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A PPt-AJ ~ j X PASSIVE SMOKING MORTALITY A REVIEW AND PRELIMINARY RISK ASSESSMENT A. Judson Wells, Ph.D. Presented at the 79th Annual Meeting Air Pollution Control Association Minneapolis, Minnesota June 24, 1986 Includes minor updatino through September 16,1986

86-80.6 INTRODUCTION In 1981 when Hirayamal and Trichopoulas, et al.2, first published their studies associating passive smoking with lung cancer, and in the years immediately following, there was considerable controversy and skepticism that such an effect could indeed be real. However, as more papers appeared and many of the earlier issues were resolved, there now appears to be a growing concensus among epidemiologists that passive smoking does indeed cause lung cancer, or at least that there is a strong association. 't.awrence Garfinkel, who was one of the most quoted early skeptics, and his coworkers have recently published a paper3 In which they find a statistically significant doubling of lung cancer risks for women married to smokers of 40 or more cigarettes per day compared to women married to nonsmokers. A dose response relationship was confirmed. Also there is now little disagreement that the number of U.S. deaths from lung cancer associated with passive smoking probab l y l i es w i th i n the 500 to 5000 range suggested by Repace and Lowrey's risk assessment4. In 1983 papers started to appear associating passive smoking with deaths from other cancers, chronic bronchitis, emphysema and heart disease. These papers, like the earlier lung cancer papers, have attracted debate, but more recent papers support rather than refute the earlier ones, indicating that a consensus eventually may be reached in this broader area as well. I t i s the purpose of th i s paper to present a summary of the epidemiological literature on passive smoking for four major disease categories, namely, lung cancer, other cancer, emphysema, and heart disease, to discuss differences in disease patterns observed between direct and passive smoking and the probable reasons therefor, and to assess at least in a preliminary way the significance of these findings on expected deaths from passive smoking If the underlying epidemiological results turn out to be correct. Because of the many specialties involved in such a calculation, namely, epidemiology, statistics, population estifiates of passive smokers, aerosol deposition theory, lung structure, chemistry and carcinogenesis, it is not possible In a paper of this scope to give a detailed and sophisticated explanation of each step. Nonetheless, the estimates made Lre believed to be the most probable numbers considering the data now available although it must be realized that the confidence limits are still broad because of the uncertainties that exist at every step. The objective here is to determine the probable future extent of the public health risk from passive smoking if the trend in the epidemiological results continues along the lines it has taken since 1981. METH00§ The epidemiological literature was searched primarily through the 2

86-80.6 publications of the U.S. Government's Office of Smoking and Health5,6 which also provided a printout of all of its documents on passive smoking from 1970 through 1982. In addition many references were received directly from workers In the field. The scope of the Inquiry included all papers that contained original data on adult, nonsmoker mortality or cancer morbidity from passive smoking. All of these papers are iisted'in the subsequent tables or text. From these papers those pertaining to lung cancer, other cancer, emphysema and heart diseRse were selected for analysis and calculation of death rates. " Because some of the papers have rather glaring weaknesses, four criteria were used to admit data to the death rate calculations: 1. Retrospective studies should have controls. 2. Observations should be based on exposure beyond five years. 3. A study should not have serious Internal inconsistencies. 4. Sufficient data should be presented to allow the calculation of a variance. For the eleven studies that met these criteria a relative risk for each disease and sex was estimated (to the extent data were available) by averaging over all exposures Including exposure to ex-smokers, light, medium and heavy smokers. Combined relative risks for each disease category were calculated by a meta- analysis technique which weights the individual relative risks by the Inverse of the variances7. No other. weighting of the accepted studies was attempted. Some of the cancer papers reported morbidity relative risks rather than mortality relative risks. However, an estimate based on published data8 indicates that five year survival rates for both exposed and unexposed cases are similar. Therefore, the incidence ratios were used as good approximations to the mortality ratios. The method used to calculate possible deaths from the combined relative risks in the preliminary risk assessment Is described under that heading. RESULTS Epidemioloav There are eighteen studies now available that bear on adult mortality or cancer morbidity from passive smoking. Luna Cancer - Female. Table Ia lists the papers on female lung cancer. Shown Is the lead author on the paper, the locale of the study, the number of cases, the relative risk for the highest exposure (in most cases 20 or more cigarettes per day smoked by a spouse) and the two-tail p-value for that exposure, a relative risk for all exposures combined, including exposure to ex-smokers if those data are available, and a two-tail p-value for that exposure. A one-tail p-value for a Mantel extension test for trend is shown if available. 3

J TABLE i a RELATIVE RISKS: LUNG CANCER FROM PASSIVE SMOKING Exposed Highest Exposure All Exposures Mantel'Trend F l Locale Cases R/R 2-Tail p R/R 95% C.L. 1-Tail p ema es Cohort Studies: Hirayama20 Japan 163 1.9 0.002 1.6 1.1- 2.2 0.002 Garfinkelll U. S. 88 1.1 - 1.2 0. 8- 1.6 - Gillis, et al.13 Scotland 6 - - 1.1 0.2-5.6 - Combined Cohort 257 1.34 1.1-1.7 Case Control: Trichopculos, et al10Greece 53 2.6 0.19 2.1 1.2 - 3.6 0.005 Correa, et a1.12 Louisiana 14 3.5 0.017 2.1 0.8 - 5.2 ~ 14 Koo et a1 Hon Kon 64 - - 1.3 0.7-2.3 - w . , Sandler, et a1.15 g g N. Carolina 2 - - inf. Garfinkel, et al.3 U. S. 73 2.0 0.05 1.3 0.8-1.9 0.025 Combined C/C 206 1.54 1. 2- 2.0 Combined Cohort & C/C 463 1.44 1.2 - 1.7 Males Cohort Studies: Hirayama 20 Japan ~ 2.3 0.16 2.2 1.1- 4.8 0.023 Gillis, et a1.13 Scotland 33 07-164 . Combined Cohort 11 2.5 1.2 - 5.2 Case Control: Correa, et al. 12 Louisiana 2 - - 2.0 0.4-10.0 Combined Cohort & C/C 13 2.5 1.3 - 4.7 Ej0LStZ6

TABLE Ib RELATIVE RISKS: LUNG CANCER FROM PASSIVE SMOKING Highest d Exposure E All Exposures Mantel Trend Locale xpose Cases R/R 2-Tail p R/R 95% C.L. 1-Tail p Rejected Studies Case Control: Knoth, et a1.16 W. Germany 24 - - 2.5 1.0- 6.4 (no controls) Chan, et a1.17 Hong Kong 34 - - 0.8 0.4 - 1.3 ~ (current exp. only) Kabat and Wynderl8 Cr Females U.S. 33 - - 0.5 0.2 - 1.2 Males U.S. 20 - - 3.7 1.1-12.7 (current exp. only) Wu, et a1.19 California ? - - 1.2 ? (insufficient data) Data from Dr. Kabat re Kabat and Wynder18 Females Males Exposure Cases Controls Cases Controls Never 20 13 5 12 Work only 17 23 14 10 Home only 7 9 2 2 Work & home 9 8 4 1 Total Exposed n + 2U 13 ViaZscZb

86-80.6 There are eight studies that pass the aforementioned criteria. •Trichopoulos, et al. 10, have a numerical error In the calculation of relative risks. The values for 1-20 and 21+ cigarettes per day should be 1.95 and 2.55 instead of 2.4 and 3.4, respectively. The value in Tabiela-of 2.1 Is a weighted average of exposure to ex-smokers as well as to the two categories of smokers. Koo, et al. 14, report on exposures both at home and at work. The work exposures for nonsmokers average only 2.0 years so these data were rejected for being less than five years. Data for exposures at home and at home plus work are combined here to"*.give the relative risk of 1. 3 shown in Table Ia. The Sandler, et a1.15 , paper was directed largely at total cancer, but they did pick up two lung cancer cases among nonsmokers. These were determined to be female per private communication from Dr. Sandier. Four of the eight lung cancer studies (Trichopoulos, et al.10_, Correa, et al. 12, Koo, et al. 14, and Sandier, et al.15 ) are dise se Incidence studies; Hirayama4, Garfinkelll and Gillis, at al.~3, are mortal ity studies. Garfinkel, et ai.3 , is mixed. Since there is no reason to believe that the very low survival rate from lung cancer is significantly different for nonexposed and exposed cases, the incidence relative risks were used as mortality relative risks. There are four studies that do not pass the criteria, namely, Knoth et al.16, which is a case study with no controls, Chan, et a l. 1~, and Kabat and Mlynder 1g wh i ch are for current exposure only, and Wu, et al. 19, which does not report the number of cases and hence does not ai low the calculation of a variance. The relative risks and significance data for Knoth, Chan and Kabat and Wynder were calculated from data In the papers and from data In a private communication from Dr. Kabat. L uno Cancer - Ma l e. As shown i n Tab l e Ia there are three acceptable passive smoking studies of nonsmoking males with lung cancer. The total of exposed cases is small but the data are consistent. Combined relative risk is 2.5 and p=0.009. Inclusion of the three rejected female studies for which variances can be calculated and the one rejected male study would raise the combined male relative risk for lung cancer to about 2.7 and would lower the female relative risk to about 1.42. These changes would change the overall death date for lung cancer from passive smoking only slightly and In an upward direction. Other Cancer - Female. There are now four studies relating passive smoking to cancer other than lung or to total cancer In females (see Table IIa). This relatively new area is more important in terms of potential number of deaths from passive smoking than is lung cancer because the relative risks are In the same range while the underlying death rates for non-smokers are many times higher. The relative risk shown for Hirayama in 5

TABLE IIa RELATIVE RISKS: CANCER OTHER THAN LUNG FROM PASSIVE SMOKING Highest Exposed Exposure All Exposures Mantel Trend l Locale Cases R/R 2-Tail p R/R 95% C.L. 1-Tail p Fema es Cohort Studies: Hirayama 9 Japan 1879 1.11 0.055 1.08 1.0 - 1.2 0.05 Gillis, et al.13 Scotland 33 - - 1.2 0.6-2.5 - Combined Cohort 1912 1.1 1.0 - 1.2 Case Control: Miller 21 Penna. 66 1.9 1.1 - 3.4 et al.15 Sandler N. Carolina 113 2.0 1.3 - 3.0 rn 0 , Combined C/C 179 2.0 1.4-2.7 Combined Cohort & C/C 2091 1.56 1.3 - 1.9 Males Gillis, et a1.13 Scotland 2 0.6 0.1 - 2.7 Sandler, et a1.15 N. Carolina 5 1.5 0.4-5.7 Combined Cohort & C/C 7 0.9 9t0LSL46

TABLE IIb RELATIVE RISKS FROM PASSIVE SMOKING ISCHEMIC HEART DISEASE, EMPHYSEMA AND CHRONIC BRONCHITIS Highest osed Exposure Ex All Exposures Mantel Trend p Locale Cases R/R 2-Tail p R/R 95% C.L. 1-Tail p Heart Dis. - Female Cohort Studies: Hirayama9 Japan 240 1.3 0.038 1.16 0.9 - 1.4 0.02 Gillis, et a1.13 Scotland 19 - - 3.6 0.9-13.8 Garland, et al.22 California 17 - - 3.5 0.9-13.6 rn Combined 276 1.27 1.0 - 1.6 Heart Dis. - Male Cohort Studies: Gillis, et al.13 Scotland 14 - - 1.3 0.7 - 2.6 Svendsen, et al.23 U.S. (MRFIT) 5 - - 2.1 0.7 - 6.2 Emphysema and Chr. Bronc it s - Female Cohort Study: Hirayama9 Japan 102 1.6 0.08 1.4 0.9 - 2.1 0.05 LTOLSLZ6

86-80.6 Table IIa of 1.08 is obtained by combinfng his values for higher and lower exposures. The Mtller'1 result is for total cancer. bur interest here is in a relative risk for cancer other than lung, not total cancer. However, according to the calculation described later, less than 3% of Miller's total cancer cases should be lung cancer, and the relative risks for lung and total cancer are similar. Therefore, his total cancer relative risk Is a good approximation to the relative risk for cancer other than lung. The paper by Sandier, et al.t5 , is also directed at total cancer. Here the number of lung cancer cases is known to be two. Therefore, again the total cancer relative risk 14 a good approximation to other cancer relative risk. Other Cancer - Male. The data for cancer other than lung for males (See Table IIa) are much scarcer 13hrn for females. The results from the two available papers • are conflicting, neither result Is statistically significant nor is the combined relative risk. Therefore. a value of 1.0, indicating no association, Is assumed for the death rate caiculations until more data become available. Heart Disease - Female. There are now three papers associating passive smoking with heart disease among females (see Table IIl). Htrayama's paper9 contains data for ischemic heart disease in women by smoking habit of the husbands for two levels of exposure. The relative risk for all exposures of 1.16 Is a weighted average of the two exposure levels. Gillis, et al. 13, report data for myocardial Infarction (M1-410) and for other ischemic heart disease (1H0-411-414). These have been combined to yield the ischemic heart disease relative risk of 3.6 shown In Table IIb. Garland, et al. 22, report data for nonsmoking women who were married either to nonsmokers, ex-smokers, or current smokers. The overal t relative risk of 3.5 In Table IIb is ca l cu l ated from a we i ghted average of thei r age adjusted mortality rates for exposure to ex-smokers and smokers. Heart Disease - Male. There are two papers associating passive smoking with heart disease In males. One, shown In Table IIb is Gillis, et al. 13 Their relative risk of 1.3, although not statistically significant, is reinforced by Svendsen, et a1.23 , who found a relative risk of 2.12 (p=0.19) for the MRFIT cohort of relatively high risk individuals. Since the two papers concur and there are no negative or neutral results, the Gillis, et ai. result, 1.3, Is used as the passive smoking relative risk for male Ischemic heart disease In the general population until better data become available. ' Emphvsema and Chronic Bronchitis. Hlrayama9 has the only data on these diseases, and they are for females only. As shown in TableIIb,a relative risk of 1.4 is obtained by combining his results for high and low exposures. 7

86-80.6 Specific Cancer Sites Other than lun9. Table III shows results on passive smoking risks for specific cancer sites other than lung. It Is interesting that the sites other than lung that are normally associated with direct smoking are absent, with the possible exception of cervix. The data on breast cancer are very preliminary. Hirayama 20 reported that risk elevation for all cancer sites becomes non-significant when lung, nasal sinus, brain and breast are excluded. The Sandier, at ai. 15, relative risk is of borderline tatistical significance. It is interesting that Hirayama 2~ found stomach cancer, with 635 cases, to be specifically not associated with passive smoking. Table III. Epidemioloaical studies on aassive Specific cancer sites other than lun9. Cancer Site Nasal Sinus Brain Breast: Endocrine Cervix: Stomach Investigators Locale Hirayama 20 Hirayama 20 Japan Japan H i rayama Sand l er, Sandier, 20 et et a l. al. 15 15 Japan N. Carolina N. Carolina Buckley, et al.24 Brown, et al. 25 Sandier, et al.15 Hlrayama 20 England Canada N. Carolina Japan a Some statistical significance claimed by authors. se R1R 23 2.1a 31 4.5a - >1.0 32 2.0 13 4.4a 27 4.fia 30 3.7a 56 2.1a 635 1.0 All Causes of Death. There are five studies that contain data on passive smoking and all causes of death. The relative risks are diluted by a large number of deaths that are not related to passive smoking at all so the results are scattered and lower. The Miller study26 In 1978 is the pioneer study on mortality from passive smoking. He observed a lowering of life expectancy from 78.8 years to 74.7 years for 601 non-smoking wives whose husbands smoked compared with those whose husbands did not smoke. Gillis, et al. 13, observed a relative risk of 1.5 (81 cases, p=0.17) for f ema l es and 1.0 (28 cases ) for ma l es . Gar l and, et a l. 22 , observed a relative risk of 1.05 (57 cases) for females. Svendsen, et al. 23, observed a relative risk of 2.0 (11 cases, p= 0. 0 7) f or ma l es i n the MRF I T cohort. The on l y negat i ve relative risk comes from Vandenbroucke, et al. 27, In Holland (0.8 for females; 207 cases, p=0.12). However, this study Is flawed in that non-exposed non-smokers had a death rate 15% higher than direct smokers so it would not pass criterion number three that a study should not have a serious inconsistency. Having reviewed the mortality literatures on passive smoking, what does it ali mean? First, there is quite a bit of It. Second, taken as a whole there is growing evidence of an association 8

86-80.6 between passive smoking and fatal disease. The lung cancer data are particularly persuasive, and there are preiiminary data that indicate an association with total cancer, ischemic heart disease and emphysema and chronic bronchitis. Third, the cancer patterns in direct smoking and passive smoking appear to be different. Cancer Sites Table IV shows a comparison of cancer sites for direct smoking (from reference 28), and passive smoking (from Table IIF;). It is ev i dent that the entry s i tes are di fferent, there i s a qualitative difference in the location of the lung cancer sites 29,30 , and the sites elsewhere in the body (except for cervix) are different. Possible reasons for these differences are discussed later. One conclusion that can be drawn, however, Is that passive smokers are not a mixture of true non-smokers and a small percentage of misclassified direct smokers. Such a mixture would exhibit the same pattern of excess disease rates as direct smokers except that the Increases in relative risks would be smaller. Table IV. Cancer site aatterns in direct and oassive smokina Direct Smoking • Passive Smoking Buccal Cavity - - Nasal Sinus Pharynx - Larynx - Lung - largely Lung - largely bronchial peripheral Esophagus - Stomach - Urinary Bladder - Kidney - Pancreas - - Breast - Brain - Endocrine glands Cervix Cervix Particle Size Effects Probably the most important difference between mainstream and sidestream smoke Is the difference in effective particle size and its effect on where the smoke particles are deposited. A careful study of the smoke and aerosol deposition literature discloses a number of differences which are summarized in Table V. Direct smokers retain about 82% 31 of the inhaled particulate of wh i ch about 37% i s reta i ned i n the bucca 1 cav i ty and 45% i n the lower respiratory tract. Although particle size measurements made as mainstream smoke is generated indicate a mass median 9

86-80.6 aerodynamic diameter of about 0.5}anz, the particles, in the moist, high concentration conditions of direct smoking, apparently Table V. Deposition patterns in direct and passive smoking. Entry Site Particulate inhaled per day, mg. Effect i ve part i c l e s i ze i nha l ed, ~um. Percent retained in mouth Percent retained In nose Percent retained in bronchus Percent retained In near alveolar region Direct P_assive Mouth 240 a Nose 0.5 to 3.5 b 5 , 0.4 37 '` 0 0 8 20 0 21 0 Percent retained in or near alveoli -A IL Percent retained, total 82 19 Percent exhaled IS 81 Particle size exhaled, pm 0.7 0.4 aBased on 15 mg. per ci arette and 20 cigarettes per day. bBased on 100-700 ,ug/m ~32 and 10 1 iters/min. inhaled for S hrs. agglomerate to a much larger effective particle size. To exhibit deposition behavior such as that cited above the effective particle size would have to be in the 5,um range33. This Increase could be brought about either by direct agglomeration34, by electrical charges generated on the particles 35, by a dense layering effect36, or by some combination of these. Particles of this effective size would deposit heavily in the larger bronchial a i rways 37 , part i cu l ar l y at the b i furcat i ons, and i n the l arger airways of the alveolar region. The exhaled smoke has a particle s i ze of about 0. 7,um 31. On l y about one-f i fth of th i s s i ze wou i d be deposited, being 25% of the 18% exhaled or about 4% of the total Inhaled, and this would come down deep in the alveolar region, in or near the alveoli themselves 33,37. In contrast sidestream smoke is very dilute. It has a mass med i an aerodynami c diameter of about 0.4}im3g and does not agglomerate. This is a very difficult size to trap in the respiratory tract because It is too large to deposit by diffusion and too small to deposit by impaction. Some of the larger particles in the sidestream smoke (about 8% of the amount inhaled) would be deposited in the nose 33. The other 11% that will deposit 38 apparently goes all the way through the bronchial and larger alveolar airways and deposits in or near the alveol i 33,37. The particulate from direct smoking is either deposited in the mouth directly, or in the bronchial region or near alveolar region where it will be cleared into the mouth. It is then swallowed and is either eliminated or absorbed Into the blood stream via the gut. This is believed to result in the cancers shown in Table IV except possibly for cervix. The particulate l0

86-80 . 6 from passive smoking deposits either in the nose, resulting In nasal sinus cancer, or deep in the alveoli from whence it is very difficult to clear into the mouth. It is speculated that most of this particulate is solubilized or metabolized'directiy into the blood or lymph system. It then circulates In these systems and results in the cancers observed. In passive smoking the digestive related cancers are absent. Chemistry and Other Effects Another difference between mainstream and sidestream smoke is the chemistry. Side stream smoke Is formed at a lower temperature than mainstream smoke, and, therefore, a larger fraction of the more complex molecules is preserved. The amounts of tumorigenic agents in sidestream and mainstream smoke have been measured 39. The sidestream/mainstream ratios for such amounts vary from 0.7 for catechol to 39 for 2-naphthylamine. The mean value is 12. Therefore, It would be expected that sidestream smoke particulate, per milligram deposited, would have higher carcinogenic potential than mainstream particulate. Another difference between direct smoking and passive smoking is the difference in disease susceptibility between the direct and passive sfiokers. Deaths attributed to direct smoking constitute about 18% of total deaths. Thus a direct smoker dying of a smoking related disease, while perhaps more sensitive than the average of the total population, would not be substantially more sensitive. Passive smokers dying of passive smoking disease, on the other hand, constitute only a very small percentage of total deaths, in the range of 0.025 to 2.5%. This is a much smaller proportion than in the case of direct smoking; only the very most sensitive individuals would be dying from such an effect, and the expected dose to achieve such a response would be less than that for a direct smoker. One approach to predicting the health effects of passive smoking has been to factor down the health effects of direct smoking by the ratio of inhaled or deposited smoke dose. As can be seen from the data in Table V the dose ratio is quite high, being about 70 to 500 for Inhaled dose and about 300 to 2100 for deposited dose. However, taking into account the differences in particle size effects, chemistry and individual susceptibility, it Is seen that such a simplistic dose/response approach is unlikely to yield results that are accurate even within an order of magnitude. Risk Assessment Just how dangerous might passive smoking be? Table VI provides a summary of the combined relative risks for each sex and disease. Probably the most reliable number In the table is the 1.44 relative risik for female lung cancer, based, as it Is, on eight 11

86-80.6 stud i es i nc l ud i ng those by some of the most promi nent investigators in the field. The least reliable numbers are those for male other cancer, where an arbitrary relative risk of 1.0, denoting no association, was adopted, and for male ischemic heart disease. Clearly more work Is needed in these areas. The relative risk for emphysema and chronic bronchitis also has poor statistical significance, but the underlying death rates for non- smokers from these diseases is so low that only a very few deaths would be involved. , . ~ Table Vi. Combined Risk Ratios from Eeidemlological Studies Disease Cases g /R 2-taii p 951 conf. int. , Female: Lung cancer 463 1.44 <0.001 1.2 - 1.7 Other cancer 2091 1.56 <0.001 1.3 - 1.9 ischemic heart dis. 276 1.27 0.04 1.0 - 1.6 Emphysema & chr. br. 102 1.4 0.18 0.9 - 2.1 li8.L1L= Lung cancer 13 2.5 0.009 1.3 - 4.7 Other cancer 7 1.0 - - Ischemic heart dls. 14 1.3 0.46 0.7 - 2.6 To calculate numbers of deaths per year from the relative risks In Table VI it Is necessary to know the total non-smoking population, the percent exposed to sidestream smoke and the death rates for non-smokers by disease category. The non-smoker population was estimated from the national health statistics. The percent of non-smokers exposed to spouse's smoke was estimated from the controls in the U.S. studies In Tables I and 11. Other exposure was estimated using data developed by Friedman, et a1.40 Non-smoker death rates for each sex and disease were obtained from Hammond ¢t. By combining these inputs it was possible to calculate excess death rates due to passive smoking, again by sex and disease. Applying these death rates to the non-smoking population passively exposed, the desired number of deaths per year in the U.S. was obtained. Details of this calculation are In a manuscript that has been submitted for publication elsewhere. By this procedure deaths from passive smoking for lung cancer for ma l es p l us fema l es came to 1800 per year, we 1 l centered i n the range of 500 to 5000 obtained in a previous study . For other cancer and heart disease the relative risks are in the same range as lung cancer (Table VI), but the underlying non-smoker death rates are much higher. Therefore, the estimated deaths are much higher. The total deaths came to 47,000 per year of which 22,000 were from cancer (Including the 1800 lung cancer deaths) and 25,000 were from heart disease. This assumes no excess deaths from male cancer other than lung but does include deaths from male ischemic heart disease at a relative risk of 1.3. This 12

86-80.6 value, as noted eariler, Is supported by Svendsen, et a123, and •is very close to the female relative risk of 1.27. Even If these male deaths are excluded, the total passive smoking deaths would still calculate out to 32,000 per year. CONCLUSIONS The epidemiological literature on mortality from passive smoking is growing. An association between passive smoking and lung cancer Is becoming increasingly evident, and th_ere are beginnings, at least, of evidence that other cancers and heart disease are also Involved. If these trends continue, lung cancer will become only the tip of the Iceberg with deaths from these latter diseases amounting to ten to twenty times those from lung cancer. Tobacco smoke is known to be carcinogenic and to produce heart disease. Millions of non-smokers, estimated in this study at 32 mlliion, are exposed. What we have, in other words, are the slowly emerging shapes and dimensions of a major public health problem. Furthermore it is an indoor problem. That means that it is a home-oriented and workplace problem because that is where the average passive smoker spends most of his or her time. There may not be much that can be done about the home setting, but officials and managers who are responsible for worksites need to become aware of this increasingiy acknowledged threat to the safety of Indoor air and the workers who are exposed to it. Also this is not a traditional workplace air pollutant that emanates from some facet of the work Itself and on the factory floor. Rather it occurs in offices, smoke break rooms, washrooms and other places that have always been considered safe; and the po l l utant ar i ses not from the work i tsel f but from the other workers. The first action required is to protect the non-smokers from the smokers. The next thing to consider is a smoke-free workplace. ACKNOWLEOGEMENTS The author wishes to acknowledge maJor assistance from Graham A. Co l d'i t z, M. D., who d i d the stat i st i ca l meta-ana l ys i s, and very helpful suggestions from William J. Blot, Ph.D., Kenneth P. Cantor, Ph.D., Norman H. Edelman, M.D., Edwin B. Fisher, Ph.D., F. Charles Hiller, M.D., James L. Repace, Ph.D., Jonathan M. Samet, M.D., Dale P. Sandier, Ph.D., and Frank E. Speizer, M.D. This work was supported In part by the American Lung Association. The opinions expressed are those of the author. No official endorsement by the American Lung Association should be inferred. 13

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