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Scand J Work Environ Healrh' 19g9:IS:245-264 Cardiovascular diseases and the work environment A critical review of the epidemiologic literature on chemical factors by Tage S Kristensen, MSc' 7fJ~ '•-. /'- c~r J, I t:Rl5TEN5EN'T5. Cardio.asculardrseases and'the work enstronment: a critical review ofthe epidemio- logic literature on chemical factors. ScandJ K'ork £nvrron Heolfh~19B9:1':24S-26a. This is the second of twc articles reviewrnQ the epidemioloQic research on card+ovascular diseases (CVD) and the work environment. It deals wtth chemtcal'factors. te. lead.,cad'mtum. cobalt, arsenic. arbon monoxtde, pas- crve smoking. organic solvents, carbon disulGde. nitroglycerin. nitroglycol. and others. The epidemiolog- ic literature relating to each is assessed on the basis of a number of mnhodolb;ical criterta. and the need for future research, the methodology of literature resiews. and~preventove implications and perspectives are discussed, It ii concluded that the causal relationship between two ofirhe chemieals. carbon disulfide and nitroglycerin nnroQVycol, and CVD a very well documented'. Forlead'and passive smoktnga causal relation to CVD is llkeh. I tore research is needed concerning eobaltL arsentc. antimony, and other chemi- cal'compounds. Etposure to carbon monoxide mcreases the acute risk of CVD but has probablv no Iastan` atherosclerotic effect. Cadmium and organic solvents are probably not causally related to CVD. Kw rerms arr.imony.,arsenic. berylhum, cadmium. carbon disulfide, carbon monoxtde. chemtcals, cobalt. combusnon products, dtnrtrotoluenes hypertenston, ischemtc heart dtsease. kad, nstroglycenn, nnroglycol', occupauon. organic solwems. orQanophosphatesn pusive smoking. This is the second of two articles on the work environ- ment and cardiovascular, diseases (CVD). It reviews the epidemiologic literature om occupational chemical' fac- tors and CVD. The results of the review are compared with those of earlier reviews in this field' O-13). As in the previous article (14). 1 have dealt with*c- cupationall factors, but not with, individual habits or characteristics. Thus, for example, f discuss passive but not active smoking, lead and cadmium but not soft water. To facilitate the best, possible clarification of the occupational factors considered! I have also in. cluded investigations which are not strictly occupa- tionalibecause most of the exposures are also found outside 2he work environment. The objectives of this article are the same as those ofl the previous one, ie. (i) to record and integrate the epidemiologic literature on CVD and the work environ- ment; (ii) to evaluate the research with the objective of elucidating possible causalities between omspationali factors and CVD; (iii) if possible, to point out areas where enough is known to start employing the research results for,the purpose of prevention, and (iv) to point out defects and deficiencies in existing research with the objective of strengthening and improving future research efforts. Institute of Social Medicine, University of Copenhaaen:. Copenhagen, Denmark. Reprint requeau to: Mr TS Ki•istensen. University of Copen- hagen, Panum Institute. 6Ie=d:msvej 3, DK-2200 Copenha- =en N, Denmark. Mst.rial• and mathods The criteria for collecting and evaiuating the epidemi- ologic literature have been described in detail in the previous anicle (,14): The objectivehu been to include all epidemiologic studies on the exposures in English,. German or the Scandinavian languages (or which have summaries in one of these litttguages). That objective has not been fully realized„although this review is more comprehensive than earlier reviews on the same topic. To give the readers an opportunity to supplement the review of the individual exposures, some special reviews from recent years have also been included.. They contsin extensive lists which also cover the nonepidemiologic literature. The most important objective of the review has been to identify causal risk factors for CVD. With this in mind, lhave evaluated the following five central methodological points for each study: (i) the time dimeruion. (ii) confounding, (iii) selection; (iv) mea- surement of exposure and disease, and (v) adequate design and statisticalanalysis. On the basis of this t3it- ical evaluation, each study ha-s been given a score be- tween "x" and "xxxxx"' for methodological quality: (For more details of this scoring system, see refer- ence 14.) It should be emphasized that, when I refer to "study" in the following discussion, I do not nem- sarily rnean an "article" or "paper." An artick may contain two or more studies, eg, when the same hy- pothesis has been tested on two different popuiauons,, such as men and women or inhabitants of two differ- ent cities. If the analyses are published in such a way that the results for each individual group t:an beiden- 24S

Tabt. I Results ot 63 eDiOem o1opic stu0res of caroiovasou Ln oiseases ((rVO•1 anc leaC e.oosUre ac,,oro'nQ 1o :ne r*+emoaolcqi.ai ouality Of tne stuot.s The tzoie rs nasec oft •e,e•eaces 26 33-i(I7 Me'^o00iOQrCai . Guawy.' . .. .., .... .-...,, % ~. . N .. N . N . W - - • 53 - 0 - o+ 16 0 0 o- 0 0 0 e.. . 6 316 6 25o - 0 20 3+ 7 -s2r6I rQS 76D- o. 9,a7. 3 +6+ 9 a7. is 667 2 ,00 30 a7 6 + 7 1,, , 5 3 - 0 - 0 . 3 .a Totai r6 +QC rQ +W 24 100 21tqe> >00 •-=e.anor•s?ioo.r..Nl, uaO.aoosYn wo CVO,WOOO o.s.. 11.10 ,.ss1,Qneor,n¢ol1s,si.nr..n.Qarwr.mn.onsn.o Q.nor.rr1.o- sn.p 1~.iP,Q-1Or•nCOn~~l1MfDOS+IiWAIa/iOnfMO.• ~DOfrlw.74a- r,Onsn~3 ana I uncRtU,^ •MaPOnsn,o .. Cnf crr.r4 'o, mernooo-oQ.ca+ Qualiryan .[abn.o N.Inn r.a No swo-.s ,u .,.,. ro• ounliy ti(ied. they have been regarded as separate studies. On the other hand, the same research pro)ect is often pub- lished in several articles. eg. in prospective studies, in -hich successive results are published as the cohort grows olden. In such~cases. all articles have been evalir- ated as a whole with regard to study outcome and methodological quality. R.sults Lead' Many epid'emiologic studies have been published on, lead and CVD. tionetheless. the topic is treated very superficially in the general reviews on the relationship between environmental exposures and CVD. In several more recent reviews, lead is not mentioned at all (3. 4• 7; 8). while the topic is treated very briefly with a maximum of three references in others (1, 2, 5, 9, 12). Only in the early review, by Warshaw from 1960 (13), in Kurppa et al's review of 1994 (6), and in the reports of Rosenman (10, 11) is a reasonably thorough dis- cussion of the possible lead-CVD relationship included! These authors give six to twelve empirical references. The general conclusion drawn by the authors who men- tion the topic is that further research is necessary. In the more specific literature on lead, trace met- als, or trace elements, similar divergencies are found. There are examples of~ CVD not being mentioned in reviews on lead and health (15) and of lead not being mentioned in reviews on: trace metals and CVD (16-18). However, the most common conclusion in these reviews is again that further research is neces- sary (19-24). Some reviews do4 however, conclude thar lead has been shown to increase the risk of CVD. eg, Teleky's review from 1937 (25) and StOfen's review from 1974, which primarily deals with German and East European studies (26). In 1987 and 1988; two reviews were published which marked a new departure in this field of research: One is the comprehensive review by Sharp et al (27) on epidemiologic, clinical, and toxicologic studies con- cerning low•lntl lead exposure and blood pressure. The other is a special issue of Enerronmenra/ Healrh Perspecnves 11968, ~olume'81. which contains papers and discussions from an internauonal symposium on the relationships between lead and blood pressure. This issue contains se.eralire%tews of both experimental and obser,fational invesriganons (2g-32). The conclusion from these comprehensoe reports is that it must be considered probable. though not yrt defirritively pro~ed', that'low-le.el fead'ezposure increases blood pressure and consequently the risk of CVD. In the present re.'teN, 63 empincal studies ha%e been evaluated (table 1). The empirical research in the field can be said to fall into three periods. ie. 1920-1962. 1963- 19801 and 1980-the present. In,the first period several studies were published on the topic, especiallti% on the relationship bet%een occupauonalllead exposure and blood pressure. The methodolbgy,of most.of these studies is, naturally, rather primithe, but there are er• cepttons - for example, Vigdortchik's remarkable study from 1935 (51). I have included six of the irres- tiganons from this earJyy period in my re.te" The sec- ond period, 1963'-1980, was heralded by Dingwall- Fordyce & Lane's histoncal prospective monahty study from 1963 (64• 66). During thts period, at leasn one ini,estigation was published on the topic evem year, but, as suggested earlier• these studies did not arouse any particular attention. From I9801on• the situation has changed dramatically. Many more studies have been published (38 of the 63 investigations in table I are from the 1980s)t and also intereseis sharply rising tn, the possible relationship between lead~ and blood' pressure at veryioµ-level lead exposures, correspond- ing to those levels that the general population is ex- posed to from leaded gasoline, food, water, etc. Table Ireveals five features. First, many empirical investigations have been conducted, Second', virtual, ly all the studies have a low or medium score forr epidemiologic quality: Third, 30 investigations (48 Ifs) show a clear positive relationship between lead ex- posure and CVD (or blood'pressure); while nine (14 ro) show a positive tendency. Fourth, a very clear rela- tionship exists betwezn study quality and study out- come. The percentage of positive studies increases as one moves from "x" to "xxxx" as follows: 17, 47, 67. and 100 01.. Fifth~ there is only one study which shows a negative relationship between lead exposure and'CVD (33). The large number of positive studies and the posi- tive correlation, between study quality and studyout- come supports the hypothesis of a causal relationship between lead exposure and CVD. A more-d'etailed examination of the 63 studies in- dicates that they are very different with regard to study destgn• study end points, and'intensiry of exposure. !vtany of'the studies are, eg, ttoss-sectional'investiga- ttons of the relationship between rather low levels of lead in blood and blood' pressure. while others are historical prospective studies of mortality among 246

hea~A% eNposed µor~kers. Ho ' ~e%er, further anal}sts sho%k~ that, both the share ot pocm%r studies and the postti%e trend %ktth increastng,tud> quauts are %Irtuallye the ame when the dittereni t~re: oi studies are ana- I%zed separatel' %. %%hiie the relationship be:ween IoN-Ie%el lead ex- posure and'blood pressure. h~pertension has been dealt %%tth in detail in the earlier, mentioned revlews trom 198' and 1988 t2"-321, studies of lead'workers utth. constderably higher le%els or exposure haLe not. As these studies are of parncutar interest for occupational medicine, I ha\e included st% dealing wtth mortality in m% review. Dtngwall-Fordyce& Lane (64. 661 found increasing cerebrovascular mortalit' v . wtth increasing lead' ex- posure. The standardized mortalitc ratio (Sx 1R') values were 94. 98; an& 160 for emplo.ed lead workers as exe posure increased and 76, 1i76. and 258 for retired1ead workers. respeetisely. A latertollow-up study showed the same trend, but - as expected - converging SNiR' values (65). Cooper, and his co-workers (57-59) found' moder- atelv elevated or, normallSMR ~alues tot cerebrovas- cular mortality in two lead-exposed cohorts (SMR 132 and 93) but elevated values for "other hypertensive dis- eases" (SIv1R 475 and 320) and "hypertensive heart dis- eases" (SMR 203 and 128). Mctitichaell& Johnson (86) compared the mortali- ty of', workers with previous lead' poisoning wit'h the mortalitL of other lead workers and Austratian men in generall Using proportionate mortality ratios, they found twice as many deaths due to cerebral hemor- rhage and'24 Wo more deaths due to other cerebrovas- cular diseases among the formerly, lead~poisoned work- ers than among the other: lead'workers. In a compari- son with.4ustralian men, the differences were even greater. . Da~tes (62) also studied men with previously regis- tered lead poisoning and found an SMR of 410 for cerebrovascular diseases. Selevan et al (93. 94) found fewer cerebrovascultr deaths than expected (SMR 84), but even in tha "nega- tivc"'studv the SMR values for cerebrovascular deaths increased with increasing exposure (<5 years: SMR 17; 5-19 years:,SMR 75: 220 years: SMR 146). Finally: Gerhard'sson et al (40) found an SMR of 130 for cerebrovascular diseases among lead workers. Internal'comparisons showed a positive correlation be- tween both the mean blood-lead level and the peak blood-lead level and cerebrovascular mortality. These six, mortality studies of lead-exposed wort- ers all have a medium level of'epidemiologic quality: However, when the problems associated with histori- cal prospective mortality studies are taken into con- sideration4 the investigations show a rather consistent pattern with increased'cerebrovascular or hypertensive mortality in the highly exposed groups. In addition, most of the studies showed an increased mortality as a result of chronic renal disease. Even though studtes with high methodological qual- Ity! (-YxXx"'or "xxsxx") are few, the followtng con- clusions seem reasonable on the basis of the existing epidemiologic literature: liD there is a causal relation- ship between lead exposure and blood'pressure even at low exposure levels corresponding to blood-lead levels below 30 µg dl h2'. 28. 3E 70; "3. 74, 106t. and, even if the relattonship is weak, this relationship may ha.e considerable public health implications due to the widespread lead exposure throughout the industriall ized world (32. 72):'(ii) there is an increased'incidence of .erebrovasculhr diseases among workers who have been occupationally exposed toJeado but the c(anfi- cation~oG the dose-response relationship is not possi- bie on the basis of the existing studies: (iiif no studies have been found in which the incidence of ischemic heart disease (dHD) increased as a result of lead'ex- posure. Cadmium The relationship between cadmium and CVD has been treated with considerable variabilityy in general reviews on environmental exposures and CVD. A few authors dealt with the topic rather extensively (6, 10; 11. 13), but none gave more than 10 references. Others men- tioned the possible relationship between cadmium and CVD but treated the topic very superficially (1, 2, 5), while the remaining authors did' not mention cadmi, urn at all (3, 4, 7-9, 12): In those articles in which the topic is discussed, it is concluded that the ques, tion is not sufficiently clarified and that further re- search is nece3sary.. In the special reviews on the associations between trace metals or cadmium and CVD, the possible rela- tionship between cadmium and blood pressure is treat- ed exhaustively by all the authors. In the older, reviews from the 1960s and the first half of the 1970s, there is generally a betief in the hypothesis of a cadmium- blood pressure relationship (16-19, 108-110). Among these reviews, Schroeder's experiments on rats in the early 1960s play an important role. From 1976 on, skeptical articles and reviews (20. 23. 111-116) alternate with, more positive ones (U17-119): Con- sid'erable agreement exists regarding the relationship between cadmium exposure and increased blood pres- sure showmin animallexperimenu with rats, dogs, and rabbits, but there is no consensus on the interpreta- tion of research on humans. After more than a quar- ter of a century of research comprising hundreds of experiments and inveztigations. Spieker et al (116) con- cluded in one of the most recent reviews: "The data available up to now [about the connection between hu- man hypertension and'cadmium polliltionJ can only be considered as a fursnstep to clarify this problem [p 35)~'. This is, indeed„a modest profit from~such great efforts. In the present review, 33 investigations of cadmium and CVD (mainly blood pressure/hypertension) have been evaluated. In 11 of the studies, cadmium in blood! 247.

urine, hair, or kidneys has been compared for live hvpcrtensi.c and~normotensn:e persons. In nine studies persons Nho died from hypertenslve hearn disease or related causes hase been compared with persons who died~ of other causes. ln these studies. the cadmium conieni uas ¢enerally measured from the kldneys or Iner. Fne studies are cross-sectional investigations oi represcntati~c population groups fonwhich the blood pressure ha5 been related to cadmiumdn blood or urine. Four studies ha.e related cadmium pollution in cari+ ous nty areas to morbidiry and mortality, and the last four are occupationallmedical studies. Table 2 contains a surney' ofthe results and qualit% of these studies. The table indicates the following: (i) the studies examined have, in general, a loµ epidemiologic qualny, and none of the studies have been rated "zxxx'" or "xxxxx"; (ii)113 of the studies (39 0'o) show(a tendencytowards) a positive relationship (• or (+ IJlbetween cadmium exposure and CVD: and (iii) there is a negative rela- tionship betv.rcn study quality and "positivir)." Of the studies with a rating of -x," 46 4rro were positive; of the studies with a rating ofi"zx," 44 ro were posi- ti.e: and of the studies with a rating of "xzx," 27 °b~ were positive. Both the low share of positive studies and the nega- uve trend in the table speak against the cad'mium-CVD hypothesis. The conclusion therefore is that the null hypothesis is best supported by the investigations ex- amined. The methodological level of the research, on cad- mium and CVD (especially blood pressure/hyperten- sion) is so low that an identificatiomof the most com- mon errors and flaws is important to facilitate their avoidance in future research. One of the worst prob- lems concerns the measuremenuof cadmium exposure. Many studies estimated the exposure by measuring cad- mium in blood (77„ 80, 124, 137, 138, 140, 141, 148-151, 153): The blood cadmium level is, however, not a very reliable measure of the cadmium body bur- den. As early as 1976, Morgan (155) wrote: "Blood and urine'may be convenient fluids to measure, but neither is well correlated with kidney or liver content, which together, comprise about, one half of the body burdem(p 1361 j." In contrast, the blood contaiits only Tapbe 2. Resuns of 33 eDfaemfotopic studies orcartlfovascu- tar oiseases ICVD) ano8a0mfum exposure according to t1U metnod0i0p.cat Ouaiity ot'tfie stutlres. The taDte fs luseO on references 55. 77, 80, 95-p7, 1U7;,1'20-15r. DaQtN of .aufOnsn,a M.fflOpp/oq,cal eya/ny. _ ,:ii[ _-._[ N. % N % N N. N % f-i 0 -3 2,30 4, ao t tt., 1t1 0 3 23.1 ]33.3 S U.5 u17.3 f.f 2 t6• - o 3 273 5 152 4 70.e a ua_ 0 8 ]a29. 4 30 e - o - 0 4 1211 Totai1 13 1100 a too. 111 100 33 1(70 •$H taD14 1 1101 an e=Otana110n Of.tM er/10dll 6: L°`o ot the body burden. Morgan recommended mea- suring cadmium in hair. kidneys, or llser. This ~leµ is stron¢Ih supported b% other experts. including Lauwerys (11:) and Perry & Kopp (1 19). Several studies have emplo" yed cadmium imurine as a measure of past exposvre. but, this measure must be regarded as ban¢ estnipoorer than cadmium in blood (77. 95, 107. 138. 144. 153). Se.en of, the 13 positive studies in table 2 ha%c emploved cadmium in blood or urine as the measure of exposure. Two of the remaining six positive studies employed the cadmium content in air in a number of American cities as a measure of exposure. The results were then correlated to CVD mortality, and a posati.e relation, ship was found (131, 13'2)1 This method is problemat- ical for many'reasons. For example. r,he influence ofi cadmium in air on body burden is very slight. The stg- nificant factors are food, smoking, water, and occupa• tional exposure. Another, major methodological problem concerns the study design employed. Many of the in.estiaatlons employed a "quasi case-referent" d'estgn tn wh,ch sick persons (wtth hypertension or IHD) were compared to healthy referents (77, 123, 124, 128, I30; 133, 140--142, 14s-154). These studies are called "quasi case-referent"' because in reality they are cross- secuonal studies in which "disease" (hypenension, for example)iis measured simultaneously with "exposvre"' (forexample, cadmium in blood). Thisd'esign is prob- lematical for seseral reasons. First, because blood pres- sure and the blood'cadmium levefare measured simul- taneously, it is not possible to exclude the possibility that thcdirection of causation is reversed, ie, that per- sons with hypertension have aniincreased content of cadmium, in their blood due to metabolic changes. This possibility has, in fact, been mentioned by several'l authors, and one study directly concluded that hyper- tension increases the blood'cadmiumilevel (14'I). Sec- ond, in most studies the selection of both cases and referents has been described very superficially or not at all. Since selection is of paramount importance in ease-referent studies, this is an important potential flaw. Third, in many studies, the researchers had matched for smoking habits, and this is an error as tobacco smoking is not a risk factor for Fiytxrtension. 1'.n reality, it is overmatching because an imponant source of cadmium in the bodyis being blocked! Con- versely, relative weight and eduution/social status have not been matched, and such matching should be done since both~ are risk factors for hypertension. Fourth, comparing normotensive and hypertensive per- sons leads to dichotomy. Instead, one should rather have operated with the whole spectrum of values on the blbod'pressure scale. This problem is especially im- portant because many authors have hypothesized that the relationship between cadmium exposure and blood pressure has a reversed lJ'shapewith the largest effect at medium-high cadmium exposure levels. L"

FolioNmc rhu :nnque of inethodplop. and turn, tng back to the cmpirncal studies, I found onk three posiu%e stud+es whtch measured the:admtum contenr of the kidnets nlZ8. 1'u:. ls"), These three itudtei are oi~tht "aua, :3i2 re'trent" r~pe justidescribed and ha%r ,) man% me:!i,doioet:at trror, that the\ onk„ored "\' or "\\" for methodological qualrt~,. Thus !ht~ :_r bt :on,;der_c'.o ^r or onk .en lutl'e ,t_e- ntftc3n;e Onl% :hr-e:^~tsui:3nun, ha+e been faund whtch are not "quast a-e-reteren;' and~k%ht:h.do not mcaiure cadmium in blood. urtne., or air. te. the historical proxpe:n\e mor;3ltt~ stud+ of '000 Norkers b% fiazan!_>!s e: ai the historical prospecn~e mortalu% itud% of 525 workers b\ andersson etia! t I3a. Ii351: and'the +anous prolects concerning the Shipham inhabitants These three studies scored "\.>"' for menhodolbgtcal quality, and one of them - the Shipham stud.% - ihowed4 Keak positive rela- toonshtp betNeen cadmium and CVD. while the !wo occupational studies showed a Meak negatt+e relatoon~ ship. Thus the conclusion seems clear, te- the eptdemio- logtc research.aan in no µay be considered to support the hypothes:ts of a causal relationship between cad- mium exposure and~hypertenston or CVD in general. At this point it seems reasonable to conclude that such a relationship does not exist. Over the past 25 years. although the number of studtes tn thts field'ihas grown annuali' v. the bod% of knowled¢e has not. Despite the last three studies menuoned. there tssuB a great need for eptdemiologtcall\ sound studies on this toptc.. Finallt,, tobacco smokers are moderatak exposed to cadmium and should therefore hate increased blbod' pressure. But the cardiok ascular eptdemtology shows %ery, aearl~ that tobacco smoking is notia risk factor for hypertension. This lack of relattonshtp, which has been epidemiologically ,en thoroughly investtgated, is a further argumentaeatnst the cadmum-blbod pres- sure h+pothesis. Cobalt Inahe mid'•1960s, an epidemic of cardiomyopathies was registered in Belgium. Canada, and the United States among hea\} beer d'rinkers. The cause of the epidem- ic was relatively quickly established. Several beerr manufacturers had begun to add cobalt sulfate to the beer imorder to stabilize the foami(156-1,61). Nearly half the patients examined in the various studies died from their cardiomyopathy. In is paradoxic that the consumption of 6-8 mg of cobalt sulfate per day could have this dramatic effecu as cobalt has been used in medicine in much higher doses without adverse ef- fects. There seems to be agreemennthat the genesis of this unexpected adverse effect was a combination of cobalf exposure, long-standing high alcohol consump- tion, and poor nutritional condition. In the general reviews on CVD and environmental exposures. the cobalt-related cardiomyopathies among beer drinkers has been mentioned bv several authors (_'. 6. 9-I1 I, whdc the rematntng rertews do not:men, uon ;obalt as a risk factor for CVD at all. In addt~ uon. two case reports have been mentioned in a few ofi the re% tews:. te. those 6y Barborik & Dusek (i1d2) and F:ennedy et al (163)i These case rrports descrtbe two cobalt-erposed men /slland 48 yearsofiage) who both died from :ardtomyopath% . The authors sug- gesaed'thatcardrom%opathy caused'b%- cobalt exposure miaht often be neglf cted and misdiagnosed. In addttton. three eptd'emtologii; invesugattons of cobah-c\posed workers wcre found'. In 11980 and 1983, Alexandersson & Atterhog ('164, 165) published a study of workers in the hard~metal tndustry who Nere oc- cupataonallk exposed'ito cobalt lexposure level 0:01- 0.06 mg, m'I. The 146 exposed workers wrre compared to an unexposed reference group with regard to elec- trocardiography, pulse rate. and'blood pressure. For, the cobalttxposed workers, Alexandersson & Atterhog /I164) found' a higher prevalence of hypertension, a higher average blood pressure, and more abnormal electrocardiographic changes. The electrocardiographic changes proved to a large extent to be reversible (165).In an abstract from 1985, Horowitz et al (',166) , described cardiac manifestations of cobalt exposure in a group of 35 self-referred hard metal workers. Elec- trocardiographic abnormalities were found in 16 o7i the 35 workers. The third study is a Danish investigation of female porcelatn workers exposed to cobalt blue dye in their work Id!671. The median cobalt concentration in the air was 0.80 mg> m'. When the exposed women were compared' with an unexposed reference group, no differences were found with regard to electrocardio• graphic changes or blood pressure, but a higher aver- age pulse rate was found in the exposed group. The authors had no explanation for this finding.. Despite these empirical studies from the 11980s. a need still remains for more and better investigations of the relationship between occupational!exposure to cobalt and heart diseases. In light of the widespread use of cobalt in industry and medicine (1160), it is sur- prising that most of the literature deals with a brief epidemic of cardiomyopathy among beer drinkers. Arsertrc In the general reviews on cardiovascular diseases and envtronmental exposures, arsenic and arsenic com- pounds arementtoned in seven (1, 2. 6, 9-111. 13) but nor in six (3--5„7, 8, 12). The seven, reviews which deal wtth tlie topic include two to nine references to empirtcall studies. In Landrigan's special' review on health effects from arsenic exposure (168), the cardio- vascular effects were treated very briefly. Three epidemiologic studies of arsenic exposure and CVD ha•e been,found. Pinto et al (169) investigated mortalhy among 527 retired workers from a copper smelterv during the period 1949-1973, while Lee- Feldstetn (170, 17IV studied a cohort of more than 249

f 8000 men during the period 1938-19". Aselson et al't1"_I conducted a case-reierentstud~ in uhr4ti the evposed~pcnsons uere also copper smelter% workers.. !n alllthree itudres. the exposure Kas arsenic traoxtde. Ih :he t%%e historical prospecune studies. sllghtl% ele- %ated S\IR %alucs %%ere found ior CVD Pinto et all tound a•• alue oC !!C)9 for IHD and 113 for stroke. W hrle Lee-Feld', tern iound'S11R %alues of about 130 for IHD and abuut 1_0 ior ctroke. In bothistudies. a compari- son %%as made \% ith,rhe mortaitn experience of the rest oiithe population in the area. In the stud\ b\ Axelson ci all vhtch is the best of the three ("tx!cx" for methodological qualits t. an increasing relatt.r risk for heart disease Nnh increasing arsenic exposure was found (risk ratio 0 7, 3.0. and 5.6 for three exposure groups), The study by Pinto et al'scored "xx" for, methodologtcallquality, while the Leo-Fcldstetn study scored "rxt." Thus in these three irr.esttaations. clearer e% idence for a relationship between arsenic ex- posure and C\ D w as found as the quality of the studies increased.. Furrthermore. arsenic Has pan of the mixed exposure in Wingren &ALelsonfs case-referent studies on mor- tahtv tn,the 5.%edishiglassworks industry (52. 53). In these in+esugauonsa slight increase in CVD mortali- ty was found. In addition toahese studies of exposed workers, there ha%e been reports of a relationship betstieen hieh les- els of arsenic in drinking water and the de~elopment of both heart disease in children of northern Chile and' peripheral %ascular disease in adults from Taiwan ('1). A special "arsentc beer scandal" took place in Man- chester in 1900„when beer was accidentallv contami- nated µith arsenic. More than 6000 persons became ill and 70 died, almost all from CVD (2. 156). The relationship between another arsenic com- pound. arsine, and heart disease has been described by Pinto et al (173). This studydealuwith 13 poisoned men, of whom four died fio^ acute myocardial in- farction (AMI), while electrocardiographic changes were observed in the remainder. As far as is known, no epidemiologic studies have been conducted'on the relauonship between arsine exposure and CVD. E%en ifthe total epidemiologic research concerning the relationship between exposure to arsenic com- pounds and CVD is limited. a causal'relationship is still Iikely: Further research is needed to clarify the rela- tionship between the level'and duration of the exposure and'the risk for CVD. Carbon monoxide The relationship between carbon monoxide (CO) and CVD is dealt with iniall the generalireviews on CVD and environmental exposures(1-7, 9-13) except one (8). In a few of these reviews (1, 6. 10), the topic has been thoroughly, treated, and many references have been discussed. Naturally; no disagreement exists on the potentially very ser.ious consequences of acute high exposure to carbon monoxide, especially among per- 250 sons t~rth emstrneatherosclerosis, But there is:onsrders able uncertatnt~ and ;ontltcung %rc%ks about the poc- sible ,rgnrfJcan4e or carbon monoxide exposure in the d'e% elopmenv o( atherosc lerosis.,A iew rc~ie%% s :om cluded. ~%ithout an% iurtherdocumentatuonr thar,ar- bon monoxide increases the risk oi IHD 1'. 121' Others presented~ a more .aunous point of ~ reW .k% hich can be illustrated bp k% a% oi the rollowrne aireequotatrons "ICOt ma. prectprwte Askll or senous arrh%tFimtas m percons %kith pre-evistrog :oronar~ atherosclerosis p I!' ," t>1. " tie queinon ot .%hether CO is athcro¢en,c remains unan%+kered e%€n at the bas+cscren.e le~ell,p I'219!" (3). and "there is surprisan¢ly little e%tdence for a chronic atheroscderonc effect of CO [p'_19J" tl 1) . Ih addtuon to these general re.ieHs. there are man% special rcvicr%s on the negau.ehealth effects ofcarbon monoxide exposure t 171!-1891. The~ contain detailed descriptions oi thepn.stological mechanisms K hr.h,re- sutt irom the rormauon of carbo\%hemoelobrn rn blood and'ipresent the results of many ammalle\per,- ments. I!NiIl not drscuss these topics in the present re- % itµ: rather n should'srmph be stres;ed that the de- crease rn the o\.%gen..arrnmg capactt\ of the blood is grcaterthan ,uagested b\ the pcreentage of carbo.%- hemo¢lobrn because of the reduced release toithe tis- sue oi theo\ygen carried by the remaining hemoglobm. The spectfic resieNs on,carbon monoxide and health do not agrer on the role of carbon monoxtd'e rn the etiology of CVD. The most "posru.e" revre%%s are probabl\ the ones b' v .AronoK (171, 175), Goldsmith & AronoN t l'-1. and' .3tkins & Baker I 1'61. %% hrie others are skeptical (179, 182. 168): In the remaining re.iews no clear position is taken, .4mon¢ the most skeptical re.tcM^s, wiir & Fabiano's critical reevalua- tion from 1982 (d!8B), should be emphasized. The authors carry out an explicit and thorough discussion of the evidence for a causal relation between carbon monoxide and CVD They specify the "'. .. three ques- tions that best define the current areas of controversv: (i) Does chronicrrposure to CO influence the d'evelop- ment of atherosclerosis" (ii) By what mechanism does acute exposure to CO reduce maximallexercise ability in, healttiy persons and in persons with pre-eeisting CVD? (iii) Does acute CO exposure predispose in- dividuals to cardiac arrhythmias7 [p 520[." In the evaluatton of the empirical evidence for a causal rela- uonship betweenicarbon monoxide and CVD, it is im- portant to keep these three questions separate, and I have attempted to do so in the following discussion. For the present review„22 empirical'studies have been selected. Of them, most deal with persons who hass been exposed to carbon monoxide occupation- ally, such as firemen, policemen, toll booth operators, garage personnel, motor, vehicle examiners, bridge and tunnel officers, foundry workers. and blast furnace workers (190-210). (Reference 205 has been classi- fie&as two studies.) Four of the empirical studies are not epid'emiologic in,the strict sense, but ratherexperimencal (190-193).

In these rour ~:udie~. %%ti ch are %ern similar. 10 men wuh aneina pectorn< %%ere e\pocad to dttfercnrconcen. tra::am o+ arbon monr.,de.,and the duration of es- rro•e be;ore :hr on<e: oi paini%ta, registered All four ,n+r,t„tatton• :ound ;tia: the nme be(ore the onset of rain aa, •t.n3(i;an !.hor:rr a;ter r\po,urc to car- bun monomdr r~ :a %%icn :hc ;arbo\%hemo¢lobtn It%el kta• onl% _ anou: I ', hi,thrr in :hr evpo,ed', rtuauon than in :hr ;uniroll ,tuation 1193). Thece re.ulr- ;ould ho\e been espected because the angtna pattentc alread> had IHD. ~e%errheless, these e\pentments ~aress ho%k dangerous an increased car- bos\hemoglbbtn ie\cl :anibc ton thts group of patients., as the pre%alenea of IHD is high inithe population. and as exposure to carbon monoxide is common - predomcnantly through smoking and esposure to the e\haust fumes flrom cars - this is a frequentll occur- ring risk situation. Tt%o studies .ompartng the daily incidence oideath from t'HD Ntthithc letel of carbon monoxide in the air :anibe sai&to elucidate the same complex oflprob- lems (195. :09). (n,one. the e\pected relationship %%as found betttren carbon monoxide le.els and fatality from IHD. t%hile the same relationship could not be sho~kn in the other. Both studies had a low methodo- logical quality. %k. hile the aforementioned studies pro%tde et idence of the tntauence of acute exposure to carbon monox- ide onipersons %kitti tscfiemic heart disease. the rematn- intt_ studies hake tried to elucidate the role of carbon monoxide for the deselopment of atherosclerosis.,Ta, ble 3 contains a sura% of these 16 studies. Table 3 ik lustrates the follotktne two points: (il most empirical studies on this topic hat e a Ibw methodological quali- ty ("<" or "rr"), and tiit there is no relationship be- Meen study quality and study outcome, since half of the poor studies ("r" or "rr"),and'halGof the better studies ("trx"'or "tzxs") hate a positive study out- comc [ - or ( - I I The bes) support for the hypothesis ofa relation be- tt\een chronic carbon monoxide exposure and the de- .elopment of', atherosclerosis comes from three posi- tite studies rktth °'rxst" or "ttxx" for quality (201. :0B. :09). A closer examination shows, however, that not eten these studies support the hypothesis veryy clearly. The cross-sectional'study by Hernberg et al (_01)lon angina pectons, electrocardiographic findings. and blood pressure among foundry workers found a relationship between carbon monoxide exposure and' angina pectorts bunnot betueen carbon monoxideand' _._ctrocardiographic findings indicating IHD. Funher- more, slightly higher blood pressure was found among the persons exposed to carbon monoxide., but this finding could ha.e possibly resulted from exposure to heat radiation. Altogether only the relationship be- tween carbon monoxide and the prevalence of angina pectoris wastonvincing, and this relationship does not necessarily support the hypothesis of a lasting effect of carbon monoxide. The older of the tw o studies b- ~ Stern et al (2081 found an S%,1R of 105 for C'k D amon¢ motor %ehicte examiners Clbser anai.ses .ho%%ed than the excess d'eaths occurred among cwminers uarhizero to ntne >ears of exposure ISMR for CX D1l_31 There µas noo increasc in mortaiita among the e.amtners N1th (onger exposure. The more recennof the tn+e,ttaartons b% Stern et al (:09). %.hich con,:erned brtdQe anJ'.tunnellcirfi:ers in \c%% York Cit\ . is probabi% the best epidemtologtc stud%. of carbon monosid'e and Cl, D e%eri published. The studq sho%%ed'srgnrficantl.% h gher IHD mortaltty among the hea~uh,erposed tunnellofficers than among the brtd¢e officers. Nho had4 lokk le%el of exposure. Hoaeser. there was no relationship to the duration of the erposurc. and the excess mortality among the tun- nel officers disappeared in the aourse of a few years after the cessation ofl exposure. This pattern closely resembles than seen in studies of tobacco smokers. in which the increased risk for IHD disappears relative- ly quickly aften the cessauoniof exposure. This pat- tern d'oes not fit the htpothests of a lasting atherosclerotic ef fect ofI carbon monortd'e exposure. In light of the many studies on tobacco smoking and CVD, it is surprising that it is still not kno%%n Kh}~ smoking increases the risk for CVD. A cross-secttonal' stud± by Wa(d et al (210) 'is often quote&to show that carbon monoxide increases the risk foratherosc(ero- sts, but a later, - and methodolo¢ically better- case- referent study by Kaufman et al (203) shows that the carbon monoxide content of cigarette smoke is un- related to thc risk of IHD among smokers. All things considered, there is thus %-0ry little - 1f, anyatitng - in the emptrii:al,studtes referred to which supports the carbon monotide-atherosclerosis hypoth- ests. !n the literature, tho animal experiments by the Astrup-Kjeldsen group have played a large role, as these experiments apparently showtd increased' atherosclerosis in rabbits exposed to carbon monot- ide. However, the group published'a reevaluation in 1978. In these new investigations (211), they were not able to confirm the original findings, probably due to the fact sharthe original studies wene carried outwith small sample sizes and were not blinded. Several Tapte 3 Qesults of t6 eo aem otoqic stuolas of carGaovascu- tar O~seases.~CUDi and carpon mono=ioe taDosure accor0inp to tne.rnetnoOOiopicJt Ouapty otthe stuONS. Tirye titHe is.DiLed or. reterences 194 196-210 peqree ot' Mernoaaiop-cai ouat ty retat'~~sn'~~a ss a=: ssss Total t- t 2 0 2 t t . -t t t 2 3 t t 6 2 2 Tota; 5 5 4 2 t6 ' See +ao4e troran eaptanaUOn of tM syRNbObs. 2S1i

reviews. unfortunarelk. appear not to have been aµare of this ree~aiuataon. Re¢ardtng the first of N1 etr & Fabiano's three ques- tlons, quoted on page _'0, the iolloKtng conciusions canibe dra%%n (11 there is no relationship between stud> qualtnt and support for tAe h)pothests; (ii):%ery fe%k studies are or filehimethod'olo¢tcal quality. and these s;ud,c, g1ka altnoit no support for the hypothesis; and~ t iii l the research group behtnd the animal experiments most ~ii[en auoted in support, of the hypothesis has %%Ithdrawn its results in ~tew of established flaws In stud% destgn. Thereiore. one can only concur with the conclusion of Werr & Fabiano "that there is no e% ie den.e to support the suggestion that exposure to low to moderate le% els of CO increases the rate of the de- %esopment of atherosclerotic disease inman. We be- llese that suffictent evidence is available to support the conclustonitha[n in fact. CO is not of pathogenic con- sequence in atherosclerotic disease [p 523)7 (188). Concerning the second of the three questions menr tioned. " mr & Fablano's conclusion also seems well- founded: "Acute exposure to low levels of CO does result in reverstble. nonprogresst+e, exercise perfor- mance decrements in healthy and diseased tndisidu- als ('p t_3]r' 088). In the present re.iew, I have not examined studies on carbon monoxide exposure and cardiac rhythm, Therefore. I refer the reader again to Weir & Fabiano, who concluded: "ln summary- exposure to CO an acutely toxic levels results in, alterations of cardiac rhvthm, pnobably as a resulii of the induced'hypoxta. There is no constnctng evidence available to suggest that exposure to low to moderate levels of CO affects cardiac rhnthm [Ip 5231f' (188). Even if these conclusions on carbon monoxide and CVD seem welkfounded. there is still a need for fur- ther - and better - research in this field. !n the cpidemiologic area, there is specifically a need for the following: (i) prospective studies in which both the ex- posure and the development of the disease can be fol- lowed (none of the existing studies have been prospec- tive), aod (filstudies in which carbon monoxide is not ani integrated part of a mixed exposure. whlch 1; nce case t%lth cigarette smoke. exhaust, fumes. etc Passive smokrng Passatc smoklne has not been mentioned irra any o( the general',rettews on CVD,and-en.tronmental c\- posures. paralp due [o the fact that almosa all research on passive smoking and chronic diseases - tnci'udtn¢ lung cancer and CVD - has been conducted durln_e the 1980s Most oti the literature on passt%e smokrna and CVD has, on the other hand'. been rc%te%%cd in three thor- oueh reviews on the health effects o[i passl+e smok- mg.at, the Surgeon General"s report (212), the report from the National Research Councill (2311 - both from 1986 - and Fielding & Phenow's revlett from 1988 (214): These reviews alllconclude that furtherre- search on CVD and passive smoking is needed. The most important information concerning the studies which have been published currentlti on IHD and passive smoking is shown in table 4. These studies ha.e all been published'durung the pertod 198z-1988 and are all based on a comparison of the incidence of 1,HD in nonsmokers marned to smokers and nonsmok- ers married to nonsmokers, Five of the studies (C15-220) are prospective cohort studies. Khlle the Irist, one (2.1) is a case-referent studN. As shown in table s, the <' aes yielded'inine esti- mates of relative risk. These esl,::;a[es varied from 0.93 to 3.25 with an accumulation oi values in the area of 1.24 to 1.31. The median relative risk for all the studtes was about 1.3. and it is also approxtmateliv 1-3 when only the better studies ("xxx" or "xxxt" for qualityl are considered'separatelti. Only few ofithese relatise risk valhes are significantl~ different from 1.0 when they are regarded indisiduall.. Howc~er. Lamt inithis paper, more interested in the total pattern that appears when the studies are viewed as a whole. A relative risk of 1.3 for passive smoking seems high in relation to the relative risk of about 2.0 oftenimen, tioned for active smoking. Whencomparing the two Teble 4. Aer,ewotthceproemio/oplc stuotes on rscnem,c.nean olsease ttMDl ano passwe smokinp Stuoy Stuoy Oesrpn PoDu/at+on Mirayama t215:.2161 16-ywar fO1low,uD Gfllis et al1(217) 6- 1011•yearfo/1ow.uD GananO et, afl(116) 10-year lollpw•upSwenosen et at (2191 10-year tollow-up Me1s.n0 et at f220) '. 12•year' follOw•uD lee et, al (221) Case-referent stuayofGatrents 91 450 women~ 627 men 1 917 women 695,women 1 245 man A 162 men 14 $73 women At male IMD pathents ano 133 referents 77 temate IMD Dat+ents anC 316reterents Stuoy oualrty AR for IMD- rr 1L24 rr 1.29 3 25 urr 2 7 arsr 1 61 sar 1 31 1.24 aiz. 1 24 093 •Tne Cnteria for metlippolopical Oualily, are erDla,ne0 in the te=t ~ Relalrre rtak for.IMD among nonsmokers marrre0to smokerSCOTDareO tOnOnsmokerT matneo fOnonsmokers 252

%alues. one should keep tn mind the follot%mg three fa,ts~ ttlithe relgnse risk foractr.e smokers is usuall, "i,ulated %tith nonsmokcr; a, the reference group:tm;: nun<mokers are almost.al;says passise smokers. and~ noi raaily unespo;ed. too low a relattse risk is %te:d:J ;ora:uvr ;moktna: uu ce+eral :tudtes tndicate thacthe mar¢tnal effe.a per ;iY3rette on the risk for IHD t, hizht;t a~ a lo" Ib%rl.of consumption and is thus not linear and', tuur main;tream and side- ;trtam ,moke contain almost the same components- but, not in the same proportions. One does not knoM %.h.~ o¢arctte smot.in¢ increases the rtsk for IH'D: therafore- n ts dirfi,:ultto extrapolate dtrectl+ from ac- tne to passi%e smoking. In e+aluatmg toda> "hether there is an increased risk ior IHD among passi;e smokers. the biegest problem is not the statisucal, uncertaini or other methodoloe- tcal difficulties. In fact, the studies in table 4 are of rather high quality compared M1th the other research referred to in this article. The greatest problem must be assumed to be a possible publication btas. as it can. mtth some justificanon, be claimed that negative studies Nere of no interest until a number of positi%r studies were recently published. Therefore. more methodolbaically good studies of' IHD and passive smokine need toibe carried out and to bo published' reYardless of the result. In addition to the aforementioned studies of IHD, and passi;e smokine„there are sesrral in.estigations addresstng the time lag before the onset of pain in an- gina pectoris patients exposed to passive smoking or, carbon monoxide. These in%tstiaations have been re- terrtd to in the section on carbon monoxide since the increased ltvel of, carboxyhemoglobitt is very proba- bly the factor which provokes the earlier onset of an- gina. Finally. an abstract Kas published in 1987 by tiloskowttz et all(2_'3'1. It claims that passive smoking increases the risk of 1HD among pubertal boys. E%en if more studies on passive smoking and IHD are itill needed. it is now reasonable to conclude that the studiespubGshed hast a high methodological qual+ itc. that the results are relatii.ely consistent (relative risk for 1HD about 1.3), and that a small„but increased risk for lHD is biologically plausible. Orgpn rC SOl rerrrS A feu of the general reviews treat organic sollents thoroughlr..• (1, 2. 6. 10)t Others treat the topic more superfictaili (3, 7, 9. 11, 13), and some do not men- tion it at alli(3. 5, 8. 12) In those reviews in which the topic is dealt with, most of the emphasis is placed' on the halogenated hydrocarbons (perchloroethylene, Irichlbroethanet trichloroethylene, fluoroearbons, methclene chloride, and'other solvents containing chlo- rine, fluorine,bromine or iodine) Most of the studies mentioned have co%ered acute heavy exposures result- ing in arrhythmia or sudden death. Cardiovascular effects ofexposure to organic sol- vents have also been treated in several special reviews Retnhardt et al (_2S)',,oncluded that the sudden deaths tn,eonnection Nrth acute hea%\ exposure to.ohents uere due to %entnculhr ftbrtilanonidue to sensitization of the heart to eptnephrtnc. The re>iew bt Retnhardt etal also included a surve\ in Khtch the sol%ents were eAaluatcd according to cardiac sensiti- zation properties. The most acwe group contained', benzene, heptane. chloroform and trtchluroerh' vlene. Steffe>'s reN iew t2.61 of the cardto%ascular effects of rnhaling anesthetics is ~ern thorough. ltsting'_01 refer- :nces. I'n addition. the res ieµ by Zakhan & A.tado (.Z'Jion the cardto+ascular toctcolog~ of halogenated hsdrocarbons is both tnoroueh and' comprehenstFe (218 references and a sen useful appendix wtth chem- ical formulas and properttes)'. The empirical basis for the aforementioned re% iews consists primarily of animal experiments, which I have not discussed'in this revieM, several case reporas, and' a feN epidemtologic studies. There are tMo types of case reports. Thoy deal with exposure to very high,leveis ofisol~ents either in con- nection with glue sniffing or iniconnection with oc- cupational exposure. Gluc sniffing has prtmarily been practiced by teenagers (2241 228'-232), and many sud'. den deaths ha~e been reported~in both the United'States and the United~ Kingdom, although, a clear under- reporting is like)y since no anatomical changes can be observed in deceased~ persons.. In some of the cases described, the strongly affected young "sniffer" stood up, started running, and then dropped dead (228). The occupational case reports deal! with, workers who, in most instances, have beenexposed to very high levels of solvents (231, 233-237). Most, of the case reports concern the sudden death, of' healthy men 20-50 years of age after exposure to chlorinated sol- vents, but also after exposure to benzene (234) and' methyl-celiulose paint (233). These case reports have manv features in common- and several of the authors suggest that underreporung probably takes place with respect to this type of exposure also. In addition to the case reports mentioned, five epidemiologic studies have been found (238-242). They were published during the period 1975-1988, and there is no indication of increasing research ac- tivity in this area despite the increased interest in or- ganic solvents. The methodological quality score for these studies is medium ("xx" to "xxxx"). Speizer et al (238) studied the residents in a hospi- tal pathologydepanmentwho were exposed to fluoro- carbon aerosols during the processing of cryostat sec- tions and used radiology department employees as Ihe reference group. They found a much higher prevalence of palpitation among the pathology residents and also a dose-response relationship between exposure to fluorocarbon 22 and the prevalence of palpitation. Moreover, resting electrocardiograms and' 24-h elec- trocardiographic monitoring indicated premature atnal contractions, paroxysmalatrial fibrillation„and an in- 253

;rease in preTature %rntncular, bbeats. These results %%ere unc\peaed :n a group or %.oune. healthn adults Kramer e; al i_79t ewmtned 141 industrial workers t%ho had been crposed to I.I • 1-trichloroethane and 151 man:hed re:erent, There "as no difference wtth re• gard to ela:;rocardloeraph% . blood pressure, or serum ,hol'e tersil'. Most cit~ the persons e\amtned were %%omen. and most %%ere belot+ 35 sears of age. Blair et al I.10Leramtned the distribution ofcauses of aeath amon¢ ? 30 deceased dr} cleanine Norkers e\- posed to tetrachloroeth% lene. For C\ D. a proportion- ate mortalttn ratio ol"9 was found'. stgntficantly less than the "etpected" %alue of 100. The proportionate mortalft\ ratio has %~ell kno%% n limitations, an& this negati%e stud'y only sa.orcd'"xx" for study qualit~r. In the histortcal prospective stud) by Wilcosky & Tyroler (211 !. the mortalin of 1284 workers etposed~ to se%eralld'tffcrentisohents Kas analkzed. An excess frequenc%at deaths from IHD was found among workers who had been exposed to carbon disulfide. ethanoll and phenol. Finally. Eskenazt eral (.4:) studicd the pre%alence of ad~erse pregnancy complications among 90 Nomen exposed to oraantc sol>,ents an& 180 unexposed matched referents. The> found a significantly higher proportton of women with preeclampsia (a disorder of pregnancy characterized by hypertension. edema, and protetnuria) and hypenensiomamong the exposed women. These epidemiologic studies are %ery different with regard to exposures, study design, and study end points. Therefore it is not' possible to draw any con- clusions on the basis of thesc investigations. No studies of occupationallmortality have found increased CVD mortalit% among painters or other groups exposed to organic solvents. It is, therefore, not very likely that organic solvent exposure at moderate levels increases the risk for, CVD. Carbon disulfide Carbon disulfide has been mentioned and recognized as a risk factor for IHD in virtually all reviews of CVD and environmental exposures published during the last 20 years. As will become apparent, this unique scien- tific consensus is primarily due to the Finnish study of viscose rayon workers, which was conducted by Hernberg. Nurminen, Tolonenl and their co-workers. The first researchers to call attention to the relation- ship between carbon disulfide and IHD were Tiller et al, who in 1968 published their study of mortality among viscose rayon workers exposed to carbon dts- ulfid'c (243). It actually consisted of two studies. one of the proportion ofllHD deaths among workers from three factories, and the other a historical prospectove mortality study of a cohort from one of the factories. Both.studies showed a positive reiatlonship between carbon disulfide exposure and 1HD mortality. The results from the study on Finnish viscose rayon workers have been published in many articles during a t5-vear period (.-W-:53), Furthamore. the ,tuJ', has been used4s a pedagogtcallexample tnione of rhe fe•k te\tbooks on the eptdemtolo_e> of occupa~ionali meJicine The studs s%as a I5-~ear follb%% •up ai two cohorts uith 343 men in each. The stud~ ;ohorn was exposed~to carbon disulfide in aviscose ractor%. but otherwise resembled the reference cohort. %ktit;h worked at another factorn in, the iame tov,n. Atter, about~ fi%e.ears or folloN-up. a relan.e risk of'.6 for coronar% deaths "as determined fur the e\posed group This findine resulted in se%era+ Jtfferent inter%ennons to reduce both the carbon disulfide le%efand the e\- posure of the indt~tdual workers in the ~tscose tactor\. Eight %rars afterthis inter.ernton the relattse rt*k ..as approttmately one (.;8).. This exemplary epidemiologtc studk %%as scored "rxtrx'' forquaiit}. It is a prospective stud\ o%tr If years Ktthigood confounder control, reasonable knot%l- edae of pastand presenterposuret mam rele% ant stud% end points. a good. cleard and understandabie analk - sis, and intervention (reduced~ erposurel that was fol~ lowed b> the espected reducnon in the disease studicd'. The study demonstrates that it is posstble to con% tnee the scientific communit' % of a causallrelattonshtp via a"small"' studN of 2 x 3.43, persons tf one has well selected study groups, a good analti sas, and~ a lot of patience. The relationship between carbon disulfide and IHD has been confirmed' during the 1980s in 4mertcan studies (255. 256). of which the latest (2561 is the largest ever und'craaken.:the cohort studied comprising more than 10 000 workers. Since the causal relationship betweemcarbon disul- fhde and IHD is. withigood reason, generally accepted. there is no reason to go into more detail. R'efenences to additional studies on this subject cambe found in the very exhaustive reviews which ha-.e been published (257-261). Nirroglycerrn and ethylene glyco/ dinrtrare (nrtroglycol) The relationship between heart disease and' aliphatic nitrates is mentioned in virtually all reviews on CVD and environmental exposures, and it is one of the few relationships which all authors regard: as definitis•ely demonstrated. Nitroglyceain.has been used both in the medical'industry and for the production of dynamite since the middle of the laso century. Ethylene glycol dinitrate has been used'together with nitroglycerin for dynamite production since the 1930s„as ethylene glycoll dtnitrate improves the quality of the product and is cheaper. However, ethylene glycol dinitrate is farr more toxic and more volatilt than nitroglycerin. The first studies of the relationship between nitro- glycerin/ethylene glycol dinitrate and heart disease were published in Germany and Italy in the 1950s ((262. 263), They were case descriptions of the phenomenon which has later beemcalled "Monday morning angi+ 254

na" or "Alonda` morninc dcath." The noniatal cases zre attaa6• o hi,h ~r•emhie angzna pe~:ori,. but ~khich are nrt pr,.?, .tl.td hk :~rra.e ur pcti;hi. arousal. The O:,ur I'•1 d,3tie- e.pewre to nnroalveenn sth~;enr _,i:..ji Jtnitrace tr,.!';onscqutnt{y the Jrwrnataon -n ;ra:r ~~:;h rc al -rmPtom..' has been u•r.7. THi• es;*rr-+on,a,a• ~ar:ru• onijittons- ;uch .t..anginu. ,uronar~ •pa•m.,m~o:ardial sntar;tion, ar- rh~thmia, ancJ uJden death. Ini tho.e instances in autop,+ %va, performed. normal coronarN ar- terit• t%tre tound Simar :a,e reports ra%e been published in other ,:ountne. t.61-266t. and tlorton', :omprehensive re- ti tt%+ trom 19-- t.6"1 ;ontatns an excellent review of' the literature .:onrerning %,rrhdra%%al hazards related to occupataonal habituation to aliphatic nttrates (7-t reterencest:.Ir,appears from %(orton's re+ic%% that. dur- tng the period 195:-19'=. articles %%ere published about %londa> mormmne attacks rn,German>. ltalv. Ja- pan. France. S,ktd'en. Czechosto%al.ia. the So%iet Lnion.and theLnned Sta^.es. It appears turrhermorc that the first fimen,can des:rnption %% as not Carmichael & Lteben"s article from 1963 (_6a9, as formerlti be- lietied.,but an article fiomi 19a'3'by Foulaer (2681'. Foul- ger's article on "e\posure to toxic chemtcals- did not mention. ho%ce%er,. that it concerned nttroglycertn: ethylenc gl\ col, dinirrate. [See. in additton. the cor- respondence between Fouieer and Mt7rton (269)land%torton's article omthe ethtcal problems oficonceal- rne medical kno%% ledge %%tthtn ocrupattonal medicine (:"0)i. Half a.ear after %iorton's re~ieK. Hogstedt & Asrlson,t.'1 t introduced a nerr era in this research by publishing the first truly epidemologic study. it was a case-referent study .~hicti~ «as later supplemented kk ith a prospecti%e study (.'2) and with hygienic mea- surements (2"3). µhich together with two additionali articles formed part of Hogstedt's thesis (27.t), In these %torks of highepidemiologic quality„it is documented :n a:on% immng' Nay that, exposure to nitroglycerin/ cth.lene g(.cot dinitrate not only causes symptoms, dis- eases. and deaths due to nitrate wuhdrawal, but also raises the risik for CVD many ycars after the cessation of erposure. Hotastedr's results ha\,r beemconfirmed during the 1980s by two other investigations (275. 276)t both of .khich are historical' prospective studies. In these studies. more CVD deaths were found than expected among the erposed' workers despite preemplbyment screening and%or medical m,.nworing of the employees. Thus it is now clt;ar that nitroglycerin and, especial- (y; ethylene glycol dinitrate increase the risk for,CVD in, the following two ways: partly via the specific "tilonday morning attacks" due to nitrate withdraw- al and partly sia an increased'risk for CVD which per- sists long after the cessation of exposure. This double effect, is described in a few of the reviews, such as Fine's (,I ) and Kurppa et al's (6), while reviews on the topic were still'being published during the i980s which only or almost ecclhsi%ely describe nitrate Ktthdtawali and'-4fonday morntng attacks" (2. 3. 5. 2'")'. Other chemical sUb'srances and compounds This section brie(l~ re~icNS canous studiesconcerntng C% D and other chemical substances - areas in which onh• a fcµ studies ha%e been cond'ucted or in uhic.h se%eral' "competmg" exposures occur in the same itud+. Om(rroroliwne_ (n 1986. Levine ct al (2'8)publtshed a historical prospeeti.e study of,Workers in, two fac- tories in,which the emplotiecs had been exposed to dinurotoluenc (27$). As in so many other instances. it was a susptcion.of carc.tnogenicitv w htch mottrated the studj, but' no tncreased', incidence of cancer was found amone these .corkers. Hoµe.er, an increased, incid'ence of IHD IS51R 1511 appeared when the data firomiboth factories uere combined. with a relatton- ship between the duration and'the intenstty of the er- posure and the incidence of IHD Accordtng to the authors, only s er} few of' the workers had' been er- posed to nitroglycerin or ethylene glircol diniuate. Organoph'osphares. Two cross-sectional studies - one Danish (279) and one Indian (2801 - have shown an increased pre~alence of "ischemic" electroeardio- graphic changes among workers exposed to or ganophosphates. The Indian study included 155 ex- posed persons and 60 referents, while the Danish in- vestigation included 446 workers. of whom 114 were classified as heavily exposed'. fn the Danish study, the higher prevalence of electrocardiographic changes among the heavily exposed'individuals remained after control for age and smoking. Anrimon-v rrist,lfide. fn the work by Brieger et al from 19541(281/, a factory was mentioned in which 125 men were exposed to antimony trisulfide for eight months to twoyears. During this period, eight of the workers died suddenly. Two,of the deaths were due to chronic heart disease. Four of the deceased were under 45 years of age. Because of this finding, the workers were ex- amined. and elbctrocardiographic changes were found in 37 of the 75 examined. A review of the literature on animal experiments with antimony trnsulfide seemed to show that the substance is cardiotoxic. At, the fac- tory studied, the use of antimony trisulfide was stopped, and no further sudden deaths were observed. In 12 of 56 reexamined workers, the observed elec- trocardiographic changes persisted. No other studies on antimony trisu(fide were found in the literature. Beryllium. Im a historical prospective study by. Wagoner et al (282), mortality was investigated in a cohort of 3055 workers who had been exposed to be- ryllium. Despite an assumed healthy worker effect, an SMR of 113 (P'<0.05) was found for heart disease in comparison with the mortality of American white 255

males. The highest value (SMR 129) was recorded for those exposed for at least fiwe years. Polvcvchc aromarrc compounds. In a ease-referent stud% (383) of 6000 men employed by a primary alu- minum smeiter}, there were 306 new cases of IHD dur. ing the period 197t- i983. The persons concerned were compared with 5'9 matched referents. Among the bl'ue-tolliir workers. a relanve risk for IHD of 2J was found. The risk aas particularly elevated among workers emplo)ed' in the reduction divisions. These workers had a relative risk of 1.7 for IHD when com- pared with the remaining blue-collar workers. Unfor.- tunately, the referents were matched for duration of employment- and this type of matching prevented the researchers from uncovering a possible relationship with the duration of the exposure. Both a Danish (284) and a Swedish (285) mortality study of chimney sweeps found an excess frequency of' IHD. The Danish, studyy cohort consisted' of 713 chimney sweeps, and the SMR for, IHD was 222when employed men were used as the reference. The Swed- ish, study cohort consisted of more than 5000 chim- ney sweeps, and the SMR' for IHD was found to be 135 when all Swedish men were used as the reference group. In both instances, the excess was significant at the 5 Ma level. In a historical prospective study of gas workers, Gustavsson & Reuterwall (286) found excess mortali- ty due to IHD (SMR 125) and stroke (SMR 152): In this study;,occupationally active persons in Stockholhn were used as the reference group. Due to the small numbers, these results were not statuticallysignifiunt. Common for aluminum reduction workers„chim- ney sweeps, and gas workers is that they are exposed to combustion products. According to several authors (6, 284, 286), it can be hypothesized that polycyclic aromatic hydrocarbons or other polycyclic aromatic compounds are not only carcinogenic, but also increase the risk'for IHD: This assumption is in accordance with the monoclonal'hypothesis of atherosclerosis proposed by Bendirt & Benditt (287);, according to which atherosclerotic lesions might be derived from the proliferation of a single cell and could be considered to be benign tumors. The excess frequency of both IHD and lung cancer among, Danish cooks and bakers (288) in the national Danish, mortality study further supports this theory, as it must be assumed that many working in these trades are exposed to polycyclic aro• matic hydrocarbons. Concluding r.marhs During my collection of the material for this review of the literature, 1 found no additional'studies that could be judged as sufficiently relevant for inclusion. Since, of course, the judgment of which studies are to be regarded as relevant is inevitably sub)ective, the reader may wish to supplement this review with other comprehensive ones dealing with CVD and chemtcal exposure (1, 2, 5, 6, 9, 10). In a recently published' article (283) concerning chemical exposures at work and the risk for IHD. the authors wrote: "Several personal risk factors are known to contribute to the development of IHD, but the effects of adverse working conditions have re- mained almost unexplored [p 659)," (283). This is a very widespread conception, but both the present review of the literature concerning chemical occupational fac- tors and CVD and the previous article concerning non- chemical factors (14) have shown that the conception is not completely correct. Hundreds of studies, in fact, have been carried out in this fieid, and, in several areas, knowledge today is considerable. The present review has, inisome areas. confirmed other reviews of the literature, while in others the con- clustons reached'are contrary to the currenrvieM_ For carbon disulfide and nitroglycenn;',ethylene glycol dini- trate. the general opinion is confirmed. Ih these areas, studies have been conducted which have convineed vir- tually everybody about the causal relauonship between these substances and'CM It should be emphasized', that what has convinced'the scientific community is not the number of'studies - as a matter of fact, there are very few - but the high methodological quality of' the studies. For lead and passive smoking, this review concludes more positively than others. The research concerning lead and CVD is very old, but not until recently has in been "discovered" in earnesn. This phenomenon is, to a large extent, due to the remarkable results con- cerning low-kvelllead exposure and blood pressure from the National Health and Nutrition Examination Survey 11, which were published in highly esteemed journals (70, 72). The research eoncerning passive smoking is new, and there are still relatively few studies, but they have a high quality and the results are consistent. In other areas, the conclusions are more negative than usual; especially for cadmium and carbon monox- ide. The research concerning cadmium and CVD is genenlly of poor quality, but the few good ~ studies, together with the fact that tobacco smoking is not a risk factor for hypertension, makes it reasonable to conclude tbat cadmium is not a CVD risk factor. For carbon monoxide, the situation is more complicated, since there might be acute, short-term, and long-term effects. it is concluded'that there are acute effects and possibly short-term„revenibie effects, but that carbon monoxide does not increase the risk foratherosciero- sts in occupationally exposed individuals. In table 5, an attempt has been made to classify the possible cardiovascular risk factors which have been reviewed in this and the previous article. The basis for this classification is the view tharempirical relation- shtps are not "proved" once and for all. Hypotheses 256

are :onformed or invalidated through the collecti.e and cumulaweMork which researchers carra out, and s%s- temanc :rmcal re~le+ts oi the literature constttute an exer more Important~ pan of this process. Se%eral oi the factors mentioned under "~erc defi- ntte" and "quite deitnna" in table i' are Ntdespread in tndustrtalized countries This is true for physical inaati% it at ttorl.. noise. shttt ttork. µork stratn: lead. and~pass+,e;mokins- Even if the relato;e risk forCVD .onnected tttth e:;.:: of these factors is modest (from apprortmatel' y 1.1 to :.0)i the total'etiologic fraction tattrtbutablertski will be considerable. and therefore the potential pre+entl*e benefit' is great. Nott the classic question "ls enough known to use this kno%.ledee for pre%entive acti.itues' artses. This is naturalln not a scientific questionbut is stilllone with a hlch,researchers are often confronted and are e.r- pected to be able to answer. One ans%ker could be that enour:hiis known about the factors which have been mentioned under "ser% definlte" and "quite definne" in table S to initiate pretienuon, There could howeser be a risk, of making a mistake since one or more of the ei¢ht rtsk factors mentioned, at some point in the future, might prose not to be a risk factor (or CVD. With respect to this possibility, the fol)owing rwo points are worth making: (i/ if one chooses not to act until one has "100 °'s certain evidence," one is likel% to make mistakes whichihave serious consequences for the health and mortaliE,y of many people, and (ii) the factors wfiich~ha%e been mentioned in table S are alli risk factors for diseases other than CVD. If one or more should pro~e not to be a risk factor for CVD, there Nould'stiil be a positi.e effect from reducing or remo.tn¢ these factors. !n should be emphasized that table 5 only includes factors which,.ha%c been mentioned in the literature as possible risk factors for CVD. The absence of'evidence about a causal relationship should, of course, never be confused with evidence about an absent causal'rela- uonship. it should4urther be mentioned that the ta- ble deals with levels of exposure which occur "nor- mall% " au workplaces in Europe and North America. Marmot & Theorell (289) recentiy claimed that psy- chosocial strain at work is probably part of the expla- nation for the negative correlation between social class and CVD incidence which is seenn in industrialized countries. fnitheir review; they emphasize Karasek's job strain modetl The deliberations by Marmot & Theorell are an important: supplement and corrective to the prevailing explanations which virtually always have their starting point in individual risk factors. It should be stressed, however, that not only job strain, but also several of the other factors mentioned in ta- ble S, are more widespread in the lower social classes. Therefore changes in the work environment might con- tribute to the efforts to reduce the social,inequities in morbidity and'mortality which eonstitute an impor- tanr target in the program "Health for All by the Year :000" of the Vworld Health Organization and in the health policy of many tndi.tdual countrtes. Finally_ some remarks on~the form and content of' literature ret teKs Mtthtrnmedlcal researchi It is true for most re.iews that the eraterus for collecting the litera- ture and for esaluating the tnditi tdual studies are net~ ther explicit nor systematic. The most common mode is that the authors of the re; re>{ mention some posl- ti.e and nerratr.r studies, obser%e the evident lack of consensus. and conclude that further research is neces, san. This kind of resteN does not li;e up to elemen- tary sctentificc demands and'does not contribute to the development and claruficatton,of research. One ot the consequences of the steeply rising num- ber of scientific investigations all over the wortdis that researchers and other persons become ever more de- pendent on,reliable re.iews of the existing literature. Therefore re% iews musr, try to live up to the demands forvalidity, reliability, precision, and repooducibility which are in force for ,:^,: individual empirical studies. To the extent tharretu" 5 do live up tothese scienrif• ic demands, they will be able to ser.e two very noble purposes: (il the clarification of future research needs (one must northink only of stressing the ever present' "need'for moreresearch." but of a sharperclarifica- tton of hypotheses. method4nd design problems, mea- surement problems, etc> and (ii) to indicate those areas in which the evidence is so-certain" that preventive activities ought not be postponed further. In this con- nection, it should be pointed out that sottx uncmtatnty must alk•a,vs be accepted, as is the case in other hu- maniand social contexts. As is noted,in this and'the previous article (14), sev- eral reviews have been published in recent years in which.anempts have been made to live up to the men. tioned demands (S„27, 188, 29(}-296). One must hope that development in the direction of more systematic reviews will continue in the years to come. T.W. S. Ctass-t/eation of poss bta nak tactors for carolovas- cuWar 01s.as. tCVpt in tne roru env.lronmant. Cwsal rnal,on to Lvo NOnCMrn1CL Nr{ltactOr Ch.+n-sar v.rp e.hnmr aws,cN w+runtr Caroon msuwaoe nnm~ It .on plyc&nnrwnroplrco/ Ourlt ON,n,N won stqr/, tr,Qalaa& OMN,N oa~anps ano lo. 1narMr+nO bwnca. M,h sort was-bl. no,w Cowrt. ars.nK. can0u1110n .0.00uc,5 Sorn..nal, tiaa" . ,rrn,atwn Orqsnoonosonetta 0,. oosrel. oo.frlr.ou.ncrTaon0rotolu.n, a,t11+wRY. MI,C /yly /o.bIn'14.vA,. COOOrt /rpyNnCT "WM ,nono.qM ~OOaD,r no M.crora.H. CWO' Cao,Mwn: Mpan.C ., mas,onsnio aw..nts' ~ Inanws n,e ns. torCuD tnroupn.mc+as.o wooO waswn a Mpln.laral a.DOluta Inay 0e 44Y sso.uany n.n coMan.a .nn otn• ., „s.:tactons .aooslt,. ,na. Caus. cano%aC aHTylnrn,a anp fY04M o..fh 237

t 7 Acknowibdqments The stud% was supported b} the Dani;h lit ork Ensiron- ment Fund tgrant 198-t-::l and~b} the Danish Heart Foundaam References I. Fine L1 O..upatwna! heart disease. In- RomAi ``, ed. En,:r,nmrntalland oc:upattonal medictne. Boston: L ule. Bro•,r, and Co. 1981 359-65. _ GoidhaoerSZ Cardio~a~;ular erfeqs of'potenual haz- ards J im Coil Cardtol t983:'_:I'_10-5.. 3' Gonzales ER Vo proor of en,ironmemal ill effects on heart 1-kM-k 1980:_u?:I_ly-_01 1 Harlan %1'R. Sharret AR. K ei!! H. Turtno G%l. Borha- nt N.O. Resneiio, L. lmpa:t of the enstronmenron cardtosascularr dtsease. Circulation 1981:63:2z3A-6A. 5. Hopwtns P.%. Williams RR. .# >,ursey, of ]46 suggested coronan risk factors Atherosclerosis 198II:30:1-32. 6. Kurppa i:. Hietanen E. Klockars 1,11. erial. Chemical exposures at work and cardiotascuf4r morbtdity: atheros.-leros:ts: tscfiemic heart disease. hypenenston, ardtomyopaphy and arrh%thmtas. Scand J W ork En- .tron Health 198i:10:381-8. `fillar JD. 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