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Evaluation of Automotive Emissions as Risk Factors for the Development of Atherosclerosis en c! Coronary Heart Disease THOMAS B. CLARKSON Wake Forest University Atherosclerosis / 606 Natural History / 606 Pathogenesis / 606 Factors that Influence Atherogenesis / 609 Age / 609 Gender / 610 Genetic Susceptibility / 610 Psychosocial Phenomena / 611 Diet / 612 Animal Models / 612 Avian Species / 612 Nonprimates / 612 Nonhuman Primates / 613 Effects of Chemicals on Atherogenesis / 613 Plasma Lipoproteins as Chemical Carriers / 613 Cigarette Smoking / 614 Carbon Monoxide / 617 Clonal Character of and Carcinogen Effects on Plaques / 619 Summary / 620 Summary of Research Recommendations / 621 Air Pollution, the Automobile, and Public Health. @) 1988 by the Health Effects Institute. National Academy Press, Washington, D.C. 605

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606 Evaluation of Automotive Emissions as Risk Factors Automotive emissions, particularly carbon monoxide (CO), are thought to be risk factors in the development of atherosclero- sis and heart disease. From studies of the ~. components ot cigarette smoke, It IS known that continued exposure to high levels of CO results in a higher incidence of death and disease among smokers. Thus, it seems reasonable to suppose that significant exposure to automotive emissions could have similar results. Unfortunately, little experimental evidence exists to support that speculation. In this chapter, the ways in which expo- sure to automotive emissions might affect atherogenesis are reviewed. The develop- ment of atherosclerosis and the susceptibil- ity of various groups are reviewed as well. Although many studies have been done, research to date does not give us a clear picture of the effect of CO on atherogen- esis. For that reason, it will be necessary to undertake definitive research on the effects of automotive emissions in general. If air pollution is found to have an effect on atherogenesis, then the components of au- tomotive emissions should be studied sep- arately. Since both types of studies will probably involve animal research, the po- tential of various animal models for ath- erosclerosis research is also reviewed. Atherosclerosis Natural History Arteries consist of three layers: the inner layer called the intima, the media, and the outer layer or adventitia. Atherosclerosis is a pathological process causing the intima to be thickened by intra- and extracellular accumulations of lipids, by variable degrees of proliferation of intimal smooth muscle cells, and to some extent, by migration of macrophages into the intima (McGill 1977~. The process of atherogenesis occurs in human beings of all races and societies, but differs greatly in degree and extent of clinical complications among various eth- nic and geographic groups (Strong et al. 1972~. Atherosclerosis in the coronary ar- teries is the usual cause of coronary heart disease (a term covering the spectrum of angina pectoris, myocardial infarction, and disturbances of cardiac rhythm). Athero- sclerosis of the cerebral arteries is associated with transient ischemic (decreased blood flow) attacks and stroke. Atherosclerosis of leg arteries may result in leg pain (termed "intermittent claudication"), and occasion- ally gangrene of the extremities. The first lesions observed in the intima of arteries are fatty streaks; these lesions de- velop in nearly all children and have no physiological or pathological consequences (Strong et al. 1972~. In some, but not all populations, the fatty streaks progress to fibrous plaques, which in turn lead to arte- rial.stenosis and clinical manifestations of atherosclerosis (McGill 1968~. Although di- rect observations of the progression of fatty streaks to fibrous plaques is not possible, the occurrence of such a "progression" is accepted generally (Robertson et al. 1963; National Heart, Lung and Blood Institute 1982~. Depending on the relative exposure to certain risk factors, plaques enlarge to the extent that they reduce blood flow to the point of causing ischemic necrosis (McGill 1968~. Arterial stenosis, however, is not a simple matter of continued growth of the plaque. Although much remains to be un- derstood, plaque growth seems to be com- plicated by events that happen to the plaque itself, and by events that happen to the artery with the plaque (Ross 1981~. Plaques may ulcerate and provoke thrombus (blood clot) formation, and the thrombi may ac- celerate the growth of the plaque. Since the platelets participate in thrombus formation they may liberate physiologically active substances such as thromboxane A2, which can cause arterial spasm and possibly isch- emic necrosis (Neri-Serneri et al. 1981~. Pathogenesis The cellular and molecular events that lead to the development of fatty streaks have been the focus of intensive research in recent years and have been reviewed by Ross (1986~. Most researchers agree that the initial events are injuries to the arterial endothelium (figure 1~. Endothelial injury

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Thomas B. Clarkson 607 Endothelial injury and dysfunction Leukocyte adherence and intimal macrophage accumulation Enumerate adhering leukocytes - Intimal smooth muscle cell proliferation r Measure intimal cell | | proliferation rates l / Measure endothelial / cell reactivity rates Intimal matrix .' / accumulation Measure collagen and elastin content ~ ATHERO- j GENESIE; \~ Cholesterol and chol~s- terol ester accumulation Measure cholesterol and cholesterol ester content Figure 1. Schematic illustration of the pathogenic components of atherogenesis and methods for the evaluation of these components. can be diverse in nature and can result from exposure to mechanical forces (Stemerman and Ross 1972; Fry 1973; Moore 1973; Fishman et al. 1975), by exposure to lipo- proteins (Faggiotto et al. 1984), by various toxins (Reidy and Bowyer 1978), and by immunologic injury (Minick et al. 1978~. Recommendation 1. Research to de- termine whether exposure of endothelial cells to automotive emissions affects endo- thelial function should be undertaken with emphasis on endothelial cell replication and prostacyclin production. ~ Recommendation 2. Studies should be done to determine whether chronic ex- posure to automotive emissions affects the repair of stress-induced endothelial injury and/or the way in which the intima of . . . . arteries responds to suc ~ infuses. lnt~mal smooth muscle cell proliferation is the primary cellular response associated with the progression of atherosclerosis. There is strong evidence that this smooth muscle cell proliferation is the result of a number of growth factors associated with atherogenesis. Particularly relevant is the platelet-derived growth factor (Ross et al. 1974; Ross and Voegl 1978), endothelial- derived growth factor (Fess et al. 1978; Gajdusek et al. 1980), and finally by the monocyte/macrophage-derived growth fac- tor (Liebovich and Ross 1976; Glenn and Ross 1981~. Recommendation 3. The effect of au- tomotive emissions on the catabolism of low-density lipoprotein (LDL) particles by smooth muscle cells, the replication rates of these cells, and the kinds of connective tissue proteins they elaborate should be determined. Many human fibrous plaques have been found to be monotypic for one of the isozymes of glucose-6-phosphate dehy- drogenase (G-6-PD) (Benditt and Benditt 1973; Pearson et al. 1978; Thomas et al. 1979~. This observation was interpreted as evidence for a monoclonal origin of the smooth muscle cells of the atherosclerotic lesions, leading to the monoclonal theory of atherosclerosis (Benditt and Benditt 1973~. Monoclonality suggests that smooth muscle cells of the atherosclerotic plaque arise from a single precursor cell that has superior growth and survival characteris- tics. Lesions of monoclonal origin are gen f

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608 Evaluation of Automotive Emissions as Risk Factors orally considered to be neoplastic. Chemi- cal mutagens and viruses have been suggested as being responsible for this neo- plastic change (Benditt and Benditt 1973~. There is no doubt that many human fibrous lesions are monotypic with respect to G-6- PD. Whether these monotypic lesions are indeed monoclonal or whether the monotypism results from a selective sur- vival advantage of one or the other cell phenotypes is not clear. Thomas and Kim (1983) have recently reviewed the evidence for and against the "monoclonal hypothe- sis" versus the "phenotype/selective advan- tage hypothesis." The results of studies with experimental animals and further ex- amination of human atherosclerotic lesions . . . . nc .lcate t let monotyplsm IS not a prereq- uisite for atherosclerosis development. Al- though the exact roles of chemical muta- gens and monotypism are yet to be defined, they are probably important in atherogen- esis and provide a rational basis for the assumption that exposure to automotive . . . emissions may he important. Over the past two decades there has been extensive interest in the role of platelets in atherogenesis. Following injury of the ar- terial endothelium by such procedures as balloon catheterization, platelets can be seen to adhere to such injuries and presumably release platelet-derived growth factor. It has been shown that in association with the adherence of platelets there is migration of medial smooth muscle cells into the intima (Stemerman and Ross 1972) where they proliferate and form sizable intimal lesions. Intimal smooth muscle cell proliferation following injury can be prevented by treat- ment of animals with antiplatelet serum (Moore et al. 1976; Friedman et al. 1977~. The most important area of current re- search in atherogenesis concerns the role of monocyte-derived macrophages. The in- timal macrophages are not only important with regard to their phagocytic function, but elaborate important growth factors. Previously, the intimal smooth muscle cell was presumed to be the precursor cell for the predominant numbers of foam cells (lipid-containing cells that are "foamy" in appearance) in lesions. Most workers now agree that monocyte-derived macrophages represent the majority of the foam cells present in fatty streaks (Gerrity 1981a,b). Macrophages have high-aff~nity receptors for chemically altered LDLs (Goldstein et al. 1979; Fogelman et al. 1980; Brown et al. 1981; Schechter et al. 1981~. Alteration of LDLs by hydrocarbons, aldehydes, or other chemicals in automotive emissions may result in their being internalized by macrophages; thus intimal macrophages may be of particular importance in emis- sions-exposure atherogenesis. ~ Recommendation 4. The effect of au- tomotive emissions on the internalization of ,~VLDL (very low-density lipoprotein) and.other modified LDL particles by mac- rophages should be assayed. Progression of Fatty Streaks to Fibrous Plaques. In humans, fatty streaks appear in the aorta in the first decade, in the coronary and cerebral arteries later, and are not associated with any clinical events. Fibrous plaques with necrotic, lipid-rich cores surrounded by smooth muscle and connective tissue appear during the third decade, and it is these lesions that undergo complications and cause ischemic necrosis . . . In one or another tissue. Perhaps the most controversial subject in atherosclerosis research is whether fibrous plaques arise from fatty streaks or from some other precursor lesion (McGill 1984~. The evidence that fatty streaks are the precursors of fibrous plaques is circumstan- tial. Fatty streaks occur most commonly in the proximal portion of the left anterior descending coronary artery, and that is also the site in which the most severe fibrous plaques occur (Montenegro and Eggen 1968~. Taking advantage of that site's pre- dilection, efforts have been made to trace the pathogenic events that occur in numer- ous children and young adults (Stary 1983, 1984; Stary and Letson 1983~. The general findings from these studies were that the coronary artery intima at the lesion-prone site becomes as thick as the media does in early life, and that the thickened intima is made up of smooth muscle cells, connec- tive tissue fibers, and proteoglycans be- neath an intact and normally appearing

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Thomas B. Clarkson 609 endothelium. By age 10 there are clusters of monocytes and macrophage foam cells, and adjacent to these clusters are lipid-con- taining smooth muscle cells. By age 15 these clusters of macrophages and smooth muscle cells begin to undergo necrosis. By age 20 there are necrotic foci associated with foam cells, and the lesions become larger and more frequent. At about this age and as necrosis continues, the plaques ap- pear fibrous, and these temporal relation- ships lead many to conclude that the pro- gressing fatty streak is indeed the precursor of the fibrous plaque. Plaque Complications. One of the under- studied areas in atherosclerosis research is the pathological processes associated with the progression of fibrous plaques to com- plicated plaques. The process involves ne- crosis within the central portions of plaques, mineralization, and ulceration. And, in the process of ulceration, the plaques eventually become covered by thrombi, which can occlude the artery. Although no definitive data exist, the gen- eral belief is that necrosis is the primary event in plaque complication and that the process of ulceration and mural thrombosis is associated with necrosis. There are no published accounts of the sequence of pathogenic events in plaque complication in human beings, although the process has been well studied in pigeons (Prichard et al. 1964a). It seems likely that hypoxia is associated with plaque necrosis and the other events that lead to clinical sequelae of the athero- genic process. Studies of automotive emis- sions and the relative hypoxia that occurs from the carboxyhemoglobin may be im- portant in the process of plaque complica t~on. Recommendation 5. Since automo tive emission exposure may result In rela- tive hypoxia, it seems reasonable to suspect that plaque complications could be has ~ ~ - ~ toned by that mechanism. Cynomolgus monkeys with diet-induced atherosclerosis of two or three years' duration should be exposed to various concentrations of auto- motive emissions and their plaque compli cations compared with those in appropriate control animals not exposed to automotive emlsslons. Coronary Heart Disease. Coronary heart disease is the term used to describe the clinical syndromes and pathological events associated with inadequate or obstructed blood flow to the myocardium. The major clinical manifestation of coronary heart dis- ease is angina pectoris. The pathological event associated with interrupted blood flow to the myocardium is termed a myo- cardial infarction. In most cases, obstruc- tion of the blood flow in the coronary arteries is caused by stenotic atherosclerosis (Cohen and Braunwald 1980~. In some individuals, obstruction of blood flow in the coronary arteries is associated with cor- onary artery spasm with, or occasionally without, atherosclerotic lesions in the arter- ies (Dalen et al. 1981~. Mural thrombosis associated with coronary artery atheroscle- rosis is the usual cause of myocardial infarc- tion. Platelet aggregation and fibrin thrombi may be associated with clinical symptoms of coronary heart disease and may also be involved in the progression of coronary artery atherosclerosis (Mustard and Packham 1972~. Research in the area of myocardial isch- emia is advancing rapidly. The role of prostaglandins in coronary heart disease has been the subject of a recent monograph by Hegyeli (1981), and the exploration of endothelium-dependent relaxing factors in . . . coronary arteries Is In an ear .y stage. Factors that Influence Atherogenesis Age There is emerging evidence that young animals are less susceptible than old animals to the development of diet-induced ath- erosclerosis. The earliest work was done using Cebus albifions monkeys, and the ex- tent of aortic and coronary artery athero- sclerosis was found to be significantly less among juvenile animals compared with adult animals fed the same cholesterol

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610 Evaluation of Automotive Emissions as Risk Factors containing diet for the same lengths of time (Bullock et al. 1969; Clarkson et al. 1976~. More recently those observations have been extended to an Old World monkey, Macaca fascicularis (Weingand et al. 1986~. Although plasma lipid and lipoprotein con- centrations were the same, adults had more extensive coronary artery atherosclerosis than juveniles. Whether such age-differences exist in human primates is not known. The possi- bility that there may be age-related differ- ences in the effect of exposure to CO or to automotive emissions seems possible and should be taken into consideration in the planning of future research. Gender The most comprehensive reports compar- ing coronary artery atherosclerosis of male and female human subjects are those of the International Atherosclerosis Project (Te- jada et al. 1968~. Males had more coronary artery atherosclerosis than females in all geographic/racial groups except the Sao Paulo Negroes. The gender-specific differ- ences in extent of coronary artery athero- sclerosis are thought to account for the gender-specific differences in coronary heart disease morbidity and mortality, since the differential in clinical events and lesion ex- tent is similar (Kennel et al. 1961; Cassel 1971; Armstrong et al. 1972~. Explanations for the gender-specific differences in coro- nary artery atherosclerosis have included plasma lipoprotein concentrations (particu- larly higher high-density lipoprotein con- centrations among women), a protective effect of estrogens, and the possibility that females do not share the competitive and sometimes hostile behavior of males and are thus spared from the pathophysiolog- ical effects of such stresses (Barr 1953; Marmorston et al. 1957; McGill and Stern 1979~. Male and female cynomolgus monkeys appear to be excellent models of the gen- der-specific difference in coronary artery atherosclerosis seen in some populations, particularly Caucasian North Americans (Kaplan et al. 1982; Hamm et al. 1983; Kaplan et al. 1984a,b). They share with human males and females gender differ- ences in high-density lipoprotein choles- terol (HDLC) concentrations as well as the quotient of total serum cholesterol and HDLC concentrations. There are signifi- cant gender-specific differences in the ex- tent of coronary artery atherosclerosis, and the relative degree of female protection seems to be directly related to ovarian function as has been demonstrated by the loss of female protection among chroni- cally stressed submissive females and ovari- ectomized females. Studies of humans as well as of nonhu- man primates strongly support higher plasma concentrations of the high-density lipoproteins (HDLs) as important in "fe- male protection." As discussed elsewhere in this chapter, there is evidence that ciga- rette smoking reduces HDL concentra- tions. By analogy, there is some possibility that exposure to automotive emissions would reduce HDL concentrations. Recommendation 6. Studies to deter- mine whether and to what extent automo- tive emissions exposure may diminish or abolish the gender-specific difference in ath- erogenesis needs to be explored. Genetic Susceptibility At least two genetic mechanisms have been identified that modulate susceptibility to coronary artery atherosclerosis. The first concerns genetic control of the extent to which animals increase their plasma choles- terol concentrations when fed dietary cho- lesterol (hyper- and hyporesponsiveness). Hyper- and hyporesponsiveness to dietary cholesterol have been studied in squirrel monkeys, rhesus monkeys, and baboons. Although differences in plasma cholesterol concentrations are not apparent among squirrel monkeys fed diets free of choles- terol, some monkeys (hyperresponders) fed cholesterol-containing diets develop con- siderable hypercholesterolemia, whereas others fed the same diet maintain near normal plasma cholesterol concentrations (Lofland et al. 1970; Clarkson et al. 1971~. Rhesus monkeys have also been studied extensively to understand the mechanisms

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Thomas B. Clarkson 611 of hyper- and hyporesponsiveness to di- etary cholesterol. Unlike the other species, there are significant differences between hyper- and hyporesponsive rhesus mon- keys while they are fed control diets free of cholesterol. Like other species, the trait is exaggerated by the consumption of a high-cholesterol diet (Eggen 1976~. Differ- ences in cholesterol absorption appear to be of major importance in hyper- and hyporesponsiveness of rhesus monkeys (Bhattacharyya and Eggen 1977, 1980, 1983~. The strength of the genetic influence on hyper- and hyporesponsiveness to dietary cholesterol among baboons has also been studied (Flow et al. 1981~. Estimates of heritability for total serum cholesterol concentration were low in early life, but increased as the animals matured. Studies have also been conducted to determine the relationship between the genetic con- trol of cholesterol metabolism and plasma concentrations of HDLs (Flow and Mott 1984~. Strong evidence was provided that the size of the rapidly miscible pool of body cholesterol and the movement of cholesterol in and out of that pool are influenced to a large degree by the same genes that regulate the plasma concentra- tions of the HDLs. The second kind of genetic control of atherogenesis has been termed "mes- enchymal susceptibility." This phenome- non refers to the reaction of the artery wall to accumulated lipoproteins. Macaques ap- pear particularly useful for research on mes- enchymal susceptibility to diet-induced coronary artery atherosclerosis. Using studies of diet-induced atherosclerosis of cynomolgus mokeys, Malinow and co- workers (1976b) were the first to focus attention on this phenomenon. They intro- duced the terms hyper- and hyporeactivity in coronary artery lesion extent, and the terms hyper- and hyposusceptibility to the trait have subsequently been used. Rhesus monkeys are the macaques that have been studied the most in an attempt to develop colonies of hyper- and hyposusceptible an- imals. Considerable variation exists among monkeys of this species in their response to an atherogenic diet. The cellular mecha nisms that account for these differences have not been explained, although the de- tails of the development of breeding colo- nies for this trait have been described (Clarkson et al. 1985~. It seems useful to determine whether strains of rhesus mon- keys that are hyper- and hyposusceptible to the effects of a cholesterol-containing diet are also hyper- and hyposusceptible in re- sponse to exposure to CO and automotive . . emlsslons. The work of Watanabe and associates (1985) supports the concept of individual differences in mesenchymal susceptibility to coronary artery atherosclerosis. These investigators developed and characterized a strain of rabbits with a heritable disorder of cholesterol metabolism quite similar to fa- milial hypercholesterolemia of humans (Tanzawa et al. 1980; Kita et al. 1981; Shimada et al. 1981~. The more recent work of Watanabe and his colleagues (1985) concerns the selective breeding of animals with increased or decreased coronary artery atherosclerosis while equivalently hyper-,B . . . poprotelnemlc. Recommendation 7. Experiments that determine whether chronic exposure to CO affects coronary artery atherosclero- sis differently in genetically susceptible and resistant strains are needed. Psychosocial Phenomena There is increasing evidence that psycho- social influences might affect the develop- ment of coronary artery atherosclerosis and coronary heart disease. The most ex- tensively studied psychosocial variable has been the Type A or "coronary-prone" be- havior pattern (Glass 19771. Type A refers to a constellation of overt behaviors and stylistic mannerisms characterized by hard . . . . . ~ ~r1v1ng competltlveness, a sense ot time urgency and easily evoked hostility. Indi- viduals with a relative absence of these characteristics are termed Type B. Retro- spective and prospective studies indicate that individuals with the Type A behavior pattern or elements of this pattern (for example, potential for hostility) develop coronary heart disease more frequently and

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612 Evaluation of Automotive Emissions as Risk Factors are more likely to die of myocardial infarc- tion than individuals with the Type B behavior pattern (Rosenman et al. 1975; Zyzanski 1978; Review Panel on Coro- nary-Prone Behavior and Coronary Heart Disease 1981; Barefoot et al. 1983; Shekelle et al. 1983~. The mechanisms by which psychosocial phenomena influence coronary heart dis- ease and atherosclerosis in humans remain largely unknown. Three findings related to sympathetic arousal are relevant, however. First, individuals vary markedly in their sympathetic responsivity to behavioral stimuli (Manuck and Garland 1980; Mc- Cubbin et al. 1983) and these response characteristics are enduring attributes of individuals, reproducible over time under varying stimuli in children as well as adults (Manuck and Garland 1980~. Second, when exposed to common laboratory stressors, Type A persons have more appreciable cardiovascular and/or catecholamine re- sponsivity than do their Type B counter- parts (Friedman et al. 1975; Dembroski et al. 1978; Glass et al. 1980; Corse et al. 1982; Williams et al. 1982~. Third, sympathetic nervous system activity may be more im- portant than usually appreciated since such activity is associated with coronary artery vasospasm and probably with serious orob- lems of cardiac rhythm (Verrier and Lown 1984~. Diet Dietary influences on atherogenesis and coronary heart disease have been studied extensively. The literature on the subject cannot be reviewed here, but there have been several relatively recent reviews (Gordon et al. 1981; Scott et al. 1981: Grundy et al. 1982; Spector and Johnson 1982; Zilversmit 1982; Samuel et al. 1983~. The majority of attention about diet and coronary heart disease has focused upon dietary fat and cholesterol. Saturated fats have been shown repeatedly to increase plasma cholesterol and LDL concentrations (Ahrens et al. 1957; Keys et al. 1957, 1965a,b; Hegsted et al. 1965~. Replacement of saturated fatty acids in the diet with polyunsaturated fatty acids, particularly lin oleic acid, has been shown to be effective in the reduction of plasma cholesterol concen- tration (Ahrens et al. 1957; Hegsted et al. 1965; Keys et al. 1965a,b). The results of carefully controlled metabolic studies with humans have shown that dietary choles- terol increases total plasma cholesterol con- centrations (Connor et al. 1961a,b; Connor and Lin 1974~. Similarly, for each 100- mg/day decrease in dietary cholesterol, the total plasma cholesterol concentration de- creases by an average of about 7 mg/dl (Hegsted et al. 1965, Mattson et al. 1972~. Animal Models To explore the effects of automotive emis- sions on atherogenesis the investigator must choose a suitable animal model. The detailed characteristics of all the models cannot be presented here. Rather, the char- acteristics of the most relevant models have been summarized in tabular form along with key references to use with the models. Avian Species Chickens and pigeons are useful for exper- iments in which large numbers are needed (see table 1~. Chickens have been used in experiments designed to explore the possi- bility that atherosclerosis could be consid- ered a form of benign neoplasm of the arterial intima. Pigeons have been used for that same purpose as well as to study the effects of smoking and CO. Nonprimates Several nonprimate models of atherosclero- sis are relevant to research on automotive emissions (see table 2~. Of these, pigs and hybrid hares have the most re~evance. ~gs are useful when large samples of blood or other tissues are required and because of the similarities of their plasma lipoproteins and atherosclerotic lesions to those of humans. Hybrid hares are useful for studies of auto- motive emission effects on the clonal nature of atherosclerotic lesions.

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Thomas B. Clarkson 613 Table 1. Summary of Atherosclerosis Characteristics of Avian Models Potentially Useful for Studies of Automotive Emissions" Model Advantages Disadvantages Pigeonsb Lesions occur naturally and are exacerbated by dietary cholesterol, CO, polycyclic aromatic hydrocarbons (PAHs). Pigeons have a high frequency of plaque complications; breed and strain differences are well established, and they are inexpensive and easy to maintain. ChickensC Lesions occur naturally and are exacerbated by dietary cholesterol, herpesvirus, PAHs; chickens have gender-specific differences in coronary lesions, are readily available, and easy to maintain. Plasma lipoproteins arc diffeecnt from those in humans, occurring primarily in small intra- myocardial branches; most flocks are infected with pigeon herpesvirus. Lesion sites inconsistent, complications uncom mon, plasma lipoproteins different trom those in humans, unknown infection with herpesvirus can cause unexplained variability, coronary atherosclerosis occurs mostly in in- tramyocardial branches. a Modified from a previously published summary byJokinen et al. 1985. b Prichard et al. 1964a,b; Clarkson et al. 1965; Wagner et al. 1973; Wagner and Clarkson 1974; hermitage et al. 1976; Turner et al. 1979; St. Clair 1983; Revis et al. 1984. Pick and Katz 1965; Simpson and Harms 1969; Albert et al. 1977; Minick et al. 1979; Penn et al. Bond et al. 1982; Fabricant et al. 1983; Majesky et al. 1985. Nonhuman Primates The atherosclerosis of nonhuman primates is more like that of humans than is the case with other models (see table 3~. Their primary use for research on automotive emissions will be for experiments on pathogenesis, lipoprotein metabolism, clin- ical sequela of atherosclerosis, and for situ- ations in which reproductive and/or social function are important. Effects of Chemicals on Atherogenesis Past studies on the effect of various chem- icals on atherogenesis provide the rationale for speculations about possible automotive emission effects on atherogenesis. To de- velop working hypotheses about automo- tive emissions, the mechanisms by which chemical substances could be delivered to the cells of the arterial wall and how these substances may affect the progression of atherosclerosis must be considered. The transport of carcinogens by the plasma lipoproteins is reviewed below, as are the effects of cigarette smoking, CO exposure, and polycyclic aromatic hydrocarbons (PAHs). Plasma Lipoproteins as Chemical Carriers Following the intravenous injection of rats with chylomicrons containing benzo~a~py- rene (BaP), the carcinogen was found to be transported primarily by LDLs and VLDLs (Vauhkonen et al. 1980~. Subsequently, Shu and Nichols (1981) demonstrated that the in vitro uptake of BaP by LDL, VLDL, and HDL correlated with lipoprotein and total lipid volume. The plasma lipoproteins have also been shown to play an important role in the removal of carcinogens from cells. Remsen and Shireman (1981 a) reported that increas- ing concentrations of either LDLs, VLDLs, or HDLs resulted in increasing percentages of removal of BaP from cell membranes. Later, Busbee and Benedict (1983) demon- strated that HDL partitioning of lipophilic PAH mutagens from cell culture medium effectively reduces the concentration of car- cinogen available for interaction with the cells. Whether the LDL receptor is necessary for the incorporation of LDLs containing BaP has been investigated by Remsen and Shireman (1981b). Skin fibroblasts derived from a receptor-deficient human with ho- mozygous familial hypercholesterolemia were used for these studies. Benzo~a~py

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614 Evaluation of Automotive Emissions as Risk Factors Table 2. Summary of Atherosclerosis Characteristics of Nonprimate Models Potentially Useful for Research on Automotive Emissions" Model Advantages Disadvantages Rabbitsb pigsc Hybrid hares Lepus timidus x Lepus europaeus Dogs Extensive literature; lesions well character- ized, easily exacerbated by dietary choles- terol, immunologic injury, and perhaps CO; animals reproduce rapidly, are inex- pensive and easy to maintain. Naturally occurring lesions common, le- sions exacerbated by dietary cholesterol, lipoprotein metabolism quite similar to that of humans, animals with von Wille- brand's disease useful for studies of plate- let function and atherogenesis, large ar- tery size, miniature breeds available. G-6-PD can be used as marker for clonal origins of intimal smooth muscle cells, ef- fects of dietary cholesterol established, good literature base. Lesions can be induced, complications com- mon, convenient size, easy to handle, experience base in inhalation toxicology. Lesions composed primarily of macro- phages, complications uncommon, lipo- protein metabolism quite different from that of humans, lipid storage occurs in many organs. Domestic animals are large, difficult to han- dle, expensive to maintain. Difficult to obtain arid maintain, no reports on effects of chemical exposures. Antithyroid dogs required for lesion induc- tion, lesions primarily medial, animals . . . expensive to maintain. a Modified from a previously published summary byJokinen et al. 1985. b Prior et al. 1961; Astrup et al. 1967; Minick and Murphy 1973; Davies et al. 1976; Wilson ct al. 19X9. c Mahley et al. 1975; Gerrity et al. 1979; Bowie and Fuster 19XO; Fritz et al. 1980; Gcrrity and Naito 198(); Gerrity 1981a,b; Griggs et al. 1981; Reitman et al. 1982. Pearson et al. 1979; Lee et al. 1981; Imai et al. 1982; Imai and Lee 1983; Pearson et al. 1983. e Geer and Guidry 1965; Schenk et al. 1965; Robertson et al. 1972; Mahley et al. 1974; Innerarity et al. 1982. rene from LDLs was found to enter recep- tor-deficient cells, and Remsen and Shire- man suggested that entry was by rapid redistribution between the lipoprotein and cell membrane. Similarly, Plant and co- workers (1985) studied the uptake by cells of BaP from HDLs, LDLs, and VLDLs, as well as from laboratory-prepared vesicles. They concluded that the cellular uptake of BaP from these hydrophobic donors was by transfer through the aqueous phase. Although all of these reports involve in vitro studies, it seems plausible that the lipoproteins could transport chemicals from the lungs to the cells of the artery wall. In this regard, it is of interest that the urine of cigarette smokers has been shown to contain mutagenic substances (Yamasaki and Ames 1977~. Recommendation 8. A comparison of LDLs of different size and apoprotein com- position relative to their ability to bind hydrocarbons and deliver them to smooth muscle cells and macrophages in culture is needed. Cigarette Smoking There is a vast literature base for the con- clusion that cigarette smoking is a major cause of coronary heart disease in the United States for both men and women. The epidemiologic evidence for that con- clusion, along with supportive pathophys- iological studies, has been the topic of a major recent review monograph (U. S. De- partment of Health and Human Services 1983~. In general, the epidemiologic find- ings have established that the risk for de- veloping coronary heart disease increases with increasing exposure to cigarette smoke, that cigarette smokers have a two- fold greater incidence of coronary heart disease, that women who use oral contra- ceptives and who smoke increase the risk of myocardial infarction approximately 10- fold compared with women who neither

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Thomas B. Clarkson 615 Table 3. Summary of Atherosclerosis Characteristics of Nonhuman Primates Potentially Useful for Research on Automotive Emissions Model Advantages Lesions occur naturally, are exacerbated by dietary cholesterol, similar to those of humans; complications and myo- cardial infarction relatively common; lipoproteins similar to those in hu mans; animals are a convenient size. Lesions occur naturally, are exacerbated by dietary cholesterol but not CO, are similar to those of humans; gender differences in coronary artery lesions; have high incidence of myocardial in- farction; lipoproteins are well charac- terized; animals are convenient size, readily available. Lipoprotein changes and lesions induced by dietary cholesterol similar to those in humans; relationships between lipo- protein alterations and lesion develop- ment documented; convenient size, readily available. Disadvantages Rhesus monkeysb (Macaca mulatta) Cynomolgus macaquesC (Maraca fascicularis) African green monkeys (Cercopithecus aethiops) Not available from countries of origin, must be obtained from domestic breeding colonies, expcusivc, difficult to handle. Expensive to acquire and maintain, diff~- cult to handle. Characterization incomplete, expensive, difficult to handle. a Modified from a previously published summary byJokinen et al. 1985. b Taylor et al. 1962, 1963; Scott et al. 1967a,b; Manning and Clarkson 1972; Rudel ct al. 1979; Bond et al. 198()a; Rudel 1980. c Kramsch and Hollander 1968; Thomsen 1974; Armstrong 1976; Malinow et al. 1976a,b; Bing et al. 198(); Bond et al. 1980b; Armstrong et al. 1985. ~ Kritchevsky et al. 1977; Trillo and Prichard 1979; Rudel 1980; Rudel et al. 1983. smoke nor use oral contraceptives, and finally that the cessation of smoking results in a substantial reduction in coronary heart disease events. In this review the patho- physiological basis for the increased coro- nary heart disease is explored. Coronary Artery Atherosclerosis. In view of the large effect of cigarette smoking on coronary heart disease morbidity and mor- tality it is surprising to find that there are few data to suggest that the increased cor- onary heart disease events are related to more extensive coronary artery atheroscle- rosis. Viel and coworkers (1968) studied the coronary arteries of 1,150 men and 290 women who died accidentally in Santiago, Chile. They concluded that smoking was not related to the extent of coronary artery atherosclerosis. Earlier, Auerbach and col- leagues (1965) concluded that the percent- age of men with advanced coronary artery atherosclerosis was higher among cigarette smokers than nonsmokers and increased with the amount of cigarette smoking. Later, Auerbach and coworkers (1976) re- ported on detailed studies of the hearts from 2,257 autopsies of male patients at the Veterans Administration Hospital of East Orange, New lersey. Again they found an association between cigarette smoking and coronary artery atherosclerosis; however, this time, the precise nature of that effect was better defined. They noted that the effect was greater in the intramyocardial arteries than in the larger epicardial arteries, with the most striking effect being found in the myocardial arterioles. As a part of a large international study, Lifsic (1976) stud- ied the relationship between cigarette smoking and coronary artery atherosclero- sis as well as its complications. He con- cluded that there was no clear association between smoking and coronary stenosis, myocardial infarction, or heart weight. Although the effects of cigarette smoking on coronary artery atherosclerosis may be minimal, it does seem to increase the extent

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620 Evaluation of Automotive Emissions as Risk Factors artery and diffusely thickened intima. These observations suggested the possibil- ity that some atherosclerotic plaques may represent a form of benign neoplasm in the arterial intima. Those innovative studies prompted several investigations of the ef- fect of carcinogens on smooth muscle cell proliferation and arteriosclerotic plaque de- velopment in chickens and pigeons. In 1977, dimethylbenzanthracene and BaP were both shown to increase the fre- quency and size of atherosclerotic lesions in the abdominal aorta of chickens (Albert et al. 1977~. Dimethylbenzanthracene was more potent than BaP. Further studies showed that the chronic administration of dimethylbenzanthracene stimulated the growth of naturally occurring atheroscle- rotic lesions in the distal aorta of chickens without producing new arterial lesions (Bond et al. 1981; Penn et al. 1981~. A major recent finding has been that focal smooth muscle cell proliferation in the chicken aortic intima can be produced by an initiation/promotion sequence (Ma- jesky et al. 1985~. Chickens that were treated with the tumor initiator dimethyl- benzanthracene followed by repeated injec- tions of an a-adrenergic agonist, methoxa- mine, had foci of intimal smooth muscle proliferation in the thoracic aorta that oc- curred with a greater incidence and severity than elicited by either agent alone. The results were consistent with initiation- and promotion-like stages in the development of intimal lesions, and suggested another way that such proliferation in the arterial intima resembles benign neoplasia in other tissues. Since methoxamine is an cr-adren- ergic agonist, there may be some relation- ship between this observation and the effects of psychosocial stress on athero- genesis. The effect on atherosclerosis of BaP and dimethylbenzanthracene has been studied in another avian model, the White Carneau pigeon (Revis et al. 1984~. Dimethylbenzan- thracene, but not BaP, was found to in- crease atherosclerosis. Extensive studies have been reported to better clarify the cellular metabolic events that may relate to the effect of carcinogens on smooth muscle cell proliferation. Some of these studies have compared atheroscle- rosis-susceptible and -resistant pigeons (Hog" and Cryer 1982; Majesky et al. 1983~. Others have involved studies of the bioactivation of mutagens in cultured smooth muscle cells (Bond et al. 1979, 1980a) . Summary Epidemiologic data provide suggestive ev- idence that automotive emissions may be risk factors for the development of athero- sclerosis and coronary heart disease. Fur- ther concern about that possibility derives from analogies to cigarette smoking. Cig- arette smoking is a major risk factor for coronary heart disease, peripheral vascular disease, and other clinically significant se- quelae of atherosclerosis. There is evidence for and controversy about the extent to which atherosclerotic plaque progression among cigarette smokers can lead to the very exaggerated morbidity and mortality in that group. Studies of the atherogenic components of cigarette smoke have tended to implicate CO as the most likely substance promoting atherogenesis. The link between cigarette smoking and ex- posure to automotive emissions, in the minds of many, relates to the fact that both result in the exposure of human subjects to considerable amounts of CO. In reviewing the rise and fall of ischemic heart disease, Stallones (1980) points out that among the four common risk factors (hypertension, high serum cholesterol, physical activity, and cigarette smoking) only cigarette smoking fits the observed pattern of the rise and fall in mortality from ischemic heart disease. Interestingly, one could spec- ulate that air pollution and its control may be similar. In this chapter the pathophysiological rationales were provided for ways in which automotive emissions exposure might af- fect atherogenesis. On the basis of previ- ously reported research, it is not possible to draw a clear conclusion regarding whether and to what extent CO affects the develop- ment of atherosclerosis. For that reason, ~1

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Thomas B. Clarkson 621 recommendations refer to exposures to automotive emissions. If effects on athero- genesis are found, then components of au- tomotive emissions should be studied sep- arately. Atherosclerosis and its clinical sequelae were described in the context of the natu- ral history of its development. Emphasis was on the origin of fatty streaks, whether fatty streaks progress to fibrous plaques, and on the development of plaque com- plications. Age differences in susceptibil- ity to coronary artery atherosclerosis, gender differences in the progression of coronary lesions, genetic susceptibility to coronary atherosclerosis, and psychosocial influences on plaque progression have been reviewed. Animal models for research on atherosclerosis have also been reviewed briefly. Since little is known about the effect of automotive emissions, other than CO, on atherogenesis, analogies were made to other chemical exposures. Finally, research needs for examining the question of auto- motive emission effects on atherogenesis were presented, as well as needs for epide- miologic studies of the association between exposure and cardiovascular risk factors, morbidity, and mortality. Those needs are presented in the context of initial re- search to determine if and to what extent automotive emissions exposure affects ath- erosclerosis and directions that could be undertaken if.initial studies establish an effect of automotive emissions exposure. Summary of Research Recommendations HIGH PRIORITY The studies most likely to yield useful data are listed below. Recommendation 9 Several types of exploratory investigations could be performed that would take advantage of existing data bases and ongoing population-based cohort studies to evaluate the association between exposure to automotive exhaust and cardiovascular risk factors, morbidity, and mortality. The validity of responses to simple questionnaires and information on occupation might be evaluated as measures of personal exposure. Noninvasive techniques (, mode imaging, exercise stress tests, 2thr ambulatory ECG mon itoring) could be used as indices of cardiovascular disease. These preliminary approaches represent cost-effective ways to develop more refined epidemiologic studies. Recommendation 10 Epidemiologic studies should be undertaken to detect and mea sure associations between exposure to automotive emissions and known or suspected risk factors for atherosclerosis or cardiovascu lar disease, including lipids and lipoproteins, hemostatic factors, platelet function, pulmonary function, exercise capacity, and so on. Recommendation 11 Epidemiologic studies should be done to determine whether exposure to automotive emissions is associated with increased risk of atherosclerosis or clinical manifestations of cardiovascular dis ease in individuals characterized with respect to known risk factors (for example, cigarette smoking, hyperlipidemia, elevated blood pressure, positive family history). Recommendation 5 Since automotive emission exposure may result in relative hy poxia, it seems reasonable to suspect that plaque complications

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622 Evaluation of Automotive Emissions as Risk Factors could be hastened by that mechanism. Cynomolgus monkeys with diet-induced atherosclerosis of two or three years' duration should be exposed to various concentrations of automotive emissions and their plaque complications compared with those in appropriate control animals not exposed to automotive emissions. Recommendation 12 Research to evaluate components of atherogenesis and extent of coronary artery atherosclerosis of cynomolgus monkeys exposed to varying concentrations of automotive emissions for varying . . , . . ~ ~ ~ ~ lengths ot time should be pursued. lllustratea in figure 1 are methods that could be used for the quantification of the atherogenic components. MEDIUM PRIORITY Since there are no definitive data that establish an association between automotive emissions exposure and atherogenesis, the high-priority research should be completed before the research recommended below is considered. Recommendation 1 Research to determine whether exposure of endothelial cells to automotive emissions affects endothelial function should be under taken with emphasis on endothelial cell replication and prostacyclin production. Recommendation 3 The effect of automotive emissions on the catabolism of LDL particles by smooth muscle cells, the replication rates of these cells, and the kinds of connective tissue proteins they elaborate should be determined. Recommendation4 The effect of automotive emissions on the internalization of ,~VLDL and other modified LDL particles by macrophages should be assayed. Recommendation 8 A comparison of LDLs of different size and apoprotein compo sition relative to their ability to bind hydrocarbons and deliver them to smooth muscle cells and macrophages in culture is needed. LOW PRIORITY Recommendation 2 Studies should be done to determine whether chronic exposure to automotive emissions affects the repair of stress-induced endo thelial injury and/or the way in which the intima of arteries responds to such injuries. Recommendation 6 Studies to determine whether and to what extent automotive emissions exposure may diminish or abolish the gender-specific difference in atherogenesis need to be explored. Recommendation 7 Experiments that determine whether chronic exposure to CO affects coronary artery atherosclerosis differently in genetically susceptible and resistant strains are needed.

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