Document q37a9KxLEmxbN8G4gb8Yk5X3j

by renf dL -asc ?are of the ,os breathads exclu de periphreasing as ;ly a small .or.tilation t reliance plains the -hen mor;ivity. '"eathing -ely affect 'y admin- reath- icnsiona if apnea, often inintensive ;g control ithat de- -ack, MO 'in mstabilv (thing on en ou* sys- erniack Original Contribution covzr'D : TITLE 17 U. $. C0& | RECEIVED Hepatic Disease Among Workers at a JUN1 81980 Vinyl Chloride Polymerization Plant Shirley D. Conner Henry Falk, MD, John L. Creech, Jr., MD; Clark W Heath, Jr, MD, Maurice N, Johnson, MD; Marcus M. Key, MD Eleven cases of hepatic disease, including seven cases of hepatic ang The B. F. Good rich PVC polymer iosarcoma, have been identified to date among men employed at one vinyl ization plant in Louisville first began chloride polymerization plant. The earliest diagnosis was made in April operations in 1912. The number of 1964. The two most recent cases, both angiosarcoma, were diagnosed in persons employed at the plant di . February 1974 as a result of systematic medical screening for liver abnor rectly in PVC polymerization has malities among workers at the plant. Ages at diagnosis have ranged from 36 steadily increased, reaching a fairly to 58 years for the seven patients with angiosarcoma and from 28 to 56 years stable level of 250 to 300 workers by for the four patients with nonmalignant disease; durations of employment the late 1950s. At present, in addition : before diagnosis have ranged from 12 to 28 years and from 5 to 29 years. All to 271 persons engaged directly in i 11 persons had worked in close and continuous contact with various phases PVC polymerization, about 850 per , of the vinyl chloride polymerization process. Review of pathologic material sons are employed at the plant in 1 suggests the presence in both tumor and nontumor cases of portal fibrosis other activities such as synthetic rub | and atypical sinusoidal lining cells. A direct causal relationship between ex ber production, compounding and posure to vinyl chloride monomer and pathologic findings is postulated. (JAMA 230:59-63, 1974) milling operations, managerial and clerical positions, and maintenance work outside PVC polymerization areas. CREECH and Johnson1 recently re- tensive efforts have been devoted to Until 1966, VCM as well as PVC i ported the occurrence of three cases clinical and epidemiologic studies was produced at the Louisville plant. * of angiosarcoma of the liver among of past and present workers at the Since that time, however, all VCM j workers at a polyvinyl chloride (PVC) Louisville plant, as well as at other used at the plant has been shipped by | production plant in Louisville. Be- PVC production plants elsewhere, in tank car from other facilities. The cause this tumor is extraordinarily order to define more precisely the ex VCM is unloaded, stored, and then 1 rare (only about 25 cases are esti tent of health risks among vinyl chlo piped into large polymerization re mated to occur each year in the entire ride workers. This report summarizes actor vats through an essentially , United States), the existence of such findings to date with respect to both dosed system. Each reactor receives a cases in this particular setting malignant and nonmalignant hepatic measured amount of VCM as well as See also p 64. disease among workers at the Louis appropriate catalysts, stabilizers, ville plant, particular emphasis being emulsifiers, and additives (and other * strongly suggests a causal relation- given to epidemiologic features. monomeric compounds if copolymers ship to some phase of the PVC pro duction process. Recent animal stud BACKGROUND or terpolymers are being produced), and the reaction is carried to the de ies being conducted in Italy support The production of PVC by polymer sired end point. Polymerized material \ the concept that exposure to vinyl ization of VCM began in Germany is dropped into secondary tanks from ! chloride monomer (VCM) may be the about 40 years ago, with production which unreacted VCM is recovered * mechanism involved (C. Maltoni et al, in the United States starting about and recycled through a dosed system; ; unpublished data). five years later. The industry grew it then enters tertiary tanks from Beginning in late January 1974, in- rapidly after World War II, and which it Is concentrated, dried, and growth has continued in recent years packaged. The end product consists of From the Cancer and Birth Delects Dtvision, at a rate of about 14" per year. Cur three different materials: (1) PVC * | Bureau of Epidemiology. Center for Disease Control. Atlanta. Ca (Qrs. Falk and Heath), tha rently in the United States, 14 plants resin (a powder with the texture of B F. Goodrich Company, Louisville. Ky (Dr. employing about 1,300 workers pro refined sugar), (2) PVC paste (a very Creech) and Akron. Ohio (Dr Johnson), and tha National Institute for Occupational Safaty and Health, Center for Disease Control. Rockville, duce VCM, while 37 plants employing about 5,000 workers polymerize PVC fine powder with the texture of pro cessed Hour), and (3) PVC latex (a , Md (Dr. Key). from VCM. Current annual produc stable suspension of PVC in liquid). I Reprint requests to Cancer and Birth Detects Division, Bureau of Epidemiology, Center lor Disease Control. 1600 Clifton Rd, Atlanta. GA tion of PVC in the United States is estimated at approximately 4.1 billion For workers in PVC polymeriza tion, the point of greatest probable 30333 (Dr. Falk). pounds, or 2ono of world production. exposure to VCM occurs after poly- JAMA, Oct 7, 1974 e Vol 230, No 1 Hepatic Disease--Falk et al 59 1? merization, when reactors arc opened and cleaned. Although the air within reactors is replaced several times be fore opening, a short burst of VCM may be released from reactors imme diately on opening. In addition, some PVC remains encrusted within react ors which, because of its porous struc ture, may retain significant amounts of entrapped VCM. In the process of chipping and cleaning this material from within reactors, retained VCM is released. Until the late 1960s, this cleaning process was done manually by a man lowered into the reactor for that purpose. Since that time, highpressure water hoses have been intro duced for cleaning reactors, and man ual cleaning is done much less fre quently. This change in work practice was designed primarily to prevent acro-osteolysis, a disease peculiar to PVC workers and characterized by Reynaud phenomenon, sclerodermalike changes of the hands, and lytic lesions in the distal phalanges.2- CLINICAL AND PATHOLOGIC FINDINGS Table 1 summarizes salient fea tures for each case of hepatic angio sarcoma and nonmalignant liver dis ease diagnosed to date. Review of death records for plant employees dis closed a total of five cases of angio sarcoma of the liver diagnosed in PVC workers over the ten-year peri od between 1964 and 1973 (cases 1 through 5). No cases were found diag nosed before 1964, and no cases were found of hepatic carcinoma or of an giosarcoma primary at other sites. A further review of medical histories of PVC workers employed at the plant disclosed four additional men with a known history of nonmalignant liver disease demonstrated by tissue biopsy and diagnosed between 1968 and 1973 (cases 8 through 11). Because of concern aroused by the discovery of hepatic angiosarcoma in workers, a medical screening pro gram aimed at detecting hepatic ahnormalities was instituted at the Louisville plant. All current employ ees, whether engaged in PVC poly merization work or not, were exam ined (see p 61). As a result of this program, two additional cases of an giosarcoma of the liver were diag- Case No. H*patic Tumors 1 Ape at Diagnosis/ Race/Sex 52/W/M 2 43/W/M i. 3 36/W/M 4 49/W/M 5 58/W/M Month and Year of Diagnosis Death 4/64 4/64 8/67 5/70 3/73 1/68 9/71 3/73 12/73 12/73 Table i.- p,;-0t0CiC Initial Symptoms - kintal Finr 8/63-Fatigue If /* 1/64-Right upper quadrant; 9/66-Fatigue, "pleurisy''"" rr , ' i ^ ri 8/67-Epigastrlc "knot" and pain K- ' : Jl>' 1/70 and 5/70-Melena 12/63 and 5/65*Melena ^ 7* 1 If 'Fill and hematemesis ^ .g'v.mMj! 7/73-Weakness and weigh 4*-,. j'.'snien loss 6 45/W/M 7 43/W/M Nonmalignant Hepatic Dlaaasa 8 46/W/M 9 28/W/M 10 S6/W/M 11 56/W'M 2/74 2/74 12/66 1/72 9/73 9/73 B/73-Fatlgue, "pleurisy" Asymptomatic ! ill 10/68 and 11/68-Melena .S. 9/71-Chest pain, weight 1 2/73-Hospital ized tor her~ Skr repalr, icterus noted 9/73-Hospital Ized for choi* * lithiasis - ' - : ,t , * - - .:rr 'w ' *OL-3 ,rrJ; nosed, both in PVC workers (cases 6 and 7). At the present time, no cases of angiosarcoma of the liver or of nonalcoholic liver disease as demon strated by biopsy have yet been iden tified among non-PVC employees at the plant. All patients have been white men. Cases of Hepatic Angiosarcoma Ages at diagnosis for the seven pa tients with tumors (cases 1 through 7) have ranged from 36 to 58 years (average age, 46.7). Initial clinical features have varied widely; there were no signs or symptoms in case 7. Four patients (cases 1, 2, 5, and 6) were first seen with weakness and tiredness; two of these also had inter mittent pleuritic pain. These symp toms by themselves were not suffi- ciently severe to warrant medical evaluation until the appearance of acute abdominal pain, pronounced weight loss, or abnormal findings on serologic screening. Two patients (cases 3 and 4) were entirely asymp tomatic until the abrupt onset of gas trointestinal bleeding. Two patients had clinically obvious hepatosplfnomegalv (cases 2 and 5), but fi(cases 3, 4, 6, and 7) had normal phj s cal findings. While all seven patienthad evidence of liver function abnor mality at time of initial work-up, in consistent pattern emerged, and in several instances abnormalities were only slight (cases 2, 3, 4, 6, and 7). I ' several cases, relatively mild hepatic dysfunction coexisted with either faiadvanced portal hypertension (cases and 4), unresectable angiosarcoma- i 1 ( 11 <1 -.'II1 1 '' '' t Norn 60 JAMA, Oct 7, 1974 Vol 230, No 1 Hepatic Disease--Falk et ai- ama 0 Table 1.-^Pathologic Findings of Cases of Liver Disease -------------- >i Symptoms eivucal Findings Hepatic Work-up* (ti gtit upper quadrant ;per quadrant pt-*rC,rness 1/64-Moderate elevation in TB, SGOT \ 'oteunsy" : c `knot" piD'n<s5'nc mas3 , Melena -"f.-sa abnormalities jc-i-epatosplenomegaly -5-Mclena '.emesis "Ie-Ho gnnormahties f-$p!enomega!y 8/67-Mtld elevation in AP. SCOT, LDH Platelet count, 33,000/cu mm Liver scan: large defect, splenomegaly 5/70'Mtld elevation in TB, AP, SGOT, LDH Liver scan large defect Esophogram: varices 5/G5`Elev3ted SGOT Esophagoscopy: varices ess and weight p-Wepatosplenomegaly , "pleurisy" t'C H-fco abnormalities tso abnormalities 7/73'Marked elevation in AP Mild elevation in TB, SGOT Liver scan: diffuse disease, hepatosplenomegaly 2/74-Mild elevation in LDH Liver scan: possible defect 11/73-Mild elevation in TB, AP Liver scan and angiogram: 4-cm defect Pathologic Findingst 1/64-OLB slight focal hepatitis 3/64-NLB unchanged 4/64-PM: hepatic angiosarcoma with metastases 8/67*018 angiosarcoma 1/68-PM: hepatic sng'osnrcomo v"th spread to diaphragm ord nbdnm m;iI wall 5/70'OLB. cingicbdrcoma No PM 5/70-CLB- toxic hepatitis 10/70-NLB: hepatitis, cirrhosis 10/70-QLB: slight hepatitis 3/73-PM: hepatic angiosarcoma 7/73-NLB. fibrosis OLB periportal inflammation and fibrosis 12/73-PM: hepatic angiosarcoma spread to duodenum 2/74-OLB: angiosarcoma 2/74-OLB: angiosarcoma and extensive portal fibrosis, subcapsular fibrosis ,68-Melena ^Splenomegaly lain, weight Iasi h-^patosplenomegaly lized for hernia fW>olenomega!y trus noted ;ized for cholfi' b-No abnormalities tO/68-Marked elevation In AP, BSP Mild elevation in SGOT Esophagram: varices 9/71-Mild elevation in TB. SGOT 10/71-Liver scan; splenomegaly 3/73-Moderate elevation in TB, AP Liver scan: splenomegaly, small liver 9/73-Moderate elevation In SGOT Mild elevation in T8, LDH 11/68-OLB: porta! fibrosis, subcapsular fibrosia 12/71-OLB: portal fibrosis, subcapsular fibrosis 9/73-OLB: slight portal fibrosis 9/73-OLB: chronic hepatitis with focal fibrosis "TB indicates total bilirubin; SGOT, serum glutamic oxaloacetic transaminase; AP, alkaline phosphatase; LOH, lactic dehydrogenase: BSP. lulfobromophthalein. tOLB indicates open-liver biopsy; NLB. needle liver biopsy: PM. postmortem examination. medical 'ranee of enounced idings on patients y asymp3t of gaspatients patosplebut four >al physipatients n abnork-up, no . and in ies were ad 7). In I hepatic ther far`(cases 3 'sarcoma Falk et al ' ' , * i (case 6), or angiosarcoma with exten sive portal fibrosis (case 7). In cases 1 and 2, large hepatic masses were present at initial evaluation. The con ditions of three patients (cases 1, 4, and 5) were not diagnosed until autopsy, despite multiple liver biopsies. Preliminary pathologic review sug gests that in all 5 patients for whom nonmalignant hepatic tissue is avail able (cases 2, 3, 4, 5, and 7), similar nonmalignant hepatic lesions exist, consisting of portal fibrosis, sinusoidal dilation, and atypical sinusoidal lining cells. Conceivably, such lesions roay represent a precursor stage in the development of hepatic angiosar coma. Nonmalignant Hepatic Disaase Ages at diagnosis for these four pa tients (cases 8 through 11) range from 28 to 56 years (average age, 46.5). Ini tial clinical manifestations varied widely: one patient (case S) had gas trointestinal bleeding; one (case 9) had chest pain and weight loss; and two patients (cases 10 and 11) had unrelated problems. On physical ex amination, hepatosplenomegaly was present in one patient (case 9), sple nomegaly alone in two (cases 8 and 10), with normal findings in one pa tient (case 11). Three patients under went splenectomy either for marked splenomegaly (case 9) or as part of splenorenal shunt procedures (cases 8 and 10). Results of liver function tests varied widely and showed no consis tent patterns in relation to clinical manifestations. All four patients were found on liver biopsy to have some degree of hepatic fibrosis. Pathologic review of specimens available from these sug gests a close histologic similarity to the manifestations of portal fibrosis and sinusoidal changes described in the cases of angiosarcoma. Three pa tients (cases 8, 9, and 11), as well as one patient in the angiosarcoma group (case 7), were found at surgery to have a peculiar white, speckled ap pearance to the surface of the liver, which on pathologic section was seen to reflect diffuse subcapsular fibrosis. EPIDEMIOLOGIC FINDINGS The seven men with angiosarcoma had been employed at the plant for 12 to 28 years (average, 18.0), and the four with nonmalignant disease, be tween 5 and 29 years (average, 20.6) Jama, Oct 7. 1974 Vol 230. No 1 Hepatic Disease--Falk et al 61 Table 2.--Duration ot Employment for Patients With Angiosarcoma of Liver and Nonmalignant Hepatic Disease Duration of Employment, No. yr/mo 1 19/8 2 17/11 3 13/1 A 16/5 5 27/7 6 12/0 7 19/0 e 24/5 9 5/6 10 23/6 ii 28/11 Total 208/0 No. of yr in operation 32 Total No. of employees in 1973 PVC-Polymerization Buildings A 8/11 0/1 1/2 1/2 0/6 0 2 wk 4/1 1 wk 0 21/8 37/8 B 0/3 12/5 1/7 14/9 2/8 0/1 2 wk 4/1 1 wk 19/6 7/1 62/6 c 0 2/0 5/5 0/6 0 2/5 12/1 0 3/4 1/4 0/2 27/3 D 0 0 4/4 0 24/0 9/6 5/5 14/0 2/0 0 0 59/3 E 8/5 0/6 0 0 0/5 0 0 1/4 0 1/5 0 12/1 F 2/1 0 0/3 0 0 0 1/4 0 0 0 0 3/8 Other Buildings* GH 1 J K L 0 ooooo 2/9 0/2 0 0 0 0 0 0 0/2 0/2 0 0 000000 0 00000 0 OOOOO 0 0 0 0/2 0 0 0 0 0 0 0/11 0 0 0 0/1 0 0 0 0 01/2 0 0 0/1 0 OOOOO 2/9 0/2 9/S 0/4 0/11 0/1 32 30 27 26 27 27 29 19 S2 26 32 26 36 36 48 40 14 1 12 0 52 72 18 8 Others o' 0 o 0 0 0 0 0 0 0 0 0 321 I ~600 *ln Building E. PVC dryinQ and packaging are done; in F, alcohol synthesis [formerly monomer synthesis]; G, PVC chlorination; H, no longer in operation (formerly monomer synthesis); 1, compounding and milling; JT synthetic rubber; K, compounding (formerly warehouse nd receive Ing): L, PVC drying. tQn the whole, other buildings were in operation as long as the plant as a whole. Table 3.---Work Histories for Patients With Angiosarcoma of Liver and Nonmalignant Hepatic Disease Case No. 1 2 3 4 s 6 7 & 9 10 11 First Liver Disease Diagnosis, Date April 1964 Auo 1967 May 1970 March 1973 Dec 1973 Feb 1974 Feb 1974 Dec 1968 Jan 1972 Sept 1973 Sept 1973 Total Duration of Work Bofore Diagnosis, yr/mo 19/8 17/11 13/1 16/5 27/7 12/0 19/0 24/5 5/6 23/6 28/11 Total Duration of Works* Chemical Helper in FVC-Folymerlaetion Buildings, mo 6 2 65 20 8 43 44 47 65 0 9 C and D have more reactors (48 each) than either building A (35 reactors) or building B (25 reactors); the newer reactors have approximately a onethird greater capacity. Employment among all 11 patients involved ail four polymerization buildings. Three patients had worked in all four buildings; five had never worked in building D, three had never worked in building A or building C, and although all 11 had worked at somr time or another in building B, three had worked there less than one month. It appears unlikely that some chemical or procedure unique to any one building can be implicated as a (Table 2). Ten of the 11 patients (cases 2 through 11) worked exclu sively or predominantly in one or more of the four PVC polymerization buildings ?t the plant (Table 2, build ings A, B, 0, and D). Patient 1 worked about half of his total employ ment time in a PVC polymerization building (building A) and for an al most equal time in a separate PVC drying and packaging building (building E). Three patients never worked elsewhere than in the PVC polymerization buildings (case 4, 6, and 11). As can be seen from Table 2, buildings not involved with polymer ization (buildings E through L and all others) were only sparsely repre sented in relation to total employ ment. For the four polymerization buildings that in 1973 employed a to tal of 160 persons, 1ST man-years of employment arc represented among the 11 cases. For the remainder of the plant with a total employment of about 950 persons in 1973, only 21 man-years were recorded. Buildings A and B, opened in 1942 and 1944, respectively, are the older of the four polymerization buildings; building C (1947) and building D (1948) are somewhat newer. Buildings many man-years of employment, however, were represented among cases for buildings B and D (127 years, 9 months) as for buildings A and C (64 years, 11 months). Win'this difference may or may not 1, meaningful, some variations do exist between the various buildings that could conceivably be important ;i.; risk factors. Buildings A and C preduce homopolymer resin exclusive!; while various copolymers and terpob mers are produced in building B, ami all PVC paste and almost all PVC la tex is produced in building D. Those workers who are probably most exposed to VCM are chemical 62 JAMA, Oct 7. 1974 Vol 230. No 1 Hepatic Disease--Falk et helpers w tv;uTU>rs, :en of the :is hi inip'oyce h*. !;vr bef .idv.ineod r./.ton (ie, plant 2.;. 7 years -;n nt niiu .imi 15. L , who spent suugests ii-mship b <uro and ! i .iso All 11 :h-ir imm. whially ir hepatic dis to hepatot I'aUt-nls h; i.f c\po>urt taken hep. Cents (cas had signifi event for ailed exp' t-'Xie vhem irorntienl, r-enie or t a!> prcvii "f hepatic I -arenma in a in-lory o! ' < t U'oh'S '. a on the : l-c.ii mixed two t dxiut three c:i-e a-, ''.'oil c|s Icfo-.J tl VCM were r ' "f a no 1M. ' " :li'Pe:i '""alia of ' -u-.' can 1 'ce-phern h' SVA, Oct 7 'OCC ase Others 0 0 0 0 0 0 0 0 0 0 0 0 32T "'600 M. no longer e and receiv- s (48 each) factors) or :he newer ly a oneiployment solved all gs. Three our build1 in buildorked in . and al- at some B, three han one hat some ie to any `ted as a twice as loyment, 1 among D (121 Idings A 0. While ' not be do exist >gs that tant as I C pro-lusively terpolyX B, and ?VC la- ; T ''obably hemical et al 1 j 1 helpers whose principal job is to clean reactors. As can be seen in Table 3, ten of the 11 patients worked at some time as helpers. While virtually every employee at the plant has worked as a Klper before being promoted to more advanced work, the average work du ration (ie, time from starting work at the plant to date of diagnosis) was 23.5 years for the five patients who ^pent nine months or less as helpers and 15.1 years for the six patients a ho spent 20 months or more. This suggests indirectly a possible rela tionship between intensity of expo sure and latent period for liver dis ease. All 11 patients, or members of their immediate families, were indi vidually interviewed regarding past hepatic disease and possible exposure to hepatotoxic agents. None of the patients had a history of hepatitis or of exposure to hepatitis, and none had taken hepatotoxic drugs. Three pa tients (cases 1, 7, and 9) may have had significant alcohol intake. None, except for the patient in case 7, re called exposure to possible hepato toxic chemicals outside the work en vironment, in particular to either arsenic or thorium dioxide, two chem icals previously implicated as causes of hepatic disease and hepatic angio sarcoma in humans.1'7 Patient 7 gave a history of exposure to arsenical in secticides on the family farm be tween the ages of 6 and 15 years; he both mixed and sprayed the insecti cides two to three times a year for about three hours on each occasion. In no case was there any history of acroosteolysis, COMMENT Before the report by Creech and Johnson,' the only evidence that VCM might be oncogenic came from ani mal experiments. In 1971, Viola et al* published data suggesting oncogenic ity of VCM when inhaled by rats at very high doses; tumors of many tis sue sites, including lung, bone, and skin were recorded. Preliminary re sults of a more recent animal study in Italy by Maltoni et al (unpublished data) appear to indicate that angio sarcoma of liver as well as of other tissues can be induced in rats by at mospheric levels of VCM that are not uncommon in the human workplace environment. In light of these obser vations, it appears likely that expo sure to VCM is responsible for the Louisville cases. Further support for this hypothesis is needed, of course, from additional epidemiologic data concerning workers at other PVC and VCM plants. Further toxicologic analyses are also needed to address the possibility that the active onco genic material may be some metabo lite of VCM instead of VCM itself. Whatever the precise mechanism for oncogenicity and hepatotoxicity of VCM, the Louisville data suggest that relatively high levels of VCM ex posure and relatively long intervals since first exposure (20 years or so) are involved. This does not rule out the possibility of less marked health effects at lower doses or at shorter in tervals of exposure, but it does for the present focus attention on the imme diate problem of assessing the health status of persons exposed in the re mote past to high doses. None of the Louisville cases involved men work ing at the plant less than six years before diagnosis, and it can be safely assumed that levels of VCM exposure during earlier years of PVC produc tion were considerably higher than at present because of less stringent work practice procedures and less at tention to minimizing possibilities of VCM exposure in places of work. In humans, both thorium dioxide and arsenic have previously been re ported as causes both of hepatic dis ease and of angiosarcoma of the liver. In only one case at the Louisville plant (case 7) was there any history of exposure to either of these two ma terials (arsenic in insecticide spray). Likewise, there is little or no evidence among the Louisville cases that ex cessive alcohol intake plays any accel erating or potentially cocarcinogenic role or that any direct relationship exists between acro-osteolysis and liver disease. Various data now suggest that VCM (or some derived metabolite) may produce in addition to angiosar coma of the liver a nonmalignant he patic disorder characterized by portal fibrosis and portal hypertension. This is suggested by the fact that such fi brosis was present in at least five of the Louisville tumor cases and was in addition observed in four other Louis ville vinyl 'hloride workers without tumor. Recent observations in Ger many,- together with earlier reports from Eastern Europe," suggest that hepatic fibrosis and portal hyperten sion represent an occupational dis ease not uncommon amonc inyl chlo ride workers. Concei' i.>ly, such fibrotie liver disease represents a premalignant -tate. If this proves to be so, the early detection oi such liver disease may be of greater industrial and public health importance than de tection of tumor itself, both because hepatic fibrosis may well emerge as a more frequent condition than tumor in vinyl chloride workers, and because it remains a possibility that very early liver abnormalities may be re versible or nonprogressive after workers have been removed from high-risk areas. Laszlo Makk, MD, Lynn Ogden, MD, Edward Fadell, MD, Anne Richman, MD, Curtis Song' ster, MD, George Schrodt, MD, Edward Callahan, MD, Jerry Clanton, MD, James Kurfees, MD, Stanley Seipel, MD, and Will Ward, MD, sup plied records and pathologic material*. Louis Thomas, MD, and Hans Popper, MD, reviewed pathologic material. Refer*nets 1. Creech JL Jr, Johnson MN: Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Oeeup Med 16:150-151, 1974. 2. Wilson RH, McCormick WE, Tatum CF, et al: Occupational acro-o*teoly$i$. JAMA 0)1:577578, 1967. 3. Dodson VN, Dinman BD, Whitehouse WM, et al: Occupational acro-osteolysis: III A clinical tlttdy. Arch Environ Health 22:83-91, 1971. 4. Da Silva Horta, Cayolla da Motta L, Abbait JD, et al: Malignancy and other late effects fol lowing administration of Thorotrast. Lan-'et 2:201-205, 1965. 5. Da Silva Horta, Cayolla da Motta L: Fol lowup study of thorium dioxide patients in Por tugal. Ann NY Acad Sex 145:830-842, 1%7, 6. Regelson W, Kim U, Ospina J, et al: Hemangioendothelial sarcoma of liver from chronic arsenic intoxication by Fowler's solution. Caru-er 21:514-522, 1968. 7. Morris JS, Schmid M, Newman S, et al: Ar senic and noncirrhotic portal hypertension. Gastroenterdogy 64.36-94, 1974. 8. Viola PL, Bigotti A, Caputo A: Oncogenic response of rat skin, lungs, and hones to vinyl chloride. Cancer Ret 31:516-522, 1971. 9. Marsteller HJ, Lelbaek WK, Muller R, et a): Chronisch-toxiache Lehcrschadcn bci Arbcitem in der PVC-Production. Dtseh Med Wochenschr 98:2311-2314, 1973. 10. Suciu F, Drejman 1, Vala*kai M: Etude des maladies dues au chlorure de vinyie. Med Lav 58:261-271, 1967. JAMA, Oct 7, 1974 Vol 230. NO 1 Hepatic Disease--Falk et al 63 uco 023864