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INVOLUNTARY SMOKING AND LUNG CANCER 237 INVOLUNTARY SMOKING AND LUNG CANCER Introduction The social pressure to limit smoking in public places (6) reflects concern for protecting nonsmokers from the annoyances of others' cigarette smoke, as well as concern about the possible adverse health effects of involuntary smoking, or secondhand exposure to others' cigarette smoke. A recent publication presented the scientific evidence linking involuntary smoke exposure to adverse health effects (44). Children of smoking parents had more bronchitis and pneumonia during the first year of life (17); and acute respiratory disease accounted for a higher number of restricted activity days (1.1 days) and bed disability days (0.8 day) in children whose families smoked than in those whose families did not (3). A reduction in exercise tolerance with exposure to sidestream cigarette smoke has been demonstrated in patients with angina pectoris (I), and a decrease in small airway function of the lung equivalent to that observed in light smokers (1 to 10 cigarettes a day) has been reported in adults who never smoked themselves nor lived with smokers, but who were exposed to cigarette smoking in the workplace (49). Only recently has attention focused on the possibility that lung cancer may be caused by involuntary inhalation of tobacco smoke. This concern is based upon: (1) the occurrence of similar chemical constituents in sidestream smoke (smoke released from the cigarette between active puffs) and mainstream smoke (smoke actively inhaled); (2) the established dose-response relationship between voluntary cigarette smoking and lung cancer, and the absence of evidence establishing a threshold for effect; and (3) the recent epidemiologic studies that examined lung cancer mortality in nonsmoking spouses of cigarette smokers. Smoke Constituents The average person spends most of the time indoors where there may be significant exposure to tobacco smoke generated by others (32). For various reasons, the exposure of nonsmokers is more difficult to quantitate than that of the smoker. The constituents of the particulate and gas (vapor) phases of tobacco smoke have been quantitatively analyzed in several studies (8, 22, 37, 38). As is shown in Table 1, many of the chemical constituents of mainstream smoke are also found in sidestream smoke. Some constituents occur in markedly higher concentrations in sidestream than in mainstream smoke (note SS to MS ratio); however, sidestream smoke is released into the ambient air, resulting in dilution of constituents. The resulting concentration of smoke is dependent upon the amount of 239 TABLE l.-Constituents of cigarette smoke.' Ratio of sidestream smoke (SS) to mainstream smoke (MS) Carbon Dioxide Carbon Monoxide Methane Acetylene Propane Propene Methylchloride Methylfuran Propio+dehyde %Butan0ne Acetone A. GAS PHASE MS WMS MS SSMS 8.1 Nitrogen Oxides (NOx) 25 Ammonia 3.1 Hydrogen cyanide 0.8 Acetonitrile 4.1 f'yridine 2.1 3-Picoline 3.4 SVinylpyridine 2.4 Dimethylnitrosamine 2.9 Nitmspyrmlidine 8. PARTICULATE PHASE MS SS/MS MS WMS "Tar" Water Toluene Stigmasterol Total Phytostemls Phenol Catechol Napthalene Methyln~phthalene Pyrene Benzo(4wene 1.7 2.4 5.6 0.8 0.8 2.6 0.7 16 28 3.6 3.4 Quinoline 1.7 Irg 11 Methylquinolines 0.7 pg 11 Aniline 360 w 30 %Naphthylamine 2% 39 4-Aminobipheny! 5 m3 31 Hydrazine 32% 3 N'-Nitrownornimtine lo&x@ ng 5 NNKZ mmng 10 N&tine l-2.5 mg 27 `Nonfiltereigarette ZNNK - ~N-methyl-N-ni~mino)-1~5pyridgl~l-butanone(tobrcm c.pecificcarcinogenk nitmumim) SOlIH~`E I: S lkrwrtment 01 Health. Educatmn. and Welfaretlll smoke generated, the volume of ambient air, and the type and amount of the ventilation of that space (2, 4, 24, 34, 44). In addition, the chemical composition of smoke changes with the passage of time (24~). Further complicating factors include the continuous low-dose exposure of involuntary smokers contrasted with the intermittent high-dose exposure of the active smoker. Thus, many factors complicate the theoretical extrapolation of machine measurements of smoke constituents to the biologic effects to be expected with exposure of nonsmokers. The actual absorption of smoke c0nstituent.s by nonsmokers in smoke-filled spaces has not been completely characterized. A few studies have examined the absorption of carbon monoxide by measuring carboxyhemoglobin levels in exposed nonsmokers (44); however, the absorption of most other constituents has not been studied. Furthermore, the pattern of involuntary inhalation proba- bly differs from that of voluntary inhalation of smoke by the smoker, affecting the pattern and amount of deposition or absorption of 240 chemical constituents in nonsmokers compared to smokers. Differ- ences in the carcinogenicity of sidestream and mainstream smoke may also exist; sidestream smoke condensate is more tumorigenic per unit weight in mouse skin assays than is mainstream smoke condensate (50). Some evidence exists that suggests, however, that involuntary exposure to cigarette smoke does result in deposition or absorption of constitutents. Involuntary inhalation of cigarette smoke has been shown to produce tracheobronchial epithelial metaplasia and dyspla- sia in animals (23). The applicability of these data to human exposures is not clear, however, since the levels of smoke exposure used in this animal study were substantially higher than those normally encountered by humans in enclosed spaces where smoking is allowed (38). In a smoke-filled, unventilated, unoccupied room, the concentrations of several smoke constituents, including several volatile gases, total particulate matter, and nicotine, remained constant and were higher than when humans were present. Further, several vapor phase constituents such as nitrogen oxide, acrolein, and aldehydes were observed to decrease continuously over 3 hours when humans were placed in the room, despite fresh sidestream smoke being generated to keep the ambient carbon monoxide level stable (24). The difference in absolute levels and the continuing decrease in constituent concentrations despite the continuing addi- tion of smoke to the environment suggest absorption by humans, although the actual site(s) of deposition has not been determined. Dose-Response Relationships Examination of the dose-response relationship for voluntary smokers suggests an increased risk with any level of regular cigarette smoking (43). No threshold level of exposure for the development of lung cancer has been established and, therefore, any level of exposure is of concern. Figure 1 reflects the data that led to the scientific consensus that there is no threshold level. This absence of a clear threshold level of exposure raises the issue of whether the levels of exposure reached through involuntary smoking may also produce an increased risk of lung cancer. Epidemiologic Studies The use of epidemiologic techniques to search for an association between involuntary smoke exposure and lung cancer has a number of methodologic difficulties. 241 10 20 30 10 CURRENT NUMBER OF CIGARETTES SMOKED PER DAY 0 0 Bnttsh Physictans )6----$( Canadmn Veterans .a . . . . . . . . . . . . u s veterans v----q u s. men I" 25 states FIGURE l.-Mortality ratios of deaths from lung cancer in men. Data from four large prospective studies SOURCE Rn)al College of Physictans of London t&Y51 242 Exposure An individual's actual smoke exposure dose is difficult to quantify, even for an acute exposure. For the longer exposure periods, as in chronic disease epidemiologic studies, the exposure quantification problems are magnified. Dosage is dependent upon the amount of smoking by those around the nonsmoker, the spatial distance between the nonsmoker and smoker, the duration and frequency of exposure, and a number of other factors that complicate the quantification of involuntary smoke exposure in either retrospective or prospective studies. Several studies have used the smoking habits of the spouse of the nonsmoker as a means of identifying two groups (nonsmokers with smoking or nonsmoking spouses). This estimate of exposure is subject to misclassification, as the nonsmoker may be a former smoker. This may be true for either the nonsmoker being followed or the nonsmoking spouse in the control group. In addition, in societies with a high rate of divorce or multiple marriages, the smoking habits of the current spouse may not approximate the actual exposure. Further, there is a demonstrable correlation between the smoking habits of spouses that decreases the proportion of couples available for study who are discordant for smoking. Long Latency Periods Lung cancer follows exposures experienced over decades and, therefore, it is necessary to observe nonsmokers over an extended time in order to estimate their actual exposure. Other Carcinogenic Exposures Exposure to cigarette smoke may occur in conjunction with exposure to other occupational or environmental carcinogens. Epide- miologic studies should control for or investigate possible interac- tions with other environmental exposures as far as possible, but limitations clearly exist here as well. Accurately assessing lifetime exposures and attempting to control for such exposures are difficult, if not impossible. Current Epidemiologic Evidence To date, three epidemiologic studies have been published that examine the lung cancer risk of involuntary smoking. Two of these studies (19, 42) were conducted in the relatively traditional societies )f Greece and Japan; the third analysis was conducted in the Unit,ed states by Garfinkel (IZ), based on data originally collected by Hammond (14). Trichopoulos et al. used the case-control method of study over the oeriod of September 1978 through June 1980. They identified 51 243 Caucasian female lung cancer patients and 163 adult female orthopedic patients in Athens. All subjects were questioned on their personal smoking habits, and husbands were classified as nonsmok- ers (never smoked or quit more than 20 years prior), ex-smokers (stopped smoking 5 to 20 years prior), and current smokers (current- ly smoking or smoked within 5 years prior to interview). Single women were classified with the group having nonsmoking husbands. The cases and controls did not differ in age, duration of marriage, occupation, education, or place of residence, although specific matching on these characteristics was not performed. Involuntary exposure of the wife was estimated from her husband's daily consumption, from the date of marriage until their divorce, her husband's death, or change in his smoking habits; multiple mar- riages were also considered. Excluding 11 voluntary smokers from the 51 female lung cancer cases, and 14 smokers from the 163 controls, the remaining 40 nonsmoking lung cancer patients and 149 nonsmoking control women were compared by their husband's current smoking status, and estimated total cigarettes smoked by the husband by the time of interview. The results are shown in Tables 2 and 3 respectively. Compared with the control group, at interview the lung cancer cases showed l.&fold greater probability of being married to an ex-smoker; 2.4-fold greater odds of being married to a light or moderate smoker (20 or fewer cigarettes per day); and 3.4-fold greater odds of being married to a heavy smoker (more than 20 cigarettes per day). The trend observed in these findings was statistically significant, with a p value less than 0.02. Exclusion of single women from this analysis modified the relative risks only slightly. Table 3 shows a similar trend of increasing relative risks in nonsmoking wives with increas- ing (estimated) total number of cigarettes smoked by the husband prior to the interview. Some limitations and strengths of this study were recognized and discussed by the authors. Among the limitations were: the number of cases was small; 35 percent of the tumors lacked histologic confirma- tion; controls were chosen from a different hospital than were the cases; a single unblinded interviewer was used for both cases and controls. On the other hand, the authors suggested that the conservative social setting for this study may be less subject to errors of misclassification resulting from the exposure of nonsmoking wives of nonsmokers to the smoke of others outside the home. The number -of cases of adenocarcinoma that were excluded from the analysis is not given. Analysis including such cases would be of interest (16), as many investigators have found cigarette smoking to be a cause of adenocarcinoma of the lung as well 2s of other histologic types of lung cancer (45). Additional control groups for comparison to the cases might have enhanced the findings of this study. 244 TABLE 2.-Smoking habits of husbands of nonsmoking women with lung cancer and of nonsmoking control women Cigarettes per day lcurrent smokers1 Diagnostic group Nonsmokers Exsmokers l-10 1 l-20 21-30 31+ Total Lung cancer 11 6 2 13 4 4 40 COntr& 71 22 Q f-2 149 RRa 1.0 1.8 2.4 3.4 RRb 1.0 1.5 2.0 3.0 * Relatwe r-k-the ratio of the risk of lung cancer among women whose husbands belong to a particular .mokmg category to that among women whose husbands are nonsmokers X1=6.45. p(Z-talI~ 0 02 bAnalys~s excluding single women arbrtrardy clasafied as nonsmokers X'llrnear trendi=4.6. px 0 03 SOURCE Tnchopoulos et al (42) TABLE 3.-Distribution of nonsmoking women with lung cancer and of nonsmoking control women according to the estimated total number of cigarettes smoked by their husbands by the time of the interview Total number of cigarettes (in thousands) Diagnostic group 0 l-99 lOS199 200-299 3oLx399 400+ Total Lung cancer 8 4 6 9 6 7 40 controls 56 21 L-2 ,`2 149 RRa 1.0 1.3 2.5 3.0 `Relative risk-the ratio of the risk of lung cancer among women whose husbands belong to a particular smokmg category to that among women whose husbands are nonsmokers X2-6 50, p(2-tail]< 0.02. SOURCE: Trichopoulos et al. t1981l. Hirayama (19) used a prospective design in 29 health districts in Japan over 14 years, from 1966 to 1979, in which 91 to 99 percent of the census population was interviewed. He analyzed interview data from 265,118 adults aged 40 years and older, and found that 72.3 percent of the couples had data on the smoking habit of both spouses. Among 91,540 married women, 245 deaths from lung cancer were recorded, of which 174 were nonsmokers. He reported 2 statistically significant excess rate of lung cancer among nonsmoking wives of smokers 2s compared to nonsmoking wives of nonsmokers. Table 4 shows the standardized mortality rates for lung cancer in non- smoking wives, adjusted for age and occupation. There is an apparent dose-response relationship in each of the analyses present- ed. Certain methodologic details (e.g., the definition of an ex-smoker 245 husband, the method of age and occupation standardization, and the technique or extent of histologic confirmation) were not presented. Hirayama also examined the effects of I voluntary smoking in relationship to involuntary exposure and nonexposure. The stand- ardized annual mortality rate for nonsmokers who were not involun- tarily exposed was 8.7 per 100,000. For women who reported being exposed to cigarette smoke only involuntarily, the standardized annual mortality rate was 15.5 per 100,000. For women who voluntarily smoked, the standardized annual mortality rate was 32.8 per 100,000. He concluded that the effect of involuntary smoking was approximately one half to one third that of active or voluntary smoking. The age and, occupation standardized risk ratios in this population failed to show ,any statistically significant effect of spousal smoking on nonsmoking women's standardized risk ratios for deaths from other causes, including emphysema (although the trend in relative risk was in the same direction as for lung cancer mortality), cervical cancer, stomach cancer, or ischemic heart disease (Table 5); no significant role of spousal alcohol consumption was demonstrated for any of the above diseases. The public press has reported a possible error in Hirayama's computation of the chi square test of statistical significance (33). However, the scientist to whom this finding was attributed has subsequently stated that he raised questions about the study but denied reaching any conclusion (29u). Harris and DuMouchel (18) recalculated the chi square using the originally presented data of Hirayama by combining Tables 1 and 2. The calculated chi square of 8.09 yielded a statistically significant two-sided p value of 0.0004. In a subsequent, more detailed tabular presentation, Hirayama (21a) confirmed the statistically significant excess in lung cancer death rates in wives of smokers when adjusted for husband's age, occupation and smoking habits. In this subsequent analysis, Hiraya- ma restricted his analysis to data from one prefecture for a possible dose-response relationship of involuntary smoking and lung cancer mortality. The exposure of nonsmoking wives was calculated by multiplying the hours of the day the husband was at home by the number of cigarettes smoked per hour, assuming that the number of cigarettes smoked per hour remained constant over waking hours. There was a clear dose-response observed (Tabie 6) for each of three categories for length of hours and for number of cigarettes smoked per day. The risk of death from lung cancer in nonsmoking women increased with either the time of exposure or increasing daily number of cigarettes. In that set of analyses, the relative mortality risk (as. measured by the standardized mortality ratio) observed 246 TABLE 4.-Standardized mortality for lung cancer in women by age, occupation, and smoking habit of the husband (patient herself a nonsmoker) Husband's smoking habit Nonsmoker Ex-smoker or l-19iday > 20:day Population of wves No of deaths from lung cancer Occupation-standardized mortality/1OO,CKKl Population of wwes No. of deaths from lung cancer Occupation-standardi~d mortalityilWXKl 14,020 30.676 20.584 11 40 36 5 64 9 34 13.14 7,875 13.508 4,877 21 46 20 15 79 24 44 29 60 Standardized risk ratio far all ages 1.00 1.61 2.08 Population of wives No. of deaths from lung cancer .Age-standardized mortality/100,O(Xl 10,406 20.044 9,391 17 52 24 9.54 17.02 16.40 Population of wives No of deaths from lung cancer Age-standardized mortal~ty/1OO.OCG 11,489 24.140 16.070 15 34 32 9.13 10.46 17 78 Standardized risk ratlo for all occupations 1.00 1 43 1.90 among nonsmoking wives of smoking husbands was markedly lower than that observed for women who actively smoked (Figure 2). The observed differences between wives of smokers and wives of nonsmokers were evident for each of the four socioeconomic status classes. Hirayama's article has stimulated much discussion, which has been published as Letters to the Editor of the British Medical Journal (5, 13, 25a, 27, 27a, 30, 36, 40, 42~). In three replies to the same journal (20, 21,21a), the reader is referred to the specific issues raised and responded to in these letters. 247 TABLE 5.-Age-occupation standardized risk ratio for selected causes of death in women by smoking habit of the husband (patient herself a nonsmoker) Cause of death - Husband's smoking habit Nonsmoker Ex-smoker, 2 20/dsy p value or I-19/day * Lung cancer (n = 1741 Emphysema, asthma in-66) Cancer of cervix cn = 2501 Stomach cancer ln=716) Ischaemic heart disease ln =406) YkJlineartrendl W"RCE H,rnyama G ,.Y, 1.00 1.61 2.08 0.0001 1.00 1.29 1.49 0.474 1.00 1.15 i.14 0.249 1.00 1.02 0.99 0.720 1.00 0.97 1.03 0.393 TABLE 6.430~ often wives with smoking husbands inhale cigarette smoke passively in Japan (calculation based on a study in Aichi Prefecture, Japan) - Length of contact in a day 15 h 4h 15.0 h No. cigarettes FIX- No cigarettes FW No. cigarettes FR- No. cigarettes smoked by quency ta which they quency to which they quency to which they husband/day 1%l were exposed' (961 were exposed' (%I were exposed' 1-19 (average 101 11.8 (0.88 14.2 (2.55) 6.8 (8.821 20-29 (average 251 19.8 (2.21 I 25.4 (5.881 8.6 (22.06) 30-60 (average 451 5.6 (3.971 5.2 (10.59) 2.6 (39.71) `Length alcontact multlplwd by number smoked in an hour(numbersmoked in an hourequalsaverage number ofclyarcttessmoked I" a day divided by total hours awake) SOURCE HirayamatPll Nonetheless, the applicability of such results to the U.S. popula- tion remains to be established. Garfinkel (12) published an analysis of data from the American Cancer Society's prospective study conducted from 1960 through 1972. He reported results on 176,739 nonsmoking women who were then married (a) to men who never smoked, (b) to men who currently smoked less than 20 cigarettes per day, or (c) to men who currently smoked 20 or more cigarettes per day. In an analysis that did not attempt to control for possible confounding variables, the observed to expected lung cancer mortality ratio (expected numbers were derived from the lung cancer rates of women married to nonsmokers by s-year age groups) was 1.27 for women married to smokers of less than 20 cigarettes per day and 1.10 for women married to smokers of 20 or more cigarettes per day. These increases in mortality ratios over those of wives of nonsmokers were reported to be not statistical- 248 o FIGURE 2.-Active and passive smoking and standardised mortality rates for lung cancer: relative risks (RR) with 95 percent confidence intervals- prospective study, 19661979, Japan `Includrh o.xa~,nal smoktv~ and rx smokers SOURC'E Hway;,ma~L',u~ TABLE 7.-Observed versus expected* lung cancer deaths among nonsmoking women with cigarette- smoking husbands, ACS study, 1966-1972** Husband Husband Husband smoked 20 smoked 120 Parameter did not cigarettes cigarettes smoke per day per day - Observed deaths 65 39 49 Expected deaths 65.00 311.67 44.67 Mortality ratio 1.00 1.27 1 10 ly significant (p value not specified) (Table `7), and no dose-response effect was evident. The same three groups of nonsmoking women were compared in another analysis. In an attempt to eliminate possible confounding 249 TABLE K-Matched group study: Adjusted lung cancer deaths among women -with nonsmoking husbands matched* with women with smoking husbands GTWp Nonsmoking husband Husband smoked 20 cigarettes/day Number of adjusted lung cancer deaths 25.6 35.0 Ratio p" 1.00 1.37 NS Nonsmokmg husband 34.5 1.00 Husband smoked 120 cigarettes/day 35.8 1.04 NS variables, pairs of women were matched on multiple factors. The number of deaths in each matched diad was "adjusted" as described in a prior publication (15). The results of this analysis are shown in Table 8. Neither group of nonsmoking wives of smokers showed a statistically significant difference (p > 0.05); there is no dose-response pattern apparent. The actual size and composition of the matched study population, however, were not shown. The author concluded that any effect passive smoking had on lung cancer mortality would be small. The author presented the limitations of this analysis. The study was not designed to examine the question of effects of passive smoking and, therefore, there were difficulties with the accurate assessment of exposure. The appropriateness of this analysis of the ACS data has been questioned (16) for this reason. The difficulties include the measurement of involuntary exposure t.o smoke from persons other than the husband, and an inability to adjust for changes in husband's smoking subsequent to actual interview or for exposure(s) from previous husbands. A study should be specifically designed to measure exposure, as neither the Japanese (19) nor the ACS study met that criterion. Additionally, among 564 cases of lung cancer in nonsmoking women, the husband's smoking status was available for-only 153 (27 percent). Thus, each of the three epidemiologic studies published to date shows an increased risk of lung cancer with involuntary smoke exposure (Table 9). The results.were statistically significant in two of the three studies, which also found a dose-response effect. The evidence currently available suggests that involuntary smoke expo- sure may increase the risk of lung cancer in nonsmokers, but 250