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I I I I I i I I I I I I I I I I I I COMMENTS ON ENVIRONMENTAL TOBACCO SMOKE A Compendium of Technical Information CHAPTER ii PASSIVE SMOKING AND HEART DISEASE EPIDEMIOLOGYr PHYSIOLOGY, AND BIOCHEMISTRY Prepared by Joseph M. Wu, Ph.D. I am a Professor in the Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York. I received my Ph.D. in biological sciences from Florida State University in 1975, spent two years as a post-doctoral fellow in the Department of Biochemistry, Temple University, and joined New York Medical College in 1978. My research interests are in the following areas: (i) developmental and hormonal regulation of enzyme synthesis and degradation, (2) control of eukazyotic cellular proliferation and differentiation, (3) biochemistry of 2', 5' -oligoadenylate synthesis and expression in normal and interferon-treated mammalian cells, (4) studies of biochemical changes in Alzheimer's Disease cells, and (5) modulation of gene expression by environmental agents. I have been the recipient of I

I I I I I I I I I I I I I I I I I ! I numerous research awards from governmental agencies and private foundations. Currently I have one research grant award from the National Institutes of Health and two research grants from private foundations. My curriculum vitae is attached. I have been asked to review "Passive Smoking and Heart Disease: Epldemiology, Physiology, and Biochemistry," which is Chapter Eleven of an EPA draft compendium of technical literature on environmental tobacco smoke (ETS). The authors for this chapter are Stanton A. Glantz, Ph.D., and William W. Parmley, M.D. In this chapter, the authors give a superficial review of the data from ten epidemiological studies concerning incidences of heart diseases and exposure to environmental tobacco smoke (ETg), then proceed to offer some discussion of physiological and biochemical mechanisms in an effort to show how ETS may conceivably contribute to increasing the risk of heart disease. Changes in platelet functions, alterations in the pattern of blood flow resulting from chemicals present in ETS, the suppression of mitochondrial activity based on animal studies, and the presence of polycyclic aromatic hydrocarbons in ETS, are all cited by these authors as purported evidence to link ETS exposure to weakened heart function, leading ultimately to the initiation and establishment of atherosclerotic lesions. Alternate mechanisms unrelated to ETS exposure which would lead to the same set of physiological and biochemical changes are not - 2 -

I I I I I I I I I I I I I I I I I I I considered or eliminated by these authors. Moreover, based on circumstantial information, they postulate the existence of a different platelet sensitivity to ETS between smokers and nonsmokers, and imply that the latter group is at greater risk because of a lower threshold characteristic of their platelets. The authors also briefly discuss several animal studies involving the use of benzo(a]pyrene. Some recent experiments showing that DNA extracted from human atherosclerotic plaques is able to induce transformation in transferred mouse 3T3 cells are used to support the concept that plaque-derived human cells possess the unique ability to trigger arterial smooth muscle cell proliferation, a key event associated with the initiation, progression, and establishment of atherosclerotic plaques. The chapter closes with a brief description of a report showing the selective localization of adducts containing benzo(a)pyrene-derived moieties in heart and lung DNA. In their opening paragraph, the authors acknowledge the multi-factorial nature of heart disease. On the question of possible ETS contributions to heart disease in nonsmokers, there now appear to be altogether ten epidemiological studies considering whether ETS of heart disease in the epidemiology is outside exposure is related to an increased risk nonsmoking spouse Of a smoker. Although the area of expertise of this reviewer, there are several general scientific principles regarding the validity and/or plausibility of epldemiological findings which warrant brief mention. For example, systematic error may distort - 3 -

I I I I I I I I I I I I I I I l I I I the study base if it is selectivs in nature. It should also be recognized that the etiological link between environmental variations and the endpoints for chronic diseases such as diabetes, coronary heart disease, arthritis, asthma, and cancer is complex and is characterized by (i) continuous variations in clinical, physiological, and biochemical phenotypes that are measures of health, (2) environmental modification of the biological predisposition of an individual to disease, and (3) multiple confounding factors giving rise to the same disease endpoint. Accordingly, increased or decreased incidences of a certain disease in a group can be attributed to a specific environmental factor, e.g., ETS exposure, only where that factor is the single factor that is free to vary. that expanded knowledge base in biochemical measurements. epidemiological studies is Another complication in the analysis of chronic disease is the definition of the endpoint may change as a result of an the clinical, physiological, and A further issue regarding the character of the reference population. For example, an industrial population other than the one under study could have some totally different exposure causing the same dlsorder(s) as the exposure at issue. Hence, for example, the choice of a group of copper smelter workers as a reference population for miners would fail to reveal fully the excess risk of lung cancer due to radon exposure in the mine, since the copper smelter could also suffer from lung cancer due - 4 -

I I i ! I I l l l i I I I I l I I I I to arsenic exposure. Nor should the reference 9roup be from an urbanized area, if the index population is rural. The authors next discuss the issue of the effects of primary cigarette smoking on coronary heart diseases. They correctly point out that cigarette smoking is but one of the three reported major independent risk factors for coronary heart disease (CHD), the other two being hypercholesferolemia and hypertension. A wealth of evidence indicates that cholesterol is causally related to atheroslcerosis (McGilI, Jr., 1984; Nilsson, 1986; Kaunitz, 1988). By definition, cholesterol is present in all atherosclerotic plaques. Moreover, atherosclerosis cannot develop in animals unless they are first made hypercholesterolemic (Mcgill, Jr., 1984). Indeed, studies in nonhuman primates have shown that regression of atherosclerosis is possible if the plasma cholesterol level is sufficiently reduced. In humans, genetic studies have indicated a striking relationship between early, severe coronary disease and the presence of either elevated plasma levels of low density lipoproteins or reduced levels of high density lipoprotein. The evidence is overwhelming that reducing plasma cholesterol levels suppresses or reverses the progression of coronary artery plaque and lowers the cases of clinical coronary artery disease mortality and morbidity (Brown and Goldstein, 1986). Similarly, hypertension has been known as a risk factor for coronary heart disease as long as serum - 8 -

I I I I ! I ! I I I ! ! i I I I I I I cholesterol concentration. It is associated with accelerated atherogenesis in adult humans and in experimental animals. A strong relationship has been reported between blood pressure and arterials lesions for men in certain age groups (Holme et al., 1981). Notwithstanding their failure to emphasize hyperllpidemia and hypertension as equally important risk factors for CDH, the authors proceed to describe the salient features of atherosclerosls, and make reference to the fact that there is a lack of full understanding of the pathogenesis of the disease. Areas where cigarette smoking could theoretically influence cardiovascular efficiency and capacity are highlighted. The authors also note in this regard that components in cigarette smoke which have been claimed to have an adverse effect on the cardiovascular system of smokers have also been identified in ETS. Yet, they do not seem to recognize that ETS is not the same as the mainstream tobacco smoke inhaled by a smoker to begin with, and that there are complex, as yet poorly defined physical and chemical changes occurring during the aging of ETS in an indoor environment (Eatougb et al, 1989). Accordingly, it is misleading to imply, as the authors do, that data about the former can be employed in studying the effects Of the latter. Discussion of this sort should not be included in a compendium of technical literature on ETS. - 6 -

I I I ! I I I I I I I I i I I I I i The authors next review the data of ten epidemiological studies in several pages. AS stated above, this scientific discipline is outside the scope of expertise of this reviewer. ACUTE EFFECTS OF ETS EXPOSURE Following their limited analysis of data from epidemiological studies, Glantz and Parmley go on to review several published reports describing selective physiological reactions observed in human subjects exposed to ETS in an artificial laboratory setting. The first paper examined is the work of Aronow (1978). The scientific artefacts of Aronow's study have been repeatedly addressed in the past. The Surgeon General's Report of 1986 summarized its findings as follows: "This study was criticized because the endpoint angina was based on subjective evaluation, and because other factors such as stress were not controlled for .... More important, the validity of Aronow's work has been questioned." (USPBS, 1986, P.106). Because of the lack of control for "stress," the reported "increased resting heart rate and systolic and diastolic blood pressure" observed by Aronow may be due to stress-lnduced release of catecholamines which would likewise influence the subjects to respond in the manner described. - 7 -

I ! I I i I II I I ! I I I I i l I ,I I Glantz and Parmley then refer to the observation of McMurray et al. (1985) as the basis for arguing that ETS exposure "significantly reduced maximum oxygen uptake and time to exhaustion, . . . increased the perceived level of exertion during exercise," and "significantly increased levels of lactate in venous blood," and they suggest that "the combined effect of reduced oxygen carrying capacity and increased lactate resulted in a reduction in maximal aerobic power and duration of exercise" in "blindly exposed young healthy women." To this reviewer, there are a number of difficulties in interpreting the data of this rather small-scale study in this manner. First, only eight females of a narrowly defined age group (21.8 +/- 2.4 years) were entered into the study. Although each subject was "screened by a medical history," the details of the screening protocol were not provided. Four of the subjects were smokers while the other four described themselves as nonsmokers. NO verification of their smoking status by measuring cigarette smoke-specific products in the biological fluid of the subjects was provided. Regarding the "blind" nature of the study, it is interesting to note that the authors pointed out that "all of the smokers could tell when they were breathing the smoke but none of the nonsmokers knew for certain." It is equally intriguin@ to note the observation by McMurray et al., that "the presence of smoke raised the carboxyhemoglobin levels of the nonsmokers from a pre-level of 1.1% to 2.2% at the - 8 -

I I I I I I ! I I I I I i I i I a I I end of the exercise." This pre-level of 1.1% is some 80% higher than that found in a more recent study in which the mean carboxyhemoglobin level of the subjects was 0.6% +/- 0.02% (Allred et al., i989). It is also important to mention that the manner in which ETS was delivered to the subjects would represent an extreme, arbitrary, and unrealistic form of ETS exposure since there is virtually no dilution by ventilation nor is the normal modification of ETS in an ordinary indoor environment allowed. By far the most significant increase in the study by McMurray et al. is in the concentration of post exercise venous blood lactate, which "averaged 6.8 mM during the smoke trials, significantly greater than the controls (5.5 mM)." From a biochemical viewpoint, it is well established that lactate is generated from pyruvate by the enzyme lactate dehydrogenase. The heart and skeletal muscles, however, exhibit marked differences in their ability to oxidize glucose anaerobically. Lactate dehydrogenase in the heart muscle, because of its unique structural composition (H4), is allosterically inhibited by pyruvate and is thus unable to convert pyruvate to lactate. In contrast, the same enzyme in the skeletal muscle having a structure of M4 effectively catalyzes the enzymatic conversion of pyruvate to lactate. Lactate is expelled into the bloodstream, where it is taken up by the liver to be resynthesized into glucose via the enzymes in the gluconeogenic pathway. Since exercising muscles typically oxidize glucose anaerobically to generate ATP during periods of severe exercise, and because - 9 -

I I ! ! ! ! ! lactate is released into the blood stream, concentration of lactate in venous blood post exercise may be viewed as a biochemical marker for the severity of exercise to which the skeletal muscles were subjected. Accordingly, the 24% rise in lactate concentration during the smoke trials (6.8 r~4 versus 5.5 mM) is a strong indication that the subjects (for some unknown reason) are "exercising" harder during the "smoke trial" than the "control" periods. It may then be deduced that the increased level of exercise by the "smoke-trial" group could conceivably account for the "significant reduction in time to exhaustion," as well as the "increased perceived level of exertion during exercise." I I I i! I I I I I In short, the McMurray study is handicapped by the fact that the "control group" and the "experimental group" are not identical since the degree of exercise in the treadmill test is apparently different. It would be important in future studies tc have the "treadmill exercise output" recorded in some fashion to ensure that the same amount of effort is spent during the experimental "smoke-trial" periods as during the control "non-smoked" periods. The authors then discuss the findings of Moskowitz et al. (1990) and assert that these investigators "found evidence that adolescent children of parents who smoked may suffer from chronic tissue hypoxia such as that observed in anemia, chronic pulmonary disease, cyanotic heart disease or high altitude. These children - l0 -