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cell injury? The initiation of atherosclerosis requires some form of 1 I I I I ~ ~ I "injury" to be sustained by the arterial endothelium, although the nature of such °injury" is not well understood; genetic and environmental factors, singly or interactively, could be involved. The report of Davis and coworkers was cited in the OHSA IAQ proposal to support the claim that endothelial cell damage is ,4 induced by ETS exposure (42). The assay used for quantifying circulating endothelial cells, however, was bascu on the method of leucoconcentration first described by Hladovec and Rossman (57), in which only "presumed" endothelial cells were isolated. Davis et al. did not consider confounding by perceptual reactivity to ETS and the fact that several vasoactive compounds have been shown to cause an increase in endothelial cell count (58, 59). ~ C3. Does ETS exposure alter the uptake or the composition of lipids? According to the OHSA IAQ proposal, ETS "increases the lipolysis that increases levels of plasma free fatty acids, which result in enhanced synthesis of LDL". Moreover, ETS was suggested to have implications "in altering blood lipids". How relevant are these statements to our current understanding of the role of lipids in atherosclerosis? Although excess cholesterol is considered the primary culprit of atherosclerosis, it has become clear, within the past few years, that what has traditionally been regarded as the danger of cholesterol is, more precisely, the danger of high LDL and low HDL. 11 I

When high cholesterol reflects a disproportionally high LDL, then high total cholesterol is unhealthy. If, on the other hand, total cholesterol is high because HDL is high, then it is not dangerous. Accordingly, the newest research places more emphasis on the value of total cholesterol/HDL: a ratio of less than 3.5 is most ....... ....... .. .. desirable, one that•lies between 3.5 and 4.5 is considered normal, . , and anything over 7.0 is regarded to be dangerous (60, 61). When such an empirical relationship is applied to the study of Moskowitz et al. (62), in which the profile of blood lipor-rotein .. ...:. . ... ... ... was investigated in "adolescent children whose parents smoked", no I ~ ~ I I I I ~ I I effect of exposure to parental ETS was apparent. HDL cholesterol levels are known to be affected by diet, alcohol consumption, and physical activity (63-65). Likewise, the chemical composition of plasma LDL is modulated by lifestyle factors (66). In a recent study, Mehrabian et al. (67) showed that an increase in HDL cholesterol levels, resulting from an over- expression of the apoprotein AII gene, is accompanied by an unexpected promotion rather than retardation of aortic fatty streak development, suggesting that the relationship between HDL and atherosclerosis is complex and not totally understood. There is yet another aspect of lipoprotein that deserves some comment, especially in connection with smoking and ETS exposure, which mainly relates to the role of LDL as a risk factor for CHD. It has been suggested that the oxidation of LDL is closely linked to the process of atherogenesis (68); it has been known for some time that isolated LDL is highly susceptible to oxidation and that ~ ~ 12 ~ ~ ~ ~ ~ ~

the products of ox.ida.tion are_cytotoxic as well as chemotactic for , _ _ monocytes (69, 70). Furthermore, oxidized LDL is capable of delivering an excess of cholesteryl esters to target cells, via a receptor-independent and therefore unregulated mechanism. Accordingly, cigarette smoke, by virtue of its ability to release free radicals, might be expected to enhance the susceptibility of LDL to peroxidative modification (71). Contrary to expectation, however, smoking does not constitute a risk for CHD in Far East countries with a high prevalence of smoking, as the average plasma LDL and the LDL/HDL ratio in those populations is relatively low (72). Recent studies also suggest that native and oxidized LDL exhibit a complex, agonist-specific effect on platelet activation (73). In sum, there is no evidence to show that plasma LDL/HDL are modulated by ETS in such a way as to exert atherogenic potential. C4. Is ETS exposure associated with increased proliferation of smooth muscle cells? An increase in vascular smooth muscle cell (SMC) proliferation is thought to play a role in atherosclerosis. While SMC in normal arteries of adult animals reside in a state of quiescence, they can be induced to proliferate and ultimately migrate into the intima by autocrine and paracrine mechanisms, mediated via a variety of chemical, mechanical, or biologic factors (74-80). . . ... . .. ...... .... . _ _ Two explanations have been offered on the "quiescence-to- . ........ ........... .:... .... ....., ... ......... ......... ...................... .................... ........... _. proliferation" transition of smooth muscle cells. The "response-to- injury" injury" hypothesis suggests that systemic and local changes in the 13

arterial network result in injury to the.endothelial cell lining the arterial tree, thereby eliciting a cascade of events to trigger smooth__muscle cell proliferation (74, 76). A second "monoclonal 1 I I I I ~ ~ I I smooth muscle cell hypothesis" proposes that the monoclonal atherosclerotic plaques may, through viral infections or other insults, be activatad to proliferate uncontrollably. ..... ......... It has been speculated tat the "monoclonal" nature of SMC will permit them to proliferate when exposed to an insult such as ETS. In support of such speculation, polycyclic aromatic hydrocarbons, chemical components in ETS, were reported to induce atherosclerosis in animal studies (86-89). These speculations lack biological plausibility for the following reasons. First, the ,:..._. .. animal species used (86-89), the chicken, develops large atherosclerotic plaques spontaneously by one year of age. Second, administration of the polycyclic hydrocarbons, as a bolus, intramuscularly, in animal studies, is not representative of ETS exposure. Finally, of the many chemicals present in ETS, only a few, such as carbon monoxide, exist as gases under ambient conditions and have the potential to reach the endothelial lining in diluted quantities. Recent studies, however, show that chronic exposure to moderate levels of carbon monoxide did not accelerate atherosclerosis in cockerels (86). Other chemicals in ETS possessing potentially harmful effects, e.g., suspected carcinogens such as 2-naphthylamine, 4-aminobiphenyl, benzo(a)pyrene, N- nitrosodimethylamine, acetamine, formaldehyde, are known to have relatively high vaporization points. Thus, physically, they are 14 I

unable to remain as gases, even at lower ambient temperature, and I still less likely, at the higher temperature of the human body. Thus to imply that risk of exposure to ETS is in part attributed to such chemicals gaining excess to chemically implausible. In conclusion; the existing data do not establish the endothelial lining is an association between ETS exposure and induction of smooth muscle proliferation. C5. What is the biological relevance of exposure to ETS on oxygen supply and cardiac functions? Among the chemical components of ETS, carbon monoxide and nicotine have been suggested as most likely to adversely affect cardiovascular function. Carbon monoxide binds tightly to hemoglobin and diminishes oxygen transport in the blood stream. Nicotine acts in the brain and throughout the body, promoting the release of catecholamines and increasing heart rate and blood ......... pressure. Although high exposure to these substances might impair ;. cardiovascular performance, exposure from ETS would be too low for physiological changes to occur in healthy persons. A number of publications, notably those of Aronow (89, 90), were cited in the OHSA IAQ proposal to support the assertion that ETS exposures leads to an interruption in the coronary circulation, ........ .. ...... . .......... . .... resulting in ischemia. In the Aronow study, it was suggested that the lack of oxygen delivery to tissues may result in lactic acid I accumulation that would irritate the heart and stimulate spontaneous contraction of cardiac muscle in a.non-coordinated 0 i I5 M ~ W .;~ I W N

I ~ ~ I I I I I I I t manner, resulting in compromised cardiovascular function. These studies were largely inconclusive because of deficiencies in study design and data interpretation. For example, the premature , . ventricular contraction data were only recorded in one group after exercise. Moreover, lactate is primarily produced by exercising skeletal and not cardiac muscles (due to the unique distribution and properties of lactate dehydrogenase amongst tissues). Also, the studies lacked controls for confounding. The hypothesis that cigarette smoking has an acute effect on exercise capacity was recently evaluated by subjecting subjects to treadmill exercise (91). No important acute effects on treadmill exercise performance could be demonstrated in active cigarette smokers. Sheps et al. (92, 93) have shown blood that contained as much as 4% carboxyhemoglobin had no adverse effects on patients with ischemic heart disease. Also, in patients with frequent ventricular ectopic activity, exposure to CO producing either 3% or 5% carboxyhemoglobin does not increase arrhythmia frequency of single or multiple beats during rest or exercise (94). It is therefore highly implausible that elevation of CO levels resulting from ETS exposure would show a demonstrable harmful effect. At the cellular level, the work of Gvozdjakova et al. (95) was cited by OSHA as evidence for an effect of ETS exposuze on mitochondrial functions, which conceivably could lead to reduced energy production and..hence compromised cardiac function. The cited studies, however, were poorly performed and lacked proper controls. For example, mitochondrial function was measured inadequately using 16 I

one concentration of glutamate, instead of a number of substrates, studied over a broad range of physiologically relevant concentrations. I I I I I r I I In conclusion, there is no solid support for the notion that ....... ......... .... .... . ETS exposure compromises cardiac functions. C6. How appropriate is it to extrapolate findings from animal studies to investigations involving human subjects? Recently Zhu et al. (97) suggested that the elevated Sudan IV- stainable lipid streaks in both the aorta and pulmonary arteries of stainable New Zealand rabbits fed a high cholesterol diet followed by exposure to a "low" and "high"..concentr.ation of ETS for an extended period of time is evidence for ETS-induced endothelial damage and hence atherosclerosis. Although the use of cholesterol-fed rabbits is a traditional and easy way of initiating atherosclerosis, the high plasma cholesterol levels produced in this way are even higher than in patients with familial hypercholesterolemia. Thus, such a model is relevant only to a small atherogenesis-prone proportion of the human population and ..differs considerably from native atherosclerosis in most humans. Moreover, in the absence of other supporting evidence, it is not appropriate to interpret measured lipid streaks as being equivalent to the development of atherosclerosis. Such fatty streaks and intimal thickening have been found in most Finish and American children (98), some as young as three years (regardless of community prevalence of adult artery ..... .... . . ... .. ... . . ... disease) (99, 100), leading some to question their importance. Indeed, biliary obstruction, which can result from CNS-triggered

t ~ ~ ~ I I I I I I I I I I muscle spasm but bears no relation to atherosclerosis, also , promotes lipid deposition in vessel wall. Finally, the question of whether animal studies have predictive values in humans must also be addressed. Species differences are known to exist in susceptibility to carcinogens and other environmental•agents (101-105). Information such as route of exposure, bioavailability, and dose response obtained by using animal models must be properly and carefully evaluated before the findings can be relevantly extrapolated to humans. These types of issues, in relation to ETS exposure studies using animals, clearly have not been adequately addressed. C7. Confounding It is clear that loss of functional integrity of-the vascular endothelium is a primary initiating event in the etiology of- atherosclerosis.' Endothelial cells interact with blood components and the abluminal tissues, thus playing an active role in many aspects of vascular functions. Nutrition may play an important role in the atherosclerotic disease process. There is evidence that certain vitamins and minerals prevent some metabolic and physiological perturbations of the vascular endothelium (106-112). For example, inadequate intake of vitamin C could predispose endothelial cells to damage. Vitamin C is essential for the maintenance of the body's cornective tissue- the "glue" that holds the cell together. Even though enough of the vitamin may be present to prevent scurvy, sub-optimal amounts may lead to weakening of the connective tissue bo 18 I

cells, thus making them more vulnerable to disruption. The involvement of nutrients as a ma jor confounding factor has not been systematically addressed in epidemiological and laboratory studies dealing with the cardiovascular effects of ETS exposure. .. ....... .... D. An alternative explanation for the observed effects of ETS D 1. Psychoactive response to ETS The distinct odor of ETS and the likelihood that it could act as an irritant for some individuals (59) raises the possibility that the claimed effects of'ETS exposure on endothelium is no more than a simple psychoactive response which in turn triggers vasospastic perturbations. Over time, vasospastic episodes produce vasospasm which initiates endothelial injury and the sequelae of ....... :.:: events culminating in atherosc2erosis A vasospastic theory indeed has been proposed to explain a myriad of human diseases, including atherosclerosis, by suggesting that an increased sympathetic nervous activity could lead to focal spasm resulting in a reduction .. of oxygen supply (113, 114). D. Psychoactive factors and pathogenesis of atherosclerosis Indeed, behavioral and psychosocial factors have been implicated in the pathogenesis of atherosclerosis for decades. Animal studies have demonstrated that the sympathetic arousal invoked by,psychosocial variables, commonly known as "stress", is accompanied by endothelial dysfunction of the coronary arteries and aorta, as judged by enhanced immunoglobulin G incorporation and . 19

I I I I I I I I I I endothelial cell replication (115). The demonstration by Pettersson , et al. (116) that chlora lose- induced endothelial celll injury in rabbits is effectively blocked by m.etoprolol, a$1-adrenergic antagonist, further.support the notion that increased sympathetic •~ nervous activity and catecholamines are intimately involved in aortic endothelial-cell damage and possibly atherogenesis. Sbim, manifested not necessarily in the typical hard-driving type A personality, but as anger, frustration, powerlessness, present risks to general health and to the heart. The report of a World Health Organization Expert Committee on the prevention of CHD (117) noted that: "Several behavioral patterns and psychological and social variables have been related to CHD risk..... With respect to stress, or response to stress, the lack of definition and quantitative measurement is severely limiting..... The Expert Committee noted the danger that public and professional misconceptions about stress, whereby.it is assigned a primary role in the genesis of CHD, may divert attention from the demonstrated needs in prevention." The potential importance of psychosocial variables in CHD is further bolstered by the_results of a prospective study by Lehr, Messinger and Rosenman (118). The authors measured 12 biochemical and other biological risk factors, and 12 "social" variables (factual descriptions relating to the social background of the individuals such as parental country of birth, parent's occupation, subject's education, residence, etc). Despite the fact that these , variables do not begin to encompass the full range of psychological 20 I