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Institute A Division of The Society of The Plastics Industry, Inc. Roy T. Gottesman Executive Oiiector October 26, 1988 TO: The VI Health, Safety & Environment Committee RE: Paper By Sir Richard Doll on "Effects of Exposure to Vinvl Chloride11 The attached paper from the Scandinavian Journal' of Work, Environment and Health, April 1988.may be of interest to'you. It was received courtesy of Harold Clayton, Hydro Polymers' Vinyl Division in England. RTG/pftb Wayne Interchange Plaza II 155 Route 46 West Wayne, NJ 07470 (201) 890-9299 SL 048256 ISSN 0355*3140 A Volume 14, number 2, April 1988 CONTENTS Reviews 61 Effects, ol exposure to vinyl chloride: An assessment ol the evidence Sir R Doll Origthal articles ' 79 Associations between several sites o( cancer and ten types ol exhaust and com bustion products: Results trom a case-relerent study in Montreal J Siemtaiycki. m G4rtn. P Stewart. L Nadon, R Dewar, l. Richardson 9l Ellects ol exposure to Freon 11, 1,1,1-trlchloroelhane or perchloroethylene on the lipid and lalty-acid composition ot rat cerebral cortex T Kyrklund, P K|ellstrand, KG Haglid 95 Influence ol water on the percutaneous absorption ol 2-butoxyethanol in guinea pigs G Johanson P Fernstrom 101 Percutaneous absorption ol 2-butoxyethanol in man G Johanson. A Boman, B ) -DynesiOS J lid Prediction ol tarty-retirement on the basis.ol a health examination:-An IT-year"- follow-up of 264 mala employees in a Swedish pulp and paper company N-E Astrano. S O tsacsson. GO Olhagen i IS Comparison between surgeons and general practitioners with respect to cardio vascular and psychosocial risk lectors among physicians BS Arnetz, S Andreas- son. M Stranoberg. P Eneroth. A Kallner 125 Invariants and noninvauanls in the concept ol Interdependent ellects S Green* <3 ROC*? Case studies 130 Fatal arsenic poisoning -- A case report L Gernardsson, E Oahlgren. A Eriksson. BEA Lagerkvist. J Lundstrom, GF Nordberg Book reviews 134 Neurotoxicants ana neurooiologicai function: Ellects ol organoneavy metals '34 Ergonomics in computerized ollices 135 maoor radon ano us nazards 136 Ergonomics at work 137 A manager's guide to ergonomics in the electronic Ollice 136 industrial radiation hazards deskbook 139 Announcements , 140 Amendments ana corrections SL 048257 REVIEWS Scond J JYork Environ licahh U (1988) 61 -- H Effects of exposure to vinyl chloride An assessment ot the evidence by Sir Richard Doll, FRS' OOI.L R Effects of exposure in vinyl chloride*. An assessment of the evidence. Stand J Work Environ Hralih 14 (I9R8I hi --78. This paper reviews die possible elfects ot vmvl chloride on ihe mortality oi'oc- cupationallv csposed men and the carcinogenic elfecis that might be observed in the general population as a result of environmental pollution with vmvl chloride. The results of four studies fulfilling the criteria of providing ttibstanual iitiinhert of observations more than 25 years alter first esposure and covering j a period long enough (or more than 10 *x of the workers to have been expected to die commute ihe basis for ihe assessment of die occupational hazards. Other studies provide nnlv supplememary information. The data permit two conclusions. First, men occttpatiunally exposed to vmvl chloride have experienced a spcciiic hazard of angiosarcoma of die liver. Second, any other occupational hazards dial may have existed have been small. No positive evidence of a hazard of any noimiahgnam disease or any type of cancer oilier than angioxarcnma of die liver has been found except possibly for a small hazard of lung cancer when exposure was heavy. More definite conclusions might be reached if those who have studied exposed employees could present [heir results in appropriate and comparable wavs. A very small risk of angiosarcoma utav have occurred as a result of vmvl chloride escaping mio the environment around plants handling vmvl chloride m the past, but the evidence indicates dial ihe current risk io die general public (if any) must be negligible. krv terms: angiosarcoma of die iivef, cancer, lung cancer, mortality, polyvinyl chloride, review, vinyl chloride monomer. l-or many years the inhalation of large amounts of doses that are even lower than die current industrial sniyl chloride has been recognized as potentially haz levels of 5 ppm or less, as vtnyl chloride lias been shown ardous. Concentrations of the order of 10 0<X) ppm in to act as a mutagen (23). and it cannot be assumed that ,1 the air induce unconsciousness and cardiac arrhyth a threshold exists beloxv which no carcinogenic risk mia. while prolonged exposure to concentrations an persists. Moreover, the possibility has to be considered order of magnitude lower have been liable io cause a that vinyl chloride may cause some cancers other than specific pathological svndromc. This "vinyl chloride angiosarcoma of the-liver. partly because laboratory illness" has-been characlifized.by.fotir cardinal signs, studies'have /shown, that it causes other dancers in namely/ enlargement of-the liver and] spleen, with .a ,' animal 'experiments and*1 partly because the. -initial specific histological appearance, patchy infiltration of die skin resembling scleroderma, bony changes in die ups of the fingers described as acroosieolysis. and peripheral circulatory changes identical with the clas sical picture of Raynaud's disease. These pathologi studies demonstrating the production of angiosarcoma of the liver in humans were inadequate in size to ex clude a material increase in the risk of cancer in com mon sacs, such as the lung and large bowel. Since no ihreshold dose can be postulated, it also follows that ) 608 6-W (redaciory l cal reactions may occur singly or together and may pos some cancers may have been produced in the general sibly be accompanied hv other less characteristic ef public by the small amounts that have escaped into the ( j fects. They can, hoxvever, be completely avoided if ex general environment. posure never exceeds the level of a few hundred pans Consideration also needs io be given to Ihe possi m number | per million, ie, the level to winch exposures were bility that exposure to vinyl chloride over a long pe generally reduced in die mid-1960s. riod may have noxious effects on humans (hat cannot JO.00 air mail address adovc. maged issues unless J One other serious effect has, however, been observed be seen easily in animal experiments (by. for example, that may not be avoidable in the same relatively easy producing chronic respiratory disease), and, as it is a ( wav, namely, the production ol angiosarcoma of the mutagen, there is also a possibility (hat 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 offspring. ight Clearance Center ie imernal or personal enter's Transactional page, is paid directly rations that have been The fee code for users ' Imperial Cancer Research Fund. Cancer Epidemiology and In this review I have nol examined the possibility Clinical Trials Unit. Radclill'e Infirmary, Oxford, United that vinyl chloride acts as a teratogen or that it causes kingdom. mutations in germ cells, as there is too little serious evidence to justify inclusion. Reviews carried out for Reprint rriiuesis to: .Sir R Doll. Imperial Cancer Research I und. Univrrsilv nl Ovloid. tlibsnn lluildiug. The Radcliffe sections of the industry by Downs et al (unpublished i Inlirmary. Oxford OX2 6HE. (Jnncd Kingdom. report to (he Society of Plastic Industries fnc in 1977) 1 J l I t 61 SL 048258 and by MacMahon (unpublished report to the Chemi cal Manuiaciurcrs Association in 1977) concluded that the lew reports of positive effects could not be sub stantiated, and no additional evidence was found in a similar later review by Oarr (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 10 doses appreciably lower than those that had been used by other workers without any such effects being observed. The report of absorbed embryos (3-4) 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 of workers exposed to vinyl chloride in the manufacture of vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) have been undertaken since it was first found that vinyl chloride could cause cancer in~anunals'(28. <I8) and.man (10). These inves tigations h'avc confirmed that exposure causes a ha!-' ard ol 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 are due to oc cupational hazards or to the vagaries of chance. This problem can be solved in part with an exami nation of the results of a sutnation of data from com parable studies, (hat 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 existed) and that in each study the reference population from which the expected num bers ol deaths were derived was appropriate (that is, at tlte same risk ol developing disease as the exposed fioptil.ilion would base been in the absence ol expo sure). These requirements do not introduce any new complexity, as both are. of course, also required if cor rect conclusions are to be drawn Irom the rcsulis ol the individual studies when they arc examined on their own. Sources of information Four studies meet the aforementioned requirement, namely, two large national surveys, one reported by Jones (23) for the United Kingdom (UK) and the other by Environmental Health Associates (14) lor the United States (US), and studies of individual plains m Canada, reporicd by Theriault & Allard (46) and m Italy, reported (as a part of a national si tidy I by llelli et al (4). All four include observations on men more than 25 years alter (heir first exposure, and the ex pected number of deaths i$, m each case, greater than 10 */ of the total number of employees, a value indi cating a tong average period at risk. Earlier observa tions on UK and US employees <6.9, 12, 16. 20; 36, 39,40,45, 50) have been subsumed in the national sur veys and now serve only as sources of hypotheses and of some detailed information not included in the na tional reports. Studies of German (49), Norwegian (22), Swedish (7), Frcnelt (41, and unpublished report Ol Laplauchc et al), Japanese (33. 37), jnd some oilier Italian (4) workers provide some supplementary infor mation, but, in.gencral. the periods ol observation have not been-long enough-for useful epidemiologic data to be ubtained about diseases that are unlikely to occur within 20 years of first exposure, oi ihoy report only selected results which are difficult to in terpret, as only excess rales tend to have been selected. Studies of makers of PVC products have not been included, as (he workers have had much icss exposuic to vinyl chloride than tliusc employed in the niatiulaclure 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 ol the US Chemical Manufacturers Association is (he largest and must 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 It plants iharproduced only VCM, 6 848 men in 18 plants that produced only PVC, 935 men in three planis (hat produced both, and I 176 men in five plants ihat produced homopolymers and copolymers, with or without VCM or PVC. Twenty-two of the plants were in the southern part of the country, 14 were tn the northeastern or north central parts, and one was in the west. Men were included if (hey had been exposed to vinyl chloride for at least a year belore 31 December 1972 and had been employed in 1942 or subsequently (the lirsl year depending mi die dale llie pi.nil licc.iit iii.iknic or using sonnel n was the : idem i tie sonnel. Racial 97 /, of the purp deaths, i, Follow cial Secur died atier plants did (9) earlier present m plants win 1972 were follow-up 1982. wh,c . 'iff the men untraced w which was i Almost h belore 195; served more many cases a long laien Short-ten cohort, and ployment (q I lor 10 years I ploymem be i Fifteen hit have died, li lamed from t laincd for ih The numb causes or grc Plytng the pci national rates age groups at This impor cisms, which effects on (he compiled by t cords without sumption that caused the exp underestimate! to have had h reason for supp the proportion necessarily repr tainty was intri as 7.3 ** of thi f Two oilier cr espc.ted iiuinti, SI- 048259 roduce any new o requited if corim the results of xamined on their : i. ;w-- or using vinyl chloride and the earliest date (hat per sonnel records were deemed to be complete, whichever was the later). Individuals who met these criteria were identified from company records by company per sonnel. Racial characteristics were known only for 686 men. .t;- 97 of whom were white, and it was presumed, for the purpose of estimating the number of expected ed requirements. deaths, (hat all 10 173 men were white. . one reported by Follow-up data were obtained from plant and So UK) and the other cial Security Administration records and (for men who ues (14) for the died after 1979) from the National Death Index. Five individual plants plants did not collaborate in the extension of Cooper's k Allard (46) and (9) earlier study, which had been subsumed in the nal study) by Belli present investigation, and the 955 employees in these ons on men more plants who were known to be alive on 31 December isure. and the ex 1972 were not followed any further. For the rest, case, greater than follow-up was attempted (o death or 31 December yees, a value indi- 1982, whichever was ihc earlier. On this basis 92.7 V* t. Earlier observa- of the men were successfully traced. Those who were .9. 12. 16. 20. 36. untraccd were excluded from the last date of contact, in the national sur- which was usually the date when employment ceased. of hypotheses and Almost half of the men (46 8t) were first employed included in the na- before 1933. A large proportion was, therefore, ob n (49). Norwegian served more than 23 years after first exposure (and in unpublished report many cases for more than 30 years) when diseases with 37).and some other a long latency period might be expected to be seen. jppleincmary mfor- Short-term workers had been excluded from the ods .of observation cohort, and most of.the men had continued in em seful epidemiologic ployment for.many years, two-thirds being employed es that are unltkelv for 10 years or more and'the average duration of em t exposure, or they ployment being 16 years. t are difficult to in- Fifteen hundred and thirty-six men were found to 0 have been selected, have died. In I 439 cases, the cause of death was ob ducts have not been tained from the death certificate, but no cause was ob 1 much less exposure tained for the other 97 persons (6.3 Vo), .lyed in the tnanufac- The numbers of deaths expected from each of 38 cupational hazard to causes or groups of'causes.were obtained by mulxi- veil is more likely to plyiwg the p.ecson-/ears.at risk' by the diseise-specrfic tst. national rates for white males, for the corresponding ge groups and five-year periods of the study. ut by Environmental f of the US Chemical <e largest and most inr undertaken. It cov ed in 37 plants owned ien in 11 plants that nen in 18 plants that l in three plants that en tn five plants ihat copolymers, with or This important study is open to three minor criti cisms, which are unlikely to have had any material effects on the results. First, (he lists of employees were compiled by company personnel from company re cords without any independent check. Second, the as sumption that all the employees were white will have caused the expected deaths to have been very slightly Underestimated, as the few black employees are likely K-i?S lo 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 ;rc in the southern part northeastern or north the west. id been exposed to vinyl fore 31 December 1972 42 or subsequent^ (the e the plant began making necessarily representative. Third, an element of uncer tainty was introduced by the failure to trace as many as 7.3 Vt of the employees. Two other criticisms are more important. First, the expected numbers of deaths were calculated on the as sumption that the men would have experienced the same mortality rates as the white male population of the whole country at the corresponding dates. The use of national rates is common practice tn studies oi in dustrial populations and tends to result in an over estimation of the ex'pected 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 (he 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 1 336 deaths. This deficiency was allowed for in the calcu lation of the overall mortality by the inclusi n 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 *7*. For the present purpose, therefore, the numbers of deaths attributed to specific'diseascs have each been multiplied by f.0674 (100/(1--97/1336)1 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 (east one year in jobs that involved potential expo sure to VCM for at least 25 V of the work week and who were first employed in the .period 1940--1974. De rails 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 "/>. Seven hundred and eighty deaths were identified, and copies of the death certificates (coded lo 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 . coded according to (he eighth and ninth revisions of the IC'D was, however, experienced in obtaining suit able rates for all causes of death, and rates lor a rela tively late period had to be used for estimating the numbers of deaths from many diseases that might have been expected to occur in earlier periods. For two categories the earliest available rates were I960--1964. for one they were 1965--1969. for 24 they were 1970-- 1974, and for one 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 *ere then grouped according to whether exposure to VCM was likely to have been high (group A), expo sure to PVC dust was likely to have been high with exposure to VCM low (group B), or exposure to VCM and PVC dust was intermediate and intermittent (group C). All other men, who would generally have had low exposure to both VCM and'PVC dust, were classed as group D, Within all the groups, exposure to VCM was likely to have been higher if it had begun before 1956. The study makes an important contribution to 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 pr esumably distributed aboui lhe country,but no-details of their location are given, iii general', mortality rates tend to be higher in the parts of Britain where heavy industry is located than in other parts of the country so that the expected numbers of deaths are more likely to be biased downward; than upwards; but whether this is so or not needs to be shown. The use of recent rates to calculate expected num bers of deaths from many specific causes of death was presumably necessary if the diseases were to be studied individually and will have done no harm if the inci dence and fatality of (he diseases in question remained stable. It would have been desirable, however, for the diseases to have been specified so (hat 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 job to another was said to have (ended to be out ol groups A and 1) into 0, but even so it must be presumed that the expected numbers of deaths in the first (wo exposure categories arc likely to have been overestimated. Canadian study. The Canadian study (46) was limited to employees of a single plant tn Shawtnigan, Quebec. The plant, which was situated in an industrial com plex, was opened in 1943. VCM and PVC were both made until the late 1960s, when the production of VCM ceased, while the production of PVC continued. An attempt was made to trace all the production work ers whose names appeared on (he 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.) ***). Detailed occupational and smoking histones were obtained by questionnaire, and 156 men who had been employed by the companies for less than'five years were excluded. The remaining .men were'categorized as (i) exposed to VCM if they had worked on the production of VCM or PVC for at least five years (451 men), (ii) unexposed to VCM if they had worked similarly for less than six months (370 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'u.nexposed) 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 for all the exposed men who had died of cancer. The results were examined in two ways. First, the inurtaiities of the exposed and uncxposcu men were compared after standardization lor live-year periods of the study and five-year age groups. Second, the mor tality of the exposed men was compared wuh (hat 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 fqr more than 10 years (75 Vo), the average length of exposure was approximately 17 years, and 44 Vo 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 tiver, as well as one (hat had been diagnosed as angiosarcoma of the peritoneum. Two other cases of angiosarcoma of the liver were found to have been certified as hepatic cir rhosis. It ts also helpful to li.ive a compaiiMUi between It I I i the txposei companies for all non a healthy w recording o j nant causes 0.95). 1i One aspe* ie. the use calculate e\ period (1948 to bunch up vation so th have been ta some distort i size (and eve estimate. Fui likely to has Italian study. duction of vm was begun in employed for start up of iht still incomplet m three plant . i stgnana) begar | \ thirty-seven m ' in the other. Al. followed to the i mated by mutui corresponding i year age group a 'fi The total expect more than 10 " % i (12.4 and 12.8 r Clinical tnfoi ; death of all the had died. Revu s comparison *n deaths from ca The Ravenna 1959. Six hundre All but four we were found to hr lowed for more (3.9 Vo of the wc this plant have r cipal analyses. I death was attribi pected. 5L 048261 Cither sources. Th 'CIS.IUOIU on 45. l-><" tu Uleinjik ut deaihx in thf ;|v 10 have been i the exposed and "unexposed" employees of the same companies as it shows that the low mortality observed for all nonmalignant diseases could be attributed to healthy worker effect and was not due to bias in the ' (->6) was limited Aimgan. Quebec. 1 industrial coinJ PVC were both ie production of f PVC continued, production work mens' lists or the Ie industrial complant, between I 2, and contact was f-kin in I 611 out i occupational and questionnaire, and i **** -. > *.*-- recording of exposure (relative risk for all nonmaiignant causes compared to that of the "unexposed" men 0.95). - One aspect of (he study has to be criticized however, ie. the use of provincial rates for one year (1971) to calculate expected mortality spread over a 30-year period (1948 to 1977 inclusive). Deaths will have (ended (0 bunch up towards the end of the period of obser vation so (hat the rates for this particular year may have been fairly representative, but it must have caused tome distortion of (he expected numbers of deaths, the tile (and even the direction) of which is impossible to estimate. For most disease groups the distortion is un likely to have been large. by the companies ed. The remaining ;d to VCM if they VCM or PVC for mexposed to VCM I: Italian study, A study of all men employed in the pro duction of vinyl chloride and PVC in nine Italian plants f i . was begun in 1983. All men were included who were ss than six months employed for at least six months at any time from (he 4 m total). The last start up of the plant to the end of 1981. The study is dy. Follow-up was mil incomplete, but results are now available for men les of the deathcer- in three plants (4). Two plants (in Ferrara and Ro- . uses for all who had signana) began operation in 1953. Four hundred and VsedFwere coded ac- the ICD. Informa- thirty-seven men were employed in one plant and.181, in the other. All but three (from the Ferrara plant) were il or cyiologica! con- followed to the end of 1984. Expected deaths were esti all the exposed men mated by multiplying the person-years at risk by the corresponding national mortality rates for each five- iwo wavs. First, the inexposed men were for five-vear periods .ips. 5econd. the mormpared with that exex- and aee-specific -cc for ihe year 1971. . of death used were ificaie. and the addiias used later only for 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 Ihe employees in the iwo plants (12.4 and 12.8 Vo). Clinical information was sough; 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 . <959. Six hundred and thirty-eight men were employed, ere exposed for more ge length of exposure d 44 rn were observed exposure. ikes a useful coniribuhistological review of helpful. It showed that liver cancer (including but four were traced to ihe end of 1983. and 17 found lo have died. No man could have been folfor more than 24 years, and only 25.1 deaths 5^ of the work force) were expected. The data for fhis plant have not. therefore, been used in the prin cipal analyses. It may be noted, however, that one death was attributed to liver cancer when 0.1 was ex pected. one specified as angio- of the liver, as well as is angiosarcoma of the of angiosarcoma of the certified as hepatic ctre a comparison between Other sources. The Norwegian study (22) provided obserrations on 454 men who had been employed in a **'- pUnt in Telemark where VCM had been manufactured (rxm 1950 to 1971 and PVC from 1950 to the end of ihe study period. Every man was included whose name was recorded in the company's personnel register and health department records who had ever been em ployed from the start of production to the end of 1969 and had worked for at least one year. The men were followed from 1953 to 1979 inclusive. Deaths and cases of cancer were identified from the records of the Cen tral Bureau of Statistics and the national cancer regis try. No reference was made to any men being lost to lollow-tip, 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. FiTty men were found to have died against 59.34 expected if the sex-, age*, and quinquenniumspecific national mortality rates had operated. Twentyone men were found to have developed 23 cancers against 20.16 cancers expected from the comparable national incidence rates, the use of which was justi fied by the finding that the incidence in the county in which the plant was situated was between 90 and 95 *! of the rate of the country as a whole. One man who had been employed in PVC production developed an giosarcoma of the liver. The observed and expected numbers of cases were given for cancers of the lung, coion. and thyroid, for melanomas, and for all can cers. but no expected numbers were given for other types of cancer. It is evident that several other types of cancer must have been in deficit, as there were eight cases in-all against 14.93 expected,'and It is difficult to know what' weight to give the excesses observed for the reported types of cancer, as they seem likely to have been reported specifically because the numbers were in excess of those expected. The authors noted that one further case of melanoma had occurred after the closure of the study and that one "incipient case" was also known to (hem. The German study (49) included the following three groups: (i) 7 021 men w.ho had been exposed to VC in the caiirse of their employment.in. any of the II plants in which VC.and PVC'had been produced in ihe 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 (hey were production workers or other skilled workers or laborers assigned regularly to the plants, but not if they were employed in them only occasionally. AH the men were included from the lime of opening of the plants to the end of 1974, and they were followed to the end of 1974. Many of the men were therefore observed for only a few years after first employment, and only 14, 36. and 19 *7, 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 SL 048262' Of the exposed group 93.2 were successfully fol Two Swedish plants have produced VCM and PVC. lowed. and causes of death were discovered for 92.S one since 1945 and the other since 1971, and employees of the 4U men discovered to have died. The propor of the first plant have been studied by Byren et al (7). tions for the other two groups were respectively 89.8 All persons who had ever been employed when expo and 88.7 V for the unexposed and 92.1 and 86.9 *!* sure (o VCM could occur were listed from the per for the PVC process workers. The failure to obtain sonnel files of the factory. Twemy-one were excluded causes of death for all the men who had died was because they were foreigners who left (he country after allowed for in the subsequent analysis by the weight a short period of employment. The remaining 750 were ing of the numbers attributed to each cause by a sys followed to October 1974. Expected numbers of deaths tem which took account of the age group and calen were estimated by multiplying the person-years at risk dar period in which death with an unknown cause oc by the corresponding age-specific mortality rates for curred. The expected numbers of deaths from each the whole country, and the expected numbers of can cause was calculated by multiplying the person-years cer cases from 1958 to 1971 inclusive (during which at risk by the sex-, age-, and cause-specific mortality period all cancer cases had been registered nationally) rates for the Federal Republic of Germany. National were estimated by multiplying by the national age- data before 1968 used an idiosyncratic classification specific cancer incidence rates. In both instances, the system, and the 1968 rates had to be used to multiply rates used were those recorded in 1969. Fifty-eight all the person-years at risk up to the end of 1968. For deaths were found, but no figure was given for the ex subsequent years (1969 to 1974) the person-years at risk pected number. Detailed figures were given only for were multiplied by the corresponding rates for the same the numbers of deaths and cases observed and expected calendar year. . for cancer of the lung and for cancers of the liver and Epidemiologic studies are more difficult to carry out pancreas combined and for the numbers of deaths in the Federal Republic of Germany than in North from brain cancer and three categories of cardiovas America, the United Kingdom, or Scandinavia because cular disease. Two men known to have angiosarcoma the medical cause of death is not recorded publicly, of the liver were certified as having died of liver can and (here is no central system which can be used for cer or pancreatic cancer, and a third man died of checking whether an individual is alive or dead. In angiosarcoma of the liver 17 months after the close these circumstances, the German authors have made of the follow-up. valiant efforts to obtain reliable data, and the propor- ^ Two French studies .provide-the results of a long- lions of men in the exposed groups who .were not sue-,1 term follow-iip of men.empldyed in one plant (41) and cesslully followed (6.8 %) and (he proportions of -of a short-term follow-up of men employed in 12 plants deaths for winch the cause was not obtained (7.2 ^) (Laplanchc et al, unpublished). The first provided ob were similar to those in the study of the Environmental servations on 1 311 men exposed to vinyl chloride in Health Associates (14). the production of VCM and PVC and in selected an Two defects, however, make the data less useful. cillary operations from (he opening of the Tavaux plant First, no national mortality rates were available before in 1953 to the end of 1976 (41). Six other employees 1968. and the use of the 1968 rates to estimate the num were excluded from the study because of lack ol' oc bers of deaths in and before 1968 will have overesti cupational histories and 160 men because their vital mated the numbers attributable to diseases that were status at the end of the study period was undetermined. becoming more prevalent or were being diagnosed Twenty-five men were found to have died against 48.75 more often and underestimated those due to diseases expected from contemporaneous sex- and age-specific that were becoming less prevalent. Second, and more- national mortality rates (3.7 of the men at risk). One importantly, a large proportion of the men had been death was attributed to angiosarcoma of the liver, in first employed less than 10 years before the follow-up a man who had been exposed for more than 15 years. ended. Therefore the useful observations on the few The reported data are so incomplete and cover such men who had been exposed long enough to have had a relatively short period from the opening of the plant 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 that they add nothing of epidemiologic value to the results of the other studies, apart from the addition of a further case of angiosarcoma. tribute. The expected deaths amounted to only 6.2 7* The second study provided observations on I 100 of the exposed men, and there is, therefore, little to men aged 40 to 55 years who. in 1980. were exposed be gained, and something to be lost, by including the or had been exposed to vinyl chloride in 12 plants, German data in the overview. It may be noted, how- which constituted "most of the French VCM polym ever, that 12 deaths were attributed to cancer of (he erisation plants" (Laplanchc et al, unpublished). Many liver among the workers exposed to vinyl chloride of the men were, or had been, employed at Tavaux against 0.9 expected and that smaller excesses were also and were presumably survivors of the cohort studied observed among the unexposed chemical workers (4 by Pierre et al (41). The men were followed for five observed avaunt 1.1 expected) and the PVC process years, and their morbidity ami mortality were com worker-, (4 deaths actimvt 0.8 expected). pared wiih those ohsvrsed tm 1 too men ot <li.- -im-- ages(2 but who in both g formaoor drinking f * two group first expos first been ously. Mo< nually by t l 98 9* of tf if One of the developed. given sepai ployment..of the find, lung cancer well reflect in the reter cancers in tl One expose hematopotei none of the developed n roid. A Japane perience of before 1965 ducing YC\ tve(J7), ,Thi Twenty.eight than 20 years served more t untraced, ant tained for all initial cohort to the job in at the termin; given separate in PVC prodi classed as VC iv;. If this stud KT. *huld providi pcesem data in. 44 *han 20 years a Qie' con ^CTncer with si workers again: while only one Other workers deaths from liv workers was ce liver, and at lea was due to the not in excess (2 cxii\iedl. Nod ;-Ii.iiic ,itid iiviu SL 04826: VCM and PVC ntl employees yren et al (7). ;ye<l when expoU from the perte were excluded ihe couniry after inatning 750 were umbers of deaths rson-years at risk iortaiity rates for numbers of can-e (during which stered nationally) the national ageoth instances, the 1969. Fifty-eight is given for Ihe exere given only for erved and expected ;rs of the liver and umbers of deaths jrtes of cardiovasiave angiosarcoma i died of liver canthird man died of -.ths after the close ' r results of a longn one plant (at) and yed in 12 plants st provided obto vinyl chloride in ' and in selected an4 of the Tavaux plant Six other employees cause of lack of oe* n because their vital ` id. was undetermined', ne died against ait 75 sex- and age-specihc the men al risk). One coma of the liver. m r more than 15 sears, tplete and cover such c opening of the plant mioiogic value to the art front the addition mia, observations on l 100 in 1980. were exposed chloride m 12 plants. ; French VCM polymal. unpublished!. Many , employed at Tavaux s of the cohort studied were followed for five d mnrialilv were com- I 100 men of the same Ages ( 12 years) who were etnployeu in the same plants but who had never been exposed to VCM. The men fas both groups were interviewed personally, and inr1 jrtfonnation was obtained about their smoking and ^drinking habits, which were found to be similar in the groups. The men in ihe exposed group had been exposed for an average of about 14 years and had flat been employed in the plant about 18 years previ ously. Morbidity and mortality data were recorded an Sy*nually by the plant physician, who successfully traced M % of the exposed men and 96 *? of Ihe referents. Ooeof the exposed men. but none of those unexposed, ^developed an angiosarcoma of the liver. Data were not gjvci separately for different periods after first em^pioyment. and it is impossible to assess the significance ot the finding that six of the exposed men developed hug cancer against two of the referents, which may ^_x*il reflect a chance occurrence of unusually few cases b> the reference group, as the proportion of all lung m amoets in that group (2 out of 15) was unusually low. One exposed man developed a cancer of the lymphofeanuopoietic system against none of the referents, but of the men in either group were known to have v : ... .developed melanomas or cancer of the brain or tlty- rowl. _ , - A Japanese study lias reported the mortality expretence of 4 524 men employed for at least one year tyy:7; before 196? in 25 Japanese plants which began produring VCM or PVC between 1949 and 1964 inclu sive lJ7). The men were followed to 31 October 1975. ' Twenty-eight percent of the men were observed more rfcaa 20 years alter first employment, but none was ob- Ifev', ; rrvrvl more than 26 years. Only 0.6 V* of the men were gT-4 orravcU. and copies of the death certificates were ob- ` ume\) for all the 209 men who had died (4.6 */o of the msulI cohort). Individuals were classified according gy... . bathe job in which they had been longest employed SqTV" a*-the termination-of their follow-up, and data were tjren veparajtly for tlic 2 546 men classed as.employed in PVC production and I 978 others (including 900 dnvvxl as VCM production workers). If this study is continued for another 10 years, it tbouUl provide useful additional information, but the P,CBcnl data include too lew observations on men more i 20 years alter first exposure to be ol any material .-They confirm the evidence of a hazard of liver with six deaths among the PVC production test against 2.54 expected from national rates, i.only one such death was observed among the workers against 1.82 expected. One of the six lbs from liver cancer among the PVC production workers was certified as due to angiosarcoma of the fever. and at least one of the other liver cancer deaths i due to the same cause. Lung cancer deaths were I in excess (2 observed in PVC workers against 2.33 ^expected). No data were given for cancers of the lym i phaoc and hematopoietic systems, for cancer of the beaut or thyroid, or for melanomas. The mortality f* nvwinl by MnauUn <JJ> for JOS Japan*** vinyl chlo ride workers has presumably been subsumed in Na kamura's (37) later and larger study. Hazards of cancer The results of the four most useful studies are listed individually in tables 1 and 2. The overall results for all causes, liver cancer, and three broad groups of con ditions are shown in 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 ma)or 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 fr m 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 ihe first few years after the start of employ ment. and an SMR of 1.02 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 JO liver cancer (or, in the US series, liver and gallbladder cancer) is not entire ly accounted for by the known hazard of angiosar coma. Fifteen of the 37 deaths2 attributed to cancers of the liver and gallbladder in the US senes are known to have been due to angiosarcoma of the liver ((4). In the UK series, seven ol the 11 deaths attributed to liver cancer, not specified as secondary, were known to be angiosarcomas, and they all occurred in auto clave workers against 0.38 expected liver cancers of all types (P< 10"*) (25). In the Canadian senes, histo logical review showed (hat seven of the eight so-called liver cancers were angiosarcomas (one had been de scribed as an angiosarcoma on the death certificate, two as hepatomas, and five as unspecified liver can cers). One so-called liver cancer death was found to have been due to cancer of the sigmoid colon, while one death attributed to angiosarcoma of the perito-1 1 Increased to 39 in ubic I lo lake account of the 97 extra diMihi from n unknown 67 SL 048264 Table 1. Observed ino eipected number* ol deaths trom dilierent cancers reported in me (cur principal studies is. u. 25, 461 (O = observed numoer ot deems. E = esoected numoer ol oeamsl Type or cuss ol cancer United States O* e United Kingacm OE Canada OE Italy O E Buceai cavity and pharym Esophagus Stomach Large intestine Rectum Liver Liver and gallbladder Pancreas Other digestive Laryn* Lung Omer respiratory Bona Skin inonmtunomi Melanoma Prostate Testis Bladder Kidney Other and unspecified urinary. Stain Eye and central nervous system. `Thyroid Lympno- and retlculosarcoma Hodgtun s disease leukemia Multiple myeloma I Other lymphatic j Other All cancers 13 It 55 7 807 u 1601 21 28 79 39 5.77 17 18.40 118 115 87 S 6.38 2 t at 6 7.36 16 15.20 5 8 48 12 906 Z5 . 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 1 1 10 49 1 1 1 94 7 988 4 2 21 81 92 12 0 0 64 8 0 14 6 5 26 2 5.78 2 1 74 12 9 59 2 1 33 14 800 3 4 10 3 4 29 4 8:18 2 0 43 4 2.35 3 2.50 7 5 16 2 2 35 16 8.12 235 228 60 j 1 2 20 1 67 0 95 16 37 1 08 1 06 3 30 0 12 t 06 0 07 1 09 12 6 1 0 02 1 07 1 07 0 04 0 07 9 45 30 21.1 * Observed deaths muluplled by,1 0674 and rounded oil to the nearest integer lo allow lor deaths without discovered cause. Teble 2. Numbers ol Oeams Irons nonmahgnant and all causes reponed In the lour principal studies <4, 14, 25. 461 (O = observed numoer ol oeams. Connected numoer ot Oeatns) Cause ol deam Untied Slates O* e United Kingdom OE Canada Oe Benign and other unspecified tumors Cerebrovascular disease lacnemic hears disease Other circulatory disease Bronchitis * Pneumonia Other resoiralory disease Cirrhosis of the liver Other digestive disease Disease ol me genitourinary syitem Other diseases Suicide Accidents and other violence All nonmangnant causes All causes 4 5.08 75 91 93 521 597 73 157 123.55 44 22.63 16 31.94 1 15 32.64 1! 37 56 06 27 39.52 11 20.41 87 115 68 49 52.78 l 130 173.19 / 1 153 1 363.54 1 538 1 705.27 276 105 36 *o 5 43 40 545 780 288 141 44 1 61 ' 51 .- 1 76 50 665 894 25 31 67 1 J 1 6 3 21 2* 5 40 2 10.58 39 54 76 59 71,07 ' See footnote to table 1. * Emphysema in data trom the United Slates. ' includes iwo cases certified as cirrhosis ol the liver which proved to be angiosarcoma ol the liver. * Includes one case with cause unknown. Italy O E 0 0.5 3 5.0 4 52 3 2-7 1 2. 1 4 36 66 70 0.9 77 56 4 77,5 ncum was found to have been due to angiosarc ma of the liver I4M. In the Italian study, further evidence revealed ilr.ii three further deaths should have h,-nn ;u. iribuicd to cancer of the liver (for a total of four!, but only one of the lour was described as an antuosarcoui.i i -it Jt - Table 4. Moit lO xooserveo Type or class uouth and pm Otpeiiive systt hespiratory iy: lung Genitourinary i Ketanoma 6'em : hyrold ivmpnattc and Gmer Alt omer man p * l s United Sta T*b4eS. Monahi numoer of deem Type or class ol i Digestive letcludin( . Lung . Metenomr .Brain Thyroid ^lymoneiie Spoeenc sy: X.V Other tevc feSv Ah eietu tnetder Cancer C*ncer If'*. 0 Fttnher evid cancer (or livet ,.rn i aiiribm a/urd ol anpi t< 5 MMl**"* ` "* Italy 0 1 1 1 0 1 0 1 II E 06 06 30 12 0.6 0.7 oio 6.1 0 OZ 1 0.7 1 07 0 04 0 07 9 45 30 21.1 tout discovered cause- n;25. 461.(0 = observed Italy 0E 0 0.5 1 '9 } .3' 4 3 i2 1 1 ; 36 7 66 V* 5JD 51 27 70 09 ;; 56.4 775 T.ible 3. i<ii / inn r-inrcr of in* hvef and ome* Causes amooq vtnyi cniof'On *nr-f^ to 40 nMntA ' me tow* umw'ioAt M'Kites co"'t>med \*. i* 2V *61 tO = ooserveo oumotr of aeatns = eioecied numoer of chains. SMR * stanoarduea mortality ratioi Cause of d4in 0 E SMR Cancer of m* Cancer dt omer sues Other diseases Accidents, ooisonmgs. and violence All causes 59 609 1 547 226 2 441 6 45 . 599 35 1 844 69 295 15 2 747 94 698 02 84 77 89 including cancers ol ihe gallbladder in me series irom me umied Stales. Mortality from various cancers among vinyl chloride workers in 49 Giants in me lour orinasal studies combined, erved number ol deaths. E = exoosed numoer ol deems. SMR standaroited mortality ratio) HW**>t* HcNyt* or dess of cancer OE SMR Source of Information* SSjKevin and pharynx [mPbuKw syslem (other man llverl jffil>acnraiory system BSfiOw ipunnary system lEL'Msunome Aftr eKatbykoid rsbiKwie and hematopoietic system SjiFAR eenev (hen ot the liver IS 1657 125 154 59 223 229 36 211 214 09 70 62.61 2 1 94 29 19 54 2 0 43 57 60 8 7 S3 63.24 609 599.35 109 1. I. 3. 4 81 1. 2. 3, 4 97 1. 2. 3. 4 99 t. 2. 4 Ml i. 2. 3. 4 2. 4 148 1.2.3 2 112 i. 2. 3. 4 131 1. 2. 3. 4 102 l. 2. 3. 4 * t a Untied Slates study (t4|. 2 = United Kingdom study <251, 2 = Canadian study (461. and 4 = Italian study <4|. i'aV: Monality* Irom various cancers among vinyl chloride workers: Suoplementary evidence (4. 7, 22. 491. (0 > observed r ol deaths. E i expected number oi deaths, SMR standardised monaluy ratio) Type or class ot Cancer e. .tv***!TM* system pep lining the liver) iMeaxnme 1 "IbywwS eno ftemato* , system QtFwr Including the liver) 1^*1 axxJwding me liver Federal Republic ol Germany (It plants) OE 35.0 31 8 23.5 24,6 in 1,3 ` 16.5 7 7 107 24.3 87.S 897 Norway (t plant) Sweden (1 plani| OE OE 3* i 44* 5 2.84 ; `4 . .6.79, 2 0.16 3 I 178 6.33 a 14 93 22 20.16 5' 2.11* Italy (1 piano oE 1 t2 0. 15 . 0 o-i: 0 07 4 20 5 57 Four countries combined (14 plant si Q SMR 39.0 31.5 ' 40 4i 2.0 34 44 30 72 ,0.89 . 163 0.16 113 103 .4, 16.5 227 119.8 84 41 43 117.67 196 55 102 and cases in me Norwegian study. Ol the Intestine only, ol the lung and brain only. for a tool of Tour), bul bed as an angiosarcoma evidence that the excess mortality from liver (or liver and gallbladder cancer in the US series) be attributed principally if not wholly to the known 3r.l>*Edfd of angiosarcoma is obtained in a comparison %4 the eservs deaths with the numbers of deaths from [wpwirmttm recorded in the Register of Liver Angio sarcoma Cases (maintained on behalf of the Associa tion of Plastics Manufacturers in Europe by the im perial Chemical Industry PLC) before the end of the follow-up period (Bennett, unpublished). Fifty-one ex cess liver cancers are recorded in the combined data, and 49 angiosarcoma are recorded in the Register for 69 Tible 6. Mortality from king cincar in tha serial from ina Unites Slates (US) (14) ana me United Kingdom (UK) (25) Dy Characteristics relevant to an occupational Hazard. (0 = ooserved number ol (teams, E = eapecied numoer ol (teams. SMR 3 standardized monallly ratio) Data Characteristic * Category 1 O* E SMR Category 2 0 E SMR Observed ;o yeara or more alter lirsi employment (t), omen <2| Employed 10 yaers Or more in me US (t), omers m the US 12) Emoloyeo before (966 m me UK (1). omen in me UK <21 vf employed as autoclave worker m the UK (1), others in the UK (2) 114 113.96 100 55 52.45 105 52 51 39 101 16 17 08 94 85 93.83 91 63 83.44 99 29 40 50 72 65 74 82 87 * The numbers in parenmesas designate me category. ' * See footnote to taoie t lor observed deams in me US. the relevant periods for (he three countries and the two Italian plants1 (hat 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- (rations appreciably higher (unpublished report by Barr to Air Products and Chemicals Inc in 1981). Lung cancer. The idea that exposure to vinyl chloride might cause cancer of the lung was suggested by Monson 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 Twemy-mne were registered as occurring in the United States against an excess of 33: only 20, however, were iden tifiable in both series. Inquiry has, as yet, failed to reveal Information about the histology of the remaining 13 in the cohort study and the origin of the nine extra deaths in the register. Nine deaths were registered as occurring in the United Kingdom against an excess of nine, but one of the registered cases was certified as due to s benign hemangioma and not related to the liver (code 227 in the eighth revision ol ihe International Classification ol Diseases). Ten cases were registered as occurring in Canada against an excess of eight; two were recorded as being in men who had been employed for five years, and ii is possible that the actual duration had been slightly less than live years with con sequent exclusion from the Canadian cohort. One case was rcyisivreil as occurring in one ol (lie two Italian plants IL'JIIHI J|) iui'33 lt OIK* 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 I95S (when exposure levels are believed to have been lower), for men employed lor 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 arc, 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 34.5 when allowance is made for the number of deaths due to unidentified causes in the German study (SMR becoming 103). In the German study the SMR was higher for the men who had been exposed lor 10 years or more than for those who had been exposed for shorter periods (III against 79), and, in (he 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. Doth the German and the Swed ish studies derived (he expected-numbers of deaths -from'national mortality rates .lor.a single year towards the end of the study period. The expected numbers of deaths are likely, therefore, to have been overestimated and the SMR values correspondingly underestimated as the mortality from lung cancer had been rising throughout the period of observation. Brain cancer. The idea that vinyl chloride might cause brain cancer was also suggested by Monson et al (36) when they reported five cases against 1.2 expected. The combined data that are shown in table 4 provide some support for this hypothesis. The cases of Monson et at (36) were, however, observed in US workers and must be presumed to be included in the total reported by Environmental Health Associates (14); therefore they will have contributed a substantial proportion of the total in table 4. As a test of the hypothesis the data of Monson et al ought, therefore, to be subtracted from those in the table. Their investigation was not a cohort study, and (heir expected deaths do not cor respond exactly to those in table 4. If, however, the observed and (he expected cases are both subtracted from the totals, twenty-four observed deaths remain agatnst approximately 18.3 expected, a difference which might easily occur by chance (P one-tailed 0,I).J ` If the study of Waxweilcr et al (50) is regarded as die origin Ol the hypothesis, 26 demits .uc till aeaimi IX.`14 c\|Vciv-d (P tinr-f jilcil -i N 1)7) i i f* Additi 4 given in it little furt one of th occurred less than the excess German ; chemical deaths af causes aga PVCfabr. for deaths Cancers oj idea that vi phatic and the lympha A Gaffey (4 studies, svl from lympl against 2.5a he lymphat pected. The f the labora suggesting tl ally in anm tion. (29). T; ICC IS jlucs more f. for r men Is are ;d lor id (or angtoother small, nd the in the e like* ps is I s given icrved, jnce is mi Tied 03). In ie men ian for dstlll r of the ipattons 11st 1.82 t Swed- deaihs towards iibers of siimated .timaicd n rising hi cause cl a! (36) :ied. The ide sonic onson el kers and reported iherelorc orttett ol s tlie data ubtraacd i was tux a not coriever, llic ublracied lis remain difference ic-laded = : ( k L 3* |IlC .94 expected AdUuiotuti uWormaunti Uom (\ui other sources is given in table 5. The small excess reported provides little further evidence of an occupational hazard, 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 (lie excess death rale 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 for 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 l.l 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 Tabershaw & Gaffey (45) and by Waxweilcr et al (SO) in two cohort studies, when they lound, respectively, fixe deaths front lymphomas in the most heavily exposed workers against 2.54 expected and lour 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 interpreted as suggesting that lymphomas were produced experimen tally in animals exposed to xiuyl chloride by inhala tion (29). The idea that similar exposure might also cause lymphomas in humans, therefore, merits seri ous consideration. The data from the four principal studies that are summarized in table 4 provide little support I sir the hypothesis sshen 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 ohinmed from the separate data for cancers of the lymphatic system t Fahcrshaw & Gaffev's dclininon of l('t) list numbers, eighth revision. 200--203 and 205 being used) that are shown in table I (35 deaths against 29.40 expected). The position moreover: hardly altered if the daia.in-Tabershasv'A Gal'fcy's initial report ate subtracted (29 deaths against 23.36 expected. SMK 124). Little additional information is provided by (he results of the German study (49). (See table 5.) This study obtained an SMK 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 5MR values of 77 and 34 for an unexposed group of chemical workers and a group of PVC fabricators. It showed (bat the excess of the exposed workers was present only for men who had been exposed for more than otic year and that this ex cess was most marked lor men who had been exposed for five years or more (10.7 deaths alter allowance for the number of deaths from unknown causes against 4.0 expected. SMR 268, P one-tailed <0.01). Metanoma. Alt excess of melanoma was reported for Norwegian workers by Mcldaas et al (22). who raised the possibility that vinyl chloride might have produced the disease. Four cases were observed when 0.79 were expected, and three of the four were in men wi se oc cupations involved the highest exposures (against 0.51 expected). At (he time of (he 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 1 and 5.) 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 front their observation. Two of the three major studies that have been reported since the Norwegian observation was made gave no data for thyroid can cer; the third reported (wo 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 ol the contribution of cancers of the liver to (he 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 (hat 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- peeled. 1* two-sided <0.05). This excess ts only mar ginally significant and may be a chance observation. The most likely explanation is. however, that a few angiosarcomas of the liver were not recognized and were diagnosed as secondary liver cancer or carci nomatosis, site unknown, the number of deaths in this category therefore being increased. 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 ts presumed to be increased only because of the liver changes that were observed as pari of the "vinyl chloride illness" (24, 31. 33). Two other possibilities have, however, been raised, namely, the production of nonmalignant respiratory disease, because of (he changes in lung function and radiographic appearances that have been Teble t. Mortality `rom selected nonmalignant causes and all causes in me lour principal studies combined. (Q = observed numoer ol deaths, a expected number o< deaths, SMA a standardised mortality ratio) Type ol disease Broncnins. empnysema* 0 e SMR Source ol inlormauon * BO 66 83 120 1. 2 Other resoirslory disease 71 125.78 AJI r0trato<y (scheme heart disease Other circulatory disease4 All circulatory disease4 Cirrhosis of the liver Other disease 160 797 252 1 103 46 236 200.62 885.73 264.55 1 209.35 66 26 368 07 All nonmalignant disease All external causes t 5X7 1 844 50 226 295.15 All nonmaligoani causes All eausss 1 773 2 139.65 2**1 2 747 85 56 i, 2 80 t. 2. 3. 4 90 1,2 95 t.z 91 1. 2. 3, * 69 t, 2. 4 65 1. 2, 3, 4 84 1. 2. 3. 77 t. 2. 3. * as t, 2. 3. 4 89 t. 2. 3, 4 * t a United States study (14), 2 a United Kingdom study (25), 3 = Canadian study (46), and 4 a Italian study (4). * Broncnins tn me United Kingdom study, emphysema In me Untied Slates study. c Includes cerebrovascular disease tn the United Kingdom and Italian studies. Table I. Mortality Irom enronlc obstructive lung disease* In me senes Irom ms United Slates (US) (14) and me Uniled King dom (UK) (25) by characteristics relevant to an occupational haiaro. IO = observed number ol deems, E a or peeled number ol deems, SMR a siandardned mortality ratio) Oata characteristic* Category 1 o E SMR Category 2 0 e SMR Observed 20 yeera or more alter tlrsl employment In the US <i|. others in the US (2) Emo<oyed 10 years or more tn me US 11). other* in the US (2) Employed before 1964 In the UK (11, other* tn the UK (2) Ever employed ei an autoclave worker in the UK (1), others in me UK (7'* 30 IS 26 3 158 190 10.9 147 30.17 66 6.55 46 11 7.0 157 25 12.0 208 10 13 60 74 33 37.22 89 Descnbeo as emphysema in me US study and as broncttltls tn me United Kingdom sludy. The numbers in parentneses designate the category. Men ever employed as a bagger or drier, occupations which vouia nave caused me greatest occupational exposure lo poiyvmyi chtonoe oust, experienced one death Irom bron chitis ui;ainsi 4 96 eipected recorded for men exposed (o PVC dim (2. 26, 27. 44), and acute cardiac death, from analogy with (he efleci of other halogenaied hydrocarbons (25) and (he ob servation of an increased mortality from myocardial infarction in the few years following the cessation of exposure tn 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 increased mortality (table 2); in combination they gave an SMR of 69 based on 46 deaths. The fourth study, which did not give sepa rate data for cirrhosis of the liver, reported four deaths from all diseases of the digestive system combined against 3.85 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 nonmalignant respiratory disease are confusing in that the total SMR from the combined data for the four prin cipal studies is 80 and is the son of figure that is com monly found in healthy industrial populations, yet (he 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 are complicated by the usage of dif ferent terms to describe what it is now agreed is best called chronic obstructive lung (or pulmonary) disease, but which in the past tended to be called emphysema in the US and chronic bronchitis in the United King dom. It must, therefore, be presumed that the two categories of "emphysema" and "bronchitis" used re spectively in (he 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 cohotu 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 am ng men with dif ferent durations and intensities of exposure. Unlike the data for cancer of the lung that were shown tn table 6. they provide no consistent evidence of a greater risk in rite groups in which an iiviHitninni.il humid tumid be expectet vwonmenu o give an from empl b*tdly be d "o overall * however, th by deficienc respiratory, Other respir (be queittoi could he a Health Asso that they w* ,"V. m the out-ot the coding o "other respir included em| ' emphysema i be classified to J02, and if of the emphy (nomecaieg "umber 527,1 for both the e frotsly defici. inpiratory di No excess n and asthma" i 44 with 6.3 di umber of de Ft.- , Cmediovai > Wroric) i rtode the to acute c ;hif nation Miacreasi jfpoupof d ianertcori jj*fthe SMI d there i ' ithesubsi jjifeadla. in ed me nem it A tflgh TV deaths at raws and the '*11 vv-iion f ` t- at Utah J*ti|iiaf - SLL 048* . <2. 26. 27, 441, ^^with the effect ^P&) and the ob- 'y2M expected to be concentrated. The authors of the Enitai Health Associates report (14) were unable fgfrr* any explanation for the increased mortality from myocardial i the cessation of ;mg industry (35), deaths from these at are obtainable t given in table 2, i table 7. emphysema, and they point out that it could ' be due to excess cigarette smoking, as there was I Overall excess for cancer of the lung. It is striking. r, that the excess is more than compensated for fdeficiencies in the other categories of nonmalignant sory disease (pneumonia 13 deaths.*1 SMR 47.0; 'respiratory disease 14 deaths. SMR 42.6), and 'qaestion arises whether the emphysema excess be a classificatory artifact. Environmental he four principal rhosis of the liver, :d mortality (table -IR of 69 based on * did not give separported four deaths system combined it the four included -rhosis of the liver. 46). In the two sup* were given for this jsed on 13.1 deaths th unknown causes :i seven deaths (37). Associates (14) list all the 41 deaths which show they were coded under ICO number 327 which, lifer out-of-date seventh revision (hat was used for tending of all deaths in the study, was the code for 'respiratory disease not otherwise classified" and emphysema. Under that revision, however, that was associated with bronchitis should fMchaained with bronchitis under (CD numbers 300 and the possibility may be considered that some : emphysema deaths should have been classified [ fei ttne category of respiratory disease other than ICO ' 327. If this were the situation, it could account ItMfethe excess mortality from emphysema and the deficient mortality from other nonmalignant gRWiruory diseases. iexccu mortality from "bronchitis; emphysema, >. The data for non* confusing in that the rthe (our prin* ire that is cornpopulations. yet the increased mortality . an SMR of 180 beor deaths from un as found in the UR. cave-an SM R.of 82. Toruc nonmahgnam :d by the usage of difs now agreed is best r pulmonaryi disease. ne called emphysema s in me United Kmgesumed that the (wo "bronchitis" ysed re--jg ial studies were meant e must assume, there-. wo countries were very roth related to cohorts :s of angiosarcoma of airly similar exposures r1 - -andasthma" was observed in die German.sludy (SMR ?i^*M tiiift 6.) deaths observed after allowance for the ' of deaths from an unknown cause) (49). 1U>* ^fbnfcrrnn i ' i - disease. Data for ischemic (or arterioc) heart disease (which may be presumed to in- i the vast majority of all deaths certified as due : cardiac disease) were given only by the two &iqfMfUO(tat studies, and (hey provide no Evidence of jf^Maatrniscd mortality: The SMR'vaiues'df 90 for this ie( diseases and of 91 for all cardiovascular dis^gwmemded in (he four principal studies are typical SMR values of healthy industrial populations. Ilfeac i* no suggestion of any occupational hazard febudiary analyses provided by the two national rift particular, there is no evidence of an in* (sociality within one month of leaving em* in the UK study cither for all workers (32 0p$MR 61) or for the most heavily exposed auto* rfcm (9 deaths, SMR 42). ; inaease in ischemic heart disease mortal* brecorded for the exposed workers in the Gcrr (49), but it was less than that recorded for n table 8. where avaiU^S J among men with dif*7 of exposure. Unlike the at were shown in table.:'^ ideneeof a greater riiklS, ipational hazard would A unbilled to different groups of respiratory disI the corresponding SMR vaturs that are cited in wi fur the US study are as given by the HnvironI licaith Associates (14) and have not been adjusted tor the number of deaths from an unknown X. 1 late account of these deaths, (he observed deaths i SMR values can both be multiplied by 1.0674. the unexposed chemical workers and the 1'VC fabri cators (SMR values of 127, 131. and 138 based on V7.2. 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 IS years) meant that a large number of men had been exposed before the hazard was delected and that it will still be many years before the extent of the pr lection provided by the reduction in exposure in the 1960s and that of the further reduction that followed the recognition of (he 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 theT6 740 men; who were followed in the four prin cipal studies (hat have beeft reviewed in this report, so (hat approximately I in 333 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 (wo to three times (19). The second outstanding observation is that the mor tality of the exposed men, other than that dtie to angiosarcoma of the liver, is typical of the normally healthy industrial Worker -- that is not to say that no other hazard exists, but that the effect of any other hazard is small. The massive data that are now available provide no reason for thinking (hat any hazard other than one of cancer has been overlooked. It is, however, still dif ficult to decide whether vinyl chloride produces a risk of developing cancer other than angiosarcoma of the liver which might be small compared to the risks produced by nonoccupational causes, but yet abso lutely almost as large as the risk of developing the nor mally very rare angiosarcoma. One of the many hazards suggested can be dismissed, as there is no evidence to support it. namely, (hat of vinyl chloride as a cause of any cancer of Ihe diges tive tract other than angiosarcoma of (he liver. Two hazards (of melanoma and cancer of the thyroid) have been suggested only very recently, and few of the avail able studies have provided information about them. There is no good theoretical reason or laboratory evi dence to suggest that either should be produced by 73 SL 048270 vinyl chloride, and. in light of present evidence, the simplest explanation is that the reported excesses are the chance effects that must be expected when many different types of cancer are studied in several different populations. So far as melanoma is concerned, it has to be remembered that the disease has become much more common in recent years in Scandinavia (where the excess was reported) due, it is believed, to the popularity of sunbathing and the increased oppor tunities for Scandinavians to travel to the warmer parts of Southern Europe and North Africa. The extent to which this change may have affected the observation in Norway needs to be examined. Two other hazards (of lymphoma and brain cancer) were suggested by the early results of some of the US studies. That vinyl chloride might produce a hazard of lymphoma was initially supported by the prelimi nary results of animal studies, but the complete results of the many investigations that have been undertaken (see reference 29) do not suggest that lymphoma or any other cancer of the hematopoietic system is liable to be produced. There is, however, some evidence that brain tumors can be produced in rats (29). The hypoth eses that lymphomas and brain cancers might be produced by vinyl chloride have been supported by the observation that both these types of cancer have caused death more often than might be expected from national mortality rates, but the excesses observed in the com bined data from the four principal studies in this re view are small and not statistically significant, and (he,. ' hypotheses remain unproved.-The small excess of brain cancer is particularly difficult to evaluate, as mortal ity rates from this disease have changed rapidly over nme as methods of diagnosis have improved and the suspicion of an occupational hazard (which was raised in 1975) could have influenced the findings. What ex cess has occurred has been limited to the US and Ger many, and the German findings carry little weight, as the excess was found in each of the three occupational groups studied, irrespective of the chemicals to which they were exposed. The supplementary data from the German study showing an increased mortality from lymphatic and hematopoietic cancers are more impres sive, particularly as the excess was the most marked for men who had been employed for at least five years. In these circumstances, judgment must still be sus pended until the data for each study arc analyzed for each specific type of cancer, by intensity and duration of exposure, and by time since exposure began. There remains the suggestion that vinyl chloride might cause lung cancer. At first sight, this possibil ity is ruled out by the SMR of 97 for the combined data for respiratory cancer for the four principal studies. Lung cancer is, however, normally so com mon (accounting f r about 8 *,1 of the expected deaths) that an increase in mortality that was half as impor tant (numerically) as the increase in mortality from angiosarcoma of the liver might easily be overlooked (95 *'0 confidence limits of the SMR 85--112), The in cidence of the disease varies moreover within a coun try. and there must be doubts as to whether the na tional experience provides a suitable 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, suppons the idea that exposure to vinyl chloride involves a small hazard of lung cancer. Taken in conjunction with the knowledge that lung tumors have been produced in sev eral species of animals exposed to vinyl chloride by in halation (29). it would seem that a small hazard of lung cancer probably did occur. The evidence is not, how ever, strong enough to conclude that it definitely did. If it did; the hazard was evident only for men who had been employed for many years at a time when expo sures of several hundred parts per million or more were common, and any persisting risk can be only minute and incapable of detection. The questions that have been left unanswered by this discussion might well be answered definitely if (i) all (he exposed men could be followed to (say) the end of 1984, (ii) the investigators cpuld present their data in comparable ways', taking account of duration -of employment and time since first employment and presenting data separately for men first employed be fore (say) 1965 and between 1965 and 1974, and (iii) estimates could be made of the effect of correcting the results for each group of employees for the locality in which they lived and worked. Hazards to the general population As vinyl chloride has been proved to cause cancer in man and is a mutagen in laboratory experiments, it must be presumed that even the minute doses 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 must, 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 (I, 2. 15), and (his level is about one-ten thousandth of the concentration that has caused an occu pational hazard. It is obvious, therefore, that it would be impossible to detect the risk of any cancer that might be produced by vinyl chloride other than a risk of angiosarcoma of the liver, as it has proved so diffi cult to detect any other risk among men who were ex posed occupationally. The position with regard to an giosarco mally so to one o dioxide, annual ir these t In a man tide was i eontrollei of the efl Several whether a and Elind vicinity of and Swedi *1 (II) fot . to thorotr, with vinyl `Ion of the .,, (5) found -12-year pei hved half plane, and. Brady et al tnbuted toz fie living u ""I vinyl c law two stu.& fence of as ; (totctORiar his colleagui *nii with n - the referents ^ th neighbor ' York Si pollution wit jPJsd the disc ' tirurr ot i '* a m  iter uiilui] j tout)lo whether (hr naIc: reference for men evenly distributed stances one cannot tless it can be shown men ts independent rcted to influence it i origin, namely, the e and the time since le to examine these torts do not provide 1 information as they d in table 6. supports pride involves a small conjunction with the been produced in sev> vinyl chloride by ini small hazard of lung videncc is not. howthat it definitely did. inly for men who had jt a time when expomillion or more were k can be only minute eft unanswered b> this -ed definitely if in all wed to tsay) the end did present their data count of duration of irst employment and ten first employed be65 and 1974. and tiii) :ffect of correcting the yees for the locality in lulation ved to cause cancer in >rniory experiments, it the minute doses that iiincnt Irotn production lanufac'.urel from PVC .te risk of cancer to the ist, however, have been is of vmyl chloride, even undling vinyl chloride. >) of the order of 10 to I is about one-ten thouhat has caused an occutherefore. that it would of any cancer that might de other than a risk of s it has proved so diffimong men who were ev ismon with regard to an- i.i ' iiciiiii.i ol the liver is ilillcrcm. This disease is noravally so rare that, tit the absence of specific exposure .10 one of (he known causes (vinyl.chloride, thorium dioxide, and arsenic in pesticides and medicines), the i incidence is on the order of 1--2 -10"' (5. 8).* .la these circumstances the discovery of even one case a man living close to a factory in which vinyl chlofide was used in the days before exposure was tightly molted may be regarded as presumptive evidence '.the effect of environmental pollution. Several surveys have been undertaken to determine bether any such cases have occurred. Saric et al (43) >ad Elinder & Pershagen (13) sought for cases in the .vicinity of plants handling vinyl chloride in Yugoslavia and Sweden and found none. In Holland Daiderup et jjfrgl (II) found eight confirmed cases not attributable to thorotrast or arsenic and could trace "no contact 'SjTwuh vinyl chloride." but they made no specific mention of the patient's place of residence. Baxter et al $&;`(J) found H confirmed cases in Great Britain over a :*. 12-ycar period, one of which was in a inan who had trved half a kilometer from a PVC manufacturing plant, and. in New York State over an 18-year period, Brady et al (5) found |9 cases that could not be at tributed to any known cause, five of which were in peo ple living wuhin a mile of plants manufacturing or using vinyl chloride. The overall incidence rates in these last two studies were not unduly high, but the occur rence of as many as six cases among people living so close 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 State) 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 eight years, respectively, before developing the disease, anti this period is too short to allow for the necessary latency. The other four cases, however; all occurred after' 13 or more years of local residence, and the dis covery of these cases strongly suggests that pollution of the environment around plants manufacturing VCM or PVC inay have caused a minute hazard to the gen eral public. Current concentrations around plants handling vinyl ^.chloride are certainly much lower than those reported eviously by ihe US Environmental Protection ^Agency. Recent British measurements made within a Mew hundred meters of the VCM areas have given aver age values below the daily limit of detection (3 ppb) for three of five plants, the readings at the two others being 20 ppb (100 m outside the boundary fence) and |g ppb Oust inside it) (47), although substantially higher values were recorded on two occasions asso ciated with putting one plant into operation and with KCV- m The figure of 1.4 - It)-* cued by lieaih el al (21) seems to have been a misprint for 1.4 10-'. an accident at the other. According to any reasonable criterion the hazard to the general public tif there ts any at all) must be negligible (42). No other hazard to the genera) 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 (he 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 thai 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 23 years after their first exposure and cover a long enough period for more than 10 V* 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 the UK concern men covered more completely in the two recent national studies, and their results serve only as sources of hy potheses. Minor criticisms can be made of three of the four most useful studies. They do not seriously afreet the value of the results, except that allowance has to be made for the failure to determine the cause of 6.3 *!* of the deaths recorded in the US study. Three of the studies use national rates to estimate the numbers of deaths that might have been expected to occur in the absence of any special occupational hazard, and the fourth (Canadian) uses rates for the province in which 73 the plant was situated. It must, therefore, be kept in mind that the raics 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 (he four principal studies show that theSMR 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 times 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'certificate. The excess corresponds closely with the 49 deaths due to angiosarcoma reported to the International Register of Angiosarcoma Cases as occurring in em ployees of the plants concerned during the periods under observation. All the men who developed the dis ease were likely to have been exposed to concentrations of vinyl chloride of several hundred parts per million or more. Three other type* of cancer which have been sug gested to occur as a result of exposure to vinyl chlo ride are cancers of the lung, brain, and lymphatic and hematopoietic systems. The combined data for the mortality from respiratory cancer fail, at first sight, to support the hypothesis regarding lung cancer (SMR 97). Higher ratios for lung cancer have, however, been observed consistently in the subgroups in which the effect of an occupational hazard would be most like ly to be seen (that is, men employed for more than 10 years, exposed to higher than average concentrations, or observed more than 20 years after first exposure). In two of the supplementary studies it was also noted that the mortality from lung cancer was specifically increased among the most heavily exposed workers. The combined data show small excesses in the mor tality from cancers of the brain and of the lymphatic and hematopoietic systems. The excesses are, however, not statistically significant, and there is nothing to sug gest that ihey are occupational in origin. An excep tion is the observation of an increased mortality from cancers of the lymphatic and hcinutoputcitc systems tn the 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 mtsclassification of angiosarcomas as secondary can cers of the liver or carcinomatosis, site unknown. The following three nonmalignam causes of death have required special examination: cirrhosis of the liver because of damage to the liver in "vinyl chloride ill ness, " myocardial infarction (from analogy with the effect of other halogenaicd hydrocarbons and because of some observations from Swedish I'VC fabricators), and nonmalignam respiratory disease because of ' changes m lung function and the radiographic appear ance of. the lungs observed in men-exposed-ip-PVC:. dust'. Far from being raised, the mortality frdm 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 re ported separately. Out 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 (he third category of nonmalignam dis ease (nonmahgnant 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 191). 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 front pneumonia (SMR <<)| and other res- \fWtoryc ao ennsis pfcytcma t Mrf H sec: VSaudy On with tl Review long-term twyi chlor mm have c ; extremely SMuiy 1 it 5v readied diet y observe Si' of time the be npectei (he mortal of that of r * hazard has KK-. The data art other tl H. however ndeproduc dor to hono rver, and, i muse almos There is tc the suggest! MNtu or car Mid hematot that have be Rational haz an of the ly .(German stui 'sort of chanc many types c aadie*. (-'...The lack o fat the con doc: >h*e been a s t disease, a the diseas il rate: frmhs. The g, Id bemor other gr existed.' twee of * Clearer ans posed ir is group l in mor At vinyi chi ewnis and a t -* that hav SL 04827 jj&iti M. liny from x systems i Republic ; in excess lancer and is difficult bout these :s. jsc cancers jnt for the When this estive tract R 82 for the erogeneous d results of - marginally d. P<0.05). n due to the ondary canunknown, )ies of death :s of the liver i chloride illlogy with the . and because fabricators!. because of aphic appearosed to PVC lily from cird in the three upplementary sr the disease and 82. based mentary study e not been re;tion accouius emie heart disischcmic bean whole was unvl, iijpcCtii' re. nmaiignam disl are confusing, give conflicting four principal ominonly found !R 80). This figmonalitv from f 120). which in'ossiv increased in the US study .tity in the British :nbed as due to SMR 82), as was 50) and other res piratory diseases (SMR 46) in (lie US study. There is no consistent evidence that the mortality from em physema or bronchitis was specifically occupational, and it seems passible 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 two clear conclusions. First the men have experienced a specific hazard of the normally extremely rare angiosarcoma of the liver. Approxi mately I in 335 of the men exposed in the 49 plants studied died of the disease, and approximately 2 V* of the observed deaths were attributed to it. In the course of time the numbers of cases of angiosarcoma must be expected to increase two to three times. Second, the mortality from ail 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 sues other than the liver, and. if so, whether, in total, these risks might cause almost as many deaths as angiosarcoma of the liver. There is too little evidence either to confirm or refute the suggestion that vinyl chloride might cause mela noma or cancers of the thyroid, brain, and lymphatic and hematopoietic systems. None of the small excesses that have been recorded point specifically to an occu pational hazard, apart from that attributable to can cers of the lymphanc and hematopoietic systems in the German study reviewed, and most are likely to be the sort of chance effect dim is certain to be observed when many types of cancer are examined in many different studies. The lack of any increased mortality front 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 ihc disease, as geographic variations in the incidence of the disease throw dnubi on the validity of using national rates for estimating the expected numbers of daths. The greater mortality in groups of workers who would be more likely to show an occupational hazard than other groups suggests that a small hazard may have existed. The evidence is, however, weak, and the existence of a hazard has not been proved. Clearer answers to some of the questions that have been posed in this review might be obtained if the various groups of investigators could present their results in more appropriate and comparable ways. As vinyl chloride is a mutagen in laboratory experi ments and a proved human carcinogen, the minute doses that have escaped into the general environment as pollutants must be presumed to have caused com parably, minute risks to the general public. No such risk could possibly be detected, other than one of angiosarcoma of the liver which is normally an ex tremely rare disease. Several surveys have sought evi dence of the existence of such an effect, and sugges tive evidence that such an effect may have occurred at a time when environmental pollution was much greater than it ts now has been found in one. References i. Air Products and Chemicals. Inc. Comments on ihc pro posed standard for vinyl chloride. Letter to OR Goodwin. Environmental Protection Agency. 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F bustion c depending ;et fuel, or from the substance: without d lamp oil), profile of r is consider a propane * Epidemiol Institute i Canada. * Oepanme. versity, M * Dtparime, University Reprint reqi i-<> epidcmiu I <appier. SJ t jnjJ.i. 117