Document 2JrvQdbV89RrqVNQZYBNBOXpL

Original Contributions Hepatic Disease Among Workers at a Vinyi 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 1934. 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 58 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) REECH and Johnson1 recently re ported the occurrence of three cases of angiosarcoma of the liver among workers at a polyvinyl chloride (PVC) production plant in Louisville. Be cause this tumor is extraordinarily rare (only about 25 cases are esti mated to occur each year in the entire United States), the existence of such cases in this particular setting See also p 64. strongly suggests a causal relation ship to some phase of the PVC pro duction process. Recent animal stud ies being conducted in Italy support the concept that exposure to vinyl chloride monomer (VCM) may be the mechanism involved (C, Maltoni et al, unpublished data). Beginning in late January 1974, in- Frorn the Cancer and Birth Detects Division, Bureau of Epidemiology. Center for Disease Control, Atlanta, Ga (Drs. Falk and Heath), the B F. Goodrich Company. Louisville. Ky (Dr. Cresch) and Akron, Ohio (Dr. Johnson), and the National Institute for Occupational Safety and 1ea".h. Center (or Disease Control. Rockville, " I (Or. Key). ^sprint requests to Cancer and Birth Defects division. Bureau of Epidemiology, Center for Disease Control, 1600 Clifton Rd, Atlanta. GA 30333 (Or. Falk). tensive efforts have been devoted to clinical and epidemiologic studies of past and present workers at the Louisville plant, as well as at other PVC production plants elsewhere, in order to define more precisely the ex tent of health risks among vinyl chlo ride workers. This report summarizes findings to date with respect to both malignant and nonmalignant hepatic disease among workers at the Louis ville plant, particular emphasis being given to epidemiologic features. BACKGROUND The production of PVC by polymer ization of VCM began in Germany about 40 years ago, with production in the United States starting about five years later. The industry grew rapidly after World War II, and growth has continued in recent years 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 large 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 fromwhich unreacted VCM is recovered and recycled through a closed 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 flour), 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- JA.MA, Oct 7, 1974 Vol 230, Mo 1 Hepatic Disease--Falk et al 59 R&S 000639 merizction, when reactors are opened and cleaned. Although the air within Motors is replaced several times be^B 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, scleroderma like changes of the hands, and lytic lesions in the distal phalanges.1-1 CLINICAL AND PATHOLOGIC FINDINGS ^J?able 1 summarizes salient fea^Bs for each case of hepatic angio^Koma 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 ab normalities was instituted at the Louisville plant. All current employ ees, whether engaged in PVC poly merization work or not, were exam^B (see p 64). As a result of this p^ram, two additional cases of an giosarcoma of the liver were diag Casa No. Hepatic Tumors 1 Age at Diagnosis/ Race/Sex 52/W/M 2 43/W/M 3 36/W/M 4 49/W/M 5 58/W/M 6 45/W/M 7 43/W/M Nonmalignant Hepatic Disease 8 46/W/M 9 28/W/M 10 58/W/M It 56/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 2/74 2/74 .. 12/68 1/72 9/73 9/73 .. Table 1.--Clinic*! Initial Symptoms j 8/S3-Fatigue 1/64-Right upper quadrant pain 9/SS-Fatlgce, "pleurisy" 8/67-Epigastric "knot" and pain 1/70 and 5/70-Me!ena ' 12/63 and 5/65-Melena and hematemesis 7/73-Waakness and weight loss ; 1 I 8/73-Fatisus, "pleurisy" Asymptomatic t 10/68 and 11/68-Melena 9/71-Chest pain, weight loss 2/73-Hospitalized for hernia repair, Icterus noted 9/73-Hospltalized for chole lithiasis 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 hepatosplenomegaly (cases 2 and 5), but four (cases 3,4,6, and 7) had normal physi cal findings. While all seven patients had evidence of liver function abnor mality at time of initial work-up, no consistent pattern emerged, and in several instances abnormalities were only slight (cases 2, 3, 4, 6, and 7). In several cases, relatively mild hepatic dysfunction coexisted with either faradvanced portal hypertension (cases 3 and 4), unresectable angiosarcoma U CO Ooo CD O 1 60 JAMA, Oct 7. 1974 Vol 230. No 1 Hepatic Disease--Falk et al t and Pathologic Findings of Cases of Liver Disease Physical Findings 1/64-Risht Upper quadrant tenderness S/67 -epigastric mass and splenomegaly 1/70-No abnormalities 5/7C-Hepatosplenomegaly 12/63-Mo abnormalities 5/65-Splenomegaly 7/73-Hepatosplenornegaly /74-No abnormalities 774-No abnormalities Hepatic Work-up* 1/64-Mcderate 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 defect Esophogram: varices 5/65-Elevated SGOT Esophagascopy: 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 defect Pathologic Findingst 1/S4-OLB: slight focal hepatitis 3/64-NLB: unchanged 4/64-PM: hepatic angiosarcoma with metastases 8/67-OLB: angiosarcoma 1/68-PiM: 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-NL8: fibrosis OL8: 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.fibrosl? l/S3-Sptsnomega!y n\ osplenomegaly ^G-SpTsnomagaly ,'73-No abnormalities 10/68-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 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, sutfobromophtnalain. 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- ma. Nonmalignant Hepatic Disease Ages at diagnosis for these four pa tients (cases 8 through 11) range from 2S to 56 years (average age, 46.5). Ini tial clinical manifestations varied widely; one patient (case 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 fibrosis and sinusoidal changes described in the cases of angiosarcoma. Three pa tients (cases 8, 9, and 11), as well as one parent 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 23Q. No 1 Hepatic Disease--Falk et al 61 R&S 000641  Table 2.--Duration of Employment for Patients With Angiosarcoma of Liver and Nonmalignant Hepatic Disease A No.C Duration ol " * J ........ yr/mo 1 19/8 2 17/11 3 13/1 4 16/S 5 27/7 6 12/0 7 19/0 8 24/5 9 S/6 10 23/6 If 28/11 Total 203/0 No. of yr in operation 32 Total No. of employees in 1973 PVC-Polymeciaation Buildings t A BCD 8/11 0/3 0 0 0/1 12/S 2/0 0 1/2 1/7 5/5 4/4 1/2 14/9 0/6 0 0/6 2/8 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 7/1 0/2 0 37/8 62/6 27/3 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* G H 1 J K L' 00000 0 2/9 0/2 0 0 0 0 0 0 0/2 0/200 00000 0 0 0000 0 0 0000 0 0 0 0 0/2 0 0 0 o o o 6/n o 0 0 0/1 0 0 0 0 01/2 0 0 0/1 0 0000 0 2/9 0/2 1/5 0/4 6/11 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 C, 7 0 0 0 0 o 0 0 0 0 32t ~600 *in 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); 1, compounding and milling; J, sv thetic rubber; K, compounding (formerly warehouse and receiv ing); L, PVC drying. 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 Total Duration Total Duration of Work a3 First of Work Before Chemical Helper Liver Disease Diagnosis, In PVC-Polymeri- Diagnosis, Date yr/mo ration Buildings, mo i April 1954 19/6 6- 2 Aug 1967 17/11 2 3 May 1970 13/1 65 4 March 1973 16/5 20 5 Dec 1973 27/7 8 6 Feb 1974 12/0 43 7 Feb 1974 19/0 44 8 Dec 1968 24/5 47 9 Jan 1972 5/6 65 10 Sept 1973 51 Sept 1973 23/6 23/11 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, B, 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 |^nerization buildings (case 4, 6, 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, 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 (194S) 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 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 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 be 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 d Hepatic Disease--Falk et al 1 30 > CO ooo O) r4o* - f i i i \\ / > helpers whose principal job is to clean reactors. As can be seen in Table 3, ten of the 11 patients worked at some ^Hkie 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 (is, 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 hepato toxic chemicals outside the work en- anment, in particular to either Inic or thorium dioxide, two chem icals previously implicated as causes of hepatic disease and hepatic angio sarcoma in humans.*-' 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 al5 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 Italyr by Maltoni et al (unpublished data) appear to indicate that angiosaMfitna of liver as well as of other t^^pbs 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 chloride workers without tumor. Recent observations in Ger many, together with earlier reports from Eastern Europe,10 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 Fadell, MD, Anne Rich man, MD, Curtis Song ster, MD, George Schrodt, MD, Edward Callahan, MD, Jerry Clanton, MD, James Kurfees, MD, Stanley Seipel, MD, and Will Ward, MD, supplied records and pathologic materials. Louis Thomas, MD, and Hans Popper, MD, re viewed pathologic material. References 1. Creech JL Jr, Johnson MN: Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Med 16:150-151, 1974. 2. Wilson R1I, McCormick WE, Tatum CP, et al: Occupational acro-osteolysii JAMA 201:577578,1967. 3. Dodson VN, Dinman BD, Whitehouse WM, et al: Occupational acro-osteolysis: III. A clinical study. Arch. Environ Health 22:83-91, 1971, 4. Da Silva Horta, Cayolla da Motta L, Abbatt JD, et al: Malignancy and other late effects fol lowing administration of Thorntrast. Lancet 2201-205, 1965. 5. Da Silva Horta, Cayolla da Motta L: Fol lowup study of thorium dioxide patients in Por tugal. Ann NY Acad Sci 145:830-842,1967. 6. Regelson W, Kim U, Ospina J, et al: Hemangioendothelial sarcoma of liver from chronic arsenic intoxication by Fowler's solution. Cancer 21514-522,1958. 7. Morris JS, Schmid M, Newman S, et ah Ar senic and nonrirrhotic portal hypertension. Gas.troenteralogy 64:86-94, 1974. 8. Viola PL, Bigotti A, Caputo A: Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31:516-522,1971. 9. Marsteller fIJ, Lelback WK, Muller R, ct al: Chronisch-toxische Leberschaden bei Arbeitem in der PVC-Production. Disch Med Wochenschr 93:2311-2314, 1973. 10. Suciu F, Drejman I, Valaskai M: Etude des maladies dues au chlorure de vinyle. Med Lav 5S:261-271, 1367. JAMA. Oct 7, 1974 Vol 230. No 1 Hepatic Disease--Falk et al 63 000643 37 So CO