Document 2Jb8be0Vy42dZXYdvQRMkL7Kp

UNUSUAL SPLBNOMBGAUC LTVBR DISEASE AS EVIDENCED BY PERITONEOSCOPY AND GUIDED UVER BIOPSY AMONG POLYVINYL CHLORIDE PRODUCTION WORKERS H. I. ManteDer and W. K. Lelbacfa Jfrdfdtabc** Unhenm*kUnik MJ jam. Federal o/ Oinnaqr R. MUUtr tad P. Gedigk Paikoiogisches Institut der Univereitit Bom CK5i Bom, Federal Republic of Germany INTRODUCTION Economic Considerations; Technology At early u 1833* and 1838,M respectively, Regnault in France succeeded In preparing vinyl chloride (VC) and polyvinyl chloride (PVC). However, the road to large-ecale production wasnot opened until vinyl chloride could be synthesized from acetylene and hydrogen chloride (Klatte and Zacharies, 1912)** and or ganic peroxides were used for catalyzing VC polymerization (Klatte and Rollett, 1914).* In 1928, PVC production wu 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* (Tablb 1). PVC-producing industries in West Germany increased their production, parallel to the development in the United States (Table 2), at a rate of 10-20 percent per year from 1960 (172,673 tons of PVC) to 1972 (930,701 tons of PVC and polyvinylidene chloride).*'* Total sales of PVC amounted to 850,140 German marks in 1972.* This enormous increase in production capacity, espe cially in flexible PVC (U.S.. 1965: flexible PVC, 90 percent; rigid PVC, 10 per cent)* can be explained by the almost unlimited use that can be made of PVC. Divexiifleation of PVC markets exceeds that of any other large-volume thermo plastic and is one of the reasons for the increasingly favorable market situation (Table 3)." Rigid PVC is used for tubing and fittings (including insulation material and drainage pipes), foils, films, and sheeting (packaging, lining, recording tapes), profiles (blinds, window frames), tiles, sound records, and fibers. Flexible PVC is used for cables, foils (decoration, roof covering), profiles, tubing, artificial leather, flooring, foa^ rubber, paint, varnish (lacquer), and toys.* Thus, indus tries that manufacture the end product operate on a much larger scale than those producing the polymer, but the companies are often identical.*-* Technologically, vinyl chloride was synthesized mainly by hydrochlorination of acetylene, a process which was almost exclusively in operation up to 1960, but in the United States now accounts for only 7 percent of the production.* Vinyl chloride can also be produced by oxychlorinatioo of ethylene to 1,2-dichloroethane which is then cracked to VC and HQ by subsequent pyrolysis (now 93 percent of total production in the United States in 1972).*'*'*'*** Under 95 RSV 0016762 96 Annals New York Academy of Sdcacea Tabli i WOKLO PRODUCTION Of PLASTICS IN MILLION Tons ru Yur" Ym* UUHmTom 1930 1950 1960 1970 <0.1 1.5 6.9 30.0 Tails 2 World Production and Production Capacity for PVC Rosa (Million Tons)"**'*1 Predoctk* 1990 MO 1973 Auul CaptdQr 1910 1973* ms* Western Europe Western Germany United States Japan Eastern Europe Other areas Total 0.053 0.014 0.578 0.173 2.948 0.930 1.950 1.088 0.861 0.544 7.391 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. Taels 3 Diversification op PVC Markets114 PVCUvkit Cn--iiUw (%) Calendering Extruded products Wire and cable Calendered flooring Film and sheet Paper and textile coating Sound records Plastisols Protective coatings and adhesives Iojection and blow molding Coated flooring Other domestic uses Exports 18 14 12 10 6 5 5 5 4 2 11 5 ambient condition, vinyl chloride (CH=CHC1, 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.** Commercially pro duced VC monomer is in general highly purified; degrees of purity of 99.99 per cent art reported. Specific, declarations of individual plants state only marginal RSV 0016763 Maisteller et al.i Splenomegalic liver Disease 97 amounts of add (free HO), acetaldehyde, iron, acetylene, butadiene, water, and stabilizers.1* Avoiding impurities is a prerequisite since they retard polymerizelion."-** Liquid VC is stored and transported in steel containers.**'** Vinyl chlo ride is used mainly for polymerization, but it is also used as a refrigerating sub stance, as a propellant for sprays and aerosols, and for a small number of other chemical reactions.1* Four methods of polymerization are used for industrial fabrication of poly vinyl chloride: emulsion, suspension, bulk, and solvent polymerization.***-*** Commercially most important were the two older methods of emulsion and sus pension polymerization, but now bulk polymerization has been added.* In 1972, emulsion polymerization accounted for 7d 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, azobtsisobutyronitrile and isopropylpercarbonate.* * * Formation of free radicals also occurs by thermal decomposition of peroxide bonding (--0--0--).** Physical basis for initiation of free radical chainpolymerization is the homolytic dissociation of a pair of v-electrons (covalent bond) resulting in free radicals that contain single unpaired electrons. The single unpaired v-electron of the free radical obtained from the catalyst then reacts with the 7r-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* **' *** ** The random character of the termination steps accounts for the production of chains of different length and hence different degrees of polymerization with molecular weights statistically distributed around a mean value. One of the operating variables determining specific type of PVC produced is temperature* which influences degree and velocity of polymerization as well as vapor pressure. Ordinarily, emulsion polymerization proceeds at temperatures of 40-70*C and total reaction pressure of 8-10 atm* In emulsion polymerization reactors (size: 2000-5000 gallons) are charged with the watery phase, VC is added, the agitator is started, and the emulsion is heated. At termination of the polymerization process the reactor content is emptied into a dump tank. The slurry can then be processed by centrifug.ng 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 recyding.4-** Suspension Pvp is nlmost pure polymer since additives amount to less than 1 percent and most of that leaves when the slurry is centrifuged. For compounding, the powdery or granular polymer is dry-blended under heat and pressure using plasticizers, light and heat stabilizers, and sometimes fillers, lu bricants. and pigments or dyes.* PVC dry blends are compounded by hot mixing at fusing temperatures. Depending on the type of end product, fusion temperature lies below or within the softening range (120-I60*C). In calendering (production of endless sheets) temperatures of 100-120*C for rigid PVC and of 150-180*C for flexible PVC are reached. Tiles are fabricated by welding of several layers of calendered sheets in a heated press. In conversion to end products by extrusion RSV 0016764 98 Annals New York Academy of Sciences (profiles, pipes, conduit, ribbons) temperatures of 15Q-300*C can be reached. All ***** shows that temperature ranges, as a rule, from 10&-200*C In converting the thermoplastic PVC resin by various procedures. Toxicology, Occupational Medicine, Clinical Experience (Tables 4-6) Simultaneous with the start of large-scale production of PVC in 1930, pharmacologic properties of vinyl chloride*****"*** and problems of occupational health** were investigated. At first, vinyl chloride appeared to be a suitable narcotic which, even after Oster in 1947** and Carr in 1949* had observed severe MfHtaa arrhythmia (believed to be due to potentiation of adrenaline effect*), was considered to be one of the least dangerous chlorinated hydrocarbons.** *-** "1* With the exception of two communications concerning acute VC intoxication without serious consequence in 2 workers**" no other data on occupational health hazards in PVC production were reported until 1949 when Tribukh tt al.m pub lished results of an 'investigation at a Russian plastics factory. On ex* smiting of group of 73 workers (48 males, 25 females) engaged mostly in processing PVC polymer (compounding at temperatures up to 160"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," Parmeggiani,'* and Hervieux and Tessier* between 1953 and 1959. Acute intoxication was again reported, this time in Great Britain, with acute collapse during VC polymerization* and a second degree burn after direct contact with vinyl chloride.* Filatova et al.m,u 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* described 3 cases of acute VC intoxication oc curring in VC polymerization, 2 of them fatal. Suciu et a/.1"-1*1 were the first to give t more detailed analysis of the disease spectrum encountered in 16r 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 J. 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.m again reported on a Raynaud-like syndrome and central nervous system symptoms in PVC workers. Pushin"* 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 occumngin these cases, he diagnosed anicteric, chronie RSV 0016765 Marstdler tt 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 */ ci." 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 tt al..m Bour- richon," Wilson tt a/.,** and Harris Adams." With this clustering of publica tions the disease became known as "occupational acroosteolysis" with typical roentgenologic findings, often combined with Raynaud's syndrome and accom panied rarely by scleroderma-like skin lesions; the disease teemed to occur only in reactor cleaning ("polycleaners' disease")." *' Between 1969 and 1972, Anghe- lescu tt al..1 Filatova and Antonyuzhenko," Dinman tt (on the basis of a large-scale epidemiologic study), Liffcvre," Markowitz tt al." and Dugois tt 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* "* * " '"*M). Single deviant observations made in 1970 by McCord" and by Misgeld tt al.m in 1973 as well as warnings voiced in the past by Tribukh tt a/.1" in 1949 and by Danishevskii tt cl" 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*' " (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 tt a/.") themselves. The experiments of Maltoni tt al.m that up to now wen made known only in part, deal essentially with the carcinogenicity of vinyl chloride. These results had been preceded by the experimental work of Viola and co-workers."1**" However, re sults published by Torkelson tt al,m in 1961 induced the German Standards Advisory Committee to nduce MAC standards for vinyl chloride from 300 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 syndrc..ie "vinyl chloride disease." " Liver Disease in PVC Workers Clinical Observations; General Outline It seems quite remarkable that after the findings of Tribukh tt 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 cf portal hypertension and angioscarcoma of the liver which both are now recognized to be associated with exposure to vinyl chloride. RSV 0016766 Annals New Y ork Academy o f Sciences RSV 0016767 t i t a ll Splesomegalle Uver Dbeue RSV 0016768 Aonala New Y o rk Academy o f Science* RSV 0016769 t Mastromatteo et al. (I960) Lester et al. (1963) m (5) r (5) t (5) m (3) rm B (3) ID (5) r (5) S (3) t (3) 100,000 200,000 300,000 400,000 rf r (2) 30.000 70.000 100,000 130,000 30 min 30 min 30 min 30 min Deep narcosis--side position with tremors Deep narcosis (t mouse dead) Dead; | in deep narco sis, 1 died hours after exposure Deep narcosis, I died during, ) aftet 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 hemorrhage* and edema liver: congestion, partly fatty Infiltration(g) Kidney: congestion Clotting defect Surrlrore: "Utile difference from control animals (liver, kidney, spleen, brain, heart, adrenals, tymnh nodes, eyes) except for pulmonary congestion'* "No visible gross pathol ogy" Lung: coogcslioo/cdcma 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. RSV 0016770 A m *)* New Y o rk Academy o f Sdeacee RSV 0016771 Tabu 6 Vinyl Chlokidi Exrosuaa in Laboratory Animals--Chronic Toxicity (Rrvicw or UraATtias) AalMr Spcdca* Cwcolnlka (PP") La|th ol EipoMif* ruy Torkelson *t at. (1961) rm r (24) 900 7 fa/d, 5 d/wk for 4.5 mo 200 7 h/d, 138-144 limes in 204 d 200 4 h/d 2 h/d for 6 mo 1 end 0.5 h/d for 6 mo 100 (seme procedure as in 200 ppm) r (48) g (24) 50 7 h/d, 130 times in 189 d Normal growth Normal in appearance, mortality, end growth Normal in appearance, mortality, ana growth "Entirely normal'1 - Normal in appearance, mortality, and growth Normal in appearance, mortality, and growth Liver: average weight increase, cea> trolobular granular degeneration Kidney: interstitial and tabular changes Liver: microscopically normal la rats, guinea pigs, and dogs; cea. trolobular granular degenctaUoo in rabbits (together with necrosis and some foamy vacuolation in male and necrosis with periportal cellular infiltration la female); weight increase of rat Uvers Liver: average weight increase Liver: slight increase of average weight in rats after exposure 7 h/d, 138-144 limes in 204 d and cither 4 or 2 h/d for 6 mo Normal Lester et at. (1963) r (18) 100,000 80,000 8 h/d for 2 d 8 b/d for 13 d r (10) 50,000 8 h/d for 19 d Narcosis, 10 rats died, initial loss of weight, followed by normal growth ("tolerance to the gas") Initial loss of weight, followed by normal growth ("tolerance to the gas") Lung: acute focal necrotizing pacts* monia, edema, metaplasia Uver: parasitic cysts, moderate to marked swelling of cells, definha fine to medium or large irregular vacuoles, compression of sinusoids Spleen: lymphocytic hyperplasia in cluding most of the loterstitium Liver: parasitic cysts, marked swell ing of cells, large irregular vacuoles or clear spaces, compress! sinusoids, changes focal to diffuse I 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; no differences be tween control and experimental animals Liver: 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 Conclusions: 1.The only finding suggesting specific toxic action of VC is tbe 1 incresse in liver weight on exposure to 30,000 ppm for 19 d and to 20j000 ppm over 92 d 2. Morphological alterations with out pathologic significance Liver: increased volume, smooth sur face, sometimes subictcric, some what more brittle consistency than normal Microscopically: Alteration of kepotocytee wHb marked cytoplasmic and nuclear polymorphism (torpid degenera tion of Ine cytoplasm to necrosis) Proliferation and hypertrophy of Xupffer-celU Roma tell Infiltration of portal traett Blockade of portal capUlarieMt centrdohtdar reins and slmuoids by numerous centrally located areas of partial necrosis Intensive fibroscltrotlc reaetkm along areas of degenerative proc esses Fatty change Kidney: signs of tubulonephrosis sometimes accompanied by chronic interstitial nephritis A m a b New Y o tk Academy of Science! RSV 0016773 i Mintdler et a/.: SplenomegAlie Liver Disease 107 la December 1972, our colleagues from the Department of Dermatology alerted ua to the possible occurrence of serious liver disease in workers of a nearby chemical plant who wen engaged in vinyl chloride polymerization and to a degree in processing the polymer to the final plastic product. We started an extensive examination program that included peritoneoscopy and guided Uvcr biopsy because we felt that this procedure might yield deeper insight into nosology and pathomorphology of vinyl chloride-associated hepatic disease than merely blind percutaneous biopsy, since a larger proportion of cirrhotic or fibrotic changes may escape detection if oily blind biopsy is employed.**-**'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 this plant, either as reactor cleaners or in further processing of vinyl chloride (centrifuging, drying, sizing, and bagging the polymer). To date, we have been able to collect data from a total of 50 workers of this plant (Tablb 7). Their age distribution is shown in Fiauu 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 (Fiouxe 2) ranged from 9 months to 21 Ya yean for the 44 polymerization worken, with 15 of them having had an exposure of 9 or more yean* duration. For the 6 men working in the postpolymerization phase the length of exposure was 13, 9, 5M, 4Vi, 4, and 2 yean, respectively. Case 50 had been working in the postpolymerization phase for 2 yean and subsequently in the manufacture of high-strength paper (harden ing by epoxy compounds) at the same plant for 10 yean. Medical History In the overwhelming majority of cases previous history was uneventful. One worker (case no. 1) had a previous history of jaundice of unknown etiology 18 N* Of COM* Fiouxa 1. Aje distribution of 50 PVC production workers (age st examination). RSV 0016774 j i 5i X * 1 1 s1 J9 1` 1 1, ll asj If F 1 SB i1 II Is} Is 1 Ji fi. a 1 s l jI*s fcA. 6 Hs Za sr 1 Our 2 Om 3 Om 30 PM 36 PM 47 PM 11/t -- *9 T 16*32 t + 1.3 +2 3 2 3 1.7 6.1 13.6 13 1503) 13 19(24) 4 Om 46 PM s Om 31 PM 6 Om 31 PM 7 Om 52 PM 1 Qm a Om 10 Om ii Om 12 Om 13 Or 14 Om 13 Om 1# Or 17 Or 11 Our 13 PM 44 PM 39 PM 43 PM 27 PM 40 PM PC 32 PM 33 PM 43 PM 42 PM PC 34 PM 19 Qm 31 PM 20 Turk 33 PM 21 Or 30 PM 22 Om 34 PM 21 Or 36 PM 24 Or 30 PM 21 Or 13 PM 26 Ocr 30 PM 27 0r 11 PM 23 Or 31 PM PC 29 Turk 13 PM 30 Or 30 PM 11 Turk 36 PM 32 Turk 33 PM 33 Our 32 PM PC 34 Om 40 PM t7/6 17 16 13/3 14/6 13/9 12/6 12/3 0/9 11 9 3/6 6/3 6/0 6/6 3/9 3/9 3 3 3 5 6/9 6/9 6/9 4/0 1/0 4/0 3/9 3/9 3/6 3/6 1/0 3/6 8 43-64 16 1 8 3 16 16*32 23 __ 16 16 3 16 16 3 8 16 16 8 16 16-32 t -- S 4 t 4 16 + + + + + + + + + + + + + + + + + i.i 10.2 13(22) 13(47) 3 1.3 9.1 19 17 +t 11.3 + 2 (2) 1.2 16.7 23 22 + I.S 3.6 13 1.3 13 ttS+ 3 + 2.0 17.6 31 6.2 IS 13 + 1.1 13 23 13 13 + 2 11 1.1 13.0 16 16 3 1.1 13.1 19 t7(31) 8.3 13 13 +2 13.8 23(24) 23(63) + 10 (10) 1.4 6.9 (20) 07) + (28) + 13 + 9.6 13 13 4t- 1.3 21.3 7.6 21(21) "SS" f t.9 6 1.8 90 190 + 1.3 1.3 32(27) 30(40) 3 7.3 13 1304) f 1.3 + 6 1.7 1.3 13 7.1 23 13 23 +6 + 1.3 3 I.S 23.6 23 6.4 13 53 17 + . 1.3 1.3 2.2 22.3 23 3 6.S 23 +64 12.3 19 34 17 16 + 1.3 1.1 3.6 19(20) 15(31) 11 Or 31 PM 36 Or 33 PM 17 Or 47 PM 13 Or 30 PM 19 Turk 30 PM 40 Or 4| Or 33 PM 41 PM 42 43 Our Or 41 36 PPMM 44 Turk 33 PM PC 43 Or 43 PC 46 Or 47 Or 43 Or 4349 PC PC 43 PC 49 Or 37 PC so Our 36 PC 3/3 3/3 3/0 3/0 2/9 2 '6 2/3 1/9 1/6 0/9 0/3 13/0 3-16 6-16 (110160)2 16 -- -- -- 14 1 1 1 14 0/0 21 3/3 4/6 16 -- 4/0 44 2/0 31 + + + + + +3 +3 1.3 1 1 + 3 +7 + 6 +1 1 3.2 (20) 13 13(24) 9.7 13 8.4 17 13 6.1 19(22) 17(47) 6.3 17 17 3.1 28 3003) 9.1 13(33) 13(30) 13.1 13 17 I.S SI2 (47) 7.0 (88) 23(20) 28((5!) * Centimeters below costal margin, t For explanation see Table 11. t For exolanation see text. RSV 0016775  mo* coic , and H v r e iM ie D ata o f 90 PVC W e a u u M f.U k* pttehM aftiotat m odern "af +rtU, /\ +++ + + J++ + + +++ + + + + ++ + AfwartwRrdi H | EiMtAnwn 1 fSkia idw A *; lo , lu ++ Q/Ned U/O Ned i U oou O/N0 ed o0 u 0 oo t u u o o U/O u u C/Ned O/Ned tbmroeoodteerdc; oBoc, aiva*erpcaossetndescHrotlici f + , marked. nu ^53 o 3 * Oft M Mja S nn| i - N Sefiany HsSS ** * . Capnbf IM i V V V V V V V I V V V V V 1 V i V V I V I I i V V i I/O CapauUf vcaaefa ++ ++ ++ +++ ++++i + -Hi + +++ + + +i+ + + ++++++++ + ++ + T-t-M IT IIM ++ + e ++t++i E+ ++++ J-H-f l+ - -. + J[ ~ ~ J+ + ++ ++4+++++ Cd)|iain(loa i iilMldtl --It. ErUbwihI u4/ iwflfiiaUae el Euan! cedi ScpUJtbrafe ! M-a?m* J mww55C **85 **-.55 MMMHHHHM >.>3%8g"....w....'.e...>....4...'.4.... ..~.e. - a a SM ~ ** ++ + HMM S3 8 MMAftl *^S3 E B? 4 S5S ?S MMrRjM mwm*b*b*--" ~ ?* * S3Sw35*St* ?33ti ?*3t!ee mZ3 Z3 ? H MM NHHH HR H uf liM M M SN NHM NSfHD N RfR N | | s'*wsn'*'*r:""8lB 2 *--fi B **Mr**a*4AB **n^Bo ?--B 2 n M OM,, nm-Q * ,, **.. -**.. 5--""Hr1* **"sx--bbs 1 f-- I--*"*S|*-- S*C f * * * r* Spina SIm br SdatJcafAjr tea) ++ + +++ + M M M M ++ + +++ +++ MM -H- | EaUipani f Splm + + +++++++ + | EwpA^MlVeilMi ++ ++ +++++ ++ + +++ ++ 1 M M M 1 1 1 + +++ M M M + + ++ + | isocaan! ; PC. (+ ), pitchy "perihepatitis minimal; + , slight; RSV 0016776 no Annals New York Academy of Sciences yu Fiouu 2. Length of exposure in 44 workers engxged in the polymerization proc ess. yean prior to examination (length of exposure: 21 Yi yean), and Mchronic liver disease" was diagnosed in 1968. In 3 cases a symplomiess solitary biliary cal culus was found on cholecystography (case nos. 43, 45, 50). In one Greek laborer (case no. 48), who had been engaged in the postpolymerization phase of produc tion for 4>/t yean and who in the past 2 yean 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 pyioric 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 r-d ' Hsto.y of alcoholism. Ten did not use alcohol in aoy 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. i RSV 0016777 MtntfiUer ft al.: Splenomegalic Liver Disease Tails 8 Alcohol CoMsUhimoN in SO PVC Wokksaj EspavMi Aksfaal lataka da s haMi/4) Na. None Up to 8 g Up to 16 g , Up to 32 g < Up to 64 g ` Not stated 10 13 16 6 2 1 < Total 30 Tails 9 GAsntoiNTsrnNAL Bleidino (Esofhagial Vaaicbs) and SUROICAL iNTiaVENTION IN 30 PVC WOUUU Na. Gastrointestinal bleeding Splenectomy Splenorenal shunt Gastric resection for anaplastic carcinoma 4/30 3/30 1/30 1/30 111 Another 24 claimed to have experienced temporary central nervous symptoms, such as dizziness, slight disorientation, disturbance of vision, and mild headache, often combined with nausea and mild upper abdominal discomfort. Twelve workers spontaneously reported to have smelled "the gas** occasionally which they claimed had a faintly sweet odor. A Raynaud-like symptomatology was re ported in 8 cases. Four had experienced episodes of bleeding from esophageal varices during the past 2 years (Table 9). Methods of Investigation Besides physical examination, a broad spectrum of laboratory tests was ap plied to each case (Table 10). X-ray examination of the upper gastrointestinal tract and intravenous cholecystography were carried out in all cases z- were a plain chest film and an ECG with 12 leads. In 3 cases esophagogastroscopy was done. Scintigraphy of liver and spleen was performed in 48 cases. Peritoneoscopy and guided liver biopsy were performed by us in 41 workers, peritoneoscopy without biopsy in one, and percutaneous blind needle biopsy in two other cases (total: 44 cases). Data of case 14 were put at our disposal by courtesy of Dr. HaralJ Honing* who, during a 3-year follow-up including three peritoneoscopies, had previously classified the case as noncirrbotic portal fibrosis with portal hypertension of unknown etiology. We were given access to data of cases 10, 24, 29, and 31 which had been examined by peritoneoscopy and biopsy at the Medizinische Universitats-Poliklinikt; 1 of these 4 cases (case no. 10) later * Head, Klinik Fdhrenkatnp of the Federal Board for Employee's Insurance, D-241 Molls, Germany. t We would like to thank Prof. Dr. F. Krtlck, Dlrektor der Medianischen Uoivcrsitlts-Polikiinik, Bonn, and Prof. Dr.. A Gtitgemann, Direktor der Chirurgischen Universitkuklifuk, Bonn, for permission to include data of 3 and 2 cases, respectively. \ RSV 0016778 112 Annals New York Academy of Sciences Tail* 10 SncrauM or Labosatoky Tun Pibformid in 30 PVC Worksju 1. Blood aadimeautioa rate; hemoglobin; red cell count; white cell count; ditferea- tin! call count; hematocrit reading; number of plateleu 2. Total bilirubin 3. Glutamic oxaloacetic transamioase 4. Glutamic pyruvic trantaminate 3. Alkaline phospbatuc 6. Ladle dehydrogenase b 7. eholincttcraac f 8. Thymol turbidity f 9. Total protein 10. Scrum electropboreeii 11. Bromsulfalcin retention 12. Urinalysis 13. Blood uree nitrogen 14. 15. Serum Serum curreicetaindindejoniy in some cases 16. Serum iron 17. Serum copper 18. Blood glucose 19. Total cholesterol 20. Serum triglycerides 21. 0'Lipoproteins 22. Blood coagulation factors (II, V, VII, X, antithrombin, thrombin time, tbrombdutogram) 23. Hepatius-aisoetated antigen and antibody underwent splenectomy after repeated hemorrhage from esophageal varices. In a last case (ease no. 7) splenectomy and lienorenal anastomosis were done at the Chirurgische Univenititsklinik.t Histology of the spleen was available in 3 cues 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 cues, in 4 of which it wu not accompanied by hepatomegaly. Jaundice, spider angiomata, palmar or plantar erythema or physical demonstrable ucites were not found. Laboratory Tests The most consistently positive biochemical test wu 45-min BSP retention (Table 11). A marginally to markedly pathologic retention wu 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 a jinotransferases GOT and GPT were unequivocally pathologic RSV 0016779 Manteller ex a/.: Spkoomegalic Liver Disease 113 Tabu 11 Risults or livu Tim in SO PVC Wotuu (Cl jtnaTiON Baud on Maximal Valuh Obtainid in Multxpli UrriAMiNATiora) Normal Pathologic (Range) (Mean) U-Ubltf KAmUm CL0%) 12 38 (3.1-25.6%) (10.47%) GOTt $(14VaBwi/aioifoaUta)* 38 12 (1.1-2.2 mg/100 ml) (1.4 mg/100 ml) N.f ClM Alkali** FW*k*U**t (4* aU/nb' 40 10 (50-110 mU/mt) (71.9 mU/mi) cm Definitely normal Marginally normal Pathologic Total --12 mU/mll -- 19 mU/mlf 12-20 mU/ml 20-30 mU/ml [20-50 mU/ml 31-60 mU/ml >50 mU/mi >60 mU/ml 4 31 13' 15 2. 50 -12 mU/mlf -22 mU/mlf 12-20 mU/ml 23-30 mU/ml 20-50 mU/ml 31-60 mU/ml >50 mU/m] >60 mu/ral 11 22 12' 17 5, 50 * Upper limit. f Modification of the method described by O. A. H. Bessey et aJ. J. Biol. Chem. 164:321,1946; upper normal limit (adults): S. J. Walter and R. Gldckner. ArztL 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. 3:1,1963. 1 Substrate-optimated standard method, W. Thefeld et el. 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.*1* A more or less marked thrombocytopenia (less than 150,000 platelets/mm') was observed in 42 cases. Except for 1 patient with splenomegaly (case no. .4) who bad leukopenia besides thrombocytopenia, hematologic results were other wise within normal limits. Tests for hepatitis-associated antigen and antibody were negative in all cases. All other biochemical tests including initially intro duced but later abandoned immunologic reactions failed to contribute to the problem in question. Roentgenology; Endoscopy of Upper Gastrointestinal Tract; Scintigraphy A diagnosis of esophageal varices, in some cases combined with varices lo cated in the cardiac region of the stomach, could be made in 10 workers; in 5 of them this was done by barium meal, in 2 by x-ray plus endoscopic examina tion. in 1 by barium meal and splenoportogram, in 1 by endoscopy and spleno portogram, and in the last patient by indirect splenoportography. Only in one case (case no. 7) was intraoperative measurement of portal pressure possible, and RSV 0016780 114 Annals New York Academy of Sdcoccg Tails 12 SniNOHHUV IN SO PVC r.'otuu SpJtin size o measured by scintigraphy In 49 mmi Method*: Splenic scanning by lffH|-BMHP (40 eases (normal diameters: 11 x 7 x 4 cm) Liver scan by ,fc*Tc sulfur colloid (46 cases A. Within normal limits (4 of the cases - PVC-processing workers): 11/48* B. Exceeding normal limits (2 of the cases - PVC-procosm* workers): 37/48f C Not examined (previous splenectomy): 2/30 Splenectomy in S cases Diameters, weight: 1. 15 x 12 x 7 cm (300 g) 2. Ruptured at splenoportography (5C0 g) 3. 23 x 13 x 6 cm (1250 a) (scintiscan - 24 x 12 x 7) In 6 of the 11 cases by liver scan. t Io 2 of the 37 cases by liver scan. this proved to be only slightly elevated. Otherwise, no determinations of intraspienic pressure or of wedged hepatic venous pressure have been carried out so far. In 5 eases 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 0"Hg-labeled bromomercury hydroxy propane)! in 40 cases. Measurement of three diameters (length, breadth, depth) allowed detection of even minor degrees of splenomegaly.** "'"1" The organ proved to be alightly 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 p^pnits 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 met! xi 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* ** Based upon a compila tion of 63,845 eases in which peritonemcooy was performed with 48,766 guided liver biopsies, Brilhi" 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: I. Symptoms of hepatic enlargement. These were measured by the relation of t We wish to thank Prof. Dr. C. Winkler, Direktor dea Iastituts fQr Kliniache usd Experimentclle Nuklearmedizin sn der University Bonn, for permission to use results of sci&tigraphie examinations carried out at his institute. t RSV 0016781 Mtntelfer tt /.: SpIcoomefiUc Uver Disease 115 4 4*f . r' i'f * r Frouu 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, 2V\ yean.) 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 RSV 0016782 116 Aimak Hew York Academy of Sctaaoce Ftouu 4. a. Finely nodular surface of the liver. Goaeup view of lower edge of left lobe. (Case do. 4; length of exposure, 1714 yean.) b. Finely nodular appearance of underside of right hepatic lobe with stellate capsular fibrosis and small scan in a worker engaged in processing the polymer. (Case no. 48; duration of job assignment, 4Vt yean.) RSV 0016783 Musteller it a/.: Splenomegtllc liver Disease 117 Fiouu 5. Comely nodolar hepatic surface resembling advanced tirrfaoeis; left lobe. Histologically there was, however* only septal fibrosis and collagenization of walls. No evidence of portal hypertension. (Case no. 42; length of exposure. 1M years.) reflection* proceeding through finely nodular (Figure 4) to eventually coarsely nodular surface relief (Figure 5). 3. Presence of different degrees of load or diffuse hepatic capsular fibrosis. The capsule is a very subtle indicator of pathologic, processes taking place in the underlying tissue.1" 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 (Fioure 8). In other cases there were several or numerous small scar-like lenticular patches (Figure 9) or broader slightly concave cicatricial lesions probably indicating postnecrotic scarring. In 4 cases focal whitish capsular thickening resembled what is known as focal ''perihepatitis cartil'rinea" (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 eSort to bare the lower pole by inserting a palpation probe is some- RSV 0016784 Fiouu 7. Typical comma-lilt* capsular fibrosis on convexity of left hepatic lobe near falciform ligament (top center); in contrast to finely nodular lower anterior edge (see Fiouu 4a) of left lobe, surface on convexity is comparatively smooch. (Case no. 4; length of exposure 17ft years.) 118 RSV 0016785 Pious* S. Coarsely reticular fibrosa of GHsson'i capsule; rigbt lobe. (Cue no. 9; length of exposure, 139% yean.) i 119 RSV 0016786 Plows 10. Coarsely reticulated fibrosa sod patchy focal whitish capsular thick ening (focal ``perihepatitis cartiUginea"). resembling capsular alterations seen in thoro* trastoais of the liver. (Case no. 6; length of exposure. 16 yean.) Flows 11. Particularly pronounced increase of capsular vessels in case no. 14 (length of exposure. 11 yean) 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 i1 1 20 RSV 0016787 Mantdter tt cl.: SpteoomeyUic Uvcr Dtacito 121 Piovu 12. Crenate margin of enlarged spleen; lentfl-shaped thick milk-white peri* splenitic fibrous sod millet-sized tubcapsular hemorrhages. (Case no. 5; length or ex* posure, 17 yean.) 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 cxenate 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 Gli&son'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 thew 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 Hu<- *n pcrta! 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 Urge in testine, and especially accompanying intra-abdominal adhesions. Minima] 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 RSV 0016788 122 Aaaab New York Academy of Sdeacee Tams IS Hepatic Sukpacs AtTnunoMi Owi,tdon Paammscorv (a - 47) oa at Laparotqmy (a 2) All M*. Suffice 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 seers E. Pttcby "perihepatitis cartiiaginea" Capsular vessels A. None (normal) B. Slightly augmented C. Conspicuously increased 24/49 7/49 13/49 23/49 3/49 6/46 3/46 20/46 14/46 40/46 3/46, 23/46 18/461 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 (see Fioure 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 io the majority of positive esses it was present in the form of a more or less con spicuous reticulated capsular thickening. In esses with massive psteby perihepatitis the picture was reminiscent of hepatic "thorotrastosis" (see Fioure 10).*" 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 laparoscopicatly 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 cyto^smic 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 occasions! 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- RSV 0016789 TABU 14 HBPATQtPLSMOMaOALY AND SYMPTOMS OP POSTAL HYPtSTSNSION ON PUlTONSOtOOPY ob at Laparotomy ( - m 8nKsrHypwM ( ) Nons Present 31/49 18/49 Non* Present Spleen not vis- ualtzed* 13/36 23/36 13/49 None Qucstiontble Marked 40/49 2/49 7/49 * In 13 cases the spleen could not be visualized during peritoneoscopy even after extreme tilting owiog to its being covered by nonremovable omental fat. Tails 15 Synopsis op Pibtinent Histologic Features in 49 Patients CeUatcakatka MStaoMidal Walk EalanoMat tad/or PLiicltloifrianllkCaalokl Septal Flbtoak Fatty dun None 10 1 34 26 Present in 39 48 15 23 Grading Minimal 7 25 6 6 Slight Moderate 32 -- 20 2 8 14 13 Marked 1 ---- Ftouu 13. Degenerative changes of hepatocytes with hydropic swelling and granu larity of cytoplasm. Occasional single cell necrosis. Note proliferation and pleomorphism of littoral cells (Case no. 14; length of exposure. 11 years; biopsy several days after last exposure). H&E (X235). 123 RSV 0016790 t 124 AnoAis New York Academy of Science* Piouu 14. Micronodular appearance due to septal fibrosis with characteristic hydropic swelling of parenchymal cells (Case no. 5; length of exposure, 17 years; biopsy 2 weeks after last exposure). Trichrome Goldner stain (X94). plasm. Fibrosis, observed in somewhat less than one-third of the cases, was partly septal, partly portal, and partly midzonal; in 80 percent of the cases there was collagenization of sinusoidal walls, occasionally forming a network-like intralobular fibrosis (FtGUXB 14). Poiymorphism of liver cell nuclei was char acterized by enlargement and polyploidy of nuclei. The total number of bi- or multinudeated cells, however, did not seem to be increased. A rather character istic feature was an activation and proliferation of sinusoidal ceils. 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 (F'gure 15). Los than half of the cases had predominantly minimal to slight fatty in filtration of hepatocytes, not correlated to either length of exposure or drinking habits. More detailed information on special features of histology may be found in Dr. Gedigk's paper. Discussion Our synopsis of prior studies published between 1933 and 1973 (Table 4) in cludes a total number of about 12,500 workers employed in VC polymerization and PVC processing. However, considering the relatively high standards of oc cupational hygiene in modem chemical industry,4* -* "1** 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 yean, the number of reported cases with (mostly ill defined) liver disease seems to be surprisingly small. Other mani- i RSV 0016791 ManteUer et al.i Splenomegalie Liver Disease 125 Fiouu 15. Toxic and adaptive changes of parenchyma. Conspicuous pleomorphism of littoral cells (Case no. 3; length of exposure, 18 yean; biopsy 2 weeks after last exposure). H&E (X400). festadons associated with VC polymerization had been seen more frequently (acroosteolysis in 118, Raynaud's syndrome in 97, skin lesions in 40 of more than 12,000 workers). They evoked particular interest mainly between 1966 and 1971 and were thought to be restricted to avoidable manual cleaning of re* actora*-'* 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 publicadons. Intimations made by workers seemed to confirm this assump* non (distinct odor of VC vapors et diverse working areas even outside the loca* don of reactors, deteriorating quality of ventilation after windows had been wailed 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* RSV 0016792 126 Amah Now Yodc Academy of Sckncet oamly Inconspicuous symptomatology (for lo^tsace, minor hepatic functional in sufficiency**1) which* with reference to liver and spleen, even in advanced stages would be liable to escape dtuctioa if only conventional methods of examinations were employed. Therefore, statements given out by other plants that liver and spleen *h"g** had never been observed should be met with scepticism unless proven by morphologic methods. The dramatic discovery of eases of hemangioendotheliosarcoma of the liver in PVC workers throughout the world early in 1974 has shown that this is cer tainly not merely the problem of a specific plant. None of the clinical or morphologic findings seemed to be mutually cor related nor did we find a recognizable correlation between a certain set' of symp toms and length of exposure or alcohol consumption. The clustering of patho logic findings (liver, spleen, portal circulation) in this gioup now comprising 50 workers confirmed our previous impression*1 that we dealt with a symptomatology compatible with the diagnosis of chronic toxic liver damage,*-*'" similar to that seen after repeated or continuous exposure to halogenated hydrocarbons. The histomorphologic appearance of the liver was essentially characterized by de generative lesions (frequently observed in chronic toxic liver injury; hyperplastic smooth endoplasmic reticulum, alterations of rough endoplasmic reticulum due to toxic derangement of membrane structures"-1**1*), fibrosis (septal fibrosis or collagenization of sinusoidal walls with occasional capillarization and finally network-like interstitial fibroais), and enlargement or proliferation of littoral cells. Whereas the mostly unimpressive histologic findings permitted reflections as to possible etiology,*-*-*-1"-1* peritoneoscopic results, although usually much more suggestive of serious liver damage, could only be interpreted as unspecific evidence of injury; for instance, even pronounced capsular fibrosis merely indi cates a repair stage of underlying tissue damage due to a variety of noxious agents.* "* ** 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,M-li,"M,,-l" or of so-called idiopathic portal hypertension,""'"*",,*1""lu'" respectively. In this disease en tity, portal hypertension and splenomegaly are usually accompanied by similar alterations of hepatic surface and histologyin some cases, however, portal hypertension seemed to have been the result of sclerosis or thrombosis of the portal vein.*-"-*-1* Another analogy between liver disease as sociated with PVC prodtr*?on end 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 aberrut;"-"- BSP retention, however, can be readily explained by the character of the histologic lesions." A certain resemblance to Banti's syndrome is sug gested.1*1" It should also be realized that the degree of fibrosis in our cases was most probably underrated on microscopy since surgical biopsy material, more suited for detection of fibrosis,1" 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- RSV 0016793 MmteUfif if aL: SpteaomegaUc Liver Dbetic 127 entiv* cellular Moos) may ba suffldeat to explain an increase in portal pra gma* M. , *. IMU, UU^IB,ia,M In this connection, particular attention should be paid to the enlargement and proliferation of littoral cells, as described above, because of their relation to fibrofenesis.*'"'*"'"'"" 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 pathogenetie factor in splenomegaly?). In this context, recent reports on oncogenic properties of vinyl chloride* *'" should be evaluated since proliferative alterations of littoral cells are possibly the precursor stage of hemangioendothe!iosarcoma. If one looks for a pattern of injury similar to that seen tn VC-associated hepatic hemsngioendo- theliosarcoma, gross morphology, histologic appearance1* "* and conjectural course of events in the pathogenesis of hemangioendo- theliosarcoma occurring after exposure to Thorotrast or arsenic can perhaps serve as an example. It could be speculated that chronic stimulation of the reticuloendothelial system (possibly also of hepatocytes1*) by a toxic substance" may be the common denominator. This leads back to the question of etiology.* Quantitatively vinyl chloride monomer is the most likely suspect in VC-associated liver disease. Numerous hints (such as odor and acute symptoms of overexposure) contained in job histories point to the frequent release of considerable concentrations of VC at various working areas in VC polymerization,*'*** even if one considers the un reliability of olfactory sensations** * " " and the wide range of olfactory thresh old concentrations reported in the literature."* "` **'**'" Except for Schumann's communication in 1934," quoted by Williams" in 1959, very little is known about the kinetics and metabolism of vinyl chlo ride.*'*'" 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, "dnig-bydroxylating enzyme sys tems""), for example, by way of "lipid peroxidation." Furthermore, for mation of free radicals may also be involved in the oncogenic action of vinyl chloride." Regardless of such deliberations, results of animal experiments with long-term exposure to pure VC have demonstrated considerable hepatosplenic injury* "* apart from tumorigenesis and damage to other organs." " 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* 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 prv-essirg 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 tnat VC trapped in the polymer can principally be liber ated**" during processing (e.g., calendering, moulding, extrusion, etc.)' at temperatures of 100-200*C.**" At the moment, it is also open to discussion whether PVC dust, apart from damage to the respiratory tract,** " may cause gastrointestinal symptoms,* for instance, by penorption." RSV 0016794 12ft Annate New York Academy of Sciences la the future, periodic control examinations of oil PVC workers, especially of th^H engifed in VC polymerization, at short intervals employing sensitive methods should be obligatory unless it should prove feasible to eliminate com pletely any possible air contamination. 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Their occurrence in the absence of both intrahepatic and extnhcpatic obstruction of the portal vein. New Engl. J. Med. 261: 209. 147. Tofjcelson, T. R., F. Oven A V. K. Rowe. 1961. The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Am. Ind. Hyg. As soc J. 22:354; Bull. Hyg. 37: 3S7. 148. TRieukh, S. L.. N. P. Tikhomirova, S. V. Levina ALA. Kozlov. 1949. Usloviya truda i meropriyatiya po ikh ozdorovleniyu pri protzvodstve i izpol'xovanii khlorvinilovykh plastiJeskikh mass. Gigiena Sanit. 10: 38. 149. TEuffert, L. 1959. Aspects toxicologiques de 1'industrie des matures plastiques. Arch. Maladies Profess. 20:43. 150. UJS. 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. RSV 0016800 t 134 Aaaib New Yorfc Academy of faiencet 151. Vnu, P. L 1970. Pathology of vinyl ehloridi. Mod. Lavoco dli 174. 152. Vnu, F. L-, A. Bioom ft A. Cafutd. 1971. Oncostnic rtspooas of rat akin, |usfl. tad boooa to vinyl chloride. Cancer Rea. Jli 514. 153. Volkkumb, G., F. Sutvii F. At Asian, H. John A S. Waottxl. 1961. Aufsaugum voo Folyvinykhlorid-Pulvar dumb dk Dflnndarasrhlrtmhaut uod dareo Abuinsport rfurch die CbyJusfeflkas. Drat Gaaundhaitew. 16t 1727. 154. Von OarnNOiN, W. F. 1964. The Halojenated Hydrocarbon of Industrial and Toxicological Importance. Elsevier Publishing Company. Amaterdaa, The Netherlands. 155. Waono, H. N., Jjl, I. O. McAfee, I. M. Wbincr, M. Iuo, J. Muhnu A W. P. Cam, Jr. 1963. The uae of Hg-203 labeled bramamercurihydroxyprtN pane (BMHP) in radioiaotope stunning of the spleen. J. Nud. Med. 4s 190. 156. Warm, W. 1971. Zur Morphologic chrentscfeer tebetfcrinkhaiten. Leber Megen Derm Is 45. 157. Williams, G. M., J. M. Eluott 4 J, E Wbssurqbl 1973. Cardaoma after mHynwt eonvertion in vitro of epstheliaUika oelle from rat liver following exposure to chemical carcinogens. Cancer Rea. 33s 606. 158. Wiluams, R. T. 1959. Detoxication Mechanisms. The Metabolism end Detoxica tion of Drugs, Toxic Substances and Other Organic Compounds. 2nd edit Chapman ft Hall Ltd. London, England. 159. Wilson, r. H. 4 W. E. McCormick. 1960. Plastics. The toxidty of synthetic resins. A. M. A. Arch. ln<L Health 21: 536. 160. Wilson, R. H., W. E. McCoxmicc, C. F. Tatum ft J. L. Carnot 1967. Occupa tional acroosteolysis. Report of 31 cases. J. Am. Med. Assoc. 201s 577. 161. WtxTSCHAFra, LT.4M. W. Cxonyn. 1964. Free radical mechanism for solvent toxidty. Arch. Environ. Health ft 186. 162. Wittman, I. 1966. Peritoneoscopy. Vole. I ft IL Akadfmiai K1ADO. Publishing House of the Hungarian Academy of Sciences. Budapest, Hungary. 163. Zapp, I. A., Ja. 1962. Toxic and health effects of plastics and resins. Arch. En viron. Health 4t 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 techn :al 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. Da. M. L. Nbwhouse: M*v I ask Dr. Laibach how he selected his patients and how big was the exposed group he selected them from? Da. W. K. LelbaCH (University of Bonn, Germany): 1 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. Vcltman'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. RSV 0016801 10G4 liKSCHIPTfON Of MATRRIAL DBED rOR TESTS Vinyl < lilmiilc ((ilI('II('l) is a coloileas gas at room temperatures (boiling |Hiini, - l*t.D (!). Tho gasliaa a pleasant thcrcal odor and in alighlly soluble in wnlnr. Its limits of ioflaniiuability are 4.0 to 21.7 |>'i rf'itl by volume ill air.T '47rr* t in i I <M<ni<lo used in experiment* described in this report was a commondid product having the following' plant sjiccilicntions: Hailing range, l),1) per cent or inoro Imluw --10 C. at 7G0 tnm.; iicrliddrliydo, not morn limn 0.5 per cent; rcsiduo, not more titan 0.6 per cent. TEST APPARATUS The IH apparatus was tlio annio as that described in a previous report dealing willi ethylene oxide.* COMPUTATION AND ANALYSIS Of 0A8-AIR MIXTURES The vinyl rldmido-itir mixtures were created by adjusting calibrated flowmeters (Vrnluri type) to give the desired proportions of gas and air. Thu tiny] chloride content was then checked by analysis. The itppttviitus used was the same as that used for determining ethylene ditldnride in air* ltricfly, the method was to subject the vinyl clilni'iili' to romlnisfinn with oxygen (explosion method using elec I roly tic gits to "energize" the combustion), and absorption of tho products of ronibiintion. For mixtures containing insufficient oxygen for complete combustion, a known amount of additional air or pure oxygen wiis mixed with tlio sample before adding the electrolytic gas. A uiioiimim amount of stopcock grease was used in the apparatus to reduce emu through solubility of the gnu. For the samo reason rubber tubing ivns not used except for making joints of j>lass tubing, caution being taken In 11itv the ends hiilt together. TKHT I'llOCEIKUU:, IIKBCIIlrUON AND CAItK OP ANIMALS Tho test pmrediire, mid tho animals and their caro were tho same ns described in (lie published report dealing with ethylene dichloride.1 HV.aVII.T8 os TESTS The detailed test data are too voluminous to ho presented in this report imd only simuiiniizcd refills poitineut to aymptorns, gross pathology, ami fulnlily nio given. Speeiinens of tissue were taken for inicroHeupie exiiiiuiifttioii, n report of which will be mndo later. * fro I'lctinin a. fn I'fxluir IimIum* 4^ > Jui>r<, 11 IV . IP. s. liitirnu of Mine*, uiipubllstied dais. 1965 Aufuit 22,1030 srurrous or animals Control ortimaft.--No symptoms were exhibited by tho 18 control guinea pigs used in these tests or by the stork animals from which nil of the test animals were taken. Also, no deaths occurred. Exposed animats.--Table 1 gives tho symptoms shown by thn ani mals exposed to vapors of vinyl chloride and also tho average period of exposure required lo produce those symptoms by various concen trations of vapor in air. The reader Bhould note that the figures in parentheses indicate that the particular symptom did not occur in thn maximum period of test as given. Tho highest concentration of vinyl chloride in air used in tho expo sures (40 per cent) exerted an almost immediate narcotic effect on tlio animals. Within ono-fourlh minute the animals feli lo their sides in an apparent unconscious or narcose state, with convulsive twitching* of the trunk and extremities and jerky rapid respirations. Tho pigs 1 remained in this stato until death or termination of the lest. jeTaSLB 1.--Symptom produced in guinea mjt during exposure lo papers of vinyl fIHt cAlorid* Tjpo of ljmplMii* COMOBtiallop t( vopor md period of (apotuio firodurlni trmplonu > M lllttt n 1 3 1 1.0 0 0 u\ .Dntftef < ildti; Incmnpfolo DHcwll; Ukxw vIwdmmm; Ittrtultr iBftefUac i` N Mtnaui It*.............................................. ' VMbSIsm ra (Ml; motor aUili............... t InstH uscouaclouiMn; <J*op iwreoili; t . n* InlieMni ofoilromUln: aulrt .. . j|VjrJfwU,prapWid rraipllrooilono . itloot rautd. ...l* 1 (10> 1A-M i <0 1*1 '4X0) (MO) (400) 21 SC 00 240 (4N0I M0 jno 4w oan (400) (() urn <o) <0> (4MIJ (400) , j.*ooirit(o/>i I ropor In pm rani bp vahimo: tlm* Ip mlnolra. thnipf milrouQ*pwui*pmloa (Ireo In pucothosei. tl Not drtttUlQCil. V ^Concentrations of 10 to 25 per cent caused tho animals to fall on Ttheir sides with convulsions and with jerky, rapid respirations in II to 2 minutes. Following this tho pigs lapsed into a slate of appnr[tslly deep narcosis in which the convulsive twitching* and all inovc- gmenja ceased, Urn pigs being quiet and relaxed. This occurred {within 10 to 20 minutes at concentrations of 15 to 25 per cent anti 60 minutes at concentrations of 10 per cent. Slow, shallow Wpirations occurred with 20 minutes' exposure to 15 to 25 per cent la&d with 120 to 300 minutes1 exposuro lo 10 per cent. Tho pigs jBained in this state until death or termination of tho exposuro. iGoncentralions of 5 and 2.5 por cent did not produco the initial Qptom of "dropping to their sides and unconsciousness with conrive twitching of tho extremities." These concentrations jnoviftuetd first an unsteadiness in tho animals, a staggering on attemptrparii CM O CO <> > CO a: t i%n ing In iihiu' itI imii I, Midi signs of motor ataxia. This occurred within 2 In 5 iiiiiuiti'H. umi lasted ,'i( to 00 minutes, At tho ond of which time (hr |ii^s fell on their sides in an apparent profound narcosis, being eniiiHv relaxed n ill) im convulsions or movements nf ny kind. Thu respiMitiims wen- increased in rato and amplitude, becoming line ExrosuKt. Minuiu poo SCALE f mi hr i - ai ill* *fleci nf *ipiiui* of |uln* pic* la tlnjl cblotld* T*por In *lr rapid niul jerky in dmrarler nt llio end of 240 minutes' exposure to 0 ' per rent, iiimI slowed nnd became shallower at the end of 360 minutes, remaining in the Intfer condition until denth or termination of the exposure. Ci'iicinlmlniiis ol 0T> nnd 1.0 per cent did not produce any symptoms. 1967 Aucinf ?2. term The general symptom of narcosis was mfuiifrstcd in three degrees, increasing in severity with increasing concentrations of vinyl chloride: (1) Unsteadiness,staggering, and motor ataxia; (2) incomplete nnrrosis in which convulsions affecting the trunk and rxtrouutics persist; (3) a stale of profound or deep narcosis in wliirh tho animals arc quiet, on their aides, relaxed, and without movement, Observation showed that animals after being removed from llio exposure chamber recovered from tho most profound narcosis within 12 minutes. No signs of eye or nasal irritation were observed. BTHPTOMS emRIBKCED BY men Two of tho experimenters wore exposed to 2.S per cent vinyl ehlnrido in air for a period of approximately three minutes. They reported that the gas had a fairly pleasant odor. They soon began to feel dizzy and disoriented as to space and size of surrounding objects, and complained of-a burning sensation in the soles of llie feet. They immediately recovered on leaving the chamber and complained only of a slight headache, which lasted about 30 minutes. OROSS PATROLOQT Control animals.--A total of 18 control animals wore killed for autopsy. No gross pathology resembling that found in the exposed animals was found. Also no deaths occurred among the control animats. Exposed animals.--The gross pathological changes found in llio animals that died during exposure (see fig. 1 for conditions of exposure causing death on test) were intense congestion and edema of tho lungs and a hyperemia of the kidneys and liver. Tho lungs we.ro light pink in color; tho cut section was uniformly light red, and hied freely. A frothy exudate was present in the largo bronchi, and squeezing of the lung tissue covered the cut surface with n frothy, bloody fluid. The kidneys and liver wore deep red to purplo in color and tho cut sections wero moist and dripped blood. Tho animals that died within 1 to 8 days following exposure showed a congestion and edema of fhe lungs, with a swelling and hyperemia p/` of the kidnoys. Tho findings in animals of these same groups which were killed for autopsy immediately after exposure showed a hyper emia and edema of Iho lungs, with a congestion of tho liver nnd ' kidneys. AnimaU that were killed for autopsy 4 days following ^exposure still showed a hyperemia with areas of congestion through -out tho lungs, whereas those killed for autopsy 8 days following exposure showed atelectatic and emphysematous patches throughout the lungs. Tho findings in those animals flint wero killed immediately after exposure to conditions that did not causo denth, but which caused RSV 0016803 l Aucu't 22, lino lyes it mild degico of pailiologirnl change, were principally congestion mid slight edwi mi uf llm lungs, and hyperemia of the liver. The finding* in llie lungs were not as acvero as noted in the exposure* previously ili'xci ilied. Those changes cleared up in moat of the tiiiimnls within K days nfler exposure. A eliuidiiii; mill Miirkeiiiug of din cortex of the kidneys was noLed in those iiiiimuls killed immediately after exposure to 25 per cent for ,r minutes mid 5 per cent for I hour. This change was not noted in ineinliers of those groups killed 4 days and 8 days Inter. Nn significant gross pathological changes were found in animals exposed to Ir per emit, for 10 minutes, 5 per cent for 30 minutes, and 2.5 per cent, for 2 Iiimiih. insnipKioN or PATHOLOor Vinyl chloride in irritating to the lungs. Congestion and edema of the lungs are the most constant and prominent observations for exposure In conditions which caused death during or following expo sure. iiecoiupimying the lung changes was a passive congestion of the liver and kidneys. The signs of lung irritation winch wero found immodiaLely after ' exposure to conditions which did not cause death, practically dis appeared within H dnvs. A clouding and thickening of tho cortex of the kidney "ns nolcd immediately after exposure to 25 per cent for 5 minutes and 5 per rent for 1 hour. These kidney changes were not present in nniinids of tho same groups aftor 4 days. KATAIITr AND 6UMMAI1T OP PI11BIOLOGICAL HEBPONBH A Muninniy of the fatality nnd response of guinea pigs exposed to various concentrations of vinyl oldorido in air is shown graphically in Figure I, nnd given in conventional degrees of rcs|ioiiso in Tnhlo 2. Tho results of each experiment are designated by a symbol which represents one of six different degrees of Bovcrity. With tho excep tion of conceiil.rittioiiH causing death during exposure for which tho results ohtnined for individual animals aro given, tho solcctod symbol di'scrihca the results obtained for at least one-half tho individual ani mals, nnd in most cases (lie results nro for tho majority of a group (at least three and usually six animals) exposed to a given condition. It will hr noted from the legend on Figure 1 that the six degrees of response arc-- 1. 1 >ird tui test. 2. Majority ilied within 24 hours. 3 Majority died, 1 iIn 8 days. 4. Moderate injury, few deaths. 5. Slightly injurious , IIO deaths. Not injurious, no deaths. 1969 August 22. fp.10 In addition to representing the response of each group by symbols, the latter have been separated into four goneral fields or zones of probable response, namely, 1. Probable death, 24 hours or less. 2. Serious response, occasional death. 3. Without 6crious response. 4. Distinct symptoms. Table 2 gives the concentrations which produco the degrees of response generally reported in the literature dealing with noxious gases. These data may be compared with toxicological data for other compounds. u Table 2.--Acu( efireti / etpoiurt of guinea pige to otngl chloride in ai> Efforts Of Mpomii liter various periods ol Urea CUaooanrnrro,l nib>lyerst toIiiiiio t. Kills Is s soi* short tlmo.................................. ..................................... 1. Strlousiyinploini In eerj short tints..................................................................... .......................... I. Mndnitl* symptom! Iq rtry abort lira* ............ ..................... . d. Vancarout io life In W to on mloulos.............................................................................................. I. Mmssd symptoms Is M le so ntlnuiss......................................... ...................................................... I. Moilmum ommini Inr SO mloutoo wlihout oarloos dlaMiiboorB laodlng to dcotta.................. i. Hsi mum onsoual for M mlnutoo vllhout taorkod symptom.......................... .......................... t. MBilmurn amount Ins Mraral hours ulthnut aarlous lUMuttwmsr..................................... .... . Maslmua amoust lor siratal hours ullh but tll|lil or oo syreptems................................ .. a lo to in at Iniofst a in r 10 Io oi1.0> caoss or dbats doriho and rottowiuo exfosoub The animals exposed to 20 to 40 per cent vinyl rtilorido entered n Btnto of profound narcosis which tcrininnted in death. Kecnvory vvhh rapid and without fatality following exposure fur periods less limn those causing death during exposure. This indicated that the degree of lung irritation acquired in these relatively short periods was insuf ficient to cause death. With concentrations in tho rnngo of 6 to 10 per cent (ho period between a profound but nonfntal narcose stafo and death was much longer, and permits considerable lung irritation to take place. Also, there was a probable action of vinyl cldorido or products of its decomposition on the liver nnd kidneys. With 2.5 per cent, profound narcosis was present nfler Of) minutes and , irritation of the lungs occurred after severs! hours, but death was exceptional. 1' * * Am imvkHis footnotes J, 4, A. S Cotton, H. T., ood Yours, II. D.: Tho list of otrboo dloildo te Inrrssso llio Instcllcldnl tlDrleney of fumlpanU. Proe. Rntomoloftnt Roe. ot WssMniloa, ol 21 (IV|, pp. #;-nn. Slyer*, R. R, Yont, W. P., Thomas, R n. II., and Dergar, L 0 : riiytMntlcnl inposno otlrndlDf Sipoxirs lo yspnnol mslhyl brouiMs, mothyl rldoitdi, sibyl bromide. nnd sibyl cblorido. Tub. Ilrsltb ' Bui. No. MS (ItnO). M>p. * loltfnsllonsl Orltlml Tobin. IW*t Million (IIIT), yol a. p 311. llw vsntntt shsot, vol. 2, '** Uasdoiwu, Yaodell, sad lltffifd. Jlouard W.; Noslous |tsoa. Airotlcsu Cbsolcil Society Moonptyb No. IS, IBJT. Clwiolnl Catalofuo Co., Now York. , RSV 0016804 t Au**i< 23. M1 1970 UCAliTII HAZARD!! mOM VINYL CULOMDB Willi ri'piml <(* symptoms sud pathology, as well aa the effecting cniM-rntrnlioiiR, (ho rrsponso of guinea pigs to vinyl chloride appears to hcfiimiltiv in (heir respomo to ethyl chloride.1 In equal concentinliuiifl hihI Tiir Miigle cxpnstircs, vinyl chloride is less harmful than 1'iisoiiiir, hcii/.fiu*, chloroform, nnd carbon tetrachloride. Tlio coni|Mirntivrly linrmlcss rcaponso to concentrations of vinyl chloride (lint util iiiaittlnm n nnreose state, together with its rather plrhsant odor, tii|'grs|p n possible ubc for producing surgical anaes thesia, This could be produced quickly by high concentrations and innmtamrd uilh loirrr roiirnilralions. Much additional work is necessary, limvcm-, (o iismltuu the practicability of ils use. Vinyl chlorido does not possess adequate warning properties of the odor or irrilnlion type. With concentrations of & per cent or lass, however, it gives warning by producing symptoms of dizziness and (lisoricnlntinii in ndvnnre of barm. With higher concentrations the nnrmlic net ion is very rapid and persona would have little time to herd (lie warning symptoms before helplessness would nnsuo. Vinyl chloride boils at less lhan ordinary room temperatures. As n rule, it is ronlniiicd in cylinders under pressure. This is conducive to escape of (be gas; on (ho other hand, tlio high concentrations re quired to produce physiological harm nriniurizo tlio danger from leakage. There is, in fact, more danger from explosion lhan from harm to hcnllh front exposure. ACKNOWLEDGMENTS The writers desire to give acknowledgment to J. 0. Davidson, manager of chemical sales for (ho corporation mentioned, and E. W. Itrid, senior follow of this linn's fellowship ut the Mellon Institute, Pittsburgh, I'ii., for R|xmsoring tho investigation, to K. R. Sayers, chief surgeon, llurcnu of Mines, for suggestions and advice, and to II. h\ Unihnch, laboratory osaistnnt, Rurcau of Mines, for assistance in performing the experimental work. SUMMARY AND CONCLUSIONS Tho acute physiological response of guinea pigs lo nir containing vinyl cblmido was determined. Tho concentrations of vapor and periods of exposure ranged from those which produced death to those which caused no apparent elfcct after sovcral hours' exposure. The symptoms, gross pathology, nml fatality arc given with a discussion of potential hazards. 1. The symptoms arc principally Ihoso of narcosis. They range from uiisleiidiness nnd molor ataxia to incomplete and, finally, com- Era l-iiiiin'i-H 1971 AURUH93, 1010 plate narcosis. The respirations vary from a rapid, jerky typo accom panying the beginning of narcosis to a later, slow, shallow type. 2. The principal gross pathological findings were congestion and edema of the lungs, with hyperemia of the kidneys and liver. 3. Exposure to 20 to 40 per cent kills guinea pigs in a very short time; 10 per cent is dangerous to their lives after 30 to GO minutes' exposure; end 0.5 per cent is the maximum allowable amount for several hours without acute disturbances of a serious nature. '4. With regard to relative toxicity (concentrations causing acute harm), vinyl chloride is less- harmful than carbon tetrachloride and chloroform, and is similar to ethyl chloride. 5. Tho danger from explosion exceeds tho health hazard from exposure. 6. ' Vinyl chloride does not possess adequate warning proporlies of the odor or irritation type. It gives warning, however, by produc ing symptoms of dizziness and disorientation in advance of harm, except when present in exceedingly high concentrations which would cause almost immediate helplessness and unconsciousness. 7. The narcotic action of vinyl chloride and its comparatively low toxicity suggest its possible use for surgical anaesthesia. (. ' DEATH RATES IN A GROUP OP INSURED PERSONS Rale* far Prladpal Cassas af Daalh far Jaaa sad Flral Six Months of 1930 The accompanying tablos are takon from tlio Statistical Dullotin for duly, 1030, iasuod by the Metropolitan Life Insurance Co. They present the mortality record of the industrial insurance department of the company for June, 1030, as compared with the preceding month and with tho corresponding month of last year, nnd also give tlio rates, by white and colored policyholders, for the first six months of the years 1028, 1029, and 1930, Death ratos nro given for the prin cipal couses of death, and are baaed on a strength of approximately 19,000,000 insured persons. It should be remombored that those rates apply to a more or less .selected group of persons. In recent years the general death rato for this group has been approximately 73 per cont of the rale for the ; registration ares of the United States. . ** JUNE, 1*90 -. . The death rate for June among these persons was 8.3 por 1,000, v the same as for June of last year, and the lowest rate for the month jin the mortality records of tho company. ft rAn compared with Juno of last year, improvement is noted for .diphtheria, influenza, tuberculosis, pneumonia, accidents, and boini- fits gy>V olO CtoO o o > CD DC I 9089100 ASH i MiH---- 4* ^mn`fiyr--wNutr ' *l6`l oopqndod ftmiwmm m ovq voioomqtm apvcUq 70 smppq jaqffq v Mvq *ppopp | ei poeto tmpoa tq p*auyuoo Asq qpq pqfotopznpfdg ioomo fro* op*d#q fqpnpq ndA* tnopsA jo unosm) fupnpoid [it ] qqiw f)a*a>jds q opafoupna q q tutoqv ooq *q ppopp tiEn!A J W iv '' M vopanpo^q *ianodBn y*on *q ** (i*ai uopnox* o* modx 20 %mm Xofdw ;o qfuq *4jqq luqoas) sxq*anud *iq *q JO tp|q* qraipM q qqpaod 100 wa ii '(Mrapatfutn qqdr put mqumum >qoi[ 'nd Wfliogii wnmi 'vpftdodtmxnAamnil^ 4**|qqd 'qqnjjnq) uqtaxand jqo tnofm qia ooflq*u< Mppod ou n* w*qj, 'puno; tt* WRipuuooq* ||N 3 iqq pa* wmiq uopqoiioo Mppod * pu* fandom poo[q jqjv qaov ft p*qqqo n qqtq fuptoas uo uopr&iojui *ppopp pCq* 70 qua( oqanax* r\ wntodx* 70 (K.6I--BWI) fondCD** iopd *q Jq inpiqsq* CpfA put Miwodx* 70 qfua[ q qf* pqirpsoa * raopauaq* p^oaomoiqj q wvuaq mu "Mpofqvo qof atpo q Mmeq japraa qpa Uqtiado Mqaqim q pounaoo vpaa 3 jqq pm g jqq q --apq ^magpifp Igvantirm taqiaaf ogj, tjarjuoo *tp qip* putdmoa rnq* umfio* pnodzs q q Mmpmjouq* pootoaonp q muq tuvagiafp * t* Mqi qoqdoa qp-770 g pm ifaqnoo qpao uml 61 `PPoppiXqxXiod jo pppopp iXq* qjqatjitura qmplvo ptXoplux* msm o*q *q jo g town tg q pqpqi na wiXaoqdBiCi [Utfdpd pwrqna 01027 XSo[oqdioB ^{atoiosonD^ :vVjr\ >' Amooxqj , ;. .. (tt$I Aimaf o$ p**4*V) UlAX M*MON t pMi--m) < i--oj mnw `nAtfwp--jr *w **HPtr ***/ w"*w pwojT P* WP* 4<*o>wq*7 ofOr*^I /-* tPwav`d`ORvmup*rxaav<*KjmuoKo 'NoraaMY YNYia 'KOsavYKsni *y vsHiounao tmoimi m kiyi mnnioM aasoixs-aanioiHO ianza ni sasATVKY lYHoeowoHHO > : ani4 [t3fP>t>ig patn*H*qK/^-H 6 *> * 2**--*|f wmwtltw-tyBMti> --MB--I* -- --1K *W . mui mp w-- `mIHi ' j*`4Wv--*-14nw(tIuMHlw) iyt*"T*v*1 1MI--M Ky T--1*2 * * --fW*W `BI--IIM--1 M'f'w **(Kt-rK*WID *--* `LZVUM ; _w__N__--K* t* *-- -p--,n pai gu mMU9 f --I---- t 14 -*tt UMt) * *f K * *** I** `r * >VT--|M-- 4b --*r --i wniwim --bi --*1-- M-- |4--4B -* 4r*ivV.'i/'<tm n n--> w NHHiff *--m ! MUMr /!' Jt"*- kw .* :%*. Aa many carcinogens have ilc effects several studies on human x lymphocytes have been und to ascertain whether vinyl chloride 'produces somatic mutations. In^kro of the reports a total of 20 workers ; ^o'v were examined and an Increase in .chromosome! aberrations in vinyl chloride* exposed workers was noted (6,6Ii The report by Kslian et al. [10] described (he examination of 121 workers from a vinyl chloride production plant and no increase in the level of abnormalities was found when compared with pre employment examination. In a preliminary report of out work the results of a controlled examination of men on vinyl chloride production and polymerisa tion plants were described (14.15) and an increase in chromosomal abnormali ties was reported. We now report the results of chromosomal analyses on the men and the correlations between those results and various occupational and biochemical parameters. . Methods Sampttt Blood samples (10 ml) were taken into heparinized tubes. Cultures of peripheral lymphocytes were prepared using the standard Dlfco kits (Difco Laboratories, Detroit, Mich., UjLA.) by incubating the lymphocytes with . phytohaemaggiutiiiin at 3T*C for 48 or 72 h. The slides prepared from these cultures were coded before scoring to ensure unbiased analyses. 50 cells from each of the 48- or 72-h cultures from each individual were analysed (except for one person in whom 100 cells from each culture were analysed). The abnormal ities observed were classified using the method of Buckton and Pike (2] but ce&a with less than 45 chromosomes were excluded. This classification defines B calls as cells with either a chromatid break or gap or a chromosome gap. C cells are cells with larger chromosomal abnormali ties and are subdivided into those considered as unstable (Cu cells) Including cells with dicentric or ring chromosomes or fragments, and those considered as stable (Cs cells). Cs eells have translocations or inversions but cells with inver sions which were a constitutional abnormality were excluded. Translocations were determined by assessment of centromeric position. History Blood sampling was carried out in July 1974 and at the same time each sub ject was asked for a medical and occupational history, which was recorded on a questionnaire. Subjects with recent history of exposure to X-rays, prolonged drug treatment or recent viral infections were excluded from the study. Any experience In the period July 1973--July 1974 of exposure to vinyl chloride for short-term excursions which could be detected by smell and the description of the type of occupation were recorded. Further information on length of service and occupation was obtained from personnel records. Occupation The population examined consisted of 57 workers employed on plants manufacturing vinyl chloride (VC) or polyvinylchloride (PVC), 19 on-site con trols and 6 off-site controls. The 57 VC/PVC workers were classified into 6 groups (see Table 1). Group 1 consisted of 17 PVC autoclave workers who operated a packing th Croups 4 . and VC (7 occupation off-site cor no signifies detailed th samples. A were expo: average ex: likely to fc* operator ex 1945-1955 me-teeo 1990-1970 MM 1975 1975 Smoking hi About Z examine th fore, the ; current im were compl Livtr functi During l samples we: aminasa (Al 7-glutamyl results have not underge Statistical a As the ni for analysis lated betwe tional vans other vans variables, si using dumn smoking in! set of possik Tests for the chromo an addition: a Generalise RSV 0016807 veral studies on human whether vinyl chloride % totel of 20 workers -ations in vinyl chloride* n et el. [202 described production plant end no en compared with pre* ut work the result* of t luction end polymerise* hromoeomal abnormal!* osomel analyse* on the rious occupational and ed tubes. Culture* of lard Pifco kits <Difco he lymphocytes with s prepared from these naiysas. 60 cell* from e analysed (except for lysed). The abnormaleon and Pike (2J but chromatid break or >mosomal abnormal!* - (Cu cells) including 2 those considered as but ceils with inver*ded. Translocations same time each sub. h w** recorded on a 5 X*y*, prolonged om the study. Any * to vinyl chloride and the description ation on length of ^Ployed on plants C), 19 on-sita con. ** dasaified into 6 lave workers who operated and cleaned the autodim; Group % o! 10 am IwohredTa drying and packlng,th* PVC powderf^rpup:3 ol7 men involved in th*j*d<McUooot VC; Groups 4 and 6 consist^ of engineering maintenance men for PVC (11 fMft) and VC (Tjnen) equipment arid, plant, and Group, d of fimenfwith various occupation* in the VC7FVC plant other than processjaperatoca. The oo* mid offeite controls ware combined into a single control group of 14 mao, because no significant difference between them was observed. Thia risarifkation is mote detailed than that used for the previous report* (14.16) and now includes 11 samples. An assessment of the atmospheric levels of VC to which these men were exposed has been made (1) and this provides the best data available on average exposure level* for autoclave workers, who by virtue of their Jobs are Ukely to be exposed to the highest average lewis of VC. The estimated avenge operator exposure to VC on PVC plant* was: iMS-HU 19S6-1H0 190-1970 Ifid 1075 1976 upat * appiex. spptox. sppeox. sppsox. tOOOppm'' 40-*0ppoi ' 500-400 ppm 19 ppm 4 ppm Smoking history About 18 months after the blood samples were taken. It was decided to examine the effect of smoking history on chromosomal aberrations and. therm fore, the smoking history''was obtained from the men. Questionnaire* on current smoking habits, historical smoking habits end, the quantity noked were completed. <V<'. . ' > >- Liver function tost* During the medical surveillance of vinyl chloride expoeed workers, blood samples were analysed for bilirubin and the following snsymsa: alanine trane* aminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and 7*glutaxnyl transpeptidase (GGT). Platelet counts were also performed and the results have been included under Uver-functlon testa, the off-rite controls did not undergo liver-function tests. Statistical analyst* As the number of variables measured was so large, a subset hed to be selected tor analysis. To aid this selection process, correlation coefficients went ealev* latad between each chromosomal abnormality and each quantifiable oecup* tionat variable. Equations relating the selected ehiwscsMsil variables to the other variables were then fitted by multiple linear rsgreerioo. Qualitative variables, such as recent high exposure, were included in these equations by using dummy variable* as described by Davies and Goldsmith (4). To include smoking information in the study, a further selection had to he made from the Mt of possible smoking variables. Tests for statistical significance were carried out using Student's **1" teat. As the chromosomal abnormality variables war* dearly not normally distributed, an additional analysis treating them as a Poisson distribution wee carted out on a Generalised Linear Model programme (12). RSV 0016808 -fc*- A ( l i1 i i * * * i. The results of the chromosome analyses have been expressed as either (a) the number of abnormalities per 100 cells or (b) when totals are referred to, as the percentage of abnormal cella. The former may provide an overestimation because more than one abnormality may occur in a cell. In this study, however, no cell contained more than 1 ring or dicentric. Statistical correlations and significance estimations have been made using both methods of expressing the data. Results The results of analyses from 4S and 72-h cultures were not significantly different and the data have been pooled in Table 1 for further analyses. The average ages of the worken in the various groups are similar. The number and percentage of chromosomal abnormalities, classified according to Buckton and Pike [2], are shown in Table 1. For the majority of the abnormalities the value for the control group is lower than the value in any of the exposed groups; the exceptions are for chromosome gaps, where the control value is relatively high, and for fragments, where the control value is higher than the value of Group 6 but lower than the value in other groups. The group with the greatest number of significantly increased values is Group 1 (autoclave worken), where the values for total B cells, total Cu ceils and total C calls are significantly higher than the control values (p < 0.01). Of the other 5 groups. Croup 5 (VC maintenance) has the highest values, and Group 6 (mis cellaneous) frequently t which are ir When the VC are tabu that those ' abnormal ce In Table TABUS* thx tnrrvcN on tmbrcaci Onw Maias i. s s s c a. wakn *Uo RSV 0016809 It# JTO CatOJUOK AND CON- wr^-. t< kv *'.u- rjnas; fi/hs. *M 4* .41 40* IT TJ SS t H ST IS >0 !4 '1 14 riw--ma UM CkawN was ! 0.31 o.so ass 0.30 043 047 0.42 04 04* 0.1 S 041 o4i 140 OJ1 0.71 04* 044 04* an 0.1$ 040 04T 0.S0 04* Total a min *40* 1.1S 40 e 041 U4* 047 ass 140 74* 147 S40 U1 S41 041 fillISM - *M - *mm ( ry Cs 14** 0.4S O.SO 04* 147 04S 147 4 040 144 040 04 04 041 040 *047 044 040 041 1.00 0.44 044* 040 an 04* 040 040 041 0.00 04* 04S 0.10 040 04 4 04* 04*- 04 04 040 040 04 04 141* 044 140 040 1.4* 040 1.4S * 0.41 147 047 04* 0.40 as* an Tefal Ci 047 041 040 * 044 04* 04* 04* 04* 0.14 044 040 040 aoi 040 ToWI 140 0 041 1.4* 041 1.714 040 14 041 141 041 04* 040 04S 04* tMSilMmS wOlfiiMus MsiMOfl won au ast 140 ate *4* 0.SS 141 040 14** an 140 an 140 041 if either (s)th* erred to, as the overestijaation tudy, however, ^Relations end expressing the t significantly ly*e. The iee, classified ie majority of e value in any ?. where the >ntrol value is other groups, iee is Group 1 Is and total C >f the other 5 Iroup 6 (mis* cellaneous) the lowest with only chromatid gaps occurring significantly more frequently than in the controls (p < 0.05), The remaining 9 groups have value* which are intermediate between Groups 6 and 0. When the results from those with a history of exposure to excursion levels of VC are tabulated separately from those without such a history* It can be seen that those with a history of short-term exposure have a higher percentage of abnormal cells (Table 2). In Table 3 the correlations at various levels of significance of chromosomal TAILS* tbs mrunstct or a mcroar <ier-iT> or sxrosuas to kxcuhaiom utvua or vc ON MR mCXMTAOB ASKOaWAL CIUJ Onu HNtorr ( IWH II*MM m Ta Tout C No w>Hn ol mmiSm TU1 TtUll route Total! Tout C 1 *40 147 ao i.*e 17 aw 14* S _-- -- 10 aw 1.40 10 440 1.40 * __ -- 7 an 1.71 7 S.14 1.71 4 *40 140 4 141 1.00 11 an. 14* S * *40 147 4 7.7* 1.7S 7 7.14 1.71 * 1 7.SO 140 * 440 047 S *40 04* O -- -* -- 34 *41 o.sa 14 *41 04* a, awabw #t tavkm; Tout S. u ?*** *t l toll*;Tout C.Mtoo >nwlm of C wttb RSV 0016810 1 830 TAIUI cobiila7]OM iimw LuoTR or mrx.inrrwT ams chromosomal AiMoiUAunti duced ti somal at There OsmsMSmaI toiMv 1*1 Swifli~in~ m ssbhmm-- the smo in this test>1 wBww AB mwlMM m 9 iMii. hit TMAlBwto famwli TmiICuR TstelCi*fe aiimie smaMW TM*1 Cm Mda A list of smokers smoked might tx used to* smoked ' Cu cells Aberrations (both specific abnormalities and the classifications used in Table 1) smoker v> 1 with occupational history (length of employment) are presented. All correla tions are positive. The in ment, ex. The highest correlation Is between the length of the employment and chromatid gaps, fragments, total B cells, total Cs cells and total C cells. From a Table 5. exposed ; consideration of these corrections and the distributions of the chromosomal and to 1 data, chromatid gaps, total C cells and fragments have been selected at being the most informative measurements from the statistical point of view for present s: nen*smok further statistical analyses. If the variable for exposure to excursion levels, which was determined from the occupational history, is added to the analysis, it is found that both it and the length of employment are significantly correlated with chromatid gape, total C cells and fragments. As the length of exposure and experience of recent manufact. than for these thre abnormal! Poisson di exposure to short-term excursion are themselves positively correlated, it is impossible to estimate the relative effects of these two variables with any great confidence. The correlations between liver-function tests and chromosome TABUS TABULATIO aberrations are shown in Table 4. All are negative at either the 6% or 10% significance level. When the variable for higher short-term exposure is intro- TABU 4 coaaaLATiONS mthm uvaa-ruMcnow tcst bxiults amd chromosomal askraaTIOHS UWiMlSu MM ALT AST ALT OOT Mills ISSPIIIIMII m ** -*rJ*----- TU) B Mb TMiICnR T**al Cw mUi tescesh TmiCiMlb TiMImBi rsiiniiBH PMHIUMA IU-- SiwWw -- TiUIImOi - --- - nmniiamii AS iHHklhM an ImwI N Mail Shmi N NiawUMl * Amw AMIS* ! Amm <> Kmil. S* MMl. Mm Iim t! A '. RSV 0016811 l AlHOtUAUTIII used in Teble 1) ited. Ail correlemployment and i C cells. From a -ie chromosomal elected as being int of view for ietennined from that both it and chromatid gaps, rience of recent correlated, it is 3 with any great d chromosome -he 5% or 10% losure is intro- SOMAb aiuka. duced there is no correlation between the remaining variation In any chromo somal aberrations and liver-function tests. , There was an interval of 18 months between blood sampling and obtaining the smoking history. It ha* been aaaumsdKUt the smoking history obtained in this way adequately reflected smoking nuits at the time of blood sampling. A list of variables can be derived from the Booking history. Type of smoking, smokers versus aon-amokera, duration of smoking, total amount of tobacco smoked pm week and historical smoking habits are variables each of which might be thought important. The multiple linear regression programme waa used to select the moat significant correlations, and. although quantity currently smoked was positively correlated with total C cells (p 0.028) and with total Cu cells (p 0.05), the largest correlation was found to be between present smoker versus present non-smoker and total C cells. The individuals' percentage values of C cells in relation to length of employ ment. experience of higher short-term exposure and smoking habite are given in Table 6. The mean values of percentage of C cell abnormalities In those not exposed to VC was 0.58. increasing to 1.59 in those exposed for up to 10 years and to 1.92 in those exposed for greater than 10 years. The mean value for present smokers, irrespective of their occupational history, waa 1.80 and for non-smokers was 1.06. The mean value for those employed In VC/PVC manufacture with experience of higher short-term exposure (2.29) was high* than for those without such exposure (1.45). This tabulation illustrate* that these three fractors are associated with an increase in the percentage of C cell abnormalities. As an alternative the results were assumed to conform to a Poisson distribution and the Generalised Linear Modal programme was used for tasls s TABULATION Of INDIVIDUALS'mCSMTAOt C CXLLS WITH TUBS! OTUXX rAUUKtUS Ymi #| loilnai 0 <Cottol) 1-10 10 Fiiibi on wrkw RoooM Wo >> 1.1.1. 1.0. 0,0 0.0,1. i.i. a aaaaa 0,0.0,1,0, ,0 aat 0,1,1. o,. a IK rmou iookt liwti No wool i.o. o.o. o.i. t.o l. is* t. a. i.i. a.1. a. S, 4. 1. 4, a. 0 a a.i.s.0,1 1LM urn NoatMMkkHR IlHk Korun 0.1.0 a 1,1. 0.1.0 as in A-onoo O.SS 1.SO i.sa Aiwii lav Uooa wttfe toiwr .1 uvwm U iihhIm Imht LM. Amn tor ttM oaoS Ottk mm Muni ! wpwmw %m wiwiwlniii 1.4*. famt. MtrtMW -I mu* W mwiS-- h.tliNVCBm pm+m4 Jmm 111*--itli mmNo iinoi MMrtMM ol npMun to miwSw Imb tiVCIkihi ibM >*>*. Mou -okio Sm mom of C oS rloinoiHtf to SOS ooOo. RSV 0016812 333 equation fitting. The duration of employment variable wii found to be signifi cant at the 5% level, the present smoking variable was significant at the 10% level and the history of exposure to excursion levels was not significant. As these variables were not completely independent of one another, too much reliance cannot be placed on these estimates of relative importance. Discussion The relationship between the level of chromosomal abnormalities and the various factors which influence their level is complex. There are 4 factors which have been shown to be associated with increased chromosomal abnormalities in these VC/PVC workers: the job category, the length of employment and experience of exposure to short-term excursion levels of VC and smoking habits. The autoclave workers (Group 1) had the largest number of categories of abnormalities which were significantly different from the controls (Table 1). The only group whicn had values similar to those of controls was Group 6 which consisted of laboratory workers and managers. The autoclave workers are considered to have had the highest exposure to VC and those in Group 6 were in job* which gave them infrequent or low-level exposure. It seems, there fore, that the overall exposure level has an influence on the level of abnormali ties. Kilim et al. [10] reported no increase in chromosomal abnormalities in VC workers who were not involved in the polymerisation process. Our Group 3 probably corresponds most closely with their results. A direct quantitative comparison is not warranted, however, because so many factors may differ in the two studies (e.g. exposure levels, chromosomal-analysis techniques). In particular the job carried out by, and thus the exposure of, individual workers with job titles differs between countries and even between plants in the same country. The length of employment was positively correlated with the level of abnormalities and this effect was demonstrated in Table 3. This finding contrasts with that of Funes-Cravioto ct al. [C], who suggested that their recently employed workers had the highest chromosomal abnormality rate. The difference may be the result of other factors, such as a history of exposure to excursion levels and smoking habits, which were not recorded in the study reported by Funes-Cravioto et al. [6]. Those workers with an experience of higher short-term exposure had higher chromosomal abnormality values than those without such a history (Tables 2 and 5). This influence cannot explain why the exposed group values were higher than the controls because Groups 2 and 3 (dryers and VC operators), which did not contain individuals with experience of recent short-term expo sure to excursion levels, have statistically significant increases in abnormalities. There was a significant correlation between the smoking habits and the total C cells. The smoking data can be criticised because the questionnaire was com pleted so long after the blood samples were obtained. No accurate data on smoking habits at the time of blood sampling were obtained and thus the corre lation had to be based on the available dati on smoking, which could be con sidered less Neverthele some abno: reversed in The tut: 4 variables term expo; exemplified the level of There is testa. This i dau on live troll (GJd. much smalls One furti detecting da total B cells. random efft abnormalitie showing rint studies on ci cells is the : sUtistical vie The greatr community germ cells ar tions occur dominant let- air produced suggesting th germ cells or in a dominan colleagues [7 wives of wor Apart from tl the assumptic statistical me studies will be ti'-ns in man. An increas exposure to various group predicted acc chromosomal of controls, s data. RSV 0016813 .i Jr-#-**. was found to be signifi* significant at the 10% was not significant. As ne another, too much nportance. abnormalities and the ere are 4 factors which nosomal abnormalities \ of employment and of VC and smoking :mber of categories of he controls (Table 1). controls was Group 6 rhe autoclave workers and those in Group 6 osure. It seems, there* he level of abnormal)* J abnormalities in VC process. Our Group 3 A direct quantitative factors may differ in Jysis techniques). In of, individual workers between plants in the d with the level of able 3. This finding suggested that their bnormaiity rate. The istory of exposure to corded in the study exposure had higher i a history (Tables 3 i group values were and VC operators), :nt short-term expo* e$ in abnormalities, : habits and the total tttionnaire was com* 0 accurate data on 1 and thus the corre* vhich could be con* iklered leas satisfactory because they were obtained 18 months after --'"pMrgi Nevertheless, it seems likely that smoking does have an influence on chjoao* some abnormalities in VC exposed workers, although the effect Is, If anything, reversed in the control group. Hie statistical analysis is complicated by the inter-relationships between the 4 variables (job category, length of employment, experience of recent short* term exposure to excursion levels and smoking history). This difficulty Is exemplified in Table 5, where three of these variables are shown to influenea the level of C cell abnormalities. There is no correlation between chromosomal aberrations and Liver-function testa. This is not surprising as such significant differences as were found In the data on liver-function tests between 600 workers exposed to VC and 200 con trols (QM. Peddle, unpublished observations) would not be found in these much smaller samples. One further point of interest is that the most Informative parameters in detecting damage to chromosomes due to VC are total C cells, total Cs cells, total B cells, chromatid gaps and fragments. This suggests that VC produces e random effect in all categories of abnormality. The blologically-significant abnormalities could be considered to be the total Cs cells or the total of cells showing ring and dicentric forms of chromosome*. Nevertheless, if further studies on chromosomal aberrations in VC workers are undertaken, the total C ceils is the abnormality which would be of most v&lua from a biological and statistical viewpoint. The greatest significance of mutagenic effects to the exposed person and the community ties in the possibility that the mutational event may occur In the germ cells and be transmitted to the next generation. If chromosomal aberra tions occur in germ cells one sequela which may occur is the induction of ] dominant lethal mutations. Levels of VC u high as 30,000 ppm in the Inspired ' air produced no dominant lethal mutations in mica (Anderson et al., 1976), suggesting that the active metabolites of VC may never reach the testis end ; germ cells or if it does it is not metabolised. In man, a germ-cell effect resulting In a dominant lethal mutation would be observed es foetal loss. Infante and his colleagues [7--9] have described a study in which the history of foetal loss of wives of workers exposed to VC is compared with that of a control group* Apart from the inaccuracies inherent in a retrospective survey of this type and the assumption that the increase in foetal loss is due to a mutational event, the statistical methods have been criticised [13], Further, carefully controlled studies will be necessary to establish whether VC induces dominant lethal muta tions in man. An increased level of chromosomal abnormalities may result from high exposure to VC, but the considerable overlap in values observed between various groups in this study suggest that exposure of an individual cannot be predicted accurately from a single chromosomal analysis. The data from chromosomal analysis of groups of workers do differ significantly from that ! of controls, suggesting that the greatest reliance should be placed on group data. RSV 0016814 References i --*4. A.*. Vta>) *-- Uw iwtoilB nt PYC, hM.JUy. Im. U*CM <l*7> S77-N1. 1 KJL -- wr. PlM. TUm Ib Irtmi As HftfUtl wHM to lHiN to In ---rfitltr Hr--t AIIIHIII 4mm* toMM.1st.J.MMLHA. UM4) a CimiB. ax. bb4 MJ4. jtkMM, AMlimiM *1 Avar Is UM --hri*w ( lnli?l UmM*. :.L Mutation Xaaaartk, eCtermr/Horth-K 4 Pwm. OX. --4 px. C*w>ltt. SUOMtol MiIHH to wwi> b PuBmhIm 4to *--. OIHm m4 Mp4, Mb--. Otli).. 374-17S. k Pmmm. A* It. HlmMww Mi IXhttrit. Vtoyt *41-- wmH Mm Wiimi iw imma hmmum ri, ai om> hmii PmnOmM*. 9m >. Uakan, <1. UlftUH, U IWi*lifc A.T. Halanlu iH S.OMm4lkii, ftn humi AnwMiii to nrtmaMHUMJ AMH.taMM.1 <lt> 4M. 7 UlMif, JX WitMM. 4 AJ. MiMhHA Q-- ! M Mhti --------- . & arr) 734-714. 1 lihM, fj, JJC. ViioM, AJ. MiMIAmI. AJ. TumM iH K. PB, <1--0* Mi O Hapl miitii. -- i (iT*) lsso-iste. t IHUH, P/, JJC. WnM *M IJ, WbbbPi. Cmtoi--Ii. mwmHi m --r-tfwH M>-- 4W4 Hk vtopt (UwMl. MiuUm In. 41 (1*74) 111-141 14 KIIm. DJ, DJ. PlMtiM Mi CJ4. inrtiH, Ii4iM1*I Miltiitor A imiiili Minn>. Aba. K.Y. AMi. M. M 4117S) 4-| I. U MH44B4. C,, 0. Lrtmto*. P. CM-- Mi D. C11*10. Lb b----O imMm<H* prf----in Dm* BMiHlW *Ub 4m 4*10 ----A B Mono* 01 --Ob, A*. **04 0--4*4 41U VlU". 1 41174) 7--04. 15 N*W*r. J.A. -- A.WJ4. W--MB. Om-- ltow --ObA. 4. R*p. SUtM. S*. kl. A. 1J| 0173) 3TO-344. IS PM4I*. Oil,O--t iiik *4 vtoplB1**0Ib.LtBMt, 1 (1171) IOTA. 14 hwti*. LPJt_ CA. Rich-- ui A. BbIimib. CM----H Ui timliiii 1--1 if-- l vtorl Olirtii. Lull, u (117S) 410. It P--*. UJ). CJt. RHImiO-- Mi O. AlimiB.CWiBiHll bK*-- Ib --lrph*rm. PlM. Rp. <M. MM. 41 41174) S10-M1. i i j CHROMOSOME ACETATE EXPC L. VER3CHAEVE, iefrofeleraam uoor. (IU*iiwO SO t Jput (RbtWob --i*d 3 (AewpUd S rbniA ftimiMiy Peripheral bloc ad a control p< 'opuUtions 100 i 'loaition of th re centromere dicta? obtAined by eons metsphaae coordii By comparing t chromosome con workers from the tances after mercu From the data first the position which are involve* sity of SH-weirir sptdfle eniymet ever too low to all RSV 0016815 Introduction Cytogenetic eff the reactivity of s the formation of affects the mitotic some* is doubled mitosis leading to to foie concentmt