Document v1e4bxM6dZro2vEnaK5gXnqVZ

UNUSUAL SPLENOMEGALIC LIVER DISEASE AS EVIDENCED BY PERITONEOSCOPY AND GUIDED LIVER BIOPSY AMONG POLYVINYL CHLORIDE " 'PRODUCTION WORKERS *. . H. J. MarsteUer and W. K. Lelbach Medizinhche Univ'ersitdtsklinik 1 J>-53 Bona, Federal Republic of Germany - .. R. Muller and P. Gedigk Pathologisches lnstitut der Universitdt 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 (KJatte and Zacharias, 1912)TM 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). *1 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).u* 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.*1*1 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).3 ', II W1 Under 95 96 Annals New York Academy of Sciences Table 1 World Production of Plastics in Million Tons per Year4* Year Million Tons. 1930 1950 1960 . - 1970 <0.1 1.5 6.9 30.0 **' Table 2 World Production and Production Capacity for PVC Resins (Million Tons)17 "-*5 Western Europe Western Germany United States Japan Eastern Europe Other areas Total Production 1950 . . 1960 1972 0.053 0.014 0.578 0.173 2.948 0.930 1.950 1.088 0.861 0.544 7.391 Annual Capacity - 1960 1972* 1975* 0.583 0.195 0.610 0.270 Not stated 0.152 1.615 3.583 1.995 1.587 0.816 0.816 8.797 3.175 * Estimated capacities. Table 3 Diversification of PVC Markets114 - PVC Market Consumption (%) 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 * 18 14 12 10 6 5 5 5 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.101 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 j 1 4 j i r > Marste amounts of acid (free stabilizers.'" Avoiding tion."'101 Liquid VC is ride'is used mainly fc stance, as a propellan chemical reactions.TM Four methods of vinyl chloride: emuls Commercially most ii pension pp^^-riVatic emulsion zat percent, a ion PVC resi go ced complish* (/j :om turns,* e.f sole sium per q r en as lauro) 4s. nzot ate.4' * - g on c peroxide to , (--( polymer i the bond) r< n fret unpairec/on oi the 7t-electrons of the the VC monomer itse chain of molecules wi saturation of fhe tem growing chains,*- " " for the production of polymerization with i value. One of the opei is temperature" which vapor pressure. Ordin 40-70C and total rea In emulsion polyi with the watery phase heated. At terminate emptied into a dump i drying. The dry polym erization water-solubl stabilization .of the sus similar. Unreacted mi cycling.*-*" Suspensio less than 1 percent ar compounding, the pot pressure using plastic bricants, and pigments at fusing temperatures lies below or within th of endless sheets) tem, for flexible PVC are n calendered sheets in a Marsteller et al.\ Splenomegalic Liver Disease 97 R&S 104950 amounts of acid (free HC1), acetaldehyde, iron, acetylene, butadiene, water, and stabilizers.TM Avoiding impurities is a prerequisite since they retard polymeriza- tion."-101 Liquid VC is stored and transported in steel containers.' "101 Vinyl chlo ride is used mainly for polymerization, but it is also used as a refrigerating sub stance, as a propellant for sprajrs and aerosols, and for a small number of other chemical reactions.TM .... Four methods of polymerization are used for industrial fabrication of poly vinyl'chloride' emulsion, suspension, bulk,'and Solvent polymerization.1'''51'4'" Cbmmercially 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 isopropylpercarbon- ate.4, * " Formation of free radicals also occurs by thermal decomposition of peroxide bonding (--O--O--)." Physical basis for initiation of free radical chain- polymerization is the homolytic dissociation of a pair of --electrons (covalent bond) resulting in free radicals that contain single unpaired electrons. The single unpaired 7r-electron of the free radical obtained from the catalyst then reacts with the r-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.4'44'" " 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 40-70C 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 re cycling.4""'"" 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.4 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 (120-160C). In calendering (production of endless sheets) temperatures of 100-120C for rigid PVC and of 150-180C 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 by extrusion J 98 Annals New York Academy of Sciences (profiles, pipes, conduit, ribbons) temperatures of 150-300C can be reached. All this shows that temperature ranges, as a rule, from 100-200C in converting the thermoplastic PVC resin by various procedures.43-"*-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","I,"I,,i" and problems of occupational health1" were investigated. At first, vinyl chloride appeared to be a suitable .narcotic which, even after Oster-inJ947u*1 and Carr in 1949s had observed severe cardiac arrhythmia (believed to be due to potentiation of adrenaline effect70), was ` considered lb be one dfithe least dangerous chlorinated hydrocarbons."1,'l M'"'l:i" . With the exception of two communications concerning acute VC intoxication without serious consequence in 2 workers4" 47 no other data on occupational health hazards in PVC production were reported until 1949 when Tribukh et al,TM pub 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 1j60*C 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,40 Parmeggiani,103 and Hervieux and Tessier" between 1953 and 1959. Acute intoxication was again reported, this time in Great Britain, with acute collapse during VC polymerization*1 and a second degree burn after direct contact with vinyl chloride." Filatova et al.*'** 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*7 described 3 cases of acute VC intoxication oc curring in VC polymerization, 2 of them fatal. Suciu et al.u'ui 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. Pushin'7'1 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 I i $ .7 % i i Mar "epithelial" hepatit erization, compoui ticizers (phthalates describe acroosteo symptomatology in cases were reporte richon," Wilson e. tions the disease 1 roentgenologic fine panied rarely by sc . iffreactor clea'hing lescu et fl/.,7.Filato a large-scale epider observed further c VC polymerization any health hazard 1 Sjng|e de et al.** in 1973 as v and by Danishevsk on this concept, e; solute harmlessnes minimal risk attrib Animal expertt the assessment of ; presented results o repeated on a larg been underrated, it experiments of M; deal essentially witl preceded by the e> suits published by Advisory Commit! (in operation since gists at Bonn Univi tional acroosteolys sions." They founi more complex than "vinyl chloride dise It seems quite liver damage was < and that no intern chloride toxicity h; det-'-rinn of life-thr he tormalit str 'ith gro de it of po ar (/) :ognizec O 4s 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.,1* Bour- richon," Wilson et pi.,1" anfi Harris Adams." With this- clustering .of publica tions the disease became known as "occupational acroosteolysis" with typical roentgenologic findings?'often Combined with Raynaild's ^yndrorife ind- accom panied rarely by scleroderma-like skin lesions; the disease seemed-to occur only in reactor cleaning ("polycleanets' disease")." " Between 1969 and 1972, Anghe- lescu et al.,' Filatova and Antonyuzhenko " Dinman et al.,a, o a (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" " *1-**-1""1"). Single deviant observations made in 1970 by McCord" 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,*"" apart from the minimal risk attributed to VC inhalation"- * " " " 1M- "" (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.i:iisa However, re sults published by Torkelson et at."1 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." 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." " ... Livfli 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. Annals New York Academy of Sciences TaEle 4 Clinical Manifestations and Fatalities among Workers in Vinyl Chloride Polymerization (PM) . and Polyvinyl Chloride Processing (PC) (Review of Literature) ;1 Author No. of Workers PM PC Rarr"- Skin ** Phenomenon Lesions Liver ; Disturbances I Acute Intoxication (Fatalities)' Dublin and Vane (1933,1941) Tribukh et al. (1949) Chief Inspector of Factories (1953) Harris (1953) Devignevielie and Flucher (1953) Parmeggiani and Sassi (1955) Filatova et al. (1957, 195?) Hervieux and Tessier (1959) Danziger (I960) Suciu et at. (1963, 1967) Filatova el at. (1965) Pushin (1965) Cordier ef al. (1966) Chatelain and Motillon (1967) Marin et al. (1967) Spain Italy Bourrichon Wilson et al. (1967) Harris and Adams (1967) Anghelescu et at. (1969) McCord (1970) Filatova and Antonyuzhenko (1971) Dinman et al. (1971) Kramer and Mutchler (1972) Lfiffevre (1972) Markowitz et al. (1972) Dugois et al. (1972) Misgeld et al. (1973) 73 -t 13 -t 145 168 163 350| 123 178 441 528 1 1 100 3,000 1,000 588 300 1 -t 3,754 1,257 98 780 2 1 1 2 5 5 1 1 5 31 2 2 1 "C ; 41 19 1 1 1 10 12 12 22 3 8 23 1 10 2 1 1 21 -*(?) -*(?) 51t 15%lf Slight intoxication Collapse Second-degree burn fatalities Ht 1 Fatality Slight** t.j J*., . jut#* ' ' ' ..",V - . .................4..-...t..s.v..i...'.n..v s.'ULaoW 41 - m -L? Total 10,056 2,582 118 97 40 73 . 5 Acute intoxications 86 + x . 3 Fatalities 12.724 --------- --- - - - .=^. = es6m ssu * --, number of abnormal findings not stated. ' t --i number of wdrkers not stated. j Liver biopsy in 2 cases--diagnosis "chronic hepatitissplenomegaly in hi cases. 350 workers employed in the Swcrdlovsk plastics factory, number of PVC workers contained therein not stated. If Liver disturbances in 6.57 percent (2Viv>i of ivi chemical plant workers, in 15 percent of PVC workers. . * 2 5 i Total 10,056 2 86 + jc 12.724 5 Acute intoxications 3 Fatalities * --, number of abnormal findings not stated, f--; number of workers not stated. t Liver biopsy in 2 cases--diagnosis "chronic hepatitis;" splenomegaly in 10 cases. 5 350 workers employed in the Swerdlovsk plastics factory, number of PVC workers contained therein not- stated. 1[ Liver disturbances in 6,57 percent (23/350) of 350 chemical plant workers, in 15 percent of PVC workers.- |] Palpable liver and persistently raised serum bilirubin. ** "Some changes in liver function," with statistically significant correlation of BSP retention and exposure, Marsteller et ah: Splenomegalic Liver Disease New Y ork Academy of Sciences Table 5 ! ________ Vinyl Chloride Exposure in Laboratory Animals--Acute Toxicity (Review of Literature) Author Species* Concentration (ppm) Length of Exposure Effect . Pathology Patty et al. (1930) Schaumann (1934) Schaumann (1938) Peoples and Leake (1933) Oster et al. (1947) Carr et al. (1949) 8t Starling heartlung preparam + r{ df mf d + rbf 200,000-400,000 "Very short time" 100,000 3,000 30-60 min Several h 250,000-300,000 ? Slight nar 4 h/5-8 id; 1 h/ cosis d/4 wk 100,000 3 h/7 d during 3 wk 245,000-285,000 10 min 85,000-125,000 10 min 170,000 ? . .d (6) d (7) 100,000 (narcosis) ? (narcosis) ? ? Fatal (lethal range) "Dangerous to life" No severe acute dis turbances No cardiac failure Narcosis Narcosis Fatal (lethal range) Minimal anesthetic range Narcosis Serious cardiac arrhyth mias Narcosis: sensitiza tion of myocardium Lung: edema Liver:.hyperemia Kidney: hyperemia Liver and kidney: no . changes Liver and kidney: no con siderable changes "No apparent untoward .effects even after pro longed anesthetization" W E7T Mn?tr,`2!!12.t,,co el al. (1960) Tn (5) r (5) g (5) m (5) r (5) 100,000 200,000 30 min 30 min ***** i Deep narcosis-r-side position with tremors Deep narcosis (1 mints'- rtritr^ Fatal outcome: Lung: .vascular engorge .ment with hemorrhage and edema Liver: congestion, nn f'i - is t..\ SS6t?0t S9H Mastromatteo et al. (1960) Lester et al. (1963) m (5) r (5) g (5) m (5) r (5) : g (5) m (5) r (5) g (5) g (5). ' 100,000 200,000 300,000 400,000 rt r (2) ' 50.000 70.000 100,000 150.000 30 min 30 min 30 min 30 min Deep narcosis--side position with tremors Deep narcosis (1 mouse dead) Dead; g in deep narco sis, 1 died hours after exposure Deep narcosis, 1 died during, 1 after ex posure Moderate intoxication Righting reflex lost Corneal reflex disap peared Deep narcosis, 1 rat died of respiratory failure Fatal outcome.* Lung; vascular engorge ment with hemorrhages and edema Liver: congestion, partly fatty infiltration (g) Kidney: congestion Clotting defect Survivors: * "Little difference from control animals (liver, kidney, spleen, brain, heart, adrenals, lymph nodes, eyes) except lor pulmonary congestion" "No visible gross pathol ogy" Lung: congestion/edema * Abbreviations used: r, rats; g, guinea pigs; rb, rabbits; d, dogs; m, mice. Number of animals stated is given in parentheses, t Number of animals not stated. 9g6V0V . . Table 6 Vinyl Chloride Exposure in Laboratory Animals--Chronic Toxicity (Review of Literature) Author Species* Concentration (ppm) Length of Exposure Response Pathology Torkelson el al. (1961) Lester el al. (1963) r (20) r (24) g (9) rb (3) d (1). 500 7 h/d, 5 d/wk for 4.5 mo Normal growth 200 '7 h/d, 138-144. Normal in appearance, times in 204 d mortality, and growth r (5) ' 200 4 h/d r (5) 2 h/d for 6 mo r (5) 1 and 0.5 h/d for r (S) 6 mo 100 (same procedure as in 200 ppm) Normal in appearance, mortality, and growth "Entirety normal" Normal in appearance,' mortality, and growth r (48) * g (24) . rb (6) d (2) r (18) 50 100,000 80,000 7 h/d, 130 times , Normal in appearance, in 189 d mortality, and growth 8 h/d for 2 d 8 h/d for 13 d Narcosis, 10 rats died,* initial loss of weight, followed by normal growth ("tolerance to the gas") r (10) 50,000 8 h/d for 19 d Initial loss of weight, followed by normal growth ("tolerance to the gas") Liver: average weight increase, certtrolobular granular degeneration Kidney: interstitial and tubular changes Liver: microscopically normal in rats, guinea fcigs, and dogs; centrolobular granular degeneration in rabbits (together with necrosis and some foamy vacuolatton in male and necrosis with periportal cellular infiltration in female); weight increase of rat livers Liver: average weight increase Liver: slight increase of average weight in rats after exposure 7 h/d, 138-144 times in 204 d either 4 or 2 h/d for 6 mb Normal Lung: acute focal necrotizing pneumonia, edema', metaplasia Liver: parasitic cysts, moderate to marked swelling of cells, definite fine to medium or large irregular vacuoles, compression of sinusoids Spleen: lymphocytic hyperplasia in cluding mcrSt of the interstitium Liver: parasitic cysts, marked-swell ing of cells, large irregular vacuoles or clear spaces, compression of sinusoids, changes focal to diffuse- Annals New Y ork Academy of Sciences *&/***< r (30) 20,000 Z96HH S9U in appearance Spleen/kidney: no differences be tween contrpl and experimental animals Liver: parasitic cysts, moderate to marked swelling of cells, definite fine to' mediufci or large irregular vacuoles, compression of sinusoids Spleen: no differences between con trol an.d experimental animals - 2 'v' ' ' / ; Table 5 Vinyl Chloride Exposure in Laboratory Animals--Acute Toxicity (Review op Literature) Author Species* Concentration (ppm) Length al Exposure Effect Pathology Patty et al. (1930) Schaumann (1934) Schaumann (1938) Peoples and Leake (1933) f Oster ef al. (1947) Carr et al. (1949) 8t 1 Starling heartlung prepara tion (cat)t tn + rf dt mt d -f.rbt 200,000-400,000 "Very short time" 100,000 5,000 30-60 min Several h 250,000-300,000 7 Slight nar- 4 h/5-8 d;1 h/ cosis d/4 wk 100,000 3 h/7 d during 3 wk 245,000-285,000 10 min 85,000-125,000 10 min 170,000 7 . d (6) d (7) 100,000 (narcosis) ? (narcosis) 7 7 Fatal (lethal range) "Dangerous to life" No severe acute dis turbances No cardiac failure Narcosis Narcosis Fatal (lethal range) Minimal anesthetic range Narcosis Serious cardiac arrhythmtas Narcosis: sensitiza tion of myocardium Lung: edema Liver: hyperemia Kidney: hyperemia Liver and kidney: no Changes Liver and kidney: no con siderable changes "No apparent untoward .effects even after pro longed anesthetization" * Mnstromattco et al. (I960) tn (5) t (5) g (5) m (5) T (5) 100,000 200,000 30 min , 30 min > Deep narcosis-^side position with tremors Deep narcosis (1 mrms<* Hoad' Fatal outcome: Lung: .vascular engorge menf with hemorrhage and edema Linvnerrf:tticCotnHges,ti#on7. 1,f,.> ssem s?u Author . Table 6 Vinyl Chloride Exposure in Laboratory Animals--Chronic Toxicity (Review of Literature) Specie!* ' Cot"^trjl`oa Length of Exposure Response Pathology s- Annals New Y ork Academy of Sciences Torkelson et at. (1961) Lester et at. (1963) r (20) r (24) g (9) rb (3) d (1). 500 7 h/d, 5 d/wk for 4.5 mo Normal growth 200 7 h/d, 138-144. Normal in appearance, times in 204 d mortality, and growth r (5) ' 200 4 h/d r (5) 2 h/d for 6 mo r (5) 1 and 0.5 h/d for r (5) 6 mo 100 (same procedure as in 200 ppm) Normal in appearance, mortality, and growth "Entirely normal" Normal in appearance,1 mortality, and growth r (48) g (24) , rb (6) d (2) r (18) 50 100,000 80,000 7 h/d, 130 times . Normal in appearance, in 189 d mortality, and growth 8 h/d for 2 d 8 h/d for 13 d Narcosis, 10 rats died; initial loss of weight, followed by normal growth ("tolerance to the gas") r (10) 50,000 8 h/d for 19 d Initial loss of weight, followed by normal growth ("tolerance to the gas") Liver: average weight increase, centrolobular granular degeneration Kidney: interstitial and tubular changes Liver: microscopically normal in rats, guinea fugs, and dogs; centrolobular granular degeneration in rabbits (together with necrosis and some foamy vacuolation in male and necrosis with periportal cellular infiltration in female); weight increase of rat livers Liver: average weight increase Liver: slight increase of average weight in rats after exposure 7 h/d, 138-144 times in 204 d owf either 4 or 2 h/d for 6 mb Normal *. Lung: acute focal necrotizing pneu monia, edema', metaplasia Liver: parasitic cysts, moderate to marked swelling of cells, definite fine to medium or large irregular vacuoles, compression of sinusoids Spleen: lymphocytic hyperplasia in cluding mo$t of the interstitium Liver: parasitic, cysts, marked'Swell ing of cells, large irregular vacuoles or clear spaces, compression of sinusoids, changes focal to diffuse- ", Ct- -T. *-; 4--SPr'3-. fgji -** s - . ,i t ^ usyfry. r (30) 20,000 S6m 1 in appearance Spleen/kidney: no differences be tween control and experimental animals Liver: parasitic cysts, moderate to marked swelling of cells, definite fine to` mediufn or large irregular vacuoles, compression of sinusoids Spleen: no differences between con trol an.d experimental animals Viola (1970) r (30) r (25) I 20,000 30,000 S h/d, 5 d/vvk for 3 mo 4 h/d, 5 d/wk for 12 mo Normal in appearance Slightly soporific, nor mal in appearance and growth After 10 mo loss of weight 13 died from cardiores piratory complications, 2 from hematoperitoneum Spleen/kidney: ho differences be tween .control and experimental animals Liver i parasitic cysts, moderate to . marked swelling of cells, definite fine to medium or large irregular vacuoles, compression of sinusoids Spleen: no differences between con trol and,experimental animals Conclusions: '* 1. The only finding suggesting a specific toxic action of VC is the increase in liver weight on exposure to 50,000 ppm for 19 d and to 20,000 ppm over 92 d 2. Morpholpglcal alterations with out pathologic significance Liver: increased volume, smooth sur face, sometimes subicteric, some what more brittle consistency than normal '; Microscopically: Alteration vf hepatocytes with marked'cytoplasmic and nuclear polymorphism (torpid degenera tion o( the pytoplasm to necrosis) Proliferation and hypertrophy of Kupffer-ceifs Round- cell ' infiltration of portal tracts Blockade o/, portal capillaries, centrolobular veins and sinusoids by numerous centrally located areas of partial necrosis Intensive fibrosclerolic reaction along areas of degenerative proc esses . Fatty change.\ Kidney: signs of- tubulonephrosis sometimes accompanied by chronic interstitial nephritis Marsteller et air. Splenomegalic Liver Disease I 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 fibrotia changes may escape detection-if only blind biopsy is employed.45'13* -*1 - According to information furnished by the plant physician, a total of roughly 180*workers had in the past been exposed to vinyl chloride in thisplant, 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 21% 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!4, 4'/2, 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 of coses Figure 1. Age distribution of 50 PVC production workers (age at examination). Ta* Synopsis of Anamnestic, . Clinical, Biochemical, Pehit; Abbreviations used are: Nationality: Ger, German; Gr, Greek; Turk, Turkish;! Job Classification: PM, VC polymerization; PC, processing of the polymer; Perils neoscopy: U, slightly irregular or undulated; G, granular to finely nodular; Nod; u1 O'-i'iV.-.J-C. and HlSTCLOA ici.' :.tt -itches to brcadt - A, augment tr.;--ers:e; + ++ m- 1 PentAAs 5 A: * 1 . i* a JS. MV 5 3at Eg i "U Mc z| If 1 * j* '<u5 -I-.1 . b , |. Au JQ s3 & O' 1 Tfea y id & z 55 < *-> W <u & S V ISS id JP . r - JU 2i 26 (A ' tn i 75 -Si ' ' 6 8 id o' Js?' -1 e I . fa A t/5 n 8" </) (/) 1 Ger 2 3 Ger so PM .21/9 56 PM 47 PM 18/6 18 -- 16-32 -- + + + + + 4 Ger 5 Ger A Ger 7 Ger 46 PM 51 PM 51 PM 52 PM 8 Ger 9 Ger 10 Ger 11 Ger 12 Ger 13 Gr 14 Ger 13 Ger 16 Gr17 dr 18 Ger 53 PM 44 PM 39 PM 48 PM 27 PM 40 PM PC 52 PM 15 PM 45 PM 42 PM PC 54 PM 19 Ger 31 PM 20 Turk 33 PM 21 Gr 30 PM 22 Ger 34 PM 23 Gr 36 PM 24 Gr 30 PM 23 Gr 75 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 Ger 32 PM PC 34 Ger 40 PM 35 Gr 36 Gr 31 PM 38 PM 37 Gr 47 PM 38 Gr 30 PM 39 Turk 30 PM 40 Gr 33 PM 41 Gr 41 PM 42 Ger 41 PM 43 Gr 16 PM 44 Turk 33 PM PC 45 Gr 48 PC 46 Gr 47 Gr 48 Gr 44 PC 39 PC 45 PC 49 Gr 50 Ger 37 PC 36 PC 17/6 17 16 15/3 8 48-64 16 8 + + + + + 14/6 13/9 13/9 13 12/6 12/3 0/9 11 9 8/6 6/8 4/0 6/6 8 8 16 16-32 28 __ 16 16 8 16 5/9 5/9 5 5 5 5 4/9 4/9 4/9 4/0 1/0 4/03/9 16 8 8 16 16 8 16 16-32 8 -- 8 4 3/9 3/6 3/6 1/0 -3/6 ? -- 4 16 SJ 3/3 3/3 3/0 3/0 2/9 2/6 2/3 1/9 1/6 0/9 0/3 13/0 8-16 8-16 is(oU)0: 16 -- -- -- 18886 14 ++ + + + + ++ ++ ++ + + + -t- + + ++ ++ + 4* + ++ ++ + + ++ ++ + - > -+ ++ + + + ++ + 9/0 28 --5/3 16 4/6 ++ 4/0 44 2/0 32 ++ + Centimeters below costal margin, t For explanation see Table 11. j For explanation see text. 1.5 2 3. 2 5 3 1.5 1 2 (2) 1.5 1.5 3 (11) 1.5 2 11 3 2 1 10 (10) 1.5 1.5 6 1.5 3 1.5 6 63 1.5 l.S 1.5 3 64 1.5 3 3 1.5 11 1 3 7 6 -8 8.7 15 15(23) .3 1.1 1.2 2.0 1.1 1.1 1.1 6.1 15.6 13 19(24) 10.2 9.1 11.3 16.7 13(22) 15(47) 19 17 25 22 5.6 17.6 6.2 15 15 31 15 13 13 23 15 13 13.0 15.1 8.8 13.8 16 16 19 17(31) 13 13 25 (24) 23(63) 4 1 3 1 S IS ;< *3 j H 50 4 1.4 6.9 (20) (27) 5> (28) I 15 3 9.6 15 13 5 21.5 21(21) 23 (40) 7.6 25 -ri 1.8 90 190 -i 8.5 32(27) 30(40) 7.5 15 15(24) 8.3 15 L5 A 5 1.7 7.1 23 25 -r-jj 1.8 2.2 25.6 6.4 22.5 6.8 25 15 25 23 58 6J6p i17 34 17 12.5 19 16 J1.1 8.6 19(20) 15(31) r 5.2 9.7 8.4 m(20) JB13 15(24) `'JW} 13 17 13 6.1 19(22) 17(47) 6.3 17 5.1 28 30(23) 9.1 13(33) 13(80) <4 16 I 15.1 8.8 7.0 15 <20? (22) 17 (47) (88) (72) 28 (20) 28(38) a 3 id 4 ** 108 ; G/N<xt ls 7 oneoscopic, and Histologic Data of 50 PVC Workers scar-like patches td broader concave postnecrotic scars; PC, patchy "perihepatitis cartilaginea;" A, augmented; B, increased; Histology: {+), minimal; +, slight; j-+, moderate; +++, marked. cQ E 1 .O .ft* m '3>v Jf \ I d 1 . d4o >di < 04 Peritonocopy Histology 3* O .1 *8 nJ i e 12 (A d ` t *I" T *5 I? i3 > J3 wd *3 1 h "I <3 -"SEr 3l ".S O" k> *ST *am 02tk agj* "d *2 b -- 14 in i' & CO .1 _c "l/ui jot - * c/3 O h' ssS *w e*44) *tPfi. e if * *4 fc > ' ii- e g , "9ud, is I- ! Sv A WH t+) + <+) - ir <+) -+ <+) * (+) + G/Nod R R R A/I ? U/G Nod G U R/S R/S R/S ? AA ? G U G G/Nod G G +G u R/S R R/S R/S R/S R R S R I I A I A A G ?? G SA G C/R + ot examined R R R UA R u S/PC A +G R RA +G + + U/G + ? R S R A A I cA U` C c+) + + + + ++ + + ++ ++ + (+) + (+) + c+) + (+) + + (+) ++ <+) + + (+> (+) + + (+) + +++ + Not examined -- (+> <+) - - (+5- + (+> ++ t+) (+) (+) <+) (- -) + + + + ((++>J + + +-4- (+) <+) t+) + + + + + <+) + + (+) + (+> -i <+) Normal (liver scan) is x 11 x 12 Markedly en* larged (liver scan) I2x 7 x It 14 x 12 x 6 12 x 9 x 9 Splenectomy (IS x 12 X 7) 10x8x4 10 x 8 x 5 24 x 12 x 7 13x11x7 14x5* 12 Normal (liver 234*\l4 x 9 13 x 10x5 12x9x5 Normal (liver scan) Splenectomy (500 g) 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 14 x 6x 8 13 x 9 x 14 16 x 10 x 4 + + - + + .+ + + 14 x 13 x 6 Normal (liver + 14 x 6 x 11 13 x 5 x 11 14x9x7 Slightly enlarged (liver scan) 13x7x9 10 x 9 x 7 + + + + * + + + + ++ ++ ++ + + ++ + + + ++ +. ++ ++ + + + + + + + + + + ++ + -+ t U G/Nod G/Nod (S) C/R C/S C/R/PC s R A A A (R) (R) R/PC S C A A A - (+) -t *4 -t (+) + (+> + {+) + (+) (t++)j (+> (+) 12x6x8 15 x 12 x ? 16 x 6 x 8 13 x 7 x 12 11 x 7 x 10.5 + 12 x 9 x 7 11x8x5 12 x 8 x 6 + + + + + + + Normal (liver scan) 9x6x6 12 x 8 x 9 Normal (liver + U x5x7 12x6x 11 + + + -t+ + + + + + HQ Annals New York Academy of Sciences Marstel Alc Report* 1 u fie CO Figure 2. Length of exposure in 44 workers engaged in the polymerization proc ess. i S i O to O) w Gastrojnt; Surg Gasti Spier Splen Gasti car years prior to examination (length of exposure: 21% 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 AtVz 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 suggestive. Fifteen workers reported only slight upper abdominal discomfort. Another 24 claimed to such as dizziness, slight often combined with workers spontaneously they claimed had a fair ported in 8 cases. Foui varices during the past r Besides physical ex; plied to each case (Tat tract and intravenous c plain chest him and an done. Scintigraphy of li Peritoneoscopy and jperijoneoscopy without two other cases (total: courtesy of Dr. Harald ] peritoneoscopies, had pi with portal hypertensioi cases 10, 24, 29, and 31 at the Medizinische Uni Head, Klinik FBhre: D-241 Molln, Germany. _ t We would like to th. sitats-Poliklinik, Bonn, anversitatsklinik, Bonn, for p Marsteller et al.: 5oecisfis3: Disease 111 Alcohol Co^bthfcci* ns 53 ?VC W orkers Reported Alcohol InrSr- =z fssaati 4) * None Up to E i Up to s Up to 32 s ; .. Up to 5* f Not sta=c 10 15 16 0 \ `-f - .2 1 Total 50 Table 9 Gastrointestinal Blsding (Esophageal Varices) and Surgical Intervention in 50 PVC Workers No. Gastrointestinal bleeding Splenectomy Splenorenal shunt Gastric resection for anaplastic carcinoma 4/50 3/50 1/50 1/50 Another 24 claimed to have experienced temporary central nerv, headache' such as dizziness, slight disorientation, disturbance of vision, an often combined with nausea and mild upper abdominal^ 1SC0 workers spontaneously reported to have smelled "the gas occ they claimed had a faintly sweet odor, A Raynaud-like symptoma ported in 8 cases. Four had experienced episodes of bleeding fr Twelve ' wu:cu ^ gy P varices during the past 2 years (Table 9). Methods of Investigation Besides physical examination, a broad spectrum of laboratory *e.^. plied to each case (Table 10). X-ray examination of the upper g a tract and intravenous cholecystography were carried out in all cas plain chest film and an ECG with 12 leads. In 3 cases esophagogas r p done. Scintigraphy of liver and spleen was performed in 48 cases. Peritoneoscopy and guided liver biopsy were performed by us m .' peritoneoscopy'without biopsy in one, and percutaneous blind neeal^P y . two other cases (total: 44 cases). Data of case 14 were put at our i p courtesy of Dr. Harald Henning* who, during a 3-vear follow-up me {L peritoneoscopies, had previously classified the case as noncirrho ic po with portal hypertension of unknown etiology- We were given access o cases 10, 24, 29, and 31 which had been examined by peritoneoscopy a at the Medizinische Universitats-Pbnilimkr; 1 of these 4 cases (case n . ) Head, Klinik Fohrenkamp of the Federal Board for Employee's Insurance, D'2t m woildeir?oy thank Prof. 3c. F. Kradfc. D^ktr der^ ssiutaatiss--ProoiilKikiliinniiKk,, Buoonnnn,, aanndd PtTrootf.. EUfct. Aa.. GuigcmnTin.ifDrireTkt-oTr, d"e'r CTMhsirnuec8tive,lv. versitatsklinik, Bonn, for permissiert am inrinde csxa cs 3 and 2 cases, re pe y 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 Glutamic Qxalo.aoetic transaminase - V' * 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 creatininejonly uric acid in some cases 16. Serum iron 17. Serum copper 18. Blood glucose 19. Total cholesterol 20. Serum triglycerides 21. 6-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 al.: Splenomegalic Liver Disease 113 Table 11' , Results of Liyer Tests in 50 PVC Workers (Classification Based on Maximal Values Obtained in Multiple Determinations) 45-Min BSP Retention (5.0%)* Serum Bilirtitfn (1.0 mg/100 ml)* Alkaline Phosph&taset (48 mU/ml)* Normal Pathologic (Range) 7 (Meafi) 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) got; No. of Cues fG* tPyTiut No. of Cum Definitely ' normal 'Marginally normal Pathologic Total -12 mU/ml -19 mU/rtiIK 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 A>J 50 -- 12 mU/mlJ ` --22 mU/ml U 12-20 mU/ml 23-30 mU/ml 20-50 mU/ml 31-60 mU/ml >50 mU/ml >60 mU/ml 11 22 12| 17 5 50 * 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. Glockner. ArztI. Lab. 10 : 220, 1964. t 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. 3:1,1963It Substrate-optimated standard method, W. Thefeld et at. 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.180 A more or less marked thrombocytopenia (less than 150,000 platelets/mm8) 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 fn 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 possible, and 114 Annals New York Academy of Sciences .- ' Table Ii Splenomegaly in 50 PVC Workers Spleen size as measured by' scintigraphy in 48 cases Methods: Splenic scanning by ,,7Hg-BMHP (40 cases) (normal diameters: 11 x 7 x 4 cm) Liver scan by ,,mTc sulfur colloid (46 cases) . A{ .Within normal limits-(4 of (he cases - PVC-ptocessiug workers) : 11/48* r B. Exceeding normal-limits (2*of the bases' -- PVC-processiflg workers): 37/48f 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 (SCO 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. f In 2 of the 37 cases by liver scan. this proved to be only slightly elevated. Otherwise, no determinations of intrasplenic 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 (""Hg-labeled bromomercury'hydroxy propane)^ in 40 cases. Measurement of three diameters (length, breadth, depth) allowed detection of even minor degrees of splenomegalyThe 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.1* TM 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 I We wish to thank Prof. Dr. C. Winkler, Direktor des Institute fur Klinische und Experimentelle Nuklearmedizin an der Universitat Bonn, for permission to use results of scintigraphic examinations carried out at his institute. Marsteller et at.: Splenomegalic Liver Disease 115 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, 214 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 scattering of light Marsteller et air. Splenomegalic Liver Disease 117 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, 1W 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.TM 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 3). 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 probe is some- STELLATE FIBROSIS IRRECULARLY RETICULATED FIBROSIS CCARSELY-RETICULATED TO PATCHY CICATRICIAL FIBROSIS Figure 6. Types of capsular fibrosis of the liver observed in PVC workers. 33 fi CO 1 lengt --A O 4* to -4 Coai sure. V" ?.r~. - ''. >'TV *,> -.V' " ''^-'Vv'V V-J?v*-- "' ` ''**#! **>', < ^ - V ^7. -"V- * 'V":1-* Vv'\ ` ; ' .; *,' ^'v;' 7/y:,.'. 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'/: years.) Figure 9. Lenti lower edge of right 1 a Figure 8. Coarsely reticular fibrosis of Glisson's capsule; right lobe. (Case no. 9; length of exposure, 1314 years.) Figure 10. Coarsely reticulated fibrosis and patchy focal whitish capsular thick' tning (focal "perihepatitis cartilaginea"), resembling capsular alterations seen in thorotrastosis of the liver,1* (Case no. 6; length of exposure, 16 years.) 1 y 7 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 formerly diagnosed as "noncirrhotic portal fibrosis and portal hypertension of unknown etiology." Close-up view shot with a special magnifying peritoneoscope (Courtesy of Dr. Henning; see text.) 120 * i * * it Figure 12. Crenate splenitic fibrosis and mi. posure, 17 years.) times successful. Fc of the spleen to the as the inspection o: enlargement cannc megaly the crenate equally sensitive to capsule of the liver present in the forir delineated white ca; "*ick white coati ly that patchy 30 larked splenor fie uoms of portc. CD tl circulation c Dsity of prcfo O orm ligament, ^ e, and especi -sj ints of ascites w and the abdon lesions descrit itiology. ___ ages in hepatic Marsteller et al.: Splenomegalic Liver Disease 121 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 ( at Laparotomy in -- 2) 47) or Alteration* 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 post necrotic scars E. Patchy "perihepatitis cartilaginea" Capsular vessels A. None (normal) ^ B. Slightly augmented C. - Conspicuously increased 24/49 7/491 13/49 25/49 5/49 6/46 ' 230W/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).w 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- Table 14 Hepatosplenomegaly and Symptoms of Portal Hypertension on Peritoneoscopy or at Laparotomy ________ Hepatomegaly (n 49) Splenomegaly . ( - 36) Symptoms of Portal Hypertension <# - 49) None Present 31/49 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 extreme tilting owing to its being covered by nonremovable omental fat. Table 15 Synopsis of Pertinent Histologic Features in 49 Patients None Present in Grading Minimal Slight Moderate Marked Collagcniaation of Sinusoidal Walla 10 39 Enlargement and/or Proliferation of Littoral Cells i 48 Septal Fibrosis 34 15 7 25 6 32 20 8 --2 1 -- 1-- Fatty Change '26 23 6 14 3 -- Figure 13. Degenerative changes of hepatocytes with hydropic swelling and granu larity of cytoplasm. Occasional single cell necrosis. Note proliferation and pleomor- phism of littoral cells (Case no. 14; length of exposure, 11 years; biopsy several days after last exposure). H&E (X235). 124 Annals New Ydrk Academy of Sciences 3J fie W O 4a larstel 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 Coldner 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 hepatocytcs, 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 modem chemical industry,12*""TM1" 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 a phism of littoral cells (C last exposure). H&E (X4 festations associated v (acroosteolysis in 118, * than 12,000 workers). 1971 and were thougl actors."**" Thus, when we fir; tional etiology in the \ been particularly poor, prior publications. Inti: tion (distinct odor of \ tion of reactors, deter walled up, frequent syn cleaning). However, w evident that we dealt \ Marsteller el al.\ Splenomegalic Liver Disease 125 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 reactors.""-7` Thus, when 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 predomi- 126 Annals New York Academy of Sciences antly inconspicuous symptomatology (for instance, minor hepatic functional in sufficiency*1-'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 workers throughout the world early in 1974 has shown that this is certainly not merely the problem of a specific plant. None of the clinical or morphologic findings seemed to be mutually correlated 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*1 that we dealt with a symptomatology compatible with the diagnosis of chronic toxic liver damage,"'TM TM similar to that seen after repeated or continuous exposure to, halogenated hydrocarbons. The histoniorphologic appearance of the liver was essentially characterized by degenerative lesions (frequently observed in chronic toxic liver injury; hyperplastic smooth endoplasmic reticulum, alterations of rough endoplasmic reticulum due to toxic derangement of membrane structuresTM'1*1'TM), 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,""TM'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 noncirrhotic portal fibrosis, predominantly seen in India,11'11'11"117'"1 or of so-called idiopathic portal hypertension,"*7'*" TM 1",11""1"1`" respectively. In this disease en tity, portal hypertension and splenomegaly are usually accompanied by similar alterations of hepatic surface and histology;1*'"'"'11*'"1'TM'1'*'1" in some cases, however, portal hypertension seemed to have been the result of sclerosis or thrombosis of the portal vein.1* *7 "'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;1*1* ** BSP retention, however, can be readily explained by the character of the histologic lesions.TM A certain resemblance to Banti's syndrome is sug gested.11*'TM 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,TM was not available. On the other hand, one should keep in mind that even the rather unimpressive alterations observed histo logically (periportal and sinusoidal fibrosis, capillarization of sinusoids, degen- y * j | > *. -j | : (/) O 4k erat <0 sure (O j Ma ar Ie i,-i anne and tion fibre significance, indie tively participates splenomegaly?). 1 chloride" "1" sho are possibly the p a pattern of injur theliosarcoma, gr "' " and conject theliosarcoma oc serve as an exan reticuloendothel is may be the comm This leads ba monomer is the i hints (such as oi histories point to various working ; reliability of olfac old concentration Except for Sc 1959, very little ride.*''70111 Nevertl of events in polyi (monomer, cataly subcellular structi terns'11"), for exar mation of free ra chloride.TM Regardless of exposure to pure apart from tumor appears quite pro the effect of VC far various additi pattern in human Some commer for those engager is even more difi Detection of anal the manufacture i tion of possible V also suggested by ated""TM during temperatures of i whether PVC dus gastrointestinal sy Marsteller et al.: Splenomegalic Liver Disease 127 erative cellular lesions)-may be sufficient to explain an-increase in portal pres- qUiC^w# *** tt, u. 144. 1st, us, its 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.s,,"M"'"'"'," 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"-*1-11" 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- "11 "- " **- ** *" " TM and conjectural course of events in the pathogenesis of hemangioerido- 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 hepatocytes1") by a toxic substance"? may be the common denominator. This leads back to the question of etiology."1 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" "' even if one considers the un reliability of olfactory sensations*- " *" "* and the wide range of olfactory thresh old concentrations reported in the literature.1*- *1- *1- *1-104' "* Except for Schumann's communication in 1934,1B quoted by Williams'* in 1959, very little is known about the kinetics and metabolism of vinyl chlo- ride."-TM-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" 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."1-TM 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" 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 liber ated*-"-TM during processing (e.g., calendering, moulding, extrusion, etc.) at temperatures of 100-200*C.*- TM At the moment, it is also open to discussion whether PVC dust, apart from damage to the respiratory tract,"-"-TM'may cause gastrointestinal symptoms," for instance, by persorption.TM 128 Annals New York Academy of Sciences In the future, periodic control examinations of all PVC workers, especially of those engaged ir^ VG polymerization, at short intervals employing sensitiye methods'should be obligatory unless it should prove, feasible to eliminate com pletely any possible air contamination. Some of the many scientific questions connected with the problem of vinyl chloride disease may not be answerable until results of further extensive animal experiments""*11*7 and of prospective and retrospective large-scale studies" as well as of continuous monitoring of working areasu ,a, u* ," are available. References 1. Adam, Y. G., A. G. Huvos & S. I. Hajdu. 1972. Malignant vascular tumors of Jiver. Ann- Surg. 175: 375. Albright, L.F. 1967.'Vinyl chloride processes. Chem..Eng. 74 (March-27): 123. Albright, L. F. 1967. Manufacture of vinyl chloride. Chem.' Eng. 74 .(April 10): 219. . . Albright, L. F. 1967. Polymerization of vinyl chloride. Chem. Eng. 74 (May 8): 151. ,, .. .. . Albright, L. F. 1967.. Vinyl chloride 'polymerization by suspension processes yields polyvinyl chloride resins. Chem. Eng. 74 (June 5): 145. Albright, L. F. 1967. Vinyl chloride polymerization by emulsion, bulk and solu tion processes. Chem. Eng. 74 (July 3): 85. Anghelescu, Fl., M. Otoiu, E. Dobrinescu, L. Hagi-Paraschiv-dossios, Gh. Dobrinescu & V. Ganea. 1969. Considerate clinico-patogenice asupra feno- menului Raynaud la muncitorii din industria policlorurii de vinil. Med. Interna 21: 473. Austin, G. T. 1974. Industrially significant organic chemicals (Part 3). Chem. Eng. 81 (March 18): 87. Baader, E. W. 1960. Klinische Grundlagen der sechsundvierzig meldepflichtigen Berufskrankheiten. Urban & Schwarzenberg. Miinchen, West Germany. Baader, E. W., Ed. 1961. Handbuch der gesamten Arbeitsmedizin. Vol. II/l: Berufskrankheiten. Urban & Schwarzenberg. Miinchen, West Germany. Baghirzade, M. F., E. U. Hertel & P. Schumacher. 1971. Hamangioendor theliom (Reticulosarcoma angioplasticum) der Leber und alte Echinokokkusinfektion. Acta Hepato-Splenol. 18:224. Baretta, E. D., R. D. Stewart & J. E. Mutchler. 1969. Monitoring exposures to vinyl chloride vapor: breath analysis and continuous air sampling. Am. Ind. Hyg. Assoc. J. 30:537. Basalaev, a. V., A. N. Vazin & A. G. Koetkov. 1972. K patogenezu izmenenii voznikayushtikh pri dlitel'nom vozdeistvii vinilkhlorida. Gigiena Truda Prof. Zabolevaniya 16(2): 24. Basu, A. K,, J. Boyer, R. Bhattacharya, K. C. Basu Mallik & K. P. Sen Gupta. 1967, Non-cirrhotic portal fibrosis with portal hypertension: a new syndrome. Part I. Clinical and function studies and results of operations. Indian J. Med. Res. 55: 336. 15. Basu Mallik, K. C., K. P. Sen Gupta, A. K, BasU, S. K. Biswas, N. C. Pal & J. Boyer. 1967, Non-cirrhotic portal fibrosis with portal hypertension: a new syndrome. Part II. Histopathological studies. Indian J. Med. Res. 55: 351. Beck, K., W. Dischler, M. Helms, B. Kiani, K. Sickinger & R, Tenner. 1968. Atlas der Laparoskopie, F. K. Schattauer Verlag, Stuttgart, West Germany. Becker, V,& K. BOsscher. 1961. JLJeber das Hamangioendothfliom der Leber. Acta Hepato-Splenol. 8:356. Bianchi, L. 1970. Zum Problem der Leberfibrose. Schweiz. Med. Wochschr. 100: 1214. Bo*1*. I- L., K. P. Sen Gupta, S. K. Biswas, N. C. Pal, K. C. Basu Mallik, F. L. Iber & A. K. Basu. 1967. Idiopathic portal hypertension. Comparison with the portal hypertension of cirrhosis and extrahepatic portal vein obstruc tion. Ann. Internal Med. 66(1): 41. Brit. Med, J. 1974. Vinyl chloride and cancer. 1: 590. Bronfenmaier, S., F. Schaffner 8c H. Popper. 1966. Fat-storing cells (lipocytes) 22. in human liver. Arch. Pathol. 82:447. Broussard, G. 1969. Patologia da resine polivimliche. Med. Bull. 52(2): 102. Ma J* : <o0o --a ., w. 19 elten Le 7. 2 a, Depa SION. 1 11 inter. Ottz 25. Carr, J., R. h XXIV. Che Pharmacol. 26. Chatelain, A. fessionelle e Nucl. 48: 27 27. Chemical Eco . Chloride R 8. Chemiewirtsc 1973. 15th e 29. Chenoweth, f drodarbons. 30. Chief Inspect 8772,' H.M.S 31. Cook, W. A., tional acroos 74. 32. Cordier, J. M lesions cutar Cahiers de f cins du Trav. 33. Creech, J. L., facture of pc 34. Croll, M. N., splenic scanr 35. Dahlcren, S. : two cases. At 36. Danishevskii, komolekulya 37. Danziger, H. Can. Med. A 38. Deese, D. E. 8 posure. Am. 39. Deichmann, W Academic Pr 40. Devignevielle des resines p Vernon, avril 41. Dimov, D. & ' Toksikol. 22: 42. Dinman, B. D., check. 1971. Environ. Her 43. Dodson, V. N. Magnuson. : viron. Health 44. Domininghaus, sorten-Anwei 45. Domininghaus. formen. 2nd t 46. Dublin, L. I. i U. S. Depart Government 1960. 47. Dublin, L. I. & Department i U.S. Govern i ziger, 1960. Marsteller et alSplenomegalic Liver Disease _ 129 23. Bruhl, W.' 1966. Zwischenfalle und Komplikationen bei der Laparoskopie und gezielten Leberpunktion (Ergebnis einer Umfrage). Deut. Med. Wochschr. 91: 2297. 24. Canada, Department of National Health and Welfare, Industrial Health Division. 1949. A guide to the diagnosis of occupational diseases. King's Printer. Ottawa, Ontario, Canada. 25. Carr, J., R. M. Burgison, J. F. Vitcha & J. C. Krantz, Jr. 1949. Anesthesia. XXIV. Chemical constitution of hydrocarbons and cardiac automalicity. J. Pharmacol. Exptl. Ther. 97:1. 26. Chatelain, A. & P. Motillon. 1967. Uh syndrome d'acro-osteolyse d'origine'professioneile etde constatation nouvelie cn France.-J.- Radiol. Electrol. Med. Nucl.4*:277. - - .27. Chemical Economics Handbook. September 1973. Vinyl Chldride and Polyvinyl Chloride Resins. Stanford Research Institute. Menlo Park, Calif. 28. Chemiewirtschaft in Zahlen. Verband der Chemischen Industrie e.V., Ed. 1973. 15th edit. Econ-Verlag. Diisseldorf, West Germany, 29. Chenoweth, M. B. &. C. L. Hake. >962. The smaller'halogenated aliphatic hy drocarbons. Ann. Rev. Pharmacol. 2: 363. 30. Chief Inspector of Factories. . 1953. Annual Report for the Year 1951. Cmd. 8772, H.M.S.O. London, England. 31. Cook, W. A., P. M. Giever, B. D. Dinman & H. J. Magnuson. 1971. Occupa tional acroosteolysis. II. An industrial hygiene study. Arch. Environ. Health 22: 74. 32. Cordier, J. M., C. Fievez, M. J. Lfvre & A. Sevrin. 1966. Acro-osteolyse et lesions cutanies associ6es chez deux ouvriers affectes au nettoyage d'autoclaves. Cahiers de Medecine du Travail (Association Professionnelle beige des Medecins du Travail 4 janvier 1966). 33. Creech, J. L., Jr. & M. N. Johnson. 1974. Angiosarcoma of liver in the manu facture of polyvinyl chloride, J. Occupational Med. 16:150. 34. Croll, M. N., L. W. Brady, I. Brodsky & L. Stanton. 1965. A new agent for splenic scanning: BMHP. Radiology 84: 492. 35. Dahlgren, S. 1961. Thorotrast tumours. A review of the literature and report of two cases. Acta Pathol. Microbiol. Scand. 53: 147. 36. Danishevskii, S. L. & N. M. Egorov. 1961. Voprosyi toksikologii v khimii .vysokomolekulyarnykh soedinenii. Gigiena Truda Prof. Zabolevaniya 5 (9): 26. 37. Danziger, H. 1960. Accidental poisoning by vinyl chloride: report of two cases. Can. Med. Assoc. J. 82: 828. 38. Deese, D. E. & R. E. Joyner. 1969. Vinyl acetate: a study of chronic human ex posure. Am. Jnd. Hyg. Assoc. J. 30:449. 39. Deichmann, W. B. & H. W. Gerarde. 1969. Toxicology of drugs and chemicals. Academic Press. New York, N.Y. 40. Devignevielle, Dr. & A. M. Flucher. 1953. Etude toxicologique experimentale des resines polyvinyliques. Service Medical des Manufactures de Saint-Marcel, Vernon, avril 1953. As cited in Truffert, 1959. 41. Dimov, D. & T. Beritic. 1971. Profesionalna akroosteoliza. Arhiv. Hig. Rada Toksikol. 22; 53. 42. Dinman, B. D., W. A. Cook, W. M. Whitehouse, H. J. Magnuson & Th. DitCHECK. 1971. Occupational acroosteolysis. I. An epidemiological study. Arch. Environ. Health 22: 61. 43. - Dodson, V. N., B. D. Dinman, W. Mi Whitehouse, A. N. M. Nasr & H. J. Magnuson. 1971. Occupational acroosteolysis. III. A clinical study. Arch, En viron. Health 22: 83. 44. Domjninghaus, H. 1972. Kunststoffe I. Aufbau und Eigenschaften-Kunststoffsorten-Anwendungen. 2nd edit. VDl-Verlag. Dusseldorf, West Germany. 45. Domininghaus, H. 1973. Kunststoffe II. Aufbereiten-Oberflachenveredeln- Urnformen. 2nd edit. VDI-Verlag. Dusseldorf, West Germany. 46. Dublin, L. I. & R. J. Vane. 1933. Occupational hazards and diagnostic signs. U. S. Department of Labor, Bureau of Labor Statistics. Bulletin No. 582. U.S. Government Printing Office. Washington, D.C., p. 49. As cited in Danziger, 47. Dublin, L. I. & R. J. Vane. 1941. Occupational hazards and diagnostic signs. U. S. Department of Labor, Division of Labor Standards. Bulletin No. 41 (revised). U.S. Government Printing Office. Washington, D.C., p. 65. As cited in Dan ziger, 1960. ' . <* '\'J -)Z . :;/-w 130 Annals New York Academy of Sciences 48. Dugois, P,, P. Amblard, B* De Bignicqurt& J' Legrand. 1972. AcropatHie polyvinylique professionnelle. Bull. Soc. Franc. Dermatol. Syphiligr. 79:-197. 49. Eckardt, R. E. & R. Hindin, 1973. The health hazards of plastics. J, Occupa tional Med. 15: 808. 50. Edmondson, H. A., R. L. Peters, H. H, Frankel & S. Borowski. 1967. The early stage of liver injury in the alcoholics. Medicine 46: 119. 51. Europachemie. 1972. Handelsblatt GmbH. Diisseldorf, West Germany. 52. Fairhaix, L. T. 1957. Industrial toxicology. 2nd edit. The Williams & Wilkins* Company. Baltimore, Md. 53. Filatova, V, S. & E. Sh. Gronsberg. 1957. Sanitamo-gigieniEeskie usloviya truda v proizvodstve polikhlorvinilovoi smolyi i meryi ikh ozdorovleniya. Gigiena Sanit, No. 1: 38. 54. Filatova, V; S,, L. I. Balakhonova & E. Sh. Gronsberg. 1958. GigieniEeskaya kharakteristika proizvodstva khloristovo vinila. Gigiena Truda Prof. Zabole- . vaniya2(l): 6. ; . - 55; Filatova, V. S., E. Sh. Gronsberg, N. A, Smirnova, E. A. Stulova &. I. V. ... Oresckevic. 4965. Voprosyi gigienyi truda i sostoyanie zdorov'ya rabpEikh, zanyatyikh na proizvodstve lateksnovo polivinilkhlorida. Gigiena Truda Prof. Zabolevaniya 9:9. 56. Filatova, V. S. & V. A. Antonyuzhenko. 1971. GigieniEeskiye usloviya truda i professional'naya zabolevaemost' raboEikh proizvodstva suspenzionnovo poli vinilkhlorida v dinamike za ryad let. Gigiena Truda Prof. Zabolevaniya 15(4): 32. 57. Fischer, J., H. Mundschenk & R. Wolf. 1965. Milzszintigraphie mit 1-Bromomercuri ('*7Hg)-2-hydroxypropan (BMHP). Fortschr, Gebiete Roentgenstrahlen Nuklearmed. 103: 349. 58. Fischer, J., R. Wolf & H. Gamm. 1973. Die Milzszintigraphie. Dtsch. Arztebl. No. 7: 401. 59. Gall, E. A. 1969. Tumors of the liver. In Diseases of the Liver. L. Schiff, Ed. 3rd edit. J. B. Lippincott Company. Philadelphia, Pa. 60. Gitsios, C. T. 1971. Acro-osteolysis in PVC workers. Med. Bull. Stand. Oil Co. 31(1): 49. 61. Gunther, O. 1956. Die Kunststoffe und ihre arbeitsmedizinische Bedeutung. Zentr. Arbeitsmed. 6: 156. 62. Harris, D. K, 1953. Health problems in the manufacture and use of plastics. Brit. J. Ind. Med. 10: 255. 63. Harris, D. K. & W. G. F. Adams. 1967. Acro-osteolysis occurring in men engaged in the polymerization of vinyl chloride. Brit. Med. J. 3: 712. 64. Henschler, _D., Ed. 1972/1973. Gesundheitsschadliche Arbeitsstoffe. Toxikologisch-arbeitsmedizinische Begriindungen von MAK-Werten (Maximale Arbeitsplatz-Konzentrationen). Verlag Chemie. Weinheim, West Germany. 65. Herrle, K. 1963. Polyvinylchlorid. In Ullmanns Encyklopadie der technischen Chemie. W. Foerst, Ed. 3rd edit. Vol. 14. Urban & Schwarzenberg. Miinchen, West Germany. 66. Hervieux & Tessier, 1959. Quelques observations d'exposition et d'intolerance aux derives vinyliques et aux rEsines ethoxyliques. Arch. Maladies Profess. 20: 61. 67. Iber, F. L. 1970. Portal hypertension in the presence of normal liver morphology. Ann. N.Y. Acad. Sci. 170(1): 115. 68. International Labour Office. 1971. Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vol. I: 387. 69. International Labour Office. 1972, Encyclopaedia of Occupational Health and Safety. Geneva, Switzerland. Vol. II: 1467. 70. Irish, D. D. 1963. Halogenated hydrocarbons: I. Aliphatic. In Industrial Hygiene and Toxicology. Vol. II: Toxicology. D. W. Fassett & D. D. Irish, Eds. Inter science Publishers. New York, N.Y. 71. Javitt, N. B. 1970. Clinical and experimental aspects of sulphobromophthalein and related compounds. In Progress in Liver Disease. H. Popper & F. Schaffner, Eds, Vol. III. Grune & Stratton. New York, N.Y, 72. Judah, J. D., A. E. M. McLean & E. K. McLean. 1970. Biochemical mechanisms of liver injury. Am. J. Med. 49: 609. 73. Juhe, S. & C. E. Lange. 1972. Sklerodermieartige Hautver'anderungen, RaynaudSyndrom und Akroosteolysen bei Arbeitem der PVC-herstellenden Industrie, Deut. Med. Wochschr. 97: 1922. 4- 76. Kli * 77. Kluge, T., h sion. Surge 78. Kramer, C. ( mental me Assoc. J. 3 79. Lange, C.-E. chlorid-Kr; med. 32: 1. 80. Leake, C. D. thesia. J. A 81. Lefaux, R. ] Wejt Gern 82. Lef^vre, M. Industrie, i 83. Lehmann, K schen Losu 84. Lester, D., 1 peated exp, 24:265. 85. Lindner, H. 64:842. 86. MacSween, stone & A J. Pathol. 1 87. Malten, K, 1 in the Pro Amsterdan 88. Maltoni, C., on Cancer Medica lnt 89. Marin, A,, J. Acro-osteo centre le R 90. Markowitz, cupational 91. Marsteller, Rohner & in der PVC 92. Mastromatt: halation to. J. 5:394; B 93. Mayers, M. Baltimore, 94. McCord, C. 12:234. 95. Mikkelsen, 3 Reynolds. (hepatopori 96. Misgeld, V., Vinylchlori 48: 425. 97. Morris, J. S., Ann. Rheui 98. Netileship, > thorotrast. 99. Oettel, H. 1 Polymerisa Marsteller el al.\ Splenomegalic Liver Disease 131 74. -Kelly, R. E. 1973'. Vinyl chloride and acroosteolysis. J. Occupational. Med. 15: 858. 75. Klatskin, G. 1969. Toxic and drug induced hepatitis. In Diseases of the Liver. L. Schiff, Ed. 3rd edit. J. B. Lippincott Company. Philadelphia, Pa. 76. Klinge, O. & H. W. Altmann. 1971. Morphologie toxischer Hepatosen. Munch. Med. Wochschr. 113: 1529. 77. Kluge, T,, H. Sommerschild & A. Flatmarx. 1970. Sinusoidal portal hyperten sion. Surgery 68: 294. 78. Kramer, C. G. & J. E. Mutchler. 1972. The correlation of clinical and environ mental measurements for workers exposed to vinyl chloride. Am. lnd. Hyg. .Assoc J 33-19 79. Lange, C.-E., S. Juhe, G. Stein & G. Veltman. 1974. Die sogenannte Vinyl- -chlorid-Krankheit--eine berufsbedingte Systemsklerose? Intern. Arch. Arbeits- med. 32:1. - .. 80. Leake, C. D. 1934. The rote of pharmacology in the development of ideal anes thesia. J. Am. Med. Assoc. 102:1. 81. Lefaux, R, 1966. Chemie und Toxikologie der Kunststoffe. Krausskopf. Mainz, West Germany. _ . ... 82. Lfvre, M. J. 1972. Internationales Symp'oSion der Werksarzte der Chemischen Industrie, 27-29. April 1972, Ludwigshafen. As cited in Stein el al., 1973. 83. Lehmann, K. B. & F. Flury, Eds. 1938. Toxikologie und Hygiene der techni- schen Lbsungsmittel. Julius Springer. Berlin, Germany. 84. Lester, D., L. A. Greenbero & W. R. Adams. 1963. Effects of single and re peated exposures of humans and rats to vinyl chloride. Am. lnd. Hyg. Assoc. J. 24:265. 85. Lindner, H. 1973. Laparoscopy in alcohol-induced liver disease. Gastroenterology 64: 842. 86. MacSween, R. N. M., J. M. Vetters, S. K. Ross, J. Ferguson, J. M. John stone & A. T. Sandison. 1973. Haemangio-endothelial sarcoma of the liver. J. Pathol. 109: 39. 87. Malten, K. E. & R. L. ZielhuiS. 1964. Industrial Toxicology and Dermatology in the Production and Processing of Plastics. Elsevier Publishing Company. Amsterdam, The Netherlands. 88. Maltoni, C., M. Crespi & P. J. R. Burch, Eds. 1973. II International Symposium on Cancer Detection and Prevention, Bologna, April 9-12, 1973. Excerpta Medica Int. Congr. Ser. No. 275. 89. Marin, A., J. Strauss, R. Michiels, J. P. Benoit, R. Baltie & C. Pierre. 1967. Acro-osteolyse d'origine professionnelle (Travail present^ a la Ligue Francaise contre le Rhumatisme, stance du 18 janvier 1967). Rev. Rhumat. 34: 340. 90. Markowitz, S, S., C. J. McDonald, W. Fethiere & M. S. Kerzner. 1972. Oc cupational acroosteolysis. Arch. Dermatol. 106:219. 91. Marsteller, H. J., W. K. Lelbach, R. Muller, S. Juhe, C. E. Lange, H. G. Rohner & G. Veltman. 1973. Chronisch-toxische LeberschSden bei Arbeitern in der PVC-Produktion. Deut. Med. Wochschr. 98: 2311. 92. Mastromatteo, E., A. M. Fisher, H. Christie & H. Danziger. 1960. Acute in halation toxicity of vinyl chloride to laboratory animals. Am. Ind. Hyg. Assoc. J. 5: 394; Bull. Hyg. 36: 244. 93. Mayers, M. R. 1969. Occupational Health. The Williams & Wilkins Company. Baltimore, Md. 94. McCord, C. P. 1970. A new occupational disease is bom. J. Occupational Med. 12:234. 95. Mikkelsen, W. P., H. A. Edmondson, R. L. Peters, A. G. Redeker & T. B. Reynolds. 1965. Extra- and intrahepatic portal hypertension without cirrhosis (hepatoportal sclerosis). Ann. Surg. 162: 602. 96. Misgeld, V., H. J. Stolpmann & S. Schulte. 1973. Zur Intoxikation durch Vinylchlorid-Polymerisate und/oder deren Begleitstoffe. Z. Haul Geschlechtskr. 48: 425. 97. Morris, J. S., T. Htut & A. E. Read. 1972, Scleroderma and portal hypertension. Ann. Rheumatic Diseases 31: 316. 98. Nettleship, A. & W. J. Fink. 1961, Neoplasms of the liver following injection of thorotrast. Am. J. Clin. Pathol. 35:422. 99. Oettel, H. 1963. Gewerbetoxikologie und Physiologie einzelner Polymerisate. Polymerisate chlorierter Athylene. In Ullmanns Encyklopadie der technischen 132 ' Annals New' York Academy 6f Sciences' . .' ' . Chemie. W. Foerst, Ed. Vol. 14: 306. Urban & Schwarzenberg. Miinchen, West Germany. 100. Oster, R. H., C. J. Carr & J. C. Krantz. 1947. Anesthesia. XXVII. Narcosis with vinyl chloride. Anesthesiology 8: 339. 101. Ostermayer, H. 1967. Vinylchlorid. In Ullmanns Encyklopadie der technischen Chemie. W. Foerst, Ed. Vol. 18: 87. Urban & Schwarzenberg. Miinchen, West Germany. 102. Otto, P., P. H. Krause, H. G. Jester, F. W. Schmidt & K. H. Glatzel. 1972. Idiopathische portale Hypertension. Med. Klin. (Munich) 67: 447. . 103., Parmegciani, L. & C- Sassi. 1955.-Rischi-e patologia professionaie nella pro-- duzione e nella lavorazione.di alcune-materie plastiche. Med. Lavoro 46: 14. 104. Patty, F. A,, W. P. Yant & C. P. Waite.- 1930. Acute response of guinea pigs to vapors of some new commercial organic compounds.'V.- Vinyl chloride. Public Health Rep. 45: 1963. 105. Patty, F.-A., Ed. 1958. Industrial Hygiene and Toxicology. Vol. I. General Prin ciples. 2nd edit; Interscience Publishers. New York, N.Y. 106. Patty, F, A., Ed. 1963. Industrial Hygiene and Toxicology. V.ol. IL Toxicology. D; W. Fassett & D. D. Irish, Eds. 2nd edit. Interscience Publishers, New York, N.Y. 107. Peoples, A. S. & C. D. Leake. 1933. The anesthetic action of vinyl chloride. J. Pharmacol. Exptl. Ther. 48: 284. 108. Polish, E., J. Christie, A. Cohen & B. Sullivan. 1962. Idiopathic presinusoidal portal hypertension (Band's syndrome). Ann, Internal Med. 56: 624. 109. Popper, H., F. Paronetto, F. Schaffner & V. Perez. 1961, Studies on hepatic fibrosis. Lab. Invest. 10: 265, 110. Popper, H. 1968. Pathology of portal hypertension. In The Therapy of Portal Hypertension. N. G. Markoff, Ed. Georg Thieme Verlag. Stuttgart, West Ger many. 111. Popper, H. & F. Hutterer. 1970, Hepatic fibrogenesis and disturbance of hepatic circulation. Ann. N.Y. Acad. Sci. 170: 88. 112. Popper, H. & S, Udenfriend. 1970. Hepatic fibrosis. Correlation of biochemical and morphologic investigations. Am. J. Med. 49: 707. 113. Pushin, G. A, 1965. O porashenii peCeni i zeltnyikh putei u raboCikh' zanjatyikh w proizwodstwe nekatoryikh widow plastmass. Sov. Med. 28: 132. 114. PVC producers see good business ahead. 1969. Chem. Eng. News August 4: 18. 115. Quooss, H. 1959. Gesundheitsgefahren in der Kunststoffindustrie. Johann Am- brosius Barth Verlag. Leipzig, East Germany. 116. Ramalingaswamj, V., K. L. Wig & S. K. Sama. 1962. Cirrhosis of the liver in Northern India--a clinicopathological study. Arch. Internal Med. 110: 350. 117. Ramalingaswami, V. & N, C. Nayak. 1970. Liver disease in India. In Progress in Liver Disease. H. Popper & F. Schaffner, Eds. Vol. Ill: 222. Grune & Stratton. New York, N.Y. 118. Rappaport, A. M,, M. Knorlauch, R. G. Black & S. Ohira. 1970. Hepatic microcirculatory changes leading to portal hypertension. Ann. N.Y. Acad. Sci. 170: 48. 119. Ravenna, P. 1940. Band syndrome (fibrocongestive splenomegaly). Definition, classification and pathogenesis. Arch. Internal Med. 66: 879. 120. Remmer, H. 1970. The role of the liver in drug metabolism. Am. J. Med. 49: 617. 121. Reynolds, T. B. & A, G. Redeker. 1965, Hepatic hemodynamics and portal hy pertension. In Progress in Liver Disease. H. Popper & F. Schaffner, Eds. Vol. II: 457. Grune & Stratton. New York, N.Y. 122. Roth, F. 1957. Arsen, Leber, Tumoren (Hamangioendotheliom). Z. Ktebsforsch. 61: 468. 123. Rousselot, L. M. 1940. The late phase of congestive splenomegaly (Banti's syn drome) with hematemesis but without cirrhosis of the liver. Further observa tions on the etiology of Banti's syndrome and the effect on prognosis of certain variations in the portal venous pattern. Surgery 8: 34. 124. Sama, S. K., S. Bhargava, N. Gopi Nath, J. R. Talwar, N. C. Nayak, B. N. Tandon & K. L, Wig. 1971. Noncirrhotic portal fibrosis. Am. J. Med. 51: 160. 125. Saragoca, A,, M. H. Tavares, F. B. Barros & J. Da Silva Horta. 1972. Some clinical and laboratory findings in patients injected with thorium dioxide. Study of 155 cases. Am. J. Gastroenterol, 57: 301. 126. Schaffner, F. & H. Popper. 1963. Capillarization of hepatic sinusoids in man. Gastroenterology 44: 239. Marsteller et alSplenomegalic Liver Disease 133 127. Schavmann, O. 1934. Ueber die Herzwirkung einiger Inhalationsnarkotica. Medi- zin & Chemie, Abhandlungen aus den Medizinisch-chemischen Forschungsstat- ten der I.G. Farbenindustrie A.G. Vol. 11. Bayer-Meister Lucius. Leverkusen, West Germany. 128. Schaumann, O. 1938. In Toxikologie und Hygiene der technischen Losungsmittel. K. B. Lehmann & F. Flury, Eds. p. 130 (Monocblorathylen). Julius Springer. Berlin, Germany. 129. Schmid,. M. 1968. Zur Leberhistologie der verschiedenen Formen des portalen . Hochdruckes. In The Therapy of Portal Hypertension. N. G. Markoff, Ed. Georg Thieme Veflag. Stuttgart, West Germany. 130. Schmidt, F. W. 1969. Geringer Aktlvitatsanstieg der Serum-Transaminasen. Deut. Med. Wochschr. 94:2250. ^ - 131. Schnack, H., L. SrocKiNGER & F. Wewalka. 1967, Adventitious connective tissue ' cells in the space of Disse and their relation to fibre formation. Rev. Intern. HSpatol. 17:855. 132. Simonds, H. R., A. 1. Weith & M. H. Bigelow. 1949. Handbook of Plastics. 2nd edit. D, van Nostrand Co., Inc. Princeton, NJ. 133. Slater, T. F. 1972. Free radical mechanisms in tissue injury. Pion Ltd. London, England. 134. Smoron, G. L. & H. A. Battifora. 1972. Thorotrast-induced hepatoma. Cancer 30: 1252. 135. Smyth, H. F., Jr. 1956. Improved communication. Hygienic standards for daily inhalation. Am. Ind. Hyg. Assoc. J. 17:129. 136. Soloway, R. D., A. H. Baggenstoss, L. J. Schoenfield et al. 1971. Observer error and sampling variability tested in evaluation of hepatitis and cirrhosis by liver biopsy. Am. J. Digest. Diseases 16: 1082. 137. Stein, G., S. Juhe, C.-E. Lange & G. Veltman. 1973. Bandformige Osteolysen in den Endphalangen des Handskeletts. Fortschr, Gebiete Roentgenstrahlen Nu- klearmed. 118:60. 138. Stenger, R. J. 1965. Fibrogenesis along the hepatic sinusoids in carbon-tetra- chloride-induced cirrhosis. An electron microscopic study. Exptl. Mol. Pathol. 4: 357. 139. Stutz, F. H., D. C. Tormey & J. Blom. 1973. Hemangiosarcoma and pathologic rupture of the spleen. Cancer 31:1213. 140. Suctu, I., I. Drejman & M. Valaskai. 1963. Contributii la studiul imbolnavirilor produse de clorura de vinil. Med. Interna 15: 967. 141. Sucru, 1., I. Drejman & M. Valaskai. 1967. Etude des maladies dues au chlomre de vinyie. Med. Lavoro 58: 261; Abstr. Hyg. 43: 430 (1968). 142. Summerskill, W. H- J. 1974. Chronic active liver disease reexamined: prognosis hopeful. Gastroenterology 66:450. 143. SussMan, E. B., I. Nydick & G. F. Gray. 1974. Hemangioendothelial sarcoma of the liver and hemochromatosis. Arch. Pathol. 97: 39. 144. Symanski, H. Ed. 1963. Handbuch der gesamten Arbeitsmedizin. E. W. Baader, Ed. Vol. IV/2: Arbeitshygiene. Urban & Schwarzenberg. Miinchen, West Ger many. 145. .Tandon, B. N., R. Lakshminarayanan, S. Bhargava, N. C, Nayak & S. K. Sama. 1970. Ultrastructure of the liver in non-cirrhotic portal fibrosis with portal hy pertension. Gut 11: 905. 146. Tisdale, W. A., G. Klatskin & W. W. L. Glenn. 1959. Portal hypertension and bleeding esophageal varices. Their occurrence in the absence of both intra- hepatic and extrahepatic obstruction of the portal vein. New Engl. 1. Med. 261: 209. 147. Torkelson, T, R., F. Oyen & V. K. Rowe. 1961. The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Am, Ind. Hyg. As soc. 1.22: 354; Bull. Hyg. 37: 357. 148. Tribukh, S. L,, N. P. Tikhomirova, S. V. Levina & L. A, Kozlov. 1949. Usloviya truda i meropriyatiya po ikh ozdorovleniyu pri proizvodstve i izpol'zovanii khlorvinilovykh plastifeskikh mass. Gigiena Sanit. 10: 38. 149. Truffert, L. 1959. Aspects toxicotogiques de 1'industrie des matures plastiques. Arch. Maladies Profess. 20: 43. 150. U.S. Department of Health, Education, and Welfare--Public Health Ser vice: Center for Disease Control. 1974. Angiosarcoma of the liver among polyvinyl chloride workers--Kentucky. Morbidity Mortality Weekly Rep. 23(6): 49. 134 Annals New York Academy of Sciences 151. `.Viola", P. L.' 1970. Pathology of vinyl chloride. Med. Lavoro 61: 174. 152. Viola, P. L., A. Bioorn & A. Caputo. 1971. Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res. 31: 516. 153. Voucheimer, G., F. Szarvas, F. Al Abesie, H. John & S. Wachtel. 1961. Aufsaugung von Polyvinylchlorid-Pulver durch die Diinndannschleimhaut und deren Abtransport durch die Chylusgefasse. DeuL Gesundheitsw. 16: 1727. 154. Von Oettingen, W. F. 1964. The Halogenated Hydrocarbons of Industrial and Toxicological Importance. Elsevier Publishing Company. Amsterdam, The Netherlands. 155. Wagner, H. N., Jr., J. G. McAfee, I. M. Weiner, M. Ilio, J. Martinez & W. P. Caine, Jr. 1963. The use of Hg-203 labeled bromomercurihydroxypro- pane (BMHP) in radioisotope scanning of the spleen. J. Nucl. Med-4: 190. 156. Wepler, W. 1971: Zur Morphologic chronischer Leberkrankheiten. Leber Magen - Darm 1:45. . ' . ' *. 157. Williams,.G. M., J. M. Elliott & J. H. Weisburger. 197$. Carcinoma'after malignant conversion, in vitro.of epithelial-like cells from rat -liver following exposure to chemical carcinogens. Cancer Res. 33: 606. - 158. .Williams, R. T. 1959. Detoxication Mechanisms. The Metabolism and.Detoxica tion of Drugs, Toxic Substances and Other Organic Compounds. 2nd edit. Chapman & Hall Ltd. London, England. 159. Wilson, R. H. & W. E. McCormick. 1960. Plastics. The toxicity of synthetic resins. A. M. A. Arch. Ind. Health 21: 536. 160. Wilson, R. H,, W. E. McCormick, C. F. Tatum & J. L. Creech. 1967. Occupa tional acroosteolysis. Report of 31 cases. J. Am. Med. Assoc. 201: 577. 161. Wirtschafter, Z. T. & M. W. Cronyn. 1964. Free radical mechanism for solvent toxicity. Arch. Environ. Health 9:186. 162. Wittman, I. 1966. Peritoneoscopy. Vols. I & II. Akademiai KIADO. Publishing House of the Hungarian Academy of Sciences. Budapest, Hungary. 163. Zapp, J. A., Jr. 1962. Toxic and health effects of plastics and resins. Arch. En viron. 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. lelbach 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. i 1 ' ' .I * 1 i I B. Experimental PRELIMIN VIN R. E. i -Vinyl chloride vi ride and at ma and in 3J A fi8 ra Ui 5 --L de exposei >ma$, z> :d to coi ek for J <0 at 03 ics *4 irmatior nt time. 1 and pr to Is of VC exj inhalat conceivea the idea t pathway, and if so jugation of VCM i pected. Therefore, evaluating these po Kinetic Studies of i Male Sprague-I g were exposed to ppm (0.13-2.99 m depicts the closed, i 4 rats were concur only the nares of tt ber. Expired carbo absorption on an A was removed from manometer fitted v dual syringe pump t The chamber at in-line Miran-I infi * These studies v. Association.