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Environme.u lnuernational. Vol. 14. pp. 249-265. 1988 Printed in the USA. All rights reserved. AN ESTIMATE OF ADULT MORTALITY IN THE UNITED STATES FROM PASSIVE SMOKING A. Judson Wells 102 Kildonan Glen. Wilmington, Delaware 19807. USA (Received 9 December 1987; Accepted 7 July 1988) Ij '~~ , 1S J1 uIGU.Jl2o.'xR S3.twl , .(K) Copyright .C 1988 Pcrpmon Press plc NOTIt;E This matotial msy be Votected by CWl& i4w (iitte 17 U.S. We). The purpose of this paper is to estimate the number of adult deaths per year in the United States from passive smoking. The epidemiological literature on passive smoking and adult mortality and cancer and hean morbidity is reviewed. Combined relative risks (or lung cancer, cancers other than lung. and heart disease are calculated for each sex and disease category. These data along with estimates of nonsmoker death rates and populations exposed allow calculation of annual deaths in each ca4egory. Reduced relative risk and reduced exposure at older ages are taken into account as well as a correction for possible misclassification of smokers as nonsmokers and exposed nonsmokers as nonexposed. Al- together 46.000 deaths per year are calculated consisting of lung cancer (3000) other cancer (11.000) and hean disease (32.000). Reasons why such high estimates for other cancer and hean disease may be possible are explored. It is concluded that exposure to environmental tobacco smoke can have adverse long term health effects that are more serious 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 et al. (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 U.S. 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 procedure 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- jecte.d here for never smokers plus exsmokers. The . methods used in the National Academy report are fur- ther detailed in Wald et a!. (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 various studies 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 well 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 of reliable 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, and ischemic heart~yI~ar' The total particulate matter i" dose retained by p 3~ve smokers is too low to account for the health eKe; s ol Oassive smoking if one starts with the health effe s exhibited by direct smokers and ratios down from,t e dose retained by them. Reasons why such a discrep ncy might occur are explored. 249

,50 r , A. J. wells . 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 personal contact with workers in the passive smoking field. Criteria for admitti~"g 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). Emphysema is not included because the nonsmoker death rate is so low that less than 1% 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 based on spouse exposure or on general exposure of more than 10 years du- ration. 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 pertained 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 death rate and the fraction of the population exposed were included. In the sec- ondary 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). It 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 of 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 the two aggregates was obtained using: Rte s expw`°InR,, + w«InRn (1) K'co + K'cc where &; Rro, and RK are the relative risks for the combined total, the cohort studies, and the case control studies, respectively, and w,, and w« are the weights for the cohort aind 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 In R/x, so the weight, w=(X/In R)'-. The source of these equations is Rothman (1986). Con- fidence intervals were calculated from a combined X= w'"- In RN.'fior some studies it was necessary to calculate a chi 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). Ages of death from 35 and up were used and should include essentially all adult deaths from passive smoking. In some studits morbidity relative risks were reported whereas our interest is in mortality. The morbidity rel- ative risks were accepted as surrogates for mortality relative risks because, for cancer, the survival rates for exposed and nonexposed cases appeared to be similar while, for heart disease, incidence relative risks, if any- thing, are lower than mortality relative risks (Svendsen et al., 1987). The 1985 smoking status for U.S. residents in 5 year 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% for mates and 60% for females), all of whom were considered to be exposed, were obtained from controls of the U.S. based studies for all three diseases. These fractions were as- sumed to hold also 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- tained from Friedman val. (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 Friedman etal. (1983) were used to develop smoothed values of fraction exposed 10 years earlier (midpoint of `a 20 year exposure) for each sex and 5 year age interval normalized to 61% for males and 76% 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 deter- mined. Death rates for never smokers for lung cancer by sex and 5 year intervals were drawn from Garfinkel (1981) 50986 1060

. I , I Adult mortality from passivc smoking and 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 ages 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 iates (with the reduc- tion 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 (D,,,) for each sex. disease and 5 year age range was calculated from the never smoker death rates (D,v) using the formula: Do, = D,JR - 1)l(Fo(R - 1) + 1) (2) where Fo is the fraction of the population that is exposed and R is the combined relative risk. This excess death rate was assumed to apply to all nonsmokers. Deaths were then calculated by multiplying 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 et at. (1986). Results Relative 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 and show a combined rel- ative risk for all exposures including exposures to exsmokers of 1.34. At the time the analysts was made there were fourteen acceptable 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 1.3-1.7. 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 251 1.3-3.2. Data excluded from Tables'l and 2 along with the reasons were the following: Chan et at (1979), cur- rent exposure only; Knoth cr al. (1983), no controls; Kabat and Wynder (1984) nonspouse data, current ex- posure only; Buffier et a1. (1984), 0-32 year data, not a minimum bf 10 years exposure. A paper by Dalager et al. (1986) describes a pooling of data from Correa et at (1983), B„uffler et at (1984) and a study of males in New Jersey. ; I'hey observed an adjusted odds ratio for spouse exposure of 1.47, but since Correa et at (1983), and Buffler tt at (1984), were already included in Ta- bles I and 2 and since the New Jersey data were not available separately, it was decided to omit the Dalager et at. (1986),study from this analysis. Also. available were abstracts of two recent papers. Geng et at. (1987) from China t+vith a relative risk of 2.2 and Inoue and Hirayama (1087) from Japan with a relative risk of 2.3, both for females. Also W. 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 of Hirayama (1984a) on female lung cancer are sufficiently detailed to indicate a declining relative risk with age from 1.87 at approximately age 50 to 1.43 at approximately age 75. These data were used to de- velop a second death calculation 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 lung in females. The individual and combined relative risks for females are shown in Table 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 Sandler et a!. (1985), cover different age of death ranges. Hirayama covers 50 to 80+ while Sandler et al. cover <30 to 59. The two studies taken together would indicate a rather sharp decline in rela- tive risk with age from about 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 et al., 1986). Two calculations of U.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 relative risks. Gillis et al. (1984). Sandler et al. (1985). and Rey- nolds (private communication) also report on other can- 50986 1061

•252 Table 1. Female relative risks for lung cancer from passive smoking. A. J. Wells . T Highest Exposure All Exposures Mantel Trend Locale otal Cases RR 2-tail p RR 95 % C.L. 1-tail p Cohort Studies: Hirayama (1984a) Ja¢5n 200 1.9 0.002 1.6 1.1- 2. 2 0.002 Garfinkel (1981) United States 153 1.1 - 1.2 0.8-1.6 - Gillis er a1.'(1984) Scotland 8 1.1 0.2-5.6 Combined Cohort 361 1.34 1.1-1.7 Case Control Studies: Trichopoulos et at. (1983) Greece 77 2.6 0.19 2.1 1.2-3.6 0.005 Correa et al. (1983) Louisiana 22 3.5 0.02 2.1 0.8-5.2 Buffler et at. (19&1) Texas 27' - - 0.9 0.4-2.3 Kabat and Wynder (1984) United States 24 0.8 0.3-2.5 Sandler et al. (1985) Garfinkel et al. (1985) North Carolina United States 2 116 2.0 0.05 inf 1.3 0.8-1.9 0.025 Wu er al. (1985) California 28' 1.2 0.5-3.3 Lee et al. (1986) United Kingdom 32 - - , 1.0 0.4-2.7 Akiba et al. (1986) Japan 94 2.1 - 1.5 0.9-2.6 0.06 Koo ct at. (1987) Hong Kong 86 1.2 - 1.6 0.9-3.1 Pershagen et a!. (1987) Sweden 67 3.2 - 1.2 0.7-2.1 0.12 Humble et al. (1987) New Mexico 20 1.2 -- 2.3 0.9-6.6 Brownson et al. (1987) Colorado 19 - - 1.7 0.4-3.0 Lam et al. (1987) Hong Kong 199 1.65 1.2-2.4 Combined Case Control 813 1.50 1.3-1.8 Combined Cohort and C/C 1174 1.44 1.26-1.66 ' 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 with no 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 et dl. (1986), Martin et al. (1986a) and the important, largeHklsing et al. (1988) paper from Mary- land. The overall combined relative risk based on 1.622 cases is 1.23 with 95% confidence limits of 1.11 to 1.36 and a combined phi square of 16. Helsing et 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. Locale Total Cases RR Cohort Studies Hirayama (1984a) Japan 64 2.3 Gillis et at (1984) Scotland 6 Combined Cohort 70 Case Control Studies: Correa et at (1983) Louisiana 8 Buffler et at (1984) Texas 8' Kabat and Wynder (1984) United States 12 Lee et at. (1986) United Kingdom 1S Akiba et at (1986) Japan 19 Humble et at (1987)' New Mexico 8 Brownson et at (1987)' Colorado 4. Combined Case Control 74 Combined Cohort and C/C 144 'Private Communication. Highest Exposure 2-tail p, 0.16 All Exposures Mantel Trend RR 95'k C.L. I-tail p 2.25 1.11- 4.9 0.023 3.3 0.7 -16.5 2.5 1.2 - 5.0 2.0 0.4 -10 1.6 0.3 - 8.1 1.0 0.3 - 3.2 1.3 0.4 - 4.6 1.8 0.5 - 5.6 4.2 1.0 -16.8 2.7 0.2 -31 1.$ 1.0 - 3.3 2.1 1.3 - 3.2

, Adult mortality from passive smoking 253 . Table 3. Female relative risks for cancer other than lung"from passive smoking. Highest All Mantel Exposure Exposures Trend Locale Total Cases RR 2-tall p RR 95 % C.L. 1-tail p ~..._. • Cohort Studies: Hirayama (1984a)' y. Japan 2505 1.16 0.01 1.11 1.0 -1.2 0.05 Gillis et al. (1984) Scotland 43 - - 1.2 0.6 -2.5 - Reynolds ei al. (1987) California 70° 1.7 1.1 -2.7 I Combined Cohort 2618 1.13 1.03-1.24 Case Control Studies: Miller (1984Y Pennsylvania 84 1.25 0.7 -2.3 Sandier et a!. (1985) North Carolina 231 2.0 1.3 -2.9 Combined Case Control 315 1.7 1.2 -2.45 Combined Cohort and 2933 1.16 1.06-1.27 C!C I t 'Obtained by subtracting data for lung cancer from data for all sites. 'Provided by Dr. Reynolds. 'Age adjusted Mantel-Haenszel values for nonemployed wives. for ages up to about 50. 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 trt al. (1986) and Helsing et al. (1988). The result of Svendsen et 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 high at the younger ages, about 2,.9, but declines to a nontrend average of 1.28 which extends from age 55 out to the older ages. Svendsen et al. (1987) show that there was very little difference between never smoking men married to nonsmokers and those married to smokers in the major coronary risk factors such as baseline blood pressure, total cholesterol, and LDL cholesterol. This work was reported in more detail in Martin et al. (1986b). Small differences were found in weight (195 vs. 190 if wives were smokers) and drinks per week (10 vs. 8 if wives were smokers). On the other hand, Garland et a!. (1985) Table 4. Relative risks for heart disease from passive smoking. Highest All Mantel Exposure Exposures Trend Locale Total Cases RR 2-tail p RR 95 % C.L. 1-tail p I t Females Cohort Studies: Hirayama (1984b) apan 94 .3 0.038 .16 .9- 1.4 .02 Gillis et a!. (1984) Scotland 21 3.6 0.9-13.8 Garland et al. (1985) California 19 - 3.5 0.9-13.6 Helsing et al. (1988) Maryland 988 1.27 - 1.24 1.1- 1.4 0.005• Combined Cohort 1522 i 1.23 1.1- 1.4 Case Control Studies: Lee et a!. (1986) United Kingdom 77 0.9 0.7- 1.3 Martin et a!. (1986a) Utah 23 2.6 1.2- 5.7 Combined Case Control 100 1.29 0.8- 2.0 Combined Cohon and C/C 1622 1.23 1.1- 1.4 Ma/es Cohort Studies: Gillis et a1. (1984) Scotland 32 1.30 0.7- 2.6 Lee et al. (1986) United Kingdom 41 1.24 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 Svendsen et al. (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. 50986 1063

. . found that never smoking women married to smokers had slightly lower weight, slighily lower blood pressure, and slightly higher cholesterol, all nonsignificantly 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 m.pjor 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. Japanese women at 1.16, through American women at 1.27, and American men at 1.31, to high risk American men at 2.2. A correction for misclassification was attempted for all three disease categories. Following Wald et al. (1986), and presuming that the passive smoking studies were done somewhat more carefully than the general questionnaire studies they cite, 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-eral. (1986), and the use of a more accurate formula. In general, 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 smoktr,misclassification effect is small fo negligible, but because the relative risks are smaller and no correction was made to "eastern" data (Japan. Greece, and Hong Kong), the positive effects of ex- posure of "nonexpo$ed" 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 khe 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. Otherwise, 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 total 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. A. J. Wells Lung Cancer Other Cancer Heart Disease Females 1. Combined relative risk. 1.44 1.16 1.23 2. False relative risk due to projected 5% smoker misclassification. 1.01 1.002 1.01 3. Combined relative risk corrected for smoker misclassification, (1) + (2). 1.43 1.16 1.22 4. (3) corrected for exposure of "non• exposed" at 1/3 that of exposed. 1.48 1.21 1.32 Males 1. Combined relative risk. 2.1 1.01 1.31 2. False relative risk due to projected 5% smoker misclassification. 1.3 1.11 3. Combined relative risk corrected for smoker misclassification. (1) + (2). 1.6 1.17 4. (3) corrected for exposure of "non- exposed" at 1/3 that of exposed. 2.4 1.29 'Assumed value for lack of better data.

'• Adult mortality from passive smoking 255 • Table 6. Annual U. S. female lung cancer deaths from'passive smoking. d E Relative Risk Constant at 1.44 Relative Risk D li i Age of Death Neversmoker Death Rate per 100.000 f' Nonsmoker Population 1000's Fraction Exposed xpose Population 1000's Excess Death Rate Deaths RR ec n ng Deaths 35-39 1.6 6150 0.94 5781 0.50 29 1.70 39 i0-44 4 2 4622 0.92 4252 0.75 32 1.69 43 t 1 45-49 . 3.6 3846 0.89 3423 1.14 39 1.68 52 50-54 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 11.0 4192 0.77 3228 3.62 117 1.49 126 65-69 16.6 4160 0.70 2912 5.55 162 1.43 159 70-74 23.5 3441 0.59 2030 8.21 167 1.36 142 75-79 34 3004 0.49 1472 12.3 181 1.29 127 80-84 46 1886 0.29 547 18.0 98 1.18 43 85 + 52 1003 0.10 l00 21.9 22 1.0(t 4 Totals 13.0 40291 0.76 30595 3.0 992 - 911 ing deaths might be 46,000. half way 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. 11,000 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 for heart disease. These numbers may be useful for populations similar to that of the United States in terms of propor- tions of never smokers, exsmokers, and smokers, and in terms of the proportion of the population that is less than 35 relative to that over 35. For other populations the per million numbers are 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 Hirayama. (1984a,b) in his large prospective study. He found significantly elevated risks for all three diseases. and his result for lung cancer is now believed to be valid. (USSO 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- mation on specific cancer sites from Dr. Hirayama (pri- vate communication) it appears that cancers common to both types bf smoking are lung, liver, cervix, nasal sinus, and leukemia. Some of these cancers are on1Y weakly associated with direct smoking. Cancers asso- ciated to som degree with direct smoking, but absent in passive sm~king are buccal cavity. pharynx, larynx. esophagus, stomach (Hirayama, 1984a), urinary blad- der (Kabat et 01., 1986), kidney and pancreas. Cancers related to passive smoking, but absent in direct smoking are brain (Hirayama.1984a), endocrine glands (Sandler et aL,1985), lymphoma and breast (Sandler el a1.,1985. 1986; Hirayama, private communication). The first three are significant at the 95% level. The combined breast relative'rtsk of 1.4 is significant at only 88%. Higher relative risks for these four sites might be found for direct smoking if epidemiologists used nonpassively Table 7. Summary: U.S. annual deaths from passive smoking. Lung Cancer Other Cancer Hean Disease Total Females: 1. Constant combined relative risk. 992 8599 9768 19359 2. Relative risk declining with age. 911 11165 7602 19678 3. (1) corrected for misclassification. 1232 12280 14995 28507 Males: 1. Constant combined relative risk. 1606 0 17335 18941 2. Relative risk declining with age. 1606 0 18164 19770 3. (1) eorrected for misclassification. 2499 0 22467 24966 Totals for both sexes: 1. Constant combined relative risk. 2598 8599 27103 38.';00 2. Relative risk declining with age. 2517 11165' 25766 39448 3. (1) corrected for misclassification. 3731 12280 37462 53473 Best current estimate, both sexes (rounded). 3000 11000 32000 46000

~ . Table 8. Summary: Deaths per million population in U.S. from passive smoking. . . ' - (based on 239.000.000 U.S. population in 1985). Lung Cancer Other Cancer Heart Disease Total _._,.... Females: 1. Constant combined relative risk. 4.15 35.98 40.87 81.00 2. Relative nsk declining with age. 3.81 46.11 31.81 82.33 3. (I) corrected for misclassification. 5.15 51.38 62.74 119.27 Males: I. Constant combined relative risk. 6.72 0 ' 72.53 79.25 2. Relative risk declining with age. 6.72 0 76.00 82.72 3. (1) corrected for misclassification. 10.46 0 94.00 104.46 Totals for both sexes: 1. Constant combined relative risk. 10.87 35.98 113.40 160.25 2. Relative risk declining with age. 10.53 46.71 107.81 165.05 3. (1) corrected for misclassification. 15.61 51.38 156.74 223.73 Best current estimate, both sexes (rounded). 13 46 134 193 J 256 A Wells exposed never smokers as the referrent category rather than all never smokers as is usually done. Another dif- ference between passive smoking and direct smoking is that the ratio of lung 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 in mortality effects are probably 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 et al., 1978). More importantly, (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 high, about 80%. De- position occurs primarily in the mouth or in the larger airways of the lung where the particles are cleared rel- atively 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 dilute, with a mass median diameter of about 0.4 µm. Particles in this size range have very low deposition rates, on the order of 10%, but what does deposit does so deep in the alveolar region of the lung where clearance times are longer. Black and Pritchard (1984) estimate that cigarette tar has a 17 hour half-time rate of clearance from the alveolar region, much longer than clearance times from 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 compon,ent of direct smoking, which results in massive deposition in the mouth and larger airways of the lung, rapid,clearance, cancers of the mouth. central lung and digestive system. and possibly 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 differfnces in chemistry and physics also ex- plain, at least in part. the rather high mortality 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 in a 16 hour day (0.64 mg for the passive smoker per USSG (1986, p. 196) and 240 mg for the direct smoker assum- ing twenty 15 mg tar cigarettes and 80% retention). In comparison, the ratio of lung cancer death rates is about 1/35. For cancers other than lung in females the ratio is about 1/7, for heart disease in females about 1/ 14 and for heart disease in males about 1/3. Preliminary calculations which are shown in Appendix D indicate that the smoke retained deep in the alveolar region may have a dose ratio higher than 1/400, perhaps as high as 1/60. It may be that carcinogenic material that solu- 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 Pe n tt al. (1986) on cell transforming capability of hu n theroSclerotic plaque DNA and the earlier work ~ A~bert et at (1977) and Penn et al. (1981) on the for atiort of arterial plaques in cockerels with dimethylbe z(a)ahthracene and benzo(a)pyrene. Another possiN~ factor that might help explain the disparate mortaiity tff4cts versus dose is the level of disease susceptab,ility'itti `passive smokers versus direct ~

. 0.dutt moctatity (com passive smoking 257 smokers. The median age for passive smoking death from lung cancer for males is 66 and the deaths con- stitute 0.006% per year of the exposed population. The first 0.006% of ma)e smokers have died of lung cancer by age 46 at which age the lung cancer death rate is doubling every four years. ikt 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 question often raised is that direct smokers are also passive smokers, so why do they not get the passive smoking related cancers. We have already pointed out 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 related disease in their sixties or seventies. The passive smoking mortality calculated in this study. namely, 46,000, may be low. Repace and Lowrey (1985) calculate lung cancer deaths from passive smok- ing at 4,665, or about 50% higher than our estimate, primarily because of postulated intense exposure at the 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 correct, the higher exposure would lead to corresponding increases in deaths from heart disease and other cancer. Also, only ischemic heart disease is considered here. As the all cause data in Appendix B indicate, other cardiovascular diseases and diabetes may be sensitive to environmental 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. Acknowledgemenrs - The author is grateful to Dr. T. Hirayama for his data on individual cancer sites and for the details of his "all cause" data. to R. W. Wilson of the U.S. National Center for Health Statistics for data on the smoking status of U.S. residents by S year age inter- vals. to L. Garfinkel for the person years in his 1981 study. to J. M. Samet for data on mate lung cancer in the New Mexico study. to R. C. Brownson for male lung cancer data in the Colorado study, to P. Buffler for her 33+ year data, to Sir John Crofton for abstracts of Lam a+ al. (1987) and Geng tr af. (1987). to P. Reynolds for the number of cases in their study on female cancer, the number of lung canccr cases. and their qualitative results on males, to D. P. Sandier for nonsmoker data on breast cancer. and to S. C. Hunt for enough data from Martin cr at. (1986a) to calculate an all-exposure relative risk. confidence limits and a weighting factor. The author also wishes to thank James Robins. N. A. Dalager. J. M. Samet. W. J. Blot. L. C. Koo. A. H. Wu. G. Pershagen. D. P. Sandier. D. Trichopoulos and J. L. Repace for helpful correspondence and discussion. References Akiba. S.. Kato. H.. and Blot. W. J. (1986) Passive smoking and lung cancer among Japanese women. Cancrr Res 46. 48t1t-4807, Albert. R. D.. Vanderlaan. M.. Burns. F., and Nishizumi. M. (1977) Cancer Res 37, 2232-2235. Balin, B. J. Broadwell. R. D.. 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. 259 Adult mortality from passive smoking r Table Al. Annual U.S. male lung cancer dcaths from passive smoking. Relative Risk Constant at 2.1 Age of Death Nevcrsmoker Death Rate perr100.000 Nonsmoker Population 1000's Fraction Exposed Exposed Popqlation 1000's Excess Death Rate Deaths 35-39 1.8 5156 0.74 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 50-54 7.0 3431 0.66 2260 4.46 101 55-59 11 3423 0.63 2155 7.15 154 60-64 16 3489 0.59 2054 10.7 219 65-69 23 3150 0.54 1695 15.9 269 70-74 33 2443 0.45 1099 24.3 267 75-79 49 1712 0.37 633 38.3 242 80-g4 72 921 0.27 249 61.1 152 85+ 95 516 0.08 41 96.0 39 Totals 15.9 31944 0.61 19320 8.26 1606 Appendix A Details of death calculations Tables A1 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 that no declining relative risk calculation is shown for male lung cancer since the evidence that was available (Hirayama, 1984a) indicated no such decline. In Table A3 the details are given for the development of the never smoker relative risks for heart disease that. were used in the death calculations. As noted in the text, the 1963 neversmoker heart death rates by 5-year intervals were ob- tained by dividing the never smoker coronary heart deaths in Hammond's (1966) appendix. Table 14, by the person years in his appendix tables 2a and 2b. Reduction factors to account for the change in heart death rates between 1963 (end of Hammond's study) and 1984 were then developed by 10 year age intervals from the age specific heart death rates in table 24 of Health 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 combined never smoker reduction fattor, interpolated back to 5-year age in- tervals, for application to the Hammond never smoker death rates. These modified rates, which are for enrollment age and therefore about 2 years younger than age of death. were then plotted against age of death on semi-log graph paper. Trend 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 AS are simply the details of the heart death calculations as in Tables 6. Al, 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 range. 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 yet 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 lot 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 at 1.16 Relative Risk Neversmoker Population Declining Age of Death Death Rate per 100.000 (Table 6) 1000's Excess Death Rate Deaths RR Deaths 35-39 28 5781 3.9 225 4.5 1321 40-44 48 4252 6.7 285 2.9 1411 45-49 80 3423 11.2 383 2.0 1449 50-54 125 3355 17.6 589 1.56 1579 55-59 190 3495 26.8 937 1.30 1591 60-64 265 3228 37.7 1219 1.18 1352 65-69 355 2912 51.1 1487 1.12 1144 70-74 470 2030 68.7 ' 1395 1.08 729 Ln 75-79 600 1472 89.0 1310 1.05 431 m 80-84 85+ 750 900 537 100 114.7 141.7 627 142 1.034 1.022 138 W co 20 m i Totals 256 30595 28.1 8599 11165 N m m ~o

• • 260 A. J. Wells • Death rates from Hammond (1966) Age at enrolled age Range per 100600 1984 1984 Neversmoker Decline. Fraction Neversmpker Hammond's heart in heart of decline Death Rate N.S. D.R. death rate DR's Sfc due to as S4 of 1963 corrected by age of 1963-84 smoking (smoothed) for decline death -•Table A3. Development of 1984 neversmoker heart death rates versus age. Feinales: 35-39 7.1 49 3.5 2.0 .i8 0 40-44 14.1 55 , 7.7 4.4 45-49 20 4 60 ' 2 12 2 10 . 37 0 . . 50-54 45.5 63 ' 28.7 23 55-59 104 36 0 64 66 51 60-64 243 64 156 113 . a 65-69 475 . 64 304 24Q G 70-74 961 37 0 . 64 .. . 615'. . 480 . 75-79 1648 63 1072 870 35 0 80-84 2774 70 1942 1550 85 + - 21 0 79 - 2770 Males: 35-39 0 76 0 20 48 S0 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 25 60-64 741 75 556 412 65-69 1089 76 827 730 32 25 70-74 1936 76 1472 1150 75-79 2639 77 2024 1850 25 10 80-84 4374 81 3543 _950 85+ - 14 10 86 - 4700 (Hirayama. 1984a). The 5% of ever smokers who were as- sumed misclassified as never smokers were assumed to consist of 23% light current smokers and 77% long term exsmokers. The excess risks for current. self-reported smokers were re- duced by 2/3 to yield relative risks for misclassified current smokers and by 11/12 for relative risks of misclassified exsmokers essentially as was done by Wald a al. (1986). This resulted in misclassified ever smoker relative risks of 2.4, and 1.85 for males and females 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 females based on the proportion of ••western" and "eastern" cases. The false «lativt;', ritks shown on lines 2 in Table S were then calculated using t'he formulae in Wells' unpublished work. For female cancer other than lung, the smoker relative risk of 1.05 was taken from Hammond (1966) and used as is since the effect is too small to make any difference. For ischemic heart disease the ever smoker relative risks from Hammond Table A4. Annual U. S. female heart deaths from passiye smoking. Relative Risk Relative Neversmoker Exposed Constant at 1?3 Risk D h R P l i Age of eat ate per 100.000 opu at on (Table 6) Excess Declining Death (Table A3) 1000's D.R. Deaths RR Deaths 35-39 2.0 5781 0.38 22 4.0 91 40-44 4.4 4252 0.84 36 2.0 97 45-49 10.0 3423 1.91 65 1.32 85 50-51 23 3355 4.4 138 1.17 114 55-59 Sl 3495 9.8 344 1.17 265 60-64 113 3228 22.1 713 1.17 548 65-69 240 2912 47.7 13$S ', 1.17 1062 70-74 480 2030 97.2 1973 ' 1.17 1505 75-79 870 1472 180 2647 1.17 2010 80-8i 1550 547 334 1828 ' 1.17 1374 85+ 2700 100 607 607 1.17 451 Totals 291 30595 31.9 9768 ' 7602

- ~ Adult mortality from passive smoking 261 • Table A5. Annual U. S. male hean deaths from passive smoking. Relative Risk Relative Neversmoker D Exposed P Constant at 1.31 Risk eath Rate opulation Declining Age of 1,, pe r 100,000 (Table A I) Excess Death (Table A3) 1000's 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 t 45-49 68 2440 16.9 411 1.92 929 S0-54 128 2660 32.1 724 1.42 951 SS-59 237 21SS 59.8 1289 1.28 1201 60-64 412 2054 105 2157 1.28 2009 65-69 730 1695 189 3195 1.28 2972 70-74 1150 1099 304 3341' 1.28 3103 75-79 1850 633 S00 3162 1.28 2933 80-8.1 2950 249 819 2039 1.28 1887 85+ 4700 41 1377 565 520 Totals 521 19.120 89.3 M7335 1816i (1966) were taken as 2.3 for males and 2.0 for females. The excess risks were reduced by 2/3 to yield relative risks for misclassified ever smokers of approximately 1.4 for males and 1.3 for females. These were used worldwide with Wells' un- published formulae to calculate the false hean disease relative risks shown on lines 2 of Table S. Appendix B Relative risks for all causes ojdeath and for emphysema and chronic obstructive lung disease Data relating all causes of death with passive smoking for females have been reported for four prospective studies to- talling9537 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 only male data available are 75 cases from Gillis et al. (1984) with_a relative risk of 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. 34.164. is considerably larger than the total for cancer plus heart of 19.359 shown in Table 7. Some of the difference is due to uncertainties in the calculations, but other causes of death that might contribute to the all cause total, based on data in a private communication from Dr. Hirayanka, are cerebrovascular disease, other heart disease, diabetes, and ulcer. Hirayama (private communication. also reported preli- minarily at Sth World Conference on Smoking and Health, Winnipeg, 1983) provides data relating deaths from emphy- sema with passive smoking in women. His relative risk. based on 106 cases ls ;.3 with 95% confidence limits of 0.85 to 2.05. Kalandidi et al,. (1987) report incidence data for chronic ob- structive lung disease based on 103 cases with an adjusted relative risk of about 1.4. l,ee et al. (1986) report incidence data for chronic bronchitis from spouse exposure. Based on 17 cases the adjusted relative risk is 1.22. A weighted average of these three relative risks would be about 1.35. The only neversmoker death rate we have is from Hammond (1966) for emphysema at 2 x 10-s. Assuming 76% exposure, the excess death rate for passive smoking using Eq. (2) would be 0.55 x 10-s and the total deaths for an exposed population of 30.6 million would be about 170. Even if this number is doubled to take into account deaths from forms of chronic obstructive lung disease other than emphysema. it is still far below the total for cancer and ischemic heart disease. Table B1. Female relative risks for all causes of death from passive smoking. l T All Exposures Mantel Trend Locale ota Cases RR 95% C.L. 1-tail p Cohort Studies: Hirayama (1987) Japan 9106 1.17• l.1?- 1.23• 0.01X101 Gillis cr al. (1984) Scotland 102 1.45 0.91-2.30 Garland ci al. (1985) California 79 1.06 0.65-1.73 Vandenbroucke et al (1984)° Holland 250 79 0 57-1 0 09 . . . . -~.•--•-- Combined Chort: 9537 1.165 '' 1:11-1.2: 'Dr. Hirayama (private communication) provided the data necessary to calculate these items. 'Data from 25 year follow up. Relative risk was 0.89 (0.50-1.62) for 15 year follow up. This study is weak in that exsmoking women were included among the "nonsmokers." and rionsmo{;ing women exposed to cxsmoker husbands were included in the '•nonexposed." The weakness of the study is emphasized in that the smoking women had a lower overall death rate (33.4rXc) than the nonExposed nonsmokers (38.1rr).

262 A. J. Wells r Death rates for txposed 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 by the years of followup. The rate difference was then obtained by subtracting the nonexposed death rate from the exposed death rate. Variances 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 s 1.96 (variance)". The results of these calculations are summarized in Table Cl. The cohort data were also combined using Program 7 of Rothman and Boice (1982) with results essentially identical to those shown in Table CI for direct pooling. The relative heterogeneity of the relative risks (RR) vs. the rate differences (RD) can be approximated by considering the range of RR- I versus the range of RD. The range of RR-1 is from 0.16 to 2.6 for a factor qf 46.3. The range of the rate differences is 3.7 to 262 or a fac+tor of 71. The ratio for the two large studies. Helsing et a!. (19$8) and Hirayama (1984b), for RR-1 is 0.24/ 0.16 = 1.5 and for RD is 20.7/3.7 = 5.6. The 95% confidence limits for the rate ratio combination is tighter than for the rate difference combination. Also. the Hirayama study dom- inates the rate difference aggregation much more than in the rate ratio aggregation, providing 64% of the combined weight (last column of Table Cl) in the rate difference case vs. only 17% of the combined weight in the rate ratio case. n Table Cl. Rate difference calculations for female ischemic hean disease. Relative Risk from Table 4 Rate difference x 14` Weights RD x Total Cases RR 95% C.L. RD 95% C.L. for RD x 10•' weight x 10'' Cohort Studies: Hirayama (1984b) 494 1.16 0.9- 1.4 3.7 +-2.1- 9.6 1110 41.4 Gillis et al. (1994) 21 3.6 0.9-13.8 169.1 y 3Q.7-307.6 2 3.4 Garland etal. (1985) 19 3.5 0.9-13.6 262.2 36.0-a88.4 0.8 2.0 Helsing a al. (1988) 988 1.24 1.1- 1.4 20.7 _ '- 0.2- 41.6 ..,....~.~.. 88 18.2 Combined Cohort 1522 1.23 1.1- 1.4 5.4 70.2- 11.1 1201 65.0 'j.able B2. Annual U.S. female deaths from all causes from passive smoking. Decrement Corrected Neversmoker Relative Risk due to heart Neversmoker death rate Constant at 1.165 death at ath d t ct d i l P F i r e 1963-8a e ra e at enrolled age corre e to age of death on opu at tirposed ract on of population Excess pet100.000 per 100.000 per 100.000 1000's exposed D.R. Deaths 35-39 136 3.6 132.4 120 5781 0.94 17.1 991 40-44 178 6.4 171.6 155 4252 0.92 22.2 944 45-49 254 8.2 243.8 212 3423 0.89 30.5 1044 50-54 352 16.8 335.2 300 3355 0.87 43.3 1452 55-59 561 38 523 445 3495 0.84 64.5 2254 60-64 867 87 780 675 3228 0.77 98.8 3190 65-69 1492 171 1321 1070 2912 0.70 158.3 4609 70-74 2585 346 2239 1830 2030 0.59 275.2 .5586 75-79 4790 576 4214 3250 1472 0.49 496.1 7303 80-84 8408 832 7576 6000 5i7 0.29 944.8 5168 85+ - - - 10.000 100 0.10 1623 1623 Totals 30595 111.7 3416a Deaths per million total population 143 Neversmoker Death Rates from Hammond (1966) at Age enrolled age Range per 100.000 Lee eral. (1986) report data on chronic bronchitis life long nonsmoking in males exposed to a smoking spouse. Based on nine cases the adjusted relative risk was 0.34. However, for general exposure (4 cases) a positive relative risk was ob- served. No analysis of these data was attempted. Appendix C Rate difference model for assessing female ischemic heart 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 well established for lung cancer (Wald et 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 to combine it with that from the cohort studies.

t Adult mortality from passive smoking 263 Table Dl. Regional particle deposition from mouth breathing of side stream smoke. Aero- Relative Fraction of inhaled particle mass deposited" Mass i V l i d d dynam c o ume Mass te as epos diameter Cube of Relative (weight) Distribution mouth tracheo- % di total µm diameter eorjcsntration' per 0.1µm °k throat bronchial alveolar mass inhaled 0.20 .008 1.5 0.006 0.3 0 0 0.13 0.04 0.25 .016 6.5 0.051 2.4 0 0 0.122 0.29 0.30 .027 10.0 0.135 6.4 0 0 0.115 0.74 0.35 .043 13.0 0.280 13.2 0 0 0.108 1.43 0.40 .064 13.0 0.416 19.6 0 0 0.10 1.96 0.43 .091 6.5 0.296 14.0 0 0 0.105 1.47 0.50 .125 3.5 0.328 15.5 0 0 0.11 1.71 0.60 .216 1.25 0.270 12.7 0 0 0.115 1.46 0.70 .343 0.5 0.172 8.1 0 0 0.12 0.97 0.80 .512 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_00 2.118 99.9 11.08 •From Hiller u a!. (1982). Fig. 1. "From Heyder (1984). Table 1. 250 cm'/second mean flow rate. 4 second breathing cycle. This domination of the rate difference model by the Jap- anese study is evident from some rough death calculations. Use of the combined rate difference (5.4 x l0-`) with the exposed female population from Table A4 (30.6 million) yields total deaths of 1.652 compared with 9.768 calculated from the constant rate ratio model. When the rate differences are plotted against age of death and weighted accordingly it is found that the "western" 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 year age ranges and multiplying by the corresponding exposed pop- ulations yields a total of about,2,100 deaths compared with 7.602 in the se;ond relative risk model. Use of the Japanese data alone yields about 1.200 deaths. Use of only the ••west- ern" data (Gillis et al.. 1984; Garland et al.. 1988; Helsing et al.) at a constant rate difference yields 7.950 deaths while use of "westerA" data with the rate difference varying with age yields about 30.000 deaths. Thus. the death calculations using rate differences are quite volatile. Also, it is evident that with the rate differences it is not feasible to carry over the "eastern" experience, in ischemic heart disease at least, for use in a"western" setting. Accordingly. it was concluded that'the absolute risk model is not as suited to combining risks for passive smoking as the relative risk models. Table D2. Regional particle deposition from nose breathing of sidestream smoke. Aero- d Fraction of inhaled particle mass deposited" Mass deposited as g~r of total mass ynamic diameter Mass distribution mouth tracheo- inhaled µm K• nose throat bronchial alveolar nose alveolar 0.20 0.3 0 0 0 0.19 0.00 0.06 0:25 2.4 0.005 0 0 0.172 0.01 0.41 0.30 6.4 0.01 0 0 0.155 0.06 0.99 0.35 13.2 0.015 0 0 0.138 0.20 1.82 0.40 19.6 0.02 0 0 0.12 0.39 2.35 0.45 14.0 0.03 0 0 0.122 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 0.129 0.64 1.63 0.70 8.1 0.06 0 0 V.13 0.49 1.u5 0.80 6.0 0.077 0 0 w33 0.46 0.811 0.90 1.7 0.093 0 0 41.137 0.16 0.23 1.00 0.0 0.11 0 0 0.14 0.(10 001 3.45 1'.99 'From Table Dl. •From Heyder (198a). Table 2. 250 em' second mean flow rate. 4 second brjeathing cycle. ~

.264 A. J. Wells Table D3. Smoke Particle deposition patterns in direct and passive smoking. Direct Smoking Passive Smoking DirectrPassive Entry site Particulate inhaled per day. mg. Mouth 240 Nose 2.8 86 Particle Size inhaled. µm 0.7 0.4 Particle size exhaled. µm 0.7 0.4 Retained in nose. °k 0 3.5 Retained in mouth. % 25 0 Retained in tracheo-bronchial region. % 35 0 Retained in near alveolar region.'t: 11 0 Retained in deep alveolar region. ck 9 J3 Total retained. % 80 16.5 Particulate retained, total, mg. 192 0.16 417 Particulate retained, alveolar, rrig. 48 0.36 133 Particulate retained, deep alveolar. mg. 22 0.36 61 Appendix D Dose consideratforu 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 calculations for passive smoking are reasonably straightforward. Stober (1984) has summarized all the uncer- tainties in this type of calculation. Nevertheless, the best ap- proach 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 model of Heyder (1984) 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. yields exactly the total deposition observed by Hiller et al., (1982) indicating that the Heyder model holds for passive smoking. The same inhaled particle size distribution can then be applied to Heyder's nose breathing case (see Table D2) which yields nasal deposition of 3.5% and deposition in the alveolar region of the lung of 13.0%. The model predicts zero deposition for both the mouth/throat and the tracheo-bronchial regions. From the deposition curves of Gerrity et al. (1979) (Fig. 2) for iron oxide extrapolated to a particle size of 0.25 µm (which is equivalent 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 80% of the inhaled smoke is retained, that 15 to 35% is retained in the mouth, and that the exhaled particle size is also about 0.7 µm. The Heyder model at 0.7 µm would predict total retention of only 12%. To achieve 75% retention, the Heyder model would require an effective particle size of 6.5 µm. Main stream smoke is known to agglomerate, but if it agglomerated to 6.5 µm, the exhaled smoke, according to the Heyder model, 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 µm and that the smoke exhaled froM the lung after a 5 second retention period had a mass mediari diameter size of 0.65 µm. Let us assume that the 0.65 µm part of the smoke follows Heyder's model and that 20% 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 12% of 22.7% of the total smoke in- haled. or 2.7% of;the total inhaled smoke. The balance of the inhaled smoke (17%) would have a larger average particle size, about 1.3 µm. Black and Pritchard (1984) found. based on clearance data, that the rates of alveolar deposition to alveolar plus tracheo-bronchial deposition in direct smoking is 0.36. Also, as nQted, some amount, say 25% of the total inlet smoke should deposit in the mouth and throat, all of which would have tp come from this larger size fraction. Sum- marizing these numbers, of the 100 - 20 - 25 = 35% of total smoke particulate that reaches the lung and is not ex- haled. 0.64 x 55 * 35% deposits in the tracheo-bronchial region and 0.36 xtS - 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 larger particles. Based on the alveolar/tracheo-bron- chial split and usingthe curves of Gerrity ct al. (1979) it would be. expected that about 2/3 of the alveolar deposit or 11% 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- mentation (the Heyder model) do not account for it. Stober (1984) suggests that electrical charges in the newly generated smoke particles (se ~Aetandri et at., 1983) may account for some of it. Arlothe>~possible mechanism is the cloud settling phenomenon as de4cribed ~by Fuchs (1964). Whatever the 'trt charlisrtt, a reasonably clear idea of the regional deposition ~tjttertts from direct and passive smoking a,

•,, . _.. ... ..~~~~. num passY.•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 ol. (19$6) is correct that there is a direct passage for toxics from the nose to the brain. it could also account for the observed brain cancer. In the deep alveolar region the ratio of direct to pas- r- :hi sive deposition is much closer to the inhaled ratio than to the "total retained" iatio. It is from the deep alveolar region that the smoke panicl,es are solubilized and cleared into the blood and lymph systems possibly to cause cancers of the liver, breast and endocrine glands, leukemia. lymphoma and ar- terial plaques.