Philip Morris
Environmental Tobacco Smoke: A Compendium of Technical Information
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- Behrens, R.
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- Glantz, S.A.
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- Pukander, J.
- Randerath, E.
- Reinken, K.
- Remmer, H.
- Repace, J.L.
- Revis, N.
- Riboli, E.
- Rice, D.P.
- Rickert, W.S.
- Rigotti, N.A.
- Riley, E.C.
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- Rogers, C.C.
- Rogers, W.R.
- Roscovanu, A.
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- Ross, R.
- Rothman, K.
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- Saba, S.
- Sahin, F.
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- Schweitzer, S.O.
- See, L.C.
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- Sinzinger, H.
- Spengler
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- Stillman, F.A.
- Surgeon General
- Svendsen, K.
- Szalai
- Thomsen, H.
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- Vaughn, W.M.
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- Centers for Disease Control
- Epa, Environmental Protection Agency
- Indoor Air Div
- John B Pierce Lab
- Natl Heart Lung + Blood Inst
- Office of Air + Radiation
- Office of Prevention Education + Control
- Office on Smoking + Health
- Univ of Ca San Francisco
- Wa Business Group on Health
- Yale Univ
- Centers for Disease Control
- Master ID
- 2040225004/5288
Related Documents: - Characteristic
- DRFT, DRAFT
- OVER, OVER SIZE DOCUMENT
- Date Loaded
- 24 May 1999
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Draft - Do not cite or quote
particular, the effects observed in nonsmokers smoking without
inhaling were similar to the effects on smokers smoking two
cigarettes, despite the fact that the plasma nicotine levels in the
nonsmokers were a factor of 5 smaller than those observed in the
smokers (Davis et al, 1986). Other work in the same laboratory
comparing smoking with snuff use revealed similar changes in
platelet function in response to these two forms of tobacco use
(Davis et al, 1990). This result, combined with the finding that
smoking non-tobacco cigarettes (Davis et al, 1985a) failed to
produce changes in platelet function as large as observed with
tobacco cigarettes, suggests that nicotine is an important active
agent. Since non-tobacco cigarettes also 'affected platelet
aggregation somewhat, however, it is possible that carbon monoxide
or other combustion products are also influencing the platelets.
Sinzinger and Kefalides (1982) measured platelet sensitivity to
antiaggregatory prostaglandins (El, IZ, and D2) before, during and
after 15 minutes of exposure to ETS in healthy nonsmokers and
smokers (Table 3). Passive smoking reduced platelet sensitivity
to the antiaggregatory prostaglandins 12 and EZ significantly
(P<.01) by a factor of about 2 by the end of 15 minutes exposure
to ETS among nonsmokers. This effect persisted at 20 minutes after
the end of exposure, and was gone by 40 minutes. Platelet response
to prostaglandin Dz changed modestly in a similar pattern, but did
not reach statistical significance. Among smokers, the control
level of platelet aggregation was higher (P<.01) and the
prostaglandins had no significant effects on platelet aggregation
over time during or following exposure to ETS. Sinzinger and
Virgolini (1989) also showed that repeated exposure to ETS for one
hour per day for ten days produced lasting changes in platelet
function in nonsmokers similar to that observed in smokers. Thus,
nonsmokers' platelets seem much more sensitive to a single exposure
to ETS than do smokers' platelets, with platelet sensitivity to
disaggregating prostaglandins having similar effects in nonsmokers
acutely exposed to ETS as it does on the chronic levels of platelet
aggregation observed in long-term smokers.
Further evidence from the same_laboratory that passive smoking
increases platelet aggregation comes from work by Burghuber at al
(1986), who had smokers and nonsmokers smoke two cigarettes and
also exiosed a different group of smokers and nonsmokers to ETS in
an 18 m room in which 30 cigarettes had been smoked just before
exposing the nonsmokers. They measured the sensitivity. of
platelets to the disaggregating substance prostaglandin 12 (PGIz),
which is released by endothelium and inhibits platelet aggregation.
(PGI2 is also called prostacyclin.) Figure 3 shows the results of
this experiment. In smokers, neither smoking nor passive smoking
affected the sensitivity of the platelets to the disaggregating
effect of prostaglandin IZ. The sensitivity of platelets in
smokers was also significantly lower than nonsmokers. In contrast,
platelets were more sensitive to prostaglandin IZ in nonsmokers,
with both smoking and passive smoking producing similar reduction
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in platelet sensitivity to prostaglandin IZ. These results
suggest that the platelets of smokers are already desensitized to
the anti-aggregatory substance prostaglandin Iz, so that no further
decrease in aggregation is seen. The significant decrease in
platelet sensitivity to PGIZ after acute exposure to ETS suggests
that after ETS exposure platelets are more likely to aggregate,
with the adverse consequences described above.
Earlier work by Saba and Mason (1975) also indicated that
nicotine increased a variety of measures of platelet aggregation
in nonsmokers and smokers. While the effects of nicotine on
platelets from smokers was greater than in nonsmokers, the effect
generally did not vary with dose (between 2x10'9 and 2x10'4 molar),
suggesting that the effects of nicotine on platelets occur at low
doses and that the system saturates quickly. This observation may
explain why passive and active smoking have such similar effects
on platelets (Sinzinger and Kefalides, 1982; Burghuber et al, 1986;
Davis et al, 1989).
The probable link between nicotine and adverse physiologic
effects is nicotine-induced release of catecholamines.
catecholamines are then responsible for increased platelet
aggregation. This reasoning suggests that beta blockers might
provide some protection in smokers. This premise is borne out by
the MAPHY trial --a trial comparing the effects of the beta blocker
metoprolol to a thiazide diuretic in the control of moderate
hypertension (Wilkstrand, et al, 1988). For the same reduction in
blood pressure, the metoprolol treated group had a lower mortality
than the thiazide treated group. Virtually all of this reduction
in mortality, however, was seen in smokers, and not non-smokers.
This study provides evidence that blocking the effects of
catecholamines (released by nicotine) was the cause of the reduced
mortality in smokers who were receiving metoprolol.
In sum, passive smoking has significant effects on platelet
aggregation, of a magnitude similar to that observed in active
smoking. Moreover, the response of nonsmokers to both active and
passive smoking appears to be different from smokers, with
nonsmokers being more sensitive to low exposures to cigarette smoke
than smokers. This observation suggests that the pharmacology of
ETS in nonsmokers may be different than in smokers, with nonsmokers
being more sensitive to low doses of ETS. In particular, it
invalidates attempts to estimate "cigarette equivalent" doses of
ETS in nonsmokers or extrapolating from risks of smoking in smokers
to effects of ETS on nonsmokers. The resulting increase in
platelet aggregation can contribute to acute thrombus formation and
myocardial infarction.
In addition to the role of platelets in acute thrombus
formation, platelets are also important in the development of
atherosclerosis (Ross, 1986). Once there is damage to the arterial
endothelium, either through mechanical or chemical factors,
91
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platelets interact with or adhere to subendothelial connective
tissue and initiate a sequence which leads to atherosclerotic
plaque. When platelets interact with or adhere to subendocardial
connective tissue, they are stimulated to release their granule
contents. Endothelial cells normally prevent platelet adherence
because of the nonthrombogenic character of their surface and their
capacity to form antithrombotic substances such as prostacyclin.
Once the endothelial cells have been damaged, the platelets can
stick to them. Once the platelets are bound to the endothelium,
they release mitogens such as platelet-derived growth factor
(PDGF), which encourage migration and proliferation of smooth
muscle cells in the region of the endothelial injury (Fox and
DiCorleto, 1984). If platelet aggregation is increased because of
exposure to ETS, the chances of platelets building up at an
endothelial injury will also be increased. Thus, in addition to
contributing to acute effects through increasing the likelihood of
thrombus formation, the effects of ETS on platelets also increase
the chances that endothelial injury will lead to arterial plaque.
ETS also plays a role in causing damage to the endothelium and
initiating the atherosclerotic process. As discussed above, Davis
et al (1989, 1986, 1985, 1987, 1985b, 1990) found that acute
exposure to ETS (1989), like active smoking (1986, 1985a, 1987,
1985b) and use of chewing tobacco (1990), lead to a significant
increase (P<.002) in the appearance of anu~:lear endothelial cell
carcasses in the blood of people exposed to ETS (or tobacco or
tobacco smoke) constituents. The appearance of these cell
carcasses indicates damage to the endothelium, which is the
initiating step in the atherosclerotic process. As noted above,
in nonsmokers the appearance of endothelial cells following passive
smoking is almost as great as following primary smoking (Table 2).
The process by which endothelial injury leads to the development
of an atherosclerotic plaque, including the role of platelets, is
described in Figure 4. Based on the information presented so far,
exposure to ETS appears to produce injuries similar to those
observed with exposure to primary smoke and also affects platelets
in a way that increases the chances that they will bind to the
injured area and promote growth of smooth muscle cells.
The Role of the Polycyclic Aromatic Hydrocarbons in ETS
Many atherosclerotic plaques in humans are either monoclonal or
possess a predominantly monoclonal component (Benditt and Benditt,
1973), which indicates that the smooth muscle cells of each plaque
have a predominant cell type. Several animal studies have also
shown that injections of polycyclic aromatic hydrocarbons (PAHs),
in particular 7,12-dimethylbenz(a,h)anthracene (DMBA),
benzo(a)pyrene (Albert at al, 1977; Revis, et al 1984; Penn et al,
1981; Penn et al, 1986; Majesky et al, 1983) accelerate the
development of atherosclerosis. Others (Rogers et al, 1980, 1988)
failed to find an effect of active smoking or the extent of fatty
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deposits in the coronary arteries of baboons. (There was a
significant effect on the carotid arteries.) Benzo(a)pyrene is an
important element in ETS (USPHS, 1986). The effects of PAHs or
other carcinogenic or mutagenic elements in ETS (Remmer, 1987)
relates directly to the response to injury theory of atherogenesis
discussed above (Ross, 1986). Changes in the underlying smooth
muscle stimulated by these agents could then initiate the "injury"
that leads to platelet aggregation and plaque formation. Thus,
chronic exposure to ETS could have effects on plaque formation
through mechanisms similar to that by which long term exposures
produce cancer in other organs.
Albert et al (1977) gave chickens weekly intramuscular
injections of DBMA and benzo(a)pyrene for up to 22 weeks, then
killed the chickens at various times beginning after 13 weeks and
measured the plaque volume in the chickenso aortas. They found
that both DBMA and benzo(a)pyrene significantly increased the
volume of plaque compared to control chickens who had just received
injections of the solvent used to carry these agents. This study
provided the first evidence that known carcinogenic chemicals could
be atherogenic as well.
Penn et al (1981) extended this result in a similar experiment
by showing that the effects of DBMA on the extent of plaque buildup
in chickens was dose-dependent. The median cross-sectional area
of plaques on individual aortic segments and the plaque volume
index (an approximate measure of the total volume of plaque per
aorta) increased in a nearly linear fashion with DBMA dose. In
contrast to the marked increase in plaque area in the DBMA-treated
animals, there was only a slight increase in the percentage of
aortic sections with plaques in carcinogen-treated animals than in
controls. Plaques with a small cross sectional area were present
in all animals. Lesions of widely differing cross sectional areas
appeared to be similar histologically under the light microscopeo
Together, these data suggest that a major effect of chronic DBMA
exposure is to increase the size of spontaneous aortic lesions.
Rather than inducing some sort of cancer-like change in an
individual cell that begins the process which ultimately leads to
formation of a plaque, Penn et al suggested that chronic DBMA
exposure causes preferential division of individual cells or
patches of cells within the preexisting spontaneous lesions. From
this perspective, DBMA and other exogenous compounds would be
acting as a mitogen, similar to that released by activated
platelets, to stimulate division of aortic smooth muscle.
Revis et al (1984) found similar results in White Carneau
pigeons injected with DMBA and benzo(a)pyrene weekly for 6 months,
beginning when the pigeons were 3 months old. Compared with the
work described above, they found a greater effect on atherogenesis
of benzo(a)pyrene than DBMA, and also failed to observe a dose-
response relationship between the dose given and the amount of
aortic plaque. These differences from the work just described may
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be related to species differences, differences in the carrier used
to inject the PAHs (DMSO in the previous studies vs. corn oil in
this one) or differences in the age of the pigeons or dosing
schedule. They also found an increase in aortic plaques in pigeons
treated with the PAH 3-methylcholanthrene, but not the carcinogen
2,4,6-trichlorophenol or the PAH benzo(e)pyrene, which is not
considered a carcinogen. This result suggests that carcinogenic
PAHs, rather than carcinogens or PAHs in general, are implicated
in the atherosclerotic process.
Revis et al also studied the distribution of these compounds
after they had been radiolabelled. Forty-eight hours after the
injection of PAHs, radioactivity in the liver, aorta and lung
accounted for 75% of the injected dose, whereas in animals injected
with 2,4,6-trichlorophenol, radioactivity in the liver and kidney
accounted for 80% of the dose. In addition, 80% of the
radioactivity observed in the plasma immediately following
injection of radiolabelled PAHs was associated with the LDL and HDL
cholesterol fractions, compared with only _24% of the 2,3,6-
trichlorophenol, suggesting that plasma lipoproteins are an
important vehicle for transporting PAHs to their sites of
activation in the arteries.
There is also some evidence that ETS directly affects plasma
lipoproteins. Moskowitz et al (1990) showed that adolescent
children whose parents smoked had elevated levels of cholesterol
and depressed levels of HDL, even after correcting for age, weight,
height and sex. These effects were dose dependent; the greater the
exposure to ETS, the greater the changes in these variables. High
cholesterol and low HDL are important for the development of
plaque. Data on cholesterol and HDL froi'n adults married to
smokers, however, do not show similar differences (Garland et al,
1985; Svendsen et al, 1987).
To further elucidate the possible mechanisms by which PAHs
induce atherosclerotic changes, Majesky et al (1983) gave White
Carneau and Show Racer pigeons a single injection of
benzo(a)pyrene, then looked for metabolites of the benzo(a)pyrene
in aortic and hepatic tissues 48 hours later. White Carneau
pigeons develop severe atherosclerosis by the time they are 3 years
old, whereas Show Racer pigeons are relatively resistant to aortic
atherosclerosis. Aortic preparations of the White Carneau strain
exhibited a much greater inducibility of the microsomal
monooxygenase system than did those of the Show Racer strain,
particularly in young pigeons. Aortic tissues from White Carneau
pigeons aged 6-12 months exhibited a 3-12 fold inducibility whereas
aortic tissues from the same strain at 2-5 years of age exhibited
only minor (maximum of 3.3 fold) and, for the most part,
statistically insignificant increases. No age differences in
inducibility could be detected in the Show Racer strain.
Interestingly, the differences in inducibility manifest in aortic
tissues were greater in aortic tissues than in hepatic tissues from
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the same birds. Thus, the PAHs seem to accelerate any preexisting
tendency to develop atherosclerosis.
Regardless of the ultimate mechanism by which PAHs exhibit
atherogenic effects, it seems logical to suppose that the reactive
intermediary metabolites of these chemicals are the proximate
atherogenic or co-atherogenic agents since the parent compounds are
relatively inert both chemically and biologically. Thus,
bioactivation and inactivation (and regulatory control of these
processes) may be presumed to play extremely important roles in
their atherogenic properties. Bioactivated chemicals vary in their
stability/reactivity according to four general categories: (i)
those which are extremely unstable and persist only at the
immediate site (enzyme) of bioactivation, (ii) those which persist
only within cells in which bioactivation occurs, (iii) those which
persist primarily only within tissues in which bioactivation
occurs, and (iv) those capable of being transferred in the
circulation from one organ to another. For the first three of
these four categories, biotransformation in the aorta ger se
(target tissue activation) would -be of prime interest and
importance. Thus, it appears that PAHs could be playing eith.er a
mutagenic or mitogenic role in beginning the atherosclerotic
process in susceptible cells or individuals, depending on how the
PAHs in ETS are metabolized in the aorta.
The finding that enzymes that metabolize DMBA and benzo (a) pyrene
are in the artery wall led Penn et al (1986) to search for specific
molecular events in plaque cells that would lead to DNA changes
similar to those previously found in tumors. Identification of
such processes would be supportive of the monoclonal hypothesis of
atherogenesis. They obtained human DNA samples from coronary
artery plaques as well as DNA from normal sections of the coronary
arteries at surgery to remove the plaque. These DNA samples were
tested with the NIH 3T3 cell transection assay. Foci arose in
cells transfected with each of the DNA samples obtained from the
huwn coronary plaque, with an efficiency (number of foci per gg
of DNA) ranging from 0:016 to 0.060 (mean 0.036). The transfection
efficiencies for DNA's from normal coronary artery, liver, spleen,
lung, kidney and trachea were all below 0.008. The transformed
cells were also injected into the scalps of nude mice, where they
developed tumors. These results provide direct evidence for
similarities on the molecular level in the development of plaques
and tumors. Human coronary artery plaque DNA contains sequences
capable of transforming NIH 3T3 cells and these transformed cells
can cause tumors after injection into nude .mice. Control
experiments verified that the transforming cells did indeed contain
human DNA and that the tumorigenic (or transforming) activity was
not due to the ras oncogene family. Although these results clearly
demonstrate that human plaque DNA has transforming ability, the
temporal expression of this activity in vivo is not known. The
plaques were taken from adult patients in late stages of vascular
disease. Thus, we cannot determine from these samples whether the
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manifestation of transformation is a relatively late event in
plaque development or an early but stable event. Oncogene
activation and expression is an important early event in
transformation and tumor genesis. These results identify specific
molecular events that may underlie the proliferation of smooth
muscle cells that is a hallmark of atherosclerotic plaque
development and demonstrates that plaque cells exhibit molecular
alterations that had previously only been thought to be present in
cancer-cell transformation and tumorigenesis. These results
provide direct support for the monoclonal hypothesis.
Randerath et al (1988) also demonstrated that constituents of
cigarette "tar," including benzo(a)pyrene, are preferentially
attracted to the heart and damage DNA there. They studied
molecular mechanisms of smoking-related carcinogenesis by examining
the induction and distribution of covalent DNA damage in internal
organs of the mouse following topic application of cigarette smoke
condensate daily for 1, 3, or 6 days then killed 24 hr later. DNA
samples were obtained from skin, lung, heart, kidney liver, and
spleen. Adducts containing benzo(a)pyrene-derived moieties were
identified, together with others. At all three times, the number
of adducts in heart and lung DNA was about five times higher than
that in liver and slightly higher than that in skin. Covalent DNA
damage was estimated to be 6.2, 5.7, 3.9, and 1.9 times higher,
respectively, in lung, heart, skin and kidney than in liver,
ranging from approximately 1 adduct in 5.4x106 DNA nucleotides in
lung to 1 adduct in 3.3xl0~ DNA nucleotides in liver. Spleen DNA
was virtually adduct free. While the DNA adduct prof.iles resembled
each other qualitatively among the different tissues, there were
major quantitative differences between the different tissues, with
the highest DNA binding occurring in the lung and heart. The
reasons for the high incidence of DNA adducts in the heart are not
known, but may be related to the role of plasma lipids in
transporting PAHs such as benzo(a)pyrene and preferential binding
of these lipids to cardiac tissue, as discussed earlier.
In sum, there is a growing body of evidence at a molecular level
supporting the monoclonal hypothesis of atherogenesis, with
compounds in tobacco smoke and ETS strongly implicated as agents
which stimulate the development of coronary lesions. Regardless
of whether the monoclonal hypothesis proves to be true (or, more
likely, one of several initiators of the atherosclerotic process),
the fact is that there is clear evidence that components of ETS,
in particular PAHs such as benzo(a)pyrene, initiate or accelerate
the development of plaque. These biochemical findings are
consistent with the epidemiological finding that chimney sweeps,
which are exposed to high levels of PAHs in soot, have an increased
risk of heart disease (as well as cancer) and tend to develop these
diseases younger than other, comparable, occupations which avoid
exposure to PAHs (Hansen, 1983).
Summary
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There are eleven epidemiological studies, done in a variety of
locations, which reflect a 30% increase in risk of death from
ischemic heart disease or myocardial infarction among nonsmokers
living with smokers. The larger studies also demonstrate a
statistically significant dose-response effect, with larger
exposure to ETS being associated with greater risks of death from
heart disease.
These epidemiological studies are complemented by a variety of
physiological and biochemical data from human studies which suggest
that ETS may adversely affect platelet function and damage arterial
endothelium in a way that increases the risk of heart disease.
Moreover, ETS, in realistic exposures, also exerts significant
effects on exercise capability of both normal people and people
with heart disease by affecting the body's ability to deliver and
utilize oxygen. In animal experiments, ETS also depresses cellular
respiration at the level of mitochondria. The polycyclic aromatic
hydrocarbons in ETS also accelerate, and may initiate, the
development of atherosclerotic plaque.
It is also important to note that the cardiovascular effects of
ETS appear to be different in nonsmokers and smokers. Nonsmokers
appear to be more sensitive to ETS than smokers, perhaps because
some of the affected systems are sensitive to low doses.of the
compounds in ETS, then saturate and also perhaps because of
physiological adaptions smokers undergo as a result of chronic
exposure to the toxins in cigarette smoke. In any event, these
findings indicate that, in terms of cardiovascular disease, it is
unreliable to"compute "cigarette equivalents" for passive exposure
to ETS, then try to extrapolate the effects of this exposure on
nonsmokers from the effects of direct smoking on smokers.
These results combine to suggest that heart disease is an
important consequence of exposure to ETS. The combination of
epidemiological studies with demonstration of physiological changes
with exposure to ETS, together with biochemical evidence that
elements of ETS have significant effects on the cardiovascular
system,'lead to the conclusion that ETS causes heart disease. This
increase in risk translates into about 10 times as many deaths from
ETS-induced heart disease as lung cancer, and contributes 37,000
to the estimated 53,000 deaths annually from passive smoking
(Wells, 1988). This toll makes passive smoking the third leading
preventable cause of death in the United States today, behind
active smoking and alcohol.
97
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