2. 3. 4. 5. 6. 7. Lung Association, have played a significant role in educating the public about the hazards of tobacco use. Individual and group smoking cessation programs evolved from an emphasis on conditioning-based approaches in the 1960s. to the cognitively based self- management procedures of the 1970s to the relapse prevention and pharmacologi- cally based components of the 1980s. There has recently been an increased emphasis on targeting specific groups of smokers for cessation activities (e.g., pregnant women, Hispanics, blacks). Packaging and marketing of self-help smoking cessation materials have become more sophisticated and there is more of an emphasis on relapse prevention, while much of the content has changed relatively little over the years. Mass-mediated quit-smoking programs have become an increasingly popular strategy for influencing the smoking behavior of a large number of smokers. The 1980s have seen an increase in the promotion of smoking control efforts in the workplace in response to increasing demand and opportunity for worksite wellness programs and smoking control policies. In the last decade there has been an increasing interest in involving physicians and other health care professionals in smoking control efforts. Medical organizations have played a more prominent role in smoking and health during the 1980s than they had in the past. Part III. Antismoking Advocacy and Lobbying 1. Lobbying and advocacy efforts have expanded through the increasing commit- ment of the national voluntary health agencies to political action and the forma- tion of coalitions at the local, State, and national levels. 2. Antismoking advocacy and lobbying have evolved over the past 25 years and now focus on a growing number of local, State, and national legislative and regulatory initiatives designed to reduce smoking, regulate the cigarette product, and prevent the uptake of smoking by children and adolescents. Chapter 7: Smoking Control Policies Part I. Policies Pertaining to Information and Education 1. The Federal Government's efforts to reduce the health consequences of cigarette smoking have consisted primarily of providing the public with information and education about the hazards of tobacco use. Two of the most well-known mechanisms are the publication of Surgeon General's Reports and the require- ment of warning labels on cigarette packages. A system of rotating health wam- ing labels is now required for all cigarette and smokeless tobacco packaging and advertisements. 2. Current laws do not require health warning labels on all tobacco products and do not require monitoring of the communications effectiveness of the warnings. Fur- thermore, existing laws do not provide administrative mechanisms to update the 26 contents of labels to prevent the overexposure of current messages or to reflect advances in scientific knowledge, such as new information about the addictive nature of tobacco use. 3. There is insufficient evidence to determine the independent effect of cigarette warning labels, particularly the rotating warning labels required since 1985, on public knowledge about the health effects of smoking or on smoking behavior. 4. Information about tar and nicotine yields appears on all cigarette advertisements but not on all cigarette packages. Levels of other hazardous constituents of tobac- co smoke, such as carbon monoxide, hydrogen cyanide, and ammonia, are not dis- closed on packages or advertisements. Little information is available to the public about the identity or health consequences of the additives in tobacco products. 5. Declines in adult per capitacigarette consumption have occurred in years of major dissemination of information on the health hazards of smoking. These include 1964, the year of the first Surgeon General's Report on smoking and health, and 1967-70, when a&smoking public service announcements were widely broad- cast on radio and television, as mandated by the Federal Communications Commission's Fairness Doctrine. 6. In 1985, when cigarette advertising and promotion totaled 2.5 billion dollars, cigarettes were the most heavily advertised product category in the outdoor media (e.g., billboards), second in magazines, and third in newspapers. Over the past decade, the majority of cigarette marketing expenditures has shifted from tradi- tional print advertising to promotional activities (e.g., free samples, coupons, sponsorship of sporting events). 7. An estimated 1 percent of the budget allocated to disease prevention by the U.S. Department of Health and Human Services is devoted specifically to tobacco con- trol. These expenditures totaled 39.5 million dollars in 1986. Part II. Economic Incentives 1. Cigarette excise taxes are imposed by the Federal Government (16 cents per pack), all State governments, and nearly 400 cities and counties. On average, Federal and State excise taxes add 34 cents per pack to the price of cigarettes. Cigarette excise tax rates have fallen since 1964 in real terms because the rate and mag- nitude of periodic tax increases have not kept pace with inflation. 2. Studies demonstrate that increases in the price of cigarettes decrease smoking, particularly by adolescents. It has been estimated that an additional 100,000 or more persons will live to age 65 as a result of the price increases induced by the 1983 doubling of the Federal excise tax on cigarettes. 3. In 1964, smoking status was not considered in the determination of insurance premiums. Currently, nearly all life insurers but only a few health, disability, and property and casualty insurers offer premium discounts for nonsmokers. Few health insurers reimburse for the costs of smoking cessation programs or treat- ment. 27 Part III. Direct Restrictions on Smoking 1. Restrictions on smoking in public places and at work are growing in number and comprehensiveness, as a result of both Government actions and private initiatives. Forty-two States and more than 320 communities have passed laws restricting smoking in public, and an estimated one-half of large businesses have a smoking policy for their employees. 2. The goal of these smoking restrictions is to protect individuals from the conse- quences of involuntary tobacco smoke exposure, but they may also contribute to reductions in smoking prevalence by changing the attitudes and behavior of cur- rent and potential smokers. Insufficient research has been undertaken to deter- mine the extent, if any, of these effects. 3. There are fewer legal restrictions on children's access to tobacco products now than in 1964, despite what has been learned since then about the dangers of tobac- co use, its addictive nature, and the early age of initiation of smoking. 4. As of January 1, 1988, laws in 43 States and the District of Columbia restricted the sale of cigarettes to minors. Nevertheless, tobacco products are relatively easy for children to obtain through vending machines and over-the-counter purchases because of low levels of compliance with and enforcement of current laws. 5. Tobacco products have been exempted by law or administrative decision from the jurisdiction of Federal regulatory agencies under whose authority they might otherwise fall. Chapter 8: Changes in the Smoking-and-Health Environment: Behavioral and Health Consequences 1. All birth cohorts born between 1901 and 1960 experienced reductions in the prevalence of smoking relative to the rates that would have been expected in the absence of the antismoking campaign. By 1985, the gap between actual (reported) prevalence and that which would have been expected ranged from 6 percentage points for the eldest female cohort to 28 percentage points for the youngest male cohort. 2. In 1985, an estimated 56 million Americans 15 to 84 years of age were smokers. In the absence of the antismoking campaign, an estimated 91 million would have been smokers. 3. Adult per capita cigarette consumption has fallen 3 to 8 percent in years of major smoking-and-health events, such as publication of the first Surgeon General's Report on smoking and health in 1964. Per capita consumption fell each of the years the Fairness Doctrine antismoking messages were presented on television and radio ( 1967-70). 4. By 1987, adult per capita cigarette consumption would have exceeded its actual level by an estimated 79 to 89 percent had the antismoking campaign never oc- curred. 5. One of the most substantial behavioral responses to concerns about smoking and health has been the shift toward filtered cigarettes in the 1950s and low-tar and 28 low-nicotine cigarettes in the 1970s. The net health impact of these product chan- ges is unknown. 6. As a result of the antismoking campaign, an estimated 789,000 deaths were postponed during the period 1964 through 1985, 112,000 in 1985 alone. The average life expectancy gained per postponed death was 2 1 years. 7. The avoidance of smoking-related mortality associated with the antismoking cam- paign will represent a growing percentage of smoking-related mortality over time, as the principal beneficiaries of the campaign, younger men and women, reach the ages at which smoking-related disease is most common. Campaign-induced quitting and noninitiation through 1985 will result in the postponement or avoidance of an estimated 2.1 million smoking-related deaths between 1986 and the year 2000. 29 References AOKI. M., HLSAMICHI. S., TOMINAGA. S. (eds.) SmorC-ing and Health 1987. Proceedings of the 6th World Conference on Smoking and Health, Tokyo, November, 9-12,1987. Amster- dam: Excerpta Medica, 1988. BOYD, G., DARBEY, C.M. (eds.) Smokeless Tobacco Use in the United States, NC1 Monograph. National Cancer Institute, in press. BRITISH MEDICAL RESEARCH COUNCIL. Tobacco smoking and cancer of the lung. Statement by the Medical Research Council. British Medical Journal 1: 1523-1524, 1957. BRODERS, A.C. Squamous-cell epithelioma of the lip. A study of five hundred and thirty- seven cases. Journal of the Americ,an Medical Assncia~ion 74( 10):656&?4, March 6, 1920. BURNEY. L.E. Smoking and lung cancer. A statement of the Public Health Service. 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Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma: A study of 684 proved cases. Journal of the American Medical Association 143:329-396, May 27. 1950. 32 CHAPTER 2 ADVANCES IN KNOWLEDGE OF THE HEALTH CONSEQUENCES OF SMOKING CONTENTS Introduction ........................................................ 37 -~~~ Partl: HealthConsequences ........................................ ..3 8 Smoking and Overall Mortality ...................................... 38 LungCancer ................................................... ..4 3 Introduction .............................................. ..4 3 Dose-Response Relationships .................................. 43 WomenandLungCancer .................................... ..4 6 Type of Lung Cancer and Smoking .............................. 50 PipeandCigar Smoking ....................................... 50 Determinants of Susceptibility .................................. 50 Familial Factors .......................................... 52 Other Host Factors ....................................... 52 Occupational Exposures ................................... 52 Ambient Air Pollution ..................................... 53 Indoor Air Pollution ...................................... 53 Diet ................................................. ..5 4 Smoking Cessation ........................................... 55 Laryngeal, Oral, and Esophageal Cancer ............................... 56 BladderandKidneyCancer ....................................... ..5 6 PancreaticCancer ............................................... ..5 6 Stomach Cancer ................................................... 57 CervicalCancer ................................................. ..5 7 Endometrialcancer ............................................. ..5 8 Coronary Heart Disease ............................................ 58 Epidemiology ............................................. ..5 8 Coronary Heart Disease Risk Factors ............................ 59 Pathophysiological Mechanisms ................................ 60 Clinical Correlations .......................................... 61 Smoking Cessation ........................................... 61 Cerebrovascular Disease (Stroke) ..................................... 61 Atherosclerotic Peripheral Vascular Disease ............................ 63 Atherosclerotic Aortic Aneurysm ..................................... 65 Chronic Obstructive Pulmonary Disease ............................... 66 Pathogenesis ................................................ 67 Pathophysiology ............................................. 67 Natural History of COPD and the Role of Cigarette Smoking ......... 68 PregnancyandInfantHealth ....................................... ..7 1 InfantBirthweight ......................................... ..7 2 Fetal and Perinatal Mortality ................................... 73 Congenital Malformations ..................................... 73 Fertility .................................................. ..7 5 Long-Term Effects on the Child ................................ 75 PepticUlcer .................................................... ..7 6 35 ............................................ 76 ............................................ 77 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...* 78 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Osteoporosis . . . . . . Involuntary Smoking . . Smokeless Tobacco . . . Addiction to Smoking . Part II: The Physicochemical Nature of Tobacco . . . . . . . . . . . . . . . . . , . . . . . . . . 79 The Changing Cigarette . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . , . . . . . . . . 85 Environmental Tobacco Smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 SmokelessTobacco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Toxicity and Carcinogenicity of Tobacco Smoke . . . . . . . . . . . . . . . . . . . . . . . . 92 Nicotine . . . . . . . . . . Biological Markers . . Summary ............. Conclusions ........... . . . , . . . . . . . . ....................................... 93 ....................................... 94 ....................................... 97 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...102 36 INTRODUCTION The purpose of this Chapter is to summarize and compare the state of biomedical knowledge concerning tobacco and health in 1989 with that presented in the 1964 Sur- geon General's Report (see Table 13). The Chapter addresses major tobacco-related disorders that are well documented in the medical literature; it does not consider many areas of current research that may prove to be important but are in an early or provisional state of investigation. The 1964 Surgeon General's Report was a landmark publication that included a sur- vey of more than 7,000 available scientific articles on smoking and health. The Ad- visory Committee that prepared the 1964 Report reviewed and assessed epidemiologic, clinical, pathological, and experimental data for evidence linking smoking to disease. To reach conclusions concerning the causality of associations between smoking and disease, the Committee constructed a framework for evaluating the evidence. With regard to causality, the Committee concluded: The causal significance of an association is a matter of judgment which goes beyond any statement of statistical probability. To judge or evaluate the causal significance of the as- sociation between attribute or agent and the disease, or effect upon health. a number of criteria must be utilized, no one of which is an all-sufficient basis for judgment. These criteria include: a) the consistency of the association b) the strength of the association c) the specificity of the association d) the temporal relationships of the association e) the coherence of the association (US PHS 1964). These criteria were applied throughout the 1964 Report. When the word "cause" was used in the 1964 Report, it was felt to convey "the notion of a significant, effectual relationship between an agent and an associated disorder or disease in the host." Use of the word "cause" in relation to cigarette smoking did not exclude other agents as causes; rather, the members of the Advisory Committee shared "a common conception of the multiple etiology of biological processes." The principal findings on the health effects of smoking were summarized in the Sur- geon General's 1964 Report as follows: I. Cigarette smoking is associated with a 70-percent increase in the age-specific death rates of men. 2. 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. 3. Cigarette smoking is the most important of the causes of chronic bronchitis in the United States and increases the risk of dying from chronic bronchitis and 37 emphysema. A relationship exists between cigarette smoking and emphysema, but it has not been established that the relationship is causal. 4. It is established that male cigarette smokers have a higher death rate from coronary artery disease than nonsmoking males. Although the causative role of cigarette smoking in deaths from coronary disease is not proven, the Commit- tee considers it more prudent from the public health viewpoint to assume that the established association has causative meaning than to suspend judgment until no uncertainty remains. 5. Pipe smoking appears to be causally related to lip cancer. Cigarette smoking is a significant factor in the causation of cancer of the larynx in men. The evidence supports the belief that an association exists between tobacco use and cancer of the esophagus. and between cigarette smoking and cancer of the urinary blad- der in men, but the data are not adequate to decide whether these relationships are causal. 6. Women who smoke cigarettes during pregnancy tend to have babies of lower birthweight. It is not known whether this decrease in birthweight has any in- fluence on the biological fitness of the newborn. 7. Epidemiologic studies indicate an association between cigarette smoking and peptic ulcer that is greater for gastric than for duodenal ulcer. 8. The habitual use of tobacco is related primarily to psychological and social drives, reinforced and perpetuated by the pharmacologic actions of nicotine. Since 1967, the U.S. Department of Health and Human Services has transmitted to the U.S. Congress mandated reports on the health consequences of smoking. Some of the reports have been encyclopedic reviews similar to the 1964 Report, whereas others have focused on the relationship between smoking and a specific topic. The Federal unit charged with preparing these annual reports. the Office on Smoking and Health, now has more than 57.000 documents on smoking and health in its Technical Informa- tion Center database. Research performed during the subsequent 25 years has substantiated and strengthened the conclusions of the I964 Advisory Committee. Studies published since 1964 have also established associations between smoking and disease in areas for which data did not exist in 1964. shed light on pathogenetic mechanisms of tobacco-related disease. and added scientific depth to areas mentioned only briefly in the 1964 Report. PART I: HEALTH CONSEQUENCES Smoking and Overall Mortality [See Chapter 3 for more detailed discussion] The major prospective studies of the disease risks associated with smoking completed in the 1960s and 1970s contributed substantially to an understanding of the relation- ship between smoking and disease (US DHEW 1979). These studies provided es- timates of both the relative and attributable risks related to cigarette and other types of smoking (Table I) (US DHEW 1979). Male cigarette smokers had approximately 70 percent higher overall death rates than nonsmokers: the excess mortality of female 3x TABLE L-Mortality ratios of current cigarette-only smokers, by cause of death in eight prospective epidemiologic studies Cause of death British Males in 25 States* U.S. Japanese Canadian Males in 9 Swedish' California doctors' 45-64 65-79 veterans' study4 veteran? States6 Males Females occupationss All cancersa ( 140-205) Cancer of lung and bronchus (162-163) 14.0 Cancerof larynx (161) Cancer of buccal cavity (140-141) 13.0b Cancer of pharynx (145-148) Cancer of esophagus ( 150) 4.1 Cancer of bladder and other ( I8 I ) 2. I Cancer of pancreas ( 157) 1.6 Cancer of kidney (180) Cancer,of stomach (I 5 I) Cancer of intestines (152-153) Cancer of rectum (I 54) 2.7 All cardiovascular disease (330-334, 40@468) CHD (420) 1.6 Cerebrovascular lesions (330-334) 1.3 Aortic aneurysm (nonsyphilitic) (451) 6.6 Hypertension (440-447) General arteriosclerosis (450) I .4 2.14 I .76 2.21 7.84 I I .59 12.14 6.09 8.99 9.96 4.09 9.90' 2.93' 12.54 4.17 I .J4 6.17 2.20 2.96 2.15 2.69 2.17 1.84 I .42 I .57 I .45 I .42 I .26 I.60 1.27 I.Old 1.17d 0.98 I.90 1.31 I .75 2.08 1.36 1.74 I .38 I .06 1.52 2.62 4.92 5.24 1.40 I .42 I .67 1.86 I .62 3.64 13.59 7.04 2.8 I 2.51 0.98 1.83 I.11 I .5 I I .27 0.91 1.96 1.14 2.5 I 14.2 3.9h 3.3 I.3 2. I I .4 I .9 I .4 0.6 I .6 0.9 1.8 I.6 3.3 I .97 10.73 13.10 2.80 6.60 2.40 I .50 2.30 0.50 0.80 I .57 1.70 1.30 1.20 2.00 7.0 1.8 3.1 0.9 1.7 1.0 1.6 1.3 2.0 4.5 15.9 1 .o I .6 0.7 2.5 6.0 2.3 0.8 0.9 1.3 2.0 I.1 I.8 1.4 I.0 2.0 TABLE I.--Continued Cause of death British Males in 25 States' U.S. Japanese Canadian Males in 9 Swedish' California doctors' 45-64 65-79 veterans 1 study4 veterans5 States6 Males Females occupation\x All respiratory disease (nonneoplatic) Emphysema and/or bronchitis Emphysema without bronchius (527. I ) Bronchitis (SOGSO2) Respiratory tuberculosis (001-008) Asthma (241) Influenza and pneumonia (4X&498) Certain other conditions Stomach ulcer (540) Duodenal ulcer (541) Cirrhosis (58 I ) t'arkinsonism (3SO) All causes 24.1 6.55 II.41 S.0 I .J I .86 I .72 2.5 4.06 4.13 4.13 2.86 I so 2.98 3.0 2.06 I.97 3.38 0.4 0.26 I .64 I .X8 I .43 I.84 IO.08 14.17 4.49 2.12 3.41 I .87 I .27 2.85 2.30 I .6 2.2' 4.3 1.7 Il.3 I .4 2.60 2.4 2.06' 6.9 2.16 0.5 1.35 2.3 I .93 2.4 0.X 4.0 I .22 I .52 1.70 I .4 I.2 I .78 "Number\ in parenthexes r~prcsent Intemar~onal C'lass~iication of Dlaeax\ (ICD) codes. "Includes cancers of larynx, buccal cavity. and pharynx. `Includes cancers of buccal cawry and pharynx. "Includes cancers of mrestine\ and rectum. elncludes stomach ulcer and duodenal ulcer. `Includes emphywzma. bmnchlw, and asthma. SOURCE: Studia cited arc as (bllows. `Doll and HIII (1956): `Hammond (1966): `Kahn (1966): "Hirayama (1967): `Best. Josie, Walker (1961); ' Hammond and Horn (1958); 7ceder]ofr,.a) (1975); `Dunn. Linden, Brealow (IY60). US DHEW (197')). cigarette smokers was somewhat less than that of men, but it increased over the fol- lowup intervals. A strong dose-response relationship was found between exposure to cigarette smoke and excess mortality; cessation of cigarette smoking was associated with a decrease in this excess mortality. The relative risks were greater for smoking- related cancers and chronic obstructive pulmonary disease (COPD) than for coronary heart disease (CHD); however. because ofthe higher mortality rates for CHD the smok- ing-attributable mortality associated with CHD accounted for over one-third of the ex- cess mortality due to smoking-related diseases. There have been relatively few long-term longitudinal studies that have measured the overall effects of cigarette smoking since these earlier reports. Results from a new American Cancer Society (ACS) prospective study (Cancer Prevention Study II, CPS-II) and a detailed discussion of total smoking-related mortality are presented in Chapter 3. Based on this study, cigarette smoking is currently estimated to account for 21 percent of all CHD deaths, 30 percent of all cancer deaths, and 82 percent of all COPD deaths. The Multiple Risk Factor Intervention Trial (MRFIT) is a recent prospective study that screened 361,662 men aged 35 to 57 years between 1972 and 1974 and has been following them since then. both through the Social Security Administration and the Na- tional Death Index files. To gauge smoking status, only the number of cigarettes smoked per day at enrollment was reported. Because former smokers were included in the nonsmoker category, the risk comparisons in this study between nonsmokers and smokers are conservative in estimating the effects of smoking. Findings for the 6 years of followup for the MRFIT enrollees screened from 1972-73 are consistent with the studies reported in the 1960s despite changes in the type of cigarettes in terms of tar and nicotine yield and the increased use of filters (see later section of this Chapter and Chapter 5). The MRFIT study shows that smoking status and number of cigarettes smoked per day have remained powerful predictors for total mortality and the develop- ment of CHD. stroke. cancer, and COPD. In the study population. there were an es- timated 2,249 (29 percent) excess deaths due to smoking, of which 35 percent were from CHD and 21 percent from lung cancer. The nonsmoker-former smoker group had 30 percent fewer total cancers than the smoking group over the 6-year followup. A study of a random sample of 25,129 Swedish men between 1964 and 1979 evaluated the relationship between cigarette smoking (prevalence of 32 percent), pipe smoking (27 percent), cigar smoking (5 percent), and subsequent`mortality (Table 2; Carstensen, Pershagen, Eklund 1987). The all-cause relative death rate was 1.7-fold higher for those smoking greater than 15 g of tobacco per day (estimated as 16 to 25 cigarettes equaling 20 g or a package of pipe tobacco lasting I to 4 days equaling 16 g). The relative risks associated with cigarette smoking were consistent both with those of the current MRFIT sample and the earlier cohorts from the 1950s and 1960s. The risks were also increased for pipe and cigar smokers for many of the causes of death. Epidemiologic studies have shown that cigarette smoking exerts an adverse effect on mortality in older as well as younger age groups. The 17-year followup of the Alameda County Study (Kaplan et al. 1987) demonstrates an increased risk of death even among older cigarette smokers. The adjusted relative risk of death among smokers at entry was 1.46 (age 60 to 69) and I .43 at age 70 or more. Smoking remained the strongest 41 predictor of mortality even in this older age group. Other studies have also substan- tiated that smoking remains an important risk factor in the older age groups (Jajich, Ostfeld, Freeman 1984). TABLE 2.-Mortality ratios for selected causes in Swedish males, 19661979, by type of smoking Type of smoking' Cause of death Cancer of oral cavity and larynx (140-146.148. 161)b Cancer of esophagus ( 150) Cancer of liver and biliary passages (155-l 56) Cancer of pancreas ( 157) Cancer of trachea, bronchus, and lung ( 162) Cancer of bladder ( 188) Ischemic hean disease (4lWl4) Aortic aneurysm (nonsyphilitic) (41) Bronchitis and emphysema (490-492) Cigarettes Pipe only only 2.9 (8) 1.4 (3) 3.7 (9) 3.6 (6) 3.0(13) 1.7 (5) 3.3 (28) 2.8 (19) 7.4 (77) 7.2 (59) 4.2 (17) 4.0(16) 1.48 (399) 1.39 (366) 2.1 (II) 2.1 (11) 3.3 (18) 3.6 (16) Cigars only 0.6(l) 6.5 (2) 7.2 (4) 1.0(l) 7.6(11) 1.9(l) 1.16(42) 5.1 (4) 1.3(l) Peptic ulcer (53 l-534) Cirrhosis of liver (571) Suicide, accidents, and violence (E800-E999) All causes 2.0(11) 2.8 (13) 4.0 (3) 1.8 (21) 0.7 (4) 2.7 (3) 1.7 (90) 0.9 (35) 2.5 (10) 1.45 (I ,063) 1.29 (866) 1.39(131) NOTE: Death rates standardized for age and residence. Never smokers constitute the reference group. Number of deaths are given in parentheses. `The mean grams of tobacco smoked per day m 1%3, standardized for age and residence, was estimared to be 10.7 in cigarette smokers. 8.4 in pipe smokers, and 13.5 in cigar smokers. bNumhers in parentheses are KID-8 codes. SOURCE: Carstensen. Pershagen. Eklund (1987). 42 Lung Cancer Introduction One of the most prominent conclusions of rhe 1964 Report was the determination that "Cigarette smoking is causally related to lung cancer in men: the magnitude of the effect far outweighs all other factors. The data for women. though less extensive. point in the same direction." The epidemiologic evidence available in 1964 on smoking and lung cancer was already extensive. Sharply increasing lung cancer mortality rates in the United States across the 20th century provided indisputable documentation of a new epidemic. Clinical observations and early epidemiologic findings suggested that tobac- co smoking was associated with lung cancer. but hypotheses related to air pollurion. occupation. and other factors were also extant. By 1964, however. the epidemiologic data. derived from 29 retrospective and 7 prospective studies. were conclusive: smok- ing was causally related to cancer of the lung. Further support for this conclusion was obtained from animal studies showing that condensates of tobacco smoke were car- cinogenic and from the demonstration that tobacco smoke contained carcinogens (US DHHS 1982). The evidence compiled through 1963 also provided additional insight into quantitative aspects of respiratory carcinogenesis by tobacco smoke. The risk of lung cancer was shown to increase with the amount and duration of smoking and to decline with cessation of smoking. In the 25 years since the 1964 Report, voluminous evidence has continued to support the causal relationship between smoking and lung cancer. The new evidence has been sufficient to establish that smoking also causes lung cancer in women: more com- prehensive epidemiologic data have provided expanded descriptions of dose-response relationships between smoking and lung cancer risk. Research has also been directed at environmental and host factors determining susceptibility to tobacco smoke. New investigative techniques in molecular and cellular biology are now providing insight into the molecular mechanisms of carcinogenesis by tobacco smoke. Dose-Response Relationships The 1964 Report reviewed evidence from retrospective and prospective epidemiologic investigations that documented dose-response relationships between lung cancer risk and measures of exposure to tobacco smoke. This evidence was cited by the 1964 Report in relation to the criterion of strength of association for determin- ing causality. Investigation of dose-response relationships for lung cancer has sub- sequently been extended. Mathematical models have been applied to the epidemiologic data to gain biological insight into respiratory carcinogenesis. The cigarette has evolved substantially since 1964 with modifications designed to reduce tar and nicotine yields. Recent research has addressed the risks of smoking the newer products. Studies of lung cancer and involuntary smoking have examined lung cancer risks at low dose levels (US DHHS 1986a). Abundant epidemiologic evidence has shown dose-response relationships of lung cancer risk with cigarettes smoked per day, degree of inhalation. and age at initiation of regular smohing. For the purpose of illustration. selected examples ofdose-response relationships from two of the early. large prospective epidemiologic studies are reviewed here. Figure I shows lung cancer mortality ratios for males by the number of cigarettes smoked per day. For those who smoked more than 40 cigarettes per day, the risk of dying of lung cancer was 23 times greater than the risk experienced by non- smokers. Figure 2 illustrates the lung cancer mortality ratios for males by self-reported degree of inhalation ofciparette smoke. These dataconfirm that even those who reported "just puffing"on cigarettes still had a significantly increased risk of lung cancer. Those wlho reported inhaling "none" or "slightly" experienced a risk of developing lung cancer that was eight times greater than that of nonsmokers. The relative risk increased to I7 for those who inhaled deeply. Figure 3 shows lung cancer mortality ratios for males by the age they began smok- ing. The risk of developing lung cancer was greatest for those who began smoking at an early age. Mathematical modeling of dose-response relationships. in the biological framework of a multistage model ofcarcinogenesis. has provided further insight into the nature of dose-response relationships for smoking and lung cancer. Using data from the prospec- tive study of British doctors. Doll and Peto (197X) have performed the most widely cited analysis. They compared regular smokers and lifelong nonsmokers and showed that lung cancer incidence increased with the square of the amount smoked daily. but with the duration of smoking raised to a power of 1 to 5. This finding implies that dura- tion of smoking is the stronger determinant of lung cancer risk and that initiation of smoking during the teenage years will have serious consequences for lung cancer risk (Pet0 1986). Cotnmercial cigarettes have continuously evolv,ed through the addition of filters and other modifications designed to reduce tar and nicotine yields (US DHHS I98 I ). Since extensive modification of the cigarette began in the I YSOs. it has only recently become possible to investigate smokers with predominant use of the newer products. Evidence from prospective and casr