Document qaBzaQ5oX0oX8vgxgwERv57nM

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 Wesf Wayne, NJ 07470 (201) f SL 089550 ISSN 0355-3140 Volume 14, number 2, April 1988 CONTENTS Revie w$ 61 Effects of exposure to vinyl chloride: An assessment of the evidence Sir R Doll Original articles 79 Associations between several sites of cancer and ten types of exhaust and com* bustlon products Results from a case-referent study in Montreal J Siemiatycki, M G6nn, P Stewart, l Nadon, R Dewar, L Richardson 91 Effects of exposure to Freon 11, 1,1,1 Irichloroethane or perchloroethylene on the lipid and fatty acid composition of rat cerebral cortex T Kyrktund, P Kjellstrand, KG Haghd 95 Influence of water on the percutaneous absorption of 2-buloxyethanol in guinea pigs G Johanson. P Fernstrom 101 Percutaneous absorption of 2`butoxyethanol in man G Johanson, A Boman, B Dynesius 110 Prediction of early retirement on the basis of a health examination: An 11-year follow-up of 264 male employees in a Swedish pulp and paper company N-E Astrano, S 0 fsacsson. GO Ofhagen 118 Comparison between surgeons and general practitioners with respect to cardiovascular and psychosocial risk factors among physicians B8 Arnetz, S Andreas* son, M Stranaberg, P Eneroth. A Kallner 3 25 Invariants and nonmvariants in the concept of interdependent effects S Greeni^nn, r Pool? Case studies 130 Fatal arsenic poisoning -- A case report L Gerhardsson, Dahlgren, A Eriksson, BEA Lagerkvist, J Lunastrom, GF Nordberg Book reviews 134 Neurotoxicants and neurobioiogical function: Effects of organoheavy metals 134 Ergonomics in computerized Offices 135 Indoor radon and its hazards 136 Ergonomics at work 137 A manager's guide to ergonomics m the electronic office 138 industrial radiation hazards deskoook 139 Announcements 140 Amendments and corrections 'REVIEWS Stand J Work Environ llcoilh 14 (1488) 61--'H Effects of exposure to vinyl chloride An assessment of the evidence by Sir Richard Doll, FRS' DOl.L R Effects of exposure to vinyl chloride' An assessment of the evidence Stand J I* nrk Environ Health 14 (1988) ftl -- '8 This paper reviews ihe possible effects of vin%l chloride on the mortality of occupationalh exposed men and the carcinogenic effects that might be observed in the general population as a result nt environmental pollution with vmvl chloride The results of four studies fulfilling the criteria * of providing suhstafin.il numbers oi observations more than 25 years alter first exposure and covering { a period long enough for more than 10 *'<) of the workers to have been expected to die constitute the basis for the .assessment of the occupational hazards Other studies provide only supplementary information Hie data permit two conclusions, Firsi, men occupationally exposed to vinyl chloride have experienced j a specific hazard oi angiosarcoma of ihe liver Second, anv other occupational hazards that may have existed have been small No positive evidence of a hazard of anv nonmahgnam disease or any type of j cancer oilier than angiosarcoma of the liver has been found except possihlv for a small hazard of lung , cancer when exposure was heavy More definite conclusions might be reached if (hose who have studied exposed employees could present their results in approprtaie and comparable ways, A very small risk of * angiosarcoma max have occurred as a resuli of vmvl chloride escaping into the environment around plants * handling vmvl chloride in the past, but the evidence indicates that the current risk to the general public (if anv) iTuisi be negligible hev term';' angiosarcoma of the liver, cancer, lung cancer, mortality, polyvmvl chloride, review, vinyl chloride monomer ) 608 6^4 (redactory nt number jo.00 air mail address above. maged issues unless j j f ( | ight Clearance Center ie internal or personal enter's Transactional page, is paid directly taiions that have been The fee code for users I or many .cars ihc inhalation of lame amounts of s*nvl chloride has been recognized as potentially haz ardous. Cuncemraiions of the order ol 10 CXX) ppm in the air induce unconsciousness and cardiac arrhyth mia. while prolonged exposure to concentrations an order ol magnitude lower luxe been liable to cause a specific pathological syndrome This "vmvl chloride illness" has been characterized by lour cardinal signs, n.imclv, enlargement of the liver and spleen with a speedic histological appearance, patchy infiltration of die stin tesemblmg scleroderma, bony changes in the ups of ihe fingers described as acroosteolysts, and peripheral circulatory changes identical with the clas sical picture ol Ravnaud's disease. These pathologi cal reactions may occur singly or together and may pos sibly be accompanied by oilier less characteristic ef fects. They can, however, be completely avoided if ex posure never exceeds the level of a few hundred parts per million, ie, the level to which exposures were generally reduced in the mid-1960s. One other serious el ieel has. however, been observed llial tiuv not be avoidable in die same relatively easy way, natnelv, the production ol angiosarcoma of the liver, ll must, indeed, be presumed that some risk of developing the disease will persist Iroin exposure (0 | Imperial Canecr Resear.h fluid. C,iiu.er Epulcmioloev and t ),mvoI I rials Unit, Kadvlille Itihrmary, Oxford. United kingdom. Kiprml rei|iievls 10 Sir K Dull Imperial Cancer Research I mid. Umvcicuv tn Oxleid, tiihson Building. The RadClilTe Inimnars, Oxiord 0X2 SHE Limed Kingdom. doses that are even lower than the current industrial levels of 5 pptn or less, as vinyl chloride has been shown to act as a mutagen (23). and i( cannot be assumed that a threshold exists below which no carcinogenic risk persists. Moreover, the possibility has to be considered that vinyl chloride may cause some cancers other than angiosarcoma of the liver, partly because laboratory studies have shown that it causes other cancers in animal experiments and partly because the initial studies demonstrating the production of angiosarcoma of the liver in humans were inadequate in size to ex clude a material increase in the risk of cancer m com mon sites, such as the lung and large bowel. Since no threshold dose can be postulated, it also follows that some cancers may have been produced in the general public by the small amounts that have escaped into the general environment. Consideration also needs to be given to the possi bility that exposure to vinyl chloride over a long pe riod may have noxious effects on humans that cannot be seen easily in animal experiments (by, for example, producing chronic respiratory disease), and, as it is a mutagen, there is also a possibility that it may act as a teratogen and cause congenital malformations in offspring. In this review I have not examined the possibility that vinyl chloride acts as a teratogen or that it causes mutations in germ cells, as there is 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 and by MacMahon (unpublished repon (o (he Chemi cal Manufacturers Association in 1477) concluded ihai (he leu repons of posmve effects could not be sub stantiated, and no additional evidence was lound in a similar later review by Barr (unpublished report to Air Products and Chemicals Inc in 1981), apart from a report that embryos were absorbed and skeletal os sification was produced when pregnant rais were ex posed to doses appreciably lower than those that had been used by other workers without any such el fects being observed The report of absorbed embryos (34) could not be evaluated thoroughly, however, as the ex periment was inadequately described. I have, therefore, examined only (he possible el Teas on the personal health of men occupationally exposed to vinyl chlo ride, other than those related to their reproductive capacity, and the carcinogenic el feels that might con ceivably be observed in rhe general population as a result of the widespread disiribuiion of vinyl chloride as a pollutant Occupational hazards Many studies of workers exposed to vinyl chloride in the manulacture of vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) have been undertaken since it was first found that vinyl chloride could cause cancer in animals (28, 48) and man (10). These inves tigations have confirmed that exposure causes a haz ard ol angiosarcoma of the liver and, in several in stances, have shown excess incidence or mortality rates that were conventionally statistically significant lor other diseases. Conventional lests of statistical signifi cance are, however, designed io help answer single questions defined beforehand, and several findings that might be expected to occur by chance alone once in (say) 20 times must be expected to occur if dozens of rates arc examined in each of several seis of indepen dent data. Scientists have, therefore, been faced with the problem of deciding whether the excess rates that have been observed in individual studies are due to oc cupational hazards or to the vagaries of chance. This problem can be solved in part wnh an exami nation of lhe results of a sumation of data from com parable studies, that is, by a comparison of the sums of [he numbers of deaths observed and expected in each study. This procedure does not require (tie assumpnon lhat the exposures have been the same in each study any more lhan the same assumption is required for each individual when the results of each study are considered alone li does require however lhat each exposed population has been observed over a period when its members were at risk of developing disease 111 a genuine hazard existed) and lhat in each study the ride rente population irom which [lie cxpecled num bers ol Jeaihs were ele'ilve-d was appropriate (lhat is, at ihc same risk ol deweloping disease as the- e-xposed popul.iii,hi would have been in the absence ol expo sure). These requirements do not introduce any new eomplexuv, as both are, ol course, also required n cor rect conclusions are (u be drawn trorn (he results of the individual studies when they are examined on their ow n Sources of tnfortnuuon Four studies meet the aforementioned requirements, namely, iwo large national surveys, one reporied by Jones (25) for the United Kingdom (UK) and the other by Environmental Health Associates (14) lor the United Slates (US), and studies ol individual plants in Canada, reported by Theriault 4 Allard (46) and in Italy, reported (as a part of a national sludy) by Ueilt et al (4). All four include observauons on men more Ilian 25 years aller their Inst exposure, and the ex pected number ol deallis is, in each case, greater lhan 10 t7o of (he total number ol employees, a value indi cating a long average period ai risk. Earlier observa tions on UK and US employees (6, 9, 12, 16, 20, 36, 39. 40, 45, 50) have been subsumed m the national sur veys and now serve only as sources ol hypotheses and of some detailed information not included in the na tional reports. Studies of German (49), Norwegian (22), Swedish (7), French (41, and unpublished report ol Laplanche el al), Japanese (33. 37). and some other Italian (4) workers provide some supplementary infor mation, but, in general, the periods ol observation have not been long enough lor usclul epidemiologic data to be obtained about diseases dial are unlikely lo occur within 20 years of firsl exposure, oi iliey report only selected results which are difficult to in terpret, as only excess rates tend to have been selected. Studies of makers of PVC products have not been included, as the workers have had much less expusuic lo vinyl chloride lhan thove employed in the muiiulacture ot VCM or PVC anti any occupanonal hazard 10 which they may have been exposed is more likely to have been produced by PVC dust. US studv. The study carried out by Environmental Health Associates (14) on behalf ol (he US Chemical Manufacturers Association is die largest and mosl intormaiive invesiiganon ihus far underiaken. Ii cov ered 10 173 men who had worked in 37 planis owned by 17 companies -- I 2)4 men in II plant* tha* produced only VCM. 6 848 men in 18 planis that produced only PVC, 935 men in three planis ihai produced both, and 1 176 men in five plants Ihai produced liomopolymers and copolymers, wuh or wuhoui VCM or PVC. Twenty-two of die planis were in the sou ihern pan of die country, 14 were in die northeastern or north cenlral parts, and one was in die west Men were included if they had been exposed to vinyl chloride tor ai least a year bclorc 31 December 1972 and had been employed ill 1942 or subsequently (the I irst year depending uii i lie dale i lie plant I'cu.m mak me or using vi sonnel reec wa> die Ian identiiied sonnel. Racial ch 97 fo ol wi the purpos deaths, (ha Follow-n cial Security died alter Iplanis did in (9) earlier s present mve plants who 1972 were r follow-up w 1982, vvhiclu of ihc men w uniraced wer w hich was us Almost hal before 1955. served more t many cases fo a long latency Short-term cohort, and n ploymem lor lor 10 years oi ploymem beim Fifteen hund have died in I tamed from ihe tamed for ihc i The numbercauses or grou plying the persi national raies i age groups and This importa cisms, which ai el fects on the re compiled by co cords without at sumption ihai a caused lhe expei underesnmaied, 10 have had hig reason lor suppo the proporlion 0 necessarily repretaimy was imrod as 7 3 o'o ot die Tw o ot her cno cM>. - ted numbs r -11111ptu-11 dial 11 SL 089553 -***' MkAitif reduce any neVi o required if cor,m the results of xamtncd on their ed requirements, one reported by JK) and the other ites <M) for the individual plants l Allard (46) and mal study) by Belli ons on men more isure, and the en case, greater than iyees. a value indir. Earlier observa.9, 12. 16, 20. 36, in the national suror hypotheses and included in the nan (49), Norwegian unpublished repon 37), and some other ipplememary mforods of observation seful epidemiologic es that are unliKelv t exposure, or thev i are difficult to ina have been selected ducts have not been ) much less exposure nyed in the tnanufaccupational hazard to sed is more likely to J5l. ut by Environmental f of the US Chemical ie largest and most inr undertaken It cov ed in 37 plants owned ,en m U plants that nen in 18 plants that i in three plants that en m five plants that copolymers, with or :re in the southern pari . northeastern or north the west. id been exposed to vinyl fore 31 December 1972 41 or subsequently (the : rhe plant began making or using vinyl chloride and the earliest date that per sonnel records were deemed to be complete, whichever was Ihe later). Individuals who met these criteria were identified from company records by company per sonnel. Racial characteristics were known only for 686 men, 97 Vt 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 Irom plant and So cial Securuy Administration records and (for men who died after 1979) from the National Deailt Index. Five plants did not collaborate in ilie extension of Cooper's (9) earlier study, which had been subsumed in the present investigation, and the 955 employees in these plants who were known to be alive on 31 December 1972 were not followed any further. For the rest, follow-up was attempted to death or 31 December 1982. whichever was the earlier On this basis 92.7 of the men were successfully traced. Those who were umraccd were excluded from the last date of contact, which was usually the dale when employment ceased. Almost half of ilie men (46 ,ro) were lirst employed before 1955. A large proportion was, therefore, ob served more than 25 years afier first exposure (and in many cases for more than 30 years) when diseases wnh a long latency period might be expected to be seen. Short-term workers had been excluded from the cohort, and most ol (he men had continued in em ployment for manv years, two-thirds being employed for 10 years or more and the average duration of em ployment being 16 years. Fifteen hundred and thirlv-six men w-ere found to have died. In I 439 cases, the cause of death was oblained from the death certificate, but no cause was ob tained for die oilier 97 persons (6,3 "), The numbers of deaths expected from each of 38 causes or groups ol causes were obtained by multi plying ihe person-years at risk by the disease-specific nanonal rales for white males, for the corresponding ige groups and tive-vear periods of the study. This imporiam study is open to three minor criti cisms. which are unlikely to have had any material effects on the results. First, ihe lists of employees were compiled by company personnel from company records wnhout any independent check. Second, ihe asgumption that all ihe employees were while will have sik/x. caused the expected deaths to have been very slightly .-^^'SUVJereslimatcd, as the few black employees are likely Tvpf* IO have had higher mortality rates and [here is no N-` reason for supposing dial ihe small sample from which * the proportion of black employees was estimated was necessarily representative I turd, an element of uncer tainly was introduced by the lailure lo trace as many j,v7 as 7.3 of the eniplovecs If,' Two other criticisms are more important. First, lfie t expected numbers of Jcar-s weie calculated on ihe as| sumption that the men w mid have experienced the j! same mortality rates a- ' o .umc male population of !S the whole country at the corresponding dates The use of national rates is common practice in studies ol in dustrial populations and lends to result m an overestimation ol the expected numbers of deaths so that the employees appear to be unusually healthy. This "healthy worker effect" is well known and has been taken into account in my discussion of the results. A more serious objection to the use of national rates is the wav 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 thetr geographic distribution would be sufficiently wide to make the use of national rates appropriate. Unfortunately 22 of the plants were located in the south, and a check would have been desirable to see whether their location could have caused any material distortion of the results. Second, causes were not obtained for 97 of the I 536 deaths This deficiency was allowed for in the calcu lation of the overall mortality by the inclusion of deaths due to unknown causes. It was not allowed for, how ever, in the calculation of the disease-specific mortality rates and will have caused the standardized mortality ratios to be underestimated by an average of 6.3 V*. For ihe present purpose, therefore, the numbers of deaths attributed to specific diseases have each been multiplied by 1.0674 (100/(1 --97/1536)] and rounded off to the nearest integer. UK study. The study reported by Jones (25 and un published) on behalf of the British Health and Safety Executive covered 5 498 men who were employed for at least one year in jobs that involved potential expo sure to VCM for at least 25 'Is 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 'Is). Seven hundred and eighty deaths were identified, and copies of the death certificates (coded to the eighih 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 ihe estimation of the numbers of deaths that might have been expected in the cohort by multiplying them by the corresponding numbers of person-years under observation. Some difficulty which could have been related to the causes of death being 63 coded according to the eighth and ninth revisions of the ICD was, however, experienced in obtaining suit able rates for all causes of deaih, and rates lor a rela tively late period had to be used for estimating the numbers of deaths from many diseases that might have been expected to occur in earlier periods. For two categories the earliest available rates were 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 RVC dust, and each man's em ployment history was recorded according to 12 job titles with advice from the plants concerned. The men were then grouped according to whether exposure to VCM was likely to have been high (group A), expo sure to PVC dust was likely lo have been high with exposure 10 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 rales to calculate the ex pected numbers of deaths may be justified on the grounds that the men were employed in nine plants, which were presumably distributed about the country, but no details of their location are given. In general, mortality rates tend lo be higher in the parts of Britain where heavy industry is located than in other parts of the country so that the expected numbers of deaths are more likely to be biased downwards than upwards! but whether this is so or not needs to be shown. The use of recent rates to calculate expected num bers of deaths from many specific causes of death was presumably necessary if the diseases were to be studied individually and will have done no harm if the inci dence and fatality of 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 (hat is commonly used if precise measures of exposure arc not available. It creates some difficulties in ihc statistical analysis if men move from one job to anoiher and are classed (as in this instance) as having had high exposure if they have ever- had a particular type of employment (eg, ever been employed as an autoclave worker). No evidence is pro vided to show that the person-years at risk before a man entered the category have been subtracted and added to another exposure group before the numbers of expected deaths were calculated Movement trom one job to another was said to have tended to be out ot groups A and II into D, but even so it must be presumed that the expected numbers of deaths in the first two exposure categories are likely to have been overestimated. Canadian study. The Canadian studv (46) was limned lo employees of a single plan! in Shawtnigan, Quebec. The plant, which was situated in an industrial com plex, was opened in 194j. VCM and PVC were both made until the late 1960s, when the production of VCM ceased, while the production ol PVC continued. An attempt was made to trace all the production work ers whose names appeared on the unions' lists or the payrolls of Ihc companies in the whole industrial com plex, including the vinyl chloride plant, between I January 1948 and J I December 1972, and contact was made with the worker or his next-of-kin in I 611 out of I 659 instances (97.1 5'o). Detailed occupational and smoking histories were obtained by questionnaire, and 156 men who had been employed by the companies for less than five years were excluded. The remaining men were categorized as (i) exposed to VCM if they had worked on the production of VCM or PVC for at least live years (451 men), (ii) unexposed to VCM if they had worked similarly lor less than six months (870 men), and (in) other men (134 in total). The last group was excluded from the study. Follow-up was closed on 31 December 1977. Copies of the death cer tificates were obtained, and the causes for all who had died (59 exposed and 233 unexposed) were coded ac cording to the eighth revision of the ICD, Informa tion was also sought for histological or cytological con firmation of all ihe diagnoses lor all the exposed men who had died of cancer. The results were examined in (wo ways. First, the muriaiuies of the exposed and unexposed men were compared after standardization for five-year periods of the study and five-year age groups. Second, the mor tality of the exposed men was compared with that ex pected if the men had had the sex- and age-specific mortality rates recorded m Quebec for the year 1971. In both comparisons the causes of death used were those specified on the death certificate, and the addi tional pathological information was used later only for interpretation of the results. Most of the exposed men were exposed for more than 10 years (75 /o), the average length of exposure was approximately 17 years, and 44 "to were observed more lhan 25 years after first exposure. Although small, the study makes a useful contribu tion lo the overall results. The histological review of the cancer cases is particularly helpful. Ii showed (hat all eight cancers diagnosed as liver cancer (including two specified as hepatoma and one specified as angio sarcoma) were angiosarcomas of ihe liver, as well as one that had been diagnosed as angiosarcoma ol the peritoneum. Two oiher cases of angiosarcoma Ol the liver were found lo have been certilied as hepatic cir rhosis. ![ is also tie I pin! lo li.ivc a compai isom between the exposci companies for all non a healihv w recording o i nant causes i 0.95). One aspei ie. the use t calculate e\ period (1948 to bunch up valion so ih have been la some distort! size (and eve estimate. Foi likely to has Italian studv i. duenon of vm was begun in employed for start up of (hi still incomplet in three plant i signana) begai thirty-seven m in the other. Al followed to the i mated by multu corresponding i year age group a The total expect more than 10 (12.4 and 12.8 Clinical mloi death of all the had died. Revis comparison wu deaths from e-a The Ravenna 1959. Six hundre All but Tour wc were found to hi lowed for more (3.9 "? of the wc this plant have r ! cipal analyses I 4 death was atiribi i petted. 7 Othrr snurcet. Th 'VIV alions on 4C 1 i" Mono. C SL 089555 ot deaths Hi the ,|v to hast beet' ; (46) was limited Atmgan. Quebec, i industrial coini pvc were both le production of f PVC continued, production work' mons' lists or the he industrial com plain. between I l. and contact was ,f-kin in I 611 out i occupational and questionnaire, and by the companies ed The remaining rd to VCM if ihey VCM or PVC for mexposed to VCM ss than six months 4 in total). The last dy. Follow-up was les of the death cer uses for all who had sed) were coded acthe ICD. Informajl or cvtologtcal conall the exposed men two ways. First, the mexposed men were for five-vear periods ips Second, the mormpared with that ex,ex- and age-specific -ec for the year 1971. . of death used were ificate. and the addivas used later only lor jre imposed for more length of exposure J 44 rt were observed exposure. ikes a useful contrtbuhistological review of helpful U showed that liver cancer (including one specified as angioof the liver, as well as is angiosarcoma of the 0r angiosarcoma of the certified as hepatic cire a comparison between the exposed and "unexposed" emplovees ol the same , companies as it shows that the low mortality observed for all nonmalienam diseases could be attributed to a healthy worker elfecl and was not due to bias m ihe recording of exposure (relative risk for all nonmahg- nani causes compared to that of the "unexposed" men :44-V ' 0.95). One aspect of the studv has to be criticized however, le, the use of provmcial rates tor one year 11971) to calculate expected mortality spread over a 30-year w period (1948 to 1977 inclusive). Deaths will have tended lo bunch up towards the end of the period of obser vation so that the rates for this particular year may have been fairly representative, but it must have caused tome distortion of the expected numbers of deaths, the ff-v'v'. uze (and even the direction) of which is impossible to ferjJ'a'V estimate. For most disease groups the distortion is un likely to have been large. Italian studv. A studv of all men employed in the pro duction of vinyl chloride and PVC in nine Italian plants wax begun in 1983 All men were included who were employed for at least six months at any time from the uart up of the plant to the end of 1981. The study is still incomplete, but results are now available for men in three plants (4), Two plants (in Ferrara and Rongnana) began operation in 1953. Four hundred and thirty-seven men were employed in one plant and 181 In the other. All hut three (from (he Ferrara plant) were followed to the end of I9H4 Expected deaths were esti mated by multiplying the person-years at risk by the corresponding national mortality rates for each fiveyear age group and each five-year period of (he study. The total expected deaths in each case amounted to more than 10 % of (he employees in the two plants (12.4 and 12.8 %\. Clinical information was sought about the cause of death of all the 55 employees of the Ferrara plant who had died. Revised diagnoses, which were not used for comparison with the expected deaths, revealed four deaths from cancers of the liver in place of one. The Ravenna plant did not begin operation until 959. Six hundred anrj thir'y-eighi men were employed, but four were traced to the end of 1983, and 17 ' i found to have died. No man could have been fol- for more than 24 years, and only 25.1 deaths 8^ of Ihe work force) were expected. The data for t plant have not, therefore, been used m the prin_,S'l"dpal analyses, It may be noted, however, that one death was attributed to liver cancer when 0,1 was expeeled. Oikersource;. The Norwegian studv (22) provided ob turations on 454 men who had been employed in a piam m Telemark where VCM had been manufactured from 1950 lo 1971 and PVC from 1950 to the end of the study period E\erv 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 lor 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 (hat the number of not zero) was small, as all citizens have an identity number which is used by both employers and central agencies. Fifty men were found to have died against 59 34 expected if the sex-, age-, and quinquenmumspecific national mortality rates had operated. Twentyone men were found to have developed 23 cancers against 20.16 cancers expected from the comparable national incidence rates, the use of which was justi fied by the finding that the incidence in the county in which the plant was situated was between 90 and 95 "I* of the rate of ihe country as a whole. One man who had been employed in PVC production developed an giosarcoma of Ihe 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 Ihe 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 II plants in which VC and PVC had been produced in the Federal Republic of Germany, (ti) 4 820 men who had been employed in seven chemical plants without having had any exposure to vinyl chloride, and (iit) 4 007 men employed in two other plants where PVC was processed. Employees were included only 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 Vi, respectively, of the three groups were first em ployed before 1954 and were therefore capable of con tributing person-years at risk more than 20 years after first employment, when an occupational hazard of can cer could be expected to be observed. 65 Of the exposed group 93.2 mti were successfully fol lowed, and causes of death were discovered lor 92.8 wo of the 414 men discovered to have died. The propor tions for the other two groups were respectively 89,8 and 88 7 for the unexposed and 92.1 and 86.9 for the pvc process workers. The failure to obtain causes of death for all the men who had died was allowed for in the subsequent analysis by the weighting of the numbers attributed to each cause by a sys tem which took account of the age group and calen dar period in which death with an unknown cause oc curred. The expected numbers of deaths from each cause was calculated by multiplying the person-years at risk by the sex-, age-, and cause-specific mortality rates for the Federal Republic of Germany. National data before 1968 used an idiosyncratic classification system, and the 1968 rates had to be used to multiply all the person-years at risk up to the end of 1968. For subsequent years (1969 to 1974) the person-years at risk were multiplied by the corresponding rates for the same calendar year. Epidemiologic studies arc more difficult to carry out in the Federal Republic of Germany than in North America, the United Kingdom, or Scandinavia because the medical cause of death is not recorded publicly, and there is no central system which can be used for checking whether an individual is alive or dead. In these circumstances, the German authors have made valiant efforts to obtain reliable data, and the propor tions of men in the exposed groups who were not suc cessfully followed (6,8 t/u) and ihe proportions of deaths for which ihe cause was not obtained (7.2 Vo) were similar 10 those m the study of the Environmental Health Associates (14). Two defects, however, make the data less useful. First, no national mortality rates were available before 1968, and the use of the 1968 rates to estimate the num bers of deaths in and before 1968 will have overesti mated the numbers attributable to diseases that were becoming more prevalent or were being diagnosed more often and underestimated those due to diseases that were becoming less prevalent. Second, and more' importantly, a large proportion of the men had been first employed less than 10 years before the follow-up ended. Therefore the useful observations on the few men who had been exposed long enough to have had much chance of developing an occupational disease with a long latency period must have been swamped by a mass of other observations 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 10 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 ihe unexposed chemical workers (4 observed against l.l expected) and the PVC process workers It deaths against l) 8 expected). Two Swedish plants have produced VCM and PVC, one since 1945 and the other since 1971, and employees of the first plant have been studied by Byren et al (7). All persons who had ever been employed when expo sure to VCM could occur were listed Irom the per sonnel files of the factory. Twenty-one were excluded because (hey were foreigners who left the country after a short period of employment. The remaining 750 were followed to October 1974. Expected numbers of deaths were estimated by multiplying the person-years at risk by the corresponding age-specific mortality rates for the whole country, and the expected numbers of can cer cases from 1958 to 1971 inclusive (during which period all cancer cases had been registered nationally) were estimated by multiplying by the national agespecific cancer incidence rates. In both instances, the rates used were those recorded m 1969. Fifty-eight deaths were found, but no figure was given for the ex pected number. Detailed figures were given only for the numbers of deaths and cases observed and expected for cancer of the lung and for cancers of the liver and pancreas combined and for the numbers of deaths from brain cancer and three categories of cardiovas cular disease. Two men known to have angiosarcoma of the liver were certified as having died ol liver can cer or pancreatic cancer, and a third man died of angiosarcoma of the liver 17 months after the close ol the follow-up. Two French studies provide the results of a long term follow-up of men employed in one plant (41) and of a short-term follow-up of men employed tn 12 plants (Laplanche et al, unpublished). The first provided ob servations on I 311 men exposed to vinyl chloride in the production of VCM and PVC and in selected an cillary operations from the opening of (he Tavaux plant in 1953 to ihe end of 1976 (41). Six other employees were excluded from the study because of lack of oc cupational histones 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 Vt 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 ihey add nothing of epidemiologic value to the results of the other studies, apart from the addition of a further case of angiosarcoma. The second study provided observations on I 100 men aged 40 to 55 years who, in 1980, were exposed or had been exposed lo vinyl chloride in 12 plants, which consutuicd "most of the French VCM polym erisation plants" (Laplanche cl al, unpublished). Many ot the men were, or had been, employed at Tavaux and were presumably survivors ot the cohort studied by Pierre el al (41). The men were tollowed lor live years, and their morbidity ,uul moruliiv were com pared with those observed lm I too men ol ihe i.mic but who hai in both grot formation v drinking hah two groups, first exposed first been em ously. Morbi nually by the 98 of the . One of the ex developed an liven separat ployment, an! of the t'indini lung cancer a well reflect a i in the releren cancers in tha One exposed i hematopoietic none ot the m developed me: rotd. A Japanese perience ot 4 5 before 1965 in ducing VCM i ive (37). The r Twenty-etght p than 20 years al served more thai untraced, and ci tained lor all thi initial cohort), to the job in wl II ihe terminati given separately in PVC produc classed as VCM If this study provide t / present data inch lhn 20 years aft Mv* "** They confii c*nccr with six workers against while only one < Other workers ai deaths from livei workers was cert liver, and at least was due to the s. not in excess (2 o expe. ted). No d.t hli.ilic .mil hem,i SL 089557 -- VCM and I'VC I, and employee? i Byren ei al (7), oyed when expoed from the perne were excluded . the couniry after rmaining 750 wete lumbers of deaths trson-years at risk nortality rales for J numbers of canive (during which istered national!?) ihe nanonal ageroih instances, rhe - 1969 fifty-eight as given for [he exere given only for erved and expected ers of the liver and lumbers of deaths ones of cardiovashave angiosarcoma ,g died of liver canthird man died of nths afrer the close e results of a longn one plant (a I) and rnployed in 12 plants he firsi provided obto vinyl chloride in 7 and in selected ang of the Tavaux plant Six other emploiees cause of lack ot ocn because their s Hal id was undetermined ave died against 48 75 sex- and age-xpeulic the men at risk) One rcorria of ihe fixer m r more ihan 15 sears, iplete and coser such e opening of the plant miologic value to the art from the addition jma. observations on I 100 in I9H0, were exposed chloride in 12 plams, : French VCM polvmaJ, unpublished) Many , employed at Tasaux s of the cohort studied were followed for five d mortality were coin- I 100 men of the same igei ( t 2 years) who were employed in the same plants but wpo had never been exposed to VCM The men la both groups were interviewed personally, and in- jformation was obtained about their smoking and ^drinking habits, which were lound to be similar in the vfwo groups. The men in the exposed group had been rftnt exposed for an average of about 14 sears and had jflru been employed in the plant about 18 sears previ- ^OUlly. Morbidity and mortality data were recorded an- jB-tuaily by the plant physician, who successfully traced g $ ^ of the exposed men and 96 7o of the referents. __.Ooe of the exposed men, but none of lliose unexposed, SSt'developed an angiosarcoma of the liver. Data were not given separately for different periods after first em- r-pioynient, and it is impossible to assess the significance cToflhe finding that six of the exposed men developed lung cancer against two of the referents, which may Mil reflect a chance occurrence of unusually few cases Kj'SJ' b the reference group, as the proportion of all lung 'Trmlf' cancers m that group (2 out of 15) was unusually low. o&e exposed man developed a cancer of Ihe lympho- , hematopoietic system against none of the referenls, but , Moe of llie men in either group were known to have developed melanomas or cancer of the brain or tliy- ntl. A Japanese study has reported the mortality ex- 1 prttence of 4 524 men emploved for at least one year before 1965 in 25 Japanese plants which began pro ducing VCM or PVC between 1949 and 1964-inclu- save (J7), The men were followed to 3 I October 1975. to. r Twenty-eight percent of the men were observed more (K*; . rian 20 years alter first employment, but none was ob- ttrvtci more titan 26 years Only 0,6 5/o of the men were wraced, uud copies of the death certificates were ob- UmcJ for all the 209 men who had died (4 6 "Jo of the tfiuul cohort). Individuals were classified according to the job in which thev had been longest employed M Ihe termination of their follow-up, and data were given separately for the 2 546 men classed as employed M PVC production and 1 978 Olliers (including 900 gjtisexj as VCM production workers). If this study is continued for another 10 years, it ttauld provide useful additional information, but the - fgoenl data include too lew observations on men more 120 years alter lirst exposure to be ot any material U.-Thcy confirm the evidence of a hazard of liver with six deaths among the PVC production kcri against 2.54 expected from national rates, only one such death was observed among the 1 workers against 1.82 expected. One of the six kht from liver cancer among the PVC production wxxkcri was certified as due to angiosarcoma of the t, and al least one of the other liver cancer deaths l due to the same cause. Lung cancer deaths were iJJj Ml us excess (2 observed m PVC workers against 2.33 ijj." expecled), No data were given for cancers of ihe lym- futfra pAalic and hematopoietic systems, for cancer of the . twain or thyroid, or for melanomas. The mortality f t" r\i McntkuJn (3,1) |\*)r 303 Jnpnn* vinyl chit)- ride workers has presumably been subsumed m Na kamura's (37) later and larger study. Hazards of cancer The results of the four most useful studies are listed individually in tables I and 2. The overall results for all causes, liver cancer, and three broad groups of con ditions are shown in table 3, and those for 10 types, or classes, of cancer are presented in table 4. Data have not been reported for each type of cancer in each study, and the sources of the data are, therefore, specified separately for each type. Additional information ob tained from four other less informative studies (4. 7, 22, 49) is given in table 5 for seven types or classes of cancer. Table 3 shows that, apart from cancer of (he 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 lor diseases other than cancer is typical of the ratios that arc commonly observed for groups of emploved 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 eflect does not. however, nor mally affect the mortality from cancer beyond that ob served in the first few years after the start of employ ment, and an SMR of 102 for cancers other than can cer of the liver is compatible both with the absence of hazard and with SMR values of 84 for other diseases and 77 for accidents, poisonings, and violence. Angiosarcoma. Death certificates are an unreliable source of information about the histology of cancers that cause death, but there is no reason to suppose that the excess mortality attributed to liver cancer (or. in the US series, liver and gallbladder cancer) is not entire ly accounted for by the known hazard of angiosar coma. Fifteen of the 37 deaths1 attributed to cancers of the liver and gallbladder in the US series are known to have been due to angiosarcoma of the liver (14). In the UK series, seven of the 11 deaths attributed to liver cancer, not specified as secondary, were known to be angiosarcomas, and they all occurred in auto clave workers against 0.38 expected liver cancers of all types (P< 10"') (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 Increased 10 39 in lable 1 10 lake account of the 97 extra Uaaiht Irons an unknown came. 67 Table i. Observed and expected numbers of deaths from different cancers reported m me four principal studies 14, u, 25. 46} |0 = observed number of deaths, E = expected number of oearns) Type ot class of cancer United States 0* B United Kingdom 0 Canada 0 Italy 0 E Buccal cavity and pharynx Esophagus Stomach Large intestine Rectum Liver Liver and gallbladder Pancreas Other digestive Larynx Lung Otner respiratory Bone Skin fnonmefanoma Metanoma Prostate Tesi is Bladder Kidney Other and unspecified urinary Brain Eye and central nervous system Thyroid Lympho- and reticutosarcoma Hodgkin's disease Leukemia Multiple myeloma I Olher lymphatic ] Other All cancers 13 11 55 7 8 07 11 16 01 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__9_4 a jr 46 40 50 383 341 73 4 3 58 6 14 34 26 23 91 9 13 94 11 10 49 11 1 94 7 9 88 4 2 21 ai 92 12 0 8 6 }2 0 64 0 14 5 26 5 78 2 1 74 12 9 59 2 1 38 14 a oo 3 3 4 29 4 6 18 2 0 43 4 2 35 3 2 50 7 5 16 2 2 35 18 8 12 235 228 60 | 1 i 1 1 1 | |1 I 2 20 1 67 0 95 16 37 1 oa 1 Q6 3 30 0 12 1 06 6 07 i 0.9 12 6.1 0 02 1 07 i 07 6 04 0 07 9 45 30 21 1 Observed deaths multiplied by t 0674 and rounded off to the nearest integer to allow for deaths without discovered cause *, i. I-. * !* - Table 4. Mort lO * observed Type oi class "ouiti and ghi Oigastlva sysU flaspiraiory sy Lung rt- Gantidunnary s .i Ueiancdia ! 0'im :yioia *' irmpnaflc ana Omar AM omer than o * 1 eUmied Sla Table 2. Numbers of deaths from nonmaiignant and ail causes reported In Ihe lour principal studies (4, 14, 25. 46) (O s observed number oi deaths, E = expected number of deaths) rTaW# f. Modality wnMr ol deatnj Cause of death United Stales Oa e Benign and other unspecified tumors Cerebrovascular disease Ischemic heart disease Other circulatory disease Bronchitis Pneumonia Other respiratory disease Cirrhosis ol me liver Other digestive disease Disease ol the genitourinary system Other diseases Suicide Accidents and other violence All nonmaiignant causes All causes 4 5 08 75 91 93 521 597 73 157 123 55 44 22 83 16 31 94 15 32 64 37 56 06 27 39 52 11 20 4i 67 115 68 49 52 79 130 173 i9 1 153 1 363 54 1 536 1 705 27 * See footnote to table 1, 15 Emphysema in data Irom the United States 6 includes two cases certified as cirrhosis oi me n*< a Includes one case with cause unknown United Kingdom Oe Canada 0E 276 105 36 } to 5 288 141 44 | 6, I 51 1 43 . j 40 545 780 76 50 665 994 25 31 67 1 6 321 1 2" 5 40 2 10 58 39 54 76 59 71 07 proved to be angiosarcoma of the liver, Italy 0e 0 0.5 19 3 5,0 4 52 3 27 2 70 1 09 4 77 36 564 66 775 TP or class o! c Olgetllva jy p^` _ (eicludlng |l triylung r-w . Melanoma Ip Thyroid -X lympbatlc ai 'poMtlc ayata Oibey (Bitiuf AX aicludlr jit*'-.-* "eWanca and c. Cancar oI me m Cancar at the iu jJr1 rt jj' Funher eviden, cancer (or liver ar neutn was found to have been due to angiosarcoma of the hvcr (46), In the lulian study, further cm dunce revealed that three turther ^Icathti 'should have been at tributed to cancer of the liver (for a total of four), but only one of the tour was described as an aneimarcuina U) ' 1 aiinhiued i ` ' T,trJ ol jiK-ros, v. -k.,i SL 089559 Maly 0 E \ 08 1 06 3 30 0 \2 1 06 0 07 1 0,9 12 6 1 0 02 1 07 1 07 0 04 0 07 9 45 30 21 1 toul discovered cause, 14.25. 46) (0 = observed Italy 0 E 0 05 1 19 !3 4 3 i2 1 !4 5 36 7 66 27 4 50 52 27 70 09 77 56.4 77 5 r.ible 3 v..jn .in , I'om /*,inrci' of the iwer and other causes Amot'q vmyi chignon m -in n )M'< m me iQUf urnru'ai studies combined M u 25 46) (O =; observed number ot deaths E = ejected number of deaths. SMR = standardized mortality ratio) Cause of death OE Cancer of the liver * Cancer ol other sites Other diseases Accidents, poisonings, and violence ah causes 59 609 1 547 226 2 44 1 3 45 . 599 35 1 344 89 295 15 2 747 94 * including cancers of the gallbladder In the series from the United States SMR 698 '02 84 77 99 to 4, Mortality from various cancers among vinyl chloride workers In 49 plants in the four principal studies combined. otoMrved number ot deaths. E. = exposed number ol deaths. SMR = standardized mortality ratio) sjj|w v Claes ol cancer OE SMR Source ol information* and pharynx system (other man liven JhJNittwaiOfy system 5550 ill urinary System g*** and hematopoietic system than of the hver IB 16 57 T25 154 59 223 229 36 211 2U Q9 70 62.81 2 1 94 29 19 54 2 0 43 57 50 87 63 63 24 609 599 35 109 1. 2. 3. 4 8f 1, 2, 3. 4 97 1. 2, 3. 4 99 1. 2. 4 !M 1. 2. 3. 4 2, 4 148 i. 2. 3 2 112 1, 2. 3. 4 131 1. 2. 3. 4 102 1. 2. 3. 4 K,* 1 United Slates study (U), 2 = United Kingdom study (25). 3 = Canadian study (46). and 4 = Mahan study (4) . life" Tefeie V Mortality* from various cancers among vinyl chloride workers: Supplementary evidence (4, ?, 22, 49). (O*observed mbm ol deaths. a exoected number of deaths, SMR a standardized mortality ratio) ftp* v class of cancer Federal Republic of Germany (i i plants) OE Norway (1 plant) OE O^i+irr, system - towJMdmg the liver) ,u>* iv nd hemato- 0 IOC System QW deluding the fiver) Ijill vtovdtftQ the liver 35 0 31 0 23 5 24 6 2.1 1 3 165 7 7 107 24,3 87 8 09 7 3 1 44 5 2 34 4 0 79 2 0,16 3 14 93 22 20 16 sm nd cases in the Norwegian study, r ol the Intestine only, r ol (he tung and dram only. Sweden (1 plant) Oe 3 178 2 0 33 5C 2 11* Maly (1 plant) OE 1 12 0 15 0 0.1 0 07 4 20 5 5.7 Tour countries combined (14 plants) O E SMR 39 0 31 5 40 41 2.0 16 S 22.7 1196 34 44 30 72 0 89 1 63 0.16 6,4 41 43 117.67 113 103 196 56 102 for a total of four), but bed as an angiosarcoma pVJVriheT evidence that the excess mortality from liver Ktf (o liver and gallbladder cancer in the US series) lb**2Uibuted principally if noi wholly to the known irWfaad of angiosarcoma is obtained in a comparison 4 Use CTcev deaths with the numbers of deaths from pouroomas recorded in the Register of Liver Angio sarcoma Cases (maintained on behalf of the Associa tion of Plastics Manufacturers in Europe by the Im perial Chemical Industry PLC) before the end of the follow-up period (Bennett, unpublished). Fifiy-one ex cess liver cancers arc recorded in the combined data, and 49 angiosarcoma are recorded in the Register for 69 i Table 6, Mortality from lung cancer in the series from the United States (US) <14> and the United Kingdom iUK) (25) by characteristics relevant to an occupational hazard (0=: ob served number of deaths. E = expected number of deaths, SMR - standardized mortality ratio) Data cnaractenstic* Category i O" E SMR Category 2 0 E SMR Observed 20 years or more after first employment (1), others <2) Employed 10 years or more m the US (1). others in the US (2) Employed before t956 in the UK (1), others m tne UK (2) Ever employed as autoclave worker m the UK (i), others m me UK (2) 114 113.96 100 55 52.45 105 52 51 39 101 16 17 00 94 85 93 63 91 63 63.44 99 29 40 50 72 65 74 82 87 The numDars in parentheses designate the category D See footnote to laoie 1 for observed deaths in the US. the relevant periods for the three countries and the two Italian plants' that are covered by the survey. None of the 120 cases yet recorded in the Register were in men who were first exposed after 1969, and none of the 45 men affected in North America were first exposed after 1964. All may, therefore, have been exposed to concentrations of several hundred parts per million, and many may have been exposed to concen trations appreciably higher (unpublished report by Barr to Air Products and Chemicals Inc in 1981). Lung cancer. The idea that exposure to vinyl chloride m'ght cause cancer of the lung was suggested by Monson et al in 1974 (36), when they noted 13 cases against an expected number of 7.9 in a study of proportional mortality. The combined data shown in table 4 do not provide any support for the hypothesis, either for res piratory cancer as a whole (SMR 97) or for the speci fied data for lung cancer in the US, the UK, and Italy (SMR 99). There arc, however, consistently higher risks in the subgroups of men in the US and UK senes, in which occupational hazards would be more likely io 1 Twemy-ninc were registered as occurring in Ihe United States against an excess of 33, only 20, however, were iden tifiable in both series. Inquiry has, as yet, failed io reveal information about the histology of the remaining 13 in ihe cohort study and the origin of the nine extra deaths in the register. Nine deaths were registered as occurring in ihe United Kingdom against an excess of nine, but one of ihe registered Lases was certified as due to a benign hemangioma and noi related io Ihe liver (code 227 in ihe eighth revision ol ihe International Classification ol Diseases), fen cases were registered as occurring in Canada against an excess of eight; iwo were recorded as being in men who had been employed for live years, and it is possible lhal Ihe actual Juranon had been slightly less lhan live years with con sequent exclusiun Irom Ihe Canadian cohort,()ne case was registered as uvaiimng in one ol the two Italian plants uejmsi ail excess ol less lhan one. be seen than in other groups. This circumstance is illustrated by table 6, which shows that the SMR values are slightly higher for men observed 20 years or more after first exposure than for men observed earlier, for men employed before 1956 in the UK than for men first employed alter 1955 (when exposure levels are believed to have been lower), lor men employed for longer than for shorter periods in the US, and for autoclave workers in the UK (among whom the angio sarcoma cases have mostly occurred) than for other workers. The differences are all small or very small. They are, however, all in the same direction, and the probability that the rates should all be higher m the groups in which an occupational hazard is more like ly to be seen in each of the four pairs of groups is I in 16. Additional information from other sources is given in table 5. A total of 30 deaths (or cases) was observed, and this figure increases to 31,5 when allowance is made for the number of deaths due to unidentified causes in the German study (SMR becoming 103). In the German study the SMR was higher for the men who had been exposed for 10 years or more lhan for those who had been exposed for shorter periods (III against 79). and, in the Norwegian study, four of the five cases observed occurred in men whose occupations were regarded as involving high exposure against 1.82 of the 2.84 expected. Both the German and the Swed ish studies derived the expected numbers of deaths from national mortality rales lor a single year towards the end of the study period. The expected numbers of deaths are likely, therefore, to have been overestimated and the SMR values correspondingly underestimated as the mortality from lung cancer had been rising ihroughoui the period of observation. Addition given in tat little furthe one of the t occurred in less than a 1 the excess dt German stu chemical wi. deaths after causes againPVC fabrica for deaths fri Cancers of 11 idea that uni phaiic and h< the lymphatn A Gaffey (45) studies, whet from lymphoi giinst 2.54 e the lymphatic ported. These if the laboratc suggesting that tally in anima lion 129), The cause lymphoi out considers uudies that ar support for th E1 lymphatic and 1 g,, |nher(57 deal /y* and very little m 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 test of the hypothesis [he data of Monson et al ought, therefore, to be subtracted from those in the table. Their investigation was not a cohort study, and their expected deaths do not cor respond exactly to those in table 4. If, however, the observed and the expected cases are both subtracted from the totals, twenty-four observed deaths remain against approximately 18.3 expected, a difference which might easily occur by chance (P one-tailed = 0.1).' for cancers of th. fey's definition gt>:. 205--203 and 2t l (35 deaths age Moreover, hard GifTey'i initial r 1.36 expected, , Little addttio faults of the G favdy obtained . (based on 15 obs (llowanee is mac ufcnosvn causes) a onesposed gn Jof PVC fabncati iposed workers exposed lor was most ma , foe five years or r the number ot dt 4 o e peeled, SM ' If ihe study ol Waxweiler et al (50) is rewarded as Ihe origin 0! ihe hypothesis. 26 deaths are Ivli nu 1 sut-xied (P une-lailed - 0 071 / \ i Si *8o9l *5* *6* l* * M.C IS alues more r. for - men Is arc ;d for id for angtoother small, nd the in the e Itkeps is 1 s given ,erved, ince is ntified 03). In ie men tan for ds (I I I r of the motions nst 1.82 e Swed- dealhs towards nbers of qtmated .timatcd n rising hi cause et al ON .ted. The ide some onson et kers and reported therefore orticn ol s the data ubiracicd t was not j not cur,ever. the ubtraeted hs remain difference .e-tailed = j<; ilic 94 expected Addition,il inlurmatitni Irom two oilier sources is given m table 5. I he small excess reported provides little further evidence of an occupational hazard, as ' one of the two deaths observed m the Swedish study occurred in a young man who had been employed for less than a year when the diagnosis was made, while the excess death rate for brain cancer observed m the German study was less than that observed among chemical workers not exposed to vinyl chloride (2 9 deaths after allowance for deaths from unknown causes against 1.6 expected) and among workers in the PVC fabrication industry (5.9 deaths after allowance for deaths from unknown causes against l.l expected). Cancers of lymphatic and hematopoietic tissues. The idea that vinyl chloride might cause cancer of the lym phatic and hematopoietic tissues -- more specifically the lymphatic tissue -- was suggested by Tabershaw & Gal'fey (45) and by Waxweilcr el al (50) in iwo cohort studies, when they lound, respectively, five dealhs from lymphomas til the most heavily exposed workers against 2.54 expected and four dealhs from cancers of the Ivmphatic and hematopoietic tissues against 2.5 ex pected. These small excesses might have been ignored tl the laboratory findings had not been interpreted as suggesting that lymphomas were produced expcrtmetitally in annuals exposed to nnyl chloride bv inhala tion (29) The idea that similar exposure might also cause Ivmphomas in humans. Iherelorc, merits sen* Ous consideration. The data liom the four principal studies that arc summarized in table 4 provide little suppott lor the hypothesis when all cancers ol the lymphatic and hematopuictic tissues are considered to gether (52 deaths against 5(1 87 expected, SMR 112) and very little more ts obtained Irom the separate data for cancers ol the lymphatic system ( rahetshaw & Gaffev's dclmilioii of ICO list numbers, eighth revision, 2(H)--203 and 205 being used) that are shown m table I (35 deaths against 29.40 expected). The position is, moreover. Itardlv altered tl the data in Tabershaw & Gal ley's initial report ate subtracted (29 deaths against 23 36 expected. SMR 124). Lillie additional information is provided by the results of the German study (49). (See table 5.) This study obtained an SMR of 214 for exposed workers (based on 15 observed deaths, increased to 16.5 when allowance is made for the number of dealhs 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 lor more than one year and that this ex cess was most marked lor men w ho lud been exposed for five years or more (10 7 deaths alter allowance for the number ol dealhs from unknown causes against 4.0 expected, SMR 268, I' onc-uilcd <0.01). Melanoma. An excess ol melanoma was reported for Norwegian workets by Mcldaas et al (22), xvlio raised the possibility Mint vmvl chloride might Itase produced the disease. Tour cases were observed when 0 *9 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 counirtes have, so far, reported only two dealhs 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 cancer; the third reported two dealhs 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 trad. Suggestions (hat Vinyl chloride might cause cancers of the digestive tract in general have sometimes been made, but they have not taken adequate account ol the contribution of cancers of the liver to the total number of cancers of the digestive system, particularly when K is borne in mind that some liver cancers arc likely to be misdiagnosed as cancers of other organs. The combined data from the four principal studies shown in table 4 weigh heavily against the idea that any such effect has been produced. Other cancers. One of the remaining types, or classes, of cancer listed in table 4 shows a statistically signifi cant excess, namely, the heterogeneous group of "other cancers" (83 observed deaths against 65.24 ex pected, P two-sided <0,05). This excess is only mar ginally significant and may be a chance observation. The most likely explanation is, however, that a few angiosarcomas of the liver were not recognized and were diagnosed as secondary liver cancer or carci nomatosis, site unknown, the number of deaths in this category therefore being increased. Hazards of nonmalignanl 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, 3 1, 33). Two other possibilities have, however, been raised, namely, the production of nonmalignant respiratory disease, because of the changes m lung function and radiographic appearances that have been 71 SL 089562 Tibi# /. Modality Horn selected nonmalignant causes and all causes in Ihe lour ptmcipal studies combined |0 = observed number of deaths, -expected number ot deaths, SMR = standardized mortamy ratio) Type ol disease Bfoncnnis, emphysema6 0 e SMR Source of information * 80 66 83 120 1. 2 Other respiratory disease 71 125 78 56 1, 2 All respiratory disease Ischemic heart disease Other circulatory disease4 All circulatory disease4 Cirrhosis of the liver Other disease too 797 252 t 103 46 238 200 82 685.73 264 55 1 209 35 66 26 368,07 All nonmalignant disease Ait external causes 1 547 1 844 50 226 295 15 All nonmalignant causes All causes 1 773 2 139 65 2 441 2 747 05 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 84 1. 2. 3, 4 77 l, 2, 3. 4 as 1. 2, 3, 4 89 1. 2. 3, 4 1 1 = United States study (14), 2 = United Kingdom study (25), 3 = Canadian study (46), and 4 = Italian study (4). B Bronchitis in Ihe United Kingdom study, emphysema In the United States study c Includes cerebrovascular disease In the United Kingdom and Italian studies Table S Modality Irom chronic obstructive lung disease* In the series Irom the United Stales IUS) (14) and the United King dom IUK) (20) by characteristics relevant to an occupational hazard 10 = observed number of deaths, = expected number of deaths. SMR = standardized mortality ratio) characteristic & Category t 0 E SMR Category 2 0 E SMR Observed 20 years or more after first employment In the US (1), others in the US (2) 30 15,6 190 Employed 10 years or more In the US (1). others in the US (2) 16 10.9 147 Employed before 1956 In the UK (1), others m the UK (2) 26 30 17 86 Ever employed as an autoclave worker in the UK (1), others in me UK (2'c 3 6 55 48 11 7,0 157 25 120 208 10 13 60 74 33 37.22 89 * Described as emphysema in the US study and as bronchitis in me united Kingdom study, 13 The numbers m parentheses designate the category c Men evei employed as a bagger or oner, occupations which would have caused Ihe greatest occupational exposure to polyvinyl chloride oust, experienced one Oealh from bronChilis uijamsl J 38 expecied recorded for men exposed to PVC dust (2, 26, 27, 44), and acute cardiac death, from analogy with the effect of other halogenated hydrocarbons (25) and the ob servation of an increased mortality from myocardial infarction in the few years following the cessation of exposure in the Swedish PVC processing industry (35). Relevant figures for the numbers of deaths from these and other nonmalignant causes that are obtainable from the four principal studies were given in table 2, and they have been summarized in table 7. Cirrhosis of the liver. Three of the four principal studies gave separate figures for cirrhosis of the liver, none of which showed an increased mortality (table 2); in combination they gave an SMR of 69 based on 46 deaths. The fourth study, which did not give sepa rate data for cirrhosis of the liver, reported four deaths from all diseases of the digestive system combined against 3,85 expected and noted that the four included two that were certified as due to cirrhosis of Ihe liver, but actually due to angiosarcoma (46). In the two sup plementary studies in which data were given for this disease, the SMR was 82 in one, based on 15.1 deaths after allowance for the number with unknown causes (49), and 133 in the other, based On seven deaths (37). Nonmalignant respiratory disease. The data for non malignant respiratory disease are confusing in that the total SMR from the combined data for the four prin cipal studies is 80 and is the son of figure that is com monly found in healthy industrial populations, yet the US study recorded a substantially increased mortality from emphysema (41 deaths and an SMR of ISO be fore any allowance was made for deaths from un known causes). No such excess was found in the UK, where 36 deaths from bronchitis gave an SMR of 82. International comparisons of chronic nonmalignant respiratory disease are complicated by the usage of dif ferent terms to describe what it ts now agreed is best called chronic obstructive lung (or pulmonary) disease, but which in (he past tended to be called emphysema in the US and chronic bronchitis in the United King dom. It must, therefore, be presumed that the two categories of "emphysema" and "bronchitis" used re spectively in the two large national studies were meant to describe the same thing. One must assume, there fore, that the experiences in the two countries were very different, despite the fact that both related to cohort) that had very similar experiences of angiosarcoma of the liver and so, presumably, fairly similar exposures to vinyl chloride. Separate figures are shown in table 8, where avail able, for the mortality observed among men with dif ferent durations and intensities of exposure. Unlike the data for cancer of the lung that were shown in table 6, they provide no consistent evidence ot a greater risk in the groups in wluJi an oustipiiiHnt.il lutz,ltd would be expect vtronmer to give a from em hardly be no overal however, by deficie respirator - other re$r the quest could he Health As that they m the out the coding '"other rest ' included e mphysem beclassifie to 502, and of the emp In some can number 527 for both the grossly del i tnpuatory it-. No excess and asthma' M with 6.3 number of , Cmfhvascu ' identic) hra rtode the vas , *0 acute care l-Vt national t I increased; 9 of disc t mcordec fnflheSMR v I there is n, Ithetubsidia . In pa morti nent in t .SMR e ) workers k slight inci r was recordi i study (49 n- .* TV deaths at11 and i he i<vTion fn j1 Mualih J.Xl'Ulll It.) I ' f Ih SL 089563 lust (2. 26, 27, 44). og> with the effect ,s (25) and the obv from myocardial ng the cessation of ssing industry (35), f deaths from these hai are obtainable :rc given in table 2, in table 7, the four principal irrhosts of the liver, sed mortality (table (MR of 69 based on ;h did not give sepa rated four deaths se system combined hat the four included cirrhosis of the liver, i(46). In the two supa were given for this based on 15,1 deaths with unknown causes on seven deaths (37). ise. The data fur none confusing in that the data for the four pnni of figure that is com,al populations, yet the ||y increased mortality nd an SMR of 180 be. for deaths from un, was found in the UK, tis irave an SMR of 82. c hr on ic nunmalignant Jted by the usage of diflt now agreed is best lor pulmonary) disease, o be called emphysema mis m the United Kingpresumed that the two nd "bronchitis" used re^ tonal studies were mcanl >ne must assume, there-, f e two countries were very ,3 u both related to cohorts:j nces of angiosarcoma of Tl , fairly similar exposures n in table 8, where avaiU*j wed among men ,es of exposure Unlike the that were shown in table ' t evidence of a greater risk 3 ccupation ;l*e*peeietj to be concentrated. The authors of the Ental Health Associates report (14) were unable *ht any explanation for the increased mortality emphysema, and they point out that it could be due to excess cigarette smoking, as there was CTOill excess for cancer of the lung. It is striking, , that the excess is more than compensated for 4riksencies in the other categories of nonmalignanl ory disease (pneumonia 15 deaths,5 SMR 47.0; respiratory disease 14 deaths, SMR 42.6), and question arises whether the emphysema excess be l classificatory artifact. Environmental Ih Associates (14) list all the 41 deaths which show Ibey were coded under ICD number 527 which, (fee out-of-date sevemh revision that was used for coding of all deaths in the study, was the code for rnpiralory disease not otherwise classified" and emphysema. Under that revision, however, that was associated with bronchitis should Mctaii fied with bronchitis under ICD numbers 500 wxs. and the possibility may be considered that some emphysema deaths should have been classified iflwmccategory of respiratory disease other than ICD tar 527. If this were the situation, it could account tall) the excess mortality from emphysema and the deficient mortality from other nonmalignanl tuory diseases. ?7 Qexcess mortality from "bronchitis, emphysema, dm" was observed in the German study (SMR w-Mauh 6.3 deaths observed after allowance for the c-Dwtaw of deaths from an unknown cause) (49). iKCf- disease. Data for ischemic (or arterioc) heart disease (which may be presumed to int tta vast majority of all deaths certified as due t cardiac disease) were given only by the two B^qgttaxonal studies, and they provide no evidence of [9BlKreiMxJ mortality. The SMR values of 90 for this > of diseases and of 91 for all cardiovascular dis- xded in the four principal studies arc typical SMR values of healthy industrial populations, Ittax is tso suggestion of any occupational hazard StetaidUry analyses provided by the two national : In particular, there is no evidence of an ini mortality within one month of leaving em- In the UK study either for all workers (52 61) or for the most heavily exposed auto- pWken (9 deaths. SMR 42). pgfiM increase in ischemic heart disease mortal- I recorded for the exposed workers in the Gerlltmtr (89). bui u was less than that recorded for uttnbuied to different groups of respiratory dis* I ih< corresponding SMR values that are cited in i for [he US siud> are as given by the EnvironIttoJih A5 8cxi3ies t i 4) arid have not been adjusted for the number >f Jeaihs from an unknown IflUkr amount 01 ;ne^e death*, the observed deaths ISMH tj lues can ijdih -? miliiphed by 1.0674, the unexposed chemical workers and the I'VC labricators (SMR values of 127, 111, and 158 based on 97,2, 1 26.7, 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: mij Twin aiiwH awawBwmeotafitons miUc the detection of the kulrf ewy; tat the Ion*,latency period befbr* the dWtiiiVipptftf after first exposure (almaH,>i^^ than 15 yean) meant that a farpTatalBlK* of men hatfl been extmaaaHmliMMh4Mltfi|f|imete4 ant that of the pro! .............fie* The massive data that are now available provide no reason for thinking that any hazard other than one of cancer has been overlooked. It is, however, still dif ficult to decide whether vinyl chloride produces a risk of developing cancer other than angiosarcoma of the liver which might be small compared to the risks produced by nonoccupational causes, but yet abso lutely almost as large as the risk of developing the nor mally very rare angiosarcoma. One of the many hazards suggested can be dismissed, as there is no evidence to support it, namely, that of vinyl chloride as a cause of any cancer of the diges tive tract other than angiosarcoma of the liver. Two hazards (of melanoma and cancer of the thyroid) have been suggested only very recently, and few of (he avail able studies have provided information about them. There is no good theoretical reason or laboratory evi dence to suggest that either should be produced by If vinyl chloride, and, in light of* present evidence, the simplest explanation is that the reported excesses are the chance effects that must be expected when many different types of cancer are studied in several different populations. So far as melanoma is concerned, it has to be remembered that the disease has become much more common in recent years in Scandinavia (where the excess was reported) due, it is believed, to the popularity of sunbathing and the increased oppor tunities for Scandinavians to travel to the warmer parts of Southern Europe and North Africa, The extent to which this change may have affected the observation in Norway needs to be examined. Two other hazards (of lymphoma and brain cancer) were suggested by the early results of some of the US studies. That vinyl chlonde might produce a hazard of lymphoma was initially supported by (he prelimi nary results of animal studies, but the complete results of the many investigations that have been undertaken (see reference 29) do not suggest that lymphoma or any other cancer of the hematopoietic system is liable to be produced. There is, however, some evidence that brain tumors can be produced in rats (29), The hypoth eses that lymphomas and brain cancers might be produced by vinyl chloride have been supported by the observation that both these types of cancer have caused death more often than might be expected from national mortality rates, but the excesses observed in the com bined data from the four principal studies in this re view are small and not statistically significant, and the hypotheses remain unproved. The small excess of brain cancer is particularly difficult to evaluate, as mortal ity rates from this disease have changed rapidly over time as methods of diagnosis have improved and the suspicion of an occupational hazard (which was raised in 1975) could have influenced the findings. What ex cess has occurred has been limited to the US and Ger many, and the German Endings carry little weight, as (he excess was found in each of the three occupational groups studied, irrespective of the chemicals to which they were exposed. The supplementary data from (he German study showing an increased mortality from lymphatic and hematopoietic cancers arc more impres sive, particularly as the excess was the most marked for men who had been employed for at least five years. In these circumstances, judgment must still be sus pended until the data for each study are analyzed for each specific type of cancer, by intensity and duration of exposure, and by time since exposure began. There remains the suggestion that vinyl chloride might cause lung cancer. At first sight, this possibil ity is ruled out bythe SMR of 97 for the combined data for respiratory cancer for the four principal studies. Lung cancer is, however, normally so com mon (accounting lor about 8 of the expected deaths) that an increase m mortality that was half as impor tant (numerically) as the increase in mortality from angiosarcoma of the liver might easily be overlooked (V5 'o confidence I onus of the SMR 85--112). The in cidence of the disease vanes moreover within a coun try, and (here musi be doubts as to whether the na tional experience provides a suitable relerence for men employed in plants that are not evenly distributed about the country. In these circumstances one cannot exclude an occupational hazard unless it can be shown that the mortality of the exposed men is independent of the factors that might be expected to influence it if some of it were occupational in origin, namely, the intensity and duration of exposure and the time since exposure began. It is not possible to examine these relationships m detail, as the reports do not provide all the necessary information. Such information as they do provide, which was summarized in table 6, supports the idea that exposure to vinyl chloride involves a small hazard of lung cancer. Taken in conjunction with the knowledge that lung tumors have been produced in sev eral species of animals exposed to vinyl chloride by in halation (29), it would seem that a small hazard of lung cancer probably did occur. The evidence is not, how ever, strong enough to conclude that it definitely did. If it did, the hazard was evident only for men who had been employed for many years at a time when expo sures of several hundred parts per million or more were common, and any persisting risk can be only minute and incapable of detection. The questions that have been left unanswered by this discussion might well be answered definitely if (i) all the exposed men could be followed to (say) the end of 1984, (ii) the investigators could present (heir 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 anti worked. Hazards to the general population As vinyl chloride has been proved to cause cancer in : man and is a mutagen in laboratory experiments, it i must be presumed that even the minute doses that; escaped into the general environment from production i plants or (in the early days of manufacture) from PVC materials will have caused some risk of cancer to the general public. These risks must, however, have been very small, as air concentrations of vinyl chloride, even within a kilometer of plants handling vinyl chloride, used to be (in or around 1975) of the order of 10 to 40 ppb (1,3, 15), and this level is about one-ten thou-! sandth of the concentration that has caused an occu-T national hazard. It is obvious, therefore, that it would j be impossible to detect the risk of any cancer that might! be produced by vinyl chloride other than a risk of] angiosarcoma of the liver, as it has proved so diffi cult to detect any other risk among men who were ex posed occupationally. The position with reg n. mally so rat to one of tl dioxide, an< annual mcit In these cm (n a man (tv tide was use Controlled n of the effec Several su whether any and Elindcr vicinity of pi and Sweden al (II) fount 10 Ihorotrast with vinyl ch } iton of ihe r (J) found 14 12-year perio lived half a plant, and, in Brady e< al ( , oxbuicd to anpie living wn Hung vinyl chi t*u two studi> Knee of as m, ebte to manui &tt colleagues, bents with ma 'Ac referents liu fei* neighborho, `New York State r foUution with t the doexjy. yiMb years, respVend this period , The ot ' 15 or mor t of these r environm tryC' imay ha I public. gjOarrtm conci tare cer: usly by y. Recent * hundred me t.aahies beioi fibre* of five 120 ppb (!( 1 pp6 (just in ' values w. trd with puttt r of l - Si Ssses I oxer w 11h11) J coun lo wliether the imle reference for min evenly distributed istanccs one cannot tless it can be shown men is independent .cted to influence n i origin, namely, the e and the time since le to examine these iorts do not pro' ide i information as tney d in table 6, supports oride involves a small conjunction with the been produced in sev, vinyl chloride by in, small hazard of lung ;vidence is nol, howihat it definitely did, inly for men who had at a time when expomillion or more were k can be only minute .ft unanswered bs tins -ed definitely if m all iwed to (say) the end uld present their data count of duration of irst employment and len first employed be65 and 1974, and (in) yffect of correcting the yees for the locality in natation ,ved io cause cancer in iraiory experiments, it the minute doses that nmcnt from production lanufacture) Irnm PVC le risk of cancer to the ist, however, base been ,s of vinyl chloride, even landling vinvl chloride, i) of the order ol 10 to I is about one-ten thouhat has caused an occutherefore, that u would of any cancer that might Je other than a risk of s it has proved so diffimong men who were exismon wuh regard to an- i 1-VI KI mm ol the Incr is dil lerem This disease is norso rare ihai, in ttie absence of specific exposure to one of the known causes (vinvl chloride, thoriumand arsenic in pesticides and medicines), the MilHffitaence is on the order of t--2 I0~T (5, 8).` these circumstances the discovery of even one case l man living close to a factory in which vinyl chlo rite was used in the days before exposure was tightly rolled may be regarded as presumptive evidence .the effect of environmental pollution. . Several surveys have been undertaken to determine whether any such cases have occurred. Saric et al (43) >ad Elinder & Pershagen (13) sought for cases in the Sridnily of plants handling vinyl chloride in Yugoslavia ^ad SI weden and found none. In Holland Daldcrup et iV*l (It) found eight confirmed cases not attributable to ihorotrasi or arsenic and could trace "no contact sr, wuh vinyl chloride," but they made no specific menV lion of the patient's place of residence, Baxter et al >' (J) found 14 confirmed cases in Great Britain over a 12-year period, one of which was in a man who had irved half a kilometer from a PVC manufacturing pUm, and, in New York State over an 18-year period, Brady et al (5) found 19 cases that could not be at tributed to any known cause, five of which were in peo' P*< I' ving within a mile of plants manufacturing or wing vinyl chloride. The overall incidence rates in these tut two studies were not unduly high, but the occur rence of as many as six cases among people living so dose to manufacturing plants is surprising, Brady and his colleagues, moreover, compared their series of pa tients with matched referents and found that none of the referents lived equallv dose to a plant. Two of these ux neighborhood cases (one in England and one in New York Slate) cannot be atiribuied io environmental pollution wiih vinyl chloride, as the men who devel oped the disease had lived near the plants for six and eight years, respecnvclv, before developing the disease, and this period is too sltori to allow for the necessary latency. The other four cases, however, all occurred after 15 or more years of local residence, and the dis covery of these cases strongly suggests thai pollution of the environment around plants manufacturing VCM or PVC may have caused a minute hazard to the gen eral public. Current concemranons around plants handling vinyl c Chloride are certainly much lower than those reported evtously by lhe US Environmental Protection ency. Recent British measurements made within a few hundred meters of the VCM areas have given aver age values below the daily limit of detection (5 ppb) for ihree of five plants, the readings al the two others being 20 ppb (100 m outside the boundary lence) and W ppb (just inside u) (47), although substantially higher values were recorded on two occasions asso ciated with putting one plant into operation and with The figure al 1 4 to -" ated by Heath et al (21) seems to have been a misprint for ),4 IO-\ an accident at the other. According to anv reasonable criterion the hazard to the general public (if there is any at all) must be negligible (42). No other hazard to the general population, other than a hazard of cancer, can reasonably be postulated. Summary This paper reviews (i) the possible effects of vinyl chloride on the personal healih of men exposed by virtue of their occupation (other than the early effects of the very high concentrations to which men were ex posed when the industry was first developed -- uncon sciousness, cardiac arrhythmia, and the characteristic "vinyl chloride illness") and (ii) the carcinogenic effects that might conceivably be observed in the gen eral population as a result of the widespread distribu tion of vinyl chloride as a pollutant. The possibility that vinyl chloride might act as a teratogen or might cause mutations in the germ cells has nol 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 (hat 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 V* of the employees to have been expected to die. The results of four studies can be usefully combined for this purpose. They are two national studies, one from the US and the other from the UK, and two studies of employees in one plant in Canada and two plants in Italy. The results of other studies from the Federal Republic of Germany, Norway, Sweden, Italy, France, and Japan can be used only to provide sup plementary information. The many earlier reports of exposed workers in the US and the UK concern men covered more completely in the two recent national studies, and their results serve only as sources of hy potheses. Minor criticisms can be made of three of the four most useful studies. They do not seriously affect the value of the results, except that allowance has to be made for the failure to determine the cause of 6.3 Vt of the deaths recorded in the US study. Three of the studies use national rates to estimate the numbers of deaths that might have been expected to occur in the absence of any special occupational hazard, and the fourth (Canadian) uses rates for the province in which 75 SL 089566 ihe plant was situated. It must, therefore, be kept in mind that the rates used may not base been wholly ap propriate for the localities in which the plants were situated. This circumstance is potentially important for the US study, which covered workers in 37 plants, 22 of which were situated in the southern part of the country. The other less informative studies are, for the most part, open to more serious criticism, and the value of each set of results needs to be assessed separately in relation to each disease. The combined results of the four principal studies show that the SMR values, reflecting the ratios between the numbers of deaths observed and those expected in the absence of an occupational hazard multiplied by 100, have been (t) 77 for accidents and other violence, (n) 84 for diseases other than cancer, and (iii) 102 for cancers other than cancer of the liver. Alt theie muds are what might be anticipated for an industry devott of any specific occupational hazard.The low ratio for diseases other than cancer reflects the "healthy worker effect," which results from the selection process that inevitably excludes some of the less healthy members of the population from industrial employment and is compatible with a higher ratio for cancer, as the mor tality from cancer is not normally subject to such an effect, apart from the first two or three years imme diately following the start of employment. The mortality from cancer of the liver was nearly seven times that expected. Most of the it 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 chloride are cancers of the lung, brain, and lymphatic and hematopoietic systems. The combined data for the mortality from respiratory cancer fail, at first sight, to support the hypothesis regarding lung cancer (SMR 97), Higher ratios for lung cancer have, however, been observed consistently in the subgroups in which ihe effect of an occupational hazard would be most like ly to be seen (that is, men employed for more than 10 years, exposed to higher than average concentrations, or observed more than 20 years after first exposure). In two of the supplementary studies it was also noted that the mortality from lung cancer was specifically increased among the most heavily exposed workers. The combined data show small excesses in the mor tality from cancers of the brain and of the lymphatic and hematopoietic systems. The excesses are, however, not statistically significant, and there is nothing to sug gest that they are occupational in origin. An excep tion is the observation of an increased mortality from cancers of the lymphatic and hematopoietic systems tn the supplementary study from the Tederal Republic of Germany. Two types of cancer were reported to be in excess in the Norwegian study, namely, thyroid cancer and melanoma. The significance of this finding is difficult to assess because very little information about these cancers has been provided by other studies. Suggestions that vinyl chloride might cause cancers of the digestive tract have failed to account for the contribution of angiosarcoma of the liver. When this disease is excluded, the mortality from digestive tract cancer decreases to below the average (SMR 82 for the four principal studies). A small excess mortality from the heterogeneous group of "other cancers" in the combined results of the four principal studies was statistically marginally significant (83 deaths against 65.25 expected, P<0.05), Some of the excess was likely to have been due to the misclassificatlon uf angiosarcomas as secondary can cers of the liver or carcinomatosis, site unknown. The following ihree nonmalignant causes of death have required special examination; cirrhosis of the liver because of damage to the liver m "vinyl chloride ill ness, " myocardial infarction (from analogy with the effect of other halogcnated hydrocarbons and because of some observations from Swedish PVC fabricators), and nonmalignant respiratory disease because of changes in lung function and the radiographic appear ance of the lungs observed in men exposed to PVC dust. Far from being raised, the mortality from cir rhosis of the liver was less than expected in (he three principal studies and in one of the two supplementary studies which gave separate figures for the disease (SMR values of 69, based on 46 deaths, and 82, based on 15 deaths), while in the other supplementary study the increase was trivial. Data for myocardial infarction have not been re ported separately. Out myocardial infarction account] 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 prelerentially described as due 10 bronchitis, was less than expected (SMR 82). as wax the mortality trnm pneumonia (SMR SOI and other rex- fxratory disc: o consistent t*)*ma or b _ aad it seems U3 nudy was with the l Review of leaf-term hca t*ty| chloride wo have expe ; cvranely rart >mtely | in 33 studied died ot ' rfc* observed d ot time the nc ; h* expected tc ; the mortality V of that of norr - hoard has ex; The data pn and other than M. however, sit rdt produces s, doe to nonoccu ' fever, and, if si cause almost as fever. There ij too li the suggestion oma or cancer aad hematopoie that have been i atonal hazard n of the lymp '(German study rt of chance eft Many types of ca The lack of an rbtihecombin I does no *e been a sma t disease, as g< ' the disease it nalrates fo a. The great I be more It i other group [existed. The tenet of a ha (CVartr answer posed in tb us groups x Utt in more a At vinyl chloru mix and a pro thai have e- 'h SL 089567 % aluv from ic svsicms 1 Republic ; in excess anver ant) is difficult bout these es. use cancers jnt for the When this estive tract R 82 for the erogeneous d results of ' marginally d. PcO.O?). n due to the ondary canunknown. iset of death is of the liter i chloride illlogy with the , and because fabricators), because of aphic appearosed to PVC hty from cird in the three upplementary jr the disease and 82, based mentary study j t t A ! 1 0 7 l e V f e not been rection accounts iemic heart disischemic heart whole was un92, icspccuv;- re nmalignant dis) are confusing, gise conflicting four principal ommoitlv found IR 80), This figmortality from l 120). which inirossly increased m the US study .lily in the British cribed as due to iMR 82). as was 50) and other res- f piratory diseases (SMR 46) in tlie US study. There is no consistent evidence ihat 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 lo 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 lead* to two ctcar conclusions. First the men have experienced a specific hazard af the normally extremely rare angiosarcoma of the liver. Approxi mately l in 3JJ of The men exposed fn the 49 plants studied dtad of the disease, and approximately 2 % of the observed deaths were attribured 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, tts 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 nonoccupalional causes, at sues other than the liver, and, if so, whether, in total, iliese risks might cause almost as many deaths as angiosarcoma of the liver. There is too little evidence either lo confirm or refute the suggestion that vinyl chloride might cause mela noma or cancers of the thvroid. brain, and lymphatic and hematopoietic sysiems. 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 ihe German study reviewed, and most are likely to be the sort of chance efleci that is certain lo 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 ihe disease ihrnw dnubt on the validity of using national rales for estimating Ihe expected numbers of deaths. The greater mortality m 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 ihe questions ihat 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 lo the general public. No such 2 risk could possibly be detected, other than one of angiosarcoma of the liver which is normally an ex tremely rare disease. Several surveys have sought evi dence of the existence of such an effect, and sugges tive evidence that such an effect may have occurred at a time when environmental pollution was much greater than it is now has been found in one. References 1. Air Products and Chemicals. Inc. Comments on ihe pro posed standard for vinyl chloride. Letter lo DR Goodwin. Environmental Protection Agency. Washing ton, DC 23 Sepiember 1976. (Cited in an unpublished report by Barr to Air Products and Chemicals, Inc. in 1981). 2. Baser ME. Tockman MS. Kennedy TP Pulmonary Funciion and respiraiory symptoms in polyvinyl chlo ride fabrication workers. Am Rev Respir Dis 131 (1983) 203-208. 3. Baxier P3. Anthony PP, MacSween NM, Scheuer PJ. Angiosarcoma of Ihe liver in Great Britain. 1963--73. Br Med J 2 (1977) 919-921. 4. Belli S, Benazzi PA, Comba P, Foa V, Maltoni C, Masina A, Pirastu R, Regianm A, Vigotti MA. Indagine sulla morialua del produtton di PVC in lialia: Disegno dello studio c primi nsulion. Cancer Lett (in press). 3. Brady J, Liberaiore F. Harper P. Creenwald P. Bur nell W. Davies TN, Bishop M. Polan A, Vianna N. Angiosarcoma of the liver: An epidemiologic survey. J Nall Cancer Inst 39 (1977) 1383-1385. 6. Buffler PA. Wood S, Eifler C. Suarez L. Kiliane DJ. Mortality experience of workers in a vinyl chloride monomer production plant. J Occup Med 21 (1979) 195-203. 7. Byren D, Engholm G, Engtund A, Westerholm P. Mor tality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ Health Perspect 17 (1976) 167 -- 170. 8. Byren D, Holmberg B. Two possible cases of angiosar coma of the liver in a group of Swedish vinyl chloride workers. Ann NY Acad Sci 246 (1975) 249--250. 9. Cooper WC. Epidemiologic study of vinyl chloride workers: Mortality through December 31. 1972. Environ Health Perspeci, 41 (1981) 101 -- 106. 10. Creech JL, Johnson MN. Angiosarcoma of liver in Ihe manufaciure of polyvinyl chloride. J Occup Med 16 (1974) 150--151. It. Dalderup LM, Freni SC, Bras G. Bronckhursl FB. An giosarcoma of ihe liver. Lancet I (1976) 246. 12. Duck BW, Carter JT, Coombes EJ. Mortality study of workers in a polyvinylchloride production plant. Lancet 2 (1975) 1197--1199. 13. Blinder CG, Pcrshagen G. Pitot study concerning the mortality in Njurunda Community. Swedish Nature Conservancy Board, 1978. (Cited in an unpublished report by Barr to Air Products and Chemicals, Inc. in 1981). 14. Environmental Health Associates. An update of an epi demiological sludy of vinyl chloride workers 1942---82; Final report lo the Chemical Manufacturers Association. Environmental Health Associates. Oakland, CA 1986. 15. Environmental Protection Agency. Standard support document and environmental impact siatcmeni: Emis sion standard for vinyl chloride. Environmental Protec tion Agency, Washingion. DC 1973. (EPA 430/2-75009). 16. Equitable Environmental Health. Epidemiological study oT vinyl chloride workers: Final report to Manufacturing Chemists Association. Rockville, MD 1978, 77 Ir I 1 I t 1 f I i j k 1: l i Falk H, Telles NC, Ishak KG, Thomas LB, Popper H. Epidemiology of ihoroirasi-induccd hepatic angiosar comas. Environ Res 18 (1979) 65--73 Fiechtner J, Reyes C, Remmerster K, ei al. Epidemi ologic notes and reports: Angiosarcoma of ihe liver -- Wisconsin. Morb Mortal Wkly Rep 25 (1976) 57 -- 58. Forman 0, Bennett B. Stafford J, Doll R. Exposure to vinyl chloride and angiosarcoma of (he liver A report of ihe register of cases. Br J Ind Med 42 (1985) 750-- 753. Fox A J, Collier PF. Mortality experience of workers ex posed lo vinyl chloride monomer m ihe manufacture of polyvinyl chloride in Great Britain. Br J Ind Med 34 (1977) I --10. Heath GW, Falk H, Creech JL. Characteristics of cases of angiosarcoma of the liver among vinyl chloride work ers in the United States. Ann NV Acad Sci 246 (1975) 231--236. Heldaas SS, Langard SL, Andersen A. Incidence of can cer among vinyl chloride and polyvinyl chloride work ers. Ur J Ind Med 41 (1984) 25-40. International Agency for Research on Cancer. Some monomers, plastics and synthetic elastomers and acro lein, Lyon 1979, pp 377--438 (IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans, volume 19), Jones DP. Smith PM. Progression of vinyl chloride in duced hepatic fibrosis to angiosarcoma ol the liver Ur J Ind Med 39 (1982) 306 -- 307, Jones RD A mortality study of vinyl chloride monomer workers employed in the United Kingdom tn 1940--1984, Scand J Work Environ Health (in press). Lilts R, Anderson H, Miller A, Sclikoff l. Pulmonary changes among vinyl chloride polymerisation workers. Chest 2 (1976): suppl. 299-305. Lloyd MH, Gauld S. Copland L, Soutar CA. Epidemi ological study of lung function of workers at a factory manufacturing polyvinyl chloride. Rr J Ind Med 41 (1985) 328-333. Maltoni C, Gilbert! A, Gianni L, Chicco P Vinyl chlo ride carcinogenesis: Current results and perspectives. Med Lav 65 (1974) 421--444. Maltoni C, Lcfemine G. Carcinogenicity bioassays of vinyl chloride: Current results. Ann NY Acad Sci 246 (1975) 195 -- 218. Maltoni C, Lefemtnc G, Cilibcni A, Cotti G, Ciffctii D, Experimental research on vinyl chloride carcino genesis. In: Maltoni C, Mehlman MA, ed Archives of research on industrial carcinogenesis. Volume 2. Prin ceton Scientific Publishers, Princeton, NJ 1984, Marsteller HJ, Delbach WK, Muller R, Gedigk P, Un usual splenomcgalic liver disease as evidenced by peri toneoscopy and guided liver biopsy among polyvinyl chloride production workers. Ann NY Acad Sci 246 (1975) 95 -- 134. Marsteller HJ, Delbach WK Muller R, Juhe S, Lange CE, Rohncr HG, Veltman G. Chromsch-ioxische Leberschaden bei Arbcttern in der PVC-Produkuon. Dtsch Med Wochenschr 98 (1973) 2311--2314 Masuda Y. Long term mortality study ol vnvl chloride and polyvinyl chloride workers in a Japanese Gant Arch Ind Hyg Toxicol 30 (1979): suppl, 403-4.N 34. Mirkova E, Mihailova A, Nosko M. Embriotakrichno i ter.uogenno dcstuige no vmilkhlonde, khig Zdraveopaz 21 (1978) 440 (Cited in an unpublished report by, Harr to Atr Products and Chemicals, Inc. in 1981). 35. Molan l, Molan G, Holmberg B, tlofsson S, Hoimund L, Moosing R. 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Etude de la mortalue chez des travuillcurs exposes an chlorure de vmyle, Arch Mai Prof Mod Trav Sccur Soc 40 (1979) 1131 -- 1145 42. Royal Society Study Group. Risk assessment: Report by a study group. Royal Society. London 1983. 43. Sane M, Kulcar Z. Zortca M, Gehc J. Malignant tumors of the liver and lungs in an area with a PVC industry. Environ Health Perspect 17 (1976) (89--192. 44. Soutar CA. Epidemiological study of respiratory diseases in workers exposed to polyvinyl chloride dust. Thorax 35 (1980) 644-652, 45. Tabershaw IR, Gaffey WR, Mortality study of workers m the manufacture ol vinyl chloride and its polymers. J Occup Med 16 (1974) 509 -- 518. 46. Theriault G, Allard P. Cancer mortality of a group of Canadian workers exposed to vmylchloride monomer. J Occup Med 23 (1981) 671--676 47. Turner CA, Payne AP, Bushby BR, Determination of ambient levels of vinyl chloride monomer (VCM) around nidiiufauurers in ihe UK, Part 7 Warren Spring Labo ratory, Department of Trade and Industry, Stevenage (United Kingdom) 1984. 48. Vtola PL, Bigoin A, Capuio A. Omogcnic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31 (1971) 516--519. 49. von Greiser E, Rein! W, Weber H. Vinyl-chlorid ex position und monalitat deutscher chemiearbeiter im vergleich zur monalitat nichtexponierier chemiearbetter und PVC-verarbeiier. Zentralbl Arbeitsmed Ar* beussch Prophyl Ergonomic 32 (1982) 44--62. 50. Waxweiler RJ, Stringer W, Wagoner JK, Jones J, Falk H, Carter C. Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Sci 271 (1976) 40--48, Received for publication: 16 February 1988 ORIGINAI Scand J li Assoc exhau Results by Jack : Ron Dew Si be rei ret CM Cat Ar fui ga* adi lOt A"f A large pc study was c cupationa! < About 20 si For each pat past exposu a. analytic stra at a time to t \ remarkable This repot cancers tn on V F bust ion pro<! classes. Kou i busuon eng depending o jet fuel, or pi t from the "n substances: . without dtst r lamp oil), n. Hf; profile of pro is considered a propane-bi ** 1 Epidemiolog i. Insntute An fc Canada. * Department < verstty, Mon Wii ' Department S''- University ot SL 089569 Reprint reques cm epidemiolot 1 iappier, 531 1 (. jikiJ.i irv