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EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 223 12 Exposure to Environmental Tobacco Smoke and Lung Cancer The risk of lung cancer in cigarette smokers is directly related to the number of cigarettes smoked. At low- to-average levels of smoking, this relationship is approximately linear and with no apparent threshold, although there are good theoretical reasons to believe that the true dose-response curve should be curvilinear and probably quadratic (Doll and Peto, 1978; Gart and Schneiderman, 1979). Among smokers, an increase in exposure leads to an increase in risk, as long as the additional tobacco smoke, whether through active or passive smoking, reaches the bronchial epithelium. Passive smoking would, therefore, be expected to cause some increase in risk of lung cancer in active smokers, as well as in any other persons in whom the appropriate tissues are exposed. The studies reviewed in this chapter have attempted to address the questions of whether an increase in risk of lung cancer does occur in nonsmokers exposed to ETS and whether the dose-response relationship is similar to that in smokers. In part, this depends on whether there is a threshold dose of cigarette smoke exposure below which there is no increase in risk. Biological theory and current evidence on low-dose exposure to carcinogens do not provide evidence for such a threshold, and it is generally thought that one is unlikely (Office of Science and Technology Policy, 1985). If there is no threshold, it follows that exposure to tobacco smoke at low concentrations, such as that experienced by nonsmokers exposed to ETS, will cause an increased risk of lung cancer. The risk, of course, will be expected to be very much smaller than that associated with active smoking because of the much lower exposure of the bronchial epithelium to tobacco smoke.
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 224 TABLE 12â1 Urinary Cotinine (ng/ml) in Nonsmokers According to Number of Reported Hours of Exposure to Other People's Tobacco Smoke Within the Past 7 Days (Including Day Urine Sample Was Collected) Duration of Exposure Urinary Cotinine, meanÂ±SDa Quintile Limits (h) No. 1st 0.0â1.5 43 2.8Â±3.0 2nd 1.5â4.5 47 3.4Â±2.7 3rd 4.5â8.6 43 5.3Â±4.3 4th 8.6â20.0 43 14.7Â±19.5 5th 20.0â80.0 45 29.6Â±73.7 All 0.0â80.0 221 11.2Â±35.6 aTrend with increasing exposure was significant (p<0.001). SOURCE: Wald et al. (1984). USING BIOLOGICAL MARKERS TO ESTIMATE RISK Cotinine, a metabolite of nicotine, while of itself not considered a carcinogen, is a useful marker of exposure to tobacco smoke, whether through active or passive smoking. Table 12â1 shows that the mean urinary cotinine concentration increases with the estimated exposure to other people's tobacco smoke over the past 7 days. Much of these data, collected in the United Kingdom (Wald et al., 1984), showed that nonsmokers had, on average, about 0.4% of the concentration of urinary cotinine found in active smokers. Similar work done in Japan suggested that nonsmokers had relatively high cotinine levels, about one-seventh the levels in average Japanese smokers (Matsukara et al., 1984). The reason for this difference is not known and it needs to be investigated. However, in both countries studies showed increasing urinary cotinine levels in proportion to the estimated increasing ETS exposure. In most of the epidemiologic studies that assessed the relationship of lung cancer to ETS-exposed nonsmokers, the measure of exposure used was âliving with a smoking spouse.â The observed risks of lung cancer for nonsmokers were compared for those living with a smoking spouse and those living with nonsmokers. While it is reasonable to believe that people living with smokers would be more heavily exposed to ETS than people living with nonsmokers,
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 225 this would seem to be a relatively insensitive measure of exposure. Many people who are exposed to other peoples' smoke may not always be married to smokers. Even if they are married to smokers, they are likely to be exposed to their spouses' smoke for only a relatively small proportion of the day. The possibility exists that they may be exposed to other people's smoke, for instance, at work, or while in other public places. A study using urinary cotinine levels as a measure of exposure, however, showed that âmarriage to a smokerâ may identify individuals who are more exposed to tobacco smoke in general, not simply from their spouses (Wald and Ritchie, 1984). Table 12â2 shows that the exposure to other people's smoke was greater for men married to smokers than for men married to nonsmokers (median hours of reported exposure of 21.1 and 6.5 hours per week, respectively). Of particular relevance for epidemiologic studies is the fact that exposure is greater outside the home as well as within the home. A reasonable interpretation of this fact is that men married to smokers might be more tolerant of other people's smoke than men married to nonsmokers and are less likely to seek out smoke-free environments outside the home. Similar results, based on questionnaire information, have been reported by others (Friedman et al., 1983). These results corroborate the use of a spouse's smoking history as a method of classifying nonsmokers into groups that have different exposure levels to tobacco smoke. Using data from the TABLE 12â2 Urinary Cotinine Concentration and Number of Reported Hours of Exposure to Other People's Tobacco Smoke Within the Past 7 Days in Nonsmoking Married Men According to Smoking Habits of Their Wives Smoking No. of Urinary Cotinine Exposure to Other People's Smoke in Preceding Category of Wife Men Concentration, ng/ml Week, h Total Outside Home Mean (SE) Median Mean (SE) Median Mean (SE) Median Nonsmoker 101 8.5(1.3)a 5.0 11.0(1.2)b 6.5 10.0(1.2)c 6.0 Smoker 20 25.2(14.8) 9.0 23.2(4.1) 21.1 16.4(3.3) 10.7 NOTE: Differences (nonsmoking wife versus smoking wife): ap<0.05; b p<0.001; cp<0.06 (Wilcoxin rank sum test). SOURCE: Wald and Ritchie (1984).
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 226 British study (Table 12â2), the relative urinary cotinine levels in three groupsânonsmoking men married to nonsmoking women, nonsmoking men married to smoking women, and men who were themselves active smokersâwere in the ratio of 1:3:215 (actual mean values were 8.5, 25.2, and 1,826 ng/ml, respectively; Wald and Ritchie, 1984, and personal communication). Assuming a similar half-life of cotinine in smokers and nonsmokers, this suggests that exposure to ETS among nonsmokers who are exposed is about 1% (i.e., 25.2/1826) of that of active smokers. Similar results were reported by another United Kingdom study (Jarvis et al., 1984) and one from the United States (Haley et al., 1986). However, the half-life of cotinine in nonsmokers may be roughly 50% longer than in active smokers (Kyerematen et al., 1982; Sepkovic et al., 1986), thereby changing the estimate of relative exposure by up to 50%. Assuming a usage of 20 cigarettes (one pack) per day by active (male) smokers and assuming a linear relationship between number of cigarettes smoked per day and urinary cotinine level, this represents exposure to smoke equivalents of roughly 0.1 to 0.2 cigarettes per day. Others have estimated cigarette equivalent exposures of 0.2 to 1 cigarettes per day (KlosterkÃ¶tter and Gono, 1976; Hugod et al., 1978; Vutuc, 1984). Urinary cotinine is at present the best marker of tobacco smoke intake for passive smoking dosimetry because it is highly sensitive and specific for tobacco smoke. Because it can be measured directly in nonsmokers as well as active smokers, it makes it possible to estimate the relative exposures of the two groups (see Chapter 8). With other markers or with other substances in tobacco smoke, this is not currently possible. Estimates must be made of the extent to which these substances are inhaled in mainstream smoke, on the one hand, and released into room air, diluted, and then inhaled by nonsmokers, on the other (Chapter 7). Both of these estimates involve more assumptions in estimating the actual intake. Whether a urinary cotinine measurement can provide a reasonable basis for computing a first estimate of the risk of lung cancer arising from ETS exposure depends in part on whether the intake of the relevant carcinogens in active and passive smokers is directly proportional to the relevant intake of nicotine, from which cotinine is derived. Our lack of knowledge of which specific smoke components are responsible for causing lung cancer and our
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 227 present inability to measure their intake directly creates uncertainty. But, as a first approximation, it is reasonable to assume proportionality. Based on the above dosimetric considerations, the risk of lung cancer from ETS exposure among nonsmokers in the United Kingdom and United States would be small. Assuming linearity in the dose-response relationships, the risk would be about 1% of the excess risk in active smokers. This is equivalent to a relative risk of 1.14 in males, given that the relative risk in average male active smokers is 10 to 15 times greater than in nonsmokers (Hammond, 1966; Doll and Peto, 1978). For ETS-exposed women, the average relative risk may be less. If the cotinine data suggesting greater ETS exposures in Japan are correct, the excess risk in Japan would be greater. ASSESSING THE RISK FROM EPIDEMIOLOGIC STUDIES OF LUNG CANCER AND EXPOSURE TO ETS Some of the epidemiologic studies on the possible relationship between ETS exposure of nonsmokers and lung cancer have been discussed elsewhere (Rylander, 1984; Samet, 1985; IARC, 1986). The majority of studies of lung cancer in nonsmokers and ETS exposure classify subjects on the basis of whether the nonsmoker lives with a smoker. Eighteen such studies were identified, and the analysis presented below is based on 13 studies listed in Tables 12â3 and 12â4. The other 5 studies were excluded for the following reasons: â¢ Knoth et al. (1983), no reference population was given; â¢ Miller (1984), study reported all cancers but did not report on lung cancers separately; â¢ Sandler et al. (1985), included very few lung cancer cases; â¢ Koo et al. (1984), a more recent analysis of the population was presented in Koo et al. (1986); and â¢ Wu et al. (1985), raw data were not presented. Otherwise our analysis used data from all the studies, thereby reducing the possibility of bias arising out of selecting only some of the studies that met minimal standards. Table 12â3 gives the characteristics of the 13 studies included in the analysis. The relative risk estimate, together with its 95%
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 228 Subjects Exposure Assessmenta Comments Type of Proxy Not Married Exsmokersb Environments Interview Informants? Assessed Chan and Hong Interview, No criteria No criteria No criteria Home and Little Fung, 1982 Kong, not blind given given given workplace information on <39:84 methods or cases (out selection of of 189); controls; no 139 adjustments of orthopedic odds ratio; high controls cancer rate for South China Trichopoulos, Greece: Interview, No âUnexposedâ Exclude if Spouse Excluded et al., 1983 62 cases not blind smoked (current and adenocarcinomas (out of within prior former) and terminal 102); 190 20 yr; bronchial; orthopedic ânonsmokerâ original sample controls if no similar age and (out of smoking in SES, no match 251) 20 yr; on final sample âexsmokerâ if stopped 5â 20 yr before Correa et al., Louisiana: Interview, Yes (24% Excluded, Exclude; Spouse, No adjustment 1983 30 (22F, blinded of cases, include used pack yr parents for age, race, or 8M) 11% of âever of husband hospital cases (out controls) marriedâ admission; of 35) reported odds 313 ratio for older (133F, than 40; 180M) excluded hospital bronchioalveolar controls cancer (diseases not related to smoking)
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 229 Kabat and Multicenter Interview, No 24 cases and Only data for Workplace, Cases, Wynder, USA: 78 not blind 25 controls 1 yr home controls 1984 (25M, 53F) had no spouse matched for cases; 78 age, sex, (25M, 53F) race, controls hospital, (nontobacco and date cancers) interviewed Buffler et Texas: 41 Interview Yes No criteria No criteria Spouse Original al., 1984 cases (out of given given population 460); 192 matched population- age, race, based vital status, controls (out county; no of 482) match on final sample Garfinkel NJ, Ohio: Interview, Yes Used data on Exclude, Home, No dose- et al., 1985 134 cases blinded relative, exposed outside response age 40+; 402 otherwise home effect; colon cancer âunexposedâ corrected for age, SES, date diagnosed Pershagen Sweden: 67 Mailed Yes âUnexposedâ Exclude Spouse, Previous et al., in registry parents, interview press cases; 347 workplace 1961, 1963 controls with follow-up 1984; possible interaction with radon; adjusted for occupation, radon, urban; matched for age, vital status Akiba et Japan: 113 Interview, Yes, Excluded Exclude; Spouse, Selected al., 1986 (94F, 19M) not blind (90% of spouse parents from atomic cases (out of cases, ânonsmokerâ bomb 164); 380 88% of if no smoking survivors; (270F, controls) in prior 10 yr average age 110M) more than controls 70; no (match age, adjustment city, vital for radiation status) dose
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 230 Study Subjects Exposure Assessmenta Comments Type of Proxy Not Exsmokersb Environments Interview Informants? Married Assessed Koo et al., Hong Interview, No Used Exclude; Workplace, Original in press Kong: 86 not blind workplace exposed home, parents sample cases (out matched for of 200); 136 age, SES; no controls data on (out of 200) match in final sample; data on former spouses Lee et al., England: 47 Interview No Excluded Exclude Home, Follow-up; 1986 (32F, 15M) workplace, original cases (out leisure, daily sample of 1,863); travel matched for 96 (66F, age, sex; not 30M) matched in controls final sample Garfinkel USA Mailed Yes Used Exclude Spouse Interviewed et al., 1981 survey: relative 1959, 1960 375,000 followed up women 1972; (176,739 adjusted for married) age, race, (total 153 education, cases) occupation, disease Gillis et Scotland: Interview No Excluded Exclude Spouse Survey al., 1984 4,061 self-report 1972, 1976 married with pairs (total mortality 6 cases) through 1982; age adjusted Hirayama, Japan: Interview, No Excluded Exclude; Spouse Interviewed, 1981, 142,857 blinded calculated (current) follow-up 16 1984 women age risk yr later; 40+ (91,450 separately differences married) in age, (total 200 occupation cases by death certificates) aThese columns include the criteria for certain aspects of exposure assessment treated in the data analyses of the study. b Disposition if subject is exsmoker; disposition if husband is exsmoker.
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 231 confidence interval, is shown in Figure 12â1 for each of the studies. Also shown in Figure 12â1 is the summary estimate based on the studies combined. The relative risk estimates of lung cancer in nonsmokers in association with ETS exposure, together with the data used for calculating them, are given in Table 12â4. The data given in this table permit readers to combine any subset of the 13 studies which they may wish to consider. A summary estimate of the relative risk for the selected studies can then be calculated using the general method described in Appendix B. The method weights each study by its statistical precision and avoids making inappropriate comparisons across different studies. In the course of examining the data, several such subset analyses were conducted and the results are presented below. The overall summary relative risk of lung cancer among nonsmokers in association with ETS exposure was 1.34 (95% confidence limits 1.18â1.53). For all women the relative risk was 1.32 (1.16â1.51); for men it was 1.62 (0.99â2.64). The wide confidence limits for men reflect the fact that most of the data were based on nonsmoking women rather than nonsmoking men. For studies conducted in the United States, the relative risk was 1.14 (0.92â 1.40). Considering only the largest studies (those with expected number of lung cancer deaths of 20 or more), the relative risk estimate was 1.32 (1.15â1.52). The confidence limits on each of these estimates all include the overall summary estimate of 1.34. CORRECTIONS TO ESTIMATES FOR SYSTEMATIC ERRORS Two alternative explanations can be given for the finding of an increased risk in the epidemiologic studies. The finding may represent a direct and causal effect of ETS exposure on lung cancer in nonsmokers; or it could be due in whole or in part to bias, either in the form of systematic errors in the reporting of information or a confounding factor that is associated both with lung cancer and the fact of living with a spouse who smokes. An important question to answer is âWhat true risk, modified by a reasonable set of bias-producing factors, could lead to the average risk indicated by the epidemiologic studies?â In the following sections two computations are given that estimate how much the true relative risks might be modified as a result of these possible kinds of misclassification.
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 232 TABLE 12â4 Summary of Epidemiologic Studies of Risk Based on Exposure Assessed by Spouse Smoking Habits, When Available, or Smoking by the Household Cohabitants Study Study Authors Location Sex Lung Cancers OâE Var. Riska 95% No. in âExposedâ of (Oâ Confidence Group E) Limits Obs. Exp. Case- Control Studies 1 Chan and Hong F 34 37.7 â3.7 13.01 0.75 0.44 1.30 Fung, 1982 Kong 2 Trichopoulos Greece F 38 29.3 8.7 11.70 2.13 1.18 3.78 et al., 1983 3 Correa et al., U.S.A. F 14 10.6 3.4 4.75 2.03 0.83 5.03 1983 M 2 1.2 0.8 0.98 2.29 0.31 16.50 4 Kabat and U.S.A. F 13 13.7 â0.7 3.06 0.79 0.26 2.43 Wynder, 1984 M 5 5.0 0.0 1.52 1.00 0.20 4.90 5 Buffler et al., U.S.A. F 33 34.1 â1.1 4.78 0.80 0.32 1.99 1984 M 5 6.6 â1.6 2.37 0.50 0.14 1.79 6 Garfinkel et U.S.A. F 92 89.5 2.5 22.33 1.12 0.74 1.69 al., 1985 7 Pershagen et Sweden F 33 29.6 3.4 13.88 1.28 0.75 2.16 al., in press
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 233 8 Akiba et al., Japan F 73 67.4 5.6 14.19 1.48 0.88 2.50 1986 M 3 1.8 1.2 1.38 2.45 0.46 13.06 9 Koo et al., in Hong Kong F 51 45.3 5.7 13.19 1.54 0.90 2.64 press 10 Lee et al., 1986 England F 22 21.9 0.1 4.71 1.03 0.41 2.47 M 8 7.3 0.7 2.56 1.30 0.38 4.42 Overall for Case-Control Studies 426 401.0 25.0 114.40 1.24 1.04 1.50 Cohort, Prospective Studies 11 Garfinkel, 1981 U.S.A. F 88 81.8 6.2 30.82 1.18b 0.90 1.54 12 Gillis et al., Scotland F 6 6.0 0.0 1.58 1.00 b 0.20 4.91 1984 M 4 2.3 1.7 1.40 3.25 b 0.60 17.65 13 Hirayama, 1984 Japan F 146 129.5 16.5 34.83 1.63 1.25 2.11 M 7 3.3 3.7 3.02 2.25 1.04 4.85 Overall for Prospective Studies 251 222.9 28.1 71.65 1.44 1.20 1.72 Overall for All Studies 692 637.7 53.1 186.0 1.34 1.18 1.53 aRisk is given as calculated odds ratios for case-control studies (see Appendix B for calculations) and published relative risk for cohort, prospective studies. b Ratio of age standardized mortality rates.
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 234 FIGURE 12â1 Passive smoking and lung cancer. The relative risk (point estimate and 95% confidence interval) of lung cancer in nonsmokers whose spouses smoke compared with nonsmokers whose spouses do not smoke for each of the studies given in Table 12â4 and the summary estimate based on all the studies combined. The figures for females are shown first for studies based on male and female subjects. STUDIES: 1. Chan and Fung, 1982; 2. Trichopoulos et al., 1983; 3. Correa et al., 1983; 4. Kabat and Wynder, 1984; 5. Buffler et al., 1984; 6. Garfinkel et al., 1985; 7. Pershagen et al., in press; 8. Akiba et al., 1986; 9. Koo et al., in press; 10. Lee et al., 1986; 11. Garfinkel, 1981; 12. Gillis et al., 1984; 13. Hirayama, 1984. Misclassified Exsmokers and the Tendency for Spouses to Have Similar Smoking Habits One source of potential bias that would influence the estimates of relative risk is that some people who occasionally smoke or who have smoked in the past may report that they have never smoked. Having smoked, these people are somewhat more likely to develop lung cancer than would true lifelong nonsmokers. Because smokers tend to marry smokers, they are also more likely to have a spouse who smokes or did smoke in the past. Table 12â5 shows
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 235 that the bias produced by this misreporting could be serious. The arguments presented in this table are an extension of ideas discussed by Lee (Lehnert et al., 1984). From the table it is apparent that for this misclassification to fully account for the observed excess risk, it would be necessary that 8% or more of smokers and exsmokers report themselves as nonsmokers and that their smoking habits and history be identical with those of the self-reported smokers. The proportion of people who say that they are nonsmokers, but who in fact do smoke, can be estimated using biochemical markers of tobacco smoke absorption. They appear to constitute about 0.5â3%, depending on the population studied and the questionnaire used (Wald et al., 1981; Saloojee et al., 1982). The proportion of people who smoke or have done so in the past but who say they have never smoked has also been estimated in two cohort studies (see Chapter 6). In one of these studies (N.Britten, England, personal communication University of Bristol, England; see Table 6â4), information on smoking was obtained in detail in a longitudinal study. A proportion (4.9%) of the subjects said they had never smoked as much as one cigarette a day in 1982, when in fact they had previously smoked and reported so in previous interviews. These subjects, however, had smoked at a rate of about half that of the current smokers and nearly all of them (93%) had stopped smoking 10 or more years earlier. Similar, or slightly higher, misreporting has been noted for older persons (see Chapter 6). However, older persons are likely to have smoked less and to have quit longer ago. Table 12â5 is based on the assumption that people who fail to report that they have been smokers have the same risk of lung cancer as the average current smoker. As indicated in Table 6â4, âmisclassified smokersâ are more likely to have been exsmokers who failed to record the fact that they had smoked at some time in the past or, if they were current (or recent) smokers, they smoked fewer cigarettes per day than the average smoker (Table 6â4). In either event, their spouses' risk of lung cancer would be lower than for the spouse of a current smoker. The American Cancer Society's study of smoking (Hammond, 1966) reported that women who smoked 20â30 cigarettes a day had a 4.9-fold increased risk of lung cancer compared with reported nonsmokers. The British Physicians' Study (Doll et al., 1980) yielded an estimate of 6.4. Both studies were conducted a number
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 236 TABLE 12â5 Illustration of a Bias Likely to Affect Passive Smoking Studies
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 237 of years ago. With the increased duration of smoking in women in recent years, these relative risks also should have increased. The relative risk estimate may be as high as 8.0. To the extent that this may be an overestimate, it will tend to exaggerate the effects of misclassification. The lung cancer relative risk for persons misclassified as nonsmokers is, for the reasons given, probably less than half of that for correctly classified active smokers (relative risk of 4) and probably closer to one-quarter (relative risk of 2). Applying the same argument illustrated in Table 12â5, the misclassification effect on the relative risk is given in Table 12â6 (N.Wald and K.Nanchahal, personal communication), assuming that the risk of lung cancer of misclassified nonsmokers is half that of current smokers (relative risk=4.0) or one-quarter (relative risk=2.0). Table 12â6 shows the possible effect of a nonrandom marriage (aggregation) pattern. In this table the extent of nonrandom association is described by an âaggregationâ factor. The degree of aggregation is estimated by the ratio of the cross-products in a 2 Ã2 table of smoking status of study subjects by spouse smoking status. For the computations in Table 12â6, three aggregation factors are assumed, 2.5, 3.5 and 4.5. The smoker aggregation factor (from epidemiologic studies) appears to be about 3 to 4 (see Table 12â7; Wald et al., personal communication). The overall effect on an assumed true association between passive smoking and lung cancer, i.e., the âtrueâ relative risk, is shown in Table 12â6 for relative risks ranging from 1.0 (i.e., no association) to 1.25 (i.e., 25% increase in lung cancer risk associated with passive smoking). It is assumed that 35% of women smoke and 50% of men smoke. Also, the effects of the misclassification of between 2% and 10% of smokers as nonsmokers is shown. The most plausible assumptions are a relative risk of 2.0 to 4.0, an aggregation factor of 3 to 4, and a misclassification rate of 2 to 7%. To use Table 12â6, locate the rows and columns that correspond the the above most plausible assumptions. The entries in the body of the table that are approximately 1.34, i.e., the observed overall relative risk, correspond to the set of parametric values that, with plausible assumptions of the bias, would inflate a true relative risk to the observed values. Inspection of the data within the body of Table 12â6 shows that an observed relative risk of 1.34, given the range of assumptions specified in the table, could come about if there were a true relative risk of no less than 1.15. That is,
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 238 TABLE 12â6 Estimates of the Observed Relative Risk of Lung Cancer from Studies of Married Nonsmokers; Assuming 35% of Women and 50% of Men in the General Population Are Current Smokers True Relative Risk Marriage Aggregation Factorb Proportion of Misclassified Smokers Passive Smokers Misclassified Smokersa 2% 4% 6% 8% 10% 1.00 2.0 2.5 1.01 1.02 1.03 1.04 1.04 3.5 1.01 1.03 1.04 1.05 1.06 4.5 1.02 1.03 1.04 1.06 1.07 4.0 2.5 1.03 1.05 1.08 1.10 1.12 3.5 1.04 1.08 1.11 1.14 1.17 4.5 1.05 1.09 1.13 1.17 1.20 8.0 2.5 1.06 1.12 1.17 1.21 1.25 3.5 1.09 1.17 1.24 1.30 1.36 4.5 1.11 1.20 1.29 1.37 1.43 1.05 2.0 2.5 1.06 1.07 1.08 1.08 1.09 3.5 1.06 1.08 1.09 1.10 1.11 4.5 1.07 1.08 1.09 1.11 1.12 4.0 2.5 1.08 1.10 1.13 1.15 1.17 3.5 1.09 1.12 1.16 1.19 1.21 4.5 1.10 1.14 1.18 1.22 1.25 8.0 2.5 1.11 1.17 1.21 1.26 1.29 3.5 1.14 1.21 1.28 1.34 1.40 4.5 1.16 1.25 1.33 1.41 1.48 1.10 2.0 2.5 1.11 1.12 1.13 1.13 1.14 3.5 1.11 1.12 1.14 1.15 1.16 4.5 1.12 1.13 1.14 1.16 1.17 4.0 2.5 1.13 1.15 1.17 1.19 1.21 3.5 1.14 1.17 1.20 1.23 1.26 4.5 1.15 1.19 1.23 1.26 1.30 8.0 2.5 1.16 1.21 1.26 1.30 1.33 3.5 1.19 1.26 1.33 1.39 1.44 4.5 1.20 1.30 1.38 1.45 1.52 1.15 2.0 2.5 1.16 1.17 1.17 1.18 1.19 3.5 1.16 1.17 1.18 1.20 1.20 4.5 1.17 1.18 1.19 1.21 1.22 4.0 2.5 1.18 1.20 1.22 1.24 1.26 3.5 1.19 1.22 1.25 1.28 1.31 4.5 1.19 1.24 1.27 1.31 1.34 8.0 2.5 1.21 1.26 1.30 1.34 1.38 3.5 1.23 1.31 1.37 1.43 1.48 4.5 1.25 1.34 1.43 1.50 1.56 1.20 2.0 2.5 1.21 1.22 1.22 1.23 1.24 3.5 1.21 1.22 1.23 1.24 1.25 4.5 1.21 1.23 1.24 1.25 1.27 4.0 2.5 1.22 1.25 1.27 1.29 1.30 3.5 1.24 1.27 1.30 1.33 1.35 4.5 1.24 1.28 1.32 1.36 1.39
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 239 True Relative Risk Marriage Aggregation Factorb Proportion of Misclassified Smokers Passive Smokers Misclassified Smokersa 2% 4% 6% 8% 10% 8.0 2.5 1.26 1.30 1.35 1.38 1.42 3.5 1.28 1.35 1.42 1.47 1.52 4.5 1.30 1.39 1.47 1.54 1.61 1.25 2.0 2.5 1.26 1.27 1.27 1.28 1.29 3.5 1.26 1.27 1.28 1.29 1.30 4.5 1.26 1.28 1.29 1.30 1.31 4.0 2.5 1.27 1.30 1.31 1.33 1.35 3.5 1.29 1.32 1.35 1.37 1.40 4.5 1.29 1.33 1.37 1.40 1.44 8.0 2.5 1.30 1.35 1.39 1.43 1.46 3.5 1.33 1.40 1.46 1.52 1.57 4.5 1.35 1.44 1.52 1.59 1.65 aSubjectswho have smoked either in the past or currently, but claim to be lifelong nonsmokers. b Marriageaggregation factor defined as ratio of cross-products of 2Ã2 table of smoking status of study subject by smoking status of spouse. NOTE: The values inside the boxes indicate those situations that are most plausible, based on other sources of data for parameters, and yield observed relative risks of about 1.34.
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 240 a true relative risk of 1.15 or more could, by a reasonable set of misclassification biases, be elevated to 1.30 in an epidemiologic study. Stated differently, this implies that reasonable misclassification does not account for the total increased risks reported by the epidemiologic studies, leaving the conclusion that the risk of lung cancer following exposure to other people's smoke, as judged by whether a nonsmoker has a smoking spouse, would be increased by a minimum of 15%, and most probably increased by 25% (i.e., 1.25). (If the percentage of women smokers were as high as 50%, it would be 1.20.) TABLE 12â7 Number of Smokers and Nonsmokers According to the Smoking Habits of Their Spouses and the Odds Ratio Indicating the Extent of Such Marriage Aggregationa Spouse Females Males Smoker Nonsmoker Total Smoker Nonsmoker Total Smoker 53 17 70 20 11 31 Nonsmoker 47 83 130 53 80 133 All 100 100 200 73 91 164 Odds ratio 3.1 2.3 aBased on interviewing 200 women and 164 men attending a health screening center in London or working in the Civil Service in Newcastle in 1985. SOURCE: Wald et al., personal communication. The study by Garfinkel et al. (1985) provides data relevant to the misclassification of exsmokers and the tendency for spouses to have similar smoking habits. In this study, subjects were interviewed if the hospital record indicated nonsmoker or made no mention of smoking status. From interviews by the investigators, it was determined that 40% of the women had actually smoked. Among these women who smoked, 81% had husbands who smoked, but only 68% of the women who were in fact nonsmokers had husbands who smoked, yielding an aggregation factor of 2.0. Effects of Incorrectly Classifying Persons as Unexposed to ETS In the studies that classify nonsmoker exposure based on whether or not the spouse smokes, some of the âunexposedâ nonsmokers, i.e., married to nonsmokers, are likely to be exposed in other settings. For instance, some nonsmokers married to nonsmokers may be exposed to ETS in the workplace. Therefore, some individuals in the baseline, âunexposed,â group for these studies must have been exposed, and hence have risks greater than unity if there is an ETS effect. In the studies, which do ask about exposure to ETS in all environments, there still tends to be misclassification of some nonsmokers as âunexposed,â because there may be a tendency to overlook episodes of exposure. The data from urinary cotinine studies and the observed relative risks can be used to estimate this effect. The only known source of cotinine in the body is from nicotine, which is virtually exclusively derived from tobacco, with the exception of nicotine chewing gum and nicotine aerosol rods. Therefore, if people who actively use tobacco or nicotine-containing aids to help stop smoking are excluded, cotinine can be used as an objective measure of
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 241 (recent) exposure to tobacco smoke in nonsmokers. For the following argument, the cotinine in body fluids is compared for the two groups of nonsmokers, those who reported exposure to ETS and those who reported no exposure. Since both groups are nonsmokers, the concern of whether or not the clearance rates for nicotine or nicotine metabolites differ between smokers and nonsmokers is not germane to these estimates. In the study by Wald and Ritchie (1984), the urinary cotinine levels among nonsmokers exposed to smoking spouses were 3 times those of nonsmokers married to nonsmokers. Using a linear model of risk and assuming that the 3:1 ratio represents a lifetime difference, the implied relative risk of these two groups would be equal to: (12â1) where dN is the dose received by nonsmokers who are self-declared âunexposedâ and Î² is the increase in risk per unit dose received (for details, see Appendix C). This equation assumes that the lifetime carcinogenic dose received by nonsmokers who say that they are âexposedâ is 3 times that of truly unexposed nonsmokers, assuming cotinine levels to be a proxy for carcinogenic constituents of ETS. When Equation 12â1 is set equal to the relative risk, one can solve for Î²dN. In the previous section, it was noted that the true relative risk is likely to be 1.25 and, as argued above, probably lies between 1.15 and 1.35. Consequently, relative risk values of 1.25, 1.15, and 1.35 will be considered. Using these values, Î²dN will be 0.14 (ârangingâ 0.08 to 0.21). Therefore, the relative risk of self-identified âunexposedâ nonsmokers compared with truly unexposed nonsmokers is: (12â2) which would be 1.14 (ârangingâ 1.08 to 1.21). The relative risk of âexposedâ nonsmokers compared with a truly unexposed nonsmoker is: (12â3)
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 242 which would be 1.42 (ârangingâ 1.24 to 1.61). That is, the increased risk of lung cancer as a result of chronic exposure to ETS, corrected for the effect of not identifying a truly unexposed reference group of nonsmokers, is likely to be at least as large as the observed risk. We can say, therefore, that while the epidemiologic studies show a consistent and, in total, a highly significant association between lung cancer and ETS exposure of nonsmokers, the excess might, in principle, possibly be explained by bias. However, detailed consideration of the nature and extent of the bias shows that given some reasonable assumptions the bias would be insufficient to explain the whole effect. In fact, there are some types of bias that lead to underestimates of the effect. It must be concluded, therefore, that some, if not all, of the effect reported in spouse studies is causal. OTHER CONSIDERATIONS Some of the spouse-smoking studies show a dose-response effect with rates increasing with increasing exposure as measured by increasing levels of cigarette consumption by the smoking spouse (see Tables 12â8 and 12â9). A dose-response relationship also suggests a causal explanation, although biases could also operate to affect this estimation. It is possible that a person misclassified as a nonsmoker married to a smoker will have a cigarette consumption that is correlated with that of his or her spouse. A misclassified nonsmoker married to a heavy smoker would, therefore, have a higher risk of lung cancer independent of spouse is smoking than a misclassified nonsmoker married to a light smoker, thus giving the appearance of a dose-response relationship between ETS exposure and lung cancer. This possible pseudo-dose-response effect arises only as a result of misclassifying smokers as nonsmokers. It is of interest, therefore, that one study has reported an effect of passive smoking in smokers as well as nonsmokers (Akiba et al., 1986). However, it does not appear that adjustment has been made for amount smoked. To the extent that smokers married to smokers may smoke more than the smokers married to nonsmokers, this would bias the results.
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 243 TABLE 12â8 Risk of Lung Cancer in Nonsmokers According to Cigarette Consumption of Spouse Authors Findings Case-Control Studies Trichopoulos et al., 1983 Exsmoker 1.0 1â20 cig. per day 2.4 21+ cig. per day 3.4 Garfinkel et al., 1985 1â19 total cig. per day 0.84 20â39 total cig. per day 1.08 40+ total cig. per day 1.99 Cigar/pipe 1.13 Akiba et al., in press 1â19 cig. per day 1.3 20â29 cig. per day 1.5 30+ cig. per day 2.1 Cohort Studies Hirayama, 1984 1â19 cig. per day 1.45 20+ cig. per day 1.91 Garfinkel, 1981 1â19 cig. per day 1.27a 20+ cig. per day 1.10 a aMortality ratios, not relative risks. NOTE: Relative risk for self-reported unexposed is assumed to be 1.0. Most of the studies considered the histological type of lung cancer. In general they showed a higher proportion of adenocarcinoma in ETS-exposed nonsmokers than would be expected among active smokers. This is to be expected in view of the fact that the proportion of adenocarcinomas is, in general, higher among nonsmokers. Adding some nonadenocarcinoma-type disease, possibly as a result of ETS exposure, would reduce this proportion. It would nonetheless leave the proportion of adenocarcinomas higher than would be found among lung cancer cases among active smokers. If there were a high relative risk of adenocarcinoma associated with ETS exposure of nonsmokers, it would suggest a real effect, but the published data are insufficient or not presented in a way to allow assessing this issue at this time. Two studies have examined the risk of lung cancer associated with passive smoking using parental smoking as a measure of exposure instead of spouse smoking (Correa et al., 1983; Sandler et al., 1985b). The first found an association with maternal smoking (RR=1.66, p<0.05) but not with paternal smoking (RR=
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 244 0.83). The second found no significant association with smoking of either parent. The bias discussed in connection with spouse-smoking studies is likely to apply also to parental-smoking studies. In addition, these two studies included active smokers as well as recorded nonsmokers, and it is likely that the children of smokers start smoking at a younger age and possibly smoke more than do smoking children of nonsmoking parents (U.S. Public Health Service, 1984). This would also be a source of bias. TABLE 12â9 Risk of Lung Cancer in Nonsmokers According to Duration of Smoking of Spouse or Other Measures of Exposure Not Shown in Table 12â7 Authors Findings Case-Control Studies Trichopoulos et al., 1983 Total no. of cig. (in thousands): 1â99 1.3 100â299 2.5 300+ 3.0 Correa et al., 1983 Total pack-years: Males Females 1â40 â 1.18 41+ â 3.52 All 2.0 2.07 Koo et al., 1984 Total hours: 1â3,499 1.28 3,500+ 1.02 Any 1.24 Garfinkel et al., 1985 No. of h/day: Last 5 yr Last 25 yr 1â2 1.59 0.77 3â6 1.39 1.34 >6 0.94 1.14 Pershagen et al., in press Kreyburg I Kreyburg II Less than 15 cig./day or 50 g tobacco/wk for less than 30 yr 1.8 0.8 More than 15 cig./day or 50 g tobacco/wk for more than 30 yr 6.0 2.4 Akiba et al., in press Pack-days within last 10 yr: <5,000 1.0 5,000â9,999 2.8 10,000+ 1.8 NOTE: Relative risk for self-reported unexposed is assumed to be 1.0.
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 245 Pershagen et al. (in press) reported that the relative risk for lung cancer in women married to smokers and living in a home that had measurable radon levels was increased relative to the effects of living with a smoker or living in a home with radon. They suggested that this might represent an interaction between exposure to ETS and radon. Research needs to be done that explores this association further in light of recent reports of high radon concentrations in homes (Code of Federal Regulations, 1985). SUMMARY AND RECOMMENDATIONS The weight of evidence derived from epidemiologic studies shows an association between ETS exposure of nonsmokers and lung cancer that, taken as a whole, is unlikely to be due to chance or systematic bias. The observed estimate of increased risk is 34%, largely for spouses of smokers compared with spouses of nonsmokers. One must consider the alternative explanations that this excess either reflects bias inherent in most of the studies or that it represents a causal effect. Misclassification can have contributed to the result to some extent. Computations of the effect of two sources of misclassification were presented. Computations taking into account the possible effects of misclassified exsmokers and the tendency for spouses to have similar smoking habits placed the best estimate of increased risk of lung cancer at about 25% in persons exposed to ETS at a level typical of that experienced by nonsmokers married to smokers compared with those married to nonsmokers. Another computation using information from cotinine levels observed in nonsmokers and taking into account the effect of making comparisons with a reference population that is truly unexposed leads to an estimated increased risk of about one-third when exposed spouses were compared with a truly unexposed population. The finding of such an increased risk is biologically plausible, because nonsmokers inhale other people's smoke and, as a result, absorb smoke components containing carcinogens. What Is Known 1. A summary estimate from epidemiologic studies places the increased risk of lung cancer in nonsmokers married to smokers compared with nonsmokers married to nonsmokers at about 34%.
EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER 246 Assuming linearity at low-to-average doses and a constant proportionality of nicotine and carcinogens in mainstream smoke and ETS, extrapolation from studies of active smokers using relative urinary cotinine places the risk at about 10%. 2. To some extent, misclassification (bias) may have contributed to the results reported in the epidemiologic literature. However, bias is not likely to account for all of the increased risk. The best estimate, allowing for reasonable misclassification, is that the adjusted risk of lung cancer is increased about 25% (i.e., RR =1.25) in nonsmokers married to smokers compared with nonsmokers married to nonsmokers. When one allows for exposure to nonsmokers who report themselves as unexposed, the adjusted increased risk is at least 24%. The adjusted increased risk to a group of nonsmokers married to nonsmokers is at least 8% (i.e., RR=1.08) compared with truly unexposed subjects. This excess risk may come about from exposures in the workplace or other public places. What Scientific Information Is Missing 1. It would be useful to quantify the dose-response relationship between ETS exposure and lung cancer more precisely using biological markers of exposure. Studies should be done that incorporate these biological markers. 2. Laboratory studies would be important in determining the carcinogenic constituents of ETS and their concentrations in typical daily environments and in facilitating understanding of possible dose- response relationships. 3. The interaction between ETS and radon exposure, which can increase risk of lung cancer, is worth examining further. REFERENCES Akiba, S., W.J.Blot, and H.Kato. Passive smoking and lung cancer among Japanese women. Fourth World Conference on Lung Cancer, Toronto, Canada, Aug. 25â30, 1985. Akiba, S., H.Kato, and W.J.Blot. Passive smoking and lung cancer among Japanese women. Cancer Res. 46:4804â4807, 1986. Buffler, P.A., L.W.Pickle, T.J.Mason, and C.Contant. The causes of lung cancer in Texas, pp. 83â99. In M.Mizell and P.Correa, Eds. Lung Cancer: Causes and Prevention. New York: Verlag-Chemie International, Inc., 1984.
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