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Testimony of STANTON A. GLANTZ, Phl) Pro~.sor of Me~cine Member) Cardio~mcular Res~mv.h Imtitut~ Member, ImtiW_t~ of Health Policy Studies University of California San Francisco, CA 94143-0124 regarding Environmental Tobacco Smok~ prepared for Occupational Safety and Health Administration August 11, 1994 My name is Stanton A. Glantz. I hold a Ph.D. in Applied Mechanics and Engineering Economics fi'om Stanford University, where I wrote my dissertation on the mechanics of cardiac muscle. I am now a Professor of Medicine at the University of California, San Francisco in the Division of Cardiology and a member of the Cardiovascular Research Institute and the Institute for Health Policy Studies, as well as th~ Graduate Group in Biostatistics. I also serve as an associate editor of the Journal of the American College of Cardiolo~, the largest clinical cardiology academic journal, and serve as a member of the California State Scientific Review Panel on To0dc Air Contaminants, a body somewhat analogous to the federal EPA'¢ Sdence Advisory Board. I am here today to discuss the reasons that passive smoking causes heart disease and also to summarize work done on the economic impacts of 100% smoke-f~ec restaurants. In recent ycars,-most of the public discussion on the health effects .of ~ smoking has dealt with lung cancer, probably because of the ~ ~ by the tobacco industry regaling the 1992 Eavh-onmental Protection Agency risk assessment of 1 T102322.204

envi,.-onmenml tobacco smol~.c (ETS) and lung cancer (1). In fact, hcs..-t disea~ is acma~ a much more important endpoint oi~ passiv~ smoking than lung cancer (2-7). 'Whereas E'rs cauls 3,000-5,000 lung cancer deaths annually, it causes 30,000-60,000 he~_n disease deaths annually. The increase in individual risk of heart disease death due to ETS exl3asure is similar to lung cancer; the much larger number of attributable deaths for heart disease occurs because it is much more common than lung cancer. The American Heart Association has concluded that ETS is a major risk factor fi3r hear~ disease in both adults (8) and children (9). The biological and sdentific situation surrounding heart d.i.eease is qualitatively different from that of cancer, including lung cancer. Whereas cancers take a long time to develop, making it essentially impossible to demonstrate an effect of e~posure to a specific carcinogen in an individual, it is possible to demonstrate effects of envimmental tobacco smol¢~ (El'S) and its constituents on the cardiovascular function of specific individuals with relatively short term e.A'posums. This information complements population-based epidemiological studies demonstrating that passive smoking increases the risk of death or morbidity from heart disease. The reason for this is that, while some of the effects of smoking on the heart, such as the induction of athems~:lerosis (narrowing of the coronary arteries because of build up of fat deposits), occur over a long period of time, many of th~ other effects, such as alterations in blood chemistry, effects on blood vessels and the heart muscle itseE, and the ability of the heart to respond to the stress of ischemia (reduced oxygen delivery) occur immediately upon exposure to stooled. Th~se effects have b~en observed both in people and in laboratory stodies. The ability to induce negative ch~ in the cardiovas~ar system by short-term e~xmum to secondhand smoke is impormm from T102322205

heart disease. From epidemiological studies a very consistent picture of an devotion of about 30% in risk (for both death and non-fatal coronary events) has emerged, even after controlling for other known cardiovasaflar disease risk factors (7). These population studies are, in fact, more consistent in thei~ findings than even the studies demonstrating that passive smoking causes lung cancer. Many of these studies also show a dose-response relationship; people who are exposed to higher doses of secondhand smoke suffer more death and ~ab~l/ty from heart disease. The consistency of these studies, par~culady a~ter controlling for other risk factors for heart disease, together with the fact that they are done in many different countries with dif~ring diets and lifestyle factors, the presence of the dose-response relationship in many of the studies (10), and the fact that active smoking causes heart disease in smokers, would be enough to conclude that passive smoking causes heart disease in nonsmokers and to proceed with a quantitative risk assessment. An Overview of the Effect of Secondhand Smoke on the Cardiovascular System The cardicr~ascular system transports c~gen fl'om the lungs to the organs of the body and transports waste products of cellular activities so they can be removed by the kidneys, liver and lungs (11). In contrast to other muscles in the body, which only have to work some of the time, the heart muscle contracts continuously, around once every second, throughout a person~s entire [fie. The fact that the heart muscle has to operate continuously makes it d~!ferent in speci~zed ways from oth~ muscles. Unlike other muscles, the heart muscle has a con "tmuous demand f~ u~ygen, whk:h the heart muscle ce~ (like all cells) turn into 3 T102322206

c~a .tracdoa and other ~ process~ Coatrol of t~ heart mmd~ is ~ ~e~ adj~. It d~s ~ ~u# a ~mb~fion of ~o~ ~at m b~t ~to ~c s~ of ~c ~cr a lo~er period of ~e, o~cr ~ ~ ~ ~ m~me m ~ dem~ds on ~e ~~ ~ For ~ple, ~ ~ M~ hem e~n~y at ~a our bodies ~d adapt by ~~ h~t~t Im~ ~e ~on of bl~ ~pied ~ ~ese ~ ~mple~ sm~g up or m~ to Den~r, ~ but ~ ~ ~t ~e caMi~l~ ~tem adap~ bo~ ~ ~e ~o~-~d lo~-te~ to ~g~ ~ en~,n~ conditiom. Indee~ ~, c~i~~ ~mm ~ so ~lomly ~apfi~ ~m ff ~n~ues to function enou# to ~ ~ e~n ~cr ~c hem i~ ~ scfio~ly d~g~ ~ a h~ attack or if ~c en~mcnt ~ wMch ~c h~m opcrmcs ~ s,fiomly comp~cd ~u# cithcr cn~romcn~ t~ or o~cr fo~ of ~c~c. ~is abiH~ of ~ h~m ~d ~ ~tcm to adapt to ch~ con~fi~ ~ ~ when one ~~s ~e ~ ~ ~ ~ no~mo~ W ~o~. People who smo~ 4 T102322207

the o~yg~-cm'ryi~ c~pacity of blood ~e of the carbon ~ in the smog) m~d by incre~_sing the demands on the heart muscle itseN becm~se ~/co "tine ~ heart r~e m~d makes blood vessels get ~er (v~soconstricffon), thereby incrensing blood pressure. These ~ changes increase the amount of v~rk that the heart has to do per mifiute while, at the same time, reducing the available supply of o~ygen to the heart. Nicotine also interferes with th~ normal reflex control of the heart (12). Compounds in the smoke alter the chemical and physical characteristics of blood. The cardiovascular system therefore undergoes changes to attempt to compensate for all the deleterious effects of smoking. Nonsmokers, however, do not have the ~benefit" of ~ adaptation, so the effects of passive smoking on nonsmokers are much greater than on smokers. This is probably for two reasons: first, nonsmokers' hearts and vascular systems have not attempted to adapt to the acute poisoning from the chemicals in the secondhand smoke. Second, it appears that the cardiovascular system is ex~emely sensitive to many of the chemicals in secondhand smoke and that smokers may have achieved the maximum response poss~le to at least some of the toxins in the smoke, so the small additional exposures a~ociated with passive smoking have ~ktle or no effect on habitual smokers because the additional dose of these toxins is ~mall c~>mpared with what the smoker normally receives. These two fac~ make it imperative to consider the effects of environmental tobacco smoke on the cardio~asc~lar system of passive smokers separately from the effec~_s on active smokers. The quz]~tative differences between the effects of ETS on smokers and nonsmokers explains the relatively high relative ~ a~ociated with passive smoking. compared to active smoking, even though passive smokers absorb much ~er doses of ~e T102322208

tobacco industry i~ f~nd of saying that even a heavily exposed passive smoker only breathes in the equivalent of about of 1 cigarette per day. Leaving aside the philosophical question of whether anyone ought to be required to breathe one cigarette a day under any : circumstances, the smoke from one cigarette is enough to produce substantial effects on the cardiovascular system. The Use of Animal Models in Ca~ovascular Research Animal studies complement human data bemuse it is often not poss~le to do the necessary studies to define biological mech~i~ms of disease in humans f~r ethical reasons. To get around this problem, scientists develop animal models of disease that mimic human disease. Over the years~ these animal models become well characterized and add significantly to our knowledge of the mechanisms and treatment of a wide ~riety of inuess. For example, rabbits and rats are widely used models f~r studying cellular p~ in the heart, as well as the development and modification of athemsclerosis (13). Birds are used to study athemsclerosis. Dogs are used to study mechanical function of the heart. The availability of these animal models has conm'buted significantly to our understanding of the precise mechanisms by which passive smoking damages the heart. Carbon Monc0dde and Ox~_ gen Delivery The fact that passive smoking produces immediate effect.s in nonsmokers, howeve~ significantly strengthens the scientific case that passive smoking causes heart disease. Passive smoking reduces the ability of the blood to deliver mTgen to ~e heart ~e. TI023222.09

o° ~ the ~ygem, thus mdccing the m3,gen carrying capacity of the blood (14-18). If the ca~bo~yhemoglobin (amotmt of carbon moncmide bouml to the blood) gets high cntragh, it can effectively suffocate the individual and prove fatal. Carbon mona~ide poisoning was the o "nginal method of suicide attempted by the lawyer in the opetting sequence of The Cli~nt. Even at the lower levels of carboxyhemoglobin observed in passive smoke~.'it can have an effect on exercise performance and how the heartbeats, in people who already have heart disease. Children of smoking parents have elevated levels of a chemical called 2,3- diphosphoglycerate (DPG). This chemical appears in red blood cells in an effort m modify how they handle oxygen to compensate for chronic ox'ygen staneation (9,16,19-21). When considering the impact of carbon monoxide in ETS on the heart, it is important to remember that ETS is not the only source of carbon monoxide. Given that carbon monoxide has a long half-life in blood, the effects of ETS will add to the carbon monoxide from other sources, and can provide the marginal increase necessary to precipitate adverse effects on the cardiovascular system. Oxygen. Processing in Cells There is also direct evidence from animal studies showing that passive smoking reduces the ability of the heart muscle to convert the oxygen which gets to the heart into the Nenergy molecule~ adenosine triphosphate (ATP), which is like a little chemical battery that is then used by the cell to power the energy-requiring processes. The body needs oxygen because elements within cells called mitochondria take this c~tygen and through a chain of chemical reactiom convert it into ATP. In heart muscle, the ATP is particularly important because it fuels contraction of the muscle (which is n~ for the heart to be.m) as well as the che~ pumps which move calcium and other ions atmmd the mmcie 7 T102322210

mi~ are h3~ an assembly line in which o~'ygen l~oe-s in cm~ end ~ ~ ~ ~t Sm~ h~ ~ ~t ~ese ~ ~ n~ ~rk ~ ~~y ~ ~i~ ~sed ~n ~mp~d m ~e ~e~ of a rabbit. E~n a s~e ~s~ ~ en~en~ tobac~ ~o~ ~du~d ~e ra~ at w~ch ~en w~ ~n~ned ~m ~. F~er ~e~en~ us~ rabbi~ h~ ~ed ~amrs to ~late w~ step ~ ~e ch~ of ~om ~ ~ed ~ ~e E~. ~e e~e ~c~me ~d~e ~bited a ~% ~du~on ~ i~ a~ (i.e. e~en~) ~er a s~e 3@~ute ~s~ to secondh~d ~o~, ~d ~e a~w ~n~ued to ~p ~ pmlo~ed ~s~e. ~er ei~t ~e~ of 3~ute a ~ e~ i~ ~ ~ ~t ~ ~ (~). ~ ~t o~ d~s ~a~ seconded ~o~ ~du~ ~e ~M~ of ~e b~ m get ~n ~gen it does get (~). E~ on ~e~se ~ese bioche~ e~ o~ ~n~d smo~ e~u~ (toge~er ~ o~er ch~ges d~ed later) help e~l~ ~e ~ ~at people s~ly ~ot ~ ~ ~. when ~osed to se~n~d ~o~ (18~). ~e ~c e~ depend on me~u~men~ berg ~ed ~d whe~er ~e subje~ ~ no~ he~ ~ople or people e~e ~ long or ~ach ~ ~ a le~l of ~ ~er b~ ~~d smo~ T102322211

pe~ level of exertion during eaercise, the rn~a,~m]lrn heart rate, and carbon dioxide output. Other studies compardng the ~ ability of healthy individuals to people with heart disease f~tmd that exposure to secondhand smoke lengthened the time to recover resting heart rate at the end of exercise, to the point that the normal healthy individuals took as long as people with heart disease to recover their resting heart rate following exercise. Patients exposed to secondhand smoke who have preexisting myocardial infarction have more ventricular arrhythnfias (irregular heart beats) during passive smoke exposure than when breathing clean air. Passive smoking also significantly increased the amount of a chemical called lactate in venous blood, which indicates that during passive smoking the heart was switching to a greater reliance on anaerobic (i.e., not oxygen requiring) metabolism (27). This finding means that the circulatory system was not able to deriver enough oxygen to the heart muscle to fully meet its demands. The combined effects of reduced cgygen carrying capacity and increased lactate led to less mechanical power being developed during the exercise as well as shbrter duration of exercise before the person reached exhaustion. Even the relatively low (by comparison with smokers) levels of carbcayhemoglobin observed in passive smoke~s may be important because the body normally extracts more than 90% of the oxygen from the blood during exercise, so even small reductions in the efficiency of the caygen transport system can a~ct exercising in nonsmokers (28). These negative eflY.~ act ~tically with the reduced efficiency with which the hea~ muscle conve~.s the vaygen it does received into the ~ molecule ATP beca~__~ of the zztiom of e~avcmm~al tobacco ~taoke o~ 9 T102322212

P1me]ets Secondhand cigarette smok~ affects blood platelcts, in a way which incma~s the likelihood of formation of a thrombus (blood clot). Platclets play an important role in blood dotti~ when they are activated and become sticky in re~spons¢ to a cut ~en blood platelets aggregate inappropriately and form a thrombus, they can precipitate a ~al infarction. In addition, when platelets are activated, the platelet activation factor itself can damage the ~g of the coronary arteries and facilitate the development of atherosderotic lesions (29-34). Platelet deposition in the coronaries and formation of a thrombus can contribute to the growth and progression of an atherosclerotic plaque. Both active and passive smoking increase the aggregation of platelets and thus the likelihood of thrombus formation at myocardial infarction and, through platelet activation, they increase the chances of developing atherosclerosis. Several studies in which nonsmokers are exposed to re~li~ti¢ levels of environmental tobacco smoke, such as levels experienced while sitting in a hospital waiting room for fifteen to t~venty minutes while people arc smoking, show that ETS can increase platelet aggregability to levels approaching those observed in smokers. Large platelets and mean platelet volume are independent risk factors for recurrent or more serious m~nm~lial infarction (35). These data support the epidemiological evidence that passive smoking is a risk factor for both fatal and nonfatal heart disease. In one experiment, nonsmokers and smokers were asked to smoke two cigarettes (32). The smokers" platelets, which were "stickier" than the nonsmokers platelets at the beginning of the experiment, did not s~canfly ~ activity in response to the two cigarettes.. Most ~ the smokers' ~|e~s were ~ ~ becm~ of the 10 T!02322213