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I I I I I ~ I I I I cardiovascular Effects of ETS Exposure: Comments on Biological Plausibility of Proposed Mechanisms 1 I

Table of Contents A. Coronary Heart Disease Al. xajor events associated with atherosclerosis I I I I I I I 1 A2. The'.tiology of atherosclerosis remains unknown B. Summary of epidemiological studies relating cardiovascular effects with exposure to ETS C. commeats on deficiencies and lack of biological plausibility in the mechanisms proposed for the cardiovascular efAfects of ETS C1. Thrombus formation and platelet activation: Does- exposure to ETS contribute to an altered platelet function? C2. Vascular wall injury: Is ETS exposure associated with endothelial cell injury? C3. Does ETS exposure alter the uptake or the composition of lipids? C4. Is ETS exposure associated with increased proliferation of s.m.ooth muscie cells? . . ....... . ......... C5. What is the biological relevance of exposure to ETS on oxygen supply and cardiac functions? C6. How appropriate is it to extrapolate findings from animal studies to investigations involving human subjects? C7. Confounding D. An alternative explanation for the observed effects of ETS ............. D1. Psychoactive responses to ETS D2. Psychoactive factors and pathogenesis of atherosclerosis B. conclusion I

I I I I I I I A. Coronary Heart Disease Heart disease and related cardiovascular ailments are the primary cause of death in all developed countries and in many developing countries. Coronary heart disease (CHD), which accounts for a quarter of the 21 million deaths each year among Americans, is a complex clinical composite of a more fundamental vascular pathology affecting circulation (1). The majority of these deaths _..:.... _ are due to myocardial or cerebral infarction, severe atherosclerosis being the principal cause, accounting for 90% of CHD mortalities (1). CHD is known to have a substantial diagnostic error (2). In addition, a significant percentage (36% in women and 38.7% in men) of CHD among'adults aged k65 years is subclinical (3), suggesting that assessment of CHD-linked morbidity and mortality, based on traditional clinical parameters, may be imprecise (4). Unfortunately, these factors, insofar as CHD is concerned, are rarely considered in large-scale epidemiologic studies. Al. Major events associated with atherosclerosis Atherosclerosis refers to the process in which cholesterol- laden, hemorrhagic deposits, referred to as atheromas, are formed in the tunica intima and media of large and medium sized arteries. Although atheromas develop in all arteries, they are more common in areas of high'blood turbulence, such as coronary arteries and aorta. In the case of coronary arteries, damage of endothelium lining the arterial wall triggers a series of events, culminating Y

I I I I I I I I I I I in the attachment of cholesterol and related lipids to damaged - endothelial cells. Cholesterol intermingles with cells of the lining, and develops into a plaque. With time the plaque, soft and fibrous at first, stiffens and weakens the artery wall (5). The arteries become brittle and more vulnerable to tears and hemorrhages. The thickened vascular wall, in addition to becoming prone to coronary thrombosis, also compromises the vessel lumen and causes a decrease in blood flow. Since coronary arteries supply the ,, heart with blood, the "narrowing of the arteries° mav eventually show itself in the form of clinical symptoms. The person may experience angina.pectoris,-or severe chest pains, when the heart is insufficiently oxygenated or placed under extra demands, e.g., rigorous physical exercise. Another clinical manifestation of atherosclerosis is myocardial infarction which can result in fatal destruction of heart tissues. Fiqure l illustrates the sequence of events that result in atheroma formation. The whole process is believed to be initiated by some form of injury, arising from systemic and local changes in the arterial network, to endothelial cells lining the arteries. Subsequent to endothelium damage, atherosclerotic lesions develop over time and are thought to be the collective end-product of three somewhat inter-dependent events: (i) proliferation of previously quiescent smooth muscle cells and activation of macrophages recruited to site of damage, (ii) deposition of large amounts of connective tissue matrix proteins, e.g., collagen, elastic fibers, proteoglycan, around the smoQth muscle cells, and (iii) lipid I

I I I I I I I I I I I accumulation in the form of foam cells within smooth muscle cells and macrophages, and as deposits within the extracellular matrix surrounding these cells. A2. The etiology of atherosclerosis remains unknown Despite the strides that have been made in vascular biology in recent years, including those at the molecular level, the etiology of atherosclerosis remains uncertain. This uncertainty is reflected in the following question:!'what is the nature or mechanism of the primary injury of the vessel wall which appears to initiate the process of atherogenesis?" Based on leads provided by epidemiological investigations, suggestions have been made of association between atherosclerotic disease and a series of pathologies, habits of the population, genetic, biochemical, physiological and environmental.factors, all of which influence directly and/or indirectly the early development, frequency, severity and prognosis of atherosclerosis. These have come to be known as coronary risk factors (CRF). CRFs can range from more esoteric risks such as noise, and behavior, to more commonly accepted risks such as elevated plasma LDL cholesterol levels, lowered HDL cholesterol levels, triglyceride and beta/alpha lipoprotein ratio, serum clotting times, fibrinogen concentrations, cigarette smoking, high blood pressure, obesity, diabetes mellitus, and sedentary lifestyles (7-20). It is also .. important to note that the classical risk factors, such as hypercholesterolemia, hypertension, hemodynamic stresses, smoking, which have been traditionally cited for their predisposing roles I

leading to endothelial cell injury - both, in animal and human ,._ studies - are still unable to account for the mechanism of atherogenesis, or predict >50% of new cases of the disease (21). To summarize, because of the multifactorial nature of CHD, in which magnitude and severity of disease are influenced both by duration of exposurP and by the particular combination of the CRFs, it is extremely unlikely that an increase in the risk of CHD may be traced and assigned exclusively to a single CRF. B. Summary of epidemiological studies relating cardiovascular effects and ETS exposure ETS is a combination of smoke emitted from the burning cigarette and smoke exhaled by the smoker. It consists of a vapor and a particulate phase, formed by a multifaceted kinetic process (22). The particulate phase of ETS is created when combustion_ components are emitted into the atmosphere. These components act as "nuclei" for condensation of vapor phase material. The final droplets of ETS are in a dynamic state of flux which is influenced by humidity, dissipation, and dilution (22, 23). The effects of ETS exposure are dependent upon many factors, such as bioavailability of particulate and vapor_phase constituents, as well as duration and level of exposure (24). The relationship between exposure to ETS and incidence of CHD is a subject of controversy. Reasons for not associating between the two include the following: (i) ETS exposure occurring over an extended period of time involves multiple, ill-defined modes of exposure and is subject to

t 1 I I I I I I I known and unknown quantification/measurement errors (22-24). Given •that CHD is associated with many CRFs and requires years of incubation to surface clinically, it is unlikely that a significant , risk is attributable to ETS exposure. (ii) Of the numerous epidemiological studies that examine possible associations between CHD and ETS exposure (25-34), only three of the studies, involving exposure at home to spousal ETS, report a statistically significant association between ETS and CHD (26, 28, 34). In the single study to assess the health effects of workplace ETS exposure, no statistically significant association , . was found (34). Since, by their very nature, epidemiologic studies deal with masses of data, it is unclear whether sample homogeneity can be maintained and whether the quality of the observations can be preserved. Furthernaore, there is often confounding of effects. Indeed, issues such as indices for ETS exposure; lifestyle factors; ,.... _ _ _. and misclassifications, in relation to the purported effects of ETS, have not been completely resolved. . _ .............. .... ........... (iii) Although probable carcinogens such as benzo(a)pyrene (H(a)P) and dimethylnitrosamine (DMNA) have been detected in sidestream tobacco smoke (in some cases, in concentrations exceeding those present in mainstream tobacco smoke (23)), they are substantially diluted when present in ETS. In addition, with the addition of carbon monoxide, it is not known whether and how many of the potentially harmful chemical components present in ETS can gain access to the cardiovascular system in concentrations sufficient to do damage. i

In addition to the fact that all of the published I I I I I I I I ~ I i I I ; epidemiological studies attempting to show an adverse effect of ETS on CHD have problems in experimental design, data analysis and result interpretation, it is also important to emphasize that for CHD/ETS association to be valid, biologically plausible mechanisms must be established. My conclusion, based on a critical evaluation of currently available scientific data, is that the proposed link between exposure to ETS and increased risk of CHD is not warranted. C. Comments on deficiencies and lack of plausibility in the biological mechanisms proposed for the cardiovascular effects of ETS C1. Thrombus formation and platelet activation: Does exposure to ETS contribute to an altered platelet function? A thrombus is an abnormal manifestation of normal hemostasis occurring on the internal surface of blood vessels. Thrombus formation requires a concerted interaction between the endothelium and platelets, and appears to proceed in the following manner. Protection afforded by the vascular endothelium against platelet aggregation and adhesion (35-37) is lost upon injury of the endothelium, resulting in a state in which arterial thrombosis is greatly predisposed. Damaged endothelium enhances platelet _ .11. ., aggregation and responsiveness to a number oagonists, and induces platelet adherence to the subendothelial components, concomitant with platelet activation and release of a number of mediators, - e.g., thromboxane A2, which aggregate new platelets. In parallel,

thrombin is generated on the platelet surface to further stimulate these reactions. Several conditions known to increase cardiovascular disease are also associated with increased platelet aggregation; in contrast, polyunsaturated fatty acids decrease platelet aggregation and protect against vascular diseases (38-40). The OSHA IAQ proposal states that "there is evidence that ETS I I I I I I I I I I exposure can cause platelets to become more easily activated thus predisposing the platelets to become involved in forming clots and atherosclerotic plaques." To support this claim, OSHA cites the study by Burghuber et al. (41), which involved placing non-smokers in a confined environment (i8mZ room) and exposing them for an extended period of time (20 min) to ETS generated by testers smoking "30 heavy brand" cigarettes. The proposal fails to note that such artificial experimental settings are unlikely to be present in real-life situations. Moreover, the 1 mM ADP used to induce irreversible platelet aggregation is unrealistically high .... . and is at least 10-20 times greater than the physiological concentration of ADP. Another cited study, by Davis et al. (42), also involved a non-standard platelet aggregation method. Platelet aggregation is widely recognized to be subject to a variety of artifacts such as the drawing of blood, presence of anticoagulant, and centrifugation (43). Platelet reactivity also displays donor variation, circadian and seasonal changes (44-46), and extraordinary sensitivity to aggregating agents (47). In general, there is poor correlation between platelet aggregation and atherogenic potential of an agent. For example, although saturated 9 I

I I I I I I I I I fatty acid diets are regarded to be atherogenic, they have no demonstrable effect on platelet function (48). Active smoking studies do not show a correlation between smoking and thrombi incidence. In fact, smoking may actually exert a "protective" effect in certain situations. Haire et al. (49) investigated the response of fibrinolytic system to active smoking and observed no difference between control subjects and healthy . male smokers challenged with "smoking two cigarette within 15 min". ..... .... Smoking has no effect on regional cerebral blood flow and on platelet aggregation in the normal aged volunteers (50) Doll and Peto found no association between mortality from thromboembolism and smoking (107). A protective effect of cigarette smoking on venous thromboembolic disease has been observed after myocardial infarction and surgery (52, 53). In patients undergoing emergency laparotomy, cigarette smokers had a significantly lower incidence of deep venous thrombosis than pipe smokers or nonsmokers (54). When smokers refrained from smoking and were then challenged with a cigarette, no difference in collagen-induced platelet aggregation, thromboxane B2 production by platelets, plasma . ..... . .. . thromboglobulin and plasma fibrinopeptide A levels, could be observed before and after smoking, showing that acute smoking did not induce a prothrombotic state (55). Cholesterol-fed rabbits did not show hypersensitivity of platelets to agonists (56). Thus,-- there is no concrete and consistent evidence for increased platelet reactivity due to ETS exposure. C2. Vascular wall injury: Is ETS exposure associated with endothelial 10