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*57 Institute A Division of The Society of The Plastics Industry, Inc Roy T. Gottesman Executive Director October 26, 1988 TO: The VI Health, Safety & Environment Committee RE: Paper By Sir Richard Doll on "Effects of Exposure to Vinyl Chloride" The attached paper from the Scandinavian Journal' of Work, Environment and Health, April 1988 may be of interest to you. It was received courtesy of Harold Clayton, Hydro Polymers' Vinyl Division in England. RTG/pmb SL 106749 Wayne Interchange Plaza II 155 Route 46 West Wayne, NJ 07470 (201) 890-9299 ISSN 0355-3140 i - 1 J '1 i J1 I.- \ . i ! 1 I * i '' -! V - '' t Volume M, number 2, April 1988 i3 ^1 CONTENTS Reviews 51 Elects ol exposure 10 vinyl chloride; An assessment 0/ the evidence Sir R Doll Original articles 79 Associations between several sites of cancer and ten types of exhaust and corn- bus Hon products: Results from a case-referent study in Montreal J Siemiatyckt, M G6nn. P Stewart, l Nadon, fl Dewar, L Richardson 91 Effects of exposure to Freon 11, 1,1,1 -trlchloroethane or perchloroethyfene on the lipid and iattyacid composition of rat cerebral cortex T Kyrklund, P Kiellstrand, KG Hagtid 9S Influence of water on ihe percutaneous absorption of 2 butoxyethanol in guinea pigs G Jonanson P Femsirom 101 Percutaneous absorption of 2 butoxyethanol in man G johanson, A Soman, B DynesiuS 11O Prediction of early retirement on the basis of a health examination: An 11-year foltow-up ol 264 male employees in a Swedish pulp and paper company N-E Astrand, S O Isacsson, GO Olhagen 116 Comparison between surgeons and general practitioners with respect to cardio vascular and psychosocial risk factors among physicians SB Arnetz, S Andreasson, M Stranoberg, P Eneroth. A Kaliner 125 Invariants and noninvariants in the concept of Interdependent effects S Green land, C Pool? Case studies 130 Fall! arsenic poisoning -- A case report L Gemarasson, E Oanlgren, A Eriksson. 8EA Lageikvist, J Lundstrom, GF Nordoerg Booh reviews 134 Neuroloxicanis ana neurOOiological lunclion' Effects ol organoneavy melals 134 Eigonomics in computerized oKices <35 indoor radon ana its nazards 136 Ergonomics at work 137 A manager's guide io ergonomics in ihe eleclronic oltice 135 industrial radiation nazards deskDook 139 Announcements 140 Amendments and corrections SL 106750 REVIEWS Scond J It otk Ertvtron Hcalm N (l9Sfil 61--TH Effects of exposure to vinyl chloride An assessment of the evidence sl 106751 by Sir Richard Doll, FRS*1 001.L R Lffectx of exposure in vin\I chloride: An .ixsc^mem of (he evidence S<und J K nrk Environ Health U (I98fi) M --'3 Thu riper reviews ihe possible eifccis ol unsl chloride on ihe mortality oi occupanoiullv exposed men and the carcmocenic elfects (hat might be observed in ihe general population as a result ol environmental pollution with vmvl chloride The results of four studies fulfilling the criteria j of providing subsinmn! numnrrs ol nhservanons more than 25 >ears alter first exposure and covering j a period long enough for more than 10 ff'o of the workers to have been expected to die constitute the basis ' for the assessment of ihe occupational hazards. Other studies provide nnlv supplememarv information * The data permit two conclusions firsi. men occupanonallv exposed to vmvl chloride base experienced t a specific hazard oi angiosarcoma of ihe liver. Second, anv other occupational hazards (hat mav have ' existed have been xnuil No positive evidence of a hazard of anv nonmahenam disease or any tvpe ot ^ cancer other thnn angiosarcoma of the liver has been found except possibly for a small hazard of lung ( cancer when exposure was heavy More defmue conclusions might be reached if (hose who have siudied exposed cmplovces could present their results m appropriate and comparable waw A very small risk of angiosarcoma mav have occurred as a result of wnvl chloride escaping into ihe environment around plants 1 handling vmvl chloride m ihe past, but the evidence indicates that the current risk to ihe general public (if anv) must be negligible. Acv ttrntv angiosarcoma of (he liver, cancer, lung cancer, mortality, polyvmv! chloride, review, vinyl ihlonde monomer ) 608 644 (redactory nt number , X3.00 air mail address aoove. maged issues unless ight Clearance Center ie internal or personal enter's Transactional page, ts paid directly rations that have been The fee code for users Y i | 4 j i ( I j ! l or many years the inhalation of large amounts of snivl chloride has been recognized as potentially haz ardous. Concentrations of tlie order of 10 0(X) ppm in die air induce unconsciousness and cardiac arrhyth mia, while prolonged exposure to concentrations an order of magnitude lower have been liable to cause a specific pathological svndromc. This "vmvl chloride illness" has been characterized by lour cardinal signs, n.unclv, enlargement of the liver and spleen with a M'cctlic histological appearance, paicliy infiltration of the slm resembling scleroderma, bony changes m the ups of the fingers descrihed as acroostcolysis, and peripheral circulatory changes identical with the clas sical picture of Raynaud's disease- These pathologi cal reactions may occur singly or together and may pos sibly be accompanied by other less characteristic ef fects. They can. however, be completely avoided rf ex posure never exceeds the level of a few hundred parts per million, te. the level to which exposures were generally reduced in the mid-1960s. One other serious effect has. however, been observed tltal ntay not be avoidable in the same relatively easy way, namely, the production of angiosarcoma of the liver. It must, indeed, be presumed that some risk of developing the disease will persist from exposure to 1 Imperial Cancer Research fund. Cancer Epidemiology and Omic.-il Trials TJml, Kadclille Inlirmary, Oxford. United Kingdom. Reprint rertucxix to* Sir R Hull. Imperial Cancer Research I und, Umversus oi Osloid, Gibson Huilding. The RadciifTe tnlinuary. Oxford OX2 fiUE. Untied Kingdom. Joses that are exen lower than the current industrial levels of 5 ppm or less, as vinyl chloride has been shown io act as a mutagen (23). and it cannot be assumed that a threshold exists below which no carcinogenic risk persists Moreover, the possibility has to be considered (hat vinyl chloride may cause some cancers other than augtosarcuma of llte liver, parilv because laboralory studies have shown ihat it causes other cancers m animal experiments and partly because the initial studies demonstrating the production of angiosarcoma of the liver m humans were inadequate tn size to ex clude a material increase in the rtsk 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 diseased 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) SL 106752 and by MacMahon (unpublished report 10 the Chemi cal Manutacturers Association in 1977) concluded that the lew reports ot' positive effects could not be sub stantiated, and no additional evidence was found 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 rats were ex posed to doses appreciably lower than those that had been used by other workers without any such effects being observed. The report of absorbed embryos (j-t) could not be evaluated thoroughly, however, as the ex periment was inadequately described. I have, therefore, examined only ihe possible effects on the personal health of men occupationally exposed to vinyl chlo ride. other than those related to tlietr reproductive capacity, and the carcinogenic effects that might con ceivably be observed in the general population as a result of the widespread distribution ol vinyl chloride as a pollutant. Occupational hazards Many studies of workers exposed to vinyl chloride in the manufacture of vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) have been undertaken since it was first found (hat vinyl chloride could cause cancer in animals (28, 48) and man (10). These inves tigations have conlirmed that exposure causes a haz ard ol angiosarcoma of the liver and, in several in stances, have shown excess incidence or mortality rales that were conventionally statistically significant lor other diseases. Conventional tests of statistical signifi cance are, however, designed to help answer single questions defined beforehand, and several findings that might be expected to occur by chance alone once in (say) 20 times must be expected to occur if dozens of rates are examined in each of several sets of indepen dent data. Scientists have, therefore, been faced with the problem of deciding whether the excess rates that have been observed in individual studies are due to occupanonal hazards or to the vagaries of chance. This problem can be solved in part with an exami nation of the results of a sumation of data from com parable studies, that is. by a comparison of the sums of the numbers of deaths observed and expected in each study. This procedure does not require the as sumption that the exposures have been the same in each study any more than the same assumption is required for each individual when the results of each study are considered alone. It docs require however that each exposed population has been observed over a period when its members were at risk of developing disease (if a genuine hazard exisied) and that in each study ihe reiercnce population from which the expected num bers ul deaths were derived was appropriate (that is, at Ihe same risk of developing disease as the exposed popiiiaiitni would have been in ihe absence ol expo sure). These requirements do not introduce any new complexity, as boih are. ol course, also required if cor rect conclusions are lo be drawn iroin titer results ol ihe individual studies w hen they are examined on iheir own. Sources of information Four siudies meet the aforementioned requirements, namely, two large national surveys, one reported by Jones (25) for ihe United Kingdom (UK) and ilie oilier by Environmeni.il llealih Associates (14) lor itie Unued Slates (US), and siudies ol individual plants in Canada, reporled by Theriault A Allard (4(5) and iri Italy, reponed (as a part of a naliorial siudyl by Belli el al (4) All four include observanons on men more lhan 25 years alier ilieir first exposure, and ihe ex pected number ol deailis is, in each case, greater than 10 'o of ihe 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. 29, 40, 45. 50) have been subsumed in the national sur veys and now serve only as sources ol hyputhesey and of some detailed inlormaiion noi included in Ihe na tional reports. Studies ol German (49), Norwegian (22), Swedish (7), Freneli (41, and unpublished report ot Laplanche et al), Japanese (33, 37). and some oilier Italian (4) workers provide some supplementary mlormalton. but, in general, die periods ol observation have HOI been long enough lur uselul epidemiologic data to be obtained about diseases dial are unlikely to occur within 20 years ol lirsl exposure, ui iliey report only selected results which are dilficuli to in terpret, as only excess rates tend to have been selected. Studies of makers of PVC products have not been included, as (he workers have had much less cxpusuic to vinyl chloride than those employed in the maiiul acture ol VCM or PVC and any occupational hazard io which ihey may have been exposed is more likely to have been produced by PVC dust. US study. The study carried out by Environmental Health Associates (14) on behalf of the US Chemical Manufacturers Association is die largest and most In formative investigation thus far undertaken. It cov ered 10 173 men who had worked in 37 plants owned by 17 companies -- I 214 men in II plants that* produced only VCM, 6 848 men in 18 plants that produced only PVC, 935 tnen in three plants that produced both, and I 176 men m five plants that produced homopolymers and copolymers, with or without VCM or PVC. Twenty-two of ihe plants were in the southern part of the country. 14 were in the northeastern or north central parts, and one was in die west. Men were included if they had been exposed to vinyl chloride for at least a year bet ore 31 December 1972 and had been employed in 1942 or subsequently (the first year depending on die date the plant Iku.iii makme or using s sonnel rev was the la identified sonnel. Racial c 97 Q't ol w the purpo deaihs, ih. Follow.i Cial Securii died atler plains did i (9) earlier presem mv plants wins 1972 were follow-up w 1982, which, of ihe men v uniraced we; which was us Almost hj helore 1955. served more many cases It a long latenc Short-term cohort, and i ploymem lor lor U)years o ploymem bet Fifteen hur have died. In tamed worn th lamed for ihe The number causes or groL plying die pers national rates : age groups ant This import; cisms, which a effects on the re compiled by cc cords without a sumption that a caused the ex pc underestimated, to have had hit reason for suppe the proportion o necessarily repre tainty was miroc as 7.J *' ol (he To oilier crit espcxled mimhci -11111(i 11>11 di.it d um1 m.Mi.ihtv t. SL 106753 ibkaMMMiifiatt k, reduce any tic" o required if cor-m ihe results of xamincd on their j , or using vlnvl chloride and the earliest date that personnel records were deemed to be complete, whichever was the later). Individuals who met these criteria were identified from company records by company personnet. Racial characteristics were known only for 686 men, sti ` 97 Vi of whom were white, and it was presumed, for " the purpose of estimating the number of expected ed requirements, 1 deaths, that all 10 173 men were white. one reported by .... Follow-up data were obtained Irom plant and So JK) and the other cial Security Administration records and (for men who ties (14) for the ... died after 1979) from the National Death Index. Five individual plants plants did not collaborate in the extension of Cooper's i Allard (46) and (9) earlier study, which had been subsumed in the mal study) by Belli |. ' present investigation, and the 955 employees in these ons on men more ; , plants who were known ro be alive on 31 December isure, and (he ex i . : 1972 were not followed any further. For the rest, case, greater than (- follow-up was attempted to death or 31 December 'yees, a value tndi- 1982. whichever was the earlier. On this basts 92,7 Vi r. Earlier observa- of Ihe men were successfully traced. Those who were . 9. 12. 16. 20. 36. umraccd were excluded from the last date of contact. in ihe national sur- 5 which was usually the date when employment ceased. of hypotheses and J Almost half of tlie men (46 Vi) were lirst employed included in the na- y before 1955. A large proportion was, therefore, ub- n (49). Norwegian f served more than 25 years after first exposure (and in unpublished report t many cases for more than 30 years) when diseases with 37). and some other ippleinemary infor- } | a long latency period might be expected to be seen. Short-term workers had been excluded from the ods of observation 1 cohort, and most of the men had continued in em seful epidemiologic it ployincm for many years, two-thirds being employed es that are unlikely ^ for 10 )cars or more and the average duration of cm- t exposure, or they i are difficult to ina have been selected, ducts have not been t \ ` jf ployment being 16 years. Fifteen hundred and thirty-six men were found to have died. In I 439 eases, the cause of death was obtamed from the death certificate, but no cause was ob- J much less exposure g. lamed for the other 97 persons (6.3 Vt). ayed in the tnanufac- i The numbers of deaths expected from each of 38 cupattonal hazard to f- causes or groups of causes were obtained by multi- sed is more Itkeli 10 6 plying the person-years at risk by the disease-specific tst. j national rates for white males, for the corresponding F age groups and livc-ycar periods of the study. ut by Environmental f of the US Chemical >e largest and most inr undertaken. It cov ed in 37 plants owned 'en tn 11 plants that nen tn 18 plants that i tn three plants that en in five plants that copolymers, with or This important study is open to three minor erttiJj ctsms, which are unlikely to have had any material effects on the results. First, the lists of employees were compiled by company personnel from company re cords without any independent check. Second, the asrC*r^gumption that all the employees were white will have j.ii/.xfoaused the expected deaths to have been very slightly [^^Mnderesttmated, as the few black employees are likely iJSlv l<* *'*ve higher mortality rates and there is no reason for supposing that the small sample from which the proportion of black employees was estimated was :re in the southern part northeastern or north the west. wj been exposed to vinyl fore 31 December 1972 42 or subsequentlv (the c the plant began making necessarily representative. Third, an element of uncer tainty was introduced by the failure to trace as many as 7,3 Vi of the employees. Two other criticisms are more important. First, the expected numbers of deaths were calculated on the as sumption that the men would have experienced the same mortality rates as the white male population of the whole country at the corresponding dates. The use of national rates is common practice tn studies ot in dustrial populations and tends to result in an oieresttmatton of the expected numbers of deaths so that the employees appear to be unusually healthy. This "healthy worker effect" is well known and has been taken into account m my discussion of the results. A more serious objection to the use of national rates is the way mortality varies from one part of the country to another, due to differences in the prevalence of en vironmental and social factors unrelated to the occu pation of interest. It is. therefore, generally preferable to use state (if not county) rates in place of national rates. With 37 plants, however, it might be thought that their geographic distribution would be sufficiently wide to make the use of national rates appropriate. Unfortunately 22 of the plants were located m the south, and a check would have been desirable to see whether their location could have caused any material distortion of the results. Second, causes were not obtained for 97 of the 1 536 deaths. This deficiency was allowed for in the calcu lation of the overall mortality by Ihe inclusion of deaths due to unknown causes. It was not allowed for. how. ever, in the calculation of the disease-specilic mortality rates and will have caused the standardized mortality ratios to be underestimated by an average of 6,3 For the present purpose, therefore, the numbers of deaths attributed to specific diseases have each been multiplied by 1.0674 [ 100/(1--97/1536)1 and rounded off to the nearest integer. UK study. The study reported by Jones (2J 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 Vi 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 Vi). Seven hundred and eighty deaths were identified, and copies of the death certificates (coded to the eighth revision of the International Classilication of Diseases tlCD) if they occurred before 1979 and to the ninth revision if they occurred later] were sent to the investigators. Several specific points about the study need to be noted. First, national mortality rates for England and Wales were calculated for five-year age groups over quinquennial periods for 66 causes of death, and these rates were used in the estimation of the numbers of deaths that might have been expected in (he 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 SL 106754 coded according 10 the eighth and ninth revisions of the IC'D was, however, experienced in obtaining suit able rates tor all causes of death, and rates tor 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. Tor two categories the earliest available rates were !%0--1964, for one they were 1965 -- 1969. for 2-1 they were 1970-- 1974, and for one they were 1975 --1979. Second, an attempt was made to classify men ac cording to whether they had high, intermediate, or low exposure to VCM or PVC dust, and each man's em ployment history was recorded according to 12 job titles wuh advice from the plants concerned. The men were then grouped according to whether exposure to VCM was likely to have been high (group A), expo sure to PVC dust was likely to have been high with exposure to VCM low (group B), or exposure to VCM and PVC dust was intermediate and intermittent (group C). All other men, who would generally have had low exposure io both VCM and PVC dust, were classed as group D. Within all the groups, exposure to VCM was likely to have been higher if it had begun before 1956. The study makes an important contribution to the knowledge concerning the long-term effects of vinyl chloride. The use of national rates to calculate the ex pected numbers of deaths may be justified on the grounds that the men were employed m nine plants, which were presumably distributed about the country, but no details of their location are given. In general, mortality rates tend to be higher in the parts of Britain w here 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 (he diseases in question remained stable. It would have been desirable, however, for the diseases to have been specified so that the reader would know which were liable to be distorted. The system used to classify the men into four expo sure groups is the sort of system that is commonly used if precise measures of exposure are not available. It creates some difficulties in the statistical analysis if men move from one job to another and are classed (as in this instance) as having had high exposure if they have ever had a particular type of employment (eg, ever been employed as an autoclave worker). No evidence is pro vided to show that the person-years at risk before a man entered the category have been subtracted and added to another exposure group before the numbers of expected deaths were calculated. Movement from one job to another was said to have tended to be out ol groups A and II into D, but even so it must be presumed that the expecied numbers ol deaths in the first two exposure categories arc likely io have been overestimated. Canadian study. The Canadian study (46) was limited io employees of a single plant in bhawtmgan, 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 ihe production of VCM ceased, while the prodticnon oi PVC continued. An attempt was made to trace all the production work ers whose names appeared on the unions' lists or the payrolls ol the companies in (he whole industrial comp'ex, including Ihe vinyl chloride plant, between I January 1948 and 31 December 1972. and contact was made with the worker or his next-of-kin in I 611 out ol I 659 instances (97 I s'j). 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 (t) 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 for less than six months (870 men), and (iii) oiher men (IJ4 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. Inlormation was also sought for histological or cylological con firmation of all the diagnoses lor all ihe exposed men who had died of cancer. The results were examined in two ways. First, the mortalities of the exposed and unexposed men were compared after standardization lor live-year periods of the study and five-year age groups. Second, the mor tality of the exposed men was compared with that ex pected if the men had had the sex- and age-specific mortality rates recorded in Quebec for the year 1971. In both comparisons the causes of death used were those specified on the death certificate, and Ihe addi tional pathological information was used later only for interpretation of (he results. Most of the exposed men were exposed for more than 10 years (75 */o), the average length of exposure was approximately 17 years, and 44 were observed more than 25 years after first exposure. Although small, the study makes a useful contribu tion to the overall results. The histological review of the cancer cases is particularly helpful. It showed that all eight cancers diagnosed as liver cancer (including two specified as hepatoma and one specified as angio sarcoma) were angiosarcomas of the liver, as well as one that had been diagnosed as angiosarcoma of the peritoneum. Two other cases of angiosarcoma of the liver were found to have been certitied as hepatic cir rhosis. It is also helplu! to lime a vOiiipaiiMin iviuecu j iheexposet j companies j for all non j ahcalihyn 1 recording o jf nani causes 0.95). j One aspei i ie. the use i j calculate ex t period (1948 j 10 bunch up | vaiion so th ; have been la I some distort i | size (and eve estimate. Foi hkely io hav ! Italian study. duenon ol vm was begun in employed for start up of th. still incomplei in three plant I signanal begai thirty-seven m m the other. Al, followed to the i mated by multi. corresponding i >car age group a Tlte total expect more than 10 (12.4 and 12.g Clinical infot death of all the had died. Revis comparison wit deaths from ca The Ravenna 1959, Six hundre All but four we were found to h; lowed for more (3.9 >i of the wc this plant have r cipal analyses. I death was atlnbi peered. j Other sources. Th 'Civ.uions un 45. . I nti m I victual k I *t ' l06T55 si* ___ aim ji deaths in (In: jiv io ha1-; been the exposed and "unexposed" employees of the same companies as it shows that the low mortality observed for all nonmalignam diseases could be altribuled to a healthy worker clfect and was not due to bias in the l46l was limited wimgan. Quebec, i industrial comI PVC were both ie production of f PVC continued, production work mens' lists or (he de industrial complanl, between I 2. and contact was f-kin in I 611 out J occupational and questionnaire, and recording of exposure (relative rise for all nonmalignant causes compared to that ol the "unexposed" men 0.95). One aspect of the studs nas to be criticized however, ie, (he use of provincial rates for one vear (1971) to calculate expected mortality spread over a 30-vear period (1948 to 1977 inclusive). Deaths will have tended to bunch up towards (he end of the period of obser vation so that the rates for tins particular year mav have been fairly representative, but it must have caused some distortion of the expected numbers of deaths, the sire (and even the direction) of which is impossible to estimate. For most disease groups the distortion is un likely to have been large. bv the companies ed. The remaining :d to V CM if thev Italian stndv A siudv of all men employed in the pro- VQM or PVC (or mexposed to VCM y 1, w duciion of vinyl chloride and P VC in nine Italian plains was begun in 1983 All men were included who were ss than six. months Ja- ; employed for at least Six months at any time from ihe 4 in total) The last Jy. Follow-up was jAy-.' Wart up of (he plant to the end of 1981. The study is S'\ Hill incomplete, but results are now available for men ics of the death cer in three plants (4). Two plants (in Ferrara and Ro- uses for all who had 5 ` ngnana) began operation in 1953. Four hundred and sed) were coded ac- J Ihuiy-seven men were employed in one plant and 181 the ICD. Informail or cytologtcal con- * J in the other. All but three (from the Ferrara plant I were followed to the end of 1984. Expected deaths were cstt- all the exposed men y mated by multiplying the person-years at risk by the ?! corresponding national mortality rates for each fivc- two ways. First, the mexposed men were for five-vear periods ips. Second, the mormpared wh that ex-cx- and age-specific ec for the year 1971. . of death used were ificate. and the addt'as used iater only for L" jvS'," fti p .' , Q vr*. Jj~ )ear age group and each five-year period of the study, The total expected deaths in each case amounted to more than 10 7 of the 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 (he Ferrara plant w/io had died. Revised diagnoses, which were not used for comparison wuh the expected deaths, revealed four deaths from cancers of the liver in place of one. The Ravenna plam did not begin operation until 1959. Six hundred and thirtv-eiphr men were employed. ere exposed for more gc length of exposure d 44 ri were observed exposure. ikes a useful contribuhistological review oT helpful, ll showed that liver cancer (Including ib.AU but four were traced io the end of 1983. and 17 found to have died. No man could have been folfor more than 24 years, and only 25.1 deaths V* of the work force) were expected. The data for pltti plant have not. therefore, been used m the prin cipal analyses. It may be noted, however, that one '"death was attributed to liver cancer when 0.1 was ex pected. one specified as angto- of the liver, as well as is angiosarcoma of the of angiosarcoma of the certified as hepatic ore a comparison between fjvj. E/i Olhfr sources. The Norwegian study (22) provided obsetvations on 454 men who had been employed in a plant in Telemark where VCM had been manufactured from 1950 to 1971 and PVC from 1950 (o the end of ihc study period. Every man was included whose name was recorded in the company's personnel register and health department records who had ever been em ployed from ihe start of production to the end of 1969 and had worked for at least one year. The men were iullowed from 1953 to 1979 inclusive. Deaths and cases ol cancer were identilled from the records of the Cen tral Bureau of Statistics and the national cancer regis try No reference was made to any men being lost to lollow-up, but it can be assumed that the number (if not zero) was small, as all citizens have an identity number which is used by both employers and central agencies. Fifty men were found to have died against 59.34 expected if the sex-, age-, and quinquenniumspeciFc national mortality rates had operated. Twemvone 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 (he county in which the plant was situated was between 90 and 95 *r ot the rate of the country as a whole. One man who had been emploved in PVC production developed an giosarcoma of ihe liver The observed and expected numbers of cases were given lor cancers of the lung, voion. 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 nnc further case of melanoma had occurred after the closure of the study and that one "incipient case" was also known to them. The German studv (49) included the following three groups: (i) 7 021 men who had been exposed to VC m the course of their employment in any of the 11 plants in which VC and PVC had been produced in ihe Federal Republic of Germany, (n) 4 820 men who had been employed in seven chemical plants wuhout having had any exposure to vinyl chloride, and (lit) 4 007 men employed m 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 ?*, 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. SL 106756 Of the exposed group 93.2 "o were successfully fol lowed, and causes oi death were discovered lor 92.S Vo of ihe 4 14 men discovered (O 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 Vo for the PVC process workers. The failure to obtain causes of death for all the men who had died was allowed for in the subsequent analysis by the weight ing of the numbers attributed to each cause by a sys tem which took account of the age group and calen dar period in which death with an unknown cause oc curred. The expected numbers of deaths from each cause was calculated by multiplying the person-years at risk by the sex-, age-, and cause-specilic mortality rates tor 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 lor (he same calendar year. . Epidemiologic studies are more difficult to carry out in the Federal Republic of Germany than in North America, the United Kingdom, or Scandinavia because the medical cause of death is not recorded publicly, and there ts 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 succcsstully followed (6.8 Vo) and the proportions of deaths for winch the cause was not obtained (7.2 Vo) were similar to those in the study of the Environmental Health Associates (14). Two defects, however, make the data less useful. First, no national mortality 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 (he men had been first employed less than 10 years before the follow-up ended. Therefore the useful observations on the few men who had been exposed long enough to have had much chance of developing an occupational disease with a long latency period must have been swamped by a mass of other observations that had little to con tribute. The expected deaths amounted to only 6.2 Vo of the exposed men, and there is, therefore, little to be gained, and something to be lost, by including the German data in the overview. It may be noted, how ever, that 12 deaths were attributed to cancer of the liver among the workers exposed to vinyl chloride against 0.9 expected and that smaller excesses were also observed among the unexposed chemical workers (4 observed against 1.1 expected) and the PVC process wotkerv 11 deaths against 0.8 expected). Two Swedish plants have produced VCM and PVC, one since 1945 and the other since 1971, and employees of the first plant have been studied by Byren et al (7). All persons who had ever been employed when expo sure to VCM could occur were lisicd from the per sonnel files of the factory. Twenty-one were excluded because they were foreigners who left (lie country al ter a short period of employment. The remaining 7J0 were followed to Ociober 1974. Expected numbers ol deailis were esumaied by multiplying the person-years at risk by the corresponding age-specific mortality rates lor the whole country, and the expected numbers ol can cer cases from 1958 to 1971 inclusive (during which period all cancer cases had been registered nanonally) were estimated by multiplying by the national agespecific cancer incidence raies. In boih instances, the rates used were those recorded in 1969. Fifiy-eight deaths were found, but no ligure was given for the ex pected number. Detailed figures were given only lor the numbers of deaths and cases observed and expected for cancer of (he lung and for cancers ol the liver and pancreas combined and for ihe numbers oi 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 Ihe results of a long term follow-up of men employed in one plant (41) and of a short-term follow-up of men employed in 12 plants (Laplanche et al, unpublished). The tirsi 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 the Tavaux plant in 1953 to the end of 1976 (41). Six other employees were excluded from the study because ol lack ol oc cupational histories and 160 men because their vital status at the end of the study period was undetermined. Twenty-five men were found to have died against 48.75 expected from contemporaneous sex- and age-specific national mortality rales (3.7 Vo of the men at risk). One death was attributed to angiosarcoma of the liver, in a man who had been exposed for more than 15 years. The reported data are so incomplete and cover such a relatively short period from the opening of the plant that they add nothing of epidemiologic value to the results of (he other studies, apart from the addition of a further case of angiosarcoma. The second study provided observations on I 100 men aged 40 to 55 years who, in 1980, were exposed or had been exposed to vinyl chloride in 12 plants, which constituted "most of the French VCM polym erisation plants" (Laplanche et al, unpublished). Many of the men were, or had been, employed at Tavaux and were presumably survivors of the cohort studied by Pierre et al (41). The men were lollowcd for live years, and their morbidity ami mortality were com pared with those observed loi I 100 men ol the s.iiuc t ages (2 y, 1 but who h. in both gn formation Ji drinking ha wo groups l first expose first been cr ously. More K nually by ih f 98 V. of!he One oi thee developed a; given separc ployment, a, \ \ of Ihe finUm lung cancer i well reflect a < in the reterer * cancers in ihe i- One exposed f. hemaiopoiein. none of the n developed me roid. (; A Japanese P perience ol 4 before 1965 i. duemg VCM uve (J7). The Tweniy.eight ; *>i than 20 years a f- served more th 1 untraced, and lined lor all t, 1 initial cohort) It the tcrmin, given separate in PVC prod classed as VC if this stud JgT. should provtd f'r petseni data in fV thin 20 years i They con F^ dneer with si workers again while only oni Other workers - deaths from IF . workers was ci liver, and at le; was due to the not m excess (2 expe.ted). No <. ph-iiic and lieu ' mm in iIhhii.I ,.i M.:-, SL 106757 VCM and PVC i, and employees . Syren et al (') ;ved when expoj from ine per;e were excluded he country after naming 750 were umbers of deaths rson-years at risk ortaliiy rates for numbers of cane (during which stered national!)) ,he national ageoth instances, the 1969 Fifty-eight is given for the exere given only for erved and expected jrs of the liver and jinoers of deaths ?ries of cardiovasiave angiosarcoma a died ol liver canhud man died of ;:hs after the close e results of a longn one plant (41) and nployed in 12 plants e first provided obto vinyl chloride in and in selected anz of the Tavaux plant Six other emplosces cause of lack of oc:i because their xnal d was tindcierinined, ixe died agamsi 4,8 75 sex- and age-speeme ihe men ai risk). One coma of ihe luer. m - more ihan 15 xears. plcte and coser such e opening of Ihe plani Tnologic value to the art from the addition rma. reservations on I 100 m 1980, were exposed chloride in 12 plants. : French VCM polymaJ, unpublished). Many , employed at Tavaux s of the cohort studied were followed for five d mortality were com- I 100 men of the same iles ( 11 years) who were employed in the same plants Fk'Tj.-r.; but who had never been exposed to VCM. The men la both groups were imerviewed personally, and in formation was obtained about their smoking and drinking habus, which were lound to be similar in the rtro groups. The men in ihe exposed group had been firw exposed for an average of about 14 years and had tku been employed in the plani about 18 years previ "f ously. Morbidity and mortality data were recorded an nually by the plant physician, who successlully (raced * 9 'H of the exposed men and 96 "7j 0f the referents. .One of (he exposed men, but none of (hose unexposed. -'developed an angiosarcoma ol the liver. Dala were not ^ prol separately for different periods afier first rm^wyptojrmem, and it is impossible to assess the significance Of the finding that six of the exposed men developed king cancer against two of the referents, which may ,, ^ ,eii reflect a chance occurrence of unusually few cases JJi|' la the reference group, as the proportion of all lung cancers in that group (2 out of 15) was unusually low. One exposed man developed a cancer of the lymplto- (JijfeV'; hatuiopotetic system against none of the reterents, but feT;'':v'" aooe of the men in either group were known to have |ivT.,/ developed melanomas or cancer of the brain or thy- ||*Wro*d. A Japanese study has reported the mortality ex L^/C' per settee of 4 524 men employed for ai least one year rr,V7" before 1965 in 25 Japanese plains which began pro ducing VCM or PVC between 1949 and 1964 inclu- fe?.'.save (37). The men were followed to Jl October 1975. fe. V Tmenly-eight percent of the men were observed more H".*; . rtao 20 years alter first employment, but none was ob- fov, ; xervexl more titan 26 years. Only 0,6 ah of the men were wmraced, and copies of the death certificates were ob- ' limed for all the 209 men who had died (4.6 "h of the ouiliI cohort). Individuals were classified according u> the job in which Ihcv had been longest employed M the termination of their follow-up. and data were EVc": green separately for the 2 546 men classed as employed v^"*- ' m PVC production and I 978 others (including 900 IK*,*./ Classed as VCM production workers). If (his study is continued for another 10 years, it fcA; should provide useful additional information, but the i peocni data include too lew observations on men more 20 years alter lirst exposure to be ol any material They confirm the evidence of a hazard of liver ith six deaths among the PVC production .erf against 2.54 expected from national rates, (Only one such death was observed among the workers against 1.82 expected. One of the six tu from liver cancer among the PVC production workers was certified as due to angiosarcoma of the , and at least one of the other liver cancer deaths due to the same cause. Lung cancer deaths were to excess (2 observed in PVC workers against 2.33 'tpeeted). No data were given for cancers of the lym- 4 'phasic and hematopoietic systems, for cancer of the brain or thyroid, or for melanomas. The mortality Wuwl by Manilla (45) fur 404 Ja|sana#a vinyl ehlxs- ride workers has presumably been subsumed in Na kamura's (37) later and larger study. Hazards of cancer The results of the four most useful studies are listed individually in tables I and 2. The overall results for all causes, liver cancer, and three oroad groups of con ditions are shown in table 3, and those for 10 types, or classes, of cancer are presented in table 4. Data have not been reported for each type of cancer in each study, and the sources of the data are, therefore, specified separately for each type. Additional information ob tained from four other less informative studies (4. 7, 22. 49) is given in table 5 for seven types or classes of cancer. Table 3 shows that, apart from cancer of the liver, ihe overall monaluy is what would be anticipated for an industry without any major hazard of accident or disease. In particular the standardized mortality ratio (SMR) of 84 for diseases other than cancer is typical of the ratios that are commonly observed for groups of 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 effect does not. however, nor mally affect the mortality from cancer beyond that ob served in the first few years alter 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 ts no reason to suppose that the excess mortality attributed to liver cancer (or, in ihe US series, liver and gallbladder cancer) is not entire ly accounted for by the known hazard of angiosar coma. Fifteen of the 37 deaths2 attributed to cancers of the liver and gallbladder in the US series are known to have been due to angiosarcoma of the liver (14). In the UK series, seven ol the 11 deaths attributed to liver cancer, not specified as secondary, were known to be angiosarcomas, and they all occurred in auto clave workers against 0.38 expected liver cancers of all types (P< 10"') (25). In the Canadian series, histo logical review showed that seven of the eight so-called liver cancers were angiosarcomas (one had been de scribed as an angiosarcoma on the death certificate, two as hepatomas, and five as unspecified liver can cers). One so-called liver cancer death was found to have been due to cancer of the sigmoid colon, while one death attributed to angiosarcoma of the perito-1 1 Increased to 39 in table I to take account of the 97 extra death# ironi an unknown eaui*. 67 Table 1 Observed and expected numbers of fleams from different cancers reported m ine lour ortncipal studies 14. 1 a, 25. i6i <0 = ooserveo number of deaths, = expected numoer ol aeatnsi Type or Class ol cancer United States O' United Kmgocm 0c Canada 0 Italy 0 E BuCCat cavity and pharynx Esophagus Siomacn Large intestine Rectum Liver Liver and gallbladder Pancreas Other digestive Larynx Lung Other resoiratory Bone Skm monmeunoma Melanoma Prosiaie Testis Bladder Kidney Other and unsoecilied urinary Brain Eye and central nervous system Thyroid Lympho- and redculosarcoma Hodgkin's disease Leukemia Multiple myeloma | Olher lymphatic ] Other All cancers 13 li 55 7 8 07 11 16 Oi 21 28 79 39 5,77 17 IS 40 118 1 15 87 5 6 38 2 1 81 6 7 36 16 15 20 5 a 46 12 906 25 12.76 12 7 9B 3 5,45 14 13 94 46 40 50 363 341 73 4 3 53 6 14 34 26 23 91 9 13 94 11 10 49 11 1 94 0 0 64 3 0 14 7 9 83 6 4 2 21 at 92 i2 i 5 26 5 78 2 i 74 12 9 59 2 l 23 14 8 CO 3 4 10 3 4 29 4 6 18 2 0 43 4 2 35 3 2 50 7 5 16 2 2 35 10 8.12 235 220 60 ] 1 | J t 1 ) i 2 20 1 67 0 95 16 37 1 oa 1 06 3 30 0 )2 l 06 0 07 1 09 12 5 1 0 02 1 07 1 07 0 04 0 07 9 45 30 21 t * Observed deaths multiplied by 1 06/4 and rounded off to the nearest integer to allow tor deaths without discovered cause Tefefe 4 Mon |Q = observed Type or cuss - uouth anp pn< Ogeulve aystt nfpiriory jy. lung CemtcurinarY Weisnoma 6'ain hyiold t-vmpnatic and Gmer ah other man o * 1 s United Sta Table 2. Numbers o! deaths from nonmaiignant and alt causes reported In the lour principal studies 14, 14. 25, 46) (0 = observed numoer ol deems. = expected number ot deaths) TebJ* 5, Mortality number ol fleams Causa ol again UmieO Stales O' e United Kingdom 0 Canada 0e Italy O E Benign ano other unspecified tumors 4 5 08 0 0,5 Cerebrovascular disease 75 91 93 ischemic heart disease Other circulatory dneaae 521 597.73 157 123 55 278 288 105 141 25 31 67 \ I Bronchitis* Pneumonia Other respiratory disease 44 22.63 36 16 31.94 1I 10 15 32 64 44 1 51 1 t 6 3 21 3 50 Cirrhosis of the liver Other digestive disease 37 56 06 27 39.52 5 51 l4 4 52 3 2,7 Dlaaasa ol ina ganilounnary tyaiam 11 20.41 Other diseases OD in Suicide r-~ Accidents and other violence lo o All nonmaiignant causes t--i AM causes 67 115.68 49 52.76 t 130 173.19 } 1 153 1 363.54 1 536 1 705.27 43 40 545 760 76 50 665 894 2? 5 40 2 1058 39 5476 59 71 07 2. 1 4 36 66 70 09 77 56 4 775 a C/3 See footnote to tebte 1. * Emphysema In data from the United States. e includes two cases certified as cirrhosis ol the liver which proved to De angiosarcoma ol the liver. 4 includes one case with causa unknown. TP# or class of c Digestive system ffj[` , Excluding me iiv , Lung w . Melanoma tBrmn Thyroid g Lympnatic and h* fcPOisuc system y Om#f (excluding t jjfwv Ah excluding me * Sffifc.** Incidsnce and c. * Csncer of ine m Cancer oi tne iu ?3*v li Further evident cancer (or liver ar neum was found to have been due to angiosarcoma of tlic liver (46). In the Italian study, further evidence revealed ihat three lurther deaths should have been at* tributed to cancer of the liver <tor a total of four), but only one of the four was described as an angiosarcoma 14). can t * attributed f ' -I.Mrd Of JMCIOS. 1 . * XwCw Jc.it " I K. .W'i Italy 0 1 08 1 06 3 30 3 i2 1 06 0 07 1 09 12 6 1 , 1 ^ 0 02 t 07 1 01 0 04 0 07 9 45 30 21,1 >out discovered cause SL 106759 'able 3. iiM , imm rmccr ol me bvor and other causes .imonrj vinyl cnionan *orkAf^ m an o'-hjK i'ie mu* L,'ri<, i(jai Mumes co^tnnpej (4 a 25 *6i (0 = ooserved numoer o* aeams 5 = e*oected numoer ol ceams, SMR = standardized mortality rai`01 Cause ol oeam Cancer ol me liver * Cancer ol other sues Other diseases Accidents, poisonings, and violence Ait causes O 59 609 1 547 226 2 J4t a 45 . 599 35 1 344 89 295 15 2 74 7 94 * Including cancers ol the gallbladder in me series from me United Stales SMR 698 '02 84 77 99 >< Mortality Irom various cancers among vinyl chloride workers in 49 plants in me lour principal Studies comomed. nfxtntri number of deaths. = exposed ngmoer of deafhs, SMR = standardized monaiity ratio) or ciaaa of cancer O SMR Source ol Information EKlftMA and pharynx ?Qyrfetrre system (other than liver) WilhlCiilixy system urinary system ifc'Uss ancma jjgnfriMn AftfxnoftAitc and hematopoietic system ffir;wr than ol the liver 18 16 57 125 i54 59 223 229 36 211 214 09 70 62 81 2 1 94 29 19 54 2 0 43 57 50 37 83 63 24 609 599 35 109 1. 2. 3. 1 61 I. 2. 3. 4 92 1. 2. 3. 4 99 1. 2, 4 111 l. 2. 3. 4 2. 4 148 1. 2. 3 2 M2 1 2, 3, 4 >31 1, 2. 3, 4 102 1. 2. 3. 4 * * \ n United States study (14). 2 = United Kingdom study (25). 3 = Canadian study 146). and 4 = Mahan study (4). SttsjV: ii, :s. i6i. iq = observed Italy O 0 05 1 '9 13 27 4 50 , 4 52 3 22 i 2 70 1 09 > 1 77 3 36 56.1 7 66 275 j', Tehee V Mortality * from various cancers among vinyl chloride workers; Supplementary evidence (4, 7, 22* 49). (O a observed ..heemev ol deaths. E = expected number ol deaths, SMR a standardized mortality ratio) Tyoa or CISSS ol cancer wAy.; O m Federal Republic Of Germany (11 plants) Norway (1 plant) OE Sweden (1 plant) 0e Italy (t plant) OE Four countries combined (14 plants) O E SMR |V. O^PSlrre system pv ^aUMding the liver) &`>v- Lam* Maaanama )E*Lr; l wn*sic and nematoU03, *mwnc lylt*rn tojSv Qfeor tcacludiriQ the liver) (--rtiirlr j tn# liver 35,0 31 8 23 5 24 6 2.1 1 3 165 7 7 10.7 24 3 87,8 89.7 3" 1 44* 5 2 84 4 0 79 2 0.16 3 1 28 2 0.33 8 14 93 22 20.16 5C 211* 1 12 0 15 0 0,1 0 07 4 20 57 39 0 31,5 40 41 2.0 16.5 22.7 1196 34 44 30 72 0 89 1 63 0.16 64 41 43 117.67 113 103 196 55 102 and cases m the Norwegian study, of me intestine only, of the lung and bram only. for a total of four), but bed as an angiosarcoma r evidence that the excess mortality from liver r (or liver and gallbladder cancer in the US series) l bf attributed principally if not wholly to the known of angiosarcoma is obtained in a comparison ^ruw cicru deaths with the numbers of deaths from fSVMpoMfoomas recorded in the Register of Liver Angio- fe. l<-v sarcoma Cases (maintained on behalf of the Association of Plastics Manufacturers in Europe by the Im perial Chemical Industry PLC) before the end of the follow-up period (Bennett, unpublished). Fifty-one ex cess liver cancers are recorded in the combined data, and 49 angiosarcoma are recorded in the Register for 69 SL 106760 Tible 6. Monthly from lung cancer in me series from me United States (US) (14) and the UntieQ Kingdom (UK) (25) by characteristics relevant to an occupational hazard. tO-ob served number of deaths. Es expected numoer of aeatns. SMR = standardized mortality ratio) Oata characteristic * Category 1 O* E SMR Category 2 G* SMR Observed 20 years or more after first employment (i), otners <2) Employed to years or more m me US (t). others in tne US (2) Employed before t9S6 m me UK (1), others in 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 oa 94 85 93 S3 91 63 63.44 99 29 40 50 72 65 74 02 37 * The numoers m parentheses designate the category. See footnote to taoie t for observea deaths in tne US. the relevant periods for (he three countries and the two Italian plant*1 that are covered by the survey. None of the 120 case* 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). Luns cancer. The idea that exposure to vinyl chloride might cause cancer of the lung was suggested by Monson et al in 1974 (36), when they noted 13 cases against an expected number of 7.9 in a study of proportional mortality. The combined data shown in table 4 do not provide any support for (he hypothesis, either for res piratory cancer as a whole (SMR 97) or for the speci fied data for lung cancer in the US, the UK, and Italy (SMR 99). There are, however, consistently higher risks in the subgroups of men in the US and UK series, in which occupational hazards would be more likely to 1 Twenty-nine were registered as occurring in the United States against an excess of 33; only 20, however, were iden tifiable in both series. Inquiry has, as yet, failed to reveal .information about the histology of the remaining 13 in the cohort study and the origin of the nine extra deaths in the register. Nine deaths were registered as occurring in the United Kingdom against an excess of nine, but one of ihe registered cases was certified as due to a benign hemangioma and not related io ihe liver (code 227 in the eighth revision of ihe International Classification of Oiseases). Ten cases were registered as occurring in Canada against an excess of eight; two were recorded as being in men who bad been employed for five years, and it is possible that the actual duration had been slightly less than live years with con sequent exclusion from Ihe Canadian cohort. One else was registered as occurring in one ul the two Italian plants jjfjii.ii ail excess ot 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 alter 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 arc 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 arc all small or very small. They arc, however, all in the same direction, and the probability that the rates should all be higher in the groups in which an occupational hazard is more like ly to be seen in each of the four pairs ol groups is I in 16. Additional information from other sources is given in table 5. A total ol 30 deaths (or casesl was observed, and this figure increases to 31.5 when allowance is made for the number of deaths due to unidentified causes in the German study (SMR becoming 103). In the German study the SMR was higher lor the men who had been exposed lor 10 years or more than for those who had been exposed for shorter periods (III against 79), and, in the Norwegian study, four of the five cases observed occurred in men whose 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 ol deaths from national mortality rates tor a single year towards the end of the study period. The expected numbers of deaths are likely, therefore, to have been overestimated and the SMR values correspondingly underestimated as the mortality from lung cancer had been rising throughout the period of observation. Brain cancer. The idea that vinyl chloride might cause brain cancer was also suggested by Monson et al (36) when they reported five cases against 1.2 expected. The combined data that are shown in table 4 provide some support for this hypothesis. The cases of Monson et al (36) were, however, observed in US workers and must be presumed to be included in the total reported by Environmental Health Associates (14); therefore they will have contributed a substantial proportion of the total in table 4. As a test of the hypothesis the data of Monson et al ought, therefore, to be subtracted from those in the table. Their investigation was not a cohort study, and their expected deaths do not correspond exactly to those in table 4. If, however, the observed and the expected cases are both subtracted from ihe totals, twenty-lour observed deaths remain against approximately 18.3 expected, a difference which might easily occur by chance (P one-tailed* 0.1).-1 1 If the study of Waxweiler et al (SO) is regarded as the origin of the hypothesis, 26 deaths are leli tieamsi IX -/-I cmvuvJ (P oiie-i4ili-ii-iH17). Addition given m ta little furthc one of the occurred in less than a the excess d German sir chemical w< deaths afte causes again PVC fabric; for deaths fr Cancers of / idea that vin1 phattc and h. the lymphati II Gaffey (45) studies, whe from lympho against 2.5-1 e the lymphatic peeled. These if the laboratc suggesting tha tally m antma non 129). The cause lympho out constderai - studies that ar lupport lor if lymphatic and grlher (57 deal and very little n for cancers of it fey's definition 5&. 200--203 and 2 HJJ deaths agi {j'nweeover, hard ^CgfTey's initial i 3.36 expected, -- Utile addttic gtantM of the G dy obtained , r flxwedon 15 obs jXUdwtnce is mac oust causes) a I ttrsotposed gn fcfPVC fabricate Jisposed workers 1km exposed for was most nta toe fixe years or r the number of di * t* e peeled, SM SL 106761 ii.e is .dues more r, for men is are :d lor id for angioothcr small, nd ihc in ihe e like* ps is I s given ,erved. tnce is niifled 03). In ie men ian for ds (III r of tire ipalions nsl 1 S2 e Swed- deaths towards nbers of wimated timaicd n rising hi cause jt al <3M .ted. riie ide some onson ct kers and reported therefore onion ol s the data ubtracted t was not a noi correver, t he ubtracted lis remain difference .e-tailed = as the origin 94 expected i t t \ ) Addition.tl inloriiMiKiii Irtun two other sources is eoen in table 5. Hie small excess reported provides little further evidence of an occupational hazard, as one of the two deaths observed in the Swedish study occurred in a young man who had been employed for less than a year when (he diagnosis was made, while the excess death rale for brant cancer observed in the German study was less titan 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 isomers in the PVC fabrication industry (5.9 deaths after allowance for deaths front unknown causes against 1.1 expected). Cancers of /emphatic and hematopoietic tissues. The idea that vinyl chloride might cause cancer of the lym phatic and hematopoieiic tissues -- more specifically ihc lymphatic tissue -- was suggested by Tabershasv & Gaffey (45) and by Waxweilcr et al (50) in two cohort studies, is lien they lound. respectively, five deaths from lymphomas in the most heavily exposed workers against 2.54 expected and lour deaths from cancers of ihe lymphatic and hematopoieiic tissues against 2.5 ex pected. These small excesses might have been ignored il Ihe laboratory findings had noi been interpreted as sucgesiuig that lymphomas were produced experimen tally m animals exposed to xinyl chloride bv inhala tion (29). The idea that similar exposure unglii also eausc Ixntphonias in humans, ihcrelore. uterus seri ous consideration. The data lioin ihe four principal studies that are summarized in lablc 4 provide lillle support lor ihc hypothesis when all cancers ol the lymphatic and hematopoietic tissues are considered to gether (57 deaths against 50.S7 expected, SMR 112) and sery little more is obtained I rout Ihe separate data for cancers ol tire lymphatic svsicm ( Tabcrsltaw & Gaf* rev's dclmuiou of ICO list numbers, eighth revision, 200--21IJ and 205 being used) lliat arc slto'vn in table I (.15 deaths against 29,40 expected), rite position is, morcO'er. hardlv altered il the daia in Tabershasv <St Galfcy's mmal report ate subtracted (29 deaths against 23.36 expected. SMR 124). Lillie additional information is provided by ihe results of ihe German study (49). (Sec (able 5.) This study obtained an SMR of 214 for exposed workers (based on 15 observed deaths, increased to 16.5 when alloss-ance is made lor the number of deaths from un known causes) against SMR values ol 77 and 34 for an une.xposcd group of chemical svorkers and a group of PVC fabricators. It shosved that the excess of the exposed workers was present only for men who had been exposed for more titan one year and that this ex cess was most marked for men xslto had been exposed for five years or more (10.7 deaths alter allowance for the number of deaths from unknown causes against 4.0 expected. SMR 268. I' one-tailed <0.01). Melanoma. An excess ol niclummia was reported for Norwegian workers by Itcldaas ct al (22). xxho raised ihe possibility that vinyl chloride might have produced the disease. Four cases were observed when 0.79 were expected, and three of the four were m men whose oc cupations involved the highest exposures (against 0.51 expected). At the time of the writing of their report, one further ease had been detected with onsei three sears after the closure of the study. Subsequent studies in oilier countries have, so far, reporied only two deaths against 2.0 expected. (See tables I and 5.) Thyroid cancer. An excess of thyroid cancer was also reported in Ihe 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 (heir observation. Two of the three major studies that have been reported since the Norwegian observation was made gave no daia for thyroid can cer; the third reported two deaths against 0.43 ex pected. (See table I.) One death from thyroid cancer, it may be noted, was reported in ihe US by Monson et al (36). Cancers of the digestive tract. Suggestions lhat vinyl chloride might cause cancers Ol Ihe digestive tract in general have sometimes been made, but they have not taken adequate account ol the contribution of cancers of ihe liver io ihe (olal number of cancers of ihe digestive system, particularly when u is borne in mind lhat some liver cancers are likely io be misdiagnosed ax cancers of oiher organs. The combined data from ihe four principal studies shown in table 4 weigh heavily against (he idea that any such effect has been produced. Other cancers One of the remaining tvpes. or classes, of cancer listed in table 4 shows a siatixtically significanl excess, namely, Ihe heterogeneous group of "oiher 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 (he liver were not recognued and were diagnosed as secondary liver cancer or carci nomatosis, site unknown, ihe number of deaths in this category therefore being increased. Hazards of nonmali/inanl disease No previous study has suggested that any nonmaiignant 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 svere observed as part of ihe "vinyl chloride illness" (24. 31. 33). Two other possibilities have, however, been raised, namely, the production of nonmaitgnant respiratory disease, because of the changes in lung function and radiographic appearances that have been V 71 Tbi* /. Mortality tfom selected nonmattgnant causes and alt causes it ine lour principal studies comomed (O = ooserved nutnoer ol oeatha. 6 -expected number ol deaths, SMR = stanoaroireo mortality ratio) Type ot Cuease flfoocnifts. emohysema0 Olher respiratory <Mea$e 0 5MR Source of information4 so 66 S3 120 1. 2 ?! 125.76 56 1. 2 recorded for men exposed to PVC dust (2. 26, 27, 44), and acme cardiac death, front analogy with the eflect ol other halogcnatcd hydrocarbons (25) and ihe ob servation of an increased monaliiy from myocardial infarction in the few years following the cessation of exposure in ihc Swedish PVC processing industry (35). Relevant figures for the numbers of deaths Irom these and other nonmaltgnam causes that arc obtainable from the four principal studies were given m table 2, and they have been summarized in table 7. he expectec viTorunenta la give an> from empf hardly be d overalle however, ih by deficienc respiratory , other respir AM respiratory disease ischemic heart disease Other circulatory disease* 160 200.82 60 t, 2. 3, 4 ?97 885,73 90 1,2 252 264 55 1 95 i.2 Cirrhosis of (he liver. Three of the four principal studies gave separate figures for cirrhosis of ihe liver, none of which showed an increased mortality (table Ibe questtoi could he a Ilealih Asso ihai they we m the out-oi Ail circulatory disease4 Cirrhosis ot me liver Other disease 1 103 236 t 209 35 66 26 368 07 9t 1, 2. 3. 4 69 1. 2, 4 65 V 2, 3, 4 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 theeodmg o "other respir included emi " emphysema t All nonmahgnafl! disease AM external causes AM nonmalignani causes Am causes 1 547 1 844 50 226 295.15 t 773 2 139 65 2 441 2 747 85 84 1. 2, 3. 4 77 1, 2, 3. 4 as 1, 2, 3. 4 89 t. 2. 3. 4 against 3.85 expected and noted that the lour included two that were certified as due to cirrhosis of the liver, but actually due to angiosarcoma (46). In the two sup plementary studies in which data were given for this disease, (he SMR was 82 in one, based on 15.1 deaths after allowance for the number with unknown causes he classified to 502, and it of the emphy in some categ number 527, I for both (he e * 1 = United Stales study (U), Z = United Kingdom study 125), 3 = Canadian study (46). and 4 = Italian study (4). * Bronchitis in me United Kingdom study, empnysema in the (49), and 133 in the other, based on seven deaths (37). frostly defict. expiratory dt United Slates study. * includes cerebrovascular disease In the United Kingdom and Italian studies. Nonmalignaru respiratory disease. The data for nonmatignam respiratory disease are confusing in that the No excess n and asthma" i 44 with 6.3 d <N CO total SMR from the combined data for the lour prin cipal studies is 80 and is the sort of figure that is com ownher of dc l*.- r~ monly found in healthy industrial populations, yet the v` \o ]4d-o r-t Table I. Modality from chronic obstructive lung disease* in the series irom me united Stales (US) (14) and the United King dom tUKi (25) by characteristics relevant to an occupational hazard. |0 = opserved number ol deaths, = eipected number US study recorded a substantially increased mortality from emphysema (41 deaths and an SMR of 180 be fore any allowance was made for deaths from un C&dhvascula. heart l.`i ch*de the vast C/3 ol deaths, SMR = standardized mortality ratio) known causes). No such excess was found in the UK, where 36 deaths from bronchitis gave an SMR of 82. Category 1 Category 2 International comparisons of chronic nonmalignani characteristic* 0 e SMR 0 SMR respiratory disease are complicated by the usage of dif Observed 20 yeera or more alter first employment in the US 01, others <n the US (2) Employed 10 years or more in the US (11. others In the US (2) Employed before 1956 In the UK |1), others in the UK <21 Ever employed es an autoclave worker in me UK (1), others in the UK (2>* 30 19 26 3 15 8 190 10.9 147 30,17 M 6.55 46 11 7.0 157 25 12,0 206 10 13.60 74 33 37.22 89 ferent terms to describe what it is now agreed is best called chronic obstructive lung (or pulmonary) disease, but which in the past tended to be called emphysema in the US and chronic bronchitis in the United King dom. It must, therefore, be presumed that the two categories of "emphysema" and "bronchitis" used re spectively in (he two large national studies were meant to describe the same thing. One must assume, there fore, that the experiences in the two countries were very different, despite the fact that both related to cohort: that had very similar experiences of angiosarcoma of the liver and so. presumably, fairly similar exposures to vinyl chloride. j. acute cardia t-.Nl national sti i increased m< of diseas e recorded it gw the SMR val I there is no i the subsidiary In parti mortalii new in the t*. SMR 61) > workers (g I slight meres was recorded I Study (49). I * Described as emohysema in the US ltudy end es bronchitis m the United Kingdom study. 1 The numbers m oarentheses dtsignale the category. 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 ' TV deaths ntnb raws and the coi '*" wvtion for t ` Men ever employed as a bagger or ottet. occupations which would nave caused me greatest occupehonei exposure to polyvinyl chloride dust, espenenced One death Irom bron chitic ugamsl 4 96 eipected. data for cancer of the lung that were shown in table 6, they provide no consistent evidence of a greater risk in ihe groups in which an occupational hazard would i- at Health A ivstMifii lor i I i.skV ,1*. SL 106763 .St (2. 26. 27, 44). iY will) the ffeet |25) and the obrom mvocardial i ihe cessation of if.t' y,, N expected to be concentrated, i lie authors of the En^IVUUusenial Health Associates report (Id) were unable any explanation for the increased mortality emphysema, and they point out that it could be due to excess cigarette smoking, as there was .mg industry (35) deaths from these at arc obtainable ; given in table 2, i table 7. overall excess for cancer of the lung. It is sinking, that the excess is more than compensated for deficiencies in the other categories of nonmalignant ory disease (pneumonia 15 deaths,5 SMR 47.0: respiratory disease 14 deaths. SMR 42.6), and -qaeuion arises whether the emphysema excess U be classificatory artifact. Environmental he four principal rhosis of the liver, d mortality (table IR of 69 based on 1 did not give sepa* ported four deaths system combined ;i the four included -rhosis of the liver, 6). In the two sup*ere given for this ised on l 5.1 deaths ih unknown causes i seven deaihs (37). lOb Associates (14) list all the 41 deaths which show they were coded under ICD number 527 which. Itteout-of-date seventh revision that was used for csding of all deaths in the study, was the code for roptratory disease not otherwise classified" and emphysema. Under that revision, however, that was associated with bronchitis should Ijhf ekaaMfied with bronchitis under ICO numbers 500 :. and the possibility may be considered that some ft*emphysema deaths should have been classified out category of respiratory disease other than ICD bee 527. If this were the situation, it could account Itoll the excess mortality from emphysema and the deficient mortality from other nonmalignant ^flMvadory diseases. excess mortality from "bronchitis, emphysema, The data for nonronfusing in that the ia for the four pun- 1-indauiviu" was observed in the German study (SMR 6.3 deaths observed after allowance for Ihc ol deaths from an unknown cause) (49). f figure that is conipopulations, yet the increased mortality an SMR of ISO beor deaths from un as found in the UK. gave an SMR of 82. ionic nonmahenant J by (he usage of difs now agreed is best r pulmonary) disease. >e called emphysema s in me United King* esumed that the (wo i j[i0Mftii>iiim/ar disease. Data for ischemic (or arterio- e) heart disease (which may be presumed to int U< vast majority of all deaths certified as due : cardiac disease) were given only by the two &lMguaxonal studies, and they provide no evidence of f^Bt*(reused mortality. The SMR values of 90 for this diseases and of 91 Tor all cardiovascular disr recorded in the four principal studies are typical 5AIR values of healthy industrial populations, Ittere is no suggestion of any occupational hazard Sftbudiary analyses provided by the ties national rU particular, there is no evidence of an in- "bronchitis" used re-f [ Mortality within one month of leaving em- al studies were meant ^ I In ihe UK study either for all workers (52 e must assume, there-, ;sur 61) or for the most heavily exposed auto* wo countries were very ^ rkers <9 deaths. SMR 42). oth related to cohorts ' [ increase in ischemic heart disease mortal- es of angiosarcoma of k recorded for the exposed workers in Ihe Ger- airly similar exposures r(49), but it was less than that recorded forl n table 8. where avail J among men wuh dif-,7 of exposure. Unlike the at were shown in table:' idence of a greater risk :' jpattonal hazard would i l ttinbuted to different groups of respiratory disI the corresponding SMR values that are cited in sn (or the US study are as given by the EnvironI IVexilh Associates (14) and have not been adiusted Ml (or the number of deaihs from an unknown .Intake account of these deaths, the observed deaths I5A4R values can both be multiplied by 1.0674. ihe unexposed chemical workers and the I'Ve fabri cators (SMR values of 127, 131, and 158 based on 97.2, 126.7, and 109.7 deaths, respectively, after allowance for the number of deaths from unknown causes). Discussion The information that has now been obtained about the long-term health of men occupationally exposed to vinyl chloride is massive and compares favorably with that available for any other occupational group. Two facts are outstanding. First, the men have experienced a specific hazard of a type of cancer that is normally extremely rare, namely, angiosarcoma of the liver. The rarity of this disease under other conditions made the detection of (he hazard easy: but the long latency period before the disease appears after first exposure (almost always more than 10 years and usually more than 15 years) meant that a large number of men had been exposed before the hazard was detected and that it will still be many years before the extent of the pro-lection provided by the reduction in exposure in the 1960s and that of the further reduction that followed the recognition of (he hazard in 1974 are known. There is, unfortunately, no effective treatment for the dis ease, and the number of cases is reflected in the num ber of deaths. Some 50 deaths have occurred among the 16 740 men who were followed in the four prin cipal studies that have been reviewed in this report, so that approximately I in 335 men have been affected, 2 of the deaths having been due to this one cause. Eventually many more men must be expected to de velop the disease. One estimate (38) suggests that the total may be increased 10 times, but a more realistic estimate is two to three limes (19). The second outstanding observation is (hat the mor tality of the exposed men, other than that due to angiosarcoma of the liver, is typical of the normally healthy industrial worker -- (hat is not to say that no other hazard exists, but that the effect of any other hazard is small. The massive data that are now available provide no reason for thinking that any hazard other than one of cancer has been overlooked. It is, however, still dif ficult to decide whether vinyl chloride produces a risk of developing cancer other than angiosarcoma of the liver which might be small compared to the risks produced by nonoccupational causes, but yet abso lutely almost as large as the risk of developing the nor mally very rare angiosarcoma. One of the many hazards suggested can be dismissed, as there is no evidence to support it, namely, that of vinyl chloride as a cause of any cancer of the diges tive tract other than angiosarcoma of the liver. Two hazards (of melanoma and cancer of the thyroid) have been suggested only very recently, and few of the avail able studies have provided information about them. There ts no good theoretical reason or laboratory evi dence to suggest that either should be produced by 73 SL 106764 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 10 be remembered that the disease has become much more common in recent years in Scandinavia (where the excess was reported) due, it is believed, to the popularity of sunbathing and the increased oppor tunities for Scandinavians to travel to the warmer parts of Southern Europe and North Africa, The extent to which this change may have affected the observation in Norway needs to be examined. Two other hazards (of lymphoma and brain cancer) were suggested by the early results of some of the US studies. That vinyl chloride might produce a hazard of lymphoma was ininally supported by the prelimi nary results of animal studies, but the complete results of the many investigations that have been undertaken (see reference 29) do not suggest that lymphoma or any other cancer of the hematopoietic system is liable to be produced. There is, however, some evidence that brain lumors 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 lime as methods of diagnosis have improved and the suspicion of an occupational hazard (which was raised in 1975) could have influenced the findings. What ex cess has occurred has been limited to the US and Ger many, and the German findings carry little weight, as the excess was found in each of the three occupational groups studied, irrespective of the chemicals to which they were exposed. The supplementary data from the German study showing an increased mortality from lymphatic and hematopoietic cancers are more impres sive, particularly as the excess was the most marked for men who had been employed for at least five years. In these circumstances, judgment must still be sus pended until the data for each study are analyzed for each specific type of cancer, by intensity and duration of exposure, and by time since exposure began. There remains the suggestion that vinyl chloride might cause lung cancer. At first sight, this possibil ity is ruled out bythe SMR of 97 for the combined data for respiratory cancer for the four principal studies. Lung cancer is, however, normally so com mon (accounting for about 8 f* of the expected deaths) that an increase in mortality that was half as impor tant (numerically) as the increase in mortality from angiosarcoma of the liver might easily be overlooked (95 *' confidence limits'of the SMR 85--112). The in cidence of the disease varies moreover within a couniry, and there must be doubts as to whether the na tional experience provides a suitable reference for men employed in plants that are not evenly distributed about the country. In these circumstances one cannot exclude an occupational hazard unless it can be shown that the mortality of the exposed men is independent of the factors that might be expected to influence n if some of it were occupational in origin, namely, the intensity and duration of exposure and the time since exposure began. It is not possible to examine these relationships in detail, as the reports do not provide all the necessary information. Such information as they do provide, which was summarized in table 6, supports the idea that exposure to vinyl chloride involves a small hazard of lung cancer. Taken in conjunction wuh 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 lime 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 J984, (jj) the investigators could present their data in comparable ways, taking account ol 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 (lii) estimates could be made of the effect of correcting the results for each group of employees for the locality in which they lived and worked. Hazards to the general population As vinyl chloride has been proved to cause cancer in . man and is a mutagen m laboratory experiments, it i must be presumed that even the minute doses that! escaped into the general environment from production^ plants or (in the early days of manufacture) from PVC. materials will have caused some risk of cancer to the general public. These risks 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 40ppb (1,3, 15), and this level is about one-ten iho*f sandth of the concentration that has caused an occu* pational hazard. It is obvious, therefore, that it would ^ be impossible to detect the risk of any cancer that might 1 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 eiposed occupationally. The position with regard to an- giosarcoma \ "ally so rai to one of tl sL dioxide, an, annual inen. r In these cirt In a man hv ride was use controlled n of the effec *1vigi whether ai and Elinde vicinity of and Swede *1 III) fou to thoroira with vinyl c ion of ihe , . 13) found I 12-year per bved half a plant, and, i Bndy et al , htbuted to ai fie living wi dn| vinyl c) Iasi two stud fence of as it tkoseto mam his colleague! Izetlts wuh m, referents h tlx neighborh W*w York Sta pollution with the disea years, res this periot ' r firure of | . SL 106765 , )\ w n lun *i -o m.iitfihcjf ihe na* le reference for men evenly distributed fiances one cannot alcss it can be shown men is independent :cicd to influence n , origin, namely, the c and the time since le to examine these ions do noi pros ide a information as they d in table 6, supports ande involves a small conjunction with the been produced tn sevi vmyi chloride bv mi small hazard of lung evidence is not. how* that u definitely did. inly for men who had at a time when expomillion or more were V, can oe only minute eft unanswered bv this ed definitely if m all wed to (say) the end uld present their data count of duration of rst employment and icn first employed be65 and 1974, and <m> :ffect of correcting the yees for the locality in natation ,ved lo cause cancer tn .ratory experiments. it the minute doses that mncni Iroin production lanufacture) Irom FVC ,ie risk of cancer to the ist, however, have been iS of vinyl chloride, even landltng vmvl chloride, () of the order of 10 to I is about one-ten thou* hat has caused an occuiherefore, that n would of any cancer that might de other than a risk of s tt has proved SO diffimong men who were exismon with regard to an- i i-'.Hvimta ol the liver is dillcrcm. This disease is norB-.aily so rare that, m the absence of specific exposure .10 one of the known causes (vmvl chloride, thorium dioxide. and arsenic in pesticides and medicines), the jJAnuai incidence is on the order of 1-- 1 - \0-7 (5. 8).` U tJtese circumstances the discovery of even one case 1a a man living close to a factory in which vinyl chlo ride was used in tlte 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) >od Elinder & Pershagen (13) soughc for cases in the ,vicinity of plants handling vinyl chloride in Yugoslavia aod Sweden and found none. In Holland Dalderup et (II) found eight confirmed cases not attributable !W Ihoroirasi or arsenic and could trace "no contact . with vinyl chloride." but they nude no specific men'lion of the patient's place of residence. Qaxter et al '(J) found 14 confirmed cases in Great Britain over a . 12-year period, one of which was in a man who had kved half a kilometer from a PVC manufacturing plant, and, m New York State over an 18-year period, Brady cl al (5) found 19 cases that could not he at tributed to any known cause, five of which were in peo i`^- ple living within a mile of plants manufacturing or using vinyl chloride. The overall incidence rates m these last two studies were not unduly high, but the occur rence of as many as six cases among people living so Hose to manufacturing plains is surprising. Brady and Hu colleagues, moreover, compared their series of pa tients with matched referents and found that none of the referents lived equally close to a plant. Two of these ax neighborhood cases (one in England and one m New York State) cannot be attributed to environmental pollution with vmyl chloride, as the men who devel oped the disease had lived near die plants for six and eight years, respectively, before developing the disease, and this period is too short to allow for the necessary Latency. The other four cases, however, all occurred after 13 or more years of local residence, and the dis covery of these cases strongly suggests that pollution of the environment around plants manufacturing VCM ot PVC may have caused a minute hazard to the gen eral public. Current concentrations around plants handling vinyl Chloride are certainly much lower than those reported rviously by the US Environmental Protection ency. Recent British measurements made within a hundred meters of the VCM areas have given aver'tg* values below the daily limit of detection (5 ppb) , b for three of five plants, the readings at the two others ^ being 20 ppb (100 m outside the boundary fence) and 14 ppb (just inside it) (47), although substantially higher values were recorded on two occasions asso'C. dated with putting one plant into operation and with The figure of 1.4 to-* cued by Heath et al (21) seems to have been a misprint for 1.4 10--'. .in accident at the other. According to any reasonable criterion the hazard to the general public (if there is any at all) must be negligible (42). No other hazard to the general population, other than a hazard of cancer, can reasonably be postulated. Summary This paper reviews (i) the possible effects of vinyl chloride on the personal health of men exposed by virtue of their occupation (other than the early effects of the very high concentrations to which men were ex posed when the industry was first developed -- uncon sciousness. cardiac arrhythmia, and the characteristic "vinyl chloride illness") and (ti) 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 vmyl chloride might act as a teratogen or might cause mutations m the germ cells has not been exam ined, as the little evidence that has been adduced relating lo such possible effects has been reviewed else where and the conclusion was reached that no such ef fects have been demonstrated. Many groups of workers exposed to vinyl chloride in the manufacture of VCM or PVC have been studied since the carcinogenic potential of vinyl chloride was first recognized. Some results have shown that occu pational exposure can cause angiosarcoma of the liver, and others have suggested that it may cause several other types of cancer as well. The actual situation can be determined only in an examination of all the evi dence, especially (he combined results of those studies that include a substantial proportion of observations on men more than 23 years after their first exposure and cover a long enough period for more than 10 Vt of the employees to have been expected to die. The results of four studies can be usefully combined for this purpose. They are two national studies, one from the US and the other from the UK, and two studies of employees in one plant in Canada and two plants in Italy. The results of other studies from the Federal Republic of Germany. Norway, Sweden, Italy, France, and Japan can be used only to provide sup plementary information. The many earlier reports of exposed workers in the US and the UK concern men covered more completely in the two recent national studies, and their results serve only as sources of hy potheses. Minor criticisms can be made of three of the four most useful studies. They do not seriously affect the value of the results, except that allowance has to be made for the failure to determine the cause of 6.3 it of the deaths recorded in the US study. Three of the studies use national rates to estimate the numbers of deaths that might have been expected to occur in the absence of any special occupational hazard, and the fourth (Canadian) uses rates for the province in which 73 i S i 106766 the plan! was situated. It must, therefore, be kept in mind that ihe rales used may not have been wholly ap propriate for the localities in which ihe plants were situated. This circumstance is potentially important for ihe US study, which covered workers in 37 plants, 22 of which were situated in the southern part of ihe country. The other less mlormative studies are, lor Ihe 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 ihe numbers of deaths ooserved and (hose expected in the absence of an occupational hazard mulnplicd by 100, have been ti) 77 for accidents and oiher violence, (m) 84 for diseases other than cancer, and (m) 102 for cancers other than cancer of the liver. All these results are what might be anticipated for an industry devoid of any specific occupational hazard. The low ratio for diseases other lhan cancer reflects the "healthy worker effect." which results from the selection process that inevitably excludes some of the less healthy members of the population from industrial employment and is compatible with a higher ratio for cancer, as the mor tality from cancer is not normally subject to such an effect, apart from the first two or three years imme diately following the start of employment. The mortality from cancer of the liver was nearly seven times that expected. Most of the 51 excess deaths were known to be due to angiosarcoma, even though this diagnosis was not recorded on the death 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 type* of cancer which have been sug gested to occur aj a result of exposure to vinyl chlo ride are cancers of the lung, brain, and lymphatic and hematopoietic systems. The combined data for the mortality from respiratory cancer fail, at first sight, to support the hypothesis regarding lung cancer (SMR 97). Higher ratios for lung cancer have, however, been observed consistently in the subgroups in which the effect of an occupational hazard would be most like ly to be seen (that is, men employed for more than 10 years, exposed to higher than average concentrations, or observed more than 20 years after first exposure). In two of the supplementary studies it was also noted that the mortality from lung cancer was specifically increased among the most heavily exposed workers. The combined data show small excesses in the mor tality from cancers of the brain and of the lymphatic and hematopoietic systems. The excesses are. however, not statistically significant, and there is nothing to sug gest that they are occupational in origin. An excep tion is the observation of an increased morialilv from cancers of the lymphatic ami hematopoietic systems m ihe supplementary study from the Federal Republic of Germany. Two types of cancer were reported to be in excess in the Norwegian siudy, namely, ihyroid cancer and melanoma. The significance of this finding is duficult to assess because very little information about these cancers has been provided by ulher sludies. Suggestions that vinyl chloride might cause cancers of the digestive tract have failed to account for (he contribution of angiosarcoma ol the liver. When this disease is excluded, the mortality from digestive tract cancer decreases to below ihe average (SMR 82 for the Tour 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, I' <0 05). Some of the excess was likely to have been due to the mtsclassification of angiosarcomas as secondary can cers of the liver or carcinomatosis, site unknown. The following three msnmalignant causes of death have required special examination: cirrhosis of ihe liver because of damage to the liver m "vinyl chloride ill ness. " myocardial infarction (from analogy wuh the effect of other halogenated hydrocarbons and because of some observations tront Swedish l`VC labrtcatorsl. and nonmalignant respiratory disease because of changes in lung function and the radiographic appear ance of the lungs observed m men exposed lo PVC dust. Far from being raised, ihe monaluy from cir rhosis of the liver was less than expected in the three principal sludies and in one of the two supplementary sludies which gave separate figures for ihe disease (SMR values of 69, based on 16 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. But myocardial infarction accounts for most of the deaths attributed to ischemic heart dis ease, and there is no evidence that either ischemic heart disease or cardiovascular disease as a whole was un duly common (SMR values of 90 and 92, respective ly) or related to occupational exposure, The data for the third category of nonmalignant dis ease (nonmalignant respiratory disease) are confusing, because the two large national studies give conflicting results. The combined data for the four principal studies show the low mortality that is commonly found .jj in Healthy industrial papulations (SMR 80). This fig ure hides, however, an increased mortality front chronic obstructive lung disease (SMR 120), which in cludes emphysema and is due to a grossly increased mortalily attributed to emphysema in the US study (SMR 193). The corresponding mortality in the British study, which was preferentially described as due to bronchitis, was less than expected ISMR 82), as was the mortalily from pneumonia (SMR 50) and other rex- 76 f- pratory dis ennimer MT*ma or it seems V% study wa ti** with the Review oi k*f-tenr> hr '**! chlorid mhaveexr t.. OEfwntly fa .... Kfy I in readied died the observed 0/ lime the r t^."* be expected the tnortahtv of that of not hazard has e ; The data p aed other tha b. however, s. rxde produces de to nonocc trvcT, and, if easts* almost. kttr. There is too the suggestion rn* or cancr ' ad hematopo sh*i have beer l >)onal hazai tofthclym ijciGerman study .*** of chance t '.many types of p* i, &!&.. The lack ofc rtnthe combidoesn been a sm * disease, as f the disease (Ml rates f a. The grec d be more ) other grot lexisted. Th aence of a h IClearer answf i posed in t us groups tits in more As vinyl chlor and a pr< that hate t .Mllutunis mu ' MIHIIIIC SL 106767 dm. slitv from c systems , Republic f in excess unccr ami is difficult bout these :s. jse cancers jnt for the When this estive tract R 82 for the crogeneous d results of marginally J. P<0,05). n due to the ondary canunknown, ses of death s of the liver chloride ill,ogy with the . and because fabricators), because of aphic appearosed to PVC lily from Or el m the three upplementary x the disease and 82. based memary study 4 i t \ ! ( E f e not been re gion accounts tmic heart distschemic ncan whole was uuyZ, iCipCClivi' rc nmalignant dis- 1 are confusing, give conflicting four principal ominouly found |R 80). This figmortal n v from t 120), which tnrossly increased m the US study ,my in the British cubed as due to 5MR 82). as was 50) and other res- r ii * >* f piratory diseases tSMR 46) in itic US study. There is no consistent evidence that the mortality from em physema or bronchitis was specifically occupational, and it seems possible that the reported excess in the US study was an artifact due io nosological difficul ties with the use of the seventh revision of the (CD. Review of the massive data now available on ihe long-term health of men occupationally exposed to vinyl chloride leads to two clear conclusions. First the men have experienced a specific hazard of the normally extremely rare angiosarcoma of the liver. Approxi. mately I in 335 of the men exposed in the 49 plants studied died of the disease, and approximately 2 % of the observed deaths were attributed to it. In the course f 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 heaithy industrial workers. If any hazard has existed, its effect has been small. The data provide no reason to think that any haz ard other than one of cancer has been overlooked. It is, however, still difficult to decide whether vinyl chlo ride produces small risks of cancer, compared to those due to nouoccupational causes, at sites other than the liver, and, if so. whether, in total, these risks might cause almost as many deaths as angiosarcoma of the liver. There is too little evidence enlier to confirm or refute the suggestion that vinyl chloride might cause mela noma or cancers of Ihe thyroid, brain, and lymphatic and hematopoietic systems. None of the small excesses that have been recorded point specifically to an occu pational hazard, apart from that attributable to can cers of the lymphatic and hematopoietic systems in the German study reviewed, and most are likely to be the sort of chance effect that is certain io be observed when many types of cancer are examined in many different studies. The lack of any increased moriality from lung can cer in (he combined results of (he four principal studies reviewed does not exclude the possibility lhat there may have been a small occupational hazard of developing the disease, as geographic variations in the incidence of the disease throw doubt on ihe validity of using national rates for estimating the expected numbers of deaths. The greater mortality in groups of workers who would be more likely to show an occupational hazard than other groups suggests that a small hazard may have existed. The evidence is, however, weak, and the existence of a hazard has not been proved. Clearer answers to some of the questions that have been posed in this review might be obtained if ihe various groups of investigators could present their results in more appropriate and comparable ways. As vinyl chloride is a mutagen in laboratory experi ments and a proved human carcinogen, the minute doses that have escaped into the general environment as pollutants must be presumed to have caused com parably, minute risks to the general public. No such risk could possibly be detected, other than one of angiosarcoma of the liver which is normally an ex tremely rare disease. Several surveys have sought evi dence of the existence of such an effect, and sugges tive evidence lhat such an effect may have occurred ai a time when environmental pollution was much greater than it is now has been found in one. References 1. Air Products and Chemicals. Inc. Comments on the pro posed standard for vinyl chloride. Letter to DR Goodwin. Environmental Protection Agency. Washing ton. DC 23 September 1976. (Cued in an unpublished report by Barr to Air Products and Chemicals, Inc, in 1981). 2. Baser ME, Tockmin MS. Kennedy TP Pulmonary function and respiratory symptoms in polyvinyl chlo ride fabrication workers. Am Rev Respir Dis 131 (1983) 203 -- 208. 3. Bauer PJ. Anthony PP, MacSwetn NM, Scheuer PJ. Angiosarcoma of the liver in Great Britain. 1963--73. Br Med J 2 (1977) 919-921. 4. Belli S. Beriazzi PA. Combi P. Foa V. Maliom C. Masina A, Pirasiu R. Regiannt A, Vigoiti MA. Indagine sulla niorialua dei produilori di PVC in Italia: Disegno dello studio c pnini risuliou. 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Tabcrshaw IR, Gaffey WR, Mortality study of workers in the manufacture ot vinyl Udonde and its polymers. J Occup Med 16 (1974) 509-518 46. Theriault G. Allard P. Cancer mortality of a group of Canadian workers exposed io unylchloride monomer. J Occup Med 23 (1981) 671-676 47. Turner CA, Payne AP, Qushby BR. Determination of ambient levels of vinyl chloride monomer (VCM) around utaiiufjcturers in ihe UK: Pari 7 Warren Spring Labo ratory, Department ot Trade and Industry, Stevenage (United Kingdom) 1984. 48. Viola PL, Bigotti A, Caputo A. Omogentc response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31 (1971) 516-519. 49. von Grciscr E, Rem! W, Weber H, Vinyl-chlorid ex position und mortality deutscher chemiearbeiter im vergleich zur morialuat nichtexpomerter chemiearbet* ter und PVC'verarbcitcr. Zemraibl Arbeusmcd Arbeitssch Prophyl Ergonomie 32 (1982) 44--62. 50. Waxweiier RJ. Stringer W, Wagoner JK, Jones J, Falk H. Carter C. Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Set 271 (1976) 40--48. Received for publication; 16 February 1988- SL 106768 ORIGINA Scj/id J I Assoc exhai Results by Jack Ron Oev fc fe re C\ kj Ar fui iaad. *.Q\ A> study was c cupattonal < About 20 s For each pa past exposi analytic sit at a time to remarkable This repc rfrVt Cincers ir; c bustion pro classes. Foe 3! busnon ene V depending o i jet fuel, or p from the "r substances: without dist a/ lamp oil), n. profile of pre Lx',- is considered a propane-bi \JT\1 * 1 Epidemtolof i'ii Institute An Canada. * Department < versity, Mor * Department University o Reprint reques vu <pidcmioio> I <4ppier, 531 f t jnjd.i. 117V I