Philip Morris
Environmental Tobacco Smoke: A Compendium of Technical Information
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CHAPTER 6
PASSIVE SMOKING AND HEART DISEASE:
EPIDEMIOLOGY, PHYSIOLOGY, AND BIOCHEMISTRY~
Stanton A. Glantz PhD
William W. Parffiley MeD.
Division of Cardiology
School of Medicine
University of California San Francisco, CA 94143
Introduction
The first disease linked to active smoking was lung cancer. It
is, therefore, not surprising that the first disease linked to
passive smoking was also lung cancer (USPHS, 1986). Before the
advent of mass marketed cigarettes, lung cancer was a rare disease.
The fact that smoking is the major identifiable cause of lung
cancer made identifying this link -- for both active and passive
smoking -- relatively straightforward. This situation contrasts
i4ith heart disease, which has many risk factors, so it is not
surprising that it took longer for the scientific community to
conclude that active smoking caused heart disease (USPHS, 1983).
Once the link between smoking and heart disease was established,
it became clear that smoking accounted for more heart disease
deaths than lung (and other) cancers because of the high prevalence
of heart disease. Similarly, smoking is the most important
preventable cause of coronary disease. Given this history, it is
not surprising that exposure to environmental tobacco smoke (ETS)
has now been linked to heart disease in nonsmokers (Wells, 1988;
Kristensen, 1989) and may result in a substantial number of
unnecessary coronary heart disease deaths in nonsmokers.
Most of the evidence linking ETS and coronary heart disease has
appeared since the US Surgeon General (USPHS, 1986) and National
Academy of Sciences (NRC, 1986) last reviewed the evidence on the
health effects of ETS. Based on the information available as of
early 1986, both these reports concluded that the evidence linking
ETS and heart disease was equivocal and that more research was
necessary before any definitive statements could be made. These
conclusions were reasonable at the time they were made. In the
four years since these reports were written, considerable
information on both the epidemiology and biological mechanisms by
which ETS may cause heart disease has accumulated from several
areas of scientific investigation. In fact, most of the results
1This chapter is an adaptation of a peer-reviewed manuscript
of the same title (Glantz and Parmley, 1990).
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presented in this chapter were published after the 1986 Surgeon
General and National Academy of Science reports.
First, there are now 11 epidemiological studies on the
relationship between exposure to environmental tobacco smoke in the
home and the risk of heart disease in the nonsmoking spouse of a
smoker. All but one of these studies yielded a relative risk
greater than 1.0. There are several lines of biologic evidence
which make this association plausible. There is evidence that
exposure to ETS reduces exercise tolerance of healthy individuals
as well as people with existing coronary artery disease. Such
reduced exercise capability is one of the landmarks of acute
compromises to the coronary circulation. There is evidence, from
both human and animal studies, that exposure to tobacco smoke,
including passive smoking, increases aggregation of blood
platelets. Such increases in platelet aggregation are an important
step in the genesis of atherosclerosis. In addition, increasing
platelet aggregation contributes to coronary thrombosis, the cause
of acute myocardial infarction. Finally, carcinogenic agents in
ETS, including benzo[a]pyrene have been shown to produce injuries
to the endothelial cells which line arteries. Such injuries are
the first step in the development of atherosclerosis. Thus,
exposure to ETS can contribute to both short term and long term
insults to the coronary circulation and the heart.
Effects of Primary Smokinq
Before reviewing the evidence linking ETS with coronary artery
disease, it is worth summarizing the evidence linking active
smoking with coronary artery disease. This evidence was summarized
in the 1983 Surgeon General's Report, which was devoted entirely
to cardiovascular disease (USPHS, 1983); it concluded:
In 1980, diseases of the circulatory system were responsible
for approximately one-half of the total U.S. mortality. CHD
was the sinale most important cause of death, accounting for
approximately 30 percent of all U.S. deaths.
Cigarette smoking is one of the three major independent CHD
risk factors. The magnitude of the risk associated with
cigarette smoking is similar to that associated with the
other two major CHD risk factors, hypertension and
hypercholesterolemia; however, because cigarette smoking is
present in a larger percentage of the U.S. population than
either hypertension or hypercholesterolemia, cigarette
smoking ranks as the largest preventable cause of CHD in the
United States. Cigarette smoking also acts synergistically
with the other major risk factors to greatly increase the
risk for CHD.
Arteriosclerosis is the predominant underlying cause of
cardiovascular disease, and atherosclerosis is the form of
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arteriosclerosis that most frequently causes clinically
significant disease, including CHD, atherothrombic brain
infarction, atherosclerotic aortic disease, and
atherosclerotic peripheral vascular disease. Cigarette
smoking contributes both to the development of
atherosclerotic lesions and to the clinical manifestations
of atherosclerotic vascular disease, including sudden death.
Although the precise pathophysiologic basis of these clinical
manifestations is not understood, it may be related to
several deleterious cardiovascular effects of cigarette
smoking, including production of an imbalance between
myocardial oxygen supply and demand, a decrease in threshold
for ventricular fibrillation, and an increase in platelet
aggregation. Nicotine and carbon monoxide are the tobacco
smoke constituents most closely associated with these adverse
effects; other cigarette smoke constituents such as hydrogen
cyanide, oxides of nitrogen, and carbon disulfide are being
studied for possible pathologic cardiovascular effects.
Since 1983, evidence has also mounted that the polycyclic aromatic
hydrocarbons in cigarette smoke can injure the arterial endothelium
and initiate the atherosclerotic process.
~ All the compounds implicated as damaging to the cardiovascular
system of smokers have been identified in ETS (USPHS, 1986; NRC,
1986).
Enidemioloaical Studies on ETS and Heart Disease
Since 1984, the epidemiological evidence linking exposure to
ETS with heart disease has rapidly accumulated. The results of the
eleven published studies are summarized in Table 1 and Figure 1;
four studies present data on men, nine on women, and one on both
sexes combined. Despite minor differences in methodology or end
points (some used death from ischemic heart disease of any origin
and some were limited to death from myocardial infarction), the
results of these studies are remarkably consistent. All the
studies on men yielded relative risks of death from heart disease
exceeding 1 for nonsmoking men married to smokers, with a median
risk of 1.2. All but one of the studies on women (Lee et al, 1986)
yielded relative risks exceeding 1, with a median relative risk of
1.4. Several studies also suggested an increase in the risk of
nonfatal coronary symptoms (Svendsen et al, 1987; Palmer et al,
1988; Hole et al, 1989; Dobson et al, 1990); quantitative results
in Table l only reflect risk of death, not coronary symptoms.
Consistency of an observation across different studies increases
the confidence one can have in the belief that an association is
causal, unless all studies have the same bias.
When interpreting the results of such epidemiological studies,
it is always important to consider biological plausibility and
potential confounding variables which could explain the results.
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Aside from noting that the compounds in mainstream smoke that have
been implicated in heart disease are in ETS, we will defer the
discussion of biological plausibility until later in this chapter,
when we discuss the effects of ETS on platelets and the atherogenic
agents in ETS. For now, we will concentrate on potential
confounding variables. These are particularly important in a
disease like heart disease, because it is known to be caused by
multiple risk factors.
All of the studies controlled for the most important confounding
variable, age, and several (Garland et al, 1985; Svedsen et al,
1987; He, 1989; Hole et al, 1989; Humble et al, 1990) controlled
for several known risk factors for coronary artery disease, in
particular levels of cholesterol, blood pressure and weight (or
body mass or body mass index). Most of the studies also included
one or more measures of socioeconomic status, such as the nature
of the housing or amount of education.
Lee (1988, 1989, 1990) has suggested that the elevated risk of
heart (and other) disease with passive smoking could be due to
misclassification of nonsmokers who are really smokers. In
addition, Wald (1986) has noted that some people who say they live
yith nonsmokers-Yrave detectable levels of the nicotine metabolite
cotinine in their blood, indicating that they are actually exposed
to ETS, either at work or at home. The former type of
misclassification will tend to lead to an overestimate of the risks
associated with ETS and the latter will lead to an underestimate
of the risk. Careful analysis of the question of misclassification
-- which applies generally to studies of ETS and not just heart
disease -- have demonstrated that the observed risks cannot be
explained by this technical problem (Wald, 1986; Wells, 1986, 1988,
1990; Kawachi and Pearce, 1989; Reinken, 1989). In addition, both
the Surgeon General (USPHS, 1986) and the National Academy of
Sciences (NRC, 1986) were presented with the argument that
misclassification errors accounted for the link between ETS and
lu W cancer and concluded that ETS caused lung cancer in healthy
nonsmokers. To date,.no compelling case has been made that this
technical error explains consistent findings linking ETS with heart
(or lung) disease. Indeed, the net effect of these two types of
misclassification errors is to lead to an underestimate of the
effects of passive smoking for lung cancer.
There is.always the possibility that there is some other
confounding variable relating to cultural factors,'such as the
nature of housing or employment or the nature of time spent outside
the home. Most studies look only at a crude measure of
exposure-spouse smoking-and it is possible that this is an
indicator variable for other things, such as poor diet, risky
lifestyle, or stress. The fact that results are similar from all
over the world in widely varying cultural settings -- including
several regions in the United States, the United Kingdom, Japan,
and China -- argues against this concern.
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Several authors also observed a dose-response relationship
(Table 1) between increasing amounts of smoking by the spouse and
the risk of heart disease in the nonsmoking spouse (Helsing et al,
1988 (statistically significant in women, but not men); Hole et al,
1989; Garland et al, 1985 (although not statistically significant);
Humble et al, 1990; He, 1989; Hirayama, 1984). The presence of
such dose-response effects across multiple studies, done in
different locations with different criteria supports the hypothesis
that the epidemiology is revealing a real effect of ETS on heart
disease in nonsmokers.
While all but one of the studies in Table 1 and Figure 1 yielded
relative risks greater than 1, the fact remains that 3 of the
studies in men and 4 of the studies in women had 95% confidence
intervals for the relative risk of passive smoking for heart
disease that fell below 1.0, meaning that the risk was not
statistically significantly elevated above 1.0 (with P<.05). It
is important to note that the 95% confidence intervals do not lie
symmetrically about 1.0, but rather are skewed towards higher
risks. To avoid false negative conclusions, Rothman (1978)
suggested examining the confidence interval, as we have done, in
concluding the exposure to ETS elevates the risk of heart disease.
One can assess formally how confident one can be in reaching a
negative conclusion by computing the power of the study to detect
an effect of specified size (Friedman et al, 1978). Table 1 shows
estimates of the power of each of the studies to detect a 20%
increase in risk-of heart disease (i.e., a relative risk of 1.2)
with the available samples. The power was computed as described
in Muhm and Olshan (1989), using a two-sided test for the relative
risk with a Type I risk of 5% (i.e., requiring the 95% confidence
interval for the relative risk to exclude 1.0 before concluding a
statistically significant elevation in risk in an individual
study). Most of the studies have low to moderate power. The two
(Helsing et al, 1988; Hole et al, 1989) that have power above the
desirable level of 80% both identified significant increases of
heart disease risk with ETS exposure. Interestingly, the study by
Lee (1986) which was the only one with a relative risk below 1,
also had the lowest power to detect an effect, only 3%.
It is possible to combine the results of these studies in a
formal analysis to derive a global estimate of the relative risk
and associated 95% confidence interval. By combining the studies,
the sample size and so the power to detect an effect increases.
Pooling the studies in Table 1 yields an estimate of the relative
risk of death from heart disease of 1.3 (95% CI 1.1-1.6) for men
and 1.3 (95% CI 1.2-1.4) for women. These results are consistent
with those reported by Wells (1988) who used the studies by Gillis
et al (1984), Lee et al (1986), and Helsing et al (1987) to compute
a pooled relative risk of 1.3 (with a 95% confidence interval from
1.1 to 1.6) for men and the studies by Hirayama (1984), Gillis et
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al (1984), Garland et al (1985), Helsing et al (1988), Lee et al
(1986), and Martin et al (1986) to compute a pooled relative risk
of 1.2 (with a 95% confidence interval from 1.1 to 1.4) for women.
Exposure to ETS significantly (p < 0.001) increases the risk of
death from heart disease in nonsmokers.
Finally, it is worth noting that all these studies are based on
the smoking habits of the nonsmoker's spouse, and so exposure to
ETS at home. Household exposures to ETS at home are generally much
smaller than exposures at work, where the density of smokers is
generally higher (Repace and Lowrey, 1985,1987). As a result,
these studies will generally underestimate the risk and attendant
public health burden due to ETS-induced heart disease if a
substantial proportion of the controls are exposed at work.
Kawachi et al (1989) have adjusted Wells' (1988) relative risks to
account for workplace exposures to ETS and found that the relative
risks increase to 2.3 (95% CI 104 - 3.4) for men and 1.9 (95% CI
1.4 - 2.5) for women. In addition, Wells (1988) and Kawachi et al
(1989) indicate that the number of heart disease deaths due to
passive smoking is an order of magnitude greater than the number
of lung cancer deaths due to passive smoking.
These epidemiological studies demonstrate a connection between
ETS exposure and death from heart disease. We now turn our.
attention to possible physiological and biochemical mechanisms
which could explain these observations.
Acute Effects of ETS Ex
osure
Chronic exposure to ETS exerts carcinogenic effects by
increasing the cumulative risk of a molecule of one of the
carcinogens in the ETS damaging the DNA in a cell and initiating
or promoting the carcinogenic process. To date, no one has
identified any effects of acute exposure to ETS (or, for that
matter, any other carcinogen) on cancer. The situation with heart
disease is different. In heart disease there are both important
chronic changes (i.e., the development of atherosclerotic lesions)
and acute changes. The latter include an increase in myocardial
oxygen demand which may outstrip the oxygen supply and produce
ischemia, and increased platelet aggregation which can lead to
coronary thrombosis and acute myocardial infarction.
When the coronary circulation cannot provide enough oxygen to
the myocardium to meet the demand, the result is ischemia which can
be silent or result in anginal chest pain. Earlier onset of angina
or hypotension during exercise is a reflection of more severe heart
disease. oxygen supply can be reduced by atherosclerotic narrowing
or vasoconstriction of the coronaries or by reducing the oxygen
carrying capacity of the blood by forming carboxyhemoglobin.
Khalfen and Klochkov (1987) confirmed earlier work by Aronow (1978)
demonstrating that exposure to ETS significantly reduced exercise
ability in patients with coronary artery disease and the rate
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pressure product (heart rate times systolic blood pressure). In
both studies, patients were exposed to realistic levels of ETS by
simply sitting in a waiting room while someone was smoking. These
effects were present in both smokers and nonsmokers (Khalfen and
Klochkov, 1987) and regardless of whether or not the room was
ventilated (Aronow, 1978; Khalfen and Klochkov, 1987). Exposure
to ETS also increased resting heart rate and systolic and diastolic
blood pressure, and resulted in a lower heart rate at the onset of
angina (Aronow, 1978). Blood carboxyhemoglobin was increased by
about 1% after exposure to ETS (Aronow, 1978). Sheps et al (1987)
found no change in cardiovascular function in subjects with angina
in response to mild elevation in blood carbon monoxide similar to
that experienced in passive smokers when they exposed their
subjects to pure carbon monoxide. In contrast, Allred et al (1989)
found a significant dose-response relation between
carboxyhemoglobin level and the change in the length of time to
both electrocardiographic and symptom manifestation in men with
angina pectoris exercising after exposure to CO. Even a small
increase in the carboxyhemoglobin level, representing a seemingly
minor reduction in the oxygen-carrying capacity of hemoglobin, was
associated with the statistically sIgnificant effects. Acute
exposure to ETS leads to an imbalance between myocardial oxygen
$upply and demand during exercise in patients with coronary artery
disease. While this discussion has concentrated on the carbon
monoxide in ETS as the active agent, it is likely that some other
component of the ETS is also contributing to this effect.
The effects of ETS on cardiac performance are, in fact, severe
enough to affect exercise performance in young healthy subjects
with no evidence of heart disease. McMurray et al (1985) blindly
exposed young healthy women to pure air and air contaminated with
ETS while they exercised on a treadmill. The results were similar
to those observed in patients with coronary artery disease.
Resting heart rate was increased during exposure to ETS, which
increased blood carboxyhemoglobin by about 1%. Exposure to ETS
significantly reduced maximum oxygen uptake (by 0.251/min and time
to exhaustion (by 2.1 min). Exposure to ETS also increased the
perceived level of exertion during exercise, maximum heart rate,
and COz output. It also significantly increased levels of lactate
in venous blood (from a mean of 5.5 mM during control period to
6.8 mM after exposure to ETS). This greater lactate at a lower
oxygen consumption during the passive smoking trials indicates a
greater reliance on anaerobic metabolism. The combined effect of
the reduced oxygen carrying capacity and increased lactate resulted
in a reduction in maximal aerobic power and 'the duration of
exercise. Thus, even in healthy subjects, exposure to ETS
adversely affects exercise performance.
The acute effects of CO and direct tobacco smoke on exercise
performance are well documented in the literature. Exposure to CO ~
(or CO in tobacco smoke), and the subsequent elevation of blood Q
carboxyhemoglobin levels to ca. 3%, has been shown to decrease
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exercise duration in patients with ischemic heart disease and
decrease short-term maximal exercise duration in young healthy men.
It is conceivable, therefore, that elevations in COHb due to ETS
could have similar effects. While the association between active
smoking and cardiovascular disease is well known (USPHS, 1983),
little is known about the relative importance of each component of
tobacco smoke that may be responsible for this relationship. Most
experts agree, however, that both CO and nicotine are important,
and other constituents of the smoke may play a role as well.
Active smoking clearly aggravates the decrease in 02 capacity
induced by CO through an increase in the OZ demand of the heart
(Deanfield et al, 1986). Passive smoking exposes an individual to
all components in the cigarette smoke, but the CO component
dominates heavily because only 1%- or less of the nicotine is
absorbed from passive smoking compared to 100% in an active smoker
(Wall et al, 1988; Jarvis, 1987). Currently available information
indicates that acute exposure (1 to 2 h) to passive smoke will
increase a nonsmoker's COHb level by about 1% (Jarvis, 1987). This
small incremental increase in COHb due to ETS alone may not be
enough to trigger acute cardiovascular effects unless combined with
other sources of CO or with other components of ETS having a
similar effect (e.g., nicotine).
Lamb (1984) has suggested that at maximal exertion. levels, up
to 90% of the oxygen carrying capacity of the blood may be needed.
Because of the carbon monoxide, and perhaps other constituents, ETS
reduces this capacity, so the muscle cannot maintain its high rate
of aerobic metabolism unless cardiac output is further increased;
people with heart disease and reduced ventricular reserve have
difficulty meeting this demand. In sum, exposure to ETS increases
the demands on the heart during exercise and reduces the capacity
of the heart to respond. This imbalance increases the ischemic
stress of exercise in patients with existing coronary artery
disease and can acutely precipitate symptoms.
Moskowitz et al (1990) found evidence that adolescent children
of parents who smoked may suffer from chronic tissue hypoxia such
as that observed in anemia, chronic pulmonary disease, cyanotic
heart disease or high altitude. These children had significantly
elevated levels of 2,3-diphosphoglycerate (DPG), which suggests
that the body is attempting to compensate for hypoxia by increasing
DPG level in blood to meet tissue oxygen 'requirements, even after
correcting for age, weight, height and sex. These changes were
dose-dependent; the greater the exposure to ETS (measured both in
terms of parental smoking and serum thiocyanate in the children),
the greater the increase in DPG.
There is also evidence that acute exposure to ETS directly
affects the myocardial muscle at a cellular level. Gvozdjakova et
al (1984) exposed rabbits in a 50 liter child's incubator to the
smoke of three burning cigarettes smoked over a 30 minute period
and measured several variables related to the metabolism of cardiac
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mitochondria. (Mitochondria are the subcellular elements that
control cellular respiration; they convert oxygen into usable
energy in the form of ATP.) They had three groups of rabbits: one
group exposed to a single dose of ETS, one group exposed to 30 min
of ETS twice daily for two weeks, and one group exposed to 30
minutes of ETS twice a day for eight weeks. They measured
mitochondrial respiration (Q02) as the consumption of oxygen after
adding ADP to a vessel containing mitochondrial fragments. Using
pyruvate as a substrate, mitochondrial respiration QO was reduced
significantly compared to control (pure air) for all hses of ETS,
even a single exposure (Figure 2), to about half the control value.
The oxidative phosphorylation rate was also reduced significantly
at all exposures by about one-third. There were no significant
changes in the coefficient of oxidative phosphorylation (ADP:02)
with ETS exposure. Gvozdjakova et al concluded that pyruvate as
a substrate was a sensitive indicator of the toxic action of the
ETS on the oxidative process.
Later, to further isolate where in the process of mitochondrial
respiration, the ETS acted, Gvozdjak et al (1985, 1987) reported
data on succinate, NADH, and cytochrome oxidase activity in the
mitochondria in the four groups of rabbits. Figure 2 shows the
lFesults of exposure to ETS on the activity of NADH oxidase,
succinate oxidase and cytochrome oxidase of myocardial
mitochondria. The activity of the first two oxidases exhibited no
changes compared with the control group -- neither after a single
exposure to ETS or following exposures up to 2 weeks. Cytochrome
oxidase activity decreased both after a single exposure to ETS and
over time, with increasing effects as the duration of exposure to
ETS is extended. The observation that cytochrome oxidase and not
NADH or succinate oxidase activity was affected by ETS suggests
that the deleterious effects of ETS on myocardial mitochondrial
respiration occur at the terminal segment of the mitochondrial
respiration process.
Prolonged exposure to carbon monoxide has been shown in some
studies to induce ultrastructural changes in myocardium (Kjeldsen
et al, 1974; Thomsen and Kjeldsen, 1974; Lough, 1978). Later,
Kjeldsen and co-workers (Hugod et al, 1978), using a blind
technique and the same criteria to assess morphological myocardial
damage found no significant changes in the coronary arteries or
aorta in normocholesterolemic rabbits exposed to CO at
concentrations from 200 to 4000 ppm for' up to 12 weeks. They
suggested that the positive results obtained earlier were due to
the non-blind evaluation techniques and the small number of animals
used in these studies. Later, Hugod (1981): confirmed these
negative results using electron microscopy. In addition, the
earlier studies were conducted at "moderate" levels of CO (100 to
150 ppm) which are considerably higher than levels of CO found in
smoke-polluted environments (reported to be as high as 40-50 ppm,
but more typically are around 10 ppm) (NRC, 1986). These negative
studies only argue against an effect of CO in inducing coronary
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atherosclerosis, and not a direct effect of CO on myocardial oxygen
supply and demand (Deanfield et al, 1986).
Acute exposure to ETS not only increases the demand and
compromises the supply of oxygen to the heart as a whole, but also
reduces the myocardium's ability to use this oxygen to create ATP
to provide energy to support the heart's pumping activity. This
effect probably results from several of the compounds in ETS acting
simultaneously on the cardiovascular system.
Effects on Platelets
The action of ETS to increase platelet aggregation is another
way in which ETS can acutely increase the risk of a coronary event.
When blood platelets aggregate inappropriately and form a thrombus
(blood clot), this clot can form in a fissured plaque in the
coronary circulation and precipitate a myocardial infarction.
Platelets are important for the normal body process of hemostasis,
to prevent blood loss after an injury. Hemostasis depends on
complex interactions among the dynamics of blood flow, components
of the vessel wall, blood platelets and plasma proteins. A
thrombus can be considered as an inappropriate form of hemostasis
and is composed-of a mass of cellular material held together by a
network of fribrin. Definitive evidence has confirmed that
platelets play a major role in thrombus formation and embolization,
especially in the arterial system. In addition, increasing
evidence has shown that platelet deposition and thrombus formation
can contribute to the growth and progression of atherosclerotic
plaques (Fuster and Chesebro, 1981; Ross, 1986). An arterial
tbrombus appears to develop in three phases: platelet adhesion,
platelet aggregation, and activating of clotting mechanisms.
Passive smoking increases platelet aggregation and so increases the
likelihood of thrombus formation and myocardial infarction.
Table 2 summarizes the results of three studies (Davis et al,
1985a, 1986, 1989) on the effects of cigarette smoke on platelet
aggregation and damage to the arterial endothelium (lining). (We
will discuss the effects on the endothelium below.) Davis et al
(1989) also measured platelet aggregate ratios and endothelial cell
counts in nonsmokers before and after being exposed to 20 minutes
of ETS while sitting in a hospital atrium. Mean values before and
after passive smoking were 0.87 and 0.78 (P=.002) for platelet
aggregate ratios and 2.8 and 3.7 (P=.002) for counts~ of anuclear
endothelial cell carcasses in venous blood. These changes are in
between the effects observed after nonsmokers smoked two tobacco
cigarettes and the effects observed after smoking two non-tobacco
cigarettes (Davis et al, 1985a) and similar to the values observed
in nonsmokers who smoked two cigarettes while trying not to inhale
(Davis et al, 1986). These effects were not correlated with the
level of nicotine in the blood of the experimental subjects in any
of these or other (Davis et al, 1985, 1987), related studies on how
drugs modify platelet aggregation and endothelial cell counts. In
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