Document NGOL4EKJ0MK6eaj8g4vjDLaJb

A Division of The Society of The Plastics Industry, Inc. OCT 311988 JCL October 26, 1988 TO: The VI Health, Safety & Environment Committee RE: 'Paper By Sir Richard Doll on ' r"Effects of Exposure to Vinvl Chloride11 The attached paper from the Scandinavian ' Journal of -Work', Environment and Health, April 1988 may be of interest to you. It was received courtesy of Harold Clayton, Hydro ''Polymers7 Vinyl Division in England. RTG/pmb Wayne Interchange Plaza II 155 Route 46 West Wayne, NJ 07470 (201) 890-9299 BOR 001S93 ISSN 0355-3140 ft 3 i." \ . r '\1 j-i | . ia H3 i' j rl 3 L* J , !! :j M n j* : H jiii1i :t Volume 14, number 2, April 1988 ill CONTENTS Reviews _____ 61 Effect* of exposure to vinyl chloride: An esseesment of the ovidehce Sir R Doll " Original articles 79 Associations between several sites of cancer and ten types of exhaust and com bustion products: Results from a case-referent study in Montreal J Siemialycki. M G6rin, P Stewart. L Nadon, R Dewar, L Richardson 91 Effects of exposure lo Freon 11, 1,1,1-trichloroelhane or perchforoelhylene on the lipid and tatty-acid composition ol rat cerebral cortex T Kyrklund, P Kiellstrand, KG Hagiid 95 Influence ol water on the percutaneous absorption of 2-butoxyethanol in guinea pigs G Johanson. P Fernstrom 101 Percutaneous absorption of 2 butoxyethanol in man G Johanson, A Boman, B Dynesius 110 Prediction of early retirement on the basis of a health examination: An 11-year foliow-up of 264 male employees in a Swedish pulp and paper company N E Aslrand. S-0 Isacsson. GO Olhagen 118 Comparison between surgeons and general practitioners with respect to cardio vascular and psychosocial risk factors among physicians BB Arnelz, S Andreasson, M Strandberg. P Eneroth. A Kallner 125 Invariants and noninvariants in the concept of Interdependent effects 5 Green land, C Pooie Case studies 130 Fatal arsenic poisoning -- A case report L Gerhardsson, E Dahlgren, A Eriksson, BEA Lagerkvist, J Lundstrom, GF Nordberg Book reviews 134 Neurotoxicants and neurobiological function: Ellects ol organoheavy metals 134 Ergonomics in computerized offices 135 Indoor radon and its nazards 136 Ergonomics at work 137 A manager's guide to ergonomics in the electronic oltice 138 Industrial radiation nazards deskbook 139 Announcements 140 Amendments and corrections BOR 001594 REVIEWS Scond J Work Environ Heaith 14 (1988) 61--^8 Effects of exposure to vinyl chloride An assessment of the evidence by Sir Richard Doll, FRS' DOLL R. Effects of exposure to vinyl chloride: An assessment of the evidence Stand J It nrk Environ Health 14 11988) ft I --78. This paper reviews the possible effects ol vtnvl chloride on the mortality of oc cupationally exposed men and the carcinogenic effects that might be observed in the general population as a result of environmental pollution with vinyl chloride. The results of four studies fulfilling the criteria of providing substantial numbers of observations more than 25 years alter first exposure and covering j a period long enough for more than 10 'It of the workers to have been expected to die constitute the basis ' for the assessment of ihe occupational hazards. Other studies provide onlv supplementary information ! The data permit two conclusions. First, men occupationally exposed to vinyl chloride have experienced l * a specific hazard of angiosarcoma of llir livcr.,5ccontL.Aflg.pl hr tiOaoupolMiwI kaurdstim^aay fvw*_ > existedjiave been small.^No potittysjtiqdenef,nf J nf any nonmaltgnant disease or any type of [ ^an^er'dther'ilhan'anfibsarcotria of the liver has been found except possibly for a smalt hazard of lung , ` cancer when exposure was heavy. More definite conclusions might be reached if lliose who have studied exposed ctnplovces cnuld present iheir results in appropriate and comparable wavs. A Very small risk of ' angiosarcoma may have occurred as a result of vinyl chloride escaping imp the environment aroundplants "handling sinyl chloride in thepast."fnfr rhe evidence ihdicatesihai the current risk to the general public '(if *hyj must be'neglfgiblc.'' A>v terms: angiosarcoma of the liver, cancer, lung cancer, mortality, polyvinyl chloride, review, vinyl chloride monomer ) 608 6*4 (redactor^ m number JO.00 air mail address above, maged issues unless ight Clearance Center ic internal or personal enter's Transactional page, is paid directly rations that have been The fee code for users lor many vears the inhalation of large amounts of UoseYiha? are even lower Ilian the current industrial vinvl chloride has been recognized as potentially haz levels of Jj)pm or less, as vtnyl chloride has been shown ardous. Concentrations of the order of 10 000 ppm in to act as a mutagen (23). and it cannot be assumed that the air induce unconsciousness and cardiac arrhyth a threshold exists below which no carcinogenic risk mia, while prolonged exposure to concentrations an r persists. Moreover, the possibility has to be considered ^ order of magnitude lower have been liable to cause a that vinyl chloride may cause some cancers other than specific pathological svndromc. This "vinyl chloride angiosarcoma of the liver, partly because laboratory I illness" has been characterized bv four cardinal signs, studies have shown that it causes oilier cancers in J namely, enlargement of the liver and spleen with a animal experiments and parity because the initial speed ic histological appearance, patchy infiltration of studies demonstrating the production of angiosarcoma I the skin resembling scleroderma, bony changes in Ihe of the liver in humans were inadequate in size to ex ups of the fingers described as acroosteolysis. and clude a material increase in the risk of cancer in com peripheral circulatory changes identical with the clas mon sites, such as the lung and large bowel. Since no sical picture of Raynaud's disease. These palhologi- threshold dose can be postulated, it also follows that i cai reactions may occur singly or together and may pos- some cancers may have been produced in the general j stbly be accompanied hy other less characteristic ef- public by the small amounts that have escaped into the . fects. They can, however, be completely avoided if ex- general environment. } posure never exceeds the level of a few hundred parts Constderaiton also needs 10 be given to the possi |_per million, ic, the level to winch exposures were bility that exposure to vinyl chloride over a long pe generally reduced in the mid-1960s, riod may have noxious effects on humans that cannot i One other serious effect has. however, been observebde seen easily in animal experiments (by, for example, that may not be avoidable in the same relatively easy producing chronic respiratory disease). tnd7As if is a . wav, namely, tlie production of angiosarcoma of the mutagen, there is also a possibility that it may act as k liver.?ft must, indeed, be presumed ihai some risk of; a teratogen and cause congenital malformations in t developing the disease will persist from exposure to offspring. 1 Imperial Cancer Research Fund, Cancer Epidemiology find In this review | have not examined the possibility 1 Cluncnl Trial* Unit, KadclMIe Infirmary, Oxford, Untied that vtnyl chloride acts as a teratogen or that n causes Kingdom, mutations in germ cells, as there is too little serious Reprint request* 10. Sir R Doll. Imperial Cancer Research I und. University ol Ostoid, t'nbson lluiitlmg, The Radcliffe evidence to justify inclusion. Reviews carried out for sections of the industry by Downs et al (unpublished * Infirmary. Oxford OX2 fiHE, United Kingdom. report to the Society of Plastic Industries Inc in 1977) and by MacMahon (unpublished report to the Chemi cal Manutacturers Association in 1977) concluded that the leu reports of positive effects could not be sub standard, and no additional evidence was found in a similar later review by Barr (unpublished report (o Air Products and Chemicals Inc in 1981). apart from a report that embryos were absorbed and skeletal os sification was produced when pregnant rats were ex posed to doses appreciably lower than those that had been used by other workers without any such effects being observed. The report of absorbed embryos (34) could not be evaluated thoroughly, however, as the ex periment was inadequately described. I have, therefore, examined only (he possible effects on the personal health of men occupationally exposed to vinyl chlo ride, other than those related to their reproductive capacity, and the carcinogenic effects that might con ceivably be observed in the general population as a result of the widespread distribution of vinyl chloride as a pollutant. Occupational hazards Many studies of workers exposed to vinyl chloride in the manufacture of vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) have been undertaken since it was first found that vinyl chloride could cause cancer in animals (28, 48) and man (10). These inves tigations have conlirmed that exposure causes a haz ard oi angiosarcoma of the liver and, in several insiances, have shown excess incidence or monality raics tfiat were conventionally statistically significant lor other diseases. Conventional tests of statistical signifi cance are, however, designed to help answer single quesnons defined beforehand, and several findings that might be expected to occur by chance alone once in (say) 20 times must be expected to occur if dozens of rates are examined in each of several sets of indepen dent data. Scientists have, therefore, been faced with the problem of deciding whether the excess rates that have been observed in individual studies are due to oc cupational hazards or to the vagaries of chance. This problem can be solved in part with an exami nation of the results of a sumation of data from com parable studies, that is, by a comparison of the sums of the numbers of deaths observed and expected in each study. This procedure does not require the as sumption that the exposures have been the same in each study any more than the same assumption is required for each individual when the results of each study are considered alone. It docs require however that each exposed population has been observed over a period when its members were at risk of developing disease (if a genuine hazard existed) and that in each study the reierence population front which the expected num bers ul deaths were dcnved was appropriate (iliat is, ai the same risk ol developing disease as the exposed popul.iiion would have been in the absence ol expo sure). These requirements do not introduce any new complexity, as both are. of course, also required il cor rect conclusions are lo be drassn Irom ilie resulis ol the individual siudies when they are examined on their own. Sources of information Four siudies meet the aforementioned requirements, namely, two large national surveys, one reported by Jones (25) for the United Kingdom (UK) and the other by Environmental Health Associates (14) lor the United States (US), and siudies of individual plains in Canada, reported by Theriault Sl Allard (46) and in Italy, reported (as a part of a national study) by Belli et al (4). All four include observations on men more lhan 25 years after their first exposure, and the ex pected number of deaths is, in each case, greater lhan 10 Vt of the total number of employees, a value indi cating a long average period at risk. Earlier obsersanons on UK and US employees (6, 9, 12, 16, 20, 36, 39, 40, 45, 50) have been subsumed in tlie national sur veys and now serve only as sources of hypotheses and of some detailed inlormation not included in the 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 other Italian (4) workers provide some supplementary mlormation, but, m general, the periods of observanon have not been long enough lor usclul epidemiologic data to be obtained about diseases that are unlikely to occur within 20 years of first exposure, oi llicy report only selected results which are difficult to interpret, 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 cxpusuic to vinyl chloride than those employed in the nianulacture of VCM or PVC and any occupational hazard to 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 largest and most in formative investigation thus far undertaken. It covered 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 homopoiymers and copolymers, with or without VCM or PVC. Twenty-two of the plants were in the southern part of the country, 14 were in the northeastern or north central parts, and one was in the west. Men were included if they had been exposed lo vinyl chloride for at least a year bclore 31 December 1972 and had been employed m 1942 or subsequently dhe lirsl year depending ml ilie dale the pi.ml bee.in makme j | | O' JJJ O 0J O or using vi sonnel recc was the lal idenniied sonnel. Racial ch 97 "o oi wl the purpos deaths, (ha Follow -ii ctal Security died alter I1 plains did ii. (9) earlier s present mve plants wtio 1972 were t tollow-up w 1982, whiclii of the men w untraced wer which was us Almost hai belorc 1955. served more t many cases to a long latenc) Short-term cohurt, and n ployment tor . lor It) years oi ployment beui Fifteen him. have died. In l tamed Irom the tamed for the The number causes or grou plying the pers. national rates t age groups ano This imports cisms, which ai effects on the re compiled by co cords without at sumption that a caused the ex pet underestimated, to have had hig reason for suppo the proportion o necessarily repretainty was mirod as 7.3 z0 oi Two other trii exjii.v led iiumlki umpiuMi ih.it il roduce any new required if corthe results of xamined on their ed requirements, . one reported by JK) and the other ties {14) for the individual plants fc Allard (46) and mal study) by Belli ons on men more rsure, and the ex case, greater than iyees, a value indi<. Earlier observa. 9. 12, 16. 20, 36. in the national surof hypotheses and included in the nan (49), Norwegian unpublished report 37). and some other jpplementary inforods of observation seful epidemiologic es that are unlikelv exposure, or thev are difficult to in0 have been selected ducts have not been J much less exposure nyed in the manufaccupational harard 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 ien 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 sinyl fore 31 December 1972 42 or subsequemlv (the e the plant began making or using vinyl chloride and the earliest date that per sonnel records were deemed to be complete, whichever was the later). Individuals who met these criteria were t- identified from company records by company per .**' * sonnel. Racial characteristics were known only for 686 men. 97 % of whom were white, and it was presumed, for the purpose of estimating the number of expected deaths, that all 10 173 men were white. Foliow-up data were obtained from plant and So cial Security Administration records and (for men who died after 1979) from the National Death Index. Five plants did not collaborate in the extension of Cooper's (9) earlier study, which had been subsumed in the present investigation, and the 955 employees in these plants who were known to be alive on 31 December 1972 were not followed any further. For the rest, follow-up was attempted to death or 31 December 1982, whichever was the earlier. On this basis 92.7 of the men were successfully traced. Those who were untraccd were excluded from the last date of contact, which was usually the date when employment ceased. Almost half of the men (46 %) were first employed before 1955. A large proportion was, therefore, ob served more than 25 years after first exposure (and in many cases for more than 30 years) when diseases with a long latency period might be expected to be seen. Short-term workers had been excluded from the cohort, and most of the men had continued in em ployment for many years, two-thirds being employed for 10 years or more and the average duration of em ployment being 16 years. Fifteen hundred and thirty-six men were found to have died. In I 439 cases, the cause of death was ob tained from the death certificate, but no cause was ob tained for the other 97 persons (6.3 'o). The numbers of deaths expected from each of 38 causes or groups of causes were obtained by multi plying the person-years at risk by the disease-specific national rales for white males, for the corresponding age groups and five-year periods of the study. This important study is open to three minor criti cisms, which are unlikely to have had any material effects on the results. First, the lists of employees were compiled by company personnel from company re Hi cords without any independent check. Second, the as- (umption that all the employees were white will have used the expected deaths to have been very slightly underestimated, as the few black employees are likely 10 have had higher mortality rales and there is no reason for supposing that the small sample from which Ihe proportion of black employees was estimated was & necessarily representative. Third, an element of uncer tainty was introduced by the failure to trace as many as 7.3 of the employees. &.- Two other criticisms are more important. First, the i- expected numbers of deaths were calculated on the as sumption that the men would have experienced the i t: same mortality rates as the white male population of g the whole country at the corresponding date*. The use of national rates is common practice in studies oi in dustrial populations and tends to result in an oseresttmation or the expected numbers of deaths so that 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 For the present purpose, therefore, the numbers of deaths attributed to specific diseases have each been multiplied by 1.0674 [100/(1--97/1536)] 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 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 %j. 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 (he 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 revisions of the ICD was, however, experienced in obtaining suit able rates tor all causes of death, and rates lor a rela tively late period had to be used for estimating the numbers of deaths from many diseases that might have been expected to occur in earlier periods. For two categories the earliest available rates were I960--1964, for one they were 1965--1969, for 24 they were 1970-- 1974, and for one (hey were 1975--1979. Second, an attempt was made to classify men ac cording to whether they had high, intermediate, or low exposure to VCM or PVC dust, and each man's em ployment history was recorded according to 12 job titles with advice from the plants concerned. The men were then grouped according to whether exposure to VCM was likely to have been high (group A), expo sure to PVC dust was likely to have been high with exposure to VCM low (group B), or exposure to VCM and PVC dust was intermediate and intermittent (group C). All other men, who would generally 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 had begun before 1956. The study makes an important contribution to (he knowledge concerning the long-term effects of vinyl chloride. The use of national rates to calculate the ex pected numbers of deaths may be justified on the grounds that the men were employed in nine plants, which were presumably distributed about the country, but no details of their location are given. In general, mortality rates lend to be higher in the parts of Britain where heavy industry is located than in other parts of the country so (hat ihe expected numbers of deaths are more likely to be biased dosvnwards than upwards! but whether this is so or not needs to be shown. The use of recent rates to calculate expected num bers of deaths from many specific causes of death was presumably necessaryjf the diseases were to be studied individually and will have done no harm if the inci dence and fatality of the diseases in question remained stable. It would have been desirable, however, 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 four expo sure groups is the sort of system that is commonly used if precise measures of exposure are not available. It creates some difficulties in the statistical analysis if men move from one job to another and arc classed (as in this instance) as having had high exposure if they have ever had a particular type of employment (eg, ever been employed as an autoclave worker). No evidence is pro vided to show that the person-years at risk before a man entered the category have been subtracted and added to another exposure group before the numbers of expected deaths were calculated. Movement from one job to another was said to have tended to be out ol groups A and li into D, but even so it must 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 limned to employees of a single plant m Shawmtgan, Quebec. The plant, which was situated m 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 31 December 1972, and contact was made with the worker or his next-of-km m I 61 I out of I 659 instances (97.1 '). 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), (ti) unexposed to VCM if they had worked similarly lor less than six months (870 men), and (tii) other men (134 in total). The Iasi group was excluded from the study. Follow-up was dosed on 31 December 1977. Copies of the death cer tificates were obtained, and (he 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 cytologtcal 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 five-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 "/ were observed more than 25 years after first exposure. Although small, ihe study makes a useful contribu tion to the overall results. The histological review of the cancer cases ts 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 ol the peritoneum. Two other cases of angiosarcoma of the liver were found to have been certilied Js hepatic cir rhosis. It is also helptul to li.no a comptu non between t the expose: companies for all non a healthy recording o nani causes 0.95). One aspe, t ie, the use i calculate e\ period (I94 to bunch iip f vation so ih have been la some distort! size (and eve estimate. Foi likely to has Italian study i Unction ol vin 'vas begun in employed for start up of th< still incomplei in three plant I stgnana) begai thirty-seven m in ihe other. Al followed to the mated by mult corresponding year age group t The total expe, more than 10 > '( (12.4 and 12.8 r Clinical tnfot \ 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 Vt, of the wc this plant have r ctpal analyses, I death was anribi co peeled. Os m r*4 O o Oiht'i sources, Th -cl \ annus i in as. O ji k m of death' in ihc |y to have been i (46) as limited #inigan. Quebec, i industrial cotn1 PVC were both ie production of f PVC continued, production work mens' lists or the ile industrial complant. between I l. and contact was f.ktn in 1 611 out i occupational and questionnaire, and by the companies ed. The remaining ;d to VCM ir they VCM or PVC for inexposed to VCM ss than six months 4 in total). The last dy. Follow-up was ,es of the death cer uses for all who had sed) were coded acihe 1CD. Informa^1 or cytological conWl the exposed men two ways. First, the inexposed men were for five-year periods ips. Second, the mormpared with that ex;ex- and age-specific ,ec for the year 1971. , of death used were ificate. and the addivas used later only for ere exposed for more ,ge length of exposure d 44 "mi w ere observed exposure. ikes a useful contribuhistological review of helpful. It showed that liver cancer (including one specified as angioof the liver, as well as is angiosarcoma of the of angiosarcoma of the certified as hepatic cir<h 3 mmoarison between I-:-' the exposed and "unexposed" employees of the same companies as it shows that the low mortality observed for all nonmalignant diseases could be attributed to a healthy worker effect and was not due to bias in the recording of exposure (relative risk for all nonmalig nant causes compared to that of the "unexposed" men 0.9S). One aspect of the study has to be criticized however, ie, the use of provincial rates for one year (1971) to calculate expected mortality spread over a 30-year period (1948 to 1977 inclusive). Deaths will have tended to bunch up towards the end of the period of obser vation so that the rates for this particular year may have been fairly representative, but It must have caused some distortion of the expected numbers of deaths, the size (and even the direction) of which is impossible to estimate. For most disease groups the distortion is un likely to have been large. Italian studv. A study of all men employed in the pro duction of vinyl chloride and PVC in nine Italian plants was begun in 1983. All men were included who were employed for at least six months at any lime from the start up of the plant to the end of 1981. The study is still incomplete, but results are now available for men P in three plants (4). Two plants (in Ferrara and Rosignana) began operation in 1953. Four hundred and thirty-seven men were employed in one plant and 181 in the other. All but three (from the Ferrara plant) were followed lo the end of 1984. Expecied deaths were esti mated by multiplying the person-years at risk by the corresponding national mortality rates for each fiveyear age group and each five-year period of the study. The total expected deaths in each case amounted to more than If) Vo of the employees in the two plants (12.4 and 12.8 Vo) Clinical information was sought about the cause of death of all the 55 employees of the Ferrara plant who had died. Revised diagnoses, which were not used for comparison with the expected deaths, revealed four deaths from cancers of the liver in place of one. The Ravenna plant did not begin operation until 1959, Si* hundred and thiriv-riqht men were rmnloved. '&M but four were traced to the end of 1983, and 17 found to have died. No man could have been folfor more than 24 years, and only 25.1 deaths Vi of (he work force) were expected. The data for pW plant have not, therefore, been used in the prin(Sxdpal analyses. It may be noted, however, that one "death waj attributed to liver cancer when 0.1 was ex pected. Other loitrccs. The Norwegian study (22) provided ob servations on 454 men who had been employed in a plant in Telemark where VCM had been manufactured (rom 1950 to 1971 and PVC from 1950 to the end of the study period. Every man was included whose name was recorded in the company's personnel register and health department records who had ever been em ployed from the start of production to the end of 1969 and had worked for at least one year. The men were followed 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 quinquenniumspecific 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 Vo of the rate of the countrv 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 expecied 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 ihe closure of the study and that one "incipient case" was also known to ihem. 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 (he II plants in which VC and PVC had been produced in the Federal Republic of Germany, (it) 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 tney 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 Vo, 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. Of the exposed group 93.2 7o were successfully fol lowed. and causes of death were discovered for 92.8 of the 414 men discovered to have died. The propor tions for the other two groups were respectively 89.8 and 88.3 for the unexposed and 92.1 and 86.9 for the PVC process workers. The failure to obtain causes of death for all the men who had died was allowed for in the subsequent analysis by the weight ing of the numbers attributed to each cause by a sys tem which took account of the age group and calen dar period m which death with an unknown cause oc curred. The expected numbers of deaths from 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 1968. For subsequent years (1969 to 1974) the person-years at risk were multiplied by the corresponding rales for the same calendar year. Epidemiologic studies are more difficult to carry out in the Federal Republic of Germany than in North America, the United Kingdom, or Scandinavia because the medical cause of death is not recorded publicly, and there is no central system which can be used for checking whether an individual is alive or dead. In these circumstances, the German authors have made valiant efforts to obtain reliable data, and the propor tions of men in the exposed groups who were not suc cessfully followed (6.8 Vt) and the proportions of deaths for which the cause was not obtained (7.2 %) were similar to those in the study of the Environmental Health Associates (14). Two defects, however, make the data less useful. First, no national mortality rates were available before 1968, and the use of the 1968 rates to estimate the num bers of deaths in and before 1968 will have overesti mated the numbers attributable to diseases that were becoming more prevalent or were being diagnosed more often and underestimated those due to diseases that were becoming less prevalent. Second, and more' importantly, a large proportion of the men had been first employed less than 10 years before the follow-up ended. Therefore the useful observations on the few men who had been exposed long enough to have had much chance of developing an occupational disease with a long latency period must have been swamped by a mass of other observations (hat had little to con tribute. The expected deaths amounted to only 6.2 Vt of the exposed men, and there is, therefore, little to be gained, and something to be lost, by including the German data in the overview. It may be noted, how ever, that 12 deaths were attributed to cancer of the liver among ihe workers exposed to vinyl chloride against O.y expected and that smaller excesses were also observed among the unexposed chemical workers (4 Observed against 1.1 cxpectedl and the PVC process workers C 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 Byrcn 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 alter 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 lor the numbers of deaths and cases observed and expected for cancer of the lung and for cancers of (he 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 alter the dose ot 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 1 311 men exposed to vinyl chloride m 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 ol oc cupational histories and 160 men because thetr 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 7o 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 vinyl chloride in 12 plants, which constituted "most of the French VCM polym erisation plants" (Laplanche et al, unpublished). Many of the men were, or had been, employed at Tavaux and were presumably survivors of ihe coliori siudied by Pierre et al (41). The men were followed lor live years, Jtid their morbidity and mortality were com pared with those observed loi I Mid men ol the mine ages (t 2 ye. but who ha. in both groi formation i drinking hat two groups, first exposed first been cm ously. Morbi nually by the 98 of the One of the ex developed an given separat ploymem, an. of the tlndini lung cancer a well reflect a i in the reteren cancers in tha One exposed i hematopoietic none ol the m developed me: rotd. A Japanese perience ot 4 5 before 1965 in ducing VCM i sive (37). The r Twenty-eight p than 20 years at served more tha untraced, and c lained lor all th initial cohort), to the job in w it the terminati given separately in PVC produc classed as VCM If this study Ihould provide t r proem data inch ,, than 20 years aft use. They conlii ' oncer with six workers against while only one > Other workers ai deaths from livei workers was cert liver, and at least was due to the s. not in excess (2 o ex pc. ted). No da ph.inc ami Item.t mi m tin 11>t,| - VQJ and PVC. ^^kemployees ,^|nn et al (Cl oyed when expo* ed from ihe perne were excluded : the country after .-matning 750 were lumbers of deaths trson-years at risk iiortality rates for J numbers of canive (during which isiered nationally) the national age* ,oth instances, the , 1969. Fifty-eight as given for the ex<ere 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 longn one plant (91) and mployed in 12 plants provided obtUffyl chloride in ; and in selected ang of the Tavaux plant Six other employees cause of lack ol ocn because their ' ual id was undetermined ave died against 98 75 . sex- and age-specilic i the men al risk). One rcoma of ihe li\er. in r nrom than 15 sears, iplete and cover such e opening of the plant mtologic value to the art from the addition jma. observations on I 100 in 1980. were exposed chloride in 12 plants. : French VCM polymaJ, unpublished). Many , employed at Tavaux s of the cohort studied were followed for five d mortality were com1 100 men of the same ages ( 2 years) who were employed in the same plants but who had never been exposed to VCM. The men la both groups were interviewed personally, and in formation was obtained about their smoking and drinking habits, which were found to be similar in the (wo groups. The men in the exposed group had been ilnt exposed for an average of about 19 years and had flnt been employed in the plant about 18 years previ ously. Morbidity and mortality data were recorded anually by the plant physician, who successfully traced 9V 4k of the exposed men and 96 4e of the referents. Ooe of the exposed men. but none of those unexposed, developed an angiosarcoma of the liver. Data were not given separately for different periods after first em ployment. and it is impossible to assess the significance of the finding that six of the exposed men developed luag cancer against two of the referents, which may weii reflect a chance occurrence of unusually few cases la the reference group, as the proportion of all lung atoevrs in that group (2 out of 15) was unusually low. st Odc exposed man developed a cancer of the lymphobxmuopoietic system against none of the referents, but aoae of Ihe men in either group were known to have developed melanomas or cancer of the brain or thy roid. - A Japanese study lias reported the mortality ex perience of 4 524 men employed for at least one year before 1965 in 25 Japanese plants which began prodining VCM or PVC between 1949 and 1964 incluMe(J7). The men were followed to 31 October 1975. Twenty-eight percent of Ihe men were observed more rhao 20 >cars alier first employment, but none was ob served more than 26 years. Only 0,6 / of the men were Btraced, and copies of the death certificates were obumcxJ for all the 209 men who had died (4.6 Vt of the will cohort). Individuals were classified according to ihe job in which they had been longest employed M the termination of their follow-up, and data were gmn separately for the 2 546 men classed as employed in PVC production and I 978 others (including 900 dbtvrd as VCM production workers). If this study is continued lor anoiher 10 years, it tbxMld provide useful additional information, but the praent data include too lew observations on men more 20 years alter lirst exposure to be ol any material They confirm the evidence of a hazard of liver with six deaths among the PVC production ers against 2.54 expected from national rates, nly one such death was observed among the workers against 1.82 expected. One of the six tu from liver cancer among the PVC production Vhxkers was certified as due to angiosarcoma of the , and at least one of the other liver cancer deaths due to the same cause. Lung cancer deaths were Ml ta excess (2 observed in PVC workers against 2.33 expected). No data were given for cancers of the lympfcatK and hematopoietic systems, for cancer of the teaxn or thyroid, or for melanomas. The mortality lW mint by NlaauUn (JJ) for SOS Japanese vinyl shin- ride workers has presumably been subsumed m Na kamura's (37) later and larger study. Hazards of cancer The results of the four most useful studies are listed individually in tables 1 and 2. The overall results for all causes, liver cancer, and three broad groups of con ditions are shown in tabie 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 arc. 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 ciasses 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 after 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 deaths; 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 all occurred in auto clave workers against 0.38 expected liver cancers of all types (P< 10-)) (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 the 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 dulhi Irom an unknown eauie, 67 Table 1. Observed and expected numbers of deaths from different cancers reported rn ine tcur principal studies 14, 14. 25, 46) |0 = observed number ot deaths, E = expected number ol deaths) Type or class ot cancer Untied States 0* E United Kingdom 0E Canada OE Italy O E Buccal cavny and pharynx Esophagus Stomach Large intestine Rectum Uver 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 retlculosarcoma HodgKm's disease Leukemia Multiple myeloma 1 Other lympnauc Other j All cancers 13 11,55 7 8.07 11 16 01 21 28.79 39 5.77 17 18.40 ns 115.87 5 6.38 2 1 81 6 7 36 15 1520 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 2 1 74 12 9 59 2 1,38 14 800 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 0 0 64 a 0 14 6 5.26 2 5 78 t 1 67 2 0 95 20 16.37 1 08 1 06 3 30 0 12 1 06 0 07 1 09 12 6 1 0 02 1 07 1 07 0 04 0 07 9 45 30 21 1 * Observed deaths multiplied by 1 0674 and rounded off to the nearest integer Id allow lor deaths without discovered cause v T*6*# 4. Mort iO - observed Typa or class - fit * Mouth ind phi Digestive sysit Respiratory $y* lung r Genitourinary < a Melanoma 0'jm nyroid Umpnailc and Giher iv All other than o t = United Sta Table 2. Numbers ot deaths from nonmaltgnant and alt causes reported In the tour principal studies |4.14, 25. 461 (0 = observed number ol deaths E = expected number ol deaihsi Cause ol death United Stales O* E United Kingdom OE Canada OE Benign and other unspecified tumors Cerebrovascular disease Ischemic hean disease Other circulatory disease Bronchitis * Pneumonia Other respiratory disease Cirrhosis of lha liver Other digestive disease Disease ol the genitourinary system Other diseases Suicide Accidents end other violence 4 5.08 75 91.93 521 597.73 276 157 123.55 105 44 22.83 36 16 15 31.94 32.84 1 40 37 56 06 5 27 39.52 11 20 41 67 115.68 43 49 130 52.78 173.19 I 1 40 288 ) 141 44 i 61 1 51 .1 76 50 25 3167 | 1 I 6 3.21 3.85 2s 5 40 2 10.58 All nonmailgnant causes All causes 1 153 1 363.54 1 536 1 705.27 54S 665 780 894 39 54 76 59 71.07 See footnote to table t. * Emphysema In data Irom the United Stales. e includes two cases cerutied as cirrhosis of the liver which proved lo be angiosarcoma of the fiver. 4 Includes one case wim cause unknown. Italy O E 0 05 19 3 50 4 5.2 3 27 2 7.0 1 09 4 77 36 564 66 77,5 neum was found fo have been due lo angiosarcoma of ilie liver (46). In ilte Italian study, lurtlier evidence revealed iliai iliree I tin her deaths should have been ai- iribuied io cancer of the liver (lor a focal of four), bin only one of the lour was described as an angiosarcoma (4). Table 5. Mortality number of oealhs Type or class ol c Digestive system (excluding me tiv . Lung . Melanoma Srun Thyroid R-r; Lymphatic and he jKoPMetlC system Sejw Other (excluding I ftf'". Ah excl^u--ding me i * fneldence and e. " * Center of the In rtPti- Cancer of the lu Sfjf"' [i 1 if- Further evident cancer tor liver ar i.m i attributed i BOR 001602 it siufliw^ |4 I4 25 Italy 0 1 08 1 06 3 30 0 1.2 1 0.6 0 07 t 09 12 6,1 0 02 1 07 1 07 0 04 0 07 9 45 30 21.1 lout discovered causa. Table 3 Mo'i'ii'iy t*nm cancer ol the liver and other causes among vmyi chloride workers m 49 nMitts m ihe lour urmr.ipai studies combined (4. 14, 25. 46) (O = observed number o! deaths. E = expected number ol deaths. SMR s standardized mortality ratio) Causa ol death OE Cancer of the liver* Cancer o< other sues Other diseases Accidents, poisonings, arid violence All causes 59 609 1 547 226 2 441 8 45 . 599 35 1 644.89 295,15 2 747 84 * including cancers of Ihe gallbladder in the series from Ihe United States. $MR 698 >02 54 77 89 I 4, Mortality from various cancers among vinyl chloride workers In 49 plants in the four principal studies combined. )*Observed number of deaths, E = exposed number of deaths. SMR = standardized mortality ratio) feMfliMV <* class ot cancer OE SMR Source of Information * and pharynx BftftCttONthre system (other than liver) BM|MMe44Mory system BBgfetts'SSt urinary system FSfiE'atoaftoma SikM effj&Tiiwpftshc and hematopoietic system Eng.?** pjgpgMI attser then ol Ihe liver 18 16.57 125 154 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 1. 2. 3. 4 81 1. 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 1. 2. 3. 4 131 1. 2. 3, 4 102 1. 2, 3. 4 r* 1 nUntied States study (14), 2 = United Kingdom study (25), 3 = Canadian study (46). and 4 = Italian study (4). 14.25.461. (0 = observed 1 1 i 5 7 itiy 0 E ------- 0 05 27 4 '9 3 5.0 4 52 3 2.7 2 70 1 09 4 77 36 564 66 77 5 'feti# 1. Mortality1 from various cancers among vinyl chloride workers: Supplementary evidence |4, 7, 22, 49). (O observed -v v*ee of deaths. 6 = expected number of deaths, SMR = standardized mortality ratio) frtm sr cisss Cl cancer R-o,., Oanirre system (aiouding ihe liver) Massms IkfWI and hemato* me system QBw deluding the liver) MBtwdmg Ihe liver Federal Republic Germany PI plants) OE 35.0 31 8 23.5 24 6 2,1 1.3 16.5 7 7 10.7 24 3 87 8 89.7 Norway (1 plant) OE 3" t 44 5 2.64 4 0.79 2 0.16 Sweden (1 plant) 0E 3 1.78 2 0.33 8 14 93 22 20.16 5C 2.11= Italy (t plant) OE 1 12 0 15 0 0.1 0 07 4 20 5 5.7 Four countries combined (14 plants) 0 E 5MR 39.0 31,5 4.0 41 2.0 16.5 22.7 119.8 34 44 30 72 0 89 1 63 0.16 84 41 43 117.67 1t3 103 196 55 102 and cases in the Norwegian study, ot the intestine only, ol the lung and brain only. for a total of four), bul bed as an angiosarcoma ^ftnhcr evidence that the excess mortality from liver (or liver and gallbladder cancer in the US senes) be attributed principally if not wholly to the known Xuard of angiosarcoma is obtained in a comparison acres deaths with the numbers of deaths from comas 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 BOR 001603 Table 6. Mortality Irom lung cancer in tne series from the Unned Stales (USI |ia> and me United Kingdom (UK) (25) by characteristics relevant to an occupational Hazard. (0 = ob serves numoer ol deaths, E = expected number ol deaths. 5MR = standardized mortality ratio) Data characteristic' Category 1 O' E SMR Category 2 O' E SMR Observed 20 years or more alter first employment (1), others (2) Employed 10 years or more n me US (1), others in ma us (2) Employes 00fora 1956 m tne UK (1), others in tha UK (2) Ever employed as autoclave worker tn the UK (t), others m me UK {2) 114 113.96 100 55 52.45 105 52 51.39 101 16 17 08 94 85 93.83 91 63 63.44 99 29 40 50 72 65 74.82 87 > The numoers in parentheses designate the category. ' See looinoie to laDle I lor observed deaths in the US the relevant periods for the three countries and the two Italian plants1 that are covered by the survey. None of the 120 cases yet recorded in the Register were in men who were first exposed after 1969, and none of the 45 men affected in North America were first exposed after 1964. All may, therefore, have been exposed to concentrations of several hundred parts per million, and many may have been exposed to concen trations appreciably higher (unpublished report by Barr to Air Products and Chemicals Inc in 1981). Lung cancer. The idea that exposure to vinyl chloride might cause cancer of the lung was suggested by Mon- son et ai in 1974 (36), when they noted 13 cases against an expected number of 7.9 in a study of proportional mortality. The combined data shown in table 4 do not provide any support for the hypothesis, either for res piratory cancer as a~whole (SMR 97) or for the speci fied data for lung cancer in the US, the UK, and Italy (SMR 99). There are, however, consistently higher risks in the subgroups of men in the US and UK series, in which occupational hazards would be more likely to ' Twenty-nine were registered as occurring in the United Slates against an excess of 33; only 20, however, were iden tifiable in both series. Inquiry has. as yet, failed to reveal information about the histology of the remaining 13 in the cohort study and the origin of the nine extra deaths in the register. Nine deaths were registered as occurring in the United Kingdom against an excess of nine, but one of the registered cases was certified as due to a benign hemangioma and not related to the liver (code 227 in the eighth revision of the International Classification of Diseases). Ten cases were registered as occurring in Canada against an excess of eiglu; iwo were recorded as being in men who had been employed for five years, and it is possible that the actual duration had been slightly less than live years with con sequent exclusion from the Canadian cohort. One case was registered as oecumug in one ol the two Italian plants aeamsl an essL-ss ol less lhan one be seen than in other groups. This circumstance is illustrated by table 6, which shows that the SMR values are slightly higher for men observed 20 years or more after first exposure than for men observed earlier, for 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 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 I 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 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 lor the men who had been exposed for 10 years or more than for those who had been exposed for shorter periods (III 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 rales lor 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 as the mortality from lung cancer had been rising throughout the period of observation. Brain cancer. The idea that vinyl chloride might cause brain cancer was also suggested by Monson et at (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 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 * 0.1 ).J * 01 * IT the study of Waxweiler cl j| (SO) is regarded as ttie origin 01 the hypothesis, 26 deaths are letl ay.nnsi IS -14 esn--- led (P oiie-laileil - 0 07), Addition, given in tat little furthe; one of the t occurred m less than a \ the excess di German stu chemical wo deaths after causes again; PVC fabrtca for deaths fri phattc and he the lymphati. & Gaffey (45) studies, wher from lymphoi against 2.54 e' the lymphatic peeled. These if the laborato suggesting that tally in amma' non (29), The cause lymphor ous considerat studies that ar< support lor th lymphatic and l grther (57 deal and very little n foe cancers of tl fey's definition 200-203 and 2 *>;'1 (33 deaths agz eeover, hard JGlfTey's initial r r23.36 expected, CpUitie addttio skwlts of the G< ?mdy obtained ; |<bwed on 15 obs |aBowance is mac gjnown causes) a l emexposed gre I*fPVC fabricati r**posed workers fl exposed for i was most ma foe five years or n the number of dt fi'c - peeled, SM BOR 001604 >cc is alucs more r, for r men Is are ;d for id for angioother small, nd the in the e likeps is I s given served, ince is ntified 03). In ic men lan for ds (111 r of the ipations list 1-82 c Swed' deaths towards nbers of -ttmated .timated n rising 'lit cause ci al (36) :ted. The ide some onson el kers and reporied iherelore orticii ol s the data ubtractcd i was not 3 not coricver, the ubtracted hs remain difference le-tailed = ; = I j ; kL as die origin ,94 expected ' > i i. i Additional iiilortiiution lioin two other sources is the possibility that vinyl chloride might have produced given in table 5. The small excess reported provides the disease. Four cases were observed when 0.79 were little further evidence of an occupational hazard, as expected, and three of the four were in men whose oc one of the two deaths observed in the Swedish study cupations involved the highest exposures (against 0.51 occurred in a young man who had been employed for expected). At the time of (he writing of their report, less than a year when the diagnosis was made, while one further case had been detected with onset three the excess death rate for brain cancer observed in the years after the closure of the study. Subsequent studies German study was less than that observed among in other countries have, so far, reported only two chemical workers not exposed to vinyl chloride (2.9 deaths against 2.0 expected. (See tables I and 5.) deaths after allowance for deaths from unknown causes against 1.6 expected) and among workers in the PVC fabrication industry (5.9 deaths after allowance for deaths from unknown causes against 1.1 expected). Thyroid cancer. An excess of thyroid cancer was also reported in the Norwegian study (22), in which two cases were observed against 0.16 expected. The inves Cancers of lymphatic and hematopoietic tissues. The idea that vinyl chloride might cause cancer of the lym phatic and hematopoietic tissues -- more specifically the lymphatic tissue -- was suggested by Tabershaw & Gaffey (45) and by Waxweilcr et al (50) in two cohort studies, when they lound, respectively, five deaths from lymphomas in the most heavily exposed workers against 2.54 expected and four deaths from cancers of the lymphatic and hematopoietic tissues against 2.5 ex 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 for 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 reporied in the US by Monson et al (36). pected. These small excesses might have been ignored il the laboratory findings had not been interpreted as suggesting dial lymphomas were produced experimen tally in animals exposed lo vinyl chloride by inhala tion (29). The idea dial similar exposure might also cause Iviiiphomas in humans, iherelore, merits seri ous consideration. The data from the four principal studies that are summarized in table 4 provide little support lor die hypothesis when all cancers of the lymphatic and hematopoietic tissues are considered togcilier (57 deaths against 50.87 expected, SMR 112) and very hide more is obtained Irom die separate data 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 ol (he contribution of cancers of the liver to the total number of cancers of the digestive system, particularly when it is borne in mind (hat 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 the idea that any such effect has been produced. for cancers of the lymphatic system ( Tabershaw & Gaffev's ilclininon of It'D list numbers, eighth revision, 200--203 and 205 being used) that arc shown in table I (35 deaths against 29.40 expected). The position is, moreover, hardly altered if the data in Tabershaw & Galfey's initial report are subtracted (29 deaths against 23,36 expected. SMR 124). Little additional information is provided by the results of the German study (49). (See table 5.) This study obtained an SMR of 214 for exposed workers (based on 15 observed deaths, increased to 16.5 when allowance is made for the number of deaths from un 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 not recognized and were diagnosed as secondary liver cancer or carci nomatosis. site unknown, the number of deaths in this category therefore being increased. known causes) against SMR values of 77 and 34 for an unexposed group of chemical workers and a group Hazards of nonmalignant disease of PVC fabricators. It showed that the excess of the No previous study has suggested that any nonmalig exposed workers was present only for men who had nant cause of death other than cirrhosis of the liver been exposed lor more than one year and that this ex would be likely to be increased as a result of exposure cess was most marked for men vs ho had been exposed to vinyl chloride, and cirrhosis of the liver is presumed for five years or more (10.7 deaths alter allowance for to be increased only because of the liver changes that the number of deaths from unknown causes against were observed as part of the "vinyl chloride illness" 4.0 expected, SMR 268, I* one-tailed <0.01). (24, 31. 33). Two other possibilities have, however, been raised, namely, the production of nonmalignant Melanoma. An excess of melanoma was reported for respiratory disease, because of the changes in lung Norwegian workers by Heldaas et al (22). who raised function and radiographic appearances that have been 71 Tibi* /. Mortality `rom selected nonmalignanl causa* and all causes in me lour principal studies comoined. (O a oDserved number ol deaths. = expected number ol deaths, SMR = standardized mortality ratio) Type ol disease Bronchitis, empnysema* Other respiratory disease 0 E SMR Source Of informationA 80 66.83 120 1, 2 71 125.7B 56 1. 2 AM respiratory disease Ischemic heart disease Otner circulatory disease^ All circulatory disease4 Cirrhosis ol tne liver Other disease too 797 252 1 103 46 238 200.82 805.73 264 55 1 209,35 66 26 368.07 All nonmalignanl disease All axierna! causes 1 547 1 844.50 226 295 15 Alt nonmalignanl causes All causes 1 773 2 139 65 2 441 2 747.85 80 1. 2. 3, 4 90 1,2 95 1,2 91 1, 2, 3. 4 69 1. 2. 4 65 V 2, 3, 4 84 1, 2, 3, 4 77 1. 2. 3, 4 85 t. 2. 3, 4 89 1, 2, 3, 4 1 a United Slates study (1*), 2 = United Kingdom study (25). 3 = Canadian study MS), and a = Italian study (4) * Bronchitis m the United Kingdom study, emphysema In the United Slates study. c Includes cerebrovascular disease in the United Kingdom and Italian studies. Table 1. Mortality from chronic obstructive lung disease* In the senes from the United Stales (U5I (14) and the United King dom (UK) (25) by characteristics relevant to an occupational hazard. (0 = observed number of deaths, E = expected number ol deaths, SMR = standardized mortality rallo) characteristic* _ Category 1 0 E SMR Category 2 0 E SMR Observed 20 yeera or more alter first employment tn tne US (t), others In the US (2) Employed 10 years or more In the US (1), others in the US (2) Employed before 1956 In the UK (1), others In Ihg UK (2) Ever employed es an autoclave worker in tne UK (1), others m tne UK (2>c 30 18 20 3 (5.8 190 10.9 147 30.17 80 6 55 48 11 7.0 157 25 12.0 208 10 13.00 74 33 37.22 89 1 Described as emphysema in the US study and as bronchitis in the United Kingdom study. * The numbers in parentheses designate the category. c Men ever employed as a bagger or drier, occupations which would have caused the greatest occupational exposure to oolyvinvi chloride Oust, experienced one death ttom bronchiin, ugainsi 4 9b expected recorded for men exposed to PVC dust (2, 26, 27, 44), and acuie cardiac death, from analogy with the effect of other halogenated hydrocarbons 123) and the ob servation of an increased mortality from myocardial infarction in the few years following the cessation of exposure in the Swedish PVC processing industry 05). Relevant figures for the numbers ol deaths from these and other nonmalignanl causes that are obtainable from the four principal studies were given in table 2, and they have been summarized in table 7. 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 deaths. The fourth study, which did not give sepa rate data for cirrhosis of the liver, reported four deaths from all diseases of the digestive system combined against 3.83 expected and noted that 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 deaths after allowance for the number with unknown causes (49), and 133 in the other, based on seven deaths (37). be expect vironmen to give a from em hardly be no overal however, by deficte: respirator other resp the quest! could he Health Asthat they > tn the out the coding "other resp included e. emphysem. he classify to 302, and of the emp in some cair number 527 for both the grossly deli Nonmalignanl respiratory disease. The data for nonmalignant respiratory disease are confusing in that the total SMR from the combined data lor the lour prin cipal studies is 80 and is the son of figure that is com irsptraiory No excess od asthma1 44 with 6.3 wnber of , 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 deaths from un known causes). No such excess was found m the UK, where 36 deaths from bronchitis gave an SMR of 82. International comparisons of chronic nonmalignanl 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 m 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 large 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 cohoci (hat 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 (he lung that were shown in table 6, they provide no conxixtent evidence of a greater risk lit the groups in wliu.li an tivCiip.mon.il h.iz.nd wiiulil Cmdiovaseu aeicrotic) he? (hade the va; ta acute care Ml national increased fjnwpof dise recordec IheSMR i id (here is tv (he (ubsidia In pa mort; icnt in t i, SMR t workers Slight inrr was record study (49 *-> 1 The deaths ip stn and the ***** wviion fo : sIIIl-jIiIi BOR 00X606 i (2. 26, 27, 44). y with the effect it 125) and the obv from myocardial ng the cessation of tssing industry (35). 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, i (-16). 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 lia for the four prmJt figure that is comial populations, yet the lly increased mortality nd an SMR of 180 be: for deaths from un- was found in the UK, us gase an SMR of 82. chronic nonmahgnam aied by the usage of difii is now agreed is best (or pulmonary) disease, o be called emphysema mis in me United Kingpresumed that the two nd "bronchitis" used re-yjj lonal studies were meant )ne must assume, there*. ' ie two countries were very it both related to cohoru nces of angiosarcoma of '*& . fairly similar exposure* n in table 8, where avail ved among men with dif* ies of exposure. Unlike the j (hat were shown in table.ij t evidence of a greater risk S3 ccupational hazard would peeled to be concentrated. The authors of (he Enlal Health Associates report (14) were unable He any explanation for the increased mortality emphysema, and they point out that it could be due to excess cigarette smoking, as there was Overall excess for cancer of the lung. It is striking, ; that the excess is more than compensated for 'deficiencies in the other categories oT nonmalignant lory disease (pneumonia IJ deaths,1 SMR 47,0; respiratory disease 14 deaths, SMR 42.6), and Ooestion arises whether the emphysema excess be a dassificatory artifact. Environmental kfc Associates (14) list ail the 41 deaths which show they were coded under ICD number 527 which, * out-of-date seventh revision that was used for 'Coding of all deaths in the study, was the code for ropiratory disease not otherwise classified" and emphysema. Under that revision, however, that was associated with bronchitis should doMiftcd with bronchitis under ICD numbers 300 (pX&.and the possibility may be considered that some the emphysema deaths should have been classified wme category of respiratory disease other than ICD feer 327. If this were the situation, it could account the excess mortality from emphysema and the deficient mortality from other nonmalignant ^flManuory diseases. exerts mortality from "bronchitis, emphysema, ivc. , vinf asthma" was observed in the German study (SMR ^ill J| 6.3 deaths observed after allowance for the of deaths from an unknown cause) (49). ^fV^iiiiii ill'll! iiVn iin Data for ischemic (or arteriorie) heart disease (which may be presumed to in* :tbe vast majority of all deaths certified as due cardiac disease) were given only by the two >1 studies, and they provide no evidence of jfDBiWfwtKxi mortality. The SMR values of 90 for this >ol diseases and of 91 for all cardiovascular dis mantled in the four principal studies are typical rt&MR values of healthy industrial populations, Ittera is no suggestion of any occupational hazard ISeb&idiiry analyses provided by the two national ' U particular, there is no evidence of an in, Modality within one month of leaving emIfl the UK study either for all workers (32 |SMR 61) or for the most heavily exposed autopnrkcn (9 deaths, SMR 42). ; increase in ischemic heart disease mortali recorded for the exposed workers in the Ger (49), but it was less than that recorded fori i attributed to different groups of respiratory disk4 the corresponding SMR values that are cited in own for the US study are as given by the EnvironI Health Associates U 4) and have not been adjusted for ihe number of deaths from an unknown '.Iwukc account of these deaths. Ihe observed deaths I8MR values can both be multiplied by 1.0674. the unexposed chemical workers and the I'VC lubri cators (SMR values of 127. 131. and 158 based on 97.2, 126.7, and 109.7 deaths, respectively, after allowance for 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 (he 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 7o 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 (he 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 angiosarcoma 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 (he thyroid) have been suggested only very recently, and few of (he 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 m BOR 001607 vinyl chloride, and, in light of present evidence, the simplest explanation is that the reported excesses are the chance effects that must be expected when many different types of cancer are studied in several different populations. So far as melanoma is concerned, it has to be remembered that the disease has become much more common in recent years in Scandinavia (where the excess was reported) due, it is believed, to the popularity of sunbathing and the increased oppor tunities for Scandinavians to travel to the warmer 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 brain cancer) were suggested by the early results of some of the US studies. That vinyl chloride might produce a hazard of lymphoma was initially supported by the prelimi nary results of animal studies, but the complete results of the many investigations that have been undertaken (see reference 29) do not suggest that lymphoma or any other cancer of the hematopoietic system is liable to be produced. There is, however, some evidence that brain tumors can be produced in rats (29). The 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 have caused death more often than might be expected from national mortality rates, but the excesses observed in the com bined data from the four principal studies in this re view are small and not statistically significant, and the hypotheses remain unproved. The small excess of brain cancer is particularly difficult to evaluate, as mortal ity rates from this disease have changed rapidly over time as methods of diagnosis have improved 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 US and Ger many, and the German findings carry little weight, as the excess was found in each of the three occupational groups studied, irrespective of the chemicals to which they were exposed. The supplementary data from the German study showing an increased mortality from lymphatic and hematopoietic cancers are more impres sive, particularly as the excess was the most marked for men who had been employed for at least five years. In these circumstances, judgment must still be sus pended until the data for each study are analyzed for each specific type of cancer, by intensity and duration of exposure, and by time since exposure began. There remains the suggestion that vinyl chloride might cause lung cancer. At first Sight, this possibil ity is ruled out bythe SMR of 97 for the combined data for respiratory cancer for the four principal studies. Lung cancer is, however, normally so com mon (accounting for about 8 Vt of the expected deaths) that an increase in mortality that was half as impor tant (numerically) as the increase in mortality from angiosarcoma of the liver might easily be overlooked (95 'o confidence limits of the SMR 85--112). 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 reletence for 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, the intensity and duration of exposure and the time since exposure began. It 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 i must be presumed that even the minute doses that) escaped into the general environmem from production^ plants or (in the early days of manufacture) from PVCj materials will have caused some risk of cancer to thel general public. These risks must, however, have been! very small, as air concentrations of vinyl chloride, evens within a kilometer of plants handling vinyl chloride,] used to be (in or around 1975) of the order of 10 to] 40 ppb (1, 3. 15), and this level is about one-ten thou-1 sandth of the concentration that has caused an occu^1 pational hazard. It is obvious, therefore, that it would] be impossible to detect the risk of any cancer that mights be produced by vinyl chloride other than a risk of: 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 with regard to an- giosarcoma mtlly so rai to one of 11 & dioxide, an, annual mac In these cin in a man hv tide was use controlled n of the effec Several su whether any - and Blinder Hcinily of pi and Sweden al (II) foun> to thoroirasi with vinyl ch Don ofihe p (3) found 14 12-year pene lived half a Plant, and, in Brady et al ( otbuied io an fie living wit ng vinyl chi Um two siudi. ftrxt of as m. stole io manui tot colleagues, . Dntts with ma referents In, i?r ah neighborho " 'New York State pollution with C?--d the disea\ years, resp this period . The oi IJ or mot of these environm f^VC may ha public. ;,Cterem conci are cert lily by Recem 'hundred me r,aahiei belov line of five JOppbtlf Ppb (just in values w< sj;--- with putti : r f*eurc of I . I >- *- 74 BOR 001608 E iner ei(dim d connto whether the naJe reference for men leveniy distributed iistances one cannot iless it can be shown men is independent :cted to influence it i origin, namely, the e and the time since le to examine these iorts do not provide i information as they d in table 6. supports ortde involves a small conjunction with the been produced in sev* i vmyl chloride bv ini small hazard of lung evidence is not, howthat it definitely did. inly for men who had at a time when expomillion or more were k can be only minute -ft unanswered b\ this red definitely if til all >wed to (say) the end uld present (heir data count of duration of irst employment and ^icn first employed beJ5 and 1974, and on) Effect of correcting the yees for the locahiy in citation ived to cause cancer in uatory experiments, ii the minute doses that mncni from production lanufacture) from PVC ne risk of cancer to the ist, however, have been is of vinyl chloride, even landling vinyl chloride, 5) of the order of 10 to I is about one-ten thouhat has caused an occutherefore, that it would of any cancer that might de other than a risk of s ii has proved so diffimong men who were exisinon with regard to an- (.<-i.ncoma oft lie liver is dil It-reiH, This disease is norpully so rare that, in the absence of specific exposure n,? m one of the known causes (vinvl chloride, thorium jjf dnxide. and arsenic in pesticides and medicines), (he Litonual incidence is on the order of 1--2 I0-1 (5, 8).` these circumstances the discovery of even one case a man living close to a factory in which vinyl chlonde was used in the days before exposure was tightly jpooirolled may be regarded as presumptive evidence [the effect of environmental pollution. . Several surveys have been undertaken to determine whether any such cases have occurred. Saric et al (43) Elinder & Pershagen (13) sought for cases in the .vicinity of plants handling vinyl chloride in Yugoslavia yfaad Sweden and found none. In Holland Oalderup et K;*l (II) found eight confirmed cases not attributable to thorotrast or arsenic and could trace "no contact /. with vinyl chloride," but they made no specific menE'lion of the patient's place of residence. Baxter et al J'(J) found 14 confirmed cases in Great Britain over a 12-year period, one of which was in a man who had lived half a kilometer from a PVC manufacturing plant, and. in New York Stale over an 18-year period, Brady et al (5) found 19 cases (hat could not be at tributed to any known cause, five of which were in peoEPif'?.'" pie living within a mile of plants manufacturing or using vinyl chloride. The overall incidence rates in these last two studies were not unduly high, but the occur rence of as many as six cases among people living so dose to manufacturing plants is surprising. Brady and his colleagues, moreover, compared their series of paItems with matched referents and found that none of the referents lived equally close to a plant. Two of these ux neighborhood cases (one in England and one in New York Stale) cannot be attributed to environmental pollution with vmyl chloride, as the men who devel oped the disease had lived near the plants for six and eight years, respectively, before developing the disease, and this period is too short to allow for the necessary latency. The other four cases, however, all occurred after 15 or more years of local residence, and the dis covery of these cases strongly suggests that pollution of the environment around plants manufacturing VCM or PVC may have caused a minute hazard to the gen eral public. Current concentrations around plants handling vinyl chloride are certainly much lower than those reported jjweviously by the US Environmental Protection CtAgcncy. Recent British measurements made within a |*few hundred meters of the VCM areas have given aver age values below the daily limit of detection (5 ppb) jfoe three of five plants, the readings at the two others being 20 ppb (100 m outside the boundary fence) and jji\ U ppb (Just inside it) (47), although substantially higher values were recorded on two occasions asso- ' Gated with putting one plant into operation and with Bfr-v- * The figure of i.4 l()~* cncU by licaih et al (21) seems 10 have been a misprint for 1.4 - IQ-1. an accident at the other. According to any reasonable criterion the hazard to the general public (if 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 (other than the early effects of the very high concentrations to 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 It 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, Norw-ay. Sweden, Italy, France, and Japan can be used only to provide sup plementary information. The many earlier reports of exposed workers in the 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 to determine the cause of 6.3 % 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 the plani was situated. It must, therefore, be kept in mind that the rates used may not have been wholly ap propriate for the localities in which the plants were situated. This circumstance is potentially important for the US study, which covered workers in 37 plants, 22 of which were situated in the southern part of the country. The other less informative studies 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 principal studies show that the SMR values, reflecting the ratios between the numbers of deaths observed and those expected in the absence of an occupational hazard multiplied by 100, have been (i) 77 for accidents and other violence, (it) 84 for diseases other than cancer, and (iii) 102 for cancers Other than cancer of the liver. All these results are what might be anticipated for an industry devoid of any specific occupational hazard. The low ratio for diseases other than cancer reflects the "healthy worker effect," which results from the selection process that inevitably excludes some of the less healthy 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 subject to such an effect, apart from the first two or three years imme diately following the start of employment. The mortality from cancer of the liver was nearly seven limes that expected. Most of the JI excess deaths were known to be due to angiosarcoma, even though this diagnosis was not recorded on the death certifi cate. The excess corresponds closely with the 49 deaths due to angiosarcoma reported to the International Register of Angiosarcoma Cases as occurring in em ployees of the plants concerned during the periods under observation. All the men who developed the dis ease were likely to have been exposed to concentrations of vinyl chloride of several hundred parts per million or more. Three other types of cancer which have been sug gested to occur-as a result of exposure to vinyl chlo ride are cancers of the lung, brain, and lymphatic and hematopoietic systems. The combined data for the mortality from respiratory cancer fail, at first sight, to support the hypothesis regarding lung cancer (SMR 97). Higher ratios for lung cancer have, however, been observed consistently in the subgroups in which the effect of an occupational hazard would be most like ly to be seen (that is, men employed for more than 10 years, exposed to higher than average concentrations, or observed more than 20 years after first exposure). In two of the supplementary studies it was also 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 lymphatic and hematopoietic systems. The excesses are, however, not statistically significant, and there is noihing to sug gest dial they are occupational in origin. An excep- 76 tion is the observation of an increased mortality from faamory disc cancers of the lymphatic and hematopoietic systems iX m ennsisten in (he supplementary study from the Federal Republic jpdtytema or of Germany. md it setms Two types of cancer were reported to be in excess 1)5 study wa in the Norwegian study, namely, thyroid cancer and dai with the melanoma. The significance of this finding is difficult Review of to assess because very little information about these Isof-zerm he cancers has been provided by other studies. vwtyl chloride Suggestions that vinyl chloride might cause cancers wt have exp of the digestive tract have failed to account for the : coremely rar contribution of angiosarcoma of the liver. When this lely I in 3 disease is excluded. Ihe mortality from digestive tract studied died o cancer decreases to below the average (SMR 82 for the ' observed t four principal studies). - Of time the n A small excess mortality from the heterogeneous hr expected t group of "other cancers" in the combined results of ^ Use mortality the four principal studies was statistically marginally of that of nor significant (83 deaths against 65.25 expected, P<0.05). 'if- hazard has c> Some of the excess was likely to have been due to the misclassificanon of angiosarcomas as secondary can The data pi !$' art other that cers of the liver or carcinomatosis, sue unknown. : fify ft.however, si The following three nonmalignant causes of death rsde produces have required special examination: cirrhosis of the liver doe to nonocc because of damage to the liver in "vinyl chloride ill brer, and, if * ness, " myocardial infarction (from analogy with the cause almost < effect of other halogenated hydrocarbons and because V*CT. of some observations from Swedish RVC lubricators), There is too and nonmalignant respiratory disease because of the suggestion 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 ftoma or cance tad hematopoi Out have been rhosis of the liver was less than expected m the three I pMtonal hazar principal studies and in one of the two supplementary studies which gave separate figures for the disease t'omof the lym p/,German study (SMR values of 69, based on 46 deaths, and 82, based of chance c on 15 deaths), while in the other supplementary study Many types of the increase was trivial. * mdie*. Data for myocardial infarction have not been re The lack of a ported separately. Out myocardial infarction accounts fat the combi 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 does n been a sm i disease, as j the disease i 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 mortality from chronic obstructive lung disease (SMR 120), which in itl rates ft . The grea be more I Other grou aisted. Th ence of a h '`i Clarer answc eft posed in t rtous groups cludes emphysema and is due to a grossly increased mortality attributed to emphysema in the US study (SMR 193). The corresponding mortality in the British study, which was preferentially described as due to bronchitis, was less than expected (SMR 82), us wax ! mill in more As vinyl chlor and a pr< that have t the mortality from pneumonia tSMK Mb ami mlier rex BOR 001610* > * ality from it systems 1 Republic : in excess :ancer and is difficult bout these cs. use cancers uni for the When (his :estive tract R g2 for the erogeneous d results of marginally d, P<0.05). n due to the ondary canunknown, ises of death is of the liver I chloride illlogy with the , and because fabricators), because of aphic appearosed to PVC liny from cirfd m the three upplementary yr the disease and 82, based mentary study e not been rection accounts iemtc heart dislschemic heart whole was utt'*2. respective* re. nmalignani dis) are confusing, give conflicting four principal omtnonly found IR 80). This figmortality from t 120), which in;rossly increased in the US study ,luy in the British cribed as due to SMR 82), as was 50) and other res piratory diseases (5MR 46) in the US study. There is no consistent evidence that the mortality from em physema or bronchitis was specifically occupational, and it seems possible (hat the reported excess in the US study was an artifact due to nosological difficul ties with the use of the seventh revision of the ICD. Review of the massive data now available on the long-term health of men occupationally exposed to vinyl chloride leads to two clear conclusions. First the men have experienced a specific hazard of the normally extremely rare angiosarcoma of the liver. Approxi mately I in 335 of the men exposed in the 49 plants studied died of the disease, and approximately 2 % of the observed deaths were attributed to it. In the course of time the numbers of cases of angiosarcoma must be expected to increase two to three times. Second, the mortality from all other causes has been typical of that of normally healthy industrial workers. If any hazard has existed, its effect has been small. The data provide no reason to think that any haz ard other than one of cancer has been overlooked. It is, however, Still difficult to decide whether vinyl chlo ride produces small risks of cancer, compared to those due to nonoccupattonal causes, at sties other than the liver, and. if so, whether, in total, 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 mela noma or cancers of the thyroid, brain, and lymphatic and hematopoietic systems. None of the small excesses that have been recorded point specifically to an occu pational hazard, apart from that attributable to can cers of the lymphatic and hematopoietic systems in the German study reviewed, and most are likely to be the sort of chance effect that is certain to be observed when many types of cancer are examined m many different studies. The lack of any increased mortality from lung can cer in the combined results of the four principal studies reviewed does not exclude the possibility that there may have been a small occupational hazard of developing the disease, as geographic variations in the incidence of the disease throw doubt on the validity of using national rates for estimating the expected numbers of deaths. The greater mortality in groups of workers who would be more likely to show an occupational 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 been proved. Clearer answers to some of the questions that have been posed in this review might 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 ments and a proved human carcinogen, the minute doses that have escaped into the general environment as pollutants must be presumed to have caused com parably, minute risks to the general 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 standard for vinyl chloride. Letter to DR Goodwin, Environmental Protection Agency. 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Warren Spring Labo ratory, Department of Trade and Indusiry. Stevenage (United Kingdom) 1984. 48. Viola PL. Biguiii A, Caputo A. Omogenic response of . rat skin, lungs, and bones to vinyl chloride. Cancer Res 31 (1971) 516-519. 49. von Grctscr E, Reinl W. Weber H. Vinyl-chlorid ex position und mortalital dcutscher chcmiearbeiter im vcrglcich zur morlalitat nichlexponicrter chemicarbeiter und PVC-verarbeiter. Zentralbl Arbeitsmed Arbeitssch Prophyl Ergonomic 32 (1982) 44--62. 50. Waxweiler RJ. Stringer W. Wagoner JK, Jones J. Falk H, Carter C. Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Set 271 (1976) 40--48. Received for publication: 16 February 1988' BOR 0016X2 78 origina; Scand J it Assoc exhau Results by Jack : Ron Dew si be re i ret Cxi CJI Ar fui gaad. CGI Ke A large pc study was c cupaiional t About 20 si For each pat past exposu analytic sir: at a time to remarkable This repc cancers >n o bustion pro classes. Fol bunion eng depending o jet fuel, or pi from the "n substances; wiihout dist lamp oil), n. profile of pro is considered propane-bi 1 Epidemiolog Institute An Canada. 1 Department versuy, Mon 1 Department University oi Reprint reques "oidemioloj --r. 531 f . 117 V