Document np3Z2MG3Ep1bDMjQKxvkMege6

i i i i V _t-m ] 1 j 1 H i.- \ 't* a a r4 , 111 Volume 14, number 2, April 1988 3h ISSN 0355-3140 n ft 'I '! \i":! 1! - 1 :q ' ,H j CONTENTS Reviews 61 Effects of exposure to vlny chloride: An assessment ot the evidence Sir R Doll Original articles 79 Associations between seve al sites of cancer and ten types of exhaust and com- bustlon products: Result^ from a case-referent study in Montreal J Siemiatycki, M Germ. P Stewart. L N 3i1don, R Oewar, L Richardson 91 Effects of exposure to Freor 11,1,1,1-trfchloroethane or perchloroethylene on the lipid and fatty-acid comp<isition of rat cerebral cortex T Kyrklund. P Kjellstrand, KG Haglid 95 Influence of water on the p < rcutaneous absorption ot 2-butoxyethanol in guinea pigs G Johanson. P Fer istrom 101 Percutaneous absorption o 2-butoxyethanol in man G Johanson, A Boman. B Oynesius 110 Prediction of early retiremefi t on the basis of a health examination: An 11-year follow up of 264 male e rfoloyees in a Swedish pulp and paper company N-E Astrand. S-O Isacsson. <50 Olhagen 118 Comparison between surgei nns and general practitioners with respect to cardiovascular and psychosoci risk factors among physicians BB Arnetz, S Andreasson. M Strandberg. P Er eiroth. A Kallner 125 Invariants and noninvariant! in the concept of Interdependent effects S Greenland. C Poo* Case studies 130 Fatal arsenic poisoning -- A ease report L Gerhardsson. E Dahlgren, A Eriksson, BEA Lagerkvist, J Lunds: rom, GF Nordberg Book reviews 134 Neurotoxicants and neurobi ^logical function: Effects of organoheavy metals 134 Ergonomics in computerized offices 135 Indoor radon and its hazard ; 136 Ergonomics at work 137 A manager s guide to ergonbimics in the electronic office 138 industrial radiation hazards leskbook 139 Announcements 140 Amendments and correctior SPI-01271 REVIEWS Scand J I* ork Environ Heanh 14 (19881 61 --'8 Effects of exposure to vinyl chloride An assessment c f the evidence by Sir Richard Doll FRS' DOLL R. Erie ts of exposure to vmvl chloride \n assessment of the evidence St and J H'nric Environ Health 14 (1981 ) M -- This paper reviews the possible effects of vmxI chloride on the mortality of occupanonallv ex iosed men and the carcinogenic effects that might be observed m the general population as a result of e ironmental pollution with vmvl chloride. The results of four studies fulfilling the criteria of providing s manual numbers of observations more than 25 years alter fitm exposure and covering a period long er ough for more than 10 of the workers to have been expected to die constitute the basis for the a.ssessm nt of ihe occupational hazards. Other studies provide onlv supplementary information, The data perm two conclusions. First, men occupationally exposed to vinyl chloride nave experienced a specific hazarjd of angiosarcoma of the liver. Second, any other occupational hazards that mav have existed have b n small. No pos cancer other th n angiosarcoma cancer when osure was heavy exposed empios :es could present angiosarcoma rr a\ have occurred 1 ) 608 644 (redactory l | nt number JO.OO air mail address above, maged issues unless ight Clearance Center ,e internal or personal enter's Transactional page, is paid directly tations that have been The fee code for users chloride nionon er I or many years the ii i It alauon of large amounts of x myl chloride has been recognized as potentially hazardotis. Concentration: of the order of 10 000 ppm in ltic air induce unconsc ou.sne.ss and cardiac arrhythmia. while prolonged I xposure to concentrations an order of magnitude lov ier have been liable to cause a specific pathological s y]ntlronic. This "vinyl chloride illness" has been charatjt erized by four cardinal signs, namely, enlargement the liver and spleen with a specific histological apple:arance, patchy infiltration of the skin resembling scle -ioderma, bony changes in the lips of the fingers desfr ibed as acroosteolysis. and peripheral circulatory anges identical with the classical picture of Rayttau|d 's disease. These pathologicai reactions may occur s|mgly or together and may possibly be accompanied hv oi ther less characteristic effects. They can, howeve , be completely avoided if ex posure never exceeds th level of a few hundred parts per million, le. the le I to which exposures were generally reduced in th mid-1960s. One other serious effei t has, however, been observed that may not be avoidaql e in the same relatively easy wav, namely, the produ non of angiosarcoma of the liver. It must, indeed, b 1 presumed that some risk of developing the disease ill persist from exposure to Imperial Cancer Research Fund. Cancer Epidemiology and Clinical Trials Unit, Rad lilfe Inhrmarv, Oxford. United kingdom tcprilll rct|ticsls lo: Sir R Toll. Imperial Cancer Research mid. University m Oxford Ciibson Building. The Radchffe rinarv. Oxlord OX2 6LE. United Kingdom doses that are even lower than the current industrial levels of 5 ppm or less, as vinyl chloride has been shown to act as a mutagen (23). and it cannot be assumed that a threshold exists below which no carcinogenic risk persists. Moreover, the possibility has to be considered that vinyl chloride may cause some cancers other than angiosarcoma of the liver, partly because laboratory studies have shown that ii causes other cancers in animal experiments and partly because Ihe initial studies demonstrating the production of angiosarcoma of the liver in humans were inadequate in size to ex clude a material increase in the risk of cancer in com mon sites, such as the lung and large bowel. Since no threshold dose can be postulated, it also follows that some cancers may have been produced in the general public by ihe small amounts that have escaped into the general environment. Consideration also needs to be given to the possi bility that exposure to vinyl chloride over a long pe riod may have noxious effects on humans that cannot be seen easily in animal experiments (by, for example, producing chronic respiratory disease), and, as u is a mutagen, there is also a possibility that it may act as a teratogen and cause congenital malformations in offspring. In this review I have not examined the possibility that vinyl chloride acts as a teratogen or that it causes mutations in germ cells, as there is loo little serious evidence to justify inclusion. Reviews carried out for sections of the industry by Downs et al (unpublished report to the Society of Plastic Industries Inc in 1977) 61 and bn Mac.Mahon (unpublished report to t le Chemi cal Manufacturers Association in 1977)cont luded that the less reports of positive effects could n >t be sub stantiated, and no additional evidence wa: found in a similar later review by Barr (unpublishec report to Air Products and Chemicals Inc in 1981), apart from a report that embryos were absorbed and skeletal os sification was produced when pregnant rat were exposed to doses appreciably lower than thosl that had been used by other workers without any su h effects being observed. The report of absorbed em|>r yos (34) could not be evaluated thoroughly, however as the experimem was inadequately described. I have, herefore, examined only the possible effects on the| personal health of men occupationally exposed to yl chloride, other than those related to their rep1 oductive capacity, and the carcinogenic effects that rrli ght conceivably be observed m the general popula|[ ion as a result of the widespread distribution of viny chloride as a pollutant. Occupational hazards Many studies of workers exposed to vinyl chloride in the manufacture of vinyl chloride monome (VCM) and polyvinyl chloride (PVC) have been u overtaken since it was first found that vinyl chloride cot Id cause cancer in animals (28, 48) and man (10). The te inves- tigations have confirmed that exposure caus :s a haz- ard of angiosarcoma of the liver and, in se |eeral in- stances, have shown excess incidence or morta it y rates that were conventionally statistically signifi ant for other diseases. Conventional tests of statistics I signifi- cance are, however, designed to help - single questions defined beforehand, and several findl ngs that might be expected to occur by chance a!one| once in (say) 20 times must be expected to occur if dbzens of rates are examined in each of several sets of pdepen- dent data. Scientists have, therefore, been fa< od with the problem of deciding whether the excess r; tes tI hat have been observed in individual studies are due to oc- cupational hazards or to the vagaries of cih nee. This problem can be solved in part with ar| exami- nation of the results of a sumation of data fr<qm icom- parable studies, that is, by a comparison of t he sums of the numbers of deaths observed and exiPfcted in each siudy. This procedure does not require! the as- sumption that the exposures have been the samq in each study any more than the same assumption is required for each individual when the results of each study are considered alone. It does require however t h|at each exposed population has been observed over period when us members were ai risk of developing disease (if a genuine hazard existed) and that in study the rclerence population from which :he expected nuin- hers ul Jcalhs were dmved was appropriate (hhat is, al the unie risk ul developing disease as ihe i xposed jsopui.il util would have been iit ihe absence ll ex po sure). These requirement do not introduce any new complexity, as both are. of course, also required if correci conclusions are to be drawn Irom Die results ol ihe individual studies svhen [hey are examined on [heir own. Sources of information Four siudies meet the aforementioned requirements, namely, iwo large national surveys, one reporied by Jones (25) for ihe Untied Kingdom (UK) and the other by Environmental Health Associates (14) for the United States (US), and studies of individual plants in Canada, reported by Theriault & Allard (46) and in Italy, reported (as a part of a national siudy) by Belli et al (4). All four include observations on men more than 25 years after their first exposure, and the ex pected number of deaths is, in each case, greater than 10 % of the total number of employees, a value indi cating a long average period at risk. Earlier observa tions on UK and US employees (6, 9, 12, 16. 20, 36, 39, 40, 45, 50) have been subsumed in die national sur veys and now serve only as sources of hypotheses and of some detailed information not included in ihe na tional reports. Studies of German (49). Norwegian (22), Swedish (7), French (41, and unpublished report of Laplanche et al), Japanese (33, 37), and some oilier Italian (4) workers provide some supplememary infor mation, but, in general, the periods of observation have not been long enough for useful epidemiologic data to be obtained aboui diseases ihai are unlikely to occur within 20 years of first exposure, or they report only selected results which are difficult to in terpret, as only excess rates tend to have been selected. Studies of makers of PVC products have not been included, as the workers have had much less exposutc to vinyl chloride than those employed m the manufac ture of VCM or PVC and any occupational hazard io which they may have been exposed is more likely to have been produced by PVC dust. US study. The study carried out by Environmental Health Associates (14) on behalf of the US Chemical Manufacturers Association is the largesi and most in formative investigation thus far undertaken. It cov ered 10 173 men who had worked in 37 plants owned by 17 companies -- I 214 men in II plants that produced only VCM, 6 848 men in 18 plants that produced only PVC, 935 men in three plants that produced both, and I 176 men in five plants that produced homopolymers and copolymers, with or without VCM or PVC. Twenty-two of the plants were in the southern part of the country, 14 were in ihe northeastern or north central parts, and one was in the west. Men were included if they had been exposed io vinyl chloride for al least a year bclore 31 December 1972 and had been employed in 1942 or subsequent Iv 11 he I irst yejr depending on die dale i lie pl.iiu Ik e.m m.ik me h2 SPI-01273 or using sonnel re. was ihe identtfiea sonnel. Racial . 9' Ol W (he purpe deaths, tf Follow cial Securt: died after plants did ; (9) earlier present ins plants who 1972 were follow-up 1982, which of ihe men uniraced wc which was u Almost ha before 1955 served more many cases t a long latent Shori-terrr cohort, and ployinent lor lor 10 years c ployment be: Fifieen hur have died. In lamed from ir lamed for the The numbe causes or grot plying the per-, national rates age groups an. This import, cisms, which a effects on the re compiled by ce cords without a sumption that a caused the expe underestimated, io have had hit reason for suppo the proportion e necessarily repre (ainty was intro, as 7 3 'o of the Two oilier eru expected mimhe; - nmjil IsMI 1 11.11 : 1 reduce anv new o required if corim ihe results of xamined on their ed requirements, one reported by JK) and the other ites (14) for the individual plants i: Allard (46) and >nal study) by Belli ons on men more isure, and the ex case, greater than iyees, a value indit. Earlier observa, 9, 12, 16, 20, 36. in the national surof hypotheses and included in the nan (49), Norwegian unpublished report 32). and some other jpplementary inforods of observation seful epidemiologic es that are unlikelv t exposure, or they i are difficult to m0 have been selected, ducts have not been J much less exposure oyed in the manufaccupational hazard to sed is more likely to JSt. ut by Environmental f of the US Chemical ie largest and most inr undertaken. It cov ed in 37 plants owned ten in 11 plants that nen in 18 plants that 1 in three plants that en in five plants that copolymers, with or :re in the southern part ; northeastern or north the west. id been exposed to s myl fore 31 December 1972 42 or subsequently nhe e the plant began making or using vinyl chloriqe and ihe earliest date that per- sonnei records'were d femed to be compleie, whichever was the later). Indivicjuals who met these criteria were identified from comifany records by company per- sonnei. Racial characteristics were known only for 686 men, 97 Vt of whom were hue, and it was presumed, for Ihe purpose of estirrat ing the number of expected deaths, that all 10 17) men were white, Follow-up data weie obtained from plant and So- cial Security Admmistfat ton records and ifor men who died after 1979) from he National Death Index. Five plants did not collaboijatie In the extension of Cooper's (9) earlier study, whi| h had been subsumed in the present investigation ^tnd the 955 employees in these l plants who were knos n to be alive on 31 December 1972 were not follow [ied any further. For the rest, follow-up was attemf ted to death or 31 December 1982, whichever was t earlier. On this basis 92.7 of the men were succe: fully traced. Those who were untraccd were excluded from the Iasi date of contact, which was usually the ^late when employment ceased. Almost half of the (46 %) were first employed before 1955. A large proportion was, therefore, ob- served more than 25 v< arsa, fter first exposure (and in many cases for more I han 30 years) when diseases with a long latency period ight be expected lo be seen, | Short-term workers had been excluded from the * cohort, and most of the men had continued in em- ploymeni for many ye; rs. two-thirds being employed * for 10 years or moreT, the average duration of emy ployment being 16 ye I Fifteen hundred andl thirty-six men were found to I have died. In I 439 cas| s. the cause of death was ob- tained from the death c^rtificate. but no cause was ob- lained for the other 9 persons (6.3 "to). The numbers of deal hs expected from each of 38 causes or groups of cakj ses were obtained by multi- plying the person-yearsl at risk by the disease-specific national rates for whitq males, for the corresponding age groups and five-y r periods of the study, This important studyl is open to three minor criti- cisms, which are unlikfl y to have had any material effects on the results st. the lists of employees were compiled by company personnel from company re- cords without any indepjendent check. Second, the as- gumption that all the erjiployees were white will have ^ikk.^ auied the expected de^t hs to have been very slightly underestimated, as the (lew black employees are likely IO have had higher m qrtality rates and there Is no ,'*i~ ' reason for supposing th^t the small sample from which the proportion of black [employees was estimated was oecessarily representati p. Third, an element of uncer- lainty was introduced bl ithe failure to trace as many as 7.3 % of the employees. Two other criticisms re more important. First, the expected numbers of de4t hs were calculated on the as- sumption that ihe men would have experienced the same mortality rates as Ihe white male population of the whole country at the corresponding dates. I he use ol national rates ts common practice in studies oi in dustrial populations and lends to result in an oserestimation of ihe expected numbers of deaths so (hat the employees appear to be unusually healthy. This "healthy worker effect" is well known and has been taken into account in my discussion of the results. A more serious objection to the use of national rates is the way mortality varies from one part of the country to another, due to differences in the prevalence of en vironmental and social factors unrelated to the occu pation of interest. It is. therefore, generally preferable to use state (if not county) rates in place of national rates. With 37 plants, however, it might be thought that their geographic distribution would be sufficiently wide to make the use of national rates appropriate. Unfortunately 22 of the plants were located in the south, and a check would have been desirable to see whether their location could have caused any material distortion of the results. Second, causes were not obtained for 97 of the I 536 deaths. This deficiency was allowed for in the calcu lation of the overall mortality by the inclusion of deaths due to unknown causes. It was not allowed for, how ever, in the calculation of the disease-specific mortality rates and will have caused the standardized mortality ratios to be underestimated by an average of 6.3 w9. For the present purpose, therefore, the numbers of deaths attributed to specific diseases have each been multiplied by 1.0674 (!00/( 1 --97/1536) j and rounded off to the nearest integer. UK study. The study reported by Jones (25 and un published) on behalf of the British Health and Safety Executive covered 5 498 men who were employed for at least one year in jobs that involved potential expo sure to VCM for at least 25 8h> of the work week and who were first employed in the period 1940--1974. De tails of the men were compiled from the personnel records of nine chemical plants manufacturing or poly merizing vinyl chloride, and the vital status of the men was determined at the end of 1984 from the records of the National Health Service Central Register, Five thousand four hundred and ninety-eight men were traced (98.9 wo). Seven hundred and eighty deaths were identified, and copies of the death certificates (coded to the eighth revision of the International Classifica tion of Diseases (ICD) if they occurred before 1979 and to the ninth revision if they occurred later) were sent to the investigators. Several specific points about the study need to be noted. First, national mortality rates for England and Wales were calculated for five-year age groups over quinquennial periods for 66 causes of death, and these rates were used in the estimation of the numbers of deaths that might have been expected in the cohort by multiplying them by the corresponding numbers of person-years under observation. Some difficulty which could have been related to the causes of death being 63 coded according to (he eighth and ninth rivisions of the ICD was, however, experienced in obtaining suit able rates for all causes of death, and rates for a rela tively late period had to be used for estit sating the numbers of deaths from many diseases that i night have been expected to occur in earlier periods For two categories the earliest available rales were 19 60--1964, for one they were 1965--1969, for 24 they w ire 1970-- 1974, and for one they were 1975--1979, Second, an attempt was made to classifV men ac cording to whether they had high, intermedii te, or low exposure to VCM or PVC dust, and each r tan's em ployment history was recorded according o 12 job titles with advice from the plants concerned The men were then grouped according to whether exaosure to VCM was likely to have been high (group k), expo sure to PVC dust was likely to have been ligh with exposure to VCM low (group B), or exposur: to VCM and PVC dust was intermediate and intermittent (group C). All other men, who would genet ally have had low exposure to both VCM and PVC dust, were classed as group D. Within all the groups, exposure to VCM was likely to have been higher if it hid begun before 1956. The study makes an important contributi >n to the knowledge concerning the long-term effect! of vinyl chloride. The use of national rates to calcula e the ex pected numbers of deaths may be justifies on the grounds that the men were employed in plants, which were presumably distributed about[ thetaountry, but no details of their location are given, general, mortality rates tend to be higher in the partssdf Britain where heavy industry is located than in othetl parts of the country so that the expected numbers of d raths are more likely to be biased downwards than upw!bids; but whether this is so or not needs to be showri The use of recent rates to calculate expectpi numbers of deaths from many specific causes of d[ ath was presumably necessary if the diseases were to>be studied individually and will have done no harm if he incidence and fatality of the diseases in question rfcmained stable. It would have been desirable, howeveij for the diseases to have been specified so that the reader would know which were liable to be distorted. The system used to classify the men into fo|iir exposure groups is the sort of system that is commlohly tused if precise measures of exposure are not avai able. It creates some difficulties in the statistical analysis if men move from one job to another and are classed (as in this instance) as having had high exposure if ey have ever had a particular type of employment (eg, c 'er been employed as an autoclave worker). No evidenc| : is provided to show that the person-years at risk qefore a man entered the category have been subtrac| ed and added to another exposure group before the n|umbers of expected deaths were calculated. Moveme|tit from one job to another was said to have tended t be out of groups V and I) into l), blit even so it ihust be presumed that the expected numbers of deaths in the first two exposure categories are likely to have been overestimated. Canadian study. The Canadian study (46) was limited to employees of a single plant in Shawinigan, Quebec. The plant, which was situated in an industrial com plex, was opened in 1943. VCM and PVC were both made until the late 1960s, when the production of VCM ceased, while the production of PVC continued. An attempt was made to trace all the production work ers whose names appeared on the unions' lists or the payrolls of the companies in the whole industrial com plex, including the vinyl chloride plant, between I January 1948 and Jl December 1972, and contact was made with the worker or his next-of-kin in l 611 out of I 659 instances (97.1 7o). Detailed occupational and smoking histories were obtained by questionnaire, and 156 men who had been employed by the companies for less than five years were excluded. The remaining men were categorized as (i) exposed to VCM if they had worked on the production of VCM or PVC for at least five years (451 men), (ii) unexposed to VCM if they had worked similarly for less than six months (870 men), and (iii) other men (134 in total). The last group was excluded from the study. Follow-up was closed on 31 December 1977. Copies of the death cer tificates were obtained, and the causes for all who had died (59 exposed and 233 unexposed) were coded ac cording to the eighth revision of the ICD. Informa tion was also sought for histological or cytological con firmation of all the diagnoses lor all the exposed men who had died of cancer. The results were examined in two ways. First, the mortalities of the exposed and unexposed men were compared after standardization for live-year periods of the study and five-year age groups. Second, the mor tality of the exposed men was compared with that ex pected if the men had had the sex- and age-specific mortality rates recorded in Quebec for the year 1971, In both comparisons the causes of death used were those specified on the death certificate, and the addi tional pathological information was used later only for interpretation of the results. Most of the exposed men were exposed for more than 10 years (75 *!), the average length of exposure was approximately 17 years, and 44 "it were observed more than 25 years after first exposure. Although small, the study makes a useful contribu tion to the overall results. The histological review of the cancer cases is particularly helpful. It showed that all eight cancers diagnosed as liver cancer (including two specified as hepatoma and one specified as angio sarcoma) were angiosarcomas of the liver, as well as one that had been diagnosed as angiosarcoma ot the peritoneum. Two other cases of angiosarcoma ot the liver were found to have been certified as hepatic cir rhosis. It IS also helplul to luve a vomp.ti ivon between SPI-01275 i i ! the expose ] companies i for all not | a healthy . i recording \ nant cause! 0.95). I One aspc | ie, the use j. calculate e j period (194j to bunch ur j vation so tr ; have been ta j some disior' i size (and eve [ estimate. Fe | likely to hav i Italian study duction of nr was begun in employed for siart up of th still incomple in three plant I signana) bega thirty-seven rr in the other. A followed to the mated by mul corresponding year age group The total expe more than 10 (12.4 and 12.3 Clinical info death of all the had died. Revis comparison wit deaths from ca The Ravenna 1959. Six hundre All but four we were found to h; lowed for more (3.9 % of the wc this plant have r cipal analyses. ! death was attrtb pected. Otht" sources. Ti -vi v .itioris on 4-. T oi death1' in the :ly to have been (461 was limited winigan. Quebec, i industrial comJ PVC were both le production of f PVC continued, production work mens' lists or the ile industrial complant, between 1 2. and contact was T-kin in I 611 out i occupational and questionnaire, and by the companies ed. The remaining :d to VCM if they VCM or PVC for inexposed to VCM ss than six months 4 in total). The last dy. Follow-up was ies of the death cer uses for all who had sed) were coded acthe ICD. Informall or cytological conall the exposed men two ways. First, the inexposed men were for five-year periods ips. Second, the mormpared with that ex sex- and age-specific ec for the year 1971. , of death used were ificatt. and the addivas used later only for ere exposed for more ge length of exposure d 44 lri) were observed exposure. ikes a useful contribuhistological review of helpful. It showed that liver cancer (including one specified as angtoof the liver, as well as is angiosarcoma of the of angiosarcoma of the certified as hepatic cire a comparison between fiiL lhc exposed and "une posed" employees oi the same companies as it show that the low mortality observed for all nonmalianant diseases could be attributed to healthy worker effel t and was noi due to bias in the recording of exposuri (relative risk for all nonmalignant causes compared[ to that of the "unexposed'' men 0.95). One aspect of the s tltdv has to be criticized however, ie, the use of provi rates for one year (1971) to calculate expected m|artallty spread over a 30-year period (1948 to 1977 i r elusive). Deaths will have tended to bunch up towards :he end of the period of obser- vation so that the rat| s for this particular year may have been fairly repre:s^ntative, but it must have caused tome distortion of the xpected numbers of deaths, the tire (and even the dire| tion) of which is impossible to estimate. For most disease groups the distortion is un likely to have been I afge. Italian studv. A study pf all men employed in the pro- duction of vinyl chloride and PVC m nine Italian plants u begun In 1983. Al men were included who were employed for at least s x months at any time from the start up of the plant ttl the end of 1981. The study is Mill incomplete, but ref ults are now available for men in three plants (4). T plants (in Ferrara and Ro- signana) began operatjoin in 1953. Four hundred and thirty-seven men were mployed in one plant and 181 in the other. All but thr| te (from the Ferrara plant) were followed to the end of 1984. Expected deaths were esti- mated by multiplying he person-years at risk by the corresponding nationa] mortality rates for each five- year age group and eacp five-year period of the study, The total expected hs in each case amounted to more than 10 "it of th employees in the two plants (12.4 and 12.8 "). Clinical information eas sought about the cause of tdeath of all (he 55 em yees of the Ferrara plant who had died. Revised diagt} oses, which were not used for comparison with the expected deaths, revealed four deaths from cancers o the liver in place of one. The Ravenna plant id not begin operation until f1959. Six hundred and t irty-eight men were employed. 1,/UI but four were tracad to the end of 1983, and 17 (Were found to have diecj|. No man could have been fol- for more than years, and only 25.1 deaths fc of the work forde ) were expected. The data for )fcis plant have not, thanefore, been used in the prin- dpal analyses. It may |be noted, however, that one death was attributed to liver cancer when 0.1 was ex- peeled. Other sources. The Nor+egian study (22) provided obserrations on 454 men ^vho had been employed in a pfant in Telemark where VCM had been manufactured Irom 1950 to 1971 and t'VC from 1950 to the end of !he studv period. E'-erv man was included whose name was recorded in the company's personnel register and health department records who had ever been cmployed from the start of production to the end of 1969 and had worked lor at least one year. The men were lollowed from 1953 to 1979 inclusive. Deaths and cases of cancer were identified from the records of the Cen tral Bureau of Statistics and the national cancer regis try. No reference was made to any men being lost to follow-up. but it can be assumed that the number (if not zero) was small, as all citizens have an identity number which is used by both employers and central agencies. Fifty men were found to have died against 59.34 expected if the sex-, age-, and quinquenmumspecific national mortality rates had operated. Twentyone men were found to have developed 23 cancers against 20.16 cancers expected from the comparable national incidence rates, the use of which was justi fied by the finding that the incidence in the county in which the plant was situated was between 90 and 95 of the rate of the country as a whole. One man who had been employed in PVC production developed an giosarcoma of the liver. The observed and expected numbers of cases were given for cancers of the lung, colon, and thyroid, for melanomas, and for all can cers, but no expected numbers were given for other types of cancer. It is evident that several other types of cancer must have been in deficit, as there were eight cases in all against 14.93 expected, and it is difficult to know what weight to give the excesses observed for the reported types of cancer, as they seem likely to have been reported specifically because the numbers were in excess of those expected. The authors noted that one further case of melanoma had occurred after the closure of the study and that one "incipient case" was also known lo them. The German study (49) included the following three groups: (i) 7 021 men who had been exposed to VC in the course of their employment in any of the II plants in which VC and PVC had been produced in the Federal Republic of Germany, (ii) 4 820 men who had been employed in seven chemical plants without having had any exposure to vinyl chloride, and (iii) 4 007 men employed in two other plants where PVC was processed. Employees were included oniy if they were of German or Austrian nationality, and they were regarded as exposed to vinyl chloride if they were production workers or other skilled workers or laborers assigned regularly to the plants, but not if they were employed in them only occasionally. All the men were included from the time of opening of the plants to the end of 1974, and they were followed to the end of 1974. Many of the men were therefore observed for only a few years after first employment, and only 14, 36, and 19 respectively, of the three groups were first em ployed before 1954 and were therefore capable of con tributing person-years at risk more than 20 years after first employment, when an occupational hazard of can cer could be expected to be observed. 65 Of the exposed group 93.2 To were succes fully followed, and causes of death were discovered fir 92.8 Ti of the -114 men discovered to have died. Th proporlions for the other two groups were respect vely 89.8 and 88.7 for the unexposed and 92.1 an i 86.9 To for the PVC process workers. The failure o obtain causes of death for all the men who had died was allowed for in the subsequent analysis by th: weight ing of the numbers attributed to each cause by a sys tem which took account of the age group a id calen dar period in which death with an unknown tause oc curred. The expected numbers of deaths ft am each cause was calculated by multiplying the person-years at risk by the sex-, age-, and cause-specific mortality rates for the Federal Republic of Germany. National data before 1968 used an idiosyncratic classification system, and the 1968 rates had to be used to multiply all the person-years at risk up to the end of I )68. For subsequent years (1969 to 1974) the person-yea-s at risk were multiplied by the corresponding rates for he same calendar year. Epidemiologic studies are more difficult to c arry out in the Federal Republic of Germany than i i North America, the United Kingdom, or Scandinavia because (he medical cause of death is not recorded f ublicly, and there is no central system which can be used for checking whether an individual is alive or cead. In these circumstances, the German authors hate made valiant efforts to obtain reliable data, and the oroporttons of men in the exposed groups who were tor suc cessfully followed (6.8 To) and the proport ons of deaths for which the cause was not obtained 7.2 To) were similar to those in the study of the Enviroi mental Health Associates (14). Two defects, however, make the data less useful. First, no national mortality rates were availablt before 1968. and the use of the 1968 rates to estimate tf e num bers of deaths in and before 1968 will have o 'crestttnaied the numbers attributable to diseases th n were becoming more prevalent or were being dia [nosed more often and underestimated those due to c iseases that were becoming less prevalent. Second, an I more' importantly, a large proportion of the men had been first employed less than 10 years before the fol ow-up ended. Therefore the useful observations on t le few men who had been exposed long enough to ha te had much chance of developing an occupational < isease with a long latency period must have been sw imped by a mass of other observations that had little (} con tribute. The expected deaths amounted to only 5.2 To of the exposed men, and there is, therefore, liule to be gained, and something to be lost, by includi tg (he German data in the overview. It may be noted how ever, that 12 deaths were attributed to cancer of the liver among the workers exposed to vinyl chloride against o 9 expected and that smaller excesses we e also observed among the tinexposed chemical workers (4 observed jgjinsi I I expected) and the PVC.' p ocess worker-, ' 1 deaths against 0.8 expected). Two Swedish plants have produced VCM and PVC. one since 1945 and the other since 1971, and employees of the first plant have been studied by Bvren et al (7) All persons who had ever been employed when expo sure to VCM could occur were listed from the per sonnel files of the factory. Twenty-one were excluded because they were foreigners who left the country after a short period of employment. The remaining 750 were followed to October 1974. Expected numbers of deaths were estimated by multiplying the person-years at risk by the corresponding age-specific mortality rates for the whole country, and the expected numbers of can cer cases from 1958 to 1971 inclusive (during which period all cancer cases had been registered nationally) were estimated by multiplying by the national agespecific cancer incidence rates. In both instances, the rates used were those recorded in 1969. Fifty-eight deaths were found, but no figure was given for the ex pected number. Detailed figures were given only for the numbers of deaths and cases observed and expected for cancer of the lung and for cancers of the liver and pancreas combined and for the numbers of deaths from brain cancer and three categories of cardiovas cular disease. Two men known to have angiosarcoma of the liver were certified as having died of liver can cer or pancreatic cancer, and a third man died of angiosarcoma of the liver 17 months after the close of the follow-up. Two French studies provide the results of a long term follow-up of men employed in one plant (41) and of a short-term follow-up of men employed in 12 plants (Laplanche et al, unpublished). The first provided ob servations on I 311 men exposed to vinyl chloride in the production of VCM and PVC and in selected an cillary operations from the opening of the Tavaux plant in 1953 to the end of 1976 (41). Six other employees were excluded from the study because of lack of oc cupational histories and 160 men because their vital status at the end of the study period was undetermined. Twenty-five men were found to have died against 48.75 expected from contemporaneous sex- and age-specific national mortality rates (3.7 T of the men at risk). One death was attributed to angiosarcoma of the liver, in a man who had been exposed for more than 15 years. The reported data are so incomplete and cover such a relatively short period from the opening of the plant that they add nothing of epidemiologic value to the results of the other studies, apart from the addition of a further case of angiosarcoma. The second study provided observations on I 100 men aged 40 to 55 years who, in 1980, were exposed or had been exposed to vtnyl chloride in 12 plants, which constituted "most of the French VCM polym erisation plants" (Laplanche et al, unpublished). Many oi the men were, or had been, employed at Tavaux and were presumably survivors of ihe cohort studied by Pierre et a'l (41). The men were followed for live years, and their morbidity and mortaltiv "ere com pared with those observed loi i loo men oi ihe s.imc ages ( 2.ve but who in both gre formation drinking ha two groups first expose, first been er ously. More nually by the 98 % of the One of the e' developed ar. given separa ploymem, ar of the findir lung cancer . well reflect a in the referer cancers in the One exposed hemal opoiet is none ol the ir dcveloped me roid. A Japanese pertence of 4 before 1965 ir ducing VCM stve (37). The Twenty-eight *- than 20 years a served more t h _ umraced, and . tamed for all t: initial cohort l to the job in vs *( the terminal given separate!;, in PVC produs classed as VC.\ If this study should provide ' present data inc! ( than 20 years at use- They confi ti' cancer with six workers against while only one ' Ofher workers a. deaths from live workers was cer liver, and at leas was due to the x. not in excess (2.^ c\|'s\ ted). No d.i (li.itis .uni Iiciii. "M ,i| Ills | VI tit. SPI-01277 VCM and PVC I, and employees y Byren el ai (7). oyed when expoed from (he perme were excluded : ihe country after maining 750 were lumbers of deaths ;rson-years at risk uortality rates for J numbers of canive (during which istered nationally) the national age>oth instances, the 1969. Fifty-eight as given for the exere given only for erved and expected ers of the liver and lumbers of deaths ones of cardiovashave angiosarcoma g died of liver canthird man died of nths after the close e results of a lonzn one plant (41) and mployed in 12 plants he first provided obto vinyl chloride in 5 and in selected ang of the Tavaux plant Six other employees cause of lack of ocn because their vital >d was undetermined, ave died against 48 ~5 sex- and age-speeilic the men at risk). One rcoma of the liver, in r more ihan 15 tears, iplete and cover such e opening of the piant miologic value to the art from the addition ima. observations on I 100 in 1980. were exposed chloride in 12 plants, e French VCM polvmal. unpublished). Many , employed at Tavaux s of the cohort studied were followed for five d mortality were com1 100 men of the same *4 ( t 2 yearsl Who were ejn ploved in the same plants bui who had never been e posed to VCM. The men to both groups were inter' wed personally, and in formation was obtained bout their smoking and jdrinking habits, which wer^ found to be similar in the groups. The men in th exposed group had been exposed for an average)|of about 14 years and had flni been employed in the about 18 vears previ- OwJy. Morbidity and morta ity data were recorded an- utoly by the plane physiciali , who successfully traced 9* of the exposed men ahd 96 % of the referents, ..Ooeof the exposed men, butj none of those unexposed, dosdoped an angiosarcoma bf the liver. Data were not gtoen separately for differed periods after first em- vploymem. and it is impossible to assess the significance Si*-of the finding that six of thf exposed men developed tong cancer against two of he referents, which may reflect a chance occurrede of unusually few cases to (he reference group, as t proportion of all lung <Wers in that group (2 out [if 15) was unusually low. One exposed man developed a cancer of the ivmphotomaiopoietic system against] none of the referents, but Ooe of the men in either grp up were known to have developed melanomas or cab cer of the brain or thy- raid. - A Japanese study has eported the mortality ex- ptficncc of 4 524 men empltj ved for at least one year before 1965 in 25 Japanese plants which began pro- during VCM or PVC betw< n 1949 and 1964 inclu ***(27). The men were To11c|d' ed to 31 October 1975, Twenty-eight percent of the (nen were observed more ttaa 20 yCjrs af(er first empi(^ ymem, but none was ob- 'txJ more than 26 years, y 0.6 of the men were siraerd, and copies of the d| ath certificates were ob- lamed for all the 209 men w hb Ihad died (4.6 % of the *ul cohort). Individuals vfere classified according W (he job in which they hacj been longest employed * the termination of their fibllow-up. and data were py*n separately for the 2 546 men classed as employed to PVC production and I 8 others (including 900 <tosvcd as VCM production vorkers). fH (his study is continued or another 10 years, it bouW provide userul additj information, but the it data include too few observations on men more years alter first exposljire to be ot any material They confirm the evtdejuce of a hazard of liver with six deaths amotj g the PVC production at against 2.54 expectid from national rates. only one such death w||as observed among the workers against 1.82 pected. One of the six b* from liver cancer am ring tI he PVC production workers was certified as due :o angiosarcoma of the . and at least one of the (ther liver cancer deaths due to the same cause. L|ung cancer deaths were excess (2 observed in PVCvworkers against 2.33 ; 'pecietl). No data were giverj for cancers of the lym- ptotK and hematopoietic syystems. for cancer of the brain or thyroid, or for m elhnomas. The mortality reported by Masuda (33) for jo5 Japanese vinyl chlo- ride worxers has presumably been xuosuined m Na kamura s (37) later and larger studv. Hazards of cancer The results of the four most useful studies are iisted individually in tables 1 and 2. The overall results for all causes, liver cancer, and three broad groups of con ditions are shown in table 3. and those for 10 types, or classes, of cancer are presented in table 4. Data have not been reported for each type of cancer in each study, and the sources of the data are. therefore, specified separately for each type. Additional information ob tained from four other less informative studies (4, 7, 22, 49) is given in table 5 for seven types or classes of cancer. Table 3 shows that, apart from cancer of the liver, the overall mortality is what would be anticipated for an industry without any major hazard of accident or disease. In particular the standardized mortality ratio (SMR) of 84 for diseases other than cancer is typical of the ratios that are commonly observed for groups of employed men. A low SMR of this order reflects the "healthy worker effect." which results from the selection process that inevitably excludes some of the least healthy members of the population from indus trial employment. This effect does not. however, nor mally affect the mortality from cancer beyond that ob served in the first few years alter the start of employ ment, and an SMR of 102 for cancers other than can cer of the liver is compatible both with the absence of hazard and with SMR values of 84 for other diseases and 77 for accidents, poisonings, and violence. Angiosarcoma. Death certificates are an unreliable source of information about the histology of cancers that cause death, but there is no reason to suppose that the excess mortality attributed to liver cancer (or, in the US series, liver and gallbladder cancer) is not entire ly accounted for by the known hazard of angiosar coma. Fifteen of the 37 deaths2 attributed to cancers of the liver and gallbladder in the US series are known to have been due to angiosarcoma of the liver (14). In the UK series, seven of the 11 deaths attributed to liver cancer, not specified as secondary, were known to be angiosarcomas, and they ail occurred in auto clave workers against 0.38 expected liver cancers of all types (P< I0~') (25). In the Canadian series, histo logical review showed that seven of the eight so-called liver cancers were angiosarcomas (one had been de scribed as an angiosarcoma on ihe death certificate, two as hepatomas, and five as unspecified liver can cers). One so-called liver cancer death was found to have been due to cancer of the sigmoid colon, while one death attributed to angiosarcoma of the perito-1 1 Increased to 39 in table I to take account of the 97 extra deaths from an unknown cause. 67 Table 1. Observed and expected numbers of deaths f om different cancers reported m tne four principal studtes i4. 14 25 46) )0 = observed number of deatns, 6 = expected nur ber ot oeatnsi Type or class ol cancer United State: 0M e United Kingdom O6 Canaoa OE Italy O E 8uccai cavity and pharynx Esophagus Stomach Large intestine Rectum Liver Liver and gallbladder Pancreas Other digestive Larynx Lung Other respiratory Bone Skin (nonmelanoma Melanoma Prostate Testis Bladder Kidney Other and unspecified urinary Brain Eye and central nervous system Thyroid Lympno- and reticulosarcoma Hodgkin's disease Leukemia Multiple myeloma ) Other lymphatic ) Other AH cancers 13 11.55 7 8.07 11 1601 21 28 79 39 5 77 17 18.40 118 115.67 5 6 38 2 1 81 6 7.36 16 15.20 5 8 46 12 906 25 12.76 12 7 98 3 5.45 14 13 94 46 40.50 383 341.73 4 3 58 6 14 34 26 23 91 9 13 94 11 10 49 11 1 94 7 988 4 2.21 81 92.12 0 0 64 a 0U 6 5 26 . 2 5 78 2 1.74 12 9 59 2 1 38 14 8 00 3 4 10 3 4 29 4 6.18 2 0 43 4 2.35 3 2 50 7 5.16 2 2.35 18 8.12 235 22860 ) J l 1 1 I 2 20 1.67 0 95 16 37 1 08 1 06 3 30 0 12 1 06 0 07 1 09 12 0 02 1 07 1 07 0 04 0 07 9 45 30 21.1 * Observed deaths multiplied by 1 0674 and rounded otf o the nearest integer to allow lor deaths without discovered cause T*6le 4. Morr <0 = observed Type or class . Mouth and phe Ogestive syste Respiratory sy: Lung Genitourinary Melanoma B'jm thyroid Lymphatic and Other ah other man c t = United Sta Table 2. Numbers of deatns from nonmaiignant and all causes reported in the four principal studies (4. 14, 25. 46) (0 = observed number of deaths. 6 = expected number ot deaths) Cause of death United States United Kingdom Canada Italy Benign and other unspecified tumors Cerebrovascular disease Ischemic head disease Other circulatory disease Bronchitis6 Pneumonia Other respiratory dlseasa Cirrhosis of the liver Other digestive disease Olsease of the gemtoonnary system Other diseases Suicide Accidents and other violence All nonmaiignant causes All causes 4 5.08 75 91 93 521 597 73 157 123.55 44 22.83 16 31.94 15 32 84 37 56 06 27 39.52 11 20.41 87 115 66 49 52.78 130 173.19 1 153 1 363.54 1 536 1 705.27 276 105 36 ! 40 5 43 } 40 545 780 288 141 ' 144 1 6, 15 1 79 50 665 894 I25 31.67 l 6 3.21 j 3 85 2 5 40 2 10 58 39 54 76 59 71 07 * See footnote to table i 0 Emphysema m data from the United States c includes two cases certified as cirrhosis of the liver wfich proved to be angiosarcoma ol the liver J includes one case with cause unknown 0 0.5 19 27 4 3 5.0 4 52 3 2.7 2. 1 4 36 66 70 0.9 77 564 77 5 neum was found to have been due to angiosarcoma ot' (lie liver (46). In the Italian study, further evidence reve.ileJ that ihree further deaths should have been ; 6.X tribuied to cancer of the liver (for a total of four), but only one of the four wa* described as an angtosareoiua (4). SPI-01279 Tm* 5. Mortality number ol deaths Type or class of < Ofgestive system (eluding the nv Lung Melanoma Efc.ew. _ Thyroid Ivcc Lympftetlc and he potetic system V Owtef (eicluding t l deluding the Viy* Incidence end c. *_'[ Cancer ol the m fjfr Cancer ot the lu SyK' Ft ' Further evident cancer (or liver ar - .m 1 attrihtited i i .Iftl Ol .lltlJIOV 1 . . t.Ct de.ll ia _ Italy 0 E t 08 i 06 3 30 0 :2 1 05 0 07 1 09 12 6.1 0 02 1 07 1 07 0 04 0 07 9 45 30 21.1 iout discovered cause. 14, 25. 46). 10 = oBserved } 1 i ! 5 7 Italy 0 E 0 0.5 19 27 4 3 50 4 52 3 27 2 70 1 09 4 77 36 56 4 66 77 5 r.ible 3 " 1' ' ''''m r ^ 'HP hver anrj Ol hp' ' Joses 9mnr g , m v i - mof' - ;p Anr-U'- '> ;hP fqijr 'ii"'i[Mi -turtles coi^oinpo id 14 25 46) O = observed numcp' o' jeams E r i number of eaths. SMR = standardized mortality fano' Cause of a Cancer of ! ie liver * Cancer of c Iher sites Other disea ses Accidents. JOiSOnings. and violence ah causes 5g 609 i 547 226 2 44 1 3 45 599 35 1 844 89 2957 5 2 747 84 Including cancers of the gallbladder m the series from tne United States. 698 02 94 77 39 Mi 4. Mortality from > anous cancers among vinyl chloride workers m 49 plants in the four principal studies combined. OOaecveO number of 3eaths. E = eiposed number of deaths. SMR = standardized mortality ratio) I or class of cancer OE SMR Source of information i and pharynx thre system (other t|tan liver) ttory system g.HABftrtfurtnary system ^Msaanoma fetbr--d fi--fUc and hematopoetic system r than of the liver 18 16 57 '25 154 59 223 229 36 211 214 09 70 62 81 2 1 94 29 19 54 2 0 43 57 50 87 83 63.24 609 599 35 109 i. 2. 3. 4 81 i. 2. 3. 4 97 1. 2. 3, 4 99 1. 2. 4 111 1. 2. 3. 4 2. 4 148 1. 2. 3 2 112 i. 2. 3. 4 131 i. 2. 3, 4 102 i. 2. 3, 4 l*. I United States study 14), 2 = United Kingdom study (25). 3 = Canadian study (46). and 4 = Italian study (4). #7t.: Tefete V Mortality* from i arious cancers among vinyl chloride workers Supplementary evidence (4, 7, 22. 49). (0 = observed f of deaths. E = ex reeled number of deaths. SMR = standardized mortality ratio) :.vT. * Py?r > tw or class of cancer Federal Republic of Germany <ii plants) Norway (1 plant) Sweden (1 plant) Italy (1 plant) Four countries combined (14 plants) SMR gjfc-t Blgninre system ?t --rinding the liver) Meeenoma 1 and hematoSjJgj --ic lyittm rjv QW --eluding the liver tOidtno me liver 35 0 31 8 23.5 24 6 2.1 1.3 16.5 7 7 107 24 3 87 8 89.7 3 1 44 5 2 84 4 079 2 0.16 3 1.78 2 0.33 8 u 93 22 20.18 5C 2.11c 1 12 0 15 0 0.1 0 07 4 2.0 5 5.7 39.0 31 5 40 41 2.0 16 5 227 119.8 34 44 30 72 0 89 1 63 0.16 84 41 43 117 67 113 103 196 55 102 and cases in he Norwegian study. of the intestine 3niy of the lung and srain only. ver. for a total of four), but bed as an angiosarcoma evidence that the excess mortality from liver (or liver and gall 1 (ladder cancer in the US series) be attributed princiiqally if not wholly to the known of angiosarcom^ is obtained in a comparison cicrvt deaths wi [h the numbers of deaths from --gwronmas recorded in the Register of Liver Angio- sarcoma Cases (maintained on behalf of the Associa tion of Plastics Manufacturers in Europe by the Im perial Chemical Industry PLC) before the end of the follow-up period (Bennett, unpublished). Fifty-one ex cess liver cancers are recorded in the combined data, and 49 angiosarcoma are recorded in the Register for 69 Tab)# 6. Mortality from lung cancer in tne senek from the United States (US) <14) and the United Kingdom (UK) 125) Oy characteristics relevant to an occupational hazard (0 = ot>served numoer ot deaths. E = expected number bi deaths. SMR = standardized mortality ratio) be seen than in other groups. This circumstance is illustrated by table 6. which shows that the SMR values are slightly higher lor men observed 20 years or more alter first exposure than for men observed earlier, for Oata characteristic* Category 1 0 E SMR Category 2 0 E SMR men employed before 1956 in the UK than for men first employed after 1955 (when exposure levels are believed to have been lower), for men employed for Observed 20 years or more after first employment (i), others (2) Employed 10 years or more m (he US (i), others m me US (2) Employed before 1956 m tne UK (1), others m tne UK (2) Ever emoioyed as autoclave worker m the uk (i), others m the UK (2) 114 113.96 100 55 52.45 105 52 51.39 101 16 17 08 94 85 83 91 63 e; .44 99 29 4( 50 72 65 7* 82 87 longer than for shorter periods in the US, and for autoclave workers in the UK (among whom the angio sarcoma cases have mostly occurred) than for other workers. The differences are all small or very small. They are, however, all in the same direction, and the probability that the rates should all be higher in the groups in which an occupational hazard is more like ly to be seen in each of the four pairs of groups is 1 in 16. Additional information from other sources is given in table 5. A total of 30 deaths (or cases) was observed, and this figure increases to 31.5 when allowance is * The numoers in parentheses designate the category. 0 See footnote to table 1 for observed deaths in the US. made for the number of deaths due to unidentified causes in the German study (SMR becoming 103). In the German study the SMR was higher for the men the relevant periods for the three countries and the two Italian plants3 that are covered by the survey None of the 120 cases yet recorded in the Register were in men who were first exposed after I , and none of the 45 men affected in North Amerl ca were first exposed after 1964. All may, therefore, hive been exposed to concentrations of several hundred (karts per million, and many may have been exposed to Iconcentrations appreciably higher (unpublished reponl by Barr to Air Products and Chemicals Inc in 1981)L who had been exposed for 10 years or more than for those who had been exposed for shorter periods (111 against 79). and, in the Norwegian study, four of the five cases observed occurred in men whose occupations were regarded as involving high exposure against 1.82 of the 2.84 expected. Both the German and the Swed ish studies derived the expected numbers of deaths from national mortality rates for a single year towards the end of the study period. The expected numbers of deaths are likely, therefore, to have been overestimated and the SMR values correspondingly underestimated Lun% cancer. The idea that exposure to vinyl hloride might cause cancer of the lung was suggested tkv MI on- as the mortality from lung cancer had been rising throughout the period of observation. son et al in 1974 (36), when they noted 13 case^ against an expected number of 7.9 in a study of pro!pf>rtional mortality. The combined data shown in table do not provide any support for the hypothesis, either] for respiratory cancer as a whole (SMR 97) or for specified data for lung cancer in the US, the UK, Tand Ii taly (SMR 99). There are, however, consistently hig}<er risks in the subgroups of men in the US and UK series, in which occupational hazards would be more kely to Bram cancer. The idea that vinyl chloride might cause brain cancer was also suggested by Monson et al (36) when they reported five cases against 1.2 expected. The combined data that are shown in table 4 provide some support for this hypothesis. The cases of Monson et al (36) were, however, observed in US workers and must be presumed to be included in the total reported by Environmental Health Associates (14); therefore they will have contributed a substantial proportion of Twenty-nine were registered as occurring in th* United States against an excess of 33; only 20, however, ire iden- uftable in both series. Inquiry has, as yet, failed o reveal information about the histology of the remaining 3 in the cohort study and the origin of the nine extra deatlhs in the register. Nine deaths were registered as occurriqg in the United Kingdom against an excess of nine, but oi e of the tregistered cases was certified as due to a benign hem ngioma and not related to the liver (code 227 in the eighth revision of the International Classification of Diseases). 1 |en cases were registered as occurring in Canada against excess of eight; (wo were recorded as being in men who l|ad been employed for live years, and it is possible that ivLa,ctual Jurjnon had been slightly le^s than live years con- woueiii exclusion from the Canadian cohort. One ase was reei>ural .I'v tKiumng m one ol the two luha i plants .icjuiw oi s.\^es% v>i less ihjn one the total in table 4. As a test of the hypothesis the data of Monson et al ought, therefore, to be subtracted from those in the table. Their investigation was not a cohort study, and their expected deaths do not cor respond exactly to those in table 4. If, however, the observed and the expected cases are both subtracted from the totals, twenty-four observed deaths remain against approximately 18.3 expected, a difference which might easily occur by chance (P one-tailed = O.l).4 ` If the study ol Wjxweilet et jl 150) is regutded .is ihc origin ol I he hypolllCMS, 2ts de.illlx .if v li/ll .iv.intsl is 'U , s pclvj l P one ijitcJ - 11 117) SPI-01281 AdditlO' given in ic little furth one of the occurred it less than a the excess ,, German s; chemical w deaths aftc causes agair PVC fabric, for deaths f- Cancersof. idea that nr phatic and h the lymphat & Gaffey (45 studies, whe from lymphe gainst 2.54 = the lymphatic petted. These if the laborau suggesting tha tally in antmc non (29). The cause lymphe Otts considera studies that a: support for tr lymphatic anc jrther (57 dea and very little fo cancers of: fey's definitior .200--203 and 2 ! <35 deaths as ^oreover, hare ^Giffey's initial g23.36 expected, "'Utile additic Remits of the G dy obtained f(bt*edon 15 ob- ance is ma. i causes) a lonexposed gr, gtBfPVC fabricat Jegposed workers 2been exposed foi was most m_ for fise years or the number of u t " e peeled. IvC IS allies more t. (or men Is are ;d for id for angioother small, nd the In the e likeps is I > given ;erved, ance is ntified 03). In ie men lan for ds (111 r of the ipations nst 1.82 e Swed- deaths towards nbers of nimated timated n rising hr cause ct al (3b) .ted. The ide some onson et kers and reported therefore ortiou of v the data ubtracicd i was not a not eorvever, the ubtraeied hs remain difference .e-tailed = as the origin .94 expected \ddii uni.il ml urmai inn I ro 1 r-.vi' other sources is alien in iable 5 I lie small ex ss reported provides little further evidence of an o cupational hazard, as one of the iwo deaths observe m the Swedish itudv occurred in a young man who lad been employed lor less than a year when the dliagn osis was made, while the excess death rate for brain uncer observed m the German study was less than lx at observed among chemical workers not exposed to vinyl chloride (2.9 deaths after allowance for c e.aihs from unknown causes against 1.6 expected) am among workers in ihe PVC fabrication industry (5.9 ieaths after allowance for deaths from unknown causek against I. I expected). Cancers of lymphatic and hemhtnpoienc tissues. The idea that vinyl chloride might c; luse cancer of the Ivm- phatic and hematopoietic -- more specifically the lymphatic (issue -- was su gesied by Tabershaw & Gaffey (45) and by Waxweiler et al (50) in iwo cohort studies, when they lound, res pectivelv, five deaihs from lymphomas in ihe most ht a vilv exposed workers against 2.54 expected and four i ea ills from cancers of the lymphatic and heniatopoiett tissues against 2.5 e\- pected. These small excesses m :ht have been ignored if the laboraiorv findings had i )t been interpreted as suggesnng that lymphomas wert produced experimen- tally m animals exposed to vi I chloride by mhala- non (29). The idea that suntlat exposure might also cause lymphomas m humans, hetefore. merits xeri- ous consideration. The data I the four principal studies that are summarized in table 4 provide little support lor the hypothesis w n all cancers of the lymphatic and hematopoietic us ties are considered lo- get her (57 deaths against 50.87 xpectcd, SMR I 12) and very little more is obtained Irom theseparaiedata for cancers of the lymphatic sysi m iTabcrshaw & Gaf- fev's deli ii it ion of IC'D list nun bers. eighth revision, 200--203 and 205 being used) t al are shown in table I (35 deaths against 29.40 expev edl. The position is. moreover, hardly altered if the Jata in Tabershaw & Gal fey's initial repori are subtractled (29 deaths against 23.36 expccicd, SMR 124). Lurie additional inforinaiioi is provided by the results of tlie German study (4`) (See table 5.) This study obtained an SMR of 214 for exposed workers (based on 15 observed deaths, i rjereased lo 16.5 when allowance is made for the num b t of deaihs from un- known causes) against SMR v a i tics iof 77 and 34 for an unexposed group of chemical workers and a group of PVC fabricators. It showed hat the excess of the exposed workers was present c ly for men who had been exposed lor more than one vear and that this ex- cess was most marked for men u lio had been exposed for five years or more (10.7 dealt s alter allowance for rhe number of deaths from un kliow n causes against 4.0 expected. SMR 268, P one ailed <0.01). Melanoma. An excess ol mclaii tna was reported for Norwegian workers by Heldaas t al (22). who raised ihe possibiluv 'hat vmsl chloride might have produced the disease. Lour caves were observed when t) '9 were expected, and three of the four were in men whose oc cupations involved the highest exposures tagainst 0.51 expected) At the time of the writing of their report, one further case had been detected with onset three years alter the closure of Ihe study. Subsequent studies in other counrries have, so far, reported only two deaihs against 2.0 expected. (See tables I and 5.) Thyroid cancer. z\n excess of thyroid cancer was also reporred in the Norwegian study (22). in which iwo cases were observed against 0.16 expected. The inves tigators were not aware of any other studies indicating an excess of this type of cancer, and they drew no con clusion from their observation. Two of the three major studies that have been reported since the Norwegian observation was made gave no data lor thyroid can cer: the third reported two deaths against 0.43 ex pected. (See table I.) One death from thyroid cancer, it may be noted, was reported in the US by Monson ei al (36). Cancers of the digestive tract. Suggestions that vinyl chloride might cause cancers of the digestive tract in general have sometimes been made, but they have not taken adequate account of the contribution of cancers of the liver to the total number of cancers of the digestive system, particularly when it is borne in mind that some liver cancers are likely to be misdiagnosed as cancers of other organs. The combined data from the four principal studies shown in table 4 weigh heavily against (he idea that any such effect has been produced. Other cancers. One of the remaining types, or classes, of cancer listed in table 4 shows a statistically signifi cant excess, namely, the heterogeneous group of "other cancers" (83 observed deaths against 65.24 ex pected. P two-sided < 0.05). This excess is only mar ginally significant and may be a chance observation. The most likely explanation is. however, that a few angiosarcomas of the liver were nol recognized and were diagnosed as secondary liver cancer or carci nomatosis, site unknown, ihe number oi deaths m this category therefore being increased. Hazards of nonmahgnant disease No previous study has suggested that any nonmalignant cause of death other than cirrhosis of the liver would be likely to be increased as a result of exposure to vinyl chloride, and cirrhosis of the liver is presumed to be increased only because of the liver changes that were observed as pan of the "vinyl chloride illness" (24, 31. 33). Two other possibilities have, however, been raised, namely, the production of nonmalignant respiratory disease, because of the changes in lung function and radiographic appearances that have been 71 TiDle 7. Mortality 'rom selected nonmalignant auses and all causes ,n Ihe lour principal studies combined ) = observed numoer of deaths. E= expected numper ol deams. SMR = standardised mortality ratio) Type of disease Bronchitis, empnysema Other respiratory disease 0 SMR Source of nformation 80 66 83 120 . 2 71 125.78 56 , 2 recorded for men exposed to PVC dusi (2, 26, 27, 44), and acute cardiac death, from analogy with ihe effect of other halogenated hydrocarbons (25) and ihe ob servation of an increased mortality from myocardial infarction in the few years following the cessation of exposure in ihe Swedish PVC processing industry (35). Relevant figures for the numbers of deaihs from these and other nonmahgnant causes that are obtainable from ihe four principal studies were given in table 2, and they have been summarized in table 7. AM resoiraiory disease ischemic heart disease Other circulatory disease' AM circulatory disease- Cirrhosis ol lha liver Other Oisease ISO 797 252 1 103 46 238 200.82 885.73 264.55 1 209 35 66 26 368 07 AM nonmahgnant disease AM external causes 1 547 1 844 50 226 295.15 AM nonmalignant causes AM causes 1 773 2 139.65 2 441 2 747 65 80 , 2. 3, 4 90 ,2 95 .2 91 . 2. 3, 4 69 . 2. 4 65 . 2, 3, 4 84 . 2, 3. 4 77 . 2. 3, 4 85 1 , 2, 3. 4 89 1 , 2. 3, 4 f = United States study (ta). 2 = United Klngdofi study (25), 3 = Canadian study (46). and 4 = Italian study < Bronchitis in tne united Kingdom study. empn^s<lema In the United States study. Includes cerebrovascular disease in tne United Kingdom and Italian studies. Table 4. Mortality from chronic obstructive lung disease* In Ihe series from tne United States <US)(14) and the Jmted King dom (UK) 125) by characteristics relevant to an o xupational hazard. (0 = observed number of deaths, E = eipeqted number of deatns, SMR = standardized mortality ratio) Data characteristic0 Category i SMR Cat igory 2 SMR Observed 20 years or more after first employment In the US (t). others in the US (2) 30 15.8 190 11 7.0 157 Employed 10 years or more in the US (i), others in the US (2) 16 10.9 147 25 2.0 208 Employed before 1956 In (he UK (1), others in tn# UK (2) 26 30.17 86 10 3.60 74 Ever employed es an autoclave wonter tn me UK (1), others m me UK (2>c 3 6.55 46 33 7 22 89 Described as empnysema in the US study and as bronchitis in the United Kingdom study. The numbers in parentheses designate the cat qgory Men ever employed as a bagger or oner, occupat ons w< hich wou'd nave caused Ihe greatest occupational e posure to polyvinyl chloride dust, experienced one death rom brononuic xijamst 4 98 expected Cirrhosis of the liver. Three of the four principal studies gave separate figures for cirrhosis of the liver, none of which showed an increased mortality (table 2); in combination they gave an SMR of 69 based on 46 deaihs. The fourth study, which did not give sepa rate data for cirrhosis of the liver, reported four deaihs from all diseases of ihe digestive system combined againsi 3.85 expected and noied [hat the four included two that were certified as due to cirrhosis of the liver, but actually due to angiosarcoma (46). In the two sup plementary studies in which data were given for this disease, the SMR was 82 in one, based on 15.1 deaihs after allowance for the number with unknown causes (49), and 133 in the other, based on seven deaths (37). Nonmalignant respiratory disease. The data for nonmalignam respiratory disease are confusing in that the total SMR from the combined data for the four prin cipal studies is 80 and is the sort of figure that is com monly found in healthy industrial populations, yet the US study recorded a substantially increased mortality from emphysema (41 deaths and an SMR of 180 be fore any allowance was made for deaihs from un known causes). No such excess was found in the UK, where 36 deaihs from bronchitis gave an SMR of 82. International comparisons of chronic nonmalignant respiratory disease are complicated by the usage of dif ferent terms to describe what it is now agreed is best called chronic obstructive lung (or pulmonary) disease, but which in the past tended to be called emphysema in the US and chronic bronchitis in the United King dom. It must, therefore, be presumed that the two categories of "emphysema'' and "bronchitis" used re spectively in the two targe national studies were meant to describe the same thing. One must assume, there fore, that the experiences in the two countries were very different, despite the fact that both related to cohorts that had very similar experiences of angiosarcoma of the liver and so, presumably, fairly similar exposures to vinyl chloride. Separate figures are shown in table 8, where avail able, for the mortality observed among men with dif ferent durations and intensities of exposure. Unlike the data for cancer of ihe lung that were shown in table 6, (hey provide no conhihieni evidence ol a greuier risk in ihe groups m whiv.li an iks.uimhomjI hu/.ud would be expecte vTronmen; to give ar from erne hardly be n no overall however, : by deficier respirators other respi the questic could be . Health Asss that they w m the out-c the coding L "other respi ' included en~ nnphysema be classified <o 502, and t of (he empfr in some catec oumber 527. lor both the e irossly defic respiratory c No excess r tod asthma" ** with 6,3 c amber of dc 2- Crnfiovascu/c "y derotic) hear ^ tfodc the vast , 10 acute cardi sbg national si Increased m ^groupof disea; i recorded : Etfthe SMR va I there is no Idle jubsidiar- . In part mortal: nem in the S, SMR 61 t workers ri slight incre, Irecordec l study (49), * TV deaths ittnb and the cr >*'' *eviion for 4l Health a inr SPI-01283 t iUiifHWI itMft'n iTfl'i lust (2. 26, 27, 44), ogy with the effect s (25) and the ob. from myocardial ng the cessation of ssing industry (351. f deaths from these hat are obtainable :re given in table 2, in table 7. the four principal irrhosis of the liver, sed mortality (table iMR of 69 based on ch did not give separeported four deaths ve system combined hat the four included cirrhosis of the liver, t (46). In the two supa were given for this based on 15.1 deaths with unknown causes on seven deaths (37). ise. The data for none confusing in that the data for the four pnnt of figure that is comtal populations, yet the fly increased mortality nd an SMR of 180 be: for deaths from un> was found in the UK, ns gave an SMR of 82. chronic nonmalignant ated by the usage of difit is now agreed is best (or pulmonary) disease, o be called emphysema utis in the United Kingpresumed that the two nd "bronchitis" used re- ji tonal studies were meant a )ne must assume, there* e two countries were very ' it both related to cohoru nces of angiosarcoma of , fairly similar exposures n in table 8, where avaif ved among men with dif-; ies of exposure. Unlike the that were shown m table t evidence of a greater ruk ccupauonal hazard would j- N expected lo be concern rated. The authors of the En ^toKMuental Health Asst cemies report (14) were unable i'ght any explanation for the increased mortality emphysema, and they point out that it could r be due to excess t garette smoking, as there was I overad excess for car|cer of the lung. It is striking, r, that the excess simore than compensated for j'ddldenaes in the oth r categories of nonmalignant gory disease (pneum onia 15 deaths.5 SMR 47.0; 'respiratory diseas1 14 deaths, SMR 42.6), and ' question arises whrither the emphysema excess be a classificatc ry artifact. Environmental I Associates (14) lis all the 41 deaths which show [they were coded un(ier ICD number 527 which, r out-of-date seventh revision that was used for tcoding of all deaihs the study, was the code for r respiratory disease| not otherwise classified" and I emphysema. U hder that revision, however, i that was ass<opiated with bronchitis should (daauficd with bronchi! is under [CD numbers 500 JQ3.and the possibility may be considered that some t the emphysema death should have been classified -^laeiaccategory of respiraitory disease other than ICD r 327. If this were the:situation, it could account rboUi the excess morta |ity from emphysema and the r deficieni mortality from other nonmalignant aory diseases, tcacess mortality frd|im "bronchitis, emphysema, 14 atihma'' was observed in the German study (SMR Iwwh 6.3 deaths obseirKed after allowance for the Gfttftfxr of deaths from an unknown cause) (49). Pjflmtkiiiin n 'ii disease. Data for ischemic (or arteriohe) heart disease (w!(tich may be presumed to inI the vast majority all deaths certified as due : cardiac disease) Iwere given only by the two anal studies, and |hey provide no evidence of jfgBl mortality Trie SMR values of 90 for this >o< diseases and of for all cardiovascular dis- trecorded in the four (jrincipal studies are typical N SMR values of heal thy industrial populations, : is no suggestion [of any occupational hazard Subsidiary analyses ndftrwtw<iriwriAwHd Kt/jr fvKi tav #t /v/> <nlunkiieivtintu'tli ria particular, therie is no evidence of an in [ mortality within sane month of leaving em- la the UK studl either for all workers (52 UR 61) or for thq most heavily exposed auto- (9 deaths, $MR 42). 1 increase in iscnemic heart disease mortalkrecorded for the e: posed workers in the Gerr (49), but it was| less than that recorded for i attributed toi diffcirent groups of respiratory dis- I the corresponding SMR values that are cited in wt for the US are as given by the Environ- I IWaJih A'tociates ( j4) and have noi been adjusted aaMt for the numbei| of deaths from an unknown . to Like account of t hlese deaths, the observed deaihs 13MX values can both pe multiplied by 1.0674. ihe unexposed chemical workers and ttie PVC lanricators (SMR values of 127. 131, and 158 based on 97.2. I 26.7. and 109.7 deaths, respectively, after allowance lor the number of deaths from unknown causes). Discussion The information that has now been obtained about the long-term health of men occupationally exposed to vinyl chloride is massive and compares favorably with that available for any other occupational group. Two facts are outstanding. First, the men have experienced a specific hazard of a type of cancer that is normally extremely rare, namely, angiosarcoma of the liver. The rarity of this disease under other conditions made the detection of the hazard easy; but the long latency period before the disease appears after first exposure (almost always more than 10 years and usually more than 15 years) meant that a large number of men had been exposed before the hazard was detected and that it will still be many years before the extent of the pro tection provided by the reduction in exposure in the 1960s and that of the further reduction that followed the recognition of the hazard in 1974 are known. There is. unfortunately, no effective treatment for the dis ease. and the number of cases is reflected in the num ber of deaths. Some 50 deaths have occurred among the 16 740 men who were followed in the four prin cipal studies that have been reviewed in this report, so that approximately I in 335 men have been affected, 2 *<t of the deaths having been due to this one cause. Eventually many more men must be expected to de velop the disease. One estimate (38) suggests that the total may be increased 10 times, but a more realistic estimate is two to three times (19). The second outstanding observation is that the mor tality of the exposed men, other than that due to angiosarcoma of the liver, is typical of the normally healthy industrial worker -- that is not to say that no other hazard exists, but that the effect of any other hazard is small. The massive data that are now available provide no reason for thinking that any hazard other than one of cancer has been overlooked. It is. however, still dif ficult to decide whether vinyl chloride produces a risk of developing cancer other than artgiosarcoma of the liver which might be small compared to the risks produced by nonoccupational causes, but yet abso lutely almost as large as the risk of developing the nor mally very rare angiosarcoma. One of the many hazards suggested can be dismissed, as there is no evidence to support it, namely, that of vinyl chloride as a cause of any cancer of the diges tive tract other than angiosarcoma of the liver. Two hazards (of melanoma and cancer of the thyroid) have been suggested only very recently, and few of the avail able studies have provided information about them. There is no good theoretical reason or laboratory evi dence to suggest that either should be produced by 73 SPI-01284 vinyl chloride, and, in light of present evidence, the simplest explanation is that the reported e tcesses are the chance effects that must be expected v hen many different types of cancer are studied in sever tl different populations. So far as melanoma is concerned, it has to be remembered that the disease has became much more common in recent years in Scandinavia (where the excess was reported) due, it is believed, to the popularity of sunbathing and the increa-ed oppor tunities for Scandinavians to travel to the wi rmer parts of Southern Europe and North Africa. The extent to which this change may have affected the observation in Norway needs to be examined. Two other hazards (of lymphoma and br tin cancer) were suggested by the early results of somt of the US studies. That vinyl chloride might product a hazard of lymphoma was initially supported by t ie prelimi nary results of animal studies, but the comp lete results of the many investigations that have been t ndertaken (see reference 29) do not suggest that lympht ma or any other cancer of the hematopoietic system s liable to be produced. There is, however, some evidence that brain tumors can be produced in rats (29). T be hypoth eses that lymphomas and brain cancers might be produced by vinyl chloride have been supported by the observation that both these types of cancer h ave caused death more often than might be expected fro m national mortality rates, but the excesses observed i i the com bined data from the four principal studies in this re view are small and not statistically significa it, and the hypotheses remain unproved. The small exct ss of brain cancer is particularly difficult to evaluate, as mortal ity rates from this disease have changed r< pidly over time as methods of diagnosis have improvtd and the suspicion of an occupational hazard (which was raised in 1975) could have influenced the findings. What ex cess has occurred has been limited to the U > and Ger many, and the German findings carry little weight, as the excess was found in each of the three oc rupational groups studied, irrespective of the chemica s to which they were exposed. The supplementary dat i from the German study showing an increased mortality from lymphatic and hematopoietic cancers are mi ire impres sive, particularly as the excess was the me st marked for men who had been employed for at least five years. In these circumstances, judgment must s ill be sus pended until the data for each study are ar alyzed for each specific type of cancer, by intensity an i duration of exposure, and by time since exposure icgan. There remains the suggestion that vin I chloride might cause lung cancer. At first sight, th s possibil ity is ruled out by the SMR of 97 for the combined data for respiratory cancer for the foui principal studies. Lung cancer is, however, normal y so com mon (accounting for about 8 % of (he expec led deaths) that an increase in mortality that was half as impor tant (numerically) as the increase in mortality from jngiosarcoma of the liver might easily be i verlooked tvs J,o vonlidence limits of the SMR 85 -- 11 2). The in cidence of the disease varies moreover within a coun try, and there must be doubts as to whether the na tional experience provides a suitable reference lor men employed in plants that are not evenly distributed about the country. In these circumstances one cannot exclude an occupational hazard unless it can be shown that the mortality of the exposed men is independent of the factors that might be expected to influence it if some of it were occupational in origin, namely, (he intensity and duration of exposure and the time since exposure began, li is not possible to examine these relationships in detail, as the reports do not provide all the necessary information. Such information as they do provide, which was summarized in table 6, supports the idea that exposure to vinyl chloride involves a small hazard of lung cancer. Taken in conjunction with the knowledge that lung tumors have been produced in sev eral species of animals exposed to vinyl chloride by in halation (29), it would seem that a small hazard of lung cancer probably did occur. The evidence is not, how ever, strong enough to conclude that it definitely did. If it did, the hazard was evident only for men who had been employed for many years at a time when expo sures of several hundred parts per million or more were common, and any persisting risk can be only minute and incapable of detection. The questions that have been left unanswered by this discussion might well be answered definitely if (i) all the exposed men could be followed to (say) the end of 1984, (ii) the investigators could present their data in comparable ways, taking account of duration of employment and time since first employment and presenting data separately for men first employed be fore (say) 1965 and between 1965 and 1974, and (iii) estimates could be made of the effect of correcting the results for each group of employees for the locality in which they lived and worked. Hazards to the general population As vinyl chloride has been proved to cause cancer in man and is a mutagen in laboratory experiments, it' must be presumed that even the minute doses than escaped into the general environment from production 1 plants or (in the early days of manufacture) from PVC. materials will have caused some risk of cancer to the general public. These risks must, however, have been very small, as air concentrations of vinyl chloride, evenwithin a kilometer of plants handling vinyl chloride,j used to be (in or around 1975) of the order of 10 toj 40 ppb (1,3, 15), and this level is about one-ten thou-j sandth of the concentration that has caused an occu-1 pational hazard, ft is obvious, therefore, that it wou/d| be impossible to detect the risk of any cancer that mights be produced by vinyl chloride other than a risk of3 angiosarcoma of the liver, as it has proved so diffi cult to detect any other risk among men who were ex posed occupationally. The position wuh regard (u an liosarcom.: mally so ra lo one of : dioxide, ar annual inc. In these cir in a man lr. ride was us. controlled of the effe. Severals. whether an-, and Elinder vicinity of p and Sweden *1 (I I) four. 10 thorotras with vinyl c- (J) found U If 12-year peric '* m hved half a plant, and, ir Brady et aJ , E, tnbuted to an & Pte living wn *"ng vinyl ch 'ft SPI-01285 i \ e r vs ii lull a touii' 10 whether the rjle reference lor men evenly distributed istances one cannoi iless it can be shown men Is independent rcted to influence it i origin, namely, r.he e and the time since le to examine these >orts do not provide i information as they d in table 6. supports oride involves a small conjunction with the been produced in sev> vinyl chloride by ini small hazard of lung rvidence is not, howthat it definitely did. >nly for men who had at a time when expomillion or more were k can be only minute .ft unanswered b> this ed definitely if m all 'wed to (say) the end uld present their data count of duration of irst employment and len first employed be'65 and 1974, and dii) rffect of correcting the yees for the locality in tulation wed to cause cancer in matory experiments, it the minute doses that nment from production lanufacture) from PVC le risk of cancer to the ist. however, have been is of vinyl chloride, even landling vinyl chloride. ') of the order of 10 to I is about one-ten thouhat has caused an occutherefore. that n would of any cancer that might de other than a risk of s it has proved so diffimong men who were exisition with regard to an- . ' - .it voniii ol i he in e hiioreni i ins disease is nor- sulU so rare that, m t|he- absence of speed ic exposure to one of the known auses tunyl chloride, thorium tfcoxide. and arsenic n pesncides and medicines), the '--niml incidence is on |the order of I -- 2 I0_: (5. 8).* .la these circumstanced the discovery of even one case a man living close a factory in which vinyl chlo- was used in the d ys before exposure was tightly roiled may be reg^ rded as presumptive evidence ' the effect of envirtjnmental pollution, Several surveys havi been undertaken to determine ^beiher any such case have occurred. Saric et al (43) 'ad Elinder & Pershaj e n (13) sought for cases in the *iriflity of plants handl ng vinyl chloride in Yugoslavia and Sweden and founc none. In Holland Dalderupet i (11) found eight Tirmed cases not attributable 1(0 ihorotrast or arsem|it and could trace "no contact with vinyl chloride." ut they made no specific menlion of the patient's p ace <of residence. Baxter et al gx- 0) found 14 confirmed cases in Great Britain over a 12-year period, one of which was in a tnan who had lived half a kilometer from a PVC manufacturing plant, and. in New Vfork State over an 18-year period. Brady et al (5) found 9 cases that could not be atUibutcd to any known ejause, five of which were in peo- pie living within a m of plants manufacturing or using vinyl chloride. Th overall incidence rates in these last two studies were n t< unduly high, but the occur- lence of as many as so) cases among people living so dose to manufacturing jplants is surprising. Brady and his colleagues, moreov . compared their series of pa nems with matched rel> rents and found that none of the referents lived equal v dose lo a plant. Two of these ux neighborhood case: (one in England and one in New York State) cannotl be attributed to environmental pollution with vinyl ch| oride, as the men who devel- oped the disease had li ed near the plants for six and eight years, respectively before developing the disease, and this period is too s ion to allow for the necessary laiency. The other fou{ cases, however, all occurred after 15 or more years local residence, and (he dis- covcry of these cases s ongly suggests that pollution of the environment arouridtplants manufacturing VCM or PVC may have caus 4d a minute hazard to the gen oil public. Current concentration s around plants handling vinyl : chloride are certainly mil|ach lower than those reported eviously by the U$ Environmental Protection ency. Recent British measurements made within a hundred meters of the VCM areas have given aver- values below the d4 ily limit of detection (5 ppb) for three of five plants, |the readings at the two others being 20 ppb (100 m ou side the boundary fence) and U ppb (just inside it) (47). although substantially higher values were recdrded on two occasions asso- dated with putting one plant into operation and with The figure of 1.4 10 ucd by Healh et al (21) seems lo have been a mispnm fol 1.4 10-'. .in accidem at the oiher According to an\ reasonable criterion ir.e hazard to the general public m there is any at all) must be negligible (42). No other hazard to the general population, other than a hazard of cancer, can reasonably be postulated. Summary This paper reviews (i) the possible effects of vinyl chloride on the personal health of men exposed by virtue of their occupation (oiher than the early effects of the very high concentrations lo which men were ex posed when the industry was first developed -- uncon sciousness. cardiac arrhythmia, and the characteristic "vinyl chloride illness") and (ii) the carcinogenic effects that might conceivably be observed in the gen eral population as a result of the widespread distribu tion of vinyl chloride as a pollutant. The possibility that vinyl chloride might act as a teratogen or might cause mutations in the germ cells has not been exam ined, as the little evidence that has been adduced relating to such possible effects has been reviewed else where and the conclusion was reached that no such ef fects have been demonstrated. Many groups of workers exposed to vinyl chloride in the manufacture of VCM or PVC have been studied since the carcinogenic potential of vinyl chloride was first recognized. Some results have shown that occu pational exposure can cause angiosarcoma of the liver, and others have suggested that it may cause several other types of cancer as well. The actual situation can be determined only in an examination of all the evi dence, especially the combined results of those studies that include a substantial proportion of observations on men more than 25 years after their first exposure and cover a long enough period for more than 10 Vt of the employees to have been expected to die. The results of four studies can be usefully combined for this purpose. They are two national studies, one from the US and the other from the UK. and two studies of employees in one plant in Canada and two plants in Italy. The results of other studies from the Federal Republic of Germany, Norway, Sweden. Italy. France, and Japan can be used only to provide sup plementary information. The many earlier reports of exposed workers in ihe US and the UK concern men covered more completely in the two recent national studies, and their results serve only as sources of hy potheses. Minor criticisms can be made of three of the four most useful studies. They do not seriously affect the value of the results, except that allowance has to be made for the failure lo determine the cause of 6.3 Vo of the deaths recorded in the US study. Three of the studies use national rates to estimate the numbers of deaths that might have been expected to occur in the absence of any special occupational hazard, and the fourth (Canadian) uses rates for the province in which 75 ;he plane was situated. It must, [herefere, be kept in mind that the rates used may not have b ten wholly ap propriate for the localities in which tie plants were situated. This circumstance is potentially important for ihe US study, which covered workers ir 37 plants, 22 of which were situated in the souther r part of the couniry. The other less informative stud :s are, for the most part, open to more serious criticism, and the value of each set of results needs to be assessed separately in relation to each disease. The combined results of the four prii cipal studies show that the SMR values, reflecting the r itios between the numbers of deaths observed and tho: e expected in the absence of an occupational hazard i nuliiplied by 100, have been (i) 77 for accidents and ot her violence, (ii) 84 for diseases other than cancer, ant I (iii) 102 for cancers other than cancer of the liver. All these results are what might be anticipated for an ind ustry devoid of any specific occupational hazard. The ow ratio for diseases other than cancer reflects the "hetlthy worker effect," which results from the selection process that inevitably excludes some of the less healt iy members of the population from industrial employment and is compatible with a higher ratio for cancer as the mor tality from cancer is not normally subjec to such an effect, apart from the first two or three ears imme diately following the start of employmet t. The mortality from cancer of the liver was nearly seven times that expected. Most of the 51 e tcess deaths were known to be due to angiosarcoma, tven though this diagnosis was not recorded on the death certifi cate. The excess corresponds closely with tt 49 deaths due to angiosarcoma reported to (he Inernational Register of Angiosarcoma Cases as occur ing in employees of the plants concerned during ihe periods under observation. All the men who develo led the dis ease were likely to have been exposed to con entrations of vinyl chlonde of several hundred pans >er million or more. Three other types of cancer which hav< been suggested to occur as a result of exposure to inyl chloride are cancers of the lung, brain, and lym shatic and hematopoietic systems. The combined data for the monality from respiratory cancer fail, at irst sight, to support the hypothesis regarding lung cai cer (SM R 97). Higher ratios for lung cancer have, how :ver, been observed consistently in the subgroups in which the effect of an occupational hazard would be nost like ly to be seen (that is. men employed for mo e than 10 years, exposed to higher than average conceirrations, or observed more than 20 years after first e tposure). In two of the supplementary studies it was i Iso noted that the mortality from lung cancer was specifically increased among the most heavily exposed workers. The combined data show small excesses in the mor tality from cancers of the brain and of the I rmphatic and hematopoietic systems. The excesses are, lowcver, not statistically significant, and there is nothu g to sug gest ilui ihcy are occupational in origin. An excep- non is the observation of an increased mortality from cancers of the lymphatic and liemaiopoienc sssiems in the supplementary siudv from the Federal Republic of Germany. Two types of cancer were reported to be m excess in the Norwegian study, namely, thyroid cancer and melanoma. The significance of this finding is difficult to assess because very little information about these cancers has been provided by other studies. Suggestions that vinyl chloride might cause cancers of the digestive tract have failed to account for the contribution of angiosarcoma of the liver. When this disease is excluded, the mortality from digestive tract cancer decreases to below the average (SMR 82 for the four principal studies). A small excess mortality from the heterogeneous group of "other cancers" in the combined results of the four principal studies was statistically marginally significant (83 deaths against 65.25 expected, P<0.05). Some of the excess was likely to have been due to the misclassification of angiosarcomas as secondary can cers of the liver or carcinomatosis, site unknown. The following three nonmalignant causes of death have required special examination: cirrhosis of the liver because of damage to the liver in "vinyl chloride ill ness, " myocardial infarction (from analogy with the effect Of other halogenated hydrocarbons and because of some observations from Swedish PVC fabricators!, and nonmalignant respiratory disease because of changes in lung function and the radiographic appear ance of the lungs observed in men exposed to PVC dust. Far from being raised, the mortality from cir rhosis of the liver was less than expected in the three principal studies and in one of the two supplementary studies which gave separate figures for the disease (SMR values of 69, based on -16 deaths, and 82, based on 15 deaths), while in the other supplementary study the increase was trivial. Data for myocardial infarction have not been re ported separately. But myocardial infarciion accounts for most of the deaths attributed to ischemic heart dis ease, and there is no evidence that either ischemic heart disease or cardiovascular disease as a whole was un duly common (SMR values of 90 and 92, respective ly) or related to occupational exposure. The data for the third category of nonmalignant dis ease (nonmalignant respiratory disease) are confusing, because the two large national studies give conflicting results. The combined data for the four principal studies show the low mortality that is commonly found in healthy industrial populations (SMR 80). This fig ure hides, however, an increased mortaliiy from chronic obsiructive lung disease (SMR 120), which in cludes emphysema and is due to a grossly increased mortaliiy attributed to emphysema in ihe US study (SMR 193). The corresponding mortality in the British study, which was preferentially described as due to bronchitis, was less than expected ISMK 82). as was the mortality trom pneuiiuuii.i ixMH Ni> .nul oilier re- jxeaiory dise o consisten pAytcma or Md it seems U3 study wa del with the Review of toof-term he xwsyl chloride en have expt extremely rar atttdy I in 3/ teadied died o observed ' of time the n: , be expected :. the mortality of that of nor Ward has ex The data pr art other than H. however, st. rxde produces s dor to nonoccc &*er. and, if s cause almost a Sstt. There is too i the suggestion aonu or cancer aad hcmatopoic that have been patIona! hazarc `.nof the lymp fGcman study r mn of chance e: Many types of c ndies. ;..The lack of ar Off In the combi - does nc been a sma t disease, as g the disease tr ill rates fo The great [Maid be more li other group existed. The lencc of a ha Clearer answer posed in ti ls groups Its in more a At vinyl chlor:. and a pro that hare e liif.inis lim ine SPI-01287 jlilv from ic systems I Republic .* in excess ancer and is difficult bout these es. jse cancers jnt for the When this esnve tract R 82 for the erogeneous d results of marginally d, P<0.05). n due to the ondary canunknown, ises of death is of the liver l chloride illlogy with the i and because fabricators), because of aphic appearosed to PVC licy from cird in the three upplememary ir the disease and 82. based memary study i 1t f t i i 0 l Jj c I e not been se ction accounts iemic heart disischemic heart whole was un92. respective- re. nmalignani dis) are confusing, give conflicting four principal ommonlv found IR 80). This figmortalitv from { 120), which in:rossly increased in the US study litv in the British cnbed as due to 3.MR 82), as was 50) and other res- r Ii> * piratorv diseases iSMR 46) in he US study. There is no consistent evidence that tlJe mortality from emphysema or bronchitis was spe| ificaliy occupational. and it seems possible (hat the Reported excess in the US study was an artifact due t nosological difficulties with the use of the seventhl revtsion of the ICD. Review of the massive data now available on the long-term health of men occubationally exposed to vinyl chloride leads to two clear| conclusions. First the men have experienced a specific jiazard of the normally extremely rare angiosarcoma df the liver. Approximately I in 335 of the men ex [josed in the 49 plants studied died of the disease, and pproximately 2 % of the observed deaths were attribukeid to it. In the course of time the numbers of cases df angiosarcoma must be expected to increase two to three times. Second, the mortality from all other ses has been typical of that of normally healthy ind vjstrial workers. If any hazard has existed, its effect has been small, The data provide no reason think that any hazard other than one of cancer hak been overlooked. It is. however, still difficult to deefpe whether vinyl chlo- ride produces small risks of canc| r. compared to those due to nonoccupational causes kt sites other than the liver, and, if so. whether, in to| al. these risks might cause almost as many deaths as angiosarcoma of the liver. There is too little evidence either to confirm or refute the suggestion that vinyl chloride might cause melanoma or cancers of the thyroid, |brain. and lymphatic and hematopoietic systems. Non of the small excesses that have been recorded point: sdeicifically to an occupational hazard, apart from thal attributable to cancers of the lymphatic and hemato|pl'oietic systems in the German study reviewed, and mopt are likely to be the sort of chance effect that is certaitj to be observed when many types of cancer are exam tied in many different studies. The lack of any increased mor| ality from lung can- ccr in the combined results of the our principal studies reviewed does not exclude the' posh bility that there may have been a small occupational I azard of developing the disease, as geographic variat: ons in the incidence of the disease throw doubt on i he validity of using national rates for estimating the xpected numbers of deaths. The greater mortality inigrbtiups of workers who would be more likely to show an bccupaiionai hazard than other groups suggests that |a small hazard may have existed. The evidence is,, however, weak, and the existence of a hazard has not bq|ien proved, Clearer answers to some of thel questions that have been posed in this review mighl| be obtained if the various groups of investigators could present their results in more appropriate and comparable ways, As vinyl chloride is a mutagen in laboratory experi- menis and a proved human cai liiogen. the minute doses that have escaped into the I cneral environment as pollutants must be presumed to have caused com parably minute risks to the genical public. No such risk could possibly be detected, other than one of angiosarcoma of the liver which is normally an ex tremely rare disease. Several surveys have sought evi dence of the existence of such an effect, and sugges tive evidence that such an effect may have occurred at a time when environmental pollution was much greater than it is now has been found in one. References 1. Air Products and Chemicals. Inc. Comments on the pro posed siandard for vinyl chloride. Letter to DR Goodwin. Environmental Protection Agencv. Washing ton, DC 23 September 1976. (Cited in an unpublished report by Barr to Air Products and Chemicals. Inc, in 1981). 2. Baser ME. Tockman MS. Kennedy TP. Pulmonary function and respiratory symptoms in polyvinvl chlo ride fabrication workers. Am Rev Respir Dis 131 (1985) 203 -- 208. 3. Baxier PJ. Anthony PP. MacSween NM. Scheuer PI. Angiosarcoma of the liver in Great Britain. 1963--73. Br Med J 2 (1977) 919-921. 4. Belli S. Beriazzi PA. Comba P. Foa V. Maltoni C. Masma A. Pirastu R. Regianni A. Vigom MA. Indagine sulla morialua del produttori di PVC in Italia: Disegno dello studio e prtmi risultoti. Cancer Lett (in press). 5. Brady 3. Ltberatore F. Harper P. Crcenwald P. Bur nett W, Davies TN, Bishop M. Polan A. Vianna N. Angiosarcoma of the liver: An epidemiologic survey. J Natl Cancer Inst 59 (1977) 1383--1385. 6. Buffler PA. Wood S. Eifler C. Suarez L. Kiliane DJ. 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Neoplastic risk among workers exposed wichout disi lamp oil), n profile of pre Med Wochenschr 98 (1973) 2311-2314. to vinyl chloride. Ann NY Acad Sci 271 (1976) 40--48. is considerec 33. Masuda Y. Long term mortality study of vi tyl chloride and polyvinyl chloride workers in a Japanese plant. Arch a propane o Ind Hyg Toxicol 30 (1979): suppl, 403--4 >9. Received for publication: 16 February 1988 1 Epidemioloe Institute Ar Canada. 1 Department versity. Mo' * Department University Reprint reque cn epidemioM l lappicr, 5 31 * ( jn.id.i, 11 "V 7H SPI-01289