Document LZwndrkXEJn6ZDK0Qa6n0Mnb

ISSN 0355-3140 n Volume 14, number 2, April 1988 CONTENTS Reviews 61 Effects of exposure lo vinyl chloiliide: An assessment of the evidence Sir R Doll Original articles 79 Associations between several sit is of cancer and fen types of exhausl and combusllon products: Results Iron a case-relerenl study in Montreal J Siemiatycki, M Grin. P Stewart. L Nadon R Dewar. L Richardson Effects of exposure lo Freon 11, 1 1,1-trichloroelhane or perchloroethylene on the lipid and fatty-acid composition of rat cerebral cortex T Kyrklund. P Kjeilstrand, KG Haglid 95 Influence of water on the perculah eous absorption of 2-buloxyelhanol in guinea pigs G Johanson. P FemstrOrfi 101 Percutaneous absorption ol 2- bu|loxyethanoi in man G Johanson. A Boman. B Dynesius 110 Prediction of early retirement on the basis of a health examination: An 11-year follow-up of 264 male employ >es in a Swedish pulp and paper company N E Aslrand. S O isacsson. GO Ojh agen 118 Comparison between surgeons a i id general practitioners with respect to cardiovascular and psychosocial risk actors among physicians BB ArnetZ, S Andreasson. M Strandberg, P Eneroth A Kallner 125 Invariants and noninvariants in ft e concept ol Interdependent effects S Greenland C Poole Case studies 130 Fatal arsenic poisoning -- A case report L Gerhardsson, E Dahlgren, A Eriksson, BEA Lagerkvist, J Lundstrom GF Nordberg Book reviews 134 Neurotoxicants and neurobiologi :at (unction: Ellects ol organoheavy metals 134 Ergonomics in computerized olli :es 135 Indoor radon and its hazards 136 Ergonomics at work 137 A manager's guide to ergonomic : m the electronic oil ice 138 Industrial radiation hazards desk yook 139 Announcements 140 Amendments and corrections SPI-01232 JOft REVIEWS Scand J Work En \ iron Head t I 4 ( I 9SS> 61--TH --- Effects of expos ure to vinyl chloride An assessment of th evidence by Sir Richard Doll, FRJ DOLL R Effects 01 posttre to vinvl chloride: An asse.ssment of the evidence Scand J ll'nrk Environ Health 14 (I9SR) M- This paper reviews the possible effects of vinvl chloride on the mortahtv of oc- cupanon.illv exposed men and the carcinogenic effects that might be observed in the general population 3S a result of envirom lental pollution with vinvl chloride. The results of four studies fulfilling the criteria of pros idme xtibst an al numbers of ohserv.11 ions more than 25 sears alter first exposure and covering ( 3 period long enough or more than 10 *0 of the workers to have been expected to die constitute the basis for the assessment of ihe occupational hazards. Other studies provide onlv supplementary information, The data permit two onclusions First, men occupationally exposed 10 vinvl chlonde have experienced a specific hazard of ; ngioarcoma of the liver Second, anv other occupational hazards that may have existed have been sm il No positive evidence of a hazard of anv nonmahenam disease or any type of cancer other than ant osarcoma of the liver has been found except possibly for a small Hazard of lung cancer when exposure was heavv. More definite conclusions might be reached if those who have studied exposed emplovees o jld present thetr results in appropriate and comparable wavs. A very smail risk of niigiosarcomn ntav ha e occurred as a result of vinvl chloride escaping into the environment around plants handling \invI chloric : in the past, but the evidence indicates that the current risk to the general public (if any) must be negl nbie. At'v terms; angtosarct1 ma of the liver, cancer, lung cancer, mortality, polyvinyl chloride, review, vinyl chloride monomer j ) 608 644 (redactory ni number jo.00 air mail address above. maged issues unless l >1 i | j i ! | ight Clearance Cemer ,e internal or personal enter s Transactional page, is paid directly -ations that have been The fee code for users ( 1 I or many years the inhala ion of large amounts of s mvl chloride has been reco tnized as potentially hazardotis. Concentrations of t order of 10 000 ppm in the air induce unconscious r ess and cardiac arrhvthnna. while prolonged expo< ure to concentrations an order of magnitude lower h ive been liable to cause a specific pathological svndr erne. This "vinyl chloride illness" has been characters ;d by four cardinal signs, namely, enlargement of (It liver and spleen with a specific histological nppeara ice, patchy infiltration of the skin resembling sclerode ma. bony changes in the tips of the fingers describe:) as acroosteolysis. and peripheral circulatory chang :s identical with the classical picture of Raynaud's isease. These pathologicai reactions may occur smglj or together and may pos sibly be accompanied hv ot ter less characteristic effects. They can, however, be completely avoided if exposure never exceeds the lev :l of a few hundred parts per million. ie. the level t which exposures were generally reduced in the mi I-1960s. One other serious effect ha , however, been observed that may not be avoidable the same relatively easy wav, namely, the product!lor of angiosarcoma of the liver. It must, indeed, be p umed that some risk of developing the disease will aersist from exposure to 1 Imperial Cancer Research This 1, Cancer Epidemiology and Clmicnl Trials Umi. Radclul Infirmary, Oxford. United kingdom. Reprint rcpticsls io: Sir R l)ol Imperial Cancer Research t mid. t1111 versil sni Oxloi d. , son Building. The Radcliffe Infirmary. Oxtord 0X2 6HL. jnued Kingdom. I doses that are even lower than the current industrial levels of 5 ppin or less, as vinyl chloride has been shown to act as a mutagen (23). and it cannot be assumed that a threshold exists below which no carcinogenic risk persists. Moreover, the possibility has to be considered that vinyl chloride may cause some cancers other than angiosarcoma of the liver, partly because laboratory studies have shown that it causes other cancers in animal experiments and partly because the initial studies demonstrating the production of angiosarcoma of the liver in humans were inadequate in size to ex clude a material increase in the risk of cancer in com mon sues, 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 an humans that cannot be seen easily in animal experiments (by, for example, producing chronic respiratory disease), and, as it is a mutagen, there is also a possibility that it may act as a teratogen and cause congenital malformations in offspring. In this review I have not examined the possibility that vinyl chloride acts as a teratogen or that it causes mutations in germ cells, as there is too little serious evidence to justify inclusion. Reviews carried out for sections of the industry bv Downs et al (unpublished report to the Society of Plastic Industries Inc in 1977) 61 and by MacMahon (unpublished report to theC temical Manutacturers Association in 1977) concluded that the leu reports of positive effects could not be sub stantiated. and no additional evidence was fou id in a similar later review by Barr (unpublished report lo Air Products and Chemicals Inc in 1981), apart from a report that embryos were absorbed and skelet il os sification was produced when pregnant rats we e ex posed to doses appreciably lower than those thaf had been used by other workers without any such e feets being observed. The report of absorbed embryo (34) could not be evaluated thoroughly, however, as tile ex periment was inadequately described. I have, therefore, examined only the possible effects on the per onal health of men occupationally exposed to vinyl hloride, other than those related to their reprodc ctive capacity, and the carcinogenic effects that might con ceivably be observed in the general population as a result of the widespread distribution of vinyl chloride as a pollutant. Occupational hazards Many studies of workers exposed to vinyl chloride in the manufacture of vinyl chloride monomer (V M) and polyvinyl chloride (PVC) have been under! ken since it was first found that vinyl chloride could cl^use cancer in animals (28, 48) and man (10). These it) vesligations have confirmed that exposure causes a hazard of angiosarcoma of the liver and, in several instances, have shown excess incidence or mortality (ates that were conventionally statistically significant lor other diseases. Conventional tests of statistical sig tificance are, however, designed to help answer siigle 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 dozer s of rates are examined in each of several sets of inde ten dent data. Scientists have, therefore, been faced vith the problem of deciding whether the excess rates hat have been observed in individual studies are due tq oc* cupational hazards or to the vagaries of chance This problem can be solved in part with an ex nation of the results of a sumaiion of data from com parable studies, that is, by a comparison of the s ims of the numbers of deaths observed and expecte I in each study. This procedure does not require the as sumption that the exposures have been the same in <ach study any more than the same assumption is requ red for each individual when the results of each study are considered alone. It does require however that t ach exposed population has been observed over a pci iod when us members were at risk of developing disi ase (if a genuine hazard existed) and that in each st tdy thereierence population from which the expected n lin kers ui deaths were det ived was appropriate tlha at the same risk ol developing disease as the exptised popu l.i n would lusc been in I lie absence ol e XIIO- surel. These requirements do not introduce any new complexity, as both are. ol course, also required if cor rect conclusions are lo be drawn Irotn the results ol the individual studies when they are examined on their own. Sources of information Four studies meet the aforementioned requirements, namely, two large national surveys, one reported by Jones (25) lor the United kingdom (UK) and the other by Environmental Health Associates (14) for ihe United Stales (US), and studies of Individual plants in Canada, reported by Theriault & Allard (46) and in Italy, reported (as a part of a national study) by Belli et al (4). All four include observations on men mure lhan 25 years after their first exposure, and the ex pected number of deaths is. in each case, greater than 10 ma of the total number of employees, a value indi cating a long average period at risk. Earlier observa tions on UK and US employees (6. 9, 12, 16, 20, 36, 39, 40, 45. 50) have been subsumed in the national sur veys and now serve only as sources of hypotheses and of some detailed information not included in the na tional reports. Studies of German (49), Norwegian (22), Swedish (7). French (4 I, and unpublished report of Laplanche et al), Japanese (33, 37), and some other Italian (4) workers provide some supplementary infor mation, but, in general, the periods ol observation have not been long enough for usclul epidemiologic data to be obtained about diseases that are unlikely to occur within 20 years of first exposure, or they report only selected results which are difficult to In terpret, as only excess rates tend to have been selected. Studies of makers of PVC products have not been included, as the workers have had much less expusuie to vinyl chloride than those employed in the mamilacture of VCM or PVC and any occupational hazard to which they may have been exposed is more likely to have been produced by PVC dust. US study. The study carried out by Environmental Health Associates (14) on behalf of the US Chemical Manufacturers Association is the largest and most In formative investigation thus far undertaken. It cov ered 10 173 men who had worked in 37 plants owned by 17 companies -- I 214 men in II plants that produced only VCM, 6 848 men in 18 plants that produced only PVC, 935 men in three plants that produced both, and I 176 men in five plants that produced homopolymers and copolymers, with or without VCM or PVC. Twenty-two of the plants were in the southern part of the country, 14 were in the northeastern or north central parts, and one was in the west. Men were included if iliey had been exposed to vinyl chloride for at least a year bclurc 31 December 1972 and had been employed m 1942 or subsequently (the tirst year depending oil the dale ilic pi.ml I'ee.m making or using vi sonnel recc was tlie lat identified sonnel. Racial ch 97 'o of wl (he purpos deaths, tha Follow-n cial Security died after 11 plants did m (9) earlier s present inve plants who 1972 were r follow-up w 1982, whiche of the men w untraced wer which was us Almost hal before 1955. served more t many cases to a long latencs Short-term cohort, and n ployinent for ; lor 10 years ot ! ployment beim i Fifteen hunts | have died. In I i tamed from the tamed for the i The number1 causes or grou plying the persi national rates l age groups anc This importa cisms, which at effects on the re compiled by co cords without at sumption that a caused the expo, underestimated, lo have had hie reason lor suppo the proportion o necessarily repretainty was introd as 7 J of ihe T" o other cm expelled mmihvi imipinm ih.u II "IV MJ. >1 1. 11,; \ i . 62 SPI-01234 roducc any ne* o required tf corim the result of cammed on their ed requirements. . one reported by JK) and the other ites (I*) for the individual plants t Allard (46) and >nal study) by Belli ons on men more isure, and the excase, greater than iyees. a value indit. Earlier observa.9. 12. 16. 20. 36. in the national surof hypotheses and included in the nan (49), Norwegian unpublished report 37), and some other jpplememary inforods of observation seful epidemiologic es thal are unhkelv t exposure, or (hey l are difficult to inj have been selected, ducts have not been J much less exposure nyed in the manufaccupational hazard to sed is more likely to JSl. ut by Environmental f of the US Chemical ie largest and most inr undertaken. It cov ed in 37 plants owned ,en in I I plants ihat nen in 18 plants that i in three plants that en in five plants that copolymers, with or :re in the southern part northeastern or north the west. id been exposed to vinyl fore 31 December 1972 42 or subsequenilv (the ; the plant began making ur using vinyl chloric mi the earliest dale that per- sonnel records were deemeq to be complete, whichever was the later). Individuals ho met these criteria were identified from company ecords by company per- sonnel. Racial characteristics wer| known only for 686 men, 97 % of whom were white and it was presumed, for the purpose of estimating [he number of expected deaths, that all 10 173 me i were while. Follow-up data were obiai ned from plant and So- cial Security Admimstratior records and (for men who died after 1979) from the f tional Deaih Index. Five plants did not collaborate tn| the extension of Cooper's (9) earlier study, which h been subsumed in the present investigation, and the 955 employees in these plants who were known to be alive on 31 December 1972 were not followed a y further. For the resl. follow-up was attempted death or 31 December 1982, whichever was the ear| ter. On this basis 92.7 ri [ of the men were successful! traced. Those who were I untraccd were excluded fro ihe last date of comact, i which was usually the date hen employment ceased. [ Almost half of the men ((46 *0) were first employed i before 1955. A large propo^t ion was. therefore, ob- E served more than 25 years a ter first exposure (and in t many cases for more than 30| years) when diseases wuh f a long latency period mightj be expected to be seen, \ Short-term workers had been excluded from the j cohort, and most of the m n had continued in cm- f ploymem for many years, t o-thirds being employed ^ for 10 years or more and ih average duration of cm- 'i ploymcnt being 16 years. * Fifteen hundred and thiirty six men were found io i have died. In I 439 cases, t f e cause of death was ob- f tained from the death cert ific a te, but no cause was un lained for the other 97 per:ions (6.3 %). The numbers of deaths pected from each of 38 causes or groups of causes |were obtained by multi- plying the person-years at ri k by the disease-specific 5 national rates for white mat ^s. for the corresponding r 6- age groups and five-year This important study is i:iondstootfhrtehee study. minor criii- r. cisms, which are unlikely id Itave had any material effects on the results. First, t Ije lists of employees were compiled by company persd nnei from company re- cords without any independent t check. Second, the as- sumption thal ail the em es were while will have tie:-" caused the expected deaths t {> have been very slightly -J&^.' ltnderestimaied, as the few b ack employees are likely ">> have had higher mortalijy rates and there is no reason for supposing that the [tmall sample from which * the proportion of black em plbyeees was estimated was \,'j necessarily representative T..h.t rd, an element of uncer- gjfoy tainty was introduced by the failure to trace as many as 7.3 *7o of the employees. 6." Two other criticisms are m|are important. First, the t expected numbers of deaths vere calculated on the as- j sumption thal the men wou| id have experienced the t same mortality rates as ihe liite male population of !he wl-.ile counti the corresponding daicx Hie use of national rales is common practice in studies oi in dustrial populations and tends to result in an overestimation of the expected numbers of deaths so that the employees appear to be unusually healthy. This "healthy worker effect" is well known and has been taken into account in my discussion of the results. A more serious objection to the use of national rates is ihe 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 io use state (if noi coumy) rates in place of national rates. With 37 plants, however, it might be thought [hat their geographic distribution would be sufficiently wide to make the use of national rates appropriate. Unfortunately 22 of the plants were located in the south, and a check would have been desirable to see whether (heir location could have caused any material distortion of the results. Second, causes were not obtained for 97 of the I 536 deaths. This deficiency was allowed for in the calcu lation of ihe overall mortalily by ihe inclusion of deaths due to unknown causes. It was not allowed for. how ever. in the calculation of the disease-specific mortality rates and will have caused the standardized mortality ratios to be underestimated by an average of 6.3 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 (25 and un published) on behalf of the British Health and Safety Executive covered 5 498 men who were employed for at least one year in jobs that involved potential expo sure to VCM for at least 25 Vt 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 "~i>). Seven hundred and eighty deaths were identified, and copies of the death certificates [coded to the eighth revision of the International Classifica tion of Diseases (ICD) if they occurred before 1979 and to the ninth revision if they occurred later] were sent to the investigators. Several specific points about the study need to be noted. First, national mortality rates for England and Wales were calculated for five-year age groups over quinquennial periods for 66 causes of death, and these rates were used in the estimation of the numbers of deaths that might have been expected in the cohort by multiplying them by the corresponding numbers of person-years under observation. Some difficulty which could have been related to the causes of death being 63 coded according 10 the eighth and ninth revisio is of the IC'D was, however, experienced in obtaining suit able rates for all causes of death, and rates lor a rela tively late period had to be used for esttmatin ; the numbers of deaths from many diseases that might have been expected to occur in earlier periods. For two categories the earliest available rates were I960-- 964, for one they were 1965 -- 1969, for 24 they were 1970-- 1974, and for one they were 1975--1979. Second, an attempt was made to classify met ac cording to whether they had high, intermediate, oi low exposure to VCM or PVC dust, and each man's em ployment history was recorded according to 12 job titles with advice from the plants concerned. The men were then grouped according to whether exposui e to VCM was likely to have been high (group A), e iposure to PVC dust was likely to have been high vith exposure to VCM low (group B), or exposure to V CM and PVC dust was intermediate and intermittent (group C). All other men, who would generally I ave had low exposure to both VCM and PVC dust, were classed as group D, Within all the groups, expo ,ure 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 v nyl chloride. The use of national rates to calculate the ex pected numbers of deaths may be justified on the grounds that the men were employed in nine plaits, which were presumably distributed about the coun :ry, but no details of their location are given. In general, mortality rates tend to be higher in the parts of Bri ain where heavy industry is located than in other part; 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 nt mbers of deaths from many specific causes of death vas presumably necessary if the diseases were to be slue ied individually and will have done no harm if the inci dence and fatality of the diseases in question remai ted stable. It would have been desirable, however, for he diseases to have been specified so that the reader wo aid know which were liable to be distorted. The system used to classify the men into four ex >osure groups is the sort of system that is commonly u ed if precise measures of exposure are not available It creates some difficulties in the statistical analysis if n en move from one job to another and are classed (as in this instance) as having had high exposure if they ht ve ever had a particular type of employment (eg, ever tx en employed as an autoclave worker). No evidence is p ovtded to show [hat the person-years ai risk befor1 a man entered the category have been subtracted aid added to another exposure group before the numb :rs of expected deaths were calculated. Movement frt m one job to anoilier said to have tended to be cut ol groups a jud H into 1). but even so it must ae presumed that the expected numbers of deaths in the first two exposure categories are likely to have been overestimated. Canadian study. The Canadian study (46) was limited to employees of a single plant in Shawintgan, Quebec. The plant, which was situated in an industrial com plex, was opened in 1943. VCM and PVC were both made until the late 1960s, when the production of VCM ceased, while the production of PVC continued. An anempt was made to trace all the production work ers whose names appeared on the unions' lisls or the payrolls of the companies in ihe whole industrial com plex, including the vinyl chloride plant, between I January 1948 and 3 I December 1972, and contact was made with the worker or his next-of-kin in I 61 I out of I 659 instances (97.1 ^o). Detailed occupational and smoking histories were obiained by questionnaire, and 156 men who had been employed by ihe companies for less than five years were excluded. The remaining men were categorized as (i) exposed to VCM if they had worked on the production of VCM or PVC for at least five years (451 men), (ii) unexposed lo VCM if they had worked similarly for less than six months (870 men), and (iii) other men (134 in total). The last group was excluded from the study. Follow-up was closed on 3 I 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 ihe ICD. Informa tion was also sought for histological or cytological con firmation of all the diagnoses for all the exposed men who had died of cancer. The results were examined in two ways. First, the mortalities of the exposed and unexposed men were compared after standardization for five-year periods of the study and five-year age groups. Second, the mor tality of ihe exposed men was compared with that ex pected if the men had had the sex- and age-specific mortality rates recorded in Quebec for the year 1971. In both comparisons the causes of death used were those specified on the death certificate, and the addi tional pathological information was used later only for interpretation of the results. Most of the exposed men were exposed for more than 10 years (75 do), the average length of exposure was approximately 17 years, and 44 dt 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 ail eight cancers diagnosed as liver cancer (including two specified as hepatoma and one specified as angio sarcoma) were angiosarcomas of die liver, as well as one that had been diagnosed as angiosarcoma of the peritoneum. Two other cases of angiosarcoma ot the liver were found to have been ccrtilied js hepatic cir rhosis. It is also help I III I o has e a colli pa I ISOM beiweeii I i the exposes companies for all non a healthy w recording o f nant causes I 0.951. One aspei I ie. the use i calculate ex period (1948 to bunch up I vation so th have been la some distorti sue land eve estimate. Foi likely to hav Italian study. duction of vin was begun in employed for start up of th< still incomplei f m three plant stgnana) begat thirty-seven m in the other. Al. followed to the c mated by multi: corresponding i year age group a The total expec more than 10 " (12.4 and 12.8 Clinical mfot death of all the had died. Revis comparison wit deaths from ca The Ravenna 1959. Six hundre A(l but four we were found to h; lowed for more (3.9 *!t of the wc this plant have r cipal analyses. I death was attrtbi peeted. F Cither sources. Th wi v .iiioiiv on 4 5'"I hi I clcnui k . I'l-n , , ' 64 SPI-01236 oi Je.itI" 1 I"-' :lv io have been (46) was limned wtntgan. Quebec, i industrial com* 1 PVC vxere both ie production of f PVC continued, production work mens' lists or the ile industrial complant. between I l, and contact was .f-kin in I 611 oul j occupational and questionnaire, and by the companies ed. The remaining ;d to VCM if they VCM or PVC for inexposed to VCM s5 than six months 4 in total). The last dy. Follow-up was ies of the death cer uses for all who had sed) were coded acthe ICD. Informail or cvtological conall the exposed men two ways. First, the inexposed men were for five-year periods ips. Second, the mormpared with that ex;ex- and age-specific ec for the year 1971. , of death used were ificate. and the addivas used later only for ere exposed for more ge length or exposure d 44 ro were observed exposure. ikes a useful contribuhistological review of helpful. It showed that liver cancer (including one specified as angtoof the liver, as well as is angiosarcoma of the of angiosarcoma of the certified as hepatic ar ea comparison between I lie exposed and 11 in. . os d" empiovees ol the same companies as it shows that lie low mortality observed for all nomitaiignant discak es could be attributed to l healthy worker effect ant was not due to bias in the recording of exposure (rela|t ive risk for all nonmahgnant causes compared to th; t of the "une.xposed" men 0.95). One aspect of (he study h is to be criticized however, ie. the use of provincial ra es for one year (1971) to calculate expected mortali y spread over a 30-vear period (1948 to 1977 inclusi :). Deaths will have tended to bunch up towards the e d of the period of observation so that the rates foil this particular year may have been fairly representan It. but it must have caused tome distortion of the expec| ed numbers of deaths, the lire (and even the direction of which is impossible to estimate. For most disease g|roups the distortion is unlikely to have been large. Itahan study. A study of all |mcn employed in the production of vinyl chloride and PVC in nine Italian plants as begun in 1983. All mer were included who were employed for at least six mi nths at any lime from the Marl up of the plant to the ^nd of 1981. The study is Mill incomplete, but results re now available for men In three plants (4). Two pi knts (in Ferrara and Rosignana) began operation inj 1953. Four hundred and thirty-seven men were em pii ryed in one plant and 181 in the other. All but three ( fn >im the Ferrara plant) were followed to the end of 1984 fax peeled deaths were esttmated by multiplying the p* rson-years at risk by the corresponding national mo tality rates for each five- Iyear age group and each five|-year period of the study. The total expected deaths i each case amounted to more than 10 wo of the em tloyees in the two plants (12.4 and 12.8 o). Clinical information was ought about the cause of death of all the 55 employee of the Ferrara plant who had died. Revised diagnoses which were not used for comparison with the expec tied deaths, revealed four deaths from cancers of the iver in place of one. The Ravenna plant did 4ot begin operation until j959. Six hundred 2nd thirtv tight men were employed, *,ut *ur were traced 10 the end of 1983, and 17 : found to have died. No man could have been fol- for more than 24 year s. and only 25.1 deaths 1 of the work force) wt re expected. The data for jhju* plant have not, therefoi ie, been used in the prin J5'$S?dpl analyses. It may be nted, however, that one ' death was attributed to liver cancer when 0.1 was exky;< petted. Other sources. The Norwegiaj|in study (22) provided obtervations on 454 men who had been employed in a piant in Telemark where VCfi'1 had been manufactured (rom 1950 to 1971 and Pvd from 1950 to the end of the vudv period. -rv man was included w hose name was recorded in (he company's personnel register and health department records who had ever been em ployed from the start of production to the end of 1969 and had worked for at least one year. The men were followed from 1953 to 1979 inclusive. Deaths and cases of cancer were identified from the records of the Cen tral Bureau of Statistics and the national cancer regis try. No reference was made to any men being lost to follow-up, but it can be assumed that the number (if not zero) was small, as all citizens have an identity number which is used by both employers and central agencies. Fifty men were found to have died against 59.34 expected if the sex-, age-, and quinquenmumspectfic national mortality rales had operated. Twentvone men were found to have developed 23 cancers against 20.16 cancers expected from the comparable national incidence rates, the use of which was justi fied by the finding that the incidence in the county in which the plant was situated was between 90 and 95 of the rate of the country as a whole. One man who had been employed in PVC production developed an giosarcoma of the liver. The observed and expected numbers of cases were given for cancers of the lung, colon, and thyroid, for melanomas, and for all can cers, but no expected numbers were given for other types of cancer. It is evident that several other types of cancer must have been in deficit, as there were eight cases in all against 14.93 expected, and it is difficult to know what weight to give the excesses observed for the reported types of cancer, as they seem likely to have been reported specifically because the numbers were in excess of those expected. The authors noted that one further case of melanoma had occurred after the closure of the study and that one "incipient case" was also known to them. The German study (49) included the following three groups: (i) 7 021 men who had been exposed to VC in the course of their employment in any of the 11 plants in which VC and PVC had been produced in the Federal Republic of Germany, (ii) 4 820 men who had been employed in seven chemical plants without having had any exposure to vinyl chloride, and (iii) 4 007 men employed in two other plants where PVC was processed, tmployees 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 lime of opening of the plants to the end of 1974, and they were followed tolhe end of 1974. Many of the men were therefore observed for only a few years after first employment, and only 14, 36, and 19 respectively, of the three groups were first em ployed before 1954 and were therefore capable of con tributing person-years at risk more than 20 years after first employment, when an occupational hazard of can cer could be expected to be observed. 65 l Of [he exposed group 93.2 To were successfully fol lowed. and causes of death were discovered lor 92.! To of [he 414 men discovered lo have died. The propornons for the other two groups were respectively 19.8 and 88.7 <ro for the unexposed and 92.1 and 86.! To for the PVC process workers. The failure to ob am causes of death for all the men who had died vas allowed for in the subsequent analysis by the weight ing of the numbers attributed to each cause by a ystem which took account of the age group and ca endar period in which death with an unknown cause oc curred. The expected numbers of deaths from etch cause was calculated by multiplying the person-ytars at risk by the sex-, age-, and cause-specific mortality rates for the Federal Republic of Germany. National data before 1968 used an idiosyncratic classificat on system, and the 1968 rates had to be used to multiply all the person-years at risk up to the end of 1968. :or subsequent years (1969 to 1974) the person-years at isk were multiplied by the corresponding rales for the s< me calendar year. Epidemiologic studies are more difficult to carry jut in the Federal Republic of Germany than in North America, the United Kingdom, or Scandinavia because the medical cause of death is not recorded publicly, and there is no central system which can be used ror checking whether an individual is alive or dead. In these circumstances, the German authors have mt de valiant efforts to obtain reliable data, and the propor tions of men in the exposed groups who were not s iccessfully followed (6.8 To) and the proportions of deaths for which the cause was not obtained (7.2 To) were similar to those in the study of the Environmer tal Health Associates (14). Two defects, however, make the data less useful. First, no national mortality rates were available bef ire 1968, and the use of (he 1968 rates to estimate the nu li bers of deaths in and before 1968 will have overe timated the numbers attributable to diseases that w :re becoming more prevalent or were being diagnoied more often and underestimated those due to disea es that were becoming less prevalent. Second, and mt re' importantly, a large proportion of the men had bten first employed less than 10 years before the follow- jp ended. Therefore the useful observations on the f :w men who had been exposed long enough to have hid much chance of developing an occupational disci se with a long latency period must have been swamped by a mass of other observations that had little to cc ntribute. The expected deaths amounted to only 6.2 To of the exposed men, and there is, therefore, little to be gained, and something to be lost, by including tie German data in the overview. It may be noted, hovcver, ihat 12 deaths were attributed to cancer of tie liver among [he workers exposed to vinyl chloriJe aguinsi o 9 expected and that smaller excesses were alto observed among the unexposed chemical workers (4 observed uguinst II expected) and [he I* V C 7 proctss workers i' deaths against 0 8 expected). Two Swedish plants have produced VCM and PVC, one since 1945 and ihe oiher since 1971, and employees of the first plant have been studied by Byren et al (7). All persons who had ever been employed when expo sure to VCM could occur were listed from the per sonnel files of the factory. Twenty-one were excluded because they were foreigners who left ihe country after a short period of employment. The remaining 750 were followed to October 1974. Expected numbers of deaths were estimated by multiplying the person-years at risk by the corresponding age-specific mortality rates for the whole country, and the expected numbers of can cer cases from 1958 to 1971 inclusive (during which period all cancer cases had been registered nationally) were estimated by multiplying by (he national agespecific cancer incidence rates. In both instances, the rates used were those recorded in 1969. Fifty-eight deaths were found, but no figure was given for the ex pected number. Detailed figures were given only for ihe numbers of deaths and cases observed and expected for cancer of the lung and for cancers of the liver and pancreas combined and for ihe numbers of deaths from brain cancer and three categories of cardiovas cular disease. Two men known to have angiosarcoma of the liver were certified as having died of liver can cer or pancreatic cancer, and a third man died of angiosarcoma of the liver 17 months alter the close of the follow-up. Two French studies provide the results of a long term follow-up of men employed in one plant (41) and of a short-term follow-up of men employed in 12 plants (Laplanche et al, unpublished). The first provided ob servations on I 311 men exposed to vinyl chloride in the production of VCM and PVC and in selected an cillary operations from the opening ol the Tavaux plant in 1953 to the end of 1976 (41). Six other employees were excluded from the study because of lack of oc cupational histories and 160 men because their vital status at the end of the study period was undetermined. Twenty-five men were found to have died against 48.75 expected from contemporaneous sex- and age-specific national mortality rates (3.7 To of the men at risk). One death was attributed to angiosarcoma of the liver, in a man who had been exposed for more than 15 years. The reported data are so incomplete and cover such a relatively short period from the opening of the plant that they add nothing of epidemiologic value to the results of the other studies, apart from the addition of a further case of angiosarcoma. The second study provided observations on 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 ol ihe cohort studied by Pierre et al (41). The men were followed lor live years, and their morbidity .mil mort.iluv were com pared with [hose observed l<u I It<* men ol die s.imc ago ( 2 ye; but who hat in both groi formation ; drinking hah two groups, first exposed first been em ously. Morbi nually by the 98 % of the One of the ex developed an given separat ploymem, am of the lindini lung cancer a well reflect a i in Ihe rcleren cancers in tha One exposed i hematopoietic none of the m developed me: roid. A Japanese pertence of 4 5 before 1965 in ducing VCM i vive (37). The r Twenty-eight p than 20 years al served more thai untraced, and a tamed for all the initial cohort), to the job in wl it the terminati given separately in PVC produc classed as VCM If this study should provide t r present data inch . than 20 years aft use. They confii l>< cancer with six workers against IfiA while only one < Other workers ai deaths from liver workers was cert liver, and at least was due to the s; not in excess(2 o ex pc, ted). No da ; Ii.iiic .mil hem.i mi oi iln i, ii,l SPI-01238 /CM and PVC , and employees Bvren et al ('). yed when expoJ from the per;e were excluded he country after naming 750 were imbers of deaths 50n-years at risk jrtality rales for numbers of cane (during which tered nationally) he national ageith instances, the 1969. Fifty-eight , given for the exre given only for rved and expected rs of the liver and imbers of deaths ries of cardiovasive angiosarcoma died of liver caniird man died of hs after the close results of a longone plant (41) and ployed in 12 plants First provided obo vinyl chloride in and in selected anr the Tavaux plant . other employees ause of lack of ocbecause their 'ital was undetermined e died against 48 '5 ;x- and age-specific ie men at risk). One ima of the liver, in nnre ihan 15 sears, lete and cover such opening of the plant :ologic value to the ; from the addition 1a. servations on I 100 1980, were exposed loride in 12 plants, rench VCM polymunpublished) Many mployed at Tavaux if the cohort studied :re followed for five mortality were com100 men of the same ( t I scarM v.lu) 'Aac c v|cd m the 'jmt plants but who had never been cxposell lo VCM. The men ta both groups were interviewed personally, and m- formation was obtained about thcir smoking and drinking habits, which were foul d to be similar m the two groups. The men in the exp jised group had been flra exposed for an average of a out 4 years and had flnt been employed in the plant bout I 8 years previ- QWly. Morbidity and mortality d ta were recorded an- uady by the plant physician. Ho successfullv traced 9d 84 of the exposed men and Vo of [he referents, .Ooeof the exposed men, but non of those unexposed, ^developed an angiosarcoma of th liver. Data were not given separately for different p^ riods after first cm- bpteyment. and it is impossible to ssess the significance ot (he finding that six of the ex prosed men developed lung cancer against two of the ferents. which may *dJ reflect a chance occurrence o unusually few cases in ihe reference group, as the p rloportion of all lung cancers in that group (2 out of I 5 I was unusually low. One exposed man developed a c t ncer of the lymphoIwruiopoieiic system against non[ of the referents, but ooeof the men in either group Iwere known to have developed melanomas or cancer [of the brain or thyraid. - A Japanese study has reported the mortality expetience of 4 524 men employed |for at least one year before 1965 in 25 Japanese plan s which began prodwdng VCM or PVC between I 949 and 1964 incluMve (37). The men were followed to 3 I October 1975. Twenty-eight percent of the men [were observed more rfcan20 years after first emplovnie t, but none was obvervrd more than 26 years. Only 0. 6 Vo of the men were atraced, and copies of the death Certificates were ob- lamed for all the 209 men whoi hap died (4.6 Vo of the iouuI cohort). Individuals were Classified according h> Ibc job in which thev had beep longest employed M the termination of their folio -up, and data were prtn separately for the 2 546 men| classed as employed in PVC production and I 978 o i hers (including 900 m. iktxed as VCM production wo r ters). If this study is continued for mother 10 years, it tbosdd provide useful additional formation, but the proem data include too few obserRations on men more 20 years alter first exposure be ol any material They confirm the evidence 4>f a hazard of liver with six deaths among ( PVC production ,er* against 2.54 expected flom national rates, only one such death was Observed among the workers against 1.82 expedied,. One of the six hs from liver cancer among the Pi VC production km was certified as due to angiosarcoma of the . and at least one of the othei| liver cancer deaths due to the same cause. Lung cancer deaths were in excess (2 observed in PVC porkers against 2.33 expected). No data were given for| cancers of the lympfuiie and hematopoietic system , for cancer of the brain or thyroid, or for melano (nas. The mortality repented by Masuda (33) for 305 apanese vinyl chlo- rule vvor*e.r. has presu. abiv been M.bsumcd m Na* kamura's (37) later and larger study. Hazards of cancer The results of the four most useful studies are listed individually in tables I and 2. The overall results for all causes, liver cancer, and three broad groups of con ditions are shown in table 3, and those for 10 types, or classes, of cancer are presented m 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 mortality is what would be anticipated for an industry without any major hazard of accident or disease. In particular the standardized mortality ratio (SMR) of 84 for diseases other than cancer is typical of the ratios that are commonly observed for groups of employed men. A low SMR of this order reflects the "healthy worker effect," which results from the selection process that inevitably excludes some of the least healthy members of the population from indus trial employment. This effect does not. however, nor mally affect the mortality from cancer beyond that ob served in the first few years after the start of employ ment, and an SMR of 102 for cancers other than can cer of the liver is compatible both with the absence of hazard and with SMR values of 84 for other diseases and 77 for accidents, poisonings, and violence. Angiosarcoma. Death certificates are an unreliable source of information about the histology of cancers that cause death, but there is no reason to suppose that the excess mortality attributed to liver cancer (or, in the US senes, 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 of the 11 deaths attributed to liver cancer, not specified as secondary, were known to be angiosarcomas, and they all occurred in auto clave workers against 0.38 expected liver cancers of all types (P< 10~') (25). In the Canadian series, histo logical review showed that seven of the eight so-called liver cancers were angiosarcomas (one had been de scribed as an angiosarcoma on the death certificate, two as hepatomas, and five as unspecified liver can cers). One so-called liver cancer death was found to have been due to cancer of the sigmoid colon, while one death attributed to angiosarcoma of the perito-1 1 Increased to 39 in table I to take account of the 97 extra deaths from an unknown cause. 67 T#bi* ' Observed and expected numbers o( deaths (rgm difiorom cancers roDonea m me fcur ormcipal siudtes (4,14. 25, ifil (0 = observed number ol deaths. E = expected numbe ot deaths) Type or ctass ot cancer United States 0* United Kingdom 0E Canada 0E Italy O E 8ucca/ cavity and pharynx Esopnagus Stomach Large intestine Rectum Liver Liver and gallbladder Pancreas Other digestive Larynx Lung Other respiratory Bone Skin monrneianoma Melanoma Prostate Testis Bladder Kidney Other and unspecified urinary Brain Eye and central nervous system Thyroid Lympho- and retlculosarcoma Hodgkin's disease Leukemia Multiple myeloma 1 Other lymphatic ) Other Atl cancers 13 tl 55 7 8.07 11 16 01 21 28.79 39 5.77 17 18.40 118 115.87 5 6.38 2 1 81 6 7.36 16 15.20 5 8.46 12 906 25 12.76 12 7.98 3 5 45 14 13.94 46 40 50 383 341 73 4 3 58 6 14 34 26 23 91 9 13 94 11 10 49 11 1 94 7 9 83 4 2 21 81 92.12 0 0 64 8 0 14 6 5 26 2 5.78 2 t 74 12 9 59 2 1 38 14 8 00 3 4 10 3 4.29 4 6.18 2 0 43 4 2 35 3 2.50 7 5.16 2 2 35 18 8.12 235 228 60 ` 0 60 1 1.67 2 0 95 20 16 37 1 08 1 06 3 30 0 i2 1 06 0 0.7 1 09 12 6 1 0 02 i 07 1 07 0 04 0 07 9 45 30 211 Observed deaths multiplied by i 0674 and rounded off to tt e nearest integer to allow lor deaths without discovered cause Table 2. Numbers of deaths from nonmaiignant and all cause: reported in the lour principal studies (4. M, 25. 46). (0 = observed numper ol deaths. = expected number ot deaths) Causa ol deatn United Slates 0* e United Kingdom OE Canada 06 Benign and other unspecified tumors Ceredrovaacular disease ischemic hean disease Omar circulatory disease Bronchitis* Pneumonia Other respiratory disease Cirrhosis of the liver Other digestive disease Disease of the genitourinary system Other diseases Suicide Accidents and other violence 4 5.08 75 91 93 521 597.73 276 157 123 55 105 44 22.83 38 10 15 31.94 32.84 j 1 40 37 56.06' 5 27 39.52 11 20.41 67 115.68 43 49 52.78 1 130 173.19 40 288 141 644, i1 5. 11 78 50 am nonmaiignant causes 1 153 1 363.54 545 665 All causes 1 538 1 705.27 780 894 25 31.67 1 1 . 6 3.21 4 3 85 r* 5 40 2 10.58 39 54.76 59 71 07 * See footnote to table 1. 4 Emohysema In data from the United States e Includes two cases certified as cirrhosis of the liver which proved fo be angiosarcoma of the liver. 4 includes one case with cause unknown. Italy OE 0 0.5 19 27 4 3 5.0 4 5.2 3 2.7 2 70 1 0.9 4 7.7 36 56 4 66 77.5 neum was found to have been due to angiosarcoma of the* liver UiS). In (lie Italian study, lurcher evidence revealed ihjt three further deaths should have been at tributed to cancer of the liver (for a toraf of four), but only one of the lour was described as .m angiosarcoma (4). ** V 4> f TeWe 4. Mort. (O s observed or class r Mouth and pru 0ge*tive syste Respiratory sy*. Lung Genitrunnary < U*i*noma 6'am * hyiOld lrnphattc and Ciher aii otner than o 1 s United Sfa Y Table 5. Mortality hum&ar of deaths Type or class of c Oigestive system ^excluding tne iiv Umg WeUoome ^ ' .8t*n Thyroid jv*7^ lymphatic and he poftlc system ftjy Olhef (excluding t AN excluding the > Bfo*,* Incidence and c. BE/?'" 1 Cancer ot ihe In ffjr Cancer of the lu Further evident cancer (or liver ar v.m i attributed i ` .iftl of aneios. ' . dv.ll SPI-01240 Haiy 0 1 1 3 0 1 0 1 12 6 08 06 30 12 06 0.7 09 6.1 0 02 i 07 1 07 0 04 0 07 9 45 30 21 1 >oul discovered cause. 14,25. 46). 10 = observed 1 1 i 1 5 7 Italy 0 E 0 0.5 ,9 27 4 3 5.0 4 52 3 2.7 2 70 1 09 4 77 36 56.4 66 77 5 V.Kl'O', -4 'J ^ JK, i'JSO'vC'J '' u'1 ih SMP = stanaara':ed mortality ratioi :oa r)s c t 4 Cause o death SMB Cancer of m* m Cancer o other piles Other diseases Accidents. DO'S*dn ngs, and violence ah causes 59 509 1 547 226 2 441 6 J5 599 35 1 844 89 295 15 2 74 7 84 698 '02 84 77 89 Including cancel from the United States. i 4* Mortality from vanoij s cancers among vmvi chloride wo^e's m 49 oiants in me 'our principal studies combined. ) 00*4rved number of deal = exposed number of deaths. SMR = standardized mortality ratio) ?>* or class of cancer OE SMR Source of information i and pharynx elhre system (other than ver) lUeeowaiory system j.Oei'Mif urinary system tro*d rif^pftaltc and hematopoietic system than of the liver 18 16 57 125 154 59 223 229 36 21 1 2U 09 70 62 81 2 1 94 29 19 54 2 0 43 57 50 8 7 83 63 24 609 599 35 109 1, 2. 3. 4 81 1. 2. 3. 4 97 1. 2. 3. 4 99 1. 2. 4 111 1. 2. 3. 4 2. 4 148 i. 2. 3 2 M2 1. 2. 3. 4 131 1. 2. 3. 4 102 1. 2. 3. 4 l* United States study (14). 2 = United Kingdom study (25). 3 = Canadian study (46). and 4 = Italian study (4). mr.. TafeAa Mortality* from vano4 s cancers among vinyl chloride workers- Supplementary evidence (4, 7, 22. 49). (O = Observed of deaths. E = expect number of deaths. SMR = standardized mortality ratio) Ty* or class of cancer Federal Republic pi Germany (11 plants) Norway (i plant) OE OE as**.. e>gHnr system grinding the liver) UM* MWanoma IpXhdic and hematot-- me System Owr toicluding the liver) 35 0 31 8 23.5 24.6 2.1 1.3 16.5 7.7 10.7 24 3 3" 1 44 5 2 84 4 0.79 2 0.16 3 14 93 aadvding the liver 37 8 89.7 22 20.16 and cases in the Norwegian study, of the intestine only of the lung and braml only. Sweden (1 plant) OE 3 178 2 0.33 5C 2.11* Italy (i plant) OE 1 12 0 15 0 0.1 0 07 4 2.0 5 5.7 Four countries combined (14 plants) O E SMR 390 31 5 40 41 2.0 16.5 227 119.8 34 44 30 72 0.89 63 0.16 8.4 4 t 43 117.67 113 103 196 55 102 for a total or four), but bed as an angiosarcoma evidence that the fxcess mortality from liver ^_r (of liver and gallbladt)' er cancer in the US series) ' CMb* attributed principally f not wholly to the known vkfctr4 of angiosarcoma is Obtained in a comparison occss deaths with thi numbers of deaths from >BHgn irenmas recorded in tnle Register of Liver Angio sarcoma Cases (maintained on behalf of the Associa tion of Plastics Manufacturers in Europe by the Im perial Chemical Industry PLC) before the end of the follow-up period (Bennett, unpublished). Fifty-one ex cess liver cancers are recorded in the combined data, and 49 angiosarcoma are recorded in the Register for 69 .7i Table 6. Mortality from lung cancer in the senes Iron the United States <US) (14) and the United Kingdom (UK) fi 5) by characteristics relevant to an occuoationai na^ard (O = ob served number of deaths, E = expected number of dtatns. SMR = standardized mortality ratio) Oata characteristic1 Category 1 o E SMR Category 2 Ot E SMR Observed 20 years or more alter first employment (1), others (2) Employed 10 years or more m the US (1), others in the US (2) Employed before 1956 in me UK (1), others m the UK (2) Ever employed as autoclave worker in the UK (i), others in the UK (2) 114 113.96 100 55 52.45 105 52 51 39 101 16 17 08 94 B5 93.83 91 63 63.44 99 29 40 50 72 55 74 82 87 * The numbers in parentheses designate the category.I 6 See footnote to table t for observed deaths in the UB. the relevant periods for the three countries and the|two Italian plants3 that are covered by the survey. None of the 120 cases yet recorded in the Reg ster 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 part! per million, and many may have been exposed to con :entrations appreciably higher (unpublished report by Pan to Air Products and Chemicals Inc in 1981). Lung cancer. The idea that exposure to vinyl chloride might cause cancer of the lung was suggested by N onson et al in 1974 (36), when they noted 13 cases ag: inst an expected number of 7.9 in a study of proporti- inal mortality. The combined data shown in table 4 do not provide any support for the hypothesis, either for res piratory cancer as a whole (SMR 97) or for the s[ ecified data for lung cancer in the US, the UK, and Italy (SMR 99). There are, however, consistently higher i isks in the subgroups of men in the US and UK serie , in which occupational hazards would be more iikeU to Twenty-nine were registered as occurring in the United States against an excess of 33; only 20, however, were jdentillable in both senes. Inquiry has, as yet, failed to rJveal information about the histology of the remaining 13 i the cohort study and the origin of the nine extra deaths i the register. Nine deaths were registered as occurring irj the United Kingdom against an excess of nine, but one o the registered cases was certified as due to a benign hemangiJoma and not related to the liver (code 227 in the eighth rev sion of the International Classification ol Diseases). Ten 4ases were registered as occurring in Canada against an ei| cess {ol eight; two were recorded as being in men who had >een employed for live years, and it is possible that the a lual duration had been slightly less than live years with on* sequent exclusion trom the Onadian cohort. One case] was roM'ured .is oecumiig in one ol (he two lulian p inis .iLijiHM .hi 0^0' ol k'Ns thjn one. be seen than in oiher groups. This circumstance is illustrated by (able 6, which shows that the SMR values are slightly higher for men observed 20 years or more after first exposure than for men observed earlier, for men employed before 1956 in the UK than for men first employed alter 1955 (when exposure levels are believed to have been lower), for men employed for longer than for shorter periods in the US, and for autoclave workers in the UK (among whom the angio sarcoma cases have mostly occurred) than for other workers. The differences are all small or very small. They are, however, all in the same direction, and the probability that the rates should all be higher in the groups in which an occupational hazard is more like ly to be seen in each of the four pairs of groups is I in 16. Additional information from other sources is given in table 5. A total of 30 deaths (or cases) was observed, and this figure increases to 31.5 when allowance is made for the number of deaths due to unidentified causes in the German study (SMR becoming 103). In the German study the SMR was higher for the men who had been exposed for 10 years or more than for those who had been exposed for shorter periods (111 against 79), and, in the Norwegian study, four of the five cases observed occurred in men whose occupations were regarded as involving high exposure against 1.82 of the 2.84 expected. Both the German and the Swed ish studies derived the expected numbers of deaths from national mortality rates for a single year towards the end of the study period. The expected numbers of deaths are likely, therefore, to have been overestimated and the SMR values correspondingly underestimated as the mortality from lung cancer had been rising throughout the period of observation. Brain cancer. The idea that vinyl chloride might cause brain cancer was also suggested by Monson 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 cor respond exactly to those in table 4. If, however, the observed and the expected cases are both subtracted from the totals, twenty-four observed deaths remain against approximately 18.3 expected, a difference which might easily occur by chance (P one-tailed = 0.1).4 * ol If the study of Waxwciler er al (501 is regarded -iv die origin ol I he hypothesis, 26 deaths .ire tell .ic.imu IX VJ i spccieJ (I* one I ailed - ll II7| Addition, given in tat little further one of the t occurred m less than a s the excess di German stu chemical wo deaths after causes agams PVC fabrica for deaths frt Cancers of 11 idea that virn phatic and he the lymphatk & Gaffey (45) studies, wher from lymphot giinsi 2.54 et the lymphatic pccted. These if the laborato suggesting that tally in animat non (29). The cause lymphor ous considerat - studies that are support for the lymphatic and h. frsher (57 death and very little mi foi cancers of the fey's definition 200--203 and 2t 1 (35 deaths age '^'Oftover, hard fCafTey1s initial r f 23.36 expected, ^Little addttio ^kmlu of the Gr dy obtained ; on 15 obs Jitflowince is maa i causes) a Itmexposed gri gofpvc fabricate deposed workers been exposed for was most ma foe fise years or n he number ot di 4 c pccted, SM ........ ./ \ n , > SPI-01242 ICC IS lilies more r. for - men Is are ;d for id for angioother small, nd the in the e likeps is I s given ;erved. ince is ntified 03). In le men \an for ds (I I I r of the ipations nst 1.82 e Sweddeaths towards nbers of .umated limatcd n rising ht cause cl al (36) led. The ide some onson ei kers and reported therefore s the data ubiractcd t was noi _> not corsever, the ubiracted hs remain difference ,e-iailcd = r ( . as die origin 94 expecied Addilion.il i ii I or iti.ii ion in u mlicr sources eiseit in lahlc 5 The siunll exscss rtporicd provides little further evidence of an oceupa tonal hazard, as one of the two deaths observed m t te Swedish studv occurred in a young man who had b en employed for less Ilian a year when the diagnosis was made, while the excess death rate for brain cancer observed in the German study was less than that observed among chemical workers not exposed to vinyl chloride (2.9 deaths 'after allowance for deaths from unknown causes against 1.6 expected) and amo lg workers in the PVC fabrication industry (5.9 death ; after allowance for deaths from unknown causes aganst 1.1 expected). Cancers of lymphatic and hematopn telic tissues. The idea that vinyl chloride might cause c incer of the lymphattc and hematopoietic tissues -- nore specifically the lymphatic tissue -- was suggest by Tabershaw & Gaffey (45) and by Waxweilcr et al 50) In two cohort studies, when they lound. respeett ely. five deaths from lymphomas in the most heavily exposed workers against 2.54 expected and lour death from cancers of the lymphatic and hematopoietic nssi es against 2.5 expected. These small excesses might It tve been ignored if the laboratory findings had not be rn interpreted as suggesting that lymphomas were proc uced experimentally in animals exposed to vinyl clt oride by inhalalion (29). The idea that similar ex P ' sure might also cause lymphomas in humans, there ore, merits serious consideration. The data from t I e four principal studies that are summarized in labl 4 provide little support lor the hypothesis when a cancers of the lymphatic and hematopoietic tissues : re considered togctlicr (57 deaths against 50.87 expt ctcd, SMR 112) and very little more is obtained from he separate data for cancers of the lymphatic system ( Ti bershaw & Gaffev's dclimtion of IC'D list numbers etghlh revision, 200--203 and 205 being used) that ar e shown in table I (35 deaths against 29.40 expected), The position is. moreover, hardly altered if the data m Tabershaw & Galfcy's initial report arc subtracted ( 19 deaths against 23.36 expected, SMR 124). Little additional Information is irovided by the results of the German study (49). (S e table 5.) This study obtained an SMR of 214 for xposed workers (based on 15 observed deaths, increa ed lo 16.5 when allowance is made for rite number of deaths from unknown causes) against SMR values i I' 77 and 34 for an unexposed group of chemical wor ;ers and a group of PVC fabricators. It showed that he excess of (he exposed workers was present only fi nr men who had been exposed lor more than one year and that litis excess was most marked for men who I been exposed for five years or more (10.7 deaths al cr allowance for the number of deaths from iinkuow i causes against 4.0 expected, SMR 268. P one-tai Ic I <0.01). Melanoma. An excess of melanoma as reported for Norwegian workers by Hcldaas et al ;22). who raised the possibility th.it vmvl cl Je might have produced the disease. Lour cases were observed when 0 79 were expecied, and ihree of (he four were in men whose oc cupations involved the highest exposures (against 0.51 expected). At the time of the writing of their report, one further case had been detected with onset three years after the closure of the study. Subsequent studies in other countries have, so far. reported only two deaths against 2.0 expected. (See tables I and 5.) Thyroid cancer. An excess of thyroid cancer was also reported in the Norwegian study (22), in which two cases were observed against 0.16 expected. The inves tigators were not aware of any other studies indicating an excess of this type of cancer, and they drew no con clusion from thetr observation. Two of the three major studies that have been reported since the Norwegian observation was made gave no data for thyroid can cer; the third reported two deaths against 0.43 ex pected. (See table I.) One death from thyroid cancer, it may be noted, was reported in the US by Monson et al (36). Cancers of the digestive tract. Suggestions that vinyl chloride might cause cancers of the digestive tract in general have sometimes been made, but they have not taken adequate account of the contribution of cancers of the liver to the total number of cancers of the digestive system, particularly when it is borne in mind that some liver cancers are likely to be misdiagnosed as cancers of other organs. The combined data from the four principal studies shown in table 4 weigh heavily against the idea that any such effect has been produced. Other cancers. One of the remaining types, or classes, of cancer listed in table 4 shows a statistically signifi cant excess, namely, the heterogeneous group of "other cancers" (83 observed deaths against 65.24 ex pected, P two-sided < 0.05). This excess is only mar ginally significant and may be a chance observation. The most likely explanation is, how-ever. that a few angiosarcomas of the liver were not recognized and were diagnosed as secondary liver cancer or carci nomatosis, site unknown, ihe number of deaths in this category therefore being increased. Hazards of nonmahgnant disease No previous study has suggested that any nonmalignant cause of death other than cirrhosis of the liver would be likely to be increased as a result of exposure to vinyl chloride, and cirrhosis of the liver is presumed to be increased only because of the liver changes that were observed as part of the "vinyl chloride illness" (24, 31, 33). Two other possibilities have, however, been raised, namely, the production of nonmalignant respiratory disease, because of the changes in lung function and radiographic appearances that have been 71 Table /. Mortality `rom selected nonmalignant cause i and an causes m the lour principal studies comomed. (0 = o D served numoet o( deaths, 6= expected number of deaths. SMR = standardised mortality ratiof Type of disease Bronchitis. empnysema 0 E SMR Sourr e ol mforr laiion * 80 60.83 120 1. 2 Other respiratory disease 71 125.78 56 1. 2 recorded for men exposed to PVC dusi (2. 26, 22, 44), and acute cardiac death, Irom analogy with ihe effect of other halogenaied hydrocarbons (25) and the ob servation of an increased mortality from myocardial infarction in the few vears following ihe cessation of exposure in (he Swedish PVC processing industry (35). Relevant figures for the numbers of deaths from these and olher nonmalignant causes that are obtainable from ihe four principal sludies were given in table 2, and they have been summarized in table 7. Alt respiratory disease Ischemic heart disease Other circulatory disease4 AM circulatory disease4 Cirrhosis ol tha liver Other disease 180 200 82 797 885.73 252 264.55 1 103 1 209.35 46 66 26 238 36807 80 i, 2,: , 4 90 1.2 95 1.2 91 1. 2. 3 4 69 1, 2. 4 65 1, 2. 3 4 AM nonmafignant disease All external causes 1 547 1 844 50 226 295.t5 84 1, 2. 3 4 77 1. 2. 3 4 AH nonmalignant causes All causes 1 773 2 13965 2 441 2 747 85 85 1, 2. 3 4 89 1. 2. 3 4 1 = United States study (14). 2 = United Kingdom stufay (25). 3 = Canadian study (46). and 4 = Italian study (4). 6 Bronchitis in the United Kingdom study, emphysem; In the United States study. * Includes cerebrovascular disease In the United Klngdt nn and Italian studies. Table 9. Mortality Irom chronic obstructive lung dlsei se* In the series Irom the United Stales (US) (14) and the Unite< I King dom (UK) (251 by characteristics relevant to an occup t onal hazard (0 = observed number of deaths. E = expected number o( deaths. SMR = standardized mortality ratio) Oata characteristic0 Category 1 Q E SMR Observed 20 years or more after first employment In the US (1). others in the US 12) 30 15.8 190 Employed 10 years or more in the US 11), others in the US (2) 16 to 9 147 Employed before 1956 in the UK (1), others in tne UK (2) 26 30.17 86 Ever employed as an autoclave worker m the UK (1). others in the UK (2>c 3 8 55 46 Category 2 0 E SMR 11 70 157 25 12.0 208 10 13.60 74 33 37 22 89 Oescnbed as emphysema in the US study and as Ororfcnitis in the United Kingdom study. The numbers in oarentneses designate the category Men ever employed as a bagger or drier, occuoations vhlch wou'd nave caused the greatest occupational expos ire lo polyvinyl cnioriae oust, experienced one death lrom|pron- cruris aijamst 4 96 expected Cirrhosis of ihe liver. Three of the four principal studies gave separate figures for cirrhosis of the liver, none of which showed an increased mortality (table 2); in combination they gave an SMR of 69 based on 46 deaths. The fourth sludy, which did not give sepa rate data for cirrhosis of the liver, reported four deaths from all diseases of the digestive system combined against 3.85 expected and noted that the lour included two (hat were certified as due to cirrhosis of the liver, but actually due io angiosarcoma (46). In the two sup plementary studies in which data were given for this disease, the SMR was 82 in one, based on 15.1 deaths after allowance for ihe number with unknown causes (49), and 133 in the other, based on seven deaths (37). Nonmalignant respiratory disease. The data for nonmalignant respiratory disease are confusing in (hat (he total SMR from the combined data lor the four prin cipal studies is 80 and is the sort of figure that is com monly found in healthy industrial populalions, yet (he US sludy recorded a substantially increased mortality from emphysema (41 deaihs and an SMR of 180 be fore any allowance was made for deaihs from un known causes). No such excess was found in (he UR, where 36 deaths from bronchitis gave an SMR of 82. International comparisons of chronic nonmalignant respiratory disease are complicated by the usage of dif ferent terms to describe what it is now agreed is best called chronic obstructive lung (or pulmonary) disease, but which in the past tended to be called emphysema in the US and chronic bronchitis in the United King dom. It must, therefore, be presumed that the two categories of "emphysema" and "bronchitis" used re spectively in the two large national studies were meant to describe the same thing. One must assume, there fore, that the experiences in the two countries were very different, despite the fact that both related to cohorts that had very similar experiences of angiosarcoma of the liver and so, presumably, fairly similar exposures to vinyl chloride. Separate figures are shown in table 8, where avail able, for the mortality observed among men with dif ferent durations and intensities of exposure. Unlike the data for cancer of the lung that were shown in table 6, (hey provide no consistent evidence ol a greater risk itt (he groups tit wliiji an ti~.cnpuuim.il h.i/.ml sumhl be expected v-rronmenta! 10 give any from emptvhardly be du no overall e' however, tha by deficienen respiratory d 0<her respira the question could be a m the out-of the coding of "otheT respira induded emp imphysema tl be classified v to 502, and tht of the emphys in somecatego number527. II tor both the ex grossly deficie trtfiraiory dis No excess m> and asthma" 44 with 6.3 de. amber of dea Cardiovascular ??Sr"7 lelero(ic) hear! t ffode the vast n 10 acute cardiac Mg national stu. increased mo ffgoup of disease recorded in 'ft the SMR vale "*i there is no si the subsidiary i. In pariii ______ mortalit gfaytnent in the l, SMR 61) workers (9 slight increa 'arts recorded study (49), t * TV de*th attribi. Uses and the cor t`.i9 wrion for th Health A* J>liniiu (nr 11 I . Mis tes SPl-01244 lust (2. 26, 27, 44>, ogy with the effect s (25) and the obv from myocardial ng the cessation of -ssing industry (35). f deaths from these hat are obtainable ire given in table 2, in table 7. the four principal trrhosis of the liver, sed mortality (table iMR of 69 based on ;h did not give separeporled four deaths ve system combined hat the four included cirrhosis of the liver, i (46). In the two supa were given for this based on 15.1 deaths with unknown causes on seven deaths (37). ise. The data for none confusing in that the data for the four print of figure that is comial populations, yet the lly increased mortality nd an SMR of 180 be. for deaths from un. was found in the UK, tis gave an SMR of 82. chronic nonmalignam ated by ihe usage of difit is now agreed is best (or pulmonary) disease, o be called emphysema mis in the United Kingpresumed that the two nd ''bronchitis" used re;' tonal studies were meant -' )ne must assume, thereie two countries were very 1 it both related to cohort! nces of angiosarcoma of 6) , fairly similar exposures .*1 I eipcctcd to be concentrated The authors oi the EnrWOonxntal Health Associat)::s rcpori (14) were unable ihrt any explanation fo the increased mortality emphysema, and ihe; point oul that u could ' be due to excess cigar'ttte <smoking, as there was I overall excess for cancer f the lung. It is sinking, r. lhal the excess is it re (han compensaied for ^deficiencies in ihe other cJ tcgories of nonmalignant Bory disease (pneumoi) ia 15 deaths.' SMR 47.0; respiratory disease 14 deaths. SMR 42.6). and qoesiion arises whether the emphysema excess be a classificatory rtifact. Environmental I Associates (14) list all (the 41 deaths which show litaey were coded under |ICD number 527 which, Ifce out-of-date seventh r< ision that was used for tcoding of all deaths in th study, was the code for rrespiraiorydisea.se noil otherwise classified" and i emphysema. Undei| thal revision, however, i that was associat d with bronchitis should (daastfied wiih bronchitis nder ICD numbers 500 and the possibility ma be considered that some tbb* emphysema deaths sh uld have been classified jkfiiaoar category of respiratod y disease olher than ICD fecr 527. If this were the s[ luation, it could account r both the excess mortality from emphysema and the 1 deficient mortality fno m other nonmalignant lory diseases. ' Nocuns mortality from ` bronchitis, emphysema, ^ti^aodauhnu'' w as observed in the German study (SM R 6.3 deaths observed after allowance for the IS?qiu>t of deaths from an tlnknown cause) (49). i mi unii fi i n n Data for ischemic (or arterlo- c) heart disease (which| may be presumed to in ! the vast majority of al deaths certified as due i cardiac disease) wen given only by the two ; PM tonal studies, and they] provide no evidence of JpnwrtaKxl mortality. The SHR values of 90 for this of diseases and of 91 fdr all cardiovascular diserwsxdeO in the four pri rjcipal studies are typical t*> SMR values of healthy| industrial populations, IOtoe is no suggestion of ny occupational hazard Sshsidiary analyses pro ded by the two national r 1a particular, there : no evidence of an in i mortality within one| month of leaving em! in the UK study eii|her for all workers (52 IlfSMR 61) or for the mqst hI eavily exposed auto. (9 deaths. SMR 42). increase in ischemj|ic heart disease mortalI recorded for the expo: ed workers in the Ger- r (49), but it was ies: than that recorded for n in table 8. where availved among men with dif-'3J ies of exposure. Unlike ihe that were shown in (able t evidence of a greater risk ccupational hazard would i linbuied to differed I groups of respiratory dis- d (he corresponding SNt R values lhai are ciied in Sion for ihe US study a r: as given by (he EnvironI lletJ'h Associates (14) i nd have not been adjusted for the number of deaths from an unknown R. Is* lake account of these leaihs. ihe observed deaths I values can both be multiplied by 1.0674. ihe unexposed chemical workers ami ttie I'VC ubncaiors (SMR values of 127, 131, and 158 based on 97.2, i 26.7, and 109.7 deaths, respectively, after allowance lor (he number of deaths from unknown causes). Discussion The information that has now been obtained about the long-term health of men occupationally exposed to vinyl chloride is massive and compares favorably with that available for any other occupational group. Two facts are outstanding. First, the men have experienced a specific hazard of a type of cancer that is normally extremely rare, namely, angiosarcoma of the liver. The rarity of this disease under other conditions made the detection of the hazard easy, but the long latency period before the disease appears after first exposure (almost always more than 10 years and usually more than I 5 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 tection provided by the reduction in exposure in (he 1960s and that of the further reduction that followed the recognition of ihe 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 ihe 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 R'o of the deaths having been due to (his one cause. Eventually many more men must be expected to de velop the disease. One estimate (38) suggests that the total may be increased 10 times, but a more realistic estimate is two to three times (19). The second outstanding observation is that the mor tality of the exposed men, other than that due to angiosarcoma of the liver, is typical of the normally healthy industrial worker -- that is not to say that no other hazard exists, but that the effect of any other hazard is small. The massive data that are now available provide no reason for thinking 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 is no good theoretical reason or laboratory evi dence to suggest that either should be produced by 73 SPI-01245 -*v < vinyl chloride, and, in light of present evidet ce, the simplest explanation is that the reported exce ses are the chance effects that must be expected whe t many different types of cancer are studied in several c ifferent populations. So far as melanoma is concernet , it has to be remembered that the disease has becom: 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 ihe warm :r parts of Southern Europe and North Africa. The e tent to which this change may have affected the observation in Norway needs to be examined. Two other hazards (of lymphoma and brain cancer) were suggested by the early results of some of the US studies. That vinyl chloride might produce a hazard of lymphoma was initially supported by the l^reliminary results of animal studies, but the complet results of the many investigations that have been und rtaken (see reference 29) do not suggest that lymphom or any other cancer of the hematopoietic system is able to be produced. There is, however, some evider ce that brain tumors can be produced in rats (29). The lypotheses that lymphomas and brain cancers m ght be produced by vinyl chloride have been supported by the observation that both these types of cancer havt caused death more often than might be expected from tjational mortality rates, but the excesses observed in combined data from the four principal studies in :his review are small and not statistically significant, tnd the hypotheses remain unproved. The small excess brain cancer is particularly difficult to evaluate, as nortality rates from this disease have changed rap over time as methods of diagnosis have improved ind the suspicion of an occupational hazard (which wa; raised in 1975) could have influenced the findings, h at excess has occurred has been limited to the US a id Germany, and the German findings carry little we ght, as the excess was found in each of the three occu fjational groups studied, irrespective of the chemicals; (i which they were exposed. The supplementary data ft om the German study showing an increased mortality from lymphatic and hematopoietic cancers are more mpressive, particularly as the excess was the most narked for men who had been employed for at least ftv years, In these circumstances, judgment must still ae suspended until the data for each study are anal yted for each specific type of cancer, by intensity andI d j ration of exposure, and by time since exposure beg i n. There remains the suggestion that vinyl dhloride might cause lung cancer. At first sight, this f ossibility is ruled out by the SMR of 97 for the c bined data for respiratory cancer for the four p incipal studies. Lung cancer is, however, normally cornmon (accounting lor about 8 7o of the expected deaths) that an increase in mortality that was half as mportarn (numerically) as (he increase in mortaali y from angiosarcoma of the liver might easily be ove looked 195 'o coni idcnce limns of the SMR 85--1 12). The in- cidence of ihe disease varies moreover within a coun try. and there must be doubts as to whether (he na tional experience provides a suitable reference for men employed in plants that are not evenly distributed about the country. In these circumstances one cannot exclude an occupational hazard unless it can be shown that the mortality of the exposed men is independent of the factors that might be expected to influence it if some of it were occupational in origin, namely, (he intensity and duration of exposure and the lime since exposure began. It is not possible to examine these relationships in detail, as the reports do not provide all the necessary information. Such information as they do provide, which was summarized in table 6, supports the idea that exposure to vinyl chloride involves a small hazard of lung cancer. Taken in conjunction with the knowledge that lung tumors have been produced in sev eral species of animals exposed to vinyl chloride by in halation (29), it would seem that a small hazard of lung cancer probably did occur. The evidence is not, how ever, strong enough to conclude that it definitely did. If it did, the hazard was evident only for men who had been employed for many years at a time when expo sures of several hundred parts per million or more were common, and any persisting risk can be only minute and incapable of detection. The questions that have been left unanswered by this discussion might well be answered definitely if (i) all the exposed men could be followed to (say) (he end of 1984, (ii) the investigators could present their data in comparable ways, taking account of duration of employment and time since first employment and presenting data separately for men first employed be fore (say) 1965 and between 1965 and 1974, and (iii) estimates could be made of the effect of correcting the results for each group of employees for the locality in which they lived and worked. Hazards to the general population As vinyl chloride has been proved to cause cancer in man and is a mutagen in laboratory experiments, it i must be presumed that even the minute doses that: escaped into the general environment from production , plants or (in the early days of manufacture) from PVCi materials will have caused some risk of cancer to thef general public. These risks must, however, have been! very small, as air concentrations of vinyl chloride, evens within a kilometer of plants handling vinyl chloride,! used to be (in or around 1975) of the order of 10 to] 40 ppb (1,3, 15), and this level is about one-ten thou-; sandth of the concentration that has caused an occu-fl pational hazard. It is obvious, therefore, that it would j be impossible to detect the risk of any cancer that mighli be produced hy vinyl chloride other than a risk of; angiosarcoma of ihe liver, as it has proved so diffi cult to detect any other risk among men who were ex posed occupationally. The position with regard to an- tiosarcoma "ally so rai to one of ii dioxide, an, annual mcic In these circ In a man liv ride was use controlled n of the effec Severalsu hether anv and Elinder vicinity of pi and Sweden *1 (II) foun, to thorotrasi *xth vinyl ch ---- -- `"V (. (J) found 14 f: 12-year peric lived half a piant, and, in p: Brady et al ( mbuted to an Pte living wit "n* vinyl chi Ian two studii fence of as m. ftv: xtoveio manui colleagues, .... &nstj with ma referents liv, |rr neighborho p Ntv York State >. pollution with , the uiscasi years, resp 1 this period y. The oi 5^^** 15 or mor f of these {iheenvironm tjrvc may ha public. j^CWrent conct care cer: uly by y. Recent kundred me H.Tahjes belot three of five ' |30ppb(ir kPPb (just in ' values w, td with putn ' f rure nf I , SPI-01246 >' cr '.i tt Jim d ^< >un (u whether the ru le reference for men evenly distributed istances one cannot 1 less it can be shown men is independent :cied lo influence it i origin, namely, the e and the time since le to examine these iorts do not provide i information as they d in table 6. supports oride involves a small conjunction with the been produced in sevi vinyl chloride by ini small hazard of lung evidence is not, howthat it definitely did. inly for men who had at a time when expomillion or more were k can be only minute .ft unanswered by this ed definitely if in all iwed to (say) the end uld present their data count of duration of irst employment and len first employed be65 and 1974, and (tii) effect of correcting the yees for the locality in tulation ved to cause cancer in >ratory experiments, it the minute doses that nment from production lanufacture! from PVC ,ie risk of cancer to the ist, however, have been is of vinyl chloride, even undling vinyl chloride, t) of the order of 10 to I is about one-ten thouhat has caused an occutherefore. that it would of any cancer that might de other than a risk of s it has proved so diffimong men who were exisition with regard to an- i lunnia ul ihc luer sully so rare that. n lo one of ilie known cau ictciu I lus disease is nor- sence of specilic exposure s (vinyl chloride, thorium ^'hoxjde. and arsenic in pesi| icidcs and medicines), ihe ;-4anu*J incidence is on the c|rdcr of I--2 10~' (5, S).' \ these circumstances the iscovery of even one case l man living close loaf, ctory in which vinyl chloI was used in the days bt fore exposure was tightly drolled may be regardet as presumptive evidence 'the effect of environmejnal pollution. Several surveys have bee t undertaken to determine 'Whether any such cases hav|j occurred. Sane et al (43) cyaad Hlinder & Pershagen ( 3) sought for cases in the ividoiiy of plants handling v nyl chloride in Yugoslavia r'tad Sweden and found noni|(c. In Holland Dalderup et (ftl (II) found eight confir ed cases not attributable ;t0 ihorotrast or arsenic an| could trace "no contact with vinyl chloride." but rH ey made no specific menIX' tion of the patient's place bf residence. Baxter el al ,, i` 0) found 14 confirmed casi|ps in Great Britain over a n-year period, one of whi h was in a man who had G lived half a kilometer fro 1 a PVC manufacturing . ( plant, and, in New York Sttjle over an 18-year period, Brady et al (5) found 19 c; scs that could not be atUibutcd to any known cause five of which were in peo- pie living within a mile of plants manufacturing or using vinyl chloride. The ovekall incidence rates in these . last two studies were not ur| duly high, but the occur- fence of as many as six cast s among people living so - dose to manufacturing plan s is surprising. Brady and his colleagues, moreover, ccjmi pared their series of pa- ticnts with matched referenl s and found that none of the referents lived equally e Idsie to a plant. Two of these ux neighborhood cases (o : in England and one in New York State) cannot be a tributed loenvironmenial pollution with vinyl cliloridIk, as Ihe men who developed the disease had lived iar [lie plants for six and eight years, respectively, beftjre developing the disease. and this period is too short |o allow for the necessary latency. The other four cas ::s, however, all occurred after 15 or more years of lot al residence, and the dis- covcry of these cases strong y suggests that pollution of the environment around p jams manufacturing VCM or PVC may have caused a i^iinute hazard to the gen- aal public. Current concentrations nrtjund plants handling vinyl if chloride are certainly much |ower than those reported tcviously by the US Etj vironmental Protection gency. Recent British meapurements made within a lifcw hundred meters of the VCiM areas have given aver- ge values below the daily I mit of detection (5 ppb) r ihree of five plants, the readings at the two others r being 20 ppb (100 m outside the boundary fence) and U ppb (just inside it) (47; although substantially higher values were recordec on two occasions assor ,' dated with putting one plan into operation and with * The figure of 1.4 !()- cued py Healli el al (21) seems to have been a misprint for 1.4 an accident at the "`cr. \ccordmg to .ins reasonable criterion ;lie hazi j ihe general public ul there is any ai al!) musi 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 ihe personal health of men exposed by virtue of their occupation (other than the early effects of (he 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 (li) the carcinogenic effects that might conceivably be observed in the gen eral population as a result of the widespread distribu tion of vinyl chloride as a pollutant. The possibility that vinyl chloride might act as a teratogen or might cause mutations in ihe germ cells has not been exam ined, as the little evidence that has been adduced relating to such possible effects has been reviewed else where and the conclusion was reached that no such ef fects have been demonstrated. Many groups of workers exposed to vinyl chloride in the manufacture of VCM or PVC have been studied since [he carcinogenic potential of vinyl chloride was first recognized. Some results have shown thai occu pational exposure can cause angiosarcoma of the liver, and others have suggested that ii may cause several other types of cancer as well. The actual situation can be determined only in an examination of all the evi dence, especially the combined results of those studies (hat include a substantial proportion of observations on men more than 25 years after (heir first exposure and cover a long enough period for more lhan 10 "It 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 ihe 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 lo 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 75 (he plant was situated. It must, therefore, se kept in tion is the observation of an increased mortality from mind (hat (he rates used may not have been vholly ap cancers of the lymphatic ami licinaiopotcnc svsiems propriate for the localities in which rhe p ants were in the supplementary study from the Federal Republic situated. This circumstance is potentially imp ortant for of Germany. the US study, which covered workers in 37 alants, 22 Two types of cancer were reported to be in excess of which were situated in the southern p, rt of the in the Norwegian study, namely, thyroid cancer and country. The other less informative studies a e, for the melanoma. The significance of this finding is difficult most part, open to more serious criticism, anc the value lo assess because very little information about these of each set of results needs to be assessed leparately cancers has been provided by other studies. in relation to each disease. Suggestions that vinyl chloride might cause cancers The combined results of the four princip il studies of the digestive tract have failed to account for ihe show that the SMR values, reflecting the ratio between contribution of angiosarcoma of the liver. When this the numbers of deaths observed and those ex pected in disease is excluded, the mortality from digestive tract the absence of an occupational hazard multiplied by cancer decreases to below the average (SMR 82 for the 100, have been (i) 77 for accidents and other violence, four principal studies). (ti) 84 for diseases other than cancer, and (iii) 102 for A small excess mortality from the heterogeneous cancers other than cancer of the liver. All the ;e results group of "other cancers" in the combined results of are what might be anticipated for an industry devoid the four principal studies was statistically marginally of any specific occupational hazard. The low ratio for significant (83 deaths against 65.25 expected. P<0.05). diseases other than cancer reflects the "health ' worker Some of the excess was likely to have been due to the effect," which results from the selection pro less that misclassification of angiosarcomas as secondary can inevitably excludes some of the less healthy Members cers of the liver or carcinomatosis, sue unknown. of the population from industrial employment and is The following three nonmalignant causes of death compatible with a higher ratio for cancer, as the mor have required special examination: cirrhosis of the liver tality from cancer is not normally subject to such an because of damage to the liver in "vinyl chloride ill effect, apart from the first two or three year; imme ness, " myocardial infarction (from analogy with the diately following the start of employment. effect of other halogenated hydrocarbons and because The mortality from cancer of the liver wa nearly of some observations from Swedish PVC fabricators), seven times that expected. Most of the 51 exces deaths and nonmalignant respiratory disease because of were known to be due to angiosarcoma, even though changes in lung function and the radiographic appear this diagnosis was not recorded on the death certifi ance of the lungs observed in men exposed to PVC cate. The excess corresponds closely with the 4? deaths dust. Far from being raised, the mortality from cir due to angiosarcoma reported to the International rhosis of the liver was less than expected in the three Register of Angiosarcoma Cases as occurring in em principal studies and in one of the two supplementary ployees of the plants concerned during the : ierio<ls studies which gave separate figures for the disease under observation. All the men who developed he dis (SMR. vatijjs of 69, based on 46 deaths, and 82, based ease were likely to have been exposed to concent -ations on 15 deaths), while in the other supplementary study of vinyl chloride of several hundred parts per nillion the increase was trivial. or more. Data for myocardial infarction have not been re Three other types of cancer which have betn sug ported separately. But myocardial infarction accounts gested to occur as a result of exposure to viny chlo for most of the deaths attributed to ischemic heart dis ride are cancersof the lung, brain, and lymphai ic and ease, and there is no evidence that either ischemic heart hematopoietic systems. The combined data f or the disease or cardiovascular disease as a whole was un mortality from respiratory cancer fail, at first sight. duly common (SMR values of 90 and 92, respective to support the hypothesis regarding lung cancer (SMR ly) or related to occupational exposure. 97). Higher ratios for lung cancer have, however been The data for the third category of nonmalignant dis observed consistently in the subgroups in whi h the ease (nonmalignant respiratory disease) are confusing, effect of an occupational hazard would be mos like- because the two large national studies give conflicting ly to be seen (that is, men employed for more tf an 10 results. The combined data for the four principal years, exposed to higher than average concentra ions, studies show the low mortality that is commonly found . or observed more than 20 years after first expo lure). in healthy industrial populations (SMR 80). This fig In two of the supplementary studies it was also toted ure hides, however, an increased mortality from that the mortality from lung cancer was specif ically chronic obstructive lung disease (SMR 120), which in increased among the most heavily exposed wotkers. cludes emphysema and is due to a grossly increased The combined data show small excesses in the mor mortality attributed to emphysema in (he US study tality from cancers of the brain and of the lymp hatic (SMR 193). The corresponding mortality in the British and hematopoietic systems. The excesses are, how ever, study, which was preferentially described as due io not statistically significant, and there is nothing tc sug bronchitis, was less than expected (SMR S2), js wax gest that they arc occupational in origin. An e cep- the mortality from pneumonia |SMU 'Hi .nul oilier rex fvaiory disea bo consistent pfrywma or b Bad it seems | VS Budy was fir* with the u Review of i loot-term hea iwl chloride to have expe ; extremely rare -mmely I in 33 fadied died of ' the observed di of time the nu , hr expected to the mortality t of that of nom - hazard has exi The data pre *rtf other than ts. however, sin rxde produces si doe to nonoccu iver, and, if sc exusc almost as 4ver, There is too li the suggestion t omi or cancer and hematopoie dm have been re paternal hazard, i of the lymph r.iCermin study rejj^ *t*t of chance efl\ any types of ca _ Cadies. W'fr-M The lack of an Erin thecombin I does no t been a sma fha disease, as gt 1 the disease th nil rates foi gtaths. The greatc I be more li: I other group f existed. The ttnee of a ha t Clearer answer posed in th us groups c 'T'WMJti in more a As vinyl chloric and a pro' . that have es ,'ollwr.jfifs iim-s i f 1111111 c II SP1-01248 I .llitv from tc systems l Republic : in excess :ancer and is difficult bout these es. jse cancers jnt for the When this estive tract R 82 for the erogeneous d results of marginally d. F<0.05). n due to the ondary canunknown, ises of death is of the liver I chloride illlogy with the . and because fabricators), because of aphic appearosed to PVC lity from cird in the three upplementary jr the disease and 82. based mentary study I 1 t \ fc I J ; l c Ii* ( c not been rection accounts iemic heart disischemic heart whole was un92, respective* re. nmalignant dis- ) are confusing, give conflicting four principal omtnonly found IR 80). This figmortalitv from l 120). which in:rosslv increased in the US study ility in the British cribed as due to 5MR 82). as was 50) and other res- ) I k piratory diseases iSMR 46) in the Us study. There is no consistent evidence that the m rtality from em- physema or bronchitis was specifics Uy occupational, and it seems possible that the report ed excess in the US study was an artifact due to nop ological difficul- ties with the use of the seventh lon of the 1CD. Review of the massive data nowl available on the long-term health of men occupation ally exposed to viny'. chloride leads to two dear con lusions. First the men have experienced a specific haza d of the normally extremely rare angiosarcoma of th iver. Approxi- mately I in 335 of the men exposet in the 49 plants studied died of the disease, and appra:ximately 2 of the observed deaths were attributed to it. In the course of time the numbers of cases of ang losarcoma must be expected to increase two to thrie times. Second, the mortality from all other causes has been typical of that of normally healthy industri; I workers. If any hazard has existed, its effect has b: en small, The data provide no reason to th nk that any haz- ard other than one of cancer has be n overlooked. It is, however, still difficult to decide whether vinyl chlo- ride produces small risks of cancer, cpmpared to those due to nonoccupanonal causes, at si es other than the liver, and. if so, whether, in total hese risks might cause almost as many deaths as ang| osarcoma of the liver. There is too little evidence either toloonfirm or refute the suggestion that vinyl chloride n ight cause mela- noma or cancers of the thyroid, braip . and lymphatic and hematopoietic systems. None of he small excesses that have been recorded point specif| cally to an occu- pational hazard, apart from that ibutable to can- cers of the lymphatic and hcmaiopoidt ic systems in the German study reviewed, and most afje likely to be the sort of chance effect that is certain to pe observed when many types of cancer are examined many different studies. The lack of any increased mortality from lung can- cer in the combined results of the four principal studies reviewed does not exclude the possibil t y that there may have been a small occupational haza I'd of developing (he disease, as geographic variations in the incidence of the disease throw doubt on the alidity of using national rates for estimating the expie|cted numbers of deaths. The greater mortality in group^ of workers who would be more likely to show an occtipational hazard than other groups suggests that a s rpall hazard may have existed. The evidence is, however . weak, and the existence of a hazard has not been iroved. IClearer answers to some of the qu slions that have been posed in this review might be obtained if the various groups of investigators co uld present their results in more appropriate and conf parable ways, As vinyl chloride is a mutagen in oratory experi- ments and a proved human carcmokien, the minute doses that have escaped into the geneg al environment as pollutants must be presumed to h ve caused com- tparably minute risks to the general ublic. No such 2 risk could possibiv be detected, other than one of angiosarcoma of the liver which is normally an ex tremely rate disease. Several surveys have sought evi dence of the existence of such an effect, and sugges tive evidence that such an effect may have occurred at a time when environmental pollution was much greater than it is now has been found in one. References 1. Air Products and Chemicals. Inc Comments on the pro posed standard for vinyl chloride, leiter lo DR Goodwin. Environmental Protection Agency. Washing ton. 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Department of Trade and Industry, Stevenage (United Kingdom) 1984. 48. Viola PL, Bigoili A, Capuio A. Oniogenic response of rai skin, lungs, and bones (o vinyl chloride. Cancer Res 31 (1971) 516-519. 49. von Greiser E. Reinl W, Weber H. Vinyl-chlorid ex position und mortaluai deutscher chemiearbeitcr im vcrgleich zur morialiiat nichlexponierier chemicarbeiler und PVC-verarbeiter. Zeniralbl Arbettsmed Arbeitssch Prophyl Ergonomic 32 (1982) 44--62. 50. Waxweiler RJ, Stringer W, Wagoner JK. Jones J, Falk H, Carter C. Neoplaslic risk among workers exposed to vinyl chloride. Ann NY Acad Sci 271 (1976) 40--48. Received for publication: 16 February 1988 , I 78 ORIGIN Al Scand J II Assoc exhau Results by Jack ; Ron Dew si be ret ev co i Ar fur gat adi co Ke A large pc study was c cupational t About 20 st For each pat past exposu analytic stra at a time to t remarkable This repot cancers in cu buslion prod classes. Fou buslion eng depending o. jei fuel, or pi from (he "n substances: without disc lamp oil), n; profile of pro is considered a propane-bi 1 Epidemiolog Institute Art Canada. 1 Department i versily, Mon 1 Department University oi Reprint reques cm epidemiolot I isppier, 5'l f c jn.id.t. H7V SPI-01250