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44 nurd to portal the L'nited .nmmuous ;n changes lovarcoma I issues at und in the i chloride lity to see concerned Dr Robin uiings will n reports sections r changes 'irols and of fat and Jo show ; out. hut e partieu:!l report, had quite Mimsoidal possibly hat seems Section of'Occupational Medicine 503 Dr Henry f-'alk i Cancer ami Birth Defect* Division. Bureau of Epu/ennoloev. Center tor Disease Control, i mted Stores Public Health Service. Deportment ol Health. F.dueittn >u. anti It elttnc. Atlanta. Cent i.ua .'O.LLL L S l> and Mr Richard .1 \Va\wcilcr I Du imiiii at field Studies and C hnieul Inwsti'joiions. Xatianal Institute tor Occupational Safety and Health. Center far Disease ( ann o!. L'nited States Public Health Sea ice. Department of Health. Education, ami Welfare. L S Post Other Bnildine. Cincinnati. Ohio 45202. L S.-i I Fig 9 HiZkH > < and entaveed sinusoidal lullin' < ells and lirpiilm i .v nutatte ubncirnuihl v at '/< patient as f-'tf-i. if A L'. QUt) to he sinking hepatocyic involvement, even with mitotic abnormalities I Figs $-9). Tliv question whether these lesions arc signifi cant as ptvmnlignuM changes is unanswered. as many of the alterations can be found in other conditions such as congestive cardiac failure, endothelial cell hyperplasia in eases of lymphoma, and of hepatoeyte and other changes m many drug roxiutv situations. Other pathogenetic questions also hate to be posed, such as what is the primary lesion, which cell is involved in the formation of the tumour, what is responsible for the curious fibrosis and survival of the hcpau>evtes. L inlersiandmg these processes would probably enable us to make a better assessment of iiulo alual risk factors and perhaps to work out whether there ts a tolerable exposure. REFERENCES Baker H Dc C. Pign C E * Da>*o J t1956) Journal of Pntiroioi v and Buercno/rcv 72. 173-182 Block J B 11 974) Journalnfthe 4mrncan Mrdieat .4wimmmi 229. 5J-54 Boyer J L. Scti Gupia K P. Bowk S K. Pal N C. Bu Maliicfa K C. Ibrr F L A Bisu A K (1967) 4n*ru/j of htiefutt Stedicne 66.41-67 Lrc F I A Harry O S 119741 Luo, or i. I .U6 RcerlMin VV. Kirr V. O-pina J A Holland J F l Cam rr \ PlnUnltlphuxS 21.314-522 Roll! F II4571 y.'irs.'trOt fur KirU'inrxelfiuiv 61.468-5m Thomat L B. Popprf M. Bcfk p D, SeVikotT I J A Falk H M97?| \> Cnviand Joarnutof Stedictnc 292. |7-22 V'ijfrldi ,| A Petition H < 197 21 4 no Ptn`in>noira of Mirrnhiolueu'tt Scamunttuta Section A SO. 97-108 The vinyl chloride fVQ problem ha% had a con siderable impact in the L'nited States during the past year and a half. Perhaps related to the age and conditions of the \C industry, or simply to the sheer size of it. the L'nited States lias so far had the largest share of cases of VC-indueed hepatic angiosarcoma (HAS): at the present time there have been 17 known eases in polymerization workers I'Lloyd 1975). The finding of the initial cases was a dramatic event, and unlike what has occurred with many other proven or suspect carcinogens, the confirmatory experimental evi dence arrived almost simultaneously wiih the epidemiologic results i Maltoni &. Lcfcmine 1974). The widespread industrial applications and uses by the consumer were instantly appreciated, and <mce the VC problem also arrived at a ume of growing awareness and concern among workers and consumers about cm ironniental and occupa tional hazards, it served to focus these concerns. Within the first few months after the initial cases were described a number of worrisome reports appeared. Investigators in Louisville. Kentucky, and also at Mount Sinai Hospital in New York demonstrated a high percentage of liver function abnormalities m polymerization u orkers. suggesting a broad problem < Mak k et at. 19*4, Lilis ei at. 19751. and. in addition to this, the earliest mortality studies (Monson cr aI 1974. Tabershaw Sl Gaffey 1974) suggested increased rates for nonhepatic tumours, parallelling the multiplicity of tumour types seen in experimental studies I Maltoni & Lefemme 1974), Review of records at the Connecticut Tumor Registry, started in 1935. revealed 5 definite cases of HAS: 4 eases were clusterevl in one industrialized area and laid occurred since I9A7; 3 of these (and possibly a fourth case where the diagnosis was uncertain after review of didcs) occurred in workers at two polyvinyl chloride ( PVC) fabricat ing plants or in residents liv inc nearby i Landrigan & Heath 197b). Further concern was generated by -W fa (g? [^7^ RSV 0012456 i(M ProcSOy. Soc. Med. Volume 69 April 1976 I 46 reports of the potential carcinogenicity of chemi cals siructuraily related to VC. e.g. chloroprene (Lloyd etui. 1975)and trichloroethylene(National Cancer Institute 1975. unpublished data), and by the knowledge that VC workers in many instances have been exposed to multiple related chemicals, including vinylidene chloride and acrylonitrile l v iny I cyanide). As part of the United States Public Health Service response to the V'C problem, the National Institute of Occupational Safety and Health tN'IOSHi and the Bureau of Epidemiology, Center for Disease Control (CDC). have worked nn a number of VC-rcluted epidemiologic projects during (he past year and a half; in ihis paper we will bricily review- some of the early results of three of these studies. Table 2 Htoaiit aftfiofirccma i che Ciuird Slate* 1966- 1973 ierat death < tvtieft 0-9 ID-19 :o-:9 3D-J9 J|>_J9 JO-59 dO-69 70-79 80-*- VMr 2 l l 5 7 \3 J 11 1 Female " 1 4*9 5 i 2 Total 4 2 : 9 IJ 10 14 \ 46 -- ti # From death certificates. ICD Cade 197.8 (8th Revision i. Data lor New York Ci y not deluded There was approximately I ease of HAS for every 300 death certificates reviewed. HAS Surveillance A death certificate search for all cases of HAS recorded under ICD Code 197.8 iSth Revision), which encompasses various miscellaneous forms of liver tumour including most cases of HAS. was undertaken by CDC for the years 1966-71 [n the United States. This search is almost completed, with only data for New York City not vet available at the time of this review. Table 1 shows the number of cases of HAS and non-angto hepatic sarcomas by year of death for 1966-71; there is no evidence for an increase in the incidence of these malignancies during this period. \ review of the relative occurrence of hepatic sarcomas recorded under ICD Code 197 S showed angiosarcoma to be the largest group (35"., of total hepatic sarcomas), followed by sarcoma of unspecified type (31".,). leiomyo sarcoma <12",.), fibrosarcoma l7"j. and a grouping of miscellaneous sarcomas 115 ^0?. Table I I li'fl.H iv mn-finiii in ilie L nurd >i:nc* b> reported Imioiaiii and \cnf of death. 1966.| 97J IVirr nt .irulli 191-ft 1*1(0 |Q^K \>UM 1970 1971 1071 ill :ir< )l 40 14 l q |01, .4 ilsriftwir< 9 11 T 15 <, 1 n (,S \..W-llVlO Ottm 9* ;? 14 ? Il> 1.4 4 16 i:s Fmndc.it h vert lue.itev ICD CjJb 19".5 1 Sth Re* morn. 1 V,M lrf>niV( V < fk Cm not included Mallear sample Table 2 demonstrates a male to female ratio of 2:1 for HAS. Sixty.two percent of eases occurred in the group aged 50 or more, with in the 30--19 year age group. Non-angio hepatic sarcomas differed in hav mg a male to female ratio of only 1:1, and an altered age grouping with "8 of cases aged 50 or more .md only 9u, in the 10-49 year ace group These diiTerenccs are con sistent with a hypothesis that occupational ex posure may be a more significant factor in the causation of HAS than of non-angio hepatic sarcoma. Only 2 of the patients with HAS in the death certificate review were recorded as having worked in PVC or plastics plants i I PVC polymerisation worker a.id I accountant ut a PVC fabrication plant): both were cases which had been identified prior to this study. No other occupation is recorded more than twice except for the occurrenee of 5 printers. Although all were subsequently confirmed as printers, a preliminary review of pathology records Jnd specimens suggests mat 4 of the 5 cases may have been incorrectly diag nosed as HAS. CDC has supplemented the death certificate survey with an intensive case-finding e:Tort. including a national mailing to all pathologists, state epidemiologists, and maior cancer referral centres and tumour registries, seeking informal ton on as many cases of HAS as possible diagnosed in the US during the years 1964-74. At the present time approximately 240 cases have been identified. Pathology specimens for about two-thirds of thc<e are currently under review at the National Cancer Institute and the Armed Forces Institute of Pathology. An epidemiologic evaluation of ail cases to obtain more detailed histories regarding RSV 0012457 46 1 mied Shin I9?J 'r Total 4 9 I! 10 U j ->J CoCt 19".8 (8th Revuionl. included iu(d> I case of HAS for ficates reviewed. ics a male io female ratio of wo percent of cases occurred > or more, with 26 a in the croup Non-angio hepatic '>i\ me a male to female ratio altered age grouping with 1 or more and only 9'\, in the These differences are con-hesix that occupational exore significant factor in the than of non-angio hepatic en ts with HAS in the death 'C recorded as having worked 'amx < I PVC polymerization mtant in a PVC fabrication es which had been identified No other occupation is twice except for the occur`though all were subsequent^ a preliminary review of md specimens suggests that have been incorrectly diag- uented the death eertiheate tensive case-finding effort. ` mailing to ail pathologists. . and major cancer referral veisrries. seeking information HAS as possible diagnosed cars I9b4~na At the present NO cases have been identified, lor about two-thirds of these *v iew at the National Cancer \rmed Forces Institute of cnunlogic evaluation of all . detailed histories regarding 47 Section ofOccupational Medicine 305 past occupations, toxic exposures, and places of residence is underway. Table J Lufit cJficcr among orkrr* at PVC poivmtritatisn slims m th* Lnitrd Sines bf hitteloci* type antf mtni nt V C tteosurt Medical Screening of VC It ork ers Together with the Occupational Health Studies Group of the University of North Carolina. NIOSH-CDC recently concluded a cross-sectional medical screening examination of 530 workers at a piant in Pennsylvania which contains both a large tyre-building facility as well as one of the oldest PVC polymerization plants in the United States. Included in the study were approximately 130 current PVC polymerization workers and a similar number of control workers from the tyre plant who had never worked, in the polymeriza tion facility. The 2 groups were comparable in age, alcoholic intake, and socioeconomic back ground; the controls were chosen from those areas of the tyre plant w here exposure to solvents and dusts was least. Preliminary review of the results show's no significant differences between the 2 groups for any of the 6 liver function tests performed tSGOT. btiiruhin, alkaline phosphatase. UDH. GGTP. and ornithine carbatnyl transferase). Additional analyses based on levels of VC exposure, duration and type of job. and other subgroupings are being done; these preliminary results however do not suggest the occurrence of liver function abnormalities on a broad scale secondary to VC exposure. One should of course be cautious about generalizing from the results at a single piant. and it will be important to compare these findings to studies at other PVC plants. It is also important to realize that since liver function tests are rela tively insensitive to the early finding of VCinduced hepatic disease (i.e. fibrosis), the results of this type of testing are not a reliable estimate for the prevalence of V'C-induccd disease. Liver scans were also performed on all workers with more than 10 years duration of work in the PVC polymerization plant, and no cases of HAS were detected. Some increase in Frequency of palpable livers on physical examination was found, how ever. among VC workers. A full report of findings from this comprehensive medical screening study is in preparation and will be available shortly. Cohort A lorta/iry Study or Four P VC Polymerization Plants One of the results of this NIOSH-CDC study was the demonstration of an increased SMR for respiratory system cancer among members of the cohort (Waxweiler et a/. 1976. On preliminarypathologic review, it was also noted that of the 12 lung cancer cases all 3 for which pathologic specimens were available were either large cell undifferentiated or adenocarcinoma of the lung; Exttnt of VC t rroiurr Htuniastr upe 'onr ?uiermol Srruil ceil l undilTcrtnoaied 0 AJeftOcaremom* 1 Lire* null ununfereniiaced 4 LnclaiimtJ i , Lets year i 3 1 0 0 Metre > /JWft tm* year 0 Tirol 1 0\ 46 ft ;o Oi ,,s if confirmed, this unusual cell type distribution may support the association between \ C exposjre and occurrence of lung cancer. There are. however, two additional features which should be considered in evaluating this potential relationship. When all of me workers at these 4 plants are considered, including those who were not part of the defined \ C-exposed cohort, a total of 22 cases of lung cancer tout of 43) were available for pathologic review. The increased incidence of large ceil undifferentiated and adenocarcinoma of the lung was seen m VC workers with more than 1 year of exposure, white a distribution more closely resembling the ex pected small ceil predominance was se-n for \ C workers with less than 1 year of exposure. Interestingly, however, cases of lung cancer in non-VC workers at these plants, although small in number, appeared to have a cell type distribu tion which was also predominantly large cell undifferentiated (Table 3i. In addition, unlike the situation for HAS in these plants where all but one of the cases were long-term reactor cleaners and operators, the workers with large cell un differentiated and adenocarcinoma of the lung were distributed in a number of different job categories. As a result, cases of lung cancer seem not to correlate as tightly with VC exposure as cases of HAS and it is conceivable therefore that some additional chemical exposure at ihese plants may be working together with V C i or even separately) to produce this effect. Funner studies are currently underway in an effort m confirm these preliminary pathologic findings. REFERENCES Landncan P J A Mrath C W ir (I4?6t on rreoaraiK'ni L.l. R. Vndrrson II. N.chol*n U J. Daum v I'n.-lifum A X A S'iikolTI .1 Il0-'l 4m,ait. ./< v,". ).>r- ............... " Science11 146. Lloyd J W (19*51 Journal n; Orrupauonm' r l*. } * RSV 0012450 306 Proc. roy. Soc. Med. Volume 69 April 1976 48 Ut4 J W. (Wife P A Mow' R M (\971) Journal ofOccupational -Medicine 17,26J Mahh L. Creech J L ir. Wheisn J C ir A Johnson M \ (1474) JiHimnl nfthe American Medical Association 230. 64 Miltom C A Uetemm G (1974) Enuranmenrat Heteareh 7, 317 MenttA R R. Peten J M A Johnson M N {l97*iLonreni.}97 Tsberthsw I R A Gofer W R (1974} Journal ofOccupational Medicine 16. 309 It avs etier R J. S'ringer W. Jonn J, Wagoner J K, Falk H A Carter C (19"6) 4nnals of the Sew York Academy of Sciences (in press! DISCLSSrON Dr Mitchell R Zavon iBaton Rouge. Louisiana) asked whether the clinical examiners at Pottstown knew whether or not the person being examined worked in vin>i chloride. Dr H Falk replied that none of the ciimcal examiners were aware of the occupational status of the workers at the time of theexammation. -- Dr R 1 McCallum (Cmversi/v of Xencastle upon Tvne) asked Dr Falk to give in more detail the way m which histological diagnosis was made in the case of lung cancer shown in his slide. Was this done by one individual or by a panel of pathologists? How were the specimens of tissue obtained: by biopsy, surgical resection or at autopsy? It was remarkable that in none of the cases was an oat cell carcinoma diagnosed, as this was the type often considered a characteristic result of exposure to a chemical carcinogen. Dr H Falk replied that the WHO lung cancer classifica tion scheme of Kreyberg (19671 was used. Four patho logists reviewed the slides and agreed on the inter pretation (Dr Louis 8 Thomas and Dr T Powell, National Institutes of Health: Dr M Kuschner. State University of New York: and Dr Laszlo Makk. St Anthony Hospital. Louisville. Kentucky), All avail able pathological material for each case was reviewed. The expanded pathological review currently under way would include the selection of multiple control cases of lung cancer from the same hospitals l w ith simi lar age and date of diagnosis to the study cases) and a blind review by a panel of pathologists in a more detailed evaluation of available pathology material. To Dr Falk's knowledge large cell undifferentiated carcinoma of the lung had not been related to exposure to chemical carcinogens, which made the findings in the VC cohort even more intriguing. Dr A J Fox <Employment \L'dutd Advisory Service. London) asked how many factories had been studied individually m the USA. What proportion of these had indicated vmyi-chloride-associated disease'5 Dt H Falk replied that cases of hepatic angiosarcoma had been seen at 5 of the S PVC polymeribation plants opened prior to 1950. There was some confusion m this area in that a number of the VC worker mortality studies had been overlapping. Three separate studies, for example. I the NIOSH-CDC study, the Tabershau study, and the Monson-Peters study) had all looked at the Louisville. Kentucky plant where the initial ancioorcoma cases occurred as well as at a varying number of additional plants. Compounding the problem was the fact that the definitions for entrance into the cohorts studied differed from study to study, so that the resuits even ai the same plant were not identical. Dr J A Bonnell (Central Electricity Generating Board J asked whether, since vinyl chloride monomer was a carcinogenic agent, there was any e\idence m experi mental animals or m human clinical experience that the skeletal or skin changes described might be premalig..am conditions. Dr H Falk said that cases of angiosarcoma m the USA did not have a history of acro-osicolvis or Ain problems, although they did not hrve the multiple tests for early changes of acro-tvsicolysis. It would seem, therefore, that the skin chances were not premahgnam conditions. Professor l J Selikoff (\fonnr Sinai School of Mahcme. City L'nnertity of \e- fork) aid that a review of known details of identified cases of vinyl-chlorideassociated angiosarcoma of the liver by Dr Lloyd (1975) of the National Instituic for Occupational Safety and Health had demonstrated that the median duration from onset of exposure w;is approximately seventeen years. These cases were derived from the rather small number of polynicnranon workers em ployed during the establishment and initial growth of the vinyl chloride industry Attempts were underwits to identify and trace the initial groups of workcrs, employed during the years 19.13-5?. since analysis of their experience w-ouid allow evaluation of the risks which might be sutfered by the wry much larger group of vinyl chloride workers exposed more recently, in a period during which PVC production was in creasing at the rate of approximately 10 per annum. Limited data bearing on the proclem had been obtained. In one poly merizntion process studied. 25" men had been employed for live years or more m the period between 1946. when the plant opened, and 1964. Each man had been traced to l Juiv |9"4, wuh 25 deaths from all causes: ? of the deaths were due to angiosarcoma of the liver t Nicholson et.;/ |9",<i. each confirmed on review of autopsy material iThomas & Popper 1975); in addition there was one death due to ruptured cesophaaeal varices. Another worker, examined during the clinical survey ai this facility iLilis er ul. 197?) had had a successful portacaval shunt operation for the same condition. These experi ences suggested'that vinvl-ctilondc-associuied disease wouid be jr7 important harard for vinyl chlorine workers in the future, unless control of exposure resulted in at least some reversal of the risk. Lilli! R. Anderson H. Nii-holton W J. Dawm S. Ftsihftnn V S A Sclikof! I J 110751 I/</ the AV.< )..>l loi,te<\'< S 346.21-41 Llo'd J \V i I or < | jitiif'iul. ! Oi, nn'iiuui.ii w. ... me t'. 3 t-134 Nicholson VV J. I l.ininiond t C . Sridman H A 'sIWoiI I J (l9'*5l.4ii*tfii''Miir'V',` Yon 4, rutvm or S'i icoi 246. 225 - 2 JO Thomat L 3 A Pooftr H (19731 AnnahouUe AC"r l .irC .41.iilcm wnf Scurn, f' 246. 26S-27? ^ Dr B V\ Du ' Oci upiirii' (IP Rosi iirc Sunhtn i an Medical iiur Follow mg : the first cc workers exp Chemical 1 Kingdom s. with a nuincluding or The tirs: : which comp tour Brit isii . of vinyl co i PVO. was tOX.'CO'OglCa. what action of exposed eone aspect of Ar that t: sarcoma of : rarity, there its natural r. eariy diaenc malignant fo fibrouc char.c vinyl ehlonc. suspected, be ances of liver to the Jevelobe establishe. respect of the acro-Osteoiys:nons. since it some comnuv To corrrii*. term cure:nog had not only ; ako a conxidtumours. The situutio leagues in Gov and specialists advice vv as rec overseas sourc United States that there was early detection serve as a bo.' cramrre in possibilities W diagnostic vah_ certain, vinyl asked to \oluv the grounds the disease of the