Th e Health Consequences of SMOKING 1969 SUPPLEMENT TO THE 1967 Public He&h 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. 6840025 For sala by the Superht8ndent of Document% U.S. Oommme nt Prblting omw Washington. D.C. 2041X2 - Prka 60 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 tihe health, consequences of smoking. The preceding two reports were The Health Comepnces of Smoking, A Public Hedth Service Review: 1967 and The Hedth Consequences of Smking, 1968 Supplement to the 2967 Public Eealth Service Review. The present Supplement was submitted to the Congress on July 29, 1969. iii 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. AUEBBACH, Osc~n, M.D.-Senior medical investigator, Veterans Administration Hospital, East Orange, N. J. AVIADO, DOMINIX M., M.D.-Professor of pharmacology, Department of Pharma- cology, School of Medicine, University of Pennsylvania, Philadelphia, Pa. Arass, STEPHEN M., M.D.-Director, Cardiopulmonary Laboratory, Saint Vin- cent's Hospital and Medical Center of New York, New York, N.Y. BATES, DAVY, V., MD.-Cha~lrman, Department of Physiology, McGill UniVeIFdty, Montreal, Quebec, Canada. BELLET, SAMUEL, M.D.-Director, Division of Cardiology, Philadelphia General Hospital, Philadelphia, Pa. Brno, RICHARD J., M.D.-Professor and chairman, Department of Medicine, Wayne State University, Detroit, Mich. BL~MQUIST, EDWARD T., M.D.-Chief, Chronic Respiratory Disease Control Pro- gram, Health Services and Mental Health Administration, U.S.P.H.S., Arling- ton, Va. BOCK, F'mm G., Ph. D.-Director, Orchard Park Laboratories, Roswell Park Memorial Institute, Orchard Park, N.Y. BOREN, HOLLIB, M.D.-Chief of pulmonary disease, Professor of medicine, Mar- quette School of Medicine, Wood VA Center, Milwaukee, Wis. BOUTWELL, ROEWELL K., M.D.-Professor of oncology, McArdle Laboratory for. Cancer Research, University of Wisconsin, Madison, Wis. Coo~ns, THEODOBE, M.D.-Director, National Heart Institute, National Institutes of Health, Bethesda, Md. COBNFIEL.D, Jrmobx-Biostatistics Project, Bethesda, Md. DE LA PUENTE, Jossrn-Chief, Program Studies Section, Kidney Disease Control Program, Health Services and Me&al Health Administration, U.S.P.H.S., Arlington, Va. EASTMAN, NICHOLSON J., M.D.-Professor emeritus of obstetrics, Johns Hopkins Hospital, Baltimore, Md. ELIOT, ROBEBT S., M.D.-Associate professor of medicine, Division of Cardiology, College of Medicine, University of Florida, Gainesville, Fla. V Ennrco~~, KENNGTH M., M.D.-Director, National Cancer Institute, National In- stitutes of Health, Bethesda, Md. EPSTEIN, FBEDEBICR H., M.D.-Professor of epidemiology, Department of Epi- demiology, University of Michigan, School of Public Health, Ann Arbor, Mich. FALK, HANS L., Ph. D.-Associate director for laboratory research, National Institute of Environmental Health Sciences, Research Triangle Park, N.C. FEBBIS, BENJA~~IN 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. FRAZIER, TODD M.-Assistant director, Harvard Center for Community Health and Medical Care, Harvard School of Public Health, Ro.ston, Mass. HASS, GEORCJE M., M.D.-Chairman, Division of Pathology, Presbyterian-St. Luke's Hospital, Chicago, Ill. HIGGINS, IAN T. T., M.D., M.R.C.P.-Professor, Department of Epidemiology, University of Michigan, School of Public Health, Ann Arbor, Mich. HOFFMANN, DIETRICH, Ph. D.-. 4ssociate member, Environmental Carcinogenesis, Sloan-Kettering Institute for Cancer Research, New York, N.Y. KELLEB, ANDBEW 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.) KOTIN, PAUL, M.D.-Director, National Institute of Environmental Health Sciences, Research Triangle Park, N.C. KIIUMHOLZ, RICHAU.~ A., M.D.-Director, Institute of Respiratory Diseases, Kettering Medical Center, Kettering, Ohio. LEIXHTENBEROER, CECILE, Ph. D.-Head. Department of Cytochemistry, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland. LEIJCHTENBEXGEB, RUDOLF, M.D.-Profeswr, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland. Lmsow, AVERILL A., M.D.-Professor and chairman, Department of Pathology, University of California. San Diego. La Jolla, Calif. LILIENFPZD, ABB~HAX, M.D.-Professor and chairman, Department of Chronic Diseases, Johns Hopkins School of Hygiene and Public Health, B,altimore, Md. LYOIV, HARLEY W., D.D.S., Ph. D.-Secretary, Council on Dental Research, American Dental Association, Chicago, Ill. MACMAHON, BEIAN, 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. Mrro~n;r, ROGER S., M.D.-Director, Webb-Waring Institute for Medical Re- search, University of Colorado Medical Center, Denver, Colo. MUBPHY, EDMOND A., M.D., SC. D.-Associate professor of medicine, The Johns Hopkins Hospital, Baltimore, Md. PAFFE~EAEGE~, RALPH S., Jr., M.D.-Chief, Bureau of Adult Health and Chronic Diseases, Department of Public Health, Berkeley, Callf. PETEESOB, WILIZAM F., M.D.-Chief, Obstetrics and Gynecology Service, USAF Hospital Andrew& MSHCB, Andrews Air Force Base, Washington, D.C. *Deceasea Vi PETTY, THOMAS L., M.D.-Assistant professor of medicine, University of &do- rado Medical Center, Denver, Cola. ROCHMIS, PAUL G., M.D.-Heart Diseamse and Stroke Control Program, Health Services and Mental Health Administration, U.S.P.H.S., Arlington, Va. Ross, WILLIAM L., M.D.-Chief, Cancer Control Program, Health Services and Mental Health Administr.ation, U.S.P.H.S., Arlington, Va. S~~p~cvrr~, UMBEBTO, M.D.-Associate scientific director for carcinogenesis, etiology, National Cancer Institute, National Institutes of Health, Bethesda, Md. SCHACHTER, JOSEPH-Statistician, Adult Heart Activities, Heart Disease and Stroke Control Program, Health Services and Mental Health Administration, U.S.P.H.S., Arlington, Va. SCHUMAN, LEONARII M., M.D.-Professor of epidemiology, University of Min- nesota, School of Public Health, Minneapolis, Minn. SHIMKIN, MICHAEL B., M.D.-Director, Regional Medical Programs, University of California at San Diego, La *Jolla, Calif. SILVERMAN, SOLS, Jr., D.D.S.-Professor of oral biology, School of Dentistry, University of California, San Francisco, Calif. SMITH, LOWEL.L C., D.D.S.-Chief, Preventive Services Section, Community Pro- grams Branch, Division of Dental Health, U.S.P.H.S., Bethesda, Md. STAMLEB, JEREMIAH, M.D.-Executive director, Chicago Health Research Foun- dation, Chicago, Ill. STDMAN, RUSSELL L., D. &.--Head, Smoke Investigations, Tobacco Laboratory, U.S. Department of Agriculture, Philadelphia, Pa. TIECKE, RICHARD W., D.D.S.-Director, Research Institute, American Dental Association, Chicago, Ill. TOBIN, CHABLES E., Ph. D.-Professor of human biology, University of Colorado School of Dentistry, Denver, 0010. TYLER, WALTZB S., D.V.M., Ph. D.-Professor and chairman, Department of Anat- omy, School of Veterinary Medicine, University of California, Davis, Calif. UNDERWOOD, PAUL, M.D.-Assbstant professor of obstetrics and gynecology, De- partment of Obstetrics and Gynecology, University of South Carolina Medical School, Charleston, S.C. VAN DWREN, BENJAMIN L., M.D.-Associate professor, New York University Medical Center, Institute of Environmental Health, New York, N.Y. WEIB, JOHN M.-Director, Bureau of Dental Health Education, American Dental Association, Chicago, Ill. WYNDEB, EBNE~T 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. vii Table of Contents Foreword-__-_------------------------------------------ Acknowledgments_--_----------------------------------- 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- eases ______ -_--- ________________ 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- ease_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ PW iii V 1 7 9 35 53 75 83 iX 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- ,is associated with an increase in overall mortality and mor- EL 1 1 y 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 packsla day, and an average of 4 years in "light" cigarette smokers, those who smoke less than one-half pack per day. Smoking and Cardiovascular I&eases Current physiological evidence, in combination with additional epidemiolo ical evidence, confirms previous findings and suggests additional % iomechanisms 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 P hysiological findings relating cigarette smoking to coronary leati disease, it is concluded that cigaret,te smoking can con- ,tribute to the development of cardiovascular disease and partic- ularly to death from coronary heart disease. Bnoking and Chronic Obstructiw Bronchqulmomry D&eases Additional physiolo !F `cal and epidemiological evidence confirms the previous findings t lat cigarette smokin 7 is the most important cause of chronic non-neoplastic bronchopu monary disease in the United States. 3 Cigarette smoking can adversely affect pulmonary function and disturb cardiopulmonary physiology. It is suggested that this qan lead to cardiopulmonary disease, notably pulmonary hypertension and car pulmonale in those individuals who have severe chronic obstructive bronchitis. Smoking am? Gamer Addi,tional evidence substantiates the previous fmdings 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 t.han in men. Smoking is a significant factor in the causation of cancer of the larynx and in the development of cancer of the oral cavit,y. Further epidemi- ological data strengthen ,the association of cigarette smoking with cancer of the bladder a.nd 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 lon studies on the e -range morbidity studies are needed, -as well as fi ect of smoking on uterine activities and placental blood flow. Smoking does have an effect on t.he 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. Snwking and Cardiovamdar 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- cardid 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 evaluakd. 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 Obetructive Bronchopdmwry DGenses Recent studies have demonstrated t.hat 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 t.he 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 t.he view that cigarette smoking can contribute to the development of pulmonary emphysema in man. III. Smoking and Cancer A major pathological study of histological changes in the larynx has demonstrated a dose-relationship between smoking a.nd 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. Swwking 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 5 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 nnd 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 a major health hazard in the United States. PART 2 Technical Reports on the Relationship of Smoking to Specific Disease Categories 260-2280--88----2 CHAPTER 1 Smoking and Cardiovascular Diseases Contents Ptlg.3 summary_----------T------~--------------------------- 11 Epidemiological Studies- - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ - - _ - _ _ _ - Atherosclerosis----------- _____________________ --_--_-_-_ ;i ThrombusFormationandBloodFlow __________ -_---_-__-- 27 Carbon Monoxide------------------------------- ________ Cited References---------------------------------------- E Cardiovascular Supplemental Bibliography----------------- 31 9 SMOKING AND CARDIOVASCULAR DISEASES 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 (97) 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 t:here 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 11 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 aocounted for by those risk factors independently. EPIDEMIOL~CZICAL STUDIES Hammond, et al. (11) have presented new da.ta 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, cha.nge 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 deat.h 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 TABLE I.-Death rates and mortuLi& ratios for cormay haa? disease and sttoke, by anunmi of &are& smoking, sex, and age lZqnlarly smoked clgarettee Regularly smoked cigarettea scuandsge NeFW NWW smoked Number smoked daily smoked tzgiz$ l-9 cigerottel Number smoked daily lW19 al-39 4oor regularly 1-9 1lH9 W-39 400r more more 68 267 L: 18 li9 2ea 979 DEATH RATES 256 616 &Ml 2# 57a 47 163 663 1,243 3'16 718 1, MS z.w `43 2w `642 --_ 14 39 ' 16 a1 23 40 73 a 81 96 163 219 343 273 289 660 017 S93 793 ' 446 10 IS 3S 39 167 37 34 73 72 `95 110 139 33S !a1 -_ 4a7 404 `276 022 __ MORTALITY RATIOS 1 M&5: 40-49 years-. LOO L60 269 3.76 S.lil LOO 279 `Lll 221 1.64 so-69 years.... Loo 1.68 213 240 279 LOO 19s L43 293 240 w-69 years.-. Loo 1.43 1.32 LB1 1.79 Loo 1.30 L44 162 1.73 m-79 years-... 1.00 1.14 1.41 L49 147 LOO .9S .93 L33 r.63 Females: 4049 years.-. 1.90 L31 209 3.02 `8.31 LOO 1.&l 230 299 `h70 60-0-8 years.-. 1.09 1.16 237 263 3.73 Loo 1.26 270 267 `a.S2 w-e4 years-. l.M) Lo4 L79 208 `202 1.00 1.26 216 l-33 --_- 7w9 years.-. 1.00 .76 .98 tn ---_ LOO .33 I.67 1.23 --__ ' The mortality ratb Is the observed rata divided by the qectad rats. ' F&tee based upon only 6 to 9 deaths. Sowa: Hammond, E. C., et al. (II). 13 TABLE 2.-Coronary &art disease death rates for mm and wmen &x$ied by smoking habits, age, blood pressure, and relative weight Extent of No high blood pressure, by relative weight High blood ~rassnre, by relative weight Total t% 90-109 U-119 s% 90 OVBT Total tE 90-109 110-119 iii OVW MEN None or slight: 40-49yeers _______._-__ 62 `27 46 64 128 an _-_ 195 `210 _-___ 60-59~~ ____________ 226 140 216 283 a90 620 1686 611 643 609 60-69yesrs _____-___-__ 603 542 673 701 763 1,503 1,777 1,296 1,860 1,865 70..79p-... _________ i,m 1,467 1,555 1,840 1,868 2,7a8 3,342 5038 2,651 a, 100 IIlb~di8te: 40-49yefm __-__--- _--- 116 108 104 141 245 249 `a34 266 `288 _--__ la-59 years -_-___----_- 373 352 383 405 538 876 1,424 686 1,182 995 60-69yeaR _____-_----- 888 814 890 984 973 1,876 1,913 1,999 1,447 1,710 70-79year~ ____________ 1,973 ~237 1,778 1,953 &sol 3,220 3,700 3,172 gn3 6,461 20 or molv: 40-49 years. ___________ 222 123 235 309 276 647 687 650 765 89; bo-&i9yeal2 _____-______ 630 422 636 666 641 1,137 1.148 1,153 933 1,41 6049yt?ars ___-_-_-____ 1,047 978 1,019 1,249 1,307 1,986 &leo 1,993 1,744 2,076 70-79~~ ____________ ~236 %a46 5205 2151 ~846 4,123 5,141 4,205 13,692 ----- WOMEN None or slight: 40-49 years-. _ ___- _ _ __ _ SO-69yearS __---------- 60-69yem ___-------_ _ 76-79 yea's -_--- - - - --_ - Intam'ediate: 4049 yeara ---------__ so-59 years __-__ _ _ _--_ _ 60-69 yeal7L -________-_ 70-79 years --___------- mormom: 4cM9 yeara _--- ---- -- - so-59 years _-_-__- ____ _ e&w yeam _-_-_____-_ 70-79 yeara -_-- -_ _---- 8 `6 7 41 39 32 -ii 201 153 191 265 776 832 `179 667 16 17 12 -__ 76 69 70 153 284 a37 244 422 607 736 551 -__ 36 25 a8 `42 120 118 128 ___ 467 a41 636 `637 644 `866 `la6 -_- 22 68 323 754 --_ `73 `73 ' 135 --_ 63 -__ 53 ----- 161 100 142 167 469 400 495 462 1.338 1,313 1,217 1,449 86 --- `76 281 361 231 730 732 743 1,161 ' 1,854 1,014 .144 ___ 193 368 `26a 291 811 `788 1,100 5463 ___ `a,743 __-_- `23a 848 _-_-- `b94 76 229 469 1.626 ----- `198 `484 ---_- `706 ' Rates based apon only 6 to 9 deaths. SOUBCE: Hammond, E. C., et al. (21). 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 err-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 ta.ble 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, Iamount 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 dea.th rates from the three diseases. TABLE 3.-Observed and expected number of deaths and mortality ratios for ex-cigareite smokers with a history of smoking only cigarettes, by number of years since last cigaretle smoking and for current cigarette smokers, coronary heart disease and stroke; compared to persons who never smoked regulurlyj in men aged 40-79 Type of smoker Coronary heart disease StiLe Observed Expectad Rati observed Erpeoted Ratio Ex-dgamtta smokera (former smokers of l-19 cigarettes a day) : stopped: Lea than 1 year.. ____________ 14 yeax _____________________ HI pears -_______--__-__-__---- 19-19 yeara _-__-___ _ ___ _ _ __ _- - 2oormoreytara --________-___ 29 17.9 162 ------ ------ ____-- b7 46.6 122 ______ ------ ._____ 55 46.7 L!a ___--- ------ _-_--- 62 b&l .9b ______ ----- - ______ 70 64.7 1.08 ._____ ------ -_____ Total. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 263 226.9 1.16 57 b6.9 LO9 Cnrrenteigarettes ______--__-- 1,669 569.6 1.96 207 1316 1. b4 Nevex smoked regularly- __________ ___ L.srl 1,841.0 LOO Ml 601.0 1.09 Excigarette smokers (fmmw smokeus of 20 or more cigemtte a day) : mopped: Less than 1 year _-__-__-____-_ l-4 yw'rs.. _ ___ _ ___ ---___-_-_-- b-9 yelIla.-. -- -- - ---- _ -_- _ -- - _ - lo-19 Ye...-.-..-.-...------ 2oormoreyears ____-_________ 62 3R6 1.61 ______ ______ ______ lb4 101.9 Lb1 _----- ------ -_-___ 13b 116. b 1.16 ______ ___-__ -_____ 199 166.1 1.25 _----- _----- _-___- 80 76.4 Lob --__-- ___--- __-__- Tot& _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ 4a9.7 1.28 94 1OL 1 a98 C-t cigarstb smokers ____________ Z8: l,llu7 zbb 440 2517 L87 Never smoked regulsrlym _____________ 1,841 b841.0 LOO 501 b61.0 1.66 Somar: Hammond, E. C., et aL (II). 15 TABLE 4.-Aortic aneurpm death ratee and mortality ratios for men aged 50-69, classified by cigarette smoking habits [Ratas p?r1,ooopopulation] Cnrmnt smokers, by daily cigsrette consumption 1-Q IO-19 m-39 49 or more Death rate ___-__ _ _ _ _ _ _- __ _ _ _ ___ _ 13 34 50 59 104 Mortality ratio ___________ - ______ 1. 00 2. 62 3. 85 4. 54 8. 00 Son~mHammond,E. C.,et al. (21). 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 nonsyphilitic aortic aneurysm. Stamler (2.4) has anaylzed lo-year mortality data on a total cohort of men, aged 40-59 in 1958, who were employees of the Chicago Pea pies 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. (a) 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 ($?5). 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 corn- binations of pairs of risk factors in nonfatal CHD and table 6 shows mortality ratios for combinations of risk factors in fatal CHD. 16 TABLE &-lo-year mortality rates for sudden death, coronary heart disease, stroke, cardiovascular-renal, and all causes combined among men aged 40-69, classijied according to cigarette smoking, cholesterol, and blood pressure [Peoples C&s Light Co. Study, 1956-63. Men origInally free of coronary heart disease and followed without systematic Intervention,] l0-year mortality 19@3 risk factor status-cigarette smoking (10 or more a day], Sudden death All CHD Stroke All CVR All cause8 hypercholestemlemla, hypertension r Number Nyfber Death NuFfber Death Nur$ber Death NuFfber Death Nun$ber Death of mean rate 1 rate rate rate rate In cohort deaths deaths deaths deaths deaths Noriskfactor _______ _ _____________ _ __________________ _____ ____ ____ Hypercholesterolemia or hypertension only-1 factor. _ _______ _____ Cigarette smoking only (10 or more a day)-1 factor _______________ Hypercholesterolemia and hypertension only-2 factors ____ _ _______ Cigarette smoking (10 or more a day) and hypercholesterolemia or cigarette smoking and hypertension-2 factors... _ __ _______ _ _ _ ___ Cigarette smoking (10 or more a cay), hyperoholesterolemia, hypertension-a113.-.. _____________________ _ ______________ ______ ZU 0 0 1 3.0 2 6.9 4 11.9 13 42.0 216 4 19.6 13 63.1 6 19.6 19 726 27 101.6 405 4 10.0 16 37.1 5 11. g 20 46.9 44 107.7 60 1 9.9 3 2Q.6 1 40.7 4 70.3 8 121.9 293 11 37.2 17 67. 1 6 19.9 26 36.4 53 169.9 67 2 25.1 6 76.0 2 25.4 8 101.6 17 226.8 Total-.-... ___________________ _ ______ _ ____ ____ ______________ al,325 22 16.2 55 39.2 22 14.9 61 53.6 162 113.1 1 Risk factors include: Serum cholesterol 2&I or more mg./dl.; diastolic blood pres- 8 Smoking data were not obtained for 4 of the 1,329 men. sure QO or more mm. Hg; 10 or more cigarettes/day. I A" mtee m ~-adjusted by byear age groups to the U.S. male popuh3tion. lQ69. Souncs: Stamler, J. (84). All rates per thousand. T~~~~6.--Edimatedcoronaryhea~disease dmfhrattisinal7-61 year joUowup among former college students, cla.ssi$ed according to combined presence (+) or absence (-) of each of three speci$ed risk factors, and by age Risk factor Age (years) at death from coronary heart d&ease Clg*lLgtW Systolic BP, p;?$iep Total 130 or more more/day mm. Hg les$& 30-69 30-44 4654 55-09 yea- years Years years + + + 4. 3 l(l.9) 5. 7 ' (4.8) + - + 1. 8 2. 3 1. 6 ' (2.0) + + - 4. 2 2. 9 4. 5 5. 6 - + -I- l. 9 2. 9 1. 6 1. 8 + 1. 7 2. 2 1. 9 1. 3 - + - 1. 3 1. 2 1. 2 1. 4 - + 1. 1 1. 4 1.4 .8 - 1. 0 1. 0 1. 0 1. 0 1 Numbers in parentheses indicate expected number coronary heart disease decedents less than 5. SOUBCE: Paflenbarger, R. S., et al. (18). In a study of participants in the Health Insurance Plan of New York, Weinblatt, et al. ,($?9) reported that cigarette smoking males who developed angina pectoris were more likely to develop infarction than were nonsmoking angina1 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 3949 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 3 * 1 0 . 3 B 2 3.: I 3 2 1 x0 ;: % 2 1 0 . 3 2 * 0 cl#wdta 10+/&y-A 6ys. 8? mo+mm. W-A Nd#lt/Q c 129-B spmn < 6 hr.,*-8 ciwuaa lo+/dq-A th&ht < 66 h-8 - < 66 h-8 < 6 llr./wk-8 b 3 2 1 0 6 3 2 1 0 1 3 2 1 0 4 3 2 1 0 4 3 2 1 0 Fmum l.-Morbidity ratios of coronary heart disease for paired combinations of factors in college. Souacx : Thorne, WC., et al. (2%). 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,lO). 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 $9-49 years of age, clasti$ed by smoking hietory and by currint practices a8 to cigareth smoking I&J as of the b@miu# of the 4% year period ol ob+xvatlon] Morbidity etatue Total eublecte Never smoked Smoking history :lg%~ Former dgarette Current dgarette Current dgarette smoking by number per day None l-16 16-25 260rmore Nb;;- Rate 1 Nb::- Rate Nb;~ Rate Nby- Rate Nb;y Rate Nby Rate Nbr Rate Nb2- Rata Nby- Rate Totalnumberatrisk _--_-------- a258 e-m_- 540 _--__ 496 ___._ 239 -_--- 1,974 _____ 1,191 em._. 2Il ----- 484 .____ 422 _____ TotalnumberCHDc8sm ______. 62 6.2 7 `29 3 I.6 10 J9.3 43 82.9 20 `2.7 6 63 18 ` 9.2 20 `16.5 A~myocardtallnfarctbn -_----__ 32 5.1 4 1.7 3 1.6 10 9.a 35 7.2 17 3.1. 4 4.2 la 87 18 9.s Symptomatic ____ _ __________ 33 3.7 1 .I 2 1.1 8 7.4 27 6.8 11 20 4 4.2 11 3.6 12 6.3 Unrecognlmd _______________ I4 1.4 3 1.2 1 .6 2 1.9 8 1.7 6 I. 1 9 0 2 1.0 6 3.1 Fatal _______.__----- _ -------- 1" II", 0 0 0 0 1 de 8 1.7 1 .a 0 0 6 3 ~pectiody __._________ 3 1.2 0 0 0 8 1.7 a .6 I 1.0 5 z"t 2 ti 1 Annual rate per l,ooO men at rick. : Them distributions of casm for varlow emokiop cA2orleS are el2nlflcantlY dU- ferent from chance at P =O.oOl. a Dawns in CHD frequeucy between thla noup aud thoee who never emoked dgmttss (a11 .1 and 2 eomblued) la &nIficant at P-O.01 by cbl muare test corrected for continuity. 4 Differenca in CHD frequency between this group and cumut nouoigare.tb emokers is siguifkant at P -0.01. SOUBCC: Jenkln, CL D., et aI. (Id). TABLE 8.-Annual incidence rates of coronary heart disease for men 60-69 years of age, classajied by smoking hietory and by current practices as to cigarette smoking [Age as of the beginning of the 4% year period of observation] Morbidity statue Total eublecta Never smoked fhoklng history Pipe and Former cigar only cigarette current cigarette Current cigarette emoktng by number per day None 1-15 16-25 28 or more NW- Rate 1 Nun Rate Num- Rate Nbgv Rate Nun- Rate Nbr Rate Nby- Rate Nby- Rate Nby- Rate ber ber ber ber Total number at risk- _ ___ _ ____ _ 924 _---- 182 _---- 161 _-__- 137 ---_- 444 _____ 483 ___-_ 109 _--_- 167 --__- 165 _-_-_ Total number CHD ceeea _______ 70 18.8 9 tn.0 11 15.2 9 14.6 41 20.5 al 113.3 6 122 16 21.3 119 25.8 All myocsrdial infarction ________ 52 125 6 7.3 3 11.0 5 8.1 33 16.5 19 8.7 5 10.2 15 20.0 13 17. s Bymptomatlc _______ _ _____ __ 35 8.4 4 4.9 4 5.5 4 6.5 23 11.5 12 5.5 4 8.2 11 14.6 8 10.8 umwognlwd --________-__-- 17 4.1 2 24 4 s.5 1 1.6 10 5.0 7 3.2 1 20 4 s.3 s 6.7 Fatal __________ _ _____________ 3.4 14 0 0 3 4.1 3 4.9 8 4. 0 6 28 2 4.1 4 6.3 2 2. 7 AqInapectorisonly~~...~~...~. 18 4.8 3 3. 7 3 4.1 4 6. 5 8 4.0 10 4.6 1 20 1 1.3 6 8.1 ~Ammalrat8per1,OOOmenatrfsk. *Difference in CHD kequency between this group and current noneigaretts ' These distrfbutkne of owea for various amok.ing calories could occor 0.10 of smokers is significant at P=O.Ol. the time by chance, hence are not el@lcant at P-0.06. Bowa: Jenkins, C. D., et rd. (14). TABLE 9.-Annual incidence raies of new eorbnary keart disc&se, by smoking habits, adjusted for age and seradim, for speca$ed other risk factors [Rates are annual incidence per 1,OLkl men, aged 39 to 49 years at entry into 8tudy) Specified other risk factors Never Former Pipe and smoked sc;goyeT cigar only D~ycigr&t& - p.* 1-15 16-25 26or Cholesterol _______________________ _ _____ 33 vs 22 49 89 100 0.005 Betaf~pharstfo-..--.----.---.......... 31 91 18 49 91 102 .OOl Lipalbumin _______ __ _______________ _ ____ 31 95 18 51 89 102 .002 Systolic BP _____ _____ ____ __ __ ____ _______ 31 91 18 49 95 100 . 001 Diastolic BP _.__________________________ 29 89 16 49 95 104 .OOl Ponderal index __________________________ 29 91 16 49 95 107 .OOl Physical activity __________________ _ _____ 29 93 18 47 93 104 . 001 Amount of exercise _____ ____ ____ __ ___ ____ 29 91 18 49 93 104 .OOl lncomc level _____ _________________ _ ____ _ 29 91 18 49 93 104 .OOl Alloftheabove ___________ ________ 3s 93 20 51 89 93 .097 Triglycerides ______ _ _ ___ . _ __ _ _ __ __ _ _ _ _ _ _ _ 31 88 al 40 80 104 .002 r Level of significance of F-ratio for analysis of covariance. SOWCE: Jenkii, C. D., et al. (II). TABLE IQ.-Annual inci.dence rates of new coronary heart disease, by smoking habits, adjusted for age and seriadim, for specijfied other risk factors [Rates are annual incidence per 1,OQJ men, aged 50 to 59 years at entry into study) f3pecilled other risk factors Daily cigarette Never Former Pipe and consumption smoked ;kyk;t; crgar only - p.' l-15 M-25 28 or more Cholesterol. _ _ _ __ _ _ ___ _ ___ _ ___ _ __ _ _ _ _ __ _ 115 142 153 115 211 254 0.154 Beta/alpha ratio ________________________ 107 142 144 120 213 252 .127 Lipalbumin _____________________ __ ______ 109 140 151 122 218 262 .135 SystolioBP _____ _ _______________ ______._ 118 127 144 129 211 266 .136 Diastolic BP ____________________________ 109 127 135 127 2.26 273 .066 Ponderalindex-.---..----..------------ 107 131 140 122 222 269 .084 Physical activity _______________________ 113 142 149 115 213 249 .216 Amount Of exercise ___-__________________ 113 144 151 118 211 255 .203 Income level __________________ ____ _____ _ 113 138 147 120 2a-l 256 .156 All of the above __________ ____ _____ Triglycerides _______________________ ____ 113 113 118 147 138 140 213 258 .168 144 80 195 280 .121 1 Level of siguS5cance of F-ratio for analysis of covariance. SOUBCE: Jenkins, C. D., et al. (14). 23 TABLE 1 l.-Incidmce of new coronary heart disease, by smoking category and behavior type, for men aged 39-49 [Rates ere ege-edjusted annuel incidence per 1,ooO men] Behavior type Current and former Dally cigarette consumption Forz;o?AAette pipe end cigar only Total Never smoked 1-15 E-25 26 or more Ratea cases Rates Cases Rates cases Rates CsSeS Rates CaSeS Rates C&lSeS Rates Ceses A ______ _ ____ _ ________ _ ______________ 6.3 6 13.8 7 1.3 1 1.6 1 15.8 16 14.9 18 9.3 45 B __________________ _ _.____ __ ____ ____ 1.3 2 6.1 3 22 2 7.3 4 3. 1 3 4.9 4 3.3 18 Total _________________________ 29 7 9.1 10 1.8 3 4.9 6 9.3 18 10.4 20 6.2 63 BOWCE: Jenkins, C. D., et al. (4). TABLE 12.-Incidence of new coronary heart disease, by smoking category and behavior type, for men aged 60-69 [Rates are age-adjusted annual Incidence per l,@Xl men] Behavior type Current and former Daily cigarette consumption pipe end cigsr only Tote1 Never smoked Formero~@&te 1-15 16-25 26 or more ~- Rates cas%s Rates cases Rates Cases Rates Cases Rates Cases Rates Cases Rates CCl.WS A _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ - 124 6 18.6 8 21.8 8 16.4 6 21.6 9 30.0 14 20.4 49 B ______.__-_ _ _______________________ 10.0 4 6.1 1 a4 3 4.7 1 21. 1 7 19.1 5 12.0 21 Total __.________ _ _____ __ ______ 11.1 9 14.2 9 14.9 11 11.6 6 21.3 16 28.0 19 16.8 70 BOWCE: Jenkins, 0. D., et al. (10. 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 d&rite 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 `114 age-matched controls in Munich, Schimmler, et al. (%Z') 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 t.he 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. (J) have shown that smoking one cigarette before exercising reduces t.he energy expenditure required for patients with classical angina pectoris to develop chest pain while exercising on a bicycle ergometer. AkTHEROSCLEROSIS 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 (W). Further studies have recently been published in this area. 25 Sackett, et al. (al) have demonstrated a clear dose-relationship be- tmeen cigarette smoking and t.he 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. (aS) h, zve 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 vas 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 t,hese 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. (15) compared the vascular patholo,gy in rabbits fed a high cholesterol diet and maintained iti 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 (COH:b) levels, the authors (6) 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. (18)) 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. (16) h ave 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. THROMBUS FORMATTON AND BLEND Fnow Hess, et al. (IS) 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 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 (97). In a study of 50 lvhite males with myocardial infarcts and 40 con- trols, Stables, et al. (9%`) 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. CARBON MONOXIDE 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 (9,20). 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 COD% 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. (10) 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 viva oxygen affinity of hemoglobin may be different from that implied by the static equrlibrium data. Further research is in progress. CITED REFERENCES (I) ARONOW, W. S., KAPLAN, M. A., JACOB, D. Tobacco: A precipitating factor in angina pectoris. Annals of Internal Medicine 69(3) : 529-536, Sep- tember 1968. (3) ASTRUP, P., KJELDSEN, K., WANSTB~P, J. Enhancing influence of carbon monoxide on the development of atheromatosis in cholesterol-fed rabbits. Journal of Atherosclerosis Research 7 : 343-354, 1967. (S) A~TANDUOV, G. G., ROLENOVA, V. I., PONOMA~ENKO, 0. V. Kureniye tabaka i stepen' ateroskleroticheskogo porazheniya koronarnykh arteriy serdtsa i aorty. 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CHAPTER 2 Smoking and Chronic Obstructive Bronchopulmonary Disease Contents SUmmary---------------------------------------------- ChronicBronchitis----------- ______________________ -_--- Prevalence of Chronic Obstructive Bronchopulmonary Disease- PulmonaryEmphysema___------------------------------- Experimental Studies in Man ____________________ -__-_--__ Studiesin Animals-------------------------------- ______ OtherStudies_------------------------------------------ Cited References---------------- _______________ -_-----__ Chronic Obstructive Bronchopulmonary Disease Supplemental Bibliography----------------------------------------- Page 37 37 38 38 39 40 42 43 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 prov,ides 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 brofichial epithelium, and obstruction of oapill,aries 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. CHRONIC BRONCHITIS 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 (16,35) 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 (31) and rural Australia (25) produced similar findings. A South African study (4.5) d emonstrated decreased forced expiratiry 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 t.hat 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. PULMONARY 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- tist.9 (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 neeroeis of the alveolar wall and septa. The other major theory states that chronic obstructive pulmonary emphysema results from the direct effect of t,oxic inhalants on the pulmona.ry tissue, in the areas of the terminal bronchioles and alveoli. According to this theory, changes seen in the pulmonary and bronchial vessels are 30 secondary to the destruction of nonvascular tissue. It may well be that t.he pathogenesis of pulmonary emphysema can involve several mecha- nisms and that both of these theories may be applicable but not mutu- ally exclusive (&) . EXPERIMENTAL STUDIES 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. (3) 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 wras ,approximately proportionate to the total lifetime number of cigarettes smoked. Fullmer, et al. (.%?? 23, %$) have found a high prevalence of Curseh- mann's type spirals in the sputum of cigarette smokers. The easily recognized spirals consist of inspissat.ed 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 39 360-9280-694 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 ti 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. STUDIES IN ANIMALG Frasca, et al. (17,18) 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. (II) 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 (~$9) 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 i,n 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 t'he pulmonary paren- chyma provide indirect support of a vascular theory of emphysema. Ricketts, et al. (42) 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 tlhe 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 (IS?). 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. (19, SW, 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 ( 21) 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 ( +l) parts per million led to hypertrophy of the `epithelium of the terminal bronchioles. Rats exposed to concentrations varying from 10 (+l) 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 epitihelium, 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 proteimaceus 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 NOz also produced early bronchiolar inflammation with a concomitant reduction in the size of the distal airways. 41 OTHER sTuDIE6 In a recent extensive review of the nature and role of pulmonary surfactant, Scarpelli (j&3) 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, 61, 5~!?) which can interfere with pulmonary clearance. Components of both the particulate and the gaseous phases adversely affect ciliary activity. Dalhamn, et al. (14) h ave 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. (13) 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 (97) 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 (96) found that the cytotoxic activity of cigarette smoke on pulmonary macrophages may be inhibited by glutathione and cysteine. Izard (3%`) observed that the gaseous phase of cigarette smoke or one of ,its components, ,acrolein, inhibited the multiplication of cultures of DunalieZZa 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 Ithe lung. Roque, et al. (429 found a decrease in the activity of oxiodoreduc- tases and hydrolases in the alveolar macrophages of smokers. 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Archives of Environmental Health 18(5) : 76&767, May 1969. 52 CHAPTER 3 Smoking and Cancer Contents Summary _______________________ - _______ ----__-_----_-- Epidemiological Studies- _________________ -----__-_------- Lung Cancer- ___________._______ ------_---------_-- Oral Cancer- _____________ - ______ ------------- ______ Laryngeal Cancer- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Cancer of the Urinary Bladder and Kidney------..------ Cancer of the Pancreas ________________ - ____ ---_----- General Aspects of Carcinogenicity- __ _ _ _ __ _ _ _ _- _ __ _ __ __ _ _- Tobacco Alkaloids __________________ --___------- _____ Nickel__________________________________----------- Experimental Aspects of Carcinogenesis- _ _ _ _ _ - - - _ _ _ _ _ _ - - - - - Retention of Smoke Constituents- _ _ _ _ _ _ _ _ ___ __ __ _ ___ _ Changes in Cell Cultures Induced by Cigarette Smoke- - - Experimental Studies of Bronchogenic Carcinoma in Animals_________________------______________-_-_- Experimental Aspects of Cancer of the Bladder and Eidney__________-______________________--------- Cited References_--__-_--_____________________---------- Cancer Supplemental Bibliography- _ _ _ _ _ _ _ _ _ _ _ - _ _ _ - _ - - - - - - Pane 55 55 55 58 58 60 60 61 61 62 62 62 62 63 64 65 69 53 SMOKING AND CANCER SlJadMARY 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 lungcancer 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 larynx. 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 an.d Africa as well. Lung Cancer In Norway, a study of histologically proven cases of lung cancer by Kreyberg demonstrated t.hu 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 36CLQ28 -4 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 ($4, 2%). 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 l.-Tumor prevalence among males and females 36-69 years of age, by type of tumor and smoking category [Smokers canstltuted E5 percent of populations studied] Males: Epidermoid carcinoma- - _ ______ 434 431 3 17. 0 25. 4 Small cell anaplaatic carcinoma-- 117 116 1 5. 7 20. 4 Adenocarcinoma ___________ ____ 88 83 5 28. 3 2. 9 Bronchiole-alveolar carcinoma--- __ __ _ _-_ _ _ __ _ __ __ _ _ _ -_ Carcinoid _________-__________ _ 46 39 7 39. 7 1. 0 Bronchial gland tumor-- _ ___ ___ -___ ____ -___ ______ _ ___ Total ____________________ -_ 685 669 16 90. 7 7. 4 Females : Epidermoid carcinoma- _ _ ____ __ 12 9 3 Small cell anaplastic carcinoma-- 8 5 3 : ;: 12. 0 6.6 Adenocarcinoma ___---- ___ _____ 56 14 42 10. 5 1. 3 Bronchiole-alveolar carcinoma--- _ _ _ _ _ _ - _ _ _ - - _ _ - _ _ _ _ _ _ - Carcinoid _____________________ 32 7 25 6.3 1. 1 Bronchial gland tumor- _ _ _ _ __ _ _ __ _ _ _ _ _- __ __ _ ___ _ _ __ __ Total- _ ________________ ____ 108 35 73 18. 3 1. 9 ' NW&I that would be expected if incidenca rate among smokers WBS equal to that of nonsmokers. sowcx Kreyherg, L. (B4). 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 f'rom each cigarette. Gelfand, et al. (19) in a 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 Rh0desi.a. In the 1967 Health Consequences Report (GO), 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. Brass, 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 (N) . 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. (39) 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 t,o the development of adenocarcinoma (Kreyberg Group II). An association of other diseases to cancer of the lung is found in a report by Salzer, et al. (.@) . 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 (18, &?) . Valaitis, et al. (6~3) 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 %as" (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 (6.4) 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 cpithelium 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. (IS) 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, bard 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, fand poor oral hygiene. Larynged Cancer Auerbach, et al. (1) 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 distribuiion by relative frequency of atypical nuclei among true vocal cord cells, of men classi$ed by smoking category [lo0 per cent atypical cells defined 84 carcinoma] Total-.... - None. ___ _ ___ _ __ LeesthanSQ...- so-39 _ - - _ _ _ _ _ _ _ _ w-69 _ _ _ _ - _ _ _ _ _ _ 79-79 - _ _ - _ - _ _ - _ _ w-69 _---_-- ____ QO-QQ ___- _ --____ lOlIZ 88 lQQ.0 116 loo.0 94 lw.0 126 100.0 329 loo.0 190 loo.0 66 75.0 86 74.1 1 1.1 1 .8 0 __-__ 0 _____ 8 9.1 14 12.1 4 4.3 23 20.0 4 1.2 0 __-__ 10 11.4 13 112 50 63.0 34 43.2 872a.4 29 15.3 4 4.6 1 .Q 23 246 21 16.8 116 35.3 76 39.4 0 ---__ 2 1.7 9 9.6 9 7.2 44 13.4 38 20.0 0 ---__ 0 ---__ 2 21 2 1.6 19 5.8 11 6.8 0 -____ 0 _-___ 1 1.1 0 _____ 5 1.5 0 _.___ 0 --___ 0 _____ 3 3.2 13 10.4 52 15.8 35 18.4 0 _____ 0 ---__ 1 1.1 0 -_-__ 2 .I3 2 1. 1 SOURCE: Auerbach, O., et al. (I). 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 in 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 wi,th 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 clmsi$ed by smoking category Current cigarette smokers Number of cell Neversmoked E;z$kyAte regularly l-2 packs a 2 or more _^-" day packs a day Total_..-- 88 100.0 116 10Q.o 94 loo.0 125 100.0 329 109.0 190 100.0 30 34.1 7 6.0 4 4.3 3 2.4 1 0.3 0 _--__ 23 33.0 27 23.3 20 2L3 27 21.6 33 11.6 20 10.6 8 9.1 15 12.9 15 6.0 25 20.0 61 15.4 24 12.6 6 6.8 12 10.3 18 19.1 12 9.6 36 11.6 19 10.0 8 9.1 14 121 9 9.6 13 10.4 36 9.1 23 12.1 1 11 7 6.0 7 7.4 6 4.8 26 7.9 14 7.4 6 6.8 34 29.4 21 223 39 31.2 145 44.1 96 47.4 Soumx: Auerbach, O., et al. (I). 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,,$) indicated an as- sociation between all kinds of tobacco usage and adenocarcinoma of the kidney as well as adenoma of the kidney. However, on the basis of this study alone, the relationship between "all kinds of tobacco" and cancer of the kidney cannot be considered ,as established in view of the small number of cases involved. In a preliminary report of a study on the epi- demiology of cancer of the kidney, Wynder, et al. (68) have shown a strong association between excessive cigarette smoking and adenocar- cinema of the kidney, and although the disease is not uncommon in non- smokers, they considered excessive cigarette smoking to be a contribu- tory factor. This study found no relationship to pipe smoking, and only a very weak relationship to cigar smoking. A significant association was found between cigarette smoking and epidermoid oancer of the kidney, a relatively uncommon type of cancer. Further research on the strength and mechanisms of the association between smoking and can- cers of the urinary traot is needed. Cancer of the Pancreas The previously suggested association between cigarette smoking and cancer of the pancreas was again noted in a Japanese study by Ishii, et 60 al. (22)) in which the authors reported a higher relative risk for pan- creatic cancer among smokers than among nonsmokers. GENERAL ASPECTS OF CARCINOOENICITP The mlajority of the tumorigenic agents in tobacco smoke are found in the particulate matter "tar. " The well established carcinogenicity of tobacco "tar" in a variety of animal species and tissues (66) was reconfirmed recently (21,35,40,5$`, 56). A small portion of the smoke part.iculates (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 (??8,.%9). 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 (63,86). 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