Document 8VEvKDmVEbGMGe31mkneyBjpB

V JThe ' Vinyl Institute A Division of The Society of The Plastics Industry, Inc. Roy T. Gottesman Executive Director October 26, 1988 TO: The VI Health, Safety & Environment Committee RE: Paper By Sir Richard Doll on "Effects of Exposure to Vinvl Chloride" The attached paper from the Scandinavian Journal of Work, Environment and Health, April 1988 may be of interest to you. It was received courtesy of Harold Clayton, Hydro Polymers' Vinyl Division in England. RTG/pmb Wayne Interchange Plaza II 155 Route 46 West Wayne, NJ 07470 (201) 890-9299 ISSN 0355-3140 i i i M 11.- \ 1 : J! . d3 ii i'!-; ci' A -1 :*;i1 11 A f i r; ^ ' i Volume 14, number 2, April 1988 1 'I J ii CONTENTS Reviews Si Effects ol exposure to vinyl chloride: An assessment ol the evidence Sir R Doll Original articles 79 Associations between several sites ol cancer and ten types ol exhaust and com bustion products: Results Irom a case-relerent study in Montreal J Siemiatyckt, M Girin. P Stewart. L Nadon. R Dewar, L Richardson 91 Ellects ol exposure to Freon 11,1,1,1-trlchloroethane or perchloroelhylene on the lipid and (ally-acid composition ol rat cerebral cortex T Kyrklund. P Kjellslrand KG Haghd 95 Influence ol water on the percutaneous absorption ol 2-buloxyelhanol in guinea pigs G Johanson. P Fernslrom 101 Percutaneous absorption ol 2-butoxyethanol in man G Johanson. A Boman, B Oynisius 110 Prediction ol early retirement on the basis of a health examination: An 11-year followup ol 264 male employees in a Swedish pulp and paper company N-E Astrano, S O Isacsson. GO Olhagen 11S Comparison between surgeons and general practitioners with respect to cardio vascular and psychosocial risk (actors among physicians BB ArnelZ, S Andreasson, M Strandberg, P Eneroth, A Kallner 125 Invariants and noninvariants in the concept ol Interdependent ellects S Greenland, C Poo*1? Case studies 130 Fatal arsenic poisoning -- A case report L Gerhardsson, E Dahlgren, A Eriksson. BEA Lagerkvist, J Lundstrom, GF Nordberg Book reviews 134 Neurotoxicants and neurobiologtcal function: Ellects ol organoheavy metals 134 Ergonomics in computerized Ollices 135 Indoor radon and its hazards 136 Ergonomics at work 137 A manager's guide to ergonomics in the electronic olhce 138 Industrial radiation hazards deskbook 139 Announcements 140 Amendments and corrections GOC 001435 REVIEWS Scand J I York Environ Health 14 0988) 61 --78 Effects of exposure to vinyl chloride An assessment ol the evidence by Sir Richard Doll, FRS' DOLL R. Effects of exposure to vinyl chloride: An assessment of ifce evidence St and J Work Environ Health 14 U988> 61--78. This r >pef reviews the possible effects ol *inv| chloride on the mortality of occupationally exposed men ,he carcinogenic effects that might be observed in the general population as a result of environmental pollution with vinyl chloride. The results of four studies fulfilling the criteria I of providing substantial numbers of ohservanons more than 25 >ears alter first exposure and covering j a period long enough for more than 10 Vo of the workers to have been expected to die constitute the basis ` for the assessment of the occupational hazards. Other studies provxJe only supplementary information. ; The data permit two conclusions, first, men occupationally exposed to vinyl chloride have experienced a specific hazard of angiosarcoma of the liver. Second, any other occupational hazards that may have . existed have been small. No positive evidence of a hazard of any nonmahgnant disease or any type of j cancer other than angiosarcoma of the liver has been found except possibly for a small hazard of lung t cancer when exposure was heavy. More definite conclusions might t< reached if those who have studied exposed employees could present their results in appropriate and comparable ways, A very small risk of angiosarcoma mav have occurred as a result of vinyl chloride escaping into the environment around plants handling \invl chloride m the past, but the evidence indicates (hat i.ie current risk to the general public (if any) must be negligible. A>v terms: angiosarcoma of the liver, cancer, lung cancer, mortally, polyvmyl chloride, review, vinyl chloride monomer. ) 60S W4 (redactor)' nl number J0.00 air mail address above. maged issues u'.ess 1 J | i i t | jght Clearance Center ie internal or personal enier's Transactional page, is paid direetly rations that have -ecn The fee code for users I, : k 3 5 i lor many years I lie inhalation of large amounts of rinvl chloride has been recognized as potentially hazntdous. Conccmraiions of the order of 10 000 ppm in llie air induce unconsciousness and cardiac arrhyth mia. while prolonged exposure io conccmraiions an order of magnitude lowei have been liable to cause a specific pathological ssndroiuc. This "vinyl chloride illness" has been characterized by four cardinal signs, doses that are even lower than the current industrial levels of 5 ppm or less, as vinyl chloride has been shown io act as a mutagen (23), and it cannot be assumed that a threshold exists below which no carcinogenic risk persists. Moreover, the possibility has to be considered that vinyl chloride may cause some cancers other than angiosarcoma of the liver, partly because laboratory studies have shosvn that it causes other cancers in namely, enlargement of ilie liver and spleen wuh a animal experiments and partly because the initial specific histological appearance, palcliy infiltration of ilic skin resembling scleroderma, bony changes in ihe ups of the fingers described as acroosicolysis. and studies demonstrating the production of angiosarcoma of the liver in humans svere inadequate in size to ex clude a material increase in the risk of cancer in com peripheral circulatory changes identical with the clas mon sites, such as the lung and large bowel. Since no sical picture ol Raynaud's disease. These pathologi threshold dose can be postulated, it also follows that cal rs'actions may occur singly or logeiher and may pos sibly be accompanied by other less characteristic ef fects. They can, however, be completely avoided if ex posure never exceeds the level of a few hundred parts some cancers may have been produced in the general public by the small amounts that have escaped into the general environment. Consideration also needs to be given to the possi per million, ie, the level to which exposures were generally reduced in the mid-1960s. One other serious effect has, however, been observed bility that exposure to vinyl chloride over a long pe riod may have noxious effects on humans that cannot be seen easily in animal experiments (by, for example, that may not be avoidable in the same relatively easy producing chronic respiratory disease), and, as it is a way, namely, the production of angiosarcoma of the mutagen, there is also a possibility that it may act as liver. It must, indeed, be presumed that some risk of a teratogen and cause congenital malformations in developing the disease will persist from exposure to* I offspring. 1 tmpcital Cancer Research l:uhd. Cancer Epidemiology and Clinical Trials IJnu, Radclilfe Inhrmary, Oxford, United kingdom, Reprint rcuticsn io: Sir R Doll. Imperial Cancer Research I mid, Umvcrsily of Oxloid, Cnbsnn building. The Radcliffc Inlirmary, Oxford 0X2 6HE. United Kingdom. In this review ) have not examined the possibility that vinyl chloride acts as a teratogen or that u causes mutations in germ cells, as there is too little serious evidence to justify inclusion. Reviews carried out for sections of the industry by Downs et al (unpublished report to the Society of Plastic Industries Inc in 1977) I 61 GGC 001436 and by MacMahon (unpublished report to the Chemi sure). These requirement do not introduce any new or using vi cal Manutavturtrs Association in 1977) concluded that complexity, as both are, of course, also required if cor sonnel recc the tew reports of positive effects could not be sub rect conclusions are to be drawn Irom the results of was ihe lap stantiated, and no additional evidence was found in the individual studies w hen they are examined on their a similar later review by Barr (unpublished report to own. identified sonne1. Air Products and Chemicals Inc in 1981), apart from Racial ch a report that embryos were absorbed and skeletal os sification was produced when pregnant rats were ex posed to doses appreciably lower than those that had been used by other workers without any such effects being observed. The report of absorbed embryos (34) could not be evaluated thoroughly, however, as the ex periment was inadequately described, 1 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 capacitv, and the carcinogenic effects that might conceivaoly be observed in the general population as a result of the widespread distribution of vinyl chloride as a pollutant. Sources of information Four studies meet the aforementioned requirements, namely, two large national surveys, one reported by Jones (25) for the United Kingdom (UK) and the other by Environmental Health Associates (14) lor the United States (US), and studies of individual plants in Canada, reported by Theriault A Allard (46) and in Italy, reported (as a part of a national study) by Belli et al (4). All four include observations on men more than 25 years alter their first exposure, and the ex pected number of deaths is. m each case, greater than 10 % of the total number of employees, a value indi cating a long average period at risk. Earlier observa tions on UK and US employees (6, 9, 12, 16, 20, 36. , 97 ", 0f Wj ihe purpos deaths, tha lollow-ii eta I Security died after |plants did m (9) earlier s present invc plants who 1972 were r lollow-up w 1982. whiclit of the men w 39, 40, 45, 50) have been subsumed in the national sur untraced wer veys and now serve only as sources of hypotheses and which was us Occupational hazards of some detailed information not included in the na Almost hal Many studies of workers exposed to vinyl chloride in the manufacture of vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) have been undertaken since i: was first found that vinyl chloride could cause tional reports. Studies of German (49), Norwegian (22), Swedish (7), French (41, and unpublished report of Laplanche et al). Japanese (33, 3'), and some oilier Italian (4) workers provide some supplementary infor before 1955. served more t many cases to a long latency cancer in animals (28, 48) and man (10). These inves mation, but, in general, the periods of observation tigations have confirmed that exposure causes a haz have not been long enough lor uselul epidemiologic Short-term cohort, and n ard o' angiosarcoma of the liver and, in several in data to be obtained about diseases that are unlikely ployment tor ; stances. have shown excess incidence or mortality rates to occur within 20 years of first exposure, ot they | lor 10 years ot that were conventionally statistically significant lor report only selected results which are difficult to in ! Ployment beim other diseases. Conventional tests of statistical signifi terpret, as only excess rates lend to have been selected. cance are, how-ever. designed to help answer single Studies of makers of PVC products have not been ^ Fifteen blind have died. In I questions defined beforehand, and several findings that included, as the workers have had much icss cxpusuie lamed Irom the might be expected to occur by chance alone once in to vinyl chloride than those employed in the manufac tamed for the i (say) 20 times must be expected to occur if dozens of ture of VCM or PVC and any occupational hazard to The number- rates are examined in each of several sets of indepen which they may have been exposed Is more likely to causes or grou dent data. Scientists have, therefore, been faced with have been produced by PVC dust. Plying the pers. the problem of deciding whether the excess rates that national rates l have been observed in individual studies are due to oc cupational hazards or to the vagaries of chance. This problem can be solved in part with an exami nation of the results of a sumation of data from com parable studies, that is, by a comparison of the sums of the numbers of deaths observed and expected in each study. This procedure does not require the as sumption that the exposures have been the same in each study any more than the same assumption is required for each individual when the results of each study are considered alone. It does require however that each exposed population has been observed over a period when us members were at risk of developing disease (if a genuine hazard existed) and that in each study the reiertnce population from which the expected num US study. The study carried out by Environmental Health Associates (14) on behalf of the US Chemical Manufacturers Association is the largest and most in formative investigation thus far undertaken. It cov ered 10 173 men who had worked in 37 plants owned by 17 companies -- I 214 men in II plants that produced only VCM. 6 848 men in 18 plants that produced only PVC, 935 men in three plants that produced both, and I 176 men in five plants that produced homopolymers and copolymers, with or without VCM or PVC. Twenty-two of the plants were in the southern part of (he country, 14 were in the northeastern or north central parts, and one was in the west. Men were included if they had been exposed to vinyl i, i '/`j O u j j ! age groups anc This importa cisnis, which ai effects on the re compiled by co cords without at sumption that a caused the expei underestimated, to have had hie reason lor Suppo the proportion o necessarily reprelainty was introd as 7.3 / ol the Two other iru, bers vi deaths were dciived was appropriate (that is, at the :jme risk ul developing disease as the exposed pope 111111 would have been in llie absence of expo chloride for at least a year bclore 31 December 1972 and bad been employed in 1942 or subsequently tlhe I irsl year depending on ihc date l lie - '.nil Ik "an mak nIv c'|ti\tcd mniilivi 'mupinui ill,,: it { .....^ toduce any n<" O required if COt,m the results c xamined on th-: ed requirements. , one reported b' UK) and the other lies (14) for the individual plants fc Allard (46) and mal study) by Betii ons on men more rsure. and the en case. greater than iyees, a value inoic. Earlier observa.9. 12. 16. 20. 36. in the national sutof hypotheses a.-,d included in the r.an (49). Norweg.an unpublished icrcn 37), and some miner jpplementary inferods of observation seful epidemiolocic es that are unlikely t exposure, or they r are difficult tc tno have been selected, ducts have not been J much less exposure nyed in (he man: idccupational hazard to sed is more like':- to JSt. ut by Environmental f of the US Chemical ie largest and mcs: tnr undertaken, It cov ed in 37 plants o'* tied ten in 11 plants that nen in 18 plants that x in three plants that en in five plants that copolymers, w-:h or ;re in the southern part : northeastern or north the west. id been exposed to \inyl fore 31 December 1972 42 or subsequently (the e the plant began making or using vinyl chloride and the earliest date that per sonnel records were deemed to be complete, whichever was 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 V* of whom were white, and it was presumed, for the purpose of estimating the number of expected deaths, that all 10 173 men were white. Follow-up data were obtained from plant and So cial Security Administration records and (for men who died after 1979) from the National Death Index. Five plants did not collaborate in the extension of Cooper's (9) earlier study, which had been subsumed in the present investigation, and the 953 employees in these plants who were known to be alive on 31 December 1972 were not followed any further. For the rest, follow-up was attempted to death or 31 December 1982, whichever was the earlier. On this basis 92.7 Vt of the men were successfully traced. Those who were untraced were excluded from (he last date of contact, which was usually the date when employment ceased. Almost half of the men (46 V) were first employed before 1955. A large proportion was, therefore, ob served more than 25 years after first exposure (and in many cases for more than 30 years) when diseases with a long latency period might be expected to be seen. Short-term workers had been excluded from the cohort, and most of the men had continued in em ployment for many years, two-thirds being employed for 10 years or more and the average duration of em ployment being 16 years. Fifteen hundred and thirty-six men were found to have died. In 1 439 cases, the cause of death was ob tained from the death certificate, but no cause was ob tained for the other 97 persons (6.3 ?). The numbers of deaths expected from each of 38 causes or groups of causes were obtained by multi plying the person-years at risk by the disease-specific national rates for white males. Tor the corresponding age groups and five-year periods of the study. This important study is open to three minor criti cisms, which are unlikely to have had any material effects on the results. First, the lists of employees were compiled by company personnel from company re cords without any independent check. Second, the asir^sumption that all the employees were white will have :Skjf/ij"cused the expected deaths to have been very slightly [-^^underestimated, as the few black employees are likely `JS'tJ'f.to 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 necessarily representative. Third, an element of uncer tainty was introduced by the failure to trace as many U 7.3 *!> of the employees. Two other criticisms are more important. First, the t expected numbers of deaths were calculated on (he as s' 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 in studies of in dustrial populations and tends to result in an O'erestimation 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 (o make the use of national rates appropriate. Unfortunately 22 of the plants were located in the south, and a check would have been desirable to see whether their location could have caused any material distortion of the results. Second, causes were not obtained for 97 of the I 536 deaths. This deficiency was allowed for in the calcu lation of the overall mortality by the inclusion of deaths due to unknown causes. It was not allowed for, how ever, in the calculation of the disease-specific mortality rates and will have caused the standardized mortality ratios to be underestimated by an average of 6.3 *71. For the present purpose, therefore, the numbers of deaths attributed to specific diseases have each been multiplied by 1.0674 (100/(1--97/1536)1 and rounded o(f to the nearest integer. UK study. The study reported by Jones (25 and un published) on behalf of the British Health and Safety Executive covered 5 498 men who were employed for at least one year in jobs that involved potential expo sure to VCM for at least 25 1* of the work week and who were first employed in the period 1940--1974. De tails of the men were compiled from the personnel records of nine chemical plants manufacturing or poly merizing vinyl chloride, and the vital status of the men was determined at the end of 1984 from the records of the National Health Service Central Register. Five thousand four hundred and ninety-eight men were traced (98.9 *'). Seven hundred and eighty deaths were identified, and copies of the death certificates (coded to the eighth revision of the International Classifica tion of Diseases (ICD) if they occurred before 1979 and to the ninth revision if they occurred later) were sent to the investigators. Several specific points about the study need to be noted. First, national mortality rates for England and Wales were calculated for five-year age groups over quinquennial periods for 66 causes of death, and these rates were used in the estimation of the numbers of deaths that might have been expected in the cohort by multiplying them by the corresponding numbers of person-years under observation. Some difficulty which could have been related to the causes of death being 63 G6C001438 coded according to the eighth and ninth revisions of the ICD was, however, experienced in obtaining suit able rates for all causes of death, and rates for a rela tive!) 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 1960--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 wuh advice from the plants concerned. The men were then grouped according to whether exposure to VCM was likely to have been high (group A), expo sure to PVC dust was likely to have been high with exposure to VCM low (group B), or exposure to VCM and PVC dust was intermediate and intermittent (group C). All Other men, who would generally have had low exposure to both VCM and PVC dust, were classed as group D. Within all the groups, exposure to VCM was likely to have been higher if it had begun before 1956. The study makes an important contribution to the knowledge concerning the long-term effects of vinyl chloride. The use of national rates to calculate the expected numbers of deaths may be justified on the grounds that the men were employed in nine plants, which were presumably distributed about the country, but no details of (heir location are given. In 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 arc more h-cly to be biased dowrnwards than upwards^ but whether this is so or not needs lo be shown. The use of recent rates lo 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 the diseases in question remained. stable. It would have been desirable, however, for the diseases to have been specified so that the reader would know which were liable to be distorted. The system used to classify the men into four expo sure groups is the sort of system that is commonly used if precise measures of exposure are not available. It creates some difficulties in the statistical analysis if men move from one job to another and are classed (as in this instance) as having had high exposure if they have ever had a particular type of employment (eg, ever been employed as an autoclave worker). No evidence is pro vided to show that the person-years ai risk before a man entered the category have been subtraclcd and added to another exposure group before the numbers of expected deaths were calculated. Movement from one joc to another was saiil io have tended to be out ol gr -a A and II into D. bin even so it must h.- presumed that the expected numbers of deaths in the first two exposure categories are likely io have been overestimated. Canadian study. The Canadian study (46) was limited to employees of a single plant in Shawinigan, Quebec. The plant, which was situated in an industrial com plex, was opened in 1943. VCM and PVC were both made until the late 1960s, when the production of VCM ceased, while the production of PVC continued. An attempt was made to trace all the production work ers whose names appeared on the unions' lists or ihe 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 61 I out of I 659 instances (97.1 ). Detailed occupational and smoking histories were obtained by questionnaire, and 156 men who had been employed by the companies for less lhan five years were excluded. The remaining men were categorized as (i) exposed to VCM d they had worked on the production of VCM or I'VC for at least five years (451 men), (it) unexposed to VCM if they had worked similarly for less than six months (870 men), and (iii) other men (134 in total). The last group was excluded from the study. Follow-up was dosed on 31 December 1977, Copies of the death cer tificates were obtained, and the causes for all who had died (59 exposed and 233 unexposed) were coded ac cording to the eighth revision of the ICD. Informa tion was also sought for histological or cytological con firmation of all the diagnoses for all the exposed men who had died of cancer. The results were examined in two ways. First, the mortalities of the exposed and unexposed men were compared after standardization for live-year periods of the study and five-year age groups. Second, ihe mor tality of the exposed men was compared with that ex pected if the men had had the sex- and age-specific mortality rates recorded in Quebec for the year 1971. In both comparisons the causes of death used were those specified on the death certificate, and the addi tional pathological information was used later only for interpretation of the results. Most of the exposed men were exposed for more than 10 years (75 %), the average length of exposure was approximately 17 years, and 44 r 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 (hat alt eight cancers diagnosed as liver cancer (including two specified as hepatoma and one specified as angio sarcoma) were angiosarcomas of the liver, as well as one that had been diagnosed as angiosarcoma of the peritoneum. Two other cases of angiosarcoma of the liver were found to base been certified as hepatic cir- rhnttc f f !r -ik * `x .1.x i\ j i ,, . ........... I I the expo set companies for all non a healthy w ' recording o f nant causes | 0.95). 1 One aspei l ic, the use i calculate ex i period (1948 I to bunch up ( vation so ih ! have been la I some distort! size (and eve i estimate, Foi I likely to has | Italian study. | dnction of vm I svas begun in employed for start up of thi still incomplet in three plant | signana) begai { thirty.seven m in the other. A! followed to the t mated by multn corresponding i year age group a j The total expect ] tnore than 10 j (12.4 and 12.8 ! Clinical infos ; death of all the J had died. Revis 9 comparison wu * deaths from ca The Ravenna 1959. Six hundre All but four we were found to h; lowed for more " (J-9 % of the wc l.hi 'his plant have r 'f' dpal analyses. I death was attribi pected. Ciher sources. Th 'cis.itiisns on 45. fun in I vicinal k oi' deaths in th; ;Iy to have beta the exposed and "unexposed" employees of the same companies as it shows that the low mortality observed for alt nonmalignam diseases could be attributed to a healthy worker effect and was not due to bias in the i (46) was limited winigan. Quebec. i industrial com1 PVC were beta te production of f PVC continued, production work mens' lists or the >le industrial com* plant, between 2. and contact was 'f-kin in I 611 ous i occupational and questionnaire, and recording of exposure (relative risk for all nonntalignant causes compared to that of the "unexposed" men a C.... 0,95). One aspect of the study has to be criticized however, ie, the use of provincial rales for one year (1971) to fej*v - calculate expected mortality spread over a 30-year period (1948 to 1977 inclusive). Deaths will have tended to bunch up towards the end of the period of obser m- vation so that the rales for this particular year may have been fairly representative, but it must have caused some distortion of the expected numbers of deaths, the lire (and even the direction) of which is impossible to ft:- estimate. For most disease groups the distortion is un likely (0 have been targe. by the companies ed. The remaining :d to VCM if they VCM or PVC for Italian study. A study of all men employed in the pro duction of vinyl chloride and PVC in nine Italian plants ineaposed to VCNl was begun in 1983. All men were included who were ss than sic months employed for at least six months at any lime from the 4 in total). The last start up of the plant to the end of 1981. The study is dy. Follow-up wjs ies of the death cer uses for all who had sed) were coded ac- tiill incomplele, but results are now available for men In three plants (4). Two plants (in Ferrara and Rosignana) began operation in 1953. Four hundred and thirty-seven men were employed in one plant and 181 the ICD. Inforrr-a- In the other. All but three (from the Ferrara plant) were il or cytological conall the exposed men followed to the end of 1984. Expected deaths were esti mated by multiplying the person-years at risk by the corresponding national mortality rales for each five- two ways. First, the mtxpostd men were for five-year periods Jps. Second, the mormpared with that ex sex- and age-specific >ec for the year 1971. ; of death used were ificate, and the addivas used later only for ere exposed for more .ge length of exposure d 44 were observed exposure. ikes a useful conteibuhistological review of helpful. It showed that liver cancer (including year age group and each five-year period of the study. The total expected deaths in each case amounted to more than 10 % of the employees in the two plants (12.4 and 12.8 %). Clinical information was sought about the cause of death of all the 35 employees of the Ferrara plant who had died. Revised diagnoses, which were not used for comparison with the expected deaths, revealed four deaths from cancers of the liver in place of one. The Ravenna plant did not begin operation until 1959. Six hundred and thirty-eight men were employed. VMi ,/UJ but four were traced to the end of 1983, and 17 found to have died. No man could have been folfor more than 24 years, and only 25.1 deaths of the work force) were expected. The data for )hh plant have not, therefore, been used in the prin cipal analyses. U may be noted, however, that one death was attributed to liver cancer when 0.1 was ex pected. one specified as angio- of the livtr. as well as is angiosarcoma of the of angiosarcoma of the certified as hepatic cire a comparison between Other sources. The Norwegian study (22) provided ob turations on 454 men who had been employed in a plant in Telemark where VCM had been manufactured (com 1950 to 1971 and PVC front I9J0 to the end of the study period. Every man was included whose name was recorded in the company's personnel register and health department records who had ever been em ployed from the start of production to the end of 1969 and had worked for at least one year. The men were followed from 1953 to 1979 inclusive. Deaths and cases of cancer were identified from the records of the Cen tral Bureau of Statistics and the national cancer regis try. No reference was made to any men being lost to follow-up, but it can be assumed that the number (if not zero) was small, as all citizens have an identity number which is used by both employers and central agencies. Fifty men were found to have died against 59.34 expected if the sex-, age-, and quinquenniumspecific national mortality rates had operated. Twentyone men were found to have developed 23 cancers against 20.16 cancers expected from the comparable national incidence rates, the use of which was justi fied by the finding that the incidence in the county in which the plant Was situated was between 90 and 95 Vt of the rate of the country as a whole. One man who had been employed in PVC production developed an giosarcoma of the liver. The observed and expected numbers of cases were given for cancers of the lung, colon, and thyroid, for melanomas, and for all can cers, but no expected numbers were given for other types of cancer. It is evident that several other types of cancer must have been in deficit, as there were eight cases in all against 14.93 expected, and it is difficult to know what weight to give the excesses observed for the reported types of cancer, as they seem likely to have been reported specifically because the numbers were in excess of those expected. The authors noted that one further case of melanoma had occurred after the closure of the study and that one "incipient case" was also known to them. The German study (49) included the following three groups: (i) 7 021 men who had been exposed to VC in the course of their employment in any of the 11 plants in which VC and PVC had been produced in the Federal Republic of Germany, (ii) 4 820 men who had been employed in seven chemical plants without having had any exposure to vinyl chloride, and (iii) 4 007 men employed in two other plants where PVC was processed. Employees were included oniy if they were of German or Austrian nationality, and they were regarded as exposed to vinyl chloride if they were production workers or other skilled workers or laborers assigned regularly to the plants, but not if they were employed in them only occasionally. All the men were included from the time of opening of the plants to the end of 1974, and they were followed to the end of 1974. Many of the men were therefore observed for only a few years after first employment, and only 14, 36, and 19 ?, respectively, of the three groups were first em ployed before 1954 and were therefore capable of con tributing person-years at risk more than 20 years after First employment, when an occupational hazard of can cer could be expected to be observed. 65 OGC 001440 Of the exposed group 93.2 Vo were successfully fol lowed, and causes of death were discovered for 92.8 Vo of the 4 14 men discovered to have died. The propor tions for the other two groups were respectively 89.8 and SS.7 Vo for the unexposed and 92,1 and 86.9 Vo for the PVC process workers. The failure to obtain causes of death for all the men who had died was allowed for in the subsequent analysis by the weight ing of the numbers attributed to each cause by a sys tem which took account of the age group and calen dar period in which death with an unknown cause oc curred. The expected numbers of deaths from each cause was calculated by multiplying the person-years at risk by the sex-, age-, and cause-specific mortality rates for the Federal Republic of Germany. National data before 1968 used an idiosyncratic classification system, and the 1968 rates had to be used to multiply all the person-years at risk up to the end of 1968. For subsequent years (1969 to 1974) the person-years at risk were multiplied by the corresponding rates for the same calendar year. Epidemiologic studies are more difficult to carry out in the Federal Republic of Germany than in North America, the United Kingdom, or Scandinavia because the medical cause of death is not recorded publicly, and there is no central system which can be used for checking whether an individual is alive or dead. In these circumstances, the German authors have made valiant efforts to obtain reliable data, and the propor tions of men in the exposed groups who were not suc cessfully followed (6.8 Vo) and the proportions of deaths for which the cause was not obtained (7.2 Vo) were similar to those in the study of the Environmental Health Associates (14), Two defects, however, make the data less useful. First, no national mortality rales were available before 1968, and the use of the 1968 rates to estimate the num bers of deaths in and before 1968 will have overesti mated the numbers attributable to diseases that were becoming more prevalent or were being diagnosed more often and underestimated those due to diseases that were becoming less prevalent. Second, and more1 importantly, a large proportion of the men had been first employed less than 10 years before the follow-up ended. Therefore the useful observations on the few men who had been exposed long enough to have had much chance of developing an occupational disease with a long latency period must have been swamped by a mass of other observations that had little to con tribute. The expected deaths amounted to only 6.2 Vo of the exposed men, and there is, therefore, little to be gained, and something to be lost, by including the German data in the overview. It may be noted, how ever, that 12 deaths were attributed to cancer of the liver among the workers exposed to vinyl chloride against 0.9 expected and that smaller excesses were also observed among the unexposed chemical workers (4 observed against l.l expected) and the PVC process worker |l deaths against 0 8 expected). Two Swedish plants have produced VCM and PVC, one since 1945 and the other since 1971, and employees of the first plant have been studied by Byren ct al (7). All persons who had ever been employed when expo sure to VCM could occur were listed from the per sonnel files of the factory. Twenty-one were excluded because they were foreigners who left the country alter a short period of employment. The remaining 750 were followed to October 1974. Expected numbers of deaths were estimated by multiplying the person-years at risk by the corresponding age-specific mortality rates for the whole country, and the expected numbers of can cer cases from 1958 to 1971 inclusive (during which period all cancer cases had been registered nationally) were estimated by multiplying by the national age- specific cancer incidence rates. In both instances, the rates used were those recorded in 1969. Fifty-eight deaths were found, but no figure was given for the ex pected number. Detailed figures were given only lor the numbers of deaths and cases observed and expected for cancer of the lung and for cancers of (he liver and pancreas combined and for the .-.umbers of deaths from brain cancer and three categories of cardiovas cular disease. Two men known to have angiosarcoma of the liver were certified as having died of liver can cer or pancreatic cancer, and a third man died of angiosarcoma of the liver 17 months alter the close of the follow-up. Two French studies provide the results of a long term follow-up of men employed m one plant (41) and of a short-term follow-up of men employed in 12 plants (Laplanche et al, unpublished). Th; first provided ob servations on I 311 men exposed to vinyl chloride in the production of VCM and PVC and in selected an cillary operations from the opening cf the Tavaux plant in 1953 to the end of 1976 (41). S,x other employees were excluded from the study because of lack of oc cupational histories and 160 men because their vital status at the end of the study period was undetermined. Twenty-five men were found to have died against 48.75 expected from contemporaneous sex- and age-specific national mortality rates (3.7 Vo of the men at risk). One death was attributed to angiosarcoma of the liver, in a man who had been exposed for more than 15 years. The reported data are so incomplete and cover such a relatively short period from the opening of the plant that they add nothing of epidemiologic value to the results of the other studies, apart from the addition of a further case of angiosarcoma. The second study provided observations on 1 100 men aged 40 to 55 years who, in 1930, were exposed or had been exposed to vinyl chloride in 12 plants, which constituted "most of the French VCM polym erisation plants" (Laplanche et al, unpublished). Many of the men were, or had been, employed at Tavaux and were presumably survivors of the cohort studied by Pierre ct al (41). The men were followed for five years, and their morbidity ami mcttality were com pared with those observed toi ! I'* -Men ol lie v;nli.- ages ( 2 ye; but who hai in both grot formation v drinking hat- two groups, first exposed first been cm ously, Morbi nually by the 98 Vo of the . One of the ex developed an given separat ployment, an. K' * of the finding lung cancer a i well reflect a i in the releren cancers in tha One exposed i V-- hematopoietic li none of the m developed me: roid. A Japanese perience of 4 5 before (965 in ducing VCM i live (37). The r Twenty-eight p ^ than 20 years at f-- served more that ) untraced, and c. j lained for all thi q initial cohort). 5 to the job in wi fe, *1 ihe lerminati f [ given separately in PVC produc classed as VCM If this study -pi", should provide i proem data inch ' * lhan 20 years aft use. They confii cancer with six ij! ''orkers against 1 i while only one i V Other workers ai -w deaths from livet workers was cert " Uwcr. and at least was due to the s; not in excess (2 o expe. ted). No da i'h.utc and licni.r ' mi hi tluiiM.I " ".i-i ,, 'CM and PVC. and employees Byren et at (7). red when expoI from Ihe per: were excluded he country after taining 7J0 were mbers of deaths ton-years at risk irialily rates for lumbers of cane (during which .ered nationally) te national ageth instances, the 969. Fifty-eight given for the exe given only for ved and expected s of the liver and mbers of deaths ies of cardiovasve angiosarcoma died of liver canird man died of ns after the close results of a longane plant (41) and iloyed in 12 plants first provided ob> vinyl chloride m nd in selected anf theTavaux plant t other employees use of lack of oebecause their vital wax undetermined. died against 48.75 x- and age-specific e men at risk). One ma of the liter, in tore than 15 tears. :te and cover such pening of Ihe plant ologic value to the from (he addition a. ervations on I 100 I9RQ, were exposed loride in 12 plants. rench VCM polymunpublished). Many mptoyed a! Tavaux f the cohort studied re followed for five nnrialily were com100 men of the same ltd (12 years) who were employed m the tame plants tfj'ii.r.: '* ~ ? but who had never been exposed to VCM. The men Id both groups were interviewed personally, and in formation was obtained about their smoking and drinking habits, which were found to be similar in the faro groups. The men in the exposed group had been fkw exposed for an average of about 14 years and had first been employed in the plant about IS years previ ously. Morbidity and mortality data were recorded an nually by (he plant physician, who successfully traced 91 % of Ihe exposed men and 96 % of the referents. iOot of the exposed men, but none of those unexposed, 'developed an angiosarcoma of the liver. Data were not given separately for different periods after first em ployment. and it is impossible to assess the significance of the finding that six of the exposed men developed king cancer against two of the referents, which may reflect a chance occurrence of unusually few cases (a the reference group, as the proportion of all lung 7?'X- CUMcrs in that group (2 out of 15) was unusually low. Oat exposed man developed a cancer of the lympho- terutopoictic system against none of the referents, but ;Ooeof the men in either group were known to have developed melanomas or cancer of the brain or thy roid. '-'A Japanese study has reported the mortality ex- (Kttcrtce of 4 524 men employed for at least one year before 1965 in 25 Japanese plants which began pro ducing VCM or PVC between 1949 and 1964 inclu sive (J7). The men were followed to 31 October 1975. Twenty-eight percent of the men were observed more ttan 20 years after first employment, but none was ob- vrrved more than 26 years. Only 0,6 "/ of the men were atraced. and copies of the death certificates were ob tained for all the 209 men who had died (4,6 h> of the muciI cohort). Individuals were classified according w the job in which they had been longest employed M the termination of their follow-up, and data were given separately for the 2 546 men classed as employed in PVC production and I 978 others (including 900 TT.VJ- classed as VCM production workers). if this study is continued for another 10 years, it should provide useful additional information, but the present data include loo few observations on men more 20 years alter first exposure to be ol any material ifThey confirm the evidence of a hazard of liver with six deaths among the PVC production km against 2.54 expected from national rales, only one such death was observed among the workers against 1.82 expected. One of the six h* from liver cancer among the PVC production .,`wkvvexrk,earsndwaast certified least one as of due to angiosarcoma the other liver cancer of the deaths due to the same cause. Lung cancer deaths were M in excess (2 observed in PVC workers against 2.33 expected). No data were given for cancers of the lym phatic and hematopoietic systems, for cancer of the team or thyroid, or for melanomas. The mortality r*VHiwl by Mm.>4* <JJ> fnr JOS Jttpnnai* vinyl chlo ride workers has presumably been subsumed m Na kamura's (37) later and larger study. Hatards 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 m table 3, and those for 10 types, or classes, of cancer are presented in table 4. Data have not been reported for each type of cancer in each study, and the sources of the data are, therefore, specified separately for each type. Additional information ob tained from four other less informative studies (4. 7, 22, 49) is given in table 5 for seven types or classes of cancer. Table 3 shows that, apart from cancer of the liver, the overall mortality is what would be anticipated for an industry without any major hazard of accident or disease. In particular the standardized mortality ratio (SMR) of 84 for diseases other than cancer is typical of the ratios that are commonly observed for groups of employed men. A low SMR of this order reflects the "healthy worker effect," which results from the selection process that inevitably excludes some of the least healthy members of the population from indus trial employment. This effect does not, however, nor mally affect the mortality front cancer beyond that ob served in the first few years after the start of employ ment, and an SMR of 102 for cancers other than can cer of the liver is compatible both with the absence of hazard and with SMR values of 84 for other diseases and 77 for accidents, poisonings, and violence. Angiosorcoma. Death certificates are an unreliable source of information about (he histology of cancers that cause death, but there is no reason to suppose that the excess mortality attributed to liver cancer (or, in (he US series, liver and gallbladder cancer) is not entire ly accounted for by the known hazard of angiosar coma. Fifteen of the 37 deaths2 attributed to cancers of the liver and gallbladder in the US series are known to have been due to angiosarcoma of the liver (14). In (he UK series, seven of the 11 deaths attributed to liver cancer, not specified as secondary, were known to be angiosarcomas, and they all occurred in auto clave workers against 0.38 expected liver cancers of all types (P< 10-5) (25). In the Canadian series, histo logical review showed that seven of the eight so-called liver cancers were angiosarcomas (one had been de scribed as an angiosarcoma on the death certificate, two as hepatomas, and five as unspecified liver can cers). One so-called liver cancer death was found to have been due to cancer of the sigmoid colon, while one death attributed to angiosarcoma of the perito-1 1 Increased to J9 in table I to lake account of the 97 extra d#tht front an unknown eauip. 67 GC 001442 Table 1. Observed and expected numbers of deaths from different cancers reported in me (cur prmcipa' studies (4, 14, 25, 6) tO = observed number ot deaths, E = expected number of deaths) Type or ciass of cancer Buccaf c-avity and pharynx Esophagus Stomach large intestine Rectum Liver liver and gallbladder Pancreas Other digestive larynx lung Other respiratory Bone Skm (norimetanorna Melanorr-a Prostate Tesus Bladder Kidney Other ano unspecified urinary Bram Eye and central nervous system Thyroid lympno- And reticufosarcoma Hodgkin s disease Leukemia MuHipie myeloma I Other lymphatic } Olhir AN cancels United Stales o1 E 13 11.55 7 8 07 n 1601 21 28.79 39 5.77 17 18 40 118 115.87 5 6 38 2 1 81 6 7.36 16 15 20 5 8.46 12 906 25 12.76 12 7 98 3 5 45 14 13 94 46 0,50 383 341 73 United Kingdom 0E 3 58 6 14 34 26 23,91 9 13 94 11 10.49 11 1 94 7 968 4 2 21 81 92.12 2 1 74 12 9 59 2 1 38 14 800 3 4.10 3 4 29 .4 6.16 2 0 43 4 2 35 3 2 50 7 5.16 2 2 35 18 8.12 235 228 60 Canada 0E 0 0 64 8 0 14 6 5 26 2 5 78 1 33 t 1.67 2 0 95 20 16 37 Italy O6 1 08 1 06 3 30 0 12 1 06 6 07 i 09 12 6.1 0 02 1 07 1 07 6 04 0 07 9 45 30 21.1 * Observed deaths multiplied by 1 0674 and rounded off to the nearest integer to allow for deaths without oscovered cause, TaWe 4, Wort lO observed Type or class Wouth and pna Digestive *yst Respiratory sylung Genitourinary * Ui*noma 6'iin thyroid lymphatic and Cther All other than o * 1 = United Sta Table 2. Numbers of deaths from nonmatignant and all causes reported In the lour principal studies (4, u. 25,46) (O = observed number o'* deaths. = expected number of deaths) C*U3 Of C8iin United States 0* E United Kingdom 0E Canada OE Benign and other unspecified tumors CeieOrortscular disease Ischemic Head disease Other circulatory disease Bioncmtis* Pneumonias Other respiratory disease Cirrhosis of the liver Other digestive disease Disease of tha genitourinary system Other diseases Suicide Accidents and other violence All nonmaJigninl causes All Causes 4 5 08 75 91.93 521 597.73 157 123 55 44 22.83 16 31.94 } 15 32.84 37 56 06 27 39.52 11 20.41 67 115.68 49 52.78 1 130 173,19 1 153 1 363.54 1 536 1 705 27 278 105 36 40 5 43 40 545 780 288 ) 141 6u1 1l 76 50 66$ 894 25 31.67 1 ) 6 3,21 J 4C 3 85 v 5 40 2 10 58 39 54 76 59 71 07 * See footnote to table 1. * Emphys-ema In data from the United States. Includes two cases certified as cirrhosis of the liver which proved to be angiosarcoma of the liver. 4 Includes one case wilh cause unknown. Italy 0E 0 0.5 19 27 4 3 50 4 5.2 3 2.7 2. 4 36 66 7.0 0*9 7.7 564 77,5 neum was found to have been due to angiosarcoma of the livci i4M. In the Italian study, further evidence revealed \ *ut three further deaths should have been at tributed to cancer of the liver (for a total of four), but only one of the lour was described as ir. angiosarcoma (4) febl# 5. Mortality Aumper of deaths to.1 Type or class of c , Digestive system j'Miefudlng the ttv Umg Thyroid lyffipMllc in<1 6 `ftj'.'powite iytem X| 0*h*f (eluding t \ .-- - - -- -------- AJ1 .eluding Iha i . Incidence and c* Calcar of tha in feSjjjj*! Cancer of the to Funher tvide cancer (or liver; 'Mm i attribute 1 il anvtn Jv.it |l SfUClW**1 ,J 14 " Italy 0x r 1 C 3 30 0 :2 1 C5 o C7 i e9 12 6 1 0 02 1 0.7 t 07 0 04 0 07 9 45 30 21.1 tout discoveted ejse. 14.25,46). Ids observed 1 1 1 5 7 Italy 0 E 0 05 19 27 4 3 50 4 52 3 2.7 2 70 1 0.9 4 77 36 56.4 66 77.5 table 3. Mo" ti'iy rancor of Ihe liver and oiher causes amo^g vmyi chloride woiV^s in n'/mis m ihe lour prinriy^i studies coititjmeci (4. U. 25. 46] <0 s observed number t>t deaths. E = expected number oi deaths. SMR = standardized mortality ratio) Cause of death 0E Cancer of the hver* Cancer of other sites Other diseases Accidents, poisonings, and violence All causes 59 GC9 1 547 226 2 441 6 45 , 599 35 1 544 89 295 15 2 747 04 Including cancers of ihe gallbladder In ihe series from the United Slates. SMR 693 102 84 77 69 4. Mortality from various cancers among vinyl chloride workers In 49 plants in the four principal Studies combined. Observed number of deaths. Es exposed number o( deaths. SMfl = standardized mortality ratio) or class of cancer 0E SMR Source of Information* StlflOMtft end pharynx SQgpMUv system (other than fiver) JlM4Mrei(>ry system SfcO--tdrurtn.ry system jj, Wencm* jStlNe* Sf.**' end hematopoietic system 4xw man of ihe liver 18 16 57 125 154 59 223 229,36 211 21409 70 62.81 2 1 94 29 19 54 2 043 57 50 87 83 63.24 609 599.35 109 1, 2. 3. 4 81 1. 2. 3. 4 97 1, 2. 3, 4 99 1. 2, < 111 1. 2. 3. 4 2. 4 140 t. 2. 3 2 112 1. 2, 3. 4 131 1. 2. 3, 4 102 1. 2. 3, 4 iS0+ * * United States study (14). 2 = United Kingdom study (25), 3 = Canadian study (46). and 4 = Italian study (4). a?; * "jii TeMe V Mortality from various cancers among vinyl chloride workers: Supplementary evidence (4, 7, 22, 49). (O = observed y}V.>>wm of deaths. E = expected number of deaths. SMR ** standardized mortality ratio)i Tyo* or class o( cancer m- * ' r0^*1nr* system ' e--efodmg the liver) Li*V t,4>voma ,*nu 'iptofttfic and hemato* $m*uc lysfem OVw (excluding Ihe fiver) tt4vd.no ihe liver Federal Republic of Germany (11 plants) 0E 35.0 31 8 23.5 24.6 2.1 1.3 16.5 7.7 10.7 24.3 87.8 89.7 Norway (1 plant) 0 3* 1.44* 5 2.84 4 0.79 2 0.16 8 14.93 22 20.16 i and eases tn the Norwegian study, r of Ihe Intestine only, r ot the lung and bram only. Sweden (1 plant) 0E 3 1.78 2 0 33 5` 2.11* Italy (1 plant) 0E 1 1.2 0 15 0 0.1 0 0.7 4 20 5 5.7 Four countries combined (14 plants) 0 E SMR 39.0 31.5 40 41 2.0 16.5 22.7 1198 34.44 3072 0 89 l 63 0.16 0.4 41.43 117.67 113 103 198 55 102 for a total of four), bul bed as an angiosarcoma STWlher evidence lhat ihe excess mortality from liver tea (or liver and gallbladder cancer in Ihe US series) l be attributed principally if not wholly to the known 1'Xfctard of angiosarcoma is obtained in a comparison IVu* acres deaths with the numbers of deaths from arcomas recorded in the Register of Liver Angio sarcoma Cases (maintained on behalf of the Associa. lion of Plastics Manufacturers in Europe by Ihe Im perial Chemical Industry PLC) before the end of the follow-up period (Bennett, unpublished). Fifty-one ex cess liver cancers arc recorded in the combined data, and 49 angiosarcoma are recorded in the Register for 69 J Tib)* 6. Mortality from lung cancer in in* series from ihe United Slates (US) (14) and Dio Umled Kingdom (UK) (25) by cnaracierisncs relevanl la an occupational nazaro. (Q = ob served number of deains, E = expected number of deaths, Sun - standardized monaliiy ratio) Pat* characteristic * Category 1 0* E SMR Category 2 0 6 E SMR Observed 20 years or more after first employment 0). others (2) Employed 10 years or more in the US (i). others in the L$ (2i Employed be/ore 1956 in the UK ft). Others in the UK (2) Ever employed as autoclave worker in the UK (1), others m the UK (2) 114 113.96 100 55 52.45 105 52 51-39 101 16 17 OS 94 as 93 03 91 63 63.44 99 29 40 50 72 65 74 B2 fl7 1 The numbers in parentheses designate the category. Sc* footnote to table 1 tor observed deaths in the US ihe relevant periods for the three countries and (he two Italian plants1 that are covered by the survey. None of the 120 cases yet recorded in the Register were in men who were first exposed after 1969, and none of the 45 men affected in North America were first exposed after 1964. All may, therefore, have been exposed to concentrations of several hundred parts per million, and many may have been exposed lo concen trations appreciably higher (unpublished report by Barr to Air Products and Chemicals Inc in 1981). Lung cancer. The idea that exposure to vinyl chloride might cause cancer of the lung was suggested hy 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 suppon 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 Twenty-nine were registered as occurring in the United States against an excess of 33; only 20, however, were iden tifiable in both senes. 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 rcf siered cases was certified as due to a benign hemangioma anef not related to the liver (code 227 in the eighth revision of the International Classification of Diseases). Ten cases were registered as occurring in Canada against an excess of eight; two were recorded as being in men who had been employed for five years, and it is possible that the actual durjuon had been slightly less lhan five years with eonseuucm esclustun from the Canadian cohort. One ease was registered as occurring in one til the two Italian plants j-vinsi an excess ill less than one. be seen than in other groups. This circumsfance is illustrated by table 6, which shows that the SMR values are slightly higher for men observed 20 years or more after first exposure than for men observed earlier, for men employed before 1956 in the UK than for men first employed after 1955 (when exposure levels are believed to have been lower), for men employed for longer than for shorter periods in the US, and for autoclave workers in the UK (among whom the angio sarcoma cases have mostly occurred) than for other workers. The differences are all small or very small. They arc, however, all in (he same direction, and the probability that the rates should all be higher in the groups in which an occupational hazard is more like ly lo 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 casesl was observed, and this figure increases to 31.5 when allowance is made for the number of deaths due to unidentified causes in the German study (SMR becoming 103). In the German study the SMR was higher 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 the Norwegian study, four of the five cases observed occurred in men whose occupaiions were regarded as involving high exposure against 1.82 of the 2.84 expected. Both (he German and the Swed ish studies derived the 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 al (36) were, however, observed in US workers and must be presumed to be included in the total reported by Environmental Health Associates (14); therefore they will have contributed a substantial proportion of the total in table 4. As a lest of Ihe hypothesis the data or Monson et al ought, therefore, to be subtracted from those in the table. Their investigation was not a cohort study, and their expected deaths do not cor respond exactly to those in table 4. If, however, the observed and the expected cases are both subtracted Trom the totals, twenty-four observed deaths remain against approximately 18.3 expected, a difference which might easily occur by chance (P one-tailed = 0.I).J A 07 1 If the study of Waxweilcr et al (503 iv regarded as the origin of the hypothesis. 2b deaths are tell ae.niist |x 94 wpvcied (P one tailed - I) 1)71. Addition, given in tat little furthei one of the t occurred in . less than a \ the excess di German stu chemical wo deaths after causes again; PVC fabnea for deaths fr< Cancers of h idea that vin> phatic and he ihe lymphatu AGaffcy (45) studies, wher from lymphoi ga/nsi 2.54 e< the lymphatic peeled. These if the laborato suggesting that fjlly in animat lion (29). The cause lymphor ctsis cons'detat Studies that are Mipport for the lymphatic and he grther (57 death nd very little m< file cancers of (he fey's definition ^>2.200--203 and 21 Vfi'!' * deaths age 'oeeover, hard ; .GfTey*i initial r rf33.36 expected, S^Uttle addiiio fault* of the Gi flrtdy obtained ; j(l*sed on 15 obs jsOcrw* nee is mao V)cnown causes) a Ffa tme*posed grr gftf PVC fabricate ?:*pos<d workers exposed for <c*s ws most ma 'for five years or n the number of de 4 ' e pected, SM \n c ICC II alucs more r. for r men Is ate ;d for id for angioother small, nd the in the e likeps is I s given served, ance is ntified 03). In ie men tan for ds(111 r of the ipalions list 1.82 e Swed* ' deaths towards nbers of stimated timated n rising ht cause et al (3ft) .ted. The ide some onson et kers and reported therefore Ortion cl s the data ubtracicd i was not a not corsever, the ubtraaed hs remain difference e-taifed = as the origin .94 expected 51 Addition.il informal inn Irom isso oilier sources is given in table 5. The small excess reported provides tiltIc further evidence of an occupational hazard. as one of the two deaths observed in die Swedish Mttdy occurred in a young man who had been employed for less than a year when die diagnosis was made, while the excess death rate for brain cancer observed in the German study was less than dial 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 (5.9 deaths after allowance for deaths from unknown causes against l.l expected). Cancers n/ 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 & Galley (45) and by Waxweiler et al (50) in two cohort studies, when they found, respectively, five deaths from lymphomas in the most heavily exposed workers against 2.J4 expccled and four deaths from cancers of the lymphatic and hetnalopoiciic tissues against 2.5 ex pected. These small excesses might have been ignored if the laboratory findings had not been interpreted as suggesting dial lymphomas were produced experimenlally in animals exposed to vinyl chloride by inhala tion (29). The idea that similar exposure might also cause lymphomas in hmnaus, therefore, merits seri ous consideration. The data from the four principal studies that are summarized in table 4 provide little support lor the hypothesis when all cancers of (he lymphatic and hemuinpoictic tissues arc considered to gether (57 deaths against 50.87 expected, SMR 112) and very little more is ohtnined from the separate data for cancers of the lymphatic system (Tabershaw & Gaffev's dcliniiion of It'D list numbers, eighth revision, 200--203 and 205 heing used) that are shown in table I (35 deaths againsi 29.40 expected). The position is. moreover, hardly altered if the data in Tabershaw & Galley's initial report are subtracted (29 deaths against 23.36 expected. SMR 124). Little additional information is provided by (he results of the German study (49). (See table 5.) This study obtained an SMR of 214 for exposed workers (based on 15 observed deaths, increased to 16.5 when allowance is made for the number of deaths from un known causes) against SMR values of 77 and 34 for an unexposed group of chemical workers and a group of PVC fabricators. It showed that the excess of the exposed workers was present only for men who had been exposed for more than one year and that this ex cess was most marked for men who had been exposed for five years or more (10.7 deaths after allowance for the number of deaths from unknown causes againsi 4.0 expected, SMR 268. P one-tailed <0.01). Melanoma. An excess of melanoma w as reported for Norwegian workers by Hcldaas et al (22), who raised the possibility that vmyl chloride might have produced the disease. Four cases were observed when 0.79 were expected, and three of the four were in men whose oc cupations involved the highest exposures (against 0.51 expected). At the time of the writing of their report, one further case had been detected with onset three years after the closure of the study. Subsequent studies in other countries have, so far, reported only two deaths against 2.0 expected. (See tables I and 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 from their observation. Two of the three major studies that have been reported since the Norwegian observation was made gave no data for thyroid can cer; the third reported two deaths against 0.43 ex pected. (See table I.) One death from thyroid cancer, it may be noted, was reported in the US by Monson et al (36). Cancers of the digestive tract. Suggestions that vinyl chloride might cause cancers of the digestive tract in general have sometimes been made, but they have not taken adequate account of the contribution of cancers of the liver to the total number of cancers of the digestive system, particularly when it is borne in mind that some liver cancers are likely to be misdiagnosed as cancers of other organs. The combined data from (lie four principal studies shown in table 4 weigh heavily against the idea that any such effect has been produced. Other cancers. One of the remaining types, or classes, of cancer listed in table 4 shows a statistically signifi cant excess, namely, the heterogeneous group of "other cancers" (83 observed deaths against 65.24 ex pected, P two-sided <0.05). This excess is only mar ginally significant and may be a chance observation. The most likely explanation is. however, that a few angiosarcomas of the liver were not recognized and were diagnosed as secondary liver cancer or carci nomatosis. site unknown, the number of deaths in this category therefore being increased. Hazards of non/nolignant disease No previous study has suggested that any nonmalignant cause of death other than cirrhosis of the liver would be likely to be increased as a result of exposure to vinyl chloride, and cirrhosis of the liver is presumed to be increased only because of the liver changes that were observed as part of the "vinyl chloride illness" (24, 31. 33). Two other possibilities have, however, been raised, namely, the production of nonmalignant respiratory disease, because of the changes in lung function and radiographic appearances that have been 71 GGC 001446 1* Table /. Mortality irom selected nonmalignant causes and all causes m the lout principal studies combined (0 = observed number ol deaths, E = expected number ol deaths, SMR = standardised mortality ratio) Type o< disease 0 E SMR Source of information* Bronchia, emphysema6 SO 66,83 120 1, 2 Other respiratory disease 7t 125.78 56 1, 2 AH respiratory disease Ischemic heart disease Other circulatory disease4 All circulatory disease4 Clrrhoau ol tne liver Other disease ISO 79? 252 1 103 46 238 200,82 885.73 264.55 1 209.35 66 26 368 07 80 1. 2. 3. 4 90 1.2 95 1,2 91 1. 2. 3, 4 69 1. 2. 4 65 1, 2, 3. 4 AH nonmalignant disease Ail exernat causes 1 547 1 844 50 226 295.15 84 1. 2, 3, 4 77 1. 2, 3, 4 AH nonmalignant causes AH causes 1 773 2 139 65 2 44 f 2 747 85 85 1, 2, 3, 4 89 1. 2, 3, 4 * t = United States study (la), 2 = United Kingdom study (25), 3 = Canadian study (461, and 4 - Italian study (a). * Bronchitis in the United Kingdom study, emphysema In the United States study. * Includes cerebrovascular disease In the United Kingdom and Italian studies. Table (. Mortality from chronic obstructive lung disease* In the series from me United Slates (US) (14) and the United King dom (UK) (25) by chatactensucs relevant to an occupational hazard (O = observed number of deaths, = expected number ct deaths, SMR = standardized mortality ratio) Dali characteristic6 Category 1 0 E SMR Category 2 0 E SMR Observed 20 years or more after first employment In tne US (t). others in the US (2) 30 15.8 190 Employed 10 years or more in me US ft), others In the US (2) 18 1Q.9 147 Employed b(orfl 1956 In Ihe UK (1), others In tne UK (2) 28 30.17 88 Ever employed *s an autoclave worker tn the UK (1), others in the UK (2'c a 8 55 48 11 7.0 157 25 12.0 '208 10 13.60 74 33 37.22 89 * Described as emphysema in ihe US study and as bronchitis in Ihe United Kingdom study. 1 The numbers in parentheses designate the category. 1 Men evet employers as a bagger or Oner, occupations which would nave caused the greatest occupational exposure to potyvinyt chloride Oust, experienced one death from bron chitic against a 95 expected recorded for men exposed to PVC dusi (2, 26, 27, 4-0, and acute cardiac death, from analogy with (he effect of other halogenaied hydrocarbons (25) and ihe observaiion of an increased moriality from myocardial infarction in the few years following (he cessation of exposure in [he Swedish PVC processing industry (35). Relevant figures for (he 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 ihe liver. Three of the four principal studies gave separate figures for cirrhosis of the liver, none of which showed an increased moriality (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 ihe Ever, reported four deaths from all diseases of the digestive system combined against 3.85 expected and noted that the four included two that were certified as due to cirrhosis of the liver, but actually due to angiosarcoma (46). fn 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 non malignant respiratory disease are confusing in that the total SMR from Ihe combined data for the four prin cipal studies is 80 and is the sort of figure that is com monly found in healthy industrial populations, yet Ihe 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 UR, 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 wha: it is now agreed is best called chronic obstructive lung (or pulmonary) disease, but which in the past tended to be called emphysema in the US and chronic bronchitis in the United King dom. It must, therefore, be presumed that the two categories of "emphysema" and "bronchitis" used re spectively in the two large national studies were meant j to describe the same thing. One must assume, there fore, that the experiences in the two countries were very different, despite the fact that both related to cohorts that had very similar experiences of angiosarcoma of the liver and so, presumably, fairly similar exposures to vinyl chloride. Separate figures are shown in table 8, where avail able, for the mortality obsened among men with dif ferent durations and intensities of exposure. Unlike the data for cancer of (he lung that were shown in table 6, they provide no consistent evidence of a greater risk in the groups in whkh jn iiw mat inn,il ha/aul would beexpectec 'hronmema to give an; from empl hardly be d ho overall e however, th by deficient respiratory i Wher respir ' the questtot could he a : :; Health Asso that they we m the out~o* the coding o "exher respir included crrt| . emphysema i beeljjsified 'o 502, and t) of the emphy In some categ number 527, 1 for both the e polity defici. [fi tnpiratory dt No excess n and asthma" i 44 with 6.3 d- sBnber of de Wr " . A~- Ctrdhvasculc [r/ arferotic) hear ^ ffode the vast *0 acute cardi rUf national st I increased n J of disea : recorded *flf*SMR va i there is no i the tubsidiar In par mortal . item in th AhsISMR6! workers ( slight inert *ty wti recordei study (49), i1 TV &iths >( and the **viion fi r. J/Mcafi! `Mini tor i I " I C sK J lus112, 26, 27, 4-U. ogy with the effec: is *23) am) the cby from myocardial ng the cessation of :ssing industry (33). f deaths from these hat are obtainable :re given in table 2. in table 7. the four principal irrhosis of the liver, sed mortality (tab'e iMR of 69 based on ch did not give separeported four deaths ve system combined hat the four included cirrhosis of the luer, 1(46). In the two s-pa were given for this based on 15.1 deaths with unknown causes on seven deaths (57). ise. The data for rton< confusing in that the data for the four pnnt of figure that is cont ra! populations, yet the fly increased mortality nd an SMR of JSO be: for deaths from uns was found in the UK. lis gave an SMR of 82. chronic nonmalictam ated by the usage of diftt is now agreed is best (or pulmonaryldtsease, o be called emphysema nils in the United Ktr.g* presumed lhai ihe two nd "bronchitis" usetd re*-; ional studies were meant'f )ne must assume, there', .' ie two countries were very J it both related to cchoru: nces of angiosarcoma of: , fairly similar exposures , petted to be concemraied. The authors of (he En5^|#oi(nettiaJ Health Associates report (14) were unable k'tfve any explanation for the increased mortality 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 /'deficiencies in the other categories of nonmalignant aory disease (pneumonia 15 deaths.' SMR 47.0; (respiratory disease 14 deaths, SMR 42.6), and question arises whether the emphysema excess be i dassificatory artifact. Environmental I Associates (14) list all the 41 deaths which show I they were coded under ICD number 527 which, (Ikeout-of-dale seventh revision that was used for tttkildg of all deaths in the study, was the code for r respiratory disease not otherwise classified" and I emphysema. Under that revision, however, i that was associated with bronchitis should jjfAf dauificd with bronchitis under ICD numbers 500 G. and the possibility may be considered that some rth emphysema deaths should have been classified category of respiratory disease other than ICD r 527. If this were the situation, it could account tbmbthe excess mortality from emphysema and the r deficient mortality from other nonmalignant ftearinuory diseases. No excess mortality from "bronchitis, emphysema, \4t}--s*d was observed in the German study (SMR Iwsil) 6.J dealhs observed after allowance for the SrVJr./-Jw>t)tr of deaths from an unknown cause) (49). .I toscular disease. Data for ischemic (or arterio^tftveic) heart disease (which may be presumed to in- : the vast majority of all deaths certified as due thooe cardiac disease) were given only by the two m Moonal studies, and they provide no evidence of mortality. The SMR values of 90 for this i of diseases and of 91 for all cardiovascular dis til* recorded in the four principal studies are typical flta SMR values of healthy industrial populations, lthese is no suggestion of any occupational hazard sbssJUry analyses provided by the two national U particular, there is no evidence of an ini Mortality within one month of leaving tm- in the UK study either for all workers (52 ^ShlR 61) or for the most heavily exposed auto- fien (9 deaths, SMR 42). increase in ischemic heart disease mortal- (recorded for the exposed workers in the Gertttwdy (49), but it was less than that recorded for n in table 8, where avaikSfi ved among men w,;h dif- j its of exposure. UnJke the jg that were shown in uble.'^ t evidence of a greater riik',3? ccupational hazard would s^j t tttnbuitd to different groups of respiratory disI the corresponding SMR values that arc cited in cw fur ihe US study are as given by Ihe Environ* I tteaJih A'sociaies (14) and have not been adjusted aua (or the number of dealhs from an unknown H. to Uie account of these deaths, the observed deaths I5MK values can both be multiplied by 1.0674. the unexposed chemical workers and the I'VC fabri cators (SMR values of 127, 131. and 158 based on 97.2. 126,7, and 109.7 deaths, respectively, after allowance for the number of deaths from unknown causes). Discussion The information that has now been obtained about the long-term health of men occupationally exposed to vinyl chloride is massive and compares favorably with that available for any other occupational group. Two facts are outstanding. First, the men have experienced a specific hazard of a type of cancer that is normally extremely rare, namely, angiosarcoma of the liver. The rarity of this disease under other conditions made the detection of the hazard easy; but the long latency period before the disease appears after first exposure (almost always more than 10 years and usually more than 15 years) meant 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 pro tection provided by the reduction in exposure in the 1960s and that of the further reduction that followed the recognition of the hazard in 1974 are known. There is, unfortunately, no effective treatment for the dis ease, and the number of cases is reflected in the num ber of dealhs. Some 50 dealhs have occurred among the 16 740 men who were followed in the four prin cipal studies (hat have been reviewed in (his report, so that approximately I in 335 men have been affected, 2 7o of the dealhs having been due to this one cause. Eventually many more men must be expected to de velop the disease. One estimate (38) suggests that the total may be increased 10 times, but a more realistic estimate is two to three timts (19). The second outstanding observation is that the mor tality of the exposed men, other than that due to angiosarcoma of the liver, is typical of Ihe normally healthy industrial worker -- that is not to say that no other hazard exists, but that the effect of any other hazard is small. The massive data that are now available provide no reason for thinking that any hazard other than one of cancer has been overlooked. Ir is, however, still dif ficult to decide whether vinyl chloride produces a risk of developing cancer other than angiosarcoma of the liver which might be small compared to the risks produced by nonoccupational causes, but yet abso lutely almost as large as the risk of developing the nor mally very rare angiosarcoma. One of the many hazards suggested can be dismissed, as there is no evidence to support it, namely, that of vinyl chloride as a cause of any cancer of the diges tive tract other than angiosarcoma of the liver. Two hazards (of melanoma and cancer of 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 GGC 001448 x-.r-.yl chloride, and, in light of present evidence, the simplest explanation is that the reported excesses arc the chance effects that must be expected when many d.fferent types of cancer are studied in several different populations. So far as melanoma is concerned, it has tc 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 (sec reference 29) do not suggest that lymphoma or any ocher cancer of the hematopoietic system is liable to be produced. There is, however, some evidence that train tumors can be produced in rats (29). The hypoth eses that lymphomas and brain cancers might be produced by vinyl chloride have been supponed by the coservaiion that both these types of cancer have caused death more often than might be expected from national mortality rates, but the excesses observed in the com bined data from the four principal studies in this re view are small and not statistically significant, and the hypotheses remain unproved. The small excess of brain cancer is particularly difficult to evaluate, as mortal ity rates from this disease have changed rapidly over ttme as methods of diagnosis have improved and the suspicion of an occupational hazard (which was raised in 1975) could have influenced the Endings. 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 tymphaiic and hematopoietic cancers are more impres sive, particularly as the excess was the most marked for men who had been employed for at least five years. In these circumstances, judgment must still be sus pended until the data for each study are analyzed for each specific type of cancer, by intensity and duration cf exposure, and by lime since exposure began. There remains the suggestion that vinyl chloride might cause lung cancer. At first sight, this posstbil-:y is ruled out bythe SMR of 97 for the combined data for respiratory cancer for the four principal studies. Lung cancer is, however, normally so com mon (accounting for about 8 Vs of the expected deaths) that an increase in mortality that was half as impor tant (numerically) as (he increase in mortality from angiosarcoma of the liver might easily be overlooked 95 b'ii 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 arc not evenly distributed about the country. In these circumstances one cannot exclude an occupational hazard unless it can be shown that the mortality of the exposed men is independent of the factors that might be expected to influence it if some of it were occupational in origin, namely, the intensity and duration of exposure and the time since exposure began. It is not possible to examine these relationships in detail, as the reports do not provide all the necessary information. Such information as they do provide, which was summarized in table 6, supports the idea that exposure to vinyl chloride involves a small hazard of lung cancer. Taken in conjunction with the knowledge that lung tumors hate been produced in sev eral species of animals exposed :o 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 ruk can be only minute and incapable of detection. The questions that have been left unanswered by this discussion might well be answered definitely if (i) all the exposed men could be followed to (say) the end of 1984, (ii) the investigators could present their data in comparable ways, taking account of duration of employment and time since first employment and presenting data separately for men first employed be fore (say) 1965 and between 1965 and 1974, and (iii) estimates could be made of the effect of correcting the results for each group of employees for the locality in which they lived and worked. - -TL- -r 44'h 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 most, 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, 3. 15), and this levti is about one-ten thou sandlh of the concentration tiat has caused an occtl pational hazard. It is obvious, therefore, that it would be impossible to detect the risk of any cancer that mighl be produced by vinyl chloriie 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 portion with regard to an- * r t f.i. 1v L. fifr: 7,41 l\ _ giosarcoma ntally so rat to one of tl dioxide, an, annual inen. In these cirt In a man liv ride was use controlled n of the effee Several su ;x* whether any VAj * and Elinder vanity of pi and Sweden *1 (II) foum Jy;; to ihoroirasi *xth vinyl ch Wm* 'a lion of the p (3) found U U-year perio Plani, and. in Rndy ct al ( Wbuted to an- living W|( "o'! vinyl chi law two studii trace of as m. (lose to manut Ms colleagues, twnti with ma ,_*h< referents livi F^j. tseighborhoi V.New York Slate ? iMlufion with \ v*/.(he uiiciin. jviWfa Years, resp- this period . The ot SifUr 15 or mor of these tnvironm r^VC may ha f twiblic. .Client conct are cer; tily by Recent hundred me belos three of Eve 20 ppb (If Oust in values w. with putti : r Tifurc of I Nvn J 111), over wufiin a tov to whether the i*zle reference for t::en evenfy distributed .(stances one car.-c: iless it can be sho -n men is independj-t :cted to influence :t i origin, namely. t.ne e and the time sir.ee le to examine these ions do not prov.de t information as they d in table 6. supports oride involves a small conjunction with the been produced in sevi vinyl chloride by in* small hazard of lung evidence is not, hewthat it definitely c:d. >nly for men who bad at a time when e\po million or more were It can be only minute eft unanswered by this red definitely if iti all iwcd to (say) the end uld present their data count of duration of irst employment and .ten first employed be'65 and 1974, and liii) effect of correcting the yees for the locality in filiation ved to cause cancer in iratory experiments, it the minute dotes that umcm from production tanufacture) from PVC lit risk of cancer to the ist, however, have been is of vinyl chloride, even tandling vinyl chloride, 5) of the order of 10 to I is abour one-ten thouhat has caused an occutherefore, that it would of any cancer that might de other than a nsk of s it has proved so diffimong men who were ex* isilion with regard to an* < i *.uvtinin ol the liver is dil lercnt. This disease is norB-.ally so rare that, in the absence of specific exposure ,10 one of the known causes (vinyl chloride, thorium dioxide, and arsenic in pesticides and medicines), the :!oonual incidence is on the order of 1--2 I0-' (5, 8),* r.U these circumstances the discovery of even one case Jn a man living close to a factory in which vinyl chlo- .ridc was used in the days before exposure was lightly rolled may be regarded as presumptive evidence '.the effect of environmental pollution, jvSeveral surveys have been undertaken to determine ^whether any such cases have occurred. Saric et a) (43) 'MBd Elinder & Pershagen (13) sought for cases in the tridnity of plants handling vinyl chloride in Yugoslavia fand Sweden and found none. In Holland Dalderup et &1 (II) found eight confirmed cases not attributable 1,10 Ihorotrasi or arsenic and could r' "no contact .'with vinyl chloride." but they made no specific men* 'lion of the patient's place of residence. Baxter et al t'P) found J4 confirmed cases in Great Britain over a 12-year period, one of which was in a inan who had > lived half a kilometer from a PVC manufacturing 5V:*, plant, and, in New York State over an 18-year period, Brady et al (5) found 19 cases that could not be at* li* Uibufcd to any known cause, five of which were in peopie living within a mile of plants manufacturing or jy.- using vinyl chloride. The overall incidence rates in these last two studies were not unduly high, but the occur* icnce of as many as six cases among people living so dove to manufacturing plants is surprising. Brady and !SV;' 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 esght years, respectively, before developing the disease, and this period is too short to allow for the necessary latency. The other four cases, however, all occurred after IJ or more years of local residence, and the dis covery of these cases strongly suggests that pollution of the environment around plants manufacturing VCM or PVC may have caused a minute hazard to the gen eral public. Current concentrations around plants handling vinyl chloride are certainly much lower than those reported I'jjxcvtously by the US Environmental Protection cncy. Recent British measurements made within a Sfn hundred meters of the VCM areas have given averJjttge values below the daily limit of detection (3 ppb) for three of five plants, the readings at the two others P.y' being 20 ppb (100 m outside the boundary fence) and 18 ppb (just inside it) (47), although substantially iij,], higher values were recorded on two occasions asso- i'-'C.siaied with putting one plant into operation and with The figure of 1.4 10 - cited by I teath el al (21) seems to have been a misprint for 1.4 10-', an accident at the other. Accotding to any reasonable criterion the hazard to the general public (if (here is any at all) must be negligible (42). No other hazard to the general population, other than a hazard of cancer, can reasonably be postulated. Summary This paper reviews (i) the possible effects of vinyl chloride on the personal health of men exposed by virtue of their occupation (other than the early effects of the very high concentrations to which men were ex posed when the industry was first developed -- uncon sciousness, cardiac arrhythmia, and (he characteristic "vinyl chloride illness") and (ii) the carcinogenic effects that might conceivably be observed in the gen eral population as a result of the widespread distribu tion of vinyl chloride as a pollutant. The possibility that vinyl chloride might act as a teratogen or might cause mutations in the germ cells has not been exam ined. as the little evidence that has been adduced relating to such possible effects has been reviewed else where and the conclusion was reached that no such ef fects have been demonstrated. Many groups of workers exposed to vinyl chloride in the manufacture of VCM or PVC have been studied since the carcinogenic potential of vinyl chloride was first recognized. Some results have shown that occu pational exposure can cause angiosarcoma of the liver, and others have suggested that it may cause several other types of cancer as well. The actual situation can be determined only in an examination of all the evi dence, especially the combined results of those studies that include a substantial proportion of observations on men more than 25 years after their first exposure and cover a long enough period for more than 10 Vt of the employees to have been expected to die. The results of four studies can be usefully combined for this purpose. They are two national studies, one from the US and the other from the UK, and two studies of employees in one plant in Canada and two plants in Italy, The results of other studies from the Federal Republic of Germany. Norway, Sweden, Italy, France, and Japan can be used only to provide sup plementary information. The many earlier reports of exposed workers in the US and the UK concern men covered more completely in the two recent national studies, and their results serve only as sources of hy potheses. Minor criticisms can be made of three of the four most useful studies. They do not seriously affect the value of the results, except that allowance has to be made for the failure to determine the cause of 6.3 V* 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 (he absence of any special occupational hazard, and the fourth (Canadian) uses rates for the province in which 75 GGC 001450 the plant was situated. It must, therefore, be kept in mind that the rates used may not have been wholly ap propriate for the localities in which the plants were situated. This circumstance is potentially important for the US study, which covered workers in 37 plants, 22 of which were situated in the southern part of the country. The other less informative studies arc, for the most pan, open to more serious criticism, and the value of each set of results needs to be assessed separately in relation to each disease. The combined results of the four principal studies show that thcSMR 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, (ti) 84 for diseases other than cancer, and (iii) 102 for cancers other than cancer of the liver. All these results are what might be anticipated for an industry devoid of any specific occupational hazard. The low ratio for diseases other than cancer reflects the "healthy worker effect," which results from the selection process that inevitably excludes some of the less healthy members of the population from industrial employment and is compatible with a higher ratio for cancer, as the mor tality from cancer is not normally subject to such an effect, apart from the first two or three years imme diately following the start of employment. The mortality from cancer of the liver was nearly seven limes that expected. Most of the 51 excess deaths were known to be due to angiosarcoma, even though this diagnosis was not recorded on the death certifi cate. The excess corresponds closely with the 49 deaths due to angiosarcoma reported to the International Register of Angiosarcoma Cases as occurring in em ployees of the plants concerned during the periods under observation. All the men who developed the dis ease were likely to have been exposed to concentrations of vinyl chloride of several hundred pans per million or more. Three other types of cancer which have been sug gested to occur as a result of exposure to vinyl chlo ride are cancers of the lung, brain, and lymphatic and hematopoietic systems. The combined data for the mortality from respiratory cancer fail, at first sight, :o 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 (here is nothing to sug gest that they are occupational in origin. An excep tion is the observation of ar, increased mortality from cancers of the lymphatic and hematopoietic systems in 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 aboul 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 misdassification of angiosarcomas as secondary can cers of the liver or carcinomatosis, site unknown. The following three nonrrulignam causes of death have required special examination: cirrhosis of the liver because of damage to the liver in "vinyl chloride ill ness, " myocardial infarction (from analogy with the effect of other halogenated hydrocarbons and because of some observations from Swedish l`VC fabricators), and nonmalignant respiratory disease because of changes in lung function and ihe radiographic appear ance of the lungs observed m men exposed to PVC dust. Far from being raised, the mortality from cir rhosis of the liver was less than expected in the three principal studies and in one ot ihe (wo supplementary studies which gave separate figures for the disease (SMR values of 69, based or. 46 deaths, and 82, based on 15 deaths), while in the other supplementary study the increase was trivial. Data for myocardial infarciion have not been re ported separately. But myocardial infarction accounts for most of the deaths attributed to ischemic heart dis ease, and there is no evidence that either ischemic heart disease or cardiovascular disease as a whole was un duly common (SMR values of 90 and 92, respective ly) or related to occupational exposure. The data for the third category of nonmalignant dis ease (nonmalignant respiratory disease) are confusing, because the two large national studies give conflicting results. The combined data for the four principal studies show the low mortality that is commonly found . in healthy industrial populations (SMR 80). This fig ure hides, however, an increased mortality from chronic obstructive lung disease (SMR 120), which in cludes emphysema and is due to a grossly increased mortality attributed to emphysema in the US study (SMR 193). The corresponding mortality in the British study, which was preferentially described as due lo bronchitis, was less than expected (SMR 82), as was the mortality from pneumonia iSMR 50) and other rev- . fwrfory disea fio consistent f*Tema or b ; **d it seems | US study was dci with the u Review of t laof-term hea ratyl chloride mcis have expe tttrtmcly rare -tactely I in 33 Cwdicd died of ' <is* observed d> of time the nu be expected to (! (be mortality t of that of norn , hazard has ext The data prt Jed other than h,, however, sti. rvie produces si |}> ** to nonoccu fever, and, if sc cause almost as fever. There is too li the suggestion i toms or cancer aod hematopoie that have been ri patSonal hazard. Otrt of the lymph German study re aoet of chance elT Many types of ca Cadies. '.,-The lack of an In the combin does no brve been a sma disease, as gt the disease th I rates foi . The greati be more li Other group existed. The ence of a ha Clearer answer posed in th s groups c !malts in more a As vinyl chloric tintu and a pro' - that have ev . ;villur;miv intis *. UllllUlv.* 1 1 altty from ic systems 1 Republic ; in excess :ancer and is difficult boul these es. use cancers um for the When (his ;estive tract R 82 for the erogeneous d results of ' marginally d. P<0.05). n due to the ortdary canunknown. ises of death is of the liver l chloride illlogy with the . and because ' fabricators). because of aphic appearosed to PVC dity from cird in the three upplementary ar the disease and 82, based mentary study j i j f f j j j. '* ? I v ( f f * e not been se ction accounts lemic heart dis ischemic heart whole was un92. fespcctive- re. nmalignam dis) are confusing, give conflicting four principal ominonly found IR 80). This figmorlality from < 120), which in;rossly increased in the US study ility in the British cribed as due to 5MR 82). as was 50) and other res- t 1 le piratory diseases (SMR 4A) in the US study. There is no consistent evidence that the mortality from em physema or bronchitis was specifically occupational, and it seems possible that the reported excess in the US study was an artifact due to nosological difficul ties with the use of the seventh revision of the ICD. Review of the massive data now available on the long-term health of men occupationally exposed to vinyl chloride leads to 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 Vt of the observed deaths were attributed to it. In the course of time the numbers of cases of angiosarcoma must be expected to increase two to three times. Second, the mortality from all other causes has been typical of that of normally healthy industrial workers. If any hazard has existed, its effect has been small. The data provide no reason to think that any haz ard other than one of cancer has been overlooked. It is, however, still difficult to decide whether vinyl chlo ride produces small risks of cancer, compared to those due to nonoccupational causes, at sites other than the liver, and, if so, whether, in total, these risks might cause almost as many deaths as angiosarcoma of the liver. There is too little evidence either to confirm or refute the suggestion that vinyl chloride might cause mela noma or cancers of the thyroid, brain, and lymphatic and hematopoietic systems. None of the small excesses that have been recorded point specifically to an occu pational hazard, apart from that attributable to can cers of the lymphatic and hematopoietic systems in the German study reviewed, and most are likely to be the sort of chance effect that is certain to be observed when many types of cancer are examined in many different studies. The lack of any increased mortality from lung can cer in the combined results of the four principal studies reviewed does not exclude the possibility that there may have been a small occupational hazard of developing the disease, as geographic variations in the incidence of the disease thrnw doubt on the validity of using national rates for estimating the expected numbers of deaths. The greater mortality in groups of workers who would be more likely to show an occupational hazard than other groups suggests that a small hazard may have existed. The evidence is, however, weak, and the existence of a hazard has not been proved. Clearer answers to some of the questions that have been posed in this review might be obtained if the various groups of investigators could present their results in more appropriate and comparable ways. As vinyl chloride is a mutagen in laboratory experi ments and a proved human carcinogen, the minute doses that have escaped into the general environment as pollutants must be presumed to have caused com parably, minute risks to the general public. No such risk could possibly be detected, other than one of angiosarcoma of the liver which is normally an ex tremely rare disease. 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Neoplastic risk among workers exposed to vinyl chloride, Ann NY Acad Sci 271 (1976) 40--48, Received for publication: 16 February 1988' I i I t ORIGIN At Scand J )# Assoc exhau Results by Jack i Ron Dew Si be ret ret e\i CJI Ar fur ga.` adt COl Ke A large pc study was c cupaiional t About 20 st For each pai past exposu analytic stra at a time to t remarkable This repoi cancers tp c:: bustion prod classes. Fou bustion eng depending o jet fuel, or pi from the "n substances: , without dist lamp oil), n: profile of pro is considered a propane-bi 1 Epidemtolog Instiiuie Ari Canada. * Department t verstty, Mon > Department University 01 Reprint reques cm eptdemtolos I tappier, 5)1 r l jiijJ.i, 117V