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(7irJi.,i.i,..ufL, 7" ~ " „L,.,.. .~, ~ „nJ l~Ln„n, edllc.d h, Uanroi 9aoa.,. 1h ka.cmPrc- l.W.. Nca)'ork ~ IHV^ 15 Environmental Tobacco Smoke Exposure and, Occupational Heart Disease Domingo Mi. Aviado Airttos'phc•.ric Heulth Sciences. Shnrt Hills, Neit' Ji<rser 07078 In 1991. the Occupational Safety and Health Administration (1) requested information on exposures and potential adverse health effects that map be associated with poor indoor air qualiti\ in the work environment. including information on exposure to environmental tobacco smoke (ETS). One re- view article, which focuse&on heart disease and which was published prior to the ageni request. concluded' as follows: "the combination of epide- miologicall studies with demonstration of physiological changes with expo- sure to ETS. together with~biochemicalievidence that elements of ETS have significant adverse effects on the cardiovascular system. leads to the con- clusion that ETS causes heart disease" (2). Others. however, have expressed conflicting interpretations of human ani animal studies on ETS. concluding that it has not been scientifically demonstrated that ETS exposure increases the risk of heart disease in nonsmokers (3.4). The ongoing debate should not onlv consider the claimed association between ETS work exposure and heart disease in, particular. but also occupational' heart disease in general. The primary purpose of this chapter is to review the toxicological basi" for identif'ying chemicall substances that may be associated with heart disease in the workplace. At the outset, it should be emphasized that proof of an association be- tween ETS workplace exposure and heart disease is a complex process. Workers. such as garage attendants. may he exposed to one or more suh• stances tsuch as carbon monoxide) found both in ETS and in,other sources, so the total exposure is the sum of two or more sources, for example. vehic- ul)ir emissions, ambient air pollution. and ETS. The same group of workers may have varied personal habits that have been reportedAobe associated with heart disease, such as consumption of cholesterol and fats and xanthine beverages at the employee's cafeteria, physical'inactivity on, the job, and job-related stress. Outside the workplace, there are additioni potential risk factors for heart disease. such as lack of leisure time exercise. diztar} cook- Q_5:5

456 ETS AND NEART DISEASE ing fat and'salt contenU. household exposure to cooking gas, gas heaters. and household solvents. Other major risk factors reported for heart disease in- clude the worker's familial history ofl heart disease, diabetes. hypertension. hyperlipidemia. and obesity. Any conclusion on a possible role of ETS in heart disease necessitates controlling for such risk factors. ItiVESTIGATIVE METHODS FOR INDUSTRIAL CHEMICALS Although there are over 300 potentiallh, hazardous chemicals in the work- place. there are less thcan, three scores of industrial chemicals that have been suggested to be associated withihearudisease such as ischemic heart disease. coronarv atherosclerosis, and cardiac arrhythmia and cardiomyopathyc AI~ though heart disease is the leading cause of death in the United States. oc- cupational exposure to chemicals is consid'ered! less prevalent and less im+ portant than risk factors in the diet, im, the environment, and in familial or inherited susceptibility to cardiov.ascular diseases. Although it is relativelyy simple to establish a strong association between exposure to halogenated solvents andl cardiac arrhythmias. it is more com- plex to obtain supportive evidence as to whether chemicals play a major role in coronary ischemic heart disease and atherosclerosis. Occupational heart diseases can be grouped into three major categories. These can be sub• grouped~ according to the metho&of investigation. which may involve clinical studies, pathological observations, or experimentalianimal studies (Table I): lal ischennic hecmt diseasn (Methods A. B. and C). incltiding mortality stud- ies, exercise testing for angina pectoris, an6coronary bloo&flow indicators: (b) coronan• atherosclerosis (Methods D: E. and F). demonstrable in pa- tients by angiography and histopathology. atherosclerosis in experimental animals, and in i•iiro studies of hematologic factors: and (cl cardia( crrrlii•1ii- n:ia~and invnpatln• (Method's G and H), both clinicall, and experimentally induced. The three groups of methods and eight subgroupings OA to H):are carried over to consideration, of occupational heart disease associated with exposure to chemicals in the course of manufacturing and processing of in- dustrial products. The chemicals supposedliy-, associated' with occupational'i heart diseases are listed in Table II under five classes: one inorganic an&four organics. Each compound is identified by notations on investigative methods AtoH'. Inorganic Oxides and Metals Carbon monoxide is most' widely discussed as a major substance in the etiology of occupational heart disease. Workplace exposure to carbon mon: oxide is encountere& when it is generated in manufacturing an industrial product. In the steel ind'ustry: carbon monoxide is produced in blasffurnace

ETS AND HEART DISEASE 457 TABLE 1. lhdustrial'chemicals reported to be associated with occupational heart disease Industrial chemicals Itchemic heart disease Coronary atherosclerosis Arrythmias and myopathy Inorganics: oxides and metals Carbon monoxide' A B'C D E F G H Carbon dioxide• G Nitrogen oxides' G Arsenic A H Cadmium' A Cobalt A H Lead A F Nitrogenous compounds Nicotine' A Aniline' F Catechol' G' Din trotoluene A Ethylene glycol dinitrate A C G Hydrazme' G Hydrocyanic acid' C H' Nitroglycerin A C G Pyridme' G 2-ToVwdine' F Polynuclear aromatic hydrocarbons A Benzo[aJpyrene' E 7,12=Dimelhyl (a,h) anthracene E 3-Methylcholanthrene E Nonhalogenated solvents Carbon disulfide•° A B C D E H' Acetaldehyde' G Acetbne' G Benzene' G Dimethytamine' G' tv4ethyramme'' G PhenoP G H Totuene' G Halogenated solvents Methyl chlbride' G H Methyl chloroform G H Methylene chloride F G H Trichlorofluoromethane G H 'Sidestream smoke (SSS) constituent °Metabolite carbonyl sulfide is ETS constituent. Method A, mortality studies; Method~ B: exercise testing and angina pectoris: Method C: coronary blood flow indicators; Method D, coronary angiography and histopathology: Method E. atherosclerosis in experimentallanimals: Method F, in vitro hematologic factors: Method G, irregularheartbeat; Method H; experimentally induced cardiomyopathy

4Sr" ETS AA!D HEART DISEASE smelting of iron ore. cast welding. and vehicular production. Operators of vehicles, parking attendants, tunnel workers, car emission inspectors. tool operators, and traffic police are constantly exposed to exhaust fumes and ele\ ated levels of carhoxyhemoglobin in: such workers have been reported. All eight subgroups of methods have beeniapplied to arrive at an extensive cardiac toxicologic profile of carbommonoxide (Methods A to H in Table I). The two other oxides and four heavy metals listed in Table I have been lesss thoroughly investigated. Among heavy metals reportedly associated with heart disease are arsenic. cadmium. cobalt, and lead. The pathogenesis of heart disease potentially associated with workplace exposure may vary according to volatilit} of the metallic compound and'its exposure level'. Cadmium has not been reported to influence the heart directly but may be related to hy,pertension. which ma\ lead'to cardiac complications. Lead mav influence the blood and! ulti- matelr interfere with cardiac metabolism and function. Arsenic. cobalt. and lead are cellular poisons and there are experimental heart models to support the occurrence of cardiomyopathy from these metals. Only cadmium has been detectedl in tobacco leaf and tobacco smoke: traces of cadmium are derived from soil', Nitrogenous Compounds The ten examples in this group include the following: nicotine (an alka- loid). hydrocyanic acid. and raN products for the manufacture of explosives such as ethylene glvcolldinitrate and nitroglycerin. The other six examples (aniline. catechol'. dinitrotoluene. hydrazine. pyridine. 2-toluidine) are nec- essany in the manufacture of pharmaceuticals. pesticides. and dyes, The car- diac toxicologic profiles for each of these compounds are not completely knowmand have been studied only bv one. two. or three methods. The entry on nicotine refers to handling of tobacco leaf, such as cigar manufacturers.. kiin dryers. and warehouse operators. Polynuclear Aromatic H~drocarbons (PAHI' These are forme& as a result of pyrolysis or incomplete combustion of organic materials. There are several hundred PAHs and'onh a dozem have been reported to be associated with skin tumors via skin painting in mice. Benzol'u)pyrene is the most widelv studied compound and only research sciF entists are occupationally exposed to this single PAH. Workers potentiall\ exposed to PAH mixtures include coke oven operators. creosote wood ap: plicators. asphalt'l road pavers and roofers, aluminum smelters, an& diesel engine operators. Benzo[uJpyrene and two other PAHs listed inTahl'e I have

€TS A,ti'T) HEART !)J:SLASE 454' been reported to he associated with atherosclerosis in an experimental model. There are no human studies rel'ating to heart disease other than mor- talitv statistics of workers exposed to PAK mixtures. Nonhalogenated Sof.ents Carhon, disulfid'e is a solvent used in the manufacture of viscose ravon. cellophane film. electronic vacuum tubes. sulfur-containing soil disinfec- tants. and carbon tetrachlorid'e. This is the onlv solvent for which there are stsonFaataon anatisociation with ischemic heart disease in workers. as well as coronar} atherosclerosis in experimental animals. The cardiac toxicologic profile is complete except for the lack of in i-rtre+ studies on hematologic factors and cardiac susceptibility to arrhvthmia. The seven other solvents hu.e not been studied for occurrence of ischemic heart disease and coronarv arthero5clerosis. Halogenated Solvents. The author and his colleagues have written monographs on the cardiotox- icity of chlorinated and fluorinated solvents (S-7). Four solvents are identi- fied in Table I from the original list of more than 10(1'solvents that are con- sidered cardiotoxic. The four selected solvents (methyl chloride. methyl chloroform. methylene chlorid'e. and trichlorofluoromethane) are reported to cause fatallcardiac arrhythmia and sudden death in the course of accid'en- tal industrial poisonings. Usually it cannot be proved whether cardiac arrest was caused by a direct cardiac effect or the result of respiratory paralysis and coma. since most halogenated solvents are not only cardiotoxic but alsoo central nervous system depressants. Experimental animal'studies have sup- ported the potential role of sublethal doses of solvents in, cardiac arrhyth- mias and myopathies, independently of coronary vessels and central ner- vous svstem involvement. Miscellaneous Compounds Industrial chemicals potentially related to heart disease. but which appear not to directly influence the heart. blood vessels, and circulating blood. are omitted from Table 1. lnsecticides. including organophosphates. are report- edly associated with irregular heart rhythms because of their influence on the autonomic nervous system. Chronic obstructive lung disease associated with inorganic d'usu particles canicause cor, pulmonale. Exposure to nephro- toxins. such as mercury and dyes. has been reported to lead to cardiac com- plications. including congestive heart failure.

460 ETS AND HEART DISEASE CONSTITUENTS OF ENVIRONMENTAL TOBACCO SMO~I:E Environmental tobacco smoke is a diluued an6aged mixture of constitu- ents derived from either the burning end or cigarette butt: mainstream smoke inhaled from the filtered!or unfiltered tip: and sidestream smoke from the lighted end. Nonsmokers sharing a workroom with smoking workers may be exposed to ETS. Sidestream smoke is not inhaled directly' by nonr smokers but is diluted immediately by air in the workplace and'~continuously. bv air exchanges. The magnitudes of differences between concentrations of substances in mainstream smoke inhaled by the smoker and ETS exposure of nonsmokers have been summarized in a National Research Council monograph 181. The ranges reported in the literature (parts per million or parts per billion) are as follotis; Mainstream Smoke ETS Carbon monoxide 24,900-57:400~ppm 1-18:5 ppm Nicotine 430.000-1.080.000 ppb 0.5-7•5 ppb' Benzo[aJpsrene 5-Il ppb 0.0001-0:074 ppb The dilution factors for peak values are as follows: 3100 for carbon monox- ide. 144.000 for nicotine, and 148 for benzo[lu]pyrene. There is no uniform dilution for all three because of varied levels in mainstream smoke relative to sidestream smoke. The unpredictable fates of vapor components (e.g.. carbon monoxidel and particulates (e.g.. nicotine and benzo(u)pvrenel are influenced by humidity, temperature. air movement, and adsorption by ma- chinerv and furnishings in the workplace. Work Standards for lndustrial Chemicals The minute levels of carbon monoxide in ETS, up to 3100 times less than the concentration in mainstream smoke, pose a criticall challenge to claims that ETS exposure can cause heart disease in nonsmokers. Proponent, of the claimed association between ETS exposure and heart disease in general (occupational and nonoccupationaU contend thar three ETS constituents un- derlie this relationship: nicotine. carbon monoxide, and' polynuclear aro- matic hydrocarbons. For completeness. there are 21 reported constituents of sidestream smoke that are also used as industrial chemicals, which are sometimes discussed as potentially associated with heart disease. These are the same 2li industriall chemicals listed in the first column, of Table I that are mbnufactured. processed, or emitted in workplaces an& are poten- tially associate& with heart disease (marked with superscript u in first

' ETS, An'D HEART DISEASE 461 column. Table 1l. Most halogenated solvents, heavy metal,. and'polycyclic aromatic hy_ drocarbons have not been d'etected in ETS (no superscript in Table I I. The list, of?1 sidesiream smoke constituents inputed to ETS in Table 2'is a revisioniofthe author's listing of~suspected pulmonary, carcinogens in ETS (9:10). AlsoJisted'in Table 2 are corresponding threshold limit values (TLVS)l for various substances. defined asthe recommend'ed~ standards for 8-hr daily exposure for the prevention of occupational disease (I I I'. Table 2 includes a, column of target, organs for acute or initial exposure. as, well as for chronic or iong-term, exposure. When TLV levels are exceeded. early and late signs of toxicita, appear in skinL mucosa. lungs. liver. kidneys. blood. blood ves- sels. and nervous systemL Manifestations of cardiotoxicity may occur either in acute lethal concentrations (more than, 20 times TLV) or repeated expo- sure to very high, but sublethal. concentrations (more than tv.'o to five times TLV: depending on the compoundll TABLE 2. Sidestream smoke (SSS) constituents with threshold limit values (TLV) Chemieal name Acute chronic' Max SSS (mg cig) TLV (mg m') Cigarette equivalent Nicotine M N 8.2 0.5 6 6 Carbon monoxide BIN' 108 55 50 Methyl chloride M'N 0.88, 10.3 1.170 Cadmium Mfl 0.0007 0.01 1,430 Acetaldehyde M P 1.26 180 1.430 Nitrogen oxides M N 2.8 50 1 J80 Carbon dioxide N'N 440 9000 2.040 Pyridine M H 0.39 16 4.100 Phenol M P 0.25 19 7.600 Hydtocyanic acid B'N 0.11 11 10.000 Methylamine M N 0.1 13 13.000 Benzene N'B 0.24 32 13.300 Catechol D K 0.14 23 16.500 Aniline BB' 0.011 8 44.000 Dimethylamine MiHI 0.036 18 50,000 CarbonyP suNide NV 0.0546 30b 54.945 Hydrazine M'HI 0.00009 0.13, 145.000 Acetone MIN! 1 1780: 178.000 Benzo(a]pyrene c 0.00009 0.2' 222.000 2-Toluidine M'B 0.003 9 300.000 Toluene N,B 0.000035 375 1,000.000 'Target organs: B, blood: D, dermak, H, hepatic: K, kidney:, M. mucosalc N, nervous: P.' pulmonary,: V, vascular, °A+tetabohte ot' carbon disulfide with corresponding TLV used to calculate cigarette equivalent'. 'No TLV for benzolalpyrene; TLV for coal tar pitch volatiles used to calculate cigarette equivalent.

462 ETS AA'!') HEART DISEA SE Cigarette Equivalents to Attain TLV The 21 sidestream smoke conhtituents with established workplace stan- dards are listed in the order of increasing number of cigarette equivalents. definedas the number of cigarettes burned in a sealed enclosure of I001m" to attain, but not to exceed. the corresponding TLV (last column. Table 2). The list starts with nicotine, which is a reportedi mucosal irritant (acute ex- posureY and an autonomic nervous systeml stimulant (chronic or repeated exposure). The maximum reported sidestream smoke (SSS) collected from one burning cigarette is 8.2 mg. On the basis of TLV(0.5 mg/tn'). it would take 6.6 cigarettes to attain TLV for 10&m' in a:sealed. unventilated enclo- sure (0.5 x 100 = 8?). It is unlikely for the nicotine concentration in public places to attain the TLV level. If smoking has been at an extremely high level inipoorl\ ventilated rooms. subjective discomforts would be expected! to lead to corrective measures before nicotine levels would approach the TLV. The secon& SSS constituent listed in the order of increasing cigarette equivalents is carbon monoxide: 50 cigarettes burning in a I00 m' sealed' chamber to attain the corresponding TLV' ( l'? ). Other than nicotine and' carboni monoxide. the remaining 19 SSS constit- uents would require more than 1(Ki0 cigarettes to attain the corresponding TLV Such excessively hiFhicigarette equivalents suggest that to attain TLV levels. more than 1000 cigarettes need: to be ignited simultaneously in an enclosed space of I00 m'. Consideration of cigarette equivalents clearly in- dicates that exposure to ETS constituents in workplaces rarely approximates TLVs. Nicotine as ETS Marker Thai nicotine and its maior metabolite (cotinine) are detected in blood and urine of ETS-exposed nonsmokers has been utilize& by proponents of the ETS-heam disease hypothesis. Their reasoning is as follows: since nicotine is the major cause of heart disease seen in cigarette smokers. it follows that any nicotine derived from ETS can cause heart disease in exposedi non- smokers. However. there is disagreement concerning whether any nicotine absorbed by nonsmokers can influence the heart. The estimates of ETS ex- posure are as follows: a nonsmoker's exposure might be. at most. the nico- tine equivalent of 'Y~w to '/iawi cigarette in one hr. which has not been, re- ported to have a significant pharmacolbgic action. In animal experiments. inhalation. ingestion, parenteral'injection. and dermal application of nicotine have been reported to influence cardiac function, coronary circulation. and atherogenesis. but these studies used amounts of nicotine that cannot he attainedby ETS exposure. Furthermore. coronary atherosclerosis has not~ been reproduced iniexperimental animals by in,iection of nicotine. High nic- otine levels of pipe smokers compared to cigarette smokers are not report- )

~. ETS A~A'1)~~MEAR~T DISEASE 4~6? edl\ associated with an increased' incid'ence of ischemic heart disease (113). Workers processing tobacco leaf Icigar making. leaf curing, and %karehouse uor/~~;era) also have not been reported to shov, a higher incidence of heart disease. compared to nontobacco workers (14).. Cardiac Toxicologic Rrofile of Industrial Chemicals. The 21 chemicals listed in Table 2. when individually used in factories below the corresponding TLV. have not been associated with, heart disease nor any adverse effect on corresponding target organs, that is. mucosal sur- faces. skin, blood. nervous system. lungs. kidneys, and liver (see second column of Table 21. The same ? 1 ETS constituents also appear in Table I of industrial chemicals, together with 11 industrial chemicals nuot reported to be present in ETS. As outlined in Table I. the existing methods for estab- lishing cardiac toxicologic profiles are as folloti s: Methods A. B. and C for ischemic heart disease: Methods D. E. and F for coronary atherosclerosis: and Methods G and H for card'iac arrhythmia an6myopathy. Most industrial chemicals have been studied bN one or two methods. thus contrit+uting to an uncertainty of whether these 211 chemicals are related to, heart disease. Those that have been studied by three to eight methods have a stronger basis for claims of a relationship with occupational heart disease. namel~. carbon, monoxide. ethylene glycol dinitrate. nitrogl}°cerin. carbon disulfide. and metFn•lene chloride. There are revie~u articles on industrial chemiealk re- portedly associated with heart disease (15-17). A principal' objective of this chapter is to evaluate the potentiali relation- ships between occupationallchemical's and heart disease, in terms of the ex- tent of the available data from human studies and~animallexperiments. There are reviews on individual industriallchemicals and the occurrence of diseases not limited to the heart (;li1.18.19). A standard source of reference is the Registry for Toxic Effects of Chemical Substances available in hard copy (20) as well as on-line in the TOXNET database updated by the National Library of Medicine and National' Institute of Occupational Safet\ and Health. Textbooks on internall medicine and': cardiology do not have special chapters devoted to occupational heart diseases so that it has been difficult to interest the medical profession. Because industrial chemicals are poten- tially associated with heart disease by the inhalational route, a World Health Organization monograph entitled Air Quuliry Guidelincs;(i,r Europer (' 1) is a helpful reference source. It discusses the following industrial chemicals in a uniform format: inorganic oxides such as carbon monoxide and nitrogem dioxide: heavy metals such as arsenic, cadmium. and; lead: polvnuclear ar- omatic hydrocarbons such as benzo{u]pvrene: nonhalogenated solvents such as benzene. carbon disulfiide. and toluene: and halogenated solvents such as methvl chloroform and methvlene chloride. These Il industrial' chemicals identify those that have been measured indoors (workplace envi-

46.' ETS Ah!D HEART DISEASE ronment) but also emitted' outdoors into the environment. lschemic heart disease is mentioned under carbon monoxid'e and carbon disulfide. ISCHEMIC HEART DISEASE 1'schemic heart disease is represented' clinically byy angina pectoris. myo- cardial infarction, cardiac arrhythmia. cardiogenic shock, andlsudd'en d'eath. The epidemiologic and clinical literature on work-associated ischemic heart disease consists of the following: Method A. mortality statistics: Method B. exercise testing for anginall pain: and Method C. coronary blood flbvk indi- cators. The plan is to state how each method has been applied to the concept that ischemic heart disease is related to exposure to chemical substances in the manufacture of industrial products. Although ETS levels are unlikely too attain their corresponding TLN'. it is important to discuss the existing claim that the mere presence of these chemicals is sufficient to suggest an associ- ation between ETS and occupational heart disease. Method A: Mortality Studies There are scant data on heart disease in workers differentiated by expo- sure or nonexposure to ETS in the workplace. Most published studies relate to differences in spousal smoking habits. based on the premise that mortality rates of nonsmokers might be influenced by smoking habits of their spouses. In 1984. Schievelbein and:1 Richter (22) reviewed the available literature and concluded that in concentrations of carbon monoxide and nicotine report- edly present in ETS. it is unlikely for ETS exposure to~play any role in the development and progression of ischemic heart: disease. The 1986 Reports of the Surgeon General and the National Research Council. after examining the available information. concluded than further studies on the potential relationship between ETS exposure and' cardiovascular disease are needed in order to determine whether ETS increases the risk of cardiovascular dis- ease in general. and of ischemic heart disease in particular (8?3). Recent epidemiologic studies were reviewed by Wexler (4); who~questionedi the re- ported relationship ~ between household exposure to ETS and'heart disease. Prospective (cohort)' and retrospective (case control) studies have been conducted'on the potential relationship between ETS exposure and IHD in- cidence. Although some spousal studies (smoker married to nonsmoker) re- portla statistically significant association. most studies do not. Lee and his collaborators (24) conducte& studies in Englan& consisting of administering a questionnaire to 200 hospital patients and:1200 controls for eachigenderi and age group. Patients with ischemic hearti disease an6 controls did not sho"any statistically significant difference in ETS exposure based on smoking habits of spouses. Exposure to ETS was also evaluated b~ aniindex of pres-

) ETS AND NEART DISEASE 465 ence in the workplace. during travel, and at leisure. From the standpoint of' worker ETS exposure. the negative results of Lee et al. (24) are more rele- vant than positive results of spousal studies that do not include ETS expo- sure outside the home environment. Carbon Monoxide Heart disease mortality rates have been reported for workers exposed to high levels of carbon, monoxide from vehicular emissions (tunnell workers. bus drivers, parking attendants) and industrial furnaces (steellfoundry. coke ovenL chemical manufacture) (25.26). However. the results of occupational exposure to high levels of carbon monoxide do noo support~ the argument that this substance contributes to heart disease associated~ with ETS expo- sure. in which reported levels of the gas are a tirny fraction of'the TLV. Carbon Disul,/ide/Carbon-vt Sulfide These two compounds are linke& b~ the fact that the former is ani indus- trial chemical reported to be associated with heart! disease among workers producing viscose rayonifibers. This compound is metabolized to carbonyl sulfide. which happens to be a reported SSS constituent. The concentration of' carbonyl sulfide is so low that it is unlikel'y to attain the TLV (Table 2: 54.945 cigarettes to attain TLV ). However. it is important to discuss mor- ialit~ studies of'ravon viscose workers. because other thanicarbon monoa- ide. carbon disulfide is the onlv industrial chemical for which there are ex- tensive data on, an association with ischemic heart disease. Ini a critical review of the toxicologic literature on carbon d'isulfide. Beauchamp et al. (27)ireviewed data on.the mortality rates of viscose rayon workers. In Fin- land'~ where there is a: high incidence of ischernic hearti disease. a signifi- canth-y higher mortality rate has been reportedlamong exposed workers com- pared to a control group. However, in Japan where there is a notably lower incidence of ischemic heart, disease. no increased mortality rate has been reported among viscose rayon workers. The excess deaths attnibuted to car- boni disulfide became apparenti if predisposing risk factors existed. such ass hypertension, hyperlipidemia. and excessive intake of cholesterol andisatu- rated fats (27,28)! The above observations are essential to consider in attempts to interpret mortality studies on ETS exposure. Dietaryy intakes of cholesterol and fatty food were not considered as a confounding factor in mortality studies relat- ing to workers expose& to the industrial chemicals listed in Table l(with Method A notation). The reported higher susceptibility of Scandinavians too heart disease is reflected by the lower TLV (l5 mg/m') compared to:the TLV in other European countries and the United States (30 mg/m') (18.19).

466 ETS AJx'D HEART DlSE.4SE: Polvcyciic Aromatic kvdrocarbons (PAFI), lt has been suggested by proponents of the ETS-heart disease hypothesis that Scandinavian roofers show excess mortalitvv for ischemic heart disease (3). They extrapolate from PAH-exposed roofers to ETS-exposed workers without recognizing the difference in composition of PAH. Exposures to PAH' among coke oveni workers. creosote wood appliers, and asphalt road builders have not been reported to be associated! with, excess mortality for heart disease but have been reported to be associated with excess mortality for lung cancer. From the standpoint of chemical composition:of PAH ex- posures determined by nature of product. PAH exposures of roofers are ir- relevant to ETS exposure (see also Method F). Heat!Y Metals Mortality studies on work-related exposure have been reviewed by Kris- tensen (161. Lead and cadmium workers have been reported to show a higher mortality rate from heart, disease and' hypertension. Iln the absence of ex- perimental'l animal studies. heart disease is likely to be a complication of hypertension, rather than a direct, effect of lead or cadmium onithe heart and coronary vessels. The suggestion that heart disease may, be associated with workplace exposure to arsenic or cobalt can. be traced to instances of beer drinking contaminated with either of these metals. and subsequent death from cardiomyopathy; Method B: Exercise Testing and Angina Pectoris Exercise testing is essential for the diagnosis of ischemic heart disease (?9). A positive diagnosis is based on the appearance of chest pain or clas- sical angina pectoris after completion of standardized exercise on a treadrnilll or bicyclae ergometer. Exercise testing has also beemused to evaluate sever- ity of arteriosclerotic heart disease based on time of onset of an ischemic pattern in the electrocardiogram as well as the appearance of cardiac arrhythmias. ETS Exposure of Anginal Patients All available reports on exercise testing do not relate to specific occupa- N tional groups comparing two subgroups: with ETS exposure an& no ETS C exposure. There are two studies on anginal patients that suggested to the ~ investigators that ETS exposure during bicycle ergometry may shorten the ~+? time perio& to onset of chest pain. The first study. reporte& in 1978. con- CA sisted of a group of ten American male veterans (30). For variow, reasons. ~ ~ N

ETS A~N1)~~MEAR7 UISEASE ~ 4fu~7~ the 197t+'protocol for exercise testing was evaluated by an ad hoc committee of the Environmental'Protection Agency. In 1983'. the committee concluded that the method used on American male veterans "did not meeta reasonable standard of scientific quality" (13I ). Ini 1987. a: stud'ti of exercise test- ing during ETS exposure was reported by Soviet investigators (32)h The re- sults were essentiallv similar to those reported' from American veterans. lt is this author's opinionithat shortening onset of anginal pain during exercise testing as a result of ETS exposure has not been proved pending evaluation of the Soviet protocol. Anti-anginal drugs sold in the United States arne sup• ported by results of exercise testing in European laboratories that have been approved hy the U.S, Food and Drug Administration and so far. the list d'oes not include arn Soviet laboratories. Influenre of Carbon Monoxide on Exercise Testing Proponents of' the theory that ETS exposure aggravates angina pectoris emphasize the presence of carbon monoxide in ETS. in spite of the fact that the concentration inhal'ed'is 3100 times lower than mainstream smoke. Blood carboxyhemoglobin levels of suhjects exposed to ETS in public places range from I to 3 n among nonsmokers. Slight elevations of blood carboxyhemo- globin level (to 2 and 3.97() have beenireported following administration of carbon monoxide in air (l001and''_30 mgiM') (33). Exercise testing of heart disease patients was reported'to result in an ischemic pattern of electrocar- diogram at these blood carboxyhemoglbbin levels. However, as indicated'in Table 2. this would require more than )00 and '_'G10, cigarettes burning in, a sealed enclbsure of I001m' for carbon monoxide to attain about 2 and'4 times the TLV. respectively. ETS Exposure as Risk Factor jor Angina Pectoris Proponents of the claim that'~ ETS exposure aggravates angina pectoriss have not considered the complexities of the disease separate from other manifestrations or complications of ischemic heart disease (Le., acute myo- cardial infarction and sudden deaths). Althoughi prospective and retrospec- tive studies report that cigarette smoking is one of many risk factors for acute myocardial infarction and sudden deaths. the data on angina pectoris are evenimore complex. The 1983 repornof the Surgeon General onicardio- vascular disease, referring to risk factors, conclud'ed! that "variation in the strength ofassociation between smokingand angina pectoris may be influenced by . . . methodological considerations'" lref. 34. p. 70). More recently. it has beeni argued that the 30-year results of an ongoing prospective studj at Framingham. Massachusetts. indicate that cigarette smoking is a negative risk factor in women li.e., incidence lower in women smokers compare& to

40 ETS AJ1'U H£ART 1)ISEASE uomen nonsmokers) (3i1. The results in men have indicated either a positive or no significant relationship between cigarette smoking and angina pectoris, depending on methodological variation. Some studies relating to cardiac pa- tients admitted to hospitals report that after an initial cardiac episode. the prognosis is not~ influenced b~ smoking (3637). After the initial' infarction. prior smoking was not associated with the severity of subsequent compli'. cations. These observations on cigarette smoking in relation to the prognosis of myocardiallinfarction and the influence of angina pectoris raise additional questions. How can ETS. a dilute mixture of tobacco smoke components in air, aggravate angina pectoris or influence the prognosis of acute myocardial infarction, in light of recent inconsistencies in data derived from smokers° Method C: Coronar% BJood Flos lndicators Coronar~ arteries visualized b\ angiograph\ can shoti obstruction that is organic (arteriosclerosis and'thrombosis) or nonorganic (ivasospasm) in na- ture. Total coronary blood floti is measured by a tracer clearance technique. Patients with ischemic hearti disease shoH a reduction in coronary blood flo\A that is limited to an infarcted'area. When infarction is detected in work- ers previously exposed to carboni monoxide or carbon disulfide. it is not possible to isolate the potential association with chemical exposure from other potentially confounding risk factors. Carbon monoxide alone. by in- creasing carboxyhemoglobin. cani increase coronary blood ilou: but the re- sult would be an oversupply of blood, \vithout reduced oxygen utilizationi beca.use of poisoning oxidative enzymes. Myocardial metabolism requiress the sampling of blood from the coronary sinus and a systemic artery to ob- tain arteriovenous differences of oxygen. carbon dioxide. lipoproteins. and glucose metabolites. There are more directi methods formeasuring coronary blood flow in experimental animals (dog. cat. pig. monkeyl: The relhtive importance of metabolic and neurohumoral control has been evaluated in experimental animals [see reference cited by Bove (3R)]. It has not been possible to reproduce coronary heart disease by exposure to tobacco smoke. which contains nicotine levels higher than ETS, so it is doubtful!that existing animal models can give positive results from ETS exposure. Nitroglycerin and organic nitrates are useful vasodilators for the relief of angina pectoris. The pharmacologic action, of nitrogl'Ncerin is manifeste& in workers who are expose&daily to nitroglti cerin and ethylene gl}~col dinitrate. but after a weekend of nonexposure, developichest pain on Monday morn- ing. Workers suffer from vasospastic angina as a result of nitrate withdrawal during the weekend and are relieved upon resuming nitrate work exposure.. Autopsied workers did not show coronary arterial obstruction, confirming the occurrence of vasospastic angina brought abour: hy weekend withdrawal from nitrate. Workers were acclimatized to the nitrate level in work environ- ment ( 114-16).

ETS AA'l') NEART l)ISEASE 409 CORONARY ATHEROSCLEROSIS The term coronary atlterc,.cclc•rrrai.v used in this chapter refers to histo- patholla:ic changes in arteries leading to i.sclierriic huurt di,~c•n.%c- (see preced- iitc section). Although both terms are included in, cnrorrur-N heurt di.Nru.%c-. there are differences in methodolog~. This section is de~oted to progressive organic lesions of coronary arteries. the methods for detectiom and their evolution, based on human observations and animal' experimentation. The focus is on industrial exposure to carbon disulfide andl carbon monoxide. because of the relativelti greater amounts of data on these substances. The potential relevance of these industrial chemicals to ETS exposure is also discussed. The demonstration of coronary atherosclerosis id'eally should include his- topatihologic evidence derived from autopsy (Method D). This has been ac- complished for worker exposure to carbon disulfide. ti hich has been sup- ported bN the occurrence of hyperlipidemia in exposed workers and coronarn atherosclerosis in experimental animals (Metho& EI. Onithe other hand'. some industrial chemicals are associated'.+ith the development of cor- onars atherosclerosis based on animal experiments onl} or on hematolbcic changes in workers that in animals contribute to aortic atherogenesis (see entries in Table 1). Some of these observations have been used, to supportt the claim that ETS exposure is involved in coronar} atherosclerosis. A dis- tinction is made between concepts derived from human studies (Method D). animal'.experiments (lvlethodlE). and in virro techniques bMethodlFl. Method D: Coronary AngiographN and Histopatholog) The most direct method for diagnosis of coronary atherosclerosis ik b~~ histopathologic examination and coronary angiogram. AlthouFh, there are isolated reports that workers exposed to carbon monoxide suffer from in- creased coronarv atherosclerosis (antemortem or postmorteml. this expo- sure is confounded by competing risk factors such as personal habits. famil- ial historN, and environmentallpollution. Among viscose rayon workers, the occurrence of coronary atherosclerosis reported at autops} of workers dying of heart disease led to mortalitN studies (Method A). Workers are also re- ported tb suffer from hyperlipidemia. which is not entirell due to carbon disulfide exposure. Tt is difficult to replicate earlier studies on workers using modern techniques of diagnosing coronary atherosclerosis, because expo• sure levels have come under, strict regulation. There are no case reports of coronary atherosclerosis iniwor~kers exposed to a single polynuclear aromatic amine because workplace exposure is to mixtures that inclhde tienzolulpyrene. Only research Iaboratory workers in- vestigating benzola)pyrene are candidates for long-term exposure. and so far there has been no report of a higher incidence of heart disease. There are

470 ETS A'ND HEART DISEASE also no case reports of coronary atherosclerosis from prolonged exposure to the heav~ metals and nitrogenous compounds listed in Table l. Method E: Coronary Atherosclerosis in Experimental Animals Repeated attempts to induce coronary atherosclerosis in experimental anr imals by inhalation of cigarette smoke have fail'ed'. Additional feeding with a cholesterol-enriched diet has reportedly led to the development of athero- sclerosis notl involving coronary arteries. ln baboons. after 2-3 years of oral feedine of cholesterol and saturated' fat, and d'aily inhalation of cigarette smoke. arterial lesions were compared between smokers andl controls. Among male baboons. the extent of carotid atherosclerosis was greater in smokers than in controls. but there were no significant differences in athero- sclerosis of the aorta. coronarv arteries. iliac-femoral, and bronchial arter- ies. Among female baboons., there were no significantidifferences in athero- sclerosis between smokers and controls (391'. The same general remarks appl} to experimental testing of carbon mon- oxide in levels far exceeding those reported for ETS exposure. Rabbits. pi- geons. and chickens are reported to need supplementary feeding of choles- terol to show carbon monoxide-induced aortic atherosclerosis (40). Carbon disulfide is the only industrial chemicalireported to cause athero- sclerosis in animals without supplemental cholesterol feeding. Coronary and aortic atherosclerosis and myocardial lesions were detected in rats after 4 months of inhalation exposure (28). There were elevations of serum choles- terol. phospholipid. and triglycerides, indicating similt3rity to the human form of atherosclerosis. Other investigators have tested carbon monoxide and benzo[a]pyrene an&have not observed hyperdipidemia and atheroscle- rosis similar to those reported for carbon disulfide. ln the past. research on carbon monoxide. benzo[a]pyrene. and other polynuclear aromatic hydro• carbons has not been directed to a comparison with carbon disulfide. Polynuclear aromatic hydrocarbons have been reported to induce aortic atherosclerosis in pigeons and chickens (41'--44). It has been speculated that these studies in birds relate to human subjects exposed to ETS ('). There are several reasons for the inapplicability of results of these bird experiments to coronary atherosclerosis: (a) 7,l?-dimethv lbenzo(a,li)anthracene and 3- methycholanthrene are not known, to be present in ETS: (b) although benzo[ki]pyrene is reportedly present in ETS, the d'ose administered. 50 mg- kg injection. is farfetched compare&to concentration levels in SSS. which is 0.00009 mg/cigarette: (c) hepatic metabolism is essentiallfor atherogenesis in one strain, but not in the other strain. a sequence that applies to oral or injected compounds but not to the inhalation route: andl(d) the typical result is aortic atherosclerosis and! rarely coronary atherosclerosis. Aortic athero- sclerosis is different fromi coronary atherosclerosis because ofl myocardial extravascular support in the latter. There are intracardiac mechanisms that influence coronary circulation, which are absent in other arterial beds.

ETS AND HEART DISEASE 471 There are long-term animal experiments designed to study carcinogenicit~ or polvnuclear aromatic hydrocarbons and. so far. coronary atherosclerosis t has not been reported in sacrificed animals. Method F: In Vitro Studies of Hematologic Factors Hematologic factors include alterations in hemoglobin oxygen transporv such as carbon monoxide and' methylene chloride increasing carboxyhemo- globin: andianiline and 2-toluidine leading to methemoglobinemia. The ulti- mate consequence is a reduced supply of oxygen and presumablN athero- sclerosis resulting from carbon monoxide. However. prolonged testing withh methvlene chloride or aniline has not been reported to produce experimental atherosclerosis, suggesting that these two industrial chemicals reduce hemo- globinioxygen transport differently from carbon monoxide. Several techniques have been deveiopedifor the specific purpose of dis- co\ering therapeutic agents for the prevent6on, suppression. and reversal of atherosclerosis. Drugs for influencing blood platelets, blood lipoprotein lev- els. andlend'othelial vulnerability evolved from application of in i•rtro testing of blood derived' from patients with ischemic heart disease. as well as pe- ripheral vascular diseases. The same techniques for identifying therapeutic agents have also been applied'i to investigating ho.+ carbon monoxide and ETS might play a role in:atherosclerosis. The interpretation of results de- rived from one test' has been extended to include the entire progressioni of atherosclerosis even though the test was intended to show a therapeutic. rather than toxic. effect of chemical agents.. lii ritco tests have been applied to blood from ETS-exposed subjects. . based on the assumption that any reported effect will contribute to coronary atherosclerosis. It should be pointe& out that chemically induced platelet aggregatiom leads to vascular clot formation. which does not~ necessaril\ in- volve interaction with endothelial cells and the formation of atherosclerotic plaque. Also, in the laboratory. it has not been possible to initiate aortic plaque formation by exceeding the normal level of fibrinogen. Any reported increase in fibrinogen level in the blood of ETS-exposed subjects may not, be relevant to a potential relationship with coronary atherogenesis. Iit is con- ceivable that. for some people. ETS exposure may be perceived as stressful. with release of catecholamines. and that catecholamines are responsible for in vitro testing results. It has not, been possible to conduct a double-blin& testing of ETS exposure since both, investigator and subject can detect ETS presence. Platelet Aggregation Exposure of healthy nonsmokers to ETS is alleged to alter resulus of in rirJ-o testing of platelets in platelet-richi plasma. Aggregation of platelets is

472 ETS AA'D, HEART DlSEASE tested hv the follou inF agents added in riiro: edetic acid and formaldehyde or prostaglandin. The possibility that ETS exposure increases platelet~aggre- gation is alleged to be an important step in the evolution of coronary athero> sclerosis in nonsmokers (''). In ,•iiro studies of platelet aggregation in blood derived'from~smokers have reported inconsistent results, which question the applicability of this method to ETS exposure in nonsmokers. Platelet aggregation testing using whole blood reported no statistically significant differences between nonsmokers and smokers (45). Cigarette smoking is reportedly associatedi k ith altera- tions in platelet factors involved in thrombus formation. but the change has been attributed'to the presence of carbon monoxide levels higher than those reported in subjects exposed to ETS (46). 1,7 vitrr testing does not necessar- ily reflect events in rivo. Although platelets may be activated in viro, the} become attached to ervthrocvtes or form platelet aggregates during the col- lectioni and centrifugation needed to make platelet-rich plasma. There is some evidence that acti%ated platelets are lost from supernatant "platelet- richiplasma." which includes older or less acrive platelets, Plasma Fibrinogen Levels Another in riii-n test for a clotting factor has beeni added to: the list of reports supporting the ETS-heart~ disease hypothesis. Patients with isch- emic hearti disease tiere questioned about their smoking habits. and non- smokers were queried for ETS exposure in the v.orkplace and household. Control suhlects were derived from the same community in Australia (471.. Ih was reported'that the collected blood samples showed higher fibrinogen concentrations among current smokers than nonsmokers. Subjects exposedl to ETS had higher levels thani those not, exposed. The differences Here not statistically significant because of the high variability of measured fibrinogen levels. According to the questionnaire responses. levels of ETS exposure at work were reported to be higher than at home, but the estimated odds ratio for heart disease was less than one. The investigators interpreted their re- sults to indicate inaccurate reporting of ETS exposure or the possihilitythat household exposure to ETS is associated more with heart disease than is workplace exposure. The potential relevance of fibrinogenilevels in relation to ETS exposure is further questioned' by observations that psvchosocial factors may influence the plasma fibrinogen concentration in patients with ischemic heart disease (4Y).. CARDIAC ARRHYTHAIIA AND M19ti'OPATHI The third and last group of methods for establishing cardiac toxicologic profiles for industrial chemicals relate~ to alteration, in cardiac function.

ETS AA'/2 HE-ART 1)lSEAS£ 47-3 The methods are intended to detect irregularities in heart beat or rhythm. to measure excitabilitN of the intact heart, and to record' electnicaC propertie~ of excised atrium and' papillary, muscle. Cardiac output is measured by° the tracer dilution technique and ventricular imaging in patients: invasive pro- cedures are required for application of the Fick principle in patients and insertion of blood flow recorders in,experimental animals. Perfusion of the excised heart offers an opportunity of measuring myocardial contractility and metabolism. Enzymatic studies and electron microscop~ complete the techniques for~ detecting cardiomyopathy. All these procedures have been applied to determine the occurrence and mechanism for two groups of dis- eases: irregular heart beat or arrhythmia, and cardiomyopathy. Method G: Irregular Heart Beat Industrial chemical poisoning can be manifested' by irregularities of heart beat or cardiac arrhythmia. in the order of increasingseverity: ranging from tach\cardia;or bradycardii3. atrioventricular block. atrial or ventricular ex- tra~_~ stole. atrial fibrillation. to ventricular fibrillation and cardiac arrest. The benign forms lup to atrial fibrillationYare reversible by stopping chem- ical e.posure., but ventricular fibrillation and cardiac arrest: reqNire heroic efforts. Poisonings characterized by cardiac arrhythmies have been reported for the following (see Table 1. Method G): mosti halogenated and nonhalo• genated'solvents. some nitrogenous compounds, one heavy metal (lead), and one oxide (carbon monoxide). The arrhythmia results from a direcn action of the chemical on the heart. specifically by altering excitability. conduction. and refractoriness of one or more of the following: atrial muscle. atrioven- tricular node. conducting system. and ventricular muscle. The effects have been reported in appropriate human studies and animal experimentation. The occurrence of poisoning by industrial chemicals does not support the proposition that since the same chemicals ma~ be reported:at minute le\els in ETS. then ETS also may lead to the development of heart disease in workers. Method H: ExperimentallN Induced Cardiom}opathy The most extreme example of unjustified application of results from ani- mal experiments to ETS exposure of nonsmokers is as follows: in the course of attempting to determine whether long-term cigarette smoking leads to cardiomyopathy; rabbits were exposed in an infant incubator (49). It was reported that all the smoke fromithree burning cigarettes entered the inlet of the incubator throughia mechanical device and': rabbits were kept for 30 min. This description appears to this author as a sealed! chamber with cigarette smoke entering the inlet for 30-min periods. Several groups of rabbits were

474 ETS AA'DHEART UISEASE sacrificed: controls, after one 30-min exposure. twice daily exposure for 2 weeks, and twice daily exposure for 8 weeks. The heart was studied' for mitochondrial', oxidative processes. There was a decrease in respiration as well as in phosphorylation rate that was interpreted by the investigators as card'iotnyopathy: The investigators recognized that carbon monoxide in the incubator was probably responsible for metabolic changes but they did not monitor air or blood levels. Hugod and collaborators (50-52) exposed rabbits to one of the following mixtures: carbon monoxide 220 mg/m' or four times TLV; carbonyl sulfide 130 mg'm' or five times TLV: nitric oxide 6 tng/m' or one-fifth the TLV The rabbits were in air-tight exposure chambers containing freely flowing air or predetermined! mixtures in air for periods ranging from I to 7 weeks. The results of 140 rabbits sacrificed for electron microscopic examination per formed'blindl\ showed no morphological signs of myocardial damage. The four vapor constituents. in lfvels far exceeding ETS levels, were not asso- ciated with ultrastructural changes in rabbit heart. signifying the absence of cardiomyopathy.. The rabbit exposure studies described~ above were extended to include biochemical and histomorphologic investigation of atherosclerosis. Expo- sure to each of the four gas-air mixtures was not related to intimal damage of the aorta and coronary arteries. The negative results noted for carbonyJl sulfide exposed rabbits do not support the claim,thai this known metabolite for carbon disulfide is responsible for coronary atherosclerosis reported' by other investigators. Cardiomyopathy has been reported following exposure to halbgenatedisol- vents, based on case reports of poisoning and experimentallstudies on intact and perfused heart. Cardiomyopathy from heavy metals is described'in case reports of individuals drinking beer from containers that leached' arsenic. cadmium. or lead (16): Cardiomyopathy from hydrocyanic aci&is also based on case reports of poisoning and is readily, supported by biochemical studies of heart muscle. Carbon monoxide is probably the most~ frequently encoun- tered industrial and household chemical associated with death bvy cardio- myopathy. History of exposure to vehicular emissions or household natural gas is verifiable by blood'analysis for carboxyhemoglobin. Among nonhal- ogenated solvents. only phenol has been reportedly related to cardiomyop- athy.(161~ CONCLUDING REMARKS Among more than 32 industrial chemicals potentiallN related to heart dis- ease, only four substances or chemical classes have extensive supportive evidence: carbon monoxide, carbon disulfide. ethylene glycol dinitrate and organic nitrates, and methylene chloride and halogenated solvents. The ef-

ETS AND HEART DISEASE 475 fects of other industrial chemicals (oxides, nonhalogenated solWents, nitro- genous compounds. and heavy metalsYhave not been adequbtely supported by human studies and animal experiments. Methylene chloride is a solvent prototype for industrial chemicals that! may be related to cardiac arrhythmia and myopathy in lethal or sublethal levels. Carbon disulfide is a selected prototype for industrial!chemicals that' may be related to ischemic heart disease or coronary atherosclerosis. There are no data indicating whether prolonged exposure to low levels of methyl- ene chloride is associated with!ischemic heart disease or whether high levels of carbon disulfide are associated with cardiac arrhythmia and myopathy: Methods to establish a cardiac toxicologic profile applied to one prototype need to be applied to the other. The cardiac toxicologic proCGle for carboni disulfid'e is as follows: (A ) mor- tality studies of viscose rayon workers report excess ischemic heart disease d'eath6. provided predisposing or other risk factors are present: ('B) there iss a high incidence of angina pectoris reported in workers exposed to carbon disulfide: (C) there is a reductioniin coronary blood floti< reported'lin workers developing ischemic heart disease, but there are no published results of myo- cardial tracer clearance studies: (D) coronary angiogram and' postmortem histopathologic studies reporvcoronary atherosclerosis associated'with, car- bon disulfide exposure: (E)lcoronary atherosclerosis developed in experi~ mental animals exposed toicarbon disulfide. with or without dietary choles. terol supplement. There is no information for (F)'in vitro hematologic factors and (G) cardiac arrhythmia: (H ) experimental cardiomyopathy was report- edly not detected by electron microscopy in animals exposed to five times TLV for carbon disulfide. The cardiac toxicologic profiles for carbon disulfide and ETS are com« pared in Table 3. There are no comparative studies oni workers with and without ETS exposures. The theory that ETS causes ischemic heart disease is based on inferences from the following: (A) epidemiologic studies of household exposures reported for nonsmoking spouses of smokers: (B) ex- ercise studies of anginal patients with ETS exposure. but questionable pro- tocol: (C) coronaryy blood flow assumed to be insufficient because carbon monoxide present in ETS: (D) coronary atherosclerosis assumed to occur because aortic atherosclerosis reported in animals exposed to carbon mon- oxide at considerably higher levels than ETS: (E) coronary atherosclerosis supposedly occurs because benzo[a]pyrene reportedly associated with ath- erosclerosis in cholesterol-fed birds: (F) in virrn testing for platelet aggrega- tion, and reduced fubrinogen, level. suggesting atheromatous plaque forma- tion: (G) cardiac arrhythmia postulated based on ventricular excitability studies of animals exposed to carbon monoxide: and (H) cardiomyopathy inferred from rabbit heart mitochondrial studies. It is the opinion of this author that the available studies d'o not support a judgment that ETS exposure is associated with anyy form of occupation-re-

476 ETS Ah'U HEART UISEAST TABLE 3. Cardiac toxicologic profile for carbon disutlyde and envrronmental tobacco smoke Method Carbon disulhde Env ronmental tobacco smoke (ETS) IS¢hemiC: heart disease A. Mortality studies Excess ischemic heart disease No information on workers deaths among rayon viscose exposed to ETS workers provided predispos ng factors presenfi B'. Exercise testingg Higher,incidence of angina in Anginal patlents have and anglna rayon viscose workers: shorter t me to pain pectorrs' exercise testing protocol onset when exposed to must meet U.S. agency ETS: c garette smoking standards quest onable risk factor in angina patients C. Coronary blood flow Reduced coronary blood flow in indicatbrs patients with ischemic heart disease Coronary atherosclerosis D. Coronary angiography and histopathology. E. Atherosclerosis in Coronary, atherosclerosis in rats Polynuclear aromatic experimental without choteslerolHeedrng amines causing aortic an mals atherosclerosis in cholesterol-fed b rds F. In vitro hematologic No information Platelet aggregation, factors endothel at cell damage and reduced fibnnogeni level Cardiac arrythmia and myopathy G. Irregularheart beat, No information Ventricle excitability studies of animals exposed to carbon monoxide H;,Experimentally No ultrastructural changes in Heart mitochondria stud es induced rabbit heart from rabbits exposed to card omyopathy ETS lated heart disease. Although, ETS reportiedly contains constituents that: have been associated with occupational heart disease- the concentrations are so low that it is.unlikely for any substance to attain the corresponding TLV in a:work environment. Carbon disulfide can be used as a reference model for testing whether an industrial chemical can be considered as an etiologicfactor in ischemic heart disease and coronary atherosclerosis. The most comprehensive and critical review of carbon disulfide has been written by members of the Chemical lndustry, institute of ToxicoloFy: The theory that ETS exposure causes heart disease was recent'ly summarized by university scientists wrho have di.- missed~valid criticisms,at industry-supported. All research results, including industry-funded sources. shouldi be used in evaluating the role of ETS ini heart, disease.

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ETS A'ND H€ART DlSEASE 479 sutucnu of tobacco smoke. influence of coronarp and aoruic intimal morpholoF~ Atuunh lllnd W rherr.~t/ir IB80'.IC'_iSlti-S'_4'. 5'1. Hugod C. }Nyocardial morpholog~ in rahbits exposed to various gas-pha.e constituent, of tobacco smoke. Athrrrn.Ac leruaie 1981 :40i IKl-19U. 52. i:amstrup O. Hugod C. Expocure of rahhit:,to S(I ppm carbonyllsulfid'e-a hiochemteal andihistomorpholoFical studl.,/wArch Obc up Eni irun Hr•ulth 1979:44:,109-1 16. ~