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JThe 'Vinyl Institute A Division of The Society of The Plastics Industry, Inc. Roy T. Gottesman Executive Director October 26, 1988 TO: The VI Health, Safety & Environment Committee RE: Paper By Sir Richard Doll on "Effects of Exposure to Vinyl Chloride" 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 GGC 003567 Wayne Interchange Plaza II 155 Route 46 Wesf Wayne, NJ 07470 (201) 890-9299 ISSN 0355-3140 i v-; ! 1 i m 1 1" ! : r 1 fl . .!3 ii'V d"J cr rl i - 2 h?> ; ;i i . p 11 l' Volume 14, number 2, April 1988 it** :\ t i IMS in ,i ...A `Li. CONTENTS Reviews 61 Effects of exposure to vinyl chloride: An assessment of Ihe evidence Sir R Ooll Original articles 79 Associalions between several sites of cancer and ten types of exhaust and com bustion products: Results from a case-referent study in Montreal J Siemiatycki, M G6rin. P Stewart. L Nadon. R Dewar, L Richardson 91 Effects of exposure to Freon It, 1,1,1-trlchloroelhane or perchloroelhyfene.on the lipid and Istty-acid composition of rat cartbral cortex T Kyrklund, P Kjellstrand, KG Haglid 95 Influence of water on (he percutaneous absorption of 2-butoxyethanol in guinea pigs G Johanson, P Femslrom 101 Percutaneous absorption of 2-butoxyethanol in man G Johanson. A Boman, 0 Dyn^sius 1 to Prediction of early retirement on the basis of a health examination: An 11-year follow-up ol 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 lectors among physicians B8 Arneiz. S Andreasson. M Slrandberg. P Enerolh, A Kallner 125 Invariants and noninvarianls in the concept of Interdependent effects S Green land. C Poole Case studies 130 Fatal arsenic poisoning -- A case report L Gerhardsson, E Dahlgren. A Eriksson. BEA Lagerkvist. J Lundstrom, GF Nordberg Book reviews 134 Meurotoxicants and neurobiological (unction: Effects of organoheavy metals 134 Ergonomics in computerized offices 135 Indoor radon and its hazards 136 Ergonomics at work 137 A manager's guide to ergonomics in the electronic ollice 138 industrial radiation hazards deskbook 139 Announcements 14Q Amendments and corrections Gee 003568 REVIEWS Sound J Work Environ Health 14 (1988) 61--78 Effects of exposure to vinyl chloride An assessment ol the evidence by Sir Richard Doll, FRS' DOl.t R. Effects of exposure to vinyl chloride: An assessment of the evidence. St and J Work Environ Health 14 (1988) 61 -- 78. This paper reviews the possible effects ol inyl 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 23 years alter first exposure and covering a period long enough for more than 10 % of the workers to have been expected to die constitute the basis | for the assessment of the occupational hazards. Other studies provide only supplementary information. ' The data permit two conclusions, first, men occupationally exposed to vinyl chloride have experienced t a specific hazard of angiosarcoma of the liver. Second, any other occupational hazards that may have ' existed base been small. No positive evidence of a hazard of any nonmalignant disease or any type of j cancer other than angiosarcoma of the liver has been found except possibly for a small hazard of lung t cancer when exposure svas heavy. More definite conclusions might be reached if those who have studied exposed employees could present their results in appropriate and comparable ways. A very small risk of ; angiosarcoma may have occurred as a result of vinyl chloride escaping into the environment around plants : handling sunt chloride in the past, but the evidence indicates that the current risk to the general public (if any) must be negligible. Kev terms: angiosarcoma of the liver, cancer, lung cancer, mortality, polyvinyl chloride, review, vinyl chloride monomer. I ) 608 644 (redactory m number JO.00 air mail address above. maged issues ur.Jess i t j j J ( ^ ighi Clearance Center te internal or personal enter's Transactional page, is paid directly rations that have been The fee code for users ;; t 4 5 i I or many years the inhalation of large amounts of smyl chloride has been recognized as potentially haz ardous. Concentrations of the order of 10 000 ppm in the air induce unconsciousness and cardiac arrhyth mia, while prolonged exposure to concentrations an order of magnitude lower have been liable to cause a specific pathological syndrome. This ``vinyl chloride illness" has been characterized by Tour cardinal signs, namely, enlargement of the liver and spleen with a specific histological appearance, patchy infiltration of the skin resembling scleroderma, bony changes in the ups of the fingers described as acroosteolysis, and peripheral circulatory changes identical with the clas sical picture of Raynaud's disease. These pathologi cal reactions may occur singly or logether and may pos sibly be accompanied by oilier less characteristic ef fects. They can, however, be completely avoided if ex posure never exceeds the level of a few hundred pans per million, ie, ihe level ro which exposures were generally reduced in the mid-1960s. One Olher serious effect has, however, been observed doses that are even lower than the current industrial levels of 5 ppm or less, as vinyl chloride has been shown to act as a mutagen (23), and it cannot be assumed that a threshold exists below which no carcinogenic risk persists. Moreover, the possibility has io be considered lhat vinyl chloride may cause some cancers oilier than angiosarcoma of the liver, partly because laboratory studies have shown that it causes other cancers in animal experiments and partly because Ihe initial studies demonstrating the production of angiosarcoma of the liver in humans ssere inadequate in size to ex clude a material" increase in the risk of cancer in com mon sites, such as ihe lung and large bowel. Since no threshold dose can be postulated, it also follows that some cancers may have been produced in ihe general public by ihe small amounts that have escaped into ihe general environment Consideration also needs io be given to ihe possi bility lhat exposure to vinyl chloride over a long pe riod may have noxious effects on humans that cannot be seen easily in animat experiments Iby, for example, Oral may not be avoidable in the same relatively easy way, namely, the production of angiosarcoma of the producing chronic respiratory disease), and, as it is a mutagen, there is also a possibility that it may act as liver. It must, indeed, be presumed that some risk of a teratogen and cause congenital malformations in developing the disease will persist from exposure to* I offspring. 1 Imperial Cancer Research Fund. Cancer Epidemiology and Clinical Trials Unit, Radcltlfe Intirmary, Oxford. United Kingdom. Reprint rcipicsix to: Sir R Doll. Imperial Cancer Research I und. University ol Oxloid, Gibson building. The Radcliffe Infirmary, Oxford ON2 AHE. United Kingdom. In this review I have not examined the possibility that vinyl chloride acts as a teratogen or that it causes mutations in germ cells, as (here is too little serious evidence to justify inclusion. Reviews carried out for sections of the industry by Downs et al (unpublished report to the Society of Plastic Industries Inc in 1977) I 61 GGC 003569 and b> MacMahon (unpublished report to the Chemi cal Manufacturers Association in 1977) concluded that the few reports of positive effects could not be sub stantiated, and no additional evidence was found in a similar later review by Darr (unpublished report to Air Products and Chemicals Inc in 1981), apart from a report that embryos were absorbed and skeletal os sification was produced when pregnant 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 the 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 oT workers exposed to vinyl chloride in the manufacture of vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) have been undertaken since :: was first found that vinyl chloride could cause cancer in animals (28, 48) and man (10). These inves tigations have confirmed that exposure causes a haz ard ot angiosarcoma of the liver and, in several in stances, have shown excess incidence or mortality rates that were conventionally statistically significant for Other diseases. Conventional tests of statistical signifi cance are, however, designed to help answer single questions 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 arc 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 (he 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 does 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 exisied) and that in each study the re'erence population front which the expected num bers _; dejths were dciivcd was appropriate (that is, tit the same risk of developing disease as the exposed pope .'inn would have been in the absence of expo sure). These requirements do not introduce any new complexity, as both are, of course, also required if cor rect conclusions are to be brassn Irom the results of the individual studies ss hen they arc examined on their own. Sources of information Four studies 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) for the United Slates (US), and studies of individual plants in Canada, reported by Theriault A 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 than 25 years after their first exposure, and the ex pected number of deaths is, in each case, greater iltan 10 % of the total number of employees, a value indi cating a long average period at risk. Earlier observa tions on UK and US employees (6, 9. 12, 16, 20, 36. 39, 40, 45, 50) have been subsumed ,n the national sur veys and now serve only as sources of hypotheses and of some detailed information not iuJuded in the na tional reports. Studies of German (49), Norwegian (22), Swedish (7). French (41, and unpublished report ol Laplanche et al), Japanese (33, 3'), and some other Italian (4) workers provide some supplementary infor mation, but, in general, the perioJs of observation have not been long enough for uselul epidemiologic data to be obtained about diseases that are unlikely to occur within 2Q years of first exposure, or they report only selected results which are dilficuli to in terpret, as only excess rates tend to have been selected. Studies of makers of PVC products have not been included, as trie workers have had much less exposure to vinyl chloride than those employed in the manufac ture 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 cov ered 10 173 men who had worked in 37 plants owned by 17 companies -- I 214 men in II plants that produced only VCM, 6 848 men m IS plants that produced only PVC, 935 men in three plants that produced both, and I 176 men in five plants that produced liomopolymers and copolymers, with or without VCM or PVC. Twenty-two of the plants were in the southern pari of the country, 14 were in the norihcastern or north central parts, and one was in the west. Men were included if they had been exposed to vinyl chloride for at least a year before 31 December 1972 and had been employed m 1942 or subsequently (the first year depending on the -kite the 1 '.nil bee.m iu.it me or using s i sonnel recc was the Ian identilied sonnel. Racial ch 97 'o of wl the purpos deaths, tha Follow-u cial Security died alter Iplants did m (9) earlier s present invc planis who 1972 were r lollow-up w 1982, whiclu of the men w untraced wer which was us Almost hal before 1955. served more t many cases fo a tong latenei Short-term cohort, and n ployinent lor . lor ID years oi ployment beim Fifteen hund have died. In I tamed Irom the lamed for the i The numbercauses or grou plying the persnational rates t age groups ano This importa cisms, which ai ctfects on the re compiled by co cords without ai sumption that a caused the e.xpei underestimated, to have had his reason for suppo the proportion o necessarily repretainty was imrod as 7.3 a,o ol the Two other -.no expiated inmihei wiiiipium ili.u it ,.( MftWrau. roduce any new p tcquitcd if cor- the results C' xamined on the.? ed requirements. , one reported bv UK) and the other ttes (14) (or the individual planes t Allard (46) and mal study) by BeHi ons on men more ssure, and the en case, greater than iyees, a value indit. Earlier obsena. 9. 12, 16, 20. 56. in the national scrof hypotheses and included in the r.an (49), Norwegian unpublished report 37), and some other jpplcmentarv inf orods of observation sefui epidemiologic es that are unlikely exposure, or they are difficult to in0 have been selected, .ducts have not been J much less exposure oyed in the mam.; accupational hazard to sed is more like' > to jst. ut by Environmental f of the US Chemical ie largest and most inr undertaken. It cov ed in 37 plants c* ned ien in U 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 vinyl fore 31 December 1972 42 or subsequently (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 Ihe later). Individuals who met these criteria were identified from company records by company per sonnel. Racial characteristics were known only for 686 men, 97 V* of whom were white, and it was presumed, for Ihe purpose of estimating the number of expected deaths, that all 10 173 men were white. Follow-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 Do) 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 Do). 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 rates 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* cords without any independent check. Second, the asxSjv^gumpiion that all the employees were white will have IiVv>"c*used the expected deaths to have been very slightly .--^j^l'tindcrestimated, as the few black employees are likely have had higher mortality rates and there is no reason for supposing that the small sample from which the proportion of black employees was estimated was -Jv necessarily representative. Third, an element of uncer* Uinty was introduced by the failure to trace as many u 7.3 *1% of the employees. Two other criticisms are more important. First, the t expected numbers of deaths were calculated on the as5 sumption that the men would have experienced the t same mortality rates as the white male population of the whole country at the corresponding dates. The use of national rates is common practice in studies of in dustrial populations and tends to result in an over estimation of 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 Do, For the present purpose, therefore, the numbers of deaths attributed to specific diseases have each been multiplied by 1.0674 1100/(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 *1* of the work week and who were first employed in the period I940~I974. 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 Do). Seven hundred and eighty deaths were identified, and copies of the death certificates [coded to the eighth revision of the International Classifica tion of Diseases (ICD) if they occurred before 1979 and to the ninth revision if they occurred later) were sent to the investigators. Several specific points about the study need to be noted. First, national mortality rates for England and Wales were calculated for five-year age groups over quinquennial periods for 66 causes of death, and these rates were used in the estimation of the numbers of deaths that might have been expected in the cohort by multiplying them by the corresponding numbers of person-years under observation. Some difficulty which could have been related to the causes of death being 63 GGC 003571 I coded according 10 (he eighih and ninth revisions of the ICD was, however, experienced in obtaining suit able rates for all causes of death, and rales for 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 they 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 dusi, were classed as group D. Within all the groups, exposure to VCM was likely to have been higher if il had begun before 1956. The study makes an important contribution to the 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, bur no details of their location are given. In general, mortality rales tend to be higher in the parts of Britain where heavy industry is loealed than in other parts of the country so that the expected numbers of deaths are mere likely tc be biased downwards than upwards! but whether this is so or noi needs to be shown. The use of recent rates to calculate expected num bers of deaths from many specific causes of death was presumably necessary if (he 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 are 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 jor to another was said to have tended to be out ol gri and II into D hut even m u mnrr I*.* 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 limiied (o employees of a single plan! in Shawinigan, Quebec. The plar', v'.ich was situated in an industrial com plex, was opened in 1943. VCM and PVC were both made until the late 1960s, when the produclion 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-kin in I 611 out of I 659 instances (97.1 B,). 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 it they had worked on the produclion of VCM or PVC for at least five years (451 men), (ii) unexposed to VCM if they had worked similarly for less than six months (870 men), and (iii) other men (134 in total). The last group was excluded from the study. Follow-up was closed on 31 December 1977. Copies of the death cer tificates were obtained, and the causes for all who had died (59 exposed and 233 unexposed) were coded ac cording to the eighth revision of the ICD. Informa tion was also sought for histological or cytological con firmation of all the diagnoses lor all the exposed men who had died of cancer. The results were examined in two ways. First, the mortalities of the exposed and unexposed men were compared after standardization for live-year periods of the study and five-year age groups. Second, the mor tality of the exposed men was compared sviih 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 /o), the average length of exposure was approximately 17 years, and 44 were observed more than 25 years after first exposure. Although small, the study makes a useful contribu tion to the overall results. The histological review of the cancer cases is particularly helpful. It showed that all eight cancers diagnosed as liver cancer (including two specified as hepatoma and one specified as angio sarcoma) were angiosarcomas of the liver, as well as one that had been diagnosed as angiosarcoma of the peritoneum. Two other cases of angiosarcoma of the liver were found to lva\e been cenit.ed js hepatic cir- rl'ini{ I * ! t > I. > * I .* t . , I < l * * 1 I i i i I i j (1,-4'i) 1,1 -( ;i 0 cm Ml 1-JCl the exposei companies for all non a healthy w recording 0 nant causes 0.95). One aspe* ie, the use c calculaie e\ period (19-lg to bunch up vation so th have been la some disiorn size (and eve estimate. F01 likely to has Italian study. tluctton of vin was begun in employed for start up of th. still incomplet in three plant signana) begai thirty-seven m in the other. At followed to the . mated by multi: corresponding 1 year age group a The total expec more than 10 1 (12.4 and 12.8 Clinical in for death of all the had died. Revis comparison w-u deaths from ca The Ravenna 1959. Six hundre All but four we were found to hi lowed for more (3.9 % 0p[hj this plant have r cipal analyses. I death was atmbi pected. Cither sources. Th 'cis.mous on 45. : "if 111 I clcm.i; k of deaths in the io have bsen i (46) was tinmed winigan. Quebec. i industrial coro] pVC were both ie production of f PVC continuedproduction work mens' lists or the >le industrial cornplant. between i, and contact was f-kin in I fill oui i occupational and questionnaire, and by the companies ed. The remaining id to VCM if they VCM Or PVC for inexposed to VCM ss than six months 4 in total). The last dy. Follow-up was ies of the death cer uses for all who had sed) were coded acthe ICD. Inforrr-a^^or cytological con- the exposed men two ways. First. Ebe inexposed men were for five-year periods ips. Second, the mior* mpared w-ith that ex sex- and age-speofic 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 Vo were observed exposure. ikes a useful conteibu* histological review of helpful. It showed that liver cancer (including one specified as ingioof the liver, as well as is angiosarcoma of the of angiosarcoma of the certified as hepazic cire a comparison between ;fi m' K'TvI.-'. 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 nonmalignant causes compared to that of the "unexposed" men 0.95). One aspect of the study has to be criticized however, le. the use of provincial rates for one year (1971) to calculate expected mortality spread over a 30-year period (1948 to 1977 inclusive). Deaths wiJJ 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 lize (and even the direction) of which is impossible to estimate. For most disease groups the distortion is un likely to have been large. Italian study. 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 time from the start up of the plant to the end of 1981. The study is still incomplete, but results are now available for men In three plants (4). Two plants (in Ferrara and Ro- tijnana) 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 to the end of 1984. Expected deaths were esti mated by multiplying the person-years at risk by the corresponding national mortality rates for each five- year age group and each five-year period of the study. The total expected deaths in each case amounted to more than 10 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 FAlT":' **-' hundred and thirty-eight men were emnlnved. but four were traced to the end of 1983, and 17 " found to have died. No man could have been fol- "fjowed for more than 24 years, and only 25.1 deaths 10.S Vo of the work force) w ere expected. The data for Sj&jSfhh plant have not, therefore, been used in the prinPtHytdpal analyses. It may be noted, however, that one 'J'death was attributed to liver cancer when 0.1 was ex pected. Other sources. The Norwegian study (22) provided ob?<' tervations 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 h3d ever hern 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 Ending that the incidence in (he county in which the plant Was situated was between 90 and 95 Vo of the rale of the country as a whole. One man who had been employed in PVC production developed an giosarcoma of the liver. The observed and expected numbers of cases were given for cancers of the lung, colon, and thyroid, for melanomas, and for all can cers, but no expected numbers were given for other types of cancer. It is evident that several other types of cancer must have been in deficit, as there were eight cases in all against 14.93 expected, and it is difficult to know what weight to give the excesses observed for the reported types of cancer, as they seem likely to have been reported specifically because the numbers were in excess of those expected. The authors noted (hat one further case oT melanoma had occurred after the closure of the study and that one "incipient case" was also known to them. The German study (49) included the following three groups: (i) 7 021 men who had been exposed to VC in the course of (heir employment in any of the 11 plants in which VC and PVC had been produced in the Federal Republic of Germany, (ii) 4 820 men who had been employed in seven chemical plants without having had any exposure to vinyl chloride, and (iii) 4 007 men employed in two other plants where PVC was processed. Employees were included oniy if they were of German or Austrian nationality, and they were regarded as exposed to vinyl chloride if they were production workers or other skilled workers or laborers assigned regularly to the plants, but not if they were employed in them only occasionally. All the men were included from the time of opening of the plants to the end of 1974, and they were followed to the end of 1974. Many of the men were therefore observed for only a few years after Erst 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. 65 Of the exposed group 93.2 Vo were successfully fol lowed. and causes of dealh were discovered for 92.8 Vo of the 914 men discovered lo have died. The proporuons for ihe other two groups were respectively 89.8 and SS.7 >7o for the unexposed and 92.1 and 86.9 Vo 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 in 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 rates for the same calendar year. Epidemiologic studies arc 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 valiam efforts to obtain reliable data, and the propor tions of men in the exposed groups who were not suc cessfully followed (6.8 Vo) and the proportions of deaths for which the cause was not obtained (7.2 Vo) were similar to those in the study of the Environmental Health Associates (14). Two defects, however, make the data less useful. First, r.o national mortality rates were available before 1968, and the use of the 1968 rates to estimate the num bers a: 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 that had little to con tribute. The expected deaths amounted to only 6.2 Vo of the exposed men, and there is, therefore, little 10 be gamed, and something to be lost, by including the German data in the overview. It may be noted, how ever, chat 12 deaths were attributed to cancer of the liver among the workers exposed to vinyl chloride against 0.9 expected and that smaller excesses were also observed among the unexposed chemical workers (4 Observed against 1.1 expected) and the PVC process worke- It 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 Byren 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. Twent)-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 "ere given only for the numbers of deaths and cases observed and expected for cancer of the lung and for cancers of the liver and pancreas combined and for the numbers of deaths from brain cancer and three categories of cardiovas cular disease. Two men known to have angiosarcoma of the liver were certified as having died of liver can cer or pancreatic cancer, and a third man died of angiosarcoma of the liver 17 months alter the close of the follow-up. Two French studies provide the results of a long term follow-up of men employed in one plant (41) and of a short-term follow-up of men employed in 12 plants (Laplanche et al, unpublished). The Inst provided ob servations on 1 311 men exposed to vinyl chloride in the production of VCM and PVC and in selected an cillary operations from the opening cf the Tuvaux plant in 1953 to the end of 1976 (41). S.s other employees were excluded from the study because of lack ol oc cupational histories arid 160 men because their vital status at the end of the study period was undetermined. Twenty-five men were found to have died against 48.75 expected from contemporaneous sex- and age-specific national mortality rates (3.7 Vo 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 1 100 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 the cohort studied by Pierre et al (41). The men were tollowcd lor five years, and their morbidity ami mcnality were com pared w iih those obvc". vd 11 i I ! * ",11 ill ''vs,mil 11 ,y ; * / J1 A* i' ( cT- . tff..-] b jri- f. \ B p j 5 fe. I .. Hi < ages (2 ye; but who hai in boih groi formation v drinking hattwo groups first exposed first been em ously. Morbi nually by the 98 Vo of the One of the ex developed an given Scparai ployment, am of the Imdini lung cancer a well reflect a i in the reteren cancers in iha One exposed i hematopoietic none ol the m developed me: roid. A Japanese perience ol 4 5 before 1965 in dticing VCM ! ove (J7). The r Twenty-eight p than 20 years al served more tha untraced, and c talned for all th initial cohort) to the job in wl at the terminal! given separately in PVC produc classed as VCM If this study ' present data in & than 20 years a ifvi ^bey con cancer with st workers again: * while only one " Other workers ' deaths from liv O'l workers was ce u.) liver, and at lea was due lo the not in excess (2 expv, led). No d ;4i.ilic .uni hem mi in iln n,| Mm jWluhf o i l *., VCM and PVC. , aj^mployccs fiflht al yet^vnen expoJ from (he per,e were excluded he country after naming 750 were jmbers of deaths son-years at risk irtality rates for numbers of cane (during which tered nationally) he national ageth instances, the 1969, Fifty-eight . given for the exre given Only for rved and expected s of the liver and imbers of deaths ries of cardiovasive angiosarcoma died of liver cantird man died of hs after the close results of a longone plant (41) and ployed in 12 plants nfl^rovided ob* s flip chloride in tnd in selected an>f iheTavaux plant x other employees mse of lack of ocbecause their vital was undeterminedr died against 48.75 x- and age-specific ie men at risk). One >ma of the liver, in note than 15 sears, etc and cover such opening of (he plant ologic value to the from the addition a. iervations on 1 100 1980. were exposed loride in 12 plants, rench VCM polymunpublished). Many mployed at Tavaux f the cohort studied re followed for five nnrtalily were com100 men of the same net (i2 years) who were employed in the same plants but who had never been exposed to VCM. The men cite to both groups were interviewed personally, and injformaiion was obtained about their smoking and `drinking habits, which were found to be similar in the 'two groups. The men in the exposed group had been ^fVtt exposed for an average of about 14 years and had ^flnt been employed in the plant about 18 years previr/gutiy. Morbidity and mortality data were recorded an^ually by the plant physician, who successfully traced ; of the exposed men and 96 of the referents. C.Om of the exposed men, but none of those unexposed, ?; developed an angiosarcoma of the liver. Data were not jS; given separately for different periods after first emVptoymcni, and it is impossible to assess the significance 'of the finding (hat six of the exposed men developed fPtorig cancer against two of the referents, which may ir^.weU reflect a chance occurrence of unusually few cases to the reference group, as the proportion of all lung 'cancers in (hat group (2 out of 15) was unusually low. jpf'"One exposed man developed a cancer of the lympho- botutopoietic system against none of the referents, but 5vfe^s';ooe of the men in either group were known to have developed melanomas or cancer of the brain or thy* 7fiKj!<V- A Japanese study has reported the mortality ex- ptfumee of 4 524 men employed for at least one year (^'-"'before 1965 in 25 Japanese plants which began pro- dweing VCM or PVC between 1949 and 1964 inclu>st (J7). The men were followed to 31 October 1975. * Twenty-eight percent of the men were observed more 5'^;"-.' rtan 20 years after first employment, but none was ob served more than 26 years. Only 0.6 */ of the men were smtraccd, and copies of the death certificates were ob tained for all the 209 men who had died (4.6 *! of the mmal cohort). Individuals were classified according k> the job in which they had been longest employed the termination of their follow-up. and data were pren separately for the 2 546 men classed as employed In PVC production and I 978 others (including 900 classed as VCM production workers). If this study is continued for another 10 years, it should provide useful additional information, but the proem data include too few observations on men more 20 years alter first exposure to be ol any material i^Thcy confirm the evidence of a hazard of liver with six deaths among the PVC production km against 2.54 expected from national rates, ( only one such death was observed among the workers against 1.82 expected. One of the six aha from liver cancer among the PVC production 'wsjrkers was certified as due to angiosarcoma of the jk.'lvtf. and at least one of the other liver cancer deaths i due to the same cause. Lung cancer deaths were /fro! in excess (2 observed in PVC workers against 2.33 I?expected). No data were given for cancers of the lymV'pksric and hematopoietic systems, for cancer of the beaut or thyroid, or for melanomas. The mortality '7 rnwini by Mtnutjn 03) for 303 Japan*!* vinyl chlo ride workers has presumably been subsumed m Na kamura's 137) later and larger study. Hazards of cancer The results of the four most useful studies are listed individually in tables I and 2. The overall results for all causes, liver cancer, and three broad groups of con ditions are shown in table 3, and those for 10 types, or classes, of cancer are presented in table 4. Data have not been reported for each type of cancer in each study, and the sources of the data are, therefore, specified separately for each type. Additional information ob tained from four other less informative studies (4. 7, 22, 49) is given in table 5 for seven types or classes of cancer. Table 3 shows that, apart from cancer of the liver, the overall mortality is what would be anticipated for an industry without any major hazard of accident or disease. In particular the standardized mortality ratio (SMR) of 84 for diseases other than cancer is typical of the ratios that are commonly observed for groups of employed men. A low SMR of this order reflects the "healthy worker effect," which results from the selection process that inevitably excludes some of the least healthy members of the population from indus trial employment. This effect does not, however, nor mally affect the mortality from cancer beyond that ob served in the first few years 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 scries, liver and gallbladder cancer) is not entire ly accounted for by the known hazard of angiosar coma. Fifteen of the 3? deaths1 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< 10~5) (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- Increased to 39 in table I to take account of the 97 extra tUaiht from *n unknown caul*. 67 T#blt 1. Observed and expected numbers o( deaths from different cancers reported in me !cu pnncipa' studies |4. it, 25, 46) |0 = observed number of deaths, 6 = expected number of deaths} Type or class ol cancer United Slates 0* E United Kingdom 0E Canada 0E Italy O E Buccal caviiy and pharynx Esophagus Stomach, Large intestine Rectum liver Liver anc gallbladder Pancreas Other digestive Larynx Lung Other respiratory Bone Skin fnonmelanorna Meianom-a Prostate Testis 8!adder Kidney Oiher ano unspecified urinary Brain Eye and central nervous sysiem Thyroid Lympho- and retlculosarcoma Hodgkin s disease Leukemia Multiple .myeloma 1 Olher lymphatic ) Other All cancels 13 11.55 7 8 07 1 1 1601 21 28 79 39 5 77 17 18 40 118 115 87 5 6 38 2 1 81 6 7.36 16 1520 5 B 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 It 10 49 11 1 94 7 98a 4 2 21 at 92 12 0 0 64 8 0 14 6 5 26 2 5.78 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 8.12 235 228 60 J 1 2 20 1 67 0 95 16 37 1 08 1 06 3 30 0 12 1 06 6 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 to allow for deaths without c-scovered cause Table 2. Numbers of deaths from nonmahgnant and all causes reported In the four principal studies (4, 14, 25, 46) (O = Observed number o' deaths. E = expected number ol deaths) Cause of death United States O* United Kingdom 0E Canada OE Benign end other unspecified tumors Cerebrovascular disease Ischemic neart disease Other circulatory disease Bronchitis* Pneumonr.a Other respiratory disease Cirrhosis ot the liver Other digestive disease Disease of the genitourinary system Olher diseases Suicide Accidents end other violence All nonmaiignant causes All causes 4 5 08 75 91 93 521 597.73 157 123 55 44 22.83 16 31.94 l 15 32 84 1 37 56 06 27 39.52 11 20.41 67 115,68 49 52.78 1 130 173 19 1 153 1 363.54 1 536 1 705.27 276 105 36 40 40 5 43 40 545 780 2B8 141 J 44 , 6, 1 51 j 76 50 665 894 25 31 67 ) I 1 6 3 21 j 3.85 Z> 5 40 2 10,58 39 54 76 59 7t 07 * Saa footnote to table 1. * Emphysema In data from the United Stalaa. c Includes two cases certified as cirrhosis ol the liver which proved to be angiosarcoma of the liver. 4 Includes one case with cause unknown. Italy oE 0 0.5 19 3 50 4 5,2 3 2.7 2 7.0 1 09 4 77 36 56 4 66 77.5 neum was found fo have been due 10 angiosarcoma of the lines Mb). In the Italian study, further evidence revealed 1 at three further deaths should have been at tributed to cancer of the liver (for a total of four), but only one of the four was described as ur. angiosarcoma (4). T*6f 4. Mon (0 * observed Type or class Moufh ph- O'pestlve systt ^Ipi/atory sy; lung Genitourinary Wstanoma 0'iin nyiold Lymphatic and Ctnr *ff other than o * t = United Sta TaN# 5. Mortality r>umoer of deaths T*pe or class of c ttpejtlve system w`i* ttiClodfnn me hv Ung - Uetanome , Mn Thyroid Lympniie and he ,po**(ie system , Other (excluding I Sh-rt- XU excluding Ida , ik& ! IneWanc* and c, ' Cencer ol (ha m * Cancer ol the lu f' >Z' Further evidem Oncer (or liver ar can I attributed i ' . aril ul alien's. * * s IC,11 Maly a 0- rF 1 3 0 r *,* 06 30 7 2 1 06 : 6 : 7 1 C9 u 61 ` 6 02 1 0.7 i or 6 04 0 07 9 45 30 lit ipul discovered c-ise. 14. 25. 46). (0 = observed Italy a E 0 05 } ,9 27 4 )3 5.0 4 52 3 27 i t 70 1 0.9 1 4 7.7 5 36 56.4 7 66 77 5 T.ible 3. Mo' liny cancer of me liver and oiher causes vinyl chionde wooers m a9 pI.hik m ihe lou* studies combined i<. 14. 25, 46) tO = observed number ot oeathv = expected number of deaths, SMR = standardized mortality ratio) Cause of death 0E Cancer ol tbe liver1 Cancel cl other sties Other diseases Accidents, poisonings, and violence All causes 59 609 1 547 226 2 441 8 45 . 599 35 1 844 B9 295.15 2 747 84 * Including cancers of the gallbladder in the series from the United States. SMR 698 !02 84 77 69 .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) I or class of cancer SMR Source of Information * VIAouch and pharynx system (other than liver) KJNaplraiofy system jjOwilfsirlnary system n'lManoma a**" s1tar*04d &Tli*r<C<i*tlC and hematopoietic system ,0m* ijpA* 47>*f than of the 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 8? 63 63.24 609 599.35 109 1, 2. 3, 4 81 1. 2. 3. 4 97 t. 2. 3, 4 99 t. 2. 4 m t. 2. 3, 4 2. 4 148 1. 2, 3 2 112 1. 2. 3. 4 131 t. 2. 3, 4 102 1. 2. 3. 4 Untied States study (14). 2 * United Kingdom study t2S), 3 = Canadian study (46). and 4 = Italian study (4). V-: jr-vr: * Mortally* from various cancers among vinyl chforrde workers: Supplementary evidence (4, 7, 22, 49), (O-observed l*cir of deaths. E = expected number ol deaths, SMR standardized mortality ratio) W W, ' rtp. ar Class of cancer & Federal Republic of Germany (II planls) OE Norway (1 plant) OE jS,; syslem gvt.- eluding lha liver) -)v,-L*9 sjp IMwenia |Ci:;l|ehp#4afie and hemaloagfa, feoc tyiiem ffi,.: 0wr (excluding the liver) jvfccjM occluding the liver 35.0 31 8 23.5 24.6 2.1 1.3 16.5 7.7 107 24.3 87.8 897 3s 1.44* 5 2.64 4 079 2 0.16 8 14 93 22 20.16 > and cases m the Norwegian study, i ol the Intestine only, r ol the lung and brain only. Sweden (1 plant) OE 3 178 2 0.33 Italy (l plant) OE 1 1.2 0 1.5 0 07 5= 2.11' *0 4 5 0.7 20 5.7 Four countries combined (14 plant!) O E SMR 39.0 31.5 40 41 2.0 16.5 22.7 119.8 34.44 3072 0 89 I 63 0.16 8.4 41 43 117.67 113 103 196 55 102 for a total of four), bui bed as an angiosarcoma ^Twtter evidence (hat the excess mortality from liver ww (or liver and gallbladder cancer in (he US series) \ bt attributed principally iT not wholly to the known ^Wd of angiosarcoma is obtained in a comparison ; excess deaths w:iih the numbers of deaths from tfrvtnpoaaroomas 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 fe' 69 Tibi* G. Mortality from lung cancer In me senes from the Unites States (US) (14) and Ihe United Kingdom (UK) (25) by characteristics relevant to an occupational hazard. (0 = ot> served number of deaths, E = expected number of deaths, SMR = standardized mortality ratio) Data Category t characteristic1 * ol * 0" E SMR Category 2 0" E SMB Observed 20 years or more after first employment (1), others (2) Employed 10 years or more m tne US I'). Olivers in tne US (2) Employed before 1956 in the UK (1). others m me UK (2) Ever employed as autoclave worker in the UK (i). others in the UK (2) 114 113 96 100 55 52.45 105 52 51 39 101 16 17 OS 94 65 93 63 9) 63 63,44 99 29 40 50 72 65 74.82 87 The numbers in parentheses designate the category * See footnote to table 1 for observed deaths in the US. ihe relevant periods for the three countries and the two Italian plants5 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). Lur.e cancer. The idea that exposure to vinyl chloride might cause cancer of the lung was suggested hy Mon- son et al 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 1 Twtmy-nine were registered as occurring in the United Stales against an excess of 33; only 20, however, were iden tifiable in boih series. Inquiry has, as yei, failed to reveal informaiion aboui ihe histology of the remaining 13 in the ccr.ort study and ihe origin of the nine extra deaths in ihe regisier. Nine deaths were registered as occurring in Ihe Ur.ued Kingdom against an excess of nine, but one of ihe rez'Siered cases was certified as due to a benign hemangioma ar-d noi relaied 10 ihe liver (code 227 in ihe eighth revision of the Inlernalional Classification of Diseases). Ten cases were registered as occurring in Canada agamsi an excess of eight; iwo were recorded as being in men who had been errpluyed for five years, and it is possible ihat Ihe actual deration had been slightly less lhan live years with conseci'.iciu exclusion from ihe Canadian cohort. One case was re,.ixiereil as Oiciimng in one ol tlie two Italian plants jii excess ol less than 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 (he German siudy (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 (111 against 79), and, in the Norwegian study, four of the five cases observed occurred in men whose occupations were regarded as involving high exposure against 1.82 of the 2.84 expected. Both the German and the Swed ish studies derived the expected numbers of deaths from national mortality rates for a single year towards the end of the study period. The expected numbers of deaths are likely, therefore, to have been overestimated and the SMR values correspondingly underestimated 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 el al (36) when they reported five cases against 1.2 expected. The combined data that are shown in table 4 provide some support for this hypothesis. The cases of Monson ct 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 oughi, 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 arc 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 If the study of Waxweilcr ct al (50) is regarded as Ihe origin ol ihe hypothesis. 26 dcailiv are tell ag.nmi IX `)4 expo.to) 1P unc-ladcd - 0 07) Addition, given in tat little furthei one of the t occurred in less lhan a \ the excess dv German stu chemical wo deaths after causes again; PVC fabrica for deaths fre Cancers of h idea Ihat viny phatic and he the lymphatk A Gaffey (-15) studies, wher from lymphoi against 2.54 e he lymphatic petted. These if the laborato suggesting that ally in anuna; tion (29). The cause lymphoi ous considerat Mudics that art support lor the lymphatic and ht frther (57 death *nd very little mi fix cancers of the .- tcy' i definition 200-- 203 and 2( ! (35 deaths agt [woreover, hard Coffey's initial r 23.36 expected, Uttle additio JlwuUi of the G; FJrtdy obtained ; {'(bwedon 15 obs ^tOowtnce is mao fijtaown causes) a ?* tmejposed gri Of PVC fabricati ^ttysosed workers [ibexn exposed for 4*bs*is most ma foe fixe years or n the number of dv J 11 r peeled, SM *".! \ll c- icc is .alucs more r. for r men Is are ;d for id for angioolher small, nd the in the e likeps is t s given served, snee is mified 03). In ic men lan for ds(IU r of the ipations nsi 1.82 e Swed' deaths towards nbers of stimated .limaied n rising _ht cause el al (Jh) .ted. The ide some onson el kers and reported therefore onion of s the data ubiracted t was not 3 not corvcver. the ubtracted hs remain difference ,e-iailed = as the origin .94 expected Addilion.il inl'orntulion trout ln other sources is given in table 5. The small excess reported provides little further evidence oT an occupational liarard. as one of the two deaths observed in the Swedish study occurred in a young man who had been employed for less than a year when the diagnosis was made, while the excess death rate for brain cancer observed in the German study was less than that observed among chemical workers not exposed to vinyl chloride (2.9 deaths after allowance (or deaths from unknown causes against 1.6 expected) and among workers in the PVC fabrication industry (3.9 deaths after allowance for deaths front unknown causes against 1.1 expected). 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 Tabershav & Gaffey (45) and by Waxweilcr ei al (50) in two cohort studies, when they found, respectively, five deaths front 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 pected. These small excesses might have been ignored if the laboratory findings had not been interpreied as suggesting that lymphomas were produced experimen tally in animals exposed to vinyl chloride by inhala tion (29). The idea that similar exposure might also cause lymphomas in humans, therefore, merits seri ous consideration. The data front the four principal studies that are summarized in table 4 provide little support for the hypothesis when all cancers of the lymphatic and hematopoietic tissues are considered to gether (57 deaths against 50.87 expected, SMK 112) and very little more is obtained from the separate data for cancers of the lymphatic system (Tabcrshaw & Gaffey's rlcliuition of IC'D list numbers, eighth revision, 200--203 and 205 being used) tltai are sltosvn in table I (35 deaths against 29.40 expected). The position is. moreover, hardly altered if the data in Tabershaw & Galfey's initial report arc 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 known causes) against SMR values of 77 and 34 for an unc.xposed group of chemical workers and a group of PVC fabricators. It showed that the excess of the exposed workers was present only for men who had been exposed for more than one year and that this ex cess was most marked for men w ho had been exposed for five years or more (10.7 deaths after allowance for the number of deaths from unknown causes against 4.0 expected, SMR 268, P one-tailed <0.01). Melanoma. An excess of melanoma was reported for Norwegian workers by Mcldaas cl al (22), who raised the possibility that unyl chloride might have ptoduced the disease. Four cases were observed when 0.79 were expected, and three of the four were in men whose oc cupations involved the highest exposures (against 0.51 expected). At the time of the writing of their report, one further case had been detected with onset three years after the closure of the study. Subsequent studies in other countries have, so far, reported only two deaths against 2.0 expected. (See tables I and S.) 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 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 ,!udies 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 reported in the US by Monson et al (36). Cancers of the digestive tract. Suggestions that vinyl chloride might cause cancers of the digestive tract in general have sometimes been made, but they have not taken adequate account of the contribution of cancers of the liver to the total number of cancers of the digestive system, particularly when it is borne in mind that some liver cancers are likely to be misdiagnosed as cancers of other organs. The combined data from the four principal studies shown in table 4 weigh heavily against the idea that any such effect has been produced. Other cancers. One of the remaining types, or classes, of cancer listed in table 4 shows a statistically signifi cant excess, namely, the heterogeneous group of "other cancers" (83 observed deaths against 65.24 ex pected, P two-sided <0.05). This excess is only mar ginally significant and may be a chance observation. The most likely explanation is. however, that a few angiosarcomas of the liver were not recognized and were diagnosed as secondary liver cancer or carci nomatosis, site unknown, (he number of deaths in this category therefore being increased. Hazards of nonmalignant disease No previous study has suggested that any nonmalig nant cause of death other than cirrhosis of the liver would be likely to be increased as a result of exposure to vinyl chloride, and cirrhosis of the liver is presumed to be increased only because of (he liver changes (hat were observed as part of the "vinyl chloride illness" (24, 31. 33). Two other possibilities have, however, been raised, namely, the production of nonmalignant respiratory disease, because of the changes in lung function and radiographic appearances that have been V Table 7. Modality 'rom selected nonmalignant causes and all causes in the lour principal studies combined. (0 = observed number o< deaths. E = expected number ol deaths, 5MR s standardized mortality ratio) Type of disease 0 E SMR Source of information * Bronchitis, emphysema6 80 66.83 120 . 2 Other respiratory disease 71 125.78 56 1, 2 All respiratory disease Ischemic heart disease Other circulatory diseasec All circulatory disease* Cirrhosis ot ths liver Olher disease 160 797 252 1 103 46 238 200.82 885.73 26X 55 1 209.35 66.26 366 07 All nonmalignanl disease All external causes 1 5X7 1 8XX 50 226 295 15 Alt nonmalignant causes All causes 1 773 2 139 65 2 44 t 2 7X7 85 60 1, 2. 3. X 90 1.2 95 1.2 91 1. 2. 3, X 69 1. 2. 4 65 1. 2. 3, X S4 1, 2, 3, X 77 1. 2, 3, X 85 1, 2, 3. X 89 1, 2, 3, x 1 = United States study (14), 2 = United Kingdom study (25), 3 = Canadian study (46), and 4 = Italian study (4) 6 Bronchitis in the United Kingdom study, emphysema In the United Stales study. e Includes cerebrovascular disease in the United Kingdom and Italian studies. Table 8. Mortality from chronic obstructive lung disease* In me series from me United Stales (US) (14) and the United KinQoom (UK) (251 by characteristics relevant to an occupational hazard. (0 = observed number ol deaths, = expected number of deaths, SMR = standardized mortality ratio) cherjclerisUc6 Category 1 0 E SMR Category 2 0 SMR Observed 20 years or more after first employment In the US (1), others In the US (2) Employed 10 years or more in the US (1), others in the US (2) Employed before t956 In the UK (t). others In Ihe UK (2) Ever employed as an autoclave vorKer in the UK (1), Dinars in the UK (2'e 30 10 28 3 15.8 190 10.9 1X7 30.17 88 8 55 X8 11 7.0 157 25 12,0 208 10 13.60 7X 33 37.22 89 * Described as emphysema m the US study and as bronchitis in the United Kingdom study. * The numbers m parentheses designate the category. Men ever employed as a bagger or drier, occupations which wou'O have caused the greatest occupational exposure to polyvinyl cMonde Oust, experienced one death trorn bronchilis uqamst 4 98 expected recorded for men exposed to PVC dost (2. 26. 27, 44), and acme cardiac death, from analogy with the effect of other halogenated hydrocarbons (25) 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 (35). Relevant figures for the numbers of deaths from these and other nonmalignant 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 iscreased 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 Ever, reported four deaths from all diseases of the digestive system combined against 3.85 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). Nonmalignant respiratory disease. The data for nonmalignam respiratory disease arc confusing in that the total SMR from the combined data for the four prin cipal studies is 80 and is the sort of figure that is com monly found in healthy industrial populations, yet the US study recorded a substantially increased mortality from emphysema (41 deaths and an SMR of 180 be fore any allowance was made for deaths from un known causes). No such excess was found in the UK, where 36 deaths from bronchitis gave an SMR of 82. International comparisons of chronic nonmalignant respiratory disease arc completed by the usage of dif ferent terms to describe what it is now agreed is best called chronic obstructive lung (or pulmonary) disease, but which in the past tended to be called emphysema in the US and chronic bronchitis in the United King dom. It must, therefore, be presumed that the two categories of ``emphysema" and "bronchitis" used re spectively in the two 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 cohorts, that had very similar experiences of angiosarcoma of the liver and so, presumably, fairly similar exposures to vinyl chloride. Separate figures are shown in table 8, where avail able, for the mortality observed among men with dif ferent durations and intensities of exposure. Unlike the data for cancer of the lung that were shown in table 6, they provide no consistent evidence of a greater risk in the groups ill which JII :,';iihhi,iI li.i/,iid would beexpectec rironmema 10 five an\ from empl hardly be d no overall e however, th by deficienc respiratory i - Other respir the questioi could he a Health Asso that they we m the out-o, the coding o "Other respir - included emi emphysema t he classified to 502, and if of the emphy in some categ number 527.1 foe both thee grossly delict, expiratory di No excess n tod asthma" i U with 6.3 d. torn her of de /ii; Ctrdbvascula, Sclerotic) heart ftade the vast is acute cardia big national stt m Increased m< fjrotzp of discas recorded it Jof (he SMR val id (here is no i ihe subsidiary '.`todies. In parti mortaiu ient in the <fcKfa,SMR6l) workers (5 *A slight inerc; Vis recorded .^1 study (49), I ______ j TV deaths aitnb and the co ifc.n wiion for t V. jl Health A (or i . !..t .. uu. lust 12, 26. 27. 44|. ^Wtlh the effect ^^^25) and the ob- y from myocardia.' ng the cessation of ,`ssing industry (35). C deaths from these hat are obtainable 're given in table 2. in table 7. the four principal irthosts of the liver, sed mortality (table >MR of 69 based on ch did not give separeported four deaths ve system combined hat the four included cirrhosis of the liver, i (46). In the two supa were given for this based on 15.1 deaths with unknown causes on seven deaths (37). e. The data for nonconfusing in that the for the four pnn- rfigure that is comil populations, yet the ly increased mortality d an SMR of ISO befor deaths from unwas found in the UK. s gave an SMR of 82. thronic nonmalie-iant ted by the usage of dif* t is now agreed is best or pulmonary) disease, ) be called emphysema tis m the United King* jresumed that the two 4 "bronchitis" used re*f onal studies were meant1; ne must assume, there*/.' ; two countries were very both related to cohorts tees of angiosarcoma of fairly similar exposures. opccted to be concentrated. The authors of the Enr^yirOM&cntal Health Associates report (14) were unable ft** any explanation for the increased mortality M 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, , (hat the excess is more than compensated for 'deficiencies in the other categories of nonmalignant :ory disease (pneumonia 15 deaths,1 SMR 47.0; mpiratory disease 14 deaths, SMR 42.6). and (toeuion arises whether the emphysema excess be a classificatory artifact. Environmental 111 Associates (14) list all (he 41 deaths which show Ibcy were coded under ICD number 527 which, |Wooi*of*daie seventh revision that was used for eodlnf of all deaths in the study, was the code for respiraiory disease not otherwise classified" and emphysema. Under that revision, however, that was associated with bronchitis should classi tied wilh bronchitis under ICD numbers 500 XX2, and the possibility may be considered that some "tbeemphysema deaths should have been classified MAC category of respiratory disease other than ICD her 527. If this were the situation, it could account both the excess mortality from emphysema and the deficient mortality from other nonmalignant ^jMpvaJory diseases. excess mortality from "bronchitis, emphysema, i klmhiTu" was observed in the German study (SMR l 6.3 deaths observed after allowance for the ^H***6tf of deaths from an unknown cause) (49). IJ,7i jjjpmtuiraKvIar disease. Data for ischemic (or arteriojjhjUbroric) heart disease (which may be presumed (o in* t the vast majority of all deaths certified as due )i(M( cardiac disease) were given only by the two f MUonal studies, and they provide no evidence of j[j|aibKri>rd mortality. The SMR values of 90 for this i of diseases and of 91 for all cardiovascular dis accorded in the four principal studies are typical Pkbt SMR values of healthy industrial populations, lthere is no suggestion of any occupational hazard iesfcsidUry analyses provided by the two national /(A particular, there is no evidence of an in((Mortality within one month of leaving cm* In the UK study either Tor all workers (52 ?SMR 61) or for the most heavily exposed auto- fken (9 deaths, SMR 42). ; increase in ischemic heart disease mortal- i recorded for the exposed workers in the GerRlCady (49), but it was less than (hat recorded fori t in table 8. where avail ed among men w::h :s of exposure. Un-ike the.; that were shown in tabled evidence of a greater risk'!* cupational hazard would i i attributed to different groups of respiratory dis- i md the corresponding SMR values that arc cited in MUtort for the US study are as given by the Environ* I Health Associates (14) and have not been adjusted mwmm for the number of deaths from an unknown R.lffUhe account of these deaths, the observed deaths I3MR values can both be multiplied by 1.0674. the unexposed chemical workers and the I'VC fabri 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 the disease appears after first exposure (almost always more than 10 years and usually more than 15 years) meant (hat a large number of men had been exposed before the hazard was detected and that il 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 (he 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 % of the deaths having been due to this one cause. Eventually many more men must be expected to de velop the disease. One estimate (38) suggests that the total may be increased 10 times, but a more realistic estimate is two to three times (19). The second outstanding observation is that the mor tality of the exposed men, other than that due to angiosarcoma of (he 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 (he nor mally very rare angiosarcoma. One of the many hazards suggested can be dismissed, as there is no evidence to support it, namely, that of vinyl chloride as a cause of any cancer of the diges tive tract other than angiosarcoma of the liver. Two hazards (of melanoma and cancer of the thyroid) have been suggested only very recently, and few of the avail able studies have provided information about them. There is no good theoretical reason or laboratory evidence to suggest that either should be produced by 73 GGC 005581 \:r.yl chloride, and, in light of present evidence, the simplest explanation is that the reported excesses arc 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 c: lymphoma was initially supported by the prelimi nary results of animal studies, but the complete results o; the many investigations that have been undertaken (ses 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 o bservation that both these types of cancer have caused d-eath 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 mortalicy rates from this disease have changed rapidly over tunc 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 gTOups 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 impressjve, 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 ef 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 bythc 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 % of the expected deaths) that an increase in mortality that was half as impor'ant (numerically) as the increase in mortality from angiosarcoma of the liver might easily be overlooked :V5 confidence limits of the SMR 85--112). The in cidence of the disease varies moreover within a coun try, and there must be doubts is to whether the na tional experience provides a suitable reference 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 ia 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 cvidenionly 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 ruk 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 environment from production^ plants or (in the early days of manufacture) from PVC materials will have caused some risk of cancer to the general public. These risks met, however, have been very small, as air concentrations of vinyl chloride, even 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 levei is about one-ten thou-! sandth of the concentration that has caused an occu* paiional hazard. It is obvious, therefore, that it would J be impossible to detect the risk of any cancer that might; be produced by vinyl chloride other than a risk ofj angiosarcoma of the liver, as it has proved so diffi cult to detect any other risk among men w ho were ex posed occupationally. The position with regard to an giosarcoma mally so rai to one of tl dioxide, an. annual incic In these cirt in a man liv ride was use controlled n of the effec Several su whether any and Elinder vicinity of pi and Sweden a! (11) founi to thorotrast with vinyl ch lion of the p (J) found U ! 2-year perie lived half a plant, and, in Brady et al ( tnbuted to an pie living wit sin* vinyl chi law two studii fence of as m, tVasc to manui fcn colleagues, txents with ma referents livi tb neighborhoi York State ih joUution with v r the discos*. years, resp- " Ihis period The oi ijrfUr 15 or mor of these ,dw envuonm r/yc may ha |*4blic. ;,CWrent cona are cer; tsly by J, Recent hundred me Lvalues belot Areeof five 20 ppb (If ppb (just in values w. with puttt : ' l"`(Urc nf I ' r`r j mu titer uitfiiit x to--.1 10 whether the ri le reference for r.'.tn ^Mventy distributed ^^Hances one canr.ci tress it can be she- n men is independent rcted 10 influence it i origin, namely, she e and the lime smce >le to examine these tons do not provide 1 information as they d in table 6, supports pride involves a srr.ailconjunction with the been produced in vevi vinyl chloride by mi small hazard of long evidence is nor. hcwthai it definitely c-.d. inly for men who bad at a time when e.xpo million or more were k can be only minute ,,*ft unanswered by this red definitely if (ir all iwed to (say) the end uld present (heir data count of duration of irst employment and Ijn first employed beand 1974, and tiii) Feet of correcting the yees for the locality in ulation ved to cause cancer in ratory experiments, it the minute doses that mnent from production utnufacutre) from PVC te risk of cancer to ihe ist, however, have been s of vinyl chloride, even tandling vinyl chloride, >) of the order of 10 to I is about one-ten ihouhat has caused an occutherefore. that it would of any cancer that might de other than a nsk of s it has proved so diffimong men who were exisition with regard to an- i f'.ircoina of tlte liver is dillcrcm. This disease is nor- -.ally so rare that, in the absence of specific exposure to one of the known causes (vinyl chloride, thorium ^dioxide, and arsenic in pesticides and medicines), the ioonual incidence is on the order of t --2 I0~7 (5, 8),` la these circumstances the discovery of even one case th * man living close to a factory in which vinyl chlo- ;,nde was used in the days before exposure was tightly rolled may be regarded as presumptive evidence '(he effect of environmental pollution. Several surveys have been undertaken to determine .whether any such cases have occurred. Saric et al (43) >nd ELinder & Pershagen (13) sought for cases in the .vidnity of plants handling vinyl chloride in Yugoslavia fgad Sweden and found none. In Holland Dalderupet jai<(11) found eight confirmed cases not attributable '..to thorotrast or arsenic and could trace "no contact .`with vinyl chloride," but they made no specific men- `lion of the patient's place of residence. Baxter et al (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 that could not be at7' uibuted to any known cause, five of which were in peo ple 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- fenee 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 pa tients with matched referents and found that none of the referents lived equally close to a plant. Two of these six neighborhood cases (one in England and one in New York Slate) cannot be attributed to environmental pollution with vinyl chloride, as the men who devel oped the disease had lived near the plants for six and tight 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 alter 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 of PVC may have caused a minute hazard to the genaxl public. Current concentrations around plants handling vinyl ^.chloride are certainly much lower than those reported eviously by the US Environmental Protection ^Agency. Recent British measurements made within a w hundred meters of the VCM areas have given aver age values below the daily limit of detection (5 ppb) for three of five plants, the readings at the two others being 20 ppb (100 m outside the boundary fence) and U ppb (just inside it) (47), although substantially higher values were recorded on two occasions asso- \ dated with putting one plant into operation and with Ytb'.. * The figure of 1.4 - It)** cited by Meath et al (2|) seems to have been a misprint for 1.4 IO-\ 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 Vi of the employees to have been expected to die. The results of four studies can be usefully combined for this purpose. They are two national studies, one from the US and the other from the UK, and two studies of employees in one plant in Canada and two plants in Italy. The results of other studies from the Federal Republic of Germany. Norway, Sweden, Italy, France, and Japan can be used only to provide sup plementary information. The many earlier reports of exposed workers in the US and (he 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 Ihe 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 GGC 003583 (he plant was situated. It must, therefore, be kept tn 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 5MR 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, (ii) 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 51 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 pans 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. SO 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). !n 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 nothing to sug gest that they are occupational in origin. An excep tion is the observation of an increased mortality from cancers of the lymphatic and hematopoietic systems in (he supplementary study from the Federal Republic of Germany. Two types of cancer were reported to be in excess in the Norwegian study, namely, thyroid cancer and melanoma. The significance of this finding is difficult to assess because very little information about these cancers has been provided by other studies. Suggestions that vinyl chloride might cause cancers of the digestive tract have failed to account for the contribution of angiosarcoma of the liver. When this disease is excluded, the mortality from digestive tract cancer decreases to below the average (SMR 82 for the four principal studies). A small excess mortality from the heterogeneous group of "other cancers" in the combined results of the four principal studies was statistically marginally significant (83 deaths against 65.25 expected, P <0.05). Some of the excess was likely to have been due to the misclassification of angiosarcomas as secondary can cers of the liver or carcinomatosis, site unknown. The following three nonmalignant causes of death have required special examination: cirrhosis of the liver because of damage to the liser in "vinyl chloride ill ness, " myocardial infarction (from analogy with the effect of other halogenated hydrocarbons and because of some observations from Swedish PVC fabricators), and nonmalignant respiratory disease because of changes in lung function and the radiographic appear ance of the lungs observed in men exposed to PVC dust. Far from being raised, the mortality from cir rhosis of the liver was less than expected in the three principal studies and in one of the two supplementary studies which gave separate figures for the disease (SMR. values of 69, based on 46 deaths, and 82, based on 15 deaths), while in the other supplementary study the increase was trivial. Data for myocardial infarction have not been reported separately. But myocardial infarction accounts for most of the deaths attributed to ischemic heart dis ease, and there is no evidence that either ischemic heart disease or cardiovascular disease as a whole was un duly common (SMR values of 90 and 92, respective ly) or related to occupational exposure. The data for the third category of nonmalignant dis ease (nonmalignant respiratory disease) are confusing, because (he 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 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), as was the mortality from pneumonia iSMfl Ml) and other res- . psrtfory disea so consistent gAy-terna or b **d it seems i US tludy was tin with the u Review of t fewg-term hea 1*ty! chloride rn have expe : extremely rare 'mostly 1 in 33 fwdied died of the observed di 0/ lime the nu fee expected to ttw mortality I P-^ Of that of norn Ward has ext jjvr' The data prt $ ** other than i,,T h. however, sit. J:' Die produces Si I, - duetononoccu s-r;' over, and, if st /' cause almost as XT. There is too Ii (he suggestion i soma or cancer ttwj hematopoie tiM have been re < pstiorval hazard, of the lymph .'.Orrmin study re of chance efn v Mny types of ca w *dies. S'-;vThe lack of an In the combin does no i.tew been a sma t disease, as gt ihe disease th lal rates foi sfeKhf. The greatt Wild be more Ii, other group tew existed. The tdHencc of a ha feClearer answer teen posed in th terioos groups c Wmlis in more a " As vinyl chlorit ? event' and a pro1 2 that has c es . iiiiir.int\ inns < r taliiy from systems , Republic ; in excess :ancer and is difficult bout these es. use cancers uni for the When this -.estive tract R. 82 for the crogeneous 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 appeark>sed to PVC Pity from cir- r i * s d in the three upplementary )i the disease and 82, based mentary study e not been rection accounts iemic heart dis- ischemic heart whole was un92. respcciive- re. nmalignant dis) are confusing, give conflicting four principal ommonly found IR 80). This figmortaluy from l 120), which in;rossly increased in the US study ility in the British cribed as due to SMR 82). as was 50) and other res- V?, % l ? f 1 I piratory diseases (SMR 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 that 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 [wo 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 (he 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 nonoccupational causes, at sites other titan the liver, and, if so, wheiher. in total, these risks might cause almost as many deaths as angiosarcoma of the liver. There is loo 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 thal 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 arc likely to be the sort of chance effect that is certain to be observed when many types of cancer are examined in 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 2 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, Washing ton. DC 23 September 1976. (Cited in an unpublished report by Barr to Air Products and Chemicals, Inc, in 1981). 2. Baser ME, Tockman MS, Kennedy TP. Pulmonary function and respiratory symptoms in polyvinyl chlo ride fabrication workers. Am Rev Rcspir Dis 131 (1985) 203-208. 3. Baxter PJ. Anthony PP, MaeSween NM, Scheuer PJ. Angiosarcoma of the liver in Great Britain. 1963--73. Br Med J 2 (1977) 919-921. 4. Belli S. Bertazzi PA, Comba P, Foa V. Maltoni C, Masina A. Pirastu R, Regianni A, Vigotti MA. Indagine sulla nionalita dci ptoduttori dt PVC in Italia: Disegno dcllo studio e pnmi risultoti. Cancer Lett (in press). 5. Brady J. Liberalore F. Harper P, Creenwald P, Bur nett W, Davies TN, Bishop M, Polan A. Vianna N. Angiosarcoma of the liver: An epidemiologic survey. J Natl Cancer Inst J9 (1977) 1383-1385. 6. BufDer PA. Wood S, Filler C. Suarez L, Kiliane DJ. Mortality experience of workers in a vinyl chloride monomer production plant. J Occup Med 21 (1979) 195-203. 7. Uyren D. Engholm G. Englund A, Weslerholm P. Mor tality and cancer morbidity in a group of Swedish VCM and PVC production workers. 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Warren Spring Labo ratory, Department ol Trade and Industry, Stevenage (United Kingdom) 1984. 48. Viola PL, Bigotti A. Caputo A. Ontogcnic response of .rat skin, lungs, and bones to vinyl chloride. Cancer Res 31 (1971) 516--519. 49. von Greiser E, Reinl W, Weber H. Vinyl-chlorid ex position und mortalilat deutscher chemtearbeiler im vergleich Zur mortalilat nichtexponierler chemiearbetter und PVC-verarbeiter. Zcmralbl Arbeitstned 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 lo vinyl chloride. Ann NY Acad Set 271 (1976) 40--48. Received for publication: 16 February 1988 ORIGIN Al Scand J H Assoc exhau Results by Jack : Ron Dew Si be ret rci CM LJl Ar tur adk C Ol AV A large pr study was c cupationai i About 20 si For each pat past exposu analytic stra at a time to t remarkable . This repot cancers m bustion prod classes. Fou busiton eng depending o jei fuel, or pi from the "n substances: . without dist lamp oil), m profile of pro is considered a propane bt 1 Epidemtolog Institute An Canada. 1 Department i versity, Mon ' Department University oi Reprint reques cn eptdemiolot I nippier, 531 h t jnjd.t. 117V