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H. Kasuga (Ed.) Indoor Air Quality With 155 Figures and 190 Tables Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong.

Environmental Tobacco Smoke and'~ Lung Cancer: A Critical Assessment* E. Z. Wynder and G. C. Kabat Summary The possibility that exposure to environmental tobacco smoke (ETS) may increase the lung cancer risk of nonsmokers has become a cause of public concern. It is unknown whether the levels of carcinogens in the diluted sidestream smoke of tobacco products thatreach the nonsmoker's lung are sufficient to induce cancer. Available epidemiologic studies suggest a slight increase in the relative risk of lung cancer in~nonsmokers due to exposure to ETS created by a smoking spouse. However, not all studies have found a significant association. The epidemiologic studies aretxamined in the light of the criteria of judgmenU of causality;, including strength of association, consistency„ temporality, methodological issues, and biological plausibility. Suggestions for further research, including studies in high-exposure populations and greater attention to histology, are proposed.. Introduction Epidemiologists, chemists, biologists, physiologists, physicians, and public health officials have given much attention to the association of environmental tobacco smoke (ETS) exposure and1he development of lung cancer in nonsmokers. A biological basis . for such an association clearly exists because smoke constituents demonstrated to be-=~ carcinogenic in laboratory animals are inhaled and retained by the nonsmokei;• ~ Metabolites of tobacco-specific smoke constituents have been identified in the saliva, blood, and urine of nonsmokers after exposure to ETS (Greenberg et al. 1984; Hoffmann et al. 1984; National Academy of Sciences 1986; USDHHS 1987; Sepkovic eti al. 1988). Several epidemiological studies have found a positive association between ETS exposure - usually, defined as being due to a smoking spouse - and lung cancer (Hirayama 1981!; Trichopoulos et al. 1981; Correa et al. 1983; Sa.ndler et al. 1985; Garfinkel et al. 1985; Akiba et al. 1986; DalagGr etal. 1986; Pershagen et al. 1987). Qther studies have found no significant association (Garfinkel 1981!; Chan and Fung 1982; Koo et a1.,1983; Kabat and Wynder 1984; Wu et al. 1985;! Lee et al. 1986). No consistent association has been reported for lung cancer and exposure to ETS in childhood;,which might be expected to exert a greater effect, especially when followed~by exposure throughout adulthood. Of course, recall of ETS exposure in childhood is more difficult than recall of such exposure in adulthood. ~ C • Research ~described herein was performed under USPHS, National Cancer Institute Program ~ Project Grant CA-32617: ~ . H. Kacug. (Ed.) Indoor Air Quality Zti 0 Spritrger-Verlag, Berlin Heidelbergl990 W 1.J 0

6 E.,L. Wyndcr and G. C. Kabat The epidemiological study of weak associations is burdened with problems that may yield artifactual positive findings or may ahow negative findings where a real association exists. The association of ETS and lung anar risk, even if weak, woul'd stil be of concern as a public health problem in that most people are at one time or another exposed to smoke from burning tobacco products and the exhaled pollutants of tobacca smokers. A weak association in epidemiology requires careful examination and an understanding of the variables in question and all of the factors influencing theassoeiation (Wynder 1987). In this overview we critically examine the published studies on ETS exposure and lung cancer to determine whether the evidence presented to date permits a sound conclusion as to causation: General i Exposure to ETS At the ouuet' we need to emphasize that an association betweeni ETS and lung cancer must be deemed possible. A recent survey of self-reported exposure in, a hospitalized population revealed that 66% of men and 60% of' women had ETS exposure in childhood; 32%a of the men and 61 % of the women reported ETS exposure in the home in adulthood; and 60% of the men and 62%n of the women who worked outside the home reported ETS exposure at work (Kabat and Wynder, unpublished data, 1987). Critical Assessment The first Surgeon-General's Report on Smoking and Health, published in 1964 (USPHS 1964), clearly delineated the criteria of judgment for causality. These criteria included: the magnitude of the association, consistency, temporality, and biological plausibility. Since these criteria were considered necessary to prove causation for a strong association, namely;aetive smoking andlung cancer, theyshould be equaliyrsquired to determine the causality of weak associations (Wynder 1987). Let us examine the epidemiological evidence linking ETS with lung cancer, in respect to these criteria: Strengrh of the Association An association is generally considered weak if the odds ratio is under 3.0 and particularly when it is under 2.0, as is the case in theselationship of ETS and'11tng,cancer (Table 1'): If' the observed relative risk is small, itlis important to determine whether the effect could'be due to biased selection of subjects, confounding, biased reporting, or anomalies of particular subgroups. Consistency If an association is real, internal consistency shouldi be apparent within an& between different studies. The majority, but not alllof the studies of ETS and'lung cancer have shown a positive association for ETS-exposure due to a smoking spouse (Table 1). In most of the studies, the confidence interval includes 1.0. While the prospective study by. Hirayama (1981 a) among Japanese women showed a significant association with the husband's smoking(largely adenocarcinomas), the prospective study among American

Environmental Tobacco Smoke and Lung Cancer: A Critical Assessment 7 Table 1. Summary of results of studies relating lung cancer risk in married women to their husbands' smoking habits Relative risk 95 % Confidence interval Prospective swdJes Hirayama (1981) 1.63 1.25-2.1 il Garfinkel (1981) 1.18 0.90-1.54 Case-corttroJ srYdt'es Trichopoulos et al. (1981) 2:1 1.18-3.78 Chan & Fung (1982). 0.75 0.44-1130 Correa et ali,(1983) 2.03' 0.93-5.03 Koo et al. (1983)i 1.54 0.90-2.64. Kabat & Wynder (1984) 0.79 0.26-2.43 Wu et al. (1985) 1.2 0.6 -2.5 Garfinkel etal: (1985) 1.12' 0.74-1.69 Lee et a1. (1985) 1.03 0.41-2.47 AkibA et al'. (1986) 1.48 0.88-2.50 Perahagen et al., (1987), 1.28, 0.75-2:16 Table 2. Distribution of lung cancer by histologic groups in smokers and never-smokers. (From Kabat and Wynder 1984) Smokers Never-smokers Males Females Males Females (N = 1882) (N = 652) (N = 37), (N = 97) [°kJ [tYo) [4'oJ [%J Kreyberg I 63 52 35 21 Kreyberg lli 32' 43 54 74 Mixed and undifferentiated/anaplastic 5 5 11 5 women by Garfinkel (Q981),did not. It has been suggested that Japanese and American women1 are exposed to differenU]trvels of ETS due to different conditions in the two countries. Such differences could account for this disparity (I-Iirayama 1981 b). Within those studies presenting specific histologic analysis, differences exist in respect, to the type of lung cancer involved. In active smokers, tobacco smoke exposure has a causative effect predominantly on squamous and small cellltypes of lung cancer (ICreybergl);,with a lesser, though sti11 significanUCausative effect on the glandular type (Kreyberg 1I) (Wynder and Stellman 1977). Among nonsmokers, however, the glandu- lar type of lung cancer predominates among both men and women (Kabat and Wynder 1984) (Table 2). The effect of ETS would thus be expected to be primarily responsible for the higher rate of' adenocarcinomas among nonsmokers.. The studies by Dalager et al. (1986) and Pershagen et al. (1987),, however, suggest that the effect of ETS exposure is limited to induction of squamous cell'lung cancer (Table 3). If this were, in fact, the case, then only the squamous or small cell type of lung cancer in~nonsmokers

81 E. L. Wynder and~G. C. Kabat. Table 3. Histology-specific odds ratios for spouse smoking from two studies Study Histologic type N Odds ratio 95% C.I. Dalager et al. Adenocarcinoma 16 1,.02• 0.33- 3,16 (1986) Squamousdc Small Cell Ca. 14' 2.88• 0.91- 9:10, Other 18 1.31• 0.48- 3.57 1'etshagen ~et al. Squamous or Small iCell Ca. 20 3.3 1.1 -11.4 (1987) Other 47 0.8 0.4 - 1.5 would be affected by ETS. Clearly, it, is importanT that investigations of the effect of ETS exposure on lung cancer development in nonsmokers take histology into account, so as to determine whether an effeet of ETS is limited to certain histological types. Since smoking is more prevalent in lower income groups, at least among men, lung cancer in nonsmoking women in these groups s'hould~ have a higher incidence. Thus„ the influence of the level of education on smoking habits in the examined population needs to be considered as a possible confounder. Few studies to date have done this. Merhodological7ssues A particular concern in weak associations is reporting bias, that is, potentially differentialreporting of exposures between cases and controls. In terms of ETS, does the lung cancer patient report exposure to tobacco smoke„be it at work, at home, at sociall funetions„in childhood or adulthood, differently than the control? The case is likely to have a different attitude toward this question than does the control, a handicap not applicable to prospective studies. It, needs to be determined whether the case's attitude towards questions on ETS exposure leads to under~ or overreporting. Cases are likely to underreport their own smoking (Lee 1987), and they may tend to overreporU their exposure to ETS and other potential hazards that could account for their ilihess. In studies that use proxyreports, differenvrelatives mayrespond differently. Garfinkel etial. (1985) provides some insight into this phenomenon by showing that if the response came from the patient, the odds ratio was 1.0, if from the husband ~it was 0.92„and'if from the daughter or son, 3.19(Table 4). More work is needed on the validity of ETS-exposure information obtained from different relatives before we can evalttate which of these relative risks is closer to the truth. In general, possible reporting bias represents a serious problem in case-control studies because it can produce a systematic artefact. It is particularly worrisome in that it cannot be effectively measured. We also need to consider misclassification that can occur in both retrospective and prospective studies. Lee has proposed (Lee et ali 1996; Lee 1987) that the reported ETS effect on lung cancer risk can be explained by a misclassification of smokers as nonsmokers. According to these studies, a substantiall percentage of respondents misrepresent their smoking habits. Using a 10:0% misclassification rate of ex-smokers as self-reported neversmokers coupled with the concordance of spouses' smoking,habits,

Environmental Tobacco Smoke and Lung Cancerc A Critical Assessment 9 Tab1e4: Data from Garfinkel et al. (1985) by type of respondent Husband's smoking habits at home N of cases OR 95% C.I. Self 16 1.00 0.55- 1.74 Husband 34 0.92 0.63- 1.34 Daughter/son 48 3.19 0.91-11.19 Other 36 0.77 0.57- 1.03 1-3 Mi 7-10 11.15 YEARS SiiCE OUTTNG Krsybsrp I Fla:1. Odds ratio of male ex-smokers for Kreyberg l(N = 687) and Kreyberg 17 (N = 301) lung cancer by years since quitting (controls = 6534);Source: American Healtb Foundation data Lee calculated that an apparent increase in lung cancer risk can be obtained among nonsmokers married to smokers that approximates the increased risk observed in a number of epidemiologic studies (Lee 1987). At the extreme, Garfinkel et al. (1985) showed that 40% of lung cancer cases classified as 'nonsmokers' in the hospital chart were in fact smokers as determined by interview. Although such a high rate of misclassification does not occur when cases are interviewed'personally, to some extent denial is likely to occur even then, particularly among ex-smokers who had stopped smoking ten or more years ago. The risk of lung cancer among long-term ex-smokers, and even among ex-smokers who quit more than 16 years earlier, does remain elevated above the rate among those who never smoked (Fig: 1). Denial of past smoking may also not be uncommon in populations where smoking is or was socially unacceptable, as is the case among older Japanese women.

10 E. L. Wynd'er and'G. C. Kabat' 7able S. Percent of lung cancer casa who never smoked by histologic group (A.H.F. data) Males Females KI• Ki1l• KI• KIi'• [46I N' [`J6l N [4b] N' [g.o]1 N 1969-1973 1.2 488 5.6 142 I0:7 103 23.7 76 1974'-1,976 1.6 987 3.0 305 16.4 263 25.3 146 1977-1980 2.1 628 4.6 390 5.6 231 22.0 245 1981-1985 1.4 725 5.6 463 6.9 311! 16.6 294 • Kreyberg I •• Kreyberg II Another problem for epidemiologists involves subgroup analysis (Stallones 1987), Investigators are likely to examine numerous subgroups„and then prefer to present those subgroups that best fit the hypothesis. This tendency represents an inherent problem in epidemiology. The investigator should at~ a minimum give an idea of how many subgroups were originally examined and how many subgroups were discardedl Temporality One of the factors that led to the conclusion that active smoking causes lung cancer was that the increase in cigarette consumption preceded the increase in lung cancer rates, first~ in men and later in women. Enstrom (1979) has reported an increase in the lung cancer rate in nonsmokers over recent years, suggesting that factors in addition to personal! cigarette smoking influence lung cancer mortality rates. The groups examined, however,, are not strictly comparable, and miselassification of smokers as nonsmokers in the national surveys needs to be considered. Our data from a long-term, hospital,based case- control study do not indicate an increase in the percentage of male nonsmokers with lung cancer in either of the two main histologic groupings (Ki•eyberg I and II) over the lasv 30 years (Table 5). In fact, the percentage of nonsmokers with lung cancer among women has declined, which may be a conseqpence of the diminishing pool of women who have never smoked. Bi ological Plausibility Several studies have demonstrated that most tumorigenic agents are present in undiluted sidestream smoke in higher concentrations than in mainstream smoke (Hoffmann et al. 1983; National Academy of Sciences 1986; Hoffmann and Wynder 1986) (Table 6), Biochemical'studies indicate that nonsmokers exposed to ETS have levels of nicotine or cotinine in the blood'~or urine that are about 1/100th the level seen in active smokers (Table 7) (Jarvis et al. 1984; National'Aeademy of Sciences 1986). Some of ttie nicotine measured in the blood and urine represents nicotine thatt is absorbed by, the saliva of nonsmokers and'does not reach the lung directly (Jarczyk et al. 1987). It is important to

Environmental Tobacco Smoke and Lung Cancer: A Critical'Aaasment 11 Table 6. Distribution of compounds in undiluted cigarette mainstream smoke (MS) and sidestream smoke (SS) Nonfilter cigarettes MS SS/MS (A) Vapor phase Carbon monoxide 10 - 23 mg 2.5:- 4.7 Carbon diottide 20 - 40, mg 8 - 1li Benzene 20 - 50, µg 10 Formaldehyde 5 - 100: µg 0:1-50 Acrolein 50 - 1001 µg 8 - 15 Acetone 100 - 250~ µg 2 - 5 Hydrogen cyanide 400 - 5W yQ 0:1- 0.25 Hydraune 24 - 41 ng 3.0 Ammonia 50 - 170~ µg 40 - 170 Methylaminc 11.5 - 28;7'yg 4.2- 6.4 Nitrogen oxides 50 - 600~ µg 4 - 10 N-nitrosodimeffiylamine 10, - 180 ng 20 - 100 N-nitrosopyrrolidine 2 - 110 ng 6 - 30 (B) Particulate phase Particulate matter Nicotine Phenol i Catechol Hydroquinone Aniline 2-Toluidine 2-Naphthylamine 4-Aminobiphenyl Benz(a)anthracene Benzo(a)pyrene N'-Nitrosonornicotine NNK Cadmium Nickel Polonium•210. 15 - 40 mg 1.3- 1.9 1 - 2.5 mg 2.6- 3.3 60, - 140 µg 1.6- 3.0 100 - 350 µg 0.6- 0:9 110 - 300 µg 0.7- 0:9 360 ng 30, 30 - 160 ng 19 4,3 - 27 ng 30 2:4- 4.6ng 31 40 - 70 ng 2- 4 10 - 40 ag 2.5- 3,5 120 -3,700 ng 0.5- 3 120 - 950 ng 1- 4 100 ng 7.2 20 -3,000 ng 13 - 30 0.03- 1.0 pCi 1 note that nicotine occurs in ETS primarily as a vapor phase constituentrather than in the particulate matter of the aerosol as is the case in mainstream cigarette smoke (Eudy et all 1987):. Measurement of nicotine or its metabolites will, therefore„ not reflect the proportional uptake of particulate matter from ETS. In the light of our present knowledge of dose-response in carcinogenesis and because the carcinogenic activity of tobacco smoke as measured in anuaalaystems is relatively low, the question needs to be raised whether the carcinogenic potential of inhaled ETS suffices to induce lung cancer. Hoffmann and Hecht (1985) have proposed nicotine-derived nitrosamines in ETS as organ-specific carcinogens for the lung. It is possible that these chemicals reach the lungs in sufficient dose to induce neoplastic changes. These carcinogens may also be formed endogenously from inhaled or ingested nicotine and appropriate nitrosating agents (Hoffmann and Hecht 1985). Tumor promoters are less likely to play a role in ETS . a

12 E. L. Wynder and G. C. Kabat Table 7. Approximate relations of nicotine u a parameter between non-smokers, passive smokers and active smokers'.,(From Jarvis etal. 1984), Nicotine/cot»nine Nonamokers without ETS exposure No.=46 Non-smokers with ETS exposure No.=541 Active smokers No.=94 Mean value % of active smoken value Mean value % of active smokers value Mean value Nicotine (ng/htl) in plasma 1.0 7 0.8 5:5 14.8 inaaliva 3.8 0.6 5.5 0:8 673 in urine 3.9 0:2' 12.1P 0:7 1,750 Cotinine (ng/MlJ 275 in plasma 0.8 0i3 2:0• 0.7 275 in saliva 0.7 0!2 2:Y• 0.8 310 in urine 1.6 0!I 7:74' 0.6' 1,390 ' Di}ierences between non-smokers exposed' to ETS compared with non-smokers withoutt exposure • p < 0.01. " p < 0.001 carcinogenesis than in active smoking because of their much lower concentration. In general, tumor promoters are effective only when applied repeatedly in relatively large amounts. In considering the existing data on ETS exposure and'lung cancer, it is noteworthy that Auerbach et al. (1961) showed only minor histological changes in the bronchial epithelium of nonsmokers and found that the ciliated columnar epithelium that covers their bronchi were largely intact. Deposition of carcinogenic smoke particulates can take place only upon inhibition of the protective functioning of the lung clearance system. Squamous cell lung cancer can arise only fiom~ ciliated columnar cells that have undergone squamous metaplasia. An active smoker with each puff from a cigarette inhales a volume of 35-50 ml of a concentrated aerosol containing 3-5 billion particles per m] that adversely affect' the protective cilia and mucous defense system of the bronchi (Ferin etal. 1965). The passive smoker is at no time exposed with such force to such a highly polluted inhalant. Furthermore, ET3 particles are more likely to be deposited in the upper respiratory tract and not predominantly in the bronchi as is the case in active smoking. Thus, our respitatory defense system may be able to deal more readily, with the relatively lighter deposition of particles and exposure to volatiles in ETS„as the observation by Auerbach et ali (1961) would suggest. Future Studies Future epidemiological studies on the association of ETS with lung cancer should attempt to avoid the pitfalls discussed above. The defuzitive evidence that a factor causes

Environmental Tobacco Smoke and'Lung Cancer: A Critical iAssessment 13' human cancer requires support from descriptive, metabolic, and molecular epidemiola gy:, Beyond extension of prospective studies, such as those now in progress by Garfinkel and Stellman at the American Cancer Society; we suggest: 1) Continuing ongoing case-control studies with special reference to histologic type and careful consideration of methodological issues. 2) Estimating the relative importancc of ETS exposure in different settings - in ~ the home, in the workplace, in social situations, and during transportation. 3) Further studying lung cancer rates among pipe and cigar smokers, and, if feasible, among nonsmokers exposed to ETS from these products. 4) Studying lung cancer incidence in groups occupationa)ly exposed to high levels of ETS at their worksite such as waiters, bartenders, train conductors, airplane personnel, and office workers. 5)~ Studying bronchial epithelium in autopsy materiali of established never-smokers whose exposure to ETS is known. 6) Determining the incidence of lung cancer by histological type in confirmed never- smokers., 7) Comparing the presence of adducts of tobacco-specific carcinogens with DNA in smokers, passive smokers, and "never-smokers"'(Hoffmann and Hecht 1985; Hecht et al. 1987) j In summary, verification of the possible association of ETS and lung cancer represents an important challenge to epidemiologists, laboratory scientists, and'public health authori- ties. The public is entitled to inhale the cleanest possible air regardless of whether ETS is proven to be cancer-inducingAfldditional efforts on the part of epidemiologists are required to firmly, establish the nature and significance of the reported associations between~passiwe smoking and lung cancer. References Akiba S, Kato S, Blot WJ (1986); Passive smoking and lung cancer among Japanese women. Cancer Res 46:4804-4807 Auerbacb 0, Stout AP, Hammond'EC, et al' (1961) Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N Eng] iJ Mbd 265:253-267 Cban WC, Fung SC (1982) Lung cancer in non-smokers in Hong Kong. In: Grundman E(ed) Cancer tampaign+ vol 6. Cancer epidemiology. Fiscber, Stuttgast, pp~ 199-202 Correa P, Fontham E, Pickle L, Lin Y, Haettszel W (1983) Passive smoking and lung cancer. Lancet 2:595-597 . DalGger NA, Pickle LW„Mason TJ, et a1 (1986) The relation of~passive smoking to lung cancer.. Cancer Res 46:4808-48111 Enstrom JE (I979) Risingdung cancer mortality among nonsmokers. J Natl Cancer Inst 62:755- 760 Eudy LW; Thome FA, Heavner DL, Green CR, Ingebrsthsen BJ(1985) Studies on the vapor-phase distribution of environmental nicotine by selected trapping and detection methods. Pres. 39th Tobacco Cbcmists Res Conf, 1985, p 25 Ferin J; Urbankova G, Vlokova A (1965) Influence of tobacco smoke on the elimination of N, partieles from the lungs. Nature 206:515-516 cancer mortalit Time trenda in lun amon non-smokers and'a note on assive ~ Garfinkel L(1981) g y g p , smoking. J Natl Cancer Inst 66:106M666 N: Cj ~ ~ ~ :ca 1