Document N1jJrQL2XkkabLdM86EB9JkV

* * -- - - 1^ R&S 135601 VIIIYL CHL03IDE V.'OTvKEES III THE UK1TED STATES* 12 3 Cl, irk V. Heath, Jr. ,M.D. , Henry Falk.M.D., Jonh L. Creech, Jr. ,K.D. ^Director, Cancer and Birth Defects Division, Bureau of Epidemiology, Center for Disease Control, Atlanta, Georgia 30333 2 Epidemic Intelligence Service Officer, Cancer and Birth Dornets Division, Bureau of Epidemiology, Center for Disease Control, Atlanta, Georgia 3033j 3]'lant Physician, E.F. Goodrich Company, Tost Office Do:: 9Vi, Louisville, 'Kentucky 404G1 ^Presented at the Working Group on .Tonicity or Vinyl Chlcridc-Polyviu) 1 Chlorine, Kce York City, Kay 10-11, 1974 R&S 135602 The relationship between vinyl chloride exposure and human angiosarcoma of the liver (ASL) first received serious attention in December 1972 when a case of this rare tumor was diagnosed at autopsy in a vinyl chloride (VC) worker from the B.F. Goodrich chemical plant in Louisville, Kentucky. At I that time, this case represented the third recognized among VC workers at this plant; prior cases.had been diagnosed in >'uy 1970 and March 1973. (1) While at first the possibility was considered that case occurrence night be unique to the Louisville facility, the subsequent detection of cases at three other plants lias shown the problem to be industry-wide. Ten additional cases have subsequently been identified among other VC polymerization workers in the United States (Table 1). V.'orkers at a total of four different plants have been involved. * The earliest case recorded Co date occurred in 1961, the others being scattered over subsequent years, five in the past two years 1973-74. In several instances, the diagnosis of ASL was not specifically cade until re- -wJ view of pathologic material during the early months of 1974. Death certifi cate diagnoses in such cases indicated "primary liver cancer," and in one instance merely "liver cirrhosis." The three most recent cases were diag nosed in the course of systematic medical screening, two at the Louisville plant in February 1974 and one at the South Charleston plant in May 1974, These three patients are the only ones of the thirteen who are currently alive. . All thirteen cases have occurred in white males. About half have been in their '40's with an age range from 36 to 60 years and a moan age at time of diagnosis of 4C.2 years. Length of time between first VC work and diagnosis has ranged from 12 to 29 years (mean 20.3 years), mean total duration of VC work b-ing 10.0 years. 2 R&S 135603 Comparison of Observed and Expected Incitlcr.ce The reason an otiologic association between VC work and tumor could be so readily inferred on die basis .initially of just three cases is because ASL is extraordinarily rare, based on data from the National Cancer Insti tute's Third nationalCancer Survey (1969-1971), expected annual Incidence of this tumor is on the order of 0.0014 case per 100,000, or about 25-30 cases a year in the entire U.S. population. Estimating the total VC worker population past and present in the U.S. at roughly 20,000 persons (an esti mate which may be too high), one can calculate that only about 0.03 case of this tumor might be expected in such a population over a decade. Since thirteen cases have thus far been identified (and it is not unreasonable to .think that others r,3y yet be found among other VC workers), one arrives at a risk ratio, (a ratio of observed to expected cases), of at least 400 to 1. Needless to cay, had the situation concerned a common tumor such as lung cancer, the pictute would have been much less clear cut and would have required many more cases and much more elaborate epidemiologic manipulation to associ ate tumor with industrial VC exposure. Clinical Features v"w Medical and epidemiologic data have been examined in detail for cases at the Louisville plant in particular. The remainder of this presentation sum marizes these and other data concerning VC workers at that plant. For each Louisville case, all available medical records have been reviewed. Interviews have been held with each surviving patient and with close relatives of all deceased patients to. obtain specific infer'!.it ion concerning work, history. 3 toxicologic exposures, and family history. Pathologic material, particularly sections of liver and of tumor, have been reviewed both by local pathologicts ir. Louisville and by Dr. Louie Thomas at the national Cancer Institute and Dr. Hans Popper at The Togarty International Center. Tn most cases the diagnosis of ASL was reached only with difficulty; t' three of the five fatal cases were not diagnosed until autopsy, In only one of the two remaining fatal cases v:ao ASL diagnosed unequivocally prior to death (four Months), In the other case, a diagnosis of "prireary liver csr.ccr vci s made five months before death, but ASL was not clearly identi fied until recent review of autopsy material. Presenting signs and symptoms varied widely and were relatively non specific. Abdominal macs was a presenting feature in four cases, GI bleed ing in two (diagnosed initially in each instance as peptic ulcer), fatigue and weakness in four, and noticeable weight Iocs in one. In one case no signs or symptoms referable to cancer or liver disease were present and the diagnosis was made only in the course of workup for another health problem. Duration of symptoms prior to diagnosis ranged from one to eleven months for five of the sir. cases displaying symptoms. In the sixth case, symptoms related to liver disease antedated diagnosis of tumor by eight to ten years. In tlvat particular case, a diagnosis of liver fibrosis us made in May 1965 following two episodes of gastrointestinal bleeding in the course cf two years. A portacaval shunt operation was performed because of varices, splenomegaly and Increased portal vein pressure. Six years later (May 1971) the patient was ru-evaluatad because of progressive svihiitems, and at that tin R&S 135604  ' t 4 liver scans suggested L presence of tumor. ASL, however, was not unequi vocally diagnosed until autopsy in Kerch 1973. At time of tumor diognosi.s, physical findings among the seven cnees varied considerable. In two casus, no abnormal findings at all were recorded. Three cases presented with liver enlargement, in each instance by spleno megaly. In a fourth ease, splenomegaly alone was detected. One additional *-" case presented- with severe right upper quadrant tenderness in the absence of clear cut organomegaly. Laporotomy revealed free blood in the peritonial cavity traced to what was tentatively diagnosed prior to death as "hemangioma of the dome of the. liver." ; Abnormalities of one or more liver function teste were present in every '6 ease at or around the time of diagnosis. In most instances, however, these abnormalities did not become clcar-cut until the terminal phases of illness. SCOT values were at least mildly increased in all seven cases, total bilirubin in sJ>: and alkaline phosphatase in five. LD11 was increased in four of six * _ cases tested and BSP ir one or two. * w. ** ** Diagnoses were made with the help of liver-spleen scanning in six cases and hepatic angiogram in two. Esophageal varices .wore demonstrated in two cases, one by x-ray, the other by endoscopy. Efforts at tissue diagnosis were made by open liver biopsy in all seven cases and by needle biopsy in three; autopsies .were performed in four of the five deceased cares. Open liver biopsy provided a diagnosis of tumor in four cases while in the remain ing three cases, diagnosis was made only at autopsy. R&S 135605 Kecont review of pathologic material in all severs cases has shown evi dence o! portal fibrosis as veil as of tumor. In addition, discrete subcap- sular fibrotic areas wore described at time of open liver biopsy in one of the two cases diagnosed in 1974. In tvo cases, angiosarcoma vas present in f tissues other than liver. In one the picture was that of local tuner" spread. t 4 Epidemiologic Features . % The - B. F'. Goodrich Louisville plant employs about 1,20G persons of whom about 270 or 20 per cent are engaged in VC polymer lection activities. The plant first began polyvinyl chloride (?VC) production in 1942 after pilot operations dating from 1937. The present polymerization vorV, force sir.e vns reached in the late 1950's. All seven patients had vorhed in jobs directly \ 1* related to VC polymerization, and in this capacity all seven can be assumed- 33 i * * cn to have had direct exposure to vinyl chloride monomer (VCK). Initial involve Wcn ment in VC work occurred from 12 to 28 years prior to tumor diagnosis (mean con cn 20.0 years) (Table 1). Involvement was essentially continuous during these years (mean duration of VC vork 17.0 years). Dates of initial industrial. VC exposure ranged from 1944-45 soon after the plant began production (l\:c cases), to as recently as 1957 and 1961. Ages at initial exposure ranged from 23 to 33 years (mean age 27.6 years). Although the data are far from conclusive, they do suggest a possible dose-response relationship when one tries to compare intensity of VC exposure v:ith latent period. Virtually everyone entering VC polymerization vork at the Louisville plant starts ns a "helper," a job which includes cleaning the V interiors, of polymerization, vats and hence involves a maximun exposure to Vt'.M 4 " % R&S 135607 When duration of work as a "helper" (a rough measure of VC" exposure) is correlated with interval between first exposure and diagnosis, an inverse relationship i s suggested, i'or three cases averaging only 5.3 months as "helpers," exposuve-to-diagnosis intervals averaged 22.0 years; for the four remaining cases averaging 36. S months as "helpers," this interval was 14.5 years. ... Ho evidence was found that exposure to other potentially hepatotoxic materials outside the work place played any consistent role in these parti cular cases. Only two patients had a history-of increased alcohol intake, and in one the increase was borderline. One man gave a history of exposure to arsenic insecticides for several years as a teenager. In none was there . .1 any suggestion of thorium dioxide exposure. ^Acrcostcolyais, past or present, * ; . 't * f was not observed, in any case- r * rm Kon-mr.lignnnt Liver Disease Because two of the three tumor cases .which were initially rccognlsc-d in Louisville had shown evidence of hepatic fibrosis antedating or coexisting with tumormedical records at the Louisville plant were reviewed fer cases of non-malignant liver disease. A total of four such cases have been iuenti- fied to date, again all among VC workers. Hie clinical and epidemiologic features of these,four cases closely re semble. those of the seven tumor cases (Table 2). All were white males, avers'; # age 46.5 years at time of first diagnosis. One was diagnosed in 1963, one 5r. 1972, and two in 1973. VC work hegan on the average 20.8 years prior to diag nosis and in every instance was continuous. One patient, however, a 2ri-ycmr- e v ' -r- R&S 135608 7 old man, had worked at the plant for only six years. Duration of Illness prior to diagnosis ranged from 0 to 7 months. While three of the. four patients presented with significant splenomegaly (one with he pa tome," a ly in addition), in one case physical-exv.inat ion was entirely negative. A variety of liv' ler function t'*ests showed abnormalities although none were severe and 'A no consistent patterns were evident. In two cases esophageal varices were demonstrated, ar.d in both instances, splenorenal shunt operations were per formed. All three patients with splenomegaly underwent splenectomy. Open liver biopsies were performed in all four cases. In each instance, a picture of portal fibrosis was seen accompanied by the observation in three cases of discrete nodules of subcapsular fibrosis. The latter feature was indistinguishable pathologically from the subcapsular lesions observed in ..one of the seven tumor eases. Discussion * c\.. t - in light of recent animal experiments (2) ar.d of clinical observations reported in Hurope.an VC. workers (3), it seems likely that exposure to VCM In the course of VC polymerization work Is responsible for malignant ar.d non- lualignant liver disease in these cases. Epidemiologic features further sug gest that cither prol.onged exposure and/or a long interval from initial ex posure is required before liver disease becomes apparent. While the length of time Involved seems quite variable (6 to 29 years), in all but one. case Che interval was twelve years or longer. 71 .. ^ *l1i1 I 8 We have no assurance, however, that the actual latency required for devcloprr.cnt of liver disease (as opposed to latency In relation to clini cal recognition) nay not be considerably shorter, Unfortunately, if one can judge by the clinical features of the bouisvillc cases, manifestations 30 cn cCnO o o CD of liver disease arc quite variable, and in most instances were not detected until the process of hepatic fibrosis was so far advanced that splenomegaly and increased portal pressure had already been produced. Furthermore, if one envisions angiosarcoma as a late manifestation of the same pathologic V process, then it seems even more likely that clinical detection of liver disease lags considerably behind actual disease onset. At present, therefore a major concern is to develop more sensitive means for detecting liver dis- ease, not in its late malignant phase (if in fact a single pathologic spec trum is involved), but in the early stages when fibrotic reaction first sets in. Eventual!.y, r,on-malignant liver disease, not ASb, may prove to be the most prominent disease problem associated with VCM exposure in terms of numbers of persons affected. One must also consider the possibility, however, that VCM may produce angiosarcoma at sites other than liver or that tumors of other kinds may also be induced. At present, animal experiments suggest that a wide spectrum of tumors may be involved (1), although as yet there is no clear human evidence to support the concept. In addition, no human casco of liver disease, whether fibrosis or frank angiosarcoma, have yet been strongly linked to VC exposure outside the industrial setting. While this may mean the.: risk, of disease is greatly reduced or oven nor.-cxl stent at very low levels of ~_v* J*w"* - ,t-- - I*, r i R&S 135610 9 VC exposure, it is obviously too early to draw any conclusions. In view of past oxporienco with other oncogenic chemicals, it will be prudent, until r.ncli more data have been assembled, to view any exposure to VCM as potentially harmful. ^Su uiaa- lvi i A total of l'J cases of ASL have been, documented to date among VC workers in four different plants in the U.S. In this particular industrial popula tion, this number of eases represents at least a 400-fold increase over ex pected incidence for this extremely rare tumor. The first case occurred in 1961. Average age at diagnosis is 48.2 years. Average length of time be tween initial VC work, and diagnosis has been 20.3 years. A detailed review of seven eases associated with one plant revealed that clinical features varied from little or no overt illness prior to diag nosis to advanced liver disease with portal hypertension and marked spleno megaly. Portal fibrosis was present in all seven of these ASL cases as well as in four additional cases with nor.-mal ignant liver disease among VC workers at the same plant. These findings suggest tiiat exposure to VCM in industrial settings can produce hepatic fibrosis with angiosarcoma as a late manifesta tion. Conventional liver function tests may not be sensitive indicators of such liver impairment, at least in its early stages. !'----- --V* > 1 ' 7., _f\+- J. References Creech, J-l- Jr. 5 Johnson, M.N. 1974. Ansiooarcona of liver in the n.M'iU fneture of polyvinyl chloride. J. Gccup. Med. 16: 150-151-' Kaltoni, C. Unpublished ohscfvations. Kirstellcr, H.J., Lelbnck, W.K., Muller, R-, ct: al. 1973. Chronisch-: oxische lebc-rochadcn bei Arbeitern in der PVC Production. Dtsch. Med,, Vcchn. 95:2311-2314. R&S oo CJ1 CT) Z199ZI I Table 1. Cases of Angiosarcotna cf the liver (ASL) a~ong vi nyl chloride workers in the United S tates a cf Location of slant Age at diagnosis, race,sex cc-'rich *' H tt Tl IT It 3 ir T Ccrbide * tone Louisville,Ky. P r ir Tl 11 n Niagara Falls,N-Y. It IT S. Char lo.s ten,V. Va. rr Fot totown, Fa. 52 VM 43 UFi 3 o "Ol 49 UFt 53 !*K 4 5 '.FI 43 l-.FI 40 V.FI 54 V>! 60 VFI 4 5 V.FI 52 V/. 50 VrF'I Month end year of first vinyl chloride work ciaor.osis c-?cth N'unber of years between first vinyl chloride work and A3k diaeresis 6-44 7-52 11-55 12-43 11-45 1-62 5-45 10-46 6-51 10-46 8-44 3-44 9-49 o . 4-64 6-67 5-70 3-7 3 12-73 2-74 2-74 4-61 5-63 3-70 3-63 4-7 4 5-59 4-64 1-53 .9-71 3-73 12-73 -- -- 6-61 5-68 3-70 3-63 -- 5-69 19 15 -14 ?A. 23 12 23 14 16 23 23 29 13 Total year: in vinyl chloride work IS 15 13 15 2$ 12 17 14 15 23 IS 29 15 jU. Tabic 2 Gases of non-xalipnant liver disease c~on~ Lc-aisvllle virvl chloride '..-orV.rs Number of Kenth and years hetvaen Clinical features P,-' t o.c 1c^ L'z A year of first" VC v:ork enlarged aba or:?.''. 1 Portal Subcnpr.ular c la '.-ipr-ls and dicrncsis solc-cn liver liver for-cc Lon tests'* f: ?vc e:.s fibrosis l/t Cl M 12-53 1-72 9-73 9-7 3 2U 6+ Ih 29 A?, 3ST, T3, e.COi T3, n TB, LW., SGCT SCOT + v -r + + *b + ^ cl'r.-.lir.c phosphatase I;? - brcueulpbrlcrn clearance SCCT -Intcuic cualccatic . - t o t a j )\u ara I'.hi " lactic dehydrogenase transccninace sv9sev s'sa