result in lower rates of those pulmonary and cardiovascular diseases than would be found among cigarette smokers. Only a limited analysis is available comparing the chemical com- pounds found in little cigars, cigarettes, and large cigars. The FTC analyzed the tar and nicotine content of all the little cigars (84) and cigarettes (97) currently available on the market, Little cigars have 223 generally a higher “tar” and nicotine level than cigarettes, although considerable overlap results in some little cigar brands having “tar” and nicotine levels comparable to those of some brands of cigarettes (figs. 4 and 5). Hoffmann and Wynder (44) recently compared three brands of little cigars with an unfiltered cigarette, a filtered cigarette, and a large cigar. They measured a number of smoke constituents, in- eluding: “tar,” nicotine, carbon monoxide, carbon dioxide, reducing sugars, hydrogen cyanide, acetaldehyde, acrolein, pyridines, phenols, benz(a)anthracene, and benzo(a)pyrene (table 32). Cigarette A was the Kentucky reference cigarette, cigarette B was a popular brand of filter cigarette. Cigar A was an 85 mm, little cigar, cigar B was an 85 mm. little cigar, cigar C was a 95 mm. small cigar, and cigar D was a 112 mm. popular brand of medium sized cigar. The smoke pH was analyzed puff by puff (table 39). Cigarette smoke was found to be acidic (pH less than 7) for the entire cigarette. The smoke from little cigars became alkaline only in the last puff or two, whereas about the last 40 percent of the puffs from the larger cigar were alkaline. Although the pH of the total condensate obtained from cigarettes is usually acidic and the total condensate obtained from cigars is usually alkaline, the above data indicate that smoke pH of tobacco products changes during the combustion process. Smoke from large cigars may be acidic during the first portion of the smoke and not become alkaline until the last half of the cigar is smoked. Brunnemann and Hoffmann (15), using the same techniques de- scribed above. examined the effect of 60 leaf constituents on smoke pH. For several varieties of cigarette tobacco, they found a high correlation between the total aklaloid and nitrogen content and smoke pH. Stalk position also affected smoke pH. Tobacco leaves near the top of the plant, which contain high levels of tar and nicotine, yielded a smoke with a much higher pH than leaves lower on the plant. At present it is not known to what extent. these factors influence the pH of the smoke of tobaccos commonly used in cigars or how these kinds of pH changes influence the inhalability of tobacco smoke. The inhalation of smoke, however, appears to be the most important factor determining the impact a cigar will have on overall health. Those physical and chemical characteristics of a tobacco product which most influence inhalation of tobacco smoke have not been accurately determined. Nevertheless, it appears likely that the smoke of some brands of cigars may be compatible with inhalation by a sig- nificant. portion of the smoking population, since: (a) Little cigars have tar and nicotine levels which. in some brands, are similar to the levels found in cigarettes, and (>) the pH of the smoke of some little cigar brands is acidic for the major portion of the little cigar and becomes alkaline only in the last puff or two. 224 It is reasonable to conclude that smoking little cigars may result in health effects similar to those associated with smoking cigarettes if little cigars are smoked in amounts and with patterns of inhalation similar to those used by cigarette smokers, for the reasons cited above, and these additional reasons: (a) In those little cigars for which pre- liminary data are available, the concentrations of carbon monoxide, hydrogen cyanide, acetaldehyde, acrolein, pyridine, phenol, and poly- eyclic hydrocarbon levels are comparable to those found in cigarettes: (8) cigarette smokers who switch to cigars appear to be more likely to inhale cigar smoke than cigar smokers who have always smoked cigars (74); and (c) cigarette smokers who switch to little cigars may be inclined to use them as they did cigarettes because of the physical similarities between the little cigars and cigarettes, including their size and shape, the number in a package, the burning rate, and the time it. takes to smoke them. Figure 4.-—Percent distribution of 130 brands of cigarettes and 25 brands of little cigars by “tar’’ content. 50} 4s [Cigarettes VY / /] Little Cigars | wo} g 35} i) ° 30t iY) & ) G a =. 2 ) 8 o 9 25 P i) e * ) 20} i) Z 15} 4 4 10} Z ‘| Y | of A LIM te. || Mg. “‘tar’’ 0 0 0 16.0 8.0 32.0 32.0 0 8.0 4.0 Cigarettes 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 Little Cigars 3.1 3.1 10.0 46.2 23.1 10.0 39 08 0 0 SOURCE: U.S. Department of Health, Education, and Welfare (97) and Federal Trade Commission (34), 225 Figure 5.—Percent distribution of 130 brands of cigarettes and 25 brands of little cigars by nicotine content. 50 Cigarettes 45 | Little cigars -——4 o a “OT 4 = 35+ J 5 30} iy ° 4 @ >] g 44 g 20} 4 @ 15+ 4 10} Z | iY 5 1 4 0 Vi ZI A Zl mm | 42 ££ 8 § 2 eR eB, @ = toe | m= = A WN 3 Ry ag eg 22 48 2288 < Oo oO o o + a 4 oo N A v * g2 4% © an oO 2 8 + 4© 8 6 é w ” + ” 9 q a 0 a m oe ° © © & @ G@ go ° ge = 2 XN + s s a + o 4g Go & ro Vv SOURCE: U.S. Department of Health, Education, and Welfare (97) and Federal Trade Com- mission (34). 226 TasLe 37.—Shipment of small and large cigars destined for domestic consumption (1970, 1971, 1972) Year 1970 1971 1972 Small cigars January__._______.____- 58, 328, 520 85, 753, 780 123, 477, 550 February._._-...__--___- 63, 431, 580 72, 092, 205 179, 817, 839 March. ___.-___.-___-__- 85, 881, 860 46, 542, 800 198, 165, 593 April____- 22 101, 613, 500 59, 059, 920 125, 335, 740 May..---_._-----_ ee 81, 093, 180 93, 237, 473 159, 334, 565 June__.--- 2-2. 82, 471, 120 94, 560, 140 180, 582, 243 Subtotal__________ 472, 819, 760 451, 246, 318 966, 713, 530 July. 22-222 eee 62, 143, 140 70, 332, 500 127, 713, 320 August_.._-__._________ 68, 220, 365 127, 709, 310 670, 936, 869 September_.._____._____ 79, 101, 045 95, 027, 340 422, 534, 705 October. ...-_---.-_-_- 90, 752, 880 109, 567, 900 708, 116, 830 November_______-______ 64, 290, 600 106, 666, 107 551, 326, 888 December__._..__.____- 63, 806, 010 123, 809, 553 485, 587, 014 Subtotal___.______ 428, 314, 040 633, 112, 710 2, 966, 215, 626 Yearly total__._.__ 901, 133,800 1, 084, 359,028 = 3, 932, 929, 156 Large cigars January.-.-.---2_-___. 581, 742, 001 573, 039, 120 534, 565, 488 February.__._...._.___- 595, 249, 522 586, 810, 844 562, 414, 577 March_______. 222-28 629, 977, 375 665, 998, 099 654, 827, 796 April__...--_------____- 652, 800, 200 655, 850, 213 554, 242, 048 May..._.--_- ee 748, 040, 796 670, 064, 933 719, 489, 529 June____--- 2-2 644, 539, 031 692, 436, 529 578, 501, 068 Subtotal___.__-____ 852, 348,925 3, 844, 199, 738 3, 604, 040, 506 July. 2222-2 ee 647, 397, 547 619, 838, 386 520, 873, 339 August... 222 673, 082, 971 662, 970, 148 682, 331, 630 September___.__._______ 721, 561, 449 680, 476, 418 594, 843, 957 October. ._--. 2-2. 797, 601, 253 679, 420, 968 693, 150, 668 November_._.__-__-____ 696, 526, 464 742, 948, 802 650, 746, 540 December. .____-______- 596, 244, 159 516, 879, 415 437, 429, 996 Subtotal__________ 4, 132, 413, 843 3, 902, 534,137 3, 579, 356, 130 Yearly total______ 8, 084, 762, 768 7, 746, 733, 875 7, 183, 396, 636 Source: U.S. Department of the Treasury (101). 227 TABLE 38.—Selected compounds in mainstream smoke Smoke compound Cigarette A Cigarette B Little Little Small (onfilter) (filter) cigar A cigar B elgar C “Tar”, milligram per cigarette... 36. 1 20. 3 17. 4 31.8 40. 6 Nicotine, milligram per cigarette _ 2.7 14 .6 1.8 3. 1 Carbon monoxide, volume per- cent. _-.--.----------- ieee 4.6 4.5 5.3 111 7.7 Carbon dioxide, volume percent__ 9. 4 9. 6 8.5 13. 2 12.7 Reducing sugars, percent of tobacco weight______________ 9.3 7.9 1.5 2.9 2.7 Hydrogen cyanide, microgram per cigarette____._-_-_.._._.- 5386.0 361.0 381.0 697.0 1,029.0 Acetaldehyde, microgram per cigarette.__..._._-___-_-_._- 770.0 774.0 630.0 1,238.0 1, 150.0 Acrolein, microgram per cigar- ette__----_------- eee eee. 105. 0 71.0 41.0 54. 0 66. 0 Total pyridines, micrograms per cigarette-_.__.______.__-_-_. 82.8 27. 3 58. 0 85. 3 80. 3 Phenol, microgram per cigarette_. 124. 2 33. 0 35. 1 63. 4 94, 1 Benz(a)anthracene, nanogram per cigarette_______.______-- 74,0 31.0 34. 0 25. 0 39. 0 Benzo(a)pyrene, nanogram per cigarette__......--_._----___- 47.0 20. 0 18. 0 22. 0 30. 0 Source: Hoffmann, D., Wynder, E. L. (44). TABLE 39.— The pH of the mainstream smoke of selected tobacco products [Numbers in parentheses indicate number of last puff.] Average pH Cigarette A Cigarette B Little Little Small Cigar D (nonfilter) (filter) cigar A cigar B cigar C 3d puff__._- 6. 19 6.15 6. 44 6. 55 6. 53 6. 47 5th puff.__. 6.14 6. 12 6. 34 6. 46 649 9 _LLL eee 7th puff__._ 6. 09 6. 01 7. 03 6. 51 656 = ___-uuee 9th puff._.. 6. 02 §.83 _l_ eee 6. 98 6. 59 6. 27 13th puff... 2 eee Lee eee Lee ee eee eee eee 6. 39 18th puff... 2 Lee eee eee eee eee eee eee 6. 41 Q3d puff... ee ee eee eee eee eee 6. 81 28th puff_.. _.------ eee eee eee eee eee eee eee eee 7. 22 33d puff_--8 8 eee eee eee 7.53 38th puff... 28 eee eee eee eee 7.78 Last puff___ 5.96(11) 5. 76(10) 7.73 (8) 7.25(10) 7.11(11) 7. 96(43) Source: Hoffmann, D., Wynder, E. L. (44). 228 Conclusions Pipe and cigar smokers in the United States as a group experience overall mortality rates that are slightly higher than those of nonsmok- ers, but these rates are substantially lower than those of cigarette smokers. This appears to be due to the fact that the total exposure to smoke that a pipe or cigar smoker receives from these products is relatively low. The typical cigar smoker smokes fewer than five cigars a day and the typical pipe smoker smokes less than 20 pipefuls a day. Most pipe and cigar smokers report that they do not inhale the smoke. Those who do inhale, inhale infrequently and only slightly. As a result, the harmful effects of cigar and pipe smoking appear to be largely limited to increased death rates from cancer at those sites which are exposed to the smoke of these products. Mortality rates from cancer of the oral cavity. intrinsic and extrinsic larynx, pharynx, and esophagus are approximately equal in users of cigars, pipes, and ciga- rettes. Inhalation is evidently not necessary to expose these sites to tobacco smoke. Although these are serious forms of cancer, they account for only about 5 percent of the cancer mortality among men. Coronary heart disease, lung cancer, emphysema, chronic bronchitis, cancer of the pancreas, and cancer of the urinary bladder are diseases which are clearly associated with cigarette smoking, but for cigar and pipe smokers death rates from these diseases are not greatly elevated above the rates of nonsmokers. These diseases seem to depend on mod- erate to deep inhalation to bring the smoke into direct. contact with the issue at risk or to allow certain constituents, such as carbon mon- oxide, to be systematically absorbed through the lungs or to affect the temporal patterns of absorption of other constituents such as nicotine that can be absorbed either through the oral mucosa or through the lungs. Evidence from countries where smokers tend to consume more cigars and inhale them to a greater degree than in the United States indicates that rates of ling cancer become elevated to levels approach- ing those of cigarette smokers. Available data on the chemical constituents of cigar, pipe, and cigarette smoke suggest that there are marked similarities in the com- position of these products. Pipe and cigar smoke, however, tends to be more alkaline than cigarette smoke, and fermented tobaccos com- monly used in pipes and cigars contain less reducing sugars than the rapidly dried varieties commonly used in cigarettes. Experimental evidence suggests that little difference exists between the tumorigenic activities of tars obtained from clgar or cigarette 229 tobaccos. Malignant skin tumors appear somewhat more rapidly and in larger numbers in animals whose skin has been painted with cigar tars than in those animals painted with cigarette tars. One must conclude that some risk exists from smoking cigars and pipes as they are currently used in the United States, but. for most diseases this is small compared to the risk of smoking cigarettes as they are commonly used. Nevertheless, changes in patterns of usage that would bring about increased exposure either through increased indi- vidual use of cigars and pipes or increased inhalation of pipe and cigar smoke have the potential of producing risks not unlike those now incurred by cigarette smokers. Mechanical or chemical modifications of pipe tobacco and cigars that would result in a smoke more compat- ible with inhalation could have this effect. Pipe and Cigar 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) ALLmonE, A., Fuint, F. J. Bronchitis, aspirin, smoking, and other factors in the aetiology of peptic ulcer. Lancet 2: 179-182, July 26, 1958. (3) Armitage, A. K., TURNER, D. M. Absorption of nicotine in cigarette and cigar smoke through the oral mucosa. Nature 226(5252) : 1231-1232, June 27, 1970. (4) Asurorp, J. R., Brown, 8., Durriexp, D. P., Smiru, 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. (5) AvERBACH, O., HammMonn, E. C., GARFINKEL, L. Histologic changes in the larynx in relation to smoking habits. Cancer 25 (1) : 92-104, January 1970. (6) 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(3) : 111-119, July 19, 1962. (7) AuversacH, O., Stout, A. P., HAMMOND, E. C., GARFINKEL, L. Histologic changes in esophagus in relation to smoking habits. Archives of Environ- mental Health 11(1): 4-15, July 1965. (8) AuerpacH, O., Stout, A. P.. HamMMonp, E. C., GaARFINKEL, 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, Nov. 14, 1968. (9) Best, E. W. R. A Canadian Study of Smoking and Health. Ottawa, Depart- ment of National Health and Welfare, 1966, 137 pp. (10) Boake, W. C. A study of illness in a group of Cleveland families. XVIII. Tobacco smoking and respiratory infections. New England Journal of Medicine 259(26) : 1245-1249, Dec. 25, 1958. (11) Bower, G. Respiratory symptoms and ventilatory function in 172 adults employed in a bank. American Review of Respiratory Diseases 83: 684-689, 1961. 230 (12) BrapsHaw, E., ScHONLAND, M. Oesophageal and lung cancers in Natal African males in relation to certain socioeconomic factors. An analysis of 484 interviews. British Journal of Cancer 23(2) : 275-284, June 1969. (13) Bropers, A. C. Squamous-cell epithelioma of the lip. A study of 587 cases. Journal of the American Medical Association 74: 656-664, Mar. 6, 1920. (14) Bross, I. D. J., Tipines, J, Switching from cigarettes to small cigars— is it likely to reduce the health hazards of smoking? In press: Proceed- ings of the American Association for Cancer Research, March 1973. (15) Brunnemann, K. D., Horraann, D. On the pH of tobacco smoke. Paper presented at the CORESTA/TCRC meeting, Williamsburg, Va., Oct. 23, 1972, 18 pp. (16) Bury, P., Dunn, J. E., Jr., Brestow, L. Cancer of the lung and Los Angeles-type air pollution. Prospective study. Cancer 20(12) : 2139-2147, December 1967. (17) CamMpsBeLL, J. M., Linpsey, A. J. Polyeyclic hydrocarbons in cigar smoke. British Journal of Cancer 11: 192-195, 1957. (18) CEDERLOF, R., Frizere, L., Hrupec, 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. (19) Comstock, G. W., Browntow, W. J., Srone, R. W., Sartwe.y, P. E. Cigarette smoking and changes in respiratory findings. Archives of Environmental Health 21 (1) : 50-57, July 1970. (20) CRonincER, A. B., Grauam, E. A., Wyrwoer, E. L. Experimental produc- tion of carcinoma with tobacco products. V. Carcinoma induction in mice with cigar, pipe, and all-tobacco cigarette tar. Cancer Research 18 : 1263-1271, December 1958. (21) DALHAMN, T., RYLAnveR, R. Ciliotoxicity of cigar and cigarette smoke. Archives of Environmental Health 20(2) : 252-253, February 1970. (22) 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. (23) Dawser, T. R., KANNEL, W. B., REvorTskiE, 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) : 1349-1356, October 1959, (24) DEnsen, P, M., Jones, E. W., Bass, H. E., Breuer, J, A survey of respira- tory disease among New York City postal and transit workers. I, Prevalence of symptoms. Environmental Research 1(3) : 262-286, No- vember 1967, (25) Dott, R., Hi, A. B. A study of the aetiology of carcinoma of the lung. British Medical Journal 2: 1271-1286, Dec. 13, 1952. (26) Dox, R., Hin, A. B. Mortality in relation to smoking: Ten years’ ob- Servations of British doctors. (Part 1). British Medical Journal 1(58395) : 1899-1410, May 30, 1964. (27) Dott, R., Hz, A. B. Mortality in relation to smoking: Ten years’ ob- servations of British doctors. (Concluded). British Medical Journal 1(5396) : 1460-1467, June 6, 1964. (28) Dott, R., HILL, A. B. Mortality of British doctors in relation to smoking: Observations on coronary thrombosis. In: Haenszel, W. (Editor). Epi- demioclogical 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. 205-215. (29) Do. R., Jones, F. A., Pyeorr, F. Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet 1: 657-662, Mar. 29, 1958. 231 (30) (32) (32) (33) (34) (33) (36) (37) (38) (39) (49) (41) (43) (44) (45) 232 Dove, J. T., Dawzer, T. R., KANNELL, W. B., Krncu, 8. 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 Associa- tion 190(10) : 886-890, Dec. 7, 1964. Dunn, J. E., Jr. Linpen, G., BREsLow, L. Lung cancer mortality expe- rience of men in certain occupations in California. American Journal of Public Health and the Nation’s Health 50(10) : 1475-1487, October 1960. EseEnius, B. Cancer of the lip. A clinical study of 778 cases with particular regard to predisposing factors and radium therapy. Acta Radiologica (Supplement 48) : 1-232, 1943. Epwarps, F., McKeown, T., Wuitrietp, A. G. W. Association between smoking and disease in men over sixty. Lancet 1: 196-200, Jan. 24, 1959. FepERAL TRADE COMMISSION. Report of tar and nicotine content of the smoke of 25 varieties of small cigars. In: Federal Trade Commission News, 1-0703. Jul 3 1972, 2 pp. FRANKENBURG, W. G. Chemical changes in the harvested tobacco leaf. I. Chemical and enzymic conversions during the curing process. Ad- vances in Enzymology 6 : 309-387, 1946. FRANKENBURG, W. G. Chemical changes in the harvested tobacco leaf. II. Chemical and enzymic conversions during fermentation and aging. Advances in Enzymology 10 : 325-441, 1950. GotpsMiTH, J. R., Hecuter, H. H., Perkins, N. M., Borwani, N. O. Pulmonary function and respiratory findings among longshoremen. American Review of Respiratory Diseases 86(6) : 867-874, December 1962. Hamwonp, E. C. Smoking in relation to the death rates of one million men and women. Jn: Haenszel, W. (Editor). Epidemiological Ap- proaches 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. Hamomonp, E. C., GARFINKEL, L, The influence of health on smoking habits. 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. 269-285. Haw onp, E. C., Horx, D. Smoking and death rates—Report on 44 months of followup of 187,783 men. I. Total mortality. Journal of the American Medicat Association 166(10) : 1159-1172, Mar. 8, 1958. Hamonp, E. C.. Horn, D. Smoking and death rates—Report on 44 months of followup of 187,783 men. II. Death rates by cause. Journal of the American Medical Association 166(11) : 1294-1308, Mar. 15, 1958. Hirayama, T. Smoking in relation to the death rates of 265.118 men and women in Japan. A report of 5 years of followup. Presented at the American Cancer Society's Fourteenth Science Writers’ Seminar, Clear- water Beach, Fla., Mar. 27, 1972, 15 pp. HorrMann, D., RATHKAMP, G., WYNDER, E. L. Comparison of the yields of several selected components in the smoke from different tobacco products. Journal of the National Cancer Institute 31(3): 627-637, September 1968. HorrMann, D., Wynper, E, L. Smoke of cigarettes and little cigars. An analytical comparison. Science 178(4066) : 1197-1199, Dee. 15. 1972. Howsercer, F.. TRecer, A.. BAKER, J. R. Mouse-skin painting with smoke condensates from cigarettes made of pipe, cigar, and cigarette tobaccos. (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56) (87) (58) (59) (60) (61) (62) Journal of the National Cancer Institute 31(6) : 1445-1459, December 1963. Hoop, B., Trssiin, 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. InTER-SocrETyY COMMISSION FOR Heart DIsEAsSE Resources. Atherosclero- sis Study Group and Epidemiology Study Group. Primary prevention of the atherosclerotic diseases. Circulation 42(6); A-54—A-95, December 1970. Isaac, P. F., Rann, M. J. Cigarette smoking and plasma levels of nico- tine. Nature 236 (5345) :308-310, April 7, 1972. JENKINS, C. D., RoseNMAN, R. H., Zyzansk1, S. J. Cigarette smoking. Its relationship to coronary heart disease and related risk factors in the Western Collaborative Group Study. Cireulation 38(6) : 1140-1155, December 1968. Kaun, H. A. The Dorn study of smoking and mortality among U.S. veterans : Report on 81% 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. 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. Ketter, A. Z. Cirrhosis of the liver, alcoholism, and heavy smoking asso- ciated with cancer of the mouth and pharynx. Cancer 20(6) : 1015-1022, June 1967. KENsLER, C. J. The pharmacology of tobacco smoke effects of chronic exposure. In: James, G., Rosenthal, T. (Editors). Tobacco and Health, Springfield, C. C. Thomas, 1962, pp. 5-20. KERSHBAUM, A. A. comparative study of cigarette, cigar, and pipe smoking effects on blood lipids, catecholamine excretion, and nicotine content of the urine. Acta Cardiologica 23(4) : 317-329, 1968. KERSHBAUM, A., BELLET, 8S. Cigarette, cigar, and pipe smoking. Some differences in biochemical effects. Geriatrics 23 (3) : 126-134, March 1968. 255-260, 1958. Kovroumiss, M. Smoking and pulmonary carcinoma. Acta Radiologica 39: 255-260, 1953. Kwnuptson, K. P. The pathologic effects of smoking tobacco on the trachea and bronchial mucosa. American Journal of Clinical Pathology 33(4) : 310-317, April 1960. Kuun, H. A comparative study of cigarette and cigar smoke. In: Pro- ceedings of the Fourth International Tobacco Scientific Congress. The National Tobacco Board of Greece, Athens, Sept. 19-26, 1966, pp. 967-971. Lercor, N. M., Wonnacort, T. H. The prevalence of chronic respiratory disease in the male physicians of London, Ontario. Canadian Medical Association Journal 102 : 381-385, Feb. 28, 1970. Levin, M. L., GoLpstern, H., GERHARDT, P, R. Cancer and tobacco smoking. A preliminary report. Journal of the American Medical Association 143 (4) : 3836-838. May 27, 1950. Lomsarp, H. L., SNeGIREFF, L. 8. An epidemiological study of lung cancer. Cancer 12(2) : 406-413, March-April 1959, 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. 233 (G3) (64) (65) (66) Martinez, I. Retrospective and prospective study of carcinoma of the esophagus, mouth, and pharynx in Puerto Rico. Boletin de la Asociacion Medica de Puerto Rieo 62(6) : 170-178, June 1970. Mitts, C. A., Porter, M. M. Tobacco smoking and automobile-driving stress in relation to deaths from cardiac and vascular causes. American Journal of the Medical Sciences 234 : 35-43, July 1957. Mitts, C. A., Porter, M. M. Tobaceo smoking habits and cancer of the mouth and respiratory system. Cancer Research 10: 539-542, 1950. Mutts, 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. (67) NaryYE, R. L. Structural features in Appalachian coal workers, In: Key, (68) (69) (70) (71) (72) (73) (74) (7%) (76) (77) (78) (79) (80) 234 M. M., Kerr, L. E., Bundy, M. (Editors). Pulmonary Reactions to Coal Dust. A Review of U.S. Experience. New York, Academic Press, 1971, pp. 93-110. Osman, S., Barson, J. Hydrocarbons of cigar smoke. Tobacco 159 (24): 30-32, Dec. 11, 1964. Osman, S., SCHMELTz, I., Hieman, H. C., STEDMAN, R. L. Volatile phenols of cigar smoke. Tobacco 157 (9) : 30-32, Aug. 30, 1963. Passer, R. D., BLAcKMoRE, M. Biological effects of cigar and cigarette smoke. British Empire Cancer Campaign for Research, Annual Report 44(Part 2) : 6, 1966. Passey, R. D., BLACKMORE, M. The causation of lung cancer. Some experi- mental biological effects of cigar and cigarette smoke. (Abstract) Thorax 22(3) : 290, May 1967. Passer R. D., BLACKMORE, M., WaRBRICK-SMITH, D., Jones, R. Smoking risks of different tobaccos. British Medical Journal 4(5781) : 198-201, Oct. 23, 1971. Peenu, 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. Ranoia, K. Untersuchungen zur Atiologie des Bronchialkarzinoms. (In- vestigations on the etiology of bronchial carcinoma.) Offentliche Gesun- deheitsdienst 16(9) : 305-313, December 1954. Rrmincron, 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, October 1969. Rog, F. J. C., Crack, J. C., BrsHop, D., Pero, R. Comparative circinogenicity for mouse-skin of smoke condensates prepared from cigarettes made from the same tobacco cured by two processes. British Journal of Cancer 24(1): 107-121, March 1970. Sapowsky, D. A., GILLIAM, A. G., CoRNFIELD, J. The statistical association between smoking and carcinoma of the lung. Journal of the National Cancer Institute 13: 1287-1258, 1953. SANDERUD, K. Squamous metaplasia of the respiratory tract epithelium ; an autopsy study of 214 cases. II. Relation to tobacco smoking, occupa- tion and residence. Acta Pathologica et Microbiologica Scandinavica 48: 47-61, 1958. SCHIEVELBEIN, H., EBERHARDT, R. Cardiovascular actions of nicotine and smoking. Journal of the National Cancer Institute 48(6) : 1785-1794, June 1972. ScHIMMLER, W., NeFr, C., ScHIMERT, G, Risikofaktoren und Herzinfarkt. Eine retrospektive Studie. (Risk factors and myocardial infarct. A retro- spective study.) Miinchener Medizinische Wochenschrift 110(27) : 1585- 1594, July 5, 1968. (81) (82) (83) (84) (85) (86) (87) (88) (89) (90) (91) (92) (93) (94) (95) (96) (97) ScuRrek, R., BAKER, L. A., BALLARD, G. P., Dotcorr, 8S. Tobacco smoking as an etiologic factor in disease. I. Cancer. Cancer Research 16: 49-58, 1950. Scuwakrtz, D., Denorx, P.-F., L’enquete Francaise sur l’etiolgie du cancer broncho-pulmonaire. Role du tabac. (French investigation on the etiology of bronchopulmonary cancer. Role of tobacco.) Semaine des Hopitaus de Paris 33(62/7) : 3630-3643, Oct. 30, 1957. Scuwakrtz, D., Denorx, P.-F., ANGUERA, G. Recherche des localisations du cancer associées aux facteurs tabac et alcool chez Vhomme. (Re- search on the localizations of cancer associates with tobaeco and al- coholic factors in man.) Bulletin de l’Association Francaise pour VEtude du Cancer 44 : 336-361, 1957. ScuHwartz, D., Frasant, R., Lettoucn, J., Denorx, P.-F. Results of a French survey on the role of tobacco, particularly inhalation, in different cancer sites. Journal of the National Cancer Institute 26(5) : 1085-1108, May 1961. SHaprro, S., WEINBLATT, E., Fkank, C. W., Sacer, R. V. Incidence of coro- nary heart disease in a population insured for medical care (HIP). Myocardial infarction, angina pectoris, and possible myocardial in- farction. American Journal of Publie Health and the Nation’s Health 59(6, Supplement Part 2), June 1969, 101 pp. Spain, D. M., NatHaN, D. J. Smoking habits and coronary atherosclerotic heart disease. Journal of the American Medical Association 177 (10): 683-688, Sept. 9, 1961. 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. Srett, P. M. Smoking and laryngeal cancer. Lancet 1(7751) : 617-618, Mar. 18, 1972. Stocks, P. Cancer incidence in North Wales and Liverpool region in relation to habits and environment. British Empire Cancer Campaign 35th Annual Report, Supplement to Part IT, 1957, 156 pp. Svonopa, V. An analysis of some possible epidemiological factors involved in carcinoma of the larynx. Neoplasma 15(6) : 677-684, 1968. Tresiin, G. High blood pressure in men aged 50—A population study of men born in 1913. Acta Medica Scandinavica (Supplementum 470) : 1-8, 1967, Topp, G. F. (Editor). Statistics of Smoking in the United Kingdom. London, Tobacco Research Council, Research Paper I, Fourth Edition, 1966, 103 pp. Topp, G. F. (Editor). Statistics of Smoking in the United Kingdom. London, Tobaeco Research Council, Research Paper I, Fifth Edition, 1969, 124 pp. Topp, G. F. (Editor). Statistics of Smoking in the United Kingdom. London, Tobacco Research Council, Research Paper I, Sixth Edition, 1972, 132 pp. TROWELL, O. A. The relation of tobacco smoking to the incidence of chronic duodenal ulcer. Lancet 1: 808-809, Apr. 14, 1934. Unitrep States Cope oF FEDERAL REGULATIONS. Title 26 [Internal Revenue Service] Part 270—Manufacture of Cigars and Cigarettes. (As adopted at 26 F.R. 8173, effective Oct. 1, 1961). B(270)3~-B (270)5, Oct. 31, 1970. U.S. DepaRTMENT oF HEALTH, EDUCATION, AND WELFARE, Tar and Nicotine Content of Cigarettes. Washington, Federal Trade Commission. May 1972. DHEW Publication No. (HSM) 72-7510, 2 pp. 235 495-028 O—T3— -17 (98) (99) (100) (101) (102) (103) (104) (105) (106) (107) (108) (109) (410) (111) (112) (113) (414) (115) (116) (117) 236 U.S. DeparTMENT oF HEALTH, EDUCATION, AND WELFARE. National Clear- inghouse for Smoking and Health. Survey conducted by National Analysts, Inc., Philadelphia, Pa., fall 1964. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. National Clear- inghouse for Smoking and Health. Survey conducted by National Analysts, Inc., Philadelphia, Pa., and Opinion Research Corp., Princeton, N.J., spring 1966. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. National Clear- inghouse for Smoking and Health. Survey conducted by the Chilton Research Services, Philadelphia, Pa. January 1970. U.S. DEPARTMENT OF THE TREASURY, BUREAU OF ALCOHOL, TOBACCO AND FrrearMs. Statistical Release: Cigarettes and Cigars, 1970, 1971, 1972. U.S. DEPARTMENT OF THE TREASURY. Internal Revenue Cumulative Bulle- tin. 1969-1. Revenue Ruling 69-198, p. 359. Van Bucnem, F. 8S. P. Serum lipids, nutrition and atherosclerotic compli- cations in man. Acta Medica Scandinavica 181(4: 4038-416, April 1967. Vinuicer, U., Heypen-Srucxy, 8. Das Infarktprofil. Unterschiede zwischen Infarktpatienten und Kontrollpersonen in des Ostschweiz. (The infaret profile. Differences between infarct patients and control persons in East Switzerland.) Schweizerische Medizinische Wochensebrift 96(23): 748-758, June 11, 1966. Wer, J. M., Dunn, J. E., Jr. Smoking and mortality : A prospective study. Cancer 25(1) ; 105-112, January 1970. Wicken, A. J. Environmental and Personal Factors in Lung Cancer and Bronchitis Mortality in Northern Ireland, 1960-62. Research Paper No. 9, London, Tobacco Research Council, 1966, 84 pp. Wrwoer, E. L., Bross, I. J. A study of etiological factors in cancer of the esophagus. Cancer 14(2): 389-413, March-April 1961. Wywoer, E. L., Bross, I. J.. Day, E. A study of environmental factors in cancer of the larynx. Cancer 9(1): 86-110, January-February 1956. Wrwnoer, E. L., Bross, I. J., FELDMAN, R. M. A study of the etiological factors in cancer of the mouth. Cancer 10(6) : 1800-1323, November— December 1957. Wrnper, B. L., CoRNFIELD, J. Cancer of the lung in physicians. New England Journal of Medicine 248(11): 441-444, Mar. 12, 1953. Wynoer, E. L., GraHam, E. A. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma ; a study of 684 proved cases. Journal of the American Medical Association 143(4) : 328-329, May 27, 1950. Wynoer, E. L, Horrmann, D. Tobacco and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York, Academic Press, 1967, 730 pp. Wynoer, E. L., HULTBERG, 8., JACOBSSON, F., Bross, I. J. Environmental factors in cancer of the upper alimentary tract. A Swedish study with special reference to Plummer- Vinson (Patterson-Kelly) syndrome. Can- cer 10(3) : 470-487, May-June 1957. Wrwnper, E. L., Lemon, F. R., Manter, N. Bpidemiology of persistent cough. American Review of Respiratory Diseases 91(5) : 679-700, May 1965. Wrnver, E. L., Masucui, K., Beatriz, E. J., Jr. The epidemiology of lung cancer. Journal of the American Medical Association 213(13) : 2221-2228, Sept. 28, 1970. Wrywper, E. L., NAVARRETTE, A., AROSTEGUI, G. E., LramsBes, J. L. Study of environmental factors in cancer of the respiratory tract in Cuba. Journal of the National Cancer Institute 20(4): 665-673, April 1958. Wrwnoer, E. L., Wrient, G. A study of tobacco carcinogenesis. I. The pri- mary fractions, Cancer 10(2): 255-271. March-April 1957. CHAPTER 7 Exercise Performance Contents Page Introduction_____..._-.---_----------------------------- 241 Studies of Smokers_._.___._-_--------------------------- 241 Studies Comparing Smokers to Nonsmokers: Athletie Performance -- -- - wee ee eee eee eee eee 243 Bicycle Ergometer Performance. _--.-------------------- 244 Treadmill Performance___..--------------------------- 245 Performance in Other Tests of Fitness....--------------- 245 Discussion__.______...-----_----_-_--------------------- 246 Biomechanisms_______.__.------------------------------ 246 Summary____._._.__--_-------------------------------- 247 References____.__._.__-___.--__-__--------------------- 248 239 Introduction Although it has long been held by athletes and coaches that cigarette smoking is associated with “shortness of wind” and impaired perform- ance, until recently there has been little scientific evidence to support this view. In the past few years, a variety of studies have appeared dealing with the effect of cigarette smoking on the response of man to exercise. The following is a review of these studies. Age, sex, training, health, weight, and other factors are known to influence exercise performance. Because most of the investigations were carried out in healthy, young male volunteers, the groups were quite comparable with regard to age, sex, and health; however, weight, training, and other factors were often inadequately controlled. Furthermore, problems in study design and statistical analysis limit the value of several of these studies. Many forms of exercise were performed in these experiments, in- cluding : pedaling a bicycle ergometer, running on a treadmill, running on a track, swimming, step climbing, gripping a hand dynamometer, and doing several different exercise activities as part of a battery of tests. Small to maximum amounts of work were carried out in the various studies revewed. Studies of Smokers Most of the studies of habitual cigarette smokers followed a similar format with respect to smoking: (a) The subjects refrained from smoking for a few hours prior to testing, and (6) two test runs were performed, one without smoking and one in which smoking imme- diately preceded the exercise or was incorporated with the exercise protocol. Several investigators (/, 15, 28) studied the effect of smoking on maximum grip strength. Willgoose (28) reported a greater mean per- cent recovery of grip strength after the nonsmoking trial than after the smoking trial. Kay and Karpovich (75) and Anderson and Brown (1) all followed a protocol similar to that of Willgoose except that they randomized the smoking and nonsmoking trials, and substituted 241 a “placebo” cigarette for the nonsmoking trial. In neither of these studies were statistically significant differences observed between the grip scores for the smoking and nonsmoking trials. Reeves and Morehouse (24) administered a battery of tests to 15 colleges students. The tests were: A tapping test, a strength test, a jumping test, and the short form of the Harvard step test. No statis- tically significant differences in performance were noted under con- ditions of smoking or nonsmoking. A total of 32 college students from intermediate swimming classes abstained from smoking for 15 minutes, 2 hours, and 12 hours in a study conducted by Pleasants, et al. (23). Following the abstinence, they swam distances of 100 and 200 yards. Although actual swimming times were not published, the authors reported no statistically significant differences between the mean swimming times after the different periods of abstinence for either distance. In 1946, Juurup and Muido (13) carried out several experiments in which three young cigarette smokers exercised on a Krogh’s bi- cycle ergometer. Smoking was found to increase the pulse rate at rest as well as during exercise. Although the effect was less con- sistent than on the heart rate, smoking was also associated with elevated blood pressure. Smoking had no effect on oxygen consump- tion. Henry and Fitzhenry (/2), in 1949, using the bicycle ergometer, also found that smoking exerted no effect on oxygen consumption. In the same year, Karpovich and Hale (14) studied bicycle ergometer performance in eight young men. In all subjects, the average riding time was better in nonsmoking tests than in smoking tests; how- ever, the results were statistically significant for only three of the eight subjects. Kerrigan, et al. (16) more recently measured direct arterial blood pressure, heart rate, and cardiac output in 25 habitual smokers at rest and after exercise. Smoking two cigarettes produced statistically significant (P<0.01) increases in cardiac index, heart rate, and arter- ial mean pressure compared to the immediately preceding control period. Exercise after smoking resulted in an increase in cardiac in- dex over either the resting period or the exercise period which fol- lowed abstinence; the resultant cardiac index appeared to be approxi- mately the sum of the exercise and smoking effects. Exercise tests preceded by smoking were also associated wtih significantly higher (P<0.01) and more prolonged elevations of blood pressure than those not preceded by smoking. In the study by Goldbarg, et al. (17) of nine habitual smokers performing submaximal exercise on a bicycle ergometer, cardiovas- cular responses were measured via pulmonary and subclavian artery catheters. At rest, after smoking, the mean cardiac index and mean heart rate increased. During successively increasing levels of exercise, the heart rate was greater and stroke index lower than values for 242 comparable work before smoking. The net effect of smoking was to decrease the effiicency of the heart during exercise in the upright position by causing a smaller stroke volume and a higher heart rate. Rode and Shephard (26) investigated near maximal treadmill exer- cise performance in six habitual smokers. A 1-day abstinence from cigarette smoking was associated with a 13- to 79-percent decrease in the oxygen cost of breathing. Abstinence was also followed by a slow- ing of the heart rate and a decrease in expiratory minute volume after exercise. The study of Krumholz, et al. (78) is different from those cited pre- viously in that bicycle ergometer exercise performance was measured in habitual smokers both before and after 3 to 6 weeks of abstinence. Among the 10 subjects who abstained from smoking for 3 weeks, there was a statistically significant (P<0.05) decrease in heart rate, oxygen debt, and ratio of oxygen debt to total increase in oxygen uptake pro- duced by the 5 minutes of exercise. Using a “double 9-inch progressive step test” Rode and Shephard (25) studied several hundred participants of a smoking withdrawal clinic at the time of entry and at a 1-year followup. Among those who returned for the followup and who gave up smoking, absolute aerobic power increased insignificantly ; however, the relative aerobic power diminished in both sexes among those who quit smoking because of the weight gain experienced. Studies Comparing Smokers to Nonsmokers Athletic Performance In 1968 Cooper, et al. (6) evaluated 419 airmen during their initial 6 weeks on active duty in the USAF. A 12-minute maximum running test was performed at least. 1 hour after cigarette smoking. The mean distance covered in 12 minutes by the nonsmokers was significantly greater (P<0.05) than that covered by the smokers at the beginning, the middle, and the end of training. All categories of smokers and non- smokers improved their performance at the end of training; however, the maximum change in performance of those smoking 10 to 30 cig- arettes per day was significantly (P<0.001) less than that of non- smokers. David (7) administered a battery of tests to 88 military personnel, aged 19 to 39 years. A 1-mile run was included in the testing. and cig- arette smoking was associated with a significant decrease in perform- ance in this event. 243 Some 45 special forces soldiers were investigated at sea level and 13,000 feet above sea level by Fine (8). The subjects were randomly assigned to a placebo group or an acetazolamide treated group. Cig- arette smoking was positively correlated to decrements in 600-yard running performance from sea level to altitude in both groups. Pleasants (22) studied 106 students from intermediate university swimming classes. Swimming times were measured for 100- and 200- yard distances before and after training and for 800-yard distances after training. The mean swimming times of nonsmokers were less than those of smokers in six of seven listed categories, but these dif- ferences were not statistically significant. Bicycle Ergometer Performance Chevalier, et al. (5) investigated cardiovascular parameters in 32 young physicians after a standard 5-minute ergometer test. Oxygen debt accumulation among smokers was significantly (P<0.01) greater than among nonsmokers. The heart rate at rest and 3 minutes after exercise was significantly (P<0.02) faster in smokers than in non- smokers. Using a 5-minute ergometer test, 18 housestaff physicians, half of whom smoked, were investigated by Krumholz, et al. (77). They noted the following: Oxygen debt accumulation after exercise was signifi- cantly (P<0.02) greater in smokers than non-smokers, the ratio of the oxygen debt to total increased oxygen uptake during exercise was sig- nificantly (P<0.001) greater in smokers than in nonsmokers, and the diffusing capacity at rest and with exercise was significantly (P<0.05) decreased in smokers compared to nonsmokers. Kerrigan, et al. (16) studied cardiovascular parameters in smokers and nonsmokers at rest, during, and after a 5-minute bicycle ergometer ride. Cardiac index and blood pressure values obtained during exercise performed immediately after smoking were greater than those found in nonsmokers performing the same exercise. Similarly, heart rate and blood pressure remained elevated for longer periods in those who exercised immediately after smoking than in nonsmokers performing the same task. Aerobic capacity scores were examined in 60 university student vol- unteers by Peterson and Kelley (20). Subjects worked at submaximal levels on a bicycle ergometer before, during, and after a training program. At all of these intervals, nonsmokers had significantly (P<0.05) higher mean aerobic capacity scores than smokers. Both groups increased their aerobic capacity during training but non- smokers consistently performed better throughout training. 244 Treadmill Performance In 1960 Blackburn, et al. (4) carried out several measurements of cardiovascular function after different amounts of treadmill exercise were performed by 233 professional men, 159 university students, and 414 railroad workers. The differences between the smokers and non- smokers were of small magnitude. Basal oxygen consumption was slightly higher in smokers than in nonsmokers. Also, resting pulse rates were higher in smokers of most groups. Cooper, et al. (6) studied 47 out of 419 airmen with treadmill test- ing. Cardiopulmonary indices measured on the treadmill, including maximum indices, were comparable in smokers and nonsmokers ex- cept for a significant (P<0.01) reduction in the maximum minute volume among the smokers. A total of 277 prospective Canadian firemen performed the Balke- Ware test of work capacity in treadmill studies carried out by Glass- ford and Howell (70). The mean performance scores of nonsmokers were significantly (P<0.01) greater than those of smokers. The effect of vitamin C supplementation on treadmill exercise per- formance was investigated in 40 male volunteers by Bailey, et al. (2). Significant differences in oxygen utilization and ventilatory function between smokers and nonsmokers were noted in only two of the 24 separate analyses of variance performed. Maximal oxygen intake during treadmill exercise was examined by McDonough, et al. (79) in 86 healthy, middle-aged male volunteers. Cigarette smoking was one of six variables which together provided a multiple correlation coefficient of 0.73. Performance in Other Tests of Fitness When physical fitness tests were administered to 88 military per- sonnel by David (7), cigarette smoking was found to be associated with a significant (P<0.001) decrease in performance in the dodge and jump test, and a significant (P<0.02) decrease in performance in the crawling test. Using a step test, a breath holding test, and an ergometer test, Franks (9) examined 58 middle-aged men. Nonsmokers were able to hold their breath longer and had greater vital capacity residual after the step test than the smokers. In 1971, Wysokinski (29) studied 200 young Polish soldiers using Letunov’s test which included 20 knee-bending exercises, a fast run for 20 seconds, and a run for 3 minutes. Cigarette smoking was associated with a significant (P<0.01) reduction in the vital capacity and a 245 marked rise in the pulse rate at rest and after exercise. Intense exer- cise also caused a greater rise in the systolic blood pressure in smokers than in nonsmokers. Discussion Most of the studies in habitual cigarette smokers compared exercise performance in “smoking” and “nonsmoking” runs after only a few hours of abstinence. In some studies, smoking adversely affected per- formance (11, 13, 14, 16, 18, 26, 28), while in others it did not (7, 72, 15, 23, 24). Some of these apparently discrepant results are due to dif- ~ ferences in methodology and in amounts and types of work performed. In all of the more recent studies of habitual smokers in which moderate to near maximal amounts of work were performed and sophisticated measurements of oxygen transport and cardiopulmonary function were made, impairment of function during smoking trials was found (11, 16, 18,26). The data of Krumholz, et al. (78) also raise the question of whether residual effects of cigarette smoking influence “nonsmoking” trials per- formed after a few hours of abstinence; they found statistically sig- nificant decreases in heart rate and oxygen debt produced by exercise after 3 weeks of cessation. The work of Rode and Shephard (25) suggests that physical fitness improves with cessation, but this improvement may be negated if the subject gains a substantial amount of weight after giving up smoking. Several investigators compared exercise performance or postexer- - cise cardiopulmonary function of smokers to nonsmokers. Although only minor differences between smokers and nonsmokers were found - in a few of these studies (3, 4, 22), in most of them (4, 6, 7, 8, 10, 16, 17, 20, 29) the performance or function of the nonsmokers was better than that of the smokers. Both nonsmokers and smokers improved . their performance with training, but nonsmokers maintained their ad- vantage throughout training (6. 20). Biomechanisms The cited studies indicate that cigarette smoking exerts its adverse effect on exercise performance through several mechanisms. Cigarette smoking appears to impair cardiac performance during exercise by increasing the heart rate and exerting a variable effect on cardiac 246 output (5, 11, 13, 16, 18, 26, 29). Cigarette smoking is associated with an increased oxygen debt after exercise (5, 18). Also, one study indi- cated that the oxygen cost of hyperventilation was greater among smokers than among nonsmokers (26). Some of these adverse effects of smoking on oxidative metabolism are mediated by the elevated carboxyhemoglobin levels found in smokers, CO exerts these effects through one or more of the following mechanisms: (a) Reduction of the amount of hemoglobin available for oxygen transport, (6) shift of the oxygen-hemoglobin dissociation curve to the left with consequent interference in oxygen release at the tissue level, (c) induction of arterial hypoxemia, and (d@) possible interference with the homeostatic mechanism by which 2,3,DPG controls the affinity of hemoglobin for oxygen (27). Because carboxy- hemoglobin has a half life in the body of at least 3 to 4 hours, its influ- ence may still be measurable several hours after abstinence from smoking (27). A recent investigation of maximal muscular exercise during CO in- toxication in five male volunteers demonstrated reduced maximal O: consumption in spite of a much higher heart rate and a relative hyper- ventilation (27). Astrand and Rodahl (2) commented recently on the adverse effect of cigarette smoking on oxygen transport: “All other factors being equal, a reduction in the oxygen-transporting capacity is associated with a corresponding reduction in physical performance capacity dur- ing heavy or maximal work * * *. Because a regular physical train- ing program only increases the maximal oxygen uptake by some 10 to 20 percent, a 5- to 10-percent reduction in maximal aerobic power due to smoking may play a significant role in many types of athletic events and in very heavy work.” Other studies cited in this review document the adverse effect of smoking on pulmonary diffusing capacity (78) and on pulmonary function with exercise (6,29). Summary Clinical studies in healthy, young men have shown that cigarette smoking impairs exercise performance, especially for many types of athletic events and activities involving maximal work capacity. Some of these effects are mediated by reduced oxygen transport and reduced cardiac and pulmonary function. 247 (1) (2) (3) (4) (3) (6) (7) (8) (9) (10) (11) (12) (13) (18) 248 Exercise Performance References ANpDERSON, J. M., Brown, C. W. A. study of the effects of smoking upon grip strength and recuperation from local muscular fatigue. Research Quar- terly 22(1) : 102-108, March 1951. ASTRAND, P.-O., Ropaut, K. Factors affecting performance. In: Textbook of Work Physiology. New York, McGraw-Hill Book Co., 1970, 669 pp. Battery, D. A., Carron, A. V., TEECE, R. G., WeHNER H. J. Vitamin C supplementation related to physiological response to exercise in smoking and nonsmoking subjects. American Journal of Clinical Nutrition 23(7) : 905-912, July 1970. Biackgurn, H., Brozex, J., Taytor, H. L. Common circulatory measure- ments in smokers and nonsmokers. Circulation 22: 1112-1124, December 1960. Cuevatrer, R. B., Bowers, J. A., Bonpurant, S., Ross, J. C. Circulatory and ventilatory effects of exercise in smokers and nonsmokers. Journal of Applied Physiology 18(2) : 357-360, March 1963. Cooper, K. H., Gey, G. O., Borrenserc, R. A. Effects of cigarette smoking on endurance performance. Journal of the American Medical Association 208 (3) : 189-192, Jan. 15, 1968. Davin, K. H. Age, cigarette smoking, and tests of physical fitness. Journal of Applied Psychology 52 (4) : 296-298, August 1968. Fine, B. J. Personality traits as related to symptomatology and running performance at altitude under normal and drug (acetazoleamide) condi- tions. Perceptual and Motor Skills 27: 975-990, 1968. Franks, B. D. Smoking and selected cardiovascular-respiratory measures. Research Quarterly 41(2) : 140-144, May 1970. GiassFrorp, R. G., Howeti, M. L. Smoking and physical fitness: A prelim- inary report. Canadian Family Physician 15(10): 60-62, October 1969. Gotprarc, A. N., Krone, R. J.. REsnekov, L. Effects of cigarette smoking on hemodynamics at rest and during exercise. I. Normal subjects. Chest 60(6) : 531-536, December 1971. Henry, F. M., FirzHenry, J. R. Oxygen metabolism of moderate exercise, with some observations on the effects of tobacco smoking. Journal of Applied Physiology 2 : 464-468, February 1950. Juurcup, A., Murpo, L. On acute effects of cigarette smoking on oxygen consumption, pulse rate, breathing rate and blood pressure in working organisms. Acta Physiologica Scandinavica 11: 48-60, 1946. Kagpovicy, P. V., Hate, C. J. Tobacco smoking and physical performance. Journal of Applied Physiology 3: 616-621, April 1951. Kay. H. W., Karpovicn, P. V. Effect of smoking upon recuperation from lo- cal muscular fatigue. Research Quarterly 20: 250-256, 1949. KERRIGAN, R.. Jarx, A. (.. Dorie, J. T. The circulatory response to ciga- rette smoking at rest and after exercise. American Journal of the Medi- — cal Sciences 255: 113-119, February 1968. Krumuotz, R. A., CHEVALIER, R. B.. Ross, J. C. Cardiopulmonary function in young smokers. A comparison of pulmonary function measurements and some cardiopulmonary responses to exercise between a group of young smokers and a comparable group of nonsmokers. Annals of Internal Medi- cine 60(4) : 603-610, April 1964. KrumuHotrz, 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. (19) (20) (21) (22) (23) (24) (29) (26) (27) (28) (29) McDonovanu, J. R. Kusumi, F., Bruce, R. A. Variations in maximal oxygen intake with physical activity in middle-aged men. Circulation 41(5) : 743-751, May 1970. PETERSON, F. J., KELtey, D. L. The effect of cigarette smoking upon the acquisition of physical fitness during training as measured by aerobic capacity. Journal of the American College Health Association 17(3): 250-254, February 1969. Pignay, F., Dusagpin, J., DEROANNE, R., Perit, J. M. Muscular exercise during intoxication by carbon monoxide. Journal of Applied Physiology 31(4) : 573-575, October 1971. PLEASANTS, F., Jr. Pretraining and post-training swimming endurance of smokers and nonsmokers. Research Quarterly 40(4) : 779-782, 1969. PLeasants, F., Jr., Grucan, J., Ratiirr, J. W., Jr. Effects of short periods of abstinence from cigarette smoking on swimming endurance of chronic smokers. Research Quarterly 38(3) : 474-479, 1966. REEVES, W. E., MorEHOUSsE, L. E. The acute effect of smoking upon the physi- cal performance of habitual smokers. Research Quarterly 21: 245-248, 1950. Rope, A., SHEPHARD, R. J. Smoking withdrawal and changes of cardiores- piratory fitness. American Review of Respiratory Disease 104(6) : 933— 935, December 1971. Rope, A., SuepHarp, R. J. The influence of cigarette smoking upon the oxy- gen cost of breathing in near-maximal exercise. Medicine and Science in Sports 3(2) : 51-55, summer 1971. U.S. Pustic HEALTH SERVICE. The Health Consequences of Smoking. A Re- port of the Surgeon General : 1972. U.S. Department of Health, Education, and Welfare. Washington, DHEW Publication No. (HSM) 72-7516, 1972, 158 pp. WILLGOOSE, C. E. Tobacco smoking, strength, and muscular endurance. Re- search Quarterly 18: 219-225, 1947. WysoxinskI, Z. Effects of tobacco smoking on certain parameters reflecting the condition of the circulatory system at rest and during exercise. Polish Medical Science and History 14(2) : 73-76, April 1971. U.S. GOVERNMENT PRINTING OFFICE : 1973—O-495-028 249 The Health Consequences of Smoking January 1973 INDEX Pages 251-261 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service INDEX Abortion, spontaneous effect of maternal smoking, 123,124 Acenaphthylene in cigar, pipe, and cigarette smoke, 178 - Acetaldehyde as ciliatoxic agent in cigarette smoke, 31 Aerobic capacity effect of cessation of smoking, 243 effect of exercise and smoking, 243,244 Air pollution and bronchitis, in smokers vs. nonsmokers, 36,37 effect on mortality rates from lung cancer, 73 as factor in lung cancer development, 72,73 ’ in Osaka, Japan, 44 prevalence of respiratory diseases and, 44 and smoking in military and civilian air- craft, 45 Alcohol consumption interaction with smoking and other risk factors in CHD, 10 and smoking, in cancer development, 7 and smoking, in esophageal cancer devel- opment, 76,200 and smoking, in laryngeal cancer etiology, 197 and smoking, in oral cancer etiology, 193 Alveolar macrophages effect of cigarette smoke, 52,53 effect of nitrogen dioxide, 54 Alveolar rupture in pipe/cigar smokers vs. cigarette smokers and nonsmokers, 217 Angina pectoris carbon monoxide inhalation and, 17,18 incidence in pipe and cigar smokers, 215 * Anthracene in cigar, pipe, and cigarette smoke, 178 Arterioles effect of smoking, 22,23 ‘ Atteriosclerosis obliterans smoking as cause, 19,20 Aryl hydrocarbon hydroxylase effect of benzo(a)pyrene in pregnant rats, 119 tole in metabolism of chemical carcino- gens, 82,83 Asbestos effect on pulmonary function in smokers vs. nonsmokers, 41 effect on radiological findings in smokers vs. nonsmokers, 41 effect on respiratory symptoms in smokers vs. nonsmokers, 41 and smoking, effect on mortality rates from lung cancer, 73 Athletic performance running, effect of smoking, 243,244 smokers vs. nonsmokers, 243,244 swimming, effect of smoking, 244 Autopsy studies COPD and smoking, 45-48 lung cancer in U.S. veterans, 73,74 Bacterial flora in smokers vs. nonsmokers with COPD, 54 Benzo(a)pyrene carcinogenic effect in laboratory animals, 78-80 in cigar, 177,178 effect on DNA and RNA, 86,87 effects during pregnancy in laboratory animals, 117,118 Bicarbonate in pancreatic secretions, effect of smoking, 159,160 Bicycle Ergometer performance cardiovascular parameters in smokers vs. nonsmokers, 242-244 Birth weight effect of maternal smoking, 119-122 effect of maternal smoking before and during current pregnancy by cigarette consumption, 107-109 effect of maternal smoking during pre- vious pregnancies, 112-114 effect of maternal smoking, mechanism of action, 119,120 effect of paternal smoking, 110,111 effect of tobacco smoke, nicotine, or carbon monoxide in laboratory animals, 114-118 gestation duration in smokers vs. non- smokers, 103-106 and maternal smoking, epidemiological studies, 103-114 timing of influence of smoking, 120,121 Bladder cancer see also Renal cancer pipe, and cigarette smoke, 103-114, incidence in smokers vs. nonsmokers, 77,78 smoking in etiology of, 77,78 Blood flow effect of smoking, 19,22,23 Blood lipids effect of smoking, 11,12 251 effect of smoking and relative weight, in male Parisian civil servants, 11 effect of smoking in middle-aged patients with angina pectoris, 12 effect of smoking in young Norwegian military recruits, 1! elevated, as risk factor in CHD, 11 Blood pressure effect of 242,244-246 effect of pipe and cigar smoking, 216 effect of smoking in middle-aged patients with angina pectoris, 12 Body height interaction with smoking as factor in cerebrovascular disease, 19 Body weight interaction with smoking as factor in cerebrovascular disease, 19 and smoking, as factors in CHD incidence, 44 and smoking, effect on blood lipids, 11 Bronchial epithelium histological changes at autopsy and smok- ing habit, 74 histological changes in cigar, pipe, cigar- ette smokers vs. nonsmokers, 203, 204, 209 premalignant changes in smokers, 67 Bronchiolo-alveolar cancer smoking and, 71 Bronchitis and disability, in smokers vs. nonsmokers, 43 dust exposure as a factor, 44 mortality ratios in male pipe and cigar smokers, 217,219 prevalence in Duisburg, Germany, by age and cigarette consumption, 39 prevalence in ex-coal miners and non- miners by smoking habit, 42 prevalence in miners and farmers in Hun- gary, by smoking habit, 42 prevalence in pipe and cigar smokers, 220,221 prevalence in smokers vs. nonsmokers in Bordeaux, France, 36 prevalence in smokers vs. nonsmokers in mountainous or low-lying areas, 36,37 prevalence in smokers vs. nonsmokers in Osaka, Japan, 44 prevalence in smoking vs. nonsmoking yarn mill workers, 40 in smokers vs. nonsmokers, autopsy stu- dies, 45,46 smoking vs. coal mining in etiology of, 42 smoking vs. dust inhalation in etiology of, 42 Bronchitis, chronic see Bronchopulmonary diseases, chronic obstructive 252 exercise and smoking, Bronchopulmonary diseases, chronic ob- structive see also Emphysema and bronchitis autopsy studies, 45-48 as cause listed on death certificates vs, at autopsy, 47 epidemiological studies, 36-45 mortality and morbidity studies, 36-39 mortality rates in British citizens by migra- tion patterns, 36 mortality ratios in male pipe and cigar smokers, 216,217,219 summary of previous findings, 35,36 summary of recent findings, 55 Byssinosis prevalence in cotton mill employees, smokers vs. nonsmokers, 55 prevalence in men by index of severity and smoking habits, 40,41 prevalence in smoking vs. nonsmoking cotton mill workers, 39 smoking and, 39-41 Cancer see also Specific site, e.g., Lung cancer mortality rates in alcoholics, 71 recurrent primary, incidence in smokers vs. nonsmokers, 71,74 summary of previous findings, 67,68 summary of recent findings, 88 Capillaries effect of smoking, 22 Carbon monoxide cardiovascular effects, experimental stu- dies, 17-19 effect on birthweight and neonatal mortal- ity in animals, 133 effect on cholesterol biosynthesis, in vitro, 18 effect on cholesterol level in aorta in rabbits, 18 effect on coronary hemodynamics and ventricular function in dogs, 18 effect on exercise performance in smokers vs. nonsmokers, 246,247 effect on maximal oxygen consumption, 18 effect on platelet stickiness in rabbits, 18 effect on reflex vasoconstrictor responses, 18,23 effect on vascular resistance and reflex vasoconstriction, 22,23 effects during pregnancy in laboratory animals, 116,117 Carboxyhemoglobin levels effect on exercise performance in smokers vs. nonsmokers, 246,247 following smoking of non-nicotine ciga- rettes, 17,18 in neonates of smoking mothers, 118,119 Carcinogenesis cell and tissue culture studies, 84-86 effect of tobacco curing methods, 212 experimental, 78-87 initiating and promoting agents in cigar- ette smoke, 68 mechanism of action, 78, 80-87 of respiratory tract in laboratory animals, 78-80 role of cigarette smoke condensate, 80-84 Carcinogens effect on cell transformations, 84-86 effect on respiratory tract in laboratory animals, 78-80 Cardiac index effect of 242-244 Cardiovascular diseases see also Coronary heart disease mortality ratios in male pipe and cigar smokers, 215,216 smoking and, 3-23 summary of previous findings, 3 summary of prospective epidemiological studies for cigar and pipe smokers, 216 summary of recent findings, 23 Catecholamine levels effect of cigar, pipe, and cigarette smoke in dogs, 216 Cell and tissue culture studies tobacco carcinogenesis and, 84-86 Cell cultures malignant transformations induced by to- bacco tars on carcinogens, 84-86 Cells, atypical in ex-smokers, smokers, and nonsmokers at autopsy, 74 Cerebrovascular disease interaction of smoking and other risk factors, 19 mortality ratios in pipe and cigar smokers, 215,216 Cessation of smoking compared benefits in cigarette vs. pipe/ cigar smokers, 172,173 effect on absolute aerobic power, 243 effect on infant birth weight, 107-109 112-114 effect on pulmonary surfactant levels, 55 as preventive measure in occlusive disease, 21,22 CHD see Coronary heart disease Chest illness prevalence in pipe and cigar smokers, 220,221 Cholesterol biosynthesis, effect of carbon monoxide. in vitro, 18 exercise and smoking, Cholesterol levels effect of carbon monoxide in rabbits, 18 effect of smoking and body weight, 11 effect of smoking and clinical parameters in British business executives, 1! in pipe and cigar smokers, 215,216 Chronic obstructive bronchopulmonary di- sease see Bronchopulmonary disease, chronic obstructive Cigarettes definition and processing, 175 filtered, effect on respiratory symptoms, 55 modified, effect on respiratory symptoms and ventilatory capacity, 37,38 plain vs. filtered, effect on sputum produc- tion, 37,38 similarities with little cigars, 224,225 Cigarette smoke condensate effect on RNA, 86 N-nitrosamines in, 87,88 role in experimental carcinogenesis, 80-84 Cigarettes, non-nicotine effect on carboxyhemoglobin levels, 17,18 Cigars definition and processing, 175,176 Cigars, little chemical composition of, 224,225,228 evaluation of potential public health im- pact, 222-228 shipment for domestic 1970-1972, 222-224,227 similarity to cigarettes, 224,225 sugar and pH differences with large cigars and cigarettes, 222-224 tar and nicotine content, 224-226,228 Cigar smokers relative risk in lung cancer development, 67,68 Cigar smoking effect on mortality and morbidity com- pared to cigarette smoking, 171-173 in esophageal cancer development, 197,200-202 gastrointestinal disorders and, 222 health consequences of, 179 histological effects on bronchial epithe- lium, 203,204,209 histological effects on esophagus, 200 consumption histological effects on larynx, 197 inhalation patterns and, 184-189 in laryngeal cancer development, 197-199 in lung cancer development by amount smoked, 203-206 mortality ratios from cardiovascular di- seases and, 215,216 mortality ratios from COPD and, 217,219 253 mortality ratios from esophageal cancer and, 197,200 mortality ratios from laryngeal cancer and, 193,196,197 mortality ratios from lung cancer and 203-205 mortality ratios from oral cancer and 191,193 oral cancer development and, 193-195 overall mortality rates by amount smoked, 180-182 overall mortality rates from cancer and, 189 prevalence in Great Britain, 173,174 prevalence in United States, 173,174 pulmonary histological changes and, 217 Ciliary activity effect of pipe/cigar smoke vs. cigarette smoke in cats, 217,218 Clinical laboratory tests effect of aging and smoking, in healthy male veterans, 11 Coal dust effect on pulmonary function in smokers vs. nonsmokers, 41-43 effect on respiratory symptoms in smokers vs. nonsmokers, 41-43 Combustion temperature effect on tumorigenic activity of pipe and cigarette tobacco, 210,211 Congenital malformations maternal smoking and, 136,137 Coronary heart disease epidemiological studies, 4-11 experimental studies, 13-19 incidence in European vs. American men, 9 incidence in farmers vs. nonfarmers by smoking habit, 7 incidence in Hawaiian men of Japanes: ancestry, 10 incidence in male bank employees it Brussels, Belgium, 10 incidence in men in Yugoslavia, 9 incidence in miners in Sardinia, 10 incidence in pipe and cigar smokers, 215,216 incidence in white males by body weight and smoking habit, 5 incidence in whites vs. blacks in Evans County, Georgia, 4,5 in India, 11 interaction of smoking with other risk factors, 4-11 mortality rates in Japanese men and wo- men by cigarette consumption and age a initiation of habit, 7,8 mortality rates in smoking men in Finland, 9 mortality ratios in pipe and cigar smokers, 215,216 e 254 in Nepal, 11 in New Zealand, 11 4 smoking, in individuals under 40 years, 10 and smoking, in myocardial ischemic pa- tients in Italy, 10 COPD see Bronchopulmonary diseases, chronic obstructive Cough effect of asbestos exposure in smokers vs. nonsmokers, 41 effect of coal dust exposure in smokers vs. nonsmokers, 41,42 effect of filtered cigarettes, 55 effect of modified cigarettes, 38 prevalence in pipe and cigar smokers, 220,221 prevalence in smoking vs. nonsmoking women in Bordeaux, France, 36 Cresols in cigar, pipe, and cigarette smoke, 177 Curing methods incidence of respiratory infections in rats and, 218,219 Cyanide detoxification in pregnant smokers vs. nonsmokers, 119 7H-Dibenz(c,g)carbazole carcinogenic effect in laboratory animals, 79 Diet and smoking, effect on blood lipids, 12 DNA binding of polycyclic hydrocarbons to, 86,87 Dust exposure bronchitis and, 44 as occupational hazard, 43,44 smoking and, 44 Dynamic compliance in smokers vs. nonsmokers under 30, 50 Dyspnea prevalence in cigar and pipe smokers, 220,221 Electrocardiogram abnormalities, effect of smoking and other factors, 13 effect of smoking, in middle-aged Dutch men, 12 effect of smoking, in young military re- cruits in Poland, 12 Emphysema see also Bronchopulmonary disease, chronic obstructive incidence in cigar/pipe smoking coal mi- ners vs. cigarette smokers and non- smokers, 217 mortality ratios in male pipe and cigar smokers, 217,219 prevalence in males by smoking category, at autopsy, 48 prevalence in pipe/cigar and cigarette smo- kers vs, nonsmokers, autopsy studies, 45,46 prevalence in smokers vs. nonsmokers, 55 in smokers vs. nonsmokers, autopsy stu- dies, 45-47 Epidemiological studies bronchopulmonary diseases and smoking, 36-45 coronary heart 4-13,23 lung cancer and smoking, 68-72 peptic ulcer and smoking, 155-157 Esophageal cancer alcohol consumption and smoking in de- velopment of, 200 inhalation patterns and, 197 mortality ratios for cigar, pipe, and ciga- tette smokers vs. nonsmokers, 197,200 mortality ratios in Japanese male smokers vs, nonsmokers, 76 relative risk in cigar, pipe, and cigarette smokers vs. nonsmokers, 197,200-202 smoking and alcohol consumption in de- velopment of, 76 summary of retrospective studies, 201,202 Esophagus histological changes in cigar, pipe, ciga- rette smokers vs. nonsmokers, 200 Exercise performance on bicycle ergometer, effect of smoking, 242,243 cardiac index, effect of smoking, 242,243 effect of smoking and smoking abstinence, 241 242,246,247 influencing factors, 241,246,247 summary of findings and mechanism of action, 246,247 on treadmill, effect of smoking, 243,245 Experimental studies COPD and smoking, 48-55 coronary heart disease and smoking, 13-19 effect of carbon monoxide on pregnant animals, 132,133 pregnancy in laboratory animals, effect of tobacco smoke, nicotine, carbon mono- xide, and polycyclic hydrocarbons, 114-118 Ex-smokers compared mortality rates for cigarette vs. pipe/cigar smokers, 172,173 histological changes in bronchial epithe- lium at autopsy, 74 disease and smoking, low birth weight infants of, 112-114 mortality rates from lung cancer, 71-72 prevalence of respiratory symptoms, 39 pulmonary function, 39 relative risk in lung cancer development, 71-72 survival after treatment for pharyngeal, laryngeal, or oral cancers, 75 Fatty acid levels effect of cigar, pipe, and cigarette smoke in dogs, 216 effect of smoking, 12 Fetal mortality effect of maternal smoking, 123-135 epidemiological studies in smokers vs. non- smokers, 126-132 Fibrosis in pipe/cigar smokers vs. cigarette smokers and nonsmokers, 217 Fitness tests various, smokers vs. nonsmokers, 245 Framingham study interaction of smoking and other risk factors in CHD, 8 ‘Gastric secretion effect of nicotine in laboratory animals, 158,159 effect of smoking in ulcer patients, 157,158 ‘Gastrointestinal disorders prevalence in cigarette and pipe/cigar smo- kers, 222 Gestation and low birth weight infants, effect of maternal smoking, 103-106 Gestational age effect on perinatal mortality rates in smo- king vs. nonsmoking mothers, 126-132 Glucose intolerance as a risk factor in CHD, 8 Grip strength effect of smoking, 241,242 Heart rate effect of 242-246 Histological studies lung cancer in US. veterans, 73 Histopathological studies in laboratory animals, 49,50 in smokers vs. nonsmokers, 48,49 Honolulu Heart Study interaction of smoking and other risk factors in CHD, 8,9 exercise and smoking, 255 Hypercholesterolemia incidence in male British business execu- tives, by smoking habit and clinical parameters, 1} as risk tactor in CHD, 8,9,11 Hypertension interaction with smoking as risk factor in cerebrovascular disease, 9 as risk factor in CHD, 8,9 Hypoxia carbon monoxide induced, 18,23 Infant small-for-date, effect of maternal smoking, 106-114 Infant mortality of black vs. white smoking mothers, 129-132 causes of death by maternal smoking habit, 133 effect of genetic differences and smoking, 132 effect of maternal smoking, 123-135 effect of previous obstetrical experience and smoking, 132 effect of socioeconomic background and smoking, 131,132 epidemiological studies in smokers vs. non- smokers, 126-132 factors other than smoking, 131,132 risk of low-birth-weight infants of smoking vs. nonsmoking mothers, 126-132 Influenza prevalence in pipe and cigar smokers, 220,221 Inhalation patterns effect of previous 186-189 frequency-per-puff in cigar and cigarette smokers, 186,187 of pipe, cigar, and cigarette smokers, 184-189 possible determining factors, 183,184 Intermittent claudication smoking and, 21 International Cooperative Study interaction of smoking and other risk factors in CHD, 9 smoking habits, Lactate metabolism effect of smoking, in patients with angina pectoris, 13 Lactation effect of maternal smoking, 138-141 effect of maternal smoking, summary of findings, 141 epidemiological studies, 138 experimental studies, 138,139 256 Laryngeal cancer inhalation patterns and, 193 mortality ratios for pipe, cigar, and ciga- rette smokers vs. nonsmokers, 193,196,197 mortality ratios in Japanese male smokers vs. nonsmokers, 76,77 recurrent, incidence in smokers vs, ex- smokers, 71,74-77 relative risk for cigar, pipe, and cigarette smokers vs. nonsmokers, 76,77,197-199 summary of retrospective studies, 198,199 - Larynx histological changes in cigar, pipe, cigar- ette smokers vs. nonsmokers, 197 Leukoplakia prevalence in tobacco chewing coal mi- ners, 75 reverse smoking and, 76 Lip cancer cigar smoking in etiology of, 190,191 cigarette smoking in etiology of, 190,191 pipe smoking in etiology of, 190,191 relative risk in pipe, cigar, and cigarette - smokers vs. nonsmokers, 190,191 summary of retrospective studies, 192 Little cigars see Cigars, little Lung cancer air pollution as a factor, 72 epidemiological studies, 68-72 race as a factor, smokers vs. nonsmokers, 70 incidence in smokers vs. nonsmokers in Jersey, Channel Isles, 70 incidence in smokers vs, nonsmokers in La Plata, Argentina, 70 incidence in smokers vs. nonsmokers in Philadelphia, 70 inhalation patterns and, 203 mortality rates in asbestos workers, smo- kers vs. nonsmokers, 73 mortality rates in British physicians vs. general population in England and Wales, 70 mortality ratios for cigar, pipe, and cigar- ette smokers vs. nonsmokers, 203-205 mortality ratios in Japanese by amount smoked and age at initiation of habit, 69 occupational exposures and smoking, 67 prevalence in smokers vs. nonsmokers in Czechoslovakia, 70 prospective study 68,69 relative risk in cigar, pipe, and cigarette smokers vs. nonsmokers, 203,206-208 relative risk in ex-smokers vs. continuing smokers, 72 in Japanese adults, _ relative risk in pipe/cigar smokers, 67,68 smoking as cause, 67 summary of retrospective studies, 206-208 Maternal-fetal exchange polycyclic hydrocarbons and, 119 Maternal smoking see Smoking, maternal 3-Methylcholanthrene effects during pregnancy in laboratory animals, 117 Morbidity from chronic bronchopulmonary diseases, 36-39 Mortality compared rates for cigarette vs. pipe/cigar ex-smokers, 172,173 from chronic bronchopulmonary diseases, 36-39 from COPD, in cigar/pipe smokers vs. Cigarette smokers and nonsmokers, 216,217 overall rates for cigar smokers vs, pipe smokers, 179,180 overall rates for pipe/cigar smokers and dose—response relationships, 180-189 overall rates for pipe/cigar smokers vs, nonsmokers, 179,180 overall rates from cancer in pipe and cigar smokers, 189 ratio in pipe and cigar smokers by age and inhalation, 184,187 Mortality rates CHD in Japanese men and women by cigarette consumption and age at initia- tion of habit, 7,8 Myocardial infarct incidence in European vs. American men, 9 incidence in men in Yugoslavia, 9 incidence in miners in Sardinia, 10 incidence in pipe and cigar smokers, 215 prevalence in smoking vs. nonsmoking men in Czechoslovakia, 10 and smoking, in patients in Leningrad hospitals, 10 Nicotine in cigar, pipe, and cigarette smoke, 177 clinical effects on offspring of smoking mothers, 140,141 in duodenal ulcer 158,159 effect on cardiovascular system in dogs, 17 effect on gastric secretion in cats, 158,159 effect on gastric secretion in tats, 159 effect on heart blood flow in dogs, 17 induction in cats, effect on lactation in laboratory animals, 138,139 effect on lactation in smokers vs. non- smokers, 139,140 effect on lipid biosynthesis in aorta in dogs, 17 effect on microcirculation in atrium in cats, 17 effect on pancreatic secretions in animals, 161,162 effect on pipe/cigar smoke inhalation, 183,184 effect on rat and mouse fetus, site of action, 121 effects during pregnancy in laboratory animals, 115,116 experimental studies, 16,17 in little cigars compared to cigarettes and cigars, 223-226,228 in milk of laboratory animals, 138,139 in milk of smoking mothers, 139 as potentiator of duodenal ulcers in ani- mals, 161-163 Nicotine levels in blood, new assay method, 15,23 Nicotine secretion effect of cigar, pipe, and cigarette smoke in dogs, 216 Nitrogen dioxide effect on alveolar wall cells in guinea pigs, 50 effect on bacterial retention in hamsters, 54 effect on rat lung, 49,50 Nitrosamines effect on lactating hamsters, 139 N-Nitrosamines determination in cigarette and tobacco smoke condensate, 87,88 Obesity as a risk factor for CHD, 9 Occlusive disease smoking and, 21 Occupation and smoking, as factor in CHD incidence, 5,7 Occupational diseases asbestosis, 41 byssinosis, 39-41 coal workers pneumoconiosis, 42 Occupational exposure pancreatic cancer and, 77 and smoking, bladder cancer and, 78 Occupational hazards asbestos exposure, 41,73 coal dust exposure, 41-43 cotton, flax, and hemp dust exposure, 39-41 257 dust exposure, 43,44 100% pure oxygen exposure, 43 radiation exposure in uranium miners, 72 smoking and, 39-44 smoking as additive risk for COPD, 55 Oral cancer alcohol consumption and smoking in etio- logy of, 193 inhalation patterns and, 191 mortality rates in Japanese male smokers vs. nonsmokers, 74 mortality ratios for pipe, cigar, and cigar- ette smokers vs. nonsmokers, 191-193 recurrent, incidence in smokers vs. ex- smokers, 71,74,75 relative risk of development in pipe, cigar, and cigarette smokers vs. nonsmokers, 191,194,195 reverse smoking and, 76 smoking in etiology of, 74-76 summary of retrospective studies, 194,195 Oxygen debt effect of smoking, 246,247 exercise performance and, 246,247 Pancreatic cancer occupational exposure and, 77 smoking and, 77 Pancreatic secretions bicarbonate content, effect of smoking, 159,160 effect of nicotine in animals, 161,162 effect of smoking, 159,160 Passive smoking effect on cardiovascular function in dogs, 14 Peptic ulcer see Ulcer, peptic Perinatal mortality effect of maternal smoking, summary of findings, 134,135 Peripheral arteriosclerosis smoking and, 21 Peripheral vascular disease smoking and, 19-23 pH pipe/cigar smoke inhalation and, 183 of smoke in cigarettes, cigars, and little cigars, 223,224,228 Phagocytosis effect of cigarette smoke in laboratory animals, 53,54 Pharyngeal cancer recurrent, incidence in smokers vs. ex- smokers, 74,75 Pharyngeal fungi smokers vs. nonsmokers in South Africa, 54 258 Phenols in cigar, pipe, and cigarette smoke, 177 Phenylmethyloxadiazole (PMO) protection against adverse effects of cigar- ette smoke in animals, 49,53 Physical activity as a factor in coronary heart disease, 4,5 Pipe smokers relative risk in lung cancer development, 67,68 Pipe smoking effect on mortality and morbidity com- pared to cigarette smoking, 171-173 in esophageal cancer development, 197 ,200-202 gastrointestinal disorders and, 222 health consequences of, 179 histological effects on bronchial epithe- lium, 203,204,209 histological effects on esophagus, 200 histological effects on larynx, 197 inhalation patterns and, 184-189 in laryngeal cancer development, 197-199 in lung cancer development by amount smoked, 203-206 mortality ratios from cardiovascular di- seases and, 215,216 mortality ratios from COPD and, 217,219 mortality ratios from laryngeal cancer and, 193,196 ,197,200 mortality ratios from lung cancer and, 203-205 mortality ratios from oral cancer and, 191,193 oral cancer development and, 193-195 overall mortality rates by amount smoked, 180-182 overall mortality rates from cancer and, 189 prevalence in Great Britain, 173,174 prevalence in United States, 173,174 pulmonary histological changes and, 217 Pipe tobacco definition and processing, 176 Plethysmogram abnormalities, in smokers vs. nonsmokers, 22 Pneumoconiosis in coal miners, smokers vs. nonsmokers, 42 Pneumothorax, spontaneous smoking and, 37 Polycyclic hydrocarbons binding to DNA and RNA, 86,87 effects during pregnancy in laboratory - animals, 117,118 maternal-fetal exchange and, 119 Post-operative complications in duodenal ulcer removal, smokers vs. nonsmokers, 157 smoking, obesity, anesthesia and, 39 Preeclampsia maternal smoking and, 142 in smoking vs. nonsmoking women, 142 Pregnancy effect of maternal smoking, 103-142 effect of maternal smoking, mechanism of action, 119,120 effect of tobacco smoke, nicotine, and carbon monoxide in laboratory animals, 114-118 and previous smoking habits, effect on infant birth weight, 112-114 timing of influence of smoking on birth weight, 120,12) Prematurity effect of smoking, 112 Pulmonary arterioles histological effects of pipe/cigar smoking vs. Cigarette smoking, 217 Pulmonary clearance effect of heavy smoking, 52,53 effect of smoking, 55 mechanical vs. bactericidal clearance in guinea pigs, 53 mechanism, in smokers vs. nonsmokers, §2,53 in monozygotic vs. dizygotic twins, 51 particle deposition in smokers vs. non- smokers, $3 Pulmonary diffusing capacity in smokers vs. nonsmokers in Berlin, New Hampshire, 50,51 Pulmonary emphysema see Emphysema Pulmonary function in asymptomatic young men in Romania, 39 in coal miners, smokers vs. nonsmokers, 42,43 in coal miners vs. nonminers, 42 effect of asbestos exposure and smoking, 41 effect of coal dust exposure and smoking, 4143 effect of lung hyperinflation in coal mi- ners, 42,43 effect on exercise performance in smokers vs. nonsmokers, 246,247 in ex-smokers, 39 in jet fighter pilots, smokers vs. non- smokers, 43 in pipe/cigar smokers vs. nonsmokers, 217,221 pulmonary hypertension and, 43 in smokers vs. nonsmokers, 55 in smokers vs. nonsmokers in Berlin, New Hampshire, 50,51 in smokers vs. nonsmokers, under 30 years of age, 50 smoking and, 38,39 Pulmonary histology of pipe/cigar smokers vs. cigarette smokers and nonsmokers, 217 Pulmonary macrophages effect of smoking, 55 Pulmonary surfactant levels effect of smoking, 55 Pulmonary tissue histopathological differences in smokers vs. nonsmokers, 48,49 Pyrene in cigar, pipe, and cigarette smoke, 178 Race as a factor in coronary heart disease, 4,5,23 as a factor in perinatal mortality in smok- ing vs. nonsmoking mothers, 129-132 as a factor in stillbirth rates, 124,125 Radiation exposure and smoking, as cause of respiratory can- cers, 72 Radioactive particles in tobacco leaf, tobacco smoke, and smo- kers’ lungs, 72 Renal cancer mortality ratio in Japanese men and wo- men, smokers vs. nonsmokers, 77 smoking in etiology of, 77,78 Respiratory symptoms see also Cough, Sputum production effect of asbestos exposure in smokers vs. nonsmokers, 41 prevalence in Duisburg, Germany by age and cigarette consumption, 39 prevalence in ex-smokers, 39 prevalence in pipe and cigar smokers, 217,220,221 prevalence in smokers vs. nonsmokers, 55 prevalence in smokers vs. nonsmokers in Bordeaux, France, 36 in smokers vs. nonsmokers by amount smoked, 37 Reverse smoking leukoplakia and, 76 oral cancers and, 76 RNA binding of polycyclic hydrocarbons to, 86,87 Running effect of smoking, 243, 244 Sex ratio effect of maternal smoking, 135,136 Single-breath tests smokers vs. nonsmokers, 51 259 Smoke, cigar chemical constituents in, 177-179 ciliotoxicity, 218 effect of curing methods, 218,219 effect of pH on inhalation of, 183 tumorigenic activity in laboratory animals, 210-214 Smoke, cigarette chemical constituents in, compared to pipe/cigar smoke, 177,178 effect of curing methods, 218,219 effect on bacterial retention in hamsters, 54 effect on bronchial epithelium in dogs, 49 effect on phagocytosis in laboratory ani- mals, 53,54 effect on pulmonary clearance, §1-53 effect on rat and mouse fetus, site of action, 121 effect on ventricular fibrillation threshold in dogs, 13,14 experimental studies in dogs, 13,14 reduction of adverse effects in animals by phenylmethyloxadiazole (PMO), 49,53 and sulphur dioxide, effect on glands in laboratory animals, 49 Smoke, little cigar pH of, compared to cigarette and cigar smoke, 224,228 Smoke, pipe chemical constituents in, 177,178 ciliotoxicity of, 218 effect of pH on inhalation of, 183 tumorigenic activity in laboratory animals, 210-214 Smoke, tobacco effect on air pollution in aircraft, 45 effect on nonsmokers, in aircraft, 45 effect on stillbirth rate in laboratory ani- mals, 125 effects during pregnancy in laboratory animals, 114,115 pH of, effect of leaf constituents, 224 tumorigenic activity, 210-214 Smoking effect on blood lipids, 41,12 effect on cardiac lactate metabolism, 13 effect on leg blood mean-flow capacity, 22 effect on plasma nicotine levels, 15-17 effect on precapillary sphincters, 22 health hazards of, similarities of cigarettes with little cigars, 224,225 interaction with other risk factors in CHD, 4-11 as most important cause of COPD, 35,36 prevalence in U.S. and Great Britain, 173,174 Smoking abstinence effect on exercise performance, 241,242,246,247 260 Smoking, maternal as cause of birth of small-for-dates infants 106-111 , congenital malformations and, 136,137 effect on birth weight, 103-114,119-122 effect on birth weight, summary of find- ings, 122 effect on gestation duration, 103-106 effect on Jactation, 138-141 effect on neonatal carboxyhemoglobin levels, 118,119 effect on sex ratio, 135,136 effects during pregnancy, 103-142 effects during pregnancy, mechanism of action, 119,120 indirect association with small-for-dates infants, 110-114 preeclampsia and, 142 selective action on fetus of certain women vs. others, 131 spontaneous abortions and, 123,124 stillbirths and, 124,125 timing of influence on birth weight, 120,121 Smoking, paternal effect on infant birth weight, 110,111 Sputum production effect of asbestos exposure in smokers vs. nonsmokers, 41 effect of filtered cigarettes, 55 effect of modified cigarettes, 37,38 effect of plain vs. filtered cigarettes, 37,38 in males by amount smoked and type of cigarette, 37,38 prevalence in pipe and cigar smokers, 220,221 Stillbirths effect of maternal smoking, 124,125 rates in blacks vs. whites, 124,125 in smokers vs. nonsmokers, 124,125 Sudden death incidence in pipe and cigar smokers, 215 Sulphur dioxide and cigarette smoke, effect on glands in laboratory animals, 49 Swimming effect of smoking, 242,244 Tar content effect on respiratory symptoms and venti- latory capacity, 38 Tars in little cigars, compared to cigarettes and cigars, 223-226 ,228 Thrombosis smoking and, 19 Tobacco flue-cured vs. air-cured, effect on respira- tory system in animals, 217,218 Tobacco chewing leukoplakia and, 75 Tobacco leaf extracts effect on cell cultures, 85,86 Tracheal cancer smoking and, 71 Treadmill performance cardiovascular parameters in smokers vs. nonsmokers, 242-245 effect of vitamin C, 245 oxygen intake in smokers vs. nonsmokers, 245 Triglyceride levels CHD and, 8 Tumorigenic activity of cigar, pipe, and cigarette smoke conden- sate in skin painting experiments in animals, 210-214 of tobacco smoke, 210-214 Ulcer, duodenal mortality ratios in male cigar and pipe smokers, 222 nicotine induced, in cats, 158,159 post-operative complications in smokers vs. nonsmokers, 157 potentiating action of nicotine, in animals, 161-163 prevalence in smokers, mechanism of act- ion, 160 Ulcer, peptic clinical studies, 155-157 epidemiological studies, 155-157 gastric secretion in smokers vs. nonsmok- ers, 157,158 increased mortality in Japanese smokers vs. nonsmokers, 155,156 mortality ratios in Japanese adults by age at initiation of smoking habit, 155,156 mortality ratios in male cigar and pipe smokers, 222 predisposing factors, 157 recurrence in smokers vs. nonsmokers, 157 and smoking, summary of previous find- ings, 155 Urinary bladder cancer see Bladder cancer Vascular disease, peripheral smoking and, 19-23 Vascular reconstruction effect of smoking, 22,23 Ventilatory function effect of exercise and smoking, 244,245 Ventricular fibrillation effect of cigarette smoke in dogs, 13,14 Ventricular hypertrophy as a risk factor in CHD, 8 Vitamin B, , in pregnant smokers vs. nonsmokers, 119 Vitamin C effect on treadmill performance in smo- kers vs. nonsmokers, 245 in milk of smoking mothers, 141 in pregnant smokers vs. nonsmokers, 119 Water hardness and smoking as risk factors in CHD, 9,10 261