Document JNxk3y786LddV2B0BZngGoG4a

Original Contributions Hepatic Disease Among Workers at a Vinyl Chloride Polymerization Plant 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 iosarcoma, have been identified to date among men employed at one vinyl chloride polymerization plant. The earliest diagnosis was made in April 1964. The two most recent cases, both angiosarcoma, were diagnosed in February 1974 as a result of systematic medical screening for liver abnor malities among workers at the plant. Ages at diagnosis have ranged from 36 to 58 years for the seven patients with angiosarcoma and from 28 to 56 years for the four patients with nonmalignant disease; durations of employment before diagnosis have ranged from 12 to 28 years and from 5 to 29 years. All 11 persons had worked in close and continuous contact with various phases of the vinyl chloride polymerization process. Review of pathologic material suggests the presence in both tumor and nontumor cases of portal fibrosis and atypical sinusoidal lining cells. A direct causal relationship between ex posure to vinyl chloride monomer and pathologic findings is postulated. (JAMA 230:59-63, 1974) CREECH and Johnson' recently re tensive efforts have been devoted to ported the occurrence of three cases clinical and epidemiologic studies of angiosarcoma of the liver among of past and present workers at the workers at a polyvinyl chloride (PVC) Louisville plant, as well as at other production plant in Louisville. Be PVC production plants elsewhere, in cause this tumor is extraordinarily order to define more precisely the ex rare (only about 25 cases are esti tent of health risks among vinyl chlo mated to occur each year in the entire ride workers. This report summarizes United States), the existence of such findings to date with respect to both cases in this particular setting malignant and nonmalignant hepatic See also p 64. disease among workers at the Louis ville plant, particular emphasis being strongly suggests a causal relation given to epidemiologic features. ship to some phase of the PVC pro duction process. Recent animal stud BACKGROUND ies being conducted in Italy support The production of PVC hy polymer the concept that exposure to vinyl ization of VCM began in Germany chloride monomer (VCM) may be the about 40 years ago, with production mechanism involved (0. Maltoni et al, in the United States starting about unpublished data). five years later. The industry grew Beginning in late January 1974, pi-* * rapidly after World War. 11, and growth has continued in recent years From the Cancer and Birth Detects Division, Bureau ol Epidemiology, Center for Disease Control. Atlanta. Ga (Ors Falk and Heath), the B. F Goodrich Company, Louisville, Ky (Dr Creech) and Akron, Ohio (Dr Johnson), and the National Institute for Occupational Safety and Health, Center for Disease Control, Rockville, Jvld (Dr. Key). * Reprint requests to Cancer and Birth Defects Division, Bureau of Epidemiology. Center for Disease Control, 1600 Clifton Rd. Atlanta, GA 30333 (Dr. Falk). at a rate of about 14% per year. Cur rently in the United States, 14 plants employing about 1,500 workers pro duce VCM, while 37 plants employing about 5,000 workers polymerize PVC from VCM. Current annual produc tion of PVC in the United States is estimated at approximately 4.4 billion pounds, or 25% of world production. The B. F. Goodrich PVC polymer ization plant in Louisville first began operations in 1942. The number of persons employed at the plant di rectly in PVC polymerization has steadily increased, reaching a fairly stable level of 250 to 300 workers by the late 1950s. At present, in addition to 271 persons engaged directly in PVC polymerization, about 850 per sons are employed at the plant in other activities such as synthetic rub ber production, compounding and milling operations, managerial and clerical positions, and maintenance work outside PVC polymerization areas. Until 1966, VCM as well as PVC was produced at the Louisville plant. Since that time, however, all VCM used at the plant has been shipped by tank car from other facilities. The VCM is unloaded, stored, and then piped into largo polymerization re actor vats through an essentially closed system. Each reactor receives a measured amount of VCM as well as appropriate catalysts, stabilizers, emulsifiers, and additives (and other monomeric compounds if copolymers or terpolymers are being produced), and the reaction is carried to the de sired end point. Polymerized material is dropped into secondary tanks from which unreacted VCM is recovered and recycled through a dosed system; it then enters tertiary tanks from which it is concentrated, dried, and packaged. The end product consists of three different materials: (1) PVC resin (a powder with the texture of refined sugar), (2) PVC paste (a very fine powder with the texture of pro cessed (lour), and (3) PVC latex (a stable suspension of PVC in liquid). For workers in PVC polymeriza tion, the point of greatest probable exposure to VCM occurs after poly- JAMA, Oct 7, 1974 * Vol 230, No 1 Hepatic Disease--Falk et al 59 SL 028315 4 ferizalion, when reactors are opened !nd 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 cleaning1 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, scleroderma like changes of the hands, and lytic lesions in the distal phalanges.*-1 Case No. Hepatic Tumors 1 Age at Diagnosis/ Race/Sex 52/W/M Month and Year of f Diagnosis Death 4/64 4/64 2 43/W/M 8/67 1/68 3 36/W/M 5/70 9/71 4 49/W/M 3/73 3/73 5 S8/W/M 12/73 12/73 6 4S/W/M 7 43/W/M Nonmalignant Hepatic Disease 2/74 2/74 Table 1.--Clinical Initial Symptoms 8/63-Fatigue t/64-Right upper quadrant pain L_ 1 1______ 11 i 9/66-Fatlgue. "pleurisy" 8/67-Eplgastrlc "knot" and pain 1/70 and 5/70-Melena -- 12/63 and 5/65-Melena and hematemesls 7/73-Weakness and weight loss 8/73-Fatigue, "pleurisy" Asymptomatic 1 U 1 1 I' 11-------- CLINICAL AND PATHOLOGIC FINDINGS 8 46/W/M 12/68 10/68 and 11/68-Melena Table 1 summarizes salient fea 9 ,28/W/M 1/72 9/71-Chest pain, weight loss tures for each case of hepatic angio sarcoma and nonmalignaht liver dis ease diagnosed to date. Review of death records for plant employees dis 10 11 56/W/M S6/W/M 9/73 9/73 2/73-Hospitalized lor hernia repair, icterus noted 9/73-Hospitalized tor chole1 ithiasis 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 nosed, both in PVC workers (cases 6 ciently severe to warrant medical found of hepatic carcinoma or of an and 7). At the present time, no cases evaluation until the appearance of giosarcoma primary at other sites. A of angiosarcoma of the liver or of acute abdominal pain, pronounced further review of medical histories of nonalcoholic liver disease as demon weight loss, or abnormal findings on PVC workers employed at the plant strated by biopsy have yet been iden serologic screening. Two patients disclosed four additional men with a tified among non-PVC employees at (cases 3 and 4) were entirely asymp known history of nonmalignant liver the plant. All patients have been tomatic until the abrupt onset of gas disease demonstrated by tissue white men. trointestinal bleeding. Two patients , biopsy and diagnosed between 1968 'and 1973 (cases 8 through 11). Cases of Hepatic Angiosarcoma had clinically obvious hepatosplenomegaly (cases 2 and 5), hut four Because of concern aroused by the< Ages at diagnosis for the seven pa (cases 3, 4, 6; and 7) had normal physi discovery of hepatic angiosarcoma in tients with tumors (cases 1 through cal findings. While all seven patients workers, a medical screening pro 7) have ranged from 36 to 58 years had evidence of liver function abnor gram aimed at detecting hepatic ab (average age, 46.7). Initial clinical mality at time of initial work-up, no normalities was instituted at the features have varied widely; there consistent pattern emerged, and in Louisville plant. All current employ- were no signs or symptoms in case 7. several instances abnormalities were s, whether engaged in PVC poly- Four patients (cases 1, 2, 5, and 6) erization work or not, were exam were first seen with weakness and ined (see p 64), As a result of this tiredness; two of these also had inter only slight (cases 2, 3, 4, 6, and 7), In several cases, relatively mild hepatic dysfunction coexisted with either far- program, two additional cases of an mittent pleuritic pain. These symp advanced portal hypertension (cases 3 giosarcoma of the liver were diag toms by themselves were not suffi and 4), unresectable angiosarcoma i $0 JAMA, Oct 7. 1974 Vol 230, No 1 SL 028316 Hepatic Disease--Falk et al ^^athologic Findings of Cases of Liver Disease Physical Findings 1 /64-Right upper quadrant tenderness 8/67-Epigastric mass and splenomegaly 1/70-No abnormalities 5/70-Hepatosplenomegaiy 12/63-No abnormalities 5/65-Splenomega!y 7/73-Hepatosplenomegaly 2/74-No abnormalities 2/74-No abnormalities Hepatic Work-up* 1/64-Moderate elevation in TB( SGOT 8/67-Mild elevation in AP. SGOT. LDH Platelet count. 33.000/cu mm Liver scan: large defect, splenomegaly 5/70 Mild elevation in TB. AP. SGOT. LDH Liver scan, large delect Esophogram: varices 5/GS-Elevated SGOT Esophagoscopy: varices 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 delect Pathologic Findingst 1/64-OLB: slight focal hepatitis 3/64-NLB: unchanged 4/64-PM: hepatic angiosarcoma with melastases 8/G7-OLB: angiosarcoma 1/68-PM: hepatic angiosarcoma with spread to diaphragm and abdominal wall 5/70-OLB: angiosarcoma No PM 5/70-OLB: toxic hepatitis 10/70-NLB: hepatitis, cirrhosis 10/70-OLB: 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 11 /68-Splenomegaly O^^^Lpatosplenomogaly 8/73-Splenomegaly 9/73-No abnormalities 10/68-Marked elevation in AP, BSP Mild elevation in SGOT Esophngram; varices 9/71-Mild elevation in TB, SGOT 10/71-Liver scan- splenomegaly 3/73-Moderate elevation in TB. AP 1 Liver scan: splenomegaly, small liver 9/73-Moderate elevation in SGOT Mild elevation in TB. LDH 11/68-OLB: portal fibrosis, subcapsular fibrosis 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; LDH, lactic dehydrogenase; BSP. sulfobromophthalein. tOLB indicates open-liver biopsy; NLB, needle liver biopsy; PM. postmortem examination. (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 au topsy, 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, sinusoi dal dilation, and atypical sinusoidal lining cells. Conceivably, such lesions may represent a precursor stage in the development of hepatic angiosar coma. Nonmalignant Hepatic Disease Ages at diagnosis for these four pa tients (cases 8 through 11) range from 28 to f>f> years (average age, 46.5). Ini tial clinical manifestations varied widely; one patient (ease 8) 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 fihrosis 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 pn pathologic section was seen to reflect dilfuse subcapsular fibrosis. EPIDEMIOLOGIC FINDINGS The seven men with angiosarcoma had been employed at the plant for 12 to 28 years (average, 18.0), anil the four with nonmalignant disease, be tween 5 and 29 years (average, 20.6) JAMA. Oct 7, 1974 Vol 230. No 1 SL 028317 Hepatic Disease--Falk et al 61 Table 2.--Duration of Employment for Patients With Angiosarcoma of Liver and Nonmalignant Hepatic Disease Case No. Duration of Employment, yr/mo 1 19/8 2 17/11 3 13/1 4 1G/S 5 27/7 6 12/0 7 19/0 8 24/5 9 S/6 10 23/6 11 28/11 Total 208/0 No. of yr in operation 32 Total No. of employees in 1973 PVC-Polymerization Buildings /" AB C D 8/11 0/3 0 0 0/1 12/5 2/0 0 1/2 1/7 1/2 14/9 0/6 2/8 5/5 4/4 0/6 0 0 24/0 0 0/1 2/5 9/6 2 wk 2 wk 12/1 5/5 4/1 4/1 0 14/0 1 wk 1 wk 3/4 2/0 0 19/6 1/4 0 21/8 37/8 7/1 62/6 0/2 27/3 0 59/3 r~ 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* CH 1 J 000 0 2/9 0/2 0 0 0 0 0/2 0/2 0000 000 0 0000 0 0 0 0/2 0 00 0 0 0 0/1 0 0 0 1/2 0 000 0 2/9 0/2 1/5 0/4 K 0 0 0 0 0 0 0 0/11 0 0 0 0/11 L 0 0 0 0 0 0 0 0 0 0/1 0 0/1 32 30 27 26 27 27 29 19 32 26 32 26 36 36 48 40 14 1 12 0 52 72 18 8 Others 0 0 0 0 0 0 0 0 0 0 0 0 32t ""600 *ln Building E, PVC drying and packaging are done; in F, alcohol synthesis (formerly monomer synthesis); G, PVC chlorination; H, no longer In operation (formerly monomer synthesis): I. compounding and milling; J, synthetic rubber; K, compounding (formerly warehouse and receiv ing); L. PVC drying. t tOn 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 5 6 7 8 9 10 11 First Liver Disease Diagnosis; Date April 1964 Aug 1967 May 1970 March 1973 Dec 1973 Feb 1974 Feb 1974 Dec 1968 Jan 1972 Sept 1973 Sept 1973 Total Duration of Work Before 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 Work as Chemical Helper in PVC-Polymeri zation Buildings, mo 6 2 65 20 8 43 44 47 65 0 9 (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 at the plant (Table 2, build ings A, II, C, 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 1(10 persons, 187 man-years of employment are 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 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 all four polymerization buildings. Three patients had worked in all four build ings; live had never worked in build ing D, three had never worked in building A or building C, and al though all 11 had worked at some 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 bo implicated as a causative factor; almost twice as many man-years of employment, however, were represented among cases for buildings B and D (121 years, 9 months) as for buildings A and C (64 years, 11 months). While this difference may or may not be meaningful, some variations do exist between the various buildings that could conceivably be important as risk factors. Buildings A and C pro duce homopolymer resin exclusively while various copolymers and terpolymers are produced in building B, and 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 SE 02318 Hepatic Disease--Falk et at helpers whose principal job is lo 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 helper before being promoted to more advanced work, the average work du ration (ic, time from starting work at the plant to date of diagnosis) was 23.5 years for the five patients who spent nine months or less as helpers and 15.1 years for the six patients who 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 hepatotoxic 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.4 ' Patient 7 gave a history of exposure to arsenical in secticides on the family farm be tween the ages of G 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 Heforc 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-ostcolysis 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 chloride workers without tumor. Recent observations in Ger many;' together with earlier reports from Eastern Europe,'1' suggest that hepatic fibrosis and portal hyperten sion represent an occupational dis ease not uncommon among vinyl chlo ride workers. Conceivably, such fibrotic liver disease represents a premalignant state. If this proves to be so, the early detection of 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 Faded, MD, Anne Richman, MD, Curtis Song ster, MD, George Schrodt, MD, Edward Callahan, MD, Jerry Clanton, Ml), James Kurfecs, MD, Stanley Scipel, MD, and Will Ward, MD, sup plied records and pathologic materials. l,ouis Thomas, MD, and Hans Popper; MDr re viewed pathologic material. References 1. Creech JL Jr, Johnson MN: Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Mai 16:150-151, 1974. 2. Wilson RH, McCormick WE, Tatum CF, et al: Occupational acro-ostcolysis. JAMA 201:577578, 1967. J Dodson VN, Dinman UD, Whitehouse WM, et al: Occupational aero-osteolysis: III, A clinical study. Arch Nnvirvn Health 22:83-91, 1971. 4. Da Silva Horta, Cayolla da MoLU L, Abbott JD, et al: Malignancy and other late effects fol lowing administration of Thorotrast. Lancet 2:201-205, 1965, 6. Da Silva Ilorta, Cayolla da Motta L: Fol lowup study of thorium dioxide palienLs in Por tugal, Ann NY Acad Set 145:830-842, 1967. 6. Regelaon W, Kiin U, Ospina J, et al: Hemangioendothelial sarcoma of liver from chronic arsenic intoxication by Fowler's solution. Cancer 21:514-522. 1968. 7. Morns JS, Schmid Mf Newman S, et al: Ar senic and' noncirrhotic portal hypertension. Gas troenterology 64,86-94, 1974. 8 Viola PL, Bigotti A, Caputo A: Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 3l;5lG-522, 1971, 9. Maratcller HJ, Lelback WK, Muller R, et al: Chronisch-toxische Lebcrschaden boi Arlwitcm in dor PVC-Production, Dt*ch Med Wochcnschr 98;2311-2314. 1973, 10 Suciu F, Drcjman I, Valaskai M: Etude des maladies dues au chlorure do vinyle. Med Imv 58:261-271. 1%7. JAMA, Oct 7, 1974 Vol 230. No 1 SL 028319 Hepatic Disease--Falk et al 63