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(3) En r.onmrnrlmrrnmronu!. Vol W pp _49-265. 198t; Prunted'm the U.'SA. All nghts reserved. AN ESTIMATE OF ADULT MORTALITY IN THE UNITED STATES FROM PASSIVE SMOKING A. JUdson Wells 102 Kdoonan~Glen: Wilmington Delaware 19807. USA (Rrcrrvrd 9 December 1987; Aectpred 7 hPo• 1988) (I1tXr41211 IiR Si.fMl , ,tNl Copyrtght c I90 Pergamon Press plc r+OTIeE This matanial may, be prstacted by ca1700't ttw (ritle 1711.5. Code3. The purpose of this paper is to estimate the number of adult deaths per year in the United States from passive smoking. The epidemiological hteratureon passive smoking and adult mortality and'nncer and heart morbidtt%, is reviewed. Combined relative risks for lung cancer. cancers other than, lung. and heart disease are calculated for each sex and disease categon. These data along with estimates of nonsmoker dcath rates and populations exposed allow calculation of annual deaths in each wtegory. Red'ueed relative nsk and reduced exposure at older ages are taken into aceount as well as a correction for possible mtsclassihcauon of smokers as nonsmokers and exposed'nonsmokers as nonexposed Al- together 415.000 deaths per year are calculated consisting of fung cancer (30(M1) other cancer (11.000) and'hean disease (32A00). Reasons why such high estimates for other cancer and heart disease may be possible are explored. It is rnncluded'that exposure to environmental tobacco smoke can have adverse long term health effects that are more senous than previously thought. Introduction Several attempts have been made to estimate U.S. adult mortality from passive smoking. For example, Repace and Lowrey (1985)'estimated the lung cancer deaths to be about 5000~ per year. Fong (1982) estimated total mortality at 10.000 to 50,000. Russell ernl. (1986) es- timated total U.S. mortality at more than 4000. The present estimate is based on epidemiological evidence currently available on lung cancer, cancers other than lung. and heart disease. The Surgeon General of the United States (USSG. 1986) and the UIS. National Academy of Sciences (NRC. 1986) have issued reports stating that passive smoking can cause lung cancer. In the National Acad- emy report the relative risks from the various lung can- cer studies were combined into an overall relative risk using a proced'ure somewhat similar to that which is used in this work. The Academy report then projects that about 20% of the 12,000 U.S. lung cancer deaths per year among never smokers is due to passive smok- ing. This is reasonably close to the 3000 per year pro- jected here for never smokers plus exsmokers. The methods used in the National Academy report are fur- ther detailed ini Wald etal: (1986). Blot and Fraumeni (1986) have also presented an overview of studies of lung cancer and passive smoking. They use a method of combining the relative risks from variousstudies es- sentially identical to that used here. Thus, the proce- dure of, combining relative risks from various passive smoking studies to obtain overall relative risks and tighter confidence intervals is now welli established by authorities in the field. Also, the method used here to calculate annual deaths from the relative risks appears to be validated by the National Academy results for lung cancer. However, both the Surgeon General's task force and that of the National Academy felt that the data, as of 1986, on cancers other than lung and on heart disease were still too meager to allow calculation ofireliable overall risks. Since 1985 considerably new epidemiological infor- mation has become available, particularly on heart dis- ease. This new information is reviewed and combined with the old data to calculate updated relative risks. overall confidence limits, and estimated annual U.S. deaths from passive smoking and the three main dis- eases, namely, lung cancer, cancers other than lung. an&ischemic heartidisease. The total particulate matter dose retained by passive smokers is too low to account for the health effects of passive smoking, if one starts with the health effects exhibitedby direct smokers and ratios down from the dose retained by them. Reasons why such a discrepancy might occur are explored. 249

,1 250 Methods Studies to be considered in the analyses were ob- tained originally from the literature searches of the U.S. Office on Smoking and Health (OSH', 1979-85). More recently. studies have come to light primarily through~ personai! contact with workers in the passive smoking field. Criteria for admitting data to the analysis are: 1. Studies on the association of passive smoking with adult mortality or morbidity from lung cancer. other cancer or ischemic heart disease were included. All cause data were not used because essentially no male data are available. The female data, if calculated, yield overall results that are in the same range as the results derived from the three main diseases (see Appendix B)i Emphysema: is not included because the nonsmoker death rate is so low that less than I% of deaths from~ passive smoking would be pre- dicted from this source (see Appendix B). 2. Retrospective studies should have controls. 3. Observations should be base& on spouse exposure or on general exposure of more than 10! years du- rationL The diseases under study are known to have long induction ~ periods, and it is assumed that most married people old enough to die of passive smoking would have been exposed 20 years or more. 4. Enough data should be available from the study to~ allow calculation of a weighting factor~ for combining the relative risks. Two risk models were used' and a third was consid- ered. The primary model used combined relative risks from the various studies that pertaine&to a given sex and'disease and assumed that the combined relative risk was constant with age, although variation with age of the underlying neversmoker deathi rate and'the fraction of the population exposed were included. In the sec- ondarv risk model the combined relative risk was also allowed to vary with age. These models were suggested in part by the considerations in James Robins' Appen- dix D in the National Academy report (NRC. 1986). The third risk model was based on the rate difference between the death rates for exposed and nonexposed populations. A detailed analysis of this model for heart disease in women was carried out (see Appendix C). Itl was concluded that the relative risk models were much superior to the rate difference model when combining data across different cultures as is the case here where some of the studies are from the orient. Wherever a study showed both a crude relative risk or odds ratio and an adjusted ratio, the adjusted ratio was used. To obtain a combined relative risk a method similar to that ofl Blot and Fraumeni (1986) was used. Case control studies were aggregated using Program 2 of Rothman and Boice (1982). Cohort studies were ag- gregated using Program 7. A combined relative risk for A J V.ells the two aggregates was obtained using: "',o In R« - w«, In R« Rr6 = ezp wCo t wrC where R~,. Rro, and R«, are the relative risks for the combined totall the cohort studies, an6the case control studies, respectively, and wro and wK are the weights for the cohort an& case control studies. respectively. which are the inverse of the respective variances. Vari- ance is taken as the square of the standard' deviation which is equal to InA/x, so the weight. w=(X/ln R)=. The source of, these equations is Rothman ( 1986) Con- fidence intervals were calculated fromia combine& X = w"=1n R, For some studies it was necessary to calculate a chil from the confidence limits in order to calculate a weight since no other data were available. These data were then combined with the rest using Eq,. (1). Aees of' death from 35 and up were used and should include essentially all adult deaths from passive smokinQ. In some studies morbidity relative risks were reported whereas our interest is in mortalitv. The morbidity rek ative risks were accepted as surrogates for: mortalitv relative risks because, for cancer. the survivalirates for, exposed and nonexposed cases appeared to be similar, while, for heart disease, incidence relative risks, if anv• thing, are lower than mortality relative risks (Svendsen et al.. 1987). The 1985 smoking status for U.S. residents in 5 vear age increments was obtained from the National Center for Health Statistics. Nonsmokers were equated to never smokers plus exsmokers. The fractions of never smokers living with ever smokers (24~'r for males an& 60% for~ females), all of whom were considered to be exposed~ were obtained from controls of the U.S. base& studies for all three diseases. These fractions were as- sumed to hold4lso for nonsmokers (never plus ex). The fractions of all nonsmokers exposed as nonsmokers liv- ing with nonsmokers, but still exposed at home or at work (37% for males and 16% for females). were ob- tainedfrom Friedman et al: (1983). These fractions were assumed to hold for nonsmokers living with never smok- ers. By adding the two fractions the total nonsmoker exposure of 61% for males and 76% for females was obtained. These overall exposure fractions are known to be higher at younger ages and lower at older ages. The data of Friedinan et al: (1983) were used to develop smoothe& values of fraction exposed 10 years earlier (midpoint of a 20 year exposure) for each sex and 5 year age interval normalized to 611% for males and 76c'c for females. By multiplying each population element by each fraction exposed element, the exposed popu- lation by sex and 5 year age interval could be deten- mined. Death rates for never smokers for lung cancer by sex and 5~year intervals were drawnifrom Garfinkel (1981)

i Adult mortality trom passi%c smoking an& smoothed using a semi-log plot against age. For cancers other than lung for females a semi-log plot of 1984 age specific death rates for ages 35+ was devel- oped for malignant neoplasms less malignant respira- tory neoplasms from the data of the National Center for Health Statistics (1986) Then. a parallel plot was developed using as reference points the neversmoker data of Hammond~ (1966) for ages 45-64 and 65-79 to yield neversmoker rates for a¢es 35 + for each 5 year age interval'. For heart disease never smoker death rates by sex and 5 year age intervals for 1963 were developed from the appendix tables in Hammond (1966). These were reduced to 1984 equivalent rates (with the reduc- tiom factors corrected for the effects of smoking) by a technique similar to that used by the U.S. Office of Technology Assessment (OTA. 1985). Semi-log graphs were used to estimate never smoker death rates by 5 year age intervals for the entire age range (see Appen- dix A. Table A3). The excess death rate for never smokers for passive smoking (Dp,) for each sex. disease and 5 year age range was calculated from the never smoker death rates (D.) using the formula: D: . = Dti,(R - 1)l(F,,(R - 1)+ 1): (2)1 where FD is the fraction of the population that is ezpose& and R is the combined relative risk. This excess death~ rate was assumed to apply to all nonsmokers. Deaths were then calculated bymultiplying the passive smoking excess death~ rate by the exposed population for each sex and 5 year age interval, and summed. For those calculations where the relative risk was assumed to have varied with age. the excess death rates for passive smok- ing were recalculated from the age specific relative risks for each 5 year age interval. Additional calculations were carried out to show the effects of bias including those from misclassification of smokers as nonsmokers and exposed nonsmokers as unexposed. using a method similar to that of Wald~er al. (1986) L Results Relarrve risks The results for passive smoking relative risk for fe- males for lung cancer are shown in Table 1. The three cohort studies are listed first an6show a combined rel- ative risk for all exposures including exposures to exsmokers of 1.34. At the time the analysis was made there were fourteen acceptabie case control studies with a combined relative risk of 1.50. The overall combined relative risk, based on 1,174 cases, is 1.44 with 95% confidence limits of 1.3-I.7. The male lung cancer ob- served relative risks are shown in Table 2. There are now nine studies with 144 total cases. The overall com- bined relative risk is 2.1 with~95% confidence limits of =51 1.3-3.2. Data excluded from Tables I an&2 along with~ the reasons were the following: Chan er al. (1979). cur- rent exposure onfy; Knoth et al. (1983). no controls; Kabat and Wynder (1984)' nonspouse data. current ex- posure only; Buffler er al: (1984)~ 0-32 year data. not a: minimumi of 10'vears exposure. A paper ba Dalager et al. (1986) d'escribes a pooling of' data from Correa er al. (1983), Buffler er al: (1984) and a stud~ of males in New Jersey. They observed an adjusted odds ratio for spouse exposure of 1.47, but since Correa er al: (11983). and Buffler, er a!. (1984). were already included iniTa- bles 1 and 2 and' since the New Jersev data were not available separately, it was decided to omit the Dalager er al. (1986) study from this analysis. AI'so. available were abstracts of two recent papers. Gene er al. (1987) from China with a relative risk of 2.2 and Inoue and Hirayama (1987) from Japan with a relative risk of =.3.. both for females. Also NV K. Lam (1985)~ in a thesis from the University of Hong Kong that is quoted in Lam et al. (1987) found a relative risk of 2.0 for ad- enocarcinoma among females. These inputs arrived too late to be included in the analysis. The data ofHlravama (1984a) on femalp lung cancer are sufficiently detailed to indicate a declining relative risk with age from 1.87 at approximately age 501to 1.433 at approximately age 75. These data were used'to de- velop a second death caltulation assuming a declining relative risk. but still! normalized to 1.44. However, Hirayama's data show no such decline in passive smok- ing relative risk with age for, males. Instead, the trend appears to rise with age. so no secondary calculation was made. There are now five studies relating passive smoking to total cancer or cancer, other than lune in females. The individual and combined relative risks for females are shown in Tablt 3. The total combined relative risk is 1.16. The total cases. 2.933, are two and one-half times the total cases for female lung cancer (Table 1) although 2.505 are concentrated in the large Hirayama (1984a) study. This is a large data base. The total com- bined chi square is 11 compared to 27 for female lung cancer. The two largest of the female studies. Hirayama (1984a) and Sandier et a!. (1985): cover different age of death ranges. Hirayama covers 50 to 80 t while Sandler er al: cover <30 to 59. The two studies taken together would indicate a rather sharp decline in rela- tive risk with age fromiabout 3.5 at age 40 to about 1.04' at age 80: The high relative risks at the younger ages may be due to premenopausal breast cancer (see San- dler er al., 1986). Two calculations of Ui.S. female deaths from passive smoking and other cancers were made, one using the 1.16 relative risk from Table 3 at all ages and one using the declining rela;ive risks. Gillis et al, (1984). Sandler era1. (1985). and Rey- nolds (private communication) also report on other can

252 Table 1. Female relative risks for, lung cancer from, passive smoking: A. l i We I I s Hichest All Msntel! Exposure Exposures Trend~ T l Locale ota Cases RR 2-tail p RR 95 c7c C.L. I-tail p Cohort Studiesr Hlrayama (1984a) Japan 200 1.9 0.002 1.6 1.1-2.2 0.002 Garfinkel (1981) , l.'nited~States 153 1.2 0.8-11.6 - Gillls er a1. (1984) Scotland 8 - - 1.1 0;.-5.6 Combined Cohort 361 1.34 1.1-1.7 Case Control Studies: Trichopoulos et a!: (1983) Greece 77 2.6 0.19 2.1 1.2-3.6 0.ot15, Cortea enal. (1983) Louisiana 22' 3.5 0.02 2.1 0.8-5.2 Buffler er a!. (1984)'. Texas 27' - - 0.9 0.4-2.3 Kabat and Wynder (1984) United States 24 0.8 0.3-2.5 Sandier er a6 (1985) Nbrth Carolina 2 - - inf - Garfinkel et a1. (1995) United States 11& 2.0 0.05 1.3 0.8-1.9 UA25 Wu eral. (1985'). California 28" - - 1.2 0.5-3'.3 Lee et at: (1986) lJntted Kinedom 32 - - 1.0 0.4-17, Akiba et a!: (1986) Japan 94 ::l - 1.5 0.9-_:6 T06 Koo et al. (1987) Hbng Kong 86 1.2 - 1.6 0.9-3:1 Pershagen et al. (1987) Sweden 67. 3,2 - 1.2 0.7-2.1 012 Humble er a!: (1987). 1New Mexico 20 1.2 - 2.3 09-6:6 Btownson~eraP (1987) Colorado 19 - - 1.7 0 4-3A. Lam et al.' (1987) Hong Kong 199 - - 1.65 1.2-'_-4 Combined Case Control 813 1.50 1.3-1.8 Combined Cohort and C/C 117.3 1.44 11'6-1.66 ' Private communication. "From Blot and Fraumeni (1986). cer in males. The relative risks were 0.6, 1.5 and near unity., respectively. The number of cases.in each study is very small~withino statistical significance. Therefore, it was decided to use a neutral relative risk of 1.0 for males for cancer other than lung until more data become available. There are now six studies of passive smoking and heart disease in females. The individual and combined relative risks are shown in Table 4. Studies new, since 1985 are Lee etal: (,1986), Martin era1:,(,1986a).and the important, large Helsing et al. (1988)paper from Mary- land. The overallicombinedrelative risk based~on 1.622 cases is 1.23 with 95% confidence limits of 1.11 to 1.36 and a combined chi square of 16. Helsin&er al. (1988) and Martin et al: (1986a) provide data for younger women and indicate high relative risks (average 2.45) Table 2. Male relative risks for.lung cancer from passive smoking. Highest Alli Mantel Exposure Exposures Trend Locale Total Eases RR 2-tail p RR 95 % C.L. 1-tad p Cohort. Studies Hirayama (1984a) Japan 64 2:3 0.16 2.25 1.11- 4.9 0.021 Gillis et al.. (1984) Scotland 6 - - 3.3 0.7 -16.5 Combined Cohort 70 2.5 1.2 - 5.0 Case Control ~ Studies: , Correa n ar. (;1983)'! Louisiana 8 - - 2.0 0.4I -10 - ~ Buffler er al: (1984) , TTexas 8' - - 1!.6 0:3' - 811 - O Kabat and Wynder (1984) United States 12 - - 1.0 0:3 - 3:2' - N Lee er ar. (1986), United Kingdom, 15 - - 11.3 0:4 - 4.6 - Akiba et al. (1986) Japan 19 - - 1.8 ~ 0i5 - 5.6 - Humble et al. (1987)' New Mexico 8' - - 4.2 1.0 -16,8' - ~ Brownson er al. (1987)± Colorado 4 2.7 0.2 -31 Combined Case ControV 74 1.8 1.0 - 3.3 Combined Cohort and'C1C 144 2.1, 1.3 - 3.2 ~ 'Private Communication. ~

Adult mortaltta (romipassi~e smoking =53 T'able3. Femalt relative nsks for cancer other than lung from passive smoktng. Highest, All Mantel Exposure Exposures Trend T l Locale ota Cases RR 2-tail p RR 95 % C.L. I-tail'p Cohort Studies: Hiracama (1984aY Japan 2505 1.16 0.01 1.11 1.0 -1.2 0!05 Gillis el al. (1984) Scotland 43 1.2 0~6 -2:5 Reynolds er'al: (1987) Callfornia 70, 1.7 1.1 -2.7 Combined'Cohort 2618 1.13 1 03-1.?4 Case Control Studies: Miller (1984)= Pennsylvania 84' 1.25 0.7 -:? Sandier et ad: (1985) Nonh Carofina 231 2.0 1.3 - 2.9' Combined Case Control 315 1.7 1', -2 45 Combined Cohort and 2933' 1.16 11.06-1..7 CC I 'Obtained'by subtractin@ data for lung cancer from data for all sites. 'Pro.-ided bv Dr. Revnolds. •A¢e adjusted Mantel+Haenszel values for nonemployed wives. for ages up to abouv5Q. At higher ages there is no trend with an average relative risk of 1!.17 holding out to age 84. For male heart disease and passive smoking there are now four studies (see Table 4). The two new ones are Lee er al. ('1986) and'Helsing et a!: (1988). The resulti of Svendsen er al. (1987) is shown for information, but is not, used in calculating the combined relative risk because it pertains to a high risk group. The combined' relative risk based on 443 cases is 1.31 with 95% con- fidence limits of 1.1 to 1.6 and a combined chi square of, 9.The results are remarkably uniform. As in the female data the relative risk is highi at the younger ages, about 2.9, but declines to a nontrend average ofi 1.28 which extends from age 55 out to the older ages.. Svendsen et al: (1987)! show than there was very little difference between never smoking men married to nonsmokers andIhose married to smokers in the major coronary risk factors such as baseline blood pressure.. total: cholesterol, and LDL cholesterolL Thiswork was reported in more detail in, Martin et al: (1986b). Smalli differences were found in weighr (195 vs. 190 if wivess were smokers) and drinks per week (10 vs. 8 if wives were smokers). On the other hand. Garland etal. (11985) Table 4. Relative risks for heart disease from passive smoking Highest Exposure All Exposures Mantel Trend Localt Total Cases RR 2-tail p RR 95 ri C:L. 1-tail p Females Cohort Studies< Hira}•ama (1984b) Japan 494 1 3 0.038 1.16 0.9- 1.4 0.0: Gdlis er d. (198Y), Scotland 21 - 3:6 U.9-13.8 Garland eraL (1985), California 19 3:5 0.9-13.6 Helsmg eral: (1988) , Maryland 988 1.27 1.24 1'.1- 1.4 0.005. Combined Cohort 1522 1.23 G.1- I.4 1I Case Contro1 Studies: Lee er al: (1986) United Kingdom 77 0:9' 0 7- 1!.3 Martimeral: (1986a) Utah 23 2.6 1.2- 5.7 Combined Case Control 100 1.29 0.8- 2.U Combined'{ohort and CrC 1622 1.23 1.1- 1.4 1 Males Cohort Studies: Gilliseral.(1984)i Scotland 32 1.30 0.7- 2.6 Lee er al.' (1986) United Kingdom 41 L24 0:5- 2.6 Helsing et a!.' (1988) Maryland 370 1_31 1 1- 1.6 Combined Cohort 443 1.31' 1_1- 1.6 Svendseneral: (1987)' United'States 13 2.2 0:7- 6.9 'Based on Cochran chi-square of 9.2. 'MRFIT cohort of high risk individuals. included for information only.

A. J Wells J found that never smoking women married to smokers had slightly lower weight. slightly lower bioodpressure, and slightly higher cholesterol, all nonsignificantlv dif- ferent, versus never smoking women married to never smokers. All of' these authors conclude that the in- creased passive smoking risks they observed cannot be ascribed to differences in the major coronary risk fac- tors between passively exposed and nonexposed never smokers. It is impressive that the relative risks for heart disease from passive smoking rise in an orderly manner from the lowest risk group. Japanesewomen at 11.16. through American worrten at 1.27, and American men at 1.31, to highi risk American men at 2.2. A correction for misclassification was attempted for all, three disease categories. Following Wald et aG. (1986)', and presuming that the passive smoking studies were done somewhat more carefully than the general questionnaire studies thevcite, it was assumed'that 5% of ever smokers were misclassified', as never smokers. Along with Wald et al' (1986) we assumed that the nonexposed nonsmokers were actually exposed to 1/3 the extent of the exposed nonsmokers except that for Greece. Japan, and Hong Kong, where less than 30% of women had ever smoked, the correction for nonex- posed female nonsmokers was omitted. It is believed that older. nonsmoking women in Greece and Japan. and~probably in Hong Kong also, because of their social habits, were exposed to relatively little tobacco smoke beyond that of their husband's. Since most of the mis- classified smokers were found to be light smokers or longstanding exsmokers, reduced relative risks for the misclassified ever smokers were calculated„as noted in Appendix A. The modified passive smoking relative risks are shown in Table 5. The false relative risks due to smoker misclassification are somewhat lower than calculated earlier by Wells (1986) because of the as- sumption of light smokers and long, term exsmokers among those misclassified', following Wald et al. (1986)'„ and the use of a more accurate formula. lnigeneral. the misclassification of smokers has a large negative effect on male relative risk which is more or less offset by the positive effect of exposure of the "nonexposed! "' For females the smoker misclassification effect is small to negligible, burbecause the relative risks are smaller and no correction was made to '"eastern"' data (lapan, Greece, and' Hong Kong)L the positive effects of ex- posure of "nonexposed" are also smaller. Calculation of Deaths The details for the calculation of' female lung cancer deaths from the relative risks. both constant and de- clining, are shown in Table 6 as an example. Similar calculations were made for the other disease and sex categories and are shown in Appendix A. The results of all of the calculations are summarized in~ Table 7. These results are restated per million total population in Table 8. Where the relative risk appears to decline with age and where neversmoker death rates at the younger ages are low, as in female heart~ disease and lung cancer, there is a reduction in mortality calculated' by'using the age specific relative risks. Otherwi'se, the higher exposed population at the younger ages out. weighs the higher death rate at older ages and total mortality is increased. In terms of' total deaths the ef- fects of using age specific relative risks tend to cancel out. The totaL deaths, before adjustment, for misclas- sification. for both males and females are about 19.500 for a totalI for both sexes of about 39.000. The effects of misclassification on total deaths are substantial, raising the total to 53,000. Most of' this increase is in heart disease where the numbers are large and the effects of smoker misclassification, although not necessarily small, are still heavily outweighed by the partial exposure of the "nonexposed." To be conservative a best estimate for passive smok- Table 5. Passive smoking relative risks modified'For misclassification. Lung Cancer Other Cancer Heart Disease Females 1. Combined relative risk. 1.44 l.la 1.23 2. False rttative risk due to projected 5% smoker misclassification. E011 1. t102 1.01 3. Combined relative nsk corrected for smoken eusclassification, (1) + (2): 1.43 1.16 1.22 I I 4. (3) corteaed'for exposure of"'non- ~ exposed" at 113 that of exposed dg' I 1121 1.32 © . Males 1. Combined relative risk. 2'. False relative nsk due to projected 5% . 2.1 1.0' 111 GrJ~ 1~1 I l smoker misclassificanon. 1.3 - 1.19 f 3: Combined relative risk corrected'for smoker misclassification. (1) * (2), 11.6 - 1.17 4. (3) corrected for exposure of "non- exposed" at 1/3 that of exposed. 2 4 - 1.29 ~ ~ ..~ •Assumed value tor lack of better data.

Adult mortaun, from passive smoking 25s. Tablt 6 Annual U. S. female lung cancer deaths from passive smoking, Relative Risk Relative Constant at 1 4-0 Risk Neversmoker No k E d D l A f h R nsmo er xpose ec ining ge o Death Deat ate per 100.000 Population 1000's Fraction Exposed Population 1000's Excess Death Rate Deaths RR Deaths 35-39 1.6 6150 0,94 5781 0.50 29 1.70 39 4U-44 2.4 462? 0;92 425? 0.75 32 11.69 43 45-49 3.6 3836 0:89 3423 1.14' 39 11.68 5_ SO-54 5.3 3856 0;87 3355 1.69 57 1.62 72 55-59 7.8 4161 0!84 3495 2.51 88' 1.56 104 60-64 M0 4192 0.77 3228 3.62' 117 1.J9 126 6_5--69 16.6 4160 0.70~ 2912 5.55 162 1.43 159 70-74 23.5 3447 0.59 2030 8.21 167 1.36 142 75-79 34 3004 0.49 147'_ 12.3 181 1.'_9 1_7 80-84 46 1886 0.29 547 18.0 98 1.IR 43 B5- 52 1'003 0.10 100 21.9 2-1 1.09 4 Totals 13.0 40291 0 76 30595 3.0 992 911 ing deaths might be 46.000. half'wa.• between the 39.000 calculated directly from the relative risks and the 53,000 calculated using the modified relative risks. By disease the total would consist of 3.000 lung cancer. 1'1.000 other cancer. and 32.000 heart disease. For each million of total population the deaths by disease would be 13 for lung cancer, 46 for other cancers, and 134! fon heart disease. These numbers may be useful for populations similar to that of the United States imterms of~ propor- tions of' never smokers. exsmokers, and~ smokers. and in terms of the proportion of'the population tha is less than 35 relative to that over 35. For other populations the permillion numbersare best not used, but the meth- odology can be used. That cancer other than lung and heart disease are legitimate contributors to deaths from passive smoking is supported in Hi'rayama. (1984a.b)) in, his large prospective study. He found significantly elevated risks for all three diseases, and his result, for lun¢ cancer is now believed to be valid, (USSG 1986; NRC, 1986). It'is difficult to:believe that his lung cancer result is valid while the other two are not,., Discussion The cancer sites for passive smoking appear to differ somewhat from those for, direct smoking. Using infor- mationion specific cancer sites from Dri. Hiravama (pri- vate communieation) it appears than cancers common to both types of smoking are lung. liver, cervix, nasal sinus, and leukemia. Some of these cancers are only weakly associated with, direct smoking.. Cancers asso- ciated to some de¢ree with, direct smokine. but absent in passive smoking are buccal cavity. pharynx. larvnx, esophagus, stomach (Hirayama, 1984a),. urinary blad« der (Kabat ec al:, 1986). kidney and pancreas. Cancers related to passive smoking, but absent in direct smoking are brain (Hirayama. 1984a), endocrine glands (Sandler era1., 1985). lvmphoma and breast (:Sandler et al., 1985. 1986( Hirayama. private communication) The first three are significant at the 95% level. The combined breast relative risk of 1.4 ', is significann at on1N 881~%r. Higher relative risks for these four sites might be found for direct smoking if epidemiologists used~ nonpassivel~ Table 7, Summary: IJ.S. annua/'deaths from passive smoking I I Females: 1. Constant combined relative risk. 2. Relative risk declining with,age. 3. (l,) corrected for misclassificauon. Males: 1. Constant combined relative nsk. 2. Relative risk declining with age. 3. (1,) corrected for misclassificatton. Totals for both sexes: 1. Constant combined relative nsk. 2. Relative risk declining with age. 3. (1) corrected for misclassification. Best cvrrent estimate. both sexes (rounded). Lung Other Heart Cancer Cancer Disease Total 992 8599 9769 19359 911 11165 7602 1967R 1232 12-180 14995 28507 1606 0 17335 18931 1606 0 18164 19770 2499 0 2..467' 24966 2598 8509 27103 3R?(Nt 2517 11165 25764, 39-t.SR 3731 12280 37462 53473 30W 71000 32000 46000

256 T!able 8. Summarv: Deaths per million population in U.S. from passive smoking. (based on 239.000.000 U.S. poputt+tion in 1985) . Lune Cancer Other Cancer Hean Disease Total FFemales: 1. Constant combined'relative ruk. J'.15 35.98 40.87 81.00 2. Relative nsk declinin¢ with~atae. 3;81 46,71 31.81 8?.33 3. (1J corrected for, mtsclassdicatton. 5,15 51.38 62.74 1119,27' Males: l. Constant combined relative risk. 6,72 0 7_:=3 79::5 2. Relative nsk declining with age. 6,i2 0 76.00 8'_:7_ 3. (l) corrected for misdassiGcauon. 1046 0 94.00 104.46 Totals for both.sexes: 1. Constant combined relative risk. 10.87 35.98 113:a0 I60':25 2. Reltrtive nsk declining with age. 10.53 .i6.71i 107.81 165 05 3. (1),corrected for misctassificanon. 15.61 51'.38 156:7.3 223.73 Best current esttmate, both sexes (rounded). 13 46 134 193 exposed never smokers as the referrent category rather than all' never smokers as is usually done. Another dif- ference betweenipassive smoking and direct smokinrt is that the ratio of lun¢ cancer deaths to deaths from other cancer for females or from heart disease for both sexes. is much lower in passive smoking than in direct smok- ing. These differences irt, mortality effects are probablyy real and' reflect differences in chemistry' and physics between direct, smoking and passive smoking. Environ- mental tobacco smoke is generated~ in the burning tip of the cigarette at a lower temperature than, direct smoke and therefore contains higher proportions of, complicated organic compounds that; tend to be carcin- ogenic (Brunnemann cr al:, 1978). More imponantly, (see Appendix D)' the mainstream smoke, although~ generated at a particle size of about, 0.7 µm, is very concentrated and appears to agglomerate into larger particles. Deposition rates are hieh, about, 80%. De- position occurs primarily in the mouth or in the larger airways of the lung where the particles are cleared rel- ativeiiy quickly into the mouth. This material is then swallowed.Some of it may be eliminated and produce no health effects at all or it may cause the digestive type cancers observed. Only a portion of mainstream smoke appears to remain as small particles that can penetrate deeply' into the alveolar region. Environ- mental tobacco smoke, on the other hand', is very d'ilute, with~a mass median diameter of about 0.41µm. Particles in this size range have very low deposition rates, on the order of~ 10%, but: what does deposit does so deep im the aNveolar region of the lung where clearance times are longer.. Black and Pritchard (1984) estimate that ci¢arette tar has a 117 hour half-time rate of clearance from the alveolar region, much longer than clearance times frome the ciliated parts of the lung. but much shorter than for inert particles. This means that smoke particles are very likely dissolving in the fluids in the alveolar region, and are being cleared into the blood and lymph systems for circulation throughout the body: In summary, there are two types of smoking: (a)) large particle smoking. or its equivalent, which is the major component of direct smoking. which resuits in massive deposition in the mouth, and larger airways of the lung, rapid clearance, cancers of the mouth. central lung and digestive system. and possibl v heart disease. and (b) small particle smoking. which is a minor com- ponent of direct smoking, but the entirety of passive smoking. and which results in low doses deep in the lung. slow clearance, some lung cancer, but primarily other cancers and' adverse heart effects. These differences in chemistry and physics also ex- plain, at leastin part-the rather high monality observed for passive smoking relative to the deposited dose of particulate. Smoke retention by a passive smoker is only about 1/400 that retained by a direct smoker m a 16 hour day (0.64 mg for the passive smoker per C;SSG (1986, p: 196) and 2-t0 mg for the direct smoker assum- ing twenty 15 mg tar cigarettes and 80cic retention). In comparison, the ratio of lung cancer death rates is about 1/35. For cancers other tham lung in females the ratio is about 1/7, for heani disease in females about 1. 141 and for heart disease in males about 1/3. Preliminarv calculations which are showtn in Appendix D indicate that the smoke retained deep in the alveolar region may have a dose ratio higher than 1/-100, perhaps as high as 1/60: It may be that' carcinogenic matenali that bollu- bilizes and clears from the alveoli into the blood may cause not only some of the cancers other than lung that are observed in passive smoking, but also some of the heart disease from passive as well as direct smoking. The hypothesis of Benditt and: Benditt (1973) that ar- terial'. plaques are caused by, DNA-modifying agents is receiving increasing support. See, for example. the re- cent work of Penn er al: (1986)~ on cell transforming capability of human atherosclerotic plaque DNA and the earlier work of Albert u al. (1977) an& Penn eral: (1981) on the formation of arterial plaques in cockerels with dimethylbenz(',n)anthracene and benzo(a)pvrene. Another possible factor that, might help explain the disparate mortality effects versus dose isthe le%ell of disease susceptability in passive smokers versus direcn

Adult mortality from passive smoking smokers. The median age for passive smoking death from: lung cancer for males is 66 and the deaths con- stitute 0.006rc per year of the exposed populationt The first 0i0069c of male smokers have died of lung cancer~ bv age 46 at which age the lung cancer death rate is doubling evera four years. At~ age 66 the smoker lung cancer death rate is doubling about every 13 years. In other words. in passive smoking deaths we are dealing with only the very most susceptible people, whereas in direct smoking most of the victims are much, nearer average susceptibility. Similar considerations apply to the other diseases here discussed. A qNestion often, raised, is that direcn smokers are also passive smokers. so why do theynot get the passive smoking related cancers. We have already pointedioutt that the use of nonexposed never smokers as the re- ferrent, category for smoker relative risk would increase the apparent risk for smokers. Another possible expla- nation is the probability of competing risks. Most of the highly susceptible direct smokers would have died in their forties or fifties from smoking related disease and would not be available to die of.passive smoking relatedl disease initheir sixties or, seventies. The passive smoking mortality calculated in this study. namely.46:000. mav be lbw: Repace and1owrey (1985) calculate lung cancer deaths from pa$sive smok- ing at, 4.665: or about 50% higher than our estimate.. primarily because of'postulated intense exposure atthe workplace: a factor not taken into account in this study since the relative risks are based largely on home ex- posure. If Repace and Lowrey are eorrect, the higher exposure would lead to corresponding increases in deaths from heart'disease and other cancer. Also, only ischemic heart disease is consid'ered' here. As the all cause data in Appendix B indicate, other cardiovascular diseases and diabetes may be sensitive toanvironmental tobacco smoke and may increase the total deaths. The new epidemiological studies on passive smoking support the earlier ones and indicate that not only lung cancer. but other cancer and heart disease are serious problems. In fact, lung cancer appears to be only the tip of the iceberg. To be on the safe side public health policy should be to protect nonsmokers from environ- mental tobacco smoke. Arknowledgrmenrs - The author is grateful Ito Dr. T. Hiravama for his data on mdi.idual cancerisites and for the detailf of his "all cause" daaa. to R W. Wilson of the U.S. National Center for Health Statistics for, data on the smoking status of U.S. residents bv 5 year age inter- % afs. to L. Garfinkellfor the person years in his 1981 study- to J. M. Samet fon data on male lung cancer in the New Mexico studc: to R. C. 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Adult mortalitv from passive smoking 259 Table A]. Annual U.S. male lung cancer deaths from passive smoking Rtlative Rtsk , Constant at '_.1 Age of Death Neversmoker Death'i Rate per 100.000 ~ Nonsmoker Population 1000's Fraction Exposed Exposed Populatton 1000's Excess Death Rate Deaths 35-39 1.8 ~ 5156 0.71 3815 1.09 42 40~-44, 2.9 ' 4136 0.72 2980 1.78 53' 45-49 4.5 3477 0.70 2440 2.80 68 iI 50-54, 7.01 3431i 0.66 2260 4.46 101 55-59 11 3423 0.63' 2155 7.15 154 60-63 16, 3489 0.59 2054 10.7 219 65-69 23 3150 0.54 1695 15.9 269 70r74 33 2443 0.45 1099 24.3 _'67' 75-79' 49 1712 0.3' 633, 38.3 24_°' 80i84 72 921, . 0.27 249' 61.1 15'' 85 - 95 516 0.08 41 96.0 39 Totals 15.9 31844 0.61 19420 8.26 1606 Appendix A Derails of death calculations Tables Al and A2 show the details of the death calculations for male lung cancer and female cancer other, than lung and are similar in all respects to Table 6 in the text except thart no d'eelining relative risk calculation is shown for male lung cancer since the evidence that was available (Hiravama. 1984a) indicated no suchAecline. In Table A3 the details are given for the development ofi the never smoker relative nsks for heart disease that were use&in the death ~ calculations. As noted in the text. the 1963' neversmoker heaR' death rates by 5-year intervals were ob- tained~bv dividing the never smoker coronary heart deaths in HammondTs (1966) appendix. Table 14, by the person years in his appendix tables 2a and2b. Reduction factors to account for the change in heart death rates between 1963 (end ofHammond7s study) and 1984 were then developed by 10:year age intervals from the age specific heart death rates in table 24 ofiHealth U.S. 1986(NCHS.1986): These reduction factors were modified for the fractions thought to be due to smoking which were taken from~a staff report of the Office of Tech- nology Assessment (OTA. 1985) to yield a combine&never smoker reduction factor. interpolated back to 5-vear age in- tervals. for application to the Hammond never smoker death rates. These modified rates. which are forenrollment age and therefore about 2 vearsyounger than age of death. were then, plotted~ agairut age of death on semi.loe graphipaper. Treli lines were then drawn through the female and the male points to yield the values in the last column of Table A3. Tables A4 and A5 are simply the details of the heart death calculations as in Tables 6. Ali. and'A2'for cancer. The deaths shown in Table 7 resulting from the corrections for misclassification were calculated from the relative risks in lines 4 of Table 5 taken as constant over the age ranee. The modification of the observed relative risks for smoker mis- classification as shown in Table 5 are based on misclassified smoker relative risks calculated as follows. Based on as vet unpublished work of Wells on misclassification it was assumed that self-reported current smoker relative risks for male and female lung cancer in the U.S. and U.K. were 11 and 7. and 4'.6 and 2.7 for male and female current smokers in Japan Table A2. Annual U.S. female deaths from cancer other than lung from passive smoking. Exposed Relative Risk Constant ati 1.16 Relative Risk f Neversmoker D R Population T bl 6 E Declining Age o Death eath ate per 100.000 a e ) ( 1000's. xcess Death Rate Deaths RR Deaths 35-39 28 5781 3.9 22.5 4.5 13211 \V 40-44 48 . 425'- 6.7 285 29 14'11 © 45-49 80 3423 11!.2 383 2 0 1--t9 ~ 50-54 125 3355 17.6 589 1.56' 1579 55-59 190 3495 26.8 937 1.30 1591 60-64 265 32-18 37.7 1219 1.18 1352 V1 65-69 355' 2912 5711 1487 1.12 11" ~ 70-74: 470 2030 68.7 1395 1.08 729 75-79 600 1472 89 0 1310 1.05 4'?1 ~ 80-a4 750 547 114.7 627 1.034 138 ~ 8-S* 900 100 14117 142 1.0:21 20 ~ Totals 256 30595 28.1 8599 11165 '

260 A 1 %Le11s Table A3. Development of 1984 neversmoker, heart death rates versus age. Death rates from Hammond (1966) Age at enrolltd age Range per100.000, Females:. 1984 1984 wNeversmoker Decline. Fraction Neversmoker Hammond's heart in heart of,deciine Death Rate N.S. D.R. death rate DR's 11 due to as x of1963 corrected by age of 1963-83 smoking (smoothed) for decline death 35-39 71 49 3.5 _' 0! 48 0 . 40-44 14.1 55 7.7 4.4 45-39' 20:.3 ' 60! 12.2 10.2 37 0 50-54 35:5 63 28.7 23 55-59 104 64 66 51 01 60-64 243 64 156 113 65-69 475 64 304 240 37 0 70-731 %f 64 615 480 75-79 1648 65 1072 870 35 0 80183 2774 70 1942 ' 1550 85+ - 21 0 79 - 2770 .Ncles 35-39 T 76 0 20 48 50. 40-44 79:5 77 61 36 45-49 85.5 78 67 68 42 50 50-54 220 77 169 128 55-59 397 75 298 237 37:5 ?5 60 -6s' 741 75 556 412 65-69 1089 76 827 730 32' 25 70-74 1936 76 1472 1150 75-79 2639 77 2021 1850' 25' 10 80-84 a'373'. 81 3343 2950 85+ - 1.4 10. 86 - 3700 (Hi'rayama. 1984a): The 5% of ever smokers who were as- sumed miscliissified as never smokers were assumedito consist of 239e light current smokers and 77% long term exsmokers. The excess risks for currenr, self.reported smokers were re- duced by 2/3 to yield~ relative risks for misclassified current smokers an& by 11/12' for relative risks of misclassified exsmokers essentially as was done by Wald er al: (1986). This resulted in misclassified ever smoker relative risks of 2.4. and' 1.85 for males and4emales in the U.S. and U.K. and 1.5 and 1.25 for Japan. Worldwide misclassified smoker relative risks were then calculated to be 1.8 for males and 1.6 for femalesbased on the proportion of "western" and "eastern" cases. The false relative risks shown on lines 2 in Table 5 were then calculated using the formulae in Welis' unpublished work. For female cancer other than lung. the smoker relative risk of 1.05 was taken from Hammond (11966) and used as is since the effect is too small to make any difference. For ischemic hearr disease the ever smoker relative risks from Hammond' Table A4. Annual'U. S. female heart deaths from passive smoking. Relative Risk Relative Neversmoker Exposed Constant at 1'.23 Risk Death Rate Population Declining Age of per 100:000 (Table 6) Excess Death (Table A3) 1000's D.R. Deaths RR Deaths 35-39 2.0 5781 0.38 22 4.0 91 i0ii.t 4.4 4252 0.84 36 2.0 97' ~ 45-49' 50-51 10.0 23 3423 3355 1.91 4.4 65 148 1.32 1.17 85 114 ~ 55-59' 51 3495 9.8 3" 1.17 :65' ~ 60-64 1,13 3238' _2.1 713 1.17 548 . .~ 65-69 70-7.1 240 480 2912 2030 17.7, 97? 1385 1973 1.17 1.17 1062 1505 IiA 75-79 870 1472 180 2647 1.17 2010 80- 8a 1550 517. 33+t 1828 11.17 1374 ' ~ 85+ 2700 100 607 607 1.17 J51 ~ Totals 291 30595 31.9' 9768' 7602

Adult mortality from passive smoking Table A5: Annual l' S. male heart deaths from passive smoking Neversmoker D R Exposed P Relative Risk Constant at 1.31 Relative Risk f A eath ate 000 100 opulation (Tabl A1) E Declining ge o Death per . (Table A3) e , T000's xcess D.R. Deaths RR Deaths 35-39 20 3815 4.9 187 5.2 780 40-44 36 2980 8.9 265 3.0 879 45-49 68 2440 16.9 41!1 1'.9'- 929 50-54 128 2660 32.11 723' 1.42 951 55-59 237 2155 59.8 1289 1.28 1_'01'. 60-64 412 2051 105 2157 1.28 2009 65-69 730 1695 189 3195 1.28 297. 70-74: 1]50 1099 304 3341 1.28 3103 75-79 1850 633 500 3162 1.28 2933 80-84 2950 249 819 2039' 1.28 1887 85. 4700, 31 1377 565 520 Totals 521 19420 89'3 17335 181t.s (1966) were taken as 2.3 for, males and 2.0 for females.. The excess risks were reduced by 2/3 to vield relative risks for misclassified ever smokers of approximately 1.4 for males and 1.3 for females. These were used worldwide with V4'ells' un- published formulae to calculate the false heart disease relative risks shown on lines : of Table 5. Appendix B Relatrt.e risks for all'causes of death, and for emphrsema and chronic obstructive lung disease Data relating all causes of death with passive smoking for: females have been reported for four prospective studies to• talltng 9537 cases as shown in Table B 1. The combined relative risk is 1.165 with 95% confidence limits of 1.11 to 1.22. The onlv male data available are 75 cases from Gillis et aL (1984)) with a relative risk offl 1.0 so no male analysis was made. The calculation of the total number of female deaths from all causes for passive smoking is shown in Table B2. The total., 3a.1641. is considerably larger than the total for cancer plus hean of 19.359 shown in Table 7. Some of the difference is due to uncenainties in the ealculations, but other causes of 261 death that might contribute to the all cause total. based on data in a pnvate communication from Dr. Htravama. are cerebrovascular disease, other hean disease. diabetes. and ulixr. Hirayama (private communication. also reported preli- minarilv at 5th World Conference on SmokinQ and Health. Winnipeg. 1983)provides data relating deaths from emph.- sema with passive smoking in womem Hisrelativr risk. based on 106 cases is 1.3 with 95rir confidence limits of 0:85 to'_.05. Kalandidi'et a!_ (1987) report incidence data for chronic ob• structive lung disease based on 103 cases with an adjusted relative risk of about 1.4. Lee er aC (',19861 report incidence data for chronic bronchitis from spouse exposure Based~on 17 cases the adjusted relative risk is 1.22. A,wetehted a%eraee of these three relative risks would be about 1.3i. The only neversmoker death rate we have is from Hammond (1966) for emphysema at 2 x 10-`. Assuming 76 r exposure. the excess death rate for passive smoking using Eq. (2) would be 0:55 x 10'5 and the total deaths for an.exposed population of 30.61million would~ be about' 170. Even, if this number iss doubled to take into account deaths from formsof chronic far obstructive lung disease other than emphysema. it u stillT below the total for cancer and ischemic heart dtsease. Table BL. Female relative risks for all causes of death from passive smoking. l All Exposures Mantel Trend Locale Tota Cases RR 95% C.L. 1•tail p Cohort Studies: Hiravama (1987) Japan 9106 1.17• 1.12=1.23' 0:(ItKK)1i Gillis a at.' (198t), Scotland 102 1.45 0.91-2.30 Garland et a!. (1985) California 79 1.06 0.65-1.73' Vandenbroucke et at. (1983)" Holland 250 0.79 0.57-1.09' Combined Chon: 9537 1.165 'Dr. Hiravama (private communication):provided the data necessary to calculate these items., 'Data from 25 vear follow up: Relative risk w•asA!89 (0.50-1.62)ifor 1,5 vear follow up. This stud% is weak in,that exsmokmg women,were tncluded among the "nonsmokers." and nonsmoking women,exposed to exsmoker husbands were included in the "nonexposed " The weakness of the study, is emphasized in that the smoking women had a lower overall death rate (33.a'~/rYthan thc nonexposed nonsmokers (38, l1: )_

262 ge Range Nevetsmoker Death Rates (rom Hammond (19661 at enrolled age per T00.000 35-39 136 .t0-4t 178 45-49 254 50-54 352 55-59 561 60-64 867, 65-69 1492 70+-74 2585 75-79 4790 80-8s 8J08 85+ - A. J Wells Table B_. Annual US. female deaths from all causes from passive smoking. Decrement due to heart death rate 1963-84 per 100.000 Corrected Neversrnoker death rate at enrolled age per 100.000 3.6 132.4 6.4 17;1'.6 8.2 245,8 16.8 335:.' 38 523 87 780 171 13211 346 2239 576 4214 832 7576 -- - Totals Deaths per million total population Lee er al: (1986) report data on chronic bronchitis life long nonsmoking in males exposed,to a smoking spouse. Based on nine cases the ad)usted relative risk was 0.34. However. for general' exposure (a' cases) a positive relative risk was ob- served. No analysis of these data was attempted. heversmoker: death rate t d P l9 io F Relative Risk Constant at.1.165 correc e to age of death per 100.000 opu t n exposed 1000's raction of population exposed Excess D R. Deaths 120 5781 0,94 17.1 991 155 J'-s, 0.92 21.2 9a-t 212 3323 0;89' 30.5' Ioi-t 300 3355 0.87 43.3 la5'_ 445 3495 0.81 6-t15 _254 675 3228 077 98':8 31901 1070 2912 0.70 1583, .1609 1830 2030 0.59 275.2 5596 3250 1472' 0:49' 496.1 7303 6000 547 0:29' 9-t-t.8 5168 10!000' 100 0.10 1623 1623 30595 1]1 7 31]6-t 143 Appendix C Rate difference mode!'for assessing female ischemic hearr deaths from passive smoking A rate difference or absolute risk model was investigated for female ischemic heart disease in order to compare it to the relative risk models in ability to translate experience from one type of culture to another. Female ischemic heart disease was chosen because considerable data exist and because heart disease is the largest contributor to total deaths. Also. the relative risk model seems already to be welCestablished for lung cancer (Wald ct al:. 1986; Blot and Fraumeni. 1986) so a comparison~in another disease category appeared to be ap- propriate. Data from the four: cohort studies (see Table 4) were com- bined using the direct pooling equations described on page 183 in Rothman (1986). The two case/control studies were omitted. Although their combined rate difference was essen- tially the same as that for the cohort studies, no good way could be found ao combine it with that from the cohort studies. Death rates for exposed and not exposed populations were obtained by dividing the observed deaths in each category by person years which were equated to the mid-point populations multiplied'bythe years offoll'owup. The rate difference was then obtained by subtracting the nonexposed death rate from the exposed death rate. Vanances and weights were calculated by Rothman's formulae., The combined rate difference was obtained by summing the weighted rate differences and di- viding by the sum of the weights. Confidence limits (95%): were equated',to the rate difference =1.96 (variance)°=. The results of these calculations are summarizcd'in Table Cl. The cohort data were also combined using Program 7 of Rothman and Boice (1982) ,', with results essentiallv,idemical to those shown in Table C1 for direct pooling. The relative heterogeneity of the relative nsks ('RR) vs.,the rate differences (RD) can be approximated; by considering the range of RR- 1 versus the range of RD: The range of RR-1 is from 0;16 to 2.6 for a factor of. 163. The range of~ the rate differences is 3.7 to 262 'or a factor of 71. The ratio for the two large studies, Helsingeral: (1988) land Hiravama (1984b), for RR-I': is 0:2d" 0.16 = 1.5 and for RD is 20.7/3.7 = 5.6. The 95"c confidence limits for the rate ratio combination is tighter than for the rate difference combination_ ,#lso, the Hiravama study dom- inates the rate difference aggregation muchlmore than inithe rate ratio aggregation. providing 64% of the combined weight (last column of Table Cl) in the rate difference case vs. only 17 0 of the combined weight in the rate ratio case. Table C1. Rate difference c alculations for fe male i schemic heart disease. T Relative Risk from Table 3. Rate difference x 10'' Wn¢hts fo RD ~ RD x ~ h otal Cases RR 95% C.L. RD 95Pr C.L. r x 10-" weig t x 10- yN~' Cohort Studies: Hirayama (d98sb) 394 1.16 0.9- 1.4 3.7 -2.1- 9.6 11110 41 a Gillis er al. (19fi3) : 21 3.6 0.9-13'.8 169.1 30.7-307.6 2 31 Garlan&er al. (1985) 19 3.5 0;9-13,6 262.2 36.0-188.4 0 & 2.0 Hetsin¢ n a!: (19681 988 1.25' 1.1- 1.4 :0:7 -0.2- 41.6 88 IR.2 Combined Cohort 1522' 1.23 1.1- l.l 5 1 -0:2- 11.1 1201 65 0 ~

Adult mortality from passive smoking Table D1. Regionaliparticle deposition from mouth breathing of side stream smoke Fraction of inhaled Aero- Relative particle mass deposued` dvrta i V l M m c diameter Cube of Relative o ume (Weight) ass Distribution mouth trachro• µm diameter eonantration' per 0.liam , 'ii throat, bronchial alveolar 263 F1ass deposited as r~ of totall mass inhaled' 0.20 .008'. 1.5 0.006 0.3 0 0 0.13 0.0a 0.25 .016 6.5 0.051 2.4' 0 0 0.1?' 0:29 0.30 .0.7 10I0, 0.135 6A 0 0 0.115 0:74 0.35 .043 13:0 0:280 13.2 0 0 0.108 1 43 0 40 .064 13.01 0;i 16 19.6 0' 0 0.10 1.96 0.45 .091 6.5 0;296 14.0 0! 0 0.105 1.41 0.50 .125 3.5 032S 15.5 01 0 0.11 1.71 0.60 .216 1.25 0.270 12.7 0 0 0.115 1 .4b. 0.70 .343 0.5' 0.17~_ 8.1'. 0 0 0.12 0.97 0.80 .51L 0.25 0.128 6.0 0 0 0.13 0_78 0:90 .729 0.05 0.036 1.7 0 0 0.14 0.24 1.00 1.0 0 0 0 0 0 0.15 0(K) :.1!18 99.9 11.08 •From Hiller rr a!. (19821. Fig. 1., 'From ~Hevder (1984).,Table 1. 250 cm'fsecond mean flo%% ' rate. 4 second breathing cvcle. This domination of the rate difference model by the Jap• anese study is evident from some rouch death calculations. Use of the combined rate difference (5;a x 10") with the exposed female population from Table A4: (30.6 million)) yields total deaths of L6fi2 compared with 9.768 calculate& from the constant rate ratio modell VJhen the rate differences are plotted against age of death~and weighted accordinglv it is found that the "westertr " rate differences increase sharply with age whereas the Japanese rate difference stays constant at about 4 x 10'. Constructing a weighted average of these ••western-' and ' eastern" death rates for each of the 5 vear age ranges and multiplying h}• the corresponding exposed pop- ulations yields a total of about 2.100 deaths compared with 7.602 in the second relative risk modell Use of the Japanese data alone vield's about 1.200 deaths. Use of oniv the "west- ern" data (Gillis er al.. 1994: ',Garland ei . al.. 1988: Helsing ett al: ) at a constant, rate difference yields 7,950~deaths while use of "western~' data with the rate difference van•ine with age yield5 about 30.000 deaths. Thus. the death caltulations using rate differences are quite vofatile, Also. it is evidentt that with the rate differences it is not feasible to carrn- over the "eastern° experience. in ischemic hearr disease at least, for use in a"western" setting.. Accordmglt. it' was concluded that the absolute risk model' is not as suited to combining risks for passive smoking asthe relative risk models. Table D3: Regional ~ particle deposition from nose breathing of sidestream smoke. Aero- i Fraction of inhaled particle mass deposited" Mass deposited as K of total mass dynam c Mass diameter distribution mouth ttachco- inhaled µm % . nose throat bronchiai alveolar nose alveolar 0:20 0:3 0 0 0 0.19 0.00 0.06 0125 2.4 0.005 0 0 0.172 0.01 0.41 030 6.4 0.01 0 0 0.155 0.06 0.99 0.35 13.2 0.015 0 0 0.13R 0.20 1.82 040 19.6 0.02 0 0 0.12 0.39 2.35 0.45 14.0 0.03' 0 0 0.11-2 0.42 1.70 ~ 0.50 15.5 0.04 0 0 0.125 0.62 1.94 0.60 12.7 0.05 0 0 0.1_R 0;6,t 163 0.70 8.11 0.06 0 0 0.13 0.49 1 05 0 80 6 0 077 0 0 0 0:13; 0!46 (1!Rn', L . 0.90 . 1.7 . 0.093 0 0 0:137 0!16 0;23 #" 1.00 0.0 0.11 0 0 0:1a 0.(10 0,(uiI ~ 3.45 1'_.99 °From Table D1!. ~ "From Hevden(1984). Table 2. 250 cm',second'mean.OoM rate. .4 secondbreathtng cycle..

264 A J MctIA Table D3. Smoke Particle deposition patterns in direct and passive smoking Direct Smokintt Passive Smoking Direm, Passisc Entry site Particulate inhaled per day. me. Mouth :a0 tiose 2.8 86 Particle Size inhaled. µm 0 7 0.4 Particle size exhaled.,µm 07 04 Retained in nose, 5r 0 3.5 Retained in mouth. i7', 25 0 Retained in tracheerbronchial reaion. % 35 0 Retained in near alveolar reeion_ % 19 0 Retained in deep alveolarregion. 4c 9 13 Totallretained. °k 90 16.5 Particulate retained. total. mg. 192, 046 177 Particulate retained. alveolar. mg. 48 0.36 133 Particulate retained. deep alveolar. mg. 2-1 0.36 61 Appendix D Dose considerarions As noted in the text. there is a wide difference between the observed'disease ratio between passive and active smokers and the ratio of cigarette smoke particulate retained by, each. Also, the cancer sites appear to differ. On the assumption that part of these differences may be due to differences in deposition sites between passive smoking and active smoking, calculations were carried out to try to pinpoint these differ- ences. The calt:ulations for passive smoking are reasonably straightforward. Stober (1984) has summarized all the uncer- tainties in this type of calculation. Nevertheless, the best ap- proa& appears to be to use the data of Hiller et al. (1982) for the particle size range of side stream smoke, centering around 0:4 µm, and the mathematical lung modellof Heyder (1983), for inert particles. Integration of these two data sets yields a distribution of deposited weights by particle size for mouth breathing (see Table D1) which. when summed: vields exactlv the total': deposition observed by Hiller et al:. (1982) indicating that the Heyder modeliholds for passive smoking. The same inhaled particle size distribution camthenbe applied to Hevder's nose breathing case (see Table D2) which yields nasal deposition of 3.5c%e and deposition in the alveolar region of the lUng of 13:04c. The model predicts zero deposition for both the mouth,throat and the tracheo-bronchial regions. From the depositiomcurves of Gerrity er aG (1979) (Fig. 2) for iron oxide extrapolated to a particle size of 0.25 µm.(which is eq uivalent to an aerodynamic diameter of 0.4 µm ) it appears that all of the lung deposition from passive smoking probably occurs deep in the alveolar region at generation 19 or beyond. Black and Pritchard (1984) have determined the half-time for alveolar retention for direct cigarette smoke to be 17 hours indicating that the smoke particles dissolve and clear into the blood or lymph system. There is every reason to believe that the passive smoke particles clear the same way. With direct smoking there has so far been no model de- veloped'that explains the observed phenomena, namely that the inhaled particle size is about 0.7' µm, that 70% to 809c of the inhaled smoke is retained, that 15 to 359'e is retained in the mouth, and that the exhaled~panicle size is also about 0.7 µm; The Heyder modeli at 0l7 µm, would predict total retentiomof only 12%. To achieve 75% retention, the Heyder model would require an effective particle size of 6.5 µm, Main streamismoke is knowmto agglomerate. but if it agglomerated to 6.5 µm, the exhaled' smoke. according to the He.der modeli, would be about 6 µm, much too, large compared to that observed. Mitchell (1962) observed that direct smoke particles grow in the mouth to about 1.15~µmi and that the smoke exhaled from the lung after a S second retention period had a mass median diameter size of 0.65 µm. Let us assume that the 0.65 µm part of'the smoke follows Hevder's model an&thar209c of the total smoke inhaled was exhaled', all from the 0;65 µm fraction. The inhaled part of the smoke corre- sponding with the 0.65 µm part exhaled would have the same particle size and would deposit about 12%. deep in the al- veolar region.. This is 1'217c of 22.7ro of the total smoke in- haled'~ or 2.7% of the total inhaled smoke. The balance of the inhaled smoke (77%) would have a larger average particle size„about 1.3 µm. Black and Pritchard (198-1)lfound. based on clearance data, thatthe rates of alveolar c+eposition to alveolar plus tracheo-bronchial deposition, in, direct smoking is 0.36. Also, as noted, some amount, say 25% of the total inlet smoke should deposit in the mouth and throat. all of which would have to come from thislarger size fraction.,Sum- marizing these numbers, of the 100 -'0 -'5 = 55cc of total smoke particulate that reaches the lun¢ and is non ex- haled, 0~64 x 55, = 35% deposits in the tracheo•bronchial region and 0.3& x 55 = 20% deposits in the alveolar region, We have already accounted for 3% of the alveolar deposition from the 0:65 µm particles. The remaining 17% would come from the largerparticles.,Based on the alveolar/tracheo-bron- chial split and using the curves of Gerrity er al: (1979) it would be expected that about 2/3 of the alveolar deposit or l1,rr, would deposit in the "near° alveolar region, generations 16- 18, and 6% in the "deep" alveolar region., generations 19- 21, for a total "deep" alveolar deposition of 9%. These cal- culations are summarized in Table D3. Just what the mechanisms are for so much direct smoke deposition remains unclear. Certainly impaction and sedi- mentatiom(thc Heyder model) do not account for it. Stober (196-t)isuggests that electricallcharges in the newly generated smoke particles (see Melandri er al:, 1983) mav aceounv for some of it. Another possible mechanism is the cloud settling phenomenon as described by Fuchs(196J). Whatever the mechanism, a reasonably clear idea of the regionalI deposition patterns from direct and passive smoking

Adult mortalirkfnm passn•e smoking can be obtained as shown in Table D3. The nasal deposition from passive smoking could account for the observed nasal sinus cancer. Also. if the observation of Balin er aL (1986) is correct that there is a direct passage for toxics from the nose to~ the brain, it could also account for the observed brainn cancer. Ih the deep alveolar region the ratio of direet to pas- :h` sive deposition is much closer to the inhaled'ratio ~than to the "total retained" ratio. It is from the deep alveolar region thac the smoke particles are solubilized and clearedGnto the blbo& and lymph systems possibly to cause cancers of the liver, breast and endocrine glands, leukemia. h•mphoma and ar- terial plaques.