SMOKING t I and HEALTH a report of the Surgeon General Cl The Health Consequences of Smoking 0 The Behavioral Aspects of Smoking Cl Education and Prevention WW Publcatm No (PHS) 79-50066 u S DEPARTMENT OF HEALTH, EDUCATION. AND WELFARE `Ub'lc Health Service 3tt1ce of the Assistant Secretary tar Health 3"re on Smoking and Health THE SECRETARY'S FOREWORD On January 11, 1964, the first Surgeon General's Report on Smoking and Health was published. It created an instant-and justified--- worldwide reaction. For the report, a document of impeccable scientific authority, established a frightening link between cigarette smoking and several disabling or fatal diseases. 0 The report established that cigarette smoking is causally related to lung cancer in men. 0 It revealed that cigarette smoking is directly related to illness and death from heart disease and other ailments; that cigarette smoking is the leading contributory cause of death from chronic bronchitis and other lung disorders. o The report, in short, pronounced cigarette smoking a health hazard of sufficient importance in the Unitecl States to warrant remedial action. Today, 15 years after the original report, we publish a new Surgeon General's Report on Smoking and Health. This book is more than a compendium of new data confirming the conclusions of the original report. For this document reveals, with dramatic clarity, that cigarette smoking is even more dangerous-indeed, far more dangerous--than was supposed in 1964. The new report, for example, presents sobering information about a subject not extensively treated in the 1964 report: women and smoking. Among other things, the evidence suggests that mothers who smoke during pregnancy face the possibility of creating long-term, irreversible effects on their babies. And as smoking levels among women go up, disease and death rates go up also: lung cancer has increased fivefold among women since 1955. Women who smoke like men die like men who smoke. The report sheds new light on dramatically increased risks to smokers exposed to certain occupational hazards. Workers in the asbestos, rubber, coal, textile, uranium, and chemical industries, among others, face these risks. And the new report, unlike its predecessor, takes up the subject of smoking among children. The percentage of girls aged 12 to 14 who smoke, for example, has increased eightfold since 1968. Among the age group 13 to 19, there are now 6 million regular smokers. One hundred thousand children under 13 are regular smokers. i This document is significant for another reason. It demolishes the claims made by cigarette manufacturers and a few others fifteen years ago and today: that the scientific evidence was sketchy; that no link between smoking and cancer was "proven." Those claims, empty then, are utterly vacuous now. Fifteen years of additional research overwhelmingly ratify the original scientific indictment of smoking as a contributor to disease and premature death. Indeed, even the cigarette industry's own research from January 1964 through Decem- ber 1973, at a cost of approximately $15 million, confirmed the lethal dangers of cigarette smoking. Today there can be no doubt that smoking is truly slow-motion suicide. In truth, the attack upon the scientific and medical evidence about smoking is little more than an attack upon science itself: an attack upon the epidemiological, clinical, and experimental research disci- plines upon which these conclusions are based. Like every attack upon science by vested interests, from Aristotle's day to Galileo's to our own, these attacks collapse of their own weight. But why, the reader may nevertheless ask, should government involve itself in an effort to broadcast these facts and to discourage cigarette smoking? Why, indeed? For one reason, because the consequences of smoking are not simply personal and private. Those consequences, economic and medical, affect not only the smoker, but every taxpayer. When we consider two major national problems of health policy, we find that cigarette smoking intensifies and complicates each one. First among these problems is the spiraling cost of health care. Health care costs nationwide now amount to $205 billion a year-of which the Federal Government pays $59 billion. Smoking accounts for an estimated $5 to $8 billion in health care expenses, not to mention the cost of lost productivity, wages, and absenteeism caused by smoking- related illness; an annual cost estimated at $12 to $18 billion. No person, given these staggering costs, can reasonably conclude that smoking is simply a private concern; it is demonstrably a public health problem also. A second major problem is that our health care system overempha- sizes expensive medical technology and institutional care, while it largely neglects preventive medicine and health promotion. Certainly, if the government is to shift its health strategy toward preventive rather than merely curative medicine, it cannot ignore smoking. For smoking is the largest peventuble cause of death in America. When demographers look at death rates for diseases related to cigarette smoking, they identify 80,000 deaths each year from lung cancer, 22,000 deaths from other cancers, up to 225,000 deaths from cardiovascular disease, and more than 19,000 deaths from chronic pulmonary disease-every single one of them related to smoking. That is why smoking is Public Health Enemy Number One in America. ii Having established the clear danger of smoking and the legitimacy of smoking as a public health issue, however, a final question remains: How much can government usefully do to publicize the hazards of cigarette smoking; to encourage citizens to stop smoking-or not to start? Cigarette smoking, after all, is not like most other environmental hazards. It cannot be curbed simply through massive public and private expenditures, as in the case of water pollution abatement, on which $265 billion will be spent in the next 10 years. Cigarette smoking is not subject to the same kinds of government regulation and control that are now used, for example, to check the emission of toxic substances into the environment. These hazards can be dealt with through straightforward programs of abatement and strict regulation. When it comes to smoking, there is, of course, a role to be played by regulation and by economic and other incentives. But in a free society, research and education must be the major tools of any public-health program to deal with smoking. e So the stepped-up smoking-and-health program launched by the Department of Health, Education, and Welfare a year ago is primarily one of research, education, and persuasion. I described it last year, in testimony before the House Subcommittee on Health and the Environment, in these words: `Make no mistake, our efforts are to reduce smoking. But they are efforts grounded in persuasion and information that appeal to the common sense of our citizens. They are not efforts based on coercion and scare tactics. I have the greatest empathy for the millions of Americans who want to stop smoking, but who find it very, very difficult to do so... `Jf our citizens...are given all the facts from government, or other sources, and still do not wish to give up a personal habit, however hazardous, then, except for protecting the rights of non-smokers, I think government can properly do no more.' How successful can such efforts be? Quite successful, to judge from the record: `Nay, more than 30 million Americans are ex-smokers. This does not include the number of people who, after considering the risks, chose never to take up the habit; they must also number in the millions. The number of cigarettes consumed per person in the United States has declined from 4,345 in 1963 to 3,965 in 1978. In fact, per capita cigarette consumption this past year is at its lowest level in 20 years. These facts, without a doubt, are in large part due to efforts by Public health agencies and voluntary groups to inform the public about the risks of smoking. ,.. 111 These efforts are not mere publicity; the record suggests that every time government and voluntary agencies have intensified their efforts to spotlight the risks of smoking, more smokers have given up the habit and more have decided not to take it up. Moreover, we know from surveys of public opinion and attitudes that the great majority of smokers-99 percent-have either tried to quit smoking or would probably quit, if only they could find an effective way to do so. These people need help. So, too, do millions of children and young people who must have the facts if they are to make a truly informed choice whether to smoke. Indeed, it is children who are the main focus of our efforts to inform and persuade. It is nothing short of a national tragedy that so much death and disease are wrought by a powerful habit often taken up by unsuspecting children, lured by seductive multimillion dollar cigarette- advertising campaigns. This new Report of the Surgeon General typifies the Department's approach to the issue of smoking and health. It is based on scientific research. Its purpose is to provide facts. Its persuasive power is in the weight of the scientific evidence. We set out to publish it for three reasons: First, we wished to bring together new information on smoking and health which has accumulat- ed in the 15 years since Surgeon General Luther Terry released the epochal report of 1964. * `-\. Second, we wished to extend the area of inquiry into smoking and health beyond medicine into the fields of education and behavioral science. For many of the remaining unanswered questions about smoking and health are in these latter fields. We have some evidence, for example, that women smokers have more trouble giving up smoking than men-but why? Some observers believe that women are more concerned than men about gaining weight when they stop smoking. But in fact we do not know; the answers to that and other questions &out smoking must be pursued through future behavioral research. Third and finally, we wished to provide a firm base of knowledge on which health agencies throughout this nation-and the world-can build their efforts to reduce cigarette-related death and disability. For the problem of cigarette smoking is not just domestic; it is worldwide. Smokers in the United States consume 615 billion cigarettes a year: worldwide, the consumption of cigarettes approaches three trillion each year. This, then, is the report: a compendium of 22 scientific papers on smoking and health, commissioned by the Surgeon General of the Public Health Service, compiled by 12 agencies of the Department of Health, Education, and Welfare, and reviewed by scientists who are recognized experts in their fields of inquiry. Thirteen of the papers iv comprise a report on the health consequences of smoking, which the Secretary of Health, Education, and Welfare is required t-*:. law to submit to Congress each year. The remaining chapters deal with behavioral aspects of smoking and with education and prevention. This report is, in my judgment, a major contribution to knowledge about smoking and health-and a major resource for physicians, public health officials, educators, and others who are concerned with advancing the nation's health through a sound strategy of prevention. Joseph A. Califano, Jr. Secretary Department of Health, Education, and Welfare *January 11, 1979 PREFACE On January 11, 1964, the Surgeon General's Advisory Committee on Smoking and Health concluded: "Cigarette smoking is a health hazaed of sufficient importance in the United States to warrant appropriate remedial action." Today, this report reinforces that major conclusionI It is backed up by the weight of thousands of additional studies performed throughout the world. Fifteen years later, the scientific evidence on the health hazards of cigarette smoking is overwhelming. The information in the health consequences and behavioral parts of this report has been brought together by 10 agencies of the- United States Public Health Service. As will be seen, these agencies have different research or regulatory missions but, a common concern with cigarette smoking as a contributor to illness, disability, and death. Since 1964, an estimated 30 million men and women have quit the cigarette smoking habit. The prevalence of regular cigarette smoking in the adult population has declined from approximately 42 percent to 33 percent (Appendix). Yet, in 19'78, an estimated 54 million men and women smoked 615 billion cigarettes. Each year, the health-damage resulting from cigarette smoking costs this nation an estimated 27 billion dollars in medical care, absenteeism, decreased work productivi- ty, and accidents. A great fraction of these costs are borne by the entire public-smokers and nonsmokers-through health insurance, disability payments, and other private and taxpayer-supported pro- grams. In 19'79, cigarette smoking is the single most important preventable environmental factor contributing to illness,, disability, and death in the United States (Chapters 2 and 3). This 1979 report describes our current knowledge of the health consequences of smoking, the behavioral aspects of smoking, and efforts in education and prevention. It presents strong conclusions where they are warranted by the accumulated evidence. It provides alternative working hypotheses when the available facts are not sufficient to warrant conclusions. It suggests future lines of inquiry where there are gaps in existing knowledge. Adhering to this spirit of inquiry and recognizing the magnitude of the public health problem, we must ask: What is our current knowledge about "appropriate remedial action?" What scientific, economic, and behavioral facts are important for the design of public policy toward cigarette smoking? What have we learned so far, and where do we go from here ? To answer these questions, we must confront three central facts: Individuals vary in their health risks associated with cigarette smoking. Individuals vary in their cigarette- smoking behavior. The cigarette product itself is changing. vii High Risk Populations The ad; crse health effects of smoking vary considerably in their nature and severity among individuals. They depend, for example, on the dur:ttion and frequency of smoking, on the presence or absence of concurrent illness or other environmental exposures, and on the individual's age and sex. Some health effects are immediate, while others may be delayed for years. Most importantly, certain individuals may be particularly prone to these adverse health effects. Women, youth, minorities, and workers exposed to occupational hazards in no way constitute an exhaustive list of especially high risk individuals. Every chapter in this report attempts to focus on particular types of individuals of highest susceptibility. Cigarette smoking acts synergistically with hypertension and elevated cholester- ol to enhance the risk of developing coronary heart disease (Chapter 4). Cigarette smoking may be a promoter or co-carcinogen among those individuals usposed to other cancer-causing agents (Chapter 5). It has been suggested that there may be groups of smokers highly susceptible to lung damage from cigarette smoke whose characteristics might be detected by pulmonary function tests and histological studies or by the presence of alpha-1-antitrypsin deficiency (Chapter 6). Those other risk factors which may make maternal smoking more dangerous to the fetus need to be isolated, such as anemia, poor cardiac function, unfavorable age. and other socioeconomic factors (Chapter 8). Individ- uals with rhinitis or asthma may in fact be more sensitive to the nonspecific noxious effects of smoke (Chapter 10). Cigarette smoking increases the risk of peripheral vascular disease in diabetics (Chapter 4). Women and Smoking The findinks in rhc report have grave public health implications for women of all ages. Although the prevalence of cigarette smoking among adult males has declined from approximately 53 percent in 1964 to :38 percent in 1978 (Appendix), the overall percentage of adult female smokers remains virtually unchanged at about 30 percent {.\p]Jendix). Cigarette smoking among younger women has increased, particularly among teenage girls. The mortality rate from lung cancer for women in 19% was almost three times as high as in 1964, and the ratio of male to female mortality from lung cancer has decreased by almost one-half (Chapter 5). Women who have smoking characteristics similar to men experience overall mortality rates similar to men (Chapter 2). Cigarette smoking is a major independent risk factor for fatal and nonfatal heart attacks and sudden death in both men and women (Chapter 4). The risk of heart attack is increased about tenfold in those . . . Vlll women smokers who use estrogen-containing oral contraceptives (Chapters 4 and 12). The weight of evidence demonstrates that smoking during pregnan- cy has a significant adverse effect upon the well-being of the fetus and the health of the fiwborn baby (Chapter 8). There is abundant evidence that maternal smoking directly retards the rate of fetal growth (Chapter 8) and increases the risk of spontaneous ahortion, of fetal death, and of neonatal death in otherwise normal infants. More important. there is growing evidence that children of smoking mothers may have measurable deficiencies in ph}$cal growth, intellectual development, and emotional development that are independent of other known risk factors (Chapter 8). Children of mothers who smoke (luring lbrcgnanq tlo not catch up \vith children of nonsmoking mothers in various stages of development (Chapter 8). Children and Teenagers Smoking among teenage boys has remained virtually constant, and among teenage girls it is actually increasing (Chapters 17. 18, and Appendix). The average age of experimentation with cigarettes and initiation of regular cigarette smoking has been decreasing (Chapter 1'7 and Appendix). Survey data suggest that teenage and early-youth smoking habits are major determinants of lifelong cigarette consump tion. The mortality rates from all caus& are significantly higher among those who initiate smoking earlier in life (Chapter 2). Evidence is accumulating that the health effects of smoking evolve over a lifetime (Chapters 2,3,4,.5 and 6). Even when a morbid or fatal consequence of smoking occurs in later life, its antecedents may be present even in childhood. For example, autopsy studies show that cigarette smoking is associated with more severe and extensive atherosclerosis of the aorta and coronary arteries (Chapter 4). Several scientific questions have been raisd about effects of smoking on the severity of atherosclerosis in childhood and adolescence and the premature development of adult forms of these lesions (Chapter 4). Clinical, experimental, pathological, and epidemiological studies in humans and animals demonstrate that cigarette smoking produces measurable lung damage, even in very young age groups (Chapter 6). Young cigarette smokers, even those without respiratory symptoms, have evidence of small airway dysfunction more frequently than nonsmokers (Chapter 6). A number of recent studies have established a higher prevalence of regular cough. phlegm production, wheezing, and other respiratory SyIIIptcJms in teenage and young adult smokers as compared to nUnsmokcrs (Chapter 6). The connection between pediatric respirator-~ iilness ;Lncl ;~dult chronic rcsl)iratl)ry disease has been supported in prospective stucL . in the past 25 years. In 1954, when reports linking cigarettes to !ung cancer first appeared, less than 1 percent of cigarettes produced were filter-tipped (.Appentlis). The average "tar" deliirery of cigarettes was approximate- ly 36 mp. The average nicotine delivery was over 2 mg (Chapter 14 and Appendis) In the years following this antismoking publicity, the consumption of filter cigarettes rose rapidly, and the average "tar" and nicotine deliveries of cigarettes decreased. By 1964, at the time of the Surgeon General's first report, the market share of filter cigarettes had reached 60 percent (Appendix). The average "tar" delivery of a cigarette was about 2.3 mg. The average nicotine delivery was approximately 1.3 mg c(`haptt& 11 and hppentlis). Since then. the avepnge "tar" ant1 nicotine deliveries have continued to decline. This was encouraged by a series of Government actions beginning in 1966. In that year, the Public Health Service issued its finding that "the preponderance of scientific evidence strongly suggests that the lower the `tar' and nicotine content of a cigarette, the less harmful [will] be the effect." This was followed by the decision of the Federal Trade Commission to begin measuring the "tar" and nicotine yields of cigarettes and to permit manufacturers to begin using this information in their advertising. By 19'ii, the sales-weighted average Yar" per cigarette approached 17 mg: the sales-weighted average nicotilpe per cigarette .approached 1.1 mg (Chapter 14 am1 Appendix). This decline in "tar" and nicotine resulted from important changes in cigarette production technology--- the development of tobacco sheet reconstitution, improvements in cigarette filtration and cigarette paper, the genetic manipulation of tobacco strains, and increased use of plant stems and other tobacco portions formerly regarded as waste. In the past 5 years, the market share of cigarettes with %r" delivery of 15 mg or less has increased dramatically and is now expected to exceed 30 percent. In 19'77, nearl! one-half of the cigarette industry's $0.8 billion advertising and promotional buclger was devoteal to these cigarettes. How should we interpret these changes? What do these "tar" and nicotine measurements represent? In one year, a typical one-pack-per-day smoker +&cakes in 50,000 to 70,000 puffs through the burning column of a unique chemica! factor) which contains over 2,000 known compounds (Chapter 14). Many of these compounds are established carcinogens (Chapter 14) and appear in the particulate phase or "tar" of the smoke. A nonspecific decrease in "tar," however, does not necessarily imply a specific decrease in any single dangerous substance. Moreover. there is as yet no unequivocal evidence for the existence of "safe" levels of these carcinogenic chemicals. Even if we could identify and selectively eliminate certain known carcinogenic chemicals from cigarette smoke, there may be xii numerous, as yet unidentified, dangerous substances remaining (Chapter 14). In addition to "tar" and nicotine, cigarette smoke contains a gaseous phase with numerous components such as hydrogen cyanide. volatile aromatic hydrocarbons, and carbon monoxide. Carbon monoxide, in particular, has been ideritified throughout this report as a possible critical factor in coronary heart disease, atherosclerosis and sudden death, occupationally related illness, chronic respiratory diseiease, fetal growth retardation, and the noxious effecti of passive smoking (Chapters 4, 6, `7, 8, and 11). At present, we do not have standard, reproducible measurements of the dcliveq- of carbon monoxide in all U.S. cigarettes. Yet, some published studies suggest that some allegedly less harmful cigarettes may have higher concentrations of carbon monoxide. In Great Britain, the carbon monoxide delivery of certain filter cigarettes exceeded that of other nonfilter cigarettes (Chapter 14). There is substantial experimental evidence, and some supporting data from retrospective studies, that cigarettes with reduced "tar" and nicotine delivery should in principle have reduced risks of health hazard (Chapters 2, 4 and 5). However, there is only one single controlled prospective study, quoted numeroua times throughout this report, of the effect of "tar" and nicotine content on mortality rates. Such a study has not been repeated. The risks of overall mortality and specific mortality from lung cancer and coronary heart disease were lower in those smoking lower "tar" and nicotine cigarettes than in those smoking higher "tar" and nicotine cigarettes. But the risks for 10~ "tar" and nicotine cigarette smokers were still significantly higher ' than in nonsmokers. This study did not evaluate the risk of mortality from other causes, such as chronic obstructive lung disease. It does not establish that low "tar" and nicotine cigarettes diminish the effect of smoking on the unborn fetus or the developing child. Moreover, the Period of observation in this study was 1960 to 1972 Cigarettes regarded as low in "tar" and nicotine during this time do not represent current products. This study does not establish that currently available low "tar" and nicotine cigarettes are necessarily less hazardous. The "tar" and nicotine content of cigarettes is measured by machines which smoke cigarettes according to a predetermined puff rate, butt length, duration of puff, 2nd volume of puff. An individual smoker does not necessarily consume cigarettes in this standardized manner. It is possible for a low "tar" and nicotine smoker to inhale in one day much more of these constituents than a smoker of cigarettes with higher "tar" and nicotine content. Some studies suggest that individuals who smoke low "tar" and nicotine cigarettes may in hale more deeply or smoke the cigarette further down to the butt to coW%sate for the lower concentration of nicotine (.\ppcndis). In Other experiments, individuals given 1~ " tar" ant1 nicotine cipareltes 1111 increase the number of cigarettes they smoke. In this respect, there is little epidemiological information concerning the trade-off between smoking a few higher "tar" cigarettes and smoking many lower "tar" cigarettes. A few long-term follow-up studies suggest that many smokers who voluntarily switch to low "tar" cigarettes may not increase their frequency of cigarette consumption. The interpretation of these studies is complicated; however, by our lack of understanding of the motives and circumstances of an individual's decision to switch to a lower "tar" cigarette. The effect of a decrease in "tar" and nicotine content applies not only to changes in the habits of current smokers, but also to the cigarette consumption of potential new smokers (Appendix). Although there is no conclusive evidence on this point, we need to know whether the lowering of "tar" and nicotine in cigarettes over the past 20 years has made it easier for our youth to experiment with and later become habituated to cigarettes (Appendix). Finally, the successful marketing of these low "tar" and nicotine cigarettes has required the addition of numerous flavor additives. The nature and composition of these additives is to some extent a proprietary matter. Nevertheless, we do not know whether these undisclosed additives are themselves harmless. Until these scientific and behavioral issues are resolved, there can be no final assessment of the public health benefits of our present search for less hazardous cigarettes. The preponderance of scientific evidence continues, as in 1966, to suggest that cigarettes with lower "tar" and nicotine are less hazardous. It has become clear in the years since, however, that in presenting this information to the public three caveats are in order: Consumers should be advised to consider not only levels of "tar" and nicotine but also (when the information becomes available) levels of other tobacco smoke constituents, including carbon monoxide. They should be warned that, in shifting to a less hazardous cigarette, they may in fact increase their hazard if they begin smoking more cigarettes or inhaling more deeply. And most of all, they should be cautioned that even the lowest yield of cigarettes presents health hazards very much higher than would be encountered if they smoked no cigarettes at all, and that the single most effective way to reduce the hazards associated with smoking is to quit. Public Policy The decision to smoke is a personal decision, but once this is said, it remains unquestionably the responsibility of health officials to insure that smokers and potential smokers are adequately informed of the hazards. This is especially true in a society where hundreds of millions of dollars are spent each year promoting cigarettes and where these xiv and many other influences are encouraging young people to take up smoking. The consideration of what is meant by "adequately informed" is a scientific and public health policy problem. As this report shows, our knowledge of the relevant facts regarding the health-hazards of cigarette smoking has increased manyfold since 1964. And efforts at adequately informing the public have had some success. According to survey data (Chapter 16), a majority of smokers, both adults and teenagers, respond affirmatively to questions about the health hazards of smoking and the desirability of quitting. Yet, perhaps because nicotine is a powerful addictive drug, millions of smokers seem unable to translate this information into personal action. Further, we know so little about how to prevent smoking. among children and teenagers that the numbers of new smokers have remained virtually constant. Earlier in this preface we noted changes that have taken place in the composition of the smoking population, in smoking behavior, in the character of the cigarette itself, and in smoking risks. We must take these changes into account in our efforts to inform. If we can now identify groups of people who are at high risk, what interventions can we design to reach them? Have previous educational efforts been too broadly based? Do the changes in the nature of the cigarette argue for a shift in emphasis, from less hazardous cigarettes to less hazardous smoking? Are there specific instances where the weight of the scientific evidence and the magnitude of the health problem require action by society, other than merely imparting information? In addressing these questions, we must be sure we are active rather than reactive in our approach. The hazards of cigarette smoking have been established and the question has turned to what society's response to these hazards should be. If this report is successful, it will encourage the medical and public health communities to continue their search for what the Advisory Committee 15 years ago defined as "appropriate remedial action." January 11, 1979 Julius B. Richmond, M.D. Assistant Secretary for Health and Surgeon General xv ACKNOWLEDGEMENTS This report was prepared by agencies of the l'.S. Department of Health, Education, and Welfare under thcb general editorship of the Office on Smoking and Health, John 11. Pinney, Director. These agencies have asked that indivi~lrlal authors hc listed, and this is accomplished helow. Chapter l.---Itttr~Ittc.tj(ttt n t,tI Stt ttt LHI ry. r)ffice on Smoking and Health. Leonard M. &human, M.D., I'rofc~~or anll I)irector, Division of EpidemiolokT, Uni\-crsit- of Minnesota. YinnealH)lis, Minnclsota. Chapter S.--Morfa~i~!~. Center for Disease Control. Elvin E. Adams, M.D., M.P.H., Practicing Internal Meclicine, Fort Worth, Texas. Chapter 3.-Morbidity. National Center for Health Statistics. Ronald W. Wilson, M.A., Chief, Health Status and Demographic Analysis Branch, Division of Analysis, National C,enter for Health Statistics, Hyattsville, Maryland. Chapter 4.-Ca rdiurnscula r Disecrst*s. National Heart, Lung, and Blood Institute. G.C. McMillan, M.D., Ph.D., Associate Director for Etiology of Arteriosclerosis and Hypertension, Division of Vascular Diseases, National Heart, Lung, and Blood Institute, Xational Institutes of Health, Bethesda, Maryland. Chapter 5.-Ca rmr. National Cancer Institute. Chapter 6. -Non-Neoplastic Btx~~r*hqltl nwtm qj Diseases. National Heart, Lung, and Blood Institute. Richard A. Bordow, M.D., Xssociate Research Physiologist, Universi- ty of California at San Diego, San Diego, California; Claude J.M. Lenfant, M.D., Director, Division of Lung Disease, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; Sylvia Frank, Ph.D., Consultant to Division of Lung Disease, National Heart, Lung, and Blood Institute, National Institutes of Health, Beth&a, 3larylan~l; Malvina Schweizer, Ph.D., Assistant to the Direclor, Ilit-ision of Lung Disease, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; and Suzanne S. Hurd, Ph.D., Associate Director for Planning and Evaluation, Division of `Lung Disease, Sational Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Chapter 7.-I&radon Between Smoking and Occupational Expo- su res. National Institute for Occupational Safety and Health. Jean G. French, Dr. P.H., Health Scientist, National Institute for Occupational Safety and Health, Rockville, Maryland; Harvey P. Stein, Ph.D., Senior Chemist, National Institute for Occupational Safety and Health, Rockville, Maryland; William J. McKay, M.D., Medical Officer, National Institute for Occupational Safety and Health, Morgantown, West Virginia; Bruce E. Albright, M.D., Medical Officer, National Institute for Occupational Safety and Health, Cincinnati, Ohio; George E. Casey, M.D., Medical Officer, National Institute for Occupational Safety and Health, Rockville, Maryland; and C. Ilana Howarth, M.S., National Institute for Occupational Safety and Health, Rockville, Maryland. Chapter %-Pregnancy ad Infant Health. National Institute of Child Health and Human Development. Eileen G. Hasselmeyer, Ph.D., R.N., Chief, Pregnancy and Infancy Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Mary B. Meyer, M. SC., Associate Professor of Epidemiology, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland; Charlotte Catz, M.D., Pediatric Medical Officer, Pregnancy and Infancy Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; and Lawrence D. Longo, M.D., Professor of Physiology and Obstetrics and Gynecology, Loma Linda University School of Medicine, Loma Linda, California. Chapter 9.-Peptic Ulcer LXseuse. National Institute of Arthritis, Metabolism, and Digestive Diseases. Aaron R. Harrison, M.D., Fellow in Gastroenterology, VA Wads- worth Hospital Center and the U.C.L.A. Center for the Health Sciences, Los Angeles, California; Janet D. Elashoff, Ph.D., Research Statistician, Department of Medicine, U.C.L.A. School of Medicine, Los Angeles, California; and Morton I. Grossman, Ph.D., M.D., Director, Center for Ulcer Research and Education, VA Wadsworth Hospital Center, U.C.L.A. School of Medicine, Los Angeles, California. Chapter lO.-Albrgy and Imwunity. National Institute of Allergy and Infectious Diseases. Dorothy D. Sogn, M.D., Special Assistant to the Director, Immunolo- gy, Allergic and Immunologic Diseases Program, National Institute . . . xv111 of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; Robert A. Goldstein, M.D., Ph.D., Chief, Allergy and Clinical Immunology Branch, Immunology, Allergic and Immunologic Diseases Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and Sheldon G. Cohen, M.D., Director, Immunology, Allergic and Immunologic Diseases Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. Chapter Il.-Inuoluntqy Smoking. Center for Disease Control. David M. Burns, M.D., Pulmonary Division, University of California at San Diego, San Diego, California. Chapter 12.-Interactions of Snwking with Drugs, Food Constitu- ents, and Responses to Diagnostic Tests. Food and Drug Administration. Joseph H. Gainer, D.V.M., Acting Leader, Antibiotics in Animal Feeds Staff, Bureau of Veterinary Medicine, Food and Drug Administration, Rockville, Maryland; Charles M. Ise, Ph.D., Group Leader, Division of Biopharmaceutics, Bureau of Drugs, Food and Drug Administration, Rockville, Maryland; Phil1 H. Price, M.D., Medical Officer, Division of Metabolism and Endocrine Drug Products, Bureau of Drugs, Food and Drug Administration, Rockville, Maryland; Robert Temple, M.D., Director, Division of Cardio-Renal Drug Products, Bureau of Drugs, Food and Drug Administration, Rockville, Maryland; Elizabeth M. Earley, Ph.D., Chief, Section of Cytogenetics, Division of Pathology, Bureau of Biologics, Food and Drug Administration, Bethesda, Maryland; John E. Vanderveen, Ph.D., Acting Director, Division of Nutrition, Bureau of Foods, Food and Drug Administration, Washington, D. C.; Fred R. Shank, Ph.D., Assistant to the Director, Division of Nutrition, Bureau of Foods, Food and Drug Administration, Washington, D. C.; S. I. Shibko, Ph.D., Chief, Contaminants and Natural Toxicants Evaluation Branch, Division of Toxicology, Bureau of Foods, Food and Drug Administration, Washington, D. C.; Wiley W. Tolson, Ph.D., Acting Director, Bioresearch Monitoring Staff, Bureau of Medical Devices, Food and Drug Administration, Silver Spring, Maryland; and Joseph N. Gitlin, D.P.H., Assistant to the Director for Clinical Radiology Systems, Bureau of Radiological Health, Food and Drug Administration, Rockville, Maryland. Chapter 13.-O&r Forms of Tobacco Use. Center for Disease Control. David M. Burns, M.D., Pulmonary Division, University of California at San Diego, San Diego, California. Chapter 14.-Consfif ue,nts of Tobacco Smoke. National Cancer Institute. Xix Gio Tori, Ph.l)., Delrut\. Director, Urision of Cancer Cause and Prevtntion, Xatic)nal (`3nc:c.r 1 nstitutc, Nationa! Institutes of Health, Bethescla, %iar>-lancl; (Cornelius J. Lynch, Ph.D., Program Manager, Smoking and Hrhalth l'r( qram, Enviro Control Incorporat- ed, Rockville, Maryland; Thomas E. Nightingale, Ph.D., Physiologist, Enviro Control Incorporated, Rockville, Maryland; Richard L. Ellis, Ph.D., Senior Cht~mi~t, Enviro (`ontrol Incorporated, Rockville, Maryland; and Dietrich Hoffmann. Ph.D., Chief, Division of Environmental (`arcinogenisis, Xaylor Dana Institute for Disease Prevention, American He;t!th E'ouncl:ition, Valhalla, New York. Chapter 15, -- Riolo,qicc~i irr t7 NNC'.~ (IV !`ic/m V&P Smoking. National Institute on I)rup Al)use. Murray E. Jarvik, M.D., Ph.D.. l'rol'essc~r of Psychiatry and Pharmacolom, Irniversii;; of !:a. !`,Jrnia at Los Angeles, Chief of the Ps~chopharmactJ:c)gs. Lnit. 1`eterans Administration Medical Cen- ter, Brentwood, Los Angelcbs, Clalifornia, with the assistance of Kevin Maxwell. Paula Pearlman, am1 John Fowler. Chapter 16.-&l~ /,io~rcI F;rcY~~rs ;)/ fhr' 4Afnhlishnwttf. Mainf~- r/n rice. n ntl Ccssatiuu r!f Sli?ckin{~. Yational Institute on Drug Abuse. Ovide F. Pomerleau. Ph.D., Associate Professor of Psychiatry, Department of Psych&r:<. I'nivcrsity of Pennsylvania; Director of the Center for Behavioral M(xlicinc at the Hospital of the University of Pennsylvania, Philadelphia, Pennsyl~ ania Chapter l'i.-- Sm~kiuy 11, (71 iltltv )I (1 td _ tc!tAc SCPR~S: Psyc~husw*Grrl Deferntinat2ts atd Yt,c wtitirtt< Sttntcyips. National Institute of Child Health and Human Development. Richard I. Evans, Ph.D., E'rofesbor of Psychology, Department of Psychology, LTniver.+it;, of Houst.on; Allen Henderson, M.A., Peter Hill, M.A., and Bettye Raincs, BA4., Prcdoctoral Research Fello;\s, Department of Psy'hoic,g~-, University of Houston, Houston, Tess Chapter 18. - Psydtc~.scwicrl Zttj7 tw tows ott Ciya r.pttr Srrtoki ng. National Institute on Drug Xbuse. Lynn T. Kozlowski, Ph.D., Assistant Professor of Psychology, Department of Psychology, Wcslcvan University. Middletown, Connecticut. Chapter 19.- ,23i,cf;ji~~rtic~,/ (!fSt//t,iiirt!l Bplltr C*~CW. National Institute on Drug Abuse. Terry F. Pechacck, I'h.IJ., Post-Doctoral Fellow, Laboratory of Physiological Hygiene, School of Public Health, University of Minnesota, Minneapolis, Minnesota. Chapter 20.-- Ihuth Edttcuf iou. National Institute of Elucation. XX Dorothy E. Green, Ph.D., Consulting Research Psychologist, Arling- ton, Virginia. Chapter 21.-Adult Educa,tion. Office of Education. William H. Creswell, Jr., Ed.D., M.S., A.B., Professor and Head, Department of Health and Safety Education, University of Illinois, Urbana-Champaign, Illinois; Donald B. Stone, Ed.D., M.S., B.S., Professor of Health Education, Department of Health and Safety Education, University of Illinois, Urbana-Champaign, Illinois; and Thomas W. O'Rourke, Ph.D., M.S., M.P.H., B.S., Associate Professor of Health Education, University of Illinois, Urbana-Champaign, Illinois. Chapter 22.-The Role of Health Care Prorvklers. Center for Disease Control. Betty S. Segal, Education Specialist, Bureau of Training, Center for Disease Control, Atlanta, Georgia. Chapter 23-T& Role of Educators. Office of Education. William H. Creswell, Jr. Ed. D., M.S., A.B., Professor and Head, Department of Health and Safety Education, University of Illinois, Urbana-Champaign, Illinois; Donald B. Stone, Ed.D., M.S., B.S., Professor of Health Education, Department of Health and Safety Education, University of Illinois, Urbana-Champaign, Illinois; and Thomas W. O'Rourke, Ph.D., M.S., M.P.H., B.S., Associate Professor of Health Education, University of Illinois, Urbana-Champaign, Illinois. Appendix.-Cigarette Smoikng in the United Status, 195@1978. Office on Smoking and Health. Jeffrey E. Harris M.D., Ph.D., Assistant Professor, Department of Economics, Massachusetts Institute of Technology, Cambridge, Massachusetts, Clinical Associate, Medical Services, Massachusetts General Hospital, Boston, Massachusetts. The editors acknowledge with gratitude the many distinguished scientists, physicians, and others who assisted in the preparation of this report bv coordinating manuscript preparation, contributing critical reviews of the manuscripts, or helping in other ways. Josephine D. Arasteh, Ph.D., Health Scientist Administrator, Human I,earning and Behavior Branch, Center for Research on Mothers and Children, National Institute of Child Health and Human Development. Kational lnstitutes of Health, Bethesda, Maryland. Roger W. Barnes, M.S., Staff Assistant to the Associate Commis- sioner for Health Affairs, Food and Llrug Administration, Rockville, Maryland. xxi Ruth Behrens, Director, Center for Health Promotion, American Hospital Association, Chicago, Illinois. Richard A. Bordow, M.D., Associate Research Physiologist, Universi- ty of California San Diego Medical School, San Diego, California. Lester Breslow, M.D., M.P.H., Dean, School of Public Health, University of California at Los Angeles, Los Angeles, California. David M. Burns, M.D., Pulmonary Division, University of California at San Diego, San Diego, California. Dee Burton, Ph.D., Director of Intervention, American Health Foundation, New York, New York. Thomas C. Chalmers, M.D., President and Dean, Mount Sinai Medical Center, New York, New York. Paul Cleary, M.A., Research Associate, Department of Sociology, University of Wisconsin, Madison, Wisconsin. Sheldon G. Cohen, M.D., Director, Immunology, Allergic and Immunologic Diseases Program, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Mary- land. Theodore Cooper, M.D., Dean, Cornell University Medical College, New York, New York. Lester Curtin, Ph.D., Statistician, National Center for Health Statistics, Hyattsville, Maryland. Roy L. Davis, Director, Community Program Development Division, Bureau of Health Education, Center For Disease Control, Atlanta, Georgia. Robert M. Donaldson, Jr., M.D., Professor and Vice-Chairman, Department of Internal Medicine, Yale University, New Haven, Connecticut. Joseph T. Doyle, M.D., Department of Medicine, The Albany Medical College of Union University, Albany, New York. Jean G. French, Dr. P.H., Health Scientist, National Institute for Occupational Safety and Health, Rockville, Maryland. Gerald J. Gleich, M.D., Research Laboratory for Allergic Diseases, Mayo Clinic, Rochester, Minnesota. Robert S. Gordon, Jr., M.D., Special Assistant to the Director, National Institutes of Health, Bethesda, Maryland. Vincent Garnell, Ph.D., Health Education Consultant, Department of Education, State of South Carolina, Columbia, South Carolina. Dorothy E. Green, Ph.D., Consulting Research Psychologist, Arling- ton, Virginia. Morton I. Grossman, M.D. Ph.D., Director, Center for Ulcer Research and Education, Veterans Administration Wadsworth Hospital Center, University of California Los Angeles School of Medicine, Los Angeles, California. xxii Michael R. Guerin, Ph.D., Head of Bio-Organic Analysis Section, Analytical Chemistry Division, Oak Ridge National Laboratory, Oak Ridge, Tennesse. Marian Hamburg, Ph.D., Professor of Health Education, New York University, New York, New York. Jeffrey E. Harris, M.D., Ph.D., Assistant Professor, Department of Economics, Massachusetts Institute of Technology, Cambridge, Massachusetts; Clinical Associate, Medical Services, Massachusetts General Hospital, Boston, Massachusetts. Eileen G. Hasselmeyer, Ph.D., R.N, Chief, Pregnancy and Infancy Branch, National Institute of Child Health and Human Develop- ment, National Institutes of Health, Bethesda, Maryland. Godfrey Hochbaum, Ph.D., Department of Health Education, School of Public Health, University of North Carolina, Chapel Hill, North Carolina. Dietrich Hoffmann, Ph.D., Chief, Division of Environmental Carci- nogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York. John H. Holbrook, M.D., Assistant Professor of Internal Medicine, University of Utah Medical School, Salt Lake City, Utah. Priscilla B. Holman, M.S. Ed., Writer-Editor, Bureau of Health Education, Center for Disease Control, Atlanta, Georgia. Daniel Horn, Ph.D., Frenchtown, New Jersey. Jerome H. Jaffe, M.D., Professor of Psychiatry, Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, New York. Robert B. Jaffe, M.D., Professor and Chairman, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California at San Francisco, San Francisco, California. Herschel Jick, M.D., Boston Collaborative Drug Surveillance Program, Boston University Medical Center, Waltham, Massachu- setts. William J. Jusko, Ph.D., Director, Clinical Pharmacokinetics Labora- tory, Millard Fillmore Hospital, Buffalo, New York. Harriet Page Kennedy, Technical Writer, Office of Cancer Commu- nications, National Cancer Institute, Bethesda, Maryland. Philip Kimbel, M.D., Head, Pulmonary Disease Section, Albert Einstein Medical Center, Philadelphia, Pennsylvania. Norman Allan Krasnegor, Ph.D., Deputy Chief, Clinical Behavior Branch, Division of Research, National Institute on Drug Abuse, Alcohol, Drug Abuse and Mental Health Administration, Rockville, Maryland. Eliaabeth A. Lee, Staff Specialist, American Hospital Association, Chicago, Illinois. Howard Leventhal, Ph.D., Professor of Psychology, Department of `sychology, University of Wisconsin, Madison, Wisconsin. . . . xx111 Edward Lichtenstein, Ph.D, Professor of Psychology, College of Arts and Sciences, University of Oregon, Eugene, Oregon. William M. Marine, M.D., M.P.H., Professor and Chairman, Depart- ment of Preventive Medicine, University of Colorado Medical Center, Denver, Colorado. James T. Massey, Ph.D., Mathematical Statistician, Office of Data Systems, National Center for Health Statistics, Hyattsville, Mary- land. Joseph D. Matarazzo, Ph.D., Chairman, Department of Medical Psychology, Health Sciences Center, University of Oregon, Portland, Oregon. Alfred McAlister, Ph.D., Department of Health Services, School of Public Health, Harvard University, Boston, Massachusetts. William McGuire, Ph.D., Professor, Department of Psychology, Yale University, New Haven, Connecticut. Simon A. McNeely, Senior Program Coordinator, State and Local Education Programs, Bureau of Elementary and Secondary Educa- tion, U.S. Office of Education, Washington, D. C. Harold A. Menkes, M.D., Associate Professor of Medicine, Depart- ment of Medicine, Johns Hopkins University, Baltimore, Maryland. Ann M. Milne, Ph.D., Senior Associate, National Institute of Education, Washington, D. C. Kenneth Moser, M.D., Professor of Medicine and Director, Pulmo- nary Division, University of California at San Diego, San Diego, California. Ian M. Newman, Ph.D., Professor and Chairman, Health Education, School of Health, University of Nebraska, Lincoln, Nebraska. Albert Oberman, M.D., Director, Division of Preventive Medicine, School of Medicine, University of Alabama, Birmingham, Alabama. Ralph S. Paffenbarger, Jr., M.D., Professor of Epidemiology, Department of Health Services, California State Health Depart- ment, Berkeley, California. Richard Peto, M.D., Radcliff Clinic, Oxford University, Oxford, England. Malcolm C. Pike, Ph.D., Department of Community Medicine and Public Health, University of Southern California School of Medicine, Los Angeles, California. Umberto Saffiotti, M.D., Chief, Laboratory of Experimental Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. John Salvaggio, M.D., Henderson Professor of Medicine, Depart- ment of Medicine, Tulane University, New Orleans, Louisiana. Marvin A. Schneiderman, Ph.D., Acting Associate Director for Science Policy, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. xxiv Leonard M. Schuman, M.D., Professor and Director, Division of Epidemiology, University of Minnesota, Minneapolis, Minnesota. Irving J. Selikoff, M.D., Professor, Mount Sinai Medical Center, New York, New York. Michael B. Shimkin, M.D., Professor of Community Medicine and Oncolog- Department of Community Medicine, University of California at San Diego, San Diego, California. Jesse L. Steinfeld, M.D., Dean, 31edical College of Virginia, Richmond, Virginia. William H. Stewart, M.D., Professor, Department Preventive Medicine and Public Health, Louisiana State University, New Orleans, Louisiana. Milton Terris, M.D., Professor and Chairman, Department of Community and Preventive Medicine, New Tot-k 1ledical College, New York, New York. Luther Terry, M.D., President-Director, University Associates, Washington, D.C.. Stephen B. Thacker, M.D., Chief, Consolidated Surveillance and Communication Activity, Bureau of Epidemiolo~, Center for Disease Control, Atlanta, Georgia. T. C. Tso, Ph.D., Chief, Tobacco Laboratory Plant Genetics and Germplasm Institute, United States Department of Agriculture, Science and Education Administration, Beltsville Agricultural Research Center, Beltsville, Maryland. Mary G. Turner, Assistant Superintendent, Division of Adult and Continuing Education, Public Schools of the District of Columbia, Washington, D. C. John J. Witte, M.D., Medical Director, Bureau of Health Education, Center for Disease Control, Atlanta, Georgia. Fritz P. Witti, Editorial Consultant, Alexandria, Virginia. Ernst L. Wynder, M.D., President, American Health Foundation, New York, New York. Samuel S. C. Yen, M.D., Professor and Chairman, Department of Reproductive Medicine, University of California at San Diego, San Diego, California. Louis A. Zurcher, Ph.D., Provost and Dean, Graduate School, Virginia Polytechnic Institute and State University, Blacksburg, Virginia. Finally, the editors acknowledge the help of the following staff who among many others assisted in the preparation of the report. Erica W. Adams, Editor, Informatics Incorporated, Rockville, Maryland. William D. Adams, Management Consultant, Bureau of Lahorato- ries, Center for Disease Control, Atlanta, Georgia. John L. Bagrosky, Program Analysis Officer, Office on Smoking and Health, Rockville, Marylantl. xxv Leonard S. Baker, Expert, Office on Smoking and Health, Rockville, Maryland. Sandra J. Brenman, Secretary, Office on Smoking and Health, Rockville, Maryland. Betty L. Budd, Secretary, Office on Smoking and Health, Rockville, Maryland. Harold E. Dahlgren, Editor, Informatics Incorporated, Rockville, Maryland. Lawrence Deyton, Public Health Analyst, Office of the Assistant Secretary for Health, Rockville, Maryland. Ervin S. Duggan, Special Assistant to the Secretary, Office of the Secretary, U.S. Department of Health, Education, and Welfare, Washington, D.C. Steve Fairbairn, Applications Manager, IPSD, Informatics Incorpo- rated, Riverdale, Maryland. Patricia B. Healy, Clerk, Office on Smoking and Health, Rockville, Maryland. Jerry M. Hershovitz, Public Health Advisor, Environmental Health Services Division, Bureau of State Services, Center for Disease Control, Atlanta, Georgia. Keith L. Hewitt, Editor, Informatics Incorporated, Rockville, Maryland. James W. Hicks, Chief, Technical Assistance Branch, Bureau of Smallpox Eradication, Center for Disease Control, Atlanta, Georgia. Molly Hoary, Data Entry Manager, IPSD, Informatics Incorporated, Riverdale, Maryland. Robert S. Hutchings, Associate Director for Health Information, Office on Smoking and Health, Rockville, Maryland. Bee B. Kafka, Administrative Officer, Office on Smoking and Health, Rockville, Maryland. Robert J. Kingon, Chief, Epidemiology and Program Studies Section, Venereal Disease Control Division, Bureau of State Services, Center for Disease Control, Atlanta, Georgia. Myra E. Kleinman, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland. Elizabeth L. Lillie, Librarian, Informatics Incorporated, Rockville, Maryland. Ingrid B. Meyer, Manager, Biomedical Information, Informatics Incorporated, Rockville, Maryland. Franklin R. Miller, Public Health Advisor, Venereal Disease Control Division, Bureau of State Services, Center for Disease Control, Atlanta, Georgia. Laura A. Miller, Special Assistant to the Secretary, Office of the Secretary, U.S. Department of Health, Education, and Welfare, Washington, D.C. xxvi Paulette E. Murphy, Technical Information Specialist, Bureau of Health Education, Center for Disease Control, Atlanta, Georgia. Raymond K. Poole, Manager, Manuals and Documentation, Infor- matics Incorporated, Rockville, Maryland. Randall S. Pope, Public Health Advisor, Kidney Donor Activity, Chronic Diseases Division, Bureau of Epidemiology, Center for Disease Control, Atlanta, Georgia. Chris Reisinger, Technical Director, IPSD, Informatics Incorporat- ed, Riverdale, Maryland. Donald R. Shopland, Technical Information Officer, Office on Smoking and Health, Rockville, Maryland. Karen M. Smith, Clerk-Stenographer, Office on Smoking and Health, Rockville, Maryland. Larry W. Sparks, Special Assistant to the Associate Director, Center for Disease Control, Washington Office, Washington, D.C. Estella M. Speaks, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland. Carol M. Sussman, Technical Science Editor, Office on Smoking and Health, Rockville, Maryland. Selwyn M. Waingrow, Public Health Analyst, Office on Smoking and Health, Rockville, Maryland. Ann E. Wessel, Health Information Specialist, Office on Smoking and Health, Rockville, Maryland. Paul J. Wiesner, M.D., Director, Venereal Disease Control Division, Bureau of State Services, Center for Disease Control, Atlanta, Georgia. Molly A. Wolfe, Director, Clearinghouse Services Department, Informatics Incorporated, Rockville, Maryland. xxvii TABLE OF CONTENTS The Secretary's Foreword Preface Acknowledgements 1. Introduction and Summary. Office on Smoking and Health PART I THE HEALTH CONSEQUENCES OF SMOKING 2. Mortality. Center for Disease Control 3. Morbidity. National Center for Health Statistics 4. Cardiovascular Diseases. National Heart, Lung, and Blood Institute 5. Cancer. National Cancer Institute 6. Non-Neoplastic Bronchopulmonary Diseases. National Heart, Lung, and Blood Institute 7. Interaction Between Smoking and Occupational Expo- sures. National Institute for Occupational Safety and Health xxix 8. Pregnancy and Infant Health. National Institute of Child Health and Human Devel- opment 9. Peptic Ulcer Disease. National Institute of Arthritis, Metabolism and Digestive Diseases 10. Allergy and Immunity. National Institute of Allergy and Infectious Diseases 11. Involuntary Smoking. Center for Disease Control 12. Interactions of Smoking with Drugs, Food Constituents, and Responses to Diagnostic Tests. Food and Drug Administration 13. Other Forms of Tobacco Use. Center for Disease Control 14. Constituents of Tobacco Smoke. National Cancer Institute PART II BEHAVIORAL ASPECTS OF SMOKING 15. Biological Influences on Cigarette Smoking. National Institute on Drug Abuse 16. Behavioral Factors in the Establishment, Maintenance, and Cessation of Smoking. National Institute on Drug Abuse 17. Smoking in Children and Adolescents: Psychosocial De- terminants and Prevention Strategies. National Institute of Child Health and Human Devel- opment xxx 18. Psychosocial Influences on Cigarette Smoking. National Institute on Drug Abuse 19. Modification of Smoking Behavior. National Institute on Drug Abuse PART Ill EDUCATION AND PREVENTION 20. Youth Education. National Institute of Education 21. Adult Education. Office of Education 22. The Role of Health Care Providers. Center for Disease Control 23. The Role of Educators. Office of Education Appendix: Cigarette Smoking in the United States, 1950- 1978. Office on Smoking and Health Index xxxi 1. INTRODUCTION AND SUMMARY. Office on Smoking and Health CONTENTS Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Summary ................................................................. 10 Health Consequences of Smoking ........................... 10 Mortality ..................................................... 10 Cause-Specific Mortality ............................ .12 Morbidity .................................................... 12 Cardiovascular Diseases ................................. 13 Cancer ........................................................ 15 Lung Cancer ............................................ 16 Cancer of the Larynx.. .............................. 16 Oral Cancer ............................................. 17 Cancer of the Esophagus.. ......................... .17 Cancer of the Urinary Bladder.. .................. 17 Cancer of the Kidney ................................ 17 Cancer of the Pancreas.. ............................ 1'7 Experimental Studies ................................ .17 Non-Neoplastic Bronchopulmonary Diseases ...... .18 Interaction Between Smoking and Occupational Exposures ............................... 19 Pregnancy and Infant Health ........................ .21 Birth Weight and Fetal Growth.. ............... .21 Perinatal Mortality ................................... .22 Lactation and Breast Feeding.. .................. .22 Peptic Ulcer Disease .................................... .23 Allergy and Immunity .................................. .23 Involuntary Smoking .................................... .24 Interactions of Smoking with Drugs, Food Constituents, and Responses to Diagnostic Tests.. ................................. .25 Other Forms of Tobacco Use.. ....................... .27 Overall Mortality ..................................... .27 Cancer ..................................................... 27 Tumorigenic Activity of Pipe and Cigar Smoke Condensates ....................... .23 Cardiovascular Diseases ............................. .23 Non-Neoplastic Bronchopulmonary Disease .... .28 Peptic Ulcer Disease .................................. 223 l-3 Snuff and Chewing Tobacco and Oral Lesions .................................... 29 Constituents of Tobacco Smoke ...................... .29 Smoke Formation ...................................... 29 Toxic and Carcinogenic Agents ................... .30 Physiological Response to Cigarette Smoke ... .30 Reduction in Toxic Activity of Cigarette Smoke ............................... .31 Behavioral Aspects of Smoking ............................. .32 Education and Prevention.. ................................... 33 References ............................................................... 35 l-4 Introduction In the 15 years which have elapsed since the Report of the Advisory Committee on Smoking and Health to the Surgeon General of the U.S. Public Health Service (15), there has been an increasing number of scientific studies on the relationship between tobacco consumption and health. Where the 1964 Committee had access to some 6,000 articles in the world literature on smoking and health, there are now more than 30,000 such articles. In fact, no sound epidemiologic study of chronic disease today would omit from its design a history of tobacco use as a significant factor. It is on this greatly expanded source of data that this current review and reevaluation of the evidence on the hazard of smoking to human health is based. For historical perspective, it should be remembered that concern over the effect of tobacco on health did not begin with the Report to the Surgeon General, although that evaluation was the first American review and judgmental analysis of the tobacco hazard for all aspects of human mortality, morbidity, and specific diseases other than lung cancer. Indeed, almost from the moment of its introduction into Europe in 1558, the Nicotianu tabazum prompted serious concern over the effects which uses of this leaf had on human health. In less than 60 years, tobacco had become a staple agricultural commodity in Virginia and its principal currency. The "tobacco culture" expanded rapidly both societally and agronomically in America; in Europe, in the 17th Century, Simonis Paulli published his treatise "On the Abuse of Tobacco" (6). Although the growth of tobacco use has been extensively document- ed, reliable data on its use within the total U.S. population did not become available until 1330 (8). Since then, per capita tobacco consumption has increased almost three-fold, with dramatic changes in its forms of use. Prior to World War I, tobacco chewing was the principal use in the United States, but the 1920's saw cigarette Consumption, particularly of prefabricated cigarettes, increase astro- nomically as use of chewing and other smoking tobacco declined. A cigarette consumption plateau in the 1930's was followed by a sharp increase during World War II, when widespread adoption of the cigarette habit by women was added to large-scale consumption by American troops. These changes in overall consumption and forms of tobacco use had marked influences on mortality and disease patterns. Concern over the effects of tobacco use on health increased over the Years, but it was not until the 20th century that systematic scientific studies of the problem were launched. Clinical impressions and suspicions had been recorded and some had persisted for decades and centuries before appropriate tools for scientific investigation were developed. For example, the relationship between cancer of the lip and tobacco use was noted by Holland early in the 18th century (.?) and Soemmerring made the same observation in 1795 (13). Xot until I920 however, was the first systematic approach to that association made (1). In 1900, statisticians began to note increases in lung cancer. In 1928, Lombard and Doering presented initial suspicions of a relation- ship between tobacco and disease when they noted that heavy smoking was more common among cancer patients than among control groups (7). In the 1930's, trends in diseases such as lung cancer became evident, promoting the start of intensive inquiries and animal experiments into disease relationships and into the chemical composition and pathogen- etic effects of tobacco and tobacco smoke. In 1938, Pearl found that heavy smokers had a shorter life expectancy than nonsmokers (9), and 1939 saw the beginnings of large-scale epidemiologic studies of the relationship between tobacco use and lung cancer. A large number of clinical and pathological observations on effects of tobacco smoke on man had accumulated by this time. The end of the 1930's marked the beginning of almost 40 years of retrospective (case-control) studies on selected diseases suspected of association with tobacco use (primarily lung cancer, chronic bronchitis, emphysema, and coronary artery disease) and prospective studies of diseases and mortality among cohorts of smokers and nonsmokers. By the early 1950's, there had been reports of many significant epidemio- logic studies, and four of the seven prospective (cohort) mortality studies had been launched. Tobacco was increasingly being identified as a health hazard. In 1954, a group of tobacco manufacturers, growers, and warehousemen established the Tobacco Industry Be- search Committee to launch a research program on tobacco use and health. The accumulation of consistent results from a growing number of studies on lung cancer led the then Surgeon General, Dr. Leroy E. Burney, to instigate the establishment by the National Cancer Institute, the National Heart Institute, the American Cancer Society and the American Heart Association of a scientific study group to assess the problem. The group agreed that a causal relationship between cigarette smoking and lung cancer existed (11); and on July 12, 1957 the Surgeon General placed the Service on record as saying that the weight of evidence indicated a causative relationship between excessive smoking and lung cancer. A brilliant analysis and defense by Cornfield, et al. of the evidence supporting this causal relationship by appeared in 1959 (3). In that year, the U.S. Public Health Service reiterated its position and took one step further when Burney stated that the principal factor in the increased incidence of lung cancer was smoking, particularly smoking of cigarettes (2). In the early 1960's, a trend toward policies of intervention was hastened and encouraged by a number of events. On June 1,1961, the presidents of the American Cancer Society, the American Public Health Association, the American Heart Association, and the National l-6 Tuberculosis Association urged President Kennedy to establish a commission to study the tobacco problem. On January 4, 1962, representatives of these organizations met with Surgeon General Luther L. Terry once more to urge action. A proposal from Terry to the Secretary of Health, Education, and Welfare called for an expert advisory committee to assess existing knowledge and make appropri- ate recommendations. In March, a resolution introduced by Senator Maurine Neuberger (SJR174) called for the establishment of a Presidential commission on tobacco and health, but it was never brought to a vote. On April 16, the Surgeon General presented a detailed proposal for an advisory group to re-evaluate the 1959 position of the Service. He cited new studies on major adverse health effects, evidence that medical opinion was now very strong against smoking, a request from the Federal Trade Commission for guidance on labeling and advertis- ing of tobacco products, and a recent report of the Royal College of Physicians of London which concluded that "cigarette smoking is a cause of lung cancer and bronchitis and probably contributes to the development of coronary heart disease..." (10). Consultations between the White House and Public Health Service officials led to Surgeon General Terry's announcement on June 7,1962, of the planned formation of an expert committee to review all data on smoking and health. Representatives of the American Cancer Society, the American College of Chest Physicians, the American Heart Association, the American Medical Association, the Tobacco Institute, Inc., the Food and Drug Administration, the National Tuberculosis Association, the Federal Trade Commission, and the President's Office of Science and Technology met with the Surgeon General on July 27 to establish the work of the expert committee and to agree on a list of some 150 scientists and physicians qualified to evaluate data on the relationship between tobacco use and health. Terry selected 10 from the list and, thus, the Surgeon General's Advisory Committee on Smoking and Health was launched at its first meeting on November 9, 1962. The members of the Committee were: Stanhope Bayne-Jones, M.D., L.L.D., Former Dean, Yale School of Medicine; Walter J. Burdette, M.D., Ph.D., University of Utah; William G. Cochrane, M.A., Harvard University; Emmanuel Farber, M.D., Ph.D., University of Pittsburgh; buis F. Fieser, Ph.D., Harvard University; Jacob Furth, M.D., Columbia University; John B. Hickam, M.D., University of Indiana; Charles LeMaistre, M.D., University of Texas; Leonard M. Schuman, M.D., University of Minnesota; and Maurice H. Seevers, M.D., Ph.D., University of Michigan. The judgments of the Advisory Committee led to a series of %nificant conclusions, released in 1964 in the now historic Report of l-7 the Advisory Committee to the Surgeon General of the Public Health Service on Smoking andHealth (1li): 1. Cigarette-smoking males were found to have a 70 percent excess risk of mortality over nonsmokers. Female smokers were found to have an elevated risk of mortality, but less than that of males. 2. Cigarette smoking was judged to be causally related to lung cancer in men, the magnitude of the effect of cigarette smoking far outweighing all other factors. A similar trend was noted in females, but studies then available presented insufficient grounds for a firm judgment on causality (4). Included as evidence in the judgment of causality were the several findings of a dose-response relationship: The risk of death from lung cancer increased directly with duration of smoking, number of cigarettes smoked per day, inhalation, and, indirectly, with age when smoking began; discontinuance of smoking lowered the risk. For the combined group of pipe, cigar and pipe, and cigar smokers, the risk of lung cancer was greater than for nonsmokers, but was much less than for cigarette smokers. 3. Cigarette smoking was judged to be the most important of the causes of chronic bronchitis in both men and women in the United States and was found to increase the risk of dying from chronic bronchitis and emphysema. 4. Male cigarette smokers were found to have significantly higher death rates from coronary artery disease than nonsmoking males. The data then available were borderline for a judgment of causality by the rigid criteria employed for all disease entities. 5. A causal relationship was not established at the time for a number of other cardiovascular diseases. 6. Significant associations between several other cancer sites and tobacco use were judged to be causal, including pipe smoking and lip cancer, and cigarette smoking and laryngeal cancer. `7. Although the evidence revealed associations between cancer of the oral cavity and the several forms of tobacco use, between such tobacco use and esophageal cancer, and between cigarette smoking and urinary bladder cancer, the data subjected to the judgment criteria did not at that time support a judgment of causality. A number of other diseases or conditions suggested to be associated with smoking by clinical impressions or by showing excess mortalities in the prospective studies were also scrutinized. They included: peptic ulcer, tobacco amblyopia, cirrhosis of the liver, accidents, influenza and pneumonia, and low infant birth weight. In the instance of peptic ulcer, epidemiologic studies indicated a consistent excess risk of mortality from peptic ulcer, particularly gastric ulcer, among cigarette smokers, but in 1964 a judgment of causality could not be made. Tobacco amblyopia had been clinically associated with pipe and cigar smoking, but the Committee could find no substantiation of this l-8 clinical impression, since there had been no epidemiologic studies of this now rare entity and experimental studies had not been adequately controlled. Cirrhosis of the liver had been found to contribute to excess mortality among cigarette smokers in the seven prospective studies. However, because of the relationship of alcohol consumption (and nutritional deficiencies) to cirrhosis, the correlation of heavy drinking with heavy smoking, and lack of definitive studies on the compartmen- talization of these two factors at the time, there was inadequate support of a causal association. As for accidents, an obvious relationship between smoking and fires in the home was noted in 1964. A moderate excess risk of mortality from influenza and pneumonia was noted in six of the seven prospective studies but this association had not been evaluated by further studies. Other acute respiratory illnesses had been studied in families and in college graduates and no differences had been found between cigarette smokers and nonsmok- ers. There had been some interest in the relationship between maternal smoking during pregnancy and pregnancy outcome. By 1964, five retrospective and two prospective studies revealed an association of cigarette smoking during pregnancy with lower birth weight and premature deliveries. A relationship with fetal and/or neonatal death was deemed equivocal at the time. Finally, although smokers were found to differ from nonsmokers in a number of ways, none of the studies appraised by the Advisory Committee revealed any single variable discriminating significantly between the two groups. The report emphasized that "the overwhelm- ing evidence points to the conclusion that smoking-its beginning, habituation and occasional discontinuance-is to a large extent psychologically and socially determined." The Committee concluded: "Cigarette smoking is a health hazard of sufficient importance in the United States to warrant appropriate remedial action." The release of the Advisory Committee's Report to the Surgeon General stimulated many studies and reports, the data from which augmented the earlier studies, strengthened the conclusions of the Committee, provided information in areas for which data had not existed, and shed light on the pathogenetic mechanisms of the thousands of compounds in tobacco and tobacco smoke. These studies were epidemiologic, clinical, experimental, and, in the area of smoking control, psychologic and sociologic as well. The Federal Cigarette Labeling and Advertising Act of 1965 (P.L. 89-92) required the Secretary of Health, Education, and Welfare to submit regular reports to Congress on the health consequences of smoking, together with legislative recommendations. The purpose was l-9 to monitor the scientific literature on smoking and health. This surveillance of world literature was performed by the National Clearinghouse for Smoking and Health (now succeeded by the Office on Smoking and Health). The updated reports were issued in 1967, 1968, 1969,1971,1972,1973,1974,1975,1976, and 1978. This current 15th anniversary volume on smoking and health is offered as a detailed review and reappraisal of smoking and health relationships. Its contents are the work of numerous scientists both within and outside the Department of Health, Education, and Welfare. All are acknowledged elsewhere. On the following pages, this introductory chapter seeks to summa- rize the principal findings and extensions of knowledge contributed by the scientific community over these 15 years. An attempt has been made to highlight particularly the earlier gaps in knowledge that have been closed or shortened in the intervening period. Summary Health Consequences of Smoking Mortality This 1979 appraisal strengthens earlier conclusions as to the relation- ship between smoking and mortality. Materials reviewed include the seven original prospective studies and new data derived from long- term follow-up of three of these investigations: the British doctors' study (20 years), the Hammond study (12 years) and that initiated by Dorn (16 years). Also reviewed are data from Japanese and Swedish prospective studies. The overall findings yield quantitative results over time which are substantially identical with earlier conclusions. These findings include: 1. The overall mortality ratio for all male current cigarette smokers, irrespective of quantity, is about 1.7 (70 percent excess) compared to nonsmokers. 2. Mortality ratios increase with amount smoked. The two-pack-a- day male smoker has a mortality ratio of 2.0 compared to nonsmokers. 3. Overall mortality ratios are directly proportional to the duration of cigarette smoking. The longer one smokes, the greater the risk of dying. 4. Overall mortality ratios are higher for those who initiated their cigarette smoking at younger ages compared to those who began smoking later. 5. Overall mortality ratios are higher among cigarette smokers who inhale than among those who do not. 6. Although mortality ratios for smokers are highest at the younger ages and decline with increasing age, the actual number of excess deaths attributable to cigarette smoking increases with age. l-10 7. Former cigarette smokers experience declining overall mortality ratios as the years of discontinuance increase. After 15 years of cessation, mortality ratios for former cigarette smokers are similar to those who never smoked. Although mortality ratios for any given age for former smokers are directly proportional to the amount smoked before cessation and inversely related to the age of smoking initiation, cessation of smoking does diminish such individuals' risk regardless of these former factors, provided they are not ill at time of cessation. (Actually, the mortality ratios among those who had discontinued smoking less than 1 year before enrollment in several of the prospective studies were higher than for current cigarette smokers. This was also manifest in the total mortality rates for former cigar and pipe smokers. Further analyses separating those who stopped smoking because of illness from those ex-smokers who stopped for other reasons revealed higher mortality rates among the former.) 8. Cigar smoking is not without risk of increased mortality. The overall mortality ratios for cigar smokers are somewhat higher than for nonsmokers and are directly proportional to the number of cigars smoked per day. 9. Pipe smoking seems to have a slight effect in increasing overall mortality, but individuals who combine their pipe smoking (or cigar smoking) with cigarette smoking experience a level of risk of mortality intermediate between those who smoke only pipes or cigars and those who smoke only cigarettes. A number of new findings in the relationship between smoking and overall mortality were found over the 15-year interval: 1. Calculations from prospective study data have indicated that life expectancy at any given age is significantly shortened by cigarette smoking. For example, a 30- to 35-year-old, two-pack-a-day smoker has a life expectancy 8 to 9 years shorter than a nonsmoker of the same age. 2. Overall mortality ratios increase with the "tar" and nicotine content of the cigarette. For smokers of low "tar" and nicotine cigarettes (less than 1.2 mg nicotine and less than 17.6 mg "tar"), overall mortality ratios are 50 percent greater than for nonsmokers, and 15 to 20 percent less than for all smokers of cigarettes. 3. For the 1964 report, data were inadequate for firm judgments on the mortality status of female cigarette smokers. Adequate follow-up in the prospective studies during these past 15 years has revealed mortality ratios for female cigarette smokers somewhat less than those for male smokers. This difference is deemed to be due to differences in exposure (later age of initiation, fewer cigarettes per day, and use of cigarettes with lower "tar" and nicotine content). Female dose- responses (quantity, age at initiation, duration of smoking, inhalation, "tar" and nicotine content) are the same as for male cigarette smokers. l-11 Subsets of females with smoking characteristics similar to those of men experience mortality rates similar to those of male smokers. 4. From the detailed data of two prospective studies (Hammond and Dorn) the excess in mortality is noted to be greatest for the 45- to 54- year age groups among men and women. Thus, smoking mortality is premature mortality. Cause-Specific Mortality 1. Although mortality ratios are particularly high among cigarette smokers for such diseases as lung cancer, chronic obstructive lung disease, and cancer of the larynx, coronary heart disease is the chief contributor to the excess mortality among cigarette smokers. 2. Lung cancer and chronic obstructive lung disease, in that order, follow after coronary heart disease in accounting for the excess mortality. 3. Pipe and cigar smoking are associated with elevated mortality ratios for cancers of the upper respiratory tract, including cancer of the oral cavity, the larynx, and the esophagus. Following the 1964 Report to the Surgeon General, the National Center for Health Statistics began collecting information on smoking as part of the National Health Interview Survey. On the basis of probability samples of the population, estimates can be made for the general population. These data have proven valuable in assessing the relationships between tobacco use and illnesses, disability, and other health indicators. The findings include: 1. In general, male and female current cigarette smokers tend to report more chronic conditions, such as chronic bronchitis and/or emphysema, chronic sinusitis, peptic ulcer disease, and arteriosclerotic heart disease, than persons who never smoked. 2. A dose-response gradient was noted with the amount of cigarettes smoked per day for most of the chronic conditions. Particularly impressive is the gradient for chronic bronchitis and/or emphysema, with an increase in prevalence among male smokers of two packs or more a day to four times that of those who have never smoked, and among female smokers of two packs or more, to 10 times that of those who never smoked. 3. The age-adjusted incidence of acute conditions (e.g., influenza) for males who had ever smoked was 14 percent higher, and for females 21 percent higher, than for those who had never smoked cigarettes. 4. Indicators of morbidity which are not dependent upon physicians' diagnoses include measures of disability such as work-days lost, days in bed, and days of limitation of activity resulting from chronid. diseases. l-12 (a) Male current smokers of cigarettes reported a 33 percent excess, and female current smokers a 45 percent excess, of work days lost in comparison to persons who never smoked. Male former smokers had an excess of 41 percent, and female former smokers an excess of 43 percent, of work days lost. From the 1974 survey data, this calculates to more than 81 million excess days of work lost for the U.S. population in 1 year. (b) Male current smokers had a 14 percent excess, and female current smokers a 17 percent excess, of days of bed disability over those who never smoked. Smokers in all age and sex groups, except for women over age 65, reported more days in bed due to illnesses than did persons who never smoked. From 1974 data, this calculates to more than 145 million excess days of bed disability for the U.S. population in 1 year. (c) The excesses of disability measures are dose-related. (d) For most age and sex groups, a higher proportion of current and former smokers report longer limitation of activity due to chronic diseases than do persons who never smoked. 5. A tendency was noted for higher proportions of former smokers and those who never smoked, as compared to present smokers, to assess their own health status as excellent. 6. Current smokers and former smokers reported more hospitaliza- tions than nonsmokers in the year prior to interview. Data on the reasons for these hospitalizations have not been analyzed. While most studies show a reduction in the risk of mortality among former smokers, data on disability and illness often show continued high risk among former smokers. This finding should be interpreted more as an indication of the need for both additional data and further analysis of existing data, rather than as an indication of the lack of a beneficial impact on health status from smoking cessation. These findings on morbidity are consistent with the vast amount of evidence on the relationship between cigarette smoking and mortality. Cardiovascular Diseases The tremendous amount of research on the relationship between cardiovascular disease and smoking, undoubtedly stimulated by a lack of adequate information in the areas of the nature of atherosclerosis, the mechanisms of atherogenesis, and the pathogenetic pathways for smoking components, has provided a basis for firmer judgments on the relationship than could be made in 1964. The present report on cardiovascular disease and smoking draws heavily on the 1976 reference report on smoking and health (14) and adds more recent data. Systematic observations on the association between smoking and Cardiovascular diseases have been made on considerably more than a l-13 million individuals in the United States (the majority on men) and have involved many millions of person-years of experience. Sample sizes are now extensive in both retrospective and prospective studies. Variables observed in retrospective studies have been relative- ly limited; in some prospective studies, they have been more numerous and have allowed for complex analyses in which the independence of smoking as a risk factor among other risk factors has been defined. Autopsy and experimental studies in animals have also been extended and serve to clarify earlier issues. The 1979 Report includes the following conclusions: 1. The data collected from Western countries, particularly the United States, but also the United Kingdom, Canada, and others, show that smoking is one of three major independent risk factors for heart attack manifested as fatal and nonfatal myocardial infarction and sudden cardiac death in adult men and women. Moreover, the effect is dose-related, synergistic with other risk factors for heart attack, and of stronger association at younger ages. 2. Smoking cigarettes is a major risk factor for arteriosclerotic peripheral vascular disease and is strongly associated with increased morbidity from arteriosclerotic peripheral vascular disease and with death from arteriosclerotic aneurysm of the aorta. 3. The data establish adequately that cigarette smoking is associated with more severe and extensive atherosclerosis of the aorta and coronary arteries than is found among nonsmokers. The effect is dose- related. 4. Epidemiologic data on the association between cigarette smoking and angina pectoris and cerebrovascular disease manifested as stroke are not conclusive. 5. Smoking increases the possibility of a heart attack recurrence among survivors of a myocardial infarction. 6. In acute experiments on arteriosclerotic patients with angina pectoris or with intermittent claudication of peripheral vascular disease, smoking or exposure to carbon monoxide reduces the patient's established threshold for the precipitation of angina or claudication. Both nicotine and carbon monoxide (CO) aggravate exercise-induced angina. 7. Women who smoke and use oral contraceptives are at a significantly elevated risk for fatal and nonfatal myocardial infarction. A synergistic role of cigarette smoking and oral contraceptive use is suggested for subarachnoid hemorrhage. 8. Smokers of low "tar" and nicotine cigarettes experience less risk for coronary heart disease than smokers of high "tar" and nicotine cigarettes, but their risk is considerably greater than that of nonsmokers. 9. Cigarette smoking does not induce chronic hypertension. However, in the presence of hypertension as a risk factor for coronary heart l-14 disease, smoking acts synergistically to increase the effective risk by joining the risks attributable to hypertension and to smoking alone. 10. Cigarette smoking is a major risk factor for ischemic peripheral vascular disease of arteriosclerotic type; cigarette smoking increases appreciably the risk of peripheral vascular disease in diabetes mellitus. 11. Cessation of cigarette smoking improves the prognosis of arteriosclerotic peripheral vascular disease and is advantageous to its surgical treatment. 12. Cessation of smoking reduces the risk of mortality from coronary heart disease, and after 10 years off cigarettes this risk approaches that of the nonsmoker. 13. The relationship of smoking to the incidence of stroke is not established; however, an association with subarachnoid hemorrhage has been reported in women. In summary, for the purposes of preventive medicine, it can be concluded that smoking is causally related to coronary heart disease for both men and women in the United States. Cancer The strongest evidence of a causal relationship between tobacco use and disease was delineated for lung cancer in the 1950's and 1960's and subjected to the rigid criteria of appraisal in the 1964 Report. In the intervening years, additional epidemiological, clinical, autopsy, and experimental studies have augmented and strengthened the earlier conclusions, particularly with regard to women smokers, for whom only preliminary data were then available. New evidence has also accumulated since 1964 with respect to the relationships between tobacco use and cancer of the larynx, oral cavity, esophagus, urinary bladder, kidney, and pancreas. In the case of laryngeal cancer, the accumulated evidence since 1964 has strengthened, but not materially changed, the conclusions of the 1964 Report. In the case of cancer of the oral cavity, the 1964 Report had to base its conclusions primarily on retrospective studies because of the diversity of sites, their varying incidence of tobacco exposure, and the relatively small numbers derivable in the early years of the prospective studies. These studies, unfortunately, varied in approach and either did not separate the several sites of the oral cavity or found the classes of smoking too numerous for testing their significance. Thus, the only firm judgment which could then be made was that a causal relationship exists between pipe smoking and cancer of the lip. The 1964 Report found that an association existed between tobacco use and esophageal and urinary bladder cancer, but the Committee could not determine from the available data whether there was a Causal relationship. l-15 The 1964 Report did not address kidney or pancreatic cancer. While retrospective studies were not examined, the seven prospective studies indicated that the average mortality ratio for kidney cancer was 1.5. Present knowledge about the relationship between smoking and the various cancers is summarized below, excerpted from the conclusions to be found in Chapter 5. As will be seen, the evidence is now overwhelming. Lung Cancer 1. Cigarette smoking is causally related to lung cancer in both men and women. 2. The risk of developing lung cancer is increased with increasing dosages of smoking as measured by: number of cigarettes smoked per day, duration of smoking, age of initiation of smoking, degree of inhalation, "tar" and nicotine content of cigarettes smoked, and several other measurements. 3. Lung cancer mortality rates in women are increasing more rapidly than in men and, if present trends continue, will be the leading cause of cancer death in women in the next decade. 4. Use of filter cigarettes and smoking of cigarettes with lower amounts of "tar" and nicotine decrease lung cancer mortality rates among smokers; however, these rates are significantly elevated compared to rates for nonsmokers. 5. Ex-smokers experience decreasing lung cancer mortality rates which approach the rates of nonsmokers after 10 to 15 years of cessation. The residual risk of developing lung cancer in ex-smokers is proportional to the overall dosage of lifetime cigarette-smoking exposure, and inversely related to the interval since cessation. 6. Pipe and cigar smokers have lung cancer mortality rates above nonsmokers, but these rates are lower than those for cigarette smokers. 7. Certain occupational exposures can act synergistically with smoking to significantly increase lung cancer mortality rates far above those resulting from either exposure alone. Cancer of the Larynx 8. Cigarette smoking is a significant causative factor in the development of cancer of the larynx in men and women and is directly related to several measures of dosage. 9. Pipe and cigar smokers experience approximately the same risk as cigarette smokers for cancer of the larynx. 10. There appears to be a synergistic effect between smoking and alcohol intake, as well as between asbestos exposure and smoking, for laryngeal cancer. l-16 11. There is a substantial decrease in the risk of developing cancer of the larynx with long-term use of filter cigarettes compared to the use of nonfilter cigarettes; ex-smokers, after 10 years of cessation, have mortality rates which approximate those of nonsmokers. Oral Cancer 12. Epidemiological studies indicate that smoking is a significant causal factor in the development of oral cancer. The risk increases with the number of cigarettes smoked per day. 13. Pipe and cigar smokers experience almost the same high risk for oral cancer as experienced by cigarette smokers. 14. A synergism exists between smoking and alcohol consumption for oral cancer. Cancer of the Esophagus 15. Cigarette smoking is a causal factor in the development of cancer of the esophagus, and the risk increases with the amount smoked. 16. The risk of esophogeal cancer for pipe and cigar smokers is about the same as that for cigarette smokers. 17. A synergism also exists for esophageal cancer and the marked use of alcohol and cigarette smoking. Cancer of the Urinary Bladder 18. Epidemiological studies have demonstrated a significant associa- tion between cigarette smoking and bladder cancer in both men and women. 19. Cigarette smoking acts independently and synergistically with other factors, such as occupational exposures, to increase the risk of developing cancer of the urinary bladder. Cancer of the Kidney 20. Cigarette smoking is associated with cancer of the kidney for men. No data exist to substantiate a relationship for women. Cancer of the Pancreas 21. Cigarette smoking is related to cancer of pancreas, and several epidemiological studies have demonstrated a dose-response relation- ship. Experimental Studies 22. Experimental studies on a variety of animal models have confirmed the carcinogenic effects of tobacco smoke and its constitu- ents on several sites including lung, larynx, esophagus, and oral cavity. l-17 Non-Neoplastic Bronchvpulmonary Diseases Of the non-neoplastic bronchopulmonary diseases, only chronic bron- chitis was judged to be causally related to cigarette smoking in the 1964 Report. In fact, cigarette smoking was then deemed the most important cause of chronic bronchitis in the U.S. and a cause of increased risk of mortality from chronic bronchitis. A relationship to pulmonary emphysema was deemed to exist, but a causal interpreta- tion of this relationship could not then be ascribed. Cigarette smoking was then judged to exceed atmospheric pollution and environmental exposures as a cause of chronic obstructive lung disease (COLD). These diseases rank second only to coronary artery disease as a cause of Social Security-compensated disability. In the 15 intervening years, the updating of several of the larger prospective studies and numerous retrospective and cross-sectional studies have strengthened the conclusions of the 1964 Report. 1. Cigarette smokers have a higher prevalence of chronic bronchitis and emphysema than nonsmokers and have an increased chance of dying from these diseases compared to nonsmokers. These risks are significant for both men and women who smoke, although higher rates generally exist for men than women. 2. Cigarette smokers have an increased frequency of respiratory symptoms, and at least two of them, cough and sputum production, are dose-related. 3. Pulmonary function abnormalities, as measured by various tests, are greater among cigarette smokers than nonsmokers. 4. Impairment of pulmonary function can be detected among smokers even in young age groups, and respiratory symptoms can be demonstrated in teenagers and adolescents who smoke. 5. Cigar and pipe smokers show higher mortality rates for chronic bronchitis and emphysema than nonsmokers, but these rates are not as great as those for cigarette smokers. 6. Cessation of smoking definitely improves pulmonary function and decreases the prevalence of respiratory symptoms. Cessation reduces the chance of premature death from chronic bronchitis and emphyse- ma. 7. Although the- majority of studies demonstrate a higher prevalence of pulmonary function abnormalities in smokers when compared to nonsmokers, conflicting data make it difficult to substantiate racial differences among smokers and nonsmokers. 8. Autopsy data have demonstrated more frequent abnormalities in macroscopic and microscopic lung sections among smokers compared to nonsmokers, and these effects were dose-related. 9. Several mechanisms have been suggested by which smoking might induce lung darn-age, including an imbalance of protease-antiprotease. 10. -A wide variety of alterations in the immune system have been observed due to cigarette smoking. These alterations. include macro- l-18 phages from smokers responding abnormally to migration inhibitory factor (MIF) or antigen challenges, and T lymphocytes in smokers showing a diminished response to phytohemagglutinin (PHA), com- pared to those of nonsmokers. However, the role of these alterations in lung damage is unclear at this time. 11. Individuals with severe alpha-l-antitrypsin deficiency have an excess risk for developing emphysema, and the onset of symptoms is probably abbreviated in these persons by smoking. It is unclear if individuals with mild deficiency represent a group at special risk. 12. Other genetic factors may play a role in determining the risk for COLD, but these are far outweighed by the effect of cigarette smoking. 13. Certain occupations, primarily those exposing workers to dusty occupational environments, are related to COLD, and this relationship is increased further by cigarette smoking. In none of these studies are occupational effects as strong as smoking. 14. Although an increased risk of COLD due to air pollution probably exists, it is small compared to that due to cigarette smoking under conditions of air pollution to which the average person is exposed. 15. Childhood respiratory disease appears to be a risk factor for respiratory symptoms as an adult. However, cigarette smoking appears to be a more important factor in increasing the risk for developing these symptoms. Interaction Between Smoking and Occupational Exposures An extensive review of the literature on lung cancer in chromium and nickel workers and in uranium miners was prepared (12) for the 1964 Advisory Committee. Other studies had examined the relationships among coal gas and asbestos workers as well as in exposures to arsenic, hematite, isopropyl oil, beryllium, and copper. Significant excess lung cancer mortality was noted for chromate, nickel, coal gas and asbestos workers and for uranium miners; exposure to arsenic, hematite, beryllium, and copper remained suspect. At the time of the 1964 report it was noted that "it must he emphasized quite strongly that the population exposed to industrial carcinogens is relatively small" (compared to the size of the smoking population), "and that these agents cannot account for the increasing lung cancer risk in the general population." It was further noted: "Of greater importance is the regrettable fact that in none of these occupational hazard studies were smoking histories obtained. Thus the contribution which smoking, as a contributory or etiologic factor, may have made to the lung cancer picture in these risk situations is unknown"(l5). Despite increasing recognition that smoking and occupational exposures may each contribute to the development of certain disease l-19 states, few investigators have addressed the ways in which these twc factors act together to produce disease. This chapter has identified and illustrated six ways in which smoking may act in combination with physical and chemical agents found in the workplace to produce or increase a broad spectrum of adverse health effects. The six modes of action listed below are not mutually exclusive and several may prevail for any given agent. They may be compounded by occupational exposure to multiple chemical and physical agents. 1. Tobacco products may serve as vectors by becoming contaminated with toxic agents found in the workplace, thus facilitating entry of the agent into the body by inhalation, ingestion, and/or skin absorption. 2. Workplace chemicals may be transformed into more harmful agents by smoking. Illustrative of this effect is the association between polymer fume fever and smokers as a result of cigarette contamination in the workplace. 3. Certain toxic agents in tobacco products and/or smoke may also occur in the workplace, thus increasing exposure to the agent. Carbon monoxide levels in the occupational environment, for example, add to already high blood carbon monoxide levels found in smokers. 4. Smoking may contribute to an effect comparable to that which can result from exposure to toxic agents found in the workplace, thus causing an additive biological effect. For example, exposure to coal dust may increase a smoker's risk of developing disease. 5. Smoking may act synergistically with toxic agents found in the workplace to cause a much more profound effect than that anticipated simply from the separate influence of the agent and smoking added together. For example, cigarette smoking and exposure to asbestos may interact synergistically to greatly increase the risk of lung cancer. 6. Smoking may contribute to accidents in the workplace. Those who have the highest risk for occupational exposures to toxic agents in general also have the highest smoking rates. Surveys have shown male blue-collar workers are much more likely to smoke than male white-collar workers. From 1920 to 1966, tobacco consumption increased as did the introduction into the workplace of chemicals with unstudied biological effects. During this same time period, the mortality rates for certain disease states associated with smoking and occupational exposures continued to increase. Some of the effects historically attributed to smoking may actually reflect interactions between smoking and occupational exposures. Curtailment of smoking in the workplace should be accompanied by simultaneous control of occupational exposures to toxic physical and chemical agents. 1-m Pregnancy and Infant HeaZth The 1964 report devoted approximately one printed page, including bibliography, to a discussion of the findings of five retrospective and two prospective studies on birth weight of infants born to mothers who smoked during pregnancy. Such infants tended to have a lower birth weight. The mechanism and its biologic significance were then not known and the findings were in some instances controversial. Since then, this area of scientific investigation has resulted in the amassing of significant data which provide many insights into the mechanisms of pathogenesis. The following conclusions are based on the work during this period: Birth Weight and Fetal Growth 1. Babies born to women who smoke during pregnancy are, on the average, 200 grams lighter than babies born to comparable women who do not smoke. Distribution of birth weights of smokers' babies is shifted downward, and twice as many of these babies weigh less than 2,500 grams, compared with babies of nonsmokers. There is abundant evidence that maternal smoking is a direct cause of the reduction in birth weight. 2. Birth weight is affected by maternal smoking independently of other determinants of birth weight. The more the mother smokes, the greater the baby's birth-weight reduction. 3. The ratio of placental weight to birth weight increases with increasing levels of maternal smoking. This increase may signify a response to reduced oxygen availability due to carbon monoxide and may have some survival value for the fetus. 4. There is no overall reduction in the duration of gestation with maternal smoking, indicating that the lower birth weight of smokers' infants is due to retardation of fetal growth. 5. The pattern of fetal growth retardation that occurs with maternal smoking is a decrease in all dimensions; body length, chest circumfer- ence, and head circumference are smaller if the mother smokes. 6. According to studies of long-term growth and development, smoking during pregnancy may affect physical growth, mental development, and behavioral characteristics of children at least up to the age of 11. 7. Overwhelming evidence indicates that maternal smoking during pregnancy affects fetal growth rate directly and that fetal growth rate is not due to characteristics of the smoker rather than to the smoking, nor is it mediated by reduced maternal appetite, eating, and weight gain. 1-21 Perinatal Mortality 1. When adjustments are made for age-parity differences in mothers, their socio-economic status, and previous pregnancy histories, the risk of perinatal mortality attributable to smoking is highly significant, independent of these factors, and is dose-related. 2. Maternal smoking increases the risk of fetal death through maternal complications such as abruptio placenta, placenta previa, antepartum hemorrhage, and prolonged rupture of membranes. 3. Although maternal smoking does not produce a lowering of mean gestational age, preterm births are increased in frequency among smokers, and a large proportion of the neonatal deaths occur among these preterm births. 4. Smoking by pregnant women contributes to the risk of their infants being victims of the "sudden infant death syndrome." 5. Maternal smoking can be a direct cause of fetal or neonatal death in an otherwise normal infant. The immediate cause of most smoking- related fetal deaths is probably anoxia, which can be attributed to placental complications with antepartum bleeding in 30 percent or more of the cases. In other cases, the oxygen supply may simply fail from reduced carrying capacity and reduced unloading pressures for oxygen caused by the presence of carbon monoxide in maternal and fetal blood. Neonatal deaths occur as a result of the increased risk of early delivery among smokers, which may be secondarily related to bleeding early in pregnancy and premature rupture of membranes. Considerable literature has appeared in the area of clinical and animal experimental studies on the role of tobacco smoke, nicotine, and carbon monoxide, providing evidence for pathogenetic pathways accounting for both lower birth weight and fetal death. 6. The accumulated evidence does not support a conclusion that maternal smoking increases the incidence of congenital malformations. Lactation and Breast Feeding 1. The epidemiologic studies on adequacy of lactation do not provide data for a conclusion on the effect of maternal smoking. 2. Although some animal studies reveal diminished milk production (but no reduction in release) following nicotine administration, human experimental studies have not thus far produced evidence for a reduction in lactation with forced smoking of large numbers of cigarettes over short periods of time. 3. There does exist a direct dose-response relationship between the number of cigarettes smoked and nicotine in breast milk. 4. Further detailed research in this area is imperative. l-22 ueptu: ulcer lhsease The 1964 Report appraised the evidence for a relationship between tobacco use and peptic ulcer disease in five retrospective and the seven prospective studies (mortality) and concluded that only an association existed, particularly for gastric ulcers. The biological meaning of this association was not clear, particularly since studies of the effects of cigarette smoking on secretory activity and gastric motility were not consistent. For the current report, two of the prospective mortality studies have been updated. Peptic ulcer disease mortality has continued to show excesses among smokers of cigarettes. A number of additional studies of peptic ulcer disease and smoking were also addressed. Five of these studies showed a higher proportion of smokers among ulcer patients than among controls. Six studies showed a greater prevalence among male cigarette smokers than nonsmokers, the median ratio being 1.7. The findings in women are comparable. The majority of studies provided evidence of increased frequency of peptic ulcer disease with increases in the amount smoked. Experimental and clinical studies of gastric and pancreatic secretion and pyloric reflux were extended in this period to resolve the mechanism of action of smoking on occurrence of peptic ulcer disease. On the basis of the research data surveyed, it is concluded: 1. Epidemiological studies have found that cigarette smoking is significantly associated with the incidence of peptic ulcer disease and increases the risk of dying from peptic ulcer disease. This risk is, on the average, twice as high for smokers compared to nonsmokers, and appears to be greater for gastric than for duodenal ulcer disease. 2. The risk of peptic ulcer disease is dose-responsive and exists for both men and women. 3. While the pathogenetic mechanisms have not been clearly elucidated, the association between smoking and peptic ulcer disease is significant enough to suggest a causal relationship. 4. Evidence that smoking retards healing of peptic ulcers is highly suggestive. 5. Pipe smoking appears unrelated to peptic ulcer disease. 6. Experimental and clinical studies on the effect of smoking on Pancreatic secretion and pyloric reflux suggest mechanisms by which Peptic ulcer disease may develop. Allergy and Immunity Allergic manifestations to tobacco, its smoke, or its extracts were not reviewed in the 1964 report. Various studies in the late 1960's and 1970's probed the relationship of smoking to immunologic mechanisms and immune responses, not only in the acute infectious diseases, but also in several of the chronic diseases such as pulmonary disease. 1-B The following is a summary of this research and our current understanding of this facet of human illness in relation to tobacco use. 1. Tobacco and tobacco smoke extracts have been found to act as antigens, including both precipitating and reaginic antibodies, in animals and man. These tobacco products can also sensitize lympho- cytes participating in cell-mediated immune functions. 2. Tobacco and its combustion products present such an array of natural and derived components, additives, and contaminants that the precisely defined role for tobacco in immune and allergic processes cannot be delineated. 3. Several tobacco antigens have been isolated. However, epidemio- logic studies on the frequency of true allergy to tobacco are inconclusive. 4. Tobacco smoke exerts a variety of effects on respiratory tract structures, and chronic smoking leads to consistent histologic changes in the respiratory tract. (a) Evidence indicates an adverse long-term effect on the mucocili- ary transport mechanisms and mucus composition. (b) The number of macrophages isolated from smokers' lung fluid is increased compared to nonsmokers. (c)Changes in the ultrastructure of macrophages are observed in smokers. (d) Alveolar macrophages from smokers have altered metabolism and measurable degrees of physiologic impairment. 5. Alterations in assays of cell-mediated immunity are noted locally and systemically in smokers. 6. Leukocytosis and reversible hypereosinophilia have been seen in smokers. 7. Allergic individuals, particularly those with rhinitis or asthma, may be more sensitive to the nonspecific effects of cigarette smoke than healthy individuals. 8. Because the ability to make a definitive diagnosis of tobacco allergy is complicated by the difficulty in demonstrating a cause and effect relationship between immunologic events and disease manifes- tations, additional evidence is required to establish a definitive role for tobacco sensitization in causing allergic disease. Invol u n tu ry Snwking The effects of involuntary smoking (passive or second-hand smoking) on the nonsmoker were not examined or appraised in the 1964 report but were initially discussed in the 1972 report, The Health Case- quences of Smoking, and updated in the 1975 edition. The current report's findings in this area are summarized below. It should be understood that the literature is of recent vintage and only a limited amount of systematic information regarding the health effects of involuntary smoking on the nonsmoker is available. l-24 1. Sidestream smoke, which comes from the lighted tip of the cigarette between puffs, has higher concentrations of some of the irritating and hazardous substances than does mainstream smoke (that smoke inhaled by the smoker). 2. Children of parents who smoke are more likely to have bronchitis and pneumonia during the first year of life; this effect is independent of social class, birth-weight, and parental cough and phlegm produc- tion. 3. Simple extrapolation of dose-response relationships, which are traditionally used in assessing the hazards of smoking to the smoker, cannot be employed in assessing hazards in nonsmokers. 4. Cigarette smoking in enclosed spaces can produce carbon monoxide (CO) levels well above the Ambient Air Quality Standard (9 ppm) even where ventilation is adequate. 5. Substantial proportions of the population experience irritation and annoyance when exposed to cigarette smoke. The eyes and nose are most sensitive to irritation, and such irritation increases with increasing levels of smoke contamination. Unrestricted smoking on buses and planes annoys the majority of nonsmoking passengers even under conditions of adequate ventilation. 6. Little or no physiological response to smoke was detected in healthy nonsmokers.exposed to cigarette smoke. Higher heart rates detected may be due to psychological factors. 7. A slight reduction in maximum exercise capacity was noted in older nonsmokers exposed to levels of CO occasionally found in involuntary smoking situations. 8. Changes in psychomotor function, especially attentiveness and cognitive function, at levels of CO found in involuntary smoking conditions have been noted, but these effects are measurable only at the threshold of stimuli perception. 9. Levels of COHb produced by involuntary smoking situations are functionally insignificant in healthy individuals. 10. Levels of carbon monoxide which can be reached in cigarette smoke-filled environments have been shown to decrease the exercise duration required to induce angina pectoris in patients with coronary artery disease. These levels of CO also have been shown to reduce the exercise time until onset of dyspnea in patients with hypoxic chronic lung disease. Interactions of Smoking with Drugs, Food Constituents, and Responses to Diqmstic Tests The pervasiveness of tobacco use in our society and the frequency of altered disposition and pharmacological effects of many common drugs on smokers make it apparent that cigarette smoking is one of the primary causes of drug interactions in humans. An assessment of the literature in this area provides the following conclusions: 1-z 1. Most of the experimental work in humans, animals, and tissues involving enzyme systems indicates that the dominant effect of smoking is enhanced drug disposition caused by induction of hepatic microsomal enzymes. 2. Tobacco smoke, a complex mixture of noxious materials, contains, among other compounds, enzyme inducers such as polycyclic aromatic hydrocarbons, nicotine, cadmium and some pesticides, acrolein and hydrogen cyanide. 3. The primary inducers are probably polynuclear aromatic hydrocar- bons which are potent and persistent in tissues. While several of the hepatic microsomal drug-metabolizing enzymes are stimulated in smokers, this enhancement is unpredictable, and the effects of cigarette smoke on other potential rate-limiting disposition processes for drugs are largely unexplored. 4. Cigarette smoking alters the pharmacologic effects of drugs or their pharmacokinetics. 5. Tobacco smoke can induce the metabolism in humans of therapeutic agents, such as phenacetin, antipyrine, theophylline, caffeine, imipramine, pentazocine, and vitamin C; examples of drugs not affected by smoking include: diazepam meperidine, phenytoin, nortriptyline, warfarin, and ethanol. 6. Tobacco smoke can modify the clinical effects of drugs. 7. Marijuana smoking may produce reactions similar to tobacco smoking since enzyme induction is also stimulated b;: the polycyclic aromatic hydrocarbons in marijuana smoke. 8, A woman who both smokes and uses oral contraceptives has a greater risk for myocardial infarction. 9. There is a suggestion that smoking produces a more rapid decline in influenza antibody titers after natural infection or vaccination with influenza virus. 10. Cigarette smoking appears to increase the serum carcinoem- bryonic antigen level in otherwise healthy individuals. 11. No information is available to indicate that the increase in body burden of trace elements by smoking has toxic effects. 12. Since tobacco smoking does affect the values of a number of clinical laboratory tests in humans, the knowledge of an individual's smoking status is important for the interpretation of such tests. Cigarette smoking increases the number of leukocytes, the red cell mass, the levels of hemoglobin and carboxyhemoglobin, the hemato- crit, the mean corpuscular volume, platelet aggregation, plasma viscosity, and tensile strength of the clot; cigarette smoking decreases the serum levels of creatinine, albumin, globulin (female smokers) and uric acid (male smokers). These revert to normal levels after cessation of smoking. l-26 Other Forms of Tobacco Use References have already been made to the relationships between other forms of tobacco use and a number of specific diseases and cancer sites. dSpecial attention was given in the 1973 issue of The Health Consequences of Smoking to the role of pipes and cigars. This attention was particularly relevant inasmuch as the 1964 Report appeared to have influenced a transient increase in consumption of cigars and pipe tobacco due to the prevailing belief that pipes and cigars were "safe." For the present report, the summary conclusions presented here refer to men only, since the use of pipes and cigars in the United States is limited almost exclusively to them. It can be concluded that some risk exists from smoking cigars and pipes as they are currently used in the United States, but for most diseases this is small compared to the risk of smoking cigarettes as they are commonly used. Overall Mortality 1. Overall mortality rates among pipe or cigar smokers are slightly higher than for nonsmokers. 2. Mortality rates among smokers of pipes, cigars, or both in combination with cigarettes are intermediate between the high rates of cigarette smokers and the lower rates of those who smoke only pipes or cigars. 3. Mortality associated with combinations of pipe and/or cigar and cigarette smoking is dependent upon the level of consumption and inhalation of each. 4. A dose-response relationship exists for the several forms of tobacco use and overall mortality in terms of amount smoked, degree of inhalation, duration of smoking, and age at initiation of smoking. Cancer 1. Prospective studies have shown that mortality rates from cancer of the oral cavity, larynx, pharynx, and esophagus are approximately equal in users of cigars, pipes, and cigarettes. 2. Although several factors appear to be involved in cancer of the lip, pipe smoking alone or in combination with other forms of smoking is causally related to lip cancer. . 3. Heavy alcohol consumption in combination with heavy smoking of pipes and cigars is associated with higher rates of oral cancer than for either alcohol consumption or heavy smoking of pipes or cigars alone. There is evidence that excessive alcohol consumption may increase the pipe and cigar smoker's risk for extrinsic laryngeal cancer. A distinct synergism with heavy alcohol intake exists in esophageal cancer. 4. Cigar and pipe smokers showed the same histological changes in the larynx and esophagus at autopsy as did cigarette smokers. l-27 5. Pipe and cigar smokers have histological abnormalities of the lung at autopsy that are intermediate in degree between nonsmokers and cigarette smokers. Some categories of pathologic changes in cigar smokers are similar to those seen in cigarette smokers. 6. The risk of pipe and cigar smokers developing lung cancer is higher than for nonsmokers, but is lower than for cigarette smokers. In the updated prospective studies, the relative risks of lung cancer for cigar and pipe smoking ranged from 1.6 to 3.4 for cigars only and from 1.8 to 8.5 for pipe only. `7. A dose-response gradient has been shown to be present in some studies. Tumorigenic Activity of Pipe and Cigar Smoke Condensates 1. Pipe and cigar tobacco condensates have a carcinogenic potential comparable to that of cigarette condensates. 2. The alkaline smoke from pipe and cigar tobacco is usually not inhaled, and there appears to be a lower level of exposure of the harmful components of smoke than is noted with the inhalation of cigarette smoke. Cardiovascular Diseases 1. Pipe and cigar smokers experience a small increase in coronary heart disease mortality compared to nonsmokers. 2. Similarly, pipe and cigar smokers show slight excesses of cerebrovascular death rates over'nonsmokers. Non-Neoplastic Bronchopulmonary Disease 1. Pipe and cigar smokers experience mortality rates from chronic bronchitis and emphysema that are intermediate between cigarette smokers and nonsmokers. 2. Pipe and cigar smokers have significantly more respiratory symptoms such as cough, sputum production, breathlessness, and wheezing than nonsmokers. A dose-response gradient is noted. 3. Little difference in pulmonary function was noted for pipe and cigar smokers as compared to nonsmokers. 4. Pipe and cigar smokers had far less pulmonary pathology at autopsy than did cigarette smokers. Peptic Ulcer Disease 1. Cigar and pipe smokers experience higher death rates from peptic ulcer than nonsmokers: these rates, based on prospective mortality studies, indicated higher rates for gastric ulcer than for duodenal ulcer. 2. Retrospective and cross-sectional studies failed to find an association between pipe smoking and peptic ulcer. 1-B Snuff and Chewing Tobacco and Oral Lesions Snuff and chewing tobacco have not been found to increase mortality (either overall or cause-specific) in the United States. Asian studies have found an association between tobacco chewing and leukoplakia as well as oral cancer. These differences between the American and Asian studies can partially be explained by nutritional factors but are confounded by other factors such as the use of other tobacco products along with the use of snuff and chewing tobacco in the United States. Constituents of Tobacco Smoke Extensive research has advanced the cultivation of tobacco varieties with commercially desirable characteristics. This research has also been directed toward precursor-product relationships among specific leaf tobacco components, agronomic characteristics, cigarette and smoke constituents, and biological responses involving 151 variables. Multivariate analysis has revealed that leaf characteristics serve as markers to predict individual smoke components. Thus, there is promise of modification for more desirable qualities and use of tobacco. Smoke Formation 1. The lighted cigarette generates about 2,000 compounds by a variety of processes including hydrogenation pyrolysis, oxidation, decarboxylation, dehydration, chemical condensation, distillation, and sublimation, 2. Tobacco smoke has been separated into gas and particulate phases. 3. The gas phase components shown to produce undesirable effects include carbon monoxide, carbon dioxide, nitrogen oxides, ammonia, volatile N-nitrosamines, hydrogen cyanide, volatile sulfur compounds, nitriles and other nitrogen-containing compounds, volatile hydrocar- bons, alcohols, aldehydes, and ketones. 4. The particulate phase consists generally of nicotine, water, and "tar". "Tar," which is the total particulate matter after subtracting moisture and nicotine, consists primarily of a wide variety of species of polycyclic aromatic hydrocarbons (PAH) to which carcinogenicity is attributed. (a) These PAH include non-volatile N-nitrosamines, aromatic amines (regarded as being the etiologic agents in bladder cancer), isoprenoids, pyrenes, benzopyrenes, chrysenes, anthracenes, fluo- ranthenes, carcinogenic aza-arenes such as the acridines and carbazoles, and the mutagenic aza-arenes such as the quinolines and phenanthridines. (b) In addition, the "tar" contains simple and complex phenols, cresols and naphthols, alkanes and alkenes, benzenes and naphthalenes, carboxylic acids, and metallic ions, as well as l-29 radioactive compounds such as potassium-40, lead-210, polonium- 210 and radium-226. (c)The particulate phase also contains agricultural chemicals and additives as flavoring agents and humectants. Toxic and Carcinogenic Agents Compounds in cigarette smoke have been classified by an expert panel into: 1. Those judged most likely to contribute to the health hazards of smoking. (a) Carbon monoxide (gas phase). (b) Nicotine and "tar" (particulate phase). 2. Those judged as probable contributors to the health hazards of smoking. (a) Gas phase: acrolein, hydrocyanic acid, nitric oxide and nitrogen dioxide. (b) Particulate phase: cresols and phenol. 3. Those judged as suspected contributors to the health hazards of smoking. (a) Gas phase: acetaldehyde, acetone, acetonitrile, acrylonitrile, ammonia, benzene, 2-3 butadione, carbon dioxide, crotononitrile, ethylamine, formaldehyde, hydrogen sulfide, methacrolein, meth- yl alcohol, and methylamine. (b) Particulate phase: butylamine, dimethylamine, DDT, endrin, furfural, hydroquinone, nickel compounds, pyridine. These compounds have been so designated not only because of their harmful actions but also because of their concentrations in tobacco smoke. Although other constituents are considered toxic, they are not present in concentrations deemed a health hazard. A number of tumor initiators, co-carcinogens, and organ-specific carcinogens have been isolated and identified. The majority of co- carcinogens remain to be identified. The increased risk cigarette smokers have for cancer of the esophagus, kidney, and urinary bladder suggests the possibility that cigarette smoke contains unidentified organ-specific carcinogens besides the known trace amounts of carcinogenic aromatic and N-nitrosamines. Physiological Response to Cigarette Smoke 1. The smoking of a cigarette seems to satisfy a smoker's physiological and psychological needs, and it is generally accepted that nicotine is the principal constituent responsible for cigarette smokers' pharmacologic responses. 2. Nicotine causes the release of catecholamines, epinephrine and norepinephrine. Several physiologic responses are attributed to nicotine and/or catecholamines such as increased heart rate and blood l-30 pressure, cardiac output, stroke volume, velocity of contraction, myocardial contractile force, oxygen consumption, coronary blood flow and arrythmias, increased mobilization and utilization of free fatty acids, hyperglycemic effects, and a decreased patellar reflex response. 3. Considerable evidence exists, although it is not uniformly accepted, that smoking patterns of chronic smokers are to a large degree dependent on the nicotine content of the cigarette and dependent on what the nicotine delivery would b when measured by the standard methodology. Smoking patterns are dependent, to varying degrees, on the type of cigarette smoked, the number of cigarettes smoked, the length of the cigarette burned, the number of puffs, and the depth and length of inhalation. Reduction in Toxic Activity of Cigarette Smoke 1. At the present time, selective filtration of carbon monoxide has not proven feasible. 2. Charcoal filtration has proven successful in the removal of certain eiliatoxic substances from the gas phase of cigarette smoke. 3. Selected types of cellulose acetate filter tips selectively remove volatile phenols. 4. Cigarette fillers low in wax-layer components deliver smoke reduced in catechols, but there is a question as to whether selective reduction in cathechols leads to a significant reduction of the tumorigenic potential of cigarette smoke. 5. Lowering nitrate content of tobacco reduces volatile N-nitrosa- mines in tobacco smoke, but it has not been shown that a reduction of this compound will lead to a significant reduction in the tumorigenic potential of the smoke. 6. Experimentally, a dose-response gradient is demonstrable for "tar" application or smoke inhalation and tumor yield. A number of technical approaches, including modification of the filler, has reduced the "tar" content of smoke. 7. Similar technical approaches have reduced the nicotine content of tobacco smoke. 8. There is a possibility that nonvolatile N-nitrosamines can be reduced by addition of specific bacteria during the processing of tobacco. Selective filtration is not feasible for their removal. 9. A number of methods have led to reduction of "tar" and of toxic and tumorigenic agents in the smoke of cigarettes. Several approaches have led to the reduction of the ciliotoxicity and to selective reduction of the carcinogenicity and tumor-promoting activity of the smoke of exPerimental cigarettes. Many of these methods have already been iucorporated in today's modified, blended U.S. cigarette. 1-31 Behavioral Aspects of Smoking Because of the research over the past 15 years, much is now known about the health dangers of smoking. But research into reasons why the habit is so widespread and difficult to break is still in its infancy; little is known for certain, and questions far outnumber answers. This part of the report summarizes current understanding of the biological, behavioral, and psychosocial aspects of the cigarette smoking habit and the dependence process associated with smoking. It is no exaggeration to say that smoking is the prototypical substance- abuse dependency and that improved knowledge of this process holds great promise for prevention of risk. Establishment and maintenance of the smoking habit are, obviously, prerequisite to the risk, and cessation of smoking can eliminate or greatly reduce the health threat. Among the findings, tentative conclusions, and'areas for research presented in this section are the following: 1. Nicotine, the most powerful pharmacological agent in cigarette smoke, has been proposed as the primary incentive in smoking and may be instrumental in the establishment of the smoking habit. The proposition that heavy smokers adjust their plasma nicotine levels is compatible with the observation that regular smokers commonly consume about 20 to 30 cigarettes during the smoking day (approxi- mately one every 30 to 40 minutes) and that the biological half-life of nicotine in humans is approximately 20 to 30 minutes. 2. Recent research suggests that specific central nervous system receptor sites for nicotine can be blocked in a fashion analagous to the opiate antagonists. This phenomenon has implications for understand- ing the effect of nicotine on the body as well as in helping former smokers to maintain abstinence. 3. By far the most common, and clinically the most important, symptom to appear following withdrawal from tobacco is craving for tobacco. The importance of the tobacco-withdrawal syndrome is its provocative role in relapse among abstinent smokers. Abrupt and total withdrawal from tobacco is associated with a withdrawal syndrome that subsides more quickly and is no worse than that seen in partial abstinence. A partially-abstinent smoker is in a chronic state of withdrawal that typically leads to relapse and a return to baseline rates of smoking. 4. There is fragmentary evidence suggesting that the abstinence syndrome is more severe in women than in men, and it seems likely that this is at least partly responsible for lower rates of successful cessation among women. 5. Little is known about the millions of smokers who have quit on their own. It has been estimated that 95 percent of the 29 million smokers who have quit since 1964 have done so on their own. 6. Survey data show that only one-third or less of smokers motivated to quit are interested in formal programs, and only a small minority of l-32 those who do express an interest actually attend programs when offered. It thus appears that available objective outcome data may be based on a small minority sample of smokers at large. `7. Objective data are lacking on most of the smokers who have been willing to attend formal programs. Public service clinics continue, but lack of objective outcome data precludes the evaluation of their efficacy. Similarly, proprietary programs remain virtually unmoni- tored and unevaluated in an objective fashion. Controlled research has yet to produce a clearly superior intervention strategy. However, rapidly accumulating and improving data now suggest that multi- component interventions offered by intervention teams with practical knowledge regarding the smoking problem are the most encouraging. 8. Too few carefully designed and implemented longitudinal studies exist in the area of smoking in children and adolescents to allow for true evaluation of the effectiveness of many past programs developed for them. 9. Inferences about the evolution of smoking suggest that by the end of the ninth grade very few adolescents are addictive smokers; the critical level of the onset of addictive smoking appears to be in high school. Therefore, the true impact of any deterrence-of-smoking program with adolescents may not even be measurable until after the adolescent has entered high school. This problem is not unlike the recidivism encountered in virtually all smoking cessation programs. 10. Too many programs for youth have focused on information about smoking or fear of serious disease due to smoking. Adolescents are present-oriented and appear to be less influenced by messages concerning smoking that focus exclusively on long-term dangers. 11. A focus on research into prevention of the onset of addictive smoking appears to be a reasonable parallel course to follow along with efforts at control and cessation. 12. A promising new approach may be in the "inoculation" of adolescents against various pressures to smoke which apparently override their knowledge about the dangers of smoking. The approach involves strategies to resist peer pressure, emphasis on understanding of how advertising and mass media work to influence smoking, and provision of information on ways to resist the models of parents, siblings, and older students who smoke. Also included is a focus on the immediate physiological effects of smoking rather than on long-term effects. Education and Prevention Research strongly indicates that educators and health care providers teach youth about smoking and health as much by example as through formal instruction. But, despite a proliferation of a wide variety of educational programs aimed at youth and adults, it is not known which methods are most effective in preventing the start of smoking or in l-33 promoting cessation. Summarized below are some of the research findings, program and experimental approaches, and needs in the areas of smoking education and prevention discussed in this part of the report. 1. Most educational programs are based on what seems reasonable rather than on sound theoretical models. It is logical to assume, for example, that young people who know about the harmful effects of cigarette smoking on health will resist smoking, Thus, many programs are based on knowledge dissemination and a health threat. However, we know that 94 percent of teenagers say that smoking is harmful to health and 90 percent of teenage smokers are aware of the health threat. 2. The trend in adult education programs is toward emphasis on personal responsibility for individual health and adoption of a health- promoting lifestyle. 3. Researchers find that "significant adults"-physicians, nurses, dentists, other health professionals, coaches, and parents-are power- ful influences on teenage smoking. A nationwide survey of teenagers, for example, indicated that `72 percent of the nonsmokers identified physicians as the one group that could influence them not to start smoking; 43 percent of the smokers felt that the physician's advice would influence their decision to stop smoking. 4. Health professionals as a group-have preceded the general public in improving their smoking`habits; they have stopped smoking, moved to less hazardous forms of tobacco, or reduced the amount smoked. 5. Several studies of methodologies used in smoking education reported mixed results, with no method clearly predominating. l-34 Introduction and Summary: References (2) BRODERS, A.C. Squamouscell epithelioma of the lip. A study of five hundred and thirty-seven cases. Journal of the American Medical Association 74410): 656-664, March 61920. (2) BURNEY, L.E. Smoking and lung cancer-A statement of the Public Health Service. Journal of the American Medical Association 171: 1829-183'7, 1959. (2) CORNFIELD, J., HAENSZEL, W., HAMMOND, E.C., LILIENFELD, A.M., SHIMKIN, M.B., WYNDER, E.L. Smoking and lung cancer: Recent evidence and a discussion of some questions. Journal of the National Cancer Institute 22: 173203,1959. (4) HAMMOND, E.C. Smoking in relation to the death rates of one million men and women. In: Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Diseases. National Cancer Institute Monograph 19. U.S. Department of Health, Education, and Welfare, Public Health Service, National Cancer Institute, January 1966, pp, 127-394. (5) HOLLAND, 5.3. Dissertatio inaugur. med. chir. sistens Carcinoma labii inferioris absque sectione pemanatum. In: Wolff, J. Die Lebre von der Krebskrankheit, Jena, 1911, Vol. 2, pp. 5%78. (6) JAMES, G. Treatise on tobacco, tea, coffee and chocolate. (Translated from S. Paulli's Commentarius de abusu tabaci Americanorum vet&, et herbae thee Asiaticorium in Europa novo. 1665.) London, T. Osbom, 1746. (7) LOMBARD, H.L., DOERING, C.R. Cancer studies in Massachusetts: Habits, characteristics, and environment of individuals with and without cancer. New England Journal of Medicine 198: 481-487,1928. (8) MILMORE, B.K., CONOVER, A.G. Tobacco consumption in the United States, 1880 to 1955. Agricultural Economic Research 8: g-13,1956. (9) PEARL, R. Tobacco smoking and longevity. Science 87: 2X%217,1938. (10) ROYAL COLLEGE OF PHYSICIANS. Smoking and Health. Summary and Report of the Royal College of Physicians of London on Smoking in Relation to Cancer of the Lung and Other Diseases. New York, Pitman Publishing Company, 1962,70 pp. (11) SCIENCE. Smoking and Health. Joint Report of the Study Group on Smoking and Health. Science 135(3258): 1129-1133, June 7,1957. (12) SELTSER, R. Lung cancer and uranium mining. A critique. Archives of Environmental Health lo(6): 923-936, June 1965. (12) SOEMMERRING, S. Th. De Morbis Vasorum Absorbentium Corporis Humani. Varrentrappii Wenneri, Traiectis ad Moenum, Publ. 1795,105 pp. (14) U.S. PUBLIC HEALTH SERVICE. A Reference Edition: 19'76. U.S. Depart- ment of Health, Education, and Welfare, Public Health Service, Center for Disease Control, HEW Publication No. (CDC) 78-8357,1976,657 pp. (15) U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. U.S. Dept. of Health, Education, and Welfare, Public Health Service, Center for Disease Control, PHS Publication No. 1103,1964,387 pp. l-35 PART I THE HEALTH CONSEQUENCES OF SMOKING 2. MORTALITY. Center for Disease Control CONTENTS Introduction .............................................................. 9 The Measures of Mortality ......................................... 10 The Major Prospective Epidemiological Studies .............. 12 The British Doctors Study .................................... 12 The American Cancer Society 25State Study ........... 12 The U.S. Veterans Study.. .................................... 14 Japanese Study of 29 Health Districts.. .................. 14 The Canadian Veterans Study ............................... 14 The American Cancer Society g-State Study.. .......... 15 California Men in Various Occupations .................... 15 The Swedish Study.. ............................................ 15 Mortality and Male Cigarette Smokers ......................... 15 Mortality and Amount Smoked .............................. 15 Mortality at Different Ages.. ................................ 1'7 Mortality by Duration of Smoking.. ....................... 1'7 Mortality by Age Began Smoking.. ........................ 19 Mortality by Inhalation of Cigarette Smoke.. .......... .20 Mortality by Tar and Nicotine Content of Cigarettes ....................................... .22 Mortality and Female Cigarette Smokers ..................... .25 Mortality and Ex-Smokers . . _. . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26 Mortality and Pipe and Cigar Smokers.. ...................... .30 Mortality by Cause of Death ..................................... .3'i The Constitutional Hypothesis, Social, and Environmental Factors.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41 Summary of Overall Mortality Related to Smoking . . . . . . . .42 Summary of Smoking and Mortality by Cause of Death. . . . . . .._. , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,. . . 44 2-3 References . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45 LIST OF FIGURES Figure l.-Annual probability of dying for ex-smokers who quit smoking less than 5 years, current cigarette smokers and nonsmokers, aged 55-64, U.S. veterans 1954 cohort, 16-year follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Figure 2.-Annual probability of dying for ex-smokers who quit smoking 5-9 years, current cigarette smokers and nonsmokers, aged 55-64, U.S. veterans 1954 cohort, 16 year follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Figure 3.-Annual probability of dying for ex-smokers who quit lo-14 years, current cigarette smokers and nonsmokers, aged 55-64, U.S. veterans 1954 cohort, 16 year follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ., . . . . . . . 33 Figure 4.-Annual probability of dying for ex-smokers who quit 15+ years, current cigarette smokers and nonsmokers, aged 55-64, U.S. veterans 1954 cohort, 16- year follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 LIST OF TABLES Table l.-Mortality ratios, differences in mortality rates, and excess deaths by age, as derived from two studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Table 2.-Estimated years of life expectancy (LE) for males at various ages by amount smoked, as derived from two studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Table 3.-Outline of prospective studies of smoking and overall mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 2-4 Table 4.-Mortality ratios for males currently smoking cigarettes only, by amount smoked . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Table L-Mortality ratios for male cigarette-only smokers, by number of cigarettes smoked per day and age. U.S. veterans 1954 cohort, 16year follow-up . . . . . . . . . . . . . . . . . . . . . . 17 Table 6.-Mortality ratios for male cigarette-only smokers, by number of cigarettes smoked per day and age. Males in 25 States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Table 7.-Mortality ratios for male cigarette-only smokers, by number of cigarettes smoked per day and age. Canadian pensioners.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Table B.-Mortality ratios for male cigarette-only smokers, by number of cigarettes smoked per day and age. Males in nine States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Table 9.-Age-adjusted mortality ratios for male cigarette-only smokers, by duration of smoking. Canadian veterans.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Table lO.-Age-adjusted mortality ratios for male cigarette smokers who began smoking after the age of 20, by duration of smoking. U.S. veterans . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Table Il.-Age-adjusted mortality ratios for male cigarette-only smokers, by age began smoking. U.S. veterans 1954 cohort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Table 12.-Age-adjusted mortality ratios for male cigarette-only smokers, by age began smoking. Japan.. 20 Table 13.-Age-adjusted mortality ratios for Japanese male cigarette smokers, by age began smoking and age at start of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Table 14.-Age-adjusted mortality ratios for male cigarette-only smokers, by age began smoking and age at start of study. U.S. veterans 19.54 cohort . . . . . . . . . . . . . . . 21 Table 15.-Age-adjusted mortality ratios for male cigarette-only smokers, by age began smoking and age at start of study. Males in 25 States . . . . . . . . . . . . . . . . . . . . . . . . 21 2-5 Table 16.-Age-adjusted mortality ratios for male cigarette-only smokers aged 55-64, by age began smoking and current number of cigarettes smoked per day. Males in 25 States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Table 17.--Age-adjusted mortality ratios for males smoking cigarettes only, by amount smoked and age began smoking. U.S. veterans 1954 cohort . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Table X-Percent distribution of male cigarette smokers, by degree of inhalation of cigarette smoke and age. Males in 25 States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Table lg.-Age-adjusted mortality ratios for male cigarette-only smokers, by degree of inhalation of cigarette smoke and current number of cigarettes per day. Subjects aged 4554 at start of study. Males in 25 States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Table 20.-Age-adjusted mortality ratios for male cigarette-only smokers, by degree of inhalation of cigarette smoke and age at start of study. Males in 25 States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Table 21.-Age-adjusted mortality ratios for male cigarette-only smokers, by degree of inhalation of cigarette smoke and age at start of study. Canadian veterans.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24 Table 22.-Adjusted mortality ratios for males and females, by tar and nicotine content of cigarettes usually smoked . . . . . . . . . . . . . . . . . . . . . _. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Table 23-Adjusted mortality ratios for males and females smoking low T/N cigarettes and subjects who never smoked regularly.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Table 24-Overall mortality ratios of cigarette smokers compared to nonsmokers, by sex and by tar and nicotine content of cigarettes usually smoked . . . . . . . . . . . . . . . . . . . . . . . . . 25 Table 25-Age-adjusted mortality ratios of female cigarette smokers, by number of cigarettes smoked per day and age. 25-State Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 2-6 Table 26.-Age-adjusted mortality ratios of female cigarette smo!rers, by number of cigarettes smoked per day and degree of inhalation. Subjects aged 45-54 at start of study. E&State Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Table 27.-Age-adjusted mortality ratios of female cigarette smokers, by number of cigarettes smoked per day and age began smoking. Subjects aged 45-54 at start of study. 25-State Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Table %-Age-adjusted mortality ratios of female cigarette smokers, by number of cigarettes smoked per day and degree of inhalation and age. 25-State Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Table 29.-Age-adjusted mortality ratios for males who are ex-smokers of cigarettes, by former amount smoked per day and years since stopped smoking. Males in nine States. . . . . . . . . . . . .,......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Table 30.-Mortality ratios of ex-smokers of cigarettes only who quit smoking on doctors' orders and for other reasons, by certain dosage variables. U.S. veterans 1954 cohort, E-year follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 .- Table 31.-Mortality ratios of ex-smokers compared to nonsmokers, by age and number of years since stopping smoking. Study of British doctors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Table 32.-Mortality ratios for male smokers, by type of tobacco used.. . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35 Table 33-Age-adjusted mortality ratios for male cigar and pipe smokers, by amount smoked. Males in nine States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..I... 36 Table 34.-Age-adjusted mortality ratios for male cigar and pipe smokers, by amount smoked. Canadian veterans 36 Table 35.-Age-adjusted mortality ratios for male cigar and pipe smokers, by amount smoked. Males in 25 States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Table 36.-Age-adjusted mortality ratios of current 2-7 smokers of cigars only, by amount smoked. U.S. veterans 1954 cohort, 16-year follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37 Table 37.-Age-adjusted mortality ratios of current smokers of cigars only, by age began smoking. U.S. veterans 1954 cohort, E-year follow-up.. . . . . . . . . . . . . . . . . . . . . 37 Table 38-Age-adjusted mortality ratios of current smokers of pipes only, by amount smoked. U.S. veterans 1954 cohort, Is-year follow-up.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38 Table 39.-Age-adjusted mortality ratios of current smokers of pipes only, by age began smoking. U.S. veterans 1954 cohort, X-year follow-up . . . . . . . . . . . . . . . . . . . . . . 38 Table 40.-Age-adjusted mortality ratios of males smoking cigarettes, pipes, and cigars in various combinations and at various times. U.S. veterans 1954 cohort.. . . . . . . . . . . . . . .39 Table Il.-Mortality ratios of current cigarette-only smokers, by cause of death in eight prospective epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 2-8 Introduction Cigarette smoking is the single most important environmental factor contributing to premature mortality in the United States. This preventable, premature mortality is due to increased death rates among cigarette smokers from several diseases, but primarily from ischemic heart disease, cancers of the respiratory tract, and the chronic obstructive pulmonary diseases, emphysema, and chronic bronchitis. The world's literature on smoking and health at present consists of more than 30,000 published articles from thousands of studies conducted in every major country of the world. These data are housed in the Technical Information Center of the Office on Smoking and Health in the Department of Health, Education, and Welfare. During the past 30 years, there have been eight large prospective epidemiological studies conducted that were specifically designed to delineate the relationship between tobacco smoking and the develop ment of disease. Several of these studies were in progress at the time of the first report on smoking and health by the U.S. Government (37'). Within the past 2 years, reports on long-term follow-up have been published from four of these studies, which are still in progress (9, 19, 21, 33). The longest follow-up comes from the study of British physicians, from which 20-year data have been published (9). The largest study is the American Cancer Society study of men and women in 25 States that enrolled more than one million subjects and is easily one of the largest studies of all time. Twelve-year follow-up data from this population have heen published (19). A representative population study from Sweden includes data on men and women (2). The relationship between smoking and overall mortality has been reviewed by the Department of Health, Education, and Welfare several times during the past 15 years. A report of the Advisory Committee to the Surgeon General of the Public Health Service was first published in 1964 (37). The subject was again reviewed in 1967, 1968, and 1978 in The Health Consequences of Smoking (34, 35, 36). The effect of cigarette smoking on overall mortality as reported in the eight major prospective epidemiological studies is summarized in this chapter. Recently published data from these studies have resulted in numerous refinements in our understanding of smoking and overall mortality. The major conclusions drawn in 1964 still stand, but they are reinforced by the weight of evidence accumulated from these and other sources over the past 15 years, Conclusions regarding smoking and overall mortality reported in previous reports will not be presented here. The summary appearing at the end of this chapter is a synthesis of all that is currently known about smoking and overall mortality. It includes data from previous reports as well as current conclusions based on the most recently published data. 2-9 The Measures of Mortality Overall mortality is a measure of the cumulative or total effect of a disease-causing agent on the health of a population, Overall mortality rates are particularly useful in determining the effect of agents that influence multiple organ systems and result in increased death rates from several diseases. Overall mortality is the best way to measure the sum of the risk due to cigarette smoking-related diseases. Smoking directly exposes multiple sites in the respiratory tract to the chemical constituents of tobacco smoke. This direct effect is most likely responsible for the increased mortality smokers experience from cancer of the lung, larynx, oral cavity, and esophagus, as well as the chronic obstructive diseases of the lung, emphysema, and chronic bronchitis. The more soluble compounds are absorbed into the blood stream where, unchanged or in some cases as toxic metabolites of parent compounds, they act upon susceptible tissues not directly exposed to cigarette smoke. This effect is most likely responsible for the increased mortality smokers experience from ischemic heart disease, aortic aneurysm, and cancers of the urinary bladder and pancreas. Because of these complexities, only overall mortality rates can present an accurate statement of the impact of smoking on the health of the population. Although overall mortality is frequently used by epidemiologists and statisticians, it has little immediate application to the practice of many physicians, dentists, nurses, or other health professionals whose orientation is primarily clinical and who deal more with specific diseases and disease-specific mortality rates. Usually, when a disease- causing agent results in increased mortality for only one disease, there may be a sharp increase in the death rate for that specific disease, but there will be very little change in the overall mortality rate for the population. By contrast, cigarette smoking increases the death rates for several diseases. As a result, overall mortality rates are increased more than the disease-specific death rates for several of the diseases caused by cigarette smoking. Overall mortality can be expressed in several ways. The most commonly used terms are listed below with a brief discussion of their significance. 1. Mortality Ratios: Obtained by dividing the death rate for a classification of smokers by the death rate of a comparable group of nonsmokers. A mortality ratio has been considered to reflect the degree to which a classification variable identifies or may account for variations in death rates. As such, it is a measure of relative risk that indicates the importance of that variable relative to uncontrolled variables-an indicator of potential biological sipificance. 2. Differences in Mortality Rates: Obtained by subtracting from the death rate for smokers, the death rate of a comparable group of nonsmokers. This measure reflects the added probability of death in a 2-10 TABLE l.-Mortality ratios, differences in mortality rates and excess deaths by age as derived from two studies Age US. Veterans Study (males) Total deaths Death rates: nonsmokers Death rates: cigarette smokers Mortality ratio Difference in mortality rates Excess deaths as a percentage of total 25 State Study (males) Total deaths Death rates: nonsmokers Death rates: cigarette smoker Mortality ratio Difference in mortality rates Excess deaths as a percentage of total 383 366 13,&?Aa 17,550 1,= 127 264 I,(= 2,411 6214 232 1.83 105 33 631 210 397 1.89 187 33 72s 1.819 2.76 1.72 464 763 43 21 5,i97 8,427 406 la2 925 2202 228 1.83 519 WJfJ 38 25 4,032 1.67 1,621 17 8,125 3,968 3,163 7s3 4,788 9,674 1.51 1.23 l,f=J 13 8,417 1.36 2257 8 1.811 4 SOURCE: Hammond. E.C. (17). Kahn. H.A. (%?S). l-year period for the smoker over that for the nonsmoker. As such, it is a measure of pemmal health significance, a means for the individual to estimate the added risk to which he or she is exposed. 3. Excess Deaths: Obtained by subtracting from the number of deaths occurring in a group of smokers, the number of deaths that would have occurred if that group of smokers had experienced the same mortality rates as a comparable group of nonsmokers. This measure is an indicator of the public health significance of the differences, since it measures the number of people affected and, therefore, the magnitude of the problem for society as a whole. 4. Life Expectancy: A concept that is easier to understand than to calculate. At a given age, it represents the average number of years one might be expected to live. Table 1 illustrates the first three measures for five age groups of men from the U.S. Veterans Study and the American Cancer Society Study of Men in 25 States. Table 2 illustrates the effect of cigarette smoking on life expectancy using data from the 25-State Study and the U.S. Veterans Study. When compared to non-smokers, an average Young male smoker (30 to 40 years of age) who smokes more than 40 cigarettes per day loses an estimated 8 years of life. 2-11 TABLE 2.-Estimated years of life expectancy (LE) for males at various ages by amount smoked, as derived from two studies Cigarettes smoked per day 25 State Study Nonsmokers l-9 l&19 2&39 40+ Age 30 40 50 60 LE YWR lost LE `E LE `Et LE YE 43.9 0 34.5 0 Zi.6 0 17.6 G 39.3 4.6 30.2 4.3 21.8 3.8 14.5 3.1 36.4 5.5 29.3 5.2 21.0 4.6 14.1 3.2 31.8 6.1 28.7 5.8 20.5 5.1 13.7 3.9 35.8 8.1 26.9 7.6 19.3 6.3 13.2 4.4 35 40 xl 60 U.S. Veterans Study Nonsmokers 43.5 0 38.7 0 29.4 0 20.8 C I-10 41.0 2.5 3&3 2.4 27.5 1.9 19.0 1.8 10-20 38.7 4.8 34.1 4.6 25.2 4.2 17.2 3.6 2139 36.7 6.8 320 6.7 B.4 6.0 15.8 5.c 40+ 34.8 8.7 29.9 8.8 21.6 7.8 14.4 6.4 The Major Prospective Epidemiological Studies Below are brief outlines of the eight important prospective epidemio- logical studies and their results. Taken together, the eight studies encompass more than 16 million person-years of experience and over 300,000 deaths. The data are presented in Table 3. Numbers in the table have been rounded, for ease of presentation. The British Doctors Study (4) In 1951, the British Medical Association forwarded to all British doctors a questionnaire about their smoking habits. A total of 34,400 men and 6,207 women responded. With few exceptions, all men who replied in 1951 have been followed for 20 years. Further inquiries about changes in tobacco use and some additional demographic characteris- tics of the men were made in 195'7, 1966, and 1972. More than 10,006 deaths have occurred in this population during the past 20 years. The American Cancer Society 25-State Study (17) In late 1959 and early 1960, the American Cancer Society enrolled 1,078,894 men and women in a prospective study. All segments of the population were included except groups that could not be traced easily. A lengthy initial questionnaire was administered that contained 2-12 TABLE 3.-Outline of prospective studies of smoking and overall mortality Doll Hill Dom Best Weir Cede&f Authors Pet0 Hammond Kahn Hirayama J&e Hammond Dunn Friberg Pike Roget Walker Horn Linden Hmbec (4-10) Brwlow (14,1&19) (If ,26,92,98) Lorkh (fZ,.zS-25) (l,N Gw U.&J93 (9 Males and Total population females California Probability British U.S. of Subjects Canadian White males in 29 health males in sample of doctors veterans in 2.5 the districts in pensionem various St&3 nine States Japan occupations Swedish population Population size wo@J l,CW@J 2woo =.%~ Females %W 6,~ 187,ooO 562,671 @w@J m 1.93 1.69 l.ss(>W 1.96 221 1W>16) 40+ 2.20 1.89 2.B 1.83 All smokerj 1.63 1.83 1.55 1.25 1.54 1.74 1.78 1.58 TABLE 5.-Mortality ratios for male cigarette-only smokers, by number of cigarettes smoked per day and age. U.S. veterans 1954 cohort, 16-year followup Number of Age cigarette3 per day 3b.34 3&u 45.54 5544 &74 Nonsmokers 1.00 1.00 1.00 1.00 1.00 less than 10 1.94 1.44 1.44 1.20 1.15 l&20 1.27 1.79 1.64 1.49 1.30 2139 1.76 2.23 2.10 1.67 1.42 40+ 2.33 2.72 2.13 1.&i 1.65 All smokers 1.52 1.95 1.33 1.53 1.32 SOURCE: Roget, E. (81.~8) significant mortality ratio that varies from 1.25 to 1.45. Smokers of more than two packs of cigarettes a day have an overall mortality ratio that varies from 1.33 to 2.23. Mortality at Different Ages Overall mortality ratios by amount smoked at different ages for several studies are presented in Tables 5 through 8. There is a decrease in the mortality ratio with each increase in age for each smoking category. Mortality ratios are consistently more than 2.00 for heavy smokers between the ages of 30 to 50. These ratios decrease gradually with age, but are still about 1.35 for men over 75 years of age. This decline does not imply a decrease in the effect of cigarette smoking on health. Overall mortality rates increase dramatically with age in both smokers and nonsmokers. If one uses another measure of mortality and looks at the difference. in death rates between smokers and nonsmokers as illustrated in Table 1, it can be seen that the difference in overall mortality rates increases with age even though the mortality ratio decreases. The decreasing mortality ratio with age is probably due to another factor that should be considered. The population of older males who smoke two packs of cigarettes per day is probably quite different than a younger group of two-pack-a-day smokers. Mortality by Duration of Smoking Overall mortality ratios increase with the duration of the smoking habit, Mortality ratios by number of years smoked from two studies are presented in Tables 9 and 10. The mortality ratios remain quite low, only slightly above the rates for nonsmokers for the first 5 to 15 Years of the smoking habit, and then increase more rapidly as the years 2-17 TABLE S.-Mortality ratios for male cigarette-only smokers, by number of cigarettes smoked per day and age. Males in 25 States Number of cigarettes per day Age 3544 4.554 5564 65-74 75-84 Nonsmoker 1.00 1.00 1.00 1.00 1.00 l-9 .I 1.34 1.53 1.50 1.36 l&19 1.36 2.26 1.92 1.65 1.55 20-39 1.91 2.41 205 1.71 1.26 40+ 259 276 226 1.81 o ? All smokers 1.32 2.20 1.36 1.53 1.35 SOURCE: Hammond. EC. (In. TABLE `I.-Mortality ratios for male cigarette-onl~ smokers, by number of cigarettes smoked per day and age. Canadian pensioners Number of Age cigarettes p"r day 30-34 3544 4554 55-64 674 75+ Nonsmokers 1.00 1.00 1.00 1.00 1.00 1.00 l-9 0.72 1.25 1.07 1.50 1.32 1.31 10-20 1.22 1.36 1.20 1.94 1.40 1.33 20+ 1.01 1.35 1.27 2.15 1.45 1.42 All smokers 0.90 1.63 1.21 1.39 1.45 1.31 SOURCE: Doll, R. (9) TABLE &-Mortality ratios for male cigarette-only smokers, by number of cigarettes smoked per day and age. Males in nine States Number of cigarettes per day Age 5&54 5549 w64 65-a Nonsmokers 1.00 1.00 1.00 1.00 l-9 1.43 1.15 1.46 1.37 1CKB 1.72 1.65 1.33 1.59 21-39 2.11 1.33 2.20 1.65 40+ 2.30 2.84 1.56 1.34 All smokers 1.35 1.69 1.34 1.55 SOURCE: Hammond, E.C. (PO). of smoking increase. Mortality ratios are as high as 1.66 for male cigarette smokers who have smoked for 35 or 40 years. 2-18 TABLE 9.-Age-adjusted mortality ratios for male cigarette-only smokers, by duration of smoking. Canadian veterans Duration of smoking in years Mortality ratio Under 5 1.05 5-14 1.30 lN?l 1.33 3039 1.53 40+ 1.66 All smokers 1.52 SOURCE: Best. E.W.R (I) TABLE lO.-Age-adjusted mortality ratios for male cigarette smokers who began smoking after the age of 20, by duration of smoking. U.S. veterans Duration of smoking Mortality in years ratio Under 15 1624 2534 35+ SOURCE: Kahn, H.A. (PS). 1.10 1.34 1.44 1.66 Mortality by Age Began Smoking Overall mortality ratios exhibit an inverse relationship with age of initiation of the smoking habit. Table 11 displays data from the U.S. Veterans Study. Cigarette-only smokers who began smoking after the age of 25 have a mortality ratio of i.32. For individuals who began smoking under the age of 15, the mortality ratio is 1.86. Data from the Japanese study are shown in Table 12. Again, a dose-response relationship is demonstrated but at a lower level than in the United States. When the Japanese data are broken down further "by age at start of study" and "age began smoking," as seen in Table 13, it is demonstrated that smokers who began smoking under the age of 15 have mortality ratios that are very similar to those in the United States data. Tables 14 and 15 show- overall mortality ratios by "age began smoking" and "age at beginning of study" for the U.S. veterans and U.S. males in 25 States. Overall mortality ratios by "age began smoking" and "number of cigarettes smoked per day" for the ACS Study of 25 States and the U.S. Veterans Study are presented in Tables 16 and 17. As expected, 2-19 TABLE Il.-Age-adjusted mortality ratios for male cigarette-only smokers, by age began smoking. U.S. veterans 1954 cohort Age began smoking in yea-3 Mortality ratio Nonsmokem 1.00 25+ 1.32 2iL24 1.51 15-19 1.64 Under 15 1.86 SOURCE: Roget. E. (91, SS). TABLE 12.-Age-adjusted mortality ratios for male cigarette-only smokers, by age began smoking. Japan Age began smoking Mortality in years ratio Nonsmokers 1.00 W+ 1.19 20-24 1.19 Under 20 1.27 SOURCE: Hirayama, T. (Z'.?). TABLE 13.-Age-adjusted mortality ratios for Japanese male cigarette smokers, by age began smoking and age at start of study Age began Age at start of study smoking in "ears 40 49 5&59 W-69 Nonsmokers 1.00 1.00 1.00 35+ 1.53 1.08 1.02 3&34 0.89 1.11 1.23 2529 0.91 1.17 1.19 m-24 0.82 1.16 1.19 15-19 0.92 1.31 1.29 Under 15 2.26 3.94 1.36 SOURCE: Hirayama. T. (Pe). overall mortality ratios increase the younger a person begins smoking and the greater the number of cigarettes smoked per day. Mortality by Inhalation of Cigarette Smoke Inhalation of tobacco smoke is an important dosage variable. Most of the excess mortality associated with cigarette smoking results from diseases that require inhalation of smoke well into the lungs in order to Z-20 TABLE 14.-Age-adjusted mortality ratios for male cigarette-only smokers, by age began smoking and age at start of studv. U.S. veterans 1954 cohort Age began Age at start of study smoking in years 30434 3544 45-M 5.544 &74 NonsmokeR 1.00 1.00 1.00 1.00 1.00 25+ o ? 1.48 1.67 1.36 1.20 20-24 1.41 1.87 1.72 1.56 1.39 15-19 1.44 2.00 2.11 1.70 1.45 Under 15 2.00 2.18 2.25 2.02 1.42 SOURCE: Ro& E. (SI. SS). TABLE 15.-Age-adjusted mortality ratios for male cigarette-only smokers, by age began smoking and age at start of study. Males in 25 States Age bw Age at start of study smoking in years 4554 5564 674 75-84 Nonsmokers 1.00 1.00 1.00 1.00 30+ 1.40 1.33 1.23 1.10 25-29 1.81 1.75 1.25 o ? ???? 2.13 1.73 1.52 1.27 15-19 2.49 211 1.34 1.53 Under 15 3.01 2.26 200 1.59 SOUFtCE: Hammond, E.G. (17) TABLE 16.-Age-adjusted mortality ratios for male cigarette-only smokers aged 55-64, by age began smoking and current number of cigarettes smoked per day. Males in 25 States Age began smoking in years Nonsmokers Current number of cigarettes per day 19 lo-19 as39 40+ 25+ 1.00 1.34 1.63 1.48 1.77 15-24 1.00 1.45 1.89 2.05 2.23 Under15 1.00 .I 2.15 2.19 2.53 ~URCE:Hammond, E.C.(I?). expose target organs directly or through absorption of toxic substances into the circulatory system. Ischemic heart disease, lung cancer, and chronic obstructive disease are not as likely to develop in individuals who do not inhale smoke. Techniques for quantitating inhalation have been developed using carboxyhemoglobin as an index of smoke inhalation, but these methods have not been applied to studies of overall mortality. Most studies asked the smoker to report subjectively 2-21 TABLE 17.-Age-adjusted mortality ratios for males smoking cigarettes only, by amount smoked and age began smoking. U.S. veterans 1954 cohort Age began Current number of cigarette3 smoking per day in years Nonsmokers l-20 21+ `B+ 1.00 1.36 1.59 Under 20 1.00 1.56 1.82 SOURCE: Roget, E. (31. J.?). on his own inhalation practices. Certainly, self-reporting of inhalation is subject to considerable variation, but it may not be as inaccurate as might be presumed. Available data show the expected dose-response relationship between inhalation of cigarette smoke and overall mortality. Table 18 demonstrates that with advancing age the percentage of moderate and deep inhalers drops and the percentage of none-to-slight inhalers increases. This is consistent with increased mortality for those who inhale. It also makes the interesting point that a smoker who survives to old age is different from the younger smoker. It is likely that the lower mortality ratios experienced by older smokers are partly a reflection of the fact that they smoke in a less hazardous fashion than do younger smokers. Older smokers are less likely to inhale than younger smokers. It is also likely that they take fewer puffs per cigarette and smoke fewer cigarettes per day. If they have been faithful to their brand of cigarettes, they are likely to be smoking an "older" brand. The brand is likely to be unfiltered and more typical of the cigarettes sold 30 to 40 years ago which contained twice the tar and nicotine of the average cigarettes sold today. Tables 19,20, and 21 show age-adjusted mortality ratios by degree of inhalation and number of cigarettes smoked per day and age at start of study for three of the large prospective studies. The overall mortality ratio is `2.80 for the moderate-to-deep inhaler who smokes 40 or more cigarettes per day. The overall mortality ratio is 2.53 for 45- to 54-year-old men who inhale deeply, but is 1.02 for noninhalers who are `75 to 84 years old. In the Canadian study, the highest mortality ratio was 2.11 for those 60 to 69 years old who reported inhaling cigarette smoke. Hammond reported a mortality ratio of 1.41 for noninhalers who are 45 to 54 years old (15). This suggests that cigarette smokers may underestimate the extent to which they inhale cigarette smoke. Mortality by Tar and Nicotine Content of Cigarettes Overall mortality increases with the tar and nicotine content of cigarette smoke. This relationship was recently examined by Ham mond, et al. (19). In this study, tar and nicotine levels (T/N) were defined as follows: "High" T/N, 25.8357 mg tar and 2.c2.7 mg 2-22 TABLE l&-Percent distribution of male cigarette smokers by * degree of inhalation of cigarette smoke and age. Males in 25 States Degree of inhalation 4&49 XL59 Age 6&69 70-79 i None 3.62 6.11 11.46 19.74 Slight 10.97 13.6-I 20.18 25.56 Moderate 57.94 56.31 51.10 40.82 D*P 27.65 23.91 17.25 13.83 Total 100.00 100.00 160.00 lOO.CQ SOURCE: Hammond. E.C. (19). TABLE lg.-Age-adjusted mortality ratios for male cigarette-only smokers, by degree of inhalation of cigarette smoke and current number of cigarettes per day. Subjects aged 45-54 at start of study. Males in 25 States NJ= Number of cigarettes pet day of inhalation l-9 lo-19 m-39 40+ None-slight 1.70 1.99 234 233 Moderatedeep 1.95 2.35 242 2.30 %XJRCE: Hammond. E.C. (17) TABLE 20.-Age-adjusted mortality ratios for male cigarette-only smokers, by degree of inhalation of cigarette smoke and age at start of study. Males in 25 States ~~ of inhalation Age at start of study 4544 5544 6.574 7584 None 1.41 1.43 1.32 1.02 Slight 1.67 1.71 1.31 1.19 werate 206 1.68 15.3 1.10 D=P 2.58 1.88 1.68 o ? SOURCE: Hammond, EC. (17) nicotine; "Medium" T/N, 17.6-25.7 mg tar and 1.21.9 mg nicotine; `%oW" T/N, less than 17.6 mg tar and less than 1.2 mg nicotine. Table 22 shows the overall mortality ratios of male and female smokers by thes tar and nicotine levels. In this instance, the mortality ratio of the "high" T/N smokers is represented as 1.00 so as to illustrate the reduction in overall mortality that occurs with lower T/N cigarettes. There is a small but statistically significant (P. less than 0.0005) reduction in the risk of dying with the use of lower T/N cigarettes. The rnortaIity ratio was reduced to 0.91 for the "medium" T/N smokers and 2-23 TABLE 21.-Age-adjusted mortality ratios for male cigarette-only smokers, by degree of inhalation of cigarette smoke and age at start of study. Canadian veterans Degree of inhalation 3cL-39 Age at start of study 4&49 5049 60-69 (D Nonsmokers 1.00 1.00 1.00 1.00 Do not inhale 0.61 0.61 1.10 1.78 Inhale smoke 1.29 12 1.58 211 SOURCE: Best, E.W.R. (I). TABLE 22.-Adjusted mortality ratios for males and females, by tar and nicotine content of cigarettes usually smoked Mortality ratios sex "High" "Medium" "Low" T/N T/N T/N Males 1.00 0.94 085 Females 1.00 0.88 0.33 Total l.M) 0.91 O.&p SOURCE: Hammond, EC. (19). TABLE 23.-Adjusted mortality ratios for males and females smoking low T/N cigarettes and subjects who never smoked regularly sex 3lortality ratios "h,$' T/N Nonsmokers Males 1.00 0.61 Females 1.00 0.14 Total l.GO 0.66 SOURCE: Hammond. E.C. (19). was further reduced to 0.84 for the "low" T/N smokers. The mortality ratios are lower for females than for males. In a separate analysis, a comparison was also made between the mortality ratios of "low" T/N smokers and nonsmokers. These data are presented in Table 23. The mortality ratio of the "low" T/N group was designated as 1.00. Nonsmokers have overall mortality ratios that are about half those of "low" T/N smokers. The combined data from these two tables are shown in Table ?A. Here, mortality ratios are calculated using nonsmokers as the 2-24 TABLE 24.-Overall mortality ratios of cigarette smokers compared to nonsmokers, by sex and by tar and nicotine content of cigarettes usually smoked Males Females Sex Non- "Low" "Medium" "High" smokers T/N T/N T/N 1.00 1.66 1.35 1.96 1.00 1.37 1.45 1.65 Total SOURCE: Hammond, E.C. (19). 1.00 1.52 1.64 1.80 reference. Combining these data from two separate analyses that are not exactly comparable results in figures that are only approximate. Hammond (19) also compared death rates of smokers of relatively few (1-19) "high" T/N cigarettes with those of smokers who smoked relatively large numbers (B-39) of "low" T/N cigarettes. The death rates of these two groups were very similar and the difference between them was not statistically significant. MothMy and Female Cigarette Smokers It is important that attention be called specifically to the mortality that females experience as a result of cigarette smoking. There has been an increase in smoking among teenage girls over the past 10 years. At present, the percentages of teenage boys smoking and teenage girls smoking are nearly identical. For some ages, there are more teenage girl smokers than boy smokers. Over the past 10 years, there has been a gradual reduction in the percentage of the adult population that is smoking. Men have quit in greater numbers than women. There has been only a modest drop in the percentage of women who are smoking. In Canada and several European countries, smoking is decreasing among men but increasing among women. In the United States, physicians, dentists, and pharmacists have been the most successful professional groups in giving up smoking, but in the past several years there has been an increase in smoking among nurses. Several suggestions have been made as to why women do not quit smoking. It may be that women do not generally perceive smoking as a threat to their health. Lung cancer, heart attacks, and emphysema are diseases that affect men more commonly than women. Women may feel that they are in a low-risk group. Women took up smoking later than men, generally smoked filter cigarettes, and smoked fewer cigarettes per day than men. Lower overall death rates for women smokers are due to lower exposure to cigarette smoke. Cigarette smoking for some women may be symbolic of equality with men. It is known that the smoking habits of women employed 2-25 TABLE 25.-Age-adjusted mortality ratios of female cigarette smokers, by number of cigarettes smoked per day and age. 25-State Study Number of Age cigarettes per day 544 4.554 5M4 6L74 75-84 NonsmokeR l-9 lo-19 20-a SOURCE: Hammond. EC. (17). 1.00 1.00 1.00 1.00 1.00 0.90 0.95 0.99 1.03 1.07 0.97 1.22 1.31 1.18 1.21 1.35 1.54 1.46 151 o ? outside the home match the smoking habits of men in various occupations where men and women hold equal positions. Women with the lowest rate of smoking are housewives who at present have few male counterparts with whom to identify. Recent surveys have shown that women are also concerned about weight gain that may accompany quitting smoking. Any significant weight gain on quitting represents an increased intake of food, but if one watches the diet on smoking cessation, weight gain can be avoided; in fact, weight loss can be achieved. In recent years, a few investigators have studied the relationships between cigarette smoking and the development of lung cancer and coronary heart disease in women. Death rates for these diseases are similar in women and men who have similar levels of exposure to cigarette smoke; the associations are outlined in later chapters dealing with specific diseases. Overall mortality rates for women available at present are from studies initiated 10 to 20 years ago, and thus reflect the differences in accumulated exposure that were operative at that time. Overall mortality in women varies in the same direction and in a similar degree as men for the dosage variables commonly measured. Overall mortality for women increases with the number of cigarettes smoked per day (Tables 25,26, and 2'7). Table 26 shows that the overall mortality ratio is 2.19 for females smoking more than two packs a day and inhaling moderately to deeply. Table 27 demonstrates that the mortality ratio is 1.85 for females smoking more than two packs per day who began smoking between the ages of 15 and 24. Mortality ratios by "inhalation" and "age at start of study" are shown in Table 28. Noninhaling smokers have mortality ratios that are similar to nonsmokers. Females with an average age of 50 who inhale smoke deeply have a mortality ratio of 1.78. Mortality and Ex-Smokers There is a general recognition among smokers and nonsmokers alike that cigarette smoking is a major cause of disease and death in the 2-26 TABLE 26.-Age-adjusted mortality ratios of female cigarette smokers, by number of cigarettes smoked per day and degree of inhalation. Subjects aged 4554 at start of study. 25-State Study Number of cigarettes per day Degree of inhalation of smoke None-Slight Moderate-Deep l-9 0.85 1.04 l&19 1.27 1.17 a-39 1.41 1.58 40+ .* 219 SOURCE: Hammond, EC. (I?`) TABLE 27.-Age-adjusted mortality ratios of female cigarette smokers, by number of cigarettes smoked per day and age began smoking. Subjects aged 45-54 at start of studs. 25-Stat.e Studs Number of cigarettes wr dav Age began smoking 25+ 524 Nonsmokers 1.00 1.00 l-9 0.95 0.88 l&19 1.17 1.23 2x39 1.33 1.61 40+ o ? 1.65 SOURCE: Hammond, E.C. (I?). TABLE 28.-Age-adjusted mortality ratios of female cigarette smokers, by number of cigarettes smoked per day and degree of inhalation and age. 25-State Study Dw= Age of inhalation 3544 4554 5544 f&74 7544 Nonsmokers 1.00 1.M) 1.00 1.00 1.00 None t* 1.01 1.11 1.12 0.96 Slight 1.22 1.21 1.28 1.26 1.21 Moderate 1.05 1.36 1.32 1.41 .* DeeP 1.40 1.78 1.64 ** o ? SOURCE: Hammond, E.C. (I 7). United States. Smokers are now asking the question: "Will it help me if I quit smoking ?" Some of the first evidence concerning death rates in ex-smokers required explanation. The data from the Hammond and Horn study of men in nine States are presented in Table 29. It can be seen that the mortality ratios of ex-smokers were higher in the first Year after quitting than for continuing smokers. After the first year, 2-27 TABLE 29.-Age-adjusted mortality ratios for males who are ex- smokers of cigarettes, by former amount smoked per day and years since stopped smoking. Males in nine St&?S Years since stopped smoking Cigarettes formerly smoked per day 1-19 20+ 0 (Smokers) 1.61 202 Under 1 204 269 l-10 years 1.30 1.82 10+ years 1.08 1.60 SOURCE: Hammond, E.C. (m). however, death rates for ex-smokers fell progressively so that after 10 years the former smokers of 1 to 19 cigarettes had a mortality ratio of only 1.08. The explanation for the higher death rates in the 1st year after quitting is found in the fact that both healthy and sick individuals quit smoking. The higher mortality ratio is experienced by those who quit because of illness and not by those who quit for better health. In the study of U.S. veterans, a differentiation was made between ex- smokers who stopped smoking on the recommendation of a doctor and those who quit for other reasons. About 10 percent of the smokers quit on doctors' orders; this group had much higher mortality ratios than those who stopped for other reasons. These data are presented in Table 30, where the mortality ratios for ex-smokers by "years since stopping smoking," "maximum amount smoked," "age began smoking," and "reason for quitting" are examined. There is a direct relationship between mortality rates and the maximum amount smoked, an inverse relationship between mortality and "years since stopped smoking," and also an inverse relationship between mortality and "age began smoking." A detailed analysis of the mortality experience of ex-smokers who stopped for reasons other than doctors' orders is given in Figures 1 through 4. This information is on ex-smokers, aged 55 to 64, from the 1954 cohort of the U.S. Veterans Study, who formerly smoked from 21 to 39 cigarettes per day. "Years since stopping smoking" is considered as a variable and the mortality rates are compared with those of current cigarette smokers and nonsmokers. Annual probabilities of dying are plotted on a logarithmic scale. This results in a fairly smooth and linear pattern for both smokers and nonsmokers. These lines also appear to be parallel, or perhaps to diverge slightly. This indicates an approximately constant or slightly increasing excess risk of dying 2-28 TABLE 30.-Mortality ratios of ex-smokers of cigarettes only who quit smoking on doctors orders and for other reasons, by certain dosage variables. U.S. veterans 1954 cohort, N-year followup Years since stopped smoking Mortality ratice Years Quit for since WriOUS stopped reasons <5 1.23 59 1.23 w14 1.14 lSl9 1.04 >19 1.96 Total 1.18 Quit on doctors orders 1.55 1.43 1.n 1.35 1.16 1.52 Number of cigarettes per day Mortality ratios No. of cigarettes per day a Total Quit for Quit on WlriOUS doctors rea9Ons orders 1.00 1.42 111 1.48 1.30 1.53 1.32 1.60 1.18 1.52 Age started smoking Mortality ratios Quit for various R?aSOIlS Quit on doctors orders (15 1.36 1.59 lC19 1.20 1.55 m-24 1.12 1.49 >a 1.15 1.34 Total 1.18 1.52 SOURCE: Roget, E. (33). among smokers, compared to nonsmokers over the 16-year period. It would be expected that the mortality experience of ex-smokers initially would be similar to that of smokers, but with the passing of time the mortality risk should move progressively closer to that of nonsmokers. Figure 1 illustrates this. For ex-smokers who quit less than 5 years prior to the beginning of the study, the mortality risk is at 2-29 first nearly identical to that of smokers. Over the years, the risk gradually falls to a position approximately halfway between that of smokers and nonsmokers. Figures 2 and 3 show that with longer periods of cessation the mortality risk continues to approach that of nonsmokers. In Figure 4, it can be seen that for ex-smokers who had been off cigarettes for 15 or more years before the start of this study, their mortality risk fluctuates about the mortality risk of nonsmokers for the entire E-year period. The mortality experience of British doctors who were ex-smokers is examined in Table 31. These data indicate that there are definite benefits from quitting smoking no matter how long one has smoked. After 10 to 15 years, ex-smokers have a risk of dying that is similar to that of those who have never smoked. The risk of dying from ischemic heart disease decreases rapidly immediately after stopping smoking, whereas the risk of dying from lung cancer decreases more slowly. Overall mortality measures the net benefit of quitting and, therefore, drops more slowly than do death rates for certain disease categories. Mortality and Pipe and Cigar Smoking Pipe and cigar smokers have mortality rates that are similar to those of cigarette smokers for cancers of the oral cavity, pharynx, larynx, and esophagus. Pipe and cigar smokers have much lower death rates than cigarette smokers for cancer of the lung, ischemic heart disease, and chronic obstructive lung disease. Since these last three disease categories account for the bulk of the excess mortality associated with cigarette smoking, pipe and cigar smokers experience overall mortality rates that are much lower than cigarette smokers. Inhalation of smoke is necessary to expose the heart and lungs to the harmful constituents found in tobacco smoke, and pipe and cigar smokers report much less inhalation of smoke than cigarette smokers. Pipe smoke and cigar smoke contain nearly all the same chemical compounds found in cigarette smoke, but pipe and cigar smoke tends to be alkaline in pH rather than acid as is cigarette smoke. Alkaline smoke is irritating to the respiratory tract. This is likely to be an important reason why pipe and cigar smokers report a much lower level of smoke inhalation than cigarette smokers. Table 32 summarizes the mortality ratios for male smokers by the type of tobacco used for the five studies that obtained data on pipe and cigar smoking. Cigar smokers have overall mortality ratios that are from 6 to 25 percent higher than nonsmokers. Mixing cigarette smoking with pipe or cigar smoking substantially increases the mortality ratios, although they remain somewhat less than the mortality ratios of cigarette-only smokers. Dose-response relationships between overall mortality and the amount of tobacco smoked were examined in several studies. Data 2-30 w 9.0 6.0 7.0 6.0 5.0 4.0 3.0 !!! < 2.0 2 4 f LE 8 & 1.0 8 0.9 g 0.5 1 0.7 8 0.6 i 0.5 3 0.4 0.3 0.2 0.1 0 - - 0 Never Smoked - Ex-c@am6e znwhem stopped ka lhan 5 years ego ??????? o wuntsmoked,21-39 cigsfenes per day. - Cunent dgamtle smokets. Smokii21-39cignemnp3fday 1 2 3 4 5 6 7 6 9 10 11 12 13 14 16 16 YEARS OF FOUWWP FIGURE l.-Annual probability of dying for ex-smokers who quit smoking less than 5 years, current cigarette smokers and nonsmokers, aged 55-64, U.S. veterans 1954 cohort, 16-year follow-up SOURCE: Rogot,~.(SS). 2-31 QX 9.0 0.0 7.0 6.0 5.0 4.0 3.0 ul g 2.0 8 8 9 ii g 1.0 ij 0.9 c 0.6 2 $ 0.7 f. 0.6 a 0.5 z 4 0.4 0.3 0.2 . 0.1 O---O Never.Smo@d Maximum emounr smoked 21-39 cigarenes per day. - currenl cigerelle aokefs. smoking 21-39 oigamnes Pm day. I I 1 I I I I I I I I 1 1 1 1 1 , 2 3 4 5 6 7 0 9 10 11 12 13 14 15 16 MARS OF FOLLOWUP FIGURE 2.-Annual probability of dying for ex-smokers who quit smoking 5-9 years, current cigarette smokers and nonsmokers, aged 5&64, U.S. veterans 1954 cohort, X-year follow-up SOURCE: Rogot, E (SJ). 2-32 9x 8.0 0.0 7.0 6.0 5.0 ly , - I - 4.0 3.0 , - I - I - I - , _ , - , - I - 0.3 0.2 0.1 . 0 w o---O NwerSmoked m Ex-olgemlle unduns stopped 10-14 years Maximum amount mmked 21-39 cigaMte6 wr day. I I I I I I I I I I II I I I) 1 2 3 4 5 6 7 0 Q 10 11 12 13 14 15 16 YEARS OF FOLlOWUP FIGURE S.--Annual probability of dying for ex-smokers who quit M-14 years, current cigarette smokers and nonsmokers, aged 5W, U.S. veterans I954 cohort, IS-year follow-up SOURCE: *t, E. (88). 2-33 v 9.0 8.0 7.0 6.0 5.0 4.0 3.0 !Y 5 ij 2.0 g E P ii :.c 8 0.E c 0.e 1 0.i E 0.E 3 0.5 f 0.4 0.: o---ONeversmoked 9----8 Ex-cgmne 8moh8rs Stopped 15cwmoreyeamago Maximum mnolmt mwked 21-36 cigsrs4tes psr day. m Current c4gnrett8 smokers. Sting 21-39 cigarettes pa d8y. I I I I I I i I I I I I I I I I 1 2 3 4 5 6 7 8 `9 ii 11 12 13 14 15 16 YEARS OF FOLLOWUP FIGURE I.-Annual probability of dying for ex-smokers who quit 15+ years, current cigarette smokers and nonsmokers, aged 55-64, U.S. veterans 1954 cohort, N-year follow-up SOURCE: Rqot, E. (3s). 2-34 TABLE 31.-Mortality ratios of ex-smokers compared to nonsmokers, by age and number of years since stopping smoking. Study of British doctors Years since Mortality ratios stopping Age Age All smoking a64 6.5+ ages 0 (Cumen~ smokers) 20 1.6 1.8 1-4 1.7 1.4 1.5 69 1.6 1.4 1.5 US-14 1.4 1.2 1.3 15+ 1.1 1.1 1.1 Nonsmokers 1.0 1.0 1.0 SOURCE: Doll. R. (8). TABLE 32.-Mortality ratios for male smokers, by type of tobacco used Study Men in 9 States(20) British Docto~4) Canadian Veterans(f) U.S. Veterans(26) Males ir. 25 States(l7) Non- Cigar smoker only 1.00 1.22 1.00 .I 1.00 1.06 1.00 1.16 1.00 1.25 pipe only 1.12 ** 1.05 1.07 1.19 Cigar & Pipe 1.10 1.09 0.93 1.08 1.01 Cigarette & cigar Cigarette or pipe 0ttly 1.43 1.63 1.31 1.73 1.13 1.54 1.51 1.55 1.57 1.36 from the study of men in nine States, Canadian veterans, and the ACS 25-State Study are presented in Tables 33 through 35. There is a dose- response relationship evident for cigar smoking that is small but found consistently. There was no clear dose-response relationship for pipe smoking. Data from the U.S. Veterans Study are presented in Tables 36 through 39. Again, there appears to be a dose-response relationship for cigar smoking, both for the number of cigars smoked per day and for the age began smoking cigars. For pipe smokers, a dose-response relationship was found for the number of pipefuls per day, but not for the age began smoking. The U.S. Veterans Study (31) contains the most detailed information on pipe, cigar, and cigarette smoking in various combinations and in various sequences. These data on mortality ratios are shown in Table 40 and have been arranged by "increasing risk of mortality." The first section shows the mortality experience of current cigarette smokers by the present, past, or nonuse of pipes and cigars. Cigarette smokers who have the lowest mortality ratio of 1.21 are those who also currently smoke both pipes and cigars. Current cigarette smokers who formerly smoked pipes and cigars have a mortality ratio of 1.48, which is only 2-35 TABLE 33.-Age-adjusted mortality ratios for male cigar and pipe smokers, by amount smoked. Males in nine States Type and amount smoked ratio Nonsmokers Cigar only l-4 per day 4+ per day All cigar smokers 1.00 1.03 1.24 1.09 Pipe only l-10 pipefuls per day lO+ pipefuls per day All pip smokem 1.05 1.19 1.09 SOURCE: Hammond. E.C. (SO). TABLE 34.-Age-adjusted mortality ratios for male cigar and pipe smokers, by amount smoked. Canadian veterans Type and amount Mortality smoked ratio Nonsmoker Cigar only l-2 per day t10 per day 1.00 1.14 1.19 pipe only l-10 pipefuls per day IO+ pipefuls per day 1.01 1.00 SOURCE: Best, E.W.R (I). slightly below the mortality ratio of 1.55 of cigarette-only smokers who have never smoked pipes or cigars. The second section of Table 40 shows that the mortality ratios of current cigar smokers are slightly decreased among those also currently smoking pipes and significantly increased among those also currently smoking cigarettes. The third section shows that pipe smokers with the lowest mortality are those who have never smoked cigarettes or cigars. Mortality ratios increase slightly with the addition of current cigar smoking and jump moderately with the addition of current cigarette smoking. 2-36 TABLE 35.-Age-adjusted mortality ratios for male cigar and pipe smokers, by amount smoked. Males in 25 states Type and amount smoked Mortality ratio NonsmokeR Cigar only 14 day per 4+ per day All cigar smokers 1.00 1.03 1.18 1.09 pipe only l-9 pipefuls per day 9+ pipefuls per day All pipe smokers SOURCE: Hammond, EC. (I?). 1.08 0.92 1.04 TABLE 36.-Age-adjusted mortality ratios of current smokers of cigars only, by amount smoked. U.S. veterans 1954 cohort, 16year followup No. of cigars per day Mortality ratio Nonsmokers 1.00 l-2 1.11 5-4 1.13 54 1.22 9+ 1.39 Total 1.16 ~URCE: Roget. E. (33). TABLE 37.-Age-adjusted mortality ratios of current smokers of cigars only, by age began smoking. U.S. veterans 1954 cohort, H-year followup Mortality ratio Nonsmokers 1.00 <15 1.22 15-19 1.23 20-24 1.16 >a 1.13 Total 1.16 mURf% Rc@, E. (33). Mortality by Cause of Death The underlying cause of death was obtained from the death certificate 2-37 TABLE 38.-Age-adjusted mortality ratios of current smokers of pipes only, by amount smoked. U.S. veterans 1954 cohort, M-year followup No. of Mortality t%wfuls ratio Nonsmokers 1.00 <5 0.93 .%9 1.12 l&19 1.@3 >19 1.21 Total 1.07 SOURCE: Ragot, E. (~3). TABLE 39.-Age-adjusted mortality ratios of current smokers of pipes only, by age began smoking. U.S. veterans 1%-d cohort. 16-Year followuD Mortality ratio Nonsmokers 1.00 <15 1.04 15-19 1.12 2w4 1.06 >24 1.06 Total 1.07 SOURCE: Ito@, E (33). in each of the eight prospective studies. These were classified according to the International Statistical Classification of Diseases, Injuries, and Causes of Death. The mortality ratios of current cigarette smokers by cause of death in the prospective epidemiological studies are presented in Table 41. The causes of death have been grouped into four categories: cancers, cardiovascular diseases, respiratory diseases, and other conditions. Mortality ratios for the "all cancers" category are about twice as high in smokers as in nonsmokers. Accordingly, cigarette smokers are about twice as likely as nonsmokers to die of cancer. The highest mortality ratio for malignancies is for lung cancer, followed by cancer of the larynx, oral cavity, esophagus, urinary bladder, and the pancreas. Cigarette smoking has been established as a major cause in the development of these cancers. There are associations between cigarette smoking and cancer of the kidney and stomach, but further research is needed to determine the exact nature of this association. Cancer of the intestines and rectum do not appear to be related to cigarette smoking. 2-38 TABLE IO.-Age-adjusted mortality ratios of males smoking cigarettes, pipes, and cigars in various combinations and at various times. U.S. veterans 1954 cohort Current cigarette smokers by use of other types of tobacco Cigxs Pipes Mortality ratio Current Never Current Current Former Never Former Former Never Current 1.21 current 1.28 Never 1.30 Former 1.33 Current 1.36 Former 1.47 Former 1.43 Never 1.63 NWW 1.55 Current cigar smokers by use of other types of tobacco Cigm-ettes pipes Mortality ratio Never Former Never Former Never Current Former Current Current Former 1.10 Former 1.10 Current 1.10 Current 1.13 Never 1.16 Current 1.21 Never 1.23 Never 1.30 F0rllW 1.33 Current pipe smokers by use of other types of tobacco Cigarettes Cigars Mortality ratio Never Never Former Never Former Former current Never Never Former Current Former Current Never Former 1.07 1.10 1.10 1.11 1.14 1.14 1.21 1.23 1.36 SOURCE: Roget, E. (8.9). The mortality ratio for the "all cardiovascular disease" category is about 1.6. Coronary heart disease is the most important cause of cigarette smoking-related mortality. The mortality ratios for coronary heart disease in the eight studies varied from 1.3 to 2.03. Although the mortality ratio for coronary heart disease is considerably lower than for lung cancer, it results in a greater excess mortality because Coronary heart disease is the most common cause of death in the 2-39 TABLE iI.--Wortal.ity ratios of current cigarette-only smokera, by caums of death in eight pmapective epidemiological studies All Cmcem ,14Mm. Cmcer of lung and bmnehu ,162161, Cancer nt larynx (16ll.. Cancer of bum., unly 114&141, C-of PhuYnl ,MbMn.. .,,I seqmkwy D- ,wm-~0luucl .......... EmphyTem and/w bfoncnitu .............. Empnyrav ntbout b+mch~ Lt. 15271,. ... Bmmh,,,, ,5&502, ...................... Respmtoly rubermlosu ,m,r, ......... ..... ...... Irthm Cal,. ..... ............. .............. ........... ,lul~~ md pnummu ,4m..m,. ..................... jtamwh ular ,5,O, ...................... ...... DwdenJ ulcer ,%I, .... ckrbam (~1, ............... :.:.:. .... .... ... ... Pukmaomsm 1350) ........ .......... . 140 130 4.7 21 16 . . . . . 27 1.6 1.3 66 . 1.1 24.7 . . 5.0 . . 1.4 25 3.0 0.4 1.64 214 7.84 6.04 9.90 LX L1.59 8.99 293 4.17 I?0 169 1.42 1.12 1.01 I.74 296 Zli :.51 us l.17 1.90 2ce 139 262 1.40 . . . . . . is5 . . . 1.m 4.06 2,s 203 1.3, 1.36 LOB 4.92 1.42 . . . . . L1.41 . . . . .-_ 1.R 4.13 ml 1.97 1.m 1.4 221 ,211 9.95 ,.cu I254 6.17 215 184 1.45 1.60 127 0.98 I.?!. I.74 1.52 5.24 IAl 1.m . . ,000 14.17 4.4s PI2 3.4, 181 4.1s 293 .%!a 026 1.M 1.62 3.54 w.5a 1.M 281 2.57 098 LEa 1.11 lJ1 121 0.91 . . 1.96 1.14 . . 2.51 . . . . . . . . . . 127 . . . . . PM 156 . . . lz! . . 14.2 3.9 33 1.3 21 1.1 1.9 1.4 06 .-. 1.6 0.9 1.S 1.6 3.3 ._. . . . 7.i 113 . . . . . 1.1 . . . 6.9 23 . . . 1.52 1.97 lO.TS w. 10 ?BD . . 6.m 2x3 . . 1.50 230 0.50 080 1.5, 1.n 1.30 . . la, Lea 2a5 230 ._. . . ._. . . 280 . . 218 I.1 . . 1.70 . . 7.0 . ._. . 1.0 3.1 . . . 09 . . . . . 17 1.0 L.6 13 20 . . 13 . . . . . . . .._ ._. . . .._ 2b . . 1.4 . . 4.5 . . . . . . . 1.6 25 ._. 23 . . . . . . 1.3 1.1 _.. 1.4 20 . . 1-?1 . . . . . . . . . . ._. . . . . 03 . . l.2 . . 15.9 . . 1.0 . . . 0.1 6.0 . . . 0,s 0.9 1.0 . . 20 1.8 . . . LO . . . 4.3 . . . . . . . . . . 24 ._. 0.5 *II . . . 178 United States. There are several important- risk factors for the development of coronary heart disease, including cigarette smoking, hypertension, and high blood cholesterol None appears to be more important than cigarette smoking. Cigarette smoking does not appear to be a significant cause of hypertension or-elevated serum cholesterol, but there is an adverse synergism between these risk fact&s that greatly increases the risk of ischemic heart disease for individuals who have multiple risk-factors. There is a strong and, most likely, causal relationship between cigarette smoking and death from aortic aneurysm (nonsyphylitic). General arteriosclerosis is also associated with cigarette smoking. Of the non-neoplastic respiratory diseases, cigarette smoking is most strongly associated with emphysema and chronic bronchitis. Because of difficulty in differentiating between these diseases, and since they commonly coexist in an individual, they are frequently combined and called chronic obstructive lung disease (COLD). It is clear that cigarette smoking is the major cause of COLD. .Certain industrial exposures result in COLD, and in these situations an adverse synergism with cigarette smoking exists, creating premature disability and death primarily among cigarette smokers in these industries. Asthma is not commonly caused by cigarette smoking, but this condition is seriously aggravated by cigarette smoking. -Deaths from infectious pulmonary diseases such as pneumonia and influenza are more common in cigarette smokers than in nonsmokers. The mechanisms responsible for the increased mortality from stomach and duodenal ulcers among cigarette smokers are not clearly understood. The association of cigarette smoking with cirrhosis is an indirect one. There is a strong correlation of cigarette smoking with the use of alcoholic beverages, which in turn cause cirrhosis. There is a significant negative association between cigarette smoking and parkinsonism; the cause of this association is not known. The Constitutional Hypothesis, Social, and Environmental Factors Certain critics have advanced various hypotheses in an attempt to dismiss cigarette smoking as a cause of mortality. The constitutional hypothesis and social and various environmental factors have been raised as explanations of the mortality trends that have been observed to be associated with cigarette smoking. The constitutional hypothesis holds that people with certain genetically-acquired constitutional makeups are more likely to develop Certain diseases and are also more likely to smoke cigarettes. This hypothesis maintains that the relationship between cigarette smoking and certain diseases is largely fortuitous. 2-41 Data from the United States and Swedish Twin Registries have been examined to try to clarify the constitutional hypothesis. Cederlof, et al. (3) have published the most extensive data available on the interac- tions of smoking, environment, and heredity in the development of disease. Comparisons were made between smoking discordant monozy- gotic (identical) pairs and smoking discordant dizygotic (fraternal) pairs, and between unmatched twin pairs and matched twin pairs. When smoking and overall mortality are examined, treating all twins as "unrelated" individuals, a strong correlation is found. The group smoking more than 10 cigarettes per day has a mortality ratio of about 2.0 compared to nonsmokers. This is true for both men and women in all age groups. When smokers and nonsmokers among the dizygotic pairs were compared, a mortality ratio of 1.45 for males and 1.21 for females was observed. Corresponding mortality ratios for the monozygotic pairs were 1.5 for males and 1.22 for females. Commenting on the constitutional hypothesis and lung cancer, the authors observed that "the constitutional hypothesis as advanced by Fisher and still supported by a few, has here been tested in twin studies. The results from the Swedish monozygotic twin series speak strongly against this constitutional hypothesis" (3). Preston (27'-30) has published several articles in which he examined the excess mortality-above predicted values for men and women- that has occurred in the United States and other countries. Genetic, social, and environmental factors were analyzed in an attempt to explain this phenomenon. The genetic and social hypothesis received some support from correlation analysis; however, the correlations were weak and became trivial when cigarette smoking was taken into consideration. Preston observed: "Rather than representing victimiza- tion by nature or by hostile social forces, the current abnormal rates of dying among older males appear to be largely self-imposed and avoidable" (28). Social, genetic, and environmental arguments are also weakened by the observation that epidemiological studies of the effects of cigarette smoking have been conducted in many countries on every major continent and among peoples of diverse social and cultural back- grounds who are exposed to a variety of environmental factors-all with similar results. Cigarette smoking causes the same diseases, and the same dose-response relationships are found wherever the effects of cigarette smoking are studied. Summary of Overall Mortality Related to Smoking The following conclusions summarize the relationships that have been established between smoking and overall mortality. Some conclusions were drawn 15 years ago; others are based on data that have 2-42 accumulated in the interval since publication of the first Surgeon General's Report. 1. The overall mortality ratio for all smokers of cigarettes is about 1.7 compared to nonsmokers. 2. Life expectancy is significantly shortened by cigarette smoking. A 30-year-old, two-pack-a-day smoker has a life expectancy that is 8.1 years shorter than his nonsmoking counterpart. 3. Overall mortality ratios increase with the amount smoked. The mortality ratio is 2.0 for the two-pack-a-day smoker as compared to nonsmokers. 4. Overall mortality ratios for smokers are highest at younger ages and decline somewhat with increasing age. This reflects a relative decrease of the impact of smoking on health as death rates in general increase with age. This is a relative effect. The actual number of excess deaths attributable to cigarette smoking increases with age. 5. Overall mortality ratios are proportional to the duration of cigarette smoking. The longer one smokes, the greater the risk of dying. 6. Overall mortality ratios are higher for those who began smoking at a young age as compared to those who began smoking later. 7. Overall mortality ratios are higher for those who report they inhale smoke than for those who do not inhale. 8. Overall mortality ratios increase with the tar and nicotine content of the cigarette. Overall mortality ratios of low tar and nicotine (less than 1.2 mg nicotine and less than 17.6 mg tar) cigarette smokers are 50 percent higher than for nonsmokers. 9. Overall mortality ratios for female smokers are somewhat less than for male smokers. This probably reflects differences in exposure to cigarette smoke, such as starting smoking later, smoking cigarettes with lower tar and nicotine content, and smoking fewer cigarettes per day than men. 10. Women demonstrate the same dose-response relationships with cigarette smoking as men. An increase in mortality occurs with an increase in the number of cigarettes smoked per day, an earlier age of beginning cigarette smoking, a longer duration of smoking, inhalation of cigarette smoke, and a higher tar and nicotine content of the cigarette. Women who have smoking characteristics similar to men experience mortality rates similar to men. 11. Ex-smokers experience overall mortality ratios that decline as the number of years off cigarettes increases. After 15 years, the overall mortality ratios of ex-smokers are similar to those of individuals who have never smoked. 12. Ex-smokers have overall mortality ratios that are directly Proportional to the number of cigarettes the person used to smoke. 13. Ex-smokers have overall mortality ratios that are inversely related to the age at which the person began to smoke. 2-43 14. Ex-smokers who were ill when they quit smoking have higher mortality rates than ex-smokers who quit for other reasons. 15. Regardless of how long or how much an individual has smoked, there is a decrease in overall mortal&y when the person quits smoking, provided the person is not ill at the time of quitting. 16. Overall mortality ratios for cigar-only smokers aa a group are somewhat higher than for nonsmokers. 17. Overall mortality ratios for cigar smokers increase with the number of cigars smoked per day. 18. Overall mortality ratios for cigar smokers are inversely proportional to the age at which the individual began smoking cigars, 19. Overall mortality ratios for pipe-only smokers as a group are only slightly higher than for nonsmokers. 20. Overall mortality ratios of men who smoke cigarettes in combination with pipes and cigars are intermediate between those who smoke pipes or cigars only and those who smoke only cigarettes. Summary of Smoking and Mortality by Cause of Death 1. Mortality ratios are particularly high for a number of diseases associated with smoking. These include: a. Cancer of the lung b. Chronic obstructive lung diseases, emphysema, and chronic bronchitis c. Cancer of the larynx d. Cancer of the oral cavity e. Cancer of the esophagus f. Ischemic heart disease g. Cancer of the urinary bladder h. Cancer of the pancreas i. Aortic aneurysm (nonsyphilitic) j. Ulcers of the stomach and duodenum 2. Coronary heart disease is the chief contributor to the excess mortality associated with cigarette smoking. 3. Lung cancer is the second leading contributor to excess mortality associated with cigarette smoking. 4. Chronic obstructive lung disease is the third leading contributor to excess mortality associated with cigarette smoking. 5. Pipe smoking and cigar smoking are associated with elevated mortality ratios for cancers of the upper respiratory tract, including cancer of the oral cavity, the larynx, and the esophagus. 2-44 Mortality: References (I) BEST, E.W.R., JOSIE, G.H., WALKER, C.B. A Canadian study of mortality in relation to smoking habits: A preliminary report. Canadian Journal of Public Health 52: 99-196, March 1961. (2) CEDERLOF, R., FRIBERG, L., HRUBEC, Z., LORICH, U. The Relationship of Smoking and Some Social Covariables to Mortality and Cancer Morbidity. A Ten Year Follow-up in a Probability Sample of 55,000 Swedish Subjects Age 18 to 69, Part I and II. Stockholm, Sweden, Karolinska Institute, Department of Environmental Hygiene, 1975,201 pp. (3) CEDERLOF, R., FRIBERG, L., LUNDMAN, T. The interactions of smoking, environment, and heredity and their implications for disease etiology. A report of epidemiological studies on the Swedish Twin Registries. Acta Medica Scandinavica, Supplement 612%123, September 19'77. (4) DOLL, R., HILL, A.B. Lung cancer and other causes of death in relation to smoking. A second report on the mortality of British doctors. British Medical Journal 2: 1071-1631, November 1,1956. (5) DOLL, R., HILL, A.B., Mortality of British doctors in relation to smoking: Observations on coronary thrombosis. In: Haenszel, W. (Editor). Epidemiologi- cal Approaches to the Study of Cancer and Other Chronic Diseases. National Cancer Institute Monograph No. 19. U.S. Department of Health, Education, and Welfare, Public Health Service, National Cancer Institute, January 1966, pp. 265266. (6) DOLL, R., HILL, A.B. Mortality in relation to smoking: Ten years' observations of British doctors. Part I. British Medical Journal l(5395): 1399-1410, May 36, 1964. (7) DOLL, R., HILL, A.B. Mortality in relation to smoking: Ten years' observations of British doctors. Concluded. British Medical Journal 1(X%6): 1460-1467, June 6,1964. (8) DOLL, R., PETO, R. Mortality among doctors in different occupations. British Medical Journal l(6974): 1433-1436, June 4,1977. (9) DOLL, R., PETO, R. Mortality in relation to smoking: 26 years' observations on male British doctors. British Medical Journal 2(6951): 15251536, December 25, 1976. (10) DOLL, R., PIKE, M.C. Trends in mortality among British doctors in relation to their smoking habits. Journal of the Royal College of Physicians 6(2): 216222, January 1972. (11) DORN, H.F. The mortality of smokers and nonsmokers. P&rigs of the Social Statistics Section of the American Statistical Association. Papers presented at the Annual Meeting of the American Statistical Association, Chicago, Illinois, December 2730, 1958. Washington, D.C., American Statisti- cal Association, 1959, pp. 34-71. (12) DUNN, J.E., LINDEN, G., BRESLOW, L. Lung cancer mortality experience of men in certain occupations in California. American Journal of Public Health 56(10): 1475-37, October 1969. (13) EPIDEMIOLOGY DIVISION, HEALTH SERVICES BRANCH, BIOSTATIS TICS DIVISION, RESEARCH AND STATISTICS DIRECTORATE. A Canadian Study of Smoking and Health. Department of National Health and Welfare, Epidemiology Division, Health Services Branch, Biostatistics Divi- sion, Research and Statistics Directorate, 1966,137 pp. (14) HAMMOND, E.C. Evidence on the effects of giving up cigarette smoking. American Journal of Public Health 55(5): 632691, May 1965. (15) HAMMOND, E.C. Life expectancy of American men in relation to their smoking habits. Journal of the National Cancer Institute 43(4): 951-962, October 1969. 2-45 (16) HAMMOND, E.C. Smoking habits and air pollution in relation to lung cancer. In: Lee, D.H.K. (Editor). Environmental Factors in Respiratory Disease. Fogarty International Center Proceedings No. 11, New York, Academic Press, 1972. pp. 177-198. (I?) HAMMOND, E.C. Smoking in relation to the death rates of one million men and women. In: Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases, National Cancer Institute Monograph 19. U.S. Department of Health, Education, and Welfare, U.S. Public Health Service, National Cancer Institute, January 1966, pp. 127-204. (18) HAMMOND, EC., GARFINKEL, L. Coronary heart disease, stroke, and aortic aneurysm. Factors in the etiology. Archives of Environmental Health 19(2): 167-182, August 1969. (19) HAMMOND, EC., GARFINKEL, L., SEIDMAN, H., LEW, E.A. "Tar" and nicotine content of cigarette smoke in relation to death rates. Environmental Research l2(3): 263-274, December 1976. (SO) HAMMOND, E.C., HORN, D. Smoking and death rates-Report on forty-four months of follow-up on 187,783 men. I. Total mortality. Journal of the American Medical Association X6(10): 1159-1172, March 81958. (al) HIRAYAMA, T. Operational aspects of cancer public education in Japan. In: Summary Proceedings of the International Conference on Public Education About Cancer. UICC Technical Report Series, Volume 18, Geneva, 1975, pp. 85 90. (22) HIRAYAMA, T. Prospective studies on cancer epidemiology baaed on census population in Japan. In: Bucalossi, P., Veronesi, U., Cascinelli, N. (Editors). Cancer Epidemiology, Environmental Factors. Volume 3. proceedings of the 11th International Cancer Congress, Florence, 1974, Excerpta Medica, pp. 26 35. (%!?) HIRAYAMA, T. Smoking and drinking-Is there a connection? Smoke Signals 16(7): l-8, July 1970. (24) HIRAYAMA, T. Smoking in relation to the death rates of 265,118 men and women in Japan. Tokyo, National Cancer Center, Research Institute, Epidemiology Division, September 1967,14 pp. (25) HIRAYAMA. T. Smoking in relation to the death rates of 265,118 men and women in Japan. A report on 5 years of follow-up. Presented at the American Cancer Society's 14th Science Writers' Seminar, Clearwater Beach, Florida, March 24-29,1972,15 pp. (26) KAHN, H.A. The Dom study of smoking and mortality among U.S. veterans: report on 8 l/2 years of observation. In: Haenszel, W. (Editor). Epidemiologi- cal Approaches to the Study of Cancer and Other Chronic Diseases. National Cancer Institute Monograph 19. U.S. Department of Health, Education, and Welfare, Public Health Service, National Cancer Institute, January 1966. pp. 1-125. (27) PRESTON, S.H. The age-incidence of death from smoking. Journal of the American Statistical Association 65(331): 11251136, September 1970. (28) PRESTON, S.H. An international comparison of excessive adult mortality. Population Studies 24(l): 5-20, March 1970. (29) PRESTON, S.H. Mortality differentials by social class and smoking habit. social Biology X(4): 280-289, December 1969. (90) PRESTON, S.H. Older male mortality and cigarette smoking. A demographic analysis. Institute of International Studies, Berkeley, California, University of California, 1970,156 pp. (81) ROGOT, E. Smoking and General Mortality Among U.S. Veterans, 1954-1969. U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Heart and Lung Institute, Epidemiolo- gy Branch, DHEW Publication No. (NIH) 74-544,1974,65 pp. 2-46 3. MORBIDITY. National Center for Health Statistics CONTENTS Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Past Studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Recent Studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . 11 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 LIST OF TABLES Table l.-Age-specific ratios of prevalence rates of chronic conditions for persons who had ever smoked to persons who had never smoked, by sex, age, and selected chronic conditions: United States, July 1964 to June 1965 . . . . . . . . 6 Table 2.-Ratios of age-adjusted prevalence rates of chronic conditions for persons 1'7 years old and older who have ever smoked, to persons who have never smoked, by cigarette smoking status, number of cigarettes smoked per day for present smokers-heaviest amount, sex, and selected chronic conditions: United States, July 1964 to June 1965 . . . . . . . ,.......................... `7 Table 3.-Ratios of age-adjusted incidence of acute conditions for persons 17 years old and older who have ever smoked, to persons who have never smoked, by cigarette smoking status, number of cigarettes smoked per day for present smokers-present amount, sex, and selected acute conditions: United States, July 1964 to June 1965 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Table 4.-Ratios of age-adjusted number of days of disability per person 17 years old and older per year 3-3 who have ever smoked, to persons who have never smoked, by number of cigarettes smoked per day for present smokers-heaviest amount, type of days of disability, smoking status, and sex: United States, July 1964 to June 1965 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 . . . . . . . . . . 10 Table 5.-Days of bed disability per person 1'7 years old and older, by cigarette smoking status, sex, and age: United States, 1974 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Table 6.-Days lost from work per year due to illness and injury, per currently employed persons 17 years old and older, by smoking status, sex, and age: United States, 1974.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . 13 Table 7.-Percent of persons with chronic condition(s) causing limitations of activity, by cigarette smoking status, sex, and age: United States, 1974 . . . . . . . . . . . . . . . . . . . 14 Table B.-Percent of persons 17 years old and older, who perceive their health to be "excellent," by cigarette smoking status, sex, and age: United States, 1974 . . . . . . . 15 Table 9.-Percent of persons 17 years old and older, with one or more hospital episodes in the year prior to interview, by cigarette smoking status, sex, and age: United States, 1974 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Table lO.-Percent of persons 17 years old and older, with five or more physician visits in the year prior to interview, by cigarette smoking status, sex, and age: United States, 1974 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Table ll.-Percent of persons 17 years old and older who have ever smoked and who were ever advised by a physician to stop smoking, by cigarette smoking status, sex, and age: United States, 1974 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Table 12.-Percent of present cigarette smokers 1'7 years old and older who have tried to stop smoking, by sex and age: United States, 1974 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Table 13.-Percent of persons 17 years old and older who have been told by a doctor that they had heart trouble, by cigarette smoking status, sex, and age: United States, 1974 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19 3-4 htroductlon For many years, researchers have been accumulating evidence of the relationship between cigarette smoking and mortality, as well as data on the relationship between smoking and the prevalence of selected chronic diseases. These findings are presented in detail elsewhere in this report. It has been only recently that data have also become available that indicate a relationship, although a statistical relationship and not an established causal relationship, between cigarette smoking and disability and other health indicators. This chapter of the report will present some of these data based on surveys conducted by the National Center for Health Statistics (NCHS). Past Studies One of the few sources of national data on cigarette smoking and health characteristics, and the only data set based on a large national sample, is the National Health Interview Survey. This is a continuous survey conducted by NCHS each year since 1957. Interviews are conducted in a national probability sample of approximately 40,000 households, with a new sample selected each year. Information is obtained on a wide range of health characteristics, including incidence of acute illnesses and injuries, prevalence of selected chronic diseases, short- and long-term disability associated with illness and injuries, utilization of health services, and related health topics such as health insurance coverage, usual sources of medical care, and use of prescription medicine. One of the topics on which data have been periodically collected is cigarette smoking behavior. Some data on cigar and pipe smoking have also been collected. Shortly after the Surgeon General's first report, Smoking and Health, was published in 1964, NCHS began collecting information on smoking as a part of the Health Interview Survey. The result of this effort was a report, Cigarette Smoking and Health Gharaeteristics (14, which was the first such study based on a national probability sample. While several significant studies had been conducted earlier, such as those by Hammond and Horn (5, 6), they were, for the most part, not based on scientifically designed samples, and were therefore subject to the criticism that the findings could not be generalized to the total Population. NCHS's first report on smoking, based on the fiscal year 1965 survey, presented data on the relationships between cigarette smoking, the incidence of selected acute illnesses, and the prevalence of selected chronic diseases, as well as information on the relationship between smoking and measures of disability, such as restricted activity days, bed days, and work-loss days. The data showed, for example, that male cigarette smokers were almost 2 l/2 times more likely to report chronic bronchitis or emphysema than were those who had never smoked, and almost 60 3-5 TABLE l.-Age-specific ratios' of prevalence rates of chronic conditions for persons who had ever smoked to persons who had never smoked, by sex, age, and selected chronic conditions: United States, July 1964 to June 1965 Male Female Selected chronic conditions Ratio All chronic conditions. 1.09 1.212 1.17 1.09 0.9U 1.1 1.02 0.99 Heart conditions (excluding rheumatic heart disease). _. _. Arteriosclerotic heart disease including coronary disease Hypertension without heart involvement.. _. _. _. _. Chronic bronchitis and/or emphysema Chronic sinusitis. _. __ _. _. _. Peptic ulcer.. Arthritis.. Hearing impairments.. All other chronic conditions........................ 1.00 o 1.50 t 0.91 1.25 2.30 o o 2.67 ???? 1.33 1.31 1.34 2.00 2.33 1.38 1.59 0.95 1.64 0.99 1.06 0.38 1.31 1.06 0.97 1.07 1.19 1.15 1.03 1.45 1.30 0.86 1.06 1.22 0.95 0.47 1.33 0.92 0.92 0.75 t 1.63 1.61 0.57 1.17 0.75 0.69 238 3.43 2.86 216 1.25 1.34 1.19 1.22 1.56 1.62 1.52 235 0.63 1.32 0.89 0.97 0.55 1.05 1.02 0.75 0.95 1.23 1.W 0.99 ~Prevalence rate of "ever smokers" divided by prevalence rate of "never smokers." ZExample: I.27 - 82.9/65.4. *Figure does not meet standards oi reliability or precision. tQuantity zero. SOURCE: Wilson. R.W. (14). percent more likely to report arteriosclerotic heart disease (Table 1). Among the heaviest smokers the relationships were even stronger. For example, women who smoked between one and two packs a day reported chronic bronchitis or emphysema almost five times more frequently than did women who had never smoked (Table 2). In addition, former smokers, particularly among the males, reported higher rates of chronic illnesses than did the current smokers. Data were not available to further analyze illness rates by the reason people stopped smoking, i.e., the category of former smokers is composed of both those who stopped because of poor health and those who stopped to avoid poor health. Data from this study also indicated that people who had ever smoked cigarettes also had a higher incidence of acute illnesses than did people who had never smoked. The age-adjusted incidence of acute conditions 3-6 TABLE 2.-Ratios of age-adjusted' prevalence rates of chronic conditions for persons 17 years old and older who have ever smoked, to persons who have never smoked, by cigarette smoking status, number of cigarettes smoked per day for present smokers- heaviest amount, sex, and selected chronic conditions: United States, July 1964 to June 1965 Cinarette smoking status Present smokem Sex and selected chronic conditions Male Persons Number of cigarettes who Former Present smoked per day-heaviest smokers smokers amount ever smoked Under 41 and 11 11-20 1 2140 over RatioZ All chronic conditions.. 1.17 1.26 1.13 0.92 1.04 1.30 1.54 Heart conditions (excluding rheumatic heart disease). Arteriosclerotic heart disease, including coronaly dii Hypertension without heart involvement.. Chronic bronchitis and/or emphyseme Chronic &usitis.. Peptic ulcer.. Arthritis.. . . Hearing impairments.. All other chronic mndltwna _. Female All chronic conditions 1.12 1.23 1.22 1.44 1.67 2.P 1.02 1.07 240 2.50 1.34 1.46 1.92 1.75 1.07 1.24 1.06 1.14 1.13 1.23 1.12 0.93 1.66 ' 1.00 0.93 ??? o 1.30 0.93 1.96 1.25 0.99 0.97 1.04 0.98 1.09 0.90 1.09 0.88 107 1.44 0.88 230 1.22 1.92 0.67 0.94 1.01 1.05 1.29 1.71 2.11 .3 1.20 1.27 3.10 4.10 1.57 1.78 2.17 2.15 1.16 1.16 1.14 1.34 1.25 1.50 1.39 2.00 Heart conditions (excluding rheumatic heart disease) 0.91 1.26 0.81 0.65 0.81 1.05 . Arlerioselerotic heart diaeaae, including Wmwy dweaae 1.29 o ???? ? ? o ? Hypertension without tart involvement 0.36 0.98 0.83 0.86 0.76 0.90 . Chm"ic bronchitis and/or eWwema . . . 283 2.17 3.17 1.33 3.33 4.92 9.67 Chmnk sinusitis.. . . 1.32 1.24 0.97 126 1.56 1.74 Peptic ubr. 1.26 1.63 1.63 1.56 1.25 1.56 2.13 . *fihfitis... . . 0.99 1.12 0.98 0.86 0.97 1.11 1.68 "`. -w unparmnts.. 0.93 0.97 0.90 0.72 0.91 1.14 o *iI other chronic tuitions . 1.12 1.25 1.09 0.89 1.04 1.41 208 `Even though the mk,+,ks j" this mlum" replace figurea with large sampling errurn, each of the six Of the EPld % %re larger than the ratios for the lower smoking amounb. wp`1F14 doea "ot meet standards of reliability or precision. SOUSE: Wilmn, R.W. (II). 3-7 for persons who had ever smoked was 14 percent higher among men and 21 percent higher among women than among people who had never smoked cigarettes (Table 3). As with chronic conditions, the former smokers reported higher rates of acute illness than did the present smokers. However, just as the earlier studies were subject to criticism because of their sample designs, this study was criticized because the disease information came from reporting in household interviews rather than from physician examination. Methodological studies on the accuracy of the reporting of disease in which medical records are compared with household interview data have indicated a wide range of reporting completeness depending on the nature and the seriousness of the specific disease (7). Another indication of morbidity is the impact of illness on the individual. Two of the indicators routinely collected in the Health Interview Survey are the number of days lost from work as a result of illness or injury and the number of days which a person had to spend in bed as a result of illness or injury. These indicators are independent of a physician's diagnosis and require only that a respondent attribute the disability to an illness or injury, although the data can also be analyzed by specific disease categories. The data collection procedure requires that respondents recall days spent in bed or days lost from work only for the Zweek period prior to the week of the interview, thus reducing memory loss. The data on work-loss days apply to currently employed persons only and do not reflect long-term work loss from unemploy- ment or early retirement as a result of illness or injury. The age-adjusted data from the 1965 Health Interview Survey indicated that there were about 15 percent more bed-disability days among current smokers than among people who had never smoked cigarettes, and about a third more bed disability days among the former smokers than among those who had never smoked (Table 4). The levels of bed-disability days tended to increase as the number of cigarettes smoked increased, as measured by the heaviest amount smoked. The number of work-loss days among both current and former cigarette smokers was markedly higher than among workers who had never smoked. The age-adjusted rate of work loss was 33 percent higher for male current smokers, 45 percent higher for female current smokers, and 42 percent higher for both male and female former smokers. As with disease and bed-day differentials, the heaviest smokers reported the highest rates of work loss. These data were used by the Public Health Service in its early national public education and antismoking campaigns. The campaigns included television spots that noted there were an estimated 77 million "excess" work-loss days associated with cigarette smoking; that is, if the smokers had the same rate of work loss as did those workers who had never smoked, there 3-3 TABLE 3.-Ratios of age-adjusted' incidence of acute conditions for persons 17 years old and older who have ever smoked, to persons who have never smoked, by cigarette smoking status, number of cigarettes smoked per day for present smokers-present amount, sex, and selected acute conditions: United States, July 1964 to June 1965 Cimrette smoking status Resent smokers Sex and selected acute conditions Persons Number of cigarettes who Former Present smoked per day-present ever smokers smokers amount smoked Under 11-28 2140 41 and 11 O"W Male Ratio2 Ail acute conditions 1.14 1.23 1.11 1.02 1.11 1.23 1.21 Infective and parasitic diseases . . . . Upper respiratov 1.21 1.36 1.16 o eondjtlons Influen7.a.. Other respiratory conditions..................... Digestive system conditions.. Injuries.. . . . . All other acute conditions 1.03 1.22 0.96 0.98 0.98 0.92 o 1.25 1.36 1.22 1.22 1.19 1.28 o 1.62 * 1.54 1.05 1.13 1.03 1.25 1.03 1.32 1.06 1.35 0.95 Female All acute conditions _. 1.21 1.26 1.21 o o 1.00 1.08 1.18 1.24 1.59 o ? ???? 1.41 1.35 1.56 0.35 1.11 1.20 1.31 . o Infective and parasitic diiiiS23 1.35 1.62 1.29 1.26 1.04 2.B t Upper respiratory condltlons..................... 1.26 1.20 1.27 1.29 1.28 1.26 . Influenza.. . 1.13 1.28 1.69 1.23 1.03 0.99 . Other respiratory condItIona 1.63 o 1.74 ' ' * . Digestive system conditions.. 1.07 o 1.04 0.78 1.05 * o hjuriea.. , . . . . . . . . . . . . . . . . 1.14 1.04 1.17 0.89 1.40 * * All other acute conditions 1.22 1.31 1.19 1.29 1.15 1.13 . `Adjusted by the indict method to the age distribution of the total civilian. noninstitutional population of the United States. %cidence rate for given smoking category divided by incidence rate for "never smokers." `Figure does not meet standah of reliability or precision. thntity zero. SOURCE: Wihn, R.W. (14). would have been 77 million fewer days lost from work (13). This represented 19 percent of all work-loss days from illness at that time. More recent data are presented below. 3-9 TABLE 4.-Ratios of age-adjusted' number of days of disability per person 17 years old and older per year who have ever smoked, to persons who have never smoked, by number of cigarettes smoked per day for present smokers-heaviest amount, type of days of disability, smoking status, and sex: United States, July 1964 to June 1965 Present smokers Type of disability days, smoking status, and sex Total smokers Number of cigarettes smoked per day-heaviest amount Under 11 11-20 2140 41 and over Days of work IO?& Present smokers Rati@ Male . Female Former smokers 1.33 0.87 1.35 1.41 1.65 1.45 1.09 1.57 1.63 2.74 Male Female Days of bed Disability 1.41 1.28 1.26 1.43 1.34 1.66 1.70 2.17 1.72 . Present smokers Male ...................... Female ................... 1.14 0.98 1.20 1.16 1.49 1.17 0.92 1.09 1.59 263 Former smokers Male ...................... Female ................... 1.31 1.27 1.24 1.45 1.65 1.39 1.09 1.61 1.49 4.57 `Adjusted by the mdirect method to the age distribution of the total civilian. noninstitutional population of the United States. `Days of diwbility of given smoking category divided by days of disability of "never smokenr" JDays of work loss reported for currently employed pwwns only. *Figure doea not meet standards of reliability or precision. SOURCE: Wilson, R.W. (14). The following year NCHS also collected data on smoking and published a report, Changes in Cigarette Smoking Habits Between 1955 and 1966 (I), which compared the 1966 data with similar data collected earlier as a part of the Current Population Survey conducted by the Bureau of the Census (4). The Census data, however, did not include any health-related information. NCHS continued to monitor cigarette smoking levels, but with no health data, in 1966, 1967, and 1968 3-10 through supplemental questions in the Current Population Survey. The 1970 Health Interview Survey contained many of the same smoking and health questions as the 1965-1966 surveys, with the exception that data were not collected on all chronic diseases, but only on respiratory disease. These data again showed increased reporting of selected respiratory diseases and more work loss among smokers than among those who had never smoked (15). In addition, the data continued to document the decline in the proportion of cigarette smokers, particu- larly among males, where the drop was from 51.0 percent in 1965 to 43.2 percent in 1970 (10). Smoking data were again collected in 1974 in conjunction with a special set of questions on hypertension (9). Smoking questions were also asked on the 1976 and 1977 Health Interview Surveys. Most large scale studies on smoking and health have tended to investigate the role of smoking independently of other behavioral variables, such as alcohol consumption and other life style factors, occupational and environmental hazards, and certain psychological factors. These variables are known to be related to health status and many are also related to smoking habits. Thus it may well be that the elimination of smoking without any changes in the other factors will have only a partial impact on health status. The data collected on the 1977 survey were a part of a series of questions developed by Belloc and Breslow for a study in Alameda County, California, on health behavior, including such life-style factors as amount of sleep, eating breakfast, eating between meals, physical activity, smoking and drinking practices, and weight. It was found that persons with a number of "good health habits" live considerably longer than those with "poor health habits" (2). Recent Studies Questions on cigarette smoking behavior which were added to the July- December period of the 1978 Health Interview Survey will be continued through December 1979. These questions for the first time include information needed to determine tar and nicotine as well as carbon monoxide (CO) levels. While national surveys on adult smoking behavior conducted earlier by the National Clearinghouse on Smoking and Health had inquired about brand names to determine tar and nicotine levels, they did not include data on health characteristics. NCHS has recently completed the first cycle of the Health and Nutrition Examination Survey, in which a large national probability sample of persons was brought to mobile examination units for a very extensive physical examination, including tests for cardiovascular and pulmonary diseases (e.g., chest x-ray, EKG, spirometry and single breath carbon monoxide diffusion) as well as a number of biochemical tests. Examinees were also asked about their smoking habits (8). While 3-11 TABLE 5.-Days of bed disability per person 17 years old and older, by cigarette smoking status, sex, and age: United States 1974 Sex and age Total Present smoker F0l?Iler smoker Never smoked Days per person per year 17+ 1744 4.564 65+ Female 6.1 6.7 6.1 5.1 4.2 5.3 3.6 2.9 6.5 8.0 5.1 6.5 13.9 12.9 13.2 124 17+ a.7 7.9 9.3 8.6 1744 6.6 6.9 6.8 6.1 45-64 9.6 9.3 9.4 9.1 65+ 13.9 10.3 18.4 13.6 Note: Actual number of bed-disability days Expected number of bed-disability days if all persons had same rate as persons who never smoked = 1,076,131,ooO = gw237wJ Excess beddisability days SOURCE: Wilson. R.W. (16'). = 145,394,OOO the smoking data have not yet been fully analyzed, this study will provide a valuable source of information on smoking and health. A second cycle of the Health and Nutrition Examination Survey is currently in the field (19761980) and also includes questions on smoking habits as well as data on carboxyhemoglobin, an indicator of CO in the blood. These data will be helpful in assessing the accuracy of self-reported cigarette smoking levels. Disability data from the 1974 Health Interview Survey provide results very similar to those found a decade earlier. They indicate that smokers in all age and sex groups, except for women over age 65, report more days in bed due to illness than do persons who have never smoked (Table 5). If the number of excess bed days is calculated, as it was for the earlier antismoking campaigns, it is estimated that there were almost 150 million (145,894,OOO) excess bed days among smokers and former smokers. This type of calculation assumes that smokers and former smokers would experience the same rate of bed disability if they did not smoke as did those who had never smoked cigarettes. Currently employed smokers also report more days lost from work as a result of illness and injury than do employed persons who have never smoked (Table 6). If "excess" work-loss days are calculated for 3-12 TABLE 6.-Days lost from work per year due to illness and injury, per currently employed person 17 years old and older, by smoking status, sex, and age: United States. 1974 Sex and age Male Total Present Former smoker smoker Days per person per year Never smoked 17+ 4.5 5.1 5.0 3.4 17-44 4.2 5.5 4.2 3.0 45-64 5.0 4.5 5.5 4.4 65+ 3.8 0.3 7.9 o Female 17+ 4.8 5.6 o 4.5 1744 4.6 5.3 o ? 4.3 454 5.6 6.5 . 5.4 65+ 0.9 . o ? `Figure does not meet standards of reliability or precision. Note: Actual number of work-loss days Expected number of work-loss days if all workers had the same rate BS workers who never smoked = 379,3E9,ooo = 238,OZl.OO Excess work-loss days E 81,368,OMI SOURCE: Wilson, R.W. (26). employed persons under 65 years of age, there would have been an estimated 81,368,OOO "excess" work-loss days among smokers and former smokers, accounting for over 21 percent of all work-loss days. This is about the same proportion as a decade ago. Another measure of the impact of illness is whether a person is limited in major activity, such as work or keeping house, or limited in other activities such as social or recreational activities as a result of chronic illness. This is a measure of long-term chronic disability as opposed to the bed-days and work-loss indicators that can result from both short-term acute illness or injury and chronic disease. For most age and sex groups, a higher proportion of current smokers and former smokers report they have a limitation of activity than do persons who have never smoked, although the differences are not always striking (Table 7). One factor that may attenuate these differences is the higher mortality rate for persons who have smoked cigarettes. One of the major causes of mortality that has been shown to be related to cigarette smoking, heart disease, is also one of the major causes of limitation of activity. Since the above findings were obtained from 3-13 TABLE 7.-Percent of persons with chronic condition(s) causing limitations of activity, by cigarette smoking status, sex. and age: United States, 1974 Present FOIIIPX Never smoker smoker smoked 17+ 1744 45-64 65+ 17+ 174 4LL64 65+ 17+ 174 4&f% 65+ Both sexes 18.6 17.3 22.4 18.9 8.8 9.8 9.4 8.0 23.7 26.2 24.7 223 45.8 46.3 49.2 44.7 Male 18.7 18.7 23.5 17.3 9.0 10.0 8.8 8.4 23.7 27.8 a.8 20.0 51.0 52.5 50.9 51.4 Female 18.4 15.8 XI.6 19.7 8.6 9.5 102 7.8 23.8 24.4 26.5 23.1 42.1 37.4 44.6 42.6 SOURCE: Wilson, R.W. (16) interview surveys, there is a selection process by mortality that removes a certain number of smokers and former smokers from the data base. In addition, the group of former smokers is made up of two very different kinds of people-those who quit smoking before there was any noticeable deleterious impact on their health and those who quit smoking because of poor health. There are some recent data from the Health Interview Survey, although not yet fully analyzed, that indicate whether the respondent quit smoking because of a specific condition. Respondents in the Health Interview Survey were asked whether they perceived their health to be excellent, good, fair, or poor. Although the differences are not large, there is a tendency for higher proportions of former smokers and of those who have never smoked to report their health status as excellent (Table 8). For example, among males 17 to 44 years old, about 53 percent of the present cigarette smokers said their health was excellent compared with about 60 percent for both the former smokers and those who had never smoked. The data also indicate that smokers and former smokers are more likely to be hospitalized in the year prior to the interview than are persons who have never smoked (Table 9). However, the data have not 3-14 TABLE %-Percent of persons 17 years old and older, who perceive their health to be "excellent," by cigarette smoking status, sex, and age: United States, 1974 Sex and age TOt2.1 Present Former Never smoker smoker smoked 17+ 174 454 65+ 17+ 17-44 45-64 65+ 17+ 1744 4.544 65+ Both Sexes 42.7 51.3 34.0 27.1 Male 46.8 56.7 36.9 25.5 39.0 33.7 41.2 33.7 46.3 42.0 49.2 43.7 31.3 33.0 34.1 23.9 28.3 32.4 29.3 21.7 41.5 47.1 32.6 24.7 44.1 52.9 32.3 19.2 43.0 55.4 36.7 26.5 44.0 59.9 36.0 25.4 42.8 53.1 32.0 28.2 52.0 60.8 40.9 30.0 SOURCE: Wilson. R.W. (16). been analyzed to determine if this increased hospitalization is for diseases usually associated with smoking.1 While smokers tended to report more hospitalizations than did persons who had never smoked, there was no tendency for smokers to report more frequent visits to physicians than those who had never smoked, although former cigarette smokers reported the largest proportion with five or more physician visits during the past year (Table 10). Respondents in the 1974 Health Interview Survey were also asked whether they had ever tried to quit smoking, whether a doctor had advised them to quit, and whether they had been advised to quit because of specific health conditions. Just under a quarter of all persons who had ever smoked reported that they had been advised by a doctor at one time or another to stop smoking (Table 11). Surprisingly, at least from a public health point of view, at those ages at which the effects of smoking often begin to manifest themselves, 45 to 64, less than one-third of the smokers reported that they had been advised by their physicians to stop smoking. This would appear to indicate a need `There are many types of analyses that wuld be performed on these data that have not been done became of differing priorities and Ia& of resources. Fw example, one inter&ing ar?.a of investigation that wan begun, but not mmpleted beeawe of the apparent complexities of the issue. in the relationship between cigarette smoking, he&b "titi&, and weight. However, NCHS doa make available to researchers public-use data tapes from the various s"~eyS, 80 that they can conduct their own snaly3es (la). 3-15 TABLE 9.-Percent of persons 17 years old and older, with one or more hospital episodes in the year prior to interview, by cigarette smoking status, sex, and age: United States 1974 Sex and age Both sexes Total Present Former smoker smoker Never smoked 17+ 1744 4.544 65+ Male 13.1 13.5 14.4 127 12.3 13.8 11.7 120 12.9 12.3 15.1 l2.1 16.5 16.5 19.7 15.3 17+ 10.2 10.5 ml 8.3 1744 7.0 8.6 8.0 5.3 4M4 13.1 12.4 14.5 125 El+ 17.4 19.0 18.5 14.9 17+ 15.7 16.9 17.5 14.7 17-44 17.2 19.5 16.8 15.9 4&64 12.8 12.3 16.2 X2.0 65+ 15.8 129 23.1 15.4 SOURCE: Wilmn. R.W. (16). not only for increased public education, but also for increased educational programs among health professionals. About two-thirds of all present smokers had tried to stop smoking at some time (Table 12). Since detailed smoking history information was not obtained, it is difficult with these data to determine the more precise relationships between illness, physicians' advice to stop smoking, and actual attempts to stop. Some of the studies conducted in the past by the National Clearinghouse for Smoking and Health and reported elsewhere in this report have attempted to investigate these relation- ships as well as some of the more attitudinal and psychological aspects of smoking. Respondents to the Health Interview Survey were asked if a doctor had ever told them they had heart trouble. Among persons under 65 years of age, a larger proportion of both present smokers and former smokers had been told that they had heart trouble compared with persons who had never smoked (Table 13). For example, 15 percent of the male former smokers aged 45 to 64 had been told they had heart trouble compared to 10 percent of those who had never smoked. There is some difficulty interpreting the data for persons over 65 years old, where a higher proportion of those who had never smoked report heart 3-16 TABLE lO.-Percent of persons 17 years old and older, with five or more physician visits in the year prior to interview, by cigarette smoking status, sex, and age: United States, 1974 Sex and age Total Present smoker Former smoker Nl?V6T smoked Both sexes 17+ 17-44 4544 65+ 24.8 23.7 27.0 26.1 22.0 23.0 23.4 a.3 25.5 24.3 26.4 272 34.2 27.0 37.1 34.9 Male 17+ 17.9 16.9 22.9 17.3 17-44 13.4 14.1 16.1 13.1 4544 21.3 20.7 24.1 20.8 65+ 30.2 24.8 33.5 39.4 Female 17+ 30.8 31.3 34.5 30.0 17-44 29.9 32.9 33.5 27.6 45-64 29.2 28.3 31.1 29.4 65+ 37.0 30.1 46.8 36.3 SOURCE: W'ilmn. R.W. (16). trouble, since many of the smokers with heart trouble have already died. Of those smokers who have been advised by a doctor to stop, about 28 percent were advised to stop because of respiratory disease. About 23 percent of the smokers 65 and older were advised to stop because of circulatory problems, but this proportion drops for the younger smokers. Hardly any smokers reported they were advised to stop because of cancer. However, these data on cancer are also misleading; since the survival rate for lung cancer is relatively low, many smokers would not live long enough to report that the doctor had told them to stop smoking. The first cycle of the Health and Nutrition Examination Survey contained a number of questions that, when combined, formed an Index of General Psychological Well-Being.2 This measure provides data on another dimension of the relationship between cigarette smoking and health. In general, current cigarette smokers were found ' The Index of General Psychological Well-Being ia compcmed of 18 items with a total of 128 response optiona. The "%`JnSe Option for each item that indicates the greatest diitrea is scored zero. Some of the items and their response V-iOM &o permit representations of high-level positive well-being. The total index area rangv from 0 thou 110. ritb low acres indicating diatregl and high area indicating positive well-being. Gaerelly positive affect is mhd by acorn above 78 and marginal well-being by scared of 73 to 77. The median more for the population `=`hte. Of adults, 25 to 74 yearn old, was between 83 and 84 (3). 3-17 TABLE Il.-Percent of persons 17 years old and older who have ever smoked and who were ever advised by a physician to stop smoking, by smoking status, sex, and age: United States 1974 Smoking status All ages and sex 17+ 17-44 45-m 65+ Total ever smoked Both sexes Male Female Former smoker 23.9 19.6 292 30.1 23.5 17.8 29.2 32.4 24.4 21.8 29.2 25.3 Both sexes 21.3 14.2 26.3 28.2 Male 22.7 13.5 23.0 29.6 Female 18.9 15.0 22.6 24.2 Present smoker Both sexes 25.2 21.5 31.1 32.6 Male 24.0 19.4 39.2 37.0 Female 26.6 23.9 32.1 262 SOURCE: Wilma, RW. (16). TABLE 12.-Percent of present cigarette smokers 17 years old and older who have tried to stop smoking, by sex and age: United States, 1974 sex All ages 17 1744 4s64 65+ Both sexes 64.7 66.0 62.8 61.1 Male 66.0 66.7 65.1 63.3 Female 63.3 65.3 69.2 57.9 SOURCE: Wilson. R.W. (16). to have a slightly lower level of well-being than were nonsmokers. Heavy smokers (more than 1 l/2 packs a day) under 65 years of age report the lowest levels of general well-being and report mean levels of general well-being at marginal levels or lower. Conclusions The available evidence in the relationship between cigarette smoking and illness and disability has increased markedly since the first 3-18 TABLE lh-Percent of persons 17 years old and older who have been told by a doctor that they had heart trouble, by cigarette smoking status, sex, and age: United states, 1974 Sex and age Both sexes Total Present Former smoker smoker Never smoked 17+ 9.0 7.8 12.9 9.4 1744 4.2 4.3 4.7 4.1 45-64 11.1 11.6 14.9 9.9 65+ 22.9 17.9 28.5 23.3 11+ 8.9 8.2 13.8 8.4 17-44 3.8 4.5 4.7 3.6 4544 12.0 13.0 15.2 10.0 65+ 24.5 18.6 28.5 26.5 Female 17+ 9.0 7.4 11.4 9.9 1744 4.6 5.1 4.9 4.4 45-64 10.3 10.0 14.3 9.9 65+ 21.8 16.8 23.5 22.4 SOURCE: Wilson, R.W. (26). Surgeon General's report was issued, largely as a result of data collected from national probability surveys conducted by NCHS. These data range from the standard health indicators, such as measures of chronic and acute illness and measures of disability days, to less commonly used indicators of lifestyles. The results of analysis performed on these data vary from the more frequently reported findings on disability to data from the Index of General Psychological Well-Being, first reported in this chapter. The findings tend to be consistent with the large amount of evidence on the relationship between cigarette smoking and mortality, i.e., people who smoke cigarettes report more illness and disability than people who have never smoked cigarettes. While many studies show a reduction in the risk of mortality among former cigarette smokers, data on disability and illness often show continued high risk for former smokers, indicating both a lack of refinement in the current data to distinguish between types of former smokers as well as the fact that Once certain diseases occur they do not go away. The most important aspect of these data collected by NCHS lies not iu the substantive analysis prepared by the NCHS staff, but in the 3-1s analytic potential of the data to other researchers in the smoking area through the use of NCHS's public-use data tape program. 3-20 Morbidity: References (1) AHMED, PI., GLEESON, G.A. Changes in Cigarette Smoking Habits Between 1955 and 1966. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration, National Center for Health Statistics, Series 10, No. 59, PHS Publication No. 1900, April 1970,33 pp. (2) BELLOC, N.B. Relationship of health practices and mortality. Preventive Medicine 2: 6%81,1973. (5) FAZIO, A.F. A Concurrent Validational Study of the NCHS General Well-Being Schedule. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Resources Administration, National Center for Health Statistics, Series 2, No. 73, DHEW Publication No. (HRA) 78-1347, September 1977,53 pp. (4) HAENSZEL, W., SHIMKIM, M.B., MILLER, H.P. Tobacco Smoking Patterns in the United States. Public Health Monograph No. 45. U.S. Department of Health, Education, and Welfare, Public Health Service, PHS Publication No. 463,1956,111 pp. (5) HAMMOND, E.C. Smoking in relation to death rates of one million men and women. In: Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. National Cancer Institute Monograph No. 19. U.S. Department of Health, Education, and Welfare, Public Health Serviw, National Cancer Institute, January 1966, pp. 127-204. (6) HAMMOND, EC., HORN, D. Smoking and death rates - Report on 44 months of follow-up of 187,783 men. Journal of the American Medical Association X6(10): 1159-1172,1958. (;) MADOW, W.G. Net Differences in Interview Data on Chronic Conditions and Information Derived From Medical Records. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration, National Center for Health Statistics, Series 2, No. 57, DHEW Publication No. (HSM) 73-1331, June 1973,58 pp. (8) MILLER, H.W. Plan and Operation of the Health and Nutrition Examination Survey: United States, 1971-1973. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Resources Administration, National Center for Health Statistics, Series 1, Nos. lOa, lob, DHEW Publication No. (HSM) 73-1310, February 1973,123 pp. (5) MOSS, A.J., SCOTT, G. Characteristics of Persons with Hypertension: United States, 1974. U.S. Department of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, Series 10, No. 121, DHEW Publication No. (PHS) 79-1519,197s. (In press) (IO) NATIONAL CENTER FOR HEALTH STATISTICS. Cigarette smoking: United States, 1970. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration, National Center for Health Statistics. Monthly Vital Statistics Report 21(3)(Supplement), June 2,1972,8 pp. (11) NATIONAL CENTER FOR HEALTH STATISTICS. Health, United States, 19761977. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Resources Administration, National Center for Health Statistics, National Center for Health Services Research, DHEW Publication No. (HRA) 77-l232,1977,441 pp. (l2) NATIONAL CENTER FOR HEALTH STATISTICS. Standardized Micro-Data Tape Transcripts. U.S. Department of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, DHEW Publication No. (PHS) 78-1213, June 1978,36 pp. 3-21 (IS) NATIONAL CLEARINGHOUSE FOR SMOKING AND HEALTH. Smoking and Illness. U.S. Department of Health, Education, and Welfare, Public Health Service, Bureau of Disease Prevention and Environmental Control, National Center for Chronic Disease Control, National Clearinghouse for Smoking and Health, PHS Publication No. 1662, July 1367,6 pp. (14) WILSON R.W. Cigarette Smoking and Health Characteristics United States, July 1964-June 1965. U.S. Department of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, Series 10, No. 34, PHS Publication No. 1600, May 1967,64 pp. (15) WILSON R.W. Cigarette smoking, disability days and respiratory condition. Journal of Occupational Medicine X(3): 236246, March 1973. (16) WILSON R.W. Testimony presented at Regional Forum sponsored by the National Commission for Smoking and Public Policy. Philadelphia, June 16, 1977,27 pp. 3-22 4. CARDIOVASCULAR DISEASES. - National Heart, Lung, and Blood Institute CONTENTS Atherosclerosis ............................................................ `7 The Nature of Atherosclerosis in Man.. ................... `7 The Effect of Smoking on Atherogenesis.. .............. 10 Experiments in Animals ................ . ...................... 16 Research Needs ................................................... 18 Conclusions ......................................................... 19 Myocardial Infarction .................................................. 19 The Nature of Myocardial Infarction.. .................... 19 Summary of Epidemiological Data ........................ .20 The Effect of Smoking on Myocardial Infarction in Man.. ........................................ L .. 38 The Effect of Smoking on Myocardial Infarction in Animals.. ..................................... .40 Research Needs .................................................. .40 Conclusions.........................................................4 1 Sudden Cardiac Death .............................................. .41 The Nature of Sudden Cardiac Death in Man.. ....... .41 Sudden Cardiac Death in Animals.. ....................... .43 Summary of Epidemiological Data ........................ .43 The Effect of Smoking on Sudden Cardiac Death in Man.. ............................................... .44 The Effect of Smoking on Sudden Cardiac `Death in Animals.. .......................................... .45 Research Needs .................................................. .45 Conclusions ........................................................ .45 Angina Pectoris ....................................................... .46 The Nature of Angina Pectoris in Humans ............ .46 Summary of Epidemiological Data ........................ .46 The Effect of Smoking on Angina Pectoris.. .......... .48 Research Needs .................................................. .48 Conclusions ........................................................ .49 Cerebrovascular Disease ............................................. .49 The Nature of Cerebrovascular Disease in Man.. ..... .49 Summary of Epidemiological Data ........................ .50 The Effect of Smoking on Cerebrovascular Disease . .50 4-3 Research Needs .................................................. .52 Conclusions ........................................................ .52 Peripheral Vascular Disease ....................................... .52 The Nature of Peripheral Vascular Disease in Man . .52 Summary of Epidemiological Data ........................ .53 The Effect of Smoking on Peripheral Vascular Disease ............................................. .53 Research Needs.. ................................................ .54 Conclusions ........................................................ .54 Aortic Aneurysm of Atherosclerotic Type.. ................... .55 The Nature of Atherosclerotic Aortic Aneurysm ...... .55 Summary of Epidemiological Data ........................ .55 The Effect of Smoking on Aortic Aneurysm.. ......... .56 Research Needs .................................................. .56 Conclusions ........................................................ .56 High Blood Pressure ................................................. .56 The Nature of Hypertension ................................ .56 Summary of Epidemiological Data ........................ .57 The Effect of Smoking on Blood Pressure ............. .58 Research Needs .................................................. .58 Conclusions ........................................................ .58 Other Conditions ...................................................... .58 Venous Thrombosis.. ........................................... .59 Thromboangiitis Obliterans (Buerger's Disease). ....... .66 Oral Contraceptives, Smoking, Myocardial Infarction, and Subarachnoid Hemorrhage Among Women ..... .66 The Effect of Smoking on Blood Lipids.. ............... .61 Other Constitutents of Smoke .............................. .62 Discussion and Conclusions.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 LIST OF TABLES Table l.-Autopsy studies of atheroclerosis.. . . . . . . . . . . . . . . . . . . 11 4-4 Table 2.-Coronary heart disease mortality ratios related to smoking-prospective studies.. . . . . . . . . . . . . . . . . . . . .22 Table 3.-Coronary heart disease morbidity as related to smoking.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27 Table 4.-The effect of the cessation of cigarette smoking on the incidence of CHI?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Table 5.-Annual probability of death from coronary heart disease, in current and discontinued smokers, by age, maximum amount smoked, and age started smoking.... 35 Table 6.-Coronary heart disease morbidity as related to smoking-angina pectoris-prospective studies.. . . . . . . . . . . .47 Table `7.-Age-standardized death rates and mortality ratios for cerebral vascular lesions for men and women, by type of smoking (lifetime history) and age at start of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 4-5 Atherosclerosis Most studies of the pathology of atherosclerosis have been based on autopsies of coroner's or hospital populations in which only a limited fraction of decedents have been examined. They have been valuable for an understanding of the pathogenesis and complications of atherosclerosis. Such studies cannot be taken to represent the prevalence of atherosclerosis in the general population. Studies which attempt to minimize selection bias at autopsy by examining the great majority of decedents in a defined population are rare (66,114). The most extensive and comprehensive autopsy study that has been conducted is the International Atherosclerosis Project, which collected data from 15 cities in 14 countries and recorded more than 21,000 autopsies according to a standardized protocol and method of evaluation (85). The study found a remarkably frequent occurrence of atherosclerotic lesions in the United States; detailed international or geographic differences in the severity of atherosclerosis; raised the issue of whether childhood atherosclerosis evolves into adult forms of atherosclerosis; and documented that, on the average, there are more frequent and extensive coronary plaques in cases with coronary heart disease than in comparison cases regardless of age, sex, geographic location, or race. Approximately the same prevalence and extent of advanced atherosclerosis were seen in coronary heart disease cases regardless of age, sex, and, with few exceptions, of geographic location. While individuals may show considerable variability in the severity of atherosclerosis, the conclusion is that coronary atherosclero- sis is of primary importance in the development of coronary heart disease in a population (133). Another extensive study in five towns in Europe has been reported by the World Health Organization (WHO) ( W. The Nature of Atherosclerosis in Man Information about atherosclerosis in man derives from pathological studies and from associations observed in clinical or epidemiological studies. The lesion or plaque is a cellular proliferation in the arterial intima. It contains chiefly smooth muscle cells, but also fibrocytes and cells typical of chronic inflammation. Lipid is commonly present along with cehlar products such as collagen, elastic tissue, glycosaminoglycans, and cellular debris from necrosis. Elements of thrombus are common both in and on the plaque. Focal calcification is frequent. Thus, a highly variable and complex range of lesions can be considered under the term atherosclerosis. The concept of the development of lesions is a synthetic one derived from the observation of many lesions rather than from the actual observation of a single lesion over time. At present, there is 4-7 controversy over whether the fatty streaks seen in childhood are the precursors of the more fibrous, raised, and complex adult lesions, or whether some or many adult lesions arise independently of fatty streaks (which also occur in adult life) (89). The usual prevalence of atherosclerotic lesions in adult life is such that the aorta and carotid arteries are affected about a decade before the coronary arteries and cerebral arteries, and the latter are affected a decade in advance of the arteries of the leg. However, such relationships are not constant; individual variations are common and, indeed, specific clinical syn- dromes of localized atherosclerosis are recognized. Atherosclerotic plaques distort and narrow the calibre of the affected arteries. This reduces the flow of blood through them and creates the condition called ischemia. When &hernia becomes severe, the organs and tissues deprived of blood no longer function properly and clinical disease occurs in the form of coronary heart disease, stroke, or peripheral vascular disease. The occurrence of severe &hernia may arise because of the enlargement of plaques, or it may be precipitated by the development of thrombosis (clot) on plaques, or by other complications that can affect them. The various diseases resulting from &hernia are considered subsequently in this chapter. Conditions that predispose to the onset of disease in the future, increasing the risk of its occurrence, are spoken of as "risk factors". The concept of risk factors arose from clinical experience with cardiovascular disease, particularly coronary heart disease, rather than with atherosclerosis itself. Prospective population studies such as those considered in the Pooling Project (107) further developed the predictive value of selected factors such as cigarette smoking and levels of blood pressure and cholesterol. Risk factor associations for atherosclerosis as distinct from coronary heart disease are limited in their documentation. The International Atherosclerosis Project (85), dealing with autopsy data, concluded that the severity of atherosclerosis is closely associated with the proportion of total calories derived from saturated fat in the diet of the population, with the serum cholesterol levels measured in the population, and with hypertension. The association with smoking was not examined. The WHO (66) study documented the association of a number of disease states and conditions with the extent and severity of atherosclerosis. A recent report has described the associations between several variables measured during life and the extent of atherosclero sis of the aorta and coronary arteries seen at autopsy in Japanese- Americans participating in a prospective cardiovascular risk factor study (11.2). Statistically independent associations were found by multivariate analysis between aortic atherosclerosis and age at death, cigarettes smoked per day, serum cholesterol concentration, and blood pressure level. Coronary atherosclerosis was related to relative body 4-g weight, cigarettes smoked per day, and serum cholesterol concentra- tion. Models of experimental atherosclerosis in species as different as birds, rodents, dogs, swine, and nonhuman primates have been developed. The majority of these models have been induced by feeding saturated fat or cholesterol leading to fat-rich plaques that resemble the fatty streaks of childhood or the very fat-laden plaques occasional- ly seen in adult life, Other experimental techniques of inducing lesions are: the use of physical injury to arteries leading to acute proliferative plaque development with little or no hpid accumulation; the induction of intimal thrombi with their tissue organization yielding fibro-fatty plaques; immunologic vascular injury with lipid or cholesterol feeding; and, recently (in chickens), viral infection. Among different species of nonhuman primates, the same dietary regimen will produce character- istically a somewhat different distribution of plaques in the arterial tree. Different experimental diets will produce lesions that are characteristically more fatty or more fibrous. Spontaneous fibrous or fibro-fatty plaques occur in many species including birds, rabbits, swine, and nonhuman primates. The enhancement of spontaneous atherogenesis in chickens by polycyclic hydrocarbons has been reported (1). A strong genetic control exists in pigeons both for the expression of experimental atherosclerosis and for its localization predominantly either in the aorta or in the coronary arteries. Thus, there is a wide variety of experimental and spontaneous animal models available with which to study atherogenesis. A huge body of literature deals with the pathogenesis of human and experimental atherosclerosis. Several recent reviews provide a detailed and critical consideration of current concepts (3,21,22,84,89, 117,119,126,155,156). The various interrelationships of different patho- genetic processes such as cellular proliferation, lipid accumulation, and thrombotic phenomena are not fully understood. Nevertheless, it is Possible to synthesize available data into a frequently explored major working hypothesis of the initial stages of atherogenesis based on extensive experimental data (see particularly 117,155,156) that support the Pathogenetic concept that the arterial endothelium functions normally to separate the intima and media from the blood. The hypothesis holds that local injury results in failure of this barrier function or in loss of endothelial cells and exposure of the subendothe- hum to whole plasma and to blood platelets. Platelets and plasma contain growth factors capable of inducing smooth muscle cells in the mtima and adjacent media to multiply. This loss of barrier function also allows macromolecules such as fibrinogen and very low density (VLDL), intermediate, low density (LDL), and high density (HDL) liPoProteins freer access to the vessel wall. More lipid is internalized by intimal smooth muscle cells and macrophages than their lysosomal digestive systems can catabolize, and they become overloaded with fat 4-9 and cholesterol. The amount of sterol externalized metabolically by such cells may exceed the local capacity of HDL to accept and transport it away. Cellular necrosis occurs and both intracellular and structural lipids spill into the extracellular compartment of the intima where they contribute to the lipid burden. The sequence in this hypothesis is endothelial injury, impaired barrier function, and subendothelial exposure to plasma and to platelets, followed by cellular metabolic overload, failed homeostasis, cellular proliferation, and necrosis. In addition, the stigmata of mild chronic inflammation occur promptly, and appearances suggestive of a migration of smooth muscle cells to the lesion are seen. Local cellular production of glycosaminogly- cans, collagens, and elastin follows. Progression of the lesions can be through a continuation or cyclical repetitions of the same processes or by thrombosis. Thrombosis, necrosis, calcification, hemorrhage, and ulceration may further complicate the lesion. A large number of agents are suspected to be capable of injuring endothelium and altering its barrier function. It should be noted that the foregoing views are derived from animal experimentation but appear to be congruent with the nature of atherosclerosis in humans. A novel theory of atherogenesis has been proposed recently that does not necessarily contradict the concepts stated above, but which designates a prior abnormality of the smooth muscle cells that proliferate to form plaques. It has been found that the cells that constitute individual fibrous atherosclerotic plaques in adults are homogenous for an isoenzyme marker. That is, each plaque must either be monoclonal or initially polyclonal with the development of a monotypic character as it has developed (21, 22, 104, 105, 135). If the correct interpretation is that plaques are monoclonal, it is necessary to consider whether this represents a mutation or transformation of vascular cells leading to a local proliferation analogous to benign smooth muscle cell neoplasia. In this view, environmental agents capable of inducing somatic cell mutation, including mutagens derived from tobacco, could be fundamental to the pathogenesis of atheroscle- rotic plaques, and might cause the primary cellular changes facilitating other conventional risk factors or agents to produce lesions in man. At the present time, data to settle the validity of these interpretations are not available. The Effect of Smoking on Atherogeneais Autopsy studies in which smoking behavior has been recorded are not common. Table 19 (pp. 49-51) of the 1976 reference edition of the report, The Health Consequences of Smoking (138), lists several investigations into this aspect of smoking. This table is reproduced below as Table 1. These investigations compare, within their particular group of study cases, smokers with nonsmokers and different levels of smoking, 4-10 TABLE l.-Autopsy studies of atherosclerosis. (Figures in parentheses are number of individuals in that smoking category)1 [SM = smokers NS = nonsmokers] Wilern and Plair. Mz L' S.A 989 consecutive male autopsies at New York City VA hospitals. s?verity of aort,r rlemis The authors conclude that Ahove averagt: AMXp Lklow awragp in 60 @mnt of caws. the NS. 9.9(X1) 60.2 29.8 degree of ~elems~~ at `#I Uw4) 18.1 35.4 45.9 The authors mncludc that the percentqe of men with an advanced degrre of coronary athemeekmnir was higher among EIR" mtk smokere than among nonsmokers and that the percentage "Creased with amount of cigarette smoking. This relrtion- ship plrJisted even when eases were matched for a(p and cause of death. Avtandilov. wk Russia 259 mate and 141 female autopsies. Not spwihed. hut then welt. 180 SM and 220 NS Comparative size of mean area of athemxlemtic legions in inner mat of wonmy arteries. Right mromuy tiry Left coronary artery SM NS SM NS 3&3!. t15.5@w 1.3(32) t6.3 22 4%49 Kww 11.X27) t15.g 4.4 5&59 t36.3(39j 14.8@9) tn.9 9.9 6iM9 t31.9w ZWW t26.5 a5 7079 41.9(18) X1(36) 26.1 35.8 The author concludes that the war-at changes WR found in the left and right mmnary arteries with lea were chanp in circumflex artery and aorta. Causes of death 96athem &rote, 1~accidental. 202-various di-. tT-tat for signifiince of difference between means is significant at p," (0, I I.<,., ,I,5 d t 1p:tn 114 1 11,1/ ,`,p;,rr ,,,,v 9pv a ,*11,1,11m , s 111111, "L. ilU",,\ ,"l,lll/.ili ,n `d,l/ II* ,!I/. TABLE 2.--Coronary heart disease mortality ratios related to smoking-prospective studies. (Actual number of deaths shown in parentheses)' [SM = Smokers NS = Nonsmokers]-Continued P M TABLE t.-Coronary heart disease mortality ratios related to smoking-prospective studies. (Actual number of deaths shown in parentheses)' [SM = Smokers NS = Nonsmokers]-Continued Author. Number and Fo,,ou- Nunher YW. typp of D?Str v of C,pNTtta&y %ars. ptp" A@ YuIPlW" commm(a munrry ppula1ion mllfrtm iyea") rkrlk TABLE 3.-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHD manifestations shown in parentheses)' [SM = Smokers NS = Nonsmokers EX = Ex-smokers] PROSPECTIVE STUDIES TABLE 3.-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHD manifestations shown in parentheses)' [SM = Smokers NS = Nonsmokers EX = Ex-smokersl- Contibued 12 Mycwd~nl Infarction Males Fern& NS l.cw?l) l.INl31) AIIS" 1.51(153) 1.71(zJ) Hwy SM u.w91 Fbk of CHD (ovwrll) Hale2 FFnUles NS l.a@l) mw) l-10 ,, I.WW ww 11-m l.NW ~.wS) >al 241(X) o.wa) TAlX,E &-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHD manifestations shown in parentheses)' [SM = Smokers NS = Nonsmokers EX = Ex-smokersl- Continued PROSPWTIVE STUDIFS f M TABLE 3.-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHID manifestations shown in parentheses)' [SM = Smokers NS = Nonsmokers EX = Ex-smokersJ- Continued PROSPECTIVE STUDIES Shrpwo CL al, 1969 USA Keys ,910 Yup JlPYI.4 Pmlrnd llrly Nether- lands CReee $.I.% m&z I" 5 mm- tnes4059 years of npr nt entry a 65 cdraths. NS. EX Includes all M mycc?c (534 rn, .,.. 1.31(103) dii. Ita mgina cmm PO m"m munInes I"- 155 other vesligati except US A t422 total tDiiierence between total CHD and the sum "r smokmg pups IS dw to diiimnce 1" ftgms P--M by a"th"ls. TABLE 3.-Coronary heart disease morbidity aa related to smoking. (Risk ratios-actual number of CHD manifestations shown in parentheses)' [SM = Smokers NS = Nonsmokers EX = Ex-smokersl- Continued f E TABLE 3.-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHD manifestations shown in parentheses)' [SM = Smokers NS = Nonsmokers EX = Ex-smokers]- Continued PRDSPECFIVE STUDIES Authw, Number and Data Follow- Number of Y". tyTa of collf.2km UP imidents Cipntw!day Rpe% Clgan Ap vm.bon GmlmenL? muntry populathm YCm Dunn 13.148 mall, Data only up to ,I Tod un- 3039 d&49 5059 tlncludes et II, pdt.enta I" "I! ww S,~`fled tlm NS. EX. and 1910 penodic I ,nlth inudenls U.S.A. SM l.m?sj l.cqlm l.axl57) a np- chic lCttes/day mnb Include, all CHD but exelvdea : !- deti No datr wad- able mmpannS rmken and nonsmokera Pmling 7,437 wh,te Mfdrrl IO 538 PmW. ndles 3a-59 examinalmn Includes Never smokrd l.WW 1 w-9 AllWEt." yesn of and follow. fslll and (IO..... I wa Ia54 HWi age at entry UP. nonRW al 2wm ASO3dl0n myawdial >a0 3.zql54) l910. mfurlion U S.A and a&n death. TABLE 3.-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHD manifestations shown in parentheses)' [SM = Smokers NS = Nonsmokers EX = Ex-smokersl- Continued PROSPFXTIVE STUDIES `Unlesl otherwine s+fied, dis+tiea between the total number of manifestations and the plum of the individual smoking atepories we due ta the exclusion of either ocasional, miscellaneous. mixed. or ex-smokers. Source: U.S. Public Health Service(lS8). TABLE I.-The effect of the cessation of cigarette smoking on the incidence of CHD. (Incidence ratios-actual number of cases or events are shown in parentheses) Author, yew, Results Comments ci-mntrv All CHD events All myocardial infarction Jenkins, et al., 1963 U.S.A. Never smoked . . . . 1.00(30) l.OO(21) current cigarette smokers. . . . . . 236@4) 2WW Former cigarette smokers.. . . . . . . . . 2X(19) 241( 15) Death from CHD Smoked 1-19 cigarettes/day Smoked >2O cigarettes/day Hammond Never and Garfinkel, smoked regularly ............... l.OO(1.641) 19% Cm-rent U.S.A. cigarette smokers ............... 1.90(1,063) Stopped 20 ............................... 1.06(70) All ex-cig-arette smokers ......... 1.16(253) 1.00(1,641) Male data only =5m3~) 1.61(62) 1.51(154) lsql35) 1.25(123) l.WW l.ww Total definite myocardial infarction Shapim, et al., 19% U.S.A. Never smoked . . . . . . . . . . . . . . . . . . . . . . 1.00 Current cigarette smokers . . . ,,,,,.,... ,..,,.,,.,...,., . .,..... 187 Stopped 15 years . . . ..t......... . . . . . . . . . . . . . . . . . . . . . . . 0.76 All CHD deaths First major cmmuy event Pooling Project, Never smoked ...................... l.oo(fm 1.W~) Americnn Heart > `/2 pack/day ...................... l.WW l&(72) Association 1 pack/day.. ...................... 1.70(36) 208(205) 1970, >l pack/day.. ...................... 3.90@3) 3.2q154) U.S.A. Ex-smokem .......................... 0.30(19) 1.25(51) SOURCE: U. S. Public Health Setice (1%`). 1.16 for all cardiovascular diseases in males. The reported ratios were 1.64 among men and 1.57 among women for ischemic heart disease. This effect on ischemic heart disease was related directly to the 4-34 TABLE 5.-Annual probability of death from coronary heart disease, in current and discontinued smokers, by age, maximum amount smoked, and age started stioking Maximum daily Age started smoking lC19 m-24 Age number of ciga- Discontinued retteE smoked Current smokers yoy;;yoy Cumnt smokers for five or more yeam moFe yeam (Probability x 1oJ) 5b-64 - - . . . . . . . . . . . . . . . . . . . . . . . . . I.. 0 501 501 IO-20 798 568 811 551 21-39 969 766 872 698 614 - - . . . . . . . . . 0 1,015 1,015 lC-20 1,501 1,169 1,478 1213 21-39 1,710 194 1573 1,098 `For age pup 86'74, probabiliti~ for diseonthued smokers are for 10 or more years of diintinuance since data for the &lb year diintiaumee group are not given. SOURCE: U. 9. Public He&k Service (1.98). amount smoked and to the age at which smoking began, in a study of a small subset of the population. In industrial societies which share about the same general nutrition- al and metabolic circumstances as the United States, it has been shown repeatedly that cigarette smoking is associated with a considerable increase in risk of myocardial infarction and death following infarction when compared to the risk among nonsmokers. The effect is dose- related in terms of years of smoking, number of cigarettes smoked per day, and the habit of inhaling. The association is generally consistent, reproducible, and predictive. It is independent in the sense that its effect is found when other risk factors for heart disease are controlled in statistical analysis. The effect is seen chiefly in cigarette smokers. Pipe and cigar smokers are apparently at only minor increased risk. The effect is greatest in young middle life and decreases with age to become a minor risk beyond age 65. Cessation of smoking reduces, over time, the increased risk attributable to smoking toward the risk of nonsmokers. While most of the data have been gathered on men, there are sufficient data to provide similar general conclusions that cigarette smoking is also a risk factor for myocardial infarction in women. The studies of Hammond and Garfinkle, listed in Table 2, and of Shapiro and colleagues, in Table 3, record positive associations between smoking and mortality and morbidity from CHD in large populations of women. It has been observed that women who use oral contraceptive Pills are at higher risk of infarction if they also smoke (102). Recently, a case-control study has reported that, among 55 women who had suffered myocardial infarction below the age of 50 years, the Proportion of smokers was 89 percent compared to 55 percent among 4-35 the case controls (p < 0.001). A dose relationship was present. Compared to nonsmokers, heavy smokers using 35 or more cigarettes a day had an infarction rate estimated to be increased 20 times. The women did not use oral contraceptives (124). The final report of the Pooling Project considers data from the Albany civil servant study, the Chicago Peoples Gas Co. study, the Chicago Western Electric Co. study, the Framingham community heart study, and the Tecumseh community study. It presents typical findings from prospective studies and ones that are particularly important for the United States because the data are derived from several locations in the country. In this report (IOr), fatal and nonfatal myocardial infarction and sudden coronary heart disease death have been designated as major coronary events. Cholesterol values, blood pressure readings, and smoking history observed just once in men at the beginning of a lo-year follow-up period showed a high predictibility of risk of CHD. Multiple logistic analysis showed these three characteristics to be independent. Combinations of these risks were not additive but compounded. The highest combined quintile of risk characteristics compared to the lowest quintile had a relative risk of CHD events of about 6 to 1. About 40 percent of cases emerged from the 20 percent at highest risk, while 86 percent emerged from the upper 60 percent of risk traits, and 96 percent derived from the upper 80 percent. Not only is risk of CHD events associated with the more deviant levels of these traits, but appreciabie risk may attach to combinations of mild deviations of risk factors. Smoking habit was classified as more than a pack of cigarettes a day, about a pack a day, about half a pack a day, less than half a pack, cigar and pipe only, never smoked, and past smokers. For most analyses, the report groups past smokers, never smoked, and smokers of less than half a pack a day into a single group labeled nonsmokers, noting that the majority of the less than a half pack per day smokers were only occasional users. This group of nonsmokers was then compared with those who smoked more. It was found that men who smoked a pack or more a day had a standardized incidence or risk ratio' of a first major coronary event 2.5 times that of the nonsmoker (confidence interval 2.1 to 3.1). Those who reported smoking more than a pack a day were found to have 3.2 times the risk of nonsmokers in terms of standardized incidence ratio (confidence limits 2.6 to 4.2). The risk of pipe and cigar smokers was intermediate between that of the nonsmokers and the half a pack a day smokers, but was not statistically different from either group in this study. Risk was found `This ulcul~tion removes that portion of any differemx attributable to a@ differentiala The werage rate for the total group is assigned the value of 100. The rates for subgmups are pmportiond tn the average for the entire gnwp after removing the effects of age. 4-36 to rise rapidly above half a pack a day and to be almost twice as high in the pack a day group of cigarette smokers. Among additional recent papers, the Framingham Heart Study reports that smoking 20 cigarettes a day is associated with an annual incidence of coronary events per 1,000 in the fifth, sixth, and seventh decades of life of 11.9, 19.3, and 19 per 1000 of population. The corresponding rates for nonsmokers were 3.6, 5.7, and 15.3 (69). The Western Collaborative Group Study (116) in California has detailed a dose relationship of relative risk analysed for the fifth and sixth decades of life among men smoking either less than a pack per day, a pack, and more than a pack in comparison with nonsmokers. The reported relative risks were 1.05, 1.53, and 1.93 in the fifth decade, and 0.098, 1.63, and 2.32 in the sixth. Reid and colleagues (110) have reported on more than 18,000 male civil servants in Great Britain between the ages of 40 and 64 who were followed over 5 years of prospective study. The risk of death from coronary heart disease was iowest among nonsmokers or ex-smokers. Current smokers had a significantly higher risk of death from CHD. Moreover, when classified by inhalation habit, inhalers were found to have higher risk of CHD death than those who do not inhale. In yet another study from Great Britain, more than 34,000 physicians have been followed for 20 years. It is reported that annual death rates (per 100,000, standardized for age) among light, medium, and heavy smokers for ischemic heart disease are 501,598, and 6'7'7 respectively (35). There have been inconsistent reports on the effect of smoking on the occurrence of a second or subsequent heart attack. Studies in New York (150) failed to find a relationship between smoking and second heart attacks, while the Newcastle and Scottish studies (4.3, 111) did find an adverse trend. A recent contribution to this issue has been the findings of the Coronary Drug Project Research Group (29) who reported on 2,789 male survivors of myocardial infarction in the New York Heart Association cardiac functional classes I or II. These men had been randomized to placebo treatment and usual care. They were followed for 5 years and provide a natural ~history study under usual current therapy conditions. Smokers at the time of entry into the study Were at somewhat higher risk than nonsmokers. The relative risk of smoking after myocardial infarction was appreciable, but less than for men with no prior history of heart attack as, for example, those documented in the Pooling Project (107). The absolute risk of death is much higher for men who have already experienced a myocardial infarction, however, so that the difference in mortality rates for them between smokers and nonsmokers becomes correspondingly important. In this study, the hospitalization rate was 36 percent higher for cardiovascular events among smokers than nonsmokers. Other recent papers include the Western Collaborative Group Study (% which has reported that the number of cigarettes smoked daily 4-37 correlates significantly with the occurrence of new myocardial infarction among men who have had a prior attack. Mulcahy and colleagues (97) have reported that over a 5year period, subsequent smoking after an infarction did not affect morbidity, but there was an increased mortality among those who continued to smoke. In the British civil servant study (115), it was found that among those with existing evidence of ischemic heart disease, the mortality rates over 5 years were 4.7 and 4.0 percent among those who smoked relative to nonsmokers. Again, in a Swedish study (EL& those who ceased to smoke after a heart attack had only half the rate of nonfatal recurrences, and half the rate of cardiovascular mortality of those who continued to smoke over a Z-year follow-up period. There is persuasive evidence from population studies in the United States and in the United Kingdom (35) that ex-smokers adopt a lesser risk after ceasing to smoke, which in time is little different from the nonsmoker who never smoked. The 1976 reference report on The Health Consequences of Smoking (138) tabulated several important studies in Tables 15 and 16 on page 42 (reproduced above as Tables 4 and 5). The Framingham Heart Study (50) also reports a beneficial effect below the age of 65. Men who stopped smoking had coronary attack rates only one-half those who continue to smoke 10 or more cigarettes per day. In a paper that may be germane, although it relates to differences in exposure rather than cessation, Hammond and associates (53) find that smokers of low tar and nicotine delivery cigarettes had lower death rates from coronary heart disease than those who smoked the same number of high tar-nicotine cigarettes. Both groups of smokers, however, had higher rates than nonsmokers. It is of interest in discussing other risk factors that physical activity markedly shortens the half life of carboxyhemoglobin in the blood and that active people attain lower equilibrium levels than sedentary ones when smoking (27, 5S,1.&). Physical activity, particularly when heavy, has been shown in several studies to reduce the incidence of heart attack, and it can be speculated that at least some of this effect may arise from a reduced burden of COHb among physically active smokers (I.&). Morris and colleagues obtained evidence in a study of British civil servants that, among men who did not exercise vigorously during their leisure time, smokers had 2.5 times the risk of nonsmokers. Among the physically active group, however, the relative risk of smokers was 1.5. The amount of tobacco used daily was the same in the two groups (95). The Effect of Smoking on Myocardial Infarction in Man The epidemiological data that associate cigarette smoking and myocardial infarction are summarized in the preceeding section. The effect is major and adverse for the incidence of first events; it is 4-38 apparently alsc adverse for second attacks, but this is not yet well defined. The mechanism of effect is usually attributed to an enhancement of coronary atherosclerosis in smokers and the consequent occurrence of cardiac ischemia and ischemic necrosis of heart muscle. Other phenomena have been offered as supplementary mechanisms. Aronow has recently discussed these in the context of relative ischemia and cardiac effects (5, 6). In patients with exercise-inducible angina, smoking various nicotine or non-nicotine-containing cigarettes was found to aggravate angina and in a manner related to the nicotine content. Nicotine-containing cigarettes increase heart rate and blood pressure transiently, non-nicotine cigarettes do not. The nicotine effect is mediated through catecholamine discharge. Both nicotine and non- nicotine cigarettes increase blood CO. There is a decreased availability of oxygen for the heart. Aronow reports a rise in left ventricular end- diastolic pressure and a decrease in stroke volume due to a negative inotropic effect of CO on the myocardium. Jain and associates (60) have found that, in normal subjects, smoking decreases the preejec- tion/left ventricular ejection time ratio and external isovolumetric contraction time, whereas in patients with coronary heart disease these measurements increased on smoking. They concluded that left-ventric- ular performance is diminished after cigarette smoking in the presence of significant coronary artery disease. In the individual with ischemic heart disease, it is hypothesized that nicotine may aggravate ischemia: by increasing cardiac oxygen demand but not supply; by increasing platelet adhesiveness (78) and causing circulatory obstruction at the microvascular or macrovascular level; by lowering the cardiac threshold to ventricular fibrillation (20); and by depressing conduction and enhancing automaticity (5.2) favoring the development of arrhythmias. CO might aggravate ischemia by exaggerating hypoxia, producing a negative inotropic effect, reducing the fibrillation threshold (6), or increasing platelet adhesiveness (25). Regardless of which of these several mechanisms might operate in individual cases, it can be hypothesized that patients on the border of myocardial &hernia may be pushed into impending or actual infarction by the effects of nicotine and CO. Moreover, it may be speculated that, in the presence of coronary atherosclerosis of a degree insufficient to cause ischemia, the actions of smoking on platelet Whophysiology may precipitate occlusive thrombosis and infarction. These possible mechanisms for the conversion of marginal ischemia into overt infarction may be thought to require that the attack follow immediately in time or coincide with the act of smoking. In fact, experience with myocardial infarction or sudden death does not seem to support the idea that the majority of habitual smokers suffer myocardial infarction or sudden death in such close temporal relation- ship to the act of smoking. However, the exact timing of the onset of 4-39 heart attack by clinical criteria is not possible. A considerable number of infarcts are clinically unrecognized. It is also possible that the initiation of ischemia or of platelet aggregation begun at one time might culminate in heart attack only hours later. At present, it is not possible to clarify these temporal uncertainties. The Effect of Smoking on Myocardial Infarction in Animals There are limited data on the effect of smoke constituents on experimental myocardial infarction in animals. Table A!26 (pp. 193-108) of the 1976 reference edition of The Health Gmsequertces of Smoking (137) lists 18 separate publications involving the effect of smoke and nicotine on cardiovascular function. Three studies used animals with coronary artery narrowing or ligation. In one there was an increase in the frequency of nicotine-induced arrhythmias. This was less evident as the time interval (up to 45 days) increased between artery ligation and nicotine challenge. In another study, nicotine increased coronary blood flow less in the presence of coronary narrowing than in normal animals. One paper reported that animals with damaged myocardium due to isoproterenol lesions or ligation of the coronary artery responded to a nicotine challenge with an increased expression of arrhythmias. It was found that it required more nicotine to increase coronary flow and heart rate in rabbits with dietary-induced athero sclerosis than in normal animals. It was also reported that in dogs with acute coronary occlusion that nicotine caused coronary vasodilation in the normal heart, but in ischemic myocardium, flow increased only proportional to aortic pressure. Dogs with coronary occlusion manifest excessive left atria1 pressure and ventricular arrhythmias on exposure to nicotine (36). The effect of CO inhalation on monkeys with experimental myocardial infarction produced electrocardiographic evidence of greater myocardial ischemia and increased liability to inducecl-ventric- ular fibrillation (34). Research Needs The epidemiological data relating smoking to myocardial infarction leave no doubt that smoking is a major risk factor for both fatal and nonfatal CHD. Data in certain situations need strengthening or verification. There is much less information concerning women than men. Data are few on the effect of smoking on myocardial infarction in old age. The published reports on the adverse effect of smoking on the incidence of second heart attacks are probably adequate, but are inconsistent and not well-defined. Studies to investigate the separate relationships of nicotine and CO in whole smoke to the incidence of myocardial infarction would be particularly useful. Detailed data on the effect of "less hazardous" cigarettes compared with ordinary cigarettes in relation to myocardial infarction are not available, 4-40 although, as noted above, it has been shown that there is a rising gradient of risk of cardiovascular death for smokers of the same number of low, medium, and high tar and nicotine cigarettes (53). If such studies are feasible, they could provide for the public and for cigarette production important information about the risks to be attributed to different smoke deliveries of tar, nicotine, CO, and perhaps other substances. A major need is to understand better the mechanisms by which smoking can induce 6r affect the evolution of myocardical infarction. Animal experiments using several different models of myocardial ischemia or infarction in conjunction with exposure to smoke constituents alone, and in combination, should provide some clarifica- tion. They could be conducted under precise if somewhat artificial circumstances. Nonhuman primates susceptible to experimental ath- erosclerosis have been trained to smoke in a humanlike manner without overt stress or aversion (86), and studies of whole smoke of different characteristics in a more natural setting of acute and chronic inhalation exposure can be done. Conclusions Cigarette smoking is a major independent risk factor for the development of fatal and nonfatal myocardial infarction in men and women in the United States. It also appears to be a risk factor for second heart attacks among those who have experienced one, and diminishes survival after a heart attack among those who continue to smoke. It acts synergistically with high blood pressure and elevated blood cholesterol. The effect is directly related to the amount smoked. Ceasing to smoke reduces the risk towards that of nonsmokers. Smokers of low tar and nicotine cigarettes have a higher risk than nonsmokers, but they have a lesser risk than those who smoke high tar and nicotine cigarettes. Sudden Cardiac Death The Nature of Sudden Cardiac Death in Man A recent symposium (28) on sudden cardiac death has delineated the nature of the problem and the many definitions that are used to classify it. The data gained from hospital practice and from coroner's experience differ quantitatively from the findings of prospective epidemiological studies, but the nature of the disorder is probably the same in all the samples. Coronary heart disease (CHD) accounts for 90 Percent of examples of sudden cardiac death, but there are other cardiac causes for sudden death (28). In a prospective epidemiological study, Kannel and associates (71) reported that individuals with overt CHD are four times as liable to sudden death as those without CHD. They report that about 55 percent 4-41 of cases occur in individuals with no prior clinical evidence of CHD. The standard CHD risk factors have been confirmed also to be predictors of sudden cardiac death in both a case control study (4.4) and in a prospective cohort investigation (38). Whether death from CHD is sudden does not appear to depend upon the mix of risk factors, and no combination of standard risk factors (including smoking) appears to designate those destined to die suddenly in contrast with those who will experience a more protracted death. The proportion of sudden cardiac deaths to more protracted deaths is about the same whether or not prior overt CHD has been recognized (38, 71). Evidence has been accumulated in several studies that, in the presence of recognizable heart disease, ventricular premature beats are associated with an excess liability to sudden cardiac death (142). A recent study by Ruberman and associates (118) followed 1,739 men in the New York City area who had a myocardial infarction at least 3 months before entering the study. They were examined for ventricular premature beats by means of a continuous l-hour record of the electrocardiogram The follow-up period was from 6 months to 4 years, averaging 24.4 months. During this period there were 208 deaths, of which 85 were classified as sudden cardiac deaths (defined here as occurring within minutes and in the absence of signs or symptoms suggesting acute myocardial infarction). Much higher mortality was experienced in those subjects manifesting complex beats (runs, early beats, bigeminal, and multiform beats) than in those without. The authors report that by the 3-year observation point the risk of sudden cardiac death, adjusted for age, was four times above the comparison experience, and the risk of death from any cause was 2.6 times greater than expected. Moreover, although such complex beats were often associated in this study with other findings that relate to severe heart damage, they were shown to be independent risk factors. Autopsy studies on persons dying sudden cardiac deaths have produced somewhat variable findings. In general there is a close association with extensive and severe coronary atherosclerosis, and an appreciable number of patients show evidence of old or recent myocardial infarction. Reichenbach and coauthors (109) have tabulated data from several studies. Their own experience in the Seattle, Washington area was that 97 percent of decedents had a prior history of heart disease (much higher than other studies); 55 percent had pathological evidence of old myocardial infarction; 8 percent had less than 75 percent luminal stenosis in any major coronary artery with the remainder showing 75 percent or greater stenosis in one or more vessels; and 57 percent had occlusion of one or more vessels. Recently formed thrombi were found in 10 percent of hearts, which was, generally, appreciably less than other studies; acute myocardial infarction was found in only 5 percent of hearts, which also was, generally, appreciably less than in other studies. Other reports that d--42 consider a history of smoking in relation to autopsy examinations and sudden death are those of Spain and coworkers (127, 128) and Friedman and associates (44). Two major mechanisms for sudden cardiac death may be postulated. One is asystole or arrest, generally arising in response to severe ischemia and impending or spreading acute myocardial infarction. The other is ventricular fibrillation arising from regional myocardial ischemia and ventricular ectopy and modulated by a number of circumstances that may contribute to electrical instability of the heart. Sudden Cardiac Death in Animals Sudden death has been reported in nonhuman primates that were fed cholesterol to induce atherosclerosis (58), and it has been induced in many experiments by acute coronary ligation or obstruction. The latter experiments have produced a large body of data on the ability of regional ischemia to initiate ventricular fibrillation and sudden cardiac death, and have helped to elucidate local tissue metabolism, electrical behavior, and the relation of neural and pharmacologic agents to the precipitation or control of arrythmias and fibrillation. Summary of Epidemiological Data Sudden cardiac death is the first manifestation of coronary heart disease (CHD) in about 20 percent of CHD deaths. Of all CHD deaths about 50 to 66 percent are sudden (71). The 1976 reference report on smoking and health (138) noted in Table 3 (p. 26) data on sudden cardiac death from the Pooling Project that found an increased mortality ratio of 1.9 for men who smoked either lo-or-less or 20 cigarettes a day, and a ratio of 3.36 for those smoking more than 20 a day, in comparison with nonsmokers (1.00). A more recent report combines data from Framingham and the Albany civil Servant Study (38, 71). These data relate to men only, and are derived from 1,338 subjects from Albany, New York, and 2,232 from Framingham, Massachusetts, aged 45 to 74, and were collected prospectively over 16 years. Sudden death was defined as demise within one hour of onset. Deaths within 30 days of a known heart attack were excluded as were those of subjects found dead in bed. Data are presented on the associations between sudden cardiac death and a number of factors such as age, a prior history of CHD, blood pressure, serum cholesterol, and other items. Smoking was found to be a risk factor, with smokers having a threefold higher rate than nonsmokers. In a multivariate analysis of systolic blood pressure, electrocardio- graphic evidence of left ventricular cardiac hypertrophy, relative body weight, cigarettes smoked per day, and serum cholesterol as contribu- tors to risk among men ages 45 to 54 and 55 to 64 at their biennial examination antecedent to death, it was judged that, of these factors, the use of cigarettes was the most potent contributor to sudden death. 4-43 A case control study based on the Kaiser-Permanente health insurance system in California (44) has reported on 197 sudden cardiac deaths among men. The case to control findings with reference to percentage of smokers among 40- to 54-year-old decedents were 67.9 and 39.3. It was found that smoking had a somewhat stronger relationship to deaths occurring 1 hour after onset of symptoms than to instantaneous deaths or those within 1 hour. Talbott, et al. (134) have reported on sudden death among white women and find an excess use of tobacco and alcohol among those dying suddenly. The relationship of smoking to sudden death among those with existing recognized CHD has had little attention. In a prospective study, Graham and associates (51) found no association between smoking and mode of death in patients known to have had a prior infarction. Oberman and co-workers found no relationship between the major risk factors including smoking and sudden death in patients evaluated earlier for ischemic heart disease (100). It was found that the best five variable models to predict sudden death in this group of patients included the number of coronary arteries obstructed 70 percent or more, the use of digitalis or diuretics, premature beats and ventricular conduction defects. The Coronary Drug Project (29), which was also a prospective study, reported a 5-year age and race adjusted sudden death-rate ratio of smokers to nonsmokers of 1.28 (t value 1.98) in the placebo or customary therapy group. The Effect of Smoking on Sudden Cardiac Death in Man The epidemiological associations have been noted above. The act of cigarette smoking does not appear to be immediately related in time to sudden death. In relation to second heart attacks, Moss and colleagues (96) report a prospective follow-up study of patients discharged from hospital after myocardial infarction. They reported on 42 deaths (sudden and nonsudden) of cardiac nature in the following 6 months. Information on smoking prior to death was available on 28 patients; of these, only 5 were said to have smoked in the week before death. The mechanisms postulated to explain the association of sudden cardiac death with smoking have been described under atherogenesis and under myocardial infarction as possible mechanisms for effects of smoke, nicotine, and CO. They include accelerated atherogenesis, enhancement of ischemia through inotropic effects, increased platelet adhesiveness obstructing coronary flow, or, through increased cardiac work caused by nicotine, and simultaneously reduced oxygen delivery to the heart due to CO. Any of these mechanisms can be evoked as possible initiators of critical ischemia and of sudden death due to asystole or to ventricular fibrillation. The smoking and health report of 1976 (138) tabulates in Table AZ1 (pp. 169-114) the effects of smoking and nicotine on the cardiovascular system in man. While these data 4-44 suggest hypotheses for mechanisms of sudden death in man, they do not, of course, deal directly with cases of sudden death. .The Effec! of Smoking On Sudden Cardiac Death in Animals The smoking and health- report of 1976 (1.38) has tabulated in Table A26 (pp. 103-106) papers concerned with the effect of smoke or nicotine on the cardiovascular system of animals. In the presence of myocardial &hernia, exposure to tobacco smoke or nicotine may precipitate conditions of increased cardiac demand, relative ischemia, and, in one experiment, arrhythmias. Bellet and colleagues (20) found that the ventricular fibrillation threshold was reduced in dogs exposed by intubation to cigarette smoke both in the presence and in the absence of acute myocardial infarction. Malinow and colleagues failed to induce infarction or sudden death in cholesterol-fed cynomolgus monkeys by chronic exposure to CO (SO). There are, however, no animal experiments in which animals have been brought chronically to a state of incipient myocardial &hernia by atherogenesis and then exposed to whole smoke by inhalation in a nonstressful setting. F&search Needs There are fewer data on sudden cardiac death than on myocardial infarction in general. Smoking is clearly a strong risk factor for sudden death, but present indications are that it is not unique among the mix of risk factors for coronary heart disease and that it is not highly predictive. However, there are theoretical reasons to speculate that smoking might have a relationship to sudden death, not only through its effects on the circulation, but also through a myocardial one. It should be considered whether present epidemiological and clinical research data are adequate to exclude in smokers a myocardial element in sudden cardiac death, in relation to either first or multiple heart attacks, or whether additional research is warranted. The mechanisms of sudden cardiac death, its precursor states, and preventive therapy require further elucidation. These should be clarified where possible in man and in experimental animal models with close analogy to man. The study of smoking or of smoke constituents as variables in such studies may be informative both about sudden death and the role of smoking in its occurrence. Conclusions Smoking is a powerful risk factor for sudden cardiac death. It is, however, only one of the general group of risk factors that contribute to coronary heart disease and sudden death. The mechanisms by which smoking might induce sudden death, in addition to an exacerbation of coronary artery arteriosclerosis, can be hypothesized from experiments 445 that indicate that an exacerbation of regional ischemia may promote electrical instability of the heart, fibrillation, or asystole. Further research will be required if these mechanisms are to be well understood and if they are to be shown to be actual mechanisms in man in relation to smoking and sudden death. Angina Pectoris The Nature of Angina Pectoris in Humans Pain in the thorax may have several different origins and can create a difficult problem of differential diagnosis. Angina pectoris arises typically in the face of exercise and increased demand for work and oxygen on the part of the heart which cannot be met immediately in the presence of ischemia imposed by coronary atheroscleosis. The origin of the pain is thought to be the ischemic myocardium. It can occur in individuals with or free from preexisting myocardial infarction. Since the common use of angiographic diagnostic methods, it has become apparent that angina also occurs occasionally in persons with little or no evidence of coronary arteriosclerosis. Angina pectoris is associated with an increased death rate from heart attack. Women survive better than men. Among the risk factors associated with a poorer prognosis are hypertension, cardiac hypertro- phy, congestive heart failure, and electrocardiographic abnormalities (149). Recent studies employing angiography have shown a close relationship between the extent of coronary arteriosclerosis and prognosis in angina pectoris. Reeves and associates (108) have summarized these reports to indicate that if only one of the three major coronary artery branches is significantly steno&, an annual mortality rate of about 2 percent results; if two major branches arc &nosed, the resulting annual mortality rate is about `7 percent a year; with three-vessel disease, it is about 11 percent a year. Summary of Epidemiological Data The major studies on smoking in relation to the incidence of angina pectoris in the United States are not consistent in their conclusions. The 1976 report on smoking and health (138) has tabulated four major reports in Table 5 on page 33. (Table 5 is reproduced below as Table 6.) Doyle and colleagues (38) report no association in a IO-year follow-up of men from the Albany civil servant study, together with men from the Framingham Heart Study. Jenkins, et al. (63) reported a slight positive association, but not a statistically significant one. Similarly, Kannel and Castelli (70) reported on both men and women from the Framingham Heart Study and found a positive risk association among men and a negative one among women. In a large study of 110,000 men and women enrolled in a health insurance medical care plan in New York City and followed for 3 years, Shapiro, et al. (122) reported `a 4-46 significantly increased incidence rate for smokers among men who were current users of cigarettes. Among females, the trend was positive but not significant. A study of the incidence over 5 years of angina among 10,000 Israeli men found that there was a higher incidence rate among men who smoked over Xl cigarettes a day than in those who smoked less, but the difference did not reach the 0.01 level of significance (91). In addition, a questionnaire survey (45) of about 70,000 persons has found that more smokers than nonsmokers admitted to chest pain. Some nine different kinds of angina-like and nonanginal pains were included as chest pain. Reid and associates have reported a significant association between angina and current cigarette smoking among British civil servants (110). The Effect of Smoking on Angina Pedxis As noted above, the predictive risk factor association of smoking with the incidence of angina pectoris is not clear. However, there is evidence among persons with angina that smoking lessens the threshold of exercise for the onset of pain. Aronow (7, 8, 9, 10, 12) has reported clinical studies in which smoking cigarettes with high, low, or no nicotine content aggravated angina. In these studies, high nicotine cigarettes aggravated exercise-induced angina more than low nicotine cigarettes, and low nicotine cigarettes more than cigarettes without nicotine. He has also reported in patients with angina pectoris and coronary artery stenosis documented by angiography that when 50 parts per million of CO were inhaled until the mean COHb level of venous blood was raised to 2.68 percent, it was accompanied by a significant decrease in exercise time before angina1 pain. There was also a decrease in the amount of cardiac work represented by the product of systolic blood pressure and heart rate needed before the onset of angina compared to when air was breathed. S-T segment depression of 1.0 mm or greater in the electrocardiogram occurred earlier, after less exercise and at lower cardiac work levels among these patients when they breathed CO rather than air. Although it is uncommon, there are patients in whom the act of smoking a cigarette will itself precipitate an attack of angina (26,143). An interpretation of such data is that, in the patient with a compromised regional myocardial blood supply who can provide little or no compensatory increase in circulation to meet an increased cardiac demand, smoking enhances both hypoxia and cardiac demand, resulting in a more severe &hernia and an earlier onset of angina. Resemch Needs Epidemiological data with respect to the predictive or risk factor association of smoking and angina pectoris tend to show an inconsis- tent positive association. Despite this unsatisfactory state of affairs, there would seem relatively little reason to attempt to study the issue further at this time. Conclusions Studies of the possible role of smoking as a risk factor for the incidence of angina pectoris suggest a positive association, but the findings are inconsistent. In patients with angina pectoris, smoking lowers the threshold for the onset of angina. Both nicotine and CO aggravate exercise-induced angina. Cerebrovascular Disease The Nature of Cerebrovascular Disease in Man The underlying circumstances of stroke are varied. They include tumors and bleeding dyscrasias leading to intracerebral hemorrhage or infarction, unusual diseases of blood vessels in the brain, aneurysms of intracranial vessels, embolism, thrombosis, vascular rupture, and atherosclerosis of the vessels of the neck and their distributing vessels in the brain. The great majority of strokes, perhaps more than 90 percent, may be classified either as intracerebral hemorrhage associated primarily with hypertension, or ischemic cerebral infarction associated with ather+ thrombotic disease of the vessels of the neck and their main distributing branches in the brain. Infarction is more common than hemorrhage. The clinical diagnostic subclassification or separation of hemorrhagic stroke and ischemic stroke contains an appreciable margin for misclassification. It is these conditions that are under consideration here, rather than the rare disorders. The risk factor data for stroke have been considered recently by two panels (31, 40). They are less clearly defined than those for coronary heart disease. The strongest gradients of risk are associated with age, blood pressure, preexisting cardiovascular disease, and diabetes mellitus. Prospective studies have not found a clear and direct relationship with serum cholesterol concentration. It has been of interest that a Japanese study has recently reported that among a Population with a high incidence of stroke but low levels of blood cholesterol by Western standards, there was no evidence that hypercholesterolemia defined as levels above 200 mgm/lOO ml increased the incidence of stroke. Cerebral infarct developed in 11 Percent of those with hypertension and hypercholesterolemia and 21 Percent of those with hypertension alone (101). Models of cerebrovascular disease in animals have largely been limited to acute occlusive manipulations. Only recently have experi- mental dietary and hypertensive sclerosis of cerebral vessels with cerebral hemorrhage (58) been reported in nonhuman primates. A 4-49 genetic strain of stroke-prone, spontaneously-hypertensive rats has been developed. Summary of Epidemiological Data The epidemiological data on cerebrovascular disease (stroke) and smoking were summarized in the 1976 reference edition of the report on The Health Consequences of Smoking (I.%), Table 13'7 (pp. 64-66). Kannel reviewed the subject for the Third World Conference on Smoking and Health (68). The results of various studies have not been congruent and no conclusion can be stated with confidence. Kannel has noted that the prospectively collected data have been difficult to interpret because of deficiencies, such as small sample numbers, failure to consider separately cerebral hemorrhage. and ischemic infarction, failure to consider separately men and women, and inadequate classification by age. The 1976 report on The Health Corisequewes of Smoking (1%) comments (on page 152 and in light of its data in Table `7 on page 153, reproduced below as Table 7) on the possible role of age dependency in the various studies, noting that cigarette smoking may be a risk factor for stroke at all ages, but that other causes of stroke may be proportionately so important in older ages that the smoking risk is masked by strokes due to other causes in studies that do not involve very large populations. Although two very large studies, involving about 250,000 and l,OOO,OOO respondents, found relative risks of about 1.52 and 1.41 for cigarette smokers (41), no certain conclusion can be offered at the present time because of apparently conflicting data. A recent study of a large cohort of women has reported that the risk of subarachnoid hemorrhage is significantly associated both with ciga- rette smoking and with the use of oral contraceptives. The risk to cigarette smokers was 5.7 times that of nonsmokers while it was increased 6.5 times for users of oral contraceptives. The risk was increased 22 times among women who both smoked and used oral contraceptives compared to nonsmokers and nonusers (106). The Effect of Smoking on Cerebrovaecular Disease It has been noted that risk factor data are inconclusive on the relation of smoking to the incidence of stroke. Carbon dioxide causes cerebrovascular dilatation. Both nicotine and CO increase cerebral blood flow (125). Unlike the case of cardiac metabolism, there is no evidence that nicotine affects cerebral oxidative metabolism in a dose equivalent to smoking. It is uncertain that these effects relate in any way to stroke. It may be speculated that pathogenetic mechanisms could operate through effects on blood platelets, oxygen transfer, emboli from the heart, or through vessel wall toxicity and enhanced atherogenesis of large and small vessels to the brain. There are no data 4--50 TABLE Z-Agcwkndardkd death rates and mortality mtios for cerebral wacular leaions for men and women, by typ of smoking (lifetime history) and age at start of tiy Men Neva maker re&rly 18 51 ml lpez Cigwette 33 88 815 lrn TOW 25 64 z?a l,fhll CVL mortality ntim Never mwked rephrly i.m I.00 1.m im Pk. ckw 089 l.oB 1.06 1.01 Ci*tte and other 1.00 1.40 l.aS 0.73 Cigarette only 150 1.41 137 0.65 Never meked qhly i.m i.m 1.00 1.00 Ciprette 2.11 1.54 1.98 1.18 dealing directly with experimental cerebrovascular disease in animals and smoking that examine such pathogenetic hypotheses. Research Needs Clarification of the existing conflicting epidemiological data may be sought. It has been suggested by Kannel(68) that a retrospective study of brain infarctions under the age of 55 years might help to resolve some uncertainties. Chronic experimental cerebrovascular disease of hypertensive or atherosclerotic types in animals has received little attention. Such disease has recently been produced in nonhuman primates (58). While its characterization is incomplete, it may possibly offer an opportunity to study the effects of smoking or of smoke constituents. The effect of smoke constituents on the stroke-prone rat is also an area for study. Conclusions The relationship of smoking to the incidence of stroke is not established. An association with subarachnoid hemorrhage has been reported in women. Peripheral Vascular Disease The Nature of Peripheral vascular Disease in Man Atherosclerotic peripheral vascular disease (PVD) is primarily a stenosing or occlusive disorder of the arteries of the legs. Other branches of the aorta such as the subclavian, celiac, or renal arteries may be diseased similarly, but use applies the term to the arteries that supply the leg unless noted otherwise. Atherosclerotic involvement resembles that of the coronary arteries or aorta, but the plaques are more fibrous and cellular and contain less fat. Involvement includes not only the large iliac and femoral arteries, but extends to branches in the anastomotic connections around the knee and to the lesser branches of the lower leg and foot. Thrombosis is common, and embolism from ulcerated plaques in the aorta or iliac arteries occur. The effect is to create distal circulatory ischemia of a chronic nature that can be complicated by acute occlusive events. The circulation to the leg may become inadequate to the needs of the muscles during exercise. Pain in the calf or thigh is precipitated by exercise, relieved by rest, and is designated intermittent claudication. It resembles angina pectoris in these respects and it is often a changeable and unstable symptom. Severe ischemia will result over time, in some individuals, in tissue atrophy and necrosis or ischemic gangrene. The risk factors for atherosclerotic peripheral vascular disease are generally similar to those for coronary heart disease, but an elevated blood pressure may be only a minor contributor to risk of PVD (68). 4-52 Peripheral vascular disease has been reported in experimental dietary atherosclerosis in the nonhuman primate, but the subject has only recently received systematic study (I&). Summary of Epidemiological Data Kannel has recently reviewed the data pertaining to occlusive peripheral vascular disease (68). Several clinical reports find that about 90 percent of individuals with arteriosclerotic obstructive peripheral vascular disease (PVD) are cigarette smokers. This is a marked excess of smokers compared to the general or age- and sex-matched population. Moreover, clinical experience finds that continuation of smoking worsens prognosis after surgical therapy (157). In one clinical study of 187 consecutive patients who underwent surgical vascular grafting with synthetic grafts for arterial occlusive disease of the lower abdominal aorta and iliac arteries, the patients who continued to smoke more than a pack a day had three times the graft occlusion rate of nonsmokers, both in absolute terms and in month-patency time (113). Koch (75) has reported that cessation of smoking will lead to a reversion of risk to that of nonsmokers over 5 years. Diabetes is a strong risk factor for PVD; it acts synergistically with smoking. A diabetic who smokes is reported to have a 50 percent greater risk of PVD than one who does not (151). Lawton has reported from a small series examined by angiography that smoking is associated with atherosclerotic distortion of the distal aorta and common iliac arteries in a dose-dependent manner, but not with lesions in the external iliac or femoral arteries (79. Epidemiological studies have also demonstrated an association of PVD with smoking. In one, it was concluded that cigarette smoking was more common than expected for both sexes among those with PVD, that it was an independent risk factor, and that 70 percent of nondiabetic PVD was related to smoking (152). The prospective Framingham Heart Study reports a strong association between smoking and obstructive peripheral vascular disease including inter- mittent claudication (68). At all ages and in both sexes a higher incidence of claudication was found in smokers. Heavy smokers had a three times greater incidence and the risk tended to relate directly to the number of cigarettes smoked. The effect was independent by multivariate analysis. At any level of other risk factors the smoker is at greater risk than the nonsmoker. Smoking was found to contribute as strongly to PVD in women as in men. Data for pipe and cigar smoking do not appear to be available. `b Effect of Smoking on Peripheral Vascular Disease `l'he epidemiological and clinical evidence for smoking as a risk factor has been noted above. The Framingham data on multiple risk factors allow the identification of a top decile of risk from which 40 percent of 4-53 cases will emerge (68). Wald, et al. (146) have reported a closer association between blood COHb in smokers and myocardial infarction, angina, or intermittent claudication (considered together) than with smoking history in a survey of Copenhagen workers. An acute effect of CO on intermittent claudication has been noted by Aronow, et al. (11). They have reported that patients manifesting intermittent claudication of the calf or thigh muscles, and angiograph. ic evidence of iliofemoral arteriosclerosis, who breathed CO to increase mean venous COHb levels from 1.08 to 2.77 percent, experienced a decreased exercise threshold to produce leg pain. Table A30 (pp. 129-130) of the 1976 report on !!%e Hea& Consequences of Smok&g (158) lists a number of experiments in man in which the effect of smoking or of nicotine was assessed on some aspect of the peripheral circulation of the arm or leg. The data are not consistent, although the tabulated data in normal individuals tend to show a decrease in skin temperature and a decrease in blood flow. In another study, calf-blood flow was measured plethysmographically in 51 men, aged 59, who were heavy smokers, but who ceased to smoke for about 2 months. They showed an increase in blood flow during reactive hyperemia (62) after the cessation period. No experiments on animal models of chronic peripheral vascular disease and smoking have been found. Research Needs In general, epidemiological data are adequate. It is likely that current epidemiological research will provide additional data to furnish more exact figures than are currently available. New studies appear to be unnecessary except to establish levels of risk for different "less hazardous" cigarettes. The possible association of postmenopausal estrogen treatment, smoking, and PVD in older women may warrant attention. However, it is not clear what roles atherogenesis, nicotine, CO, and perhaps tobacco allergy may play in the development and expression of PVD in smokers or in its responsiveness to smoking withdrawal. Studies of the mechanisms responsible for these aspects of smoking and PVD are warranted and may also have interest for the study of the pathogenesis of atherosclerosis in general. Animal studies involving chronic or acute smoking, hypertension, atherogenesis, and PVD are possible, particularly in nonhuman primates conditioned to smoke. These may offer a direct, if difficult, experimental approach to understanding the circulatory effects of smoking and smoke components on PVD. Conclusions Cigarette smoking is a major risk factor for ischemic peripheral vascular disease of arteriosclerotic type. It increases appreciably the 4-54 risk of peripheral vascular disease in diabetes mellitus. Clinical experience and case series studies find that cessation of smoking benefits the prognosis in peripheral vascular disease and is advanta- geous to its surgical treatment. Aortlc Aneurysm of Atherosclerotic Type The Nature of Atherosclerotic Aortic Aneurysm Atherosclerosis involves the abdominal aorta early in life about equally in males and females. Progression of the disease in some individuals is such that large plaques rich in lipid and pultaceous with necrosis hecome confluent and encroach upon the media of the vessel, causing necrosis of its cells and attenuation of the wall. Dilatation of the vessel and aneurysm formation follows. Thrombosis on the lumenal surface is common. Eventually the wall may become so thin that leakage and rupture occur. Fatal outcome is more common in men than women. The condition usually becomes clinically apparent after the age of 56 and its incidence increases with age. It is not known why some individuals develop this form of progressive disease in the abdominal aorta. An sssociation with smoking is noted below. The morphological features of the process are exaggerated but similar to those of atheroma in other arteries, and it is generally considered that aortic aneurysms of this type are variants of the general process of atherogenesis. There is a high concordance with coronary heart disease. Equivalent atheromatous lesions have not been produced in experi- mental animals. Summary of Epidemiological Data Atherosclerotic aneurysm of the aorta (nonsyphilitic aneurysm) may WIS death by rupture or, occasionally, by thrombotic occlusion. It is an uncommon cause of death, less than 1 percent of cardiovascular deaths being attributed to it. Table 29 (p. 67) of the 1976 report on The Health &nsepnces of SVJ.&&VJ (1%) lists four population studies in Which a total of 94'7 such deaths are recorded. The two largest studies-that of Kahn involving more than 248,006 U.S. male veterans, and that of Hammond and Garfinkel involving approximately 358,666 males-find a dose-dependent mortality ratio such that pack-a-day We smokers have a ratio of about 4 or 5, while smokers of more than 39 (Kahn) or 46 (Hammond and Garfinkel) cigarettes per day have a mortality ratio between 7 and 8 when compared with nonsmokers. These are unusually large ratios relative to other atherosclerotic `hse. Data pe rmitting multivariate analysis in terms of other @nventional risk factors are unavailable. 4-55 1 The Effect of Smoking on Aortic Aneurysm Aside from the strong risk factor association noted above, nothing more is known about smoking and aneurysm formation in man. It may be speculated that CO exposure enhances the circumstances that promote plaque growth and medial hypoxia, which leads to attenuation and necrosis of the aorta. It may also be speculated that smoking may lead to excessive thrombosis, which leads to excessive plaque develop ment and aneurysm formation. However, there are no data in men with aneurysm formation that allow comment on these speculations. Spontaneous medial calcific arterioslcerosis occurs in the rabbit, particularly along the thoracic aorta, leading to mild localized aneurysmal dilatations (55). It has generally not been specifically reported in relation to smoking or smoke products, although it may possibly have been observed incidentally in various experiments. Wanstrup and associates (147) reported the enhancement of such change with CO exposure. Schievelbein (120) studied the chronic effect of nicotine in animals (rabbits) liable to develop spontaneous arterio sclerosis in the absence of an atherogenic diet. There was no enhancement of morphological arteriosclerosis by nicotine, but the aortas of the experimentally treated group contained more calcium, more free fatty acids, and more lipoprotein lipase. Aneurysmal differences were not noted. Research Needs Atherosclerotic aneurysms of the aorta are uncommon. Study of their pathogenesis is not likely to be promising in the absence of convenient animal model analogues. A study of experimental poststenotic dilatation might illuminate atherogenic processes in relation t.e smoking. Research initiatives in this area show little promise at present. Conclusions Cigarette smoking is a strong risk factor for atherosclerotic aortic aneurysm. The association provides a mortality ratio of about eight among males who smoke more than about 40 cigarettes a day and a dose relationship is evident. i High Blood Pressure The Nature of Hypertension Many factors are known to be involved in and affect the control of arterial blood pressure. It is directly dependent on cardiac output and total peripheral resistance. Some of the factors influencing pressure include the renin-angiotensin system, aldosterone, catecholamines, central and peripheral nervous activity, plasma volume, changes in 4-56 vessel elasticity, red cell mass and blood viscosity, sodium metabolism, obesity, and genetic predisposition. The manner or means by which most cases of hypertension-essential hypertension-develop is not understood. The effect, however, is to enhance atherogenesis and atherosclerotic diseases, particularly heart disease and stroke, and to shorten life. Experimental models of hypertension in animals are available for research. There are both genetic models and those induced by hormonal and surgical procedures. However, smoke or smoke constitu- ents have not been assessed in such models. Summary of Epidemiological Data Arterial hypertension is a very common disorder constituting a risk factor for atherogenesis, stroke, heart attack, heart failure, renal failure, and retinal damage. Hypertension is a continuous variable and an independent risk factor. Although smoking can raise blood pressure acutely, there is no evidence that smoking induces hypertension. On the contrary, smokers appear to have, on the average, a slightly lower blood pressure than nonsmokers. Table A8 (pp. 99-100) of the 1976 report on smoking and health (138) tabulates several studies; recent reports repeat such data trends or show little relationship (23,129). An exception to these data is the finding of Kahn and associates (67) in their study of 10,000 Israeli male civil servants. In a period of 5 years, they found that the incidence of hypertension adjusted for age was about two times greater in smokers than nonsmokers. However, the conclusion can be considered in additional ways. Since weight gain is associated with an increase in blood pressure and weight loss is associated with a decrease in blood pressure and, moreover, since smokers tend not to gain as much weight as nonsmokers, this complex relationship has attracted attention. Seltzer (121) has offered data in which men who stopped smoking gained about 8 pounds and showed an increase of about 4 mm Hg in systolic blood pressure. In examining the data for weight change, it was found that continuing smokers who lost weight had a decrease in systolic blood pressure of about 3 mm Hg, while quitters who also lost weight had an increase in blood pressure of about 2 mm Hg. The gradient between these two groups was about 5 mm Hg in systolic blood pressure. The reference report of 1976 on The Health Consequences of Smoking (138) comments critically on this report (p. 133ff.), and notes a marginal sample size. Available data indicate that smoking is not a major risk factor for hypertension, and in practice, the association is slightly negative. In this sense, it should be balanced against the other strong positive risk factor associations of smoking for various expressions of heart attack, for PVD, aortic aneurysm, lung disease, and cancers. 4-57 Data from several epidemiological studies indicate that, when hypertension is present, its combination with another risk factor, such as elevated blood lipids or smoking, is synergistic. The Effect of Smoking on Blood Pressure The chronic epidemiological effects of cigarette smoke on the incidence and level of hypertension and in conjunction with hypertension as an additional risk factor for cardiovascular disease have been noted above. The acute and transient effect of smoking in man is to increase heart rate and blood pressure to a minor degree. These effects are thought to be due primarily to the action of nicotine releasing cathecholamines. In the 1976 report on The Health Collsequences of Smoking (138), Table A!20 (pp. 103-108) and Table AZ1 (pp. 109-114) summarize a series of acute effects of smoking and nicotine on the blood pressure of animals and humans. Table A22 (p. 115), notes the effects on catecholamines in humans and animals. Beaumont and colleagues (17) have recently reported on a paroxysmal arterial hypertension as a reaction to cigarette smoking in which, under clinical diagnostic testing, a single high nicotine cigarette induced a rise in blood pressure of about 50 mm Hg systolic and 20 mm Hg diastolic over about 20 minutes. The reaction was accompanied by headache, palpatations, and sweating. The reaction was elicited in 13 of 173 persons tested, all of whom were moderate to heavy smokers. Research Needs It would be of some interest for an understanding of chronic hypertension to elucidate the pathogenesis of what appears to be a very mild hypotensive chronic effect of smoking. Since genetic and induced animal models of hypertension and hypertensive vasculopathy exist, including stroke-prone spontaneously hypertensive rats, it may be informative to assess the acute and chronic effects of smoke and smoke constituents in them. Conclwions Cigarette smoking does not induce chronic hypertension. Indeed, present evidence indicates that it is associated with a mild chronic hypotensive effect. However, in the presence of hypertension as a risk factor for coronary heart disease, smoking acts synergistically to increase the effective risk by joining the risks attributable to hypertension and to smoking alone. Other Conditions Among other conditions of interest are arterial and venous thrombosis, the synergism of smoking with oral contraceptives in relation to 4-58 myocardial infarction, thromboangiitis obliterans, the effect of smoking on blood lipids and lipoproteins, and tobacco constituents other than CO and nicotine. Venous Thrombosis Pathological studies in human autopsies that address the question of a difference in the presence of venous thrombi in relation to smoking habits have not been reported. On the other hand, epidemiological studies have clearly shown that conditions such as myocardial infarction or peripheral vascular disease that are commonly induced or accompanied pathogenetically by arterial thrombosis are more common in smokers than nonsmokers. Vessey and Doll (140) reported in a case control study among 34 women with venous thromboembolism (deep vein thrombosis or pulmonary embolism) that there were no apprecia- ble differences in smoking habits of subjects with or without venous thromboembolism. In the same paper, the authors mention a mortality study conducted among British doctors and report that among 31 male deaths from venous thromboembolism over 15 years of observation, the age-standardized mortality rates per 100,909 were 96 among nonsmok- ers, 5'7 among cigarette smokers, and 71 among pipe and cigar smokers. Lawson and coworkers (7'S) report the absence of an effect of smoking on venous thromboembolism among premenopausal women who were users of oral contraceptives. It has been reported that smokers suffer less thrombosis of the deep veins of the leg after myocardial infarction (89, 8.9). The failure to confirm such a finding has also been published (57'). There have been a number of studies of various aspects of blood coagulation and platelet pathophysiology in relation to smoking. In general, these have been acute experimental investigations. Table A27 (pp. I.261133) of the 1976 report on smoking and health (158) recorded a number of such studies, including a review by Murphy. The data tend in the direction of phenomena that might be expected to promote thrombosis. However, confounding variables are uncertain and the meaning of in who tests for in viva phenomena of thrombosis is not established. From the limited data available, smoking does not appear to enhance venous thrombotic disease. The interest in venous thrombosis and smoking lies not only in the question of the presence or absence of an association but in its possible meaning for arterial thrombosis. Arterial thrombosis is involved to an important degree in atherogenesis, and in the precipitation and complication of heart attack, ischemic stroke, and peripheral vascular disease. There are research opportunities to learn more about thrombosis in general and, in particular, in relation to possible Pathogenetic associations with smoking. 4-59 Tbromboangiitis Obliterans (Buerger's Disease) Buerger's disease is a relatively rare vascular disease that severely affects the legs and sometimes affects the arms and other vessels. It is usually present as a painful ischemic disease of progressive and subacute type in young male adults. Pathologically, there is a focal subacute inflammatory phase involving the artery, nerve, and vein coursing in the limb. The vascular inflammation is accompanied by arterial and venous thrombosis and local obstruction to the circulation. A migrating thrombophlebitis is often prominent. Lesions may heal with vascular sclerosis and new lesions may appear at other sites. The ultimate outcome is ischemic loss of the limb(s) and when the lesion extends to other vessels, loss of life. While the disease has been regarded as a fulminant form of atherosclerosis (153, the more common view with stronger evidence is that it is a separate disease (87) and a vasculitis. An infectious etiology (24) has been proposed, as has a hypersensitivity cause (54). Risk factors such as hypercholesterolemia or diabetes are not present and coronary heart disease occurs only very late in the course of the disease. Smoking has been noted clinically to be strongly associated with Buerger's disease (68). Retrospective studies indicate that its occur- rence among nonsmokers must be very rare. The lesions are compatible with an angiitis of hypersensitive or immunologic pathogenesis. Therefore, it has been speculated that hypersensitivity to tobacco components may be the basis of thromboangiitis obliterans (54). The evidence for this theory is suggestive but inadequate at present. Adequate investigations will probably require the use of much purer tobacco antigens than have been available in the past (19). There is conceptual interest for the pathogenesis of atherosclerosis in such investigations that extends beyond thromboangiitis itself since ather+ sclerotic lesions commonly show evidence of a slight inflammatory component and since a form of coronary atherosclerosis bearing a remarkable resemblance to advanced plaques in man has been produced in fat-fed rabbits by immunologic means (93), and also because a glycoprotein isolated from tobacco leaves has been shown to activate Factor XII in samples of human plasma, resulting in the generation of clotting activity, fibrinolytic activity, and kinin activity U8). Oral Contraceptives, Smoking, Myocardial Infarction, and Subarachnoid Hemorrhage Among Women Extensive population studies have determined that the risk of non- fatal myocardial infarction among women during child bearing ages is increased by a factor of about two times by the use of estrogen- containing oral contraceptives, and that it is increased to about 10 times the expected value when users also smoke (61, 81, 82, 102). A recent study reports that oral contraceptive use increases the risk of 4-60 subarachnoid hemorrhage about six times and that the additional use of cigarettes increases the risk to about 20 times (106). The mechanisms that may underlie these phenomena in women are considered elsewhere, but estrogen and estrogen analogue administra- tion to men with cancer of the prostate or with preexisting myocardial infarction have been shown to increase the risk of heart attack (30, 141). These reports did not contain information on smoking, however. While the associations between smoking, oral contraceptive use, and enhanced risk of cardiovascular disease are not in doubt, research opportunities exist in seeking explanations for the effect. The Effect of Smoking on Blood Lipids The report, The Health Consequences of Smoking of 1976 (138), dealt with the question of a possible effect of smoking on blood or serum cholesterol. Acute effects in man and animals were tabulated in Tables A25 and A25a (pp. 119-124). Case control and population studies are listed in Table A7 (pp. 9498). The data are not very uniform, but there is a preponderance of results in man in which smokers have a somewhat higher blood cholesterol level than nonsmokers. Paul (103) has recently presented additional data with this same finding. Dawber has analyzed the Framingham Heart Study data in terms of pipe, cigar, and cigarette smoking (33). Since these forms of smoking deliver different amounts of tar, nicotine, and CO to the smoker, such an analysis might reflect specific responses on the part of the serum lipids. No major differences were found. Pipesmokers had average cholesterol levels of about 216.25 mg, cigar smokers of 226.95 mg, and cigarette smokers of 224.34 mg (nonsmokers 223.83 mg). These differences are too small to account for the observed differences in risk associated with type of smoking habit. There may indeed be a minor tendency for cigarette smokers to have slightly elevated blood cholesterol levels for whatever reason, but smoking and cholesterol are clearly established independent risk factors. Experimental data based on acute manipulation of smoke exposure or nicotine appear to show a consistent elevation of free fatty acids in the blood. Animals exposed to CO and high cholesterol diets have been reported to develop more hypercholesterolemia than expected, but confirmation has not been established with whole smoke (14,136). Other recent reports have found HDL levels to be a strong and independent risk factor for coronary heart disease that has an inverse relationship (49, 92, 94); high levels are protective and low levels are associated with increased risk. Both in a subset of the Tromso study (94) and in the Framingham study (@), almost identical HDL cholesterol levels among smokers and nonsmokers were found; there was no significant association between them. Observations on 10,606 males in Israel show that alpha cholesterol is depressed among smokers of cigarettes compared to nonsmokers and 4-61 ex-smokers, with the trend persisting in different age groups. The concentration of alpha cholesterol decreased according to increased amounts smoked daily when the smokers were grouped as never having smoked, and having smoked 0 to 10,ll to 20, and more than 20 cigarettes smoked per day. Total serum cholesterol, and hence beta cholesterol, were increased in direct relationship to the amount smoked (&?). HDL cholesterol has also been measured among approximately 4,000 men and women who are the adult offspring of the original Framingham Heart Study cohort. After control for reported alcohol consumption, subscapular skinfold thickness, and age in multiple regression analysis, cigarette smoking was found to be associated with significantly lower HDL levels in both men and women. There was no evidence of lower HDL cholesterol among former cigarette smokers (47'). In an examination of 447 women and 471 men aged 40 or 41 in Holland, it has been found that HDL cholesterol is (as expected) higher in women than in men. Cigarette smoking was associated with a reduced serum HDL-cholesterol in both men and women. Among the women there was also a strong negative association with the use of oral contraceptives that was independent of smoking (4). Hulley and colleagues (59) have recently reported in a multiple-risk- factor intervention trial group that over a period of a year the change in serum thiocyanate (an indirect measure of smoking activity) showed a univariate regression coefficient, with an HDL cholesterol of -.I2 that was significant at less than the 0.05 level. The multivariate regression coefficient was -.15 and significant at less than 0.01. While more data should be gathered to ascertain the effect of smoking on HDL levels, present indications are that, when other factors that also affect HDL levels are controlled in statistical analysis, cigarette smoking displays an independent inverse relationship with HDL levels. Moreover, since total cholesterol levels appear to be slightly elevated among smokers, lipoprotein cholesterol that is positively atherogenic will also be increased. Consequently, it can be hypothesized that the effect of smoking on CHD morbidity and mortality may be to some degree a reflection of altered lipoprotein metabolism. Other Constituents of Smoke Smoke is a remarkably complex mixture of chemical substances and physical chemical states. Our understanding of the relationships of nicotine and CO and of whole smoke to cardiovascular disease have been noted above. Other substances have attracted some investigation also. Those of possible cardiovascular interest include cadmium, zinc, chromium, carbon disulphide, carbon dioxide, hydrogen cyanide, oxides of nitrogen, and polonium-210. McMillan (90) concluded that, while these substances provide interesting grounds for speculation as to their possible role in cardiovascular disease, only nicotine and CO offer both data and rational concepts for a role in smoking and cardiovascular 4-62 disease that command serious attention at the present time. As noted very briefly above in the section on thromboangiitis and considered in a separate chapter, hypersensitivity to tobacco protein does offer reasonable concepts in relation to the pathogenesis of arteriosclerosis, thrombosis, and angiitis. Its investigation will require more systematic study and the use of immunologic methods superior to those employed in the past. Dlscusslon and Conclusions The present report on cardiovascular disease and smoking is able to summarize and to comment on far more extensive and detailed data than were available 15 years ago. It draws heavily on the 1976 reference report on smoking and health (138) and adds recent references. Systematic observations on the associations between smoking and cardiovascular diseases have been made `on considerably more than a million individuals in the United States alone and have involved many millions of person-years of experience. The majority of these have been gathered on men. Sample sizes are now extensive in both retrospective and prospective studies, The variables observed in retrospective studies have been relatively limited; in some prospective studies, they have been more numerous and have allowed for complex analyses in which the independence of smoking as a risk factor among other risk factors has been defined. The data collected from western countries, particularly the United States, but also the United Kingdom, Canada, and others, show that smoking is one of three major independent risk factors for heart attack manifest as fatal and nonfatal myocardial infarction and sudden cardiac death in adult men and women. Moreover, the effect is dose related, synergistic with other risk factors for heart attack, and of stronger association at younger ages. Baaed on smaller but still extensive samples, smoking cigarettes is strongly associated with increased morbidity from arteriosclerotic peripheral vascular disease and with death from arteriosclerotic aneurysm of the aorta. There is no reasonable doubt that cigarette smoking as a risk factor for these cardiovascular diseases has been proven. Its dimensions as a risk factor for them have been established for the American public. Atherosclerosis, the basic lesion of ischemic disease studied at autopsy, has been observed in restricted samples and limited numbers of cases. Nevertheless, the data establish adequately that cigarette smoking is associated with more severe and extensive atherosclerosis of the aorta and coronary arteries than is iound among nonsmokers. The effect is related to the amount smoked. Existing autopsy data have not allowed adequate multivariate analysis, but several prospec- 4-63 tive studies have now collected sufficient standard risk factor data, including smoking information and autopsy findings, to report preliminary multivariate analyses. While more data might be desirable in order to establish better the dimensions of effect as seen at autopsy, and more data are needed to extend multivariate analyses, there is no reasonable doubt that cigarette smoking enhances atherogenesis. This knowledge establishes a fundamental rationale for the findings on the incidence of heart attack, including sudden cardiac death, aortic aneurysm, and peripheral vascular disease in relation to smoking. It is somewhat uncertain, but likely, that smoking has an adverse effect on the recurrence of heart attack among survivors of a prior myocardial infarction. On the other hand, epidemiologic data on the association between cigarette smoking and angina pectoris and cerebrovascular disease manifested as stroke are not conclusive. There are major and unresolved inconsistencies between existing reports. While certain reports on these diseases may have more technical strength than others and thus provide more credible conclusions, a basis for drawing final conclusions is not established in these two conditions. It is of interest that, in acute experiments on atherosclerotic patients with angina pectoris or with the intermittent claudication of peripheral vascular disease, smoking or exposure to carbon monoxide reduces the patients' established threshold for the precipitation of angina or claudication. There is no apparent relationship between smoking and the incidence of hypertension. Available evidence indicates a neutral or slight hypotensive effect. Nevertheless, in the presence of hyperten- sion, smoking joins with hypertension to affect the patient with the cardiovascular burden of both risk factors. There are opportunities for further epidemiological research into smoking as a risk factor for cardiovascular disease; these have been detailed in each of the foregoing sections. The need and priority of such research should be debated in specific cases. It can be argued that little public health or medical therapeutic advantage would arise from a clarification of the relationship of smoking to angina or cerebrovascu- lar disease in the face of the existing conclusive evidence of its adverse effect on the incidence of heart attack and lung diseases and the benefits of smoking avoidance or cessation. On the other hand, it could be of some medical value to learn more accurately what the association may be for second heart attacks. It would be of great interest for preventive medicine to know whether smoking affects the severity of atherosclerosis of the aorta and coronary arteries in childhood and adolescence and the premature development of adult forms of lesions in youth. It would also be of great interest to learn whether presentr day cigarettes modified to deliver less tar and nicotine are less hazardous for cardiovascular health. Earlier data, which no longer represent current products, found that low tar and nicotine cigarettes 4-64 carried less risk than high tar and nicotine ones but that they also bore a considerably greater risk than not smoking. Relatively little is known about the mechanisms by which smoking enhances atherogenesis or increases the risk of heart attack. This ignorance in no way weakens the force of the information noted above; nevertheless, better insight into the pathogenesis of these effects would be of potential value in designing less hazardous cigarettes or in attempting otherwise to limit the hazard of smoking. Moreover, it is likely that there would be an appreciable gain of information about basic processes of atherogenesis, thrombosis, cardiac metabolism and ischemia, and cardiac rhythmicity and ectopic electrical activity. Some experiments can be done acutely in man; many can be done in animal models with smoke constituents. Chronic or acute experiments in nonhuman primates with natural or modified whole smoke taken by inhalation in a humanlike nonaversive manner of smoking now appear Possible. It should be emphasized that a number of strong concepts exist in atherogenesis, thrombosis, and cardiac structure and function within which to mount appropriate experiments. Date on the epidemiological relationships between smoking and heart attack, peripheral vascular disease, aortic aneurysm, and arteriosclerosis noted above have been assembled in a manner to allow a statistical statement of the nature of the correlations between cigarette smoking and cardiovascular disease. Correlation is not synonymous with causation. It is important for the public to understand the nature or character of the associations that have been found. The characteristics are fully established for heart attack and include the fact that the correlations are strong ones, generally having a relative risk of two or more. They are consistent, reappearing in different population samples over and over, and they are independent of other major risk factors. There is also a graded relationship; smoking is an antecedent event in time and the cessation of smoking is followed by a reduction in risk over time; the association has strong Predictive capacity in the same Population sample and also when applied to other samples. Within the limits of the research that has heen done, the findings of epidemiology, clinical investigation, and Pathology are generally congruent. The results from the various disciplines and techniques of study tend to support each other. Although there are reports which do not confirm the statements made above, they constitute a minor part of the data and fail to cast reasonable doubt. Animal experimentation is not yet well developed in smoking research in relation to cardiovascular disease. Smoking is not a necessary condition for atherosclerosis and heart attack since these occur in nonsmokers. Repeated and very extensive experience has found, however, that it is a sufficient condition to kicrease the mortality from heart attack among the category of people who smoke and that it does so in a predictable way. 4-65 Given the characteristics of its associations with heart attack (such as strength, graded relationship, independence, consistency, antece- dence, loss of relationship on withdrawal, predictive capability, and a degree of coherence), it can be concluded that smoking is causally related to coronary heart disease in the common sense of that idea and for the purposes of preventive medicine. It may be argued that the characteristics of the associations noted above would occur if people who were constitutionally liable to heart attack were also constitution- ally liable to smoke; that is, that smoking activity and susceptibility to atherosclerotic heart disease were both due to some underlying constitutional condition of the individual. An attempt has been made to study this point by observing large numbers of monozygotic and dizygotic twins. The result has been inconclusive. A discussion of references will be found in the 19'76 report on The HeaEth conSequems of Smoking (p. 44ff.) (138). It should be noted, however, that the fact that risk in smokers reverts to normal or nonsmokers' levels after they cease to smoke is contrary to the constitutional concept as expressed above, unless further complex assumptions are made and it is assumed that large numbers of individuals underwent a change in their underlying constitutional factor in midlife, acquired low risk, and ceased to smoke because of that new constitution. This is not to say that genetic suscefitibility or resistance may not also be a risk factor that plays a role in the individual expression of or resistance to disease along with other risk factors, or that people who stop smoking may not also adopt additional health-oriented behaviors when they stop; but the constitutional hypothesis as expressed above does not provide a credible basis to doubt that cigarette smoking is a cause of coronary heart disease. From the point of view of cardiovascular disease, research on the mechanisms whereby smoking causes its adverse effects and a more precise quantification of certain risk factors through epidemiological studies are significant topics of medical science. The major goal in smoking and cardiovascular disease research is, however, the develop ment of long-term effective methods of smoking avoidance and cessation. 4-66 Cardiovascular Diseases: References (I) ALBERT, RE, VANDERLAAN, M., BURNS, FJ., NISHIZUMI, M. 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National Cancer institute CONTENTS Introduction .............................................................. 9 Lung Cancer ............................................................. 9 Trends in Lung Cancer Mortality ........................... 10 Epidemiological Studies ........................................ 11 Dose-Response Relationships .................................. I2 Number of Cigarettes Smoked Per Day.. ........ .12 Age at Which Smoking Began.. ...................... I3 Inhalation of Cigarette Smoke ........................ 14 Tar and Nicotine Content of Cigarettes.. ........ .15 Lung Cancer in Women ....................................... 16 Trends in Cigarette Consumption among Females ......................................... 16 Epidemiological Studies ................................. .20 Dose-Response Relationships ........................... 21 Patterns of Cigarette Use.. ........................... .21 Twins ................................................................ 23 Lung Cancer and the Use of Other Forms of Tobacco ...................................................... 23 Histology of Lung Cancer.. .................................. .23 Cessation of Smoking ........................................... 24 Lung Cancer and Air Pollution.. ........................... .25 Lung Cancer and Occupational Factors.. ................ .2'7 Asbestos ...................................................... 28 Uranium Mining ........................................... 2x3 Nickel ......................................................... 23 Chloromethyl Ethers ..................................... 29 Animal Studies ................................................... 29 Skin Painting and Subcutaneous Injections ...... .2!9 Tracheobronchial Implantation and Instillation .. .29 Inhalation Carcinogenesis ............................... 30 Nitrosamines ............................................... .30 Phagocytosis ............................................... .31 Conclusions ........................................................ .31 CanCer of the Larynx.. ............................................. .32 Epidemiological Studies ....................................... .33 Asbestos ........................................................... .u Animal Studies ................................................... 34 5-3 Conclusions ......................................................... 36 Oral Cancer ............................................................ .39 Epidemiological Studies ....................................... .39 Other Fcmns of Tobacco.. .................................... .4fl Other Risk Factors.. ........................................... .&I Leukoplakia ........................................................ 41 Animal Studies ................................................... 41 Conclusions ......................................................... 42 Caner of the Esophagus ........................................... .42 Epidemiological Studies ....................................... .a Other Forms of Tobacco Use ................................ 43 Other Risk Factms ............................................. .43 Autopsy Studies ................................................. .44 Animal Studies .................................................. .bi Conclusions ........................................................ .44 Cancer of the Urinary Bladder and Kidney.. ................ .45 Bladder Cancer ................................................... 45 Epidemiological Studies ................................. .45 Other Risk Factors.. .................................... .47 Animal Studies ............................................ .4'7 Kidney Cancer.. ....................... .I ........................ .4? Epidemiological Data .................................... .47 Conclusions ........................................................ .49 Cancer of the Pancreas ............................................. .59 Epidemiological Studies ....................................... .50 Other Risk Factors.. ........................................... .51 Animal Studies ................................................... 51 Conclusions ........................................................ .53 Mechanisms of Carcinogenesis .................................... .53 Smoke Composition ............................................. .53 Experimental Models.. ......................................... .53 Concepts of Carcinogenesis ................................... .54 Aryl Hydrocarbon Hydroxylase ............................. .57 Multi-Stage Model of Carcinogenesis ...................... .58 References .............................................................. .59 5-4 LIST OF FIGURES Figure l.-Relative risk of lung cancer for males, by number of cigarettes smoked per day and long-term use of filter (F) and nonfilter (NF) cigarettes . . . . . . . . . . . . . . . . . . 18 Figure 2.-Relative risk of lung cancer for females, by number of cigarettes smoked per day and long-term use of filter (F) and nonfilter (NF) cigarettes . . . . . . . . . . . . . . . . . . 19 Figure 3.-Lung cancer mortality in continuing cigarette smokers and nonsmokers as a percentage of the rate among ex-cigarette smokers at the time they stopped smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Figure 4.--Relative risk of developing larynx cancer for males, by number of cigarettes smoked per day and use of filter and nonfilter cigarettes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Figure 5.--Relative risk of developing larynx cancer for females, by number of cigarettes smoked per day and use of filter and nonfilter cigarettes . . . . . . . . . . . . . . . . . . . . . . . . . 36 Figure 6.-Relative risk of developing larynx cancer for male ex-smokers, by years of smoking cessation . . . . . . . . . . 37 Figure `I.-Relative risk of developing larynx cancer for female ex-smokers, by years of smoking cessation . . . . . . . 33 Figure 8.--Relative risk of pancreatic cancer in males, by number of cigarettes smoked . . . . . . . . . . . . . . . . ..*....*.........*. 52 LIST OF TdsLES Table I.-Lung cancer mortality ratios-prospective studies.. . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12 5-5 Table Z.-Lung cancer mortality ratios for males, by current number of cigarettes smoked per day, from selected prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Table 3.-Lung cancer mortality ratios for males, by age began smoking, from selected prospective studies . . . . . . . . 14 Table $.-Lung cancer mortality ratios for males, by degree of inhalation, from selected prospective studies . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .I.. . ,... 15 Table 5.-Age-adjusted lung cancer mortality ratios for males and females, by tar and nicotine in cigarettes smoked.. . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16 Table 6.-Age-adjusted lung cancer mortality ratios for males and females, comparing those who smoked a few high T/N cigarettes with those who smoked many low T/N cigarettes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Table `I.-Mortality rates for lung cancer and cancer of the respiratory tract for white females in the United States per 100,000 population for selected years: 1940 to 1976 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Table %-Percent of adult population who were current cigarette smokers in selected years in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Table 9.-Percent of teenagers who were current cigarette smokers in selected years in the United States . . . . . . . . . . . 21 Table lO.-Lung cancer mortality ratios for women- prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Table Il.-Lung cancer mortality ratios for females, by number of cigarettes smoked per day: A.C.S. 25-State Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Table 12.-Lung cancer mortality ratios for females, by number of cigarettes smoked per day: Haenszel and Taeuber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Table 13.-Lung cancer mortality ratios for females, by duration of smoking: Swedish Study . . . . . . . . . . . . . . . . . . . . . . . . . 22 5-6 Table 14.-Lung cancer mortality ratios for females, by degree of inhalation: A.C.S. 25-State Study . . . . . . . . . . . . . . . . 22 Table E-Lung cancer mortality ratios in ex-cigarette smokers, by number of years stopped smoking . . . . . . . . . . . . 25 Table 16.-Mortality ratios for cancer of the larynx- prospective studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Table 1'7.-Mortality ratios for cancer of the oral cavity- prospective studies.. . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Table 18.-Mortality ratios for cancer of the esophagu- prospective studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Table lg.-Bladder cancer mortality ratios-prospective studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46 Table 20.-Kidney cancer mortality, ratios and relative risks: selected prospective and retrospective studies . . . . .48 Table 21.-Kidney cancer mortality ratios, by amount smoked: U. S. Veterans Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Table 22.--Pancreatic cancer mortality ratios-prospective studies... . . . . ,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .., . . . . 51 Table 23.-Mortality ratios for cancer of the pancreas among Swedish subjects, aged 1869, by sex and amount smoked.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52 Table 24-Carcinogenic, promoting, and ciliatoxic agents in the gas phase of tobacco smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Table 25.-Carcinogenic agents in the particulate phase of tobacco smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Table 26.-Tumor promoters and co-carcinogens in the particulate pha& of tobacco smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 5-7 Introduction Cancer has been the second leading cause of death in the United States since 1937. There were an estimated 390,000 deaths from cancer in 1978 (4). The association between tobacco smoking and the development of lung cancer was first suggested in the 1920's and early 1930's (159, 2~). In the early 1950's, more than a dozen retrospective studies were published which first generally alerted the medical and scientific community to the health hazards associated with cigarette smoking. The public was informed of the results of these studies, and as a consequence there was a significant, but brief, dip in the per capita consumption of cigarettes. The next decade brought an intensive worldwide investigation into the various diseases associated with cigarette smoking. The first official statement on smoking and health by the U.S. Government was contained in the Report of the Advisory Committee to the Surgeon General of the U.S. Public Health Service, which was released 15 years ago. The evidence available at that time warranted the conclusion that "Cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors. The data for women, though less extensive, point in the same direction. The risk cf developing lung cancer increases with the duration of smoking and the number of cigarettes smoked per day, and is diminished by discontinuing smoking" (2133. In the 15 years since the 1964 Surgeon General's Report was published, these conclusions have been confirmed by numerous investigations in many countries. Cigarette smoking has also been implicated as a significant cause of cancer of the larynx, oral cavity, esophagus, urinary bladder, kidney, and pancreas. As data concerning the relationship of smoking to the development of cancer at various sites became available, they were summarized and published in the annual issues of the Health Consequences of Smoking (209, 210, 211,212,212a,213,214,215,216). This chapter reviews the epidemiological and experimental data for each of the cancer sites associated with cigarette smoking. Discussions of the specific cancers are presented sequentially, based on the strength of the association with cigarette smoking: cancer of the lung, larynx, oral cavity, esophagus, urinary bladder, kidney, and pancreas. Lung Cancer This year more people in the United States will die from lung cancer than from any other malignant disease. In 1950, when the nation first became generally` aware that there was an association between smoking and lung cancer, there were 18,313 lmg cancer deaths. In l96% there were 45,838 deaths from lung cancer. The National Center for Health Stat' t' IS its reported that in 1976 there were 86,267 deaths from lung cancer in the United States (150). It is estimated that there 5-9 were 92,400 deaths from lung cancer in 1978 (4). For every preventable death from highway accidents, there were approximately two deaths from lung cancer which could have been prevented if the individual had not smoked cigarettes. There are about 230 deaths from lung cancer each day in the United States. This epidemic increase in lung cancer is reflected in rapidly changing mortality rates in both men and women. The mortality rate for men in 1950 was 19.9/1OO,OOO/year. This rose to 41.4 in 1964, and to 63.0 in 1976. The comparable figures for white females were 4.7 in 1950 and 8.0 in 1965, and climbing rapidly to 19.5 in 1976 (Table 7). According to results from the National Cancer Institute's Surveil- lance, Epidemiology, and End Results (SEER) Program, the mortality rates for black males and females are higher than for whites. In 1976, the lung cancer mortality rate for black males was 93.0, for black females it was 17.4 (154). Due to recent increases in death rates among females, the ratio of male to female mortality for lung cancer has dropped from 7:l to less than 4:l. While recent years have seen dramatic increases in relative survival rates for acute leukemias in children, Hodgkin's disease, multiple myeloma, and certain other malignancies, there has been little increase in survival rates for lung cancer. The 5-year survival rate for lung cancer in all states is 8 percent for males and 12 percent for females (151). The difference in survival rates between males and females can be explained by sex-specific differences in histology or stage of the disease. Trends in Lung Cancer Mortality In the United States there has been in the past few years a significant reduction in the percent of males and females who smoke cigarettes. As yet, there has not been a decline in the age-adjusted tot& mortality rates for lung cancer. When the lung cancer mortality rates by age are examined from 1950 through 1975, there is a continuining increase in older age groups for both males and females. This is probably due to the elevated risk experienced by older persons who use nonfiltered, high tar and nicotine cigarettes and who have done so for the majority of their lives. However, for female cohorts born in 1950-54 and male cohorts born in 193539 and 194044, the age-.speci& lung cancer mortality rates are below those of previous cohorts. This probably results from the reductions in cigarette consumption which have occurred in these groups. There has been a change in the epidemic of lung cancer in England and Wales, as summarized by the International Union Against Cancer (UICC) workshop on the biology of cancer (Z.&?): In England and Wales, lung cancer mortality stopped increasing in men under the age of 50 years during the 1950's and more recently has fallen in men under the age of 60 years. The death rate from 5-10 lung cancer in women ages 40 years and over has continued to rise, but has leveled, or fallen in younger women since the 196O's...The fall in lung cancer mortality among men under the age of 60 years is likely to be due to their reduced consumption since the end of the Second World War, and to the reduction in the tar yield of cigarettes since 1955; particularly with the change to filter cigarettes. Although lung cancer mortality in women over 40 years has continued to increase along with their cigarette consumption, it is unlikely that the incidence of lung cancer will ever reach the high levels recorded in men, because the increasing cigarette consumption by women has been, and is continuing to be compensated for by a decrease in tar yield. Epidemiological Studies The first comprehensive reviews of the effects of smoking on lung cancer were published in 1962 and 1964 by the Royal College of Surgeons of London and the Surgeon General of the United States, respectively (171, 217). They included data from studies on epidemiolo- gy, profiles of the consumption of tobacco, the composition and carcinogenicity of components of tobacco smoke, the effects of smoke on experimental animals, and the pathological changes observed in humans and animals. The conclusions reached in these assessments and by all of the periodic reviews that have followed at regular intervals (209, 210, 211, 212, 212q 213, 214, 215, 216) are impressively uniform and consistent. So much so that it has been observed that the results of any one of the major studies might be taken to represent all of them. There have been at least nine major prospective epidemiological studies which have examined the relationship between cigarette smoking and mortality from various causes. The results of eight of these studies are related to cigarette smoking and lung cancer and are presented in Table 1. The lowest mortality ratios are experienced by female smokers. The mortality ratios for male cigarette smokers are as low as 3.35 for Japanese males and as high as 14.0 for British doctors and Canadian veterans. Combining the data from the largest studies allows the conclusion that cigarette smokers on the average are 10 times as likely to develop lung cancer as nonsmokers. The mortality ratios are much higher for heavy cigarette smokers. This will be detailed in the section on dose-response relationships. In the past 30 years, more than 50 retrospective studies on the relationship between cigarette smoking and lung cancer have been Published. These data are too extensive for convenient summarization; they have been reviewed in recent issues of the Health Consequences *f Smoking (212,212a, 213,214,215). 5-11 TABLE l.-Lung cancer mortality ratios-prospective studies Population sii Number of deaths Nonsmokers Cigamtte SmdterS British doctms(b?a) Swedish study@?) Japanese study( 77a,78) A.C.S. 26- State Study(65) U.S. veterans(90) 34,000 males 27,000 males 23,060 females 122,066 males 143,060 females 440,000 males 562,lXUl females 239,000 males Canadian veterans(~) A.C.S. 9- State Study@@ California male3 in 9 owupa- tions(228) 78,CdlO male3 188,oM) males 68,qoO males 441 1.00 14.0 55 1.60 8.2 8 1.66 4.5 590 1.06 3.76 148 1.60 203 1,159 1.00 920 133 1.00 2.20 1zsS 1.00 1214 331 448 368 1.00 7.61 1.00 14.2 1.06 10.73 Dose-Response Relationships An important factor in the causal relationship betwe& smoking and lung cancer. is the demonstration of dose-response relationships. In most epidemiological studies, dosage has been measured by the number of cigarettes smoked per day at the time of entry into the study. Other dose variables which have been examined include the maximum number of cigarettes smoked per day, the age an individual began smoking, the degree of inhalation-of tobacco smoke, the total number of years an individual has .smoked, the total lifetime number of cigarettes smoked, tar and nicotine levels of the brand of cigarettes used, the number of puffs per cigarette, the length of the unburned portion of the cigarette, and combinations of these variables into "dosage" scores. All of these variables have been shown- in one study or another to contribute to the risk of developing lung cancer. Only a few representative samples of dosage variables as related to lung cancer mortality are examined in this section. Number Of Cigarettes Smoked Per Day `rhe risk of developing lung cancer increases with the number of cigarettes smoked per day. In the U.S. and British populations, the risk of developing lung cancer for individuals smoking more than two packs 5-E TABLE 2.-Lung cancer mortality ratios for males, by current number of cigarettes smoked per day, from selected prospective studies smoked per day Mortality ratio A.C.S. 25- state study(65) Nonsmoker 1.00 l-9 4.62 lo-19 8.62 2039 14.69 40+ 18.77 British dcctors(l7a) iNonsmoker 1.00 1-14 7.80 15-24 12.70 25+ 25.10 Swedish males(9f) Nonsmoker !.oo l-7 230 a15 8.89 16+ 13.99 Japanese males( 78) Nonsmoker 1.00 l-9 1.99 lc-14 3.52 lM4 4.11 25-49 4.57 50+ 5.78 a day is approximately 20 times that of nonsmokers (4% 65, 68, 80, 228). Data for Swedish males are of the same magnitude (32). Japanese males who smoke 50 or more cigarettes a day experience a risk which is 5.8 times greater than for nonsmokers. Hirayama noted that the slope of the dose-response curve for lung cancer was less in Japan than in the United States and that this was probably due to the lower Percentage of regular deep inhalers, a lower level of environmental Promoting conditions, and also a higher percentage of adenocarcinoma in Japan than in the United States (78). Table 2 presents lung cancer mortality ratios from selected prospective studies for males by the current number of cigarettes smoked per day. Age at which Smoking Began Lung cancer mortality ratios exhibit an inverse relationship with the age of initiation of the smoking habit. Lung cancer mortality ratios for males by age at which they began smoking are presented in Table 3. Most cigarette smokers began the habit while in high school and are at the greatest risk of developing lung cancer. Those who began smoking 5-13 TABLE 3.-Lung cancer mortality ratios for males, by age began smoking, from sele&.ed prospective studies Age began smoking in years Mortality ratio A.C.S. 25- State Study(65) Nonsmoker 1.00 25+ 4.08 ax?.4 lO.QB 15-19 19.69 under 15 16.77 J8paIlW study( 78) Nonsmoker 25+ 20-24 under 20 U.S. veterans(90) Nonsmoker 1.00 25+ 520 20-24 9.50 15-19 14.40 under 15 18.70 1.00 2.37 3.35 4.44 after the age of 25 have mortality ratios which are only 4 to 5 times greater than those of nonsmokers. Inhal4&n of Cigarette Smoke Inhalation of tobacco smoke is an important dosage variable. Inhala- tion of smoke well into the lungs is the major mechanism whereby lung tissue is exposed to the carcinogens which ultimately produce lung cancer. Techniques for quantitating the degree of tobacco smoke inhalation have been developed using carboxyhemoglobin levels or end expiratory carbon monoxide levels as an index of smoke inhalation. These objective methods of measuring inhalation have not been applied to studies of lung cancer mortality. In most investigations, the smoker was asked to report subjectively on his own inhalation practices. This is subject to considerable variation but is not as inaccurate as might be presumed. Available data show a strong dose- response relationship between self-reported inhalation of cigarette smoke and lung cancer mortality. Representative figures from selected prospective studies are presented in Table 4. These data suggest that cigarette smokers may underestimate the degree to which they inhale cigarette smoke. Those who report that they do not inhale cigarette smoke experience lung cancer mortality ratios which are 4 to 8 times greater than for nonsmokers. Deep inhalation results in mortality ratios which are as high as 17 times greater than for nonsmokers. 5-14 TABLE I.-Lung cancer mortality ratios for males, by degree of inhalation, from selected prospective studies NT= of Mortality, inhalation ratio A.C.S. 25 State Study(G) Nonsmoker 1.00 None 8.00 Slight 8.92 Moderate 13.08 DIP 17.00 Swedish Nonsmoker None Light inhalation Deep inhalation 1.00 3.70 7.FQ 9.20 Tar and Nicotine Content of Cigarettes The major constituents of cigarette smoke that cause lung cancer are among the more than 2,000 different compounds found in cigarette smoke. Cigarette filters, first introduced during the mid-1950's, have the effect of trapping tar. Data presented by Maxwell (136) show that, in 1976, more than 600 billion cigarettes were smoked and that 88.4 percent of these were filtered. It has been known that the risk of developing lung cancer increased with the tar and nicotine content of cigarettes. Until recently, however, there has not been a great deal of evidence that individuals who switch to lower tar and nicotine cigarettes experience less lung cancer mortality (27). It has been argued that, if the tar and nicotine content of tobacco were reduced, individuals might increase the number of cigarettes smoked per day and thereby abolish any benefit that might be gained. Alternatively, those who switch to low tar and nicotine cigarettes might inhale the smoke more deeply than smokers of high tar and nicotine cigarettes, and thereby exposure to tar and nicotine might not be reduced. In a large prospective study by Hammond, et al. (67), these tar and nicotine relationships were examined with respect to lung cancer. The 897,825 men and women in 23 States were divided into 3 tar and nicotine categories. The high tar and nicotine (T/N) category was defined as 2.0 to 2.7 mg of nicotine and 25.8 to 35.7 mg of tar. The medium TN ategory was defined as 1.2 to 1.9 mg of nicotine and 17.6 to 25.7 mg of tar. The low T/N category included cigarettes containing less than 1.2 mg of nicotine and less than 17.6 mg of tar. A matched-group analysis, similar to age standardization, was utilized. Individuals in each group `ere alike with respect to age, race, number of cigarettes smoked per day* age when they began to smoke cigarettes, place of residence, 5-15 TABLE 5.-Age-adjusted lung cancer mortality ratios* for males and females, by tar and nicotine in cigarettes smoked High T/N 1.00 1.00 Medium T/N 0.95 0.79 Law T/N 0.81 0.60 `The mortality ratio for the category with highest risk ~88 made 1.00 so tksl the relative reductions in risk with the use of lower T/N cigarettes could be visudiwd. SOURCE: Hammond. EC. (67) occupational exposure to dust fumes, chemicals, etc., education, prior history of lung cancer, and prior history of heart disease. Results of this analysis are presented in Table 5. The mortality ratio for the category with the highest risk was made 1.0 so that the relative reduction in risk with the use of lower T/N cigarettes could be visualized. For males smoking the same number of cigarettes per day, there appears to be a 20 percent reduction in risk of developing lung cancer with the use of low T/N cigarettes. For females, there was a 40 percent reduction in the risk of developing lung cancer with the use of low T/N cigarettes, keeping the number of cigarettes smoked per day constant. The amount of tar and nicotine taken into the body per day depends on the number of cigarettes smoked, as well as on the tar and nicotine content of each cigarette. Hammond conducted a second matched-group analysis comparing subjects who smoked 1 to 19 high T/N cigarettes per day and those who smoked 20 to 39 low T/N cigarettes per day. These results are presented in Table 6. The number of cigarettes smoked per day was a relatively more important variable than the tar and nicotine content of cigarettes. The mortality ratio was 1.6 for males and 2.1 for females who smoked 20 to 39 low T/N cigarettes a day, compared to individuals who smoked only 1 to 19 high T/N cigarettes per day. Wynder and Stellman (253) conducted a large retrospective study of 1,034 white males and females with histologically proved cancer of the lung and larynx. Relative risks were consistently lower among long- term smokers of filter cigarettes, compared to smokers of nonfilter cigarettes. These groups were standardized for number of cigarettes smoked, duration of smoking, inhalation, and cigarette butt length. These dose-response relationships are presented in Figures 1 and 2. Lung Cancer in Women Trends in Cigarette Consumption Among Females In 1964, the Advisory Committee to the Surgeon General concluded that cigarette smoking was causally related to cancer in men, and that 5-16 TABLE 6.--Age-adjusted lung cancer mortality ratios* for males and females, comparing those who smoked a few high T/N cigarettes with those who smoked many low T/N cigarettes Males Females 1-19 high T/N 2039 low T/N cigarettes/da): cigarettes/day 1.00 1.6 1.00 2.1 *The mortality ratio for the category with lowest risk was made 1.00 90 the increase in risk with smoking more ciguettes/dsy could be illustrated. SOURCE: Hammond, E. C. (60 "the data for women though less extensive, point in the same direction" (217). Today, 15 years later, the lung cancer epidemic among women is well established. Several investigators had predicted sharp increases in lung cancer mortality among women. In 1966, Linden (118) examined lung cancer mortality in California women and predicted: "One can expect to see further increase in the number of lung cancer deaths and the death rates as the increasing proportions of women who smoke cigarettes reach the age when lung cancer is most likely to OCCW." In 1964, lung cancer was the fifth leading cause of death from cancer in women. It became the fourth leading cause in 1967 and moved to the third leading cause of death from cancer in 1969, passing cancer of the uterus. Projections for 1979 indicate that lung cancer is approaching cancer of the colon and rectum as the second leading cause of death from cancer in women. If present trends are not reversed, during the next decade lung cancer will become the leading cause of death from cancer in women, exceeding deaths from cancer of the breast. In 1955, there were only 4,100 deaths from lung cancer in women. In 1976, the National Center for Health Statistics reported there were 20,455 deaths from lung cancer among females in the United States (150); the American Cancer Society estimated that in 1978 this increased to 21,900 deaths (4). These increases are not due to increases in the population. Death rates for lung cancer have been steadily rising in women, especially in the past decade. The lung cancer mortality rate for white females in 1950 was 4.7 per 100,000; by 1976 this had risen to 19.5 per 100,000. This is more than a fourfold increase (Table 7). The Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute recently reported that the lung cancer death rate for black females exceeded that of white females (16.8 blacks, 15.0 whites)(154). Data from this survey are collected from 10 geographic areas in the United States and therefore do not represent 5-17 LUNG CANCER I. MALES 126 25 62 NON F NF F NF F NF F NF F NF SMOKER l-10 11-20 21-30 31-40 41+ NO. OF CIGARETTES SMOKED PER DAY FIGURE l.-Relative risk of lung cancer for males, by number of cigarettes smoked per day and long-term use of filter (F) or nonfilter (NF) cigarettes SOURCE: Wynder, E.L. (253) national trends per se. The lung cancer mortality rate (15.0 per 100,000) among black females in the general U.S. population is equal to that of whites. Increases in lung cancer mortality among females cannot be explained by exposure to occupational carcinogens. Increases in cigarette consumption are responsible for these trends. 5-18 25 20 15 10 5 LUNG CANCER I. FEMALES N: CASES CONTROLS 20 2955 F NF F NF F NF SMOKER l-10 11-20 21-30 31+ NO. OF CIGARETTES SMOKED PER DAY FIGURE L-Relative risk of lung cancer for females, by number of cigarettes smoked per day and long-term use of filter (F) and nonfilter (NF) cigarettes SOURCE: Wynder. FL (S.53) The epidemic of lung cancer in women has lagged behind that in men, primarily because of differences in patterns of cigarette smoking. There are fewer women smoking than men, but the gap is narrowing. Among teenagers in several age categories, girls are smoking more than boys (155). Table 8 shows the percentage of the U.S. adult Population who are currently smoking cigarettes for selected years. In 1975, approximately 29 percent of adult females were smoking, whereas 39 percent of adult males were smoking (1%). It should also be noted that, over the past decade, there has been a 2.6 percent 5-19 TABLE `I.-Mortality rates for lung cancer and cancer of the respiratory tract for white females in the United States per 100,000 population for selected years, 1940 to 1976 Yew Lung and Bronchus Respiratory System 1940 - 3.6 1945 - 4.6 1950 4.7 5.4 1955 5.1 5.7 1960 5.9 6.4 1965 8.0 8.6 1970 12.3 13.1 1975 17.8 18.8 1976 19.5 20.5 SOURCE: National Center for Health Statistica (150) TABLE 8.-Percent of adult population who were current cigarette smokers in selected years in the United States Percent smokers Year Females Males 1964 31.5 529 1966 33.1 51.9 1970 36.5 422 1975 Percent reduction since 1964 28.9 39.3 2.6 13.6 SOURCE: National Clearinghouse for Smoking and Health (155) reduction in the number of adult females who smoke cigarettes, whereas there has been a 13.6 percent reduction in the number of adult males smoking. Trends in the percentage of teenagers who arc regular cigarette smokers are presented in Table 9. Cigarette smoking among girls has increased steadily, so that at the present time equal numbers of boys and girls are smoking cigarettes and many of the differences which existed in the past between male and female smokers have disappeared. Epidemiological Studies Three of the large prospective epidemiological studies contain informa- tion on lung cancer in women. Data from these studies are summarized in Table 10. A number of retrospective studies have examined the 5-20 TABLE g--Percent of teenagers who were current cigarette smokers in selected years in the United States Year Girls Percent smokers Ages 12-18 1968 8.4 14.7 1970 11.9 18.5 1972 13.3 15.7 1974 15.3 15.8 SOURCE: National Clearinghouse for Smoking and Health (1.5.%x) TABLE lo.-Lung cancer mortality ratios for women-prospective studies Study Population Number of deaths Mortality ratio Female Female nonsmokers smokers A.C.S. %- 562671 State Study(Q) Females 183 1.00 22fJ Swedish 27,732 study(SP) Females 8 l.aO 4.56 Japanese study(78) 142&57 Females 143 1.00 2.63 relationship of lung cancer to smoking habits in women (46 63,64,8% 122,128,13g,160,16~, 167,198,222,227,232,236,242,24247). &se-Response Relationships Dose-response relationships between lung cancer and cigarette smok- ing have been described for females by the number of cigarettes smoked per day, the degree of inhalation, and the duration of smoking. These relationships from selected studies are presented in Tables 11 through 14. The mortality ratios are as high as 10.0 for females who have smoked more than 20 cigarettes per day and for females who have smoked for more than 30 years. Path-728 of Cigarette Use Although death rates from lung cancer are increasing at an accelerat- ed rate in females, it may be that the peak will be somewhat less than in males; this may be due to substantial differences in the way males 5-21 TABLE Il.-Lung cancer mortality ratios for females, by number of cigarettes smoked per day: A.C.S. 25state Study Cigarettes smoked wr dav Mortality ratios . . Nonsmoker l-19 20+ 1.00 1.06 4.76 SOURCE: Hammond, E.C. (65) TABLE 12.-Lung cancer mortality ratios for females, by number of cigarettes smoked per day: Haenszel and Taeuber cigarettes smoked per day Mortality ratios Nonsmoker 1.00 Owasional 1.33 1-19 249 Xl+ 10.80 SOURCE: Heenscel W. (bl) TABLE 13.-Lung cancer mortality ratios for females, by duration of smoking: Swedish Study Duration of smoking in YeaA Mortality ratios Nonsmokem 1.0 l-29 years 1.6 30+ years 9.6 SOURCE: Cederlof. R. (W TABLE Il.-Lung cancer mortality ratios for females, by degree of inhalation: A.C.S. 25-State Study kP-= of inhalation Mortality ratios Nonsmokers 1.00 None to slight 1.78 Moderate to deep 3.70 SOURCE: Hammond. E.C. (65) 5-22 and females smoke cigarettes. A recent survey (155) of cigarette smoking behavior shows that women do not smoke as far down on the cigarette where proportionally more nicotine and tar are inhaled. More than 91 percent of females use filter cigarettes, compared with 80 percent of males. Females report that they do not inhale cigarette smoke as deeply into their lungs as males do. Women also smoke fewer cigarettes per day and select brands of cigarettes with lower tar and nicotine yields, compared to men. In 19'75, 76.7 percent of current female smokers smoked a pack or less per day, whereas this was true for only 69.6 percent of males (155). In the past, women began smoking later than men, but at the present time this is no longer true. The available evidence suggests that women who smoke cigarettes in the same amount and with equal depth of inhalation as men are likely to experience death rates similar to those found in men. Twins The best way to control genetic factors as a potentially complicating variable in studies of lung cancer and cigarette smoking is to conduct the investigation in a population of twins who are discordant as to smoking habits (one smokes, the other does not). Cederlof, et al. (33) published new data on smoking and lung cancer from the Swedish Twin Registries in 1977. Although the number of deaths from lung cancer among the monozygotic twins is quite low, the trend is clear. The authors state, "The welldocumented evidence of a causal association between smoking and lung cancer found in other studies has been further supported." Lung Cancer and the Use of Other Forms of Tobacco Pipe and cigar smokers in the United States have experienced lung cancer mortality rates that are somewhat higher than those of nonsmokers but substantially lower than those of cigarette smokers (1). Most pipe and cigar smokers report that they do not inhale the smoke, and as a consequence the total exposure is relatively low. There is little evidence that lung cancer is associated with the use of chewing tobacco or snuff. These relationships are explored in detail in the Chapter on Other Forms of Tobacco Use (specifically in Tables 15, 16, 17 and 22 of that chapter). Histology of Lung Cancer There are several different histologic types of lung malignancies in humans. These include squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, bronchiole-alveolar, and mixed and undifferentiated carcinomas of the lung. The predominent type of carcinoma in males is squamous cell carcinoma, whereas the most common lung cancer in females is adenocarcinoma. Over the past 5-23 15 years there has been little change in the incidence of large-cell, bronchiole-alveolar, and mixed and undifferentiated carcinomas. There has been an increase in adenocarcinoma and a decrease in squamous cell carcinomas. In 1962, Kreyberg (111~~) categorized epidermoid, small-cell, and large-cell carcinoma of the lung as Group I and adenocarcinoma and bronchiole-alveolar carcinoma as Group II. He noted that the risk for smokers was substantially greater for Group I than for Group II tumors. This view has been supported by some investigators (40, 47, ,221). Other investigators have disputed this classification (9,14,15,100, 230,254). Weiss, et al. (230) followed the experience of 6,136 men over a lO- year period. They found that well-differentiated squamous cell carcinoma, small-cell carcinoma, and adenocarcinoma displayed a dose- response relationship to smoking, but poordifferentiated squamous cell carcinoma did not. More recentiy, Auerbach, et al. (10) examined histologic types of lung cancer associated with smoking habits from autopsy data on 662 men who had had lung cancer. In this study all cell types seemed to be related to smoking to about the same degree. Most recently, Vincent, et al. (221) reviewed the histopathology of lung cancer in patients seen over a 13-year period at the Roswell Park Memorial Institute. Their data indicated that adenocarcinoma is becoming progressively more prevalent, compared to other forms of lung cancer. They were unable to disassociate smoking as a causative factor in any of the presently defined pathological categories of lung cancer. Cessation of Smoking There is a decrease in the risk of developing lung cancer after cessation of smoking. This decrease in risk occurs over a period of several years. After 10 to 15 years, the risk of dying of lung cancer for ex-smokers has decreased to point where it is only slightly above the risk for nonsmokers. All of the major studies show this reduction in risk. The most recent data from the British Doctor's Study are presented here for illustration (Table 15). The mortality ratios for ex-smokers were higher in the first year after quitting than they were for continuing smokers. The explanation for this is that both healthy and sick individuals quit smoking. Higher mortality is experienced by those who quit because of illness. Lower mortality is experienced by those who quit while experiencing apparently good health. In the US. Veterans Study, a differentiation is made between ex-smokers who stopped smoking on the recommendation of a doctor and those who quit for other reasons. About 10 percent of the smokers quit because of doctors' orders and were presumably ill. This group had much higher death rates from lung cancer than those who stopped for other reasons. 54% TABLE 15.-Lung cancer mortality ratios in excigarette smokers, by number of years stopped smoking Year8 smokioe Mortality ratio Still Smoking 15.8 l-4 16.0 5-9 5.9 lo-14 5.3 15+ 2.0 Nonsmokem 1.0 SOURCE: Doll. R. (UO) The magnitude of the residual risk which ex-smokers experience is determined by the cumulative exposure to cigarette smoke which the individual experienced before he quit smoking. The risk at any point in time would be determined by the maximum amount the individual smoked, the years since stopping smoking, the age when smoking began, degree of inhalation, and reasons for quitting smoking. The lung cancer mortality experience of ex-smokers is graphically present- ed in Figure 3. The risk of developing lung cancer increases with age, for both smokers and nonsmokers. The incidence in cigarette smokers is much higher than in nonsmokers. It can be seen that the lung cancer mortality of ex-smokers is initially similar to that of smokers, but, with the passage of time, the mortality risk moves progressively closer to that of nonsmokers. It is interesting to note that, except for the first 2 years after stopping smoking, there is a continued increase in the risk of developing lung cancer among ex-smokers, although it is less than that of those who continue to smoke. The slope of this line is less than that for nonsmokers, and so there is a convergence of these two curves. Lung Cancer and Air Pollution A number of studies have been conducted in which the relative influence of cigarette smoking, urban residence, and air pollution in the etiology of lung cancer is examined. Eight of the earlier studies were reviewed in the 1971 Report of the Surgeon General (212). More recent publications include: "Epidemiological review of lung cancer in man" by Higginson and Jensen (75) and a report of a task group, "Air pollution and Cancer," edited by Cederlof, et al. (31). There have also been studies by Doll (,&?), Weiss (229), Carnow (30), and Kotin and Falk (109). Lung cancer is consistently more common in urban than in rural areas. There is only a small urban-rural lung cancer gradient for nonsmokers. There is a much larger urban-rural gradient for smokers. Cigarette consumption is generally greater in urban areas, but it is 5-25 1000 lnctdencr as peer cent of rate at time of sro~~olny floyscalel I I , 1 0 5 10 15 20 Years since stoppmg FIGURE 3.-Lung cancer mortality in continuing cigarette smok- ers and nonsmokers as a percentage of the rate among ex-cigarette smokers at the time they stopped smoking SOURCE: UICC Technical Reports (24.7) difficult to estimate how much of the excess urban mortality can be 5-26 accounted for by cigarette smoking alone. It is possible that there is an interaction between the carcinogens in cigarette smoke and other compounds in the ambient atmosphere. Epidemiologic investigations thus far indicate that the most important cause of lung cancer is cigarette smoking and that urban factors such as air pollution have very little independent effect on the development of lung cancer. In the absence of cigarette smoking, the combined effects of all atmospheric agents do not increase the death rates for lung cancer more than a very few cases per 100,000 persons per year. Lung Cancer and Occupational Factors There are several occupations (described in Chapter 7) which are associated with the development of lung cancer and cancer at other sites (84). Estimates of the fraction of cancer deaths in the United States that can be attributed to occupational exposure have been made by several investigators. These estimates have been as low as 1 to 5 percent (45, 73, ?`4, 153, 241). Cole (37) has placed these estimates as high as 10 to 15 percent. There are difficulties in estimating the proportion of cancers attributable to certain occupational exposures, tobacco, alcohol, or diet. Most of these estimates are based on the assumption that specific cancers are caused by specific agents. It is more likely that cancer is a disease of interactions. The precipitating cause and subsequent development of cancer is likely to be a process with multiple phases and multiple agents. Both internal and external factors interact at each of several stages before cancer becomes clinically apparent. The development of cancer, then, is influenced by two or more different external factors acting simultaneously or sequentially. This principle is illustrated by the synergistic effects of tobacco and alcohol. Cigarette smoking by itself is an important cause of oral cancer, whereas alcohol by itself is a relatively minor cause of oral cancer. Combined exposure to cig