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f 184 Lee. P. N. An estimate of adult mortality in the U.S. from passive smoking; a response. Environ. Int: 16:179-181; 1990. Katzenstein; A. W. An estimate of adult mortality in the U.S. from passive smokiag; a response. Environ. Int. 16:173-177; 199 Repaee, J. L.; Lowrey, A. H. Risk assessment me giea in passive smoking. J. Risk Anal. lin p VYa USSG (U. S. Surgeon General cing the health consequences of smoking. 25 of progress, a report of the Surgeon tAa 1co t,.,)6, L • e. E MV. I' Y M. AN ESTIMATE OF ADULT MORTALITY IN THE UNITED STATES FROM PASSIVE SMOKING; A RESPONSE Dear Editor: • MOTICE TWs material may, b` Proteeted by coPyr;ght la* Mre 17 U S, Cod-iJ Letters to the editor General. Washington. D.C.: . ept. of Health dt Human Services; 1989 Wall .. ajor sources of benzene exposure. Environ. Health Perspecu 82:165-169; 1989: Weiu, S: T. Passive smoking and lung cancer: what ii the risk? American Rev. of Resp. Dis. 133:463-465; 1986. Wells, A. Jl An estimate of adult mortality in the United States. Environ. Int. 14:249-265; 1988. 5,,,4.. [ G C'z) ~. ~~ ~-,37 1°l `t u' with ETS exposure. These calculations do not in any way establish that ETS does, in fact, cause death in exposed individuals. Rather, such calculations: rely on an independent conclusion, based on a review of the available data, that ETS causes lung cancer, other cancers, and cardiovascular diseases. If such~ a con- clusion cannot be supported, then the estimate of ETS-associated mortality rests on the assumption that ETS causes these diseases, and it is incumbent upon the author to state this underlying assumption when reporting the results of his calculations. The issue of causation is never addresse& by Wells. The studies cited in Weils"Tables 1-4 are discussed below with particular attention to whether they es- tablish a causal relationship between ETS and dis- ease in non- or never-smokers. The vast majority of the studies were included in reviews published by the National Academy of Sciences (NAS 1986) and the Surgeon General (USSG 1986). Therefore, these re- ports are used as a starting point for addressing the question of causality. Lung Cancer: Almost all of the epidemiological studies listed in Wells' Tables 1 and 2 were consid- ered in the NAS an& Surgeon General's reports, as well as other reviews appearing at about the same time (Blot and Fraumeni 1986; ilberia 1987). The Surgeon General's Report was alone in concluding that ETS causes lung cancer in nonsmokers; the other reviews generally concluded that although a statisti- cal' association appeared to exist between marriage to a smoker and the risk of lung cancer, the lack of adequate exposure information, and the potential in- fluence of differential misclassification of smoking status precluded a conclusion of causality. The lung cancer studies published since these reviews have the same limitations as the previous studies. Little has been published since 1986 that adequately addresses the issues of exposure and misclassification. All of the studies attempting to link cancer to ETS have been epidemiological. An epidemiology study attempts to relate the frequency of a certain health effect or disease with the frequency of specific envi- An article in Inside EPA (January 13, 1989) is headlined: "EPA weighs Impact of Study Linking Passive Smoke Exposure to Heart Deaths..." It leads with the statement: "EPA is giving serious attention to a recently published study that pinpoints passive smoking ... as a significant cause of heart disease and cancer-related deaths". The article states: "Pas- sive smoking causes 46 000 deaths a year, according to a study by A. Judson Wells published last month in Environment Internationa!". An EPA source is quoted: "The 46 000 mortality was surprising be- cause such a large component was from heart disease ..." This statement is similar to one made by EPA's James Repace on national television when the report was first released. What is surprising is that anyone from the EPA can consider this recent review surprising. Dr. Wells has not completed an epidemiol'ogicat study, new or oth- erwise, and has in no way contributed to pinpointing passive smoking as a significant cause of heart dis- ease, lung cancer, or other cancer deaths. What he did was publish the results of a series of calculations based on the results of existing epidemiological stud- ies and a number of assumptions (Wells 1988). Dr. Wells presented a similar analysis at the 1986 Air Pollution Control Association meeting,, which was published in the meeting proceedings (Wells 1986). There should have been no sudden surprise at EPA; an EPA official chaired the 1986 session in which this paper was presented. Dr. Wells encourages the view that he had done something new by failing to even acknowledge his previous presentation. Wells used the data of previously published (and in some cases, unpublished) studies as a basis for calculating annual mortality statistically associated'

Letters to the editor ronmental exposures within a study group. Because of the nature of this type of study, all it can conclude is that the exposure and health effect do occur to- gether with a measurable frequency. They do not prove a cause and effect relationship. Koo et al. (1988) performed a detailed investiga- tion of potential confounding factors in the llfestyle of nonsmoking women married to either a nonsmok- ing spouse or a smoking spouse. Overall, women married to ever smokers had a less healthy li'festyle,, ate less vitamin A vegetables, ate more cured foods, ate more spicy foods, and drank more alcohol than women married to nonsmokers. Their analyses show that caution should be exercised when interpreting data on ETS without considering other factors. Feinstein (1988) described some of the problems or failings that have come to characterize many epi- demiological studies. Several examples are given where commonly used substances were accused of being a menace to daily life after epidemiologists reported a relatively weak association between use of the sub- stance and adverse health effects. Some of these accusations have subsequently been refute& or with- drawn. Feinstein states that "[d]espite peer-review approval, the current methods need substantial im- provement to produce trustworthy scientific evidence". Other Cancers: With the exception of the Reyn- olds et al. study (which is unpublished and, therefore, inappropriately included' in the analysis), all of the studies cited in Wells' Table 3 were included in the NAS and Surgeon General's reports. The NAS con- cludes that there is no consistent evidence, based on these studies, of any increased risk of ETS exposure for "cancers other than lung cancer". The Surgeon General's report similarly suggests that further in- vestigation will be needed before any conclusion can be made. Cardiovascular Disease: Wells suggests that a con- siderable body of new epidemiological data on ETS and cardiovascular disease has become available, which significantly impacts the analysis of data for this disease endpoi~nt. This assertion is emphasized in the Inside EPA report. In fact, with the exception of Helsing et al. (1988), all of these data were avail- able to the NAS and Surgeon General's review pan- els. The study of Martin et al. was available at the time but was unpublished, and for good reason, it thus was not cited in these reviews. The study re- mains unpublished, and the data should not be in- cluded in the present analysis. Both the Surgeon General's and the NAS reports find the data on ETS and cardiovascular disease, available at the time of their reviews, to be inconclu- te5 sive. The inconclusiveness of the studies reflects not only small sample sizes but also a number of signif- icant deficiencies in their design, as detailed in both the NAS and Surgeom General's reports. The ques- tionable mathematical combination of the findings of these studies, as done by Wells, overcomes the prob- lem of small sample size but in no way addresses the methodologic issues that have been raised'. The prospective study of Helsing et al. (1988) reports a statistically significant increased risk of death from cardiovascular disease in nonsmokers ex- posed to tobacco smoke im the home compared to those not so exposed. The authors of the study con- clude that "[iJt seems reasonable to suppose that tobacco smoke is a risk factor in the increased risk". That rather weak conclusion reflects, in part, some aspects of the Helsing study that are inconsistent with such a conclusion. For example, the relative risk (RR), of death from heart, disease associate& withh household exposure to ETS is reported as highest in the youngest age group studied (25-44 years old), even though the individuals in the older age groups presumably were exposed to ETS for much longer periods. Given the same estimate of household expo- sure, individuals in the older age groups would be expected to have had a higher risk of cardiovascular death than those in the younger group. Both the Surgeon General's and NAS reports are cautious in their discussions of the quantitative risk associated with ETS exposure. Appendix D of the NAS report, which Wells cites in support of his risk models, emphasizes the underlying assumptions on which the calculations for lung cancer are based. The results are summarized in a section entitled, "Sum- mary of Main Results Under the Assumption That the Summary Rate Ratio of 1.3 is Causal". The Surgeon General's report states (p. 96): "The quantification of the risk associated with involuntary smoking for the U.S. population is dependent on a number of factors for which only a limited amount of data are currently available". These factors include a better understanding of the magnitude of ETS exposure, its distribution among different segments of the U.S. population, and changes in the patterns of ETS expo- sure that have occurred over the last century. There is no better understanding of these factors now than there was in 1986. Wells bases his exposure estimates on data published by Friedman et al. (1983) - data that apparently were considered to be insufficient byy the authors of the Surgeon General's report. As Wells depended to a large extent on the Helsing (1988) report, it is important to review carefully the methodology used in that report. A general census

186 was taken in Washington County, MD, in 1963 that included, among other factors, smoking histories of families and number of rooms in the house. Twelve years later, Helsing and colleagues reviewed death certificates to determine cause of' death over the 12 years. They noted those deaths that were coded as arteriosclerotic heart disease and other myocardial degeneration. They then calculated a relative risk of death due to arteriosclerotic heart disease of non- smokers married to smokers versus nonsmokers mar- ried to nonsmokers. The relative risks were 1.31 for men and 1.24 for women after adjusting for age, marital status, years of schooling, and quality of housing. It is very important to note that the authors re- ported that there was a small difference in RR if heart disease was listed as the underlying cause of the death or just li'stedion the certificate as one of several reasons for death. The actual cause of death as listed on death certificates could in itself be a confounding factor in this study. In addition, overall' relative risks were adjusted for age, marital status„etc. There is no description of how the quality of housing is calcu- lated or adjusted for, nor is there any attempt to look at other possibly related health factors in the sub- populations to determine if these factors could have influenced arteriosclerotic heart disease. In addition, no attempt was made to measure smoking status mis- classification. Wells concludes his report by suggesting that ex- posure to ETS actually may cause more than 46 000 additional deaths per year. He quotes Repace and Lowrey (1985) and their estimate of 4665 additional lung cancer deaths as support for that suggestion. The Repace and Lowrey estimate scares a lot of people who have not taken the opportunity to review their underlying assumptions. What is overlooked in the emotionalism is what the Repace and Lowrey report really says. Repace and Lowrey start with the assumption that direct smoking and ETS both cause cancer. They do nothing to prove this. They then use a long series of estimates of exposure concentrations and exposure durations to compare ETS exposure to direct smok- ing. Finally, they calculate the death rate from lung cancer using these assumptions and estimates. What they generate is a calculated guess., not a prediction based on facts. Most of the research done since the Repace and Lowrey study has not supported its findings. One of the better studies has calculated that a person ex- posed to ETS actually retains 0.02 percent (or 1/5000) Letters to the editor of the particulates of a direct smoker (Arundel et al. 1988): Repace and Lowrey calculate a nonsmoker to be exposed to an average of 1.43 mg/day of particulates from ETS. Arundel et al. calculated the amount to be 0.07 mg/day for male nonsmokers and 0.03 mg/day for female nonsmokers. These two estimates of ETS exposure differ by a factor of between 20 and 45. Thus, estimates based on exposure assumptions and models are simply estimates. One needs only to change a few of the basic premises to arrive at a completely different set of conclusions. Wells' reliance on as- sumptions derived from the exposure assumptions of Repace and Lowrey leave his own conclusions highly questionable. It is apparent from this brief overview that Wells' computations rely on risk ratios derived froml epide- miological studies that do not establish a causal link between ETS exposure and the risk of disease. What part, if any, of the association between marriage to a smoker and lung cancer or cardiovascular disease is due to ETS is a matter of debate. Resolution of that debate depends on further research to address the exposure and misclassification issues. Pending reso- lution of these questions, Wells is obligated to state and fully discuss the assumptions that underlie his calculations. Larry C. Holcomb, Ph.D. Holcomb Environmental' Services Olivet, MI 49076 REFERENCES Arundel, A.;, Sterling, T.; Weinkam, J. Exposure and riskbased estimates of never smoking lung cancer deaths in the U.S. in 1980 from exposure to ETS. In: Indoor and ambient air quality. London: Selper Ltd.,1988; 242-251. Blot, W. J.; Fraumeni„J. F. Passive smoking and lung cancer. J. Nat. Cancer Ina. 77:993-1000; 1986. Feinstein, A. R. Scientific standards in epidemiolo8ic studies of the menace of daily life. Science 242;1257-1263; 1988. Friedman, G. D.; Petitti,, D. B.; Bawol, R. D. Prevalence nd correlates of passive smoking. Amer. J. Pnbl. Health 73:401- 405; 19Y3. Helsing, K. L; Sandler, D. P.; Comatock, G. W.; Chee. fi. Heart disease mortality in nonsmokers living with smokers. Amer. J. Epid. 125:915-922; 1988. Koo„ L. C.; Ho. J. H.; Rylander„ R. Lite-history correlates of environmental tobacco smoke: a study on nonsmoking HonB KonB Chincse wives with smoking versus nonsmoking hus- hands. Soc. Sci. Med: 7:251-260; 1988. NRC (National Research Council). Environmental tobacco smoke, measuring exposures and assessing health effects.. Washington, D.C.: National Academy P'reas; 1986.

Leaers to the editor Repace, J. L; Lowrey. A. H. A quanuutive estimate of nonsmokers' lung cancer r'uk from passive smoking. Environ. Int. 11:3-22; 1985. USSG'(U. S. Surgeon General). The health consequences of invol- untary smoking. Rockville, MD: U. S. Department of Health and Human Services; 1986. Oberla, K. Lung cancer from passive smoking: hypothesis or con- vincing evidence? Int. Arch. Qccup~ Environ. Health 59:421- 437; 1987. AN STIMATE OF ADULT MORTALITY IN' THE UNIT STATES FROM PASSIVE SMOKING;. A RESP NSE TO CRITICISM Lee (1990), Katze tein (1990), and Holcomb (1990) have commented nega ely on my paper (Wells 1988a) in Environment lnterna " nal, im which it was sug- gested that the U.S. death 11 from passive smoking may be 46 000 per year. Spa e does not allow me to deal with alU of the points raise but the more impor- tant ones are covered below. Lee, as tobacco consultants usua do, attacks the underlying studies that 11 used, partic arly the heart studies. I cannot speak for these authors. . Hirayama has written a reply of his own. Dr. Sandl (private communication) has told me that they (Helsi et al. 1988) did look at family size and found no effec The Johns Hopkins School of Public Health (Helsin et al. 1988) and the University of California, San Dieg (Garland et al. 1985) are respected schools of epide- miology, whose researchers presumably know how to adjust for confounding variables. They attempted, within the limits of the data available, to account for known heart risk factors as noted in my paper. What is striking about the heart data in my Table 4 (Wells 1988a) is the consistency of the various results. It is interesting that Lee et al. (1986) made no attempt to adjust for any of the known heart risk factors except age. Publication bias in smoking studies is an issue often raised by tobacco industry consultants, but so far no one has found a live passive smoking case that is negative. I have dealt with that issue vis-8-vis passive smoking and male lung cancer in my com- ment (Wells 1988b) on Vandenbroucke (1988)., There, it was pointed out that the only available unpublished data were on the high side of the most probable relative risk, not low or negative. In that letter, I asked investigators to send me any data on passive smoking that had not been published or that they had 187 Wells, A. J. Passive rmok'ing mortality: a review and preliminary assessment. 79th Annual Meeting. Air Pollut. Control Assoc., Minneapolis, MN; 19$6. Pittsburyh, PA: Air Pollut. Control Association; 1986. Wellit„ A. J. An estimate of adult mortality in the United States from passive smoking. Eaviron, Int. 14:249-265; 1988. not been able to get published. So far I have received none. As Lee says, the possibility of a large, unpublished data set that found nothing cannot be excluded; it is just extremely unlikely. For cancers other than lung that are passive smok- ing related, all except nasal sinus cancer and lung cancer are non-contact sites, as is heart disease. For these sites to be activated, the disease-producing entities must, in most cases, be metabolized and then circulate in the blood and lymphatic systems: Earlier work (Eatough etal. 198b) has shown that 90% of the nicotine in environmental tobacco smoke (ETS) is in the vapor phase. Now Pritchard et al. (1988) have shown that 70% of the tar in ETS is also in the vapor phase. The nicotine and the tar in direct smoking is in the particulate phase. It is true, as Lee says, that smokers are also passive smokers, but for the non- contact sites there is growing evidence that smokers have a higher risk if they are exposed to ETS other than their own than if they are not so exposed. For example, Palmer et al. (1988)~ found a relative risk for heart disease of 1.34 for spouse ezposureof light oking women and 1.32 for heavy smoking women, an ' Sandier et al. (1985) found overall cancer risks incr sing from unity to 2.4 as active smokers were expose to an increasing number of household mem- bers who oked. This means that smokers may also be at consi rable risk from passive smoking of their own smoke. I ther words, for the non-contact sites, the vapor phase and nicotine may be the primaryy culprits, with the p icutate phase having less effect. The particulate phas at least most of it, is relatively quickly cleared. It pro ably contributes heavily to the contact sites (central I g, mouth, esophagus, and stomach) but then may beel' inated in the feces. All' this means that Lee's model or passive smoking, which is based on direct smo " g and particulate phase deposition and retention, i Iikely to predict relative risks for passive smoking th are far too low for the non-contact sites and probably r peripheral lung cancer as well.