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PASSIVE Sl+IOKING AND HEART DISEASE: A Compendium of Technical•Information CHAPTER 11 PASSIVE S!lORING AND HEART DISEASE EPIDEKIOLOGY, PHYSIOhOGY, AND BIOCHEMISTRY I am Director of the Epidemiology Consulting Group at New York Medical College, and an Adjunct Associate Professor of Community and Preventive Medicine at the same institution. I received the Ph.D. degree in Epidemiology from Yale University in 1979. I was formerly a clinical research scientist at American Home Products and Pharmacia Opthalmics, two pharmaceutical companies, as well as a health care researcher at Blue Cross and Blue Shield of Greater New York. Currently, as Director of the Epidemiology Consulting Group, I have executed epidemiological analyses for numerous drug, chemical, and health companies. My curriculum vitae is attached. I have been asked to review "Passive Smoking and Heart Disease: Epidemiology, Physiology, and Biochemistry," by Stanton A. Glantz and William W. Parmley, which is Chapter 11 of a draft

EPA compendium of technical literature on environmental tobacco smoke (ETS). I will confine my comments to the epidemiology section of the chapter. I. INTRODUCTION In this chapter, Glantz and Parmley review the epidemiological evidence concerning exposure to ETS and heart disease in humans. They cite on page 3 "eleven published" 9 studies. However, they only review and discuss ten studies. Moreover, the study by Martin has not been published, although it was ostensibly presented at the American Public Health Association Conference in October, 1986. The article by Humble is ostensibly in press in the American Journal of Public Health. Neither study is available at this time for review. Therefore it is impossible to determine the validity of Glantz and Parmley's analysis of these papers. The article by He (1989) is available only in Chinese with only the abstract in English, thereby limiting my ability to comment on this study. It is clear, howeveri that the He paper is a retrospective case-control study having only 34 cases, and it is fraught with all of the methodological problems surrounding retrospective case control studies, such as poor recall of ETS exposure and smoking behaviors. I will address the remainder of this paper to the work that has been published on the reported relationship between exposure - 2 -

to ETS and cardiovascular disease. In my view, the studies conducted thus far do not demonstrate that ETS increases the risk of cardiovascular disease. Accordingly, I disagree with many of the conclusions presented by Glantz and Parmley. First of all, the authors' point that "Despite minor changes in methodology, or end points. .. the results of these studies are remarkably consistent," is inaccurate. In fact, the studies vary greatly in their ability to measure ETS exposure adequately, to control for misclassification of smoking status, and to control for numerous important confounding variables. Second, although Glantz and Parmley argue that all of the studies except one report relative risk greater than 1, and imply that this supports a finding of statistical or clinical significance, or even epidemiological proof of causation, I would argue that this is indeed not the case. Third, Glantz and Parmley contend that the conclusions of the Surgeon General (USPHS 1986) and National Academy of Sciences (NAS 1986) are no longer valid.because of studies made available since those reports. As discussed further in this critique, I disagree and believe that the conclusions of the Surgeon General and NAS remain valid. II. EPIDEMIOLOGICAL CRITERIA In epidemiology, it is crucial to distinguish between association and causation. An association merely raises the possibility that causation may exist and suggests that further investigation is warranted. To justify even an inference that - 3 - .;.:..w:.a....~...:.~....:.....;..4.~.,.,._.,.._..~.~...~-.;~. . ,.. .._

epidemiologic data may suggest causation# five criteria must be First, the statistical association shown by the data must be sufficiently strong: There must be a statistically significant increase in the incidence of the disease in the exposed population compared with the non-exposed population, and, for the association to be regarded as meaningful, a relative risk of 2.0 or greater is generally considered necessary. Although there is no precise definition of a"weak" association, relative risks of less than 2.0 are generally considered to be weak. indeed, the noted epidemiologist Jerome Cornfield contended that any relative risk under 3.0 might be considered weak (Wynder 1987). Further, the association should be dose-dependent, that is, higher doses are associated with higher incidence of disease. Second, consistency of the statistical association must exist among the relevant studies. Similar rates of disease must occur at different times and places, under comparable study designs. Third, exposure to the agent under study should have occurred at a reasonable time before the onset of disease, given what is known about how long it takes for a particular disease to develop. ..w..~„..,,,~,.>.........,Y...,.. ....~,~,,...,,~...: . R

Fourth, the statistical association must be specific to the agent under study. Exposure must be shown to be associated with the relevant disease•while controlling for all confounding variables. Fifth, there must be biological plausibility. Under experimental conditions, exposure to the pertinent substance (or similar substances) must be shown to cause biological changes that can lead to the disease in question. Given these five criteria, one must reject Glantz and Parmley's implication that consistency, standing alone, is enough to support a conclusion that an association is causal. I agree with Glantz and Parmley that it is particularly important to control for confounders in epidemiological studies of heart disease. The Framingham Heart Study (Seltzer, 1989), for example, has shown that the following variables are all potential confounders for heart disease: age, sex, cholesterol level, blood pressure, weight, socioeconomic status (including income, occupation and education), and adequate measurement of environmental factors. Glantz and Parmley take the position that, as a whole, the published epidemiological literature adequately controls for these confounding variables. A thorough analysis of this literature does not support their conclusions. Each of the published studies fails to control for one or more important confounding variables, including lifestyle, blood . _~ ~_~~: . ,... . ~. .. •.., ., ..,,-,...._ .

pressure, serum cholesterol, obesity and socioeconomic status. Furthermore, none of the studies provides an adequate measurement of ETS exposure. Additionally, none of the studies demonstrated a specificity of association between ETS exposure and cardiovascular disease. All of the studies suffer from one or more serious methodological problems, including small sample size and possible misclassification of spousal smoking status.. These confounding variables and methodological problems also preclude. any demonstration of consistency of association among the III. PUBLISHIED STUDIES There are seven published epidemiological studies examining exposure to ETS and cardiovascular disease: five are prospective studies and two are retrospective case-control studies. The designs, findings and methodological problems are summarized in Table One. To support my conclusions, a complete analysis-of each study follows. To begin with the prospective studies, I note first that Hirayama's work has several major methodological problems. First, there is potential misclassification of smokers and non- smokers. Many of the wives who stated they were non-smokers may in fact have been ex-smokers or even current smokers, and thus 6 - ~.~v.~.:v., ~.... ~.u _ _... - - .~. .~. ._ ....~.~.... ._ ~_

likely to have had or continue to have direct (as opposed to indirect) exposure to cigarette smoke. Second, Hirayama's study included a disproportionate number of women of lower socioeconomic status. In Japan, these women live in much closer proximity to their cooking quarters and may have more exposure to charcoal or kerosene stoves than women of higher socioeconomic status. This exposure has been associated with lung cancer in women in Hong Kong. Women in Japan of higher socioeconomic status live farthex away from their kitchens and are more likely to use electric burners. The Hirayama study failed to control for these confounding variables, which may well be associated with ischemic heart disease. Third, there is the problem of misclassification of dose response. Ex-smoking husbands were lumped with current cigarette smokers of 1-19 cigarettes/day. Because ex-smokers are very different in their cigarette exposure rates and lifestyles than smokers of 1-19 cigarettes/day, this factor could skew the data. Fourth, Hirayama examined only the exposure of the wife in the context of the husband's cigarette smoking behavior. No attempt was made to quantify any exposure to ETS outside of the home, such as in the workplace. Fifth, the population studied by Hirayama was not representative of Japanese society but only of an agriculturally - 7 - ,«+w...w.:+ww...*...e,~....~....v..... ~w... :,.....,.......,.~,+_ . ~..~-~.-- .«,._..,w...

based population, which is not typical for Japan. In addition, six prefectures were chosen to participate in.the study based on the fact that they appear to have had the best conditiohs for collecting data. Hence, random sampling was not used. Sixth, the Hirayama study did not control for other risk factors associated with cardiovascular disease, such as systolic blood pressure and plasma cholesterol. Although the Hirayama study offers a],arge prospective cohort to examine the relationship between presumed exposure to ETS and ischemic heart disease, one cannot draw definitive conclusions because of the methodological problems that I have mentioned. B. Garland The next study, by Garland, also exhibits important methodological difficulties. First, Garland later reported a corrected relative risk of 2.7 (not 14.9 as reported in his 1985 publication). The p value is still less than .10 and not statistically significant. Second, after 10 years of follow-up in this study, only 19 deaths from ischemic heart disease occurred.l This small sample size is compounded by the fact that 15 of the 19 deaths occurred in non-smoking women married to husbands who had stopped smoking . .~ ..~.n....»c.~..a-...,~.,... ,.. .~

at entry. As the study did not ascertain the number of cigarettes formerly smoked per day by'the ex=smoking husbands, it is not possible to measure any sustained effects;of ETS from this former smoking group. Without more detailed characterizations of these women's exposure to ETS, it is difficult to show an association between ETS and ischemic heart disease. The Garland study does attempt to control for certain important cardiovascular confounders,'such as obesity, blood pressure, and cholesterol. The small sample size and the lack of adequate measurement of ETS from a former cigarette smoking group, however, render the results at best suggestive and certainly not definitive. Next, the work by Hole and Gillis also has several methodological problems. First, it does not have sufficient statistical power to demonstrate an association between ETS and ischemic heart disease. The sample size is too small. Second, the relative risk of 2.01 detected for ischemic heart disease for non-smokers compared with controls is too similar to the relative risk of 2.27 for active smokers compared with controls to make sense. The explanation for this is not clear, but may be due to small sample size as well. 9 _ ........... ,..d. ... ~ ..~..,...,.. ..~,, ,~.::,.-. ....... .~,. .... .,.~ . ., _ ..~

Potential biases also exist in the Sole and Gillis study. For example, those exposed to ETS within the home may have had higher exposures to ETS outside of the. Kome compared with controls. A second potential bias is misclassification of women as non-smokers when they may in fact be former smokers or current smokers. Although the Hole and Gillis study suggests an association between ETS and cardiovascular mortality in non-smokers, the data lack any statistical significance. Also, the study reports so(he confusing and similar relative risks for active and passive smokers, and is vulnerable to several important methodological biases. This study would have to be replicated in a much larger study population to achieve adequate statistical power. D. Svendsen With respect to the Svendsen report, one problem is possible misclassification of the husband's smoking status either at entry or subsequently. A second problem is that the wife's smoking status was based on interviews with the husband, and not on direct questioning of the wife. There is also an alcohol-related bias in this study, as MRFIT ETS-exposed husbands had on average two drinks more per week more than non-ETS exposed husbands, and this alcohol effect

could explain the observed statistical significance in dose Finally, by combining ex-smoking husbands with never smokers, the Svendsen paper confounds any.possible past effects of active smoking by the husband with exposure to ETS. The XRFIT study serves in general as an exemplary prospective trial for its design and conduct. 8owever, lack of statistical significance, failure to control for several confounding variables such as alcohol consumption, misclassification, and misgrouping make it difficult to draw any conclusions relating to ETS'exposure from the study. The last prospective study is the work of 8elsing, Sandler and co-workers. The first problem I see here is that the only smoking data that were collected on every person were from 1963. Hence, no changes in smoking habits over the 12-year period were ascertained. In addition, no data were collected on acknowledged risk factors for heart disease such as diet, exercise, blood pressure, and cholesterol. Also, no ETS exposure outside the home was measured. And finally, death certificates were obtained only for those 1963 participants who still resided in Washington County, Maryland, at the time of their deaths. .__.__....~..,.,.,~:..~..~~,Y..,.........~.w,

The only retrospective case-control study in English thus far is the work by Lee. Although this study is one of the few to attempt to examine non-spousal ETS exposure, it raises the methodological difficulties that plague retrospective case control studies in general. In its finding of non-statistical significance for any trends of association between ETS and cardiovascular illness, the Lee paper confirms the need for execution of better controlled prospective trials. In 1989, He reported a retrospective study of 34 women. The odds ratio reported was 3.0 and a significant dose response was reported in the English language abstract of this study, which was itself published in Chinese. Methodological problems of the study include a small sample size and retrospective recall of number of cigarettes smoked. It is impossible to comment further on the study without an adequate translation of the paper from Chinese into English, which is not feasible given the short time period permitted for comments on this chapter. As noted in my critique of the seven epidemiological studies, misclassification is a pivotal variable in accurately - 12 -

determining exposure to ETS. It is critical that a mechanism for accurate measurement of ETS exposure, including exposure outside the home, and adequate follow-up of exposure status be determined. Glantz and Parmley unjustifiably minimize the potential effects of misclassification and assert, without proof, that the effect of misclassification errors leads to an underestimation of the effects of ETS. Without an accurate measure of ETS exposure, their assertion cannot be justified. The Surgeon General's 1986 Report examines the studies of Hirayama, Hole and Gillis, and Garland, and concludes that "further studies on the relationship between involuntary smoking and cardiovascular disease are needed in order to determine whether involuntary smoking increases the risk of cardiovascular disease." Likewise, in 1986 the National Research Council reviewed the prospective studies of Garland, Bole and Gillis, Hirayama, and Svendsen, as well as several experimental designs examining the biological plausibility of the association of ETS and cardiovascular disease, and concluded that: "With respect to chronic cardiovascular morbidity and mortality, although biologically plausible, there is no evidence of statistically significant effects due to ETS exposure, apart from the study by Hirayama in Japan."

In my opinion, contrary to the position taken by Glantz and Parmley, none of the more recent studies in this area provides a basis for altering the Surgeon General's and NAS's conclusions concerning ETS and.cardiovascular disease. Although Glantz and Parmley contend that cultural factors do not confound the interpretation of the ETS and CHD data, I would argue that they do, as illustrated in the previous critiques. Likewise, Glantz and Parmley assert that several studies showed a dose-response relationship between increasing amounts of ETS exposure and the risk of heart disease, and that this indicates a "real effect" of ETS on heart disease. I believe this conclusion is unjustified and is contradicted by a careful evaluation of the epidemiological studies. The few studies that reported statistically significant dose response relationships were invalidated by serious methodological flaws. I agree with the statement of Glantz and Parmley that most of the studies cited do not yield statistically significant relative risks. In addition, most of the studies have low to moderate power and are not capable of supporting a conclusion that ETS elevates the risk of heart disease. The authors assert that the two studies (Helsing 1988; Hole 1989) that have power above the desirable level of 80% "identified significant increases of heart disease with ETS exposure," and imply that these studies should be given greater - 14 -

weight than the other studies. This analysis fails to account for the fact that there were only 84 cases in the Hole study, and Helsing failed to control for important confounding variables such as diet, exerciser blood pressure, and cholesterol. Glantz and Parmley "pool the results of these studies to increase the power of the tests and so produce estimates of risk that are significantly elevated." They cite a pooled relative risk of 1.3 for men, and in a second analysis they cite a pooled relative risk of 1.2 for women. Even assuming that this pooling technique is justified, both pooled relative risks fall significantly below 2.0, which is generally regarded as necessary to support causality in epidemiology. In addition, for many of the reasons already cited in the individual critiques, pooling studies that are fraught with existing biases and confounders only leads to a pooled relative risk which combines and strengthens the effects of the biases and confounders. Such a meta-analysis is intrinsically unreliable. I disagree with Glantz and Parmley's implication that scientists currently understand the true exposure of ETS in the home, and in the workplace. Without a mechanism for accurate measurement of ETS exposure, including exposure outside the home, and adequate follow-up of exposure status, it is impossible to come to any definite conclusion as to actual ETS exposure levels. This conclusion is supported by the findings of Schieveblein and Richter (1984). They report that, under real-life conditions,

persons exposed to ETS inhale only one to two percent of the amount of particulate matter taken„up by active smokers. Also, level, and the increase in carboxyhemoglobin rarely~exceeds 1%. within a=ange that is barely distinguishable:..fr,om the,background nicotine concentration in serum of ETS-exposed individuals is The authors thus conclude that "passive smoking is not likely to have an effect on the development and progression of CBD."' At a November, 1989 international symposium on ETS'at McGill University in Montreal, in which I participated,• the participants expressed the view that the available epidemiological studies examining the relationship between ETS and coronary heart disease report at most a small statistical association, and that ETS is unlikely to contribute significantly to the incidence of coronary heart disease. This view is in sharp disagreement with Glantz and Parmley's conclusions, and provides further evidence of the weaknesses of Chapter 11 of the draft EPA ETS compendium. .~......,,,.~.~.~:a,w...~..r,..~.~_.....,.,.~..~..:~:.:,..:........~......~..~..,,,.~:~,..~.....~,..

References Ecobichon, D.J.; Wu, J.M. En'vironmental Tobacco Smoke: Proceedings of the International Symposium at McGill University. Lexington Books 1990. Environmental Tobacco Smoke - Measuring Exposures and Assessing Health Effects, National Research Council, National Academy Press, Washington, D.C., 1986. Garland, C. et al. (1985). Effects of passive smoking on ischemic Heart disease mortality of non-smokers. American Journal of Epidemiology 121(5). Helsing, K.J., D.P. Sandler, G.W. Constock, and E. Chee, (1988). Heart disease mortality in non-smokers living with smokers. American Journal of Epidemiology 127(5). Hirayama, T. (1984). Lung cancer in Japan: Effects of nutrition and passive smoking. Lung Cancer: Causes and Prevention. Verlag Chemie International, Inc. Hirayama, T. (1981). Non-Smoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan. British Medical Journal 282:183-185. Hole, D.J., C.R. Gillis et al. (1989). Passive smoking and cardiorespiratory health in a general population in the west of Scotland. British Medical Journal 299:423-427. - 17 -

Lee, P.N., J. Chamberlain, and M.R. Alderson (1986). Relationship of passive smoking to risk of lung cancer and other.r smoking-associated diseases. British Journal of Cancer 54:97-105. Schievelbein, H. and F. Richter (1984). The influence of passive smoking on the cardiovascular system. Prevention Medicine 13:626-644. Seltzer, C. (1989). Framingham study data and established wisdom about cigarette smoking and coronary disease. Journal of Clinical Epidemiology 42(8):743-750. Surgeon General's Report (1986). The Health Consequences of Involuntary Smoking. U.S. Department of Health and Human Services. Svendsen, K.H., Lewis H. Kuller et al. (1987). Effects of passive smoking in the multiple risk factor intervention trial. American Journal of Epidemiology 126(5). Wynder, E.L. (1987). Workshop on guidelines to the epidemiology of weak associations. Prevention Medicine 16:139- 141.