Tobacco Documents Online

(~ with what a smolrer receives on an ~ basis) amoum of trains in cigarettes had no additi~mal effe~. In contrast, in nonsmokers smoking j~st two ciga~ttes significantly increased platelet activity, to the point that it was not signifi_~ntly different from a habitual smoker. This situation illnstrates the fact that the responses of nonsmokers and smokers to the toxins in the cigarette smoke aze often quite different. Based on the data from smoke~s, one would conclude that additional exposure had no effect, whereas looking at the effect on nonsmokers leads to the conclusion that it has a major effect. More important, the same investigator (32) measured platelet activity in smokers and nonsmokers before and after they sat in a room for 20 minutes where cigarettes had been smoked just before the experimental subjects sat in the room. Again, there was no significant change in the platelet activity among the smokers, but a significant increase in platelet sticldness was seen among the nonsmokers to the point that their platelet activation was not discernably different from the smokers. These data, together with the results of other human experiments (30,36-39), indicate that nonsmokers are much more sensitive to secondhand smoke than smokers and that very low levels of ETS exposure can have major impact on nonsmokers' platelet activity. It also appears that the process saturates at low dbses: once'the.nonsmoker has been exposed to even a low dose of secondhand smoke, the platelets are maximally activated much like that to of a habitual smoker so that additional exposure does not increase the effect. These data also indicate that dose-based extrapolations from smokers to nonsmokers using cigarette equivalents" will grossly underestimate the risks to nonsmokers of breathing secondhand smoke. data also support this conclusion. In our stu~es of the effects of passive smoldng ¢m he.art disease, we have ~ that b~ time (another measme of platelet a : vity) is sign camb' shortened more phteL ) in both 11 T102322214

and.rats (42) eaposed at even the lowest doses of secondhand smote, with no additioml effects at higher doses. At a b'mch~ level, studies of cigarette smoke extract on the effects of platelet activity suggest that the tcains in the ¢i~ smoke increa~_se platelet activation factor by interfering with the activity of the plasma enzyme platelet activating factor acetylhydrolase -" (PAF-AH) (43). PAF-AH reduces platelet activity by neutralizing platelet activating factor. Because toxins in the cigarette smoke appear to reduce the effectiveness of PAF-AH in neutralizing platelet activating factor, these toxins may contribute to an increase in platelet activity. The nicotine in the smoke does not appear to be the active agent, but rather some other as yet undefined element in the cigarette smoke (37,43). This biochemical result is reinforced by clinical studies which find that smokers treated with nicotine patches show f~wer changes in platelet activity than continuing smokers despite having similar nicotine levels (44). Atherosderosis In addition to short term toxicity of cigarette smoke, there are long-term permanent effects. In particular, smoking contributes the development of narrowing and blockage of the coronary arteries (atherosclemsis). When someone has a heart attack, one or more of the arteries delivering blood to the heart has become completely blocked and the flow of blood - and hence oxygen - to the hear~ muscle stops. If this flow is not restored promptly, the muscle dies, causing a so-called myocardial infarction. The situation can lead to irregular heart beats (arrhythmias) which can also be fataL The coronary arteries are blocked through a proce~ ~ in ~ ways to blockage of a pipe in ~ p.~ The ~ of the ~ is fast ~ ¢Rher chemically T102322215

hardezfing aud ~ lmown as a~. As the vessel mrro~ the ~s ~e that it will become completely blocked and cau~ a heart attack, eithe~ through slow due to plaque or, more ohen, a blood dot lodging in the small remaining opening. The toxic chemicals in the cigare~ tte smoke, and particularly polyvyelic aromatic hydrocarbons (PAHs), f~:ilitatv ~ pro~s~ both by d ~ama~n~_g the cells ~ the coronary arteries and also by stimulating plaque growth through a process similar to that of a benign tumor. In addition to their role in acute thrombus f~rmafion, platelets are also important in the development of atherosderosis. Once then is damage to the arterial endothelium (that is, the lining of the coronary arteries), either through mechanical or chemical factors, platelets interact with or adhere to the arterial wall and initiate a sequence that leads to formation of atherosclerotic plaque. Ifplatelet aggregation is increased because of exposure to ETS, the chances of platelets building up at that endothelial injury site will b¢ increased. Thus, in addition to contributing to short-term effects by increasing the likelihood of thrombus formation, the effects of ETS on platelets also increase the chances that endothelial injury will lead to arterial plaque formation and atherosclerosis. ETS also plays a role in causing damage to the endothelium and initiating the atherosclerotic process. Experiments in humans have indicated that ¢v~n short-term exposur~ to ETS - like active smoking (45) - significantly increases the appearance of anuclear endothelial cell carcasses in the blood of people exposed to ETS (or other tobacco products) constituents (30). The appearance of these cell carcasses indicates damage to the endothelium, which is the initiating step in the atherosclerofic p~ The appearance of endothelial cells after passivv smoking i~ nonsmok~ aher just 20 ~tcs a hospital waiting room, is almost as g~at as in ~ smoking in nWL~~ L~ T102322216

~es to the ~e ~j~ ~a ~d promote ~i~ smo~ bo~ ~o~ adol¢~n~ whose p~n~ ~o~ ~ ~o ~ .~ ~r~ ~ pla~s wb¢m ~o~ ~ ~d ¢~bit l~r I¢~ of ~ (~¢d good cholesterol) demi~ ~popmte~ ~ people bma~ d¢~ ~ ~¢r adj~ ~r g~der ~d s~. ~ ~ ~o ~m~s ~¢ ~ of de~Iop~ ~m~ he~ ~e. ~e Role of ~v~]ic ~mafic Hy~bo~ ~) M~ a~emsdemdc pla~es (46). ~r~ 7,12-~Ib~m(~h)~ea~ ~) ~d ~(a)~a~ ~), developmem of a~emsdems~ (47-51). ~ ~ m ~~t ~fiment of E~ (15~2). Chmges • ~ inj~ ~at loa~ to p~t¢let a~gafion ~d pl~u¢ Se~r~ s~s ~ ~di~ted ~at pol~c ~fic ~~m pm~mn~y. co~e~ additio~ of ~olesteml, which m~ ~tate ~co~orafion of d~g ~ a~d~c pm~sa. T102322217

- Se~,ml eart~ ~ smdi~s de~monstrated that it was possx'bte to acce~ate ~ athe~sd~tic proce~ in experimental ~ (warious spedes of ~ and pig~om) by injection of BAP and other related PAHs (49.50). In additioa, it was possible to extract cancer-like cells from plaques, which cau then be transplauted to another ~imal and produce similar cells (50). ." In addition to ~ biochemical evidence examining the effects of specific components in ETS on the development of atherosclerotic lesions at a cellular and molecular level, there have been a series of animal experiments which demonstrated that short-term exposure to environmental tobacco smoke dramatically increases the rate in which lipids are deposited in arterial linings. This is the initial process in the development of athexosclerotic lesions. We (40) exposed three groups of rabbits on a high cholesterol diet to ten weeks of exposure to secondhand smoke from Marlboro cigarettes. (This rabbit model has been used to study atherosclerosis since 1908 (13).) The animals were exposed to the secondhand smoke six hours a day, five days a week for just ten weeks. One group was ¢xposod to smoke at levels that would be observed in a smoky bar or the others were exposed to levels about three times as high. The high dose group was exposed to pollution levels comparable to thbse observed in a Mazda 626 with the windows rolled up at 4 cigarettes/hr being smoked (53). With just ten weeks of exposure (a total of 300 hours), the fraction of pulmonary artery and aorta covered with lipid deposits nearly doubled compared to control rabbits who ate the same diet but were not exposed to ETS. This is a short term exl~sure, even fvr a rabbit. This effect appears to be directly due to elements in the cig ~arette smoke it~.lf, rather than a nervous ~ to berg ezposed to the smoke ~ ~ have ~ the T102322218

active smokers.) To ad&ress ~ question, w¢ (41) exposed rabbits in an ¢ape~cnt ~ar to that just described to second-hand smoke but gave half the rabbits the tmta-blocking drug Metropolol, which block~..s the effects of catecholamines. As expected, the anlm~i~ receiving the drug developed fewer lipid deposits than those who w~re receiving a placebo (saline), but this effect was independent of whether the rabbits were breathing secondhand smoke. Therefore, the secondhand smoke effects on the development of atherosclerotic-like lesions in the arteries was not mediated by the increased levels of catecholamines. One criticism that might be raised of this study is that the rabbits were on a high cholesterol diet (54). This experimental model of atherosclemsis, which has been used since early in the century, requires the rabbits to have a high cholesterol diet in order to develop any lesions within a reasonable length of time. Other investigators (55,56) used cockerels (another standard animal model for studying atherosclemsis) exposed to secondhand smoke showed similar increases in the amount of plaque developed in young cockerels (between 6 and 22 weeks old) who were exposed to secondhand smoke six hours a day, five days a week for twelve weeks while on a low cholesterol diet. These chickens were exposed to lower levels of secondhand smoke than the rabbits studied and were eating a normal, low cholesterol, diet. While there was no difgereuce in the plaque incidence between the cockerels breathing secondhand smoke and the cockerels breathiug clean air, there was a significant acceleration in the ~ of these plaques, in a dose-dependent ~er in the ETS-exposed bi~s. The ~gens in the smoke appear to be acting as a promoter to facilitate the development of plaques, raflaer than i~itiate that these,effects are due to the carbon mon~de in the smoke, 16 T102322219

Even so, exposure to secondhand smoke f~ a relatively brief time (con~sponding to about 0.4% of their life span) si/gtificantly accelezated the development of pla~ues. It is reasonable to conclude f~om these results that in tkis animal model, moderate exposure to secondhand smok'~ for a brief pe~od in early life is sufficient to markedly accelerate the development of atherosclemtic plaques. The exposure levels used in ~ experknents axe comparable to those observed in many workplace and household environments. The fact'that it is possible to/nduce atherosclerotic-like changes /n two different species of experimental animals with only a few weeks' exposure to secondhand smoke similar to that experienced by people in normal day to day life, is a very important finding linking the epidemiological and biochemical evidence that passive smoking causes heart disease. On one hand, the epidemiological studies show an increased risk of heart disease on a population basis among people exposed to secondhand smoke. On the other hand, there are biochemical studies showing that elements in the smoke, particularly BAP and the other PAHs, can produce cellular changes that occur in atherosclemsis. The experimental s/udies on rabbits and cockerels, which do not suffer from the potential confounding variables in epidemiological studies, bridge this gap by showing that it is possible to induce atherosdemsis in experimental animals with ETS. Finally, there are also dam in humans showing that passive smokers have f~nificanfly thicker carotid artery walls (the artery in the neck) than people who never were exposed to passive or active smoking, with a dose- response relationship (58). the animal ~ents. These results are consistent with what ~ ,,~yald expect The causal link between passive smoki~ and atherosclexosis 17 T102322220

Fr~ radicals in ETS and ig~hcmic dmna~_ As already discussed, ~ ~ s~ ~de~l~ m s~~d ~ ~¢fien~ ~ a ~mr ~o~ ~ dea~ ~ ~ h~ ~ ~d ~o non-fa~ o~n~ ~ ~ ~~ new e~den~ ~at p~ smo~ ~e~ ~e out~ of ~ ~c ~nt ~ ~e he~ ~u~ ~e ~W of ~ ra~. F~e r~ ~ ~y ~a~ ~gen p~u~ w~ch ~ e~mely deserve m ~e he~ m~de ~11 mmbr~e ce~ (59,60). ~e r~ h~ been ~pfi~ted ~ ~r ~ ~ ~ he~ ~e~e.) By dis~p~g ~e a~W of ~e ~mbr~es ~ ~e he~ m~de ~ ~e ~ ~y ~teffem ~ ~n~o~ of ~e he~ m~e. ~cy h~ ~en ~y ~fi~ted d~g ~e he~ h ~ what h ~ ~ ~pe~on ~j~." ~~ion ~j~ when bl~ st~ fl~g m he~ m~e ~er it h~ ~en ~m~pt~. ~ ~e bl~ ~ st~ped, ~e he~ m~le ~ de~ of ~ge~ a si~fion ~ ~e~ For ~ple, a re~sion inj~ ~ oc~ when ~meone s~en a he~ a~ ~e~), fog~d by ~a~ent ~ ~opl~ (fo~ ~e ~e~ o~n ~ a b~n) or a clot-bus~g ~ag ~at ~solms ~e clot (t~mb~) bl~ ~e ~m~ ~e~. Repe~ion ~j~ ~ ~o o~ when a patient h~ had o~n h~ ~ ~ ~ of blood m ~e he~ ~ s~ ~en s~ ~ ~ea he~ muscle ~ depfi~d of ~gen ~u~ the ~lls which s~e ~e radi~ ~ depleted. ~e ~ ~ n~y ~d ~ ~e ~R ~ it r~~ ~d ~d~ ~ no~ T102322221

Studies of humans aud several species of ~ indicate that low ezposums to nicotine or othar cigarette .~moke constituents significantly worsen repeffusion injury. For example, slowly infusing the nicotine of just one cigarette doubled the effect of the reperfusion injury on heart muscle of dogs (61). "Ibis is so'low a dose of nicotine that it had no effect on heart rote, blood pressure, shortening contraction of the heart muscle itself as the heart beats, or other hemodynamic measures of cardiac function commonly affected by nicotine in active and passive smokers. After an ischemic episode in which the blood supply to a section of the heart was interrupted for fifteen minutes, the shortening of the nmscle in the heart wall during repeffusion was reduced to 50% of the pre-ischemic values. When the dog was exposed to the nicotine from just a single cigarette, the muscle lengthened to only 25% of control values. Thus, exposure to a very low dose of nicotine doubled the impact of the reperfusion injury. When the dog was given a free radical scavenger which neutralized the free radicals due to the nicotine, this effect was obliterated. The effects of free radicals induced by passive smoking have been explored at the cellular level (62,63). Rats who were exposed to secondhand smoke from two cigarettes a day for two months exhibited severely damaged mitochondrial function during reperfusion injury, so that the ability of cardiac mitochondrial cells to convert c0cygen into ATP was much more compromised during ~perfusion injury among rats exposed to these low doses of secondhand smoke than among control rats This is another way in which the tc~dns in the secondhand smoke can interfere with energy metabolism in the cell. TI023~

control free radicals (64). In addition, passive smoking by h~ sensitizes lung neutrophlt~ (65). As with plate.lets, neutrop~ are an important element of the body's defenses ~ ~ction and damage. Inappropriately activated neutrophils, howevei; release oxidants and these elements can play a role in tissue damage in p~ssive smokers. In a group of passive smokers exposed to just three hours of sidestream smoke, there w~re significant increases in the circulating leukocyte counts and stimulated neutrophil migration. Like the other respomes, the responses to the exposure to secondhand smoky were greater in nonsmokers than in smokers, again suggesting that the biochemistry of ETS in passive smokers is different than in active smokers, with the passive smokers being more sensitive to these elements. Likewise, when hamsters were exposed to the ETS from six cigarette a day for eight weeks, the activity of anti-cmidant enzymes in their lungs nearly doubled. These enzymes are natural factors which act to reduce the activity of free radicals. This study deals with neutrophils in the lungs, but it is reasonable to assume that the neutrophils exhibit similar effects throughout the body, since they are transported by the blood. Myo~rdial Infarction (Hev-rt Attack) There are also direct animal data to show that secondhand smoke promotes more tissue damage following myocardial infarction (heart attack). Dogs exposed to secondhand smoke one hour daily for t~ days, then subjected to blockage of a coronary artery developed myocardial infarctions (dead tissue) that were twice as lmge as those of control dogs who breathed clean air (66). T102322223