Document YrMN0KxQbY1azwD8wkXQL1ObE

Vinyl Chloric!g^Bsociated Liver Disease Moderator: PAUL D. BERK, M.D., F.A.C.P. Discussants: JAMES F. MARTIN, M.D.; ROBERT S. YOUNG, M.D., F.A.C.P.; JOHN CREECH. M.D.; IRVING J. SELIKOFF, M.D. HENRY FALK, M.D.; PHILIp WATANABE, Ph.D.; HANS POPPER, M.D., F.A.C.P.; and LOUIS THOMAS, M.D.; Bethesda, Maryland . .. j Although polyvinyl chloride has been produced from vinyl - like dermal induration, and bon<T*lcsions, was an occii- ^%! chloride monomer for more than 40 years, recognition of pational hazard to workers involved iii the; pblynicrixatiortiiJ?^' '- toxicity among vinyl chloride polymerization workers is more of vinyl chloride monomer. At greatest risl^wcroJJiOirt who, recent. In the mid 1960s, workers involved in,cleaning r manually cleaned the'tanks in which the polymerization,?-'''''' polymerization tanks were found to have acro-ostcolysis. In reaction occurs. - i, "L;" ivj'""' 1974, the same population of workers was found to be at risk At the same lime, other reports described nonspto for an unusual type of hepatic fibrosis and angiosarcoma of ~ alterations of hepatic strueturc'and function in vinyls the liver. We describe two cases of vinyl chloride-associated ride monomer polymeri/aliomworkers .(5). apd liver injury, one of hepatic fibrosis and one of angiosarcoma. . characterized condition called "chronic epithelial hep . I Histologic features of these lesions are similar to the hepatic 1 was reported in roughly 15 Ci ^T~sueh wurkciv aumwj fibrosis and angiosarcomas resulting from chronic exposure T in Russia (61 ./These reports"W hcpalic 'afibof^iit^ to inorganic arsenicals. Preliminary studies suggest that the ^ 7'the vinyl chloride industry, puhltsheftTor tHVri toxicity of vinyl chloride may result from formation, during the industrial hygiene literature of'easlcnr high-dose exposure, of active metabolites by mixed function traded little attention until very recently. Then thc shuatu oxidases of the liver. Epidemiologic studies indicate an increased incidence not only of liver disease, but also of was dramatically altered by the almost simultaneous repdfll^ of hepatic iibrosis. ` splenomegaly,'`ani portat hyiHnFl cancers of the brain, lung, and possibly other organs. among vinyl chloride workers in Germanydiscovery of three eases j>f angiosarcoma of theiwf^-JttL^^5' otherwise rare tumor, in'workers involved in theprotfuctiom Du. Paul D. Bf.kk*: Polyvinyl chloride, the most widely of polyvinyl chloride from vinyl chloride monomer j used synthetic plastic, has been manufactured for more than 40 years by polymerization of vinyl chloride monomer plant in this country (X, U). The subsequent introduction into this plant of a systematic surveillance system has thui'/^S. J gas at a number of plants in the United States and in many far resulted in the dctcctie&i of several niore cases of angio- | other countries. Worldwide production of polyvinyl ehfo-. sarcoma, as well, as many instances in which abnormalJ ride in 1972 totaled more than IS billion pounds, of which .. tindings in liver function (jests, or seintigraphi^cvidenipVof . g about 25r/o was made in the United States, and' items T . splenomegaly, or both, wo.re detected in otherwise i manufactured from polyvinyl chloride arc virtually ubiq* tomatie workers. .Similar screening efforts at nolvvima^|g; - - \ uitous. They include buiidi latcriats such as pipes and chloride production plaids in several counlries quiCSrty^^-^.tfy' -.-J cables, home furnishings,, icords and other recrca- - brought the number of worker's with documented angiosari^tt Tjiyt- \ linnal items, clothing, pan malerial. and :i` host of other products. Although* iany years vinyl chloride mono. m--er a...n...d. polyvinyil eslidm?viwiue* wwevrue thoughi mto nhve velni"- eonia to 19 (I0)t. Not all of these eases hlaavv,e* tbvevtn'll,nptuikb.-V- lishod. L L. ">'*>: Z'i : Results of animal expei imeiiis sironjlly support ihe^feT-K' -ffii3K..' '. tirely inert, in Ihe mid-1960s Wilson anil associates (1) siimed relation hciwccn exposure to vinyl chloridc;gii$djftkl" in Louisville and investigators in Hu rope (2-1) reported hepatic angiosarcoma. Italian investigators (1,1) had' - that the development of acro-ostcolysis, a skin ^disorder ported several years ago thal rals subjected to prolitfi characterized by Raynaud's phenomenon, scleroderma* inhalation of high concentrations of vinyl chloride ' Chief. Section on of ilir l.ivcr, l>i|.cMive Uofate branch. Nulinnnr InMuuic of Arthritis, Metabolism, ami Diet--.live Diseases. opyd carcinomas of the zytnhal gland and other More recently, Maltbni and I el'eminc f IT) pro: "1 An edited transcription of .a f.'inhim-d riimcal Sl.ilf li.iil.ri'ncc ( the : * t As of iri l-'eltuiarv Ilie . ...................... .. ,, . i.lmical lenicr, Ik ilH-sdn. M..I >I;iik[. 14 Novcmt-fr IV74, h> ilie Nnti,mat t'asi-s of hepatic anniiisarciinia in vmvl eh<4tfcM7^^fi/K; Insiiii.ic of Arll)riii, Mfl.ilv.lism. am) Dmcsnic Diseases. ' National^; United States, 6 In Canada, 2 in the Uniicil institutes or Health, U.S, Department of Health, UJucauon, and WcUaw. 'iv Tilt,Franco. - -.j , Annals of Internal Modicine 81:717.731, 1376 feJUr- "V -X&y* - fflra&v# H .-'x?- '.ai Fir,ure 1. Surcic.il liver biopsy obtained from Patient 1 in 1072, Normal lobular aicbitocture is maintained, but there is enlargement and fibrosis of the portal tracts, with bile ductular proliler,ition. (Hematoxylin and eosin; original magnification, x 50.) NIH accession number S74-4U. (Reproduced by permission. Ann NY Acad Sci 240:70-77, 1975.) indicating the development of angiosarcomas of the liver and other organs, and the development of nephroblastomas in rats exposed to various concentrations of vinyl chloride gas, including levels within the 500 ppm limit that, until recently, had been the accepted occupational standard. Ex posure to as linlo as 50 ppm has produced angiosarcoma of the liver in nils and mice, with a clearctit dose-response relation seen in mice (13). To date, most cases of hepatic fibrosis and angiosarcomas in man have been delected in workers exposed to vinyl chlotidc monomer gas during the production of polyvinyl chloride, and, as with aero-osteoly sis. those who clean the polymerization tanks seem to he particularly at risk. If confirmed, preliminary anecdotal re ports of hepatic Fibrosis and an isolated instance of angio sarcoma of the liver in workers exposed only to the Finished polymer will significantly increase the population potenti ally at risk. Data collected by the U. Si. Public Health Service show that about 6500 workers in the United States arc exposed to vinyl chloride monomer during the pro duction of the gas f 14 plants) and during its polymerization to polyvinyl chloride (37 plants). However, another 30 000 to 50 000 wqriters are employed in hundreds of plants that convert ihc^golyvinyl chloride resin to Finished products (14). To dSfcfrtherc is no evidence of risk to consumers From these Finished products. The discoveiy of hot It benign and malignant liver disease in vinyl chloride workers raises several critical questions, including the following. I. Who is at risk of developiue^vinyl chloride-associated liver injury? Is the danger restricted to woikcrs exposed to tire monomer, or is there also a danger to the much larger force of polyvinyl chloride workers? Is either the incidence of liver injury or the nature of the lesion influenced by simultaneous exposure 'to various copolymers or other Sub stances? Arc there risks to consumers, such as those who use vinyl chloride sprays, those who cat food packaged in vinyl chloride wrapping, or those whose homes contain |M*lVS!l\! , fib ,1 1*1,1 |.|tl.,.l.M.J>v ? \\ li.tl i. Ill,- > tun. .d. I*u In-mu .it. nt.il lu- ti-l.-i-u- N|*rvlt uiti id viu\ 1 i 1,1, i idc a ' * i.ib'd hvei ui|iliy * In Ji *i liod.ii. r. llrir ;> 11' I,( it in I" IW'-eu tlir |>ri oh.u li',|Mln llhlon, 11-1 >i -11 it I tn \inyl ild.iii.li' v.iul.rr. .uni Hit' in- eiea'.cd III! idriiti' III ,ilil,nr..ili nni.i n| I he Il'.VI? Wli.d is the lelnlise ii idem r'd these two I',-,nms? 3. Wh.il is ihc ii.dur.it hislmy of csl.d'h.bed. Vinyl chloride-associated liver nijiuy. both in patients who have had continued exposure and in those patient., removed from further exposure? 4. What tests will con-iiluie an cli'cctivc .screening regi men for detecting vinyl chloiidc-associalcd liver injury and for following patients with established disease? 5. What arc tjie cellular and molecular mechanisms by which vinyl chloride produces hepatic Fibrosis and angio sarcoma? 6. What is the optimum therapy lor patients with both hepatic Fibrosis and angiosarcoma associated with vinyl chloride exposure? 7. What preventive incasurqs wiiyre necessary and suf ficient to pioicct vinyl chloride workers from future injury from this compound? As yet, we base Few definitive answers to these questions. The following case reports of two patients recently evalu ated at the National Institutes of Health hclriho illuminate several points that will be discussed here. Sj'hey also il lustrate some of the difficulties in defining tlif scope of the problem. Case Summaries Dr. James F. Marlin1': Patient l,is a 30-yenr-ohl white man who worked at a plastic ami rubber manufacturing plant in l.ouisville. Kentucky, fur X years. For Ihc First 5Vi years, his job involved cleaning the tanks in which vinyl chloride polymer was polymerized. Two and a half years ago, during evaluation of a nonspecific illness chai.ielerized bv fever and weight loss, lie was found lu have hcpauisplcnomcgaly. mildly elevated scrum bilirubin and SHOT conecnlraiioiis, and abnormal 4.X-mimito plasma BSI1 ick-ution I I0.ii// ). Nonspecific symptoms persisted for J months, after whiib lie w.is hospitalized for an acute hepatitislike illness. Since the patient lud been on sick lease for almost 3 months before lie developed jaundice, the ielation of this latter episode to vinyl chtoiidc exposure is unclear. because bis plivsicians were concerned about the persisting licpatosplennmegnly, they did a diagnostic laparotomy during ihc ivcosviy phase of his illness. The surgeon described Ills' liver as showing inuliipic areas of Fine nodularity ssilh fibrosis. Ail enlarged spleen ivas icniovi.l at the opeialion. A liver biopsy done dining singel'V sltossed llgil die 'pi incifvlf abnoimalitV' was inti-nse Plata! libinsis sstlti lute dniintai piolif* cV.tlion (I'lguiv 1). Additional Is'.ituies, to be sles.allied l.itct. included capsular and iiili.i-.imisoul.il libiosis, actis-niiou of sinusoidal lining cells, ansi m-nkcil anisocviosis lupalls. lit.'sc lealllivs a|f uosv known to tv Ivpical of tile lesions seen r, ssoil.eis cviuiscd to viuvl chloride. Ilicie was no evi.leuCt' <>: viral hepatitis, alcoholic liser disease, or any otliei liep.i'i: disease dial could be ili.ifii.-se.l iiimplii.logically. Ilisl.iln,'.'; cxummulif'm of the eulaige.l sptes'u sltossed Umplntid ami relieiil.ieijdollii-lial proliferation ssitbuut signiliCaul fibrosis. * t'liiiiral AssiH'i.ilc, Ncclinn on OiViwci of llir I iver. Uii'i'slnr tSnru* llr .Hell, tiuiiun.il Imtilulc u( Arthritis, Meli.liul.uii, juil I)ittsjsc ltl.sv.IMH. I 718 June 1976 Annals of Inlernol Madlelna Volume (4 Number 6 BOR 008456 /. 'w' Altrl slligi'IV I Ilf p.ili.'lil nlilliinl III twill .il (III- I'l.Hil II..IV cvcir lie was 11.11>-. 1 i i il11 m iiiiuilii i ni.-.i in 11w l*u I i v mih no applicable 1 in liter ex|Mi\iin' hi vilivl iMmi.li', .mil In- iimliiiiii'il in llnx in"' assigniiii'iil Im 2'; Mats. H'Ih'ii il ircenilv became evident lti.il vinyl clilmiili* i'M'iimiic it.is ;iw.iH'i.ili'il tviili Imlli iii.'iluniniil .iimI ^ihiu.i1i)'ii;uii tle.'Mse u( il,e livei. |)i. Iiilm l'let's It icfcrroFStUl-lo II'*' National IiimiIiiIi". of lli'.illli fill' fillllicr _stiii.lv. 'ifoil1''"' III"'' irpiexculs :i unique follow-up of .i ease of a0gjrcttl vinyl chloride-induced liter injiiiy 2'. J yc.us after removal from cxpoMiic. Ai admission lo ilie Clinical Center, the patient seeineil to fie a iiealtliy. well-developed, and well-nourished young man. I:\ccpl for several small vascular spiders on hik anteiior cliest, physical examination was normal. Complete hlood count and chest X ray were uurcm.iikahlc. However, pulmonary function studies showed evidence of mild restrictive pulmonary disease. All routine tests of liver function, including scrum hilirubin concentlalton, linnsaminascs, alkaline phosph.iiasc, scrum prolein electrophoresis, and 45-mimitc HS1' relenlion (3.4So), had normal findings, as did the liver scan. Hccaiisc we thought il impoilanl to confirm whether histologic improvement accom panied (lie apparent biochemical improvement in liver function, peritoneoscopy and liver biopsy were done with the fully in formed consent of the patient. The liver was again seen to be covered with multiple, liny, rico-grain-xizc nodules, and histologic examination again showed extensive portal fibrosis with bile duciular proliferation. Cords of hepatic cells were surrounded by fibrosis. At least one area had bridging between portal aieas and hepatic veins (Figure 2). Areas of intcnsejymphoid proliferation were seen in some of the portal tracts, and again, as in the earlier biopsy, there was considerable proliferation of collagen within the hepatic sinusoids. Although the parenchymal cells seemed relatively normal, the fibrosis in both the portal areas and within the sinusoids was at least as severe at this recent biopsy, as it had been 2W years earlier. because of the tissue abnormality, hepatic vein catheterization Studies were done. Total hepatic blood How, indocyanine green extraction, and hepatic oxygen consumption were normal. However, the wedged hepatic venous pressure was slightly elevated to 12 mm Hg with a free value of 3 mm Hg. because wc wanted to find some test of liver function that would reflect the histologic abnormalities and therefore serve as a suitable screening test, wc did several special kinetic studies.' Disappeaiance curves with radiolabeled bilirubin, llSP, and two dilferenl doses of indocyanine green (one of the most sensitive studies of liver function available) were all normal (15). Only the bile-acid disappearance lest, which is an experimental pro cedure, had abnormal findings (16). Figure 2, Nrerlle biopsy of the liver from Patient I in early 1974. There is e/tensive lilirosis o( the portal tracts amt hepatic tubules, with bile ductular proliferation. Distortion of the normal lobular architecture is indicated by the fibrotic bridge (arrow) linking the portal tract to a central vein. (Hematoxylin and eo&in; original magnification, x 50.) NIH accession number S74870. (Reproduced by permission. Ann NY Acad Sci 246;70-77. 1975.) -V *t;" /-- ' ' Iii Miiiiiii.iiv, iiiii .liul'i "1 llir. v11ivI ilihiiuh' polvmeri/u- llilll WIIlKvl Mippi-sls lll.il l lilt I I III,null' il'.Mill,ik'd hepatic liliuisis jvt'.r.ls allei M'lini'..d In.hi tinllu i cxpusiiic, and that the Ii'Shui iiiay In- 1111jft- esleiravi' i'Vi-ii fliougli sf.'iu- tl.iitl livi'i Itiintiiui tests !i.,\e completely iiniiii.d Iiu.Imi'".. I)r, Uolictt l\ Viuiii;',* : r.itieni 2 is ,. !.' yi.ir-ohl while man who was first hospitalized at the Clinical Center in March 197-1 for evaluation of angiosaicoin.i of the liver. The patient hail worked in a plasties pinducliou plant in Louisville, Kentucky, lor 20 years and Itatl hccu involved in the polymerization of vinyl chloride monomer to poly vinyl chloride. During the course of his employment, he was involved in cleaning flic polymerization vats, a phase of the operation associated with particularly high exposure to vinyl chloride monomer. A routine general examination in November 1973 showed an elevated alkaline phosphatase level. 'I lie hlood chemistry screening procedures were repeated in February 1974, and, be sides the persistently elevajed alkaline phosphatase, the scrum bilirubin concentration was abnormal. A liter scan done in February 1974 showed mottling of the right lobj^of the liver consistent with cirrhosis or lyith tumor. The palient was admi((cd (o St. Anthony's Hospital in Louisville, Kentucky, on 2(i February 1974. Hepatic artery angiography was done, and the findings were consistent with tumor in the right lobe or the liver (Figure 3/1). An exploratory laparotomy done in March 1974 showed a 4-cm bluish elevasd mass in the right lobe of the liver, and small nodules in b&h the right and left lobes. Over the rest of the surface of Ihe li*r there was small, irregular, raised ricc-likc speckling. Biopsy%( the large lesion in the right tnhc showed angiosarcoma, biopsy of the left lobe was rcpoiicd lo show hoth cirrhosis and hepatic ' fibrosis. Because of the degree of generalized cirrhosis, right hepatic lobectomy was advised against as Ivin): too hazardous. The patient's earlier medical histoiy is significant in that he had been a heavy alcohol consumer intermittently over the previous 5 to 6 years, during 3 of which he required hospitaliza tion for alcohol withdrawal, 'Ihe patient estimated maximum alcohol consumption during those periods at one pint of whis key a day. When he wax fust hospitalized at the Clinical Center later in March 1974. the positive physical findings were limited to the chest, where there was an increased anteroposterior diameter W'ith a few rales at the left base. Right paramedian and left flank incisions on the abdomen were well healed. The liver was 10 cm in span hy percussion Inn was not palpable. There was no splenomegaly, no other abdominal masses were found, and the rest of the physical examination findings were within normal limits. Pcitincnt laboratory information included strum alkaline phosphatase, K7 lU/litre (normal. <7X); I Dll, 124 1U/litre (normal, <340); SCOT. 21 IU/litre (normal, <52); SOFT, 38 IU/litre (normal, <45); bilirubin, (1,4 mg/dl total, with 0,05 mg/dl direct-reacting. Chest X ray showed only atelectatic changes in both bases. A selective hepatic angiogram showed mottling of the liver cimsistcni with rirrlinsis. 6-em x n-cin tumor mass in the right lobe, and toiiuosiiy nl the iniraliepatic vessels (Figure 3/D. The left lobe of the liver was fell to he small, as seen in the hepatic scans of 14 Maieli 1974 (Figure 3C, ,/)). Surgical intervention was eonsiileii'd .nice moie and again rejected because of the geueiali/ed einliosis. The p,picul was started on ailnamyeiu chemotherapy. (4) mg/m: body surface area intravenously every 3 weeks, because of the known effectiveness of this ding against oilier disseminated satcomas. After the initiation of chemotherapy, the patient was followed with serial liver function tests and serial liver scans. Subsequent scans showed no altetation in the size of the mass lesion, and the patient remained asymptomatic. He toler- * Chief, Medicine lirancli, National Cancer Institute. Bark et Hi. * Vinyl Ctilortdo and Liver Disease 7X9 BOR 008457 * jka - i r* *' '.' " ' ^ V >i`v ^SPl'. g *'* * '->.> *.;? .--`1 ;?\ ,''Cf :, v*. ,i;-i />-, V'-1- t Figure 3A, B. Hepatic arteriograms in Patient 2 on 26 February 1974 (A) and 1() October 1974 (iJ) show a tnmtJr in the right lobe (arrows) and tortuosity of the intrahepatic vessels. C, D. Antero posterior and lateral hepatic scan in Patient 2 on 14 March 1974. The large tumoT~is apparent as a filling defect within the right lobe. ateil chemotherapy "ell. with nadir leukocyte counts between 21100 mm' tmd 3000 mm', and ntnlir platelet counts of approximaiely X0 000 mm'. Iteeiinsc of the dose-limiting cardiac toxicity of ttdrittmycin, the patient received a maximum total dose lo ISO mg/nr, and the Iasi dose was gisen on 27 August 1974, lie had transient elevations of alkaline phosphatase during A pi il and May 1974 associated with the resumption of heavy alcohol intake. With tihstincnee, liver limetiim relumed to nor mal, and the patient temaiiied asymptomatic. The paliem was readmitted in October 1974 for recvalualion. Repent angiography tuul scans indicated persistent lesions with out definite change in st/c. Repeat liver Itlnelion tests laid normal findings except foi a.USI* retention of 99;. at 43 minutes, because of the total dose limitations ol adiinmycin. the palient u.is started on intermit tent cyclophosphamide chcmothciapy. The patient died in March 1975 of massive iiitia-ahdominal hcmmrhagc lesulling tmm a itiptincd angiosatcomatotts cyst in llie liver. At autopsy, there was extensive angiosarcoma ip both lobes of the liver, with direct extension to the diaphragm. Meinstases were found in regional lymph nodes, lung, skull, and scalp. Industrial Screening Dr. John Creech1': Data were obtained front examina tion of approximately l2&0 employees of a plastic and rub ber manufacturing factory in l.ouixvillc, Kentucky. Thu chemicals most often us&d in the manufacturing pioccsscs -i< this factory were vinyl chloride, vinylidcnc chloride, and vinyl acetate for plastic production and butadiene, ncryloniliile, and stymie fur rubber product ion. When Ihree em ployees were lounJ lo have angiosarcoma ol the liver (8), an intensive study of the health of hoth present'and former employees was begun. Two major routes of investigation were undertaken. Before the initiation of a surveillance program to screen for liver disease among present employees, investigators CTinic.nl Associate l'rofcssor. Department of Surccty, University at Louisville, laiuiivillc, Kentucky. ..'.ili bed I >i uiilii|c,Y .uni l,i,,|,',y to.mic limn pr.l olid pics- cul I'liiploM'i Si'vci.d .dmmiii.diliL". Wile icpcaicilly seen in liicse Its*,nr., in* hiding .iiigiiis.tii oiii.i ol flii- livi'l, |H>ltal liliiosis, i",ii|ili.ii'i',il v.iiin-'., and '.|iliTimm'i'.dy, Tlicic. W''if ol'Vuiiis poU nli.il inirin i.iiuni. .nni'iiy iLise alununitdili'".. I'd liiicul liudiiij". louo lb,' In si i'ij'IiI po.itive iti'i's de lected hv ibis sc.iiih .nr siimmaiired in table I. All pa tients hail had a icl.itncly high expnsme In the chemicals used ill plastic pioiluiTitni, especially vinyl chloride. Furthermore, there was a very long liisloiy of exposure in these eight winkers: more than 10 years in seven cases and 20 or more years in live. Figure 4 shows the proposed screening method. F.levcn hundred cigluy-thrcc employees have had many of the appropriate tests in this program. However, some of the proposed segments of' the program have not yet been started. We are now doing a wide range of tests, hut the results arc constantly being evaluated and the program modified lo use those tests that prove most sensitive and specific. Some of the more elaborate studies done in pa tients with known liver disease arc stpeeilwally intended not only to lie ol diagnostic value, but also lo provide in formation about the pathophysiology of liver injury in this population. Appropriate consent is obtained lor all pro cedures. Besides the studies shown in Figure 4, uthcrUcsts arc done when indicated, for example. IIB.Ag andStnti- HR,,Ag to rule out viral B hepatitis, reticulocyte couftts if hemolysis is suspected, and so forth. | All employees of the plant have now liecn tested, some of them several limes, with a standard SMA-12, augmented hy an SGPT and gamma-glutamyl lranspeplidase (GGTP). As noted in Figure 4, a liver/spleen scan is also ronlinc. To dale. 651) scans have been done. 193 in workers front areas with high vinyl chloride monomer (VCM) exposure (high VCM ) and 457 in employees with low vinyl chloride monomer exposure (low VCM). Among llie significant abnormalities repotted in these scans arc decreased hcpalic uptake, defect within llie liver, and splenomegaly (Table 2). The total percentage of abnormal liver/spleen scans in the high-VCM workers (12.4%) was comparable lo that in the low-VCM group (11,8% ). The only significant dif ference between these groups was in hepatic filling defects, which were almost three times more common in (he high- Tablo 1. Hepatic Disease in Workers in Louisville, Kentucky, with High Exposure to Vinyl Chloride: Features of the First Eight C.isos Patient 1 2 3 4 5 67 8 Duration of exposure yrs 21 30 18 20 14 28 24 6 Primal y Disease Fuiiiitl Anglo- Portal suicom.'i Fibrosis ++ --+ + -F 4* + ++ ++ -- -t--+ A'xsoci.iicil Findings -- ' 1" tri Isophapyal SpIlTlll- Vtu ices nu'i'aly ++ -- T+ ---- 4" 4-- 4+ 4-- -i- 720 June I57G * Annals of Internal Medicine * Volume 84 Number C BOR 008458 'r ;;f- ' fi i I--.I Ml M A| '.I ItlllltrHt UM v I II Fi&ur 4. A Iiroyr.ini for the systematic screenm.x of liver diseaso in vinyl chloride workers ('.ei; text for drlails), As inilicatect liy an asterisk, the frncinency Of routine scrccnmi; is determined by the extent of exposure to vinyl chloride monomer within tho plant. cue -- complete blood count; Gl -- gastrointestinal; LFT liver function test: SCOT -- scrum glutamic oxalacetic transaminase; SGI'f -.t serum glutamic pyruvic transaminase; GGTP = Gammaglutamyl transpeptnlase; LOH lactic dehydrogenase; Aik. P'taso = alkaline phosphatase. VCM group (Table 2). billing defects included not only angiosarcomas, of which there were two, hut also lesions apparently produced by a prominent porta hepatis, vascu lar abnormalities, or even congenital mul-location of the gall bladder, 'fhcse diagnoses were ullimately eonlirnied by angiography or oral cholecystography, or both. In our scries, the most common explanation for false-positive liver scans was benign vascular.delect. Scintigraphy showed enlarged spleens (> 14 cm in greatest dimension) in 55 workers, or X.4T of the total group examined, 'lhe abnormal spleens ranged from 15 cm to ll> eni. Again, the incidence of splenomegaly was no greater in workers using monomers other than vinyl chlo ride. principally for rubber production, than in those with high-VCM exposure from plastic production (Table 2). To date, liver biopsies have been done on 47 workers, 18 in the high-VCM group and 29 in tho low-VCM group. Indication lor liver biopsy has been persistent abnormal findings in the biochemical tests or an abnormal findinj in the liver/spleen scan. Fatly metamorphosis of varyinj severity has been found in 44T of the biopsies from work ers with high-VCM exposure and in 34 T of (hose Iron the low-VCM areas. Interestingly, the low-VCM group ha shown a higher prevalence of portal lihrosis (44Ca) thai the high-VCM group (3590), although the.se dilTercnee are not statistically significant. Two more cases of angio sarcoma have been diagnosed by liver biopsy, both fron workers with high exposure to vinyl chloride monomer. An important part of Ihe program is to determine wliiel l tests "'id best predict abnormal hepatic histology. Of tJv ; patients with abnormal findings fiom biopsies, N7T hat > an abnormal SC. IT level. SOT an nhnormaj. ,SOC>l' level and SOT an abnormal CiCJTP level. Within pur relalivcl' a 'rr,ad biopsy series, every patient in whom1 all three o j. these tests showed abnormal results or in whom plasm: i indocyanine greet) clearance was abnormal, lad abnorma t liver biopsy findings, whereas completely normal values fo a uh of these variables was always associates with a nor $ X \I in.il livci lu**|i`.v. | >1.-1 <- -11 I'.dy w ,r. i.,.l .. u.eliil pii'ili. lir .'I hepatic br.tulupy, . 11..- j.iiv.ilen.v >1 binp-.y pliiv.'il 1`iul.d lilat u .r. I 'm mi illv lli. ..iiiii- in iMheiil1. with u.iiiii.d '.pleeir. (`it)';.) .i*. in I In iw Wlili '.pli'iuc i-iiI.hj-*'ini hi (4 I'.n I. 1`iospeclivo i'iupli>\ei". al tins plum imw utnlrigo out i.'Mime bunhemic.-il Irsi*. iluiiui; llu-ir pie empl.'Vmeiil physicals. I lie iiiiginul testing >1 all 11X3 employees showed a 2b',/' rate ol abuurmal findings in one or more "liver fimelion tests." 'I lie abnormality rale in the precmployniciit group, cuiisisling of supposedly healthy men with no exposuie to vinyl chloride or otliei monomers, was 24Co (that is, 44 of ISI). Alcohol consumption piohahly accounts for some of this high "background" rate of abnormal liver function tests. One oilier preliminary obsetvation is worth noting. We have recorded elevated inferior \enn caval pressures (> 10 nun Jig) in 21 of 40 patients wiili splenomegaly or ab normalities in other preliminary screening tests. Wc have no definitive explanation for ibis. Hascd on our own data and (hose of%hers, we plan to ' continue an expanded screening program that will include indocyanine green and bile-add clearance studies in the initial evaluation. Other tests wc may do more routinely are HI barium swallow for varices and upper gastr&ttosiinal scries in patients with splenomegaly; 12] more Ex tensive hemodynamic evaluation, including umbilical vn ' catheterization for portal pressure measurement and potfal venography to determine the role of portal hypertension in the splenomegaly of vinyl chloride-associated portal fibro sis; and |3| extensive pulmonary evaluation, including pulmonary artery catheterization. prcssuic studies, and possible biopsy, to evaluate the high prevalence of elevated vena caval pressures. Dr. Paul llcrk: Dr. Creech has been in the forefront of developing a screening program for vinyl chloride workers. Some of the problems he faces are clearly indicated in Tahlc 3. which summarizes data obtained during admission to the Clinical Center of five workers from two vinyl chloride plants, including the two patients presented in detail here. 1 lirce, including the first patient discussed, had significant hepatic lihrosis seen on light microscopy, and. in the fourth, a characteristic pattern of lihrosis was seen wiih electron microscopy (17). Patient 5 had an extensive angiosarcoma anil severe alcoholic liver disease with cirrhosis. Note that only ibis patient had hioehemical abnormalities or defective DSP or indocyanine green metabolism. Tallin 2. linsults of{(i50 I.ivnr/Splnnn Scans in Woikers nxpnsod to Vinyl Chloride Monomer (VCM) at a Plastics and Rubber Manufac turing Plant Finding Decreased hepatic uptake 1 lepalic tilling defect Enlarged spleen Total Abnormalities | .i High VCM (193 scans) l.ow VCM (457 scans) 1.55 2.54 N.24 12.43 % 2.10 O.KK 8.75 11.M2 Dark at at. * Vinyl Chloride und Liver Disease 721 BOR 008459 . jX; liilllo 1. < nh*1'itfMiy l*iM Viliyl (i/I.) A'.VH I lvf`1 i\, Mill I'iUieill 1 Irpatiuiiig.ily Sl'llliMMi|`.tiV *`1", tek., Kunlun- 1 i\ri 1 imilIuhi It '.l'. * .|S Mllmli- ir.P Kilnilu ,u 1 -I- -I- Nonnat + + Normal 3-- -- Normal 4_ 5_ -- Normal -- Uccasiuiud increased alkaline phosphatase Normal mean SIJ * Jljimihm. MiOr/Mit*!', .likahnti plnj.pluuisf. t CiiMi^cs inJicative of VC tfl)Uty by iliUruu nmmviopy. v,-i 3.K 2.9 2.1 2.1 9,3 <5 llt'li * '"Itlltn' < M I`II K;ii<` f .Mi.i.nil'. hum >, o.:. .vo >"KlbK 0.17 0.21 0.20 0.25 0.20 0.24 0.23 . . . 0.10 0.22 0.0.1 0,18 0.02 1 It'.liiii ifii 1 i;ij*iM*.i. V( i.'iU it hi pniic 111 ll DM (M'M'IV) V{ '-avu nail'd Inputic libioMS (seviTia V< '-associated hepatic Id <11.is (niiivh Kii pathologic diagnosis Angiosaicoiua, hepatic tihrosis, cirrhosis The normal values recorded for so many tests of liver function in Patients 1-4, despite the significant histologic lesion, pose serious problems for designing an adequate screening regimen to detect liver injury among vinyl chloride workers. Furthermore, as shown by the first case presented, follow-up studies of patients with proven vinyl ehloridc-assoeiated liver injury, after their removal from exposure, cannot he based on any routine tests now avail able. The suitability of bile-acid clearance studies for this purpose certainly merits further evaluation, as these scent to be the most sensitive indicators of hepatic disease that we haw, short of liver biopsy. 'I he absence, of abnormal ities in so many tests of hepatocellular function probably reflects (he I act that the principal analogue lesion in vinyl chloride-associated liver disease is fibrosis, with relative sparing of the hepatoeytes. Unfortunately, we have no simple test for hepatic fibrosis without hepatocellular dys function. Epidemiologic Studies: A Cohort Approach Dr. Irving SclikotT1': With l.)r. Creech's discovery last year of his clinical cases of angiosarcoma, sve have come full-circle. Since Rehn first reported aniline-induced blad der cancer in 1895, there has been a discrepancy that has bothered many scientists; that is, although many chemical carcinogens have hccnjdcntified in laboratory studies, very little human canccrifias heen reported to he associated with industrial expose in the vast ami growing petro chemical industry, TWrparadox is, there!ore, one of many Itibiiruioiy carcinogens but relatively few hitnuut neo plasms. Aside from bladder cancer vine to beta-naphthylamine ami hen/.itline, and coal-tar skin cancers, wc simply had not seen much malignancy among chemical workers that was related to occupation. Recently, wi>h the recogni tion of bischloromethyl ether cancers of the lung and upper respiratory tract, our suspicions were heightened, but, until last year when Dr. Creech and associates (8, 9) reported their cases and Drs. Maltoni and l.eFemmc (12) presented uf Medicine ami Community Medicine; Director, r.nvium* mcnul Hi-.tlfU Stunu's Research Center, Mount Sinai School of Medicine, New York, New York. their elegant laboratory studies, vvf coulrf not explain .the discrepancy between our anticipated clinical findings and whal actually occurred. Recognition of this problem actually began a few years ago, in the mid-l9<i()s, when simultaneous reports came from Europe (2, 2). the United States (1), an9 Great Itritain (4) describing aero-osteolysis among workers ex posed to vinyl chloride monomer. I he syndrome Jis char acterized by a Raynaud-like phenomenon, pseudo-clubbing of the fingers resulting from the collapse of the terminal phalanx, and local hone resorption. At the suggestion of the liritish plasties industry, a .study of the pathology of aero-osteolysis was begun. Rats were exposed to gaseous vinyl . chloride in con centrations of up to 20 000 ppm. The investigators (II) reported an interesting set of data on the pathology of the bone changes and also described the appearance of zyntlul cell tumors in the rats. Unloriunately, these lindiugs did not receive much attention. Such zymhal cell tumors had been seen with polycrylic aromatic hydrocarbons, hcn/.idinc, and several other car cinogenic chemicals. It was perhaps thought that this was yet another laboratory curiosity. Nevertheless, the bone changes and some fragmentary information about liver changes did attract attention, especially because of the excellent work of investigators at the University of llonn. They found that many of llieir patients with aero-oslcoly* sis also had liver disease (7, 18, 19). However, they re ported no cancer f20). That was the stale of our Knowledge at the end of 1972. Matters changed in 107.1. with the tepoil of three eases of angiosarcoma of the liver among svorkers at (he plastics and rubber plant in l.ouisville (8. 9) and the reports of more animal studies (12) that appeared soon after. Vinyl chloride monomer was seen to he a carcinogen both in animals and humans. Because the chemical and its poly mer, polyvinyl chloride, were widely used in industry and blscsvhcrc, it was important to elucidate the true dimensions of the problem. First, we examined and did biochemical tests on more 722 Jun* 197G * Annals of Internal Medicine * Volume 84 Number 6 BOR 008460  --T _- -- - (U.m l,'till tx,nk''i'. .0 Iltit'i* |U.ml .. ii |*ir- i utiiii* lluii' 111 ^iniil sets ill lomliiious iiiiil llini1 ililliiinl nt, Hi iiposiurx. I Ih'm* wen- in addition l<> lln' I.'lll* wuil.,'11, examined by l)r. Cn-ccMlvJ onisvillc. Only uuc test. an elevated .ill.,iliin: pi iiiSpiiyHR proved valuable in 'viei'iiing ili.-sv wurkcix lor viiia^^Bpride-as'.oeialvd liver iiijm v. Ncxeial oilier lahoi.iloc^^RKIics lii.il wcie done showed many oilier nlnionnnlitidljgljpa the nvvilap with 401) simul taneous coiiiiuls ami life vnti.iinlliy in >plil samples reiulercil ihem inellieienl as diagnostic aids. We found no guide predictive of eillier liver injury or angiosarcoma (5). Whetlier ulliasound (21) or liver scanning will ullinuiely prove m he of greater help, we do not know. When angiosarcoma of die liver was described, we all appreciated that it was, in general, rare. There has been only one established ease of angiosarcoma in 52 000 con secutive autopsies at the I.os Angeles County Hospital. A search of the liics al the Hronx Veterans Administration Hospital showed not a single case of angiosarcoma in 30 000 autopsies. Wc saw a significant number of eases only at Mount Sinai Medical Center in Dr, Popper's liics, where one can lind everything hepatic, culled from many sources. besides vinyl chloride, at least two other chemicals were known to-causo hepatic angiosarcoma in man: thorotrast (22. 23) and arscnicals. Arsenical-induced hepatic angiosarcoma had been seen among vineyard workers ex posed to arsenical-containing insecticides used to spray the grapevines (24), and in patients chronically ingesting in organic medicines' containing arscnicals (25). Thorolrast angiosarcomas were particularly worrisome. Although the material had been used in diagnostic radiology since 1926, the lirst hemangiosarcomas were not seen until 20 years later. This was consistent with the long period of clinical latency we knew to he characteristic ol most environmental and occupational cancers. It also correlated with what Dr. Creech saw in Louisville. The plant had been opened in 1940, and the first angiosarcomas were seen in 1968, Dr. Creech showed us one case of angiosarcoma seen 12 years after onset of exposure, hut most of the others became apparent after a considerably longer time. Although the plastics industry is idatively new--many major segments began operating during World War IT-- we have known of vinyl chloride for a long lime. The United States began producing it on a very tentative experimental basis in 192S, and on a small commercial scale in 1938. 1 lowever^production has markedly ex panded only in the Past JHajIc. In 1950, the tolal world wide production of plaslilPwns only about a million and a half tons; in 1970, it waSBonglily 15 times more. I he question now is whether the cm relit Cases of hepatic angiosarcoma arc derived from the small population of 1940-1960 woikers, or from the full pool of vinyl chloride workers, including those beginning woik flom 19110-1974. I.xpciicncc suggests dial current cases are derived piimarily from the early group. Lloyd (26) analyzed the first 19 cases reported in this country and abroad. The average period of clinical latency, front lirst exposure to diagnosis, was about 20' i years, with a range of 11 to 30 years. Most of the people in this group had begun work in the I'MI#*, .mil t'l'.iK. Ilir , .| .iin`1,1 ,.n, .mi,! iwtw living mvii ale tln-ii-lnii- ileioisl limn a W'iv '.mall population. It* i'.iIIm' lilf'.l nt Ihe tnl.il ivnik Inicc w.r, lirst exposed to vinyl chloride m llir l.ii" 19 ,(I. and e.nlv |960s, angiosai- eomas aie nni yet seen .inmiii: them. I liese and olhei dal.i li.ne cdahli-.licd dial xn\l i liloiide-iiidoi cl cancel, as well as most oilier enviion- menlally mdiued uci-plasuis, lias a Imi". pciim! nt clinical l.dcncy. We ilo not know, liuwexci, it ii will be a common problem or an infrequent one, 'I luce groups aie studying this, using a cohort nppioacli. Liisi, die plasties industiy has mourned an extensive mvcsiig.iium <27). I lie cohort is composed of all men known to have winked in the relevant facilities for a year or mine before 31 December 1972. Data have been gathered on N3X.: men, hut. un fortunately. about 1200 men still ha\c not been traced, 'thus it is dillieult to evaluate the infoimalion gathered. Nonetheless, the data now available point to increased risk of cancers of (he lung, brain, buccal cavity, and pharynx (27), Although more information is needed lor conclusive evidence, the same suggestions haw been found, m a second study, done at the National Institute for Occupational Safety and Health (28). Our laboratory has searched for information on a key question: How common will angiosarcoma be among populations exposed to vinyl chloride monomer? At one plant wc identified all workers employed there fow 5 years or more from the time the plant opened in 194Sto 1964. There were 257 such workers, all of whom have been traced, 'I here were 25 deaths, of all causes. Three died of hemangiosareoma of I lie liver, each continued by autopsy and reviewed by Dr. I'opper ami Dr. 'I houias. Thus, approximately I of 8 deaths among vinyl chloride workers, at least in this plant, was due to angiosarcoma of Ihe liver. Another death, caused by ruptured esophageal vaiiees, was also related to vinyl chloride exposure. If these data arc confirmed hy other studies, it would seem that the risk of death from angiosarcoma of the liver will in crease greatly 15 to 25 years idler the initial exposure in those who began working with the chemical between 1955 and 1974. In closing, it is worth noting that until recently, the chemical industry had been making plastics, not doing medical research. We in the medical profession had been doing research, but not . paying great intention to the chemical industry. In both instances, changes are being made. Further Epidemiologic Studies Dr. Ilenrv I 'idk*: I In* liisi luur eases of vinyl ehloiide mouomer-indnctal liepaiie angiosarcoma idcntilicj in Louisville were all in polyviuvl chloride polymerization workers. This is as expected, since the job done by these woikers. opening and cleaning the reactor vessels alter polymerization, involves the highest exposure to vinyl chloride monomer. Other cases of the tumor have since been identified in workers, primarily among those involved in the.polymerization process. We now know of 15 eases * Mcdii'iil npidi-iniolttyjsl, f'anciT ;! Ilmli Defrets Division, hureau . of l-jHOcmiolof.y. Center for Disease Control, U.S, l*ilUc Health Si-nuc. Atlanta, Georgia. Berk et oh Vinyl Chloride and liver Disease 723 BOR 008461 'thin 4- 1 wCili'i tif lh*|<iIm Amcmi-.iim miii.i Iti hilywittyl I'tilyt* tr'ltlllllHH (l*V(.| WimIm-iis (11 '. | (I'nnli-i fn fli'.xu'.n CumIhiI, '.incut * Age It an: .Vs 1 laic <4 Hal. ,4 1 t( I*Vt ` U'ntlv 1 >M|*IHT.I`. - *--- . - I ill 1 *1 ;i|li 1 *<;i;ii<ni litill lmli.il l'V< ` Wei#It li 1 icifinr.r. * *- >'' . 1 52 E)V M 43 wJl 41 ' w4 3(i w5 49 wft ss M M M M M 7 45 w M w MX 43 w9 43 M wIt) 4(1 M wII 54 M 12 H) \v M w13 45 M w M14 52 w15 50 M U..I1 7/52 5/Ml 11/55 12.-4S 11/45 l/r.2 5/ 15 f>,'55 10/40 <i/5l 10/40 X/44 8/4 1 9/49 3 (.1 x/o/ 3 O'l 5/ 7n 3,73 . 12.71 2/74 2/74 11/74 4/01 5/OX 3/711 3 *liK 4/74 5/09 i ot l.'iat \ **'* 9 71 3/ 71 12/73 4 , 8/01 4 5/OX ,j 3/711 3 r8 7,74 5/09 )t\ 19 IS IV 14 21 :x 12 2S 19 14 10 23 2\ 2*3 19 * r.ilicm *. I llln Ill'll v IM 111 l`5|**`lll ||* 1 'V*` ii ;i itl.iiii iii 1 mhvviHc, Kfiiiiuiy. I'aticnt'i 10 lluounlt 12, ill JNiiiitaM l ulls. Ni* Vink; I'uhi'i.i'. 13 .nul |l, ill Mutilt C lin lesion. Wcm Viit*ini;t; ami I'uui'itt in IVllMown, I'viinsylviiiitii, in the United Slates (Table 4), 9 in workers at the Louis\ille plain and 6 at three other plants. Of particular con cern is that eases seem to be increasingly more common in recent years. Table 4 shows several important epidemiologic features. The latency period, as reviewed in detail hy l)r. Sclikolf, is quite long. The duration of exposure for most of these workers is equally long. However, Patient 3 worked with polyvinyl chloride only 4 years and developed a tumor 15 years later. This suggests that relatively brief periods of exposure can be signilieant, and (hat, once started, the carcinogenic process may not always be reversible with removal from thtf monomer exposure. It has been widely assumed that the highest sustained levels of vinyl chloride monomer exposure occurred in the early years of the industry (1940s and early 1950s), and that most of the patients had begun work during those years. Patient 7, however, iirst began working in 1962, and, therefore, the carcinogenic risk factors were still present in the early 1900s. Most eases of spontaneous hepatic angiosarcoma (and other hepatic sarcomas) occur in older age groups, whereas, despite the long latency period, the vinyl chloride monomer-induced cases occur at a relatively early ago for this type of tumor. In the epidemiologic .study of these initial cases, two important questions'Wrisc: |l| Why. is the disease more prevalent at the plnuirin Louisville; and [2) Why, in par ticular, did it dcvelrfffrTn these 15 workers; that is, might factors such as chemical exposure, work patterns, or past medical history serve to promote or accelerate the develop ment of angiosarcoma in these particular persons? The Louisville plant, which opened in 1942, is the second oldest polyvinyl chloride polymerization plant in the United States. Only seven such plants started operating before 1950, and the lour plants in which cases of angio sarcoma have occurred are in this group. The age of the plant is, therefore, important, and this probably relates.to both the long latency period for the disease and the less stringent precautions for working with the monomer that W pertained in the e arly years of tl ie industry. Many of these eases of angiosarcoma were initially mis diagnosed. Most sveje called hepatoma or cirrhosis, and it is only with a full review of mortality data, including re-examination of autopsy or biopsy tissues, thA some cases have heeit uncovered. Moreover, the last three cases at the Louisville plant were identified during intensive screening programs, as described earlier hv Dr. Creech. Therefore, this initial cluxlciing in Louisville may be only artificial, and, with continued surveillance in Ihc industry, a more uniform distribution of cases may become ap parent. On the other hand, there are specific`conditions in the Louisville plant uiul in the 15 reported cases that may he significant in the curly appearance of angiosarcoma in these workers. 'I here are four polymerization buildings it) the plant. "I he two that produce the siiaighlforward poly vinyl chloride resins show the least relation to the cases of angiosarcoma, whereas the tsvo that produce more complex products have a stronger relation (14). One of the latter two buildings produces polyvinyl chloride latex (.in aqueous suspension of polyvinyl chloride), and the work practices in this building dill'er slightly in that it takes longer and is more dillicult to clean these reactor vessels than the ones that produce polyvinyl chloride resins. Other factors that might also lead to greater exposure while cleaning a reaelor include age and size of the reactor vessels. I'reipieney of cleaning, and the lining material used in. Ihc icaelor. DilVciing Work practices related In product and equipment may. Iheteloie, he important in the distribution of angiosarcoma. The building most iliieetly associated with the angio sarcoma cases is (lie one where copolymers attd tcrpolymers are produced. In this process, vinyl chloride monomer and other monomers are polymerized together to produce polymers with dilfcrept qualities. Several of the monomer* that are reacted with vinyl chloride monomer, such at vinylidcnc chloride (vinyl diehloridc) and acrylonitrile (vinyl cyanide), have similar structures and chemical 724 June 1976 * Annali of internal Medicine * Volume 84 Number BOR 008462 i* wt sa o: in. ic;. M.- Pi** n: hj iff*. ' -* l lull ,Mil'll-.Ill I Ilf M\ IVl-ll ill I-I III I | ll.lltl VM'lf .if." i.- iT| ii > .ill iii iIh-m' .mil hIIiit vinyl f i nii|*i min I,, line in.hi in tin- Niag.ua I alls pl.mi worked ill llu- I'olynn'ii/.illoM >'1 polyvinyl alcohol lor 5 yearikbeTmu switching In polyvinyl dilmiilf, Since kiiiiwlfif^MBgtil ll: loiig innpc elhvts nl some ol these ehemival.'bSMfemty. WO ititist Consider the possibility tli:il they in.ijBWnCract with or i_-ii|i.hicc the clfects of vinyl chloride nwnomcr. Thus, these initial eases m.iv lie related In exposure to multiple chemicals, and in particular, to the viuvl chloride imitiomer--viuyltdene ehlmiile mixture, which is found mainly in (lie Louisville plant. Chemieals similar in ' inyI chloride monomer arc also used outside the polyvinyl chloride industry, for example, vinyl lluoride and chlorohutadiene (vinyl vinyl chloride), ami it will probably he some time before we appreciate the full scope of the hazards posed by ibis class of compounds. A recent study (26) has also suggested that eases of angiosarcoma may not be limited to the high-risk poly- meii/ation workers hut may also occur in workers who use the plastic resins to produce a variety of plastic prod ucts and in people who reside near polyvinyl chloride plants. Of the six patients with hepatic angiosarcoma in the Connecticut Tumor Registry, (wo lived within the vicinity of polyvinyl chloride fabrication plants, one was an ac countant at a polyvinyl chloride fabrication plant, and one (whose tumor, on pathology review at N1H, is classified as an indeterminate type of sarcoma and only possibly an angiosarcoma) worked at a plant where he applied both polyvinyl chloride and non-polyvinyl chloride insulation to electrical wires (29). Maltoni and LcFcmine's (12,30) inhalation studies showed that vinyl chloride monomer can induce cancers of the lung, brain', and kidney as well as angiosarcoma. Several recent studies suggest that the incidence of lung cancer, brain cancer, and lymphoreticular malignancies may also he higher in vinyl chloride monomer workers. The number of deaths among the younger workers at these polyvinyl chloride plants is still small, however, and con tinued surveillance will he necessary to confirm these asso ciations (27,28. 31). The most ominous feature of the vinyl chloride studies is the unknown in the future. It is possihlc that, in time, we will begin to sec not only more patients with angio sarcoma, hut also significant numbers of patients with other, as yet unrecognized, manifestations of vinyl chloride monomer-induced disease. Jlmtltwe do not know whether, in what has been called th^gplaslics age," related chem icals will pose similar lia/arrfyfe- Metabolism of Vinyl Chloride Dr. I'. G. Watanahe*: Angiosarcomas, y.ymhal gland carcinomas, and nephroblastomas developed in Ails ex posed to from 50 ppm to 10 00(1 ppm of vinyl chloride monomer 4 h per day. 5 days per week, for 12 months (12). The rats were observed until death occurred. The incidence of tumors at 50 ppm was less than that predicted Tiwirolftcv Research L.ihi-r.iinry, Dnw Chemical Co.. Midland, Michigan. Dr. Watnnabc's associate* in these studies were Dr*. R, E. Hefner, Jr., G. R. McGowan, and P. J. Gehring. Ii"m .1 ! ,1,1'.,' *. -1,i., in vc gri,,-|al* .1 I,,,i,i tli.* tionoj ui nlcu'f\ .0 hii'hci rhj,,i',i|i,. lewis id ?*ai ppm In lltthlt) ppm. Ileeaiise llu* lunmr iu>idi-mc at Ml ppm was lower than c\|H*cled. ami '.in, r vmvl chloiiili* iuonoin<'i per M* is not a potent alkylating .nvui. wr llmurht that 11 " car* cmnpcnie potential \m\l ihloiiile monomer might he mediated lluongh the bniualinii ol reactive Metabolites. 'I herefore. studies wcie designed to ehieid.de what happens to vinyl chloride monomer alter it is inhaled. A 4.7-lilre Plexiglas inhalation chamber was designed anil constructed so that lour rats could be* simultaneously exposed to various concentrations of viuvl chloride mon omer. To minimize contamination ol lur anti skin, only the narcs of the rats protruded through a rubber menthranc into the chamber. The appropriate initial concentra tion of vinyl chloride monomer (Maihcson Gas Products, liasl Rutherford; New Jersey, 99.97?* pure I was generated in the chamber at the start of the experiment and contin uously analyzed by circulation through an infrared spec trophotometer. Carlton dioxide was continuously removed from the recirculating system by absorption on an As- ` carite*' (Arthur H. Thomas Co., Philadelphia, Pennsylva nia) column. Filtered air was metered into the system to rc-. plcnish the oxygen consumed. Since the amount of air consumed was within 10To of baseline for all cxptm- , ments, respiratory variables were not significantly changed during the approximately l-h exposures. Rats used an these studies were .Spraguc-Dawley, Spartan suhstratn fSpartan Laboratories, Haslctt, Michigan), ranging in weight from 105 g to 200 g. Disappearance of vinyl chloride monomer from the recir culating inhalation chamber, resulting front uptake and sub sequent metabolism, occurred according to apparent first order kinetics as described by the formula: dc ----------- kC. In this equation, C is the concentration of vinyl chloride monomer (ppm) at time f (minutes), and k (minutes*1) is the rate constant for the decline in vinyl chloride monomer concentration. The rate of disappearance of the monomer and the corresponding half-lile (t ;) were calculated from the slopes of the log concentration-time curves. The rate of decline of vinyl chloride monomer in the empty chamber due to nonspecific leakage was also determined at each initial concentration, and the disap pearance rates in the animal studies were corrected for this loss. The rale of disappearance of vinyl chloride monomer from the chamber was slower at concenliations of 100ft ppm than 50 ppm (Figure 5). Other experiments using initial concentrations ranging from 50 ppm to 105 ppm of vinyl chloride monomer showed a linear disappearance with a rate of (8.03 3.40) times I0 -1 minutes-1 (mean . so), corresponding to an average b-, of 86 minutes. At initial concentrations of 220 ppm to 1167 ppm of vinyl chloride monomer, the rate of disappearance was much slower (2.65 1.35) X 10--1 minutes*1, corresponding to an average t<-, of 261 minuics. Assuming that the rate of disappearance front the inhalation chamber was primarily BerK t at. Vinyl Chloride and Liver Disease 725 BOR 008463 olized pii'iloimii.iiiilv l,y u -.iiii-.Ii' pathway lliat, we have -.pcViil.ilfd, may involve ,,1, ohol deliyili,igt-nn*.i-. However, al I'piueiiliall.-ie, r in , ilmg '.'.'0 ppm, lliiv p.illiway lie- entiles s.iliu.it,si ami Iht- .i|-iiilit iiu e ot si-eond.ily p.illi- ways, piL-Miin.ilily mi hiding niieio-oiiial mixed tum-limi oxidases, ineie.i-.es Dosc-depemleiil pioccsses lor the elimination of a chem ical arc of prime importance in toxicology. Many meta bolic and excretory processes have Unite capacities, and, as doses of a chemical aic increased, these pioccsses be come 'saturated or overwhelmed. If the tiinclion of the saturated process is detoxification, a dispropoi tionaie in crease in toxicity may ensue uhuve those doses that cause saturation. Therefore, toxicity occurring with large doses of a eheniieal must be interpreted camiously. and it does not necessarily imply that compatible types of toxicity will be observed at lower doses. Gillette (33) recently summarized the role of chemically reactive metabolites of foreign compounds in toxicity. Compounds such as bromohcu/cnc (3-1) and acetamino phen (35, 36) induce hepatic nccnJsis only after the dose is high enough to overwhelm the detoxification pathways for the reactive niclaholilcs of these compounds. Con jugation of the alkylating metabolites of these chemicals with glutathione is a primary mechanism for detoxiljcation. Necrosis is induced only after the glutathione levels are reduced sufficiently to allow the reactive metaboBtcs to Duration Of Exposure, Min. Figure 5. Decrease, with time, of vinyl chloride monomer (VCM) concentrations in the inhalation apparatus. Rats were exposed to initial VCM concentrations of approximately SO and 1000 ppm. Also shown are the respective declines in VCM concentration from the unoccupied inhalation appaiatus. The rate constants and half-lives of disappearance of VCM from the system during metabolic experi ments were corrected for nonspecific leakage from the chamber (see text). a function of metabolism, the slower rate of disappearance of the monomer at concentrations of 220 ppm or greater suggested that the metabolism of vinyl chloride monomer may be a dosc-depcndcnt process whereby low concentra tions arc metabolized through pathways that, with higher doses, become saturated. Vinyl chloride monomer metabolism was also studied using metabolic inhibitors. Pretreatment of rats with eth anol (5 mg/kg body weight, by intrapcritoneal injection) l'/j h before exposure to the monomer caused almost complete inhibition in rats exposed to 50 ppm, but only a mild inhibition in rats exposed to 1000 ppm (Figure 6). SKF-525A (Smith Kline & French Laboratories, Phil adelphia, Pennsylvania), a commonly usedk inhibitor of certain reactions mediated by the mixed function oxidase enzymes, did not inhibit metabolism of the monomer in rats exposed to concentrations up to 50 ppnt, but did cause a slight, approximately 20%, inhibition ai 1000 ppm. Con sidering these data, we hypothesized that the monomer is metabolized by several dilTcrcnt pathways, dependent on the dose. At concentrations up to 100 ppnt, it is metab Figure 6. Declines in vinyl chloride monomer (VCM) concentrations, with time, at initial concentrations ot 56 and 1034 ppm. for both pretreated and control rats. Also shown aie the respective declines in VCM concentration from the, unoccupied inhalation apparatus. 726 dune 1976 Annals Of Internal Medicine Volume 84 Number 6 BOR 008464 v* t * . . ; * <i* . k i. >. .V V V ;./ v:'"' ;y f' . ''iyi-v'.t.V ,, ' .,. .lift .v'.1'- ' r.; . i! " :'* Figure 7. Left. Irregular lilirosit of portal tract* arftl focal nodular fibrosis of the hepatic capsule. (Hematoxylin and cosin; original magnifi cation. x 45.) NIH accession number S74-411. Right. Portal tract from the same liver shown in Figure 1. Tile filnosis interrupts the limiting plate and extends into suriounding hepatic parenchyma. There is a slight infiltrate of lymphocyte* and minimal proliferation of bile ducts. (Hematoxylin and fipsin; original magnification, x 160). NIH accession number S74-411. (Reproduced by permission. Ann NY Acad Sc/ 246; 174-194, 1975.) t react with other intracellular mncromolecules (DNA, RNA, protein, lipids). Although Gillette and others have not yet attempted to correlate the covalent binding of rcaetive metabolites to DNA with carcinogenesis, such a reaction has been speculated as a potential mechanism Tor carcinogenesis. Recent work in our laboratory and elsewhere, much of it still unpublished, has included studies in rats on the fate of ingested "C-vinyl chloride monomer, and the isola tion and identification of the major urinary metabolites of this chemical. The ingestion study showed that vinyl chloride monomer is metabolized to polar products that are readily excreted in the urine. These results also sup port the hypothesis of dosc-depcndcnt metabolism. The hepatic nonprotein sulfhydry! content of rats exposed to vinyl chloride monomer showed a progressive depression related to the concentration and duration of exposure. Consistent with the sulfhydryl depression, two of the three urinary metabolites isolated thus far have been identified as ihiodiglycolic acid nndlAf-acetyl-.V (2-hydroxycthyl) cysteine. Thus it seems thapvinyl chloride monomer of ils reactive metabolites coitttenffy bind with hepatic gluta thione anil are sub.scquen(f||Rydrolyzed and excreted in the mine as conjugates of cysteine. Other studies on vinyl chloride monomer continue to support the hypothesis that its carcinogenicity is related to the metabolic fotmation of reactive metabolites.\Sludies (37-.V)) have shown an enhanced positive mutagenic re sponse in certain strains of Salmonella typhinitiriuni ex posed to vinyl chloride monomer if microsomal enzymes or fortified liver homogenates arc present. The metabolites of. the monomer identified in the urine of rats exposed to the chemical indicate that the primary deactivating mech anism is by conjugation with the hepatic nonprotcin su|> hydryl compounds, glutathione and cysteine. Our current research is directed toward further elucidating the metab olism of vinyl chloride monomer to rcaetive products and their potential to hind with intracellular mueromolecules. Resolution of the metabolism and pharmacokinetics of vinyl chloride monomer will undoubtedly be of great help in resolving its hazards and will ultimately provide a scientific basis for guidelines concerning tolerable levels of exposure. Histologic Features: Hepatic Fibrosis Dr. Mans Popper'*; Only tittle more than half a year ago, I became acutely aware of an cITeei of vinyl chloride exposure on the liver wheij, within 1 week, three persons called this connection to my attention. Doctor I.clhnch from Bonn. Germany, sent fi reprint about a peculiar intra lobular fibrosis of the liver seen by peritoneoscopy and liver biopsy in workers exposed to gaseous vinyl chloride (7): Dr. SelikolT called me and asked what I knew about hepatic angiosarcoma, a rare tumor newly observed in the same type of workers in this country; and Dr. Thomas, here in Itethesda, showed me histologic slides from several such workers. Subsequently, I have had the privilege of studying, with Dr. Thomas, a large amount of histologic material that has been collected in the l aboratmy of Pathology of the National Cancer Institute. The following report is based on this cooperation, and. I hope, shows the heuristic value of environmental pathology (40) in rapidly assembling information (hat might enlighten other areas of pathology and medicine. * Gustave L. Levy Distinguished Service Professor, Mount Sinai School of Medicine, New York, New Yoik. B*tk tt of. * Vinyl Chloride and liver Otscaa* 727 BOR 008465 Figure 8. Irregular, focal dilatation of hepatic sinusoids. The size and number of the sinusoidal lining cells are increased, The hepato- cytes also vary in size and locally appear to be proliferating. (Hematoxylin and eosin; original magnification, x 400.) Nlh acces sion number S74-41S, u In reviewing the .serious hepatic lesions encountered in vinyl chloride* poiymei i/.ation workers, we saw that two distinctive lesions were prominent. One, angiosarcoma of the liver, has been the focus of most of the attention in this study, and its histologic features will he presented by Dr. Thomas. The second is characterized by a peculiar form of hepatic fibrosis, which, in many instances, was initially diagnosed as cirrhosis. In some of these workers, the lesion was associated with portal hypertension and variccal hemorrhage, leading to the pcrlormance of a portacaval shunt, during which lime a wedge biopsy of the liver was obtained. In other eases, the lesion was diag nosed on the basis of a needle aspiration biopsy. It is of considerable interest that, in vinyl chloride workers in West German)', severe portal fibrosis with significant portal hsperlension, splenomegaly, and thombocylopenia--pre sumably on a splcnomcgalic basis--is relatively common while angiosarcoma is rare, whereas the relative incidence of these two lesions in American workers seems to be reversed. The typical lesion of vinyl chloride-associated hepatic fibrosis consists of three features (Figure 7). The first is a typical but nondiagnostic portal fibrosis, varying in degree throughout the liver. Ijjjjjplaccs, it scents aggressive, in that fibrous tissue extetapig into the lobular parenchyma distorts the limiting platS^ff also extends into the walls of the portal vein branches, separating their muscular libel's. Sometimes accumulation of dense connective tissue is as sociated with proliferation of bile ductules and pcriductular inflammation, hillanunatory cells also aggregate around some bile duels, and this pericholangitis might explain the focal canalicular cholestasis seen in some specimens. 1 he second is capsular and subeapsular librosis, in a nodular form; it is the most characteristic lesion, partic ularly visible if the surface of the liver is inspected on peritoneoscopy, as reported from Bonn (7, 20). Distinc tion from cirrhosis by gross inspection is difficult. The mini l\( il tl t-.r-. r* \nl'th* .mil ii-lb'i'b'd ill 1i focal inli.iliililil.il ,ii i iiiiiiiI.iiihii >i| i oimci |n,- Ir.-.uc lil'co., ice m-iii/cil Jc.fim Ilv liv licbl ihiciic.i n|iy niily in i'iiiiiici live liv.ue slime.. Ibclmn me i .i ,,py (I/), by conliasl. ileItvls a dense but llilu i'iiiiiici live liv.ue mal Miimimdiiii'. ilie hepalocvU's ami a'-sm i.iied with ni.itiv libioblasts amt fal-coulainini'. mcsciicliyin.il cells - lb' cells (-11) or li|'*'cytes (42) -- -wldcli have been postulated to be precursors of fibroblasts (42). 'I Iris fibrosis dills'is morphologically from dial seen both in cluoiiic active hcpaitlis ami in alco holic liver disease and suggests a difierenl mechanism of development. Where the intralobular lihiosis is conspicu ous, it is associated with bulging sinusoidal lining cells with a prominent dintlase-resisiant, periodic-acid Jiehilf reaction of the cytopfissni, which is sometimes granular, as in phngocyiosing macrophages, hut more typically dif fuse. The hepatocytcs show no significant changes except that, in the areas of prrimincut sinusoidal lining cells, they show variation in size of both cytoplasm and nuclei in that large hepatocytcs, sometimes even nnillinuclear, alternate with small cells (Figure S). In some in&iauctt, particularly, in autopsy specimens, regenerative nodules arc seen with out cirrhosis. Besides this pattern of fibrosis seen in ull specimens, sonic specimens--both front patients apparently frog df angiosarcoma and in two in whom angiosarcoma wasxiter found--a focal irregular sinusoidal dilatation was Aicd (Figure 8). It did not seem to be related to passive Jon-gesdon, since it was not predominantly in the ccnlrolomdar area. The same type qf focal sinusoidal dilatation, pro gressing almost to peliqsis. has been observed in patients after treatment with anabolic steroids (44) and contracep tive pills (45), Howcvgr, in these latter instances, there have not been any reports of progression to- angiosarcoma. Ip our vinyl chloride cases, the sinusoidal dilatation is associated with proliferation of the sinusoidal lining cells, which become enlarged1 and show bizarre nuclei and, as will be discussed below, progress lo angiosarcoma. Thus, we can conclude that this sinusoidal dilatation is a pre cursor to the tumor it) vinyl chloride exposure, hut we have not yet clearly identified the nature of the cell under going malignant transformation. In cases where we were able to study the spleen, we found it distinctly enlarged, and, particularly on laparos copy, it showed a nodular but irregular type of capsular fibrosis (7). On the cut surface, the follicles were con spicuously enlarged, in contrast to Cirrhotic fibroeongcstivc splenomegaly. Histologically, fresh hemorrhage was seen in most spleens, although some showed calcification and iron incrustation in l||e form of Gamna-Gandi bodies. The cords of the pulp contained many erythrocytes, characteristic of hemolysis. The lining cells of the sinuses were activated hub for the most part, not libroiic. Study of the pathogenesis of vinyl chloride-associated liver injury (46) showed that vinyl chloride or its metabo lites seem to induce a hyperplasia of two types of cells: the mesenchymal sinusoidal lining cells in liver and spleen, and the 'hepatocytcs. In the spleen, activation of the sinusoidal cells may result in splenomegaly, and. in the liver, in fibrosis contributing both to portal hypertension and the formation 728 Ju/10 1976 Annals of Internal Msdicine Volume S4 Number S BOR 008466 {*% -**' ,nj . i 4 4 /VW* >' Figure 9. Loft. Sinusoidal pattern of angiosarcoma. Sinusoidal spaces art large and irregular. Angiosarcoma cells line these spaces and cnslte.nh hepatic cord cells and an increased number of nomneoplastic-appearing cells in the space of Disse. Bile plugs are present in Pile canaliculi. (Hematoxylin and rosin: anginal magnification, x 392.) NIH accession number A74-3I. (Reproduced by permission. Ann NY Acad Sci 246,268-277, 1075.) Right. Another area of the same angiosarcoma shown in Figure 4. Spurlike protections of hepatic tissue project into larger, more cavernous cystic spaces. The hepatic cords are disrupted by degeneration of hepatocytes. The tissue spac%of Bisap contains in creased collagen and rcticulin fibers. (Hematoxylin and eosin: magnification, x 100.) NIH accession number A74-31. of septa. These septa may progress to cirrhosis. Although wc have not as yet noted this progression, it has been ob served by othcFs, Sinusoidal dilatation develops, and in this setting angiosarcoma ensues. The role of the activation of the hepatocytes, which seemingly form a scaffold, is problematic. However, it is worth noting that wc have anecdotal evidence of primary hepatocellular carcinoma in persons exposed to vinyl chloride. While studying these cases, wc became aware that pro longed exposure to trivalent inorganic arsenicals, such as Fowler's solution used -to treat psoriasis, results in the same clinical and histologic picture (47-49). Histologic examination of two cases made available to us by Dr. Peter Schoucr showed the same histologic changes as in vinyl chloride-induced fibrosis. Moreover, exposure to such arsenicals has also been associated with hepatic angiosar coma (25). In vineyard workers; in addition, it has been associated with primary hepatic carcinoma and cirrhosis (24),. The mechanism of toxicity of arsenic has been re ported to occur through its reaction with 6,8-dithiooctanoic acid (o-lipoic acid), with the arsenic forming a stable bridge between the two sulfhydryl groups (32). Certain hypothetical metabolites of vinyl chloride formed by the mixed function oxidases would also be expected to react in a similar fashion with tjdipoic acid, possibly explaining the similar pattern of botfigfibrosis and neoplasia seen with these two superficially mfrelatcd chemicals. Interestingly, thorium dioxide (thorotrasO also produces the same spec trum of lesions (22). The pathogenesis of the noneirrholic portal hypertension in all these instances may be related to a discrcfyncy hehvecn increased splenic blood llow, induced by the hyper plastic splenomegaly, and to the impairment of the distcnsihility of the hepatic vascular hod produced by the various forms of fibrosis, which hy themselves arc not conspicuous (50). The fact that this type of portal hyper' tension has been produced by chemicals, at least some of them environmental, suggests that idiopathic portal hyper tension, found only sporadically in the Western world but more often in some areas of Asia and Africa, might result also from toxic, possibly environmental, chemicals. Histologic Features: Angiosarcoma Dr. Louis B. Thomas': We have reviewed the available pathologic material for a group of vinyl chloride workers who had a peculiar hepatic fibrosis and focal sinusoidal dilatation associated with proliferation of sinusoidal lining cells. In addition, wc have studied the hepatic lesions of 15 vinyl chloride workers who developed angiosarcoma of the liver. The hepatic changes described by Dr. l'opper were also seen in the nonangiosarcontalous areas of the liver in all cases in which suitable sections were available for review. From these observations, we concluded that a continuous spectrum of changes occurs, starting with multifocal areas of stimulated sinusoidal cells, followed by increasing degrees of atypia and proliferation of these cells, and culminating itj progressively growing, multicentric, infiltrative angiosarcomas (51). Of those patients with angiosarcoma w-ho died and were autopsied, postmortem examination of the livers showed massive involvement by cystic, blood-filled tumors that replaced most of the tissue. The liver weights ranged from ISM) g to 7300 g. The average weight was 4236 g, la the" larger specimens some of the cystic spaces were several centimeters in diameter and were associated with large areas of hemorrhage and necrosis. Rupture of these large cavernous cysts followed hy inlraperitoncal hemorrhage occurred both spontaneously and at the time of surgery, and it was the immediate anatomical cause of death in several patients. The liver tissue was also irregularly re placed hy small cysts that varied in si/c from 1 mm to 1 cm in' diameter. Most of them were filled with blood; only 'Chief, Laboratory of Pathology, National Cancer Institute, Berk et at. Vinyl Chloride and Liver Oiseaao 729 BOR 008467 ;i Tow ci'iihuni'il llintuihi. I In- hi-p.ilii' miiI.iii' was iihT"1-' tlllL- III llllll'llll'. Ill.l'.'.t'S >! III*- .nil'll'-..in 1*111.1, .Mill |nli""-. ii|' lilt' liver nid iltvnlvi'il gius-dy l.v :iii!,iii-..iirniii.r. h.ul n iiT.nl.H ly sli;i|Hui lihrnsis. Tlu* I'm V_l,..i:.i|''.iil.il .mil | ii >i 1.11 li.nl 'Si's weiv il.nk c.ivi-n In-i .iii i- nl bile si.isis. ; Misii>scupi'c jYtVVct) lln' ;iii',iiis;iruinl;is In l-ii.' inuliiccuirit:, T sfrucmnil pnllems. I lie sinn- siiivl;iI pattern. illiSI I! 1'iglliv y.'l, consisted nl lii'n- plaslic-uppenrinfi sinilstoidnl colls that hail cnvclopcil cnrJs nl' licp.iincylcs anil formed irregular simiMinl.tl spaces. In these areas, the hepalocytes were well preserved and bile- scerelmg, with ini degeneration or necrosis. Macrophages, lihrohlasis, and lipocytes proliferated in the space of Disse. With increased growth of the angiosarcoma cells, the hepatocyles atrophied and disappeared, and the space of Disse was tilled with collagen lihers, so that larger, cystic spaces formed. The papillary growth pattern was an inter mediate stage characterized by papillary projections or blind-ending, disrupted hepatie cords extending into the irregular, multiloculatcd cystic spaces of the angiosarcoma (Figure 9 W). These spurlike projections were covered by angiosarcoma cells that enshealhed the various other cells in the space of Disse and the residual fragments of hepatic cord cells. The cavernous pattern hud larger hlood-lilled spaces surrounded by a thick wall of dense, relatively acellular fibrous connective tissue. These larger, cystic spaces were lined by variable, sometimes quite scanty, layers of angiosarcoma cells. We also observed more nodular, anaplastic focuses of angiosarcoma in some of the livers, hut in every instance these specimens also had other focuses ('f angiosarcoma that showed the progression from sinusoidal to papillary to cavernous growth patterns. Thus, this scries of changes seems to represent multi- ccntrie development of angiosarcoma', starting with the precursor lesions of sinusoidal cell proliferation and ntypin. Some of these precursor lesions progress to the fully de veloped cavernous angiosarcomas, which become clinically evident. We do not have adequate morphologic criteria to separate the earliest histologic changes of sinusoidal cell atypia and hyperplasia from the progressive, fully devel oped angiosarcomas. As noted earlier, proliferation of hepalocytes and of non-ncopiastie-appearing- fibrocyics, lipoblasts, and macrophages plays some role in the devel opment of the angiosarcomas. Proliferation of these cells was especially noted in the areas of sinusoidal and papil lary growth pattcrns^lhin the angiosarcomas. Many of the hi ic" features observed in the evolu- tion of the hepafrS glosarcomas in the vinyl chloride workers have al: described in the hepatic angio- sarcomas caused by lorotrast and by inorganic nrscnicaK. .Studies are now in progress to evaluate the similarities and dlssimilaiities between the lesions produced by these chemicals and the hepatic angiosarcoma% of unknown cause that occur sporadically. Summary Dr. Uerk: We began this conference with a, list of ques tions that 1 thought might define the scope of the problem of vinyl chloride-associated liver disease. Although at least '.null' |'i"rii V, III'. Ill'll 111.1.1ibSuwOIla rr-.'Wr fin-jP*-!*11 Ilf tlii-m. n i. . I, .it ili.it din m ItaV*1 to a ycF'bivrv^etiiiiTli )>iiif.ii--.-. in 111111 ....... .. nl tlu'iii: V j.-Vyjj/Sfc It r. v\ i a ih iiiallmr lh.it we have lieeu uwariPtd I lit* pinhleiii lor lev. than a yrai (as nl Nnvemln'i l,,7-l). I lie elloils pie-iMili-d al this iniilt'ieui c lepieseul an milsl.tiul- ill)', example nl elleeloe. il nllen iiilnrmal. cnll.iboi.ilinn ainoiig iinivei'.MV, iiulusli\. and ruvcimiiciil scientists, which, il puiMicd al it-, ctirrciil p.ue, is ceitaiu to pio- vide us in the near future with answers to at least some of the critical questions. ACKNOWI I-.IXiMI.NIS: Hit- aiiilims thank Hr. Allan llnhn.iiin of the M.ivn Clime fnr hi-lpiiit'. ns with inn lute acid .11 . i|'i>e.n."ie tests; nml l)i. Kcrnniifo Kntel.m-.ki nr It..- Velei.ms Ailminisli.iiiim Hospital, \Vusliiin;lnii. IV( , Ini (tic lie|i.aie vein catheter i/alion studies nn nnc of nnr |i)itiems. Iteeeived la l etnii.iiy I770, accepted 2 M.neli 1970. Kei|iirsls I nr reprints should he uildiessed tn Paul I). Berk, M.D.; Chief, Seelinn till Diseases id the I ivet, Dil'.eslive Diseases llianeh. National Institute of At (lit it is. Metabolism, and Digestive Diseases, llldgc It). Kuum 4D-52, Natimial liisliliiles uf tlcalill; tk-ihcxda, Ml) 2U0I4. References r ' 'iSS'-fe L. 1. Wii.son Hit, Mi'Ciimmh'K WU, Taium CT', el al: IK-eujialiiin.d aeronsleolysis.' repot t uf 31 eases. 7-l.W.I 2til :577-5H|, ;1%7 2. Siieiii I. Dm imam I, Vai askaI M: {'nun ihinii la? iMiidiul mthuliiaviiilor piiHluse de elmma dc unit. Med Interna-(iluaa) 15:907-978, 1903 g}' -U-' 3. Commit JM. I'ii.viz C, I f. Fitvi'it Ml. et al: Acro*colyse el lesions eul.mees assneiees ehc/ dens ouviiers tHcclcs <ul ncitoyage d'autuelavcs. Cali Med Tiae 4:14, 1 (H>0 afr. 1 - 4. IIakkis UK., Adams WCiF: Aern-ostenlysis ocenrri*' in men engaged in the polymciizaiion of vinyl chloride. V Med J 3:712-714, 1907 > . 5. Iiii.s It. Amh kmin II. NiniriisoN \VJ, et al: Prevalence of disease among \ iuvl chloiidc and polyvinyl chloride workers. Aim .XT .4end .Vri 240; 22-41, 1973 6. Pu.miiN CiA: [Allection of the liver and bile duets ill workcis encaged in the production of some types of plastics.) (Rus.) Sor .\/od 28(21:132-135. 1965 7. Mamsiii.init IIJ, l.iniACii WK, Mount R. ct nl: CHironiseh- loxischc l.ebcrsehadcii Itci Arhcitcrn in dcr l'VC-produkuon. Illicit Med U ni/ieiitWii- 98:2311-2314, 1973 8. Ckitui J. Johnson MN, IIiikk II: Angiosarcoma of the liver annul): polyvinyl chloride, workers--Kentucky. Morbid Mortal Weekly Her 23(h) :49.Mi. 1974 9. C'kii.ui Jl. Jit, Johnson MN: Angiosarcoma of the liver in the niamtlaclure of polyvinyl chloiidc. J Occur bled 10:150-151, 1974 10. Fjiiiomai.: Vipyl chloiidc, P.V.C., and cancer. Lancet 1:13231324. 1974 11. Viol.a PI., Itir,(11 ii A. Caih-io A: Onconenie u-spousc of rat skin, limes and bones to vinyl chloride. Cancer Hev 31:510-522, 1971 12. Mai.mini C, I.I Fi.minT. (i: Carcinogenicity hioass.ivs of vinyl chloiidc: current icsutis. .-Inn NY Acad Sci 240:195-218, 1975 13. (ioitnoN DU. Thomas Ml. Ki nv G, el al: Hepatic angiosarcoma in man and rodents lollouing prolonged exposure to vinyl ehlmiile (alisliiicl). (iatliiHiilernliiyr 07:794, 1974 14, I-'ai.k II, C'Kiriii Jl., lli.Aiu (\V Ju, el at: Hepatic tloe.isc among workeis al a vinyl chloride polyiucri/aiion lilaill. JAMA 2111:39 01. 1974 13. Hi Kk Pi). Mariin JI-, Wai.ooni it JCi: Pcisislence id iir.vl cliloride-iiiiliicod livei inimy alter cessation of exposme. Aim NY Acad Sei 240:70 77, I97S 16. I aKusmi Nl'. IIoiiman NU, lloi'MANN At', el at: Validitv and sensilouv id an mmoemms lute .aid toleianee list in paiumv with liver disease. N l.nyl J Med 292,1209-1214, 1975 17. Thiciii: T, Naniia K. IsliAK K, ct al: Hepatic uhrasiiucttiral changes in vinyl-chloride woikers (ahstracij. Clin Kes 23:259, 1975 1 ItT, Vi-i.i SIAN (!, I .am,I, (,'t:, Jilin S, ct al: Clinicai manifi'sl.da'as and course of vinyl chloride disease. Ann NY Acad Sci 240:6-17, 1973 730 June JS76 Annals of Internal Medicine Volume 84 Numbers BOR 008468 ^" *I 19. | vtn.t i I . h in \ lm i*< <, 'I 'I I ........ ** h i mIvhhvI t liliti mIi* I'ti'iliii iihm w m ki'i ' N l 'Vf ' I ** -* I. 19 ^ 1 t 2o. M aw` M t11 k til, lit it a t ti WK. Miitm P. I .l k hnr.t In mat In* A**|h kl< till I I* I S.tili II I-* I I hi IHII III mi 1I1T ViMylkliloiMl'I'tilyMK'iti.ilMMi, //ii Mann Unnn VI9h- ?H\ 19/^ 21. IaAioh k.l, WiHIAMS l*M, SMmi I'M, ( ,il' (iicy stale nil **MMhtj'.MpItY tor itNintit>iin4* iihImvIimI iKjm.uic to h*paloti\iv m-1-Mls. luihrt I r?.1.'-1 2**-l* 22. Ha Suva IIuria I: I .iU'tU^mimis in man i.mscd bv culliMil.il ihiunim dioxide (tho:oti;i^Iy4-a hi,w cast* nl sattoma of the Iner 22 yeais alter Ihe iiiS&ion. .1*.// Pada-l n2 401-118. 195o 23. \ isiiiiu J, Pool si n M: ^3f1 the ludopaiholopy uf hvei amt liver lumutns in thomim dioxide pahcni>. Ana Pntlnri Micrtt/ntri Sc.wd Ml I'72 24. Kom P; Aivn telvi-inimnen: (haiiiungioeiulotheliom) / Rtehtfamh nl ;4bS*M> I. piv/ 25. Kitill.son W, kiM LI, Om'INa J, cl al; llemuni'incndolhcliul sarcoma of Ihe liver fiom ihtnnic arsenic intoxication by Imvlci s solution. C'utuet 2l:M*l->??, I'htK 26. lioxn AV; of the. liver m vinyl t Idol idc/poly- \ hi% l chkmdc ptodmnon workers. J theup Mai 17:333*334, vns 27. 'I Mir.kMiAW tk. Gamm WK: Modality study of worker* in (he nuimf.iviuie of viml chlmidc ami tlx {Hilymcis. J Occnp Med I6509.M8, 1*174 28. UAwvtiil K KJ, SiKiNt.iK \V, Wai.oni m JK, cl l: Neoplastic link woikeis exposed to vinyl chloride. Ann NY Acad Sri 271:40-48, Wf, 29. 1 amikUiRN PJ. lli'Atti C\V Jk: llcmangioKurcomn of ihc liver, Connecticut. USP/IS Report; 111*t*74* I CM- 2t 1974. Atlanta, Center lor Disease Conuol 20. .Mai ioni C`, I.iIimini (i: Camnnpcnirity bfoaxsays of vinyl i blonde. (1) Research plan ami early results, hnviron Res 7*187-405. 1974 31. Monson KK, liurRs JM, Johnson MN; Proportional mortality among vinyl chloride woikcrs. lancet 2:397-398* 1974 32. llriNtR KI* Jk. Waianahi; P(j, Gj.hkim; PG: Preliminary studies of the late of inhaled vinyl chloiidc monomer in ruls. Ann NY Atari Set 24ft: 1 35-MS, 1975 33. Cthtiiuu JK: A perspective on the role of chemically reactive metabolites of foicigtt compounds in toxicity. J tliochem Phuiniat'td 2.V27H5-2794. 1974 34. Jot t.ow DJ. Mnun-.i.i. JK, Zami'am.ioni-: N, ct nl; llromolscn- /ene induced liver necrosis, piuiecloc lolc of glutathione and evidence for .Vl-bromnhcn/eno oxide us ihc hcpaLUioxic tttcUbo* litc. Pharmacology 11:151*169, 1974 . ... ' -J- Miir mi m liti i n I *f in* `A'/, ft ,il A* 11 itMtiiipb 11 iiidnt * d l*,'l,i!i m h> i' l * I'imH . lar |'n|i> HUtt l>i 1 /f t het 1 K / /II it.' i w.. lm l mV | >1, if, * t'l, 1*1 i m v i t al A*.11.tunit*i phcit indiii i-i i ht-piin* n liriIS Pil.tKfl.M 17. Hahimii II, Mai avi ti i i r. Mm Ml *. A * -M It t ' *s| ' it. P'M 1 ItMM.Itl, t.(1 .nut inmra* Jivri nirihalctl iiml.it '1 lilt lIV 1*1 Mil A1 1 III....... . - .n ,V /\non *>ll.ttll*.. hit j * an 11 r*.4 ** i t ; . 1 */'* 38. Kannih, 11. JmiAN*.aN A, Kami i1 i \ ii .d 3 In- umt ,t)*i`rn> itV of vnivl ehl< tide aliei t.l **lu ,iili\alim. .Iftiblit 3. PMPD, 19?^ 39. Mai avi n 11. C. llAKISIIt !' Hamii IM A. el al ; Mut.treinieiiy ol vinyl vldotidc. thhn.K doh m *l\ nil*, i. hllHO.,u ei.ildt'hv l!c and chloroethiinol. Rittehrm hatpins AVv f'iwininn (it: tM P/O, t*l75 40, Pm'i't.K l|: Ilu> hemistic iihjkvh.jiui1 of cioiionmental |.uhol* or.v: lessons Ironi ihc vinyl clihnule pitiblem. 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