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OCR for page 605
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
OCR for page 606
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
OCR for page 607
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
OCR for page 608
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
OCR for page 609
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
OCR for page 610
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
OCR for page 611
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
OCR for page 612
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.
OCR for page 613
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
OCR for page 614
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
OCR for page 615
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
OCR for page 620
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
OCR for page 621
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
OCR for page 622
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.
OCR for page 623
Thomas B. Clarkson
623
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Representative terms from entire chapter:
coronary artery
