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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-