Document 8RLgZ8OmVn8qj6GxRDGXRKjYy

94 .. Annals New York Academy of Sciences Another finding was the very high incidence of creatine phosphokinase elevation found in the black, worker (75 percent) at B. F. Goodrich as opposed to the white worker (12 percent). We know of no reason for this. Of the seven cases of acroosteolysis tested, only one had an abnormal battery. When he was asked to stop drinking, his battery returned to normal in 3 weeks. In conclusion, a protocol for testing has been presented. The results of these tests have been reviewed. It seems that no one isolated test, be it SMA-12, battery, or special procedure, is adequate for a thorough work-up. It is certain that the SMA-12 or batteries without scan will not predict a cold spot in the liver. It is also true that a scan will not always predict fibrosis. The special procedures seem quite accurate in detecting abnormal pressure studies in the liver, indicating fibrosis or cirrhosis, and may be useful in diagnosing angiosarcoma of the liver (because of the persistent tumor blush). Further, it seems that the battery of more sophisticated tests will have to be run on some of the normal SMA-12 group to see if the SMA-12 is a reliable tool in discovering liver abnormalities or in screening out normal cases. These studies will be continued through the working years of the employee and probably even after his retirement. Undoubtedly the protocol will change as more information is gathered and as research shows a better method for de tecting disease, whether it be angiosarcoma, fibrosis, or portal vessel thrombosis with splenomegalia. Summary A protocol for systematic testing of all employees of a chemical' plant is presented. This factory manufactures polyvinyl chloride compounds and resins, ABS compounds and resins, and synthetic rubber. The results were reviewed, which led to the discovery of 2 additional cases of angiosarcoma and 11 cases of portal fibrosis. Two of the 11 cases were found to have developed in employees other than polyvinyl chloride production workers. References 1. Creech, J. L. & M. N. Johnson. 1974. Angiosarcoma of the liver in the manufac ture of polyvinyl chloride. J. Occupational Med. 16: 150-151. 2. Viamonte, M. J., W. D. Warren & J. J. Formon. 1970. Liver panangiography in the assessment of portal hypertension in liver cirrhosis. Radiol. Clin. N. Am. 8: 147-167. 3. Hanafee, W. N. & M. Weiner. 1967. Transjugular percutaneous cholangiography. Radiology 88: 35-39. 4. Rosch, J., P. C. Lakin, R. Antonovic & C. Dotter. 1973. Transjugular approach to liver biopsy and transhepatic cholangiography. New Engl. J. Med. 289: 227-231. 5. Siegel, R. M., D. V. Becker & J. R. Jurley. 1970. Evaluation of spleen size during iroonutine liver imaging with 99 mTc and scintillation camera. J. Nucl. Med. 11: 4 23733001 UNUSUAL SPLENOMEGALIC LIVER DISEASE AS EVIDENCED BY PERITONEOSCOPY AND GUIDED LIVER BIOPSY AMONG POLYVINYL CHLORIDE PRODUCTION WORKERS H. J. Marsteller and W. K. Lelbach Meditinische Universitatsklinlk D-53 Bonn, Federal Republic of Germany R. Muller and P. Gedigk Pathologisches Institut der Unlversitat Bonn D-53 Bonn, Federal Republic of Germany Introduction Economic Considerations; Technology As early as 1833" and 1838," respectively, Regnault in France succeeded in preparing vinyl chloride (VC) and polyvinyl chloride (PVC). However, the road to large-scale production was not opened until vinyl chloride could be synthesized from acetylene and hydrogen chloride (Klatte and Zacharias, 1912)m and or ganic peroxides were used for catalyzing VC polymerization (Klatte and Rollett, 1914)." In 1928, PVC production was started in the United States and in 1933 in Germany." The enormous growth of VC and PVC production capacities over the past 45 years ran parallel to the rising economic importance of plastic materials" (Table 1). PVC-producing industries in West Germany increased their production, parallel to the development in the United States (Table 2), at a rate of 10-20 percent per year from 1960 (172,673 tons of PVC) to 1972 (930,701 tons of PVC and polyvinylidene chloride).*'*' Total sales of PVC amounted to 850,140 German marks in 1972" This enormous increase in production capacity, espe cially in flexible PVC (U.S., 1965: flexible PVC, 90 percent; rigid PVC, 10 per cent)* can be explained by the almost unlimited use that can be made of PVC. Diversification of PVC markets exceeds that of any other large-volume thermo plastic and is one of the reasons for the increasingly favorable market situation (Table 3)."* Rigid PVC is used for tubing and fittings (including insulation material and drainage pipes), foils, films, and sheeting (packaging, lining, recording tapes), profiles (blinds, window frames), tiles, sound records, and fibers. Flexible PVC is used for cables, foils (decoration, roof covering), profiles, tubing, artificial leather, flooring, foam rubber, paint, varnish (lacquer), and toys.* Thus, indus tries that manufacture the end product operate on a much larger scale than those producing the polymer, but the companies are often identical." " Technologically, vinyl chloride was synthesized mainly by hydrochlorination of acetylene, a process which was almost exclusively in operation up to 1960, but in the United States now accounts for only 7 percent of the production." Vinyl chloride can also be produced by oxychlorination of ethylene to 1,2-dichloroethane which is then cracked to VC and HC1 by subsequent pyrolysis (now 93 percent of total production in the United States in 1972).',','"'m Under 95 AnnaJs New York Academy of Sciences Table 1 World Production of Plastics in Million _____ Tons per Year" Yeir Minion Tons 1930 1930 1960 1970 <0.1 1.3 6.9 30.0 Table 2 World Production and Production Capacity for PVC Resins (Million ToNs),,,',, Western Europe Western Germany United States Japan Eastern Europe Other areas Total 1950 0.053 0.014 Estimated capacities. Production I960 1972 0.578 0.173 2.948 0.930 1.950 1.088 0.861 0.544 7.391 1960 0.583 0.195 0.610 0.270 Not stated 0.152 1.615 1H* 3.583 1.995 1.587 0.816 0.816 8.797 1975* 3.175 Table 3 Diversification of PVC Markets1" PVC Mirket Calendering Extruded products Wire and cable Calendered flooring Film and sheet Paper and textile coating Sound records Plastisols Protective coatings and adhesives Injection and blow molding Coated flooring Other domestic uses Exports Consumption (%) 18 14 12 10 6 5 5 3 4 3 2 11 5 ambient conditions, vinyl chloride (CH=CHCI, mol.wt. = 62.5)" is a colorless inflammable gas of faintly sweet odor. At -- 13.8*C and 760 torr it condenses to a colorless liquid of low viscosity." VC reactivity is almost exclusively due to its double bond; the chlorine atom, as second functional site, does not react easily. The most important property of VC is its ability to polymerize. It also should be mentioned that peroxidation was repeatedly observed to occur when VC came into contact with atmospheric air due to leakage.'0' Commercially pro duced VC monomer is in general highly purified; degrees of purity of 99.99 per cent are reported. Specific declarations of individual plants state only marginal 23733002 Marsteller et al.: Splenomegalic Liver Disease 97 amounts of acid (free HC1), acetaldehyde, iron, acetylene, butadiene, water, and stabilizers.1" Avoiding impurities is a prerequisite since they retard polymerization.*1,101 Liquid VC is stored and transported in steel containers.* *1,101 Vinyl chlo ride is used mainly for polymerization, but it is also used as a refrigerating sub stance, as a propellant for sprays and aerosols, and for a small number of other chemical reactions.1" Four methods of polymerization are used for industrial fabrication of poly vinyl chloride: emulsion, suspension, bulk, and solvent polymerization.**""*1 Commercially most important were the two older methods of emulsion and sus pension polymerization, but now bulk polymerization has been added." In 1972, emulsion polymerization accounted for 78 percent, bulk polymerization for 6 percent, and solution polymerization for 3 percent of the total amount of all PVC resins produced in the United States." Initiation of polymerization is ac complished with compounds that form free radicals at relatively low tempera tures,' e.g., water-soluble compounds such as peroxide, ammonium, and potas sium persulfate for emulsion polymerization or soluble organic compounds, such as lauroyl and benzoyl peroxide, azobisisobutyronitrile and isopropylpercarbonate.1, * " Formation of free radicals also occurs by thermal decomposition of peroxide bonding (--O--O--)." Physical basis for initiation of free radical chainpolymerization is the homolytic dissociation of a pair of ^-electrons (covalent bond) resulting in free radicals that contain single unpaired electrons. The single unpaired ^-electron of the free radical obtained from the catalyst then reacts with the w-electrons of the double bond contained in the VC monomer, transforming the VC monomer itself into a free radical and thus propagating the growth of a chain of molecules with a terminal free radical. Chain growth is interrupted by saturation of the terminal free radical, often involving a reaction between two growing chains.'- " " " '** The random character of the termination steps accounts for the production of chains of different length and hence different degrees of polymerization with molecular weights statistically distributed around a mean value. One of the operating variables determining specific type of PVC produced is temperature'' which influences degree and velocity of polymerization as well as vapor pressure. Ordinarily, emulsion polymerization proceeds at temperatures of 40-70*C and total reaction pressure of 8-10 atm." In emulsion polymerization reactors (size: 2000-5000 gallons) are charged with the watery phase, VC is added, the agitator is started, and the emulsion is heated. At termination of the polymerization process the reactor content is emptied into a dump tank. The slurry can then be processed by centrifuging and drying. The dry polymer is separated, screened, and bagged. In suspension polym erization water-soluble protecting colloids are added as dispersing agents for stabilization of the suspended vinyl chloride droplets. Subsequent procedures are similar. Unreacted monomer is driven out of the slurry and recovered for recycling.*'*'" Suspension PVC is almost pure polymer since additives amount to less than 1 percent and most of that leaves when the slurry is centrifuged. For compounding, the powdery or granular polymer is dry-blended under heat and pressure using plasticizers, light and heat stabilizers, and sometimes fillers, lu bricants, and pigments or dyes.' PVC dry blends are compounded by hot mixing at fusing temperatures. Depending on the type of end product, fusion temperature lies below or within the softening range (120-160`C). In calendering (production of endless sheets) temperatures of 100-120C for rigid PVC and of 150-180'C for flexible PVC are reached. Tiles are fabricated by welding of several layers of calendered sheets in a heated press. In conversion to end products extrusion 98 Annals New York Academy of Sciences (profiles, pipes, conduit, ribbons) temperatures of 150-300`C can be reached. All this shows that temperature ranges, as a rule, from 100-200'C in converting the thermoplastic PVC resin by various procedures."'"'1" Toxicology, Occupational Medicine, Clinical Experience (Tables 4-6) Simultaneous with the start of large-scale production of PVC in 1930, phar macologic properties of vinyl chloride*0'107'1*710* and problems of occupational health101 were investigated. At first, vinyl chloride appeared to be a suitable narcotic which, even after Oster in 19471"" and Carr in 1949" had observed severe cardiac arrhythmia (believed to be due to potentiation of adrenaline effect70), was considered to be one of the least dangerous chlorinated hydrocarbons.1' ,0 " "'l" With the exception of two communications concerning acute VC intoxication without serious consequence in 2 workers1*17 no other data on occupational health hazards in PVC production were reported until 1949 when Tribukh et alpub lished results of an investigation at a Russian plastics factory. On ex amination of a group of 73 workers (48 males, 25 females) engaged mostly in processing PVC polymer (compounding at temperatures up to 160C and cal endering with release of trapped VC, use of chlorinated naphthalenes and diphenylene as plasticizers, effects of PVC dust), the authors found evidence of what they termed a "more or less marked hepatitis," presenting as a slight en largement of the tender liver but with conspicuous absence of characteristic com plaints, jaundice or bilirubinuria. Other findings were: hypotension, anemia, "chronic gastritis," skin lesions, and a peculiar whitish coating of the upper respiratory tract mucosa. This spectrum of symptoms was attributed to the action of plasticizers, and long-term follow-up studies were thought to be necessary, par ticularly for prevention of later development of serious liver disease. With the exception of liver disease, similar but badly documented findings, also attributed to additives, were reported by Devignevielle,10 Parmeggiani,100 and Hervieux and Tessier" between 1953 and 1959. Acute intoxication was again reported, this time in Great Britain, with acute collapse during VC polymerization00 and a second degree burn after direct contact with vinyl chloride.** Filatova et al."M were the first to point out a prevalence of "toxic angioneuropathy" in workers engaged in VC polymerization in spite of working area concentrations below Russian maximal allowable concentration (MAC) values (1 mg of VC per liter = 391 ppm). In 1960, Danziger*1 described 3 cases of acute VC intoxication oc curring in VC polymerization, 2 of them fatal. Suciu et a/." "' were the first to give a more detailed analysis of the disease spectrum encountered in 168 workers of two Rumanian PVC-producing plants who had been studied during a 4-year period. Their paper ranks as the earliest description of vinyl chloride disease. Gastrointestinal symptoms dominated; in addition, central nervous system dis turbances were found in a number of cases, a Raynaud-like syndrome in 10 workers, contact dermatitis and pseudoscleroderma in another 10, and alteration of thyroid function in 3. The authors found hepatomegaly in 51 and spleno megaly in 10 workers. BSP retention proved to be elevated in 2 of 11 cases ex amined. Liver biopsy in 2 cases revealed chronic hepatitis. A combination of various symptoms was seen in quite a number of workers. In 1965, Filatova et al." again reported on a Raynaud-like syndrome and central nervous system symptoms in PVC workers. Pushin110 found liver and biliary tract disease in 15 percent of those workers of the Sverdlovsk chemical plant who were engaged in PVC production. On the basis of a clinically slightly enlarged tender liver with mild hyperbilirubinemia occurring in these cases, he diagnosed anicteric, chronic 23733003 Marsteller et al.: Splenomegalic Liver Disease 99 "epithelial" hepatitis. As possible etiologic factors, primary ingredients for polym erization, compounds released from the polymer during calendering, and plas ticizers (phthalates), were discussed. In 1966, Cordier et al." were the first to describe acroosteolysis of the distal phalanges combined with a Raynaud-like symptomatology in 2 reactor cleaners (VC polymerization). Subsequently, similar cases were reported in 1967 by Chatelain and Motillon,** Marin et al.," Bourrichon,** Wilson et al.,'" and Harris Adams." With this clustering of publica tions the disease became known as "occupational acroosteolysis" with typical roentgenologic findings, often combined with Raynaud's syndrome and accom panied rarely by scleroderma-like skin lesions; the disease seemed to occur only in reactor cleaning ("polycleaners' disease").0111 Between 1969 and 1972, Anghelescu et al.,'' Filatova and Antonyuzhenko," Dinman et a/.,0110'10 (on the basis of a large-scale epidemiologic study), Lefevre," Markowitz et al." and Dugois et al." observed further cases of this syndrome, occurring only in workers engaged in VC polymerization. It appeared as if processing the polymer would not entail any health hazard (in spite of reflections on the content of trapped substances,''*, *''**'|**'i"). Single deviant observations made in 1970 by McCord01 and by Misgeld et al." in 1973 as well as warnings voiced in the past by Tribukh et al.'" in 1949 and by Danishevskii et al." in 1961 obviously were not sufficient to cast doubt on this concept, especially since many standard textbooks had stressed the ab solute harmlessness of processing the polymer,*1*"*1*7"11"'1" apart from the minimal risk attributed to VC inhalation*0- **70- *" ** "* 100 (Table 4). Animal experiments between 1930 and 1963 (Table 5) were first limited to the assessment of acute VC toxicity. However, after 1961 four research groups presented results on chronic toxicity of vinyl chloride (Table 6) that were not repeated on a large-scale basis. The importance of these results seems to have been underrated, in part even by the authors (e.g., Lester et al.") themselves. The experiments of Maltoni et al." that up to now were made known only in part, deal essentially with the carcinogenicity of vinyl chloride. These results had been preceded by the experimental work of Viola and co-workers.1*''1*0 However, re sults published by Torkelson et al.'" in 1961 induced the German Standards Advisory Committee to reduce MAC standards for vinyl chloride from 500 ppm (in operation since 1966) to 100 ppm in 1970.** In 1972, a group of dermatolo gists at Bonn University were the first in Germany to report on cases of "occupa tional acroosteolysis" with Raynaud's syndrome and scleroderma-like skin le sions.70 They found the symptomatology of this disease, however, to be much more complex than was so far assumed and hence proposed calling this syndrome "vinyl chloride disease." 70 Liver Disease in PVC Workers Clinical Observations; General Outline It seems quite remarkable that after the findings of Tribukh et al.'" in 1949 liver damage was only mentioned marginally in subsequently published papers and that no intensive investigation of this feature of vinyl chloride-polyvinyl chloride toxicity had been initiated before 1972. One of the reasons for this late detection of life-threatening liver disease may be the minimal degree of functional hepatic abnormalities generally encountered in these workers which contrasts strikingly with gross morphologic changes seen at peritoneoscopy and with the development of portal hypertension and angioscarcoma of the liver which both are now recognized to be associated with exposure to vinyl chloride. 100 Annals New York Academy of Sciences II 13 55 6< zo p < N %> Jl OVN) ftOo 2)<-s 2 to |Sss?S 0-2" N <(93 ,2*0 2U***B*, t3So O5r.0-*' o5t-o Cs a C H? ^ a ty>_Ss=.-=*w t*i v c j .*"5".ovS~tS5 3S' "x: - " S S =-"rE3.9 3|.s'|fgSls J*u.c a o i> a iHOrCQcLUuXQ "So -ssXJw I rrs2-S w s "-- K<2u.Q 3 -S-C. S-a^ aP 5 "5 "a CN . 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Num ber o f animals stated is given in parentheses. 237-33007 Marsteller et al.\ Splenomegalic Liver Disease 107 In December 1972, our colleagues from the Department of Dermatology alerted us to the possible occurrence of serious liver disease in workers of a nearby chemical plant who were engaged in vinyl chloride polymerization and to a smaller degree in processing the polymer to the final plastic product. We started an extensive examination program that included peritoneoscopy and guided liver biopsy because we felt that this procedure might yield deeper insight into nosology and pathomorphology of vinyl chloride-associated hepatic disease than merely blind percutaneous biopsy, since a larger proportion of cirrhotic or fibrotic changes may escape detection if only blind biopsy is employed."I*'I`, According to information furnished by the plant physician, a total of roughly 180 workers had in the past been exposed to vinyl chloride in this plant, either as reactor cleaners or in further processing of vinyl chloride (centrifuging, drying, sizing, and bagging the polymer). To date, we have been able to collect data from a total of 50 workers of this plant (Table 7). Their age distribution is shown in Figure 1. More than half of them were of non-German origin (nationality: German, 23; Greek, 21; Turkish, 6). Among the 50 workers examined 44 had been working in the polymerization process (39 of them alternatively as reactor cleaners) and 6 in processing the polymer into the final plastic products. The length of exposure (Figure 2) ranged from 9 months to 21V* years for the 44 polymerization workers, with 15 of them having had an exposure of 9 or more years' duration. For the 6 men working in the postpolymerization phase the length of exposure was 13, 9, 5`A, 414, 4, and 2 years, respectively. Case 50 had been working in the postpolymerization phase for 2 years and subsequently in the manufacture of high-strength paper (harden ing by epoxy compounds) at the same plant for 10 years. Medical History In the overwhelming majority of cases previous history was uneventful. One worker (case no. 1) had a previous history of jaundice of unknown etiology 18 N! ol cases Fioure 1. Age distribution of 50 PVC production workers (agr xamination). Abbreviations used Job Classification: PM, Synopsis of Anamnestic, Clinical, Biochemical, ; are: Nationality: Ger, German; Gr, Greek; Turk, TurkiiL VC polymerization; PC, processing of the polymer; Perlm RbcopiC, and H1STOL091C Data of 50 PVC Workers tr-like patches to broader concave postnecrotic scars; PC, patchy 'perihepatitis Hilaginea;" A, augmented; B, increased; Histology: (+), minimal; +, slight, neoscopy: U, slightly irregular or undulated; G, granular to finely nodular; NoT "( moderate; + + + , marked. ely " J ~' " ' " ' ' ' .... t w*j I* 0 "0S *1 s5 2 3 2 u 9 >--* Exposure (yr/mo) Alcohol Intake (c/d) Central Nervous Symptoms BSP Retention (>$% after 45 min) SCOT (> 12 (18) mU/ml)t SGPT (>12(22) mU/ml)t Skin Lesions Surface relief Capsular vessels Ta5 !i >N I y 1 & 8 >% J.So 2g |P o iS a V) s 00 9 9 I 19 j o \ R i Perltonescopy M 1 4JO0 m I <3 Histology -0V. .e2~a* * CJ M .S3 1 It 5diS SIS 3" 0) 3(aK/)t J>aOs I& a 3 .> s a K CQO. *3 eX (A a Xk i if B2 jtQo .S^ wc V (2 I Ger 2 Get 3 Ger so PM 56 PM 47 PM 21/9 -- 18/6 16-32 18 + + + + 1.5 + 2 3 2 5 8.7 15 15(23) 6.1 15.6 13 19 (24) n : (+) G/Nod R <+) A/1 ? + + + ++ Normal (liver scan) + + 15 x 11 x 12 + Markedly en- + larged (liver scan) 4 5 Ger Ger 46 PM 51 PM 6 7 Ger Ger SI 52 PM PM S Ger S3 PM 9 Ger 44 PM 10 Ger 39 PM 11 Oer 48 PM 12 Ger 27 PM 13 Or 40 PM PC 14 Ger 52 PM IS Ger 35 PM 16 Or 45 PM 17 Gr 42 PM PC IS Ger 54 PM 19 Ger 31 PM 20 Turk 33 PM 2! Gr 30 PM 22 Ger 34 PM 23 Gr 36 PM 24 Gr 30 PM 2S Gr 35 PM 26 Ger 30 PM 27 Ger 31 PM 28 Gr 31 PM PC 29 Turk 33 PM 30 Gr 30 PM 31 Turk 36 PM 32 Turk 33 PM 33 Oer 32 PM 17/6 8 17 48-* 16 16 IS/3 8 + + 14/6 8 13/9 8 + 13/9 16 13 12/6 12/3 16-33 -- 28 + 0/9 11 9 -- 16 + 8/6 16 6/8 8 4/0 + 6/6 16 + 5/9 16 5/9 8 58 5 5 16 16 + 5 4/9 4/9 8 16 16-32 + + 4/9 4/0 8 -- + + 1/0 4/0 3/9 8 4 + + 3/9 3/6 --? 3/6 4 + + + 3 1.1 10.2 13(22) 15(47) 1.5 9.1 19 17 ; + + l 11.3 2 (2) 1.2 16.7 25 22 0 1 (+) + 1.5 1.5 S.6 15 15 + + 3 (11.15) 2.0 17.6 6.2 31 15 13 + 1.1 13 23 8 13 13 + 2 11 1.1 13.0 16 16 3 1.1 15.1 19 17(31) ) 8.8 13 13 +2 13.8 25(24) 23(63) + 10 GO) 1.4 6.9 (20) (27) 1 U/G Nod U G U G/Nod R/S R/S R/S ? R/S R/S R/S R/S U ? A A ? I I I A + + (28) IS C/R t + + 9.6 15 13 1.5 21.3 7.6 21(21) 2,g > ot examinee + l.S 6 1.8 90 190 + + t.s 3 8.5 32(27) 30(40) 7.5 15 15(24) UA + 1.5 + 8.3 15 6 1.7 7.1 23 15 25. u S/PC _ + 6 3 1.8 25.6 25 58 + (+) + + l.S 6.4 IS + 1.5 3 1.5 2.2 22.5 25 6.8 23 +64 12.5 19 817 { 34 17 16 t (+i) t+ + u/o ? + + -j. 4- + 12 x 7 x 11 14 x 12 x 6 + (+) (+) + 12x9x9 Splenectomy (15 x 12 x 7) (+4-) (+) + + <+) ++ (+) + It! + + 10 x 8 x 4 10 x 8 x 5 24 x 12 x 7 15x11x7 (+) 14 x 5 x 12 Normal (liver scan) + + + +. + N + (+) (+) (+i 23 x 14 x 9 13 x 10 x 5 12 x 9 x 5 Normal (liver scan) (+> ++ Splenectomy (500 g) + 4fX) +44+ 4- (+) + (++) + (+> (++) + <+) (+) 23 x 10 x 18 18 x 11 x 12 14 x 12 x 13 15 x 9 x 10 14 x 9 x 10 17 x 12 x 14 13 x lOx 10 (+) 14x6x8 13 x 9 x 14 16 x 10 x 4 14 x 13 x 6 (+) + (+) Normal (liver scan) x4- + I (++) 14 x 6 x 11 13 x 5 x 11 14 x 9 x 7 4* + + + + + 4* + + + 4* 4" + + 4* + + + + + + + 4" PC 1/0 34 Oer 40 PM 3/6 16 + l.S 1.1 8.6 19(20) 15(31) ++ ++ Slightly en* + larged (Uver 35 Or 31 PM 36 Or 38 PM 3/3 8-16 3/3 8-16 (1 to- + 5.2 (20) 13 15(24) i* u x4- (l++)i scan) 13 x 7 i 9 10 x 9 x 7 + + 37 Or 47 PM 3S Or 30 PM 39 Turk 30 PM 40 Gr 33 PM 41 Gr 4! PM 42 Ger 41 PM 43 Gr 36 PM 160)t 3/0 3/0 2/9 --16 -- 2/6 2/3 16 1/9 8 1/6 8 + + + t3 4- 3 1.5 + +3 9.7 13 8.4 17 13 6.1 19(22) 17(47) 6.3 17 17 % & A (+) + +4- 12 x 6x 8 15 x 12 x ? 16x6x8 u C/S G/Nod C/R/PC O/Nod A + It! 4(++) 13 x 7 x 12 11 x 7 X 10.5 + 12 x 9 x 7 11x8x5 12 x 8 x 6 + + + + + + + 44 Turk 33 PM 0/9 8 5.1 28 30(23) U 1 45 Gr PC 48 PC 0/3 13/0 14 +7 9.1 3(33) ;3 (80) (+) Normal (liver scan) 46 Gr 47 Gr 48 Gr 44 PC 39 PC 45 PC 9/0 28 5/3 16 4/6 -- + + 49 Gr 37 PC 50 Oer 36 PC 4/0 44 2/0 32 + + + 6 8 15.1 15 (20) 8.8 (22) 7.0 (88) 28 (20) 17 Jl (47) 111 ; r R/PC s <+) (+4*) (+) <+> xA + (+) 9x6x6 12 x 8 x 9 Normal (liver scan) 11x5x7 12 x 6 x 11 + + Centimeters below costal margin, t For explanation see Table 11. I For explanation see text. k s c5 110 Annals New York Academy of Sciences Figure 2. Length of exposure in 44 workers engaged in the polymerization proc ess. years prior to examination (length of exposure: 21SA years), and "chronic liver disease" was diagnosed in 1968. In 3 cases a symptomless solitary biliary cal culus was found on cholecystography (case nos. 43, 45, 50). In one Greek laborer (case no. 48), who had been engaged in the postpolymerization phase of produc tion for 4'/2 years and who in the past 2 years had repeatedly been hospitalized for gastric ulcer, the present examination by barium meal and gastroscopy re vealed a small anaplastic carcinoma of the stomach for which he underwent sub total gastric resection. A German worker (case no. 18) had partial gastrectomy in 1971, shortly before splenectomy was performed, because of an acute episode of bleeding from an endoscopically diagnosed pyloric ulcer; he also had esopha geal varices. One Greek worker (case no. 38) suffered from a mild form of hemophilia A, discovered at appendectomy in 1971; he had no episodes of spon taneous hemorrhage and factor VIII levels ranged between 18 and 50 percent. Another Greek worker (case no. 49) was admitted to the ENT-Department pri marily because of deafness of sudden onset, combined with labyrinthine disease; because of elevated transaminase levels he was later referred to the Medical De partment. None of the workers had a history of alcoholism. Ten did not use alcohol in any form (Table 8). Alcohol intake was not stated in one case. One Greek worker (case no. 36) had formerly consumed 110-160 g/day as wine but since entering the plant had reduced his intake to 8-16 g. Several laborers had noticed an aversion to alcoholic beverages or an alcohol intolerance after entering the plant. Complaints No clear-cut abdominal symptomatology was found. Complaints were usually not sugf ve. Fifteen workers reported only slight upper abdominal discomfort. 23733009 Marsteller et al.: Splenomegalic Liver Disease Table 8 Alcohol Consumption in 50 PVC Workers Reported Alcohol InUke (in g eth&nol/d) No. None Up to 8 g Up to 16 g Up to 32 g Up to 64 g Not stated Total 10 15 16 6 2 i 50 Table 9 Gastrointestinal Bleeding (Esophaoeal Varices) and Surgical Intervention in 50 PVC Workers 111 Gastrointestinal bleeding Splenectomy Splenorenal shunt Gastric resectionfor anaplastic carcinoma 4/50 3/50 1/50 1/50 Another 24 claimed to have experienced temporary central nervous symptoms, such as dizziness, slight disorientation, disturbance of vision, and mild headache, often combined with nausea and mild upper abdominal discomfort. Twelve workers spontaneously reported to have smelled "the gas" occasionally which they claimed had a faintly sweet odor. A Raynaud-like symptomatology was re ported in 8 cases. Four had experienced episodes of bleeding from esophageal varices during the past 2 years (Table 9). Methods of Investigation Besides physical examination, a broad spectrum of laboratory tests was ap plied to each case (Table 10). X-ray examination of the upper gastrointestinal tract and intravenous cholecystography were carried out in all cases as were a plain chest film and an ECG with 12 leads. In 3 cases esophagogastroscopy was done. Scintigraphy of liver and spleen was performed in 48 cases. Peritoneoscopy and guided liver biopsy were performed by us in 41 workers, peritoneoscopy without biopsy in one, and percutaneous blind needle biopsy in two other cases (total: 44 cases). Data of case 14 were put at our disposal by courtesy of Dr. Harald Henning* who, during a 3-year follow-up including three peritoneoscopies, had previously classified the case as noncirrhotic portal fibrosis with portal hypertension of unknown etiology. We were given access to data of cases 10, 24, 29, and 31 which had been examined by peritoneoscopy and biopsy at the Medizinische Universitats-Poliklinikt; 1 of these 4 cases (case no. 10) later * Head, Klinik Fohrenkamp of the Federal Board for Employee's Insurance, D-241 Molln, Germany. t We would like to thank Prof. Dr. F. Kriick, Direktor der Medizinischen Universitats-Poliklinik, Bonn, and Prof. Dr. A. Giitgemann, Direktor der Chir chen Universitatsklinik, Bonn, for permission to include data of 3 and 2 cases, resp ely. 112 . . Annals New York Academy of Sciences Table 10 Spectrum of Laboratory Tests Performed in 50 PVC Workers 1. Blood sedimentation rate; hemoglobin; red cell count; white cell count; differen tial cell count; hematocrit reading; number of platelets 2. Total bilirubin 3. Glutamic oxaloacetic transaminase 4. Glutamic pyruvic transaminase 5. Alkaline phosphatase 6. Lactic dehydrogenase 7. Cholinesterase 8. Thymol turbidity 9. Total protein 10. Serum electrophoresis 11. Bromsulfalein retention 12. Urinalysis 13. Blood urea nitrogen 14. 15. Serum Serum creatinineT. uric acid /only in some cases 16. Serum iron 17. Serum copper 18. Blood glucose 19. Total cholesterol 20. Serum triglycerides 21. 0-Lipoproteins 22. Blood coagulation factors (II, V, VII, X, antithrombin, thrombin time, thrombelastogram) 23. Hepatitis-associated antigen and antibody underwent splenectomy after repeated hemorrhage from esophageal varices. In a last case (case no. 7) splenectomy and lienorenal anastomosis were done at the Chirurgische Universitatsklinik.t Histology of the spleen was available in 3 cases after splenectomy; in another 8 cases we performed guided biopsy of the spleen for light microscopy; in 5 of these cases material for electron microscopy was also obtained. In addition, liver biopsy material was obtained for electron micros copy from 8 patients. Results Physical Examination On palpation, the liver was found to be slightly to markedly enlarged in 31 cases. Palpable splenomegaly was noted in 16 cases, in 4 of which it was not accompanied by hepatomegaly. Jaundice, spider angiomata, palmar or plantar erythema or physical demonstrable ascites were not found. Laboratory Tests The most consistently positive biochemical test was 45-min BSP retention (Table 11). A marginally to markedly pathologic retention was seen in 38 pa tients with a mean value of 10.5 percent. In 12 cases serum bilirubin levels were marginally elevated (maximum: 2.2 mg/100 ml). Likewise, activities of serum alkaline phosphatase were increased slightly in only one-fifth of the total. Ac tivities of serum aminotransferases GOT and GPT were unequivocally pathologic Marsteller et alSplenomegalic Liver Disease 113 Table 11 Results of Liver Tests in 50 PVC Workers (Classfication Based on Maximai Values Obtained in Multiple Determinations) 45-Mln BSP Retention (5.0%)** * Serum Bilirubin (1.0 mf/100 ml)* Alkaline Phosphatase! (43 mU/ml)* Normal Pathologic (Range) (Mean) 12 38 (5.1-25.6%) (10.47%) 38 12 (1.1-2.2 mg/100 ml) (1.4 mg/100 ml) 40 10 (50-110 mU/ml) (71.9 mU/ml) GOTt No. of Cases GPTt o' Definitely normal Marginally normal Pathologic Total -- 12 mU/ml5 --19 mU/mlH 12-20 mU/ml 20-30 mU/ml 20-50 mU/ml 31-60 mU/ml >50 mU/ml [ >60 mU/ml 4 31 13' 15 2. 50 -- 12 mU/ml} -22 mU/mlf 12-20 mU/ml 23-30 mU/ml 20-50 mU/ml 31-60 mU/ml > 50 mU/ml >60 mU/ml ,, 11 77 17 Upper limit. f Modification of the method described by O. A. H. Bessey et al. J. Biol. Chem. 164: 321,1946; upper normal limit (adults): S. J. Walter and R. Gldckner. Arzll. Lab. 10: 220, 1964. { Owing to a change in methods of determination of enzyme activities during the investigation (later use of a substrate-optimated method) two sets of reference values had to be used. E. and F. W. Schmidt. Enzymol. Biol. Clin. 3: 1,1963. V Substr&te-optimated standard method, W. Thefeld et al. Deut. Med. Wochschr. 99 : 343, 1974. in 15 and 17 Cases, respectively; however, marginal values may occasionally be the only and earliest biochemical indication of toxic liver damage."0 A more or less marked thrombocytopenia (less than 150,000 platelets/mm') was observed in 42 cases. Except for 1 patient with splenomegaly (case no. 14) who had leukopenia besides thrombocytopenia, hematologic results were other wise within normal limits. Tests for hepatitis-associated antigen and antibody were negative in all cases. All other biochemical tests including initially intro duced but later abandoned immunologic reactions failed to contribute to the problem in question. Roentgenology; Endoscopy of Upper Gastrointestinal Tract; Scintigraphy A diagnosis of esophageal varices, in some cases combined with varices lo cated in the cardiac region of the stomach, could be made in 10 workers; in 5 of them this was done by barium meal, in 2 by x-ray plus endoscopic examina tion, in 1 by barium meal and splenoportogram, in 1 by endoscopy and spleno portogram, and in the last patient by indirect splenoportography. Only in one case (case no. 7) was intraoperative measurement of portal pressure sible, and 23733010 114 Annals New York Academy of Sciences Table 12 Splenomegaly in 50 PVC Workers Spleen size as measured by scintigraphy In 48 cases Methods: Splenic scanning by "'Hg-BMHP 140 cases) (normal diameters: 11x7x4 cm) Liver scan by ,,mTc sulfur colloid (46 cases) A. Within normal limits (4 of the cases = PVC-processing workers): 11/48* B. Exceeding normal limits (2 of the cases - PVC-processing workers): 37/481 C. Not examined (previous splenectomy): 2/50 Splenectomy in 3 cases Diameters, weight: 1. 15 x 12 x 7 cm (300 g) 2. Ruptured at splenoportography (5C0 g) 3. 23 x 13 x 6 cm (1250 g) (scintiscan 24 x 12 x 7) * In 6 of the 11 cases by liver scan. t In 2 of the 37 cases by liver scan. this proved to be only slightly elevated. Otherwise, no determinations of intra- splenic pressure or of wedged hepatic venous pressure have been carried out so far. In 5 cases a diagnosis of acroosteolysis was established by x-ray examination of hands and feet. Approximate spleen size was determined by means of selective scintigraphy using labeled mercury ("Tig-labeled bromomercury hydroxy propane)! in 40 cases. Measurement of three diameters (length, breadth, depth) allowed detection of even minor degrees of splenomegaly. The organ proved to be slightly to markedly enlarged in 37 out of 48 cases (total assessment of spleen size: 39 out of 50), a proportion that was considerably larger than that obtained by either physical or peritoneoscopic examination (Table 12). Peritoneoscopy and Liver Biopsy In internal medicine, the paramount advantage of peritoneoscopy lies in the fact that it permits direct inspection of the abdominal cavity and of size, coloring, surface structures, and circumscribed lesions, especially of the two main hepatic lobes and the spleen which, otherwise, can only be accomplished by exploratory laparotomy. Besides inspection of abdominal organs, the method also allows, although only to a limited extent, minor intraabdominal manipula tions such as guided biopsy of liver and spleen, determination of organ con sistency by probe, and removal of strand-like adhesions. If contraindications are strictly adhered to, serious complications are rare.",," Based upon a compila tion of 63,845 cases in which peritoneoscopy was performed with 48,766 guided liver biopsies, Briihl" calculated a mortality rate of 0.029 percent. The rate of complications was 2.49 percent, two-thirds of which, however, had been only of minor importance. In the cases presented here, peritoneoscopic findings were categorized accord ing to the following criteria: 1. Symptoms of hepatic enlargement. These were measured by the relation of t We wish to thank Prof. Dr. C. Winkler, Direktor des Institute ftlr Klinische und Experimentelle Nuklearmedizin an der Universitat Bonn, for permission to use results of scintip"ohic examinations carried out at his institute. Marsteller et al.: Splenomegalic Liver Disease 115 2 3 ? 3 3 0 li Figure 3. Granular appearance of liver surface (conspicuous scattering of light reflection), pronounced coarsely reticular fibrosis of Glisson's capsule, patchy cicatricial fibrosis, distinctly increased capsular vessels. At left upper comer site of guided liver biopsy can be seen. (Case no. 41; length of exposure, 2'A years.) lower edge of right hepatic lobe to costal margin and a rounding-off of the normally sharp edge. 2. Changes in hepatic surface relief. Hepatic surface relief is normally smooth and glossy with well-defined lobular configuration, mirror-like capsule, and sharply defined light reflection; slightly uneven (irregular) or undulated ap pearance due to shallow concavities in connection with slight initial cicatriza tion; granular (Figure 3) appearance as initial stage of distortion of hepatic lobular architecture, characterized and recognizable by scatter' of light 116 Annals New York Academy of Sciences Marsteller et al.: S})lenomegalic Liver Disease 117 23733012 Figure 4. a. Finely nodular surface of the liver. Close-up view of lower edge of left lobe. (Case no. 4; length of exposure, YlVi years.) b. Finely nodular appearance of underside of right hepatic lobe with stellate capsular fibrosis and small scars in a worker engaged in processing the polymer. (Case no. 48; duration of job assignment, 4!/2 years.) Figure 5. Coarsely nodular hepatic surface resembling advanced cirrhosis; left lobe. Histologically there was, however, only septal fibrosis and collagenization of sinusoidal walls. No evidence of portal hypertension. (Case no. 42; length of exposure, ls/< years.) reflection, proceeding through finely nodular (Figure 4) to eventually coarsely nodular surface relief (Figure 5). 3. Presence of different degrees of local or diffuse hepatic capsular fibrosis. The capsule is a very subtle indicator of pathologic processes taking place in the underlying tissue.*" Capsular fibrosis (Figure 6) was usually irregularly dis tributed but mostly less pronounced toward the convexity; in its mildest form it was characterized by a strand-like or membranous opacity. In some cases we noticed a peculiar comma-like or stellate fibrosis (Figure 7), probably corresponding to a delicate scarring process in the underlying hepatic tissue. A more pronounced lesion seemed to be the development of a thinly or coarsely outlined more or less elevated network of thickened capsular con nective tissue covering the surface (Figure 8). In other cases there were several or numerous small scar-like lenticular patches (Figure 9) or broader slightly concave cicatricial lesions probably indicating postnecrotic scarring. In 4 cases focal whitish capsular thickening resembled what is known as focal "perihepatitis cartilaginea" (Figure 10). 4. Appearance of capsular vessels. Capsular vessels are normally not visible; pathologically, they may be slightly augmented or conspicuously increased (Figure 11) as an indication of underlying inflammatory processes of various activity. 5. Symptoms of splenic enlargement and perisplenitis. Visualization of the spleen by peritoneoscopy is not always possible, even after extreme tilting of the table because the organ may be covered by adipose greater omentum; in this case an effort to bare the lower pole by inserting a palpation pr :s some- 23733013 COMMA - LIKE FIBROSIS STELLATE FIBROSIS IRREGULARLY RETICULATED FIBROSIS COARSELY RETICULATED TO PATCHY CICATRICIAL FIBROSIS Figure 6. Types of capsular fibrosis of the liver observed in PVC workers. Figure 7. Typical comma-like capsular fibrosis on convexity of left hepatic lobe near falciform ligament (top center); in contrast to finely nodular lower anterior edge (see Figure 4a) of left lobe, surface on convexity is comparatively smooth. (Case no. 4; length of exposure 17'/i years.) 118 Marsteller et al.: Splenomegalic Liver Disease 121 73 3 ()U Figure 10. Coarsely reticulated fibrosis and patchy focal whitish capsular thick ening (focal "perihepatitis cartilaginea"), resembling capsular alterations seen in thorotrastosis of the liver." (Case no. 6; length of exposure, 16 years.) Figure 11. Particularly pronounced increase of capsular vessels in case no. 14 (length of exposure, 11 years) with finely to coarsely nodular surface. The case was fo- -]y diagnosed as "noncirrhotic portal fibrosis and portal hypertension of unknown et /." Close-up view shot with a special magnifying peritoneoscope (Courtesy of Dr. ,ienning;see text.) 120 Figure 12. Crenate margin of enlarged spleen; lentil-shaped thick milk-white perisplenitic fibrosis and millet-sized subcapsular hemorrhages. (Case no. 5; length of ex posure, 17 years.) times successful. For assessing the spleen size, the relation of the inferior pole of the spleen to the left costal margin and to the phrenocolic ligament as well as the inspection of the crenate margin are useful. Minor degrees of splenic enlargement cannot be recognized by peritoneoscopy. In marked spleno megaly the crenate margin is deeply indented. The splenic capsule seems to be equally sensitive to processes going on in the underlying tissue as is Glisson's capsule of the liver. In a number of cases minor degrees of perisplenitis were present in the form of pinhead-sized to somewhat larger lentil-sized sharply delineated white capsular plaques (Figure 12); only rarely were there patches of thick white coating resembling focal "perisplenitis cartilaginea." It is note worthy that patchy perisplenitis was found only in connection with more or less marked splenomegaly. 6. Symptoms of portal hypertension. Quite early in the development of a col lateral circulation due to portal hypertension a marked dilatation and later a tortuosity of preformed peritoneal venous vessels can be detected in the falciform ligament, on the anterior stomach wall, on the small and large in testine, and especially accompanying intra-abdominal adhesions. Minimal amounts of ascites can be observed to accumulate between the right hepatic lobe and the abdominal wall if the table is tilted accordingly. All the lesions described above are nonspecific alterations not suggestive of a distinct etiology. Changes in hepatic surface relief, degree of capsular fibrosis, and appearance 122 Annals New York Academy of Sciences Table 13 Hepatic Surface Alterations Observed on Peritoneoscopy (n -- 47) or at Laparotomy (n -- 2) Alterations No. Surface relief A. Smooth B. Slightly irregular or undulated C. Granular to finely nodular D. Coarsely nodular Capsular fibrosis (irregularly distributed) A. None Predominantly: B. Comma-like or stellate C. Finely to coarsely reticular D. Small scar-like patches to broader concave postnecrotic scars E. Patchy "perihepatitis cartilaginea" Capsular vessels A. None (normal) B. Slightly augmented C. Conspicuously increased 24/49 7/49 13/49 25/49 5/49 6/46 3/46 20/46 14/46 40/46 3/46 23/46 18/46 5/46) 23/46 of capsular vessels on the liver surface were recorded and graded on a severity scale. Table 13 shows that in about half of the cases the surface relief of the liver was altered ranging in degree from slightly uneven to coarsely nodular, the macroscopic appearance of the liver being suggestive of advanced cirrhosis in 2 cases (see Figure 5). Similarly, capsular vessels were considered to be slightly to conspicuously increased in half of the total cases. The most consistently posi tive feature of gross pathology was capsular fibrosis. It was unevenly distributed, sometimes more pronounced on the left lobe than on the right one, and in the majority of positive cases it was present in the form of a more or less con spicuous reticulated capsular thickening. In cases with massive patchy perihepatitis the picture was reminiscent of hepatic "thorotrastosis" (see Figure 10).m The proportion of peritoneoscopically determined enlargement of liver and spleen can be seen from Table 14. Pro nounced symptoms of portal hypertension were observed in 7 cases. A small amount of ascites was found in only 1 case. In contrast to gross morphology, however, histologic lesions observed in liver biopsy material were far less pronounced than might have been expected from peritoneoscopic appearance, and this also applies to the cases which laparoscopically resembled advanced cirrhosis of the liver. In essence, four histopathologic features could be observed (Table 15): a. Degenerative alterations of hepatocytes, occasionally accompanied by phe nomena of cytoplasmic adaptation. b. Slight fibrosis and collagenization of sinusoidal walls. c. Polymorphism and polyploidy of liver cell nuclei. d. Activation and proliferation of littoral cells lining sinusoids. Degenerative alterations of liver cells, manifest within relatively sharply de fined intralobular areas (Figure 13), were predominantly characterized by hy dropic swelling and granularity of cytoplasm, with occasional single cell necrosis, and were present, to some degree, in all the cases examined. In some cases adaptive changes manifested themselves as "ground glass appearance" of cyto- 23733015 Table 14 Hepatosplenomeoaly and Symptoms of Portal Hypertension on Peritoneoscopy or at Laparotomy_____________________________________________ Symptoms of Hepttomeftly (n 49) Splenomegaly 0* - 36) PorUl Hy(pner-ten4s9)ion None 31/49 Present 18/49 None Present Spleen not vis- ualized* 13/36 23/36 13/49 None Questionable Marked 40/49 2/49 7/49 ' In 13 cases the spleen could not be visualized during peritoneoscopy even after ,. . _ . _ i___;____Ln nnn pfnGU!> r"ll P AtTlPfltSl 131. Table 15 Synopsis of Pertinent Histologic Features in 49 Patients `SfiESftuP EpJE"`onno/0r Septal Fibrosis Fatty Ch.n. None Present in 10 39 1 48 34 15 26 23 Grading Minimal Slight Moderate Marked 7 32 -- -- 25 20 1 5 8 14 13 Figure 13. Degenerative changes of hepatocytes with hydropic swelling and granu larity of cytoplasm. Occasional single cell necrosis. Note proliferation and pleomorphism of littoral cells (Case no. 14; length of exposure, 11 years; biopsy several days after last exposure). H&E (X235). 123 124 Armais New York Academy of Sciences Marsteller et al.: Splenomegalic Liver Disease 125 Figure 14. Micronodular appearance due to septal fibrosis with characteristic hydropic swelling of parenchymal cells (Case no. 5; length of exposure, 17 years; biopsy 2 weeks after last exposure). Trichrome Goldner stain (X94). plasm. Fibrosis, observed in somewhat less than one-third of the cases, was partly septal, partly portal, and partly midzonal; in 80 percent of the cases there was collagenization of sinusoidal walls, occasionally forming a network-like intralobular fibrosis (Figure 14). Polymorphism of liver cell nuclei was char acterized by enlargement and polyploidy of nuclei. The total number of bi- or multinucleated cells, however, did not seem to be increased. A rather character istic feature was an activation and proliferation of sinusoidal cells. There was a definite increase in the number of littoral cells; they were occasionally arranged in a chain-like fashion and often resembled short pegs. In 6 patients, a bizarre nuclear shape was observed with enlargement and hyperchromatism (poly ploidy?), interpreted as a symptom of pronounced cytologic deviation (Figure 15). Less than half of the cases had predominantly minimal to slight fatty in filtration of hepatocytes, not correlated to either length of exposure or drinking habits. More detailed information on special features of histology may be found in Dr. Gedigk's paper. Discussion Our synopsis of prior studies published between 1933 and 1973 (Table 4) in cludes a total number of about 12,500 workers employed in VC polymerization and PVC processing. However, considering the relatively high standards of oc cupational hygiene in modern chemical industry,,,,,'0',',,, the true number of workers examined routinely by plant physicians can be assumed to have been much higher. Seen against this background and the fact that large-scale produc tion of PVC has now been going on for 45 years, the number of reported cases with (mostly ill defined) liver disease seems to be surprisingly small. Other mani Figure 15. Toxic and adaptive changes of parenchyma. Conspicuous pleomorphism of littoral cells (Case no. 3; length of exposure, 18 years; biopsy 2 weeks after last exposure). H&E (X400). festations associated with VC polymerization had been seen more frequently (acroosteolysis in 118, Raynaud's syndrome in 97, skin lesions in 40 of more than 12,000 workers). They evoked particular interest mainly between 1966 and 1971 and were thought to be restricted to avoidable manual cleaning of re- actoTrsh.uJ1s-,,Mwhen we first observed evidence of liver disease of possibly occupa tional etiology in the workers examined, we suspected plant standards to have been particularly poor, considering that liver disease was so rarely mentioned in prior publications. Intimations made by workers seemed to confirm this assump tion (distinct odor of VC vapors at diverse working areas even outside the loca tion of reactors, deteriorating quality of ventilation after windows had been walled up, frequent symptoms of acute overexposure, and mainly manual reactor cleaning). However, with a growing number of workers examined it became evident that we dealt with a disease presenting with a multisided but TM-edomi- I 126 Annals New York Academy of Sciences nantly inconspicuous symptomatology (for instance, minor hepatic functional in sufficiency"'1) which, with reference to liver and spleen, even in advanced stages would be liable to escape detection if only conventional methods of examinations were employed. Therefore, statements given out by other plants that liver and spleen changes had never been observed should be met with scepticism unless proven by morphologic methods. The dramatic discovery of cases of hemangioendotheliosarcoma of the liver in PVC worker* throughout the world early in 1974 has shown that this is cer tainly not merely the problem of a specific plant. None of the clinical or morphologic findings seemed to be mutually cor related nor did we find a recognizable correlation between a certain set of symp toms and length of exposure or alcohol consumption. The clustering of patho logic findings (liver, spleen, portal circulation) in this group now comprising 50 workers confirmed our previous impression" that we dealt with a symptomatology compatible with the diagnosis of chronic toxic liver damage,"-" " similar to that seen after repeated or continuous exposure to halogenated hydrocarbons. The histomorphologic appearance of the liver was essentially characterized by de generative lesions (frequently observed in chronic toxic liver injury; hyperplastic smooth endoplasmic reticulum, alterations of rough endoplasmic reticulum due to toxic derangement of membrane structures"'1"-1"), fibrosis (septal fibrosis or collagenization of sinusoidal walls with occasional capillarization and finally network-like interstitial fibrosis), and enlargement or proliferation of littoral cells. Whereas the mostly unimpressive histologic findings permitted reflections as to possible etiology," ,'-"-1"1" peritoneoscopic results, although usually much more suggestive of serious liver damage, could only be interpreted as unspecific evidence of injury; for instance, even pronounced capsular fibrosis merely indi cates a repair stage of underlying tissue damage due to a variety of noxious agents.1'- " *" Although granular to nodular surface relief in a number of cases suggested incipient derangement of lobular architecture, a final diagnosis of cirrhosis of the liver could be made only in two cases. Thus, the pathogenesis of portal hypertension with splenomegaly or of isolated splenomegaly at first re mained unexplained, especially since no recognizable correlation seemed to exist between degree of hepatic lesions and degree of splenomegaly or of portosys temic collateral circulation. Liver disease in PVC workers reminds one of non cirrhotic poTtal fibrosis, predominantly seen in India,"1*'1"-"'-1,` or of so-called idiopathic portal hypertension,respectively. In this disease en tity, portal hypertension and splenomegaly are usually accompanied by similar alterations of hepatic surface and histology;1'-1'"11*1"'1"1"1" in some cases, however, portal hypertension seemed to have been the result of sclerosis or thrombosis of the portal vein.1,"-" '' Another analogy between liver disease as sociated with PVC production and noncirrhotic portal fibrosis/hypertension can be seen in the frequently observed combination of a pronounced pathologic BSP retention with other laboratory parameters being normal or only slightly aberrant;,`-,' " BSP retention, however, can be readily explained by the character of the histologic lesions." A certain resemblance to Banti's syndrome is sug gested.1"-1" It should also be realized that the degree of fibrosis in our cases was most probably underrated on microscopy since surgical biopsy material, more suited for detection of fibrosis,'" was not available. On the other hand, one should keep in mind that even the rather unimpressive alterations observed histolr -lly (periportal and sinusoidal fibrosis, capillarization of sinusoids, degen Marsteller et al.: Splenomegalic Liver Disease 127 erative cellular lesions) may be sufficient to explain an increase in portal pres- sureIla **' *T' " 10*~1U* Ui* m* m* 14S In this connection, particular attention should be paid to the enlargement and proliferation of littoral cells, as described above, because of their relation to fibrogenesis.n-1'*'1"1,'1*1'1" Besides, proliferation of littoral cells is of diagnostic significance, indicating that the reticuloendothelial system is involved and ac tively participates in the process (a possibly additional pathogenetic factor in splenomegaly?). In this context, recent reports on oncogenic properties of vinyl chloride"'"1" should be evaluated since proliferative alterations of littoral cells are possibly the precursor stage of hemangioendotheliosarcoma. If one looks for a pattern of injury similar to that seen in VC-associated hepatic hemangioendo theliosarcoma, gross morphology, histologic appearance1- " " " " " " *" lu and conjectural course of events in the pathogenesis of hemangioendo theliosarcoma occurring after exposure to Thorotrast or arsenic can perhaps serve as an example. It could be speculated that chronic stimulation of the reticuloendothelial system (possibly also of hepatocytes"1) by a toxic substanceTM may be the common denominator. This leads back to the question of etiology." Quantitatively vinyl chloride monomer is the most likely suspect in VC-associated liver disease. Numerous hints (such as odor and acute symptoms of overexposure) contained in job histories point to the frequent release of considerable concentrations of VC at various working areas in VC polymerization,'1-'7"" even if one considers the un reliability of olfactory sensations"' " and the wide range of olfactory thresh old concentrations reported in the literature.1'- " " " 1M Except for Schumann's communication in 1934,'" quoted by WilliamsTM in 1959, very little is known about the kinetics and metabolism of vinyl chlo ride.**"-1" Nevertheless, considering the chemical structure of VC and the course of events in polymerization, it can be speculated that free radical mechanisms (monomer, catalysts) may be responsible for damage to cell membranes and subcellular structures (endoplasmic reticulum, "drug-hydroxylating enzyme sys tems"1"), for example, by way of "lipid peroxidation." "-1"-1'1 Furthermore, for mation of free radicals may also be involved in the oncogenic action of vinyl chloride.TM Regardless of such deliberations, results of animal experiments with long-term exposure to pure VC have demonstrated considerable hepatosplenic injury"1" apart from tumorigenesis and damage to other organs."1TM From these results it appears quite probable that the pattern of damage observed can be attributed to the effect of VC itself. It is, however, not established" whether and if so how far various additives*1 or intermediate compounds'1 contribute to the symptom pattern in human vinyl chloride disease. Some comment should be made on the question of a potential health hazard for those engaged in processing the polymer to the final product. This question is even more difficult to answer and in practice of even greater importance. Detection of analogous if less pronounced lesions in some workers engaged in the manufacture of floor tiles should be reason enough also to pursue the ques tion of possible VC-induced damage in these later stages of production. This is also suggested by the fact that VC trapped in the polymer can principally be liberated"-*'-1'' during processing (e.g., calendering, moulding, extrusion, etc.) at temperatures of 100-200*C.B- TM At the moment, it is also open to discussion whether PVC dust, apart from damage to the respiratory tract,""1" may cause gastrointestinal symptoms," for instance, by persorption.1" 2373301 128 Annals New York Academy of Sciences In the future, periodic control examinations of all PVC workers, especially of those engaged in VC polymerization, at short intervals employing sensitive methods should be obligatory unless it should prove feasible to eliminate com pletely any possible air contamination. 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Health 4: 125. Discussion Dr. H. Buchter (University of Cologne, Germany): It would seem better for statistical investigations on the reported liver function tests if you could compare the results with similar tests done before the workers came into vinyl chloride manufacturing. Second, in one of the two plants in Germany with incidence of vinyl chloride disease, there is much alcohol intake in the workers. Until now no liver damage has been found. Third, in regard to low lung-function tests, we have not confirmed a pathological diagnosis at all. There should be more discussion about the cause of this disease, i.e., whether it is vinyl chloride alone or another agent which may get together with technical vinyl chloride, or vinyl acetate or additives. This may be important in the causation of angiosarcoma. Last, it has been suggested that liver biopsy be done only after peritoneoscopy because of the risk of bleeding. Dr. M. L. Newhouse: May I ask Dr. Ielbach how he selected his patients and how big was the exposed group he selected them from? Dr. W. K. Lelbach (University of Bonn, Germany): I will begin with the answer to the second part of the question. The whole group is, as far as we know, about 180 workers in this plant. We were alerted in December 1972 by Dr. Veltman's group that patients being examined for skin and bone disease also had signs of liver disease. We examined these patients. Later we examined all patients we could bring to the clinic. It is, of course, a selected group and does not permit us to draw conclusions as to percentages. B. Experimental Studies PRELIMINARY STUDIES OF THE FATE OF INHALED VINYL CHLORIDE MONOMER IN RATS* R. E. Hefner, Jr., P. G. Watanabe, and P. J. Gehring Dow Chemical V.S.A. Health and Environmental Research Midland, Michigan 48640 Introduction Vinyl chloride monomer (VCM), extensively used for the production of poly vinyl chloride and other plastics, has been associated with the development of angiosarcoma and portal cirrhosis of the liver as well as other untoward effects in workers exposed to unknown but undoubtedly high concentrations of VCM. Angiosarcomas, zymbal gland carcinomas, and nephroblastomas developed in rats exposed to concentrations of VCM ranging from 50-10,000 ppm, 4 h/day, 5 days/week for 12 months, and subsequently maintained and observed until death.1 No information is available on the fate of VCM in the mammalian organism at the present time. Such information is essential for elucidating the toxicodynamics of VCM and providing a rationale to assess the potential hazard of exposure to low levels of VCM. Results of preliminary studies on the fate of VCM in rats exposed via inhalation are reported herein. Prior to undertaking these studies we conceived the idea that VCM might be metabolized via the alcohol dehydrogenase pathway, and if so, this pathway would very likely be saturable, and that con jugation of VCM or its metabolites with glutathione and cysteine might be ex pected. Therefore, much of the work conducted to date has been directed at evaluating these possibilities. Methods Kinetic Studies of the Uptake (Metabolism) of Inhaled Vinyl Chloride Monomer Male Sprague-Dawley albino rats of Spartan strain weighing from 165-200 g were exposed to initial concentrations of VCM gas ranging from 50.5-1167.0 ppm (0.13-2.99 mg/liter). Exposures ranged from 52.5-356.3 min. Figure 1 depicts the closed, recirculating 4.7-liter inhalation apparatus in which a group of 4 rats were concurrently exposed. To minimize contamination of fur and skin, only the nares of the rats protruded through a rubber membrane into the cham ber. Expired carbon dioxide was continuously removed from the chamber by absorption on an Ascarite column in the recirculating system. As carbon dioxide was removed from the system, the pressure drop was detected by a mercury manometer fitted with a photoelectric cell. This activated a solenoid valve and dual syringe pump to inject makeup oxygen into the system. The chamber atmosphere was continuously analyzed for VCM (10.9 p.) by an in-line Miran-I infrared analyzer (Wilks). With known concentrations of VCM * These studies were supported in part by a grant from the Manufacturing Chemists Association. 135