Document xzjzyEgNgMZmEYeob41zEg0y0

Jl RepnnTfrd from ANNALS OF INTERNAL MEDICINE Vol. 34, No. 6 June. 1976 PrinteO in U.5.A. Vinyl Chloride-Associated 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 Although polyvinyl chloride has been produced from vinyl chloride monomer for more than 40 years, recognition of toxicity among vinyl chloride polymerization workers is more recent. In the mid 1960s, workers involved in cleaning polymerization tanks were found to have acro-osteolysis. In 1974, the same population of worrers was found to be at risk for an unusual type of hepatic fibrosis and angiosarcoma of the liver. We describe two cases of vinyl chloride-associated liver injury, one of hepatic fibrosis and one of angiosarcoma. Histologic features of these lesions are similar to the hepatic fbrosis and angiosarcomas resulting from chronic exposure to inorganic arsenicals. Preliminary studies suggest that the toxicity of vinyl chloride may result from formation, during high-dose exposure, of 3ctive metabolites by mixed function oxidases of the liver. Epidemiologic studies indicate an increased incidence not only of liver disease, but also of cancers of the brain, lung, and possibly other organs. Da. Paul D. Berk*: Polyvtm.l chloride, the most widely used syntbcric plastic, has been manufactured for more than 40 years by polymerization of vinyl chloride monomer gas at a number of plants in the United States and in many other countries. Worldwide production of polyvinyl chlo ride in 1972 totaled more than IS billion pounds, of which about 25% was made in the United States, and items manufactured from poiyvmyi cmoride are virtually ubiq uitous. They include building materials such as pipes and cables, home furnishings, toys, records and other recrea tional items, clothing, packaging material, and a host of other products. Although for many years vinyl chloride monomer and polyvinyl chloride were thought to be en tirely inert, in the mid-1960s Wilson and associates (1) in Louisville and investigators in Europe (2-4) reported that the development of acro-osteolysis, a skin disorder characterized by Raynaud's phenomenon, scleroderma- - Chief. SrrtiOn on of Cie Li-r, Diiciuve Duck Branch, National Institute of Annum, Metabolism, aoa Di.ciiiyc Discasei. - An edited iranscnruon of a Combined Clinical Staff Conference at ihe Clinical Center. Reusesoa. Marvland. 14 Nj*rmber IV74. by the National Institute of \nnr.tis. Metabolism, and Dnesuse Discasei. National Lnauiutci of llealtb, L S. Department of HeaJUa. Education, and Welfare. Annali of Internal Medicine 84:717-731. 1976 like dermal induration, and bone lesions, was an occu pational hazard to workers involved in the polymerization of vinvi chloride monomer. At greatest risk were those who manuaiiv cleaned the tanks in which the polymerization reaction occurs. At the same time, other reports described nonspecific alterations of hepatic structure and function in vinvi chlo ride monomer polymerization workers (5), and a pooriy characterized condition called "chronic epithelial hepatitis" was reported in roughly 15% of such workers examined in Russia (6). These reports of hepatic abnormalities in the vmy! chloride industry, published for the most part in the industrial hygiene literature of eastern Europe, at tracted little attention until very recently. Then the situation was dramatically altered by the almost simultaneous reports of hepatic fibrosis, splenomegaly, and portal hypertension among vinyl chloride workers in Germany (7), and the discovery of three cases of angiosarcoma of the liver, an otherwise rare tumor, in workers involved in the production of polyvinyl chloride from vinyl chloride monomer at a plant in this country (S, 9). The subsequent introduction into this plant of a systematic surveillance system has thus far resulted in the detection of several more cases of angio sarcoma, as well as many instances in which abnormal findings in liver function tests, or scintigraphic evidence of splenomegaly, or both, were detected in otherwise asymp tomatic workers. Similar screening efforts at polyvinyl chloride production plants in several countries quickly brought the number of workers with documented angiosar coma to 19 C10) t- Not all of these cases have been pub lished. Results of animal experiments strongly support the pre sumed relation between exposure to vinyl chloride gas and hepatic angiosarcoma. Italian investigators (11) had re ported several years ago that rats subjected to prolonged inhalation of high concentrations of vinyl chloride devel oped carcinomas of the zymbal gland and other organs. More recently, Maltoni and LeFcmine (12) presented data t Ai of 10 February 1975, the Center for Diteate Control Knew o( 27 of hepatic anuoiireoma m vtnvl chloride worker*: 13 m the United States* o in Canada, 2 m Lbc United kingdom, J m Germany, and 1 in France. 717 R&S160578 f Figure 1. Surgical livr bioosy obtained f'cm Patient 1 in 1972. Normal lobular architecture 15 maintained, cut there i$ enlargement ana hbrosis c# the Dortal tracts, with Cue Ouctuiar proliferation, (Hematoxvim and eosm: original magnification, x SC,) NIH accession number S74-4H. (Reproduced by permiss.cn. Ann NY Acad Sc/ 246,70-77, 1975.) indicating the development of angiosarcomas of the liver and other organs, and the ceveiopmem of nepnroblastomas in -cts exposed to various concentrations of vinyl chlorice gas, including levels within the 500 ppm limit that, until recently, had been the accepted occupational standard. Ex posure to as little as 50 ppm has produced angiosarcoma of the liver in rats and mice, with a ciearcut dose-response relation seen in mice (13). To date, most cases of henanc fibrosis and angiosarcomas in man have been detec.cn in workers exposed to vinyl chloride monomer gas durtr.n the production of polyvinyl chloride, and. as with acro-osteoivsis, those who dean the polymerization tanks seem to be particularly at risk. If confirmed, preliminary anecdotal re ports of hepatic fibrosis and an isolated instance of anniosarcoma of the liver in workers exposed only to the fmsned polymer will significantly increase the population octcntially at risk. Data collected by the U. S. Public Health Service show that about 6500 workers in the United States are exposed to vinyl chloride monomer during the pro duction of the gas (14 plants) and during its polymerization to polyvinyl chloride (37 plants). However, another 30 000 to 50 000 workers are employed in hundreds of plants that convert the polyvinyl chloride resin to finished products (14). To date, there is no evidence of risk to consumers from these finished products. The discovery of both benign and malignant fiver disease in vinvl chloride workers raises several critical Questions, incloding the following. 1. Who is at risk of developing vinyl chloridc-assoeiated liver in)ury ' Is the dancer restricted to workers exposed to the monomer, or is there also a dancer to the much larger force ot polyvinyl chloride workers'.' Is either the incidence of liver iniury or the nature of the lesion influenced by simultaneous exposure to various copolymers or otner sub stances? Arc there risks to consumers, such as those who use vinyl chloride sprays, those who eat food packaged in vinyl chloride wrapping, or those whose homes contain polyvinyl chloride plumbing? 2. What is the clinical, biochemical, and histologic spectrum of vinyl chloride-associated liver injury? In par ticular, is there a relation between the peculiar hepatic fibrosis reported in vinyl chloride workers and the in creased incidence of angiosarcoma of the liver? What is tne relative incidence of these two lesions? 3. What is the natural history of established, vinyl chloride-associated liver injury, both in patients who have had continued exposure and in those patients removed from further exposure? 4. What tests will constitute an effective screening regi men for detecting vinyl chloride-associated liver injury and for following patients with established disease? 5. What are the cellular and molecular mechanisms by which vmyl chloride produces hepatic fibrosis and angio sarcoma? 6. What is the optimum therapy for patients with both hesatic fibrosis and angiosarcoma associated with vinyl cn.oride exposure? 7. What preventive measures will be necessary and suf ficient to protect vinyl chloride workers from tutors in;ury from this compound? As yet, we have few definitive answers to these Questions. The following case reports of two patients recently evalu ated at the National Institutes of Health help to illuminate several points that will be discussed here. They also il lustrate some of the difficulties in defining the scope of the prcolem. Case Summaries Dr. James F. Martin*: Patient 1 is a 30-vear-old white men who worked at a plastic and rubber manufacturing riant in Louisville, Kentucky, for S years. For the first 5h years, his job involved cleaning the tanks in which vinyi chloride poiymer was polymerized. Two and a half years ago, during evaluation of a nonspecific .i'.ness characterized by fever and weight loss, he was found to have nepaiosplenomegaiy, mildly elevated serum biliruDin and SGOT concentrations, and abnormal 45-minute plasma BSP reientton f 10.651;). Nonspecific symptoms persisted for 3 months, after which he was hospitalized for an acute hepatmsl.ke illness. Since the patient had been on sick leave for almost 3 months before he developed jaundice, the relation of this 'auer episode to vinyl chloride exposure is unclear. Because his physicians were concerned about the persisting hecatosplenomegalv, ihcy did a diagnostic laparotomy during the recovery phase of his illness. The surgeon described the liver as showing multiple areas of fine nodularity with fibrosis. An enlarged spleen was removed at the operation. A fiver biopsy done during surgery showed that the principal abnormality was intense portal fibrosis with bile ductular prolif eration (Figure 1). Additional features, to be described later, -,:;uded capsular and intrasinusoidal fibrosis, activation of sinusoidal lining cells, and marked anisocytosis hepaus. These features are now known to be typical of the lesions seen m workers exposed io vinvl chloride. There was no evidence of viral hepatitis, alcoholic liver disease, or any other hepatic disease that could be diagnosed morphologically. Histologic examination of [he eniarced spleen showed lymphoid and reticuloendothelial proliferation without significant fibrosis. Clinical Associate. Section on Dine of tlte Liver. Diinmt Diteaae Pranctt. National Institute o( Actfmul, Metaboliim, and Digestive Disease i. 718 Vun.1976 Annal* of Internal Medicine * Volume NumOer 6 R&S160579 * After surgery the patient returned to work at the plant. How In summary, our study of this vinyl chloride polymeriza ever. he was tranvterred to another area in the factory with no appreciable further exposure to vinyl chloride, and he con tinued in this new assignment for 2', ccars. when it recently tion worker suggests that vmyt chloride-associated hepatic fibrosis persists after removal from further exposure, and became evident that vinyl chloride exposure was associated that the lesion may be quae extensive even though stan with both malignant and nonmalignant disease of the liver. dard liver function tests have completely normal findings. Dr. John Creecn referred him to the National Institutes of Health for turthcr studv. This patient thus represents a unicue follow-up of a case or apparent vinyl cnlonde-induced liver injury 2': years after removal from esposure. Dr. Robert C. Young*: Patient 2 is a 42-year-old white man who was first hospitalized at the Clinical Center tn March 1974 for evaluation of angiosarcoma of the liver. At admission to ihc Clinical Center, the patient seemed to The pattern had worked in a plastics production plant in be a healihv, well-developed, and well-nourished young man. Louisville. Kentucky, for 20 years and had been involved Except for several small vascular spiders on his anterior chest, pm steal examination w as normal. Complete blood count and cnest X ray were unremarkable. However, pulmonary function stuoies showed evidence of miid restrictive pulmonary disease. in the polymerization of vinyl chloride monomer to potvvtnyi chloride. During the course of his employment, he was involved in cleaning the polymerization vats, a phase All routine tests of liver function, including serum bilirucin of the operation associated with particularly high exposure concentration, transaminases, alkaline pnospnatase, serum pro to vmyl chloride monomer. tein electrcpnorests, and 45-mmute BSP retention (3.4^), had normal findings, as did the liver scan. Because wt thought it important to confirm whether histologic improvement accom panied the aoparent Diochemical improvement m liver function, peritoneoscopy and liver biopsy were aone wuh the fully in formed consent of the patient. The liver was again seen to be covered with multiple. t:nv, riec-grain-size nodules, and histologic examination again snowed extensive portal norosis with bde ductular proliferation. Coras of hepatic cells were surrounded by fibrosis. At least one area had bridging between portal areas and hepatic veins (Figure 2). Areas of intense Ivmphoid proliferation were seen m some cf the portal tracts, and again, as in the earner biocsv, mere was considerate proliferation of collagen within the hepat.g sinusoids. Althougn the parenchyma! ceils seemed reiativeiv normal, the fibrosis in both tne portai areas and within the sinusoids was at least as severe at this recent biopsy as it had been 2'/: vears earlier. Because of the tissue abnormaiitv, hepatic vein catheterization studies were done. Total hepatic blood flow, indocyanine green extraction, and hepatic oxygen consumption were norma:. However, me wedged hepatic venous pressure was siigr.tlv elevated to 12 mm Hg with a tree value of 3 mm Hz Because we wanted to rind some test ot liver function that would retiect the histologic acnormauties and therefore serve ti a suitable screening test, we did several special kinelic stuia.es D.sappearan.ee curves "itn radioianelea bi.irugin, BSP. and two different Cases of mdoevamne green (one of the most sensitive siudicx of lr-er function available) were all normal f 1 5). Oaiv the bile-acid disappearance test, which is an experimental pro cedure, had abnormal findings 116). A routine general examination in November 1973 showed an elevated alkaline phosphatase level. The blood chemistry screening procedures were reseated in February 1974. and, be sides tne persistently eievated alkaline pnospnatase. the serum bilirubin concentration was abnormal. A liver scan done m February 1974 showed mottling of the right lobe of the liver consistent with cirrhosis or w-uh tumor. The patient was- admitted to St. Anthony's Hospital in Lsuisviiie, Kentucky, on 26 February 1974. Hepatic arterv angiography was done, and the findings were consistent with tumor in the right lobe of the liver (Figure 3,-1). An exploratory laoarotomv done in March 1974 showed a 4-cm bluish eievated mass in the rignt lobe of the liver, and small noduies in coin the rignt and left lobes. Over the rest of the surface of the liver there was smail. irregular, raised nce-like speckling. Biopsy of tne large lesion in the right lobe showed angiosarcoma. Biopsy of the left lobe was reported to show both Cirrhosis and hepatic fibrosis. Because of the degree of generalized cirrhosis, rtgnt heretic lobectomv was advised against as being too hazardous. The patient s earlier medical history is significant in that he had been a heavy alcohol consumer intermittently over :nc previous 5 to b tears, during 3 of which he reouired hospitaliza tion for alconol withdrawal. The patient estimated maximum alccr.oi consumption during those periods at one pint of whiskev a dav. hk nen .he was first hospitalized at the Clinical Center later in Maran !9Ta, the positive physical findings were limited to the chest, wnere there was an increased anteroposterior diameter wit.-, a few rales at tne left base. Right paramedian and lett fiar.k incisions on the abdomen were well healed. The liver was 10 cm in span by percussion but was not palpable. There was r.o spicnomegaiy, no other abdominal masses were found, and the rest of the physical examination findings were within r.ormai limns. . -. -' . V y., ''geaLyx Pertinent laboratory information included serum alkaline pnospnatase, S7 ILMitre (normal. <7S); LDH. 124 IU/litre i normal, <340); SCOT, 21 IL'/litre (normal, <52); SGPT. -Jv ' f-t- rs1.* - -2 33 1L', litre (normal. <45): bilirubin, 0 4 mg/dl total, with 0 05 mg'dt direct-reacting. Chest X ray showed only atelectatic chances in both bases. A selective hepatic angiogram showed ."r-it' r.v > r,fF-^^-411 mottling of the liver consistent with cirrhosis, a 6-cm .x 6-cm tumor mass in the right lobe, and lortuosity of the intrahcpatic ' *% , :r f VN ^ w , J. ' - ^ -T* . Vk Wt. m s. , J V-- `-* V , ", *>* , *: - \J -4V' vessels (Figure ID). The left lobe of the liver was felt to be smail, as seen in the hepatic scans ot 14 March 1974 (Figure 3C. D). Surgical intervention was considered once more and again rejected Decause ot the generalized cirrhosis. The patient was siaried on adriamycin chemotherapy. 60 mg'rrr bodv Figure 2, N*dle biocsy cf th* hv*r from Patient 1 m early 19?4 * eitensive f.cmsis of portal tracts and heoa; c icCuies, w.tn c.i* cuctuur crci'f^anon. C>storticn cf the rorrai locular archttecture <s indicated cy the fiCrotic CriC^e (arro> iiniunq the cortai tract to a central vein. (MemJtoivitn and eos.n, ordinal ^a^n.ftcation x 50 ) N?H accession nomper S74 370, (PeofOdLced surface area intravenously everv 3 weeks, because of the known effectiveness of this drug against other disseminated sarcomas. At:er the initiation ot chcmotherjpv. the patient was followed wun serial liver tunction tests and serial liver scans. Subsecuent scans showed no alteration in the size of the mass lesion, and the patient remained asymptomatic. He toler- Cy permission. Ann ?4f 4cjd Set 246.70-77, 1975 ) * uaict. .Medicine Bunch, Nn.oail Cancer Lo.U'ute. Sent ct t>. Vinyl Chloride end Liver Oneete 7jg R&S160580 ~ - SI GU29B Figure 3A. B. Heoat'C arteriograms in Patient 2 on 25 Feoruarv 1374 (A) ana 16 October 1974 ;31 show a tumor in the r'gh.t looe (arrows) ar.O tortuosity of the iniraneoanc vessels. C, D. Antero- OOStencr ana lateral heoauc scan in Patient 2 on 14 Marc.o ;574. The large tumor is apparent as a filling cefect within the right looe. ated chemotheraav well, with nadir .'etikocvte counts between 2C00 mrtv and 3000 mm1, and nacir platelet counts or acproximateiv sO COO mm'. Eecauso of the dosc-iimtnng caroiac tox.citv of adriamsetn. the patient received a maximum total cose to 4S0 mg'm;. and the last dose was given on 27 August 1974. He had transient elevations or a.kaii.ne phosphatase curing April ana May 1974 associated with the resumption of heavy alcohol intake. With abstinence, liver function returned to nor mal. and the patient remained asvrrtstomatic. The patient was readmitted in Octocer 1974 for rcevaiuaticn. Repeal anc-.ograpnv ar.d scans indicated persistent lesions with out definite change in sure Repeat liver function tests r.ad normal findings except tor a BSP retention of Dct at 45 m.notes. Because of the total dose limitations of aur.amvctn. the pat.ent was started on intermittent cv clopnoscnamide chemotheraev. Thu patient d.cd in March 1975 of massive intra-abdominal hemorrnac* resulting trom a rupiured angiosarcomjtous cv s; in the liver. At autopsy, there was extensive angiosarcoma in both lobes of the liver, with direct extension to the diacnracm. Metastases were found in regional lympn nodes, lung, svull, and scalp industrial Screening Dr. John Creech*: Data were obtained from examina tion of appro,ximaielv 1200 employees of a piastic and rub ber manufacturing factory in Louisville, Kentuckv. The chemicals most ouen used m the manufacturing processes at this factory were vinyl chloride-, vinyiidene chloride, and sins! acetate for plastic production ana butadiene. _ ,-\:umtrile. and styrene for rubber production. When thr:, em ployees were found to have angiosarcoma ot the liver (S), an intensive study of the health of both present and former employees svas begun. Two major routes of investigat.on were undertaken. Betorc tr.e initiation of a surveillance program to screen for liver eiisease among present empio>ees, investigators C! mcji Asvx-ijte Professor, Depanmeni cf Surgery, Uryvers.iy of Leukine Luuisvjiie. KcOtucuy. searched for autopsy and biopsy tissue from past and pres ent employees. Several abnormalities were repeatedly seen ,n these tissues, including angiosarcoma of the liver, portal fibrosis, esophageal varices, and splenomegaly. There were obvious potential interrelations among these abnormalities. Pertinent findings from the first eight positive cases de tected by this search are summarized in Table 1. All pa tients had had a relatively high exposure to the chemicals used in piasuc production, especially vinyl chiorice. Furthermore, there was a very IonTM history of exposure in these eight workers: more than 10 years in seven cases anu 20 or more years in five. Figure 4 shows the proposed screening method. Eleven hundred eighty-three employees have bad 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, but the resuits are constamlv being evaluated and the program modified to use those tests that prove most sensitive and specific. Some of the more elaborate studies done in pa tients with known liver disease are specifically intended not only to be of diagnostic value, but also to provide in formation about the pathophysiology of liver injury in this population. Appropriate consent is obtained for all pro cedures. Besides the studies shown in Figure 4, other tests are done when indicated, for example, HB,Ag and aettHB.-Ag to ruie out viral B hepatitis, reticulocyte counts t: hemolysis is suspected, and so forth. All employees of the plant have now been tested, some of them several times, with a standard SMA-12, augmented by an SCPT and gamma-glutamyl transpeptidase (GGTP). As noted in Figure 4, a liver/spleen scan is also routine. To date, 650 scans have been done, 193 in workers from areas with high vinyl chloride monomer (VCM) exposure (high VCM) and -157 in employees with low vinyl chloride monomer exposure (low VCM). Among the significant abnormalities reported in these scans are decreased hepatic uptake, detect within the liver, and splenomegaly (Table 2). The total percentage of abnormal liver/spleen scans in the high-VCM workers (12.45o) was comparable to that in the low-VCM group (ll.Sfe). The only significant dif ference between these groups was in hepatic filling defects, which were almost three times more common in the high- Table 1, Hepatic Disease in Workers in Louisville, Kentucky, with High Exposure to Vtnyl Chloride: Features of the First Eight Cases Patient Duration of Exposure Primary Disease Found Angio Portal sarcoma Fibrosis Associated Findings Esnnhaceal Vances Snlt*nr>- megaly 1 2 30 3 IS 4 20 5U 6 2S 7 24 36 4- 4- - 4- +-r 4- 4* 4* + +4* --+ --+ 4- --- 4* 4- ---- + 4-- 4- -r -- 4- R&S160581 *"i __ , S " *v 720 19/5 * Annuls of Internal Mtdicnt * Vo/urn* 84 Nwmo#r6 ill C0299 \ i;o< i > ji*v \ M.ti*`lS ^OOC*" * W*U>C figure 4, A program for the systematic screening of liver disease in vmyl cmcnce workers (see text for details). As inaicateo fcy an astertsu. the frecuency of routine screening is ceterminefl by the extent of exposure to vinyl chiorice monomer within tne plant. CSC complete fciood count; G! = gastrointestinal; LfT -- liver furct.on test. SGCT = serum glutamic exaiacstic fansamioase: SCPT ~ serum glutamic ovruvic t-ansammase: GGTP -- gamma* glutamyl transoeot.case; LCH o= lactic denycrcgerase; Aik. P'tase = aikaime phospnatase. VCM group (Table 2). Filling defects included not oniy angiosarcomas, of which there were two, bur also lesions apparently produced by a prominent porta hepatis. vascu lar abnormalities, or even congenital mal-iocation of the gail bladder. These diagnoses were ultimately confirmed fcy angiography or oral cholecystography, or both. In our senes, the most common explanation for false-positive liver scans was benign vascular defect. Scintigraphy showed enlarged spieens (> 14 cm in greatest dimension) in 55 workers, or 3.4T of the total group e.xammea. The abnormal spieens ranged from 15 cm to 19 cm. Again, the incidence of splenomegaly was no greater in workers using monomers other than vin>i chlo ride, prir.cma.ly tor rubber production, than in those with hieh-VCM exposure from plastic production (Table 2}. To date, liver biopsies nave been done on 97 workers, IS m the h:gn-VCM grouo ar.c 19 in the lcw-VCM group Indication for liver biopsy has been persistent abnormal findings in the biochemical tests or an abnormal finding in the liver.'spleen scan. Fattv metamorphosis of varying severnv has been round in 44T of the biopsies from work ers with hien-VCM exposure and in )4T of those from the low-V'CM areas. Interestingly, the low-VCM group has shown a higher prevalence of portal fibrosis (44T) than the high-VCM grouo (33T). although these differences are not statistically significant. Two more cases of angio sarcoma have been diagnosed by liver biopsy, both from workers with high exposure to vinyl chloride monomer. An important part of the program is to determine wnieh tests will best predict abnormal hepatic histology. Of the patients with aonormal findings from biopsies, S7T had an abnormal SCI'T level. SOT: an abnormal SGOT level, and SOT an abnormal GGTP level. Within our relatively small bionsv series, cverv patient in whom all three of these tests showed abnormal results or in whom plasma indocyanine green clearance was abnormal, had abnormal liver biopsv undines, whereas completely normal values for each of these vanacles was alwavs associated with a nor mal Uver biopsy. Splenomegaly was not a useful predictor of hepatic histology, as the prevalence of biopsy-provea ponai fibrosis was essentially the same in patients with normal spleens (50T) as in those wtih splenic enlarge ment (93T). Prospective employees at this plant now undergo our routine biochemical tests during their pre-emptoyment physicals. The original testing of all 1183 employees showed a 26 T rate of abnormal findings in one or more "liver function tests." The abnormality rate in the preempioyment group, consisting of supposedly healthy men wun no exposure to vinyl chloride or other monomers, was 24T (that is, 44 of 181). Alcohol consumption prob ably accounts for some of this high "background" rate of abnormal liver function tests. One other preliminary observation is worth noting. We have recorded elevated inferior vena caval pressures (> 10 mm Hg) in 21 of 40 patients with splenomegaly or ab normalities in other preliminary screening tests. We have no csnnitive explanation for this. Based on our own data and those of others, we pian to continue an expanded screening program that will induce indocyanine green and bile-aetd clearance studies in the initial evaluation. Other tests we may do more routineiv are [1] barium swallow for ttrices and upper gastroin testinal series in patients wun splenomegaly; [2] more ex tensive hemodynamic evaluation, including umbilical vein catheterization for portal pressure measurement and ponai venography to determine the role of ponai hypertension in the splenomegaly of vinyl chloride-associated portal fibro sis; and [3] extensive pulmonary evaluation, including pulmonary artery catheterization, pressure studies, and possible biopsy, to evaluate the high prevalence of elevated vena caval pressures. Dr. Paul Berk: 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 Tide 3. which summarizes data obtained during admission to the Clinical Center of five workers from two vinyi chloride plants, including the two patients presented in cetaii here. Three, including the first patient discussed, hac significant hepatic fibrosis seen on light microscopy, ana, in the rourth. a characteristic pattern of fibrosis was seen with electron microscopy (17). Patient 5 had an extensive angiosarcoma and severe alcoholic liver disease with cirrhosis. Note that oniy this patient had biochemical abnormalities or defective BSP or indocyanine greea metabolism. Taele 2. Results of 650 liver/Spleen Scans in Workers Exposed to Vmvl CMotide Monomer (VCM) at a Plastics and Rubber Manufac turing Plant Finding Decreased herauc uptake Hepatic tilling defect Hntjrevd spleen Total Abnormalities High VCM (193 scans! Low VCM (457 scans- ct+o 1.55 2.59 8.29 12.43 2.19 0.S8 8.75 11.82 Bark at at. Vinyl Cfitornfa and Livar Disease 721 BI 0-330n 0i v R&S160582 Tibi* 3. Laboratory Data in Vinyl Chlond* (VC)-Associited Liver Disease NIH Series Patient Hepatomegaly Splenomegaly Routine Liver Function Tests* 45-Minute asp Retention 1 Normal 2 -- Normal 3_ _ Normal 4_ 3-- Normal -- Occasional increased alkaline pr.ospnatase Normal mean - SD * 3. irus n. ^OOT SCPT, pnospr.itaje. ^ CbiTiiCi .nuicanve ot \ C injury by electron nuerpscop** C** 3.8 2.9 2.1 2.1 9.3 <3 indocyanine Green Rate Constants (min*1) 0.3 3.0 "I Sjhg 0.27 0.21 0.20 0.23 0.20 0.24 0.23 0.10 0.22 0.18 0.03 0.02 Histologic Diagnosis VC-associatea hepatic fibrosis t severe i VC-associated hepatic fibrosis (severe; VC-associated hepatic fibrosis (mild) No pathologic diacncsisT Angiosarcoma, hepatic fibrosis, cuTftosis The r.crmal values recorded for so many tests or liver function .n Patients 1-4, despite the significant h;-::iogio lesion, pose serious problems for designing an acecuate screening regimen to detect liver injury among .myt chloride worders. Furthermore, as shown oy the first case presentee, follow-up stuoies of patients with proven '-:n\i chior.de-cssociated liver imury, atter thetr remova; ::om exposure, cannot be based on any routine tests now avail able. The suitaoiiity of hue-acid clearance studies fer this purpose certainly merits rur.her evaluation, as these seem to be the most sensitive ir.aicators of hecatic disease mat we have, short of liver biopsy. The absence of abnormal ities in so many tests of hepatocellular function prccaciv reflects me fact that the principal anatomic lesion m %m.yi chiorida-a'sociated liver d.saase is hbrcsis, with ra.am.e sparing of the hcnaiocy res. Unfortunately, we ha'-; no simoie test tor iiepatic hbrcsis without hepatocellular dys function. Epidemiologic Studies: A Cohort Approach Dr. Irving SeiikolT*: With Dr. Creech's discover.' last year of his clinical cases of angiosarcoma, t have come full-circle Since Rehn first reported amline-incucec mad der cancer in J S95, there has been a discrepancy that has bothered many scientists; that is, although many chemical carcinogens have even iJentitied in laboratory studies, -ary little human cancer has been reported to be assorted with inuustri.il esposure in the vast arid growing petro chemical indu-iirv The paradox is, therefore, one o; r.-anv laboratory carcinoeens but relatively few human neo plasms. As.de from bladder cancer due to beta-namihy 1- amine ana retuidinc. and co.il-tar skin cancers, we simply had not seen nniuh maiienarcy among chemical workers that was related to occupation, Recently, with the recogni tion ol Risen oromethy I einor cancers ot the lung and rper respirai.'rv tract, our suspicions were heightened, hut. ..mil last year wren [)r. Creech and associates (ft. 9) reported their caws Drs. Maltom and L^Fcmanc (12) pre .anted * P'r*c-"or f 'U'Jcme jnJ C r*hum(v \ff<J s-nr; D rrctor. f'virrn- r^enia. H-j :.i Ke.cjrcft tenter, Mount Stn.n S^Iwoi ot Mru wine. '*< Ss-tw. Ne* 'i wm. their eiegant laboratory studies, we could not explain the c.screpancy between our anticipated clinical findings and wnat actually-occurred. Recognition c: this problem actually began a few years ago, in the mid-1960s, when simultaneous reports came frem Europe (2, 3), the United States (1), and Great Britain (4) describing acro-osteoivsis among workers ex posed to vinyl chloride monomer. The syndroms is char acterized by a Raynaud-like phenomenon, pseudo-clubbing of the fingers resulting from the collapse of the terminal pnaianx. and local bone resorption. At the suggestion of toe British plastics industry, a study of the pathology o: acro-csteolysis was begun. Rats were exposed to gaseous vinyl chloride in con centrations of up to 30 000 ppm. The investigators (111 reported art interesting set of data on the pathology of the bone chances and also described the appearance of zymnai ca.i tumors in the rats. Unfortunately, these findings aid not receive much attention. Such zymbai cell tumors had been seen with polycry lie aromatic hydrocarbons, benzidine, 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 Bonn. Thev tound that many of their patients with acro-osteolys.s also had liver disease (7, IS, 19). However, they reported no cancer (20), That was the state of our knowledge at the end of 1973. Matters changed in 1974, with the report of three cases of angiosarcoma of the liver among workers at the plasties anu rubber plant in Louisville (S. 9) and the reports of more animal studies (13) that appeared soon alter. Vinyl ehieriue monomer was seen to be a carcinogen both in animals and humans. Because the chemical and its poly mer, pulwinvl chloride, were widely used in industry and elscwnere, it was important to elucidate the true dimensions of the problem. First, we examined and did biochemical tests on more 722 in* 1975 * ArtnaisoflMei'nalMedicin# Volume 84 Suinber $ SI uC30 R&S160583 than 1200 workers at three plants, representing three dif ferent sets of condition* and three different sets ot ex posures. These were in addition to the 1200 workers examined by Dr. Creceh in Louisville. Only one test, an elevated alkaline phosphatase, proved valuable in screening these workers for sins I chloride-associated liver miurv. Several omer laboratory stuoies that were done snowea many other abnormalities, but the overlao with -00 'imuitaneous controls and the variability in split samples rendered them inefficient as diagnostic aids. We found no guide predictive of either liver injury or angiosarcoma (5). Whet.ner ultrasound (211 or liver scanning will uitimatelv prove to be of greater help, we do not know. When angiosarcoma of the liver was described, we a.l appreciated that it was. in general, rare. There has been only one established case of angiosarcoma in 52 CC0 con secutive autopsies at the Los Angeles County Hospital. A search of the hies at the Bronx Veterans Administration Hospital showed not a single case of angiosarcoma m 20 COO autopsies. We saw a significant number of cases cr.iy at Mount Sinai Medical Center m Dr. Peeper's hies, wnere one can find everything hepatic, culled from many sources. Besices vinvl chloride, at least two other chemicals -ere known to cause hepatic angiosarcoma in man: tr.orotrast (22, 221 and arsenical*. Arsenica.-induced hepatic angiosarcoma had been seen among vmevard workers ex posed to arsenical-containing insecticides used to spray me grapevines (2-1). and in patients chronically ingesting in organic medicines containing arsenicals (251. Thorotrcst angiosarcomas were particularly worrisome. Aithougn the material had been used in diagnostic radiology since 1925. the first hcmanciosarcomas were not seen until 23 years later This was consistent wi;n the long period of cimieai latcncv we knew to be characteristic of most environmental and occupational cancers It aiso correlated with what Dr. Crcecn saw in Louisville. The riant had been opened m 19-0. and the first angiosarcomas were seen in 1963 Dr. Creech showed us one case of angiosarcoma seen 12 veers after onset of exposure, but most of the others became apparent arte: a considerably longer time. Although the plasties industry is relatively new--marv major seemcnis began operating during World War II-- wc have known of vinyl chloride for a long time. The L'mtcd Slates began prouucmc it on a very tentative experimental basis in 1925. and on a small commercial scale in 192s. However, production has markedly ex panded onlv in the past decade. In 1950. the total world wide production of plastics was only about a million and a half tons: m 1970, it was roughly 15 times more. The question now is whether the current cases of hepatic angiosarcoma are derived from the small population ot 19-l0-1 VA0 workers, or trom the full pooi of vinvl chloride workers, including those beginning w-ork from IdftO-l 9""-, r.xpericnce suggests that current eases are derived primarily from the eariv grout), I iuvJ (2(0 anaivzed the first 19 cases reported m this country ind abroad. The average period ot clinical latency, from lirst exposure to diagnosis, was about 20': vears. with a ranee of 11 to 20 years. Most ot the people in this group had begun work in the 19-10$ and 1950s. The cases of angiosarcoma now being seen arc therefore derived from a very small population. Because most of the total work force was first exposed to vinvl chloride in the late 1950s and early 1960s. angiosar comas arc not yet seen among them. These and other data have established that vinyl cniortac-inouccd cancer, as well as most other environ mentally induced neoplasms, has a long period of clinical latencv. We do not know, however, if it will be a common prooicm or an infrequent one. Three groups are stucvmg this, using a cohort approach. First, the plastics industry has mounted an extensive investigation (27). The cohort is ccmnosed of all men known to have worsted m the relevant facilities for a year or mere before 31 December 19*2. Data have been gathered on 838-1 men. out. un fortunately, about 1200 men still have not been traced. Thus it is difficult to evaluate the information gathered. Ncr.etr.eiess, the data now available point to increased risk of cancers of the lung, brain, buccal cavity, and pharynx (27). Although more information is needed for conclusive evidence, the same suggestions have been found in a second study, done at the National Institute for Occupational Safety and Health (2S). Our laboratory has searched for information on a key question: Hew common will angiosarcoma be among populations exposed to vinvl chloride monomer? At one piar.t we identified all workers employed there for 5 years or more from the time the plant opened m 19U8 to 195-t, There were 257 such workers, all of whom have been traced. There were 25 deaths, of all causes. Three died of hemanciosarcoma of the liver, each confirmed by autopsy ana reviewed by Dr. Popper and Dr. Thomas. Thus, approximately 1 of 3 deaths among vmvl chloride workers, at least m this plant, was due to angiosarcoma of the liver. Anotner death, caused by ruptured esophageal varices, was also related to vmyl chloride exoosure. If these data ere cenrirmed by other studies, it would seem ihat the risk of death from angiosarcoma of the liver wiil increa c greatly 15 to 25 years after the initial exposure in those who began working with the chemical betw-een 1955 and i97-1. In closing, it is worth noting that until recently, the chemical industry had been making plastics, not doing medical research, Wc in the medical profession had been doing research, but not paying great attention to the chemical industry. In both instances, changes are being mnue. Further Epidemiologic Studies Dr Henry Falk*: The first four cases of vinyl chloride monomer-induced hepatic angiosarcoma identified in Lou.sviile were all in polyvinyl chloride polymerization workers This is as expected, since the job done by these workers, opening and cleaning the reactor vessels after polv mcri/anon. involves the highest exposure to vinyl chloride monomer. Other cases of the tumor have since been tdentilied in workers, primarily among those involved in the polymerization process. We now know of 15 cases Mrdi.-al rmOfmnil.itut, Canctr and B.rth Dtfrsis Divmnn. Durrau of Fr'JemnMocv, Center for Deeaae cootrol, US FuoIjc Hcaim Sconce, Atlanta. Ccorau. Ser* ef f. * Vinyl CMO'ide Lv*f Diteitt 723 SS'I 00302 jj ^ g gj -* Tibi* 4, Cis Ot Htoitic AngioSircomj in Polyvinyl Chloride Polymerization <PVC) Workers (U.S.) (Center (or Diseise Control, AtlentJ, November 1974) Pauent* Age Race Sex Daie of Initial PVC Work Daie of Diagnosis Date of Death Duration from Initial PVC Work to Diagnosis >'* I ',V M -v 43 '.V M 3 41 \V M 4 36 w M 5 49 '.V M 6 53 w M i 45 w M 3 43 W M 9 43 '.V M 10 40 w M n '.V M 12 60 w M 13 45 w M 14 -2 \v M 15 50 w M 6 44 7- 5"1 5 50 IL 55 :: 43 1 1 5-4 : 62 5 45 6 55 10 46 6 51 10,46 5 --4 $ 44 9 49 4 64 8,67 3, 69 5.70 3 73 12 73 2.74 2.74 11.74 4/ 61 5/63 3/70 3/68 4,74 5/69 4/64 1/68 3 69 9/71 3/73 12,73 8/61 5/68 3/70 3/68 7/74 5/69 yn 19 15 19 14 24 28 12 28 19 14 16 23 23 29 19 Pm.sr.is l lsfc'cn vkrfie t'Tcsed io P VC n i Siam in Lo* 5 * ,* Ni-'.CkV Patiecti 10 Ltrou?a 14. us ViJjiri Falls, New Yorit; Paueofs ij .iza U. m Souui Charieucn, \Wsi Vtry-.aia; and Paueui 15. *3 PotvSt-*Ti, Pcr-ssyivacui. in the United States (Table 4), 9 in workers at the Lzutsvi'Ie plant and 6 at three other plants. Of particular ccncern is that cases seem to be increasing!;, more common in recent years. Table a shows several important ep:cen;oicg:c restores. The latency pence, as reviewed in detail ay Cr. 5-..-.oh. is cone Iona The duration of exposure far most e: these wor-.ers is ecually long. However, Patient 3 -vgec wnn poiwinvl chloride only 4 sears and deveiopec - tumor 15 sears later. This suggests mat relatively brier pencas of exposure can oe significant, and that, once started, the carcinogenic process mas1 not always be reversible w,;h removal from the monomer exposure. It has aeen ceiv assumed that the highest Sustained levels of vmyl emeries monomer exposure occurred in the early years of 'he muustrv < 1940s and ear.v !950s), and that most a: the patterns had begun work curing ihosc years. Patient ", however, firs; began wording in 1962. and. mererore. the carcinogenic risk factors were still present in the sar.y 1960s. Most cases of spontaneous hepatic angiosarcoma (and other hepatic sarcomas 1 occur in older age graces, whereas, despite the long Lter.cy period, the vinyl ehlcr.ee monomer-induced cases occur at a relatively early age ter 'his tvpe of tumor. In the epidemiologic dudv of these initial eases, 'to import.ini questions arise, [1] Why is the diiease -".ore prevalent at the piant in Louisville; and [2] Why, in par ticular. did it develop in these 15 workers; that is, mient factors such as chemical exposure, work patterns, or cast medical historv serve to promote or accelerate the develop ment of angiosarcoma in these particular persons? The Louisville plant, which opened in 1942, is the `ecend oldest poivvmvl chloride polv mcrization pia.n; in the United .Stales Oniv 'even such plants started opera:.mg before 1950. and the lour plants in whicn eases of angio sarcoma have occurred are in this group. The age or the plant is. thcreiore, important, and this pronaciv relates to both the lone latencv period for the disease and the less stringent precautions tor vvorking with tne monomer that pertained in the eariv years of the industry. Many of these cases of angiosarcoma were initially mis diagnosed. Most were called hepatoma or cirrhosis, ana it is only with a full review of mortality data, including re-examinatian of autopsy or biopsy tissues, that some cases have been uncovered. Moreover, the last three cases at the Louisville piant were identified during intensive screening programs, as described earlier by Dr, Creeca. Therefore, this initial clustering in Louisville may be only anifciai, and. with continued surveillance in the industry, a more uniform distribution of cases may become ap parent. On the other hand, there are specific conditions in the Louisvtile piant and in the 15 reported cases that may be significant m the eariv appearance of angiosarcoma m these workers. There are four polymerization buildings in :he plant. The two that produce the straightforward poly vinyl chloride resins show the least relation to the cases of angiosarcoma, vvhereas the two that produce more complex products have a stronger relation (14). One of the latter two buildings produces polyvinyl chloride latex (an aqueous suspension of polyvinyl chloride), and the work practices in this building differ slightly in that it takes longer and is more difficult 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 reactor include age and size of the reactor vessels, frequency of cleaning, and the lining material used in the reactor. Differing work practices related to product and equipment may, therefore, be important in the distribution of angiosarcoma. The building most directly associated with the angio sarcoma cases is the one where copolymers and terrolymers are produced. In this process, vinyl chloride monomer and other monomers are polymerized together to produce poivmers with duferent qualities. Several of the monomers that are reacted with vinyl chloride monomer, sueh as vmvlidene chloride (vinyl dichloride) and acrylonitrile (vinyl cyanide), have similar structures and chemical R&S160585 724 Jun 1175 of Intefnjt Med'Cim Vofum# 8- Surrbtr6 B1GO 303 characteristics. The six workers in other plants were also exposed to these and other sinu compounds. One man in the Niagara Falls plant worked m the polymerization of polyvmvl alcohol for 5 years before switching to polwmvl chloride. Since knowledge about the long-range ctlects of some of these cnetmcals is scanty, we must consider the possibility that thev may interact with or enhance the ctlects of vinyl chloride monomer. Thus, these tnttul cases mnv be related to exposure to multiple chemicals, and in particular, to the vinvi chloride monomer--vinylidene chloride mixture, which is found mainly in the Louisville plant. Chemicals similar to vinyl chloride monomer are also used outside the polyvinyl chloride industry, for example, vinvi fluoride and chlorobutadiene (vinyl vmyi chloride), and it will probably be some time before we appreciate the fuil scope of the hazards posed fcv this class cf compounds. A recent study (26) has also suggested mat cases of angiosarcoma may not be limited to the high-risk poly merization w-orkers but may a;so occur in workers who use the plastic resins to produce a variety o: p.asuc prod ucts and in peopic w-no reside near polyvmvl chloride plants. Of the six patients with hepatic angiosarcoma in the Connecticut Tumor Registry, two lived witr.in the vicimtv of roivvmy 1 chloride fabrication plants, one was an ac countant at a poivvmyl c.nionce fabrication riant, and one (wnese tumor, on ratnoiogy review- at NIH, is classified as an indeterminate tspe of sarcoma arid omy possibly an anztcsarccma) worked at a piant where he applied both poiwmvl chloride and ncn-poiy'-myl chloride insulation to electrical w ires (29 ). Maitoni and LeFemme's f 12, 301 inhalation studies showed that 'my i chior.de monomer can induce cancers cf the lung, brain, and k.dney as well as angiosarcoma. Several recent siucies suogest that the incidence of lung cancer, brain cancer, ana lymnhoreticuiar malignancies nav also be rig-er in vinyl chloride monomer workers The number of deaths among the younger voters at these pci-.vinvl chloride plants is still smail. however, and con tinued surveillance will be necessary to confirm these asso ciations (27. 23. 31). The most ominous feature of the vinyl chloride studies is me unknown in the future, it is possible mat. m time, we will begin to sec net oniv more patients with angio sarcoma. but also significant numbers of patients with ot.ncr. as vet unrcencmzed. manifestations of v .m, 1 chloride monomer-induced doease. And wc do not know whether, in wh.it has been called the "plastics age," related chem icals wiil pose similar hazards. Metabolism of Vinyl Chloride Dr, P. G. Watan.ibc*- \ngiosnrcomns. zvmhal gland carcinomas, and nennrorlastomas developed in rats ex posed to from 50 ppm to 10 000 ppm ot vinvi chloride monomer 4 h rar dav. 5 davs per week, for 12 monies (1 2). The rats were observed until deatn occurred. The incidence ot tumor-, at 50 ppm was less than mat predicted ' -tico1 jtorv P'W ("'-cr'ic.il Co , M'dlanJ, P' w pm me i is.spci3tM ihexe muJici <*ffpe Dn. R . l(Li-.,r, Jr . Li K. and P. J, Cchnn?. from a log dose-response curve generated from the tumor incidences at higher exposure levels of 250 ppm to 10 COO ppm. Because the tumor incidence at 50 ppm was lower than expected, and since vinyl chloride monomer per se is not a potent alkylating agent, we thought that the car cinogenic potential of vinyl chloride monomer might be mediated through the formation of reactive metabolites. Theretore, studies were designed to elucidate what happens to vinyl chloride monomer after it is inhaled. A d.7-litre Plexiglas inhalation chamber was designed and constructed so that four rats could be simultaneously exposed to various concentrations of vinyl chloride mon omer. To minimize contamination of fur and skin, or.iy the nares of the rats protruded through a rubber mem brane into the chamber. The appropriate initial concentra tion of vinyl chloride monomer (Matheson Gas Products. East Rutherford. New Jersey, 99.950 pure) was generated in the chamber at the start of the experiment and contin uously analyzed by circulation through an infrared spectropnotometsr. Carbon dioxide was continuously removed from the recirculating system by absorption on an Ascarite (Arthur H. Thomas Co., Philadelphia. Pennsylva nia) column. Filtered air was metered into the system to re plenish the oxygen consumed. Since the amount of air consumed was w-uhin m 105c of baseime for ai! experi ments, respiratory variables were not significantly changed curing the approximately 1-h exposures. Rats used m these studies w-ere Sprague-Daw-ley, Spartan substrain (Soartan Laboratories. Haslett, Michigan), ranging In weigh: from 165 g to 200 g, D.saopearance of vinyl chloride monomer from the rec-.rcu.atmg inhalation chamber, resulting from uptake ana sub* seouent metabolism, occurred according to apparent firs*, area: kinetics as described by the formula: dc -------= kC. dt In t~:s equation. C is the concentration of vinvi chloride monomer (ppm) at time t (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-life (b.) were calculated front 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 rate of disappearance of vinyl chloride monomer from the chamber was slower at concentrations of 1000 ppm than 50 ppm (Figure 5). Other experiments using m.i.ai concentrations ranging from 50 ppm to 105 ppm ot -.mvl chloride monomer showed a linear disappearance with a rate of (3.03 tr 3.40) times 10'3 minutes'1 (mean rnsoi, corresponding to an average to, of S6 minutes. At initial concentrations of 220 ppm to 1167 ppm of vinvi cr.lonJe monomer, the rate of disappearanec was much slower (2 65 m 1.35) X 10-' minutes-1, corresponding to an average t-, of 261 minutes. Assuming that the rate of disappearance from the inhalation chamber w-as primarily Berk et j/. * Vinyl Chloride and Liver Disease 725 m ou3o^ R&S160586 V C M E>ipositrc C oncentration, ppm 1000 oiizcd predominantly by a single pathway that, we have speculated, may involve alcohol dehydrogenase. However, at concentrations exceeding 220 ppm. this pathway be comes saturated and the significance of secondary path ways, presumably including microsomal mixed function oxidases, increases (32). Dose-dependent processes for the elimination of a chem ical are of prime importance in toxicology. Many meta bolic and excretory processes have finite capacities, and. as doses of a chemical are increased, these processes be come saturated or overwhelmed. If the function of the saturated process is detoxification, a disproportionate in crease in toxicity may ensue above those doses that cause saturation. Therefore, toxicity occurring with large doses of a chemical must be interpreted -cautiously, and it does not necessarily imply that comparable types of toxicity wiil be observed at lower doses. Gillette (33) recently summarized the role of chemically reactive metabolites of foreign compounds in toxicity. Compounds such as bromobenzene (34) and acetamino phen (35. 36) induce hepatic necrosis only after the dose is high enough to overwhelm the detoxification pathways for the reactive metabolites of these compounds. Con jugation of the alkylating metabolites of these chemicals with glutathione is a primary mechanism tor detoxification. Necrosis is induced only after the glutathione levels are reduced sufficiently to aifow the reactive metaboutes to Figure 5. Cecease. time, cf vinyl cnioride --cnomer 'VCM' conct"'tration? in r,r*e innaiaticn asraratus. Rat$ f.**'* exposed *c initial VCM cancentrations of acdrcximateiv SO ard \ZZ2 ;:m. A so s.ocwn art ;ne 'escecv.e secures in VCM concert^atian f'cm unccc^o'ed mhaiarien aooaratus The rats constants and ha.f .es cf disoooearance cf 'CM from tMe system cunrq metaccuc exce'i* ments -"'e corrected for nonspecific ieaAd?e from tr.e cnamce'- (see text). a function of metabolism. the slower rate of disappcarar.ee of tbc monomer at concentration! of 220 ppm or greater suggested that the metabolism of vinvi chloriue monomer may be a dose-dependent process whereby low concentra tions arc metabolized through pathways that, with higher doses, become saturated. Vinyl chloride monomer metabolism was also stuoied using metabolic inhibitors. Pretreatment of rats with etnanol (5 mg'kg body weight, by intraperitoneal iniection) I'.i h betore exposure to the monomer caused almost complete inhibition m rats exposed to SO ppm. but only a mdJ inhibition in rats exposed to 1000 ppm (Figure 61. SKT-SZSA (Smith- Kline & French Laboratories, Phil adelphia. Pennsx Ivania), a commonly used inhibitor of certain reactions mediated by the mixed function oxidase enzymes, did not inhibit metabolism of the monomer id rats exposed to concentrations up to 50 ppm, but did cause a slight, jpproximaieis' 20 G-. mh-hiuon at 1000 ppm. Con sidering these data, we hypothesized that the monomer is metabolized by several ditlcrent pathways, dependent on the Jose, ,\t concentrations up to 100 ppm, it is metao- Figure 6. Declines in vinyl chloride monomer (VCM) concentrations, with time, at initial concentrations ol 56 and 1034 ppm. tor Coth piei'eated and control rats. Also mown are the respective declines m VCM concentration from the unoccupied inhalation apparatus. 726 June 1976 * Annan oflnternal MediCirtt * Volume 84 Numof 6 r ii R&S160587 ; . *, i*^ ^ .^pv ^N^Tv. , :-' 'v. - * *'7Ct'Vr*'^1;* '-' V : V :~:^^ V " Figure 7. Lett. Irrj.jiar fit.-osis of corrai t'jcts arc `coo: rccuiar `crisis of tre hecatic cansule. (Hematoxvlin ana eojm: original rragnifi- cavon. t 05 ) NIH accession nomcer S7---11. S got. -o-ai T-ac*. r-= --i .- sarre liver snown m Figure 1. The fibrosis mrerrupts the limit.ng p:ate ano eitencs into s-rrcuncirg hepat'C pare-cn.ma -? s a s gr-t ,-r. t'ate of lymcnocy.es ana minimal proliferation of Pile aucts. '"fatcirii' arc ecsm; crig.nai m.aioii.cat.cri. x ' H access or. carreer 74-411. (Reproduced by permission. Ann Ni Acao Sc.' 246. 174-15*4. 1375.) Tppct with other intracellular macromotecutes (DNA, RNA. proton, itpius). Although Gillette ur.J others have r.ct yet attempted to correlate the covalent bn.ctng e: reactive metacontes to DNA with carcinogenesis. suer, a reaction has been speculated as a potential mechanism :cr carcinogenesis. Recent wotk .n our laboratory and elsewhere. much c: it stul unntiousheu. has muiuuud studies in rats cn tre fate or inpcsted -`C-v m.vi chioriue monomer, arc :re isola tion aru .ucniircati.in of the maior urirar-' m.etaPohtes c: this unemcai. The ingestion study showed :ra; sir.'. 1 chioriue monomer is metabolized to potar predicts tra: arc reau.iv excreted in the urine. These results a.so sup port the hypothesis of dose-dependent metabolism The r.cp.itic r.onprotein stilth1. cry I content of rats excused to v inv 1 chloride monomer showed a procressive peeress,or related to the concentration and duration of exposure. Consistent with the suithwjrsl depression, two of tre tr.ree urmarv metaroiites isolated th.is tar base been iaentittea as thiiMie;-, eulie acid and A'-acetsl-S (I-hvuroxv ctr.vi ! evsteme thus it seems that sinvl chloride monomer cr Ms reactive metahnlites cos jlentlv hind with hepatic ciutathione and .ire suhsequcntlv hvuroivzcd and excreted :n the urine as uonpie.ites ot cysteine. Other studies on vinyl vnlor.de monomer continue to support ;lie inpothesis that iis cjrcinogentettv is reiatea to the m-etanolic torm.iiion ot reactive metarciites Studies i.'T-'Vi have 'Mown an enn.inced positive mutaeeme re sponse :n verttiin .trains ot iu.u'i vict/u i\ pnir-\,r:\mi e\* p'sed to >. insi vhlor.de monomer if microsomal ep.zvm.es or turtiticd ti.er homoeenates arc present. The metabolites ot the monomer identitied in the urine ot rats exposed to the onemi.al md.cnte that the prtmarx, deaettvatip.g meep- amsm :s by ccmugation with the hepatic nonprotetn suit* hycryi compounds, glutathione and cysteine. Our current researen is directed toward further eluctaating the metabc.tsm. of vinyl chloride monomer to reactive products and their potential to bind wtth intracellular macromolecules. Reiteration ot the metabolism and pharmacokinetics of -ip.yl chioriue monomer wiil unooubteclv be of great help tn resotving its hazards and wiil ultimately proviue a ;ci;"ttttc bans tor guidelines concerning tolerable levels c: exposure. Histciogic Features: Hepatic Fibrosis Dr. Hans Popper*: Onlv little more than half a year ago. I became acutely aware of an etfect of vinyl chloride exposure on the liver when, within 1 week, three persons ca.lvd this connection to my attention. Doctor Lelbach from Bonn. Germany, sent a reprint about a peculiar intra lobular fibrosis of the liver seen by peritoneoscopy and I.1.er mopsy in workers exposed to gaseous vinyl chloride (T. Dr. Selikoif called me and asked what I knew about hepatic angiosarcoma, a rare tumor newly observed in the same tvpe of workers in this country; and Dr. Thomas, here ;n Bethesda, showed me histologic slides from several suer, workers. Subsequently, I have had the privilege of stuuv me. with Dr. Thomas, a large amount of histologie material that has been collected in the Laboratory of Pathology ot the National Cancer Institute. The following report is based on this cooperation, and. I hope, shows the r.euristic value of environmental pathology 1-fOf in rapiuly assembling information that might enlighten other areas of pathology and medicine. L Levv Di-stineunhed tenner professor. Mount Sinai School of Mcj.tfine. New \ors. New Yor*. Berk ct el* * Vinyl Chloride end Liver Disease 727 1 G 'c 5 0 6 R&S160588 * Figure 8. Irregular, focal dilatation of hepatic sinuso-os. The s ze ana numoer of the sinusoidal iitt.ng cells are increased. The reratocytes also vary in sue and focaily appear to Ce cciiferat'-?. (Hematoiyim and eosin: original magnification, x 400.1 NIH acces sion numoer S74.J15. In reviewing the serious hepatic lesions encountered in vinsl chloride polymerization workers, we saw that two distinctive lesions were premtnen One, angiosarcoma cf the liver, has been the locus oi ost of the aitenf.cn :n this study, and its histologic features will be presentee by Dr. Thomas. The second is characterized by a pecu.iar form cf hepatic fibrosis. which, in many instances, was initially diagnosed as cirrhosis. In some of these workers, the lesion was associated with portal hypertension and vanceai hemorrhage, lead.ng to the performance of c portacaval shunt, during watch time a wedge biops;, of the liver w-as obtaincc. In otner cases, the lesion was c.cgnosed on the basis of a needs aspiration biopsy. It is of considerable interest that. :n vinyl chloride workers ,n West Germany, severe portal fibrosis with significant portal hypertension, splenomegaly, and thombocvtcpenia--presumaoly on a splcnomccatic basis--is relatively common w'hilc angtosarcoma is rare, whereas the relative incidence of these two lesions in American workers seems to be reversed. The typical lesion of vinvl chloride-associated hepatic fibrosis consists of three features (Figure 7). The firs: :s a typical but nondugnostic portal fibrosis, varying in decree throughout the liver. In puces, it seems aggressive, in that librous tissue extending into the lobular parenchyma distorts the limning plate. It also extends into the walls of the portal vein branches, separating their muscular libers. Sometimes accumulation of dense connective tissue is as sociated with proliferation ct bile ductules and pcriuuciuiar inflammation. Jnil.immatory cells also aggregate around Some bile ducts, and this pericholangitis might cxrlain the focal canalicular cholestasis seen in some specimens. The second is capsular and subcupsular tibrosiy, m a nndular term; it is the most characteristic lesion, partic ularly sisihle if the surtace of the liver is inspected on peritoneoscopy, as reported from Bonn (7. 201. Distinc tion from cirrhosis by gross inspection is difficult. The 723 19/6 * Annjli of Internal Mctjiem* Vo/urne 84 /ft third type of fibrosis is subtle and reflected in a focal intralobular accumulation of connective tissue fibers, rec ognized distinctly by light microscopy only in connective tissue stains. Electron microscopy (17), by contrast, de tects a dense but thin connective tissue coat surrounding the hepatoevtes and associated with many fibroblasts and fat-containmg mesenchymal cells--Ito cells (41) or lipo cytes (42)--which have been postulated to be precursors of fibroblasts (43). This fibrosis differs morphologically from that seen both in chronic active hepatitis and in alco holic liver disease and suggests a different mechanism of development. Where the intralobular fibrosis is conspicu ous. it is associated with bulging sinusoidal lining ceils with a prominent diastase-resistant, periodic-acid Schiff reaction of the cytoplasm, which is sometimes granular, as in phagoevtosing macrophages, but more typically dif fuse. The bepatocytes show no significant changes except that, in the areas of prominent sinusoidal lining cells, they show variation in size of both cytoplasm and nuclei in that large hepatoevtes, sometimes even multtnuciear, alternate wuh small ceils (Figure 3). In some instances, particularly in autopsy specimens, regenerative nodules are seen with out cirrhosis. Besides this pattern of fibrosis seen in all specimens, some specimens--both from patients apparently free cf angiosarcoma and in two in whom angiosarcoma was later fauna--a focal irregular sinusoidal dilatation was noted (Figure S). It did not seem to be related to passive con gestion, since it was not predominantly in the centrolobular zrea. The same type of focal sinusoidal dilatation, pro cessing almost to peliosis, has been observed in patients alter treatment with anabolic steroids (44) and contracep tive pills (45). However, in these latter instances, there have not been any reports of progression to angiosarcoma. In our viny 1 chloride cases, the sinusoidal dilatation is associated with proliferation of the sinusoidal lining cells, wnicn become enlarged and show bizarre nuclei and. as wiil be discussed below, progress to angiosarcoma. Thus, we can conclude that this sinusoidal dilatation is a pre cursor to the tumor in vinyl chloride exposure, but 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 fibrocongesme splenomegaly. Histologically, fresh hemorrhage was seen m most spleens, although some showed calcification and iron incrustation in the form of Gamna-Gandi bodies. The cords of the pulp contained many erythrocytes, characteristic of hemolysis. The lining cells of the sinuses were activated but. for the most part, not fibrotic. StuJv of the pathogenesis of vinyl chloride-associated liver iniury (46) showed that vinyl chloride or its metabo lites seem to induce a hyperpljsia of two types of cells: the mesenchymal sinusoidal lining cells in liver and spleen, and the hcpatocy tcs. In the spleen, activation of the sinusoidal cells mav result in splenomegaly, and. in the liver, in fibrosis contributing both to portal hypertension and the formation siCw5C7 R&S160589 4 Figure 9. Lett. Sinusoidal pattern of anjiosarecrna. Sinusd.sal spaces are *arge and irregular. Angiosarcoma cells line these spaces and ensneatn heoatic cora cells and an increased numcer ol ncn-neoc'ast c-aooearmg cells in the soace of Disse. Bile plugs are present in pile canancuii (Hematoxylin and eosm: original magnification, x 3S2 ) MH accession numcer A74-31. (Reproduced by permission. Ann NY Acao Sci 2A6 263-277. 1975.) Right. Another area of the same angiosarcoma snoein m r-gure A, Spurlike protections of hepatic tissue proiect into larger, more cavernous cystic spaces The neoanc cords a-e cisructed oy degeneration of hepatoeytes. The tissue space of Disse contains in creased collagen and reticuiin libers. (Hematoxylin and eosm; nagnticat.on. x ICO.) N1H accession number A74-31. of septa. These septa may progress to cirrhosis. A,though we have not as yet noted this progression, it has ceen ob served by others. Sinusoidai dilatation develops, ana ;n this setting angiosarcoma ensues. The roie of the act1v3t.cn of the hepatoeytes, which seemingly form a searfold, :s problematic. However, it is worth noting that we have anecdotal evidence of primary hepatocellular carcinoma in persons exposed to vinyl chloride. While studying these cases, we became aware that pro longed exposure to trivalent inorganic arsenicals. such as Fowler's solution used to treat psoriasis, reset.:s in the same clinical and histologic picture (47-49). Histoiogt: examination of two cases made available to us by Dr. Peter Seheuer shewed the same histologic chances as m vinyl chlortdc-mduecd fibrosis. Moreover, exposure to such arsenicals has also heen associated with hepatic angiosar coma (2d). In vineyard workers, in addition, it has been associated wnh primary hepatic carcinoma and cirrhosis (24). The mechanism of toxicity of arsenic has been re ported to occur through its reaction with 6,S-dithiooctanoie acid (11-hnoic acid), with the arsenic forming a stable bridge between the two stilfhvdryl groups (32). Certain hspolhetical metabolites of vmvl chloride formed by the mixed function oxidjses would also be expected to react in a similar tashwn wnh u-lipoic acid, possibly explaining the similar pattern of hoth lihrosis and neoplasia seen with these two superficial!v unrelated chemicals. Interestingly, thorium dioxide (thorotrxst) also produees the same spec trum of lesions ( 22 ). The patnoeencsis ot ihe noneirrhotic portal hypertension in all these insiunces m.iv he related to a discrepanev be tween increased splenic blood flow. induced by the hyper plastic splenomegaly, and to the impairment of the distensibilits of the hepatic vascular bed produced by the various terms of fibrosis, which bv themselves are not conspicuous (70). The tact that this tvpe of portal hyper tension nji been produced by chemicals, at least some of them environmental, suggests that idiopathic portal hyper tension. found oniv sporadically in the Western w-orid but more often in some areas of Asia and Africa, might result a.so tro.m toxic, possibly environmental, cbemicais. 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 ceils. In addition, we have studied the hepatic lesions of 15 vinyl chloride workers who developed angiosarcoma cf the liver. The hepatic changes described by Dr. Popper were also seen in the nonangiosarcomatous areas of the liver in all cases in w-hich 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 decrees of atypia and proliferation of these cells, and culminating in progressively growing, mulucemric, .ntiltrative angiosarcomas (51). Of those patients with angiosarcoma who died and were autopsiod. postmortem examination of the livers showed massive involvement by cystic, blood-filled tumors that replaced most of the tissue. The liver weights ranged from IS60 g to 7300 g. The average weight was 4236 g. In 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 by intraperitoncal hemorrhage occurred hoth spontaneously and at the time of surgery, arid it was the immediate anatomical cause of death m vcseral patients. The liver tissue was also irregularly re* placed by small cysts that varied in size from 1 mm to 1 cm in diameter. Most of them were filled with blood: only * C-.ef, Laboratory of Pathology. National Cancer Insulate. Berk et *1. * Vinyl Chloride end Liver Disease 1 729 a n v3 -J ^ R&Sl 60590 V a lew contained thrombi. The hepatic suriacc was irregular some progress has been made toward answering all of due to bulging masses of the angiosarcoma, and portions them, it is clear that there has not yet been enough of the liver not involved grossly bv angiosarcomas had progress in fully answering any of them. irregularly shared areas of capsular and portal tract It is worth recalling that we have been aware of the ribrosis. The formalin lived livers were dark green because problem for less than a year (as of November 1974). The of hilc stasis. efforts presented at this conference represent an outstand Miero'copic examination showed the angiosarcomas to ing example of effective, if often informal, collaboration be multicentric, with several structural patterns. The sinu among university, industry, and government scientists, soidal pattern, illustrated in Figure 9A, consisted of neo wnien, if pursued at its current pace, is certain to pro plastic-appearing sinusoidal cells that had enveloped cords vide us in the near future with answers to at least some of hapjtocvtes and formed irregular sinusoidal spaces. In of the critical questions. these areas, the hepaiocytes were well preserved and biieseeretmg, with no degeneration or necrosis. Macrophages, fibroblasts, and lipocytes proliferated in the space of Disse. With increased growth of the angiosarcoma ceils, the heoatocstcs atropmed and disappeared, and the space of ACKNOWLEDGMENTS: The authors thank Dr. Allan Hofmann of lie Mavo Clinic tor helping us with our biie acid disappearance tens ana Dr. Bernardo Kotelanstci of the Veterans Administration Hospital. Washington. D.C.. for the hepatic vein catneteriaauon siuc.es on one ot our patients. Received 16 Fenruary 1976; accepted 2 March 1976. Disse was filled with collagen fibers, so that larger, cystic spaces formed. The papillary grosvth pattern was an inter mediate stage character,zed cv papillary projections ct blind-ending, disrupted hepatic cords extending into the irregular, muitiloculated cystic spaces of the angiosarcoma (Figure OB), These spurlike projections were covered by Reouests for reprints should be addressed to Paul D. Bert M.D.; C'r..c:. Section on Diseases of the Liver, Digestive Diseases Branch. National Institute ot Arthritis, Metabolism, and Digestive D.seises, E.de: 10. Room 4D-52, National Institutes of Health; Beicesfla. .MD ::ou References angiosarcoma cells that onsheathed the various other ceils in ihc space of Disse and the residual fragments of herat.c cord ceils. The cavernous pattern had larger blood-filled scares surrounded by a truer wail of dense, relative.'.' aceiiular fiorous connective tissue. These larger, cvstic spaces were lined by variacie. sometimes quite scanty, 1. Wilson RH. McCormick WE. Tatum CF. et al: Occupational aaroosteolvsis: report ot 31 cases, JAMA 201:577-531. i967 2. 5-ciu I. Duejmin I, Valaskai M; Coniributn ia stuaiui impoinivinior produse de clorura de virul. Mea Interna tBuaart -.5 9o7-973. 1563 5. Couple* JM. Fievlz C. Lt Fever MJ, et al: Acro-osteoh;e ct lesions cutanees associecs ehez deux ouvriers ahectes au r.ettoyage d'autoclaves. Can Med Trav 4:14. 1966 lasers of angiosarcoma ceiis. We also observed more noduiar. anaplastic focuses of angiosarcoma in some of the livers, but m every instance these specimens also had other focuses of angiosarcoma that showed the progression from sinusoidal to papillary to cavernous growth patterns. Thus, this senes of changes seems to represent m.ul;;cc.ntric development of angiosarcoma, starting with the precursor lesions of sinusoidal ceil proliferation and atvpia. Some of these precursor lesions progress to the fully uevclopcd cavernous angiosarcomas, which become cimicaiiv evident. We do not have .adequate morphologic criteria to separate the earliest histologic changes of sinusoidal cci! atvpia and hyperplasia from the progressive, fully devel oped angiosarcomas. As noted earlier, proliferation of hepatocstes and of non-neoniastic-appearing fibreevtes, lipotalasis, and macrophages ploys some role in the devel opment of ihc angiosarcomas. Proliferation ot these ceiis a Harms DK. .Adams WGF: Acro-osteol>sts occurring in men e-.caced in the polymerization of vinyl chlonce. Br Mea J 3.712-714. 1967 I. L;-:s R, Anderson H, Nicholson WJ. et al; Prevalence of a.seasc among vrnvl chloride and polyvinyl chloride norners. Ann SY Acad Set 246.22-41, 1975 6 Pushin GA [Aifection of the liver and bile ducts in workers enraged in the production of some types of plastics.| l Rus I Sot tied 23(2): 132-135, 1965 ' Mvrsteller HJ, Lelsach WK. Muller R. et al: Chrcnischtpsiscne I ererschadcn bet Arbeitern in der PVC-proauivt.on. Discn Med H'licntnschr 93:131 1-2314. 1973 3. Creech J. Johnson MN, Block B: Angiosarcoma of ih: liver among poiwinvl chloride workers--Kentucky. Morbm Mortat ilVrur Rep 23(6) .49-50. 1974 9, Creech JL Jr. Johnson MN: Angiosarcoma of the liver in the manutacture of polyvinyl chloride. J Occttp Med 16.150-151, 1974 10 Editorial; Vinyl chloride, P.V.C., and cancer. Cancel 1:13231124. 1974 11. \ iola PL. Bigotti A. Caputo A; Oncogenic response of rat imp. lungs and bones 10 vinyl chloride. Cancer Res 31.516*522. was especially noted in the areas of sinusoidal and papil lary growin patterns within ihe angiosarcomas. Many ot the histologic leatures observed in the evolu tion of the hepatic angiosarcomas in the vinyl chloride workers have also been described m the hepatic angio sarcomas caused by thorotrast and by inorganic arsenic.;is. Studies are now in progress to evaluate the similarities and dissimilarities between the lesions produced by these .'emicals and the hepatic -ngiosarcomas ot unknown cause that occur sporadically. Summary Dr. Berk, We be can this conference wilh a list of ques tions that i thought might Jetin.c the scope of the problem of vinyl Lr.ioride-avsociateU liver discave. Allhouch at least 12 Maltoni C. LeFemine C: Careinogcnicitv hioassavs of vinvl -nlondc: current results. Ann SY Acad Set 24b: 195-213. 19*5 13 Gordon DE. Thomvs LB, Kent G, ct ul- Hepatic angiosarcoma m man and rodents following prolonged esposurc lo vinvl -nioride ubsiracil. Casirot-nlcroloey 67;794, 1974 ta Talk H, Creech JL. Heath CW Jr, et al: Hepatic disease among workers at a vinyl ghlondg polymerization pljnt. JAMA Zi: 5 9-nJ. 1974 15. Ui RK PD, Martin JF, Waggoner JG. Persistence of sin'I c.-.lorijg-induccd liver m/ury alter cessation of esposure. A'tn NT Atad St I 246 70-77, 1975 16. l aRlsso NF. I lore vian NE, Hofmann AF, et al: Valnlitv and scnsitivuv ot an intravenous bile acid tolerance test in pjuvnts Aim iivcr tiiseuse. .V Anal J Med 292.1209-1214. 1975 17. Taiche T, Nanra K. IsIIak K. et al: Hepatic uliravtructur.il changes in vinyl-ehloride workers (abstract). Clut Res 23.259, 1975 13 Veltman G, Lange CE, JLhiC S, et al: Clinical manifestations and -purse ot vinyl chloride divease. Ann SY Acad Stt 246,6-17, 1975 R&S160591 730 1776 * Annals of Internal Metjicme * Volume 34 * Numoer 6 %1 G0309 t 4 19 Lance CE. Jl'iii, S, SrriN G, ct aL Further results m polyvinvl 35. Mitchell JR. Jollow DJ. Potter \VZ, ct al, Acetaminooncn- ihloridc |*fndi:viiv>n wi*rkA-rv 4'" A Y LuiJ 5'vi 246 1975 induccd hepatic necrosis. IV Protective role of Jiuutnione. J 20. MvRvtLLLLR 111. iLLOAkii K. MllLER P. cl al. Riinivchc und Pharmacol Exp Thcr 187 211-217. 1973 lapjro'kupi^ne A-rvkic dcr Lerervenaden ret Chctnicarheitern 36. Jollow DJ, Tiiorgeirsson SS, Potter HZ. ct al: Acetamino in dcr \ invkhlond-Polvmcri'atiun. Leoer Magen Darin 5.196- phen induced hepatic necrosis. Pharmacolotn 12.251-271. !9*4 :0;. 1975 :t. TavloR KJ. Wiiiiams DM. Smith PM. ct al: Grcy-vcalc ulira- 37. Bartsch H. .Maeaveh.ee C. Montesa.no R. Human, rat and mouse liver-mediated muiacenjcny of sinyl chloride in S. sonocrapnv mi monitoring industrial exposure to hcpjtoioxic ivpnimiiruini strains. Ini J Cancer 15:429-437. 1975 agents Lancri 1 1222-1 224, 1975 38. Kasnlg U. Johansson a. Ramel C. et al: The mutacemenv " Da Mlva HuRta J, Late lesions in man caused by colloidal thorium dioxide tthorotr.istt: a p.ew case of sarcoma ot the cf .i-ivl chloride after metabolic activation. Amour 3.194-197, 1975 liver 51 >ejrs alter the inicction. Aren Pathol 62:403-918. 1956 39. Malaveille C, Bartsch H. Bardin A, et al; Muiacentcitv of 23. Visfeldt J. Pot.lsl N H: On me ristopatnoloey of liver ano vinvi chloride, chloroetnvleneoxide. chloroacetaldehyde and liver tumours in thorium diosiue patients, Acia farliol Microbiol chloroethanoi. Btocnem Btopnvs Rea Common 63:363-3*0. 19*5 Scand l-l I ad.y'-108. 1972 40. Popper H: The heuristic importance of environmental pathol- 24. Rotii F: Arscn lcoer-tumoren: fharr.anctoendotheliom) 2 Kreoslo'sch 61:46S-5U3. 1957 oev lessons from the vinyl chloride problem. Arch Pathol 99 69-71. 1975 25. Regelson w. K.ivt U. Ospina J. et al: Hemangioendotheiial 41. Ito T: Recent advances in the study of the fine structure of sarcoma of the liver from chroma arsemc intoxication fcy the hepatic sinusoidal wall. Cunma Rep Med Set 6:119-163. Fowicr s solution. Cancer 21:5 14-522. 1968 25. Leovd JW- Angiosarcoma of the liver in vinvl chloride,'polv- 19*3 42. Bronfenmaier S, Schaffner F, Popper H: Fal storing cells vmvl chlonue production workers. J Qccttp Med 1 7,333-334. (l.pocvtes) in human liver. Arch Pathol 82:447-453, 1966 1975 43. Schnack H. Stockincer L. W'ewalka F: Adventitious con 27. Tabehshaw IR. Gaffey HR: Mortality studv of workers in nective tissue cells in the space of Disse and their relation to me manulacturc of vinyl chlor.ee ar.3 its poomers. J Occup Med fiber formation. Rev Intern Hepat 17:855-859. 1967 16 599-51 i. 19*4 44. Bacheri bA. Boyer JL. Peliosis hepatitis associated with an- 23. M'axvveiler RJ. Stringer \V, Wagoner JK, et al: Neoplastic c.'bzenic-anaoolic steroid therapy. A severe form of hepatis in risk amonc workers exposed '.o vinyl cnloride. Ann SY Acaa jure Ann Intern Med 81 610-613, 1974 Sci 271 40k<, 1976 45. Pcllsen H, Winkler 32, Liver disease with periportal sinusoi 29. Landrice.n PI. Heath C\V Jr: Hemangiosarcoma of the liver. dal dilatation (abstract/. Daemon 8:441, 2973 Connecticut. LSPI1S Report: EPI-74-104-2, 1974. Atlanta, Center 46. Popper H, Thomas L3: Alteration of liver and spieen among for D.icase Control workers exposed to vinvl chloride. Ann AY Acad Set 246.172- 30. Maltom C. LeFemine G. Carc.r.ocemcity bioassavs of vinvl 194. 1975 chloride (1) P.esearcn p.an _-.o earty results, En\iron Re: 47. Wallet A, Guillaume E. Cote J, et al: Prestnusoidai portal 7 3X7-405, 1974 h'pertension following chronic arsenic mtoxicauon laostracti. 31. .Monson RR, Peters JM, Johnson MS: Proportional morramv Caifcemeroioev 62'177, 1972 amonc vind chloride workers Lancet 2.397-},i. 1974 48. .Morris JS. Schmid M. Newman S, et al: Arsenic ana non- 32. Hefner RE Jr, W'atanabe PG. Cehrjng PG. Prelirrunarv cirrhotic portai hypertension. Gastroenterology o6.36-94. 1974 stua.es of the fate of inhaied v.hvl chloride monomer in rats. 49. Rnolle J. Forster E. Roessner A. et al: Die mcat-zirrhctisehe Ann AY Atcd5ci246'135-14 3, 1975 poriale Fibrose (Hepaioportale SkJerose) nach chromsc.-.er 33. Gillette JR, A pcrsoccuve on the role cf chemically reactive Arienveriitunc. Dtscn Med llochenscnr 99:903-90S. 1974 mctaouliies cf foreign corhpouh.ds in toxicity. J Biocnem 50. T.-.ovias LB, Popper H. Berx P, et al: Vinyl chlonae-induced Pharmacol 23 2785.2794. 1 `97-1 liver disease: from idiopathic portai hypertension (Binti s syn- 34 Jollow DJ. Mitchell JR. ZamraCLIOne N. et al: Bromoben- d'cr-ie) to angiosarcoma. .V ngi J Med 292:17-22. 1975 cene induced liver necrosis, protective rcie of pruiamione and 51. 7avias LB. Popper H: Pathoioey of angiosarcoma c; the eviuencc lor 3 4-bromuncnaene cr.ee as the hepatoioxic metabo- !n:r amonc vinyl chloride-polyvinyl chloride workers. Ann AY lnc.Pharmacology 11:151-169, 1974 Acad Set 240.268-277, 1975 33 9 22 oo> c<rno0 Ber* ef el, * Vinyl Chloride and Liver OutJie 731 is J I Li