The
Health Consequences

of SMOKING

1969 SUPPLEMENT TO THE
1967 Public Health Service Review

 

 

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
Public Health Service
1969 Supplement to

Public Health Service Publication No. 1696-2

Library of Congress Catalog No. 68-60025

 

For sale by the Superintendent of Documents, U.S. Government Printing Office
Washington, D.C. 20402 - Price 50 cents
Foreword

This is the third report required by Section 5(d) (1) of the Federal
Cigarette Labeling and Advertising Act, which directs the Secretary
of Health, Education, and Welfare to submit annual reports to the
Congress on the health consequences of smoking. The preceding two
reports were The Health Consequences of Smoking, A Public Health
Service Review: 1967 and The Health Consequences of Smoking, 1968
Supplement to the 1967 Public Health Service Review.

The present Supplement was submitted to the Congress on July 29,
1969.
Acknowledgments

The National Clearinghouse for Smoking and Health, Daniel Horn,
Ph. D., Director, was responsible for the preparation of this report;
Albert C. Kolbye, Jr., M.D., M.P.H., LL.B., was consulting editor.
Staff director for the report was Daniel P. Asnes, M.D.

The professional staff has had the assistance and advice of a number
of experts in the scientific and technical fields, both in and outside of
the Government. Their contributions are gratefully acknowledged.

Special thanks are due the following:

ANDERSON, WILLIAM H., M.D.—Associate professor of medicine, University of
Louisville, School of Medicine, Louisville, Ky.

AUERBACH, OscaR, M.D.—Senior medical investigator, Veterans Administration
Hospital, East Orange, N.J.

Avi1apo, Dominco M., M.D.—Professor of pharmacology, Department of Pharma-
ecology, School of Medicine, University of Pennsylvania, Philadelphia, Pa.

Ayres, STEPHEN M., M.D.—Director, Cardiopulmonary Laboratory, Saint Vin-
cent’s Hospital and Medical Center of New York, New York, N.Y.

Bates, Davip V., M.D.—Chairman, Department of Physiology, McGill University,
Montreal, Quebec, Canada.

BELLET, SAMUEL, M.D.—Director, Division of Cardiology, Philadelphia General
Hospital, Philadelphia, Pa.

Brne, Ricwarp J., M.D.—Professor and chairman, Department of Medicine,
Wayne State University, Detroit, Mich.

Biomaquist, Epwagp T., M.D.—Chief, Chronic Respiratory Disease Control Pro-
gram, Health Services and Mental Health Administration, U.S.P.H.S., Arling-
ton, Va.

Bocr, Frep G., Ph. D.—Director, Orchard Park Laboratories, Roswell Park
Memorial Institute, Orchard Park, N.Y.

Boren, Hortis, M.D.—Chief of pulmonary disease, Professor of medicine, Mar-
quette School of Medicine, Wood VA Center, Milwaukee, Wis.

BoUTWELL, RoswEt. K., M.D.—Professor of oncology, McArdle Laboratory for.
Cancer Research, University of Wisconsin, Madison, Wis.

Coorrr, THEODORE, M.D.—Director, National Heart Institute, National Institutes
of Health, Bethesda, Md.

CorNFIELD, JeroME—Biostatistics Project, Bethesda, Md.

De La Puente, JosepH—Chief, Program Studies Section, Kidney Disease Control
Program, Health Services and Mental Health Administration, U.S.P.HLS.,
Arlington, Va.

EASTMAN, NicHOLSoN J., M.D.—Professor emeritus of obstetrics, Johns Hopkins
Hospital, Baltimore, Md.

Extot, Roserr 8., M.D.—Associate professor of medicine, Division of Cardiology,
College of Medicine, University of Florida, Gainesville, Fla.
Enpvicort, KENNETH M., M.D.—Director, National Cancer Institute, National In-
stitutes of Health, Bethesda, Md.

EPstEIN, FREDERICH H., M.D.—Professor of epidemiology, Department of Epi-
demiology, University of Michigan, School of Public Health, Ann Arbor, Mich.

Fatk, Hans L., Ph. D.—Associate director for laboratory research, National
Institute of Environmental Health Sciences, Research Triangle Park, N.C.

Ferris, BENJAMIN G., Jr., M.D.—Professor. Department of Physiology. Harvard
School of Public Health, Harvard University, Boston, Mass.

Fox, SAMUEL M., III, M.D.—Chief, Heart Disease and Stroke Control Program,
Health Services and Mental Health Administration, U.S.P.H.S., Arlington, Va.

Frazrer, Toop M.—Assistant director, Harvard Center for Community Health
and Medical Care, Harvard School of Public Health, Boston, Mass.

Hass, Grorce M., M.D.—Chairman, Division of Pathology, Presbyterian-St.
Luke’s Hospital, Chicago, 1.

Hicatns, Ian T. T., M.D., M.R.C.P.—Professor, Department of Epidemiology,
University of Michigan, School of Public Health, Ann Arbor, Mich.

HorrMann, Dietricu, Ph. D.—Associate member, Environmental Carcinogenesis,
Sloan-Kettering Institute for Cancer Research, New York, N.Y.

KELLER, ANDREW Z., D.M.D., M.P.H.—Chief, Research in Geographic Epidemi-
ology Research Service, Veterans Administration Central Office, Department
of Medicine and Surgery. Washington, D.C.

*KERSHBAUM, ALFRED, M.D.—Assistant Chief, Division of Cardiology, Philadel-
phia General Hospital, Philadelphia, Pa. (Dr. Kershbaum, who contributed
to this and previous reports, died suddenly in March 1969.)

Korin, Paut, M.D.—Director, National Institute of Environmental Health
Sciences, Research Triangle Park, N.C.

Krumnorz, Ricnarp A., M.D.—Director, Institute of Respiratory Diseases,
Kettering Medical Center, Kettering, Ohio.

LEUCHTENBERGER, CECILE, Ph. D.—Head. Department of Cytochemistry, Swiss
Institute for Experimental Cancer Research, Lansanne, Switzerland.

LEUCHTENBERGER, RupotFr, M.D.—Professor, Swiss Institute for Experimental
Cancer Research, Lausanne, Switzerland.

Lizpow, AverILL A., M.D.—-Professor and chairman, Department of Pathology,
University of California, San Diego, La Jolla, Calif.

LILIENFELD, ABRAHAM, M.D.—Professor and chairman, Department of Chronic
Diseases, Johns Hopkins School of Hygiene and Public Health, Baltimore, Md.

Lyon, Harvey W., D.D.S., Ph. D.—Secretary, Council on Dental Research,
American Dental] Association, Chicago, M1.

MacManon, Brian, M.D.—Professor of epidemiology, Harvard University School
of Public Health, Boston, Mass.

McLean, Ross, M.D.—Professor of medicine (pulmonary disease), Emory Uni-
versity, School of Medicine, Atlanta, Ga.

MrTcHeEtt, Rocer §8., M.D.—Director, Webb-Waring Institute for Medical Re-
search, University of Colorado Medical Center, Denver, Colo.

Murray, Epmonp A., M.D., Se. D.—Associate professor of medicine, The Johns
Hopkins Hospital, Baltimore, Md.

PAFFENBARGER, RaupxH §S., Jr., M.D.—Chief, Bureau of Adult Health and Chronic
Diseases, Department of Public Health, Berkeley, Calif.

Pererson, WILLIAM F., M.D.—Chief, Obstetrics and Gynecology Service, USAF
Hospital Andrews, MSHCB, Andrews Air Force Base, Washington, D.C.

 

*Deceased.

vi
Perry, THomas L., M.D.—Assistant professor of medicine, University of Colo-
rado Medical Center, Denver, Colo.

Rocumis, Pau. G., M.D.—Heart Disease and Stroke Control Program, Health
Services and Mental Health Administration, U.S.P.H.S., Arlington, Va.

Ross, Witt1am L., M.D.—Chief, Cancer Control Program, Health Services and
Mental Health Administration, U.S.P.H.S., Arlington, Va.

SaFriorT1, UMBERTO, M.D.—Associate scientific director for carcinogenesis,
etiology, National Cancer Institute, National Institutes of Health, Bethesda,
Md.

Scuacuter, JosepH—Statistician, Adult Heart Activities, Heart Disease and
Stroke Control Program, Health Services and Mental Health Administration,
U.S.P.H.S., Arlington, Va.

Scuuman, Leonarp M., M.D.—Professor of epidemiology, University of Min-
nesota, School of Public Health, Minneapolis, Minn.

SuimxKIn, MicHaet B., M.D.—Director, Regional Medical Programs, University
of California at San Diego, La Jolla, Calif.

SILVERMAN, Sots, Jr., D.D.S.—Professor of oral biology, School of Dentistry,
University of California, San Francisco, Calif.

Samrrn, LoweEtt C., D.D.S.—Chief, Preventive Services Section, Community Pro-
grams Branch, Division of Dental Health, U.S.P.H.S., Bethesda, Md.

STAMLER, JEREMIAH, M.D.—Executive director, Chicago Health Research Foun-
dation, Chicago, Tl.

Stepman, Russery L., D. Sc.-—Head, Smoke Investigations, Tobacco Laboratory,
U.S. Department of Agriculture, Philadelphia, Pa.

Trrcke, Ricuagp W., D.D.S.—Director, Research Institute, American Dental
Association, Chicago, Il.

Tosin, Cuartes E., Ph. D.—Professor of human biology, University of Colorado
School of Dentistry, Denver, Colo.

TYLER, WALTER S., D.V.M., Ph. D.—Professor and chairman, Department of Anat-
omy, School of Veterinary Medicine, University of California, Davis, Calif.

UnpEerwoop, PAUL, M.D.—Assistant professor of obstetrics and gynecology, De-
partment of Obstetrics and Gynecology, University of South Carolina Medical
School, Charleston, S.C.

Van Duvuren, Bengamin L., M.D.—<Associate professor, New York University
Medical Center, Institute of Environmental Health, New York, N.Y.

Wet, Joon M.—Director, Bureau of Dental Health Education, American Dental
Association, Chicago, Il.

Wrnoper, Ernest L., M.D—~Associate member, Sloan-Kettering Institute for
Cancer Research, New York, N.Y.

The following professional staff of the National Clearinghouse for
Smoking and Health contributed to the preparation of this report:
Louis Nemser, M.D., David V. Sharpe, M.D., Dorothy E. Green, Ph. D.,
Richard Eisinger, Robert S. Hutchings, Emil Corwin, and Richard
W. White. Special thanks are due Jennie M. Jennings, Mildred H.
Ritchie, and Donald R. Shopland.
Table of Contents

Foreword_._._..._..------------------------------------
Acknowledgments. --_.--------- pene ee eee eee e eee eee ee
Part 1. Current Information on the Health Consequences of
Smoking: Summary of the Report__---_-.-------

Part 2. Technical Reports on the Relationship of Smoking to
Specific Disease Categories_____..__--.----------

Chapter 1. Smoking and Cardiovascular Dis-

Chapter 2. Smoking and Chronic Obstructive

Bronchopulmonary Disease__-_-_--
Chapter 3. Smoking and Cancer.______._------
Chapter 4. Effects of Smoking on Pregnancy-.--
Chapter 5. Smoking and Noncancerous Oral Dis-

35
53
75

83
PART 1

 

Current Information on the
Health Consequences of
Smoking
Summary of the Report

 

This report is a review of the pertinent medical literature on the
health consequences of smoking which has appeared since the publica-
tion of the 1968 Supplement to the 1967 Public Health Service Review.
The 1964 Report of the Advisory Committee on Smoking and Health,
the 1967 Public Health Service Review, and the 1968 Supplement
have presented the broad base of converging epidemiological, physio-
logical, pathological, and clinical evidence on which knowledge of the
health hazards of smoking is based. Included in this evidence are
data which show the magnitude of the excess mortality and morbidity
among smokers.

The following conclusions regarding the health consequences of
smoking were summarized in the 1968 Supplement:

General Mortality Information

Previous findings reported in 1967 indicate that cigarette smok-
ing is associated with an increase in overall mortality and mor-
bidity and leads to a substantial excess of deaths in those people
who smoke. In addition, evidence herein presented shows that
life expectancy among young men is reduced by an average of
8 years in “heavy” cigarette smokers, those who smoke over two
packs a day, and an average of 4 years in “light” cigarette smokers,
those who smoke less than one-half pack per day.

Smoking and Cardiovascular Diseases

Current physiological evidence, in combination with additional
epidemiological evidence, confirms previous findings and suggests
additional biomechanisms whereby cigarette smoking can con-
tribute to coronary heart disease. Cigarette smoking adversely
affects the interaction between the demand of the heart for oxygen
and other nutrients and their supply. Some of the harmful cardi-
ovascular effects appear to be reversible after cessation of cigarette
smoking.

Because of the increasing convergence of epidemiological and

hysiological findings relating cigarette smoking to coronary
heart disease, it is concluded that cigarette smoking can con-
tribute to the development of cardiovascular disease and partic-
ularly to death from coronary heart disease.

Smoking and Chronic Obstructive Bronchopulmonary Diseases
Additional physiological and epidemiological evidence confirms
the previous findings that cigarette smoking is the most important
cause of chronic non-neoplastic bronchopulmonary disease in the
United States.
3
Cigarette smoking can adversely affect pulmonary function and
disturb cardiopulmonary physiology. It is suggested that this can
lead to cardiopulmonary disease, notably pulmonary hypertension
and cor pulmonale in those individuals who have severe chronic
obstructive bronchitis.

Smoking and Cancer

Additional evidence substantiates the previous findings that
cigarette smoking is the main cause of lung cancer in men. Ciga-
rette smoking is causally related to lung cancer in women but ac-
counts for a smaller proportion of cases than in men. Smoking is a
significant factor in the causation of cancer of the larynx and
in the development of cancer of the oral cavity. Further epidemi-
ological data strengthen the association of cigarette smoking with
cancer of the bladder and cancer of the pancreas.

The most recent Public Health Service review of the effects of
smoking on pregnancy was presented in the 1967 Report. The con-
clusions of that review were as follows:

Clearly, more research is needed to elucidate the significance of
the relationship of smoking in pregnancy and low birth weight.
Additional long-range morbidity studies are needed, as well as
studies on the effect of smoking on uterine activities and placental
blood flow.

Smoking does have an effect on the outcome of pregnancy. How-
ever, it is not known whether this effect is deleterious or not.

Until such evidence is presented so as to clearly define the role
of smoking in pregnancy, it is more prudent at this time to advise
pregnant women to stop or decrease their cigarette-smoking
practices.

No substantial negative evidence has appeared which refutes these
judgments. On the contrary, studies made available since the publica-
tion of the 1968 Supplement and reviewed by panels of experts in the
relevant medical areas confirm previous findings and add new evidence
that smoking is a health hazard. Highlights of the 1969 Supplement
are as follows:

I. Smoking and Cardiovascular Diseases

Further data from prospective studies confirm the judgment that
cigarette smoking is a significant risk factor that contributes to the de-
velopment of coronary heart disease, apparently by promoting myo-
cardial infarct and cardiac arrhythmias. Analyses by several investi-
gators of other associated factors (high serum cholesterol, high blood
pressure and body weight) show clearly that the effect of cigarette
smoking persists and is appreciable, even when these other factors are
carefully evaluated. Autopsy studies suggest that cigarette smoking
is associated with a significant increase in atherosclerosis of the aorta
and the coronary arteries. Experimental studies in animals have pro-

4
vided new information on the pathological effects of cigarette smoking
on the arteries. This further supports the view that cigarette smoking
promotes atherosclerosis.

II. Smoking and Chronic Obstructive Bronchopulmonary Diseases

Recent studies have demonstrated that cigarette smokers may have
significant disease of the small airways in the absence of bronchopul-
monary symptoms. This disease is demonstrated by the finding of ab-
normalities in the ventilation/perfusion relationships in the lungs of
cigarette smokers. Animal experiments have demonstrated the path-
ological effects caused in the lung by exposure to cigarette smoke or
to specified concentrations of products found in cigarette smoke. Con-
ditions similar to pulmonary emphysema in man have been produced
in some of these experiments. Other studies have investigated the path-
ological effects of smoking on pulmonary clearance mechanisms and
demonstrated that pulmonary clearance may be significantly impaired
by the effects of cigarette smoking. Epidemiological and laboratory
evidence supports the view that cigarette smoking can contribute to
the development of pulmonary emphysema in man.

IIT, Smoking and Cancer

A major pathological study of histological changes in the larynx
has demonstrated a dose-relationship between smoking and premalig-
nant changes in the larnyx. New animal models for the experimental
study of respiratory cancer, which may be helpful in elucidating
the mechanisms of respiratory tract carcinogenesis, have been de-
veloped and refined. More studies have been done to identify those
substances in tobacco smoke which take part in carcinogenesis. These
studies may help to define the exact biomechanisms involved in the
cause and effect relationship between cigarette smoking and lung
cancer.

IV. Effect of Smoking on Pregnancy

New data are presented which confirm the finding that maternal
smoking during pregnancy is associated with low birth weight in
infants and also indicate that maternal smoking is associated with an
increased incidence of prematurity defined by weight alone. In addi-
tion, it appears that maternal smoking during pregnancy may be as-
sociated with an increased incidence of spontaneous abortion, stillbirth,
and neonatal death and that this relationship may be most marked in
the presence of other risk factors.

V. Smoking and Noncancerous Oral Disease

The chapter on noncancerous oral disease is the first Public Health
Service review of this subject. The data available lead to the conclusion
that ulceromembranous gingivitis, alveolar bone loss, and stomatitis
nicotina are more commonly found among smokers than among non-
smokers. The influence of smoking on periodontal disease and gingi-
vitis probably operates in conjunction with poor oral hygiene. In
addition, there is evidence that smoking may be associated with
edentulism and delayed socket healing.

Tobacco smoke contains a large number and a wide variety of com-
pounds which may result in complex and multiple pathophysiological
effects on the various tissues and organ systems. While further research
is needed to investigate the exact biomechanisms involved in the patho-
logical effects of smoking, the evidence clearly shows that cigarette
smoking constitutes 4 major health hazard in the United States.
 

PART 2

Technical Reports on the
Relationship of Smoking
to Specific Disease Categories

360-028 O—69-——2
CHAPTER 1

 

Smoking and Cardiovascular Diseases

Contents

Page
Summary--.-.------------------------------------------ 11
Epidemiological Studies____..---------------------------- 12
Atherosclerosis..__...-_-------_--_-----------+---------- 25
Thrombus Formation and Blood Flow___.-----.----------- 27
Carbon Monoxide______.___----------------------------- 28
Cited References__._____.-------_----------------------- 29
Cardiovascular Supplemental Bibliography - - --------------- 31
SMOKING AND CARDIOVASCULAR DISEASES

Suso1ary

Coronary heart disease (CHD) among men in the Western world is
an epidemic which cuts short the lives of many in their prime produc-
tive years. The evidence linking smoking and CHD has been reported
not only from studies in the United States, but also from such diverse
areas as West Germany, the U.S.S.R., France, Israel, Italy, and the
British Isles.

The 1968 Supplement (27) stated :

Because of the increasing convergence of epidemiological and
physiological findings relating cigarette smoking to coronary
heart disease, it is concluded that cigarette smoking can contribute
to the development of cardiovascular disease and particularly to
death from coronary heart disease.

The convergence of autopsy data and experimental data presented in
this and previous reports suggests that cigarette smoking promotes
atherosclerosis, including that of the coronary arteries. The results of
physiological research and the findings of diminished risk of CHD in
those who have stopped smoking indicate that there is also a more
immediate mechanism operative. The mechanisms which might be re-
sponsible for the promotion of myocardial infarction and fatal cardiac
arrhythmias by cigarette smoking were extensively reviewed in the
1968 Supplement (27). Briefly stated, nutrient supply to the myocar-
dium in general and, perhaps more importantly, to focal ischemic
areas of the myocardium may be seriously compromised by a combina-
tion of effects caused by smoking, and the deprived myocardium may
become infarcted or develop an arrhythmia. These effects include
diminution of blood flow through atherosclerotic coronary vessels and
diminution of available oxygen for tissue use resulting from the bind-
ing of carbon monoxide to hemoglobin in the place of oxygen and

iW
possibly, although presently speculative, the poisoning of respiratory
enzymes by hydrogen cyanide.

Cigarette smoking has been shown to be an important risk factor
in the development of CHD. It is important both by itself and in
the presence of other significant risk factors. In combination with
certain other risk factors, the joint effects appear to be even greater
than those accounted for by those risk factors independently.

EPmpeMIoLogicaL STUDIES

Hammond, et al. (77) have presented new data on mortality from
CHD, stroke, and nonsyphilitic aortic aneurysm among more than
800,000 men and women who were between the ages of 40 and 79 in 1959.
The authors were attempting to evaluate the significance of multiple
factors (sex, age, diabetes, high blood pressure, body weight, change
in weight, exercise, cigarette smoking, sleep, and nervous tension) in
the variations in death rates from these three diseases. It should be
noted that this information consisted of self-reports obtained by ques-
tionnaire and were not obtained from medical examination. Causes of
death were based on death certificate reports.

As illustrated in table 1, coronary heart disease death rates and
mortality ratios increased with increased cigarette smoking for men
in all age groups and for women under the age of 70. Although the
mortality ratios were higher in the younger age groups, the differ-
ences in death rates between nonsmokers and heavy smokers became
progressively higher with increasing age. Although CHD rates were
higher for those who were 10 percent or more above the average weight
for their height-age-sex group, and for those who reported having
high blood pressure, the trend is clear that the effect of smoking persists
and is appreciable, even when these other factors are held constant
(table 2).

12
TapLE 1.—Death rates and mortality ratios for coronary heart disease
and stroke, by amount of cigarette smoking, sex, and age

 

 

 

 

 

 

 

 

 

Coronary heart disease Stroke
Regularly smoked cigarettes Regularly smoked cigarettes
Sex and age Never Never ———___————__-—
smoked Number smoked daily smoked Number smoked daily
cigarettes cigarettes
regularly 1-9 10-19 2-39 400r regularly 1-9 10-19 2-39 40 or
more more
DEATH RATES
Males:

40-49 years... 6 109 176 256 375 4 x” 216 3t 23
80-50 years... 287 409 548 616 118 40 78 53 81 96
60-69 years... 650 961 1,184 1,241 1,166 168 219 242 272 239
70-79 years... 1,730 1,970 2,431 2,573 2,548 650 617 538 792 2445

Females:
40-49 years... 13 17 a a 243 10 16 yi] 2 257
50-59 years_... 59 68 140 158 220 27 ue 3 72 295
60-69 years... - 268 279 479 558 3 B42 110 139 236 201 --
70-79 years... . 979 740 963 («1,243 a 487 404 «2.276 622 =

MORTALITY RATIOS!
Males:

40-49 years... 100 460 25 376 551 LOO 279 2114 2.21 1,64
30-59 years... 100 169 213 240 279 100 195 Le 2,03 2.40
60-69 years... L00 «21.48°0«2182)0 «L978 100 1.30 144 1.62 1.72
70-79 years... 1.00 Li4 141 149 147 1,00 - 95 .92 1.22 2,68

Females:
40-49 years... 1.00 L331 208 3.62 33.31 100 1.50 260 290 75.70
50-59 years... 1.00 1.15 237 268 3.73 L0 | 61 270 267 %3.52
60-69 years.... 1.00 10 Lv 208 2202 100 16 215 1.83 wees
70-79 years... - 1.00 76 8 L277 ease 100 83 «2.57 LB anne

 

! The mortality ratio is the observed rate divided by the expected rate.

2 Rates based upon only 5 to 9 deaths.
Source: Hammond, E. C., et al. (11).
TABLE 2.—Coronary heart disease death rates for men and women
classified by smoking habits, age, blood pressure, and relative weight

 

 

 

 

No high blood pressure, High blood pressure,
Extent of by relative weight by relative weight
elgarette smoking

and age Less 120 Less 129

Total than 90-109 110-119 and Total than 90-109 110-119 and

90 over 90 over

MEN
None or slight:

64 128 204 ase 1968 32100 ewe

216 263 390 620-1686 611 643 609
573 701 763 «1,503 1,777 1,206 1,860 1,835
1,555 L840 1,868 2,738 3,342 2,688 2,651 3,100

104 141 245 -w9 «1 364 26 16 CLL

%
890 984 973 «1,876 «41,913 1,999 1,447 1,710
1,778 1,953 2,901 3,220 3,700 3,172 2,213 65,451

235 309 276 647 687 550 765 88,
836 666 641 «1,137, 1,148 1,158 933441

2,205 2,151 2,846 4,123 5,141 4,205 13,692 9 __._.

 

WOMEN

 

32 64 68 161 100 142 187 229

779 667 764 «1,388 «1,313 1,217) «1,449, 626

 

12 a wee 86 ass 2 (re
70 153 173 231 361 Bl 123 1198
24 422 w= 730 732 743 848 i494
551 2 --- 12,161 '1,854 1014 -..-. 0 -...-
38 142 1% 144 a WE ee ae ee
128 --- 1185 3381263 201 =| 584 1706
467 341 5391 637 a BIL 1708 «(1,100 eee ete
644186601585 a --- 2,468 wes '8,748 22. wee

 

1 Rates based upon only 5 to 9 deaths.
Source: Hammond, E. C., et al. (71).

Hammond, et al. also studied CHD mortality among men who were
ex-smokers of cigarettes. The death rates from CHD were lower
among the ex-smokers than among those still smoking at the beginning
of the study, the size of the difference being larger the longer they
had been off smoking (table 3). Some people stop smoking because
of illness or symptoms and these people would be expected to have
higher death rates than those who stop for other reasons. Early deaths
among those with preexisting disease may account, at least in part,
for the high death rates from CHD among ex-smokers in the early
years of abstention.

14
Mortality ratios for stroke were higher among cigarette smokers
with the exception of those over 70 years of age. Male ex-cigarette
smokers had mortality ratios for stroke approximately equal to those
of nonsmokers.

A clear increase in mortality from nonsyphilitic aortic aneurysms
with increasing cigarette smoking among men aged 50-69 is seen in
table 4. The mortality ratio for heavy smokers was 8.00.

Hammond, et al. found that death rates from the three diseases var-
ied considerably with relative weight, amount of exercise, amount of
cigarette smoking, and hours of sleep per night. Subjects who were
obese, took little or no exercise, smoked many cigarettes a day, or slept
9 or more hours per night had high death rates. Those with a combi-
nation of these factors have especially high death rates from the three
diseases.

TABLE 3.—Observed and expected number of deaths and mortality ratios
for exz-cigarette smokers with a history of smoking only cigarettes, by
number of years since last cigarette smoking and for current cigarette
smokers, coronary heart disease and stroke; compared to persons who
never smoked regularly, in men aged 40-79

 

Coronary heart disease Stroke

Type of smoker
Observed Expected Ratio Observed Expected Ratio

 

 

Ex-cigarette smokers (former smokers
of 1-19 cigarettes a day):

 

 

 

 

 

Stopped:

Less than 1 year. 29 17.9 LhO2 eee eee eee ee
14 years. 87 46.6 Leet eee
5-9 years. 55 43.7 RB eee eee nee eee
10-19 years. 52 54.1 QE eee eee eee
20 or more years 70 64.7 108 0 eee eee wee ee
Total 263 226.9 1.16 57 56,9 1.00
Current cigarette smokers. ._........- 1, 063 550. 5 1.90 207 134.5 1.54
Never smoked regularly --_........--. 1,841 1,841.0 1.00 SOL 501.0 1.00

Ex-cigarette smokers (former smokers

of 20 or more cigarettes a day):
Stopped:

Less than 1 year.........--... 62 38.6 LOL enn eee tee eee
ns 154 101.9 |)
&9 years... 2-2-2... eee 135 116. 5 LWW cane eee eee
10-19 years.........---.2..--- 133 106.1 LQ eee eet wee
20 or more years. _.........-.- 80 76, 4 5 Or
Total._....------.---------. SA 439.7 12 94 10L.1 0.93
Current cigarette smokers... ........- 2, 822 1, 104.7 2. 5 440 4.7 L8&7
Never smoked regularly .............. 1,841 1,841.0 1,00 501 501.0 1,00

 

Source: Hammond, E. C., et al. (/7).

15
Tasrz 4.—Aortic aneurysm death rates and mortality ratios for men
aged 50-69, classified by cigarette smoking habits

 

 

 

[Rates per 1,000 population]
Never Current smokers, by daily
Measure smoked cigarette consumption
regularly
1-9 10-19 20-39 40 or more
Death rate..-....---22- 22  -  e 13 34 50 59 104
Mortality ratio._--....2. 222-222. 1, 00 2. 62 3. 85 4. 54 8. 00

 

Source: Hammond, E.C., etal. (1).

They also found that death rates from CHD and stroke were lower
in ex-cigarette smokers than in men who were currently smoking ciga-
rettes at the time they enrolled in the study. The death rates of male ex-
cigarette smokers who had not smoked for 10 to 20 years were no higher
or only slightly higher than the death rates of men who had never
smoked regularly. Death rates from the three diseases were lowest
among subjects without a history of diabetes or high blood pressure
who were not obese, took at least moderate exercise, never smoked reg-
ularly and slept 6 to 8 hours per night. Nevertheless, even these sub-
jects had substantial death rates from CHD, stroke and nonsy philitie
aortic aneurysm.

Stamler (24) has anaylzed 10-year mortality data on a total cohort
of men, aged 40-59 in 1958, who were employees of the Chicago Peo-
ples Gas Light and Coke Co. Of 1,465 men examined, 1,325 were found
initially to be free of definite CHD and have been followed without
systematic intervention. Higher overall death rates were found among
the smokers in the study. Table 5 shows the death rates from CHD and
from all causes for men with various risk factors.

Recent papers by Thorne, et al. (25) and by Paffenbarger, et al.
(19) report further results of studies of CHD among former college
students. College health records and other college records were re-
viewed to ascertain the presence or absence of factors under considera-
tion. Cases were identified from death certificates in the study of fatal
CHD (19) and from questionnaires and physical examinations in the
study of nonfatal CHD (25). Matched controls were obtained for each
case. In both nonfatal and fatal CHD, significantly more smokers
were found among the cases than among the controls. Combinations
of risk factors resulted in greater CHD morbidity and mortality ratios
than did single factors. Figure 1 shows the morbidity ratios for com-
binations of pairs of risk factors in nonfatal CHD and table 6 shows
mortality ratios for combinations of risk factors in fatal CHD.

16
Zi

TaBLE 5.—10-year mortality rates for sudden death, coronary heart disease, stroke, cardiovascular-renal, and all causes
combined among men aged 40-59, classified according to cigarette smoking, cholesterol, and blood pressure

[Peoples Gas Light Co, Study, 1958-68. Men originally free of coronary heart disease and followed without systematic intervention.)

 

 

 

 

 

 

; 10-year mortality
1958 risk factor status—cigarette smoking (10 or more a day), Sudden death All CHD Stroke AlLCVR All causes
hypercholesterolemis, hypertension !
Number Number Death Number Death Number Death Number Death Number Death
of mean of rate ? of rate of rate of rate of rate
incohort deaths deaths deaths deaths deaths
No risk factor. ._...- 2.2. 2-2-2 0ene ene ne en een nee reenter 284 0 0 1 3.0 2 5.9 4 11.9 B 42.6
Hypercholesterolemia or hypertension only—1 factor... ---------- 216 4 19.6 13 63.1 6 19.5 19 72.6 27 101.5
Cigarette smoking only (10 or more a day)—1 factor. .--.---------- 405 4 10.0 15 37.1 5 11.8 20 48.9 44 107.7
Hypercholesterolemia and hypertension only—2 factors......-.---- 60 1 9.9 3 29.6 1 40.7 4 70.3 8 121.9
Cigarette smoking (10 or more a day) and hypercholesterolemia or
cigarette smoking and hypertension—2 factors.........-....----- 293 ll 37.2 17 67.1 6 19.9 26 86.4 53 169.9
Cigarette smoking (10 or more a day), hypercholesterolemia,
hypertension—all 3.........------------------2--+ 222-22 seen eee 67 2 25.1 6 76.0 2 25.4 8 101.5 17 225.8
Total... 22.220 - enn eee eee ee ee eee eee mene 31,325 22 16.2 55 30. 2 22 14.9 81 56.6 162 113.1
1 Risk factors include: Serum cholesterol 250 or more mg./dl.; diastolic blood pres- 4 Smoking data were not obtained for 4 of the 1,329 men.
sure 90 or more mm. Hg; 10 or more cigarettes/day. SouRcE: Stamler, J. (#4).

8 All rates are age-adjusted by 6-year age groups to the U.S. male population, 1960.
All rates per thousand.
TaBie 6.— Estimated coronary heart disease death ratios in a 17-51 year
followup among former college students, classified according to combined
presence (+) or absence (—) of each of three specified risk factors,
and by age

 

 

 

Risk factor Age (years) at death from coronary heart disease
Cigarettes, Systolic BP, Ponderal Total
10 or 130 or more index, 30-69 30-44 45-54 55-69
more/day mm. Hg less o years years years years
+ + + 4.3 1(1.9) 5.7 1(4, 8)
+ ~_ + 1.8 2.3 1.6 1 (2.0)
+ + _ 4,2 2.9 4.5 5. 6
_ + + 19 2.9 1.6 1.8
+ _ - 1.7 2,2 1.9 1.3
- + _ 1.3 1.2 1,2 1.4
- _- + 11 14 14 8
_ _ - 1.0 1.0 1.0 1.0

 

1 Numbers in parentheses indicate expected number coronary heart disease decedents less than 5.
Source: Paffenbarger, R.S., et al. (19).

In a study of participants in the Health Insurance Plan of New
York, Weinblatt, et al. (29) reported that cigarette smoking males who
developed angina pectoris were more likely to develop infarction than
were nonsmoking anginal patients, but there were not enough cases to
draw definite conclusions.

Weinblatt, et al. (30) also reported that the prognosis after the de-
velopment of a myocardial infarction appears to be independent of
smoking status prior to the infarct. In the absence of data indicating
which patients stop smoking and how stopping smoking is related to
the severity of myocardial damage, one cannot evaluate the effect of
smoking on prognosis. If the persons who stop smoking tend to in-
clude the most debilitated, the effect of continued smoking on prog-
nosis would be underestimated.

In a prospective study of over 3,000 men, Jenkins, et al. (14) re-
ported that the incidence of CHD in men aged 39-49 was three times
higher among the cigarette smokers than among the nonsmokers (ta-
ble 7). The incidence of CHD increased with increased daily cigarette
consumption. For men aged 50-59, the relationship between cigarette
smoking and CHD was found to be significant only for the heavy

18
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

4 | Cigarettes 10-+-/day—A L. Sys. BP 130-+mm. He.—A 4
3 Sys. BP 130+mm. He.—B 4 Height < 68 in.—B 3
2 4 49 2
“0 39
, =] ae [=] T (] | ,
0 9
4 T cigarettes 10-+/day—A 4— Sys. BP 130+mm. Hg. —A 4
3 | Heignt/ Voveight < 129-8 Sports < 5 b/w 8 3
2 =] + 7 2
3a .
i 1 3.0 at + x] 1
[ 25 ] f 7] |
5 :
4 | Cigarettes 10+/day—A LL Height; Vneight 12.9—A 4
3 | Aegnt < 68 in Height < 68 in.-8
+ 3
2 52 2
ei] 4 =< 48
34 38
1 i
8 =] Tr [=]
20 °
e4 Cigarettes. 10-+/day—A aL Height) Yoeight 129-A 4
E 3 Sports < 5 hr./wk.—B Sports < 5 br./wh.—B 3
Te —
2 + 37 3.6 2
27 32
1 25 +4 da
f Te | | 16 |
° 0
4 | Sys. BP 130-+-mm. Hg. —A f= Height < 68 in. A ‘4
3 Height/ Vvreight < 129-8 LL Sports < 5 hr./wk.—B 3
2 5 2
_ a= 7 a5
: T
1 2 _ 3. 1
[*] 20 el
o °
AW At An At Aa A+ AW At
8 B- B+ B+ B- a B+ B+

PRESENCE (+) OR ABSENCE (—) OF FACTORS (A or B)

Numbers in bars are age- and interval-edjusted attack rates of nonfatel CHD from
college case-taking to 1962.

Fiqaure 1.—Morbidity ratios of coronary heart disease for paired combinations
of factors in college.

Source: Thorne, M.C., et al. (25).

19
smokers (table 8). Former cigarette smokers also had significantly
higher CHD incidence rates, but no data are given on length of time
since stopping smoking, or reasons for stopping. Pipe and cigar smok-
ers did not have higher CHD incidence rates. After controlling for
other risk factors such as lipid levels, diastolic blood pressure, and
body build, the authors found that the association between cigarette
smoking and CHD remained (tables 9, 10). The relationship between
smoking and CHD was stronger among those men who exhibited be-
havior type A than those exhibiting behavior type B (tables 11, 12).
Behavior type A is characterized by enhanced competitiveness, drive,
aggressiveness, hostility, and an excessive sense of time urgency. Be-
havior type B indicates an absence of these characteristics. Analysis
of the data on behavior and cigarette smoking showed that both fac-
tors have effects on the CHD rate. Again, these associations were
stronger in the younger age group.

20
TABLE 7.—Annual incidence rates of coronary heart disease for men 39-49 years of age, classified by smoking history
and by current practices as to cigarette smoking

(Age as of the beginning of the 434 year period of observation]

 

 

 

 

   

 

a Smoking history Current cigarette smoking by number per day
0
subjects Never Pipe and Former Current None 1-15 16-25 26 or more
Morbidity status smoked cigar only cigarette cigarette
Num- Rate! Num- Rate Num- Rate Num- Rate Num- Rate Num- Rate Num- Rate Num- Rate Num- Rate
ber ber ber ber ber ber ber ber ber .
Total number at risk......---.-. 2,258 ...-. BO -..-- 405.2... 29... 1,074 _.... 1,191... 2... 4348 4220 Le
Total number CHD cases....... 63 6.2 7 129 3 1.6 10 «(49.3 43 «38.9 20 33.7 5 5.3 18 49.2 2 410.5
All myocardial infarction... .... 52 5.1 4 17 3 1.6 10 9.3 35 7.2 17 3.1 4 4.2 18 67 18 9.5
Symptomatic. ---. sess 38 3.7 1 4 2 11 8 7.4 27 5.6 i 20 4 4.2 il 5.6 12 6.3
Unrecognized - . nese Bc 14 3 1.2 i 6 2 19 8 1,7 6 11 0 0 2 10 6 31
Fatal............- aoe 9 9 0 0 0 0 1 9 8 1.7 1 2 0 0 5 26 3 16
Angina pectoris only......--.--- il 11 3 L2 0 0 0 0 8 17 3 6 1 1.0 5 26 2 11
1 Annual rate per 1,000 men at risk. for continuity.

2 These distributions of cases for various smoking categories are significantly dif-
ferent from chance at P =0.001.

3 Difference in CHD frequency between this group and those who never smoked
cigarettes (col. 1 and 2combined) is significant at P=0.01 by chi square test corrected

4 Difference in CHD frequency between this group and current noncigarette
smokers is significant at P=0.01.

Source: Jenkin, C. D., et al. (14).
ae

 

Taste 8.—Annual incidence rates of coronary heart disease for men 50-59 years of age, classified by smoking history
and by current practices as to cigarette smoking

[Age as of the beginning of the 444 year period of observation]

 

 

 

 

 

Tol Smoking history Current cigarette smoking by number per day
‘o
subjects Never Pipe and Former Current None 1-15 16-25 26 or more
Morbidity status smoked cigar only cigarette cigarette
Num- Rate! Num- Rate Num- Rate Num- Rate Num- Rate Num- Rate Num- Rate Num- Rate Num- Rate
ber ber ber ber ber ber ber ber ber
is 1820 Lo. 16L 0 _.--. 17 oe 4440 483... 109 _--.- 167)... 1650s ‘
70 16.8 9 2110 H 15,2 9 14.6 41 20.5 29 213.3 6 12.2 16 21.3 319 25.6
52 12.5 8 7.3 8 11.0 5 8.1 33 16.5 19 8.7 5 10,2 15 20.0 13 17.6
35 8.4 4 4.9 4 6.5 4 6.5 23 11.5 12 5.5 4 8.2 11 14.6 8 10.8
17 4.1 2 2.4 4 5.5 1 16 10 5.0 7 3,2 1 2.0 4 53 5 6.7
14 3.4 0 0 3 4.1 3 4,9 8 4.0 6 2.8 2 4.1 4 53 2 2.7
8 4.3 3 3.7 3 4.1 4 6.5 8 4.0 10 4.6 1 20 1 1.3 6 8.1
1 Annual rate per 1,000 men at risk. 3 Difference in CHD frequency between this group and current nonoigarette
2'These distributions of cases for various smoking categories could occur 0.10 of smokers is significant at P=0.01.

the time by chance, hence are not significant at P=0.05. Source: Jenkins, C. D., et al. (14).
TasLe 9.—Annual incidence rates of new coronary heart disease, by
smoking habits, adjusted for age and seriatim, for specified other risk
factors

{Rates are annual incidence per 1,000 men, aged 39 to 49 years at entry into study]

 

Daily cigarette

 

 

 

 

Never Former Pipe and consumption
Specified other risk factors smoked cigarette cigar only -——————_——_— p.t

smokers 1-15 16-25 2or

more
33 93 22 49 89 1000. 005
31 91 18 49 o1 102 001
31 95 18 51 89 102 002
91 18 49 95 100 001
29 89 16 49 95 104 001
Ponderal index..........---------------- 29 91 16 49 95 107 001
Physical activity. 7 29 93 18 47 93 104 001
Amount of exercise......-.-..----------- 29 91 18 49 93 104 - 001
Income level......--.-..---------------- 29 91 18 49 93 104 001
All of the above____..-_-.......-.- 36 93 20 51 89 98 007
Triglycerides......---.....-------------- 31 88 20 40 80 104 - 002

 

1 Level of significance of F-ratio for analysis of covariance.
Source: Jenkins, C. D., et al. (14).

TABLE 10.—Annual incidence rates of new coronary heart disease, by
smoking habits, adjusted for age and seriatim, for specified other risk
factors

[Rates are annual incidence per 1,000 men, aged 50 to 59 years at entry into study]

 

Daily cigarette

 

 

 

 
  

Never Former Pipe and consumption
Specified other risk factors smoked cigarette cigar only -————————_ p.l

smokers 1-15 «16-25 226or

more
Cholesterol.._.-----.---------.---.----- 118 142 153 hs 211 264 0.154
Beta/alpha ratio.......----------------- 107 142 144 120 213 262 -127
109 140 151 122 218 262 -135
118 127 144 129 211 266 . 136
109 127 135 127 220 273 - 066
Ponderal index. -- 107 131 140 122 222 269 - 084
Physical activity__._...- 3 142 149 115 213 249 » 216
Amount of exercise._.._- 113 144 151 118 211 255 - 203
Income level.......------------2-------- 118 138 47 120 220 258 156
All of the above._.-.--...-....---- 113 118 138 140 213 258 158
Triglycerides. .........----------------+ 113 147 14 80 195 260 121

 

1 Level of significance of F-ratio for analysis of covariance.
Source: Jenkins, C. D., et al. (74).

23
360-928 O—69 8
%

TasiE 11.—IJncidence of new coronary heart disease, by smoking category and behavior type, for men aged 39-49

 

 

 

 

 

 

 

 

 

 

 

(Rates are age-adjusted annual incidence per 1,000 men]
Current and former Daily cigarette consumption
Former cigarette pipe and cigar only Total
Behavior type Never smoked smokers 1-15 16-25 26 or more
Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases
Fae ns ee eee ees 5.3 13.8 7 1.3 1 1.6 1 15.8 18 14.9 16 9.3 45
Boon nec nee nee e eee cee en ens 1.3 5.1 3 2.2 2 7.3 4 3.1 3 4.9 4 3.3 18
Total ....-.-.-..-------------- 2.9 91 10 18 3 4.9 5 9.3 18 10.4 20 6.2 63
Source: Jenkins, C. D., et al. (14).
TABLE 12.—IJncidence of new coronary heart disease, by smoking category and behavior type, for men aged 50-59
[Rates are age-adjusted annual incidence per 1,000 men]
‘ Current and former Daily cigarette consumption
Former cigarette pipe and cigar only Total
Behavior type Never smoked smokers 1-15 16-25 26 or more
Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases
AL. wenn ne nee nen nee ee eee eee 12.4 5 18,6 8 21.8 8 16.4 5 21.5 9 30.0 14 20.4 49
B_ ow... enn on wane nen e een e eens 10.0 4 §.1 1 8.4 3 4.7 1 21.1 7 19.1 5 12.0 21
0) 7) 11.1 9 14,2 9 14.9 11 11.5 6 21.3 16 26.0 19 16.8 70
Source: Jenkins, C. D., et al. (14).

 
Epidemiological studies linking smoking and CHD have been car-
ried out in various countries. In a retrospective study in Dublin, of
400 patients under the age of 65 who experienced myocardial infarc-
tion, Mulcahy, et al. (18) observed a definite association between
smoking and the development of the disease.

A prospective epidemiological study of risk factors of CHD, in an
Israeli population, indicates that smoking is associated with a higher
risk of CHD (17).

In a retrospective study of 503 male patients with myocardial in-
farction and 714 age-matched controls in Munich, Schimmler, et al.
(22) report that cigarette smoking plays a significant role as a risk
factor.

A recent paper by Cederlof, et al. (6) employs the twin-study
method on a population of American twins, using a similar approach
to that previously employed in a Swedish twin population. The pur-
pose is to compare the contribution of genetic and environmental in-
fluences to the development of angina pectoris. The authors imply that
their study indicates a more important role for genetic factors than
for smoking. However, this study can be criticized on several grounds.
The authors based their detection of angina pectoris on the results of
a self-administered questionnaire designed to elicit a history of chest
pain of presumable cardiac origin; previous studies in Swedish twins
have shown a low rate of clinical confirmation of heart disease in
those classified positive by questionnaire. No data are available on
the health and smoking habits of 58 percent of the original group or
the 41 percent of the “eligible twin pairs” who were nonrespondents.
The authors’ definition of a present smoker includes persons who have
stopped smoking cigarettes for up to 3 years and thus includes per-
sons who in other studies have been classified as ex-smokers. This
definition of a cigarette smoker might contribute to an underestima-
tion of the immediate effect of current cigarette smoking, since an
unstated number of recent ex-smokers are included in the same cate-
gory as current cigarette smokers.

The relationship between cigarette smoking and the development
of angina pectoris has not been clarified. However, Aronow, et al,
(1) have shown that smoking one cigarette before exercising reduces
the energy expenditure required for patients with classical angina
pectoris to develop chest pain while exercising on a bicycle ergometer.

ATHEROSCLEROSIS

A review of autopsy studies by Strong and Auerbach, suggesting
that cigarette smoking has a chronic effect leading to advanced degrees
of atherogenesis, was presented in the Health Consequences of Smok-
ing, 1967 (26). Further studies have recently been published in this
area.

25
Sackett, et al. (27) have demonstrated a clear dose-relationship be-
tween cigarette smoking and the severity of aortic atherosclerosis at
autopsy. Their study of 1,019 consecutive autopsies, on patients who
had been interviewed about their smoking habits prior to death,
showed a significant increase in the severity of aortic atherosclerosis
with increasing use of cigarettes, measured both by intensity and by
duration of smoking.

An autopsy study from Russia by Avtandilov, et al. (3) demon-
strated a significantly greater degree of atherosclerosis in the coronary
arteries of smokers than in those of nonsmokers.

Viel, et al. (28) have reported on the severity of coronary athero-
sclerosis at autopsy of 1,150 men and 290 women who died violent
deaths in Chile. Information on smoking habits was available on 566
men. The authors report no relationship between atherosclerotic le-
sions and the use of tobacco. The degree of atherosclerosis was ex-
pressed as the percentage of the surface of the intima of the left
anterior descending coronary artery covered by fatty streaks and
fibrous plaques. An examination of the data presented in graphic
form indicates that the moderate and heavy smokers appear to show
consistently higher percentages of diseased areas than the nonsmokers.
But the statement of the authors implies that these differences were
not statistically significant when subjected to an analysis of variance.

A study by Astrup was reviewed in the 1968 Report (27). This
study showed that in rabbits on a high cholesterol diet, chronic carbon
monoxide exposure has a marked atherogenic effect.

Kjeldsen, et al. (75) compared the vascular pathology in rabbits
fed a high cholesterol diet and maintained in an hypoxic atmosphere
(10 percent oxygen) with that in rabbits exposed only to the high
cholesterol diet. The authors demonstrated that hypoxia leads to an
increase in the degree of plaque formation in the coronary arteries and
in the amount of visible aortic atheromatosis, as well as to an increase
in the aortic content of cholesterol and triglycerides. In addition, the
hearts of the hypoxic animals showed marked perivascular xantho-
matosis, often infiltrating the surrounding myocardium. In sum-
marizing this experiment and their previous findings of increased
atheromatosis in hypercholesterolemic rabbits subjected to high
carboxyhemoglobin (COHb) levels, the authors (2) state that tissue
hypoxia seems to be an important factor in initiating these lesions,
regardless of the manner in which the hypoxia is produced. Although
the COHb levels in the rabbits and the degree of hypoxia were much
higher than that experienced by human smokers, these results suggest
a mechanism by which smoking might contribute to atherosclerosis.

Hass, et al. (72), extending studies reviewed in the 1968 Report
(27), have demonstrated that the administration of injections of nico-

26
tine to hypercholesterolemic rabbits who are also given vitamin D
enhances the peripheral atheromatous calcific arterial disease which
is produced by the combination of hypercholesterolemia and vitamin
D administration. The addition of nicotine to the regimen also resulted
in the frequent occurrence of thromboarteritis in the distal calcified
arteries of cardiac and skeletal muscle, and of the smooth muscle of
the gastrointestinal tract. The nicotine effect was reproduced by sub-
stituting appropriate dosages of adrenalin for nicotine and abolished
by adrenalectomy.

Lellouch, et al. (46) have reported that the administration of a
mono-amine oxidase (MAO) inhibitor to rabbits on a regimen of
daily nicotine injections significantly reduced the number of animals
who developed fibrotic lesions of the aorta in response to nicotine.
Further work is in progress to elucidate the mechanism of the MAO
effect.

Evidence presented in this and previous reports suggests that ciga-
rette smoking promotes atherosclerosis.

Turomsus Formation anp Bioop Frow

Hess, et al. (23) discovered aggregations of platelets, erythrocytes,
fibrin, detached epithelial cells, and some as yet unidentified cells on
the aortic and carotid walls of rabbits subjected to cigarette smoke.

The discovery of a plasma factor which increases the in vitro syn-
thesis of fibrinogen by human liver biopsies has been reported by
Pilgeram, et al. (20) in older patients who have recovered from myo-
cardial infarction. This factor has been tentatively identified as free
fatty acid (FFA). The authors state that the association between
FFA and fibrinogen synthesis may provide the link between hyper-
lipemia and clotting. Cigarette smoking causes an increase in FFA
through its stimulation of catecholamine release.

Several recent studies have begun to elucidate the role which
changes in blood viscosity and certain features of the microcirculation
might play in the development of atherosclerosis and coronary heart
disease. .

Dintenfass (7) has suggested that myocardial infarction and coro-
nary thrombosis may be the result of a number of factors, separate
or interrelated, all leading to a high viscosity of the blood. These
factors may affect the migration and adhesion of platelets, the volume
of plasma, and the rigidity of the red blood cell. Phenomena leading
to high blood viscosity may occur in focal areas leading to occlusion of
small vessels, resultant ischemia, and an infraction of either subclinical
or catastrophic proportions, depending on the location and number
of vessels involved. Dintenfass also believes that an increase in blood

27
viscosity precedes the clinical manifestations of the high blood vis-
cosity syndrome and that the increased blood viscosity seen in post
myocardial infarct patients is a reflection of the etiology rather than
the effect of the disease.

Local hypoxia leading to an increase in the rigidity of the blood cell
might be produced by cigarette smoking through the increase in
COHb. Platelet adhesiveness is increased by smoking, probably sec-
ondary to the release of catecholamines (27).

In a study of 50 white males with myocardial infarcts and 40 con-
trols, Stables, et al. (23) found that the patients with myocardial
infarct had a mean hematocrit level significantly higher than that of
the controls. Studies of blood volume indicated that a reduction in
plasma volume rather than an increase in red cell mass among the
myocardial infarct patients accounted for the elevated hematocrit.

Carson MonoxipE

Several reviews of the pathophysiology of exposure to carbon mon-
oxide (CO) have appeared recently. These are pertinent to the discus-
sion of the relationship of smoking to health, since cigarette smoke
contains amounts of CO sufficient to cause a COHb level of 5 to 10
percent in the smoker, depending on the amount smoked and degree
of inhalation (9,70).

Bartlett (4) has pointed out that because the absorption of CO from
the ambient environment is dependent upon the concentration of CO
in the environment as contrasted to that in the blood, smokers with a
COHb level of 5 percent will not absorb CO from inspired air unless
the concentration of CO in the air exceeds 30 parts per million. How-
ever, he also states that because the excretion of CO between cigarettes
will be lower in CO polluted air, the smoker will have a higher long-
term average COHb level in a polluted environment. Patients with
heart disease may be particularly susceptible to the hypoxic burden
caused by the presence of COHb.

Goldsmith, et al. (70) have stated that for the U.S. urban popula-
tion, cigarette smoking is probably the most important cause of
increased COHb above the endogenous level produced by heme catabo-
lism, followed by automobile exhaust, occupational sources, and home
heating and cooking devices, in that order.

Although Dinman (6) minimizes the importance of the effect of CO
levels of 5 to 10 percent on the myocardium, he states that a short-
coming in his approach is that focal areas of myocardial ischemia are
not reflected in the determination of oxygen saturation made from
samples of blood taken from the coronary sinus. Such areas of ischemia
might be important in initiating fatal arrhythmias. Levels of COHb

28
which decrease further the oxygen supply to the ischemic myocardium
might be readily provided by cigarette smoking.

Eliot, et al. (8) have reported effects of cigarette smoking on the
oxygen affinity of hemaglobin independent of the presence of CO.
Their results suggest that cigarette smoking may have both acute and
chronic effects on oxygen affinity which differ in direction. The authors
caution, however, that the in vivo oxygen affinity of hemoglobin may be
different from that implied by the static equilibrium data. Further
research is in progress.

CITED REFERENCES

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in angina pectoris, Annals of Internal Medicine 69(3) : 529-536, Sep-
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(2) AstRruP, P., KsELpsen, K., WaNsTEUP, J. Enhancing influence of carbon
monoxide on the development of atheromatosis in cholesterol-fed rabbits.
Journal of Atherosclerosis Research 7 : 343-354, 1967.

(3) Avtanpiwov, G. G., Korznova, V. I., PONOMARENKO, O. V. Kureniye tabaka i
stepen’ ateroskleroticheskogo porazheniya koronarnykh arteriy serdtsa i
aorty. (Tobacco smoking and the degree of atherosclerotic lesions of
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January-February 1965.

(4) BarttettT, D., Jr. Pathophysiology of exposure to low concentrations of
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(5) Cevervor, R., Frmere, L., Hrusec, Z. Cardiovascular and respiratory symp-
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(6) Dinman, B. D. Pathophysiologic determinants of community air quality
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(7) DinvenFass, L. Blood rheology in pathogenesis of the coronary heart
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(8) Exror, R. S., Strerr, R., Sacwany, J. M., MizvKaml, H. Personal Com-
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(9) Gotpsmrra, J. R. Carbon monoxide. Science 157 : 842-844, August 18, 1967.

(10) GotpsmirH, J. R., Lanpaw, 8. A. Carbon monoxide and human health.
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(11) Hammonp, E. C., GARFINKLE, L. Coronary heart disease, stroke, and aortic
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(12) Hass, G., Henson, D., LANDERHOLM, W., HEMMENS, A. Prevention of nico-
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(18) Hess, H., Frost, H. Rauchen und arterielle Verschlusskrankheiten.
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(14) Jenxrns, C. D., Rosenman, R. H., Zyzanski, 8. J. Cigarette smoking. Its
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29
(15) Kzetpsen, K., Wansrevp, J., Astrup, P. Enhancing influence of arterial
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CHAPTER 2

 

Smoking and Chronic Obstructive
Bronchopulmonary Disease

Contents

Page
Summary-__-..------------------------------------------ 37
Chronie Bronchitis. ___...._.---------------------------- 37
Prevalence of Chronic Obstructive Bronchopulmonary Disease_ 38
Pulmonary Emphysema-.-----.-------------------------- 38
Experimental Studies in Man-_ ---------------------------- 39
Studies in Animals__.___..__.--------------------------- 40
Other Studies__._._..__.-_------------------------------- 42
Cited References. _.___---------------------------------- 43

Chronic Obstructive Bronchopulmonary Disease Supplemental
Bibliography _._-_------------------------------------- 46

35
SMOKING AND CHRONIC OBSTRUCTIVE
BRONCHOPULMONARY DISEASE

Summary

Additional evidence which supports the previous judgment of a
cause and effect relationship between cigarette smoking and chronic
obstructive bronchopulmonary diseases, especially chronic obstructive
bronchitis, continues to accumulate from both the United States and
abroad. New work has been published in the past year which provides
additional information on the possible mechanisms by which cigarette
smoking can lead to the production of pulmonary emphysema. These
mechanisms include collapse of small airways, changes in pulmonary
surfactant, impairment of pulmonary clearance, disruption of the
normal architecture of the bronchial epithelium, and obstruction of
capillaries of the bronchi and alveoli. At present, there is no unified
hypothesis for the pathogenesis of pulmonary emphysema; however,
the pathogenetic mechanisms may involve more than one component
‘of lung tissue. Epidemiological and laboratory evidence supports the
view that cigarette smoking can contribute to the development of
pulmonary emphysema in man.

Curonic BroNcuitis

Cigarette smoking is the most important cause of chronic bronchitis.
In the past year, studies from various countries have appeared in the
literature reconfirming this association. In studies of populations of
working men in Italy (15), the Netherlands (6), England (26, 35) and
the United States (9), smokers were found to have a significant in-
crease in either incidence or prevalence of chronic bronchitis as com-
pared to the nonsmokers. Studies of populations from rural and urban
Sweden (37) and rural Australia (25) produced similar findings. A
South African study (45) demonstrated decreased forced expiratory
volumes (FEV,) and peak expiratory flow rates (PEFR) with in-
creased tobacco consumption, even in those who did not have chronic

bronchitis.
37
PREVALANCE OF CHRONIC OBSTRUCTIVE BroNCHOPULMONARY DIsEAsE

The prevalence of chronic obstructive bronchopulmonary disease is
probably underestimated. In a study of death certificates, Moriyama,
et al. (39) have reported that chronic obstructive bronchopulmonary
disease is often omitted as a contributing cause of death. Mitchell,
et al. (38) also found that the disease often goes unreported. Barach,
et al. (5) maintain that much of the reported increase in the preva-
lence of chronic obstructive bronchopulmonary disease can be ac-
counted for by better diagnosis. However, Barach, et al. base their
statement on the supposition that the rising death rates from chronic
obstructive bronchopulmonary disease are incompatible with the fact
that many people are giving up smoking. However, it should be
pointed out that chronic obstructive bronchopulmonary disease asso-
ciated with cigarette smoking may be the result of many years of ex-
posure to cigarette smoke and the mortality rates from bronchitis and
emphysema would not reflect large-scale smoking cessation for some
time to come. Burrows (10) has pointed out that the effects of cessa-
tion of smoking on the course of already existing chronic obstructive
bronchopulmonary disease may be difficult to assess, since it may be
that those who are disabled by severe disease tend to stop smoking
more often than those who have milder forms of the disease. The bene-
ficial effects of cessation of smoking could thus be masked.

PutmMonary EMPHYSEMA

Many agents appear to contribute to the development of emphysema,
but epidemiological and experimental evidence indicates that cigarette
smoking is the most important agent in the development of pulmonary
emphysema in man. Mention of the theories of pathogenesis of pul-
monary emphysema, long the subject of debate among medical scien-
tists (1, 34, 46, 47, 48), may help to serve as background for the
presentation of recent research on the role of cigarette smoking in the
development of emphysema.

Two major theories of the pathogenesis of chronic obstructive pul-
monary emphysema have been proposed. One theory states that the
primary lesion of emphysema is vascular and involves obstruction
either by thrombosis or by endarteritis of the pulmonary or bronchial
arterial branches. The resultant loss of nutrient supply is thought
to result in ischemic necrosis of the alveolar wall and septa. The other
major theory states that chronic obstructive pulmonary emphysema
results from the direct effect. of toxic inhalants on the pulmonary tissue,
in the areas of the terminal bronchioles and alveoli. According to this
theory, changes seen in the pulmonary and bronchial vessels are

38
secondary to the destruction of nonvascular tissue. It may well be that
the pathogenesis of pulmonary emphysema can involve several mecha-
nisms and that both of these theories may be applicable but not mutu-
ally exclusive (44).

ExprrIMentaL Srupres in Man

Anderson, et al. (2) have reported preliminary results which indi-
cate that cigarette smoking causes acute changes in the ventilation/
perfusion relationships of the lung and that patients with chronic
obstructive bronchopulmonary disease appear to be particularly liable
to these changes. In some patients the changes are predominantly in
perfusion, a finding which lends support to the vascular theory of
pulmonary emphysema. In other patients, the changes are predomi-
nantly in ventilation, a finding which lends support to the theory of
the direct effect of inhalants in the pathogenesis of pulmonary
emphysema.

Anthonisen, et al. (2) investigated pulmonary function in 10 male
smokers with clinically mild chronic bronchitis, all of whom had
smoked cigarettes for at least 20 years. Besides the usual pulmonary
function tests, these investigators employed a technique for the assess-
ment of regional pulmonary function using radioactive xenon. Despite
the fact that overall pulmonary function was nearly normal in several
patients, all had decreased ventilation and depressed ventilation/per-
fusion ratios in some lung regions, with the basal areas being those
most commonly affected. The author suggested that significant dis-
ease in the peripheral airways may exist in patients whose chronic
bronchitis is clinically mild and who show no present impairment of
ventilatory capacity. The radioactive xenon test may reveal severe
compromise of the overall gas exchange when usual studies of ventila-
tory capacity do not reveal impairment. These changes in the distal
airways may become more significant clinically as the patient ages,
since aging has been shown to be associated with a diminution in the
compliance of the lung (29). Peters, et al.(40) have reported that the
lower flow rates found among college students who smoke, especially
at lower lung volumes, may reflect disease in the small airways. The
diminution in flow in these subjects was approximately proportionate
to the total lifetime number of cigarettes smoked.

Fullmer, et al. (22, 23, 24) have found a high prevalence of Cursch-
mann’s type spirals in the sputum of cigarette smokers. The easily
recognized spirals consist of inspissated mucus and are casts of the
lumens of small bronchioles. These spirals were found in the sputum
of 23 of 24 cigarette-smoking women and in 97 of 100 cigarette-
smoking men. The total number of spirals on four slides prepared for

39
360-928 O—69——_4
microscopic examination varied from 0 to 500. Six of 10 ex-smokers
had spirals in their sputum, but the number of spirals was reduced to
a total of 10 or less on four slides. A nonsmoking control group ex-
posed to cigarette smoke at work showed a low prevalence of spirals,
while a control group of nonsmokers not exposed to cigarette smoke
at work showed no spirals in their sputum. Fullmer has suggested that
Curschmann’s spirals may play a role in the development of em-
physema by producing obstruction at the bronchiolar level. The spirals
may also allow prolonged contact between admixed inhalants includ-
ing cigarette smoke and the bronchiolar walls. A study of the presence
of spirals in the sputum of a group of nonsmoking asthmatic bron-
chitics would be useful in an attempt to determine whether the presence
of spirals is a direct result of exposure to cigarette smoke, or is a charac-
teristic of the sputum of bronchitics, whatever the cause of their
bronchitis.

Sroupres 1n ANIMALS

Frasca, et al. (27,18) have reported on electron microscopic observa-
tions of the bronchial epithelium of dogs exposed to cigarette smoke
by active inhalation through a tracheostoma. The epithelium of a dog
exposed to 44 days of smoking by methods previously described by
Cahan, et al. (17) showed a proliferation of goblet cells and a partial
loss of cilia in the surface lining cells. After 420 days of exposure to
cigarette smoke, the number of cell layers in the epithelium was found
to be twice that of the nonsmoking dogs. Goblet cells and ciliated
columnar cells were no longer present; instead, the surface was lined
with columnar and cuboidal cells with stubby projections in place of
cilia, Mitotic figures were frequently observed in the basal cells. These
findings may be relevant to carcinogenesis as well as to the develop-
ment of chronic obstructive bronchopulmonary disease.

Tyler (49) and McLaughlin, et al. (37) have studied the physiology
and morphology of pulmonary emphysema in the horse. The lung of
the horse has been reported to be similar in subgross anatomy to that
of man (36). They have studied both the spontaneous disease, one of
the several causes of the syndrome known as “heaves,” and a similar
but not identical pulmonary disease induced by the injection of chlor-
promazine or of styrene beads into the bronchial arterial circulation.
Their findings of obstructive lesions in the bronchial circulation and
of accompanying emphysematous changes in the pulmonary paren-
chyma provide indirect support of a vascular theory of emphysema.
Ricketts, et al. (47) were unable to produce emphysematous lesions
in sheep by occlusion of the bronchial artery; however, species dif-
ferences in the distribution of this vessel may be an important factor

40
in both experimental and spontaneous disease. The bronchial artery
in the horse is reported to supply the alveolar septa, whereas in the
sheep it is reported to reach only as far as the terminal bronchioles
(36).

A pulmonary disease similar histologically to pulmonary emphy-
sema in man appears spontaneously in certain populations of rabbits
(72). Boatman, et al. (8) have studied this disease by means of the
electron microscope. Three of their findings which tend to support the
theory that the disease is primarily vascular in origin are as follows:
loss of capillary endothelium, partial or complete filling of the capil-
lary lumens with collagen, and frequent recanalization of the damaged
capillaries.

Freeman, et al. (29, 20, 21) have investigated the effect of chronic
exposure of rats to varying concentrations of nitrogen dioxide (NO.),
a gas which is found in cigarette smoke and in industrially polluted air.
These investigators showed that the exposure of rats over their lifetime
of 2 to 3 years to concentrations of 2 (+1) parts per million of NO,
resulted in reduction in cilia of the bronchial epithelium, a reduction
in normal exfoliation, and the appearance of unidentified crystalloid
inclusions. Exposure for only 16 weeks to a higher concentration of 4
(+1) parts per million led to hypertrophy of the epithelium of the
terminal bronchioles. Rats exposed to concentrations varying from 10
(+1) to 25 (+2) parts per million of NO, developed large, heavy,
nonedematous lungs accompanied by dorsal kyphosis. The increase in
weight of the lung was shown to be caused by widespread hypertrophy
of the respiratory epithelium, especially in the bronchioles closely asso-
ciated with alveolar ducts and in the terminal bronchioles. Hyper-
trophy of the bronchial epithelium and accumulation of amorphous
proteinaceus material, fibrin strands, and macrophages resulted in nar-
rowing of the lumens of the terminal bronchioles at their junctions
with the alveolar ducts. Focal hypertrophy of alveolar epithelium
appeared to be associated with compression of alveolar capillaries. The
airspaces of the lung were increased in volume.

Other investigators have also reported an increase in alveolar size
in rodents exposed to NO,. Blair, et al. (7) exposed mice to 0.5 parts
per million of NO, for 6, 18, or 24 hours each day. The animals were
exposed to NO, for periods varying from 3 to 12 months; the degree
of change in the pulmonary histology appeared to increase with in-
creased total length of exposure. Besides producing enlarged alveoli,
exposure to NO, also produced early bronchiolar inflammation with a
concomitant reduction in the size of the distal airways.

41
OrueEr Srupies

In a recent extensive review of the nature and role of pulmonary
surfactant, Scarpelli (43) states that the lowering of surface tension
produced by the action of cigarette smoke on surfactant may pre-
dispose to the development of emphysema.

Cigarette smoke contains powerful ciliostatic agents (50, 51, 52)
which can interfere with pulmonary clearance. Components of both
the particulate and the gaseous phases adversely affect ciliary activity.
Dalhamn, et al. (74) have pointed out that in assessing the effect of
one or another of the components of cigarette smoke on ciliary activity
in various animal systems particular attention must be paid to the
level of exposure, since at different dosages the particulate and gaseous
phases have different relative effects on ciliary activity. Other recent
work by Dalhamn, et al. (73) has further clarified the extent to which
certain components of cigarette smoke are retained in the human lung
and includes the observation that retention of gaseous components
depends in part on adsorption of the gases on particulate matter.

Ballenger, et al. (4) have indicated that the in vitro ciliostatic
effects of oxidized nicotine are enhanced by prior infection of the
tissue explants with Influenza B Virus.

Holma (30) has reported that cigarette smoke has acute depressant
effects on pulmonary clearance in living rabbits.

Recently, observations have been published on the metabolism and
function of the pulmonary alveolar macrophage which, together
with mucus transport, performs the function of ridding the lung of
both inanimate particles and bacteria. Green (27) points out the im-
portance of the alveolar macrophage in pulmonary clearance of
infectious agents. He has also observed a deleterious dose-response
effect of cigarette smoke on the phagocytic activity of the macro-
phage and suggests that this effect may be related to the development
of chronic bronchopulmonary disease.

In another paper, Green (26) found that the cytotoxic activity of
cigarette smoke on pulmonary macrophages may be inhibited by
glutathione and cysteine. Izard (32) observed that the gaseous phase
of cigarette smoke or one of its components, acrolein, inhibited the
multiplication of cultures of Dunaliella bioculata and also observed
that the addition of cysteine to the medium protected against these
effects of acrolein.

Heise, et al. (28) have reported that rabbit pulmonary alveolar
macrophages secrete lysozyme into a culture medium. Lysozyme may
be active in the clearance of bacteria from the lung.

Roque, et al. (42) found a decrease in the activity of oxiodoreduc-
tases and hydrolases in the alveolar macrophages of smokers. They

42
also found that the reduction in these enzymes was directly propor-
tional to the amount of stored fluorescent material present in the
macrophages. This material is thought to originate in tobacco smoke.
Roque, et al. suggested that the tobacco smoke may have induced
abnormalities in the mitochondria of the macrophage.

Kilburn (3%) theorizes that the pathogenesis of chronic obstructive
bronchopulmonary disease is related to the failure of macrophages
to be cleared from the alveoli and bronchioles because of impaction
of mucus. He suggests that dissolution of the cells exposes the alveoli
and bronchioles to damaging enzymes and to the phagocytosed par-
ticles contained in the macrophage.

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52
CHAPTER 3

 

Smoking and Cancer

Contents

Epidemiological Studies_______.-.-..___--.----- 2-2 eee
Lung Cancer_________---.---------- eee
Oral Cancer____---.-----.-------------2- 2 e eee
Laryngeal Cancer..__.-.-.--------------------------
Cancer of the Urinary Bladder and Kidney_____.._____-
Cancer of the Pancreas________..____-.--------------

General Aspects of Carcinogenicity__....___....__.-.-_-__-
Tobacco Alkaloids._____.-..-_----.--_---- eee

Experimental Aspects of Carcinogenesis. ___._______...____-
Retention of Smoke Constituents. .____.....__._..22--
Changes in Cell Cultures Induced by Cigarette Smoke. __
Experimental Studies of Bronchogenic Carcinoma in

Page
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58
60
60
61
61
62
62
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62

63

64
65
69

53
SMOKING AND CANCER

SuMMARY

Previous reports (59, 60, 61) have presented the evidence that ciga-
rette smoking is a major cause of lung cancer and that cessation of
cigarette smoking sharply reduces the risk of dying from lung cancer
as compared to the risk taken by those who continue to smoke. Ciga-
rette smoking was also shown to be a significant factor in the causa-
tion of cancer of the Jarynx. A strong association between various forms
of smoking and cancers of the buccal cavity, pharynx, and esophagus
was also shown. Data were presented which indicated that cigarette
smoking was associated with cancer of the urinary bladder. Data were
aiso presented which suggested that cancer of the kidney and pancreas
may be related to cigarette smoking.

During the past year, both population studies and laboratory studies
from various countries have added to the weight of the evidence
linking smoking and cancer. A major study of histological changes
in the larynx has demonstrated the higher risk of premalignant
changes among smokers. More studies have been done to identify those
substances in tobacco smoke which take part in carcinogenesis. New
animal models for the experimental study of respiratory cancer, which
may be helpful in elucidating the mechanisms of respiratory tract
carcinogenesis, have been developed and refined.

EPIDEMIOLOGICAL STUDIES

It is interesting to note that epidemiological information on ciga-
rette smoking and lung cancer, similar to that which has been collected
in the United States and Western European countries, is now being re-
ported from Eastern Europe and Africa as well.

Lung Cancer

In Norway, a study of histologically proven cases of lung cancer
by Kreyberg demonstrated the low frequency of lung cancer among
nonsmokers. The cases were collected between 1950 and 1964 from two
hospitals and a diagnostic laboratory which service all parts of Nor-
way. The author states that the population represented in this study
is most probably geographically representative of the whole country.
In comparing his results in Norway with those in other European

55
360-928 O—69-——5
countries, Kreyberg stated that a nonsmoking Norwegian population
today should present lung cancer cases in the same number, with the
same sex ratio, and with the same representation of histological types
as prevailed in Norway 40 years ago, and in Europe in general at the
beginning of this century (24, 25). The risks of developing various
histological types of lung cancers among smokers, as contrasted to
nonsmokers, are presented in table 1. Two facts are strikingly apparent
from the table. First, the preponderance of the higher risk of lung
cancer in smokers lies in the categories of epidermoid carcinoma and
anaplastic small cell carcinoma. Second, while female smokers have a
higher risk of developing lung cancer than female nonsmokers, the
relative risks are smaller than those for males. At least part of this
difference may be accounted for by differences in smoking habits be-
tween men and women. Women tend to smoke fewer cigarettes, to
smoke brands lower in tar and nicotine, inhale less and smoke less of
each cigarette than do men; therefore, women have lower exposure to
cigarette smoke.

TaBLE 1.—Tumor prevalence among males and females 36-69 years of
age, by type of tumor and smoking category

[Smokers constituted 85 percent of populations studied]

 

Smoking category Expected Risk
Sex and type of tumor —_—_- Os onumber ratio
Total Smoking Non- among among

all methods smokers smokers! smokers

 

 

 

 

Males: .
Epidermoid carcinoma. --_------ 434 431 3 17.0 25. 4
Small cell anaplastic carcinoma__ 117 116 1 5.7 20. 4
Adenocarcinoma.__...-.--.-..- 88 83 5 6.28.3 2.9
Bronchiolo-alveolar carcinoma... - __ ---- weoe weeeee ----
Carcinoid__.....-----..-.----. 46 39 7 39.7 1.0
Bronchial gland tumor-_.._____. ---- ---- ween Hone ee a
Total__...-2.2--- 22 lee 685 669 16 «©90.7 74
Females:
Epidermoid carcinoma. ---..... 12 9 3 75 12.0
Small cell anaplastic carcinoma... 8 5 3 75 6.6
Adenocarcinoma.._--------.... 56 14 42 10.5 1.3
Bronchiolo-alveolar carcinoma... __-_ —— wane eee eee ——
Carcinoid_.._---.-------.--..- 32 7 25 6.3 lil
Bronchial gland tumor-__._._.__ a--- wee eae ow eeee ~---
Total. ....---2 2-2 ee 108 35 43 18.3 1.9

 

' Number that would be expected if incidence rate among smokers was equal to that of nonsmokers.
SovuxncE: Kreyberg, L. (#4).

56
Brett, et al. (8) found that the mortality rate for lung cancer in
smokers in England was especially high for the smokers who
“drooped” the cigarettes off the lip while they smoked, a habit which
may result in the delivery of a greater dose of smoke from each
cigarette.

Gelfand, et al. (79) ina study of lung cancer in Rhodesian Africans,
reported a preponderance of smokers among the lung cancer patients
as compared to a control group. The authors express the opinion that
air pollution does not play a role in respiratory cancer in Rhodesia.

In the 1967 Health Consequences Report (59), it was pointed out
that the lung cancer risk of ex-smokers declined, relative to those who
continued to smoke. It equalled that of nonsmokers about 10 years
after stopping smoking, and the rate of decline depended on the num-
ber of cigarettes previously smoked and the duration of smoking.
Bross, et al. (10) reported that the risk of developing lung cancer is
lower among filter cigarette smokers than nonfilter cigarette smokers.
Since filter cigarettes are generally lower in tar content than nonfilter
cigarettes, this study supports the inference that the tar content of
cigarettes is a meaningful measure of exposure to risk.

In view of the fact that practically all lung cancer patients started
to smoke nonfilter cigarettes and have smoked filter cigarettes only in
recent years and for a variable length of time, a more exact comparison
of the risks run by smokers of filter and nonfilter cigarettes must await
further studies (67).

The relationship of smoking to lung cancer in women is an area of
continuing concern, since we may expect a continued increase of lung
cancer in women with the increase in cigarette smoking among them
since World War II. Lombard, et al. (32) show a relationship of
cigarette smoking to epidermoid lung cancer in women but not to
adenocarcinoma. It is generally agreed that the contribution of ciga-
rette smoking to the development of epidermoid and oat-cell lung
cancer (Kreyberg Group I) in males is significantly greater than to
the development of adenocarcinoma (Kreyberg Group It).

An association of other diseases to cancer of the lung is found in
a report by Salzer, et al. (48). Salzer and his colleagues have reported
in an autopsy study that lung cancer and scars from stomach ulcers
are statistically associated and suggested that cigarette smoking may
have contributed to both conditions. A study by Stamler, et al. (53)
indicated that male cigarette smokers with elevated cholesterol levels
had higher rates of lung cancer than those with lower cholesterol
levels, Additional studies are needed to confirm and elucidate these
observations.

Programs have been recently established to perform cytological
examinations on the sputum of smokers, since they represent
a population at a high risk for the development of carcinoma of

57
the lung. These programs have detected individuals with atypical or
frankly malignant cells in their sputum before a shadow has appeared
in the lung fields of x-ray (78, 62). Valaitis, et al. (62) reported that
some degree of cytological abnormality was found in the sputum of
4.8 percent of the smokers and 0.9 percent of the nonsmokers.

Oral Cancer

In the Soviet Union, Orlovskiy has shown an association between
cigarette smoking and lung cancer, as well as an association between
the use of “nas” (a mixture of tobacco and ashes) and the development
of cancer of the oral cavity (37). Other studies of interest from around
the world include one by Pindborg, et al. (39) on the epidemiology
and histology of oral leukoplakia and leukoedema among Papuans
and New Guineans. They report that smoking may be more closely
associated with these conditions than is the chewing of betel nut
which previously was considered the obviously associated habit. A
study by Wahi (64) reports on the relationship of tobacco chewing
to oral and oropharyngeal cancer in a district in India. Pindborg also
presents evidence from India indicating that oral submucous fibrosis
(38) may be associated with tobacco use and may result in an oral
epithelium more susceptible to the carcinogenic substances in tobacco.
In a study of oral malignancies indexed in a large tumor registry in
California, Chierici, et al. (73) found that 88 percent of the cancer
patients were smokers. The proportion of smokers ranged from 81 to
83 percent for cancers of the gingival and alveolar mucosa, buccal
mucosa, hard palate, and lip, to 94 percent or more for cancers of the
floor of the mouth, soft palate, tonsil, or oropharynx. Unfortunately,
comparable percentages of smokers in a control population are not
presented. No new studies have appeared which clarify the relative
contributions of other environmental risk factors for oral cancer,
such as alcohol consumption, nutritional problems, and poor oral
hygiene.

Laryngeal Cancer

Auerbach, et al. (7) studied the histology of the larynx of 942 men,
aged 21 to 95, who were autopsied at a single hospital between 1964
and 1967. Cases of primary cancer of the larynx were excluded from
the study. Smoking histories for all cases were obtained from family
members of the deceased by trained interviewers. The numerous ran-
domized histological sections were graded by one observer. Table 2
shows the percentage of cells with atypical nuclei found in the true
vocal cord. Of the men who never smoked, 75 percent had no cells with
atypical nuclei, only 4.5 percent had sections with areas containing
60 to 69 percent of cells with atypical nuclei, and none had a higher

percentage.
58
TaBLE 2.—Number and percent distribution by relative frequency of
atypical nuclei among true vocal cord cells, of men classified by smoking
category

[100 per cent atypical cells defined as carcinoma]

 

Never Erx-cigarette Cigar/pipe
Ke ker:

 

smoked smokers smokers Current cigarette smokers
regularly
Percent
atypical nuclei Lessthanl 1-2 packsa 2 or more
Num- Per- Num- Per- Num- Per- packaday day packs a day

ber cent ber cent ber cent

 

Num- Per- Num- Per- Num- Per-
ber cent ber cent ber cent

 

 

Total..... 88 100.0 116 «100.0 $4 100.0 125 100.0 329 100.0 190 6100.0
None_-.-...---.. 66 75.0 86 74.1 1 Li 1 8 0 ...-- 0 ..-..
Less than 50...- 8 91 14 «121 4 4.3 2 20.0 4 1.2 0 Lu...
50-59... ----.-.. 10 «ine 13° (11.2 50 «53.0 54 43.2 87 4 29 15.3
60-69. -.-.----.. 4 465 1 9 23 (24.5 21 «168 116 35.3 75 = (30.4
70-79. 2. 2---2- 0 ..... 2 UL? 9 926 9 7.2 44 °«13.4 3820.0
80-89. 2.22228. 0-2... 0 -LLL. 2 2.1 2 16 19 5.8 11 5.8
90-09. 22.22... 0 .LL- 0 ..L. 1 Lt 0 Le 5 15 0 ...--
100:

Carcinoma in

situ_._...... 0 Le. Q@ we. 3 3.2 13° 10.4 52 15.8 35 18.4
Invasive car-

cinoma. _-__- 0 2... O@ 2.2L. 1 Ld OQ we... 2 6 2 Li

 

Source: Auerbach, O., et al. (/).

The 116 ex-smokers had laryngeal histology similar to that of the
nonsmokers, as far as atypical nuclei were concerned. However, dis-
integrating nuclei were found in 40.5 percent of the ex-cigarette
smokers and in only 0.4 percent of the remaining cases, Only one of
the 94 cigar and/or pipe smokers had no atypical cells. Three had car-
cinoma zn situ and one case had a section showing early invasive pri-
mary carcinoma. The highest percentage of atypical cells was found
among the cigarette smokers. The proportion of cases with a high de-
gree of cellular change increased with increased daily smoking. None
of the pack-or-more-a-day smokers was free of atypical nuclei. Of
those who smoked two or more packs per day, 85 percent had lesions
with 60 percent or more atypical cells as compared to 4 percent of the
nonsmokers. Between 10 and 18 percent of the cigarette smokers had
areas of carcinoma in situ, and four of the 644 cases showed early
microscopic invasion. The thickness of the basal level of the true vocal
cord was also directly related to the amount smoked (table 3).

59
TaBLe 3.—Number and percent distribution, by highest number of cell
rows in the basal layer of the true vocal cord, of men classified by
smoking category

 

Current cigarette smokers

 

Never oan Excigarette Cigar/pipe than x 2
regularly smokers smokers Less than 1-2 packs a or more
Number of cell pack a day day packs a day

Num- Per- Num- Per- Num- Per- Num- Per- Num- Per- Num- Per-
ber cent ber cent ber cent ber cent ber cent ber cent

 

 

 

Total_..-_ 88 100.0 116 100.0 94 100.0 125 100.0 329 «100.0 190 = 100.0
Less than 5 cell
rows.......--- 30 34.1 7 60 4 43 3 24 1 03 0 -..-.
5 cell rows. ...-. 2 693.0 27 23.3 2 «(21.3 27 «216 38 «11.6 2 810.5
6 cell rows. -_... 8 9.1 15 129 15 6.0 25 «420.0 5115.4 24 12.6
7 cell rows. ..-. 6 68 12 10.3 18 19.1 12 9.6 38 «11.6 1910.0
8 cell rows_.-.-. & 91 4 «(121 9 9.6 13 10.4 30 9.1 23 12.1
9 celi rows.....- 1 Ll 7 60 7 #7.4 6 48 6 7.9 “4 74
10 or more cell
TOWS..-.----- 6 68 34 (29.4 21 22.3 3931.2 145 44.1 90 «47.4

 

Source: Auerbach, O., et al. (1).

Cancer of the Urinary Bladder and Kidney

Several studies have dealt with the relationship of smoking to can-
cer of the bladder and kidney. James, et al. (23) demonstrated that an
association existed for cancer of the bladder. The study by Fraumeni
(17) also showed epidemiological evidence for such a relationship for
bladder and kidney cancers. Bennington, et al. (3,4) indicated an as-
sociation between all kinds of tobacco usage and adenocarcinoma of the
kidney as well as adenoma of the kidney. However, on the basis of this
study alone, the relationship between “all kinds of tobacco” and cancer
of the kidney cannot be considered as established in view of the small
number of cases involved. In a preliminary report of a study on the epi-
demiology of cancer of the kidney, Wynder, et al. (68) have shown a
strong association between excessive cigarette smoking and adenocar-
cinoma of the kidney, and although the disease is not uncommon in non-
smokers, they considered excessive cigarette smoking to be a contribu-
tory factor. This study found no relationship to pipe smoking, and only
a very weak relationship to cigar smoking. A significant association
was found between cigarette smoking and epidermoid cancer of the
kidney, a relatively uncommon type of cancer. Further research on the
strength and mechanisms of the association between smoking and can-
cers of the urinary tract is needed.

Cancer of the Pancreas

The previously suggested association between cigarette smoking and
cancer of the pancreas was again noted in a Japanese study by Ishii, et

60
al. (22), in which the authors reported a higher relative risk for pan-
creatic cancer among smokers than among nonsmokers.

GENERAL ASPECTS OF CARCINOGENICITY

The majority of the tumorigenic agents in tobacco smoke are found
in the particulate matter “tar.” The well established carcinogenicity
of tobacco “tar” in a variety of animal species and tissues (66) was
reconfirmed recently (11, 35, 40, 52, 56). A small portion of the smoke
particulates (0.03 percent) is made up of polynuclear aromatic hydro-
carbons (PAH) with two or more rings. A concentrate containing
polynuclear aromatic hydrocarbons and amounting to 0.6 percent of
the whole “tar” was found to be the most carcinogenic fraction of to-
bacco smoke (66). Another preparation of a PAH concentrate induced
significant cytologic changes in mouse trachea and human fetal lung
when grown in organ culture (28, 29). Other applications of concen-
trations of selected polynuclear aromatic hydrocarbons have produced
similar results (27).

Of the identified PAH, at least 12 are known tumor initiators. These
particular compounds have been shown to be carcinogenic, even when
applied in doses of a few micrograms (63,66). Tumor initiators induce
changes in the target cells, especially in DNA (9, 14). Tumor pro-
moters are agents which promote the neoplastic transformation of ini-
tiated cells. Although the structures of most of these tumor promoters
are still unknown, there appear to be several different types in tobacco
smoke (5, 41, 59, 66). Recently, Bock, et al. (6) published data which
confirmed earlier findings that whole cigarette tar, the neutral frac-
tion, two neutral subfractions and the weak acidic (phenolic) fraction
contain tumor promoters. One recent study indicated that “tar” ob-
tained from tobacco stems only had essentially no tumor promoting
activity (65).

During the last year, several studies have reconfirmed the finding
that selection of tobacco and the use of tobacco sheets and filters can
lead to a significant reduction of “tar” and PAH in cigarette smoke,
as well as to a reduction of the tumorigenicity of tobacco “tars.” Simi-
lar results have also been reported for commercial cigarettes (27, 34).
Experimental studies demonstrated that with tobacco additives one
can reduce “tar,” nicotine, PAH and tumorigenicity of cigarette smoke
(72, 21). In terms of selective reduction of tobacco smoke components,
these investigations may be of practical value, as well as of academic
interest (57).

Tobacco Alkaloids

Present evidence does not indicate that tobacco alkaloids are car-
cinogenic. A possible exception may be cotinine, which was reported
to induce malignant tumors in rats [principally leukemias (58) ] and

61
adenomas of the bladder in mice (7). Boyland recently suggested that
one or more of the three possible nicotine-N-oxides may be present in
tobacco smoke and may be carcinogenic (7).

Tobacco alkaloids could theoretically contribute to the overall car-
cinogenicity of tobacco smoke, based on the possibility that in tobacco
smoke nornicotine and other secondary amines may react with nitro-
gen oxides to form the N-nitrosamines, of which several are known
carcinogens, especially N-nitrosonornicotine and N-nitrosoanabasine
(36). So far, however, N-nitrosamines of nornicotine and other alka-
loid N-nitrosamines have not been detected in tobacco smoke (36).

Nickel

The relationship of nickel compounds to the development of cancer
has been discussed in a recent review by Sunderman (55), who sug-
gests that there is a possibility that nickel carbonyl may be present
in cigarette smoke and may act as a cocarcinogen by inhibiting the
induction of pulmonary benzopyrene hydroxylase, an enzyme which
converts 3,4-benzpyrene to noncarcinogenic hydroxylated derivatives.

EXPERIMENTAL ASPECTS OF CARCINOGENSIS

Retention of Smoke Constituents

Studies on human smokers by Dalhamn, et al. (15) demonstrated
that about 60 percent of the volatile, water soluble compounds of
cigarette smoke, 20 percent of the volatile, nonwater soluble com-
pounds, and 16 percent of the particulate matter of cigarette smoke
can be retained in the mouth when the smoke is held in the mouth for
up to 2 seconds. Under conditions in which the smoke is immediately
deeply inhaled, between 91 and 99 percent of the components of ciga-
rette smoke investigated (particulate matter, toluene, acetonitrile, ace-
tone, isoprene, acetaldehyde) were retained, with the exception of
carbon monoxide, of which 50 to 60 percent was retained (16).

Changes in Cell Cultures Induced by Cigarette Smoke

Leuchtenberger, et al. (30) have reported that passing cigarette
smoke through a charcoal filter prevented the damage caused by either
whole smoke, or the isolated gas phase of cigarette smoke, to cultures
of mouse kidney cells. In the same paper, they reported that the single
exposure of tissue cultures to puffs of charcoal-filtered smoke produced
a significant increase in the mitotic index of the kidney cells. In an-
other study, Leuchtenberger, et al. (97) reported that single exposure
to nine puffs of the gas phase from charcoal-filtered cigarette smoke
quickly stimulated the synthesis of DNA and RNA by cultures of
mouse fibroblasts. Repeated exposure of the cultures to the filtered gas
phase resulted in morphological and cytochemical changes indicative

62
of abnormal proliferation. Since the same alterations were found to be
present, to a much lesser extent, in some control cultures, the authors
considered that the filtered gas phase enhanced characteristics already
possessed by the cells. They concluded that the gas phase of unfiltered
cigarette smoke contains not only substances which inhibit cellular
metabolism, but also factors which stimulate cellular metabolism. These
latter factors may be unmasked by passing the gas phase through a
charcoal filter. The identities of the specific gases removed by the char-
coal filter and the extent to which each was removed were not reported
by the authors. Investigation of the relationship between the changes
observed in the tissue cultures and in vivo metabolism is necessary for
the interpretation of the results of these experiments.

Euperimental Studies of Bronchogenic Carcinoma in Animals

Because of the technical problems involved in inhalation experi-
ments in small animals (49, 67), various animal models have been de-
veloped which do not employ the inhalation of smoke. These models
have been used to study the role played by carcinogenic substances
found in tobacco smoke in the induction of bronchogenic carcinoma.

Saffiotti (43) in a recent review of experimental respiratory tract
carcinogenesis described the development of experimental models
for the induction of. pulmonary tumors and discussed a method of in-
ducing bronchogenic carcinomas in Syrian golden hamsters by intra-
tracheal instillation of a finely particulated crystalline carcinogen
(e.g., benzo(a)pyrene) attached to a suspension of fine particles of
a carrier dust (e.g., ferric oxide). This method reproduces some of the
conditions of human exposure to inhaled carcinogens and has resulted
in incidences of up to 100 percent of respiratory tumors, mostly squa-
mous cel] and anaplastic carcinomas of the larger bronchi. These
tumors have been found to be invasive, metastasizing, and transplant-
able. Saffiotti reported that the carrier dust particles play an essential
role in transporting the carcinogens through the bronchiolar and alveo-
lar wall into the lung tissues where they are phagocytized. The carcino-
gens are then eluted by the plasma and diffused into the lung tissue,
reaching up to the mucosa of the larger bronchi (42, 44, 45, 46). Varia-
tions in particle size and distribution in the suspended particulate
matter affect the retention rates of benzpyrene in the lungs (47). The
development of this experimental model has led to the undertaking of
new research in many laboratories attempting to define the factors
responsible for carcinogenesis in the respiratory tract.

Two other techniques used to produce squamous cell carcinoma in
small laboratory animals are the passage of threads impregnated with
carcinogenic hydrocarbons into the lung and the implantation of wire

63
mesh pellets in the bronchus. The latter technique gives a dose-response
relationship between carcinogenic hydrocarbons and squamous cell
carcinoma of the lung in rats (27). In order to overcome the traumatic
effects of the surgery involved in these procedures, two additional tech-
niques have been utilized. In one method, the carcinogen is suspended
in Freund’s adjuvant and upon trachea] instillation can lead to bron-
chial cancer (69). In this experiment, even more cancers were found
when the rats were pretreated with tubercle bacilli. Pretreatment of
the animals with tubercle bacilli produced infarcts, as well as scarring
of the lung. This finding is of interest because earlier studies showed
that scarring of rat lung by the halogenated hydrocarbon hexachloro-
tetrafluorobutane increases their susceptibility to the development of
squamous carcinoma when exposed to carcinogenic hydrocarbons (54).
That scarring of the lung may increase the susceptibility of the lung
to carcinogens is in line with some recent observations on humans by
Bennett, et al. (2) who showed the frequent occurrence of pulmonary
scars in males with adenocarcinoma of the lung.

Experimental Aspects of Cancer of the Bladder and Kidney

Tobacco smoke appears to contain traces of several aromatic amines
which are established bladder carcinogens. Of these, however, only
Betanaphthylamine has thus far been identified in tobacco smoke with
2.2 x 10° g. per cigarette (20). At concentrations such as this, it ap-
pears unlikely that such aromatic amines can account for the increased
risk among cigarette smokers of developing kidney and bladder cancer.
A more likely correlation may exist between these types of cancers in
smokers and their elevated urinary excretion rate of carcinogenic
metabolites of tryptophan, and their oxidation products (49, 50).

Recently, the tobacco alkaloid cotinine was reported to induce ade-
nomas in the bladder of mice [16 percent (7) ]. This observation needs
further testing. Cotinine is one metabolic product of nicotine and is
found in tobacco, cigarette smoke (26) and the urine of smokers (33).

A study by Schlegel, et al. (57) indicates an elevated concentration
of certain o-aminophenols plus their phenoxazon-oxidation products in
the urine of certain types of bladder cancer patients and cigarette
smokers, when compared to the urine of nonsmokers. Further studies
are needed on this problem,
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CHAPTER 4

 

Effects of Smoking
on Pregnancy

Contents
Page
Summary....------------------------------------------ 77
Epidemiological Studies___.._..........-.-.-------------- 77
Experimental Studies__---------------------------------- 80
Cited References___.._..__.______-_--_--_-__-_---------- 81

75
EFFECTS OF SMOKING ON PREGNANCY

Summary

Maternal smoking during pregnancy is associated with decreased
infant birth weight and increased incidence of prematurity, as defined
by weight alone, and may be associated with an increased incidence of
spontaneous abortion, stillbirth, and neonatal death. Changes in the
metabolism of the placenta and in various hematological factors in
the newborn infant have been found to be associated with maternal
smoking, but the mechanism of the effect of smoking on the outcome
of pregnancy remains to be determined.

New studies on the effect of maternal smoking on the outcome of
pregnancy have been published since the review of this topic in the
1967 Report (77). In the 1967 review, the literature cited supported a
relationship between maternal smoking and low birthweight and pre-
maturity in infants. However, the evidence relating the maternal
smoking to fetal or neonatal death was not definitive. The addition
of new studies has reconfirmed the relationship between maternal
smoking and low birth weight and prematurity. The relationship
between maternal smoking and spontaneous abortion, stillbirth, and
neonatal death has been investigated in several studies. As detailed
below, some of the studies reported a statistically significant increase
in unsuccessful pregnancies in mothers who smoked when compared
with mothers who did not smoke.

Ermemio.ocicaL SrTupies

In a prospective study of more than 2,000 pregnant women, Russell,
et al. (8) examined the effect of the mother’s smoking habits and
blood pressure on the outcome of the pregnancy and on the birth
weight of the infant. A smoker was defined as one who regularly
smoked five or more cigarettes a day. In each blood pressure category,
the percentage of unsuccessful pregnancies (abortion, stillbirth, neo-
natal death) was higher for smokers. Although fewer smokers were
found in the higher blood pressure categories, women who smoked
and had blood pressure levels equal to, or greater than, 150/100 had
a rate of unsuccessful pregnancy of 31.4 percent as compared to a
rate of 14.5 percent among nonsmokers with the same blood pressure

77
levels. Although the number of women in the two groups was small
(35 and 188, respectively), the difference observed was statistically
significant. For those with blood pressure levels of less than 140/90,
the percentage of unsuccessful birth was 6.5 among smokers and 2.7
among nonsmokers; for those with blood pressure levels in the range
of 140/90, the percentage was 6.8 among smokers and 4.1 among
nonsmokers.

Extrapolating from his series, Russell (7) estimated that one out of
every five unsuccessful pregnancies in women who smoked regularly
would have been successful if the mother had not smoked regularly
during the pregnancy. This statement implies a cause-and-effect rela-
tionship between maternal cigarette smoking during pregnancy and
abortion and perinatal death. In the absence of proof of a cause-and-
effect relationship, the least that can be said is that on the basis of the
findings of Russell, et al., one out of every five unsuccessful pregnancies
among women who smoke regularly during pregnancy would not have
been unsuccessful if these women had the same risk of unsuccessful out-
come of pregnancy as women who do not smoke.

In keeping with previous findings, Russell, et al., found that the mean
birth weight of the infant was lower for the smoking mothers in each
blood pressure category. Various factors were examined as confound-
ing variables for their possible effect on birth weight and the produc-
tion of spurious associations. These included: social class of consort,
maternal age, parity, maternal height, social class of woman’s father,
educational level, age of consort, maternal attitude toward the preg-
nancy, work during pregnancy, and sex of offspring. For each variable,
the smoking effect was clearly distinguished as a separate effect even
when the individual factor was itself associated with smoking (con-
sort’s social class, father’s social class, and maternal educational level).

A study of increases in the infants’ weight and in their head circum-
ference during the early weeks of life revealed that the babies of smok-
ing mothers grew faster than those of nonsmokers through the sixth
month after birth. However, the mean weight per week of conception
age (duration of pregnancy, plus age after birth) was greater in babies
of nonsmokers through the sixth week after birth, the effect not being
visible at the sixth month examination. These last two findings support
the theory that smoking during pregnancy acts as a. retarding influence
on fetal growth and that a catching-up phenomenon begins among the
babies of smoking mothers at birth when the toxic influence is removed.

In acontrolled study of 197 premature births among Negroes, Terris,
et al. (9) found a significantly higher prevalence of smoking among
the mothers of premature infants. Prematurity was defined as a birth
weight of 2,500 grams or less.

78
Mulcahy, et al. (6) studied the relationship between smoking habits
and the outcome of pregnancy in 3,681 women admitted to the Coombe
Lying-in Hospital in Dublin, Ireland. Besides finding significantly
lower birth weight for infants born to mothers who smoked, they dis-
covered a significant increase in the incidence of neonatal death, still-
birth, and spontaneous abortion. These effects were independent of age
or parity. No significant difference in the rate of congenital abnor-
malities was found between the offspring of the smokers and those of
the nonsmokers.

Kizer (4) studied the effect of maternal smoking on the outcome of
pregnancy in 2,095 patients in Venezuela. He found a significant dim-
inution in the birth weight of infants of smoking mothers and a
higher incidence of premature rupture of the membranes, but did not
find a difference in the incidence of abortion or perinatal mortality.

Duffus, et al. (2) studied the relationship between smoking during
pregnancy and the incidence of albuminuric preeclamptic toxemia in
2,543 married, urban primigravidae attending antenatal clinics in
Aberdeen in 1960. Albuminuric preeclampsia is defined as albuminuria
in pregnancy in which the urine contains at least 0.25 grams of al-
bumin per liter accompanied by a rise in diastolic blood pressure to 90
mm Hg. or more, on 2 or more days after the 26th week of gestation
or progressively during labor. The incidence of albuminuric pre-
eclampsia was lower in smokers than in nonsmokers. Among the
preeclamptics, however, smokers lost more babies in the perinatal
period than the nonsmokers. The babies of smokers, both normal and
preeclamptic, had a lower mean weight than the babies of nonsmokers.
In the preeclamptic group, a greater percentage of the babies of
smokers weighed less than 5 pounds. These differences are in keeping
with those found in other studies but do not reach statistical signifi-
cance. The implication is that smoking mothers are less likely to be
preeclamptic, possibly by way of blood pressure effects, but are more
likely to have their pregnancies result in perinatal death in the event
they are preeclamptic.

In a study of 5,848 deliveries in Hungary, Fiilép (3) found a sta-
tistically significant increase in premature births among women who
smoked during their pregnancies, whether the women were married
or unmarried, held a job, or were unemployed. Lacuska, et al. (5)
found a higher frequency of premature births and abortions among
women who smoked during pregnancy than among nonsmokers,
although the differences fell short of statistical significance.

Tokuhata (10) analyzed the fertility history in relation to smoking
in groups of married women who died of breast cancer, genital can-
cer, and various noncancerous diseases. Statistically significant in-
creases in both the rate of infertility (as judged by absence of preg-

79
nancy) and in fetal loss (defined as abortions and stillbirths) were
found in smokers who died of noncancerous diseases. These differences
withstood analysis for a number of possible confounding factors.
However, since the sample was made up of women who died in a
certain geographical area in a given amount of time, biases may have
been introduced. Retrospective findings in a group of dead people
are not necessarily the same as findings derived in a prospective study
of a living population.

Although by this time the evidence for reduction in birth weight
of babies born to smoking mothers is overwhelming, a problem that
remains to be solved is why some studies do and others do not appear
to show fetal wastage as measured by abortion, stillbirth, and neonatal
death. It may be that the method of selection of the population under
study, especially the degree to which entire obstetrical histories are
included, accounts for this variation.

ExrrerRiIMENTAL Srupies

Younoszai, et al. (47) compared various hematological factors in
the blood of 16 smoking mothers and newborn infants with those of
16 nonsmoking mothers and their offspring. Both groups of infants
were delivered at term and appeared clinically well. The smoking
mothers had a mean carboxyhemoglobin saturation of venous blood
of 8.3 percent as compared to 1.2 percent in the nonsmoking mothers.
Corresponding figures for the umbilical vein cord blood were 7.3 per-
cent and 0.7 percent. A mild metabolic acidosis was seen in the infants
of smokers. These infants also had a higher mean capillary hematocrit
than those of the nonsmoking mothers. The authors point out that the
differences, although real, probably are not of clinical significance in
the newborn. However, the effect of chronic exposure of the embryo and
fetus to carboxyhemoglobin levels and other hematological abnor-
malities has not been elucidated.

Welch, et al. (72) reported that the placentas from women who
smoked during pregnancy show a much greater ability to hydroxylate
benzo(a)pyrene than the placentas from women who did not smoke
during pregnancy. The placentas from women reporting similar
cigarette consumption varied greatly in the degree of BP hydroxylase
activity. However, no information is available on the brand of ciga-
rettes smoked or the degree of inhalation, differences which may result
in different dosages of BP. It is possible, but not likely, that car-
cinogens in tobacco smoke reach the fetus in significant amounts. The
ultimate effect of the exposure of the human fetus to carcinogenic
substances is unknown.

Becker, et al. (7) studied the effect of subcutaneous injections of
increasing doses of nicotine on groups of pregnant rats and their off-

80
spring. They found that the rats receiving nicotine injections con-
sumed legs food and gained less weight than control animals and that
the magnitude of this effect increased when the dose of nicotine was
greater. Whereas no other differences were found in the rats receiving
lower dosages, those receiving 3.0 mg./kg. or 5.0 mg./kg. daily had
offspring which differed from those of the controls in being lighter,
having a longer gestation, a higher mortality rate during the first 48
hours of life, and a fetal appearance.

(1)

(2)
(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

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Lacuska, A., Bonuntcxy, F., Fino, 8. Fajcenie a gestacia. (Smoking and
pregnancy.) Ceskoslovenska Gynekologie 33(3) : 197-200, 1968.

Moutcany, R., Knaaeos, J .F. Effect of age, parity, and cigarette smoking on
outcome of pregnancy. American Journal of Obstetrics and Gynecology
101(6) : 844-849, July 15, 1968.

Russet, C. 8S. Another hazard of smoking. New Scientist 41 (631) : 64-05,
January 9, 1969.

Russe. C. 8., Taytor, R., Law, C. E. Smoking in pregnancy, maternal
blood pressure, pregnancy outcome, baby weight and growth, and other
related factors. A prospective study. British Journal of Preventive and
Social Medicine 22(3) : 119-126, July 1968.

Terris, M., Gotp, E. M. An epidemiologic study of prematurity. I. Relation
to smoking, heart volume, employment, and physique. American Journal
of Obstetrics and Gynecology 103(3) : 358-370, February 1, 1969.

Toxunata, G. K. Smoking in relation to infertility and fetal loss. Archives
of Environmental Health 17(3) : 358-359, September 1968.

U.S. Pustic HeaLtuH Service. The Health Consequences of Smoking. A
Public Health Service Review: 1967. Washington, U.S. Department of
Health, Education, and Welfare, Public Health Service Publication No.
1696, 1967. 199 pp.

We cn, R. M., Hanrison, Y. E., Gomi, B. W., Poppers, P. J., Frnster, M.,
Connery, A. H. Stimulatory effect of cigarette smoking on the hydroxyla-
tion of 3,4-benzpyrene and the N-dimethylation of 3-methyl-4-monomethyl-
aminoazobenzene by enzymes in human placenta. Clinical Pharmacology
and Therapeutics 10(1) : 100-109, January-February 1969.

Younoszar, M. K., Kactc, A. Haworrg, J. C. Cigarette smoking during
pregnancy : The effect upon the hematocrit and acid-base balance of the
newborn infant. Canadian Medical Association Journal 99(5) : 197-200,
August 3, 1968.

81
CHAPTER 5

 

Smoking and Noncancerous
Oral Disease

Contents
Page
Summary -----------------------------------------2-°7- 85
Epidemiological and Clinical Studies--_--.------------------- 85
Cited References____------------------------------------ 88

83
SMOKING AND NONCANCEROUS ORAL DISEASE

Summary

~The previous reports have not presented findings on noncancerous
oral disease. Several recent studies have made a review appropriate at
this time. This review of the available literature leads to the conclusion
that ulceromembranous gingivitis, alveolar bone loss, and stomatitis
nicotina are more commonly found among smokers than among non-
smokers. The influence of smoking on periodontal disease and gingivitis
probably operates in conjunction with poor oral hygiene. In addition,
there is evidence that smoking may be associated with edentulism and
delayed socket healing. While further experimental and clinical studies
are indicated, it would appear thatnonsmokers have an advantage over
smokers in terms of their oral health.

EPIDEMIOLOGICAL AND CurnicaL Sropres

Periodontal disease is a chronic destructive process affecting the sup-
porting structures of the teeth (gingiva, periodontal fibers, and alveo-
lar bone). It is generally considered inflammatory in nature. Solomon,
et al. (22) studied data on 3,552 nonsmokers and 3,639 smokers, all
white and between the ages of 20 and 79. He found that periodontal
disease occurred without significant statistical difference in male and
female nonsmokers of the same age, but that smokers of both sexes had
a higher prevalence of the disease. The prevalence in female smokers
paralleled that in male smokers in the younger age groups but re-
sembled that of the nonsmokers in the older age groups. The authors
believe that this difference is related to increased smoking in younger
women.

Brandtzaeg, et al. ($3) examined 206 Norwegian Army recruits be-
tween the ages of 19 and 25 and found a trend toward increased perio-
dontal disease with increased smoking. However, when an analysis of
covariance was performed, most of the changes in periodontal disease
severity were accounted for by changes in oral hygiene. This finding
suggests that tobacco consumption may influence the periodontal tis-
sues but only with accompanying changes in oral hygiene.

A seemingly contradictory paper reporting on periodontal diseases
in 8,206 Ceylonese was published by Waerhaug (25). He found to-
bacco smokers to have less periodontal disease than nonsmokers. He
pointed out, however, that for many individuals the alternative to
smoking tobacco is chewing betel nuts, which is associated with even
more periodontitis than cigarettes. Thus, tobacco users are relatively
better off.

The relationship of smoking to gingivitis, the initial stage of perio-
dontal disease, has also been studied. Arno, et al. (2) examined 1,846
employees of a manufacturing company in Oslo and found that to-
baceo smoking was associated with an increase in the prevalence of
gingivitis. However, its importance as compared with that of oral hy-
giene was not a dominating one. Ludwick, et al. (15) studied 2,577
naval enlistees at the Great Lakes Naval Training Center and found
no relationship between smoking and simple marginal gingivitis, but
a significant one between smoking and ulceromembranous gingivitis
(necrotizing ulcerative gingivitis, Vincent’s gingivitis, trenchmouth).
This is an acute form of periodontal disease of apparent sudden onset,
characterized by ulceration of the tips of the interdental papillae, gin-
gival bleeding, pain, and foul odor. In the United States and Europe, it
occurs primarily in adolescents and young adults. Bacteria, local fac-
tors, systemic factors, and psychogenic factors have been suggested
as contributing to its etiology (10).

Pindborg’s study (17) of 1,433 Danish Royal Marines between the
ages of 16 and 28 revealed that the prevalence of chronic marginal gin-
givitis was not affected by smoking, but that the prevalence of ulcero-
membranous gingivitis was much greater in smokers than nonsmokers.
A second study by Pindborg (16) of 3,505 Danish military personnel
confirmed these findings: nonsmokers had a prevalence of ulceromem-
branous gingivitis of 2.2 percent, while for those who smoked 10 g. or
less of tobacco daily, the prevalence was 7.0 percent, and for more than
10 g. a day it was 9.5 percent.

Smitt (20) found a prevalence of ulceromembranous gingivitis of
2.5 percent in Dutch Navy recruits. In those who smoke 50 g. of to-
bacco for a week or more, the prevalence was 10.5 percent.

Frandsen, et al. (9) investigated the correlation between the form
of tobacco used and occurrence of gingivitis in Danish Marines. He
found that 1,848 cigarette smokers and 273 pipe smokers had essentially
the same rates of simple marginal and ulceromembranous gingivitis.

Arno, et al. (1) and Herulf (71) have investigated alveolar bone
changes in smokers. Arno studied 728 men between the ages of 21 and
45 and found that alveolar bone loss, measured as the percentage of
maximum height adjacent to the mesial and distal surfaces of each
tooth present, was higher among those with high tobacco consumption.
The author suggested that tobacco consumption is a complicating fac-
tor in periodontal disease and when accompanied by poor oral hygiene

86
and unfavorable systemic background may help speed up the destruc-
tion of the supporting tissues of the teeth.

Herulf measured interdental boney septa in 389 men and 215 women
at the Institute of Dentistry in Stockholm. He, too, found 8 significant
relationship between smoking and bone loss.

The relationship between cigarette smoking and edentulism has been
studied by Summers, et al. (22) in a sample of residents of Tecumseh,
Mich. Information on 324 dentulous and 84 edentulous people revealed
that among males in both groups those with the greatest evidence of
periodontal disease smoked significantly more cigarettes than those
with medium or little evidence of the disease. Solomon, et al. (27)
found significantly more edentulism and advanced periodontal disease
in both men and women who smoked cigarettes than in nonsmokers
of the same age.

Jackson (12) has cited heavy smoking as a factor in delayed healing
of tooth sockets after extraction.

Stomatitis nicotina is a form of palatal leukoplakia (4). It is charac-
terized by raised umbilicated papules with small central red depres-
sions located primarily on the soft palate and the posterior region of
the hard palate. The papules represent blocked palatal mucus glands
and the red depressions are their inflamed duct orifices. Saunders (18)
notes that the lesions begin as tiny red dots and may progress very
rarely to ulceration. Although it sometimes occurs in cigar and ciga-
rette smokers, stomatitis nicotina is found most frequently in pipe
smokers (4, 6, 19). According to Chapman, et al. (4), pipe smoking
points a stream of smoke directly onto the palate, thereby allowing
longer contact between it and the smoke than in other forms of tobacco
use. The condition disappears with the cessation of smoking (6, 7, 8,
14, 18, 19, 24), though Kerr (23) warns that healing may be slow, some-
times requiring months before no lesions are present.

Thoma (23) observed a patient who wore dentures for over 40
years and showed lesions of stomatitis nicotina only on the part of the
palate that was not covered by the prosthesis. He concluded that the
changes were due to local surface rather than to systemic influences.

Lewis (14), Saunders (28), and Thoma, et al. (24) advise biopsy
to rule out malignancy in advanced cases. Forsey, et al. (8) feel that
no association between stomatitis nicotina and cancer has been
demonstrated.

360-928 0O—69——-7
(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(16)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

CITED REFERENCES

Agno, A., ScHEY, O., Lovpal, A., WarrnHave, J. Alveolar bone loss as a func-
tion of tobacco consumption. Acta Odontologica Scandinavica 17: 3-10,
1959.

Anno, A., WarrHaue, J., Lovpal, A., Scuezr, O. Incidence of gingivitis as
related to sex, occupation, tobacco consumption, toothbrushing, and age.
Oral Surgery, Oral Medicine, and Oral Pathology 11(6) : 587-595, June
1958.

BeanpTzaze, P., Jamison, H. C. A study of periodontal health and oral
hygiene in Norwegian army recruits. Journal of Periodontology 35 : 302—
307, July-August 1964.

Cuapman, I., Mackin, M. Palatal leukoplakia in a female cigarette smoker.
Contribution to study of tobacco-induced epithelial hyperplasia in human
beings. New York State Journal of Medicine 61(12) : 2044-2045, June
15, 1961.

CHarman, 1, RepisH, C. H. Tobacco-induced epithelial proliferation in
human subject. Long-term effects of pipe smoking on epithelium of hard
palate. Archives of Pathology 70(2) : 1383-140, August 1960.

DecHaume, M., GRELLET, M., PAYEN, J. Leucoplaste papuleuse chez ies
fumeurs ou stomatite nicotinique. Presse Medicale 69(56) : 2583-2585,
December 25, 1961.

El tabaco y la mucosa oral. Odontoiatria 12(10) : 619-621, October 1955.

Forsey, R. R., Sutzivan, T. J. Stomatitis nicotina. Archives of Dermatol-
ogy 83(6) : 945-950, June 1961.

Franpsen, A., Prnpgore, J. J. Tobacco and gingivitis. III. Difference in the
action of cigarette and pipe smoking. Journal of Dental Research 28(5) :
464-465, 1949.

Geant, D. A., Steen, I. B., Evenert, F. G. Necrotizing ulcerative gingivitis.
Chapter 18. In: Orban’s Periodontics. A Concept—Theory and Practice.
8d edition. St. Louis, C. V. Mosby Co., 1968. Pp. 285-298.

HEgvtr, G. On the marginal aleolar ridge in students: A roentgenographic
study. Acta Genetica et Statistica Medica 2(3): 236-288, 1961.

Jackson, J. A. Heavy smoking—a factor in delayed socket healing. Na-
tional Dental Association Quarterly : 15-18, October 1960.

Kerr, D. A. Nicotine stomatitis. Journal of the Michigan State Dental
Society 30: 90-91, May 1948.

Lewis, A. B. Effects of smoking on oral mucosa, Oral Surgery, Oral Medi-
cine, and Oral Pathology 8(10) : 1026-1033, October 1955.

Lupwicx, W., Massrez, M. Relation of dental caries experience and gin-
givitis to cigarette smoking in males 17 to 21 years old (at the Great Lakes
Naval Training Center). Journal of Dental Research $1(3) : 319-322,
June 1952.

Prnpaore, J. J. Gingivitis in military personnel with special reference to
ulceromembranous gingivitis. Odontologisk Tidskrift 50(6): 403-499,
1951.

Prxpsore, J. J. Tobacco and gingivitis. I. Statistical examination of the
significance of tobacco in the development of ulceromembranous gingi-
vitis and in the formation of calculus. Journal of Dental Research 26:
261-264, 1947.
(18) Saunpers, W. H. Nicotine stomatitis of the palate. Annals of Otology,
Rhinology and Laryngology 67 : 618-627, 1958. ;

(19) Scuwagrz, D. L. Stomatitis nicotina of the palate. Report of two cases.
Oral Surgery, Oral Medicine, and Oral Pathology 20(3): 306-315,
September 1965.

(20) Smrrr, P. A. E. 8. Some clinical and epidemiological aspects of Vincent's
gingivitis. Dental Practitioner and Dental Record 15(8) : 281-286, April
1965.

(21) Soromon, H. A., Priore, R. L., Bross, I. D. J. Cigarette smoking and peri-
odontal disease. Journal of the American Dental Association 77 (5) : 1081-
1084, November 1968.

(22) Summerss, C. J., OperMan, A. Association of oral disease with 12 selected
variables: II. Edentulism. Journal of Dental Research 47 (4) : 594-598,
August 1968.

(23) Tuoma, K. H. Stomatitis nicotina and its effect on the palate. American
Journal of Orthodontics and Oral Surgery 27(1) : 38-47, January 1941.

(24) THoma, K. H., GorpMan, H. M. Oral Pathology, 5th ed., 1960. St. Louis,
C. V. Mosby Co. Pp. 955-958.

(25) Warrnaue, J. Prevalence of periodontal disease in Ceylon. Association with
age, sex, oral hygiene, socioeconomic factors, vitamin deficiencies, mal-
nutrition, betel and tobacco consumption, and ethnic group. Final report.
Acta Odontologica Scandinavica 23 (2) : 205-231, 1966.
Index

Acrolein
effect on Dunalielia biocuiata, 42
Adenocarcinoma
risk ratio of smokers, 56
smoking and, for men, 57
Adenocarcinoma, kidney
smoking and, 60
Age
coronary disease incidence rates and
smoking history by, 21-24
coronary disease mortality rates by,
18-14, 17
coronary disease mortality ratios
by, 13, 18
stroke mortality rates by, 18, 17
stroke mortality ratios by, 13
Albuminuric preeclampsia
see Pregnancy toxemias
Alkaloids, tobacco
see Tobacco alkaloids
Alveolar bone loss
smoking and, 85-87
Alveoli, pulmonary
changes in rates after exposure to
nitrogen dioxide, 41
o-Aminophenols concentration
in urine of cancer patients and
amokera, 64
Angina pectoris
incidence rates and smoking history,
21-22
smoking and, 18
in twins, genetic and environmental
factors, 25
see also Coronary disease
Aortic aneurysm
mortality, for men by amount
smoked, 16
see alao Cardiovascular diseases
Aromatic hydrocarbons
carcinogenicity, 61
Arrhythmia
smoking and, 4
Arteriosclerosis
aortic, 26

coronary, 26

experimental studies, 20-27

hypoxia and, hypercholesterolemia
in, 26

severity of, and smoking, 26

smoking and, 4-5, 26-27

see also Cardiovascular diseases;
Coronary disease

Atherosclerosis
see Arteriosclerosis

Behavior
and coronary disease, 20, 24
Benzo(a)pyrene
hydroxylation by the placenta, 80
hydroxylation by pulmonary benzo-
pyrene hydroxylase, 62
Benzopyrene hydroxylase
inhibition of by nickel carbonyl in
cigarette smoke, 62
Betanaphthylamine content
in cigarettes, 04
Betel nut chewing
smoking and oral leukoplakia, 58
Birth weight
effect of maternal smoking on, 5,
77-78, 80
effect of maternal smoking on, and
other factors, 78
Bladder neoplasms
cotinine and, 64
experimental aspects of, 64
smoking and, 60, 64
Blood chemical analysis
comparison for smoking and non-
smoking mothers and their in-
fants, 80
Blood cholesterol levels
and lung neoplasms in male smok-
ers, 57
and coronary disease mortality, 17
Blood circulation
effect of smoking on, 11, 27-28
Blood flow
effect of smoking on, 27-28

91
Blood platelets
effect of smoking on, 27-28
Blood pressure
coronary disease mortality and, 14,
17
coronary disease and smoking, 14
smoking and, effects on pregnancy
outcome, 77-78
Blood viscosity
and arteriosclerosis, 27
Body weight
relationship to coronary disease
mortality rates and smoking, 14
Bronchial epithelium
effect of nitrogen dioxide on, in rats,
41
effect of smoke on, in dogs, 40
Bronchial neoplasms
risk ratio of smokers, 56
Bronchitis
incidence of among smokers, 37
smoking and, 4
smoking as cause, 37
see also Emphysema
Bronchogenic carcinoma
see Carcinoma, bronchogenic
Bronchopulmonary disease, chronic
prevalence of, 38
Bucéal neoplasms
see Oral neoplasms

Cancer
sce Neoplasms and specific listings,
eg., Lung neoplasms
Carbon monoxide
and carboxyhemoglobin levels, 28-29
effects on myocardium, 28
Carboxyhemoglobin
levels, 26, 28
levels in smokers, 28-29, 80
Carcinogenesis
experimental, 62-64
possible role of tobacco alkaloids in,
61
Carcinogens
aromatic hydrocarbons, unspecified,
61
bladder, in tobacco smoke, 64
implantation of, 64
use in experimental bronchogenic
carcinoma, 63-64
Carcinoid
risk ratio of smokers, 56
Carcinoma, alveolar cell
risk ratio of smokers, 56

92

Carcinoma, bronchogenic
animal models for, 63-64
experimental induction of, 63-64
risk ratio of smokers, 56
Carcinoma, epidermoid
experimental induction of, 63-64
risk ratio of smokers, 56
Carcinoma, larynx
sce Laryngeal neoplasms
Carcinoma, small cell
risk ratio of smokers, 56
Carcinoma, squamous cell
see Carcinoma, epidermoid
Cardiovascular diseases
and mortality rates, 17
smoking and, 3-5
see also Aortic aneurysm; Arterio-
sclerosis; Coronary disease;
Thrombosis
Cessation of smoking
effect on risk of lung neoplasms, 55,
57
stomatitis nicotina resolution, 87
Cholesterol
see Blood cholesterol
Chronic bronchitis
see Bronchitis
Cigarettes
filter, and risk of lung neoplasms, 57
filter vs. nonfilter, comparison of
safety, 57
Cigarettes, daily consumption
aortic aneurysm mortality by, 16
and atypical nuclei in larynx, 59
coronary disease incidence rates by,
15, 21-24
coronary disease mortality by, 138
Cigarette smoke
see Smoke, cigarette
Cigarette smoking
see Smoking
Cilia
effect of cigarette smoke on, 42
Cocarcinogens
nickel carbonyl as, 62
in tobacco smoke, 61
Coronary disease
epidemiological studies, 25
incidence rates by age, 21-22, 24
incidence rates by behavior type, 20,
24.
incidence rates by smoking and
other risk factors, 23
Coronary disease—Continued
incidence rates by smoking history,
21-24
incidence rates in men, 21-22
incidence rates, smokers vs. non-
smokers, 18, 20-22
morbidity ratios, 19
mortality among former college
students, 16, 18
mortality rates by age, 13-14
mortality rates by amount smoked,
13 :
mortality rates by blood pressure,
14
mortality rates by relative weight,
14
mortality rates by sex, 13-14
mortality rates by smoking classifi-
cation, 14
mortality ratios by age, 13
mortality ratios by amount smoked,
13
mortality ratios by sex, 13-14
smoking and, 3-5, 11,20
smoking as etiologic agent in, 11
see also Angina pectoris; Arterio-
sclerosis; Cardiovascular  dis-
eases; Myocardial infarction
Coronary heart disease
see Coronary disease
Cotinine
effect on rats and mice, 61-62
in experimental induction of bladder
adenomas, 64
sec also Tobacco alkaloids
Curschmann’s spirals
in sputum of smokers, 39-40
Cysteine
inhibition of smoke cytotoxic action
on macrophages, 42
Death, sudden
rate by smoking, cholesterol and
blood pressure, 17
DNA
effect of aromatic hydrocarbons on,
61
effect of cigarette smoke on synthe-
sis, 62-63
Edentluism
relationship to smoking, 87
Emphysema
in horses, 40
pathogenesis of, 38-40

smoking as cause, 37-38
see aiso Bronchitis
Epidemiological studies
coronary disease and smoking, 12-25
laryngeal neoplasms and smoking,
58-60
lung neoplasms and smoking, 55-56
maternal smoking and outcome of
pregnancy, 77-80
oral neoplasms and smoking, 58
pancreatic neoplasms and smoking,
60-61
urinary tract neoplasms and smok-
ing, 60
Epithelium
hypertrophy caused by nitrogen
dioxide, 41
Ex-smokers
coronary disease mortality for men,
by amount smoked, 15
coronary disease mortality for men,
by years stopped smoking, 15
coronary disease mortality for men,
compared to nonsmokers, 15
decrease of lung neoplasm risk, 57
stroke mortality for men, compared
to nonsmokers, 15
thickness of vocal cords, 60

Fertility
and smoking, 79-80
Fetal death
and maternal smoking, 77-78
Filters, charcoal
and effect of cigarette smoke on cell
cultures, 62
Free fatty acid
plasma factor, smoking effect on, 27

Gingivitis
incidence among Danish Royal
Marines, 86
incidence among Dutch Navy re-
cruits, 86
incidence among U.S. Naval train-
ees, 86
and smoking, 85-88
Gingivitis, uleeromembranous
relationship to smoking, 86
Glutathione
inhibition of smoke cytotoxic action
on macrophages, 42
Hemoglobin

effect of smoking on oxygen affinity,
29

93
Hydrolases
reduction of in smokers’ alveolar
macrophages, 42-43
Hypercholesterolemia
and hypoxia, in arteriosclerosis, 26
Hypoxia
and arteriosclerosis, 26
Infant mortality
and maternal smoking, T7~78
Infants
growth rate, effect of maternal
smoking on, 78
Influenza B virus
enhancing effect in vitro on oxidized
nicotine, 42
Inhalation depth
and retention of particulate matter
of smoke, 62

Kidney neoplasms
epidermoid, associated with ciga-
rette smoking, 60
and smoking, 60, 64
Kreyberg study
lung neoplasms and smoking, 55-56

Laboratory techniques
for induction of experimental neo-
plasms, 63-64
Laryngeal neoplasms
smokers vs. nonsmokers, 58-59
Larynx
atypical nuclei in cells of smokers,
58-59
effect of cessation of smoking on, 59
premalignant changes in, and smok-
ing, 5, 55
see alao Vocal cords
Leukoplakia
smoking and betel nut chewing, 58
stomatitis nicotina, 87
Lung cancer
see Lung neoplasms
Lung function
effect of smoking on, 5, 42
effect of smoking on ventilation/
perfusion relationships, 39.
Lung neoplasms
and blood cholesterol levels in male
smokers, 57
decrease in risk of for ex-smokers,
57
detection of by sputum analysis of
smokers, 58
epidemiological studies, 55-58

94

epidermoid, in male smokers, 57

incidence rates in female smokers,
4,57

incidence rates in male smokers, 4

incidence rates in Norway, 55-56

Kreyberg study, 55-06

mortality rate, 57

oat-cell, in male smokers, 57

of smokers, in Rhodesia, 57

and smoking, 4-5

and ulcers, relation to smoking, 57

sec also Respiratory tract neoplasms

Lungs

effect of nitrogen dioxide on rats’, 41

pathological effects of smoking on, 5

sears and susceptibility to carcino-
gens, 64

Lysozyme

secretion by rabbit pulmonary alve-

olar macrophages, 42

Macrophages, alveolar
effect of cigarette smoke on, 42
lysozyme secretion by rabbits’, 42
and pathogenesis of chronic bron-
chopulmonary disease, 43
reduction of enzymes in smokers’,
42-43
Maternal smoking
see Smoking, maternal
Men
incidence of lung neoplasms and
smoking in, 57
Monoamine oxidase inhibitors
effect on rabbits receiving nicotine,
27
Morbidity ratios
coronary heart disease, 19
Mortality
and smoking, 3
study of Chicago Peoples Gas Light
and Coke Co. employees, 16-17
Mortality rates
aortic aneurysm, for men by amount
smoked, 16
cardiovascular diseases, 17
coronary heart disease, by age,
13-14
coronary heart disease, by amount
smoked, 12-13, 17
coronary heart disease, by blood
cholesterol, 17
coronary heart disease, by blood
pressure, 14, 17
Mortality rates-—Continued
coronary heart disease, by relative
weight, 14
coronary heart disease, by sex, 13-14
coronary heart disease, by smoking
classification, 14
coronary heart disease, smokers vs.
ex-smokers, 15
coronary heart disease, smokers vs.
nonsmokers, 12~13, 15-17
lung neoplasms, 57
stroke, 17
stroke, by age, 12-13
stroke, by amount smoked, 12-13
stroke, by sex, 12-18 ‘
stroke, smokers vs. ex-smokers, 15
stroke, smokers vs. nonsmokers,
12-13, 15
Mortality ratios
aortic aneurysm, for men by amount
smoked, 16
coronary heart disease, by age,
12-18, 18
coronary heart disease, by amount
smoked, 12-13, 18
coronary heart disease, by sex, 12-18
coronary heart disease, smokers vs.
ex-smokers, 15
eoronary heart disease, smokers vs.
nonsmokers, 12-13, 15
stroke, by age, 12-13
stroke, by amount smoked, 12-13
stroke, by sex, 12-13
stroke, smokers vs. ex-smokers, 15
stroke, smokers vs. nonsmokers,
12-13, 15
Mucous membrane
smoking and neoplasms of, 58
Myocardial infarction
etiology of, 27-28
incidence rates and smoking history,
21-22
and smoking, 4, 18
Myocardium
effect of cigarette smoking on, 11

Nas (tobacco and ashes)
and oral neoplasms in the USSR, 58
Negroes
maternal smoking and prematurity
in, 78
Neoplasms
by sex, 56
prevalence of, smokers vs. nonsmok-
ers, 56

by type of tumor and smoking his-
tory, 56 .
see also Specific type of neoplasms,
eg., Lung neoplasms; Neoplasms,
experimental
Neoplasms, experimental
bronchogenic carcinoma, 63-64
epidermoid carcinoma, 64
Nickel carbonyl
as a cocarcinogen, 62
Nicotine
effect on hypercholesterolemic rab-
bits, 27
effect on pregnant rats, 80
see also Nicotine metabolites ; Nico-
tine, oxidized; Tobacco alkaloids
Nicotine metabolites, 61-62
Nicotine-N-oxides
- presence in tobacco smoke, 62
Nicotine, oxidized
in vitro ciliostatic effects, 42
Nitrogen dioxide
effect on rats’ lungs, 41
N-nitrosamines, 62

. N-nitrosoanabasine, 62

N-nitrosonornicotine, 62
Noncancerous oral disease
sce Oral disease, noncancerous
Nornicotine, 62
Norway
incidence rates of lung neoplasms,
55-56

Oral disease, noncancerous and smok-
ing, 5-6, 85-87
see also Gingivitis; Leukoplakia ;
Periodontal diseases; Stomatitis
nicotina
Oral hygiene
relationship to smoking and noncan-
cerous oral disease, 85-86
Oral neoplasms
incidence of and smoking, 58
and smoking, 58
and tobacco chewing, 58
Oxidoreductases
reduction of in smokers’ alveolar
macrophages, 42-43

Palate

smoking and stomatitis nicotina, 87
Pancreatic neoplasms

and smoking, 60-61

95
Periodontal diseases
and smoking, 85-86
and smoking, in Ceylon, 85-86
and smoking, in Norwegian Army
recruits, 85
Plasma
and thrombus formation, 27-28
Polynuclear aromatic hydrocarbons
see Aromatic hydrocarbons
Population studies
bronchitis and smoking, 37
Preeclampsia
see Pregnancy toxemias
Pregnancy
effect of blood pressure and smoking
habits on, 77-78
ecarboxyhemoglobin levels of smok-
ers, 80
effect of nicotine on, in rats, 80
effect of smoking during, 4-5, 77-81
effect of smoking during, in Hun-
gary, 79
effect of smoking during, in Ireland,
79
effect of smoking during, in Scot-
land, 79
effect of smoking during, in Vene-
zuela, 79
Pregnancy toxemias
preeclampsia, and smoking, 79
Prematurity
and maternal smoking, 77, 79
and maternal smoking, among Ne-
groes, 78
Pulmonary disease
in rabbits, similar to emphysema, 41
Pulmonary emphysema
sec Emphysema

Respiratory function tests
of smokers with mild bronchitis, 39
using radioactive xenon, 39
Respiratory tract neoplasms
experimental induction of, 63-64
RNA synthesis
effect of cigarette smoke on, 62-63

Sex

coronary disease incidence rates and
smoking history by, 21-22, 24

coronary disease mortality rates by,
18,17

coronary disease mortality ratios by,
18

stroke mortality rates by, 13, 17

96

stroke mortality ratios by, 13
tumor prevalence among smokers
by, 56
Smoke, cigarette
effect on alveolar macrophage, 42
effect on bronchial epithelium of
dogs, 40
effect on ciliary activity, 42
effect on DNA and RNA synthesis,
62-63
effect on Dunalielia bioculata, 42
effect on pulmonary surfactant, 42
effect on tissue cultures, 62
gas phase, 63
inhalation methods, 62
nickel carbonyl in, 62
reduction of tar content, 61
retention of tars in mouth, 62
Smokers
arteriosclerosis in, 26
reduction of life expectancy, 3
sputum analysis of, 39-40, 57-58
Smokers, cigar/pipe
incidence of atypical nuclei in
larynx, 59
incidence of coronary heart disease,
21-24
incidence of gingivitis, 86
incidence of stomatitis nicotina, 87
thickness of vocal cords, 60
Smokers vs. ex-smokers
atypical nuclei in larynx, 59
coronary disease mortality for men,
by amount smoked, 15
coronary disease mortality for men,
by years stopped smoking, 15
coronary disease mortality for men,
compared to nonsmokers, 15
stroke mortality for men, compared
to nonsmokers, 15
thickness of vocal cords, 60
Smokers vs. nonsmokers
aortic aneurysm mortality, 16
atypical nuclei in larynx, 59
comparison of blood factors of moth-
ers and infants, 80
concentrations of o-aminophenols in
urine, 64
coronary disease incidence, 18, 20-22
coronary disease incidence and be-
havior type, 24
coronary disease mortality, by age,
18
Smokers vs. nonsmokers—Continued

coronary disease mortality, by
amount smoked, 13

coronary disease mortality, by sex,

18

coronary disease mortality ratios,
by age, 13

coronary disease mortality ratios,
by amount smoked, 13

coronary disease mortality ratios,
by sex, 18 :

Curschmann’s spirals in sputum of,
39-40

incidence of edentulism, 87

incidence of gingivitis, 86

incidence of periodontal disease,
85-86

incidence of preeclampsia among
pregnant women, 79

prevalence of neoplasms, by type of
tumor, sex and age, 56

stroke mortality, by age, 13

stroke mortality, by amount smoked,
13

stroke mortality, compared to ex-
smokers, 15

stroke mortality, by sex, 13

stroke mortality ratios, by age, 13

stroke mortality ratios, by amount
smoked, 13

stroke mortality ratios, by sex, 13

thickness of vocal cords, 60

urinary excretion of tryptophan
metabolites, 64

Smoke, tobacco

aromatic hydrocarbons in, 61
bladder carcinogens in, 64
carcinogenicity of, 62
cocarcinogens in, 61
nicotine-N-oxides in, 62

Smoking

and alveolar bone loss, 85-87
and angina pectoris, 18

and arrhythmia, 4

and arteriosclerosis, 4, 5

and behavior type, 20, 24

and bladder neoplasms, 60

and bronchitis, 4

and cardiovascular disease, 3-5
as cause of bronchitis, 37-40

as cause of emphysema, 37-38
as cause of laryngeal neoplasms, 55
and coronary disease, 3-5, 20
effect on blood circulation, 11

effect on blood platelets, 27-28

effect on free fatty acid, 27

effect on hemoglobin oxygen affinity,
29

effect on larynx and true vocal
cords, 59-60

effect on lung function, 5

effect on pregnancy, 4-5, 77-81

effect on thrombus formation, 27-28

effect on ventilation/perfusion rela-
tionships of lung, 39

and fertility history, 79-80

and gingivitis, 85-86

and kidney neoplasms, 60

and lung neoplasms, 4, 55-58

and lung neoplasms in men, 57

and lung neoplasms in women, 57

and mortality, 3

and myocardial infarction, 4, 18

and noncancerous oral diseases, 5-6,
85-87

and oral neoplasms, 58

and pancreatic neoplasms, 60-61

and pregnancy toxemias, 79

and premalignant changes in larynx,
5

relation to blood cholesterol and
lung neoplasms, 57

relation to lung neoplasms and
stomach ulcers, 57

see also Smoking, maternal

Smoking characteristics

and incidence rates of lung neo-
plasms for men, 56

and incidence rates of lung neo-
plasms for women, 56

and lung neoplasm mortality rates,
57

Smoking history

aortic aneurysm mortality rates by,
16

aortic aneurysm mortality ratios by,
16

and coronary disease incidence
rates, 21-24

coronary disease mortality rates by,
18-14, 17

coronary disease mortality ratios
by, 13, 15, 18

incidence of atypical nuclei in
larynx by, 59

stroke mortality rates by, 13, 17

stroke mortality ratios by, 13, 15

97
Smoking, maternal
and ability of placenta to hydroxy-
late benzo(a)pyrene, 80
and abortion, T7-79
carboxyhemoglobin levels, 80
effect on birth weight, 5, 77-78, 80
effect on infants’ growth rate, 78
effect on pregnancy, in Ireland, 79
effect on pregnancy, in Scotland, 79
effect on pregnancy, in Venezuela, 79
epidemiological studies of effects,
77-80
and fetal death, 77—78
incidence of preeclampsia, 79
and infant mortality, 77~78
and prematurity, 77, 79
and prematurity, among Negroes, 78
Squamous cell carcinoma
see Carcinoma, epidermoid
Stomatitis nicotina
and pipe smoking, 87
Stroke
mortality rates, by age, 13
mortality rates, by amount smoked,
13
mortality rates, by sex, 13
mortality ratios, by age, 13
mortality ratios, by amount smoked,
13
mortality ratios, by sex, 13
Surfactants
effect of cigarette smoking on, 42

Tar content
of cigarette smoke, reduction of, 61
of cigarette smoke, and tumorige-
nicity, 61
Tars, cigarette
retention in mouth, 62
Tars, tobacco
carcinogenicity, 61
Thrombosis
effect of smoking in, 27-28
plasma and, 27-28
Thrombus formation
and smoking, 27-28
Tissue cultures
effect of cigarette smoke on, 62-63

PB-3375-5-54-5B
75--48T

C
B/T

Tobacco
form used and relation to gingivitis,
86
and oral submucous fibrosis, 58
see also Tobacco alkaloids
Tobacco alkaloids
and experimental
plasms, 64
possible role in carcinogenesis, 62
see also Cotinine ; Nornicotine
Tobacco chewing
and oral neoplasms, 58
Tooth extraction
effect of smoking on healing of
socket, 87
Tryptophan metabolites
urinary excretion of by smokers, 64
Twin studies
genetic and environmental factors in
angina pectoris, 25

bladder neo-

Ulceromembranous gingivitis
see Gingivitis, uleeromembranous
Uleers
and lung neoplasms, relation to
smoking, 57
Urinary tract neoplasms
and smoking, 60, 64
Urine
o-aminophenols concentration in, of
smokers and cancer patients, 64
excretion of tryptophan metabolites
by smokers, 64

Vincent's gingivitis
relationship to smoking, 86

Vitamin D
and nicotine, effect on hypercho-

lesterolemic rabbits, 27

Vocal cords

” effect of smoking on thickness, 59-60
sec also Larynx

Women
blood pressure and smoking habits
during pregnancy, 77-78
incidence of lung neoplasms and
smoking, 4, 57

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