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Advances in Internal Medicine and Pediatrics (Vinyl Chloride, Associated Diseases) i" * Ergebnisse der Inneren Medizin und Kinderheilkunde Advances in Internal Medicine and Pediatrics Neue Folge - Herausgegeben von P Frick G.*A.von Harnack K.Kochsiek G. A. Martini A.Prader Mit 24 Abbildungen und 23 Tebellen R&S 105154 G Vinyl Chloride-Associated Disease WJC. LELBACH and HJ. MARSTELLER ' I Introduction 2 Technological Details.......................................................................................... 2.1 VinyfChtoride Monomer (VCM)................................................................ 2.1.1 Hiitory......................................... 2.1.2 Production of VCM......................................................................... 2.2 Production of Polyvinyl Chloride (PVC)................................................... 2.2.1 Technology of Polymerization........................................................ 2.2.2 Method* of Polymerization............................................................. 2.2.3 Compounding .............................................................................. 2.24 Sources of Exposure to VCM in PVC Production........................ 2.2i The Explosion Hazard................................................................... 2.2.6 The Odour Threshold *............................................................... 2.2T VCM as an Anaesthetic Agent....................................................... 2.2.8 Effects of Acute Ovetexpasuic m Man............ ............................ 2.2.9 Monitoring VCM Concentrations in Working Areas...................... 2.2.10 Exposure to VCM in PVQProcessing (-Fabricating) Plants.......... 4 4 4 J 6 6 7 g 8 9 10 |0 n 13 15 2.2.12 Exposure to VCM Outside the Woricing Area................................ 18 3 Toxicology of VCM............................................................................................ 3.1 Acute Toxicity............................................................................................ 32 Chronic Toxicity........................................................................................... 33 Oncogenic Properties............................... 3.4 Toxieodynamic*.................. .'.................................................................... 3.4.1 Uptake and Distribution................................... 3.4.2 Metabolism.......... ........................................................................... 3 A .2.1 Relation between Chemical Structure. Reactivity and Mutagenic or Careinofenic Effect.............................. 3.422 Metabolic Pathways........................................................ 21 21 21 22 24 25 26 26 26 4 Clinical Spectrum................................................................. ........ 4.1 The Triad: Raynaud's Phenomenon. Pseudoscleredenna and Aeroosteolysis........................................................................... 4.1.1 Familial and Idiopathic Acrooeteoiyris........................ 4.1.2 Epidemiology of Occupational Aeroocteolyiis.......... . 4.1.3 Clinical and Roentgenological Features...................... . 4.1J.1 Occupational Acroosteotysa........................... 4.1J.2 Pseudoeclerodcims..................................... .... 4.1.4 Histology......................................................................... 4.1.4.1 Cutaneous Lesions............................................ 4.1.4.2 Bone Lesions................................................... *15 Arteriography. CapBlarenropy. Infrared Thermography 4.1.6 Immunological Studies................................................... 1 29 31 34 34 36 36 38 39 39 39 40 42 1 Department of Mcdfehie. Director Prof. Dr. HJ. Dengler. University of Bonn. FRG 2* W.E. Lclbach and HJ. Mameilltler 4.1.7 Pathogenetic Considerations............................................... 4.2 N n-malignant Liver Disease in Vinyl Chloride/Poiyvinyl Chloride Production Workers.....................................................'................... 4.2.1 Clinical Manifestations of Nonenalignant Liver Disease. .. 4.2.2 4.23 Gross Inspection of the Liver and Spleen . 4.2.4 Histology.......... ......................................... 4.2.4.1 Hepatic Fibrosis........................ 4.2.4.2 Sinusoidal Lining Cells............... 4343 Hepatocytes................................ 4.2.4.4 Histology of the Spleen............ 4.2.5 Pathophysiology of Portal Hypertension . 4.2.6 43 43.1 Epidemiology................................................................................. 43.2 Clinical Manifestations.................................................................. 433 Peritoneoscopy............................................................................... 4 3.4 Gross and Histological Morphology............................................... 433 Therapy........................................................................................... 43.6 Risk Assessment............................................................................ 43.7 Mortality and Cancer Morbidity Studies..................................... 4.4 Miscellaneous Aspects............................................................................... 4.4.1 Thrombocytopenia and Platelet Function Tests......................... 4.4.2 Central and Peripheral Nervous System....................................... 4.43 Pulmonary Changes....................................................................... 4.4.4 Genetic Effects of VCM...................................................... 5 Conclusion and Outlook.................................. ................................................ References............................................................................................................... 44 44 48 49 50 51 51 54 54 54 55 57 57 57 74 76 78 80 80 81 82 82 84 85 87 88 89 Key words: Acrooueolysd - Angiosarcoma ofthe Liver ~ Portal Fibrosis and Portal Hypertension - Pseudosektodma - Raynaud's Phenomenon - Vinyl Chloride 1 Introduction The history of vinyl chloride-associated disease, la recognition and prophylaxis is a classic example of shutting the stable door after the hone has bolted. It should help to emphasize the need to shift our attention to preventing exposure from occurring rather than to reparative measures. In view of the large number of new and potentially hazard ous chemicals introduced each year into the workplace and the environment, this ac count should again alert us to the necessity of pretesting chemicals adequately for their potential health effects, even at the risk that technological progress will develop at a mote modest rite. Large-scale production of the synthetic resin polyvinyl chloride (PVC), a thermo plastic material suitable for the most widely diversified industrial use, was begun around 1930 in the United States and in Germany. The monomer, vinyl chloride (VCM), a rather simple aliphatic compound, was believed until the early 1960s to be Vinyl Chloride-Associ. ne of the least harmf1 later turned out, had n evaluation of acute eff to reveal its carcinogei: might have continued: place, considering that vapour phase under am reactive double-bond. Today vinyl chlorid formation and data on cisely a quarter of a cei tributable to this new <r with the shocking disci tion workers heavily ex. ing that the monomer r pound did not alert the in workers engaged in r lished in 1949 (Tribukh Ultimately, it was tl curred in workers expo a causal relationship: (1 pseudosleroderma; (2) liver. Particularly, the d: nancy among a compare alarming experience wh a connection between \ lungs or the (istraintc. the prolonged latency p sarcoma of the liver, p*. these two fatal consequ. the conclusion that Vk cancer meeting in Hour, to VCM was a very seri : It should be stresses precise,an intermediate mainly in the mammal, merization products (P\ Gated from the polymer, they contain unr PVC (thermal d< toxicity of pyro mainly due to ti co Abar 1969 ;Dyi ^ and only very s q (OlWis/sctal. 1 2 cn o> MafSteller 48 49 50 51 . 51 54 54 54 53 5T 57 57 74 76 78 80 SO 81 83 82 84 85 87 88 89 IFontl rtdt Aba M help to -mg rather Dy heardthis ac> y for develop thermogun tide Oitoba Vinyl ClilonJe-Awociaud Disease 3 one of the least harmful chlorinated hydrocarbons. Early animal experiments, as it later turned out. had indeed been carried out with dosages wfllciendy high for the evaluation of acute effects, but chronic exposure had not been of sufficient duration to reveal its eardnogenic properties. On purely theoretical pounds, however, one might have continued to feel uneasy with this compound as a pollutant of the work place, considering that it is (1) a halogenated hydrocarbon which (2) exists in its vapour phase under ambient conditions (inhalattve exposure) and (3) contains a highly reactive double-bond. Today vinyl chloride-associated pathology is w*Q documented. A large body of in formation and data on this topic has been accumulated, notably since 1974, but pre cisely a quarter of a century had to pais before the full range of symptomatology at tributable to this new occupational health hazard became recognized in January 1974 with the shocking discovery that haemangiosarcotna of the liver occurred in produc tion workers heavily exposed to PVC. Early and not eady accessible reports suggest ing that the monomer might be an environmental risk for workers handling this com pound did not alert the experts sufficiently.The earliest indication of adverse effects in workers copied in the production and ptocersini of PVC, a Russian study pub lished hi 1949 (Tribukh ct al. 1949), received little attention. Ultimately, It was the exceptional character of the three major lesions which oc curred in workers exposed to VCM that contributed most to the final appreciation of a causal relationship: (1) the syndrome of acroosteolysis. Raynaud's phenomenon and pscudodetoderma: (2) non<inbonc portal hypertension; and (3) angiosarcoma of the fiver. Particularly, the discovery ofa duster of four cases of this extremely nue malig nancy among a comparatively small group of workers (Cmch et al. 1974a) was an alarming experience which called for immediate action. It can easily be imagined that a connection between VCM and the mote common malignancies, sudi as cancer of the lungs or tiie gastrointestinal tract, might stiD have gone unnoticed. On the other hand, the prolonged latency periods of both noo-dnhotic portal hypertension and angio sarcoma of the liver, roughly 10 and 20 yean respectively, delayed the recognition of there two fatal consequences of chronic exposure to VCM. But one can hardly escape the condusiQn that Viola's discovery ofcancer in experimental animals, presented at a cancer meeting in Houston in 1970, was sufficient evidence to indicate that exposure to VCM was a very serious occupational hazard (Peters 1976). It should be stressed that the noxious agent is solely the monomer, or to be more precise, an intermediate of the monomer's metabolic bioictiviation, which takes place mainly in the mammalian liver and yields certain highly reactive epoxides. The poly merization products (PVC), is., the solid plastic and the plastic consumer goods fabri cated from the polymer, are chemically inert articles which cany no health risk unless they contain uareacted nridual monomer. Even the combustion of strides made from PVC (thermal decoaspodtion in fires) docs not yield fret vinyl chloride monomer; the toxicity of pyrolysis products of polyvinyl chloride polymers and formulations is mainly due to the release of hydrochloric add and carbon monoxide (Cornish and Abtr 1969:D)T andk* 1976;5orensM 1976:5fojcr 1976;Cokmtyn et al. 1976) and only very small or no quantities of phosgene derived from residual monomer (OJfor et aL 1971 dtad by Coierdvn et aL 1976). 4 2 Technological Details 2.1 Vinyl Chloride Monomer (VCM) W.K. Lelhach and HJ. Marsicllcr At standard (ambient) conditions of temperature and pressure, vinyl chloride (CHj* CHQ: chloroethylene, chloroethene) is a non-irritating, colourless gas with a faintly sweet odour, inflammable at concentrations above 3.8% by volume in air. which is only slightly soluble in water, soluble in ethyl alcohol and easily soluble in ether and carbon tetrachloride. VCM is mainly used as an intermediate in the manufacture of plastics, as a refrigerant and in organic synthesis. It was formerly aho employed as a propellant for aerosoles. It is easily liquefied under pressure and is usually handled anB shipped as a liquid. Caseous VCM condenses at --13.8*C and 760 tore ( 1013 kPa) to a colourless liquid of low viscosity (Lefmix 1966). Its physical properties are listed in Table 1, the most important of which are its low boiling point, its high specific grav ity (gaseous VCM is 2.15 times heavier than air), its low solubility in water and the half-life in air, ranging from 3 to 20 h. Table 1. Physical properties of VCM Mol. wt.; B.p.: F.p.: Flash point: Limits of flammability: Autoignition temperature: 62-503 '-13-8'C(-13.7 to-13.9) --153.7*C --78.5*C (Cleveland open cup) 3.8"-29.3% by volume in air above -78.5*C (. 38 000-293 000 ppm) 472*C Vapour pressure: mm Hg 10 100 692 2300 *C -87.5 -55.8 -15.8 20 2660 *25 Vapour density: 2.1$ g/litre (calculated at 25*C and 760 mmHg <airl) Sp. gr. of liquid VCM: 0.9121 at -20*C/4*C 0.99 at -2S*C/4*C Sources: FairhaH \9ST,Irish 1963; Zapp 1964; L*faux 1966; Ostermaver 19b7: Roubal 1972. 2.1J Histoty The French chemist, Regnaub (1835) was apparently the first to study systematically the synthesis and analysis of vinyl chloride. Liebig, who had done tome earlier prelim inary experiments, encouraged Regnault to investigate this compound when Regnault spent several months in Liebig'% laboratories. All compounds containing the vinyl group (CHj <TH-) polymerize readily (Fairhall 1957). Spontaneous polymerization of vinyl chloride to a white opaque solid mass under the influence of sunlight was fint described by Baumann in 1872; he also quotas a paper by Sayner and Glinsky (who Vinyl Oil. succeeded izing subsr 2.1.2 ProL Large-sealL.. - - Tioj' 3) rers (/) CH -4 o ersi c_ni Be;' e0r0e Cl* 1-: VCM w Thus, any h tions in the in the rang (IARC 197 when VCV mayer 196" in conuncr. 1966: Qrrc; In the econjecture^ retrieved V( ysescairie!. sum of all ii genetes) wu reacted moc in prepolyn the concen* that even 10 methyl chic isobutane, ference in p and HJ. Mantellcr 1 chloride (CH: with a faintly in air. which is able in ether and nanufacturc of 0 employed as a suaily handled and irr( 101J kPa) opemes art listed high specific gnv1 water and the i * -75.5'C 2300 20 2660 23 H mtytr 1967; udy systematically ome taiiiet preliznnd when Rtgnault mini the vinyl s polymerization f sunlight was first iod Glinsk}' (who Vinyl Chloride-Associated Disease 5 succeeded in decomposing vinyl chloride to monochloroaldehyde with the aid of oxid izing substances such as hypochl rous acid. 2.1-- Production of VCM Large-scale commercial synthesis ofVCM with a high vieid was made possible much later by employing two principle methods, the second having now largely replaced the fust: 1) Conversion of acetylene to VCM by hydioehlorination: CH"CH + HQ--CHi^HO (catalyst: HgOi on charcoal) (Austin 1974) Z) Conversion ofethylene by vapour-phase or liquid-phase oxychiorination to 1 --dichloroethane and subsequent pyrolysis (thermal cracking) to VCM (Albright 1967a): CHj<H; 2HOM/2 0, - 01*0-01,0 + 11,0; CHjCl-CH-Cl 4<0*C-510*C-> CH--CHO +HO pumice cataiyn (pyrolysis: thermal cracking,Darrin 1974). VCM was usually manufactured in dosed systems and stored in outdoor facilities. Thus, any leakage of the gas was readily diluted in the ambient air. VCM concentra tions in the atmosphere at some distance from manufacturing plants were found to be in the rings 1-2 ppm. In dose proximity, the concentration ranged up to 50 ppm (IARC 1974). Spontaneous polymerization in light has abo been repeatedly observed when VCM comes into contact with atmospheric air due to container leakage (Out* rmyer 1967). A prerequisite for the polymerization process is a high degree of purity in commercially produced VCM. Impurities retard the polymerization process (Lefaa \966\Oaemaye' 1967). In the early discussion about the cause of vinyl chloride-associated disease it was conjectured that other compounds or impurities contained in prtpolymerization or in retrieved VCM might have been the causative agentfi) (Thkss and Verun 1974). Anal yses carried out by six West German manufacturers of PVC, however, ritowed that the sum of all impurities (sudi as saturated or unsaturated hydrocarbons and their halofences) wn 0.01% by volume for prepolymerization VCM and 0.1% for retrieved un learned monomer. Only methyl chloride was found in concentrations of50-300 ppm in prtpolymerization VCM and 100-500 ppm in retrieved VCM (in one instance only, (he concentration ranged between 1000 and 3000 ppm). But it should be kept in mind that even 1000 ppm methyl chloride In VCM would mean, at 500 ppm VCM in air, a methyl chloride concentration in air ofonly 03 ppm. AH other impurities (propylene, isobutane,n-butane etc.) would then be in the ppb range. Besides, no significant dif ference in purity could be found between VCM from acetylene and from ethylene. V 31 #> (/> o tn ui <0 A m m w m xm L 21 Production f Polyvinyl Chloride (PVC) W.K. Lelbach and HJ. Marsteller 21.1 Technology fPolymerization The following description'll meant to serve merely as a rough sketch of the procedures and technological details involved in the production of polyvinyl ehloride. Vinyl chloride monomer is polymerized in Urge autoclaves (reactors) at tempera tures between 40*C and 80*C and pressures of 6-16 (8-12) atmospheres. TVre are usually several reactors (up to 10-30) located in one building. The reactivity of the monomer is a function ofits double-bond. The second functional site of the vinyl chloride molecule, the chlorine atom, docs not react easily. The double-bond of VCM is not only the site from which the polymerization originates but is also the source of the toxicity and carcinogenicity of this compound when it is being metabolized in die body. The polymerization ofVCM, which is a strongly exothermic reaction (Barnes 1976), is initiated with the aid of compounds soluble in VCM that form free radicals at relatively low temperatures. Initiators are such compounds as Uuroyl peroxide, isopro pyl percarbonate, ixo-bis-isobutyronitride, and others. The free radicals react with the double-bond of the monomer, transforming it in turn into a free radical and thus prop agating the growth of a chain of molecules with a terminal free radical. Chain growth is interrupted by saturation of the terminal free radical which often involves a reaction between two growing chains (Molten and Zielhuis \9(A\Lefaux l966;Albright 1967 e-c&ominiiighaus 1972,Slater 1972). The random character of such termination steps accounts for the production of chains of different length and hence different de grees of polymerization, with molecular weights of the finished PVC being statistically distributed around a mean value. Commercial PVC polymers have average molecular weights that vary from about SO 000 to 150 000 daltons (Albright 1967b). Degree and velocity of polymerization, which are influenced by temperature and the concentration of initiators, determine the specific type of PVC produced (Frey 1973). During polymerization considerable amounts of the monomer am at first dissolved in the polymer, but most of this is later also transformed to PVC as polymerization progresses. The polymer which is not sol uble in the liquid monomer precipitates out. The process of polymerization slows down towards the end of the reaction. It is tciminated, depending on the method used, when approximately 80%--90% ofVCM is polymerized. The timing of this termina tion of the process is essential for the physical properties of the retins produced. The heat generated during the exothermic process of polymerization must be removed to keep the temperature of die reaction under control. Mechanical agitation aids in trans ferring the heat acres die colloidal system to the cooling jacket of the reactor. During the process of polymerization certain quantities of the polymer adhere to the walls of the reactor and form a dowiy thickening continuous film or crust. This polymer crust on the inner surface of the reactor vessel, which contains cavities filled with unreacted monomer,impedes the conductance ofheat;it has, therefore, to be cleaned away after termination of the batch proces (Barnes 1976). After completion ofdie polymerization proces, the slurry is released from the re actor into a dump tank. Residual unreacted vinyl chloride monomer is partly solvated in the polymer (abmit 10%); the remainder is dispersed in the water phase or is present Vinyl Chloride*.' in the vapour ph-. VC monomer is r is then purified h the finished poly and must diffuse Raw PVC resin, t! (VKE 1975). Bar. proximateiy 500 The slurry fro huge enough to hare then pumped wet polymer, a gr. drying methods, i merization, yieldifine solid particle? drying temperatu; polymer. A cycle The solid polymer storage bins or sil> dried powder con 222 Methods o Four different m. PVC (Frey 1973> Suspension Polyn which monomer (such as polyvfm1 conduction with b this method whi. Emulsion Pofym* .* was added in the except that large. are added. Emul<' emulsifiers cannot Bulk fMassI Polyr the additon of oil The first reactor* second one is we. solid state,toesw reaches a level f chaiacte ' * *"1 good op 31 fie C/> ij HJ. Manteller of the procedures iride. n) at temperaitem. Then ate .activity f the : of the vinyl ik-bood ofVQ1 iso the source of otaboiized in the action (Bonus tm fits radicals at peroxide, isoproals react with die ea! and din propd. Chain growth is olve a reaction r.AIbnght 196" t termination mbs different de tail statistically an from about pctyroerizat'.m, or-, determine jb considerable Offals is later rflSb not *o>aadonslowi the method used, tf this terminat produced. The t be removed to don aids in ttansreactor. During n to the walls of ds polymer crest d with unreacted leaned away after aed from the le ts pertly rotated ihase or is present C' Vinyl Chi ridc-Assodated Disease ? in the vapour phase above the shiny. While a batch is in the dump tank, this umeacted VC monomer is retrieved by pumping it ofT into a VCM storage tank. Retrieved VCM is then purified by subsequent distillation f r recycling purposes. Monomer solvated in the finished polymer cannot easily be extracted since it has a strong affinity for PVC and must diffuse through the panicles: this diffusion depends on time and temperature. Raw PVC resin, therefore, still contains certain quantities of unreacted monomer (VKE 1975). Bonus (1976) reponed that the polymer in the slurry still contains ap proximately 500 ppm of vinyl chloride. The slurry from the dump tank is pumped into a storage tank (blend tank) which is large enough to hold several batches of the product. The contents of the blend rank are then pumped into a centrifuge which separates the wet solids from the water. The wet polymer, a granular mass, is dried cither in rotating tubular dryers or by spray- drying methods, the latter being used mainly for products formed by poly merization, yielding a polymer which is similar to a very fine white flour. These very fine solid particles are fed directly into a Jpray-drying column without dewatering. The drying temperature should not exceed 60*C to prevent thermal decomposition of the polymer. A cydon separator at the exit end of the dryets remoras coarser particles. The solid polymer particles are then sized by multiple-layer screens, air-conveyed to storage bins or silos and finally packaged for shipment (Albright I967d). The resultant dried powder contains about 50 ppm ofmonomer (Barnes 1976). 222 Methods ofPolymerization Four different methods of polymerization are used for the commercial production of PVC (Frey 1973), the first two now being the most widely used: Suspension Polymerization. Polymerization is carried out in an aqueous system in which monomer droplets are maintained in suspension by means of protective colloids (roch as polyvinyl alcohol, gelatin, substituted celluloses) under heat and pressure in conduction with brisk agitation. Relatively hip polymer panicles can be obtained by this method which `dry blend' well. Emulsion Polymerization b the olden technique, to which suspension polymerization was added in the 1950s. The pieces is similar to that in suspension polymerization, except that large amounts ofemulsifying agents (such as soaps or other surfactants) are added. Emulsion polymerization yields resins ofa very TMn particle she. The emulsifiers cannot be completely removed. Bulk (Mass) Potymmtzation. fit this process VCM is polymerized la two stage without the additon of other Squids. The two reacton are operated batch-wise and in scries. The first reactor (a `prcpoiymerizcr') provide for the initial liquid phase, while the second one is used for agitating the slurry, which is transformed, through a sticky solid state, to essentially dry particle until the conversion from monomer to polymer teache a level of about 75%--SOft.The resins obtained by bulk polymerization are dtaracterized by high purity and particle uniformity, resulting in an end-product of good optical clarity. s t R&S 105161 8 W.K. Lclbach and H i- Manuller Solution Polymerization. Thu type of precipitation polymerization it carried out in organic solvents such at n-butane or cyclohexane. It accounts for only a small percent age of the total amount f all PVC resins produced and it is used for the production of copolymen. Copolymen ate mixtures of comonomers (such as vinyl acetate, vinylstearate, vinylidene chloride, propylene, acrylonitrile etc.) and vinyl chloride. The comonomers tend to improve flexibility and limited solubility of the product in solvents and exert an influence on the temperatures required for compounding. 223 Compounding As a next step, depending on the end use, the dried polymer, a whitish powdery or granular product, is then compounded (or dty blended) under pressure at fusion tem perature with the aid of plasticizers (mainly phthalat; or other organic esters) and light and heat stabilizers (heavy metal salts, organotui compounds, and other stabilizers). 'Lubricants or dyes can be added. Plasticizers are added for the production of flexible PVC: rigid PVC contains little or no plasticizer. These additives can also be a source of toxicity. The plasticizers may slowly diffuse out of the final product depending on its compatibility. Lead-containing stabilizers may also pollute the working atmosphere {SmoKif 1966; Tola 1975). Compounding is carried out by hot mixing at fusion tem peratures below or within the softening range (120C-160*C). Diversified compound ing and processing technologies were developed about 1950. The compounded polymers ate used for the production of diverse epd-products. The final convenion of the thermoplastic PVC resins into consumer etid-products is accomplished by such procedures as extruding, calendering, injection or compression moulding, blow moulding, dipping (coating) and hot spraying. Temperatures used in these processes range from 100*C to 300*C. End-products include a vast number of articles used in almost every sphere of daily life. The temperatures during the fabrica tion operations (compounding and conversion of compound polymer into consumer articles) drive off part of the small concentrations of residual monomer still contained in the polymer. Barnes (1976) calculated that the final fabricated articles contained approximately 5 ppm VCM and those for foodstuff packaging (bottles, films, foils) even less. 2.2.4 Sources ofExposure to VCM in PVC Production Both polymerization ofVCM and subsequent processing (centrifuging, drying, screen ing, bagging) are usually carried out in closed buildings. Exceptions can be found in hot climates {Aryenpur 1977). Polymerization is of necessity a batch process that re quires a large number of single operations. Therefore, valves, gaskets, shaft-openings and control gear are subject to heavy wear and thus to leakage. Other sources of pollu tion of the working atmosphere are exchange of parts and repair jobs. The degree of pollution also depends to a large extent on the quality and effectivity of monitoring equipment and special exhaust systems. Opening of autoclave vats for cleaning and control purposes resulted in larger spill-over of the tank atmosphere into the work en vironment Numerous reports of workers with prenarcotic symptoms (dizziness etc.) Vinyl O. permit t> in the p? Ther clave va; walls (*p ton, haJ degassed and large were opc edthefr. tion still manly, t! those wi(ccntrifu ties of:: ventilatii shipmen oomer, v are drivr Table 2. +ppi 1 mg (At; 1 mg/li i 1 mg/ni 1 ppm IS- 223 * In the r nant m> covers: (Lefiwx led as; anened danteller out in I percent' The oo solvents ry or :on temand light an), flexible entree of ugonits Theie m temrnpound- uucts. JCtsis sion :*ed in of U.-ncaMtmer -`aineU screennd in hat re sting! f poflureeof iorfng and otkeni etc.) Vinyl Chloride-Awodaied Di<ea*e 9 permit the conclusion that episodes of acute overexposure to VCM were not tare events in the past. There is no doubt, however, that those workers who manually cleaned the autodare vats by scraping away or chipping off the *poI> mer skin* formed on (he reactor walls (`polydeanen*). and who in the past had to spend several hours inside the reac tors. had been exposed to the highest concenitations of VCM. Although the vats were degassed prior to entry, unreacted monomer remained trapped in the polymer skin, and larger amounts of VCM were released when cavities formed in tite polymer oust were opened by chipping. The later introduction of automatic cleaning systems reduc ed the frequency of entry into the reactors, but some manual dcaning of shorter dura tion still had to be done after every 20th-30th run. It is. therefore, plausible that, pri marily. the most severe advene effects ofexposure to VCM were fully recognized in those workers who had been employed in this job category. But the subsequent steps (centrifuging, drying, screening) also involve the release of some of the lesser quanti ties of unreacted residual monomer from the particles to pollute the environment if ventilation, notably of the drying facilities, is inadequate. Finished polymer, ready for shipment or subsequent compounding, still contains small quantities of unreacted mo nomer. which either1 slowly diffuse out and pollute the bagging areas during storage or are driven out by the high temperatures necessary for compounding. Table 2. Conversion table for concentration of VCM in ambient air Mol. wt. lt,pn'" ToOO x 24.45 mtmtK 24.45 x I 000 1 mg per litre ---- ppm ifltrtr 1958) I mg/litre 1 mg/m* 1 ppm 2.5ft mg/m* Vi 10 000 ppm 391 ppm 0.391 ppm 0.00256 mg/litre 25.6 mg/litre 2--J The Explosion Hazard In the past only the explosion and fire hazard of VCM was thought to be the domi nant monitoring problem in handling gaseous vinyl chloride (frith 1963). This hand coven a concentration tinge of 4ft-22ff by volume of air (40 000-220 000 ppm) (Ltfaux 1966). It was observed that VCM, being 2.15 times heavier than air, may col lect as a compact layer at the floor of a polymerization building after spill-over from opened tanks and may catch fire. At least two instances of disastrous VCM explosions became known: In 1964, a large plant for the polymerization of VCM in the United 10 VJC. Lelbach and HJ. Marsteller States was almost completely destroyed when VCM escaping from a leak detonated (Albright 1967a). Another explosion in one f the two Rumanian factories operating at that time was menti ned bySueiu et al. (1975). Monitoring of VCM concentrations polluting the work environment was then directed largely towards preventing VCM from reaching the flammability limit. 22 The Odour Threshold Unfortunately, gaseous VCM has no irritating or unpleasant warning properties. Its mild odour is described as faintly pleasant, sweet or ethereal. Some of the PVC workers we interviewed reported that they had even enjoyed `sniffing the gas', which soon resulted in a feeling of light-headedness. For the early days of PVC production, * when appropriately sensitive monitoring equipment eras not yet available, workers' re ports about perception of the odour of VCM can be taken as circumstantial evidence for a rough estimate of the actual degree ofexposure. It should be kept in mind, how ever, that in chemical production units the presence ofother odoriferous chemicals and the possibility of olfactory fatigue, as well as different levels of individual sensitiv ity, may tender it very difficult to determine the factual odour threshold of a certain gaseous substance unless it possesses irritating warning properties. In \929,Schmidt and Schaurrmnn declared that the faintly sweet gas is practically odourless at concentrations of 5%--10% by volume. Veltman and Lange (1977a, b) assumed an odour threshold of 5 000-10 000 ppm. Volunteers exposed to VCM detected a slight odour at 4 100 ppm; a distinct odour was noted at 6 600 ppm for 30 min and this was accompanied by subjective symptoms of dizziness and sleepiness (Irish 1963). Gchrinf et al. (1979) recently mentioned a threshold of approximately 3500 ppm. Others have claimed that a concentration of400-500 ppm is the lower limit for detection of VCM by its odour (Bantu et al. 1969; Cook et al. 1971 \Marko witz et al. WTl\Lefim 1975,cited by Hubkt 1975). Barer et al.(!969) conducted experiments with concentrations of 50,250 and 500 ppm in an exposure chamber, in which 13 volunteers participated. At 500 ppm only some of them claimed that they were able to detect the odour, but this was inconstant Table 3 shows that differences between the various estimates are at least one order of magnitude. The close proximity between the perception of the odour of VCM and incipient CNS symptoms as reported by Irish (1963), however, makes it likely that the actual odour threshold can be as sumed at or above 4000 ppm. In contrast to VCM, the comonomer vinyl acetate, for instance, has distinct warn ing properties and can be detected by its odour at a level as low as 0.4 ppm;eye and throat irritation begin upward of 5 ppm and are noted by all test subjects at a concen tration of 216 ppm (Deese and Joyner 1969). 2.2.7 VCM as an Anaesthetic Agent VCM was once even considered for use as an anaesthetic agent. In 1929. Schmidt and Schautmnn speculated about usingVCM as a supplementary narcotic at concentra tions of 3%-5% (v/v) (< 30 000-50 000 ppm) in combined nitrogen oxide oxygen Vinyl Chlori Table 3. Odo Lower limit >- 5 000-10 00 5 00 4 1C 3 50 5C< 400-50i 40' 40 anaesthesia be tic and lethal. oxygen; concc however, that eluded. Into.' 10% VCM to i several hours t comm mined 3.5-5 30 mmol Ostcr cardie ^ man t cn like o amine the pi 22 Effects Some individu: listed in Table without acute symptoms sud adequate warm exposure to hif: A 21-year-old. 10 min after en which had bee cardiac enlargehave been acut. which occurred doubt that hex found dead wit; lJ. Marsteller detonated operating ations fries. Its PVC as', which oduction. writers'rel evidence nind, how* lemicals ailsenstivr a certain practically '77a, b) o VCM pm for sleepiness Jmateiy : lower M:.UzrfcoLOoducted amber, in proximity x reported be as- t- Vinyl Chloride-Associated Disease Tabk 3. Odour threshold Lower limit t detection S 000-10 000 ppm 5 000 ppm 100 ppm 3 500 ppm 500 ppm 400-500 ppm 400 ppm 400 ppm Author Vtlman and Lange 1977a, b I'toieJpTj Irish 1963 Cehringttsi. 1979 tarettettsl. 1969 Ltfbm 1975 (cited by Hubltt !9?5> Cookctal. 1971 Ntrkowitx et al. 1972 11 anaesthesia because of its potent narcotic action and the wide margin between narco tic and lethal concentntioRs. In animals it produced anaesthesia at 7%-lQ% in air or oxygen:concentrations above 1 2% proved to be dangerous. The authors pointed out, however, that adverse late effects of this hrdogenated hydrocarbon could not be ex* eluded. In toxicity studies with guinea pigs Patty et aL (1930) found concentntons of 10% VCM to be lethal within 30-60 min, 5% to eause marked narcosis, and QJ% tot several hours to be the maximum tolerable exposure without serious effects. They also commented upon the potential use ofVCM for surgical anaesthesia but wet* undeter mined about its practicability. In mice, the minimal anaesthetic range was found to be 3.5-5 mmol (85 000-122 000 ppm) for 10 min, the minimal lethal range 10-12 mmol (244 000-293 000 ppm) {ftoplcs and Ltakt 1933). It was not until 1947 that Osttr et al- in contrast to Sehaumann'% earlier assumption (1934) of a relatively low cardiotoxicity, warned against the use ofVCM is a potential general anaesthetic in man because of serious cardiac irregularities and CG changes observed in dogs. VCM, like other halogenated hydrocarbons, sensitizes the heart to the effect of catechol amines (Irish 1963). We could not ascertain whether VCM has actually been used in the post foranaesthesia in man. 2.2-8 Effects of Acute Overexposure is Man Some individual lesponaes ofeohuiteets to increasing concentrations ofVCM an listed in Table a.Lattr et al. concluded in 1963 that the maximum concentration without acute effects in nun lies between 8 000 and 12 000 ppm for 5 min, and that symptoms such as dizziness, light-headedness and disorientation should be taken as adequate warning signs for imminent acute danger. Two fatalities after occupational exposure to high concentrations ofVCM an nportad in the Sternum (Oamiger 1960). A 21-year-old autodavt deaner at a Canadian polymerization plant was found dead 10 min after entry at the bottom of a probably insufficiently ventilated reactor tank which had been declared safe solely after an explotiometer teat. Heart failure cells and cardiac enlargement found at autopsy, however, implied that the cause of death might have been acute functional disturbance in pre-existing heart disease. In the second case which occurred at the same plant, however, circumstantial evidence apparently left no doubt that heavy VCM exposure was the eause of death in a 39-year-old worker. He was found dead within 20 min, lying in a pit near the opened valve of a recycling pipeline O b * ' 12 W.K. Lelbach and HJ. Mamcller Table 4. Individual responses of volunteers to incteasini concentrations f VCM Concentration 500 ppm Duration of Symptoms exposure' Reference 7.5 h (Inconstant odour detection) Baretta et al. mild headache, dryness of (1969) eyes and throat in 2 of 7 subjects) "W 000 ppm - Generally accepted odour threshold Irish 11963) 6 600 ppm 30 min . (Distinct odour) dizziness, sleepiness /rirA (1963) S 000 ppm \ 12 000 ppm 1 5 min* (twice on 16 000 ppm I each of 3 succes- live days) 20 000 ppm / 2 of 6 subjects 'slightly heady' 1 of 6 subjects had reeling, swimming head, lust like getting gas' 5 of 6 subjects, various degrees of intoxication Ail 6 subjects bad more intense symptoms of acute intoxication than at 16 000 ppm Utter et al. (1963) 25 000 ppm 3 min 2 experimenters: dizziness, disorientation. burning sensation in the soles of the feet Patty et al. (1963) a Exposure to six different concentrations: 0 ppm; 4 000 ppm; 8 000 ppni; 12 000 ppm; 16 000 ppm: 20 000 ppm through which non-polymerized residual VCM was pumped back into a reserve tank: another man coming to his rescue was himself overcome by the gas and only just scaped. Two non-fatal cases ofVCM gassing were reported in Great Britain in 1951 (Spinas t al. 1975). A maintenance worker experienced acute narcosis while repairing a VCM leak, and a worker cleaning a polymerization vat from outiide with a water jet sudden ly collapsed across the open manhole. Subsequently he complained about tightness of the chest, nausea, abdominal pain and headache. Occasional loss of consciousness was also reported by LUis et aL (1975) in 14 of 554 workers at Niagara Falls and by Suciu t al. (1963) at a Rumanian plant. VCM-induced narcosis, at least on one occasion in the past, had occurred in 46 of 58 workers (79%) referred for medical surveillance from one British PVC-produdng plant (Ward et al. 1976), with a 100% incidence of narcosis in 28 symptomatic workers (Raynaud's syndrome and/or acroosteolysis). Successful resuscitation after VCM-induced narcosis of several hours' duration with out evidence of permanent damage was mentioned by Rety et al. (1974). Vinyl Chlor> 2.2.9 Monii During the ft ed data on V was directed an apparent!; 1954;W/jc' Gronsberg to Russian polyi. 005-008 tn; centration of' Inspectorate i. or from the d: mg/litre ( 1 ] mg/litre ( 34 In the cen. air ranged frot ppm, which w ventilation. Tl trations, some pursuit ofimp. ment in the vie ic drying facili centrati ns of1 continued to b mitted concent In a plant ; the range of0/ ppm (2.93 mg' ication apparat remarkable the the liver, althi past have prob. Bytin et ai. which occurred cited peak exp between 1962; Rumanian PVC bout 120 mg/r exposures to V( 300 Rumanian Greek plant wh resulted in high (Ginioi 1971).: f the reactors t up to 10 000 pi 31 <* (/) O--ii. O) O) h 11963) MI 963) ,a. 1: ooo 951 {Sptrjs ring a VHM -jet sudden* ifhtneis of >usness was ldby&icnr ccarionbt efliaiux idenceof olyw)* ion with* t Vinyl Chloride-Associated Discaw! 13 223 Monitoring VCM Concentrations in Working Areas During the first two decades of PVC production 0930-19501 no publication contain* ed data on VCM concentrations in the working environment. Tire main interest then was directed towards prevention of the explosion hazard. In 1957. the observation of an apparently* toxic angfoncurosis in Russian PVC production workers {S/mniwa 19SA:Pleshehiner et al., cited in Fihron and Gtonsbcrr 1957) induced FUantra and Grvnsbcrf to investigate environmental VCM concentrations m various r->am of a Russian polymerization plant in Gor'kij. Although most readings were in the range of OjOS-O.08 mg/litrc ( 20-313 ppm), e.g. below the maximum permitted VCM con centration of 1 mg/Utte (approximately 400 ppm) as specified by the State Sanitary Inspectorate at that time. escapes ofVCM in the reactor areas from detective fittings or from the discharge of operating autodam resulted in excursions up to 29.5-41.4 mg/Iitre ( 11 500-16 200 ppm) for periods of 5--10 min. One peak reading of 87J mg/litre ( 34 000 ppm) was recorded. - In the centrifuging and drying area of this plant the VCM content of the ambient air ranged from 4 ppm to 3 100 ppm with most readings between 20 ppm and 195 ppm, which was attributed to release of residual VCM from wei PVC resin and poor ventilation. The screening and bagging area was characterized by high dust concen trations, sometimes exceeding the official upper limits set for non-toxic dusu. In the pursuit of improving industrial hygiene, the installation of modem ventilation equip ment in the vicinity of the autoclaves, substitution of hand-operated by semi-automat ic drying facilities, and avoidance of leakages succeeded in reducing the ambient con centrations of VCM to below 0.05 mg/Iitre ( 20 ppm), but toxic angioncuroris still continued to be diagnosed. This led the authors to recommend that the per mitted concentration of VCM should be reconsidered. In a plant producing VCM, FHutora etal. (1958) found lower concentrations in the range of 0.04--1.1 mg/litre (16-430 ppm), with maximum values of about 1200 ppm (2.93 mg/litre), the latter having been observed in dose proximity to the rectif ication apparatuses and having resulted from spillage during sample collection. It is remarkable that up to now the Soviet Union bit reported no cases of angiosarcoma of the liver, although production of PVC resins started early and VCM exposures in the past have probably been in the same range as those observed in Western countries. Bytin et al. (1976) pointed out that during the 1950s episodes of unconsciousness which occurred among workers of the one Swedish plant operating at that time indi cated peak exposures of at least 10 000-15 000 ppm. Suriu et al. (1975) noted that between 1962 and 1972 a reduction of the average VCM concentration in the two Rumanian PVC piano bad been achieved from 2298 mg/m* ( 900 ppm) in 1962 to about 120 mg/m* ( 50 ppm) in 1965--1972. In 1969,Anj/:rirsnr et al. mentioned exposures to VCM concentrations of 112-545 mg/m* (44-213 ppm) for a group of 300 Rumanian workers, sight ofwhom (2.7%) had Raynaud's phenomenon. At a Greek plant which started operation in 1967. certain stages in the production process resulted in high concentrations of VCM in the work environment for brief periods (Grows 1971). In air displaced from reactao during addition of water and on opening of the reactors to obtain PVC samples at the end of a reaction cyde, concentrations of up to 10 000 p{m were found. In open wasterininu into which waste polymer scraped V , ^, ->bV-r~ or-'v-A T^r *{ ' .1 r* -41 *>* -Ir., ft . fc ` -- a * mI -- ;;^'^ . rr'-'-.rt't ?rV-; VSusZxii: ~ * :? -f t** ^ . Vi 14 W.K. Lelbach and HJ. Mameller away from reactor walls during cleaning was placed, concentrations of up to 600 ppm were measured. In the report of a World Health Organization (WHO) working group on vinyl chlor ide (1ARC 1974) it was stated that in a reactor of 15 m* (production of4-5 tons of PVC per cycle) a crust of 4 kg PVC containing 356-596 VCM can be formed on the inner surface. During the cleaning procedure 30%-50% of this VCM content is liber ated. It was calculated that the probable concentration ofVCM within the reactor after a 1-h cleaning operation was about 2700 ppm, but that it could be reduced to 90 ppm by 30 renewals of air per hour. In the past a polydeaner used to spend 4-5 h/ day inside the reactor but later the introduction of(not fully sufficient) automated cleaning reduced manual deaning procedures to shorter periods of 10-15 min follow ing every 20th--30th reactor cycle. A Belgian company, where monitoring in the work ing area was started in 1967, claimed that measurements at various sites inside a 9000litre autoclave during the manual cleaning operations had shown VCM concentrations varying between 50 and approximately 540 ppm, with a mean of 413 ppm (Hublet et al. 1977). According to data provided by Cook et al. (1971), VCM concentrations within the reacton prior to ventilation were in the order of3000 ppm. The reactor deaners usually did not enter the autodaves until an aeration period of 15-20 min had reduced-the VCM concentration to what was considered satisfactory limits. In the early days, this was tested either by toiiffing at the manhole opening' (the lower limit of detection of VCM by its odour having then been accepted as 400 ppm) or by use of a flammable vapour indicator which required a minimum of400 ppm for positive read ings, equalling 4% of the lower explosive limit of VCM. Later more sensitive methods such as gas chromatography were said to have shown that VCM concentrations inside the reacton tended to be below 100 ppm during deaning operations, but VCM releas ed from the residue during scraping resulted in concentrations of 600-1000 ppm measured dose to the hand. The Dow Chemical Company started monitoring the work environment in 1950 by means ofgrab samples; continuous monitoring was installed in 1959. While timeweighted average (TWA) concentrations ranged from 10 to 385 ppm during this period (1950-1959), excursions up to 4000 ppm occurred, agreeing with employees* reports of experiencing dizziness while loading or unloading reacton {Ott et al. 1975). In a second unit with modernized equipment excursions up to 600-1300 ppm still occur red during the period of 1953-1959. In 1959, when toxicological data indicating ad verse effects in animals exposed to 100-500 ppm VCM had become available (Torktlson et al. 1961), the Dow Chemical Company introduced a new 50 ppm guideline for the work environment. Excursions and peaks up to 500 ppm did continue. Measure ments ofTWA exposures for various specified job categories in two production units of this plant between 1950 and 1966 were presented by Ott et al. (1975). In 1968 BASF (Wen Germany) introduced continuous monitoring by infrared absorption spectrophotometry for VCM concentrations well below 500 ppm; in 1974 more sensi tive equipment was installed and concentrations were kept below 25 ppm and later below 10 ppm, with occasional ceiling values of 70 ppm (FJeig and Thiest 1974). In several surveys individual jobs were grouped into three exposure categories ac cording to job classification to evaluate past exposure experiences (Spinas et al. 1975; Williams et al. 1976; Bkndis et al. 1978). These exposure indices were: (a) light less Vinyl' than 5 ppm). plants sampU Estim* morec averag. Table i atmosr Cbemk 1945-1 1955lOfiO- O in W U1 oo n' me e? (3) The I fy specif roentshi peak con for the c. Cum compris. tion date. (Ton flu which cat conditier lag of res, A catindustrial to 1975 b 2.2.10 E Raw PVC unreacted tanreller OO ppm Ins U Vinyl Chloride-Aisodared Disease 15 than 50 ppm: (b) medium 50-200 ppm;tc) high 200 ppm and above (up t 1500 ppm). In the past, however, estimates of exposure concentrations were based in most plants not on continuous monitoring during the entire work shift but at best on spot samples not necessarily representative of the different phases of a given operation. Estimates of past exposure levels such as those represented in Table 5 are, therefore, more or less conjectural. It can be assumed that considerable deviations from these average values have occurred all too often in the past. Table 5. Arenas concentrations of VCM in the working atmosphere of WC-producing plans3. (Estimated by Chemical Industries Association Ltd.) 1945-1955 1955-1940 1960-1970 mid-1973 1974 1975 's.lOOO ppm ^400-500 ppm 200-400 ppm % 150 ppm ' 50 ppm and 1 v 5 ppm 3 According to Fltif and Thua I974;&rm 1976 Equipment for optimal continuous multipoint monitoring of exposure concentra tions in the working areas should meet certain basic requirements: (1) For stationary equipment strategically placed sample probes should yield data representative ofindi vidual exposure levels in the breathing zone of workers, preferably to be used in com bination with personal tampleti. (2) Analysing methods should have a high selectivity. (3) The limit of detection should be a: least one order of magnitude below the current ly specified standard regulating the permissible upper tore! of exposure. (4) Measure- * ment should be instantaneous (within seconds) to guarantee rapid detection of critical 'peak concentrations. (5) Recording and data processing techniques should be provided 'for the daily estimation ofTWA exposure during the whole work shift. Currently available methods for the determination ofambient VCM concentration comprise such analytical tools as loog-psth infrared spectrophotometry, flame ioniza tion detection, gas chromatography, mass spectrometry, combustion-conductivity (ionofluxO, and personal samplers in combination with gas chromatography, none of which can at present be eonridered as absolutely satisfactory for all individual plant conditions because they all differ with regard to selectivity, limit ofdetection and time lag of response. A catalogue of the methodologies that have proved to be of value in the control of industrial hygiene and personnel protection regarding exposure to VCM was coapQad in 1975 by Row* 2.2.10 Exposure to VCM in PVC-Proctssmg (fabricating) Plants Raw PVC powder ready for compounding and fabricating purposes contains residual unreacted vinyl chloride monomer in varying amounts. In the past, monomer content O J ) 16 W.K. Lclhach anti HJ. Uwitlter was reported to have been as high as 6000-7000 ppm (w/w) in some types of raw PVC, but a level of 500-1000 ppm probably was a more representative range (Schwrirerr 1975: VKE 1974:firjrcdr 1976). The monomer slowly escapes into the environment exponentially with time, depending on length of storage period, tempera* tore, size and porosity of particles and other physical properties of the polymer and, more recently, on the eftbetivity of special degassing techniques (Pn-er I916:5clwt: and Wolf 1977). In 1975, the Association of the German Plastics Industry announced that in future only PVC powder with a maximum monomer content of 10 ppm would be put on the market due to the development of special degassing technologies (VKE 1975) . Analyses of the types of raw PVC. chiefly suspension polymer, which are now used in German plants showed that in most products the content of unreacted mono mer was now leu than 20 ppm but in some foreign products it still ranged between 150 and 250 ppm; it also turned out that there may be considerable variation between different batches of the same product iScfiHr: and Wolf 1977). Cold and particularly hot mixing or compounding of PVC. a procedure which usu ally precedes fabricating processes, favours the escape of unreacted monomer and, therefore, requires special ventilation equipment. Depending on the content of residual monomer, considerable amounts of VCM could be set free during the mixing process, as was shown by Bruder and Stnby (1975). Apart from hot compounding, other ther moplastic operations, such as extruding, calendering and welding of tiles, also resulted in release of unteseted monomer into the work environment. Although recently con ducted measurements of the concentration of VCM in working areas of six German PVC fabricating plants have shown that in 90% of the readings mean levels integrated over I *h periods now range below 0.1 ppm, numerous short bunts with excursions up to 60 ppm during a workshift were recorded in one instance (ScliUrz and Wolf 1977). Simiiariy low concentrations of VCM in breathing zone samples (maximum: 12 ppm) with 60% of the values ranging below 1 ppm had been found in 1974 in nine United Staffs fabricating plants, but source samples had ranged up to 340-540 ppm (Kantadt 1976) . These present results, however, do not permit any conclusions as to past levels of atmospheric VCM during the yean when residual monomer content of PVC resins was high and ventilation insufficient, particularly in compounding and extruding units. Whatever the extent of the risk might have been in the past, it can be safely assumed that the ambient monomer concentrations in fabricating plants have always been con* riderabty lower than in PVC-preducing plants. ' When it was suspected that certain VCM-related symptoms might also have afflict ed PVC process workers, this problem was investigated by our group. Although no cases of acroosteolysis, pseudoscieroderma or angiosarcoma of the liver were observed, evidence was presented which demonstrated that minor and inconspicuous lesions such as mild hepatic fibrosis, bromsulphalein (BSP) retention, thrombocytopenia and slight enlargement of the spleen could be found in 28 process workers who had been em ployed for years in compounding and fabricating units (Lange et al. 1975,1976a: Wcgman 1975 ,Morzteller et al. 1976). In principle, these lesions were identical with those seen after heavy exposure as we will describe, but the degree of damage attribut able to occupational VCM exposure observed in these workers was not considered suf ficient to entitle them to disability compensation under German law. Although the in- Vinyl conspi sponsquanti bserv progrr male F findar At two G. died re' lation i "health, overall records 2J.11 Industr; of expo JO tl S itr CO if. di> o mcnJ. si: *r O jo M in ------ jm discier*. red to r The not a*- should I- tendy ; available new inf list fM various i so-callei' tool for ysisof t! In tk ppm in I !| 1 Manteller of raw aage dymer and. >76;SWirr yannounced Q ppm would Ingres (VK rich are new wtedmono2 between itoo between e which usumar and, nt of residual ing process, pother theribo resulted centiy conv German . integrated -cunioru up lu//1977V n- 12 ppm) United pin (Kjrrtjiit ftof t was nK*iuWSa y assumed been con- love afflict* oughno tc observed, t iesiotts such hand slight jmb cm* 1976a: deal with ige attiibut* redcredsufaugh the in Vinyl ChloriUc-AnoviatcJ Disease 17 conspicuous character of titese lesions agrees well with the assumption of a dosere sponse teiati nship of VCM-cdaied disorders and the alterations may seem to be. quantitatively, of little importance, they should not be minimized. Nevertheless, an observation period up to the present of almost 7 years did not reveal any spontaneous progression. In a proportional mortality study* for 1970-19T2 among roughly 35 000 male PVC fabrication workers in England and Wales. Baxter and fox (1976) did not And an excess of angiosarcoma or other liver diseases. A recently completed cohort study of4007 people who had been employed by two German PVC*fabricaring plants between 1934 and 1974 and of whom 360 had died revealed that overall mortality, although marginally below that of the male popu lation of the Federal Republic of Germany, was slightly elevated with respect to the healthy worker effect*. No angiosarcomas of the liver were observed and no excess in overall cancer mortality was noted, but an excess mortality from brain turnouts was recorded in one of the two plants (Reotl ct ah 19*8). ` 2--.11 National Standards for the Control of Exposure Industrial hygienists have used several designations for acceptable or permissible limits of exposure to chemicals at the work place, such as `maximum allowable concentra tion* or `maximum acceptable concentration* (MAC), threshold limit value' (TLV). industrial hygiene standard* in the United States and as `Maximale Arbeiuplatzkonzentratjon* (MAX.) in West Germany. There empirical standards were defined by the American Standards Association as setting a limiting concentration "for exposures not exceeding 6 hours daSy during a 40-hour work week with the understanding that varia tions should fluctuate below this value** (Irish 1963). An extensive discussion of the basic approach to the principles used in retting environmental quality standards for oc cupational respiratory exposure to toxic agents can be found in the paper ofZiethuis (1974). In this paper, the conceptual differences between threshold limit values as used in the United States and maximum allowable concentrations as used in the USSR are summarized and the differences fat approach and emphasis, which may explain past discrepancies between permissible limits, are elucidated. For details the reader is refer red to this paper. The standard is nor an index of relative toxicity, far less ofhazard, and certainly not a son of "average', a standard ret as the ceiling level implies that arty fluctuations should be around a median of perhaps half die standard and that it should be compe tently used in full awareness of in phytiobgical basis and the limitations of currently available knowledge <frith 1963). The standard will be subject to revision as soon as new* information is available. An enential dement of the annually published German list of MAK values (MAX-Werte) is its preamble, which exhaustively detines the various modalities for the interpretation ofsuch standards (Hemchkr 1972/73). The so-called TWA, an integration ever time of fluctuating concentrations, will be a useful tool for estimating the probability of injury only If it represents a comprehensive anal ysis of the normal fluctuation Mow the standard. * In the Federal Republic ofGermany the standard for VCM (MAJC) was set at 500 ppm in 1966. The German Standards Advisory Committee redured this to 100 ppm V 18 W.K. Lelbach and H.J. Marstcller in 1970 in conformity with the proposal of roritc&wretal. (1961). which was based * on the results of their animal experiments. In June 1974, when the carcinogenic prop erties ofVCM had been well established, the MAK regulation for this chemical was re pealed and instead a preliminary technical guideline (Technische Richtkonzentration) of 50 ppm was instituted (VKE 1975). Die Chemical Industries* Liability Insurance Association (Berufsgenossenschaft der Chemischen Industrie) also issued instructions for the prevention of health hazards arising from handling ofVCM in July 1974. As of July 1975, a technical guideline (TRK * Technische Richtkonzentration) of 5 ppm. defined as annual mean, for FVC-produdng and -fabricating plana was instituted, per mitting excursions up to 15 ppm during periods of not more than 1 h. In order to adapt operating plana, a provisional regulation was issued with reduction of the an nual mean concentration to 20 ppm as of July 1975, and to 10 ppm as of July 1976 and peak concentrations over 1-h periods not exceeding 60 or 30 ppm, respectively (Veltman and Lange 1977a). The technical guideline (TRK value) was revised in 1977 (2 ppm annual mean/5 ppm per 1 h). In the United States the threshold limit value for VCM was originally set at 500 ppm in 1947. It was reduced to 50 ppm in April 1974 as a temporary emergency stan dard and finally reduced to 1 ppm/8 h in 1976. Haley (1975) summarized the conflict ing views on vinyl chloride regulations proposed by Government and industry in 1974. Table 6 shows thresholdlimitvaluesm'a number 6TPVC-ptodudn| 2-2.12 Exposure to VCM Outside the Working Area The Environmental Protection Agency estimated that FVC-producing piano in the United States discharged about 90 million kg VCM annually into the environment (4%-8?r losses), most of it as air emissions and lesser quantities dissolved in water effluent streams and entrapped in sludge and solid wastes {Schweitzer 1975). In a pioneer study, concentrations of 1-2 ppm VCM were found in the ambient air near such a plant (IARC1974), 2--3 ppm in the primary water effluent and 100-200 ppm in the sludge at the plant site, but sampling and analysis methods used were later found to have been inadequate so no conclusions were drawn from these figures since they could have been in error by as much as one order of magnitude (Schweitzer 1975). For people who Ito within 5 miles of monomer and polymer production facil ities in the United States an forage exposure of 17 ppb during the yean of uncontrol led emissions was calculated {ffiehohon 1977). In the past VCM has beenjirfdeljHued as an aerosol propellant, either alone or mix ed with nuoro^aibotisTHydrocarbons and inert organic gases, in household and cosmet \ ic prognetSthair sprays, deodorann, pesticides, room disinfectants, paint sprays, fjwrilture palish and window deaners). In Germany, VCM was proposed as propellant 'tor aerosols in 1958 (Ottermayer 1967), in Japan it has been used as a propellant since 1958, in the United States this use was probably introduced after 1962 {Schweitzer y 1475). As an aerosol ptopdlant, VCM has been a possible source of exposure for the public at large, particularly for women, the extent and the potential health implica tions of which are unknown. Use of aerosol products in confined spaces has been re ported to result in air concentrations ofVCM of up to 400 ppm in closed rooms, even after only short butsu (30 s) {Gay et al. 1975), which could persist for several. V ID T^ T CD O cn Bi ->i ro Ct Fi France German DiRepublic > Iran Italy Japan Ncthcriand Rumania USSR Federal Rei Germany Sources: 5. 73; (ARC R 1977;Sehiii f{ I md HJ. MaifttUer .which was bated axroiotetuc prop hetical was it* icMKzentration) ability insurance issued instruenons in July 19*4. As nnation) of 5 ppm. was instituted, per1b. In order to iuction of the an* mas of July 1976 -pm. respectively was ttvised in 1977 anally *t at 500 ary emergency start* marized the conflictnd industry in 1974. y countries. ing plants in the he environment * tived in water iztr 19751 In a f ambient air near c100-300 ppm era later tCG fuies since tie (Sckwttrzer ser production facile yeas of uncontrol* '. cither alone or mix* uuaehoid and cosmet* is. paint sprays, >poaed as propellant I as a propellant since 1963 (Scftwcftrer of exposure for the al health implica* spaces has been re* n dosed rooms, persist for several o Vin> I Chionde-Awociated Disease 19 Table 6. Threshold limit values iTLV) in various countries Country Year TLV (ppm) Comment Belgium Canada Finland Franc.* German Democratic Republic (DDR) Inn Italy Japan Netherlands Rumania 1975 1975 1975 1975 1976 1976 1975 (funue) 1970 1974 1975 1975 * Sweden Switzerland United Kingdom USA 1975 1976 1975 (future) 1975 October 1975 1947 April 1974 October 1974 1976 25/50 10/25 5/10 25 200 12 25/50 50 (25/50) 500 200 10 10 100 mg/m1 (40 ppm) 5/20 1/5 too 10 25/50 10/30 500 50 25 1/5 TWA(S h/15 min) TWA (8 h/15 min) TWA <8 h/15 min) TWA i.8 h) MAC {Sehottwk 1969) (Koottskt ct al. 1978) TVA(8h/lh) TWA (8 h) (TWa 8 h/15 min) MAC MAC (25 mg/m1) TWA (8 h) MAC (Prodm et al. 1975) TWA (8 h/15 min) TWA (8 h/15 min) MAC TWA (8 h> TWA (8 h/15 min) TWA (personal/ceiling) MAC (Amt. Con/. Governm. Industr. Hygienists) TWa (8 h>. temporary emergen cy standard (OSHA) TWa (8 h). temporarily permit ted exposure TWa (8 h/15 min) USSR I mg/Iitic (391 ppm) 30 mg/m* (* 12 ppm) MAC. provisional ceiling concen tration: State Sanitary Inspec torate. 1957 (filerove and Grotuborj 1957) MAC ISehonwk 1969;Krrmrr 1975) (Sanitarnye nonny) Federal Republic of Germany . 1966 1970 June 1974 1975 1977 500 100 so 5/15 2IS MAK MAK TRK (preliminary technical guideline). Annulment of MAK regulation. TRK (annual mcan/1 h) TRK (annual mcan/l h) Sources: Smyth 1956-.FUerov* and Grontbtrf 1951;Schottek 1969; Hensckler 1972/ 73:IARC Report \91-i; Holey |97S;JfUie 1975;/Voden et al. \915;Arymnpur \9Tl\StMn and Volf!977; MAK-Werte-Lute 1911;Kottntr 197S c. , * R&S 105173 r 20 <* * tV.K. Lclbach and H J. Maruallcr bouts after repeated spraying in smaller-sized room* (IARC 1974). Haley (1975) pre sented a list of pesticide products containing VCM as a propellant and registered for indoor use, which were banned in 1974 bv the Food and Drug Administration. In Japan, the monomer was also banned as a propellant in 1974 (JAMA 1974.229:855). There is a case on record of a worker who died from noncirrhotic portal hypertension and angiosarcoma of the liver after 14 yean' employment at a chemical plant in south ern Germany where he had been engaged in loading such pesticide cans (ftt'i>r/and Weber 1974), The report of a female office worker suffering from typical Raynaud's phenomenon, pseudoscleroderma, acroosteolysis and mandibular osteolysis who never bad occupational contact with VCM (Meyrnon and Meier 1972) is apt to make one wonder what influence the frequent indooruse of VCM-propelled spray cans (Bridbord t al. 1975) may have had in this unique case. Sputum samples collected from frequent users of pressurized spray cans who had no respiratory symptoms were found to con tain a significant excess of moderate and marked atypical metapiastic bronchial cells compared with two groups of controls {Good et al. 1975). PVC bottles, films and foils have been used for many years for packaging food and beverages (cooking oil, margarine,meat, mineral water, fruit squashes and other soft drinks, hard liquor etc.). The content of residual VCM in PVC bottles was found to have ranged fotmeriy between 5 and 400 ppm (w/w), and in PVC foils up to 800 ppm (ran Exh and van Logten 1975). The problem of migration of unreaettd VCM from the PVC containers into the foodstuffs became recognized in 1973. Reports of un pleasant tastes in American brands of vodka and whisky which had been stored in PVC bottles led to the discovery that VCM had leaked into the liquors; in some samples levels up to 10-20 ppm (w/w) were found (van Exh and ran Lopen l975:Davies and Pern' 1975). Data available in 1974 to a group ofWHO experts revealed that samples of gin and whisky had contained 057 and 0.62 ppm (w/w) or VCM respectively, after storage in miniature PVC bottles for periods up to 3 years; VCM concentrations in range squash and cooking oQ were found to be in the range of 0D1-0DS ppm and 001 --0.04 ppm, respectively (IARC 1974). Levels of 0-04 ppm found in British PVC-bottled liquids were mentioned by Davies and Perry (1975): in their own analyses ofsamples of PVC-bottled spirits supplied by British Airways they found concentra tions of 0-0.25 ppm (w/w). Methods were developed for the detection of VCM in liquids with a maximum sensitivity down to the 1 ppb level (raw Lierop and Stek 1976: Chessman and McFarren 1977). It was tentatively estimated that even during the years when PVC-packaged food and beverages had not been heeded as a potential source of contamination, the likely average daily human intake of VCM from this source could have been in the order of 0.1 mg/person (IARC 1974). Schlatter (1976) calculated that today it would be less than OjOI mg/person (equalling 250 mg during a whole life time); in comparison, he calculated that the inhalational intake of VCM in diseased workers who had been exposed to concentrations of 500-1000 ppm during a period f 10-20 yean would have amounted to at least 25 kg. The Association of the German Plastics Industry expects that the use of technology available at present for the production of PVC food-packaging materials decreases the VCM content of food stuffs to below 50 ng/kg (50 ppb) even after prolonged storage (VICE 1975). Results of carcinogenicity assays in experimental animals after oral administration of VCM are discussed in Sect. 3J. Vinyl Chi 3 Toxa 1 CO 3.1 Acute oO! During the i ^ the assessme ^ concentrate and Leake l1 mattto et al. I960;I< anaesthesia, deep narc this range of exposure tive and haemorrhagic hepatocellular injury u inducing substances (se 32 Chronic Toxicity Torktlson et al. (1961) exposure to concentrate 42-6 months. All spec however, caused an mcr. histological changes in r` pigs and dogs. An incre: in rats exposed to 20 0C (1963); no histological ` Gorlcij Institute were it exposure of experimeu; mias, bradycardia, dun;. 005 mg/litre) for 5 mo;creased secretion of cate, posterior hypothalamus 3500-4000 ppm (9-IC of the cortex and the am comitant changes in chv posure of rats and rabbit resorptive bone changes: nervous system dysfuncu available evidence for V( VCM should be suspecieu statutory maximal allows cratic Republic) should b Of particular importai Viola et al. 1971) with c.v full year. It wb only aftei j llJ. Mamdher r(!97J)pitipstered for (ration. In ^|p:8S5) .jj^tension plant in south' Rcil and J Raynaud's sis who newt intake one ans (Bridbord trwn frequent >und to con* actual cells jng food and I other soft i found to t 800 ppm VCM from ns of tin* tored in PVC samples S.Oeriwand tat samp'is twely. after inons in ppm and Brush <wnanal>.es liJ*Fl76: if the yean source of nee could culated whole in diseased ; period the stent for t ffood* L' Vinyl CliluriUC'Aoocutcd Diiwase 3 Toxic lojyofVCM J.I Acute Toxicity Z1 During the first three decades or PVC production, animal experiments were limited to the assessment of the acute inhalational toxicity of VCM in short-term exposures to concentrations varying between SO 000 and 400 000 ppm (Pjity et al. 1930;7ap/cr and Leake 1933\Sdmanami 1934.1938; Direr et al. l947.Cc/r et al. l949:.ltemomttco et al. I960:rrrcr et ai. 1963). in mice, rats, guinea-pigs, rabbits and dogs anaesthesia, deep narcosis, cardiac arrhythmias and lethal effects were observed within this range of exposure but no relevant organ pathology was noted except for conges tive and haemorrhagic changes in lungs, liver and kidneys on fatal outcome. Acute hepatocellular injury was later found only in animals pretreated with potent enzymeinducing substances (see Sect. 3A22). 32 Chronic Toxicity Torkeison et al. (1961) were the first to describe results of experiments with prolonged exposure to concentrations ranging from 50 to 500 ppm, 7 h/day, 5 days/week, for 43-6 months. All species tolerated exposure to 50 ppm for 6 months: 100 ppm, however, caused an increase in fiver weight and 200-500 ppm caused, in addition, histological changes in the liver and kidneys of rats and rabbits, but not in guineapigs and dogs. An increase in liver weight and decrease in spleen weight was also seen ir. rats exposed to 20 000 ppm, 8 h/day. 5 days/week, for 3 months by Later*i al. (1963); no histological lesions were found after 3 months. Soviet investigators at the GorTcij Institute wet* mainly interested in neuroendocrine changes after prolonged exposure of experimental animals to various concentrations of VCM. Cardiac anyth* mias. bradycardia, change in phonocardiogram in rats exposed to 12-20 ppm (003OjO5 mg/litre) for 5 months were reported (Item and Hokhova 1969b) as well as in creased secretion ofcatecholamine in rabbits and change in the biopotential of the posterior hypothalamus (Vesm and Nokhme 1969a). After a 53-month exposure to 3500-4000 ppm (9-10 mg/litre)change in the bioelectric activity (EEC recordings) of the cortex and the anterior and posterior hypothalamic nudei in rabbits with con comitant change in circulatory functions were seen {Va:ai and Nokhore 1968). Ex posure of mu and rabbits to 0.03-0.04 mg/litre (12-16 ppm) for 6 months produced resorptive bone change and osteoporosis in addition to cardiovascular and central nervous system dysfunction {Basaker ai. 1972k Is 1969cAotre* summarized available evidence for VCM toxicity and warned urgently that chronic exposure to VCM should be suspected of causing toxic Uvtr damage. He moved that the currently statutory maximal allowable concentration of200 ppm (MAC value, German Demo cratic Republic) ritould be lowered. Of particular importance as pioneer work were I'Ma't experiments (1970a, b; lloh et al. 1971) with exposure of rats to 30 000 ppm, 4 h/day, 5 days/weak, for a full year. It an only after this length ofexposure that histopathoiuglcal examination R&S 105175 t 2: W.K. Laibach and HJ. Manteller revealed lesions similar to human aeroosteolysis and also similar to the type of non* tumorous liver diseases which we observed in PVC workers 3 yean later (Manteller et al. 1973). Viokt described lesions of the skin, the Small arterial vessels, the connective tissue and elastic reticulum of the paws, and periosteal proliferation with chondroid metaplasis of metatarsal bones. Fibrosis of small peripheral nerves and degenerative changes of the grey and white matter of the brain were prominent, whereas the kid* neys were not markedly affected. The liver showed pronounced degenerative lesions with parenchymal necrosis, cytoplasmic and nuclear polymorphism, abnormal prolifer* ation of hypertrophic Kupffer cells and intense flbrosderotic reactions. )3 Oncogenic Properties The earliest documentation of the carcinogenic action ofVCM was Viola't preliminary report prerented at the 10th International Cancer Congress in Houston, Texas in May 1970a. Of 26 Wistar rats exposed to 30 000 ppm for 12 months 17 developed cpider* moid carcinoma, mostly in the panauricular region; 6 also developed adenocarcinoma of the lungs end 5 osteochondroma of metacarpal and metatarsal regions of all 4 limbs (Viola et al. 1971; Viola 1974). Maltoni and Lefemine (1975) later interpreted these panauricular tumours as arising from the sebaceous glands of the exterior acoustic duet, also known as ZymbaTs glands, the cell matrix of which seems to be the target tis sue of a number of carcinogens. They were of the opinion that the pulmonary malig nancies were mefastases from the Zymbal gland tumours. Autoradiograms of sections of whole tats dosed orally with [,4C}4*befled VCM revealed a discrete localization of 14C m the panauricular region (Zymbal gland?) and in the region of salivary glands and Harder* glands (Green and Hathway 1975). In this contextAfcimomi et al. (1979). who analyred the peroxidase activity in Zymbal glands ofWistar rats, proposed the concept that peroxidase-mediated bioactivation ofcarcinogens (in their study: stilbene derivatives) might offer an explanation for these tissue-specific effects. At the end of 1910 Maltoni and his group, with the support of Italian, British, Belgian and French chemical companies, started to plan and subsequently execute a large-scale carcinogenicity biosssay designed to study the effects of chronic exposure to VCM in relation to vinous experimental factors such as route of administration, dose level, length of treatment, and spedes, strain, sex and age of animals (/Maltoni 1973,1971:Maltoni and Lefemine 1974a, b, l915;Meltoni et al. 1974a. 1975). Con centrations used in the inhalation experiments were 30 000,10 000,6000,2500,500, 250 and 50 ppm, with length of exposure ranging up to 52 weeks and observation peri ods up to 143 weeks. Apart from the induction of Zymbal gland carcinoma other mehgnandes developed, notably angiosarcoma of the liver but also extrahepadc angio sarcomas. nephroblastomas, pulmonary tumours and mammary carcinoma, as well as a number of single tumours of other target tissues. Different types of turnouts were found to coexist in the same animal. On oral administration ofVCM dissolved in olive ofl (5 days/week) angiosarcoma of the liver was found after 50 weeks in two animals of the-two groups of 80 Sprague-Dawiey rats each of which had been treated with the .highest doses of 50 and 16.65 mg/k{ body wt. (Maltoni et al. 1975). Maltoni (1977) succeeded in demonstrating that the route of administration of this dearly muitipo- Vii 30 ten 9 (/) stuc soN> O 6 da in ratio -d tion 1 o> place them angiosarcon Sprague-Dav proved to 1m genic in rats be carcinogc 10,5 and 1; 1979). Anot' the doK-reb exposure lev histologica] * the liver and the inductior posure to 10 aL 1974b; IA endothelial t< perplasia and even in the a' was scanty a- doses. In the fibrosis was t of ossifying :i feet was sugg offspring of r mine 1975). I posed to VC ed from Grici it was seen u maturity of t; to 2000 ppm fodofhepati Hobnberr week, for 52 spleen chang. malt exposed cutaneous an. ppm group ar i See also II' mm imeller ten der et tive ladion* rolifer- ninsy iMay siderinoma Umbs hese tic rge: tisialignom on of nds 1979). he tilbene M jsure *n, mi Coo- 1.500. Ml plirr nu ll0* die m iolh* mils ththe )77) ipo- 1 Vjnil Chlonde-Associated Disease 23 tentill carcinogen may significantly vary the type of neoplastic response. In a subacute study of otal VCM toxicity, lasting only 13 weeks, in which rats were given VCM dis solved in soya bean oil by savage in daily doses of30.100 and 300 mg/kg body wt,, 6 days/week.FrnjM et al. (1975) found a significant increase in liver-to-body weight ratio only at the highest dose level. This was interpreted as a merely nonspecific reac tion not necessarily indicative of a toxic response. Based on these results. Ftron ct al. placed the oral no-toxiC'ffect level at 30 try VCM/kg body wt^day and suggested that the no-toxic-eiTect level may actually be even higher. Zymbal gland carcinoma, hepatic angiosarcomas anJ nephroblastomas had never occurred spontaneously in the breed of Sprague-Dowity ns used at the Bologna Institute. The neoplastic response to VCM proved to have a direct dose-time relationship. Even levels of 50 ppm were carcino genic in no and mice. LuuMaboni (1977) found exposure to 25 ppm VCM also to be carcinogenic in ns. whereas no carcinogenic effect was observed at lower levels of 10.5 and I ppm in a study which, however, is stfll incomplete (quoted from Gririurc 1979). Another American study designed to complement Maltonfi results confirmed the doserelated induction ofliver angiosarcoma and mammary carcinoma in mice at exposure levels of 2500,200 and 50 ppm (KepHngtr et al. 1975). On reexamining histological slides ofhis past experimens, Viola later also detected angiosarcomas of the liver and other malignancies of skin, lung and intestine in his rats: he also reported the induction of skin acanthomas and pulmonary adenocarcinomas in rabbits after ex posure to 10 000 ppm VCM,4h/day, 5 days/week, for at least 15 months {Maltoai et al. 1974b; (ARC 1974).,Vu/>h and Lefenint (1975) considered the effect of VCM on endothelial tissue to be a systemic one since they found.dilatation of blood spaces, hy perplasia and atypia ofendothelial cells also in organs and tissues other than the Over, even in the absence of angiosarcomas or benign angiomas. Evidence of hepatic fibrosis was scanty and inconstant in their animals end was mote likely to occur at the lower doses. In the spleen of treated rats and mice fibroangioblastic proliferation undergoing fibrosis was frequently observed. No tcrooeteolytic lesions were found, but a few caws of ossifying angiosarcoma were observed. A potential transplacental carcinogenic ef fect was suggested in 1975 by the development of subcutaneous angiosarcomas in the oflspring of breeding animals axposed for 7 da}1! during pregnancy {Maitoai and Leftirtme 1975). Later, Mtltoni (1976) detected angiosarcoma in the offspring of rats ex posed to VCM during the period between ttie 12th and 18th day of pregnancy (quot ed from Grteiitt 1979). Hepatocellular carcinoma was cot found in adult animals but U was seen to develop readily in newborn animals, possibly in connection with the im maturity of their bioactivation pathways (Maltoni 1977). Exposure of newborn rats to 2000 ppm VCM, 8 h/day,5 day*/week, for at least 4 weeks elicited pteneoplastic foe of hepatocellular AlPax deficiency, notably in female animals (Laib ct al. 1979). Hotmbcrj ct al. (1976) exposed mice to 50 and 500 ppm VCM, 6 h/day, 5 days/ week, for 52 and 26 weeks respectively. They did not observe hepatic fibrosis or spleen changes, but multiple benign atveotogenic adenomas developed in 18 of 24 ani mals exposed to 50 ppm and in ail 24 animals exposed to 500 ppm1. In addition, subcutanemu and/or subperitoncal haanangiosarcoma developed in 14 animals of the 50ppm group and la 8 of the 503-ppra group. Only one haemangiosaicoma of the liver I See also WinettataL (1976) / -X- 33 (/) o DCri -4 -4 4 t i 't :* W.K. Lelbach and HJ. Manteller was found in an animal exposed to 500 ppm. A few mammary adenocarcinomas, one rhabdomyosarcoma and one renal haemangiotarcoma were also seen. From their ex* pertinents Holmbetf et at. concluded that a lower exposure over a longer period may intensify the cancerogenic response and that an inverted relationship between dose level and latency timeseems to exist in the case of VCM. as had already been observed with other carcinogens. Recently the results of still another animal experiment with exposure of Wistar rats to 5000 ppm. 7 h/day, 5 days/week, for S2 months was pub* lished by Feron et al. (1979a, b; Feron and Kroes 1979) in an eventually fruitless at* tempt to elaborate suitable parameters for early detection of VCM-disease in man. Ear* ly effects were a shortening of blood clotting time and. the occurrence of swollen and malformed hepatocytic mitochondria. At a later stage progessive tubulonephrotic changes in the kidneys, fod of cehrlar alterations in the liver with reduced glucose^* phosphatase activity in hepatocytes, strong sinusoidal activity of alkaline phosphatase and increase of smooth endoplasmic reticulum in parenchymal liver cells were observ ed. In the final stage areas of necrosis in the liver parenchyma, focal dilatation of sinus oids and proliferation of normal and atypical sinusoidal cells, multicentric hepatic an giosarcoma and Zymbal gland carcinoma occurred. Feron et al. (1979b) also observed hepatocellular carcinoma in three animals. Surprisingly, the induction of very malig nant metastasizing carcinomas of the nasal cavity originating from the olfactory epi thelium and Bowman's gland was noted, which had not been reported before in con nection with VCM. Marked hepatic flbrosis was only seen within fully developed an giosarcoma or as a reaction to extensive necrosis of the hepatic parenchyma. The in vestigators were of the opinion that hepatic parenchymal changes preceded those of the hepatic stroma, but they stressed the fact that the true relationship between VCMinduced alterations ofhepatocytes and sinusoidal cells has yet to be elucidated. 3.4 Toxieodynamics Prior to 1974 very little information was available about the fate and the toxicodynarnics of VCM in the mammalian organism, but the discovery ofVCM-induced angio sarcoma of the liver in humans and experimental animals provoked a Urge number of studies which resulted in a flood of publications on the metabolism of VCM. In 1934 Schatmann reported that in mammals unchanged VCM was excreted via the lunp after inhaUtional administration; the pulmonary route is the-main excretory route of nonmetaboiized VCM (Green and Hathway 1975). Blocking of nonprotein sulphydryl groups in the blood of vinyl chloride operatives, less pronounced after dis continuous contact, we observed at early as 1964 by Gabor et al. and indicated deple tion of the glutathione pool, which has since also been found in exposed rats (Hefner et al. 1975a). Hepatic glutathione pUyt a fundamental role in protecting tissues against attack by alkylating agents. The appearance of monochloroacttic add in the urine of workers expoaed to VCM was reported in 1966 by Ghgoretcu and Toba. indicating that a polar excietable metabolite of VCM had been formed (Vamh 1978). Toxicodynamic studies have revealed that VCM per te Is not the ultimate toxin or carcinogenic. It is the process of blotnnsfoimation (metabolic activation) of VCM. primarily by hepatic microsomal enzymes (mixed function oxidases) that yields short Vinyl Chlorii lived but high, mutagenic <tn> cretable ptodi 1975). The t. tivt velocities tionofits teanation of VC so that above following a zc cordance with 3AA Uptake Pulmonary up' in the animal'* with the pool < shown by com Boltet ii.(l9* as albumin, arc pound goes ini After oral ingcJus to be cons: is excreted via > 1976c). This e able process. 1* body wt. adm. vestigation ol gavage in dose-, found a signili. plasmic teticuh but only mini' rats on a diet c almost all the testinal tract. h< in this way. Fercutanei keys following 800 ppm of-< was negligible ( Studies of that the liver (p polar meubolit. spleen, lunss an kidne) ofirre irteve go t. CO -l 0 -0a1 VI 00 HJ. Mamelkr cinemas, one Jtn their ex* been observed riment with ths was pubfruitless si te in nun. Earswollen and rephrotic d glucose-6: phosphatase were observ ation of sinus* ic hepatic analso observed very maligfactoty-epifore in conveloped anma. The ined those of etween VCMdated. s number of at acreted via tin excretory tonprotein ad after disiicated depietats CHefner tissues against the mine of indicating *)tate toxin or of VCM. yields short- o Vinvl ChioriUc-AssociateU l)bcje lived but highly reactive alkylating mtermedatet which are responsible for the toxic, mutagenic and oncogenic etTects. VCM is metabolized rapidly to polar nonvolatile ex* ctetable products (Hefner et al. 1975a: ran Duurcn 1975: RaJwm and Hemehter 1975). The toxicity of VCM seems to be largely determined by the ratio of the rela tive velocities of both biotransfomution of the compound and protective detoxifica tion of its reactive intermediates (Hcntchkr 1977a). The capacity for metabolic elimi nation of VCM in ran is saturable at an atmospheric concentration of 200-250 ppm. so that above this concentration VCM is metabolized at a constant maximal velocity following a zeroorder kinetic, whereas bciow 200*250 ppm it is metabolized in ac cordance with first-order rat* kinetics (Hefner et al. !975a;5ofr et al. 1977). 3.4.1 Uptake and Distribution Pulmonary uptake of VCM from the atmosphere depends on the rate of its metabolism in the animal's organism. The atmospheric concentration of the compound equilibrates with the pool ofunmetaboUzed VCM distributed In the animal's tissues, as has been shown by complete inhibition of microsomal oxidative metabolism {Bolt et aL 1977a), Bolt et al. (1977a) also concluded that lipids or lipoproteins, rather than proteins such as albumin, are the vehicles that transport VCM in the blood and from which the com pound goes into the adipose tissue or is taken up by the liver for metabolic conversion. After oral ingestion and absorption from the gastrointestinal tract, a fust pass effect' has to be considered, but an increasingly substantial percentage of unmetabolized VCM is excreted via the lungs in direct relation to the dose administered (Waramie et al. 1976c). This confirms the finding that VCM metabolism is a dose-dependent and satur able process. Pulmonary elimination of ever 92% within 4 h of a dose of 300 mg/kg body wt. administered orally to rats eras also reported by Feron et al. (1975) in an in vestigation of the subacute toxicity of VCM incorporated in soya beanaril and fed by gavag* in doses of30,100 and 300 mg/kg daily, 6 days/week, for 13 weeks. They found s significant increase in lim-to-body weight ratio and hypertrophy of the endo plasmic reticulum ofhepatocvtes as indications of a toxic effect at the highest dose but only minimal histological changes in the liver. In a second experiment, they fed rats on a diet containing PVC powder with a high monomer content and observed that almost all the VCM was released from die PVC powder during passage through the intestmil tract, but only about 10 mg VCM/kg body wt. per day could be administered in this way. Percutaneous absorption was studied by Hefner et al. (1975b) in male Rhesus mon keys following whoie-body exposure (head excluded) to concentrations of7000 and 800 ppm of ,4C-labefled VCM for 2-2.5 h. The quantity absorbed via the intact skin was negligible (002%--003%) end most ofh wm expired. Studies ofthe dfctribution of [l^-,4C)-labefled VCM in the body dearly revealed that the liver (predominant rite of metabolism) and the kidneys (rite ofexcretion of polar metabolites) cousin the highest concentrations of ,4C activity, followed by spicen.tunp and small tateitine(Mritabeetal. 1976c;So/r et si. 1976a,b). Liver, iudneys.spleen,lung and small intestine (in this order) also contain the largest amounts of irreversibly protein-bound metabolites (Bolt et al. 1976a). Only minor amounts of irreversibly bound metabolites ofVCM were found in muscle, adipoee tisue and brain. *i 20 fio (/) o cn --t >4 <0 It . ; .i F- 26 W.K. Lelbach and H.J. Marsteller Total radioactivity 48 h after a single exposure decreased considerably in these organs, in accordance with the relatively rapid metabolization of VCM and excretion of its polar metabolites. In contrast, the amount of irreversibly protein-bound radioactivity remained constant during this time. Buchner et al.(1977) also showed that unmetab olized VCM possesses a great affinity for adipose tissue, in contrast to its metabolites, which are concentrated primarily in liver and kidneys. 3.41 Metabolism 3.4.2.1Relation between Chemical Structure, Reactivity and Mutagenic or Carcinogenic Effect Before discussing the metabolic pathways of VCM (monochloroethylene) and its pre sumptive toxic intermediates two features of the chemical structure of this compound should be mentioned. Vinyl chloride is a monohahgenated ethylene and its chlorine substitution is asymmetric. Chlorination of alkenes (olefinic compounds), in general, tends to stabilize the double bond by exerting an electron withdrawal effect on the carbon atom involved. Thus, the chemical reactivity of alkenes decreases with increas ing degree of chlorine substitution, as was shown in 1968 by Williamson and Cvetanovid for reaction rates with ozone. Vinyl chloride, as a monohalogenated alkene, is the least stable compound with the highest reaction rate in the series of chlorinated ethylenes and ranks next to unsubstituted ethylene. Secondly, the first step in the oxidative metabolism of all chlorinated alkenes is a transformation to epoxides (oxiranes) which are short-lived, highly reactive electro philic intermediates (Bonse et al. \97$;Hensehler 1977b). Such chlorinated epoxides may react, by alkylation, with essential cellular constituents, a mechanism which Rannuget al. (1974), Bansch et al. (1975a, b) and Malaveille et al. (1975) claimed to be responsible for the carcinogenic and mutagenic effects of VCM and vinylidene chloride. Epoxides resulting from biotransformation of asymmetrically substituted ethylenes, such as VCM, vinylidene chloride and trichloroethylene, seem to be particu larly unstable with increased electrophilicity and thus enhanced alkylating effect. Their mutagenicity and, inversely, the nonmutagenicity of oxiranes of symmetrically chlorine-substituted ethylenes was indicated by the studies of Grem et al. (1975, 1977). ' 3.4.22 Metabolic Pathways From 1974 onwards the fate of VCM has been studied extensively in vitro with rat liver microsomes in the presence of a NAOPH-generating system (Kappus et al. 1975, \97b\Bansch et al. 1975b, l976;Malaveifle et al. 1975;Bolt et al. l976a;Pcssajrc et al. 1979), with the aid of isolated perfused liver preparations (Radwan and Hensch* ter 1975 ;Botseetal. 1975\Radwan 1977; Henschler 1977a) and in vivo (Hefner et al. 1975a; Watanabe et al. 1976d, 1978a. b ;Bolt et al. 1977a, b) in both control animals and animals pretreated with various types of enzyme-inducing and enzyme-inhibiting substances. Present biochemical knowledge strongly suggests that the first step of the predo minant metabolic pathway is the oxidation of the double-bond of VCM by the hepatic i j ! , ' Vinyl Chlor: microsomal > ly highly tea. via the form? bon monoxii' prcciable rok in vitro an an systems and i 1976a). The. .H (/> O a--Lt 00 o Fig. 1. Metabr metabolized t< acetic acid are methylene oxi protein sutph\ wnry(I977).Si: (Norpoth et a!. S-carboxymetl; acid) (Henschl identified in tl. Marsteller :ese organs. ctaboiites. r nd iu pre compound ; chlorine n general, t on the th inereasi Cveanovic . is the least ethylenes kenes is a electro1 epoxides which claimed to lidene snorted metrically (1975, with rat t al. 1975, Pessayrt nd HensehHefner et al. rot animals inhibiting hepredothe hepatic Vm\! Chlor.de-Associuted Diseac microsomal mixed-function oxidase system, forming ehtoroethyknc oxide, a chemical ly highly reactive epoxide (Fig. 1). A negligible amount of VCM can be meubolized via the formation of peroxides, very unstable compounds decomposing rapidly to car bon monoxide, HG and formaldehyde which, however, do not seem to play any ap preciable role in the toxicity of VCM (HentcMer 197^b). It has also been shown that in vitro an artitical superoxide (07) generating system can replace rat liver microsomal systems and transform VCM to the active intermediate (Kappus et al. 1975: Bo/r et al. 1976a). The epoxide rearranges spontaneously to chloroacetaldchydc. which is rapidly Cmjleni Kindinf ro cellular macromolccukf laikxlationi l: H Ox|da*< l II V\DPH. o:' ir cn.h m/ C!ilnmethvk'Hf Oxide < Vt`M epnvulei Cmirugjtnjn with sulphydryl grour* rgluuthione. cysteine i Thermal rearrangement H n-tj-- H ill droit > (epoxide hydrate) OH OH n--<--c--h II II (ldoruaceuldeli> Je Fig. 1. Metabolic pathways. Adapted from Henschter (1977b) metabolized to monochlotoacetic add. Both chloioacetaldehyde and monochioroacetic add are also metabolites which are chemically reactive but less potent than chlomethylene oxide. AO three intermediates can be detoxified by conjugation with nonprotein sulphydryl compounds (glutathione, cysteine) as described by Green and Hath`wry (1977),Sulphur<containing excretabie metabolites such as S-hydroxyethyicysteine (Norpoth et al. 1976), N-ecetyl-S<2 chioro)-ethyl-cysteine (Green and Hathwav 1975), Sorboxymethyicysteme (Wannabe et al. 1976a), and thiodiglycolic acid (thiodiacetic sad) (Hcnschicr l9TJt;MiiOer et al. 1976.1978 Matter and Norpoth 1975) have been identified in the urine of exposed workers and animals. A progressive depression of the V' ;s I W.K. Lclbacli and H J. Msrvteller level of hepatic nonprotein sulphydryl content has been observed in rats after expo* sure to"VCM in concentrations from 150 to 2000 ppm for 2-7 h. No depression was seen after 10 ppm and a concentration of 50 ppm caused only an inconsistent rcduc* tion (Waranabe et al. 1976b). Protein-bound hepatic sulphydryl content remained. unaffected. Hepatic microsomal cytochrome P4 j* the coenzyme of microsomal monooxigenases, also decreases linearly with time in animals exposed to VCM (Reynolds et al. 1975b). This destruction of cytochrome P4 s 0 may prevent further metabolism and toxicity of VCM (Pcssayre et al. 1979). Another mode of deactivation of the primary reactive intermediate, the epoxide, is its transformation to the inactive dihydrodiol by the inducible microsomal enzyme epoxide hydrase. The reactive metabolite ofVCM, chloroethylene oxide, is a powerful alkylating . agent which covalently binds to various cellular macromolecules, notably vital proteins and nucleic adds. By binding to cellular DNA and RNA or critical proteins the metab olite may alter vital functions and the genetic information of the cell and thus exert its hepatotoxic,mutagenic and carcinogenic effect.Eventually, however, the only fraction of the formed epoxide that binds to macromolecules is the one that is not detoxified by protective scavenging mechanisms such as conjugation with cytosolic glutathione or inactivation by epoxide hydrase. Simultaneous presence of other xenobiotics which have to be detoxified will impair the effectiveness of the detoxification mechanisms. In assessing the risk of exposure to VCM, Henschler (1977a) concluded that there might be a greater risk in intermittent peak exposures over brief periods than might be ex pected from simple integration over time and that the chances for effective detoxifica tion are greater in long-term exposure to relatively low levels. U was shown by Waranabe et al. (1978a) that repeated exposures of rats to VCM do not appear to induce its biotransformation, but significantly augment the binding of the reactive metabolite with hepatic macromolecules and may thus enhance the po tential toxicity of VCM. On single exposures of rats to increasing concentrations of labelled VCM ranging from 1 ppm to 5000 ppm, the amount of radioactivity covalent ly bound to hepatic macromolecules did not increase proportionately to the increase in concentration but followed a sigmoid curve with low and high inflection points be low 50 ppm and above 250 ppm, respectively, when binding was plotted as a function of the log of the exposure concentration (Waranabe et al. 1978b). This correlates well with Afalronts report (1975) of a linear percentage induction of hepatic angiosarcoma in rats between 50 ppm and 500 ppm when expressed as the log of the exposure con centration. Metabolites of VCM can alkylate nucleic acids, a commonly accepted mechanism for carcinogenesis. Covalent binding to the adenosine (Barbin et al. 1975 \Laib and Bolt 1977), cytidine (Laib and Boh 1978), and guanine moiety of nucleic adds (Ostermann-Golkar et al. 1977) has been described. But the degree of covalent binding of electrophilic metabolites of labelled VCM to hepatic nucleic acids seems to be very small (Waranabe et al. 1978b ;Laib and Bolt 1977). Laib and Bolt (1977) presented evidence showing that the alkylating potency of VCM metabolites cannot be deter mined solely by measuring the incorporation oflabel into nucleic adds after exposure to radioactive VCM. Waranabe et al. (1978b) conducted that covalent binding to nudeic adds is not the preferential reaction, but they pointed out that this does not Vinyl Chi. exclude tlu of cellular > duded as t above all. i This ay work will 1; endoplasm* tible to VC phologicall; mixed funi lobular, mit.. found (Jan 1978). Sec. end ces 37 the sor (/> (3) O tiss VI ran 19 0to0 no Raynaud's " drome was t. man. Besideliver lesion* bioactivatio: portal Obrtment of the a direct or ir tic nervous y Iining cells o. tion) orwhi* 4 Clinical During the n* might prove: presented in marked the u* pational haz. Mareteller rexpoion was nal raono11olds et ilism and poxide. is izyme dating tl proteins te metab* is exert its y fraction toxified athione or i which tinisms. In ire might be exetoxifica- toVCM binding ;; the po tions Of covalent- lates well usarcoma tureeon- chanism iib and ads (Osterding of levery nented : deterexposure ig to does not u Vmyl Chioriiie-Ajsoaaiid Diseasi: 'O exclude the possibility of other, more subtle interactions which may impair the contr I of cellular replication. Alkylation of nudeic acids, however, cannot at present be ex cluded as the mechanism for VCM-induced carcinogenesis after repeated exposure and. above all, in the target cells rather than the iiepatocytes. Tilts aspect carries on to an unresolved problem on which future experimental work will have to focus. Although the sire of formation of the active metabolite is the endoplasmic reticulum of the hepatocyte. the liver cell itself is not particularly suscep tible to VCM-induced toxicity. Acute hepatocellular injury has not been observed mor phologically after exposure to VCM unless pretreatment with potent inducers of the mixed function oxidase system had preceded the exposure;in pretreated tats centrelobular, midzonal and panlobuiar hepatocellular vacuolization and even necrosis was found (Jaeger et al. 1974,1975.1977:Reynolds et aL 1975a. 1976: Conotty et al. 1978). Secondly, the site of carcinogenicity in the liver is not the hepatocyte but the endothelial cell of the hepatic sinuses. At present it can only be speculated which of the following four most likely pro cesses are effective, either singly or in conjunction: (1) The active metabolite leaves the hepatocyte and is conveyed to the endothelial cell. (2) The endodielium itself has some metabolic capacity (Bolt 1978). as may tissues of organs other than the liver. (3) Mechanisms for the detoxification of the active metabolitefs) are insufficient in tissues other than the hepatocytes. (4) Repair mechanisms for the correction of aber rant cell replication are less effective than they are in the hepatocyte (Watanabe et al. 1978b). An equally puzzling problem is the role of VCM in the pathogenesis of the distal nunneoplastic vascular lesions which are responsible for the development of the triad, Raynaud's phenomenon.sclerodermoid skin indurations and acroosteolvsis. This syn drome was the earliest indication of adverse effects of chronic exposure to VCM in man. Besides, its latency period was considerably shorter than either the nonmalignant liver lesions or angiosarcoma of the liver. Whereas it is now established that hepatic bioactivation of VCM plays the central part in the pathogenesis of both noncirrhotic portal fibrosis and angiosarcoma of the liver, it is not at all clear whether the develop ment of the acral lesions is due to VCM itself or to active metabolites which may exert a direct or indirect toxic action on (a) medullary vasomotor centres, (b) die sympathe tic nervous system, (c) smooth muscle cells of the media of arterioles, (d) endothelial lining ceQs of small arteries (with fibroblast transformation and endothelial prolifera tion) or whether (e) the action is mediated by the fotmation of immune complexes. 4 Clinical Spectrum During the mid-1950s it began to emerge that chronic occupational exposure to VCM might prow to be not quite is harmless as had been claimed. The historical synopsis presented in Table 7 summarizes those clinical studies from the world literature that marked the gradual recognition of the full spectrum of damage due to this new occu pational hazard. R&S 105183 kij. P 30 W.K. Lelhjch and H.J. Marsteller Table 7. Gradual emergence of evidence for VCM*aociated pathology Year Reference Findings 1949 Tribukh et al. Hepatomegaly, more or less marked 'anicteric hepatitis', 'chronic gastritis*, hypotension, anaemia, skin lesions 1954 1957 1957 1960 Smirnova Filatova and Gronsberg Kubota Danzifrr Toxic angioneurosis Toxic angioneurosis Symptoms similar to Raynaud's phenomenon Two cases of accidental fatal poisoning by VCM. 1 nonfatal acute overexposure 1961 Smirnova Reversible osteolytic lesions of distal phalanges. Pseudoclubbing, thickening of skin on volar side of forearms, slight haemolysis and retkulocytosis 1963 Suciu et al. CHS: prenarcotic symptoms (dizziness, euphoria, somnolence), nervousness, insomnia, blunting of memory. general asthenia, headache Vascular: Raynaud's syndrome Dermatol: pruritus, reversible sclerodermalike skin induration, chemical and allergic dermatitis Digest, symptoms: anorexia, nausea, fullness, hepatomegaly without hyperbilirubinaemia, splenomegaly Endocrine: hypothyroidism 1966 Coniier et al. Raynaud's syndrome, sclerodermalike skin changes, acroosteolysis, pseudoclubbing, joint pain, tiredness, sleep reversal; 2 episodes of acute overexposure (loss of consciousness) 1967 Harris and Adams Acroosteolysis, skin lesions. Raynaud's phenom* enon. pseudoclubbing, involvement of sacroiliac joints and patella, hepatomegaly with persistent* ly raised serum bilirubin. Skin biopsy 1967 1967 Benoit Wilson et al. Arteriography. Skin and bone biopsy 'Occupational acroosteolysis' with Raynaud's symptoms, sclerodermalike skin changes, pieudodubbing >968 1971 Antonyuzhenko Dinman et al. Mentions thrombocytopenia Prevalence of acroosteolysis and Raynaud's phenomenon 1971 1972 Dodson et al. Kramer and Mutschler Vascular lesions preceding the bone lesions Increased BSP retention and raised icterus index related to degree of exposure Vinyl Chlon Table 7 (con Year Rc 1972 Me 1972 Jul 1973 Mis 1974(a) Crv 4.1 The Trie A first indicat. plant ptodudr non (toxic ar in dr Tpersi 3) houi go dron (/) (Kul morr O and! " (195 oo . dux. * then of re evidence of dc acroosteolysis operators) aft> junction with was found in t lesions to be c. reversible cha; vibration trau the full range v eupational acr In 1963 So analysis of the 1I.J. Mareteller ^ l 'onicteric tension. icnomenon ning by VCM. ial phalanges. in on volar t and teucuio- ness. euphoria, nia. blunting dache roderm alike rgic dermatitis a. tuilness. ubmaemia like kin ubbing. jctnt Booties ot ss*) audTpftet nom- nt of sacroiliac with persistent<>P*V i*y Raynaud's changes. Uynaud's n* lesions d icterus index ) Vinyl Chionde-Asociated Disease 31 Table 7 < continued) Year 1972 Reference Marlcoyiitz et ai. 1972 /She and Lange 1973 Manteller et al. 19741a) Creech et al. FinUinp Progressive thickening of hands and forearms, arthralgia. Blanching upon exposure to cold with cyanosis of bands accompanied by severe pain. Skin biopsy l't German report of 7 workers with scleroderma like skin lesions. Raynaud's syndrome, and acroosteoiysis. Tests showed abnormal liver is 3. occlusion of digital arteries in 1 worker Noncirrhotic portal fibrosis with portal hyper tension and splenomegaly 4 cases of angiosarcoma of the liver 4.1 The Triad: Raynaud's Phenomenon. Pseudosclerodcnna and Acroosteoiysis A first indication of advene effects due to chronic VCM exposure arose in workers at a plant produani VCM who presented with symptoms similar to Raynaud's phenome non ("toxic angioneurosiO- This was reported by Smirnova in 1954 and later described in detail in her thesis (1959). The syndrome was found predominantly in laboratory personnel who had intermittently been exposed to high concentrations of VCM during hourly sampling for chemical analysts (purity of the product). In 1954 Raynaud's syn drome was also observed among several workers at a Japanese PVC producing plant (Kubota 1957). Apart from a painful vasospastic disorder of the hands, impaired ther moregulation, acrocyanosis, positive cold test. capQlaroscopic alterations, panesthesias, and CNS symptoms such as headache, blunting of memory and sleep reversal,Smirriora (1954) also mentioned swelling of fingers and development of circumscribed skin in durations on the volarside of the forearms in those most severely affected. In addition, there was evidence of mild haemolysis (borderline anaemia, decreased osmotic fragility of red cells, urobilintuia, and reticulocytosisj. In 1961 Smirnova described radiographic evidence of destructive bone lesions of teiminai phalanges in the hands identical with acroosteoiysis in three workers at a PVC-preducing plant (one fitter, two centrifuge operatots) after exposure for 3-9 yean. Since these bone lesions developed in con junction with toxic angroneurosis' and since complete recaidficadon of the defects was found in two workers 3 yean after removal from exposure,Smirnova believed the lesions to be characteristic of chronic VCM intoxication. She pointed out that their reversible character might serve to distinguish the lesions from similar defects seen in vibration trauma. In retrospect, Smirnova's observations are the earliest descriptions of the full range ofsymptoms which much later became known as The syndrome of oc cupational acroosttolysu. In 1963 Sudu et ai. (see also 1967 and 1975) published the lint comprehensive analysis of their observation of a multiform symptomatology' in subactue and chronic ) ! I f i % 1 32 1 W.K. Lclbacll and H.J. Mjr-ieller VCM intoxication. During a 4-year period, they examined 168 mostly young workers from two Rumanian PVC-producing plants who had not previously been employed in other industries. In their classic paper, the authors described in detail the various cen tral nervous, digestive, angioneurotic and cutaneous symptoms (listed here in their order of manifestation). Acroosteolysts, however, was not mentioned. Episodes of acute overexposure (usually occurring at the end of a batch run. during retrieval of unreacted monomer, or at repair jobs) rapidly resulted in a state of light-headedness and transient euphoria similar to a mild degree of inebriety and were accompanied by a feeling of heaviness in the legs and disturbed locomotor coordination. Several workers claimed to have been able to identify escaping monomer by its faint but agreeable odour. Apparently during periods of particularly high ambient concentrations, workers repeatedly noticed formication in the lower limbs and a general feeling of bodily warmth. Six subjects had experienced loss of consciousness when repairing leakages, but recovered rapidly after being carried out into the open sir. After a few months of work, Unusual fatigue and sleepiness set in. there were complaints about persistent somnolence, even outside the work premises, and a tendency to fall asleep at the work place, particularly during night-shifts. In addition, headache, dizziness, irritability, blunting of memory, paraesthesias, and general weakness were reported: some workers noticed insomnia or sleep reversal. A reappraisal of these nonspecific complaints (see also Vale et al. 1976) 6 years later, after improvement in industrial hygiene, revealed that the frequency of their oc currence had considerably decreased (Suciu et al. 1975). Following a prolonged period of repeated overexposure, vague nonspecific digestive symptoms also developed, such as anorexia with ensuing weight loss, nausea, fullness, upper abdominal discomfort, bloating and epigastric pains. Enlargement of the liver was found in 51 workers (30%); in 6?r there was also splenomegaly. Classic Raynaud's phenomenon was found in 6%, but a tenfold higher percentage of the total work force showed evidence of vasospastic alterations on plethysmography (Rougher et al., cited by Suciu et al. 1975). Pruritus of the hands, forearms and face was an early complaint followed later by what was theought to be (allergic?) `contact dermatitis'; finally, nodular and scleroderma- or sderoedema-like cutaneous lesions developed in some workers, involving the dorsal surface of the hands, the volar side of wrists and forearms and the face, with firm thickening of subcutaneous tissue or formation of whitish papular or slightly elevated ptaquelike indurations. The cutaneous manifestations largely disappeared after removal from the work place. In addition, mention was made of features of hypothyroidism in a few workers. Also, transient loss of libido in 24% was recorded, with return to nor mal after a break from work or during holidays. With the exception of aeroosteolysis and the two most alarming late sequelae -- noncirrhotic portal hypertension and hepatic angiosarcoma - Suciu't early documen tation of the prevalence of disease in PVC production workers encompassed a com paratively complete description of the various aspects of chronic VCM intoxication. Later publications supplemented the spectrum of knowledge mainly by providing ad ditional information on epidemiological, roentgenological, thermographic, angiograph ic, and histomorphological aspects of the lesions encountered in subjects chronically exposed to VCM. Vinyl JJ fio TT CD twoB classif marke syndre year a O CJ1 0O0) Unitec cases 0* wnw the various pi. end of 1979. vascular phen. symptoms th:. begin with ill- the fingers arc tips on hard to cold accorr are likewise a; ance of painfu osteolytic pro with striation. Table 8. Public Year 1966 1967 1967 1967 1967 1969 1969 1971 1972 1972/1973 1973 1974 1974 1975 1975 1976 1978 1979 a One of 2 cL pm w Mars*e!ler workers .J i their <les of oval of dedness 'anted by ral workers .eable is. workers niily -akages. lonths of listen! i the work nitty. e workers ' yean i their occed period led. such >mfort. im3(TV. ;d m 6~. ..-.spastic Pruritus Wtt Jffln firm elevated ;;r removal ruidismin n to nor- teiae locurnena corri:ication. riding adngiognphonically ii Vinyl Chli'ndc-Associjied Disease 33 The discovery of unusual osteolytic defects in the distal phalanges of the hands of two Belgian autoclave cleaners ho had suffered from Raynaud's phenomenon and undassifiable degenerative lesions of the dermal connective tissue (ConJicr et al. 1966) marked the recognition of this new occupational disease in the Western World. The sy ndrome was termed `occupational acroosteolysis' (OAOL). and during the following year a number of additional cases were reported from France. Great Britain and the United States. Later Lefirre (1972) who together with Cordicr described the first two cases of OAOL. reported that a subsequent investigation revealed another *en cases in the various plants affiliated to the same corporation in Spain. Italy and Brazil. By the end of 1979.a total number of 126 cases had been published In detail (Table 8). The vascular phenomena preceding or accompanying OAOL comprise a broader range of symptoms than those characteristic of Raynaud's syndrome. The conditions seems to begin with ill-defined pains in fingets, wrists and also large joints (shoulders, knees): the fingers ate numb and tingling, tender on palpation, handgrip and upping finger tips on hard surfaces is painful: there is increasing sensitivity of the hands and fingers to cold accompanied by a tendency to cyanotic discolouration, in some cases, the toes are likewise affected. Later, classic Raynaud's phenomenon develops (sudden appear ance of painful, sharply demarcated blanching) and. concomiunt with the onset of osteolytic processes, there is a shortening and broadening of the terminal phalange with striation of naiis (pseudodubbing). Table 8. Publications on 'Occupational Acroosteolysis* since 1966 Year 1906 1967 1967 1967 1967 1969 1969 1971 1972 1972/1973 1973 1974 1974 1975 !975 1976 1978 1979 Country Number Authors of cases Belgium France France United Kingdom USA Rumania Yugoslavia USA USA Fed. Republic of Germany Japan France USA USA United Kingdom United Kingdom * 5 S 2 31 * 8 41 6 1 4 I 4 I 4 Brazil Israel S 2 126 Coniter ct al. Benoit: Chatelain and MnnHon Boumchon (cited by Marin et al. 1967) Harris and Adams, Wilson et al. AnfhelescJ et aL JCoroTet al. Dinman et al. Markowitz et al. Juke and Veitmm: Stein et al. ta. b) Tekeuehi and Mabuehi3 Moulin et al. Trapp ct al. IMistt al. Stewart et al. Preston et ai.; Walker Mitchell Johnston 0978) Gama and Mein Hahn et al. One of 2 clear cases, in addition. 48 suspected cases i see Sakatx 1975 > 34 W.K. Lelbach and H.J. Marsteller 4.1.1 Familial and Idiopathic Acroosteolysis Aeroosteolysis is a very rare disease. The aetiology and pathogenesis of this condition is still obscure. Osteolytic bone changes in late stages of so-called Raynaud's disease (accompanied by necrosis and gangrene), characteristically presenting as loss of part or of an entire distal phalanx of one or more fingers and also of toes, have been mention ed in the literature since 1921 (Assmann \92l;Monahan 1926:Bonk \921\Komblum 1929). Komblum attributed the lytic bone defects to vascular abnormalities and noted that he had found identical lesions in early stages of scleroderma and in leprosy. The term acroosteolysis was fust introduced by Laroche and Hochfetd (1948), who held a neuroendocrine syndrome responsible for the lesions. Independently Hamasch (1949) reported another case of symmetrical idiopathic acroosteolysis, particularly involving * the terminal phalanges of the fingers with preservation of tufts, progressive clubbing and shortening, and ill-defined symptoms of disturbed peripheral circulation. By 19S2 Giacci mentioned that 68 cases of the familial type of acroosteolysis and 33 cases of the nonfamilial, idiopathic form had been reported in the medical literature. He added another five cases, but his case reports pertain almost exclusively to mutilating proces ses involving only the feet, with recurrent ulceration and discharge of bone fragments (see also Harms 1954). In 1957 Lievre and Gama listed 16 observations of idiopathic acroosteolysis and commented extensively upon these lesions; the whole range of dif ferential diagnosis (various congenital, neurogenic and endocrine osteolytic diseases, leprosy, arthritis mutilans, progressive systemic sclerosis, ainhum etc.) was considered in their study and could be rejected with reasonable certainty. In a later review, Cheney (1965), who added another four cases of the familial type, stared that this variety and the nonfamilial idiopathic type may actually belong to the same disease entity and may be part of a degenerative bone process more generalized than the term implies. It was the puzzling character and the rarity of this peculiar bone lesion that captured the attention ofsite medical personnel and industrial hygienists when in November 1963 the condition was detected in two Belgian autoclave cleaners (Lefirre 1972). 4.1.2 Epidemiology of Occupational Acroosteolysis Attempts at assessing the prevalence of OAOL among personnel involved in VCM manufacture and polymerization revealed that in general this occupational type of osteolytic bone lesion was found in only 1%--35t of the work population at risk. Hublet et al. (1977) considered the fact that only 3% of all workers who had been engaged in manual cleaning of autoclaves at a Belgian plant suffered from OAOL and Raynaud's phenomenon to be indicative of the importance of individual factors. Wilson et al. (1967) observed 31 cases among 3000 employees of one large company. In 1971 Dinman et al. conducted a survey in 32 plants belonging to 19 corporations throughout the United States and Canada. The details of this elaborate epidemiologi cal study, comprising a total of 5011 employees, illustrates the difficulties and limita tions encountered in a retrospective study of this dimension. All of these 5011 workers had been engaged in various stages of VCM and PVC manufacturing, but 1257 of them were workers who only handled finished PVC polymer. Five of the 32 plants worked Vinyl Chlor exclusively v only 25 clea: defined as clenon; 18 of with experic drome were. jobs, both re (1 case per 7 appeared not was detected use for reactentry into th Table 9. Pni' S Country j Franc* USA Unite JCinj Fed. I Gen Unitei King T tal 3 C/3 O Ul 00 oo Mo related v>uk Lange and i t ol gicalchec) pathological were affected cold, 15 work morbidity wafound classic 1 numbness ami 8.7% and invr Allen test ind' people with p pseudodubbit finding that tl durati n of pi1 i HJ Mameller ndition luuttrNemffisseease s lots of part or been mention027: Kombium lities and noted leprosy. The 8),wh held a tmaseh (1949) arty involving sive dubbing ldon. 3y 1952 d 33 cases of ture. He added ulating procesone fragments of idiopathic e range of dtfytic diseases. as considered review. d that this ime disease than the term c lesion that :s when in aaners (Lefbrrt dinvai nil type of n at risk. < had been m OAOL and it factors. rge company, corporations epidemioiogites and linritac 5011 workers r 1257 of them dints worked i Ii Vinyl Chloride-Associated Disease 35 exclusively with the finished PVC-derived consumer products. Dinman et al. found only 25 dcar-cut cases of OAOL among the 5011 employees (mean age: 35.S years), defined as characteristic X-ray film abnormalities combined with Raynaud's phenom enon; 18 of them had been reactor cleaners at some time; another 16 individuals (10 with experience in reactor cleaning) with early stages or minimal degrees of the syn drome were suspected of suffering from OAOL. It emerged that the two lowest-paid jobs, both reactor cleaning and bagging/packing, had a strong association with OAOL t.1 case per 72. or 86 workers at risk, respectively). Manipulation of the finished polymer appeared not to be associated with a risk of contracting OAOL Only l case of OAOL was detected in those plants where high-pressure water lances or solvents had been in use for reactor cleaning. Furthermore, it seemed that the extent of degassing prior to entry into the autoclaves correlated with the manifestation of the disease. Table 9. Prevalence of acral disease in VCM-exposed populations Country Number of eases Size of group at risk OAOL Classical Severe Sclero Raynaud's sensitivity dermoid phenomenon to cold skin lesions References France 130 USA 354 United 37 Kingdom Fed. Rep. 100 Germany United 104 Kingdom Total 725 3 12 4 20 15 99 1 25 20(-v3*> 7l(-uKTr) 15 63 ' 8 33 5 23 4 10 1 119(M6%* 43<^6^j Benoit 1967 Liliset al. 1975 Walker 1976 Lange and Velman 1977 Maricq et al. 1978 Mote commonly seen than OAOL were Raynaud's phenomenon (see Table 9) and related symptoms of abnormal peripheral circulation (Benoit 1967;!// et al. 1975; Lange and Vthmm 1977). Benoit pointed out that a complete medical and roentgen ological check-up of all 528 employees at a French PVC-ptoducing plant revealed pathological manifestations only among the group of 130 reactor cleaners of whom 32 were affected (OAOL, 5; Raynaud's phenomenon without OAOL 12; sensitivity to cold, 15 woifcets). He stressed the fact that in this group of workers at risk the overall morbidity was almost 25%. Similar results were obtained by LiBs et al. (1975), who found classic Raynaud's phenomenon in 5j6% of 354 heavily exposed PVC workers, numbness and tingling in 24%, excessive sensitivity to cold in 18%, pseudodubbing in 8.7% and involvement of the toes In 7%. Besides, in 26j6% of the total an abnormal Allen test indicated impaired peripheral arterial circulation. It was noted that in some people with pan exposure Raynaud's phenomenon had gradually faded, whereas pseudodubbing persisted or even progressed. Most important, however, was Lilts' finding that the prevalence of all these abnormalities increased significantly with the duration of past expowre to VCM. 'r P \ fV 5 u :t B * CD k o cn 00 <0 D r M * r* ** ef 9s f> f) 36 ) W.K. Lcthach and HJ. Manstcller Occupational acroosteolysis is a condition predominantly observed in y anger w rkers. The age range was 20--45 yean and half of all cases reported fell in the 30-39 yean age-group. Duration of VCM exposure prior to onset of Raynaud's phenomenon ranged from 1 to 23 months (Dodson ct al. 1971). For OAOL the latency period was at least 12 months (Wilson et al. 1967): in most cases. OAOL developed insidiously within 2 to 4-6 yean. There is at least one patient on record in whom OAOL was fint discovered two yean after termination of exposure (Benoit 1967). Longitudinal studies of the bone lesions demonstrated partial or complete but mosdy defective restitution, resulting in shortened and deformed distal phalanges, within 2-3 yean after removal from VCM exposure, but Raynaud's phenomenon and cutaneous lesions may persist (Williams znd McLachian 1976). Stein et al. (1973a, b) reported partial healing with restitution of tufts but progressive lysis of the proximal portion of terminal phalanges 3 yean after termination of exposure. Although OAOL developed predominantly in PVC production workers who had at least for some time been engaged in reactor cleaning, the syndrome has also been ob served in association with other job assignments which were believed to carry a sub stantially lower risk of exposure. Trapp et al. (1974) reported a 31-year-old white male suffering from Raynaud's phenomenon, clubbing of the fuigen and typical bilateral acroosteolysis,in whom specific inquiry revealed that his employment by an industrial chemical company had included daily handling of small concentrations of vinyl chlo ride (no details given). Typical OAOL was also observed in a worker after 6 years' em ployment as spray dryer/bagger, premix operator, recovery and charging operator who had never cleaned autoclave vats (Stefan et al. 1975). According to routine plant monitoring of VCM levels in the past and as measured in 1973 by gas chromatography of grab samples, his average exposure had been within the threshold limit values of the day (200 ppm). Radiographs taken in 1966 at the end of his fust year during an earlier survey of OAOL were normal; in 1972 he presented with Raynaud's phenom enon, pseudodubbing, typical OAOL and dermal thickening of hands and wrists. Ar teriography demonstrated narrowing of most digital arteries, even in fingers without bone defects, and abnormal collections of small vessels in the pulps of deformed finger tips, but no vascular oedusion. Apart from the chemical insult by inhalational (rather than transdermal -Dinman et al. 1971;Srewarr et al. 1975) exposure to VCM, individual susceptibility or idio syncrasy appears to have played some (undefined) role in the development of the syn drome. It does not seem likely, however, that repeated physical microtrauma during cleaning operations (removal of polymer crusts by hand scraping or chiselling) was a decisive factor in the pathogenesis of the condition as had been speculated by Wilson etal.(1967). 4.13 Clinical and Roentgenological Features 4.1.3.1 OccupationalAcroosteolysis In the majority of cases osteolytic lesions are confined to the hands. Involvement of the feet was observed only rarely in OAOL. Wilson et al. (1967) believe that OAOL differs from familial or idiopathic acroosteolysis in several respects. Although the bone Vinyl Ch defects in osteopori skull, des* shorteniru nonoccup genol git:.. 1)The one or mo 2) In t: tufts, or a: 3) The tufts togeti defects (set (`bandlike. ' *;' - tv v .ts mi) HJ. Mantcllsr ed in younger J fell in the 30-39 ~ Jafccnomenon ..^P^riod was ped insidiously >m OAOL was fust ongitudinal studies ective restitution, an alter removal ions may persist rial healing with nrainal phalanges orfcers who had at tas also been obto carry a sub ear-old white male .ypical bilateral it'by an industrial >ns of vinyl chloafter 6 yean' emging operator who routine plant . chromatography imit values of year during an naud's phenom* i and wrists. Arrtngen without '^raiimed le^m --Pinman ability or idio* iment of the synotrauma dunng htsefling) was a dated by Wilson involvement of ve that OAOL dthough the bone t Vinyl Chloride-Associated Disease 37 defects in the distal phalanges are similar in both conditions, other features, such as osteoporotic compression fractures of the spine, basilar impression fracture of the skull, destruction f mid-phalanges or osteosclerotic changes of wrists and hand bones, shortening of metacarpals and cortical thickening of the shafts of long bones seen m the nonoccupational type have never been found in OAOL. Wilson e: al. worked out roent genological criteria for the diagnosis of OAOL: 1) The earliest changes in OAOL are marginal defects and lots of cortex in tufts of one or mote of the terminal phalanges of the hands. 2) In the next stage this is followed by small lulf-moon' cuts in the cortex of the tufa, qr a so-called slice-effect along one or more tufts. 3) The advanced stage of destruction is characterized by either a complete loss of tufts together with a portion of the shaft or there may be transverse or oblique bone deteca (see Fig. 2) cutting off the shafts from the remaining distal rim of the tufa (tnndlike acroosteolysis'). Fig. 2. Occupational acroosteolysis. Transverse or oblique bone defeca (`bandlike acroosteolysis') or partial loss of terminal phalanges in all fingers of both hands. (33year-old autoclave cleaner: duration of exposure 2 1/2 years) 4) In the healing stage there may be either complete bony union with shortening and broadening of the residual pans of the end phalanx or a fibrous union of bone fragmentt. Fingertips remain short and plump with persistent dubbing of soft ri?*>* and increased lateral and longitudinal curvature of fingertips. Sodium fluoride1 * F scintiscan data of affected bones suggested that active de mineralization (tesorptive) and remineralization (reparative) processes may occur si multaneously even in the same hand (Dodson et aL 1971). In some cases, bones of R&S 105191 38 W.K. Lelbach anil H.J. Marsteller other body regions were also involved. Erosive and sclerotic changes in the sacroiliac joints and circumscribed resorptive defects (conical erosions) in patella, clavicle, man dible, humerus, styloid process of ulna, femoral condyles, os calcis, cuneiform and metatarsal bones have repeatedly been observed (Conlier et al. 1966 .Harris and Adams l967:Dodson et al. 1971: Julie et al. 1974;Lange et al. 1974a:Preston et al. 1976: Jayson et al. l976t;Lange and Veltman 1977). 4.1.3.2 Pseudoscleroderma Concomitant with the manifestation of paraesthesias, pain, tenderness of the fingers and Raynaud's phenomenon, cutaneous lesions similar to stigmata seen in progressive scle roderma develop with thickening of the skin of fingers, hands and forearms, sometimes accompanied by swelling or puffiness and coarsening of the skin of the face (mostly on the forehead and cheeks). Raised, ivory-coloured, firm nodules or elevated, sharply de lineated piaquelike skin indurations are seen on the dorsal surface of fingers and hands and on the volar side of the wrists and lower forearms. It was this combination of Ray naud's phenomenon and cutaneous lesions which first prompted a search for other symptoms of progressive systemic sclerosis in affected workers. The syndrome of OAOL. however, can be dearly distinguished (Table 10). Notably, the diffuse immobil- Table 10. Differential diagnosis: syndrome of occupational acroosteolysis (Raynaud's phenomenon, sclerodermoid skin changes, AOL) / progressive scleroderma with (rare) osteolytic lesions Occupational AOL Progressive scleroderma Sex ratio Exclusively e d>v * 1:2 Hands Dubbing and shortening of Anger tips: hypertudrosis; no ulceration Atrophy and tapering off of fingertips: anhydrosis; ulcerative lesions Perioral puckering of skin Skin appendages Telangiectases Shortening of frenulum Subcutaneous deposits of calcium salts Dysphagia (oesophageal involvement) Renal, cardiac and intestinal involvement Occupational history Prognosis Not observed Preserved Not observed Not observed Not observed Not observed Not observed Obligatory Favourable (skin and bone lesions tend to heal after removal from exposure) Common Loss of skin appendages Common Early symptom Common Common (Common) * Usually spontaneous progression Vinyl Chloride- izing sclerosis o tional syndrom* readily than the 4.1.4 Histolofc. 4.1.4.1 Cutaru Several investig; disease (Conifer al. 1972\Langc we found only c 1967;,Vann et a neural changes v who s' Dt n mis w 3J broad faintl) 80 CD II n Schiff o .i: histioc cn The m ofelas ttoo full th; sue. Si Walker ywio) f not exceeding i. some fibrous thi Vascular lc > capillaries were * and pericapillar thelial cells with tion oflumina. * myocytes, was. to narrowing or Degenerative (Benoit 1967 ;.lf hyaiinosis of :h- Meissner, Pacini' 4,1.43 Bone I. The most strike worker with OA' ening and hyain most layer. Sup; ; ;1 n. r1!' * * " >Vf V'!.'" HJ. Miinieller the sacro-iliac "^^icle. mao* ^Btand Adzms -etal. 1976: of the fingen and jroeressive sdearms. sometimes : faee fmostly on ited, sharply deneers and hands `unation of Rav* ch for other lidrome of diffuse immobil- . sis (Raynaud's r.na with i rare) v -<:!eroderma jr I tapering off ^nhshydrosis: kin appendages i nptom n) pontaneous Mon Via >1 Chloride-Associated Disease 39 izing sclerosis of the skin with tapering off of fingertips was never seen in the occupa tional syndrome. After cessation of exposure the skin lesions seem to regress more readily than the osteolytic changes. s.i.4 Histology 4.1.A. I Cutaneous Lesions Several investigators described the histomorphology of skin lesions in vinyl chloride disease (Conifer et al. l966;Hanis and Adams l967:Morm et al. 1967iMarkowit: et al. 1972:Lange et al. 1974a: Velnnan et al. 1975; Walker 1976:Hahn et al. 1979). but we found only one description of bone histology in OAOL in the literature (Benojt 1967,Marin et al.1967). Skin biopsies showed various degrees of deimal. vascular and neural changes which were essentially identical in patients showing OAOL and in those who suffered `merely' from Raynaud's phenomenon. Dermal changes consisted of hyperkeratosis and pronounced thickening of the der mis with disorientation, swelling and nonfibrillary eosinophilic homogenization of broad interlacing collagen bundles. There was some degree of interstitial oedema which faindy stained metachromatically with toluidine blue, alcian blue and periodic aridSciiiff (PAS). An inflammatory reaction with infiltration of lymphocytes and a few histiocytes was scanty and, if present at aU, of predominantly perivascular distribution. The most notable feature was marked disorganization, fragmentation and rarefleation of elastic fibres. In areas corresponding to nodular or plaqueiike skin indurations, the - full thickness of the dermis consisted of an acellular, partly hyalinized collagenous tis sue. Skin appendages were preserved. In 15 apparently less severely affected workers. Walker (1976) found only some destruction of elastic tissue of the dermis, probably not exceeding normal age changes; in one worker with severe Raynaud's phenomenon some fibrous thickening of the media of dermal arterial was seen. Vascular lesions affected capillaries and small dermal arteries. Numerous dilated capillaries were seen in the subepidetmal papillae with swelling of endothelial cells and petteapillar oedema. Capillaries of the cutis showed cufflike hyperplasia of peri* thelial cells with fibroblast transformation, hyalinosts of vessel walls and final oblitera tion of iumina. Marked medial thickening of dermal arterioles, due to hypertrophy of myocytes, was accompanied by parietal fibrosis and hyalinosis, which ultimately led to narrowing or even complete occlusion of the lumen. Degenerative lesions of small dermal nerves were mentioned by French investigators (Ben-tit 1967,Marin et al. 1967: Otatelain ani Morillon 1967). They found sclerosing hyalinosis of the perineurium with atrophy of neuroflbrils. Tactile corpuscles (Wagner* Meissner. Parini) were unaffected. 4.1.4J Bone Lessons The most striking feature in a biopsy specimen of the bone, obtained from a French worker with OAOL (case 4 of both Benoit \967:Mann et al. 1967) was marked thick ening and hyalinization of the periosteum with chondroid metaplasia of the inner most layer. Supplying capillaries and arterioles showed occlusive changes identical with r-) ' : w lf !' t % r. p 3J 0) o CJ1 to 03 40 ty.K. Lei bach and II.J. Marsieller those observed in the dermis. The bone matrix per se was barely affected. There was minimal thinning of cortex, normal spongy bone and only mild fibrosis of the bone marrow. Experience with histomorpholugy of bone lesions in the familial and idiopathic type of acroosteolysis is limited. In the few eases where biopsy material could be ob tained, there was replacement of bone by nonspecific fibrous tissue, but inflammatory and degenerative changes or osteoid formation were not found (Dupes et al. 1936: Bison and Bumstein 1954; Cnwihery and Street 1957: Schwarzwcilcr 1957). In this context, it should be kept in mind that Viola succeeded in reproducing dermal, vascular, neural and skeletal lesions in the skin of the paws and in small meta tarsal bones of experimental animals which were very similar to those observed in man. Viola exposed rats to 30 000 ppm VCM,4 h/day. 5 days/week, for 13 months and de scribed the histology of these lesions in detail (1970b). 4.15 Arteriography, Capillaroscopy. Infrared Thermography Arteriographic evaluation of the vascular tree of the hands revealed patency of the large arteries in all cases examined. Hie vascular lesions were almost invariably con fined to the small digital arteries, although the superficial and deep palmar arterial arch may occasionally show some narrowing and a paucity' of side-branches (Lange et al. 1974a\Muutin et al. 1974). The most prominent arteriographic features were ir regularities and segmental stenosis of digital arteries, ranging from localized or diffuse narrowing to subtotal or even total occlusion with development of collateral vessels. Besides, a conspicuous retardation of flow of contrast medium was noted, and peculiar tortuosities of patent digital arteries were found. Circumscribed hypervascularity of the terminal tufts and in the region of the wrists was noted in some cases (Benoit 1967:Lange et al. 1974a; Veltman et al. \91i\Preston et al. 1976;5/eurr et al. 1975; Came and Mean 1978). Angiographic findings in a larger group of 19 symp tomatic PVC workers with either Raynaud's phenomenon and/or acroosteolysis (5/19) were recently described in detail by Koiscltwitr et al. (1980). Raynaud's phenomenon had been observed to persist in these patients for prolonged periods after termination of exposure and even after roentgenological evidence of healing of resorptive bone defects in those who had formerly suffered from acroosteolysis. In addition to vary ing degrees of stenosis or occlusion of digital arteries with reopening of small collat eral vessels, acral hypervascularity and considerable retardation of perfusion in spite of premedication with tolazoline (Priscoline. United States), the most conspicuous features observed in the majority of these patients (14/19) were circumscribed elonga tions and tortuosities of digital arteries resembling cirsoid aneurysms. An example is shown in Fig. 3 of generalized tortuosity and elongation of digital arteries in a 54year-old patient who started to complain of severe sensitivity to cold 3 yean after cessation of VCM exposure (about 1 year prior to death from both angiosarcoma of the liver and hepatocellular carcinoma). The pathogenesis of these peculiar vascular alterations is not dear, but the possibility presents itself that they may be due to de struction ofelastic fibres in the vessel walls in analogy to similar alterations of digital arteries seen in rheumatoid arthritis (Laws et al. 1963.1967). Vinyl Stud vatioiu. Gngerp.i ed a van lararear those s, ferent d larosco, control ence in r PVC w< of distu: induced A si; aPVC-p chemica normali was con number employ: related i It also s ' 1 Mintellet ^Vre was ne Impathic aid be ob* ilammatory 1.1936; iJuang small metarved in man. itiisandde- v of the mly conarteriai * ttjngv et were ir or diffuse iI vessels, 'il peculiar inty of il. mp. MS/19) i>:i^menon - tmmation bone ro varyall coiiati in spite V'CUOUS bed elonpvampleis in a 54- after t coma of vascular due to de< of digital i/ Vinyl Chloride-Associated Disease 41 Fig. 3. C onspicuous tortuosities and elongation ot Jigiial arteries Studies of microvaseular changes by wide-field cupillan- microscopy (direct obser vations complemented by photography) of selected skin sites - such as nail folds, fingetpads, dorsum of phalanges and of proximal interphalangeal joints - demonstrat ed a variety of capillary abnormalities, ije. dilated or giant capillary loops, pale avascu lar areas, capillary and subungual haemorrhages. The abnormalities were similar to those seen in scleroderma but were usually less conspicuous, less numerous and of dif ferent distribution. In a survey of a group of 152 American FVC workers, them cap3laroscopic findings proved to be significantly more prevalent than in 50 nooexposed control subjects Qtaricq et al. 1976). Then was also a statistically significant differ ence in the prevalence of these abnormalities between symptomatic and asymptomatic PVC workers. The alterations wen not only found in workers with clinical symptoms of disturbed acral circulation but also in 6 nonsymptomatic males with either VCM* induced angiosarcoma of the liver (2) or splenomegaiic portal hepatic fibrosis (4). A similar survey was later undertaken in an unselected sample of 129 employees of a PVC-produdngchemical plant in England with 26 employees of a non-PVC-produdng chemical plant serving as controls (Maricq et al. 1978). The prevalence of capillary ab normalities found in these British workers, which were of the same type and degree, was comparable to that in the American sample, although the latter included a larger number of mote severely affected symptomatic patients with greater mean length of employment (15 yean vs 25 yean). In the mithon* opinion, this suggested that VQlrelated disease may develop independently of differences in manufacturing procedures. It also suggested that this easily detectable type of microvascuiar lesion may precede mote serious VCM-induced disorders. In a small subgroup of 15 clinically affected ) 42 W.K. Lelbach and IU. Marstellcr British workers wlio were examined 6-24 months after leasing the plant (termination of exposure), the prevalence f capillary abnormalities was not less than that among those who continued work. For an evaluation of the reversibility of this condition, however, the group was considered to be too small. The same type of capdlaroscopic changes was also observed in three of4 Polish workers (2 reactor cleaners, 2 fitters) who were found to suffer from Raynaud's phenomenon after exposure for 2-5 years (Byczkowska and Langauer~Lewowicka 1974). Infrared thermography, another non-invasive method, used by Rc;r et al. (1974) for the study of acral circulation, revealed abnormalities of surface temperature rang ing from marked hypothermia of terminal phalanges (which are normally warmer than the test of the fingers) to Complete terminal amputation** in four FVC workers suf fering from OAOL. In one of them vascular disturbances as evidenced by infrared thermography persisted in spite of complete healing ofOAOL Stewart et al. (1975) demonstrated uneven blood flow in the fingers and patchy hyperthermia in the distal part of the OAOL-affected left index and middle finger of their atypical case. Local ized acral hyperthermia seen on IR thermography corresponded to the angiographic finding of circumscribed abnormal collections of small vessels (compensatory collat erals?) in the pulps of the affected fingers. Using IR thermography in a survey involv ing 143 FVC production workers and 56 controls, Williams et al. (1977) assessed the time needed for heat return after immersion of one hand for 10 s in a water bath kept at 19C: however, no difference between VCM-exposed subjects and controls and be tween groups within the exposed population was noted. 4.1 JS Immunological Studies Early experience with the syndrome of occupational acroosteolysis suggested certain similarities between this disorder and corresponding lesions seen in progressive systemic sclerosis (diffuse scleroderma). Differential diagnosis of these two unrelated conditions is now well established (Table 10). Such similarities stimulated the search for other manifestations of a systemic collagen disease, notably immunological features, as pro posed by Marin et aL in 1967. Ward et al. (1976a, b) carried out immunological studies in 58 workers from a British polymerization plant who were referred to them out of a total past and present work force of 320. Mean duration of exposure to VCM was 39 months (6-75 months). Of these 58 workers, 28 were symptomatic (Raynaud's phen omenon. 9: scleroderma of hands or feet, 6; OAOL, 2; sensitivity to cold, excessive fatigue,limb pain, paraesthesias). Slight hyperimmunogiobulinaemia, usually IgG, the presence of mixed cyroglobulins, and in vivo convetsion of both C, and C4 were found in 19 patients in the symptomatic group, with additional evidence of reduced T<ell population and increased B-cell proliferation. Mixed cryoglobulins, in vivo con version of complement and depressed values for Cj or C* were taken as evidence for the presence of circulating immune complexes. Autoantibody screening demonstrated low-titie antinuclear antibodies (IgG 1/20--1/50) in eight of the nine patients with Raynaud's phenomenon. Aggregates of IgG, C4, C1( and ftbrinogen/tibrin were reveal ed by direct immunofluorescence in the lumen of vessels, adherent to vascular endo thelium. Aggregates were similarly seen in the media and subintimal regions of small Vinyl Chic and isc 30 Ut'i 8 C! CO m I v c o t--nI. <0 j: ir is. a 0) o- ai $< tc 1. jt/n vi ll- suffering fro than in non', ride disease : Inaneai in fourPolii' decrease in! tmulangfiu after Sephat 6 together v. agglutinins J were obien. sponses play (1974a) anc dence ofau* tion of rheu termination immunoflu<-' were later ai creases in in-, taken up ag ed to suggest hypergamn- with far adv three patiei- with Rayna'j degrees of n nins were fo range: 'Sts sderodermo of which is Insumrr autoimmune establish the in VCM-indt v] HJ. Mantclicr t (termination ~^^mong |^Kon. puiKscopic is. 2 fitters) for 2-5 yean etal. (19?4) <erature rangy warmer than workers sufy infrared ?tal. (1975) 1 in the distal case. Local* ngiognphic story collatutvey involvassessed the uer bath kept itrols and be- .sted cena;stive sys;-...u vd conditions jmJ" .^teprological stir lies 'liem out ot a VCMwas3*J ynaud's pht.ii.excessive rally IgC. the C were of reduced . in vivo conevidence for demonstrated ients with n were revealtcuiarendoms f small I Vinyl CbloriJe>Ais<Kuud Diwjw 4? and medium-sized arterioles in biopsy specimens of the skin (10 cases), muscle and lung 11 case each). Tlie authors proposed as explanation for the induction and pathogenesis of skin and bone changes in VCM-induced disease 3 theoretical model based on reactive meta bolic intermediates of VCM formed during biotransfotmatinn binding covalently to plasma proteins.These may act as antigens las a result of a structurally abnormal protein) which stimulate B-ceil proliferation and antibody response. Platelet aggregation, vas cular occlusion and ischaemia wete thought to be secondary to complement activation as a result of foimation of immune complexes which were implicated as possible medi ators of tissue injuty. Ischaemia, in turn, by leading to collagen synthesis, was believed to further activate the complement pathway and thus to recycle the mechanism. Jayson et al. (1976b). who carried out collagen studies in a skin biopsy of one patient suffering from OAOL found the rate of collagen synthesis to be considerably higher than in normal controls. The pathogenesis of excess collagen foimation in vinyl chlo ride disease has not been fuily elucidated. In an earlier study no ciyoglobulinaemia or presence of cold agglutinins was found in four Polish workers with severe Raynaud's phenomenon: in two of them a slight decrease in IgC was noted (ByczkoMika and Longauer-Lewowicka 1974). Later, how ever. Latigaucr-lewowicka et al. (1976) observed latent cryoglobulinaenua, detectable after Scphadex G-200 nitration, in 18 of 22 workers with Raynaud's phenomenon (in 6 together with acroosteolysis and sclerodcrmalike changes). Again, there were no cold agglutinins detectable, but in five patients marginal to slight elevations of IgC levels were observed. The authors suggested that a pathological alteration of immune re sponses plays a key role in the pathogenesis of vinyl chloride disease. Lange et al. f!974a) and Velrtmm et al. (1975) concluded from their results that convincing evi dence of autoimmune disease was lacking. Immunological studies including determina tion of rheumatoid factor (latex agglutination test), quantitative immunoglobulin de termination (Manzini radial diffusion technique) and autoantibody screening (indirect immunofluorescence) were initially introduced in our first series of 50 patients but were later abandoned because of mostly negative results, except for occasional in creases in immunoglobulin lewis {ManteUer et aL 1975a). These studies were later taken up again with an additional 43 patients engaged in PVC production but still fail ed to suggest mote than an erratic connection (unpublished data). We did not observe hypergammaglobulinemia (see comment in Ward et al. 1976a) except in a few patients with far advanced portal fibrosis and portal hypertension and in the terminal phase of three patients who died from angiosarcoma of the liver. In a group of 18 PVC workers with Raynaud's phenomenon in whom arteriography of the hands disclosed various degrees of oedusion of digital arteries, autoantibodies, cryoglobulins and cold aggluti nins were found in none; a moderately increased IgG level (1.93-3.68 g/litre; normal range: Ixi* OB--16 g/litre) was seen in five patients who suffered from OAOL and sclerodermoid skin chanps (unpublished data). Elastin antibody litres (the specificity of which is doubtful) were negative. In summary, currently available evidence does not seem sufficient to suggest an autoimmune disease as a pathogenetic mechanism. Further studies will be needed to establish the true significance of the possibly transient immunological abnormalities in VCM-induced disorders. ) i II 2D B CO 0 01 (O M 3 i. > u t hl () 44 W.K. Lelbach and H J. .Marstdler 4.1.7 Pathogenetic Considerations Raynaud's phenomenon as a premonitory clinical symptom, histomorphology in man and experimental animals and angiological experience suggest that the common de nominator in the pathophysiology of both skin and bone lesions in chronic VCM in toxication is probably to be sought in the local impairment of blood circulation in peripheral regions, as Benoit pointed out as long ago as 1967. By reason of their vas culature, the distal phalanges are the skeletal segments which may be most susceptible to impairment of blood supply, particularly to disturbances of microcirculation (Gama ea&Meira 1978). Yet the answer to the next question, the pathogenesis of peripheral vascular injury in vinyl chloride disease, is unknown. It still remains largely a matter of conjecture how a volatile toxic compound that is taken up via inhalation, distributed throughout the systemic circulation and metabolized (bioactivated) in the liver, can bring about, apparently only in a small number of predisposed individuals, after a vari able period of latency severe vascular injury and (probably secondary) damage to peri pheral tissue. Some conceivable mechanisms are briefly listed in a previous chapter (see Sect. 3 A2.2), but no conclusion can be drawn as to their relative significance. 42 Non-malignant Liver Disease in Vinyl Chloride/Polyvinyl Chloride Production Workers Long before Raynaud's phenomenon or osteolytic lesions were observed in PVC pro duction workers, Tribukh et al. (1949) studied environmental conditions in a Russian plant where polyvinyl chloride resins were produced and compounded. Without going into detail, the authors pointed out that moderate nontender hepatomegaly was found in a larger porportion of a group of 73 workers (48 males. 25 females) mostly engaged in PVC compounding; `anicteric hepatitis* was diagnosed in 21 of them (IS d, 6 9). Al though the authors knew about the narcotic action of high concentrations of VCM (75-250 mg/litre * 30 000-98 000 ppm) from the literature, which they explicitly mention, and also knew about the release of unreacted monomer from the powdery PVC resins during thermoplastic compounding, they apparently held other volatile compounds derived from halogenated aromatic hydrocarbons (such as chlorinated naphthalenes and diphenyls) used as plasticizers responsible for the systemic toxicity. They urged, however, that strict monitoring of the health of these workers should be introduced to prevent the development of severe liver damage, and they suggested the installation of ventilation facilities of sufficient capacity. Nonicteric hepatomegaly was again recorded by Suciu et <1. (1963) 14 years later in almost one-third of the total work population (51 of 168 employees) of two Rum anian PVC-producing plants, including 10 cases with additional splenomegaly. Liver biopsy in two of these workers revealed chronic hepatitis. Studying the prevalence of temporary disablement due to liver disease among 350 employees of the Sverdlovsk plastics industry .Piuhin (1965) found the highest morbidity among employees of the PVC production unit, compared with other units engaged in the production of nonPVC plastic materials; 170 workers of ancillary industries served as control subjects. Vinyl Chloride^ The clinical sympt< many as 15$ of tli survey was describe developing chronic character of nonnu In 1972 Kramt: had been routinely time-weighted avera environmental data wise multiple linear tion and, to a lesser level of past exposu: the individuals stud: TWA levels of 300 p; m clinical laborator ed BSP retention wo ease (MarsteUtr et a. In West German' dermatologists in Be At first sight, the sy derma. This provoke Progressive systemic a first group of 13 p< from a nearby PVC-p from either OAOL < phageal varices due ! a group of 20 relativ previous liver disease Medical Department patient and revealed capsularfibrosis of :< ly, marked portal h> al. 1973). It was now encompassed a large: Hence Jiihc -* - 'y; In tetre t spleen alter 20 Ct the long lat io disease whi CO >rr hepatic par -L it Only 3 o cn 4* was surpass to a fa liter, an ext 00 r work force np ican plant 1 t upper gastroiiitcauiiai d HJ. Marne!ter k'inman ton de rmic VCM inuculation in ii of their vas* ,ot susceptible rculauon (Cana u of peripheral VTly a matter of hi. distributed he liver, can inis, after a vandamage to peri lous chapter (see iticance. :J in PVC prons in a Russian Without going vA\y was found mostly engaged r 15 d,6 ?). Al- the powdery' the: volatile chlorinated -teraic toxicity, kers should be > suggested the 114 years later ;) of two Rumuiegaly. Liver ; prevalence of ie Sverdlovsk npioyees of the coon of nonitrol subjects. Vinyl Oilohtle-AssociaU'd DiwiiM.* 45 The clinical symptomatology of - typically nonicteric - liver disease observed in as many as 15" of the current work force of the PVC production unit during a 3-year survey was described as having been consistent with the diagnosis of an insidiously developing chronic hepatitis- No histological data were available, however, and the true character of nonmalignant liver disease found in these workers remained obscure. In 1972 Kramer and Mutchkr examined a group of 98 healthy male workers who had been routinely exposed to VCM for periods up to 25 years and for whom career rime-weighted average exposure estimates were available. In an attempt to correlate environmental data and results of a medical surveillance programme by means of step wise multiple linear regression analysis, it emerged that brumsulphthalein (BSP) reten tion and. to a lesser degree, the icterus index were significantly correlated with die level of past exposure to VCM. Although no oven dinieal disease was found in any of the individuals Studied, Kramer and Mutchkr conduded that exposure to VCM at TWa levels of 300 ppm or more for a working lifetime could result in certain changes in clinical laboratory parameters. As it later turned out slightly to moderately increas ed BSP retention was the most consistently pathological test for VCM-induced liver dis ease (Manrcller et al. 1975a). In West Germany the first cases of occupational OAOL were observed in 1972 by dermatologists in Bonn (Juhc and Lange 1972; Julie et al. 1973:Stein et al. 1973a. b). At tint sight, the symptomatology appeared to resemble atypical progressive sclero derma. This provoked a thorough search for manifestations of visceral involvement Progressive systemic sclerosis, however, could be excluded. On medical examination of a first group of 13 polydcanen who were referred to the Department of Dermatology from a nearby PVC-ptoducmg plant it emerged that 3 of them, who did not suffer from either OAOL or scleroderma, had a history of unheralded bleeding from oesopliageal varices due to portal hypertension (Juhc et al. 1973). Further investigation of a group of 20 relatively young PVC production workers (mean ige:40 years), in whom previous liver disease could be excluded, was carried out in collaboration with the Medical Department Peritoneoscopy and guided liver biopsy were performed in each patient and revealed varying degrees of nondrriioric portal, pemimisoidal and mb* capsularflbrods ofthe lieer, with splenomegaly, thrombocytopenia and, less frequent ly. marked portal hypertension, but strikingly little hepatic dysfunction (MameOcr et al. 1973). It was now realized that the disease spectrum in VCM-exposeJ individuals encompassed a larger scope of injuries and, in fact, suggested a systemic toxic effect. Hence Jihe et al. (1973) proposed the term *vinyl chloride disease*. In retrospect, this comparatively late recognition of the true nature of liver and spleen alteration; in chronic VCM intoxication can be attributed, at least in pan. to the long latency period as well as the insidious onset and course of this type of liver disease which is accompanied, even far into the advanced stages, by only minimal hepatic parenchymal dysfunction. Only 3 months later, however, in February 1974 the significance of this discovery was surpassed by the alarming announcement that four cases ofangiosarcoma of the liter, an exceedingly rare malignant tumour, had been found among a comparatively smalt work force of 274employees of the PVC polymerization section of a large North Amer ican plant (Creech et al. 19?4i). Two of these four pstients had first presented with upper gastrointestinal bleeding due to portal hypertension between 1964 and 1970. D R (/) o tn --l to to .; !: . ; :L . * t. i. r. i I r 46 W.k. Lelbach anil H.J. Marsitller There is no longer any doubt that chronic exposure to vinyl chloride monomer can produce two different types of liver disease in man as well as in experimental animals: 1) Nondrrhotic portal hypertension 2) Angiosarcoma of the liver. The two conditions have one feature in common: they are both rare disorders which are not easily recognized during life. Noncirrhotic portal hypertension and (often inconspicuous) portal fibrosis are not pathognomonic. Primary splenic enlargement and gastroocsophageal haemorrhage due to marked portal hypertension in the absence of, or preceding, the development of cirrhosis was first described by Banti in 1894. As `Band's syndrome*, this symptom complex and its aetiology and pathogenesis have continued to be a matter of debate. Under the designation `idiopathic', or `primary, portal hypertension* the syndrome has been observed notably in India and other South-East Asian regions (Ramalingaswami et al. \96l\Imanaga et al. 1962;&ra* et al. 1967a,b;Boyer et al. \961.Samn et al'. 1971). It has been seen only sporadically in the Western World (Rousselot 1940; Ravenna 1940; Tisdale et al. l9S9\Polish et al. 1962; Atiller and Bnndt 1962;Sider)<s and VeUioi \964\Mikkclsen et al. l965;/6er 1970;Escartin Marin et al. 1974; Mendenhall et al. 1974; Grannis 1975; ViUeneuveet al. 1976). Iber (1969) estimated that "centers throughout the world reviewing their experience with portal hyperten sion encounter 3 to 5% of patients who do not dearly fit into the category of cirrhosis or blockage of the portal vein." In the absence of an identifiable aetiology it has been speculated that in noncirrhotic portal fibrosis observed in India,unknown toxins contained in indigenous drugs, herbal medicines or adulterated food might have been responsible for the condition (Some et al. 1971). Vllleneuve et al. (1976) suggested that, apart from VCM and inorganic arsenicals, other still unidentified toxins could be the cause of this syndrome. Idio pathic portal hypertension has also been observed to occur in assodation with known hepatotoxic agents, their common link with VCM being, so far with the exception of vitamin A, the induction of angiosarcoma of the liver. These agents are: , si) Inorganic arsenical* (Zecgen el al. 1970;Me/c and Azzopardi 191 \\Kmlle et al. 1974;Afomset al. l974;Ai/eretal. 1975; ViUeneuveet al. 1976; Cowlishaw et al. 1979); b)Hypervitaminons A (Muettter et al. 1971;AusscJ7et al. 1973,1974;Hruban et al. 1974; JOsr/er et al. 1977); and c) Recently, copper sulphate in Portuguese vineyard workers (Pimentel and .Veneer 1977). Arsenicalpreparations (usually prescribed as Fowler's solution - potassium arsenite) have in the past been used as a tonic in neurasthenia, as an adjunct to iron therapy for anaemia, as antiepileptic drugs and well into the 1950s for the treatment of psoriasis. In this context. Band's remark in his original paper (1898) that anaemia accompanying primary splenomegaly responded best to arsenical preparations is of note. In a renowned German pharmacology textbook of this period (Notlutagel and Rossbach 1880) Fowler's solution is also listed as a traditional antimalarial drug of 00ZS0V v*. anil HJ. Mar.teller oride monomer can jtal animals: , rue disorders rul flbrosis are not d haemorrhage due development of this symptom matter of debate, i* the syndrome has (Ramaiingeswann 1967:Sama et al. ussebr 1940: and: 1962:Sultrys et al. 1974; (1969) estimated i portal hypertenrategory of cirrhosis i that in noncirrhotic venous drugs, herbal k*ondition fJt/me et and inorganic syndrome. 1Jio* .ation with known li the exce< lion of ' et al. ..owiishaw ft al. 5.1974;Hruhan et imtnttland Mcncsct -potassium n adjunct to iron i for the treatment 898) that anaemia 'reparations is of d (Nothnagel and (malarial drag of o Vinyl Chloride-Auociated OUease 47 long standing. Chainuvati and Virmuratti (1979) recently implicated an indigenous Thai medicine contaning arsenic as a possible aedol gical factor in a case of idiopathic portal hypertension. Dana et al. (1979) found significantly elevated levels of arsenic in liver tasue specimens of four of nine Indian patients with idiopathic portal hyperten sion resulting from chronic arsenic intoxication (contaminated drinking water, use of Ayurvedic medicines). Typically. liver disease in these cases occurs in conjunction with other evidence of chronic arsenic intoxication, such as skin pigmentation, palmar and plantar hyperkeratosis, skin cancer and sometimes carcinoma of other sites. However, neither histological nor radiological or haemodynamic criteria permit a clear distinc tion between Idiopathic* portal hypertension and noncirrhotic portal hypertension caused by chronic arsenic toxiflcation or chronic exposure to VCM, as was demon strated by VUkncuvt et al. (1976) in a study of five patients. After prolonged treatment with excessively high doses of vitamin A (psoriasis, ichthyosis and other dermatological conditions, adjuvant cancel therapy and in health faddism) chronic intoxication has been seen to cause hepatic fibrosis and cirrhosis (Mutrtter et al. \97l:Fkischmann etal. 1977;A'trr/eret al. 1977;Russell et al. 1973, 1974). Storage of vitamin A in hepatocytes and one type of fat storing, nonphagocytic perisinusoidal cells [Ito calls (/to and Nemoto 1952)] could be demonstrated by fluo rescence microscopy. Stimulation and proliferation of Ito cells, which ate probably fibroblast precursors (Popper and Udtnfricnd 1970;Schnack et al. 1967), provokes an increase in bascment-membrane-Uke material and collagen within the perisinusoidal space and leads to perisinusoidal fibrosis with partial obliteration of Disse's spaces and the sinusoidal lumen (Hruban et al. 1974). The recognition of idiopathic portal hypertension, hepatic fibrosis, cirrhosis and angiosarcoma of the liver coexistent with excessively abundant hepatic deposition of copper (besides evidence of "vineyard sprayer's lung*) in a group of 30 vineyard workers in Portugal is. to our knowledge, the first report in which chronic copper intoxication is implicated as the aedological agent. For periods varying from 3 to 45 years, these workers had been engaged in spraying vineyards with a mixture containing copper sulphate on 15-100 days per year. The authors noted a dose morphological resem blance of the lesions to those resulting from exposure to inorganic arsenicals and to vinyl chloride (Pimentel and Mcnezcz 1977). Although extrinsic chronic copper intoxi cation is virtually unknown in man, potential hepatotoxicity of long<onrinued uptake of copper ws discussed by Btomflehl et al. in 1971 in connection with recurrent haemodialysis. Although nonmalignant liver disease seems to be a more common lesion in PVC production workers than angiosarcoma, it lus received less attention than the spectac ular discovery of tne rare hepatic neoplasm. In continuation of our first two surveys (Mantclicr et al. 1973,1975a, b), we have now (end of 1980)observed 17 patients (all members of a total work fores of approximately 180 polymerization workers) in whom clinical and morphological examination, including peritoneoscopy and guided liver biopsy, revealed advanced portal hypertension (Table 11). A larger proportion of them first presented with symptoms ofunheralded gastrointestinal bleeding. On follow, up. we strongly suspected that angiosarcoma was developing in four of them but were unable to prove it during life. Only post-mortem examination finally confirmed the diagnosis. In a smaller series of seven patients with nondrrhotic portal fibrosis and o aj co o cn NJ o 48 W.K- Lelbach and h.3. Matsteller Table 11. 17 PVC worker: with advanced portal hypertension (marked oesophageal varices, episodes of upper Cil bleeding, splenomegaly) Age at diagnosis Duration of cxposuie reritoneoKOpic and Xo. (years) (yean,-months) histological diagnosis 1 30 + 31 3 32 4 35 5 a 35 6 39 7 39 8 41 9 41 10 * 47 11 50 12 51 13 52 14 52 15 54 16 a 58 17 a 61 5 5/9 3/6 4 9 10/6 13/6 7 18 18 6/6 17 15/3 H 6/6 21 13 Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis a On follow-up patients 5,9,10,16 and 17 subsequently developed angiosarcoma of the liver and died 3-6 years after diagnosis of portal hypertension. Patients 6 and 14 are at present (1981) under observation for suspected development of angio sarcoma of the liver, 6 and 1.1 years after peritoneoscopic diagnosis of portal fi brosis associated portal hypertension,Smith et al. (1976a) observed later development of angiosarcoma in one of them. If a rough estimate based on these two small series were acceptable, it would appear that approximately one of five to seven individuals suffer ing from advanced VCM-induced portal hypertension might be expected to develop angiosarcoma later, although PVC-induced hepatic fibrosis per se is probably not a premalignant lesion. 4.2.1 Clinical Manifestations of Non-malignant Liver Disease Physical examination is usually disappointing. In the more advanced stages of VCMinduced nonmalignant liver disease, palpable splenomegaly and a slightly to moderate ly enlarged liver may be the only physical signs. On palpation, we found hepatomegaly in 31 and splenomegaly in 16 of SO selected PVC production workers who had been heavily exposed in the past (ManteUcr et al. 1975a). Lila et al. (197J) reported hepa tomegaly fat 15% and splenomegaly in 3.4% of 354 consecutively examined employees (267 currently employed, 87 former workers) of one PVC polymerization plant in New York State, USA, a number which included virtually the entire current produc tion work force. A significantly higher prevalence ofhepatomegaly was found in those Vinyl Chlon- exposed for r splenomegaly In contra* mentofhepa ectases, gyna, not seen. Eve phalopathy d` workers only It is puzzli preceded adv. only one case development - 4.22 Labors Owing to the . not the target value for the C This makes it y 1974; Creech thrombocytop logical biochei: the levels of squent (Monte (ICC; 02 and ' liver function workers of a (Tamburro et progressively ;of abnormal S there was over phosph alkaluu megaly g Exc and Vet the retii panme: present Sion (Sr w ^ o jjJJ o M be dealt Assc matiew iken facture of PVC coproporphyri: H.J. Marteller -<ophageal and ai diagnoMv tic fibrosis tic fibrosis uc fibrosis ..tic fibrosis tic fibrosis tic fibrosis tie fibrosis tic fibrosis tic cirrhosis tic fibrosis tic fibrosis uc fibrosis tic fibrosis uc fibrosis me fibrosis I.- cirrhosis uc ilbrcsis 'jrcoma oi n.ents b and " .it anfio- p.<rui fi- .'jsent of mli w e Isunci.iu^Rdefvieclop ably not a pie- yes ofVCM tc moderate* ; Hepatomegaly ho had been -.`ported hepancJ employees -m plant in rent preduci<*id in those L- Vin>! Cliioride*Associated Disease ' 49 exposed for more than 5 yean, whereas the difference in the prevalence of palpable splenomegaly was not significant. In contrast to cirrhosis of the liver, clinical symptoms indicating serious impair* ment of hepatic function such as jaundice, vascular spiden. palmar erythema, telangi ectases: gynaccomastia. peripheral oedema and ascites or hepatic encephalopathy are not seen. Even after massive bleeding from oesophageal varices portosystemic ence phalopathy does not develop. Ascites and hepatic coma have been observed in these workers only in terminal stages of angiosarcoma of tiie liver. It is puzzling that acroosteolysis and sclerodermoid skin induration have only rarely preceded advanced stages of VCM-induced liver disease. To our knowledge there is only one case of angiosarcoma of the liver on record which was associated with prior development of acroosteolysis (Roche et ai. 1978). 4,2.2 Laboratory Findings Owing to the fact that hepatocytes. although being the primary site of metabolism, are not the target of toxidty, standard biochemical liver function tests are only of limited value for the detection of liver disease in populations at risk (Williams et al. 1975b). This makes it very difficult to devise adequate screening programmes (Martin et al. 1974:Oeec/i and Makk 1975; Wyatt et al. I975;e/*etal. 1975,1976). Apart from thrombocytopenia, we found 45-min BSP retention to be the most consistently patho logical biochemical test: usually minimal hyperbttirubinaemia and minor elevation of the levels of serum alkaline phosphatase. SCOT and SGPT were considerably less fre* quent (MarsteBer et ai. 1975a). Another dyeemovaI test, indocyanine green clearance fICG: 03 and 5j0 mg/kg), also proved to be mote reliable than standard biochemical liver function tests in correctly identifying early hepatic injury in 1200 vinyl chloride workers of a chemical plant in Louisville, Kentucky, during a 4-year screening period (Tamburro et al. 1978b). Tltt exposure rank was found to be closely correlated with progressively increasing frequency of abnormal ICC clearance, whereas the frequency of abnormal SCOT, and alkaline phosphatase only increased in late stages, often when there was overt clinical disease. In the survey conducted by LiUs et al. (1975), alkaline phosphatase levels were elevated in 16.65* of the 354 workers examined. In their series, alkaline phosphatase was also closely correlated with the clinical symptom of hepato megaly and/or splenomegaly. Except for thrombocytopenia (less than 150 x 10* piatelets/litre) which Lange and Veltman (1977) found to be present in 76 of 100 workers, and a slight increase in the reticulocyte count On 35 of 79 workers,Lunge and Veltman 1977), haematological parameters usually do not contribute to the diagnosis. Thrombocytopenia was also the presenting feature in two of seven British workers with noncirrhotic portal hyperten* rion (Smith et aL 1976a). Thrombocytopenia and abnormal platelet function tests will be dealt with separately in Sect. 44.1. Assessment of urinary' excretion of porphyrins and porphyrin precursors in sympto matic workers who had been engaged in the production of FVC (n * 23) or the manu facture of PVC articles (n " 17) revealed varying but mostly mild degrees of secondary coproporphyrinuria in the m^ority of them (Lange et al. 1976b). Tlie significance of i I r. *4 iv 20 CD O 6 t F t Br; 4 it ii- 4. * 50 W.K. Lelbach and H.J. Manteller these findings as an indication of toxic liver damage is not clear and the relation to previous exposure to VCM remains to be determined. 4.23 Gross Inspection of the Liver and Spleen The gross appearance of the liver, as assessed by peritoneoscopy {Manteller et al. 1975a,b'fManteUcr and Lelbach \9Tl\Lelbach andMarstellcr 1977; or at exploratory laparotomy, is that of a normalized or slightly to moderately enlarged organ with often blunted and irregular anterior edge. Inspection of the liver at peritoneoscopy also permits exclusion of partial nodular transformation as described by Sherlock et al. (1966). In most cases, the surface of the liver is smooth or slightly uneven with shallow indentations, but it may be finely granular, trabeculated or have a peau d'orange-like appearance. At most, there are micronodular changes but the diffuse coarse nodularity of cirrhosis is only rarely teen. Progression to frank cirrhosis with severe derangement of hepatic lobular architecture was observed by Smith and Williams (1974), and also in two of our recent cases in combination with development of angiosarcoma. On palpation (direct or by peritoneoscopic probe), the texture of the liver is normal or only slightly firmer than usual. Indirect peritoneoscopic evidence of portal hyper tension is presented by increased vascularity of the falciform ligament and the intes tinal serosa or numerous dilated tortuous vessels in adhesions draining to the abdomi nal wall. Even in advanced stages, symptoms of pronounced portal hypertension often Fig. 4. Peritoneoscopic view of left hepatic lobe in noncirrhotic portal hypertension (January 1979). Blunted anterior edge, smooth to finely granular surface, conspicuous patchy capsular fibrosis. (42^year-otd autoclave cleaner. VCM exposure 1963 -74. 1973 thrombocytopenia as first sign. From 1974 to 1979, marked progression of portal hypertension with splenomegaly and one episode of bleeding from oesophageal varices.) See also Fig. 5 (patient 6 in Table 11) Vinyl Chi contras: si' pectedly s. is a focal c opacities.' stellate sc." ing (Mann tissue in G' ing > tiss S5j teed,,i! refc ll in Ocn g Hist. -gicai rally sis.sinkinr fibrosis are (Fig. 5a-d) reactions. throughout fibrosis. Su: tological e-. 1978). Depend date of bio; nant liver u ject to mark ations is sc: Thomas 197 1976). but (/topper et a- 42.4,1 Hu In its fully J of dense, pabile ducts a: with format! central and r of connect^' with enlargeperisinusoid, oidal walls, it Muller et al. : '! J Manttlltff relation to *:f et al. it exploratory i>igan with 'neoscopy aiso lock et al. i with shallow !'orange-like ne nodularity derangement ' t't, and also roma. liver is normal Hrtal hyper* d the intes* the abdomiriension often yperrension conspicuous 65 -74. :-.on of i esophafeal Vinyl C'hlomle-A'iiociaid Disease 51 contrast sharply not only with minimal alterations of the surface but also with unex pectedly scanty histological evidence of hepatic fibrosis. The most conspicuous feature is a focal or diffuse capsular fibrosis of varying pattern (Fig. 4). presenting as whitish opacities. The degree of capsular involvement ranges from diffuse tiny commalike or stellate scars to coarsely reticular and irregularly patchy milk-unite capsular thicken ing {Marstettcr ct al. 1975a). Histology showed that this focal increase of connective tissue in Clisson's capsule may extend into the parenchyma and connect with septa extending from enlarging fibrosed portal tracts lPopper and Thomas I *>75). The con nective tissue capsule of the enlarged spleen also seems to be sensitive to VCM-induced processes that have taken place in the underlying tissue so that focal white thickening or more diffuse opacities together with circumscribed subcapsuiar haemorrhagic cysts are seen in cases with marked splenomegaly. 4.2.4 Histology Histological examination of biopsy specimens shows that normal lobular architecture is generally maintained, but varying patterns of portal and. in some cases, septal fibro sis, striking intralobular perisinusoids! fibrosis, and focal capsular and subcapsuiar fibrosis are found in combination with peculiar alterations of sinusoidal lining cells (Fig. 5a-d). Hepatocellular changes usually play a negligible role and inflammatory reactions, if piesent at all, are insignificant. The lesions are distributed quite irregularly throughout the liver and may vary from minor inconspicuous degrees to quite striking fibrosis. Surgical wedge biopsy of sufficient depth appears to be more suitable for his tological evaluation than needle biopsy specimens (Smith et al. 1976a: Blendis et al. 1978). Depending on length and degree of exposure, interval between last exposure and date of biopsy, as well as individual factors, histopathology of VCM-induced nonmalignant liver disease is represented by the following features whose manifestation is sub ject to marked intetindividual and topical variation: the same variability of tissue alter ations is seen in the nontumorous areas of the liver in angiosarcoma (Popper and Thomas 1975; Thomas et al. 1975;Sent et aL 1976; Gedigk et al. 1975: Wainbren 1976). but in these cases the nontumorous lesions may be even more conspicuous (Popper et al. 1978). O.4.1 Hepatic Fibrosis In its fully developed form, minimal to marked enlargement of portal tracts by excess of dense, paudcellular connective tissue, which in advanced cases contains proliferated bile duett and some periductular inflammation, may in rare instances be combined with formation of periportal sepu linking portal tracts or. even more rarely, connect central and portal canals. Other portal areas appear almost normal. Focal accumulation of connective tissue in the thickened Glisson's capsule may be connected by septa with enlarged infracapsular portal tracts. A more striking feature is an intralobular perisinusoidal *netlike* fibrosis with more or less prominent coOagenization of sinus oidal walls, in some areas even progressing to frank capiUarization (Ctdigk et al. 1975; Matter et al. 1975). The focal intrasinuaoidal fibrosis may be subtle and in some cases ) 33 (/> ;2 W.K. Lelbach and HJ. Marsreller Vin- OS '-Ms. fey J..4 ----------- ----------- --- - m ,N"dl! "W ,pe1cimen of the Uver *hown in Fi. 4. Enlargement and fibrosis - fn v Mo?tr3te y l,,*e droplet steatosis. Focal dilatation of sinusoids. H &.E. x 80. b Close-op of Fig. 5a. Indistinct border of enlarged and fibrosed portal tract to- (> *'*" rl>mon>hin" r ^. v -r - ** Mameiler "Twilit;* ; * :j#*'..>"5j * y.* .. * r -'sr:> i . *v/, >S3 --vr* o Vinyl ChlcriJe-Ajiix-uted Disease # /" k ivw* % F 'i \> `V 4< 'ihrosis H4E, ract toand Flf Sc. Focal portal fibrosis Cleft upper eomeri tad reticulated petisinusoidal fibrosis with activated proliferating aad pleomorphic sinusoidal lining cells. Trichrame (Goldner) stain, blue filter, x 250. d Conspicuous focal dilatation of sinusoids. Activation and moderate polymorphism of proliferated hyperchromatic sinusoidal liningcells. Enlarged hepatocytcs with hyperchromatic nuclei, some of them binuclear. t Potential precursor stage of angiosarcoma?) Courtesy of Professor MDUer-Wailraf. Institute of Pathology. Amber*. H E. x 400 .0 * < 54 W.K. Lelbach and H.J NUrucller may be recognized nly in connective tissue stains. Triclte et al. (1975) pointed out that in one worker with severe acroosteoiysis but normal hepatic function and essen tially normal liver histology on light microscopy (except for a minimal and easily oxerlooked increase of perisinusoidal collagen in occasional lobules), electron microscopy revealed a striking cenirilobular increase in collagen between hepatocytes and in Disset spaces together with proliferation and hyperplasia of sinusoidal lining cells (see also Kurokawa et al. 1977). The same ultrastructural deposition of perisinusoidal collagen was observed by Schattenberg et al(1977) in 15 PVC workers in whom we could ob tain liver tissue for electron microscopy at peritoneoscopy. Similar changes (enlarge ment of Kupffer cells, abundant deposits of collagen in the Disse's space and resulting reduction of sinusoidal diameter suggesting a possible factor in the pathophysiology of `sinusoidal' portal hypertension) were seen on electron microscopy in a number of cases of idiopathic portal hypertension of unknown aetiology (occupational histories not mentioned) (,Sommerschild and Kluge 1971; Kluge et al. 1970; Tandon et al. 1970). 4.2.4.2 SinusoidalLining CeUs Marked focal proliferation and hyperplasia of sinusoidal lining cells with nuclear poly morphism and hyperchromasia are the most impressive features of the mesenchymal lesion. The hyperchromatic nuclei of these cells may show a bizarre shape or resemble short pegs, and are often arranged in a chainlike fashion (Gedigk et al. 1975). These perisinusoidal and sinusoidal cells include three types: (1) normal endothelial cells, (2) lipocytes (Ito cells), considered to be precursors of fibroblasts and (3) plump cells with spindle-shaped nuclei and PAS-positive cytoplasm. Formation of excess reticulin suggests fibroblastic activity of some of these cells. Focal dilatation of sinusoids, not explained by passive congestion, is another peculiar feature usually associated with particularly pronounced alterations of these mesenchymal cells. There is reason to be lieve that this combination of changes may represent a premalignant stage. 42.4J Hepatocytes Unimpressive, nonspecific, degenerative and adaptive lesions (such as minor degrees of fatty degeneration, cloudy swelling, ballooning or vacuolar degeneration, increase of lipofuscin pigment and proliferation of smooth endopiasmstic reticulum of hepato cytes in focal areas without inflammatory reactions), can be seen to disappear gradual ly with increasing intervals between the last exposure and the date of biopsy, in con trast to the apparently irreversible damage to mesenchymal structures (<Gedigk et al. 1975,1977;A/<tffer et al. 1975). In poorly demarcated areas there is hyperplasia and hypertrophy of hepatocytes with polyploidy and increased number of binudeated cells. Two types of focal hepatocytic proliferation associated with varying degrees of sinusoidal cell alterations were recently described and are thought to play some as yet undefined role in the precutsor stage of angiosarcoma (Popper et al. 1978). 42.4.4 Histology ofthe Spleen Unless splenectomy is carried out in vinyl chloride disease. tissue specimens of the spleen are less easily obtainable than liver biopsy material. Popper and Thomas (1975) Vinyl Chloride and Thomas et. to be character!/ geneous red pul;- folliclei with me endothelial cells occasional fresh ' spicuous fibrosis In ten cases vu Heusermann and terial, together \\ splenectomy. T1k process. Excess at tive tissue, nota^ and white pulp, p There was scarrin. meshwork and re.' and diameter of si of the pulp cords. formation of biza> collagen fibrils. N the reticular conn. volume with parai mation of capillar f und within the thrombocytes by / hanced porw" n* help to ex stages of y and Hcus fio VCM-ind W of the liv in the sp dicate a portcoi tients is the splr Q cn h> 00 ;n -Y ic. able for compuisr - 4.2.5 Pathophysn The pathophysi 1 unresolved problei t splenoportograp' of intrahepatic vasvenous radicles (Bit and a normal, or oi : HJ Mamel'.er minted out "^dessen- over* i microscopy s and in Disse* Us (see also idal collagen ive could Ob* jes (enlargeand resulting physiology a number of mal histories on et al. nudear poly* esenchymal s or resemble >75). These .elial cells, ) plump cells cess reticulin tusoids, not iated with reason to be* or degrees of .increase of ofhepato* spear gradual* 'pty, in con* fdigkn al. rrpiaria and nucleated ig degrees of /some as yet S). :iu of the tomes (1975) o Vinyl Chloride-Associated Disease 55 and Thomas et al. (1975) found the cut surface of surgically removed enlarged spleens to be characterized by conspicuously hyperplastic Malpighian foUidcs in a beefy homo geneous red pulp. Histologically, they noted large germinal centres of the Malpighian foUides with merging of perifollicular zones, dilatation of red pulp sinuses lined by endothelial cells of variable, often cuboidal shape, thickening of the pulp cords with occasional fresh haemorrhages, and in one case Gandy-Camna bodies, but only incon spicuous fibrosis of the red pulp. In ten cases we obtained needle biopsy spedmens of spleen tissue at peritoneoscopy'. Htuscrmann and Stune (1977b) andSrttne andHeusemwnn (1978) studied this ma terial, together with spleen tissue specimens available from three spleens obtained at splenectomy. They found evidence for an involvement of the spleen in the fibrosis process. Excess amounts of newly' formed extracellular elements of reticular connec tive tissue, notably collagen, produced by stimulation of fibroblastic cells of the ted and white pulp, particularly in perifollicular and subcapsular areas, were observed. There was scarring of periarterial lymphatic sheaths, obliteration of the pulp cord tneshworic and reduction of pulp cord volume, in addition to an increase in number and diameter of sinuses. The reticular connective tissue of the walls of the sinuses and of the pulp cords showed marked alterations with thickening of reticular fibres and formation of bizarre piatelike amorphous structures containing inegularly distributed collagen fibrils. Narrowing of the labyrinthine cordal tissue with marked increase of the reticular connective tissue caused a reduction of nucrotircuiatory sequestration volume with parallel decrease of the number of pulp cord macrophages and approxi mation of capillaries and sinuses. Frequently, focal accumulation of platelets was found within the narrowed pulp cordbed in addition to increased phagocytosis of thrombocytes by residual macrophages. This lends support to the hypothesis of en hanced pooling of platelets in the spleen (Htustrmmn and Same 1977a), and may help to explain the pathogenesis of thrombocytopenia often seen even in the early stages of vinyl chloride disease. By structural analysis of histometrical results.Sturte and Heusamann (1978) outlined certain diagnostic criteria for the differentiation of VCM-induced splenic alterations from those seen in portal hypertension due to cirrhosis of the liver or extrahepatic portal vein occlusion. They concluded that fibtotic changes in the spleen in vinyl chloride disease are not the result of portal hypertension but in dicate a primary action ofVCM or its metabolites on the spleen. A comprehensive re port correlating dinical and morphological data gathered from this group of 13 pa tients is being prepared for publication at present. Results of histometrical studies of the spleen in nondrrhotic portal hypertension of unknown aetiology are now avail able for comparison (Sekt 1965; Yamamoto 1978,1979). 4.2.5 Ptthophynology of Portal Hypertension The pathophysiology of portal hypertension in VCM-induced liver disease is as yet an unresolved problem. Patency of the portal vein was demonstrated in all cases subjected to splenoportography. Portography usually showed no or only minimal derangement of intnhepatic vascular pattern such as tapering or `cut-off of small peripheral portal venous radicles (Blendis et aL 1978; VUleneuwe et al. 1976). High intraspienic pressure and a normal, or only slightly raised, wedged hepatic vein pressure indicate that the I ft W.K. Lclbach and HJ. Marsiolier portal flow is obstructed at the sinusoidal or presinusoidal level. In a group of five PVC workers selected for haemodynamic studies, Blcndis et al. (1978) could not demon* stratc a direct relationship between the degree of hepatic fibrosis in needle biopsy spec imens and portal hypertension. But it should be kept in mind that the distribution of fibrosis in these workers is quite irregular. It lias also been suggested by Popper and Thomas (1975) and Thomas et al. (1975) that the increased splenic and hepatic blood flow, as a result of decreased splenic resistance in splenomegaly cannot properly be ac comodated in the hepatic portal vein bed owing to impairment of adaptive distension of portal veins and sinusoids by the subcapsular, portal and perisinusoidal fibrosis. Bkndis et al. (1978) found no correlation between spleen or estimated liver blood S3. i. ?i m Fig. da, b. Progression of noncinhotic portal hypertension despite termination of ex posure. Oesophageal varices. (Autoclave cleaner, age at diagnosis: 35 years. VCM-ex posure,.1962-1972. 1972 Raynaud's phenomenon, sklerodermoid skin indurations, thrombocytopenia, splenomegaly, and grade 1 oesophageal varices. Gradual progression of portal hypertension. Sudden death from ruptured anaplastic angiosarcoma of the liver in June 1978. Histologically only mild perisinusoidal fibrosisin non tumorous areas) Vinyl Diopsy ofbrid the fib) cytesfi ing cellfollow-' massive exposui sarcom. or less c terrain i oped (s. Live determi: (BN1HP after h< and toil aid of >! the reu. increase PVC p: sack et 43 An 43.1 1 Primar> (angi b! haemair. cell sarc< sarcoma, vascular! one at e: hood (ft' the nunf< Lelbach and HJ. Mantelier level. In a group of five PVC could not demonib^Bin needle biopsy' spec* :nd that the distribution of suggested by Popper and d splenic and hepatic blood galy cannot property be acnent of adaptive distension i perisinusoidal fibrosis, or estimated liver blood i despite termination of exptosis: 35 yeaa. VCM<xdermoid skin indurations. I varices. Gradual propession lastic angiosarcoma of the fibrosis in nontumorous o Vinyl Chloride-Associated Debase ) 57 flow and the portal pressure. H wever, they point ut that this relationship may be veiled by the amount of blood bypassing the liver via a collateral circulation. 4.2.6 Follow-up of Non-malignant VCM-induced Liver Disease In 1974 Martin et al. (see also Berk et al. 1975) pointed out that VCM-associated hepa tic fibrosis, once established, may progress even after cessation of exposure. They could demonstrate this progression despite normalization of all routine liver function tests in a 27-year-old worker on a follow-up examination including peritoneoscopy and biopsy 2 1'2 yean after cessation of exposure. Progression of fibrosis and appearance of bodging between portal and central veins were indicative of persisting activity-of the fibroblastic process, whereas the previously observed activation of both hepatocytes (marked variation of cell size and numerous binudeated cells) and sinusoidal lin ing cells had disappeared. Since 1973 we have observed a number of worken who on follow-up showed evidence of progressing portal hypertension with development of massive oesophageal varices and subsequent bleeding episodes despite removal from exposure (Fig. 6). In five (7?)of these patients with progressing portal hypertension angio sarcoma of the liver finally developed. In this context, it is of interest to note that more or less conspicuous hepatic fibrosis (or rare progression to cirrhosis) was the parental terrain in which the majority of cases of VCM-induced angiosarcoma of the liver devel oped (see Tables 13-18). Liver and spleen scans with technetium-labelled sulphur colloid, quantitated determination of spleen size with the aid of ,,7Hg-bromomeroury-hydtoxypropane (BMHP) labelled artificially damaged red cells, and sequential perfusion scintigrams after bolus injection of "R,Tc-pertechnetate have been found useful in the diagnosis and follow-up of nonmalignant liver disease in PVC-poiymeruaaon workers. With the aid of these nonmvasive methods, inhomogeneous uptake of labelled sulphur colloid in the reticuloendothelial system of the liver and enhanced uptake in the spleen, gradual increase in spleen size and reduction of portal venous perfusion have been observed in PVC polymerization workers developing portal fibrokis and portal hypertension (Biersack et at 1975a, b, 1977a. b). 43 Angiosarcoma of the Liver 43.1 Epidemiology Primary angiosarcoma of the liver (ASL) is described under a variety of synonyms (sngiobltstic sarcoma,sngiobiastic reticulosarcoma. endothelioma, endothelioblastonu. haemangiofelastoma, haemaagtoendotheiionn, haemangtoendothcBal sarcoma, Kupffer ceil sarcoma, malignant haemangioma, metastasizing haemangioma, reticuloendothelial sarcoma, primary sarcoma of the liver). It is an exceedingly t>r* malignancy, arising from vascular lining celts. It occure spontaneously with two peaks in the age distribution: one at cariy infancy (infantile haetnangiocndotheUoiRa) and the other in late adult hood (fourth to sixth decade). The numerous synonyms render it difficult to estimate the number of reported cases and to determine its true incidence. In a recent review R&S 105211 58 W.K. Lelbacli and HJ. Manteller of the literature,Airenga (1975) listed 165 published cases of primin' angiosarcoma of the liver in adults. In the six autopsy series collected by Alrcnga. ASL constituted only 1 A% (Q9%-2.7%) f all primary malignant tumours of the liver, which of them* selves are rare findings in the Western World. Autopsy statistics show that the incidence of ASL ranged from 2 to 20/100 000 autopsies during different periods with a mean incidence of 12/100 000 autopsies (Table 12). According to Heath et al. (1975) it was estimated that in the United States the expected annual incidence of ASL is 0.014 in 100 000 inhabitants or 25-30 cases per year for the entire United States. Table 12. Incidence of angiosarcoma of the liver (ASL) in autopsy series Authors Observation N.o. of No. of cases Year period autopsies of ASL Region Simpson et al. 1955 1914-1953 24 196 1 Mayo Clinic, Rochester, Minn.. USA Edmondson 1958 1918-1954 52 000 MaeSween et al. 1973 1900-1969 _ a I 3 Los Angeles. County Hosp.. USA Western Infirmary Glasgow, U.K. Alrenga 1975- 1951-1973 39 700 6 Cook County Hosp. Chicago, USA Rein and Huth 1975 1954-1974 30079 Byrin and Holmberf 1975 1958-1969 _ b 4 (6) c Dtisscldorf, Fed.Rep. Germany 12 Sweden (adult cases) Dalderup et al. 1976 1960-1975 At least 40000 8 Netherlands (population: 10- 14 million) * Among 120 cases of primary malignant liver tumours studied post mortem during this 70-year period, b Among 8 million inhabitants. c 4 Angiosarcomas. I haemangioendothelioma, 1 malignant haemangiopericytoma Accordingly, the identification of 4 cases of ASL among approximately 270 em ployees of the vinyl chloride polymerization section at a BJ. Goodrich plant near Louisville, Kentucky, between September 1967 and December 1973 was duly recog nized as an alarming situation indicative of a serious new occupational hazard (Creech etal. 1974a: Creech and Johnson 1974). Until 1974, only two carcinogenic agents were known to be associated with the development of ASL in man,ix. the administration of a radioactive colloidal prepara Vinyl C tion of t inorgatudioxide i tern and Thor contrast ing evidi reported been the had been and Mon A special caused b;thorotra from a lc ASL (A Deve! man vine tensively 1950--1*> tion revtj of multip! approved occurred i but notah produced Haustrun1 (3%-s:Roth (19* 18.6-88 Fowler's s l igi< 33 >h,: fio i w! W urii --x rich g *13' N> * pr to ited i 18 >' of lit' observed' therhan ' 391 autop J. Mameller *''vcoma he incidence th a mean 1975) it was is 0.014 in imc. tr.Minn.. eles. Hosp.. USA Infirmarv . U.K. untv Hosp. ISA ft Fed Rep. ids urn: lillion) cm during ncytoma ' 270 era* intnear uiy rtcogrrd (Creech with the ial prepara Vinyl Chloride-Associated Disease 59 tion of thorium dioxide (thorotrast) for diagnostic purposes, and chronic exposure to iuur$anK anenicah. Both substances arc stored mainly in the liver: injected thorium dioxide particles are rapidly taken up by phagocytic cells of the reticuloendothelial sys tem and are permanently retained: arsenical* are only slowly released from the liver. Tnorotrsst came into use in 1928 and was internationally employed as an injectable contrast medium until the mid-1950s, when its use was abandoned because of mount ing evidence of the carcinogenic action of thorium dioxide deposits..UacMahon et al. reported the first case of thorium dioxide-induced ASL in 1947. Since then ASL has been the type of liver tumour which occurred most frequently among patients who had been given thorotrast injections in the past (da Sih a Mona 1967: da Silra Horn andMotta 1967; U'ege/rer et ai. I97l;futh andPiake l974;Selutgcr andKoff 1975). A special type of progressive portal and subcapsular hepatic fibrosis was another lesion caused by thorium dioxide retained in the liver, da Silva Mom (1967) considered this Thorotrast fibrosis* to be dearly distinguishable from true cirtiiosis. Gamma radiation from a lost radium needle has also been implicated as a causative agent in one case of ASL (Ross 1932). Development ofASL as a late complication of chronic arsenic intoxication in Ger man vineyard workers was first described by Liebejoti (1949,1952) and has been ex tensively documented by Roth (1956,1957a, b, 1959). During the 10-year period, 1950-1959, autopsies of 82 Moselle vintners suffering from chronic arsenic intoxica tion revealed ASL in 8 cases among a total of 61 individuals (74%), with cancer often of multiple sites (Roth 1959). In 1925, anenic insecticide sprays and dusts had been approved for use in German vineyards but they were banned by law in 1942. Exposure occurred not only via inhalation during spray periods (approximately 30 days/year) but notably by daily consumption of quantities of cheap grape wine (`Haustrunk*). produced from a second pressing of the grape skin residue by addition of water. This Haustrunk, an allowance in kind to the vineyard workers, had a low alcohol content (3%-5% v/v) but contained high leveis of residual arsenic (0.2-8.9 mg As-Os/Utre). Roth (1956) calculated the mean total ingestion of AijO* to have been 53.7 g (range: 18.6-88.8 g) for a 12-ycar period. ASL was also seen after tong-term treatment with Fowler's solution for psoriasis (Reckon et al. 1968:LanJer et al. 1975). Chowduty et al. (1977) reported an anecdotal case of apparently benign diffuse haemangtoendotheiiomatosis of the liver with considerable fibrosis and portal hyper tension but normal liver function. This condition was found in a middle-aged black woman who had been exposed to various chemical fumes (including carbon tetrachlo ride) during 20 yean in a drycleaning establishment, though it must be noted that she had a high alcohol consumption. The possibility that these symptoms could have been manifestations in later life of congenital disease cannot be ruled out. The proportion of patients with ASLin whom a pertinent history of exposure could be elicited has varied considerably. In an earlier survey of the literature covering the period 1875-1960, von Backer and Busscher (1961) fisted 12 of 54 adult cases with a history of exposure to either thorium dioxide (7) or arsenical! (5 ofRoth's cases). Among more than 15 000 autopsies performed in Bonn during 1950-1959, all 8 cases observed were found exclusively in vintners exposed to arsenical* (Roth 1959). On the other hsnd,.cVecAmcr and Ryes (1976) recently observed a duster of 4 cases among 391 autopsies during a 29-month period at a hospitai in rural central Wisconsin serving 60 W.K. Leibach and H.J. Marstellcr Table 13. Personal data of 68 polyvinyl chloride production workers with angiosarcoma of the liver reported to NTOSH up to August 1978 (Spinas and Kaminski 1978) Birth date No. Country3 (m/d/y) Dale of death <m/d/y) Age at death Total years exp. Job classification'' 1 B(l) 01-12.13 06.29.76 63 17 1.2 CND(l) 12.15.13 3 CND (2) 03.06.14 4 CND (3) 08.26.19 5 CND (4) 04.05.19- 6 CND (5) 05.07.11 7 CND (6) 12.15.19 8 CND (7) 11.09.19 9 CND (8) 05.13.20 to CND (9) 07.19.21 11 CND f 10) 05.16.15 09.02.55 1231.57 0332.62 0131.68 07.05.68 04.10.71 1234.72 06.12.73 09.04.74 04.00.77 41 43 42 48 56 51 52 53 53 61 11 1.2 14 2,3. 12.13 20 2.5 *m 1.2.5.14 5 1. 14 23 1,12.13.15 25 1.9.17 5 1.12.17 26 3.12.16 14 2.16 i: SR(1) 13 CSR (2) 00.00.28 00.00.26 14 D(l) 15 D (2) 16 D (4) 17 D (5) 18 D (7) 19 D (8) :o D (9) 21 D(10) a<* D(U) 23 0(12) 24 F(l) 25 F (2) 26 F (3) 27 F (4) 28 F (5) 29 F (6) 30 F (7) 31 F (81 32 F<9) 33 F(10) 34 GB (I) 35 CB(3) 06.04.30 07.2631 09.04JO 01.01.32 09.29.26 10.19.17 12.13.34 07.23.29 12.29.36 06.14J8 04.15.24 06.03.11 01.06.20 01.27.27 01.2938 04.1434 00.00.27 04.0134 10.08.14 05.24.19 04.20.01 06.0237 12.00.73 00.00.66 (64?) 45 40 (37?) 01.25.69 12.14.71 1135.74 01.09.75 11.13.75 1235.75 03.24.78 0638.77 03.07.77 10.07.77 38 39 44 43 49 58 42 47 41 39 02.19.67 0134.75 0636.75 01.03.76 05.13.76 09.12.76 07.02.76 0130.77 1235.77 0130.78 43 63 55 49 38 42 49 42 62 58 12.03.72 1234.74 71 37 16 15 (14?) 12 ii 17 12 12 21 15 22 16 6 1 1 1 2 2,4.5 11.(1) 1 10 10 10 I 19 1.2 12 2 29 i 26 2.6 II 1.2 13 6.7 1 19 1 28 2 21 *i *w 8 41 (3 1/2?) 36 1(2) 37 1(3) 11.1339 03.1430 1237.72 43 07.10.75 55 62 21 38 3(1) 39 3(2) 40 Nil) 08.0132 08.0239 12.23.15 rO.24,75 08.10.76 01.04.72 52 37 56 13 21 2D - CD at 0 01 ro a -to 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 3 B. fND CSK > f' GB b 00. d c I.ji 2, at. 3.pr 4, p.' 5, fC: 6,*fii 7. `p: 8. pr 9. clu (Tables ! referem. Mursteilcr ttitarcoma ' rication1' 12.13 !* . 13.15 17 . 17 . 16 Vinyl Chloride-Associated Disease 61 Table 13 (continued) Birth date No. Country3 im/d/yt*' 41 Si 1) 42 S (3) 43 S *4) 06.23.27 06.10.10 11.16.14 44 USA(1) 10.17.23 45 USA (2) 08.19J3 46 USA (3) 05.25.15 47 USA (4) 01.15.24 48 USA (5) 01.25.12 49 USA (6) 11.23.28 50 USA (7) 05.03.22 si USA (8) 05.06.20 52 USA (9) 11.08.31 53 USA (10) 08.16.13 54 USA (11) 05.27.09 55 USA (12) 11.17.18 56 USA (13) 12.01.21 57 USA (16) 11.04.27 58 USA (17) 05.06.31 59 USA (18) 04.22.28 60 USA (19) 00.00.15 61 USA (20) 08.31.17 62 USA (21) 09.02.09 63 USA (22) 10.02.23 64 USA (23) 00.00.23 65 USA (24) 05.07.17 66 USA (25) 08.07.10 67 USA (26) 7(1978) 68 YU (I) 04.05.14 Date of death (m/d/y) 10.20.70 03.19.76 05.12.77 Age at death 43 65 62 Total years e.\p. 18 21 31 Job classification' 03.03.73 09.27.71 12.19.73 01.07.68 04.09.64 07.24.75 03.23.68 08.28.61 03.00.75 05.10.68 03.16.70 05.02.69 07.04.74 03.27.69 1978 alive 11.02.75 04.06.76 01.30.77 01.02.77 12.04.76 04.06.73 05.27.77 C3.10.77 ?(1978) 49 37 58 43 52 46 45 41 43 55 61 50 52 41 43 46 60 58 67 52 50 60 67 7(1978) 21 13 28 IS 20 12 17 IS 24 17 23 19 28 4 19 11 22 21 21 28 14 26 20 7(1978) 9 9 10 10 10 10 9(1) 08.04.73 59 20 1,2.5 a B. Belgium CND, Canada. CSR, Czechoslovakia D. West Germany F, France CB Great Britain b 00, data not available. c I. autoclave cleaner 2. autoclave operator. 3. pipe fitter 4. potymerizer 5, foreman 6. Ultreur* 7. *prepantcur de solution' 8, process worker 9. chemical operator 1. Italy J. Japan N. Norway S, Sweden USA. United States of America YU, Yugoslavia. 10, polymerization wotker 11, technical asistent 12. maintenance wotker 13, millwright 14. water cooling unit 15.reaper -16, furnace operator 17, machine shop worker (Tables 13-15 are compiled with the aid or information contained in the literature; references we Table 15) y 62 ! W.K. Lelbach and H.J. Mameilcr Vinyl a population of 130 000. One of the four had a history of occupational exposure to polyvinyl acetate, which has hitherto not been related to ASL. The other three may have had nondocumented exposure to arsenical pesticides, which were used for many years in this region, but such conjectural deliberations must await further investigation for confirmation. Death certificates for the periods 1963--1973 in England and Wales and 1965-1973 jn Scotland recorded 41 cases of ASL (1 -9 cases per year: mean: 4 cases per year). An unexplained peak was observed in 1968/1969 (Baxter and Fox 1975). Six additional cases not mentioned on the death certificates were detected by a panel of specialists (Baxter et al. 1977). In reassessing 36 of these 47 patients for whom histological sec tions were available, the panel of histopathologists unanimously agreed on the diagno sis in only 14 cases (7 doubtful, 3 unclassifiable, 12 non-ASL). For 12 of these 14 cases occupational and residential histories were obtained which revealed one un doubtedly VCM-induced case, two cases with possible exposure to (low levels of?) VCM and one case attributable to thorium dioxide. After the first three cases ofASL among vinyl chloride polymerisation workers in the United States had come to the attention of the National Institute for Occupational Safety and Health (NIOSH) in January 1974 (Lloyd 1974), this institution continued to collect information on additional cases reported to them from nations with an im portant PVC industry (Lloyd \92S\Spinas and Kaminski 1977). As of August 1978, data had been presented on a total of 68 cases of ASL among polymerization workers (Spinas and Kaminski 1978, pets, comm.); another eight cases had been observed among nonpolymerization workers exposed to VCM in various jobs. On the basis of this data collection communicated to us in 1978 - for which we wish to thank Drs. R. Kaminski and/?. Spirtas, NIOSH, Cincinnati, USA -- we attempted to trace these cases and their individual symptomatology as well as other relevant information pub lished in the literature up to 1979 (see Tables 13-18). The ten Canadian cases of VCM-induced ASL (cases 2--11) are dealt with summarily in the papers published by Delorme (1978a) and Delorme and Makk (1975); seven of them were described in more detail by Makk et al.(1976). Cases 19 and 23 were observed at our clinic in Bonn but details have only been published for case 19 (E.U. in Lelbach and Manteller 1977). In reviewing the literature we could not trace cases 37--40,43,50,51,53-67 and C, F and H. According to the latest annual report of the Staatlicher Cewerbearzt, DQsseldorf (Reinl et al. 1978), the number of deaths from VCM-induced ASL in the Federal Republic of Germany had increased to 16 by the end of 1978, to which we now add a 17th case (Figs. 8 and 9). In retrospect, it was discovered that the first case of VCM-induced ASL had already occurred in 1955 in a Canadian polymerization worker. For the 67 VCM polymeriza tion workers for whom details were available, total yean of exposure ranged from 4 to 31 yean (mean and median 18 and 19 yean, respectively). In comparison, mean dura tion of exposure in our group of 17 individuals with advanced nonmalignant liver dis ease (see Table 11) was 10 3/4 yean (range: 3 1/2-21 yean). The latency period (yean from fint exposure to diagnosis of ASL) ranged from 9 to 38 yean (mean and median: 21 yean). The average age at diagnosis of ASL was 50 yean (range: 37-71 yean). . s ft c fi & * 9O 1 Si 2o e fomt O r* W g9 ' jnd HJ. Mannller * 3l5 I^ " * S' <a/S s s - | -p|ls r MihH3` lr 3 Vinyl Chloride-Associated Disease Tshlt 14. CHtifcal anti morphidogleal ilala in <iB polyvinyl chloride (I*VC) production winter* with angiosarcoma tif the liver reported to NfOStl by Aml 1971 IfepaloNo. megaly Spleen Omiphafiil Hepatic varices fibrosis Thromlto- Aeroeytopenia osteolysis Raynaud's phenomenon Mutaslases 1 Atrophic. () (29001) slightly inihtrated Noncirrbollc T perisinusoid al & capsular O' 0 0 Capsular 1 y 3 Capsular, portal. perisimisiiidsl 4 S it Team: <)- 7 > (IS60- S 200 yl . No details available a 9 Sderusis of wall of portal vein Capsular, portal, peristuusrtidal f Capsular, portal. perisinusitidal l [ Capsular, porlat. perisinusi tidal Portal, per nimisi ihlal No details available 1 rate: multiple melaslases (lulls, pleura, pericardium. lieuhi, colim, kidney*. left adrenal 1 l t rare: media*tinid lymph ' tunic - I rate: peritoneal sprearl .? laii r local *|ticad 10 Capsular, portal. perisimiM tidal II ) Capsular, portal. petisinnsuidal V HZ9QI SSfcf o t/f'i'Jv'i 'rC Table 14 (continued) Hepato No. megaly Spleen Oeiophageal llepallc varices fibrosis Thrombo cytopenia 12 4 Moderately (4) (7300 g) enlarted (Cirrhosis), * fibrosis 13 4(27JOg| ; 4 (Cirrhosis) 7 14 Spleno 7 7 4 megaly fS Slightly 7 7 4 enlarged U9I IIJ * 16 Spleno (2630 g) megaly (030 g) 4 Capsular, portal, septal 17 Spleno 4 4 * megaly IS 7 Perisplenitis 7 7 4 (134 000, 6S 000) 19 () Spleno (MSOgl megaly 1400 g> (*> Progressive . 4 perisinusoids), (SO 000, portal and 47 000, septal cfrririK)* 30000) 20 4 7 7 7 4 21 4 Spleno 4 4 7 (1900 g> megaly Armosteolysis 0 P P P P P 0 P 7 P Raynaud's phenomenon Mctaslases 49 0 Left lung P 4th tef) rib 00 P 1st thoracic vertebra P Brain 4 3rd luipbar vcrlcbra PP 44 0P W.K. Lalbach.and H.J. MameUer 22 4 Spleno megaly 7 Capsular, 4 0 P P portal, perisinusoldsl 81-3901- SSH 23 4 Spleno- 0 (2700 g) megaly (455 g) M *1 * Focal perisinusoidal r 7 f PP t* t 4 < | n ST 3O * * I* 20 7 1 7 r 7 f f 7 21 Spleno (1900 gl megaly ft* 3j*1* if 22 Spfcnonwtalr 7 2J Sfbau- 0 (2700 g) megaly (455 g| Capsular, t portal, pertslnusoidal IM pert- 7 sinusoidal f < e* snr 24 t 7 T 0 * Local spread to oral rein 3Cv.. 2S S3T 1161061 Partd, 4 perisinusoidat (60000, 4 > I MSOgi fibrosis 10 000) 26 7 7 7 Duodenal wall nP. O i* 27 Spleno (22JO gj megaly 7 Reticulated 7 capsular fibrosis, f s (400 ) microuodulat cirrhosis M SpknaMuly (650 g| Portal, peri* 4 sinusoidal, (10000) capsular (Omuls 4lh and 7lb thoracic rcrlehra. Sib left rib, left adrenal 29 tfodlficalinoa 0 (l7S0g) fibfo- Sbghl portal 0 Ithrosts t iungntlw' 20 Mfubual fibrosis 0 f Small intestine 21 Splenomegaly 7 (JOOO g) (270 g| 7 7 Paraaorlal lymph nodes 22 7 7 * (10000, t 40 0001- 22. 7 Capsular. 0 0 portal fibrosis L/t 6E.Z90I. S9U v---/' ^ :*'s- \4* * v4'-"*v W.K. Lelbaeh and HJ. Marsteller oxzsov Table 14 (continued) Hepato No. megaly Spleen Oesophageal llepalic varices fibrosis Thrombo cytopenia 34 4 Slight f P 4 (26251) splenomegaly (80 000) 3S Congested, 4 (3240 g) firm (200 g) Nondfthotic 7 fibrosis 36 7 47 7 Acroosteofysh 0 i f 37 31 39 40 41 42 7 43 44 Splenomegaly 7 77 Sptenumegaty 4 45 Spleno megaly 4 46 4 Spleno (I8601> megaly 7 77 V7 Snbcapsular 4 and portal fibrosis Markedly 4 thickened capsule; marked fibrosis Portal fibrosis 7 V 7 t i t Raynaud's phenomenon Metaslases 0i i0 t Local spread to abdominal wall and colon; lymph nodes 77 77 ff tP i Spread to duodenum 47 4 46 4 Spleno megaly a 7 7 Portal fibrosis SIifIII focal t 4 4 (35 000) t ff p t rf Spread to diaphragm and abdominal wall l imits, hree mil sm:ilt Vin>: U . Manteller Vinyl Chlonde-Associated Disease Mikcui) mAk'keiMtl marked fllirmh 7 Cuild fibrosis PrP f*t Spread to duodenum ? Portal + a / Spiead to diaphragm ami fibrosis 135 000) abdominal wall i? Slight focal * * i.tragi, large and mmall hepatitis bnwel, pleura, pericardium ('minimal Mynuliiim, kidneys, kqMlilM'l tell adrenal 7 Capsular and 7 P 0 Diaphragm, regional, retro portal peritoneal and mediastinal fibrosis lymph nodes, longs, Irena! glands, ccrebetlnm 7 Peculiar 7 4 - portal tihrosis, nioderate cirrhosis A Diaphragm, gallbladder, regional lymph mnles, lungs, sealp, skull 7 _________ (5I 0001 ff'___________ L 0k (3ZS01 S^U lPSgl" -- oI ,I *, 68 ) W.K. Leibach and H J Mar-teller Tabic 15. Publication! on the 68 cases of angiosarcoma of the liver listed in Tables 13 anil 14 No. References Additional relevant information 1 tfuA/eretal.(1977) Hypertrophic, hyperchromatic and aispical endothe lial cells in the glomeruli: foci of haematopoctic cells in liver and spleen Delorme and AfefcJt (1975) Afakiet al. (1976) Delorme (1978a, b) Delorme and Theriault (1978) Case no. 7: ASL associated with hepatocellular carcinoma (Delorme 1978b) (All cases from one plant in Shawinigan. district Trois Rivieres. Quebec) >= 1[ Schmidt and Bitom J3 !f (1976) 14 1| Lange etal.( 1974b) 15 ][ Gedigk ctal. (1975) 16 Gofce/ctal. (1976) 17 A menu (1975) Riibsamen (1976) 18 Reintet al. (1976) 19 (Observed in Bonn) 20 Reinltt al.(1976) 21 Reinl et al. (1977) 22 Reinl et al-(1977) 23 (Observed in Bonn) 24 JUvieret al. (1975) 25 Roche et ai.(l 978) 26 Rety et al. < 1976) At the same plant: 4 cases of VCM-induced cirrhosis of the liver plus 1 case of cirrhosis and generalized icticulosarcoma and 4 cases of carcinoma of the G! tract or lungs See also Reinl and Weber (1974) See also Reinl and Weber (1974) Foci of haematopoesis within the tumour areas 1974 portocaval anastomosis: cholecystectomy. Hypertrophic, hyperchromatic and markedly atypical endothelial cells in the glomeruli and-in the capillaries of the lungs Moderate hepatic siderosis: chronic fibrosing pancrea titis: tubular and interstitial fibrosis of the testes Focal interstitial fibrosis of the pancreas See also Berrod et al. (1978) 1942 gastrectomy. 1974 splenectomy, right hepatic lobectomy (640 g). See also Roche (1977): Rueeh et al. (1977);Bonneton et al. <1975.1977),Berrod et ml. f 1978) No autopsy (sec also Berrod et al. 1978) Vinyl ChiTable 15 u No. Rei 27 R* 28 Rot 29 Roi 30 31 32 33 34 35 36 Me. 37 38 39 40 41 By42 Bvr. 43 44 Bl. (ca- 45 Bio (ca-- 46 R&S 105222 eller 13 utlie* cells lm* ed 01 epical diaries MM* vatic eh t <d et Vinyl Chloride-Associated Dhok 69 Table 15 continueil)_____________________________ _____ No. References Additional relevant information 27 Roeht ct al. 11978) Chronic alcoholic. See also Roeht 11977): hitch ct al. f 1977); Retrod et al.( 1978) 28 Roeht et al. 11978) Pint symptom: vertebral and costal metastases. Right hepatic lobectomy. Sec also Roche 1101?): hitch et al. 1197?):KIiehowiki et al. (1979); Coudtre et al. (1976).Btrrod et al. (1978) 29 Roche et al. (1978) 1960 jcltmdtntulikt skin induration (hand*), swell* in| of face, upper extremities and feet. 1971 bilateral mcrootttolyat. Tumour penetration of the abdominal wall (fistula). Severe interstitial fibrosis of rearer; fibrosis of interstitial wall; slight mesangial fibrosis of giomtndl Variable but generally slight fibrohyalinosis of arterial and venous vessel walls (skin, heart, lungs, intestine, testes) 30 31 32 Retrod etal. 1.1978) 33 34 Let and Harry (1974) 35 Smith ct el. (1976b) Latency period (1st exposure -* death) only 8 years (sec also Fox and Coilitr 1977) 36 Meltoni (1974) 37 38 39 40 41 Bvritt and Hoimbtrx (1975) 42 Ryrrti etal. (1976) 43 Block (1974) (cam 3) 1965 portocaval shunt. 1970 cholecystectomy. See also fettet aL 0974a) (cam 4); Whelm et al. (1976) 45 Jfocfc (1974) (cam I) No autopsy. See also Crttch and 'Johiuon (1974); Folk ct aL(t974a) (cam 3); Mkettn et aL (1976) (cam JY.Umkk et at (1976) (case 6) 46 Block (1974) Sec also Platt et aL (1974a) (cam 5): Jiokk et al. (case 4)______________(1976) (cam 10)________________ ______ 70 \ * Table 15 (continued) No. References 47 Block (1974) (case I) . 4S Block (1974) (case 5) 49 Block (1974) (case 6) 50 51 -- 52 Whelan et al. (1976) (case 3) 53-67 68 Zotieaet al.(l975) I W.K. Lelbach and HJ. Manteller Additional relevant information See also Falk et al. < 1974a) < case 2):.Vekk et al. (1976) (case 4) See a)sofalk et al. (1974a) (case l);Afe& et al. (1976) (case 2) See also Falk et al. (1974a) (cave 6); Whelan et al. (1976) (case 4)\Makk et al. (1976) (case 14) - Chronic alcoholic. See also Makk et al. (1976) (case 13). Berk et al. (1976) (case 2) Among a work force of 180 (120, PVC polymerization; 60, production of VCM) employed at this plant. 15 died of malignant disease (2 ASL. 5 bronchogenic carcinomas. 1 case each of carcinoma of the larynx, rib. mamma, spermatic cord; glioma, meianosarcoma, leukaemia. Hodgkin's disease) First exposure to VCM for these 67 cases of ASL dated back to the period 19391966 (median; 1951). Twentyone years later, i.e. from 1972 onwards, a gradual in crease in the number of new cases diagnosed and reported to NIOSH can be observed (Fig. 7). The onset of this gradual increase coincides with the calculated mean latency period of 21 yean (Spirtas and Kaminski 1977). Spirtas and Kaminski also suggested that in future cases the age at diagnosis and the length of the latency period may in crease as a result of the later reduction in levels of exposure. From the synopsis in Table 13-18 it can be seen that in about two-thirds of the cases ofASL for which morphological details are available varying degrees of associat ed hepatic fibrosis in nontumorous areas ofthe liver were mentioned. Less often, evi dence ofportal hypertension and splenomegaly were noted. Metastasis of angiosarco ma to distant sites was obrerved in approximately half the published cases. It is of note that acroosteolytis and cutaneous stigmata ofscleroderma have been observed in only 1 of these 76 patients, a French FVC worker who had apparently not been engaged in reactor cleaning (case 29 ,Roche et al. 1978). Another noteworthy piece of informa tion is that strikingly atypical endothelial cells with hypertrophic and hyperchromatic nuclei have also been found in organs other than the liver (kidney's, lungs) in autopsy material Isom two patients (cases 1 and 17,Hubiet et al. \911\Riibsemcn 1976). Hubkt et al. (1977) also found such cells in the myocardium and in the adipose tissue enveloping the adrenals. All this may lend support to the idea that the effect of VCM metabolites is not restricted to the vascular endothelium of the liver and spleen. Angio- anteller ll. til. (care niuv plant, ogenic rynx. rcoma. I>39al in*-rved ttency 4 i the sodatn.evisarcoof note o only t*ed nfonnaomatie topiy ; time VCM . Artgio- (V 7 Vinyl Chloride-Areodated Disease "M Table 16. Personal data on eight cates of anpourcoma of the liver among VCM-e\posed personnel not employed in PVC production (at reported to NIOSH by Augutt 197113 Birth date No. Country i.m/d/y)D A D(3> 07.16.30 Date of death tm/d/y) 10.10.73 a D(6) 05.09.36 12.16.74 Total Age at yean Job death exp. classification 43 14 Loading pesticide cans with VCM propellant 38 33 Assistant factory chemist * X GB(2) 09.08.1 A 12.00.70 1 D 1(1) 06.15J4 04.16.71 55 36 11 , Pouring PVC oil mix ture onto fabric bases 3 Fabrication of PVC sacks and wnppinp (extrusion at tempera tures of 120*0 E 50 11.27.11 08.16.71 61 33 Assistant factory chem ist (production of VCM) F USA (15) 00.00.35 02.15.73 47 * Accountant at plant producing PVC fabric C YU (3) 11.15.31 07.12.73 42 18 Production of VCM H YU (3) 12.21.31 01.11.76 45 +o+ Production of VCM * Update of NIOSH register, August 1978. prepared by Kaminski as in Table 13. * 00. data not available sarcoma anting from the kidneys or other types ofmalignant renal neoplasms, how* ever, have not been described in VCM-exposed individuate, although malignant nephxoblastoma has been induced in experimental animals. The extremely tare coincidence of angiosarcoma and hepatocellular carcinoma was found in three instances (case l.Daiorme 1978b: case E,Byrin and Holmberg 1975, and a case not induded in the 1978 NIOSH update Tambutn et al. 1978a). In the case repotted by Tambwro et al. chronic alcoholism may have played a cofactor role in the development ofliver cancer. We can now add a fourth case obrerved in 1978 at the Department of Medicine fat Bonn (see Sect. 4.1.5 and Fig. 3). This patient (patient 9 in Table 1 i), a PVC-poiymerizinon worker (total period of exposure: 18 yean) was first admitted to our department in February 1975 and was found to suffer from atyp ical dnhotis of the liver with portal hypertension, splenomegaly and Raynaud's phe nomenon. During follow-up ASL was clinically suspected but could not be confirmed during life, despite exploratory laparotomy and generous surgical biopsies. The patient rTrV*.:.  * i i.? * .y-if'^i*. ..* '.'V ; i Table 17. Clinfeel and morphi CVC polymerization ' .f* ? data on eight cases of angiosarcoma of the liver among VCM-esprrsed pemmncl not employed in 14 Hepato Mo. megaly Spleen Oeaophageal Hepatic varives fibrosis Thromhucytopenia A Splcno- (6000 g) megaly Portal fibrmis B Splcno- (3650 g) megaly (425 g> focal capsular 0 fibrosis, porlal and centrolobular fibrosis Acroosleadysis 0 0 i IFi I Itaynaud's phenomenon 0 Diaphragm, gastric mucosa, abdmninal lymph nudes 0 Diaphragm, pleura, abdominal lymph nodes C D (> H p Not enlarged 0 T? 7 t y (104 0001 0 0 0 0 Lungs, pericardium y V, + ti Splenomegaly ? y * 0 4 Dura, cranium W.K. Lcibach and H.J. Marsicller gB ;S * S aE'32,s<3fi a $ & I ?. >> 2" F y ? a n r. g* , ? m OO >< S' lamcller ) Vinyl CKioniltiUiodand Disease 73 Table I8. Publications on the eight cases of angiosarcoma of the liver listed in Tables 16 and 17 X . References Additional relevant information A Rtinl and h'eber <19741 1967 idiopathic portal hypertension; portacaval shunt B Zimmtrmattn and Eck 1973 right hcmincphrectomy for unilateral hydro- t19751 nephrosis associated with bilateral double kidney. Rent/ (1975) Foci of hacmatopoetic cells in spleen and kidney. Fibrosis of the pancreas. Slight fibrosis of testes and of the small intestinal serosa c D Moitom < 1974> Autopsy; angiomatous epulis. Angiosarcoma involv ing liver, lungs and pericardium. The pericardium might have been the primary site! E Bytin and ttobnbcrg Probable coexistence of a hepatocellular cancer of f 1975) both low and high grade differentiation e G ZoHct et al. (1975) H - died on 7 August 1978, after a massive haemorrhage from oesophageal vaticcs. Autop sy revealed both multicentric metastasizing angiosarcoma and hepatocellular carcino ma of the liver as well as slight fibrosis of the pancreas (to be published in detail). It is stiD unexplained why hepatocytes are generally exempted from the carcino genic effect ofVCM metabolites bat, ss predicted by Copper in 1975, three anecdotal cases of hepatocellular carcinoma, one German (Gokd et al. 1976) and two British PVC worksn (Fox and Cottier 1977), have now also been observed after exposure to VCM. It may be mentioned that a review of the distribution of primary liver cancer in the Province of Quebec covering the period 1969-1972 showed a preponderance ofadult male cases in urban areas clustered in the district ofTrois-Riviere in congru ence with the distribution of the plastics industry, a coincidence which calls for further investigation ofa possible exposure to industrial carcinogens (Jacob and Thmult 1975). . Not included in the NIOSH register are several anecdotal ceres of ASL, capillary and cavernous angiosarcoma of the liver and haemangiosaicomatosis ofsites other than the liver, for which a relation to occupational or even possibly residential exposure to VCM has been dtecusred (Jtorta et L 1977;Brady et aL 1977;Xfer et al 1975; Mr#mtyer and Zinnagi 1977). Although ofundetermined relevance, it should finally be mentioned that, in addi tion to hepatic fibrosis, varying degrees of interstitial fibrosis of the pancreas were noted at autopsy in four German workers (cases 19,23, B and the above-mentioned !*ir*'. U 74 V.K. Lelbach and HJ. Marsteller patient with both angiosarcoma and hepatocellular carcinoma). Fibrosis f the testes was observed in three cases (19,29, B). and Roche et al. (1978) also reported flbrosis/ hyalinosis in vessels ofskin, heart, lungs and intestinal wall. CUMULATIVE N* OF CASES REPORTED TO NIOSH Fig. 7. Cumulative number of cases of ASL among PVC production workers reported to NIOSH up to August 1978, arranged according to year of diagnosis (data from Spinas and Kaminski 1977,1978) 4JJ Clinical Manifestations The clinical symptomatology ofusually multicentric ASL is unspecific. Gradually dedining general health and loss of weight combined with fll-deflned upper abdominal discomfort and slight epigastric or right upper quadrant pain are usually the first symptoms. Recurrent bleedings from oesophageal varices may have been antecedent events in patients with portal hypertension who otherwise fejt fairly well. In a number imcllcr Vinyl Chloride-Associated Disease 75 of caws, the tumour first came to attention with raassrvt. often fatal, intraperitoneal haemorrhage, tmportant tender hepatomegaly (hcpatospienomegaly), slightjaundice and occasionally development of moderate ascites and oedema were observed. Except for mild to moderate hyperbilinibinaemia, some elevation of serum levels of alkaline phosphatase and gmmaglutamyl transpeptidase and only slightly abnormal levels of serum transaminases, the spectrum ofbiochemical tests is hardly revealing. Alpha-feto protein determination has not been helpful in the diagnosis. Ultrasonography, scinti graphy,hepatic engjography and, notably, computer tomography of the upper abdomen ate the diagnostic procedures of choice if ASL. is suspected. A technetium-9*" -liver scan visualizes iatrahtpstie tumour defects (Bitnack et al. 1977b) together with abnormal splenic fixation, but peripheral defects of uptake may be difficult to interpret (Whdan et al. 1976). Characteristic features of angiography are a normal-sized hepatic artery with possible displacement caused by tumour enlarge ment. a certain degree ofcentral hypervascularity of the tumour, a peripheral tumour stain, and puddling of contrast medium persisting into the late venous phase. In addi tion, varying degrees ofpciioos hepatis may be obwrvtd in some eases. However, even repeated hepatic angiography may fail to confirm the suspected diagnosis, as was evi dent in one case reported by Roche et aL (1978). The example of a 54-year-old polymerization worker who died of metastasizing angiosarcoma of the liver in February 1980 may serve to illustrate die dinteal course. In 1972/73. after an exposure of 18 years' duration, we found him to suffer from Ray naud's phenomenon and nondnhotic portal fibrosis and portal hypertension with sple nomegaly and moderate thrombocytopenia. Despite termination ofexposure, there was progressive splenomegaly and development of massive oesophageal and gastric 76 W.K. Lelbach and HJ. Mantcller varices during the following yean with repeated episodes of bleeding which required (successful) sclerosing therapy (major surgery was declined by the patient). In August 1979 he presented again with recurrent epistaxis and slight but permanent epigastric and upper right quadrant pain, but declared that he felt otherwise fairly well. He com plained about a sharp localized epigastric pain on sneezing. There was marked spleno megaly, and an ill-defined hard mass was palpable in the epigastrium. Apan from mod erate elevation of alkaline phosphatase and borderline hyperbilirubinaemia, biochem istry was normal. Computer tomography showed a large irregular hypodense tumour mass in the liver, involving both right and left lobes (Fig. 8). which became practically isodense after intravenous injection of contrast medium. A liver scan corroborated the tumour defect. Shortly after this there was mounting evidence of brain involvement and rapid deterioration. Computer tomography now revealed multiple brain metastases (Fig. 9). Autopsy confirmed the tentative diagnosis of metastasizing angiosarcoma of the liver (Fig. 10). 'K1 Fil- 9. Computer tomography showing multiple brain metastases of angiosarcoma of tbe liver. See text. Courtesy of Professor Thum, Department of Radiology. University of Bonn 4JJ Peritoneoscopy Little information is available in the literature concerning the peritoneoscopic aspect ofVCM-induced ASL (Rocht et aL 1978). It may be impossible to make a diagnosis of the initial phase of ASL in VCM-exposed workers by peritoneoscopy and needle biop sy of the liver, as documented in one ofour patients who died of multicentric ASL X- 78 W.K. Lelbach and HJ. Mantcller 11 months after pctitoneoscopic diagnosis of severe hepatic fibrosis (case 19: see also Ltlbach and ManteUer 1977). In addition to the findings described in connection with hepatic fibroris, there may be hypervascularized or cystic tumour formation visible on the surface ofa nodular, quasi-cirrhotic liver, or a gross aspect resembling hepatic metastases if the vascular malignancy involves the superficial regions of the liver. It should be stressed here that needle biopsy is absolutely contraindicated if there Is any suspi cion of ASL. 43A Cross and Histological Morphoiogy The liver is usually markedly enlarged. Liver weight in cases of ASL ranged from 1600 to 7300 g (Thomas and Popper 1975 .Roche et al. 1978). The gross appearance oCangioaarcoma of the liver is mostly that oflarge bulky, irregularly shaped cystic tumour masses; a multinodular form with numerous, sometimes umbilicated nodules, is less often encountered. Extensive haemorrhagic and necrotic areas or solid and spongy por tions of tumour tissue replace much of the liver parenchyma. Rupture of large cavern ous cysts may cause fatal intraperitoneal haemorrhage. Thomas et al. (1975) and Thomas andPopper (1975) distinguished four basic devel opmental patterns ofhistomorphoiogy of ASL, which can be found in different por tions even of the same tumour and appear to represent stages of progressive evolution: sinusoidal, papillary, cavernous and anaplastic patterns. Indistinct areas of transition and merging of patterns can be observed. Dilated sinusoidal spaces lined by hypertrophic and hyperplastic sarcoma cells with pleomorphic, elongated, hypejchromatic and often bizarre nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells ofvarying differen tiation envelop liver cell plates and may invade enlarged and fibrosed portal tracts, ac companied by proliferation ofbfie ductules (Fig. 11). In papillary angiosarcoma atro phy ofliver cells results in larger and more irregular blood-filled vascular spaces, into which loose papillary strands ofsurviving hepatic cords on an axis ofconnective tissue project, lined by sarcomatous cells (Weinbrtn 1976). Even larger blood-filled spaces are seen in the cavernous type, where they may be surrounded by thick fibrotic walls. In a smaller percentage of cases,solid areas or nodules ofanaplastic sarcoma art found, resembling solid spindle-cell sarcoma, or even suggesting an epithelial type of tumour. Gtdigk et al. (1975) also observed a teticulosarcomalike pattern. The differentiation of the tumour cells varies widely: it ranges from the inconspicuous endothelial lining cell type to irregularly shaped, grossly distorted giant<ell forms. Morphologically, vinyl chloride-related ASL cannot be distinguished from ASL associated with other aetiological factors or from the cryptogenic type (Popper at al. 1978). In tumour-fret portions ofliven with angiosarcoma widely varying degrees of ex cess formation offibrous connective tissue are usually observed, analogous to that seen in nontumorous liven ofheavily exposed penons. Fibrosis ofenlarged portal tracts with modest proliferation ofbOe ductules, mostly only scant)' infiltration of lympho cytes and occasional formation of perilobular septa or thin connective-tissue septa ex tending into the lobular parenchyma can be found. A more or less conspicuous intra lobular. petisinusoidal fibrosis is often detected only by special staining methods for collagen or reticulin fibres. As a rule, irregular focal or nodular fibrotic thickening of V; ' * X & (/> CrJo1 w ro Ult nu. per Ins ft !>"* Thi ore Ufcr oidu t play. inci reti. eyu-f dego retii; r creav !I J Mantcllcr 19: sn also --Slsion with Wl(Me on 3cme> liter. It should isanysuspi- ti from 1600 to mce of snpoic tumour uies, is less id spongy por'large eavcm- ur basic develifferent porive evolution: >f transition oma cells with terize the ing difftren tal tracts, scarcomaattospaces, ssii** tissue n^^aces flbrotic walls. hm are found, of tumour, ferendation f ilal lining cell ally, vinyl other aetiol- agrees of ex>us to that seen octal tracts moflymphoscjesepuraicuous intramethods for hicfceningof Vinyl Chloride-Associated Disease f 79 Fig. I!. Angiosarcoma of the liver (upper part of photomicrograph) invading adjacent liver parenchyma (case 14* D1 ;sce Table 13). Note hyperplastic and hyperchronutic nuclei of proliferating neoplastic lining cells enveloping hepstic cords. Reproduced by permission. Ann NY Acad Sci 246:278-285 (1973). Courtesy of Professor Gedigfc, Institute of Pathology', University of Bonn. H A E. x 230 ofGlisson's capsule is present; these fibroue capsular areas may extend into the under lying parenchyma and may connect with adjacent enlarged subcapsular portal tracts. The cellular and midcar dzs ofhepatocytes may vary widely; groups of b(nucleated or even muitinudesr parenchymal ceBs with abundant cytoplasm are seen. Focal proliferation of dnmoidal lining edit may be encountered, especially within fod ofsinus oidal dilatation. In connection with conspicuous sinusoidal dilatation, two types of focal hyper plastic precursor Itztons were described by Popper et at. (1978); 1) Poorly circumscribed fod ofhyperplastic, often binudeated hepatocytes with incretsed number ofvarious sinusoidal lining cells and only insignificant increase of reticulum framework. 2) Almost nodular areas ofconspicuously hyperplastic and hypertrophic hepato cytes with more pronounced variation ofmarkedly increased sinusoidal cells without degeneration or necrosis ofliver parenchyma, but accompanied by excess formation of reticulum framework and compression ofsurrounding parenchyma. The transition ofsinusoidal lining cells to angiosarcoma cells is characterized by in creasing atypia and anaplasia of these proliferating endothelial cells accompanied cither ) so W.K. Lclbach and H.J. Maisreller by fonnation ofexcess connective tissue r by accentuation of sinusoidal dilatation leading to primary peliosis. Involvement of portal areas in the evolution of angiosarco ma results in considerable fibroplasia and fonnation ofhyalinized collagen together with proliferation of bOe ductules. In occasional cases connective tissue bridging be tween portal tracts or between portal tracts and central veins with subdivision of lobu les followed by teanangementofhepatocytic plates may lead to a cirrhosislike picture. 4JJ Therapy The multicentric development of ASL (Thomas and Popper 1975) as well as the dif fuse spread of the tumour usually encountered by the time of diagnosis predudes ef fective surgical or radiation therapy in the majority ofcases. A survival period of two years after surgery (fierrod et al. 1978) or chemotherapy (Dannaher et al. 1979) is a rare exception. Results of systemic chemotherapy studied in a small group of five pa tients showed that, at best, quality and duration of survival may improve to a very limited extent (Dannaher et al. 1979). At present, no generally accepted guidelines for chemotherapy ate available. 4Jjfi Risk Assessment When in the United States 13 white male cases of ASL had been detected from 1961 to May 1974,among an estimated total population ofVCM polymerization workers of roughly 20 000, a risk ratio (ratio of observed to expected cases) for this population of at least 400:1 was calculated (Heath et al. 1975). This calculation was based on data from the National Cancer Institute's Third National Cancer Survey (1969-1971), which expeeted for the total United States population an annual inddcnce of this tu mour in the order of0.014/100 000. This would have meant only about 0j03 cases per 20 000 polymerization workers within a 10-year period. Dose-response and attendant brofransformation data on experimental animals have since been used to elaborate sev eral different models of extrapolation to man. These were calculated with reference to relative body surface areas, for estimating the risk of ASL in human populations ex posed to VCM and for establishing guidelines to assist the research for `realistic safe doses* that do not affect the average lifespan ofa person exposed (Schnciderman et al. 1975: Gehring et al. 1979,1978: Woods 1979). Gehring et al. (1979) consider a probit percent model to be a reliable tod for risk prediction, which works without the assump tion of a threshold. They predicted a cancer risk of 1.5 cases of ASL in 100 000 000 workers on exposure to the current National Standard in the United States of 1 ppm VCM 8 h/day, 5 days/week, for a 35-year working life, an incidence which does not significantly deviate from the spontaneous incidence rate. A linear model modified by adjustments for differences in the rate ofinhalation, distribution, metabolism, cell proliferation and tumour latency times between rats and humans was described by Woods (1979).This model arrives at an incidence of3.9 cases per 100 000 000 workers after a lifetime exposure to 1 ppm. Much controversy, however, about the validity of risk extrapolation from animal experiments to nun and from high- to low-level expo sure and the problem of threshold doses has been voiced (Maugh 1978 -.Hooper et al. \919.Schnciderman 1979; Weigm I979:/?7r et al. 1979). Vin\ R. (excl. ASL This the l' conO' had d the re polyr was o< viron; ceedelesser magniting.c miUioi vinyl c model theesi grour. 4J.7 " 33*9 teller in' n eobuture. If- efwo is par sfor <61 ris of on of ita tu- ;s per Vinyl Chloride-Auooiated Disease SI Results ofa recent survey by Brady et al. (1977) indicated that for New York State (excluding New York Gty), a highly industrialized area, the annual incidence rate of ASL during the 6-year period from 1970 through 1975 was 0.25 per million residents. This considerably exceeded the national avenge rate of 0.14 per million per year in the United States. In a concomitant case<ontrol study. 26 patients with histologiealiy confirmed ASL were found in the study area from 1958 to 1975. and 7 of these had had documented long-term exposure to either As. ThO; or VCM. Five (all female) of the remaining 19 patients lived at a distance of 500-4500 feet from VC fabrication or polymerization facilities for long periods. No pertinent exposure or residential history was obtained from the other 14 patients. Discharge of unreacted monomer into the en vironment as result oflosses in the PVC production process was estimated to have ex ceeded 200 million pounds annually, most of which escaped into the atmosphere with lesser amounts dissolved in water effluent (Schweictr 1975). Concerning the older of `magnitude ofambient exposure beyond the work place. Le. outside the industrial set ting, an average annual exposure concentration of 17 ppb was estimated for the 4.6 million persons throughout the United Sates who resided within a 5-mile radius of vinyl chloride emission sources (Kuzmack and McCaufhy 1975). If the risk assessment model elaborated by Woods (1979) is applied to this population of4.6 million people, the estimated incidence of angiosarcoma per year would not be above expected back ground levels. 4.3.7 Mortality and Cancer Motbidity Studies For a tumour disease as rare as angiosarcoma of the fiver even quite small increases m hazard over background levels should be detectable (DoB1975). The situation with the common types of cancer is far mote difficult. Since 1974 a number ofmortality studies of VCMwxposed populations have suggested that in humans long-term expo sure to VCM may also be assodated with cancer ofrites other than the liver, notably the lungs, and the lymphatic and central nervous system (Monson et aL 1974: Ott et aL 1975: Tabershew and Gaffey l974;f/icholson et aL 1975; Msgo/ier et aL 1976:' WaxwtQcr et al. \9^\Nkhoison 1977;Baffler ti aL 1979). Epidemiological studies ofBritish workers failed to confirm this suggestion (Duck et aL 1975;Duck and Carter 1976;Fb.v and Collier 1976,1977). as did a prospective study of a VCM/PVOexposed cohort of 1618 employees of a West German chemical plant (FrcnttcLBeyme et al. 1978). Criticism of design and interpreation ofsome of the studies has been voiced (Folk et al. 1974b;AtfrAeje and Williamson l974;Rryer 1977,DaUerup 1975: Berry and Rossuer 1976). A follow-up of aO VCMwxpoaed persons (750 traced) ever employed at the one Swedish factory, which started operation in 1945, for mortality and cancer morbidity patterns tevealed a fourfouid excess of pancreas/liver tumours but no deviation in the number ofbrain tumours bom the expected level (B\-ren et at 1976). In addition to the three extenrive mortality studies ofTabenhew and Coffey (1974). Waxwcilcr er aL (1976), and Fox and Collier (1977), a fourth comprehensive epidemiological study (Reinl and Weber 1976) was completed in 1977 by Reinl et aL (1978). which induded three study populations from 11 VCM- and PVC-produdng factories in the Federal Republic ofGermany, covering the period from before 1959 A.- r` 4___ . 33 CD -Q D s: W.K. Lelbach and HJ. Mameller' through 1974: (a) 7021 worken engaged in the production of VCM and PVC;(b) 4910 chemical workers from the same plants not exposed to VCM: and (c) 4007 workers engaged in PVC manufacture. Not included were non-German workers of Mediterranean origin. This German study permits comparison not only with the mor tality ratio of the total male population but also with a comparable occupational group exposed to VCM. With regard to the healthy worker effect* (McMichaet et al. 1975), overall mortality was elevated for the VCM-exposed population (group a), but not for the other chemical workers (group b). Apart from the markedly elevated stan dardized mortality ratio (SMR) for malignant liver tumours (1523), which proved to have been closely related to the duration ofexposure, a significantly elevated SMR was found for tumours of the lymphatic and haematopoetic system (214). The group of chemical workers not exposed to VCM (b) also showed a significant elevation of the SMR for liver tumours (401), a result that deserves further investigation. No signifi cantly increased risk was found concerning tumours of the central nervous system or the respiratory tract. It has already been mentioned (Sect. 2.2.10) that an excess mortality from brain tumours (SMR 535) was recorded among PVC workers engaged in manufacture at one of two plants; in the second plant an elevated SMR (434) for liver tumours was found. At present, there is no explanation for the increased SMR for accidents found in the VCM-exposed population, particularly during the period 1970 through 1974, about 40$ of deaths having occurred in ex-PVC workers. A recalculation of the available data would have been necessary for the evaluation of a conceivable influence of VCM on vigilance. As an addendum it may be noted that determination of plasma carcinoembryonie antigen title (CEA) in 200 Canadian PVC production workers (mean duration of em ployment: 10 yean) showed a more than threefold higher frequency oflevels above 10 ng/ml than in a normal healthy population (1.7$ vs. 0.5%) {Page et al. 1976). Levels of CEA were also determined in 1363 worken offive different VCM polymeri zation (3) and PVC processing (extruaon) plants (2) in the United States (Anderson et al. 1978). After removal of possible confining factors (smoking, alcohol intake, past medical history), it emerged that the distribution of CEA titres among the polymeriza tion worken was significantly different from that in the extrusion plant group and in a nonexposed reference group. Significant differences were also found for two of six job categories examined (polymerization and maintenance) compared with extrusion woiken and the reference group. However, the usefulness of the CEA ritre as a predic tive indicator of possible increased risk seems doubtful. 44 Miscellaneous Aspects 44.1 Thrombocytopenia and Platelet Function Tests Thrombocytopenia in chronic VCM intoxication was fust mentioned - rather paren thetically and without further comment - in a paper published by Antonyttzhenko in 1968. Later Juhe et al. (1973) noticed that each of the fint 13 autoclave deanen re ferred to them during 1972 from a West German plant because of suspected skin and Vi bo Bo tio <*i we or. the del ph; tl. fab b. i up bar res: 1 u; cou of* in i al.tk JO U1 TO CO a> A B C D a pea: pte; litre hmi' Fix The eller 5r- 1. *ut ino was f c n me ild. e t lua i tic n- :n- * in x m iic- n1 in i* id I Vinyl Chloride-Associated Disease 13 bone lesions presented with mild to marked thrombocytopenia (30--119 X lO^ Titre). Bone marrow aspirates in 6 patients permitted exclusion ofdisturbed platelet forma tion or osteomyelofibrosis/sclerosis. but in 12 of them splenomegaly was found. Ex cept for slight reticulocytosis in 8 and leueopenia in 5 of the workers, other haematological tests were negative. The reduction of the number ofleucocytes and platelets as well as reticulocytosis appeared to be attributable to splenomegaly, but further studies on the nature of thrombocytopenia were thought necessary, and it was suggested by the authors that a decrease in the number of platelets might serve as an early and easily detectable symptom. The high prevalence of thrombocytopenia (as determined by phase-contrast microscopy) found later on detailed analysis ofplatelet function and other parameters of blood coagulation in the total cohort of PVC production (and also fabrication) workers from this plant strengthened this suggestion (Bachncr et al. 1974a, b. 1975a, b, 1976;Sthn-Bachner and Etzel 1977). Wepnan (1975) also commented upon abnormal platelet counts in 13 of37 PVC fabricating workers who had only handled PVC powder which, however, might have contained substantial amounts of residua! monomer. In contrast,iflti et aL (1975) detected thrombocytopenia in only 1 of354 polymerization workers, but an electronic ccQ counter was used for platelet counts (personal communication). According to Sehn-Bachner and Etui (1977). the mean platelet count in a cohort of 132 PVC polymerization (and processing) workers was significantly lower titan that in a nonexposed control group of ISO healthy men. As could be expected,Bachner et al. (1975b) also demonstrated a positive correlation between the degree of thrombo cytopenia and the prevalence of an enlargement of the spleen (palpable splenomegaly or spleen size determined by selective tomography with `*'-Hg-btomo-mercury-hydroxypropane-labelled red ceils) m 70 PVC polymerization wotkets (see Table 19). It ap- Table 19. Prevalence of enlatgemcnt of the spleen3 among 70 PVC-polymcrization worker* in relation to mcrcasini degrees of thrombocytopenia (Bachner et al. 1975a) Group No. of workers - Platelets (x 1 IT*/litre) examined Range Mean Enlargement of the spleen A 14 B 24 C 25 D7 > 130 100-130 70- 99 < 70 168 117 87 44 3(21*) 11 1463) 19(765) 6(6") As determined by palpation or by selective spleen scintigraphy. pears, however, that the development ofthrombocytopenia is not dependent on the presence ofsplenomegaly since we observed mild thrombocytopenia (100-120 x 10**/ litre) in a small number of workers in whom spleen size was definitely within normal Emits on selective spleen scintigraphy (Mnzfi5ehenindcx < 45 x 10** according to Fucher ana Wolf 1963). Thrombocytopenia was accompanied by abnormalities in platelet function tests. There was an increase in the number oflarge (> 10 pm) ^uvenfle' platelets (increased U"'-' 5T St-VSF CD <tSK (V *') *84 ) W.K. Lclbjvh anti HJ. Marsttller platelet spreading), enhanced response (platelet aggregation) to addition of ADP and collagen (Bom test) and increased availability of phospholipid-containing platelet fac tor 3 (Bodmer et al. 1975a). This pattern was thought to be compatible with the no tion of an increased turnover rate due to derangement of microcirculation (CD1C) in liver and spleen and defective reticuloendothelial system (RES) clearance of activated clotting factors (Bodmer et al. 1974b). Ward (1916) and Ward et al. (1976) suggested that thrombocytopenia could be construed as confirmatory evidence of an immune complex disorder. Hcuurmann and Srutte (1977a) noted unusual focal aggregation of platelets in klatsch preparations of spleen tissue and increased platelet pooling (plate lets trapped within the subsutusoidal meshwork of pulp cords) in the red pulp of the spleen on electron microscopy as well as phagocytosis ofthrombocytes by sinusoidal macrophages. $chqffncr*i al. (1976) found platelet thrombi in and around hepatic sinusoids in mice after exposure to VCM. A direct toxic action of VCM (or metabo lites) on the bone manow has not been demonstrated so far. Although the pathogenesis of thrombocytopenia in VCM-induced disease is not fully understood, it seems at present most likely that it is caused by increased turnover and consumption of platelets within the abnormal vascular spaces of the liver and spleen. A similar type ofconsumption coagulopathy was described as complication of spon taneous haemangiosarcoma of the liver by Trued et al. (1973). A haemostatic defect more complex than mere pooling and destruction of platelets in the enlarged spleen has also been commented upon in the paper by Gtrrin et al. (1974) in connection with splenomegaly ofvarious nondnhotic origin. . 4.4.2 Central tnd Peripheral Nervous System Miscellaneous nonspecific and somewhat indefinite symptoms have been described in connection with chronic inhalations! exposure to VCM in PVC-production workers, such as dizziness, disorientation, blurring ofvision and memory, headache, irritability, excessive fatigue and somnolence, sleep reversal or insomnia and other pseudoneur asthenic symptoms (Sudu et al. 1963, MS.Schottek \969:Lilii et al. 1975 and others). This ptenarcotic syndrome was interpreted as a manifestation of a potentially reversible ecute toxic encephalopathy. Its danger to the individual was thought to lie mainly in resultant inadequate reactions to critical situations (Schonck 1969). How ever, Vole et al. (1976) reported that several individuals in i group of 95 comparatively young ex-workers, the majority of whom had no other symptoms, complained of fa tigue. headache, listlessness and depression, with onset of symptoms having been de layed as long as 2 years after cessation ofemployment. With reference to such 'pseudoneuresthenic complaints', which may be interpreted a the mildest degree ofa toxic encephalopathy.Penin et al. (1975) examined a group of 21 autodive cleaners at varying intervals after cessation of exposure, all of whom presented with other (cutaneous, angioneurotic, hepatic) manifestations of vinyl chlo ride diseae. Clinical symptoms of a more or less distinct encephalopathy (induding cerebellar ataxia in 4) were found in all but one of them. EEC recordings were normal in only five of these patients; in the others, parenrhythmia, dyrenrhythtnia or a socalled subvigil electroencephalogram was observed. Evidence ofdistal polyneuropathy, found in 19 patients, was attributed in the first place to an abnormal peripheral circu- Vir 4.4. tinteller )Pand )IC)in :tivated giested nune ationof tplateof the midal paiic tabo- nor fully **rand ipieen. sponJefect pteen tion with bed in rears, jK' ntfaUy 'io lie Hownatively of fa st de- rrpreted group horn yicbloding normal > soopathy. idrcu- (i Vinyl Chloride-Associated Disease 85 Unon with resultant hypoxic damage. Tiie pathogenesis fa possibly VCM-induced encephalopathy is not dew. It would be conceivable that clinical and bioelectric alter ations found in some patients, in whom portosystemic encephalopathy could be ex cluded. may have been due to toxic or hypoxic brain damage. However, no other con vincing evidence has so fw emerged to indicate that chronic irreversible cerebiotoxic damage may have resulted from prolonged exposure to VCM. notwithstanding the pos sibility of an induction of btain turnouts. 4.4J Pulmonary Changes Tire suspected development of nonmalignant pulmonary changes due to VCM and/or PVC dust exposure is still a miner ofcontroversy. Soon after VCM was recognized as a potent carcinogen, three groups ofemployees (n * 290.250,445, respectively) from three large North American PVC-produdng plants (A, B, O, characterized by different duration and levels ofpast environmental exposure to VCM as well as to PVC dust, were studied with respect to chest x-ray film abnormalities and pulmonary function defects as assessed by spirometry and determination ofmaximum expiratory flow vol ume (Miller 1975;MUUr et aL 1975\LUa et al. 1975,1976,1977). All cates with pre vious exposure to asbestos, silica or coal dust had been excluded in these studies. Un expected linear, reticular and, less often, rounded opacities on chest x-ray films were found in about one-fifth of the two groups ofemployees from plants A (highest ex posure) and B (22.75, and 18J5, respectively), but fat only 43% of those from plant C, with the lowest exposure level. The prevalence of these radiological abnormalities, for which no pathogenetic explanation was available, was found to be significantly increased with longer duration ofVCM-PVC expoeure (more than 10 yean), but the pre valence ofa positive history ofsmoking, although identical in both groups A and B, was also found to be significantly higher in workers with abnormal chest x-ray plates. The overall prevalence ofa positive history of chronic bronchitis (British Medical Re search Council criteria) was 20.45far group A (highest exposure) and 162)5 in group B, although group B was significantly older. The somewhat higher prevalence of chronic bronchitis in workers with abnormal chat x-ay pitta did not attain statistical signif- On the other hand, age did not appew to be an important factor. Pulmonary func tion tesu showed a strikingly high prevalence ofobstructive changes, but since both smoking and age were related to changes in pulmonary function, it appeared difficult to isolate potential specific effects ofoccupational exposure to VCM and PVC dust. A restrictive pattern wn found in 9J5 ofgroup A and in only 22% ofgroup B, al though group A was significantly younger. In coodurion, this extenrive study, includ ing a total of985 workers expoad in the pot to VCM as weO a PVC dun, may point to a potential multiple factor effect ofsmoldng and VCM-PVC exposure. In this con nection,it is ofinterest to note that according to a cohort study of mortality among VCM polymerization workers the SMRs for respiratory oncer as wefl as for "other respiratory disease'were found to have been in excess ofexpected figures (156 and 176, respectively) (Mnrwetfer et aL 1976). Bronchopulmonary changes thought to be due to long-continued, intense expoeure to PVC dust were observed by several authors (Pvnteggiwt/ and Sent 19S5;Bwuasrd u 86 WJC. Lelbach and HJ. Marsieller 1969; Szaide et al. 1970; Verrkin and Mamontov 1970\Frongkt et a!. 1974:Darke l976;Anmtd et al. 1978). Considerable exposure to VPCdust is the rule in the drying, bagging and storage areas ofPVC-produdng plants. Photographs contained mKarstadi'i paper (1976) give a general idea of the potential dust exposure. Measurements of the concentration ofPVC dust at various sites of the bagging operations were reported as long ago as 1955 by Parmejgiani and Saai. In 1969 Broussard mentioned the possibil ity of development ofchronic bronchitis caused by the inhalation ofPVC dust. The insoluble and inactive dust particles were thought to accumulate in the lungs blocking alveolar spaces and being taken up by alveolar cells. This could lead to elimination of these cells via lymph vessels to regional lymph nodes, with either enlargement of the hilar region or a micronodular aspect ofinterstitial pulmonary fibrosis without hilar lymph node enlargement but progressive respiratory insufficiency. Szende et al. (1970) reported the case of a 31-year-old worker who presented with severe dyspnoea; a chest x-ray examination revealed diffuse micronodular pulmonary lesions. He had been engaged for only I year in shovelling PVC powder at a processing factory. Lung biopsy' revealed moderate diffuse fibrosis and small focal granulomatous lesions containing ovoid or polygonal birefringent foreign material which could be eluted by treatment with a known solvent ofPVC. Microscopic examination of PVC dust particles collected at the patient's place of wotk showed.them to be morphologic ally identical with the particles found in the patient's lungs. Another anecdotal case of pneumoconiosis after 23 yean of employment in a PVC bagging area, with radiologicalevidence of diffuse micronodular infiltrates and granu lomatous lesions found in a lung biopsy identical with those recorded by Szende et al., was published by Ammd et al. fat 1978. Histology ofopen lung biopsies fat 1 of 14 VCM-exposed British woriceis, who complained ofbreathlessness, revealed focal alveo lar wall thickening with macrophages in alveolar spaces and increased reticulin and col lagen on electron microscopy (Darke 1976). Although chest x-ray appearances were normal and routine respiratory function tests showed only slightly impaired C02 dif fusion in six individuals. perfusion and ventilation scans revealed strikingly abnormal pictures, ineluding marked perfusion defects of upper lobes. Darke pointed out that some of the men worst affected had been enpged In the polymerization of `plastisol', a very fine PVC powder with particle size around 0.5 ion. Selikoff(1976) called attention to results obtained by Frongia et al. (1974), who observed significant histopathdogical changes in the lunp ofguinea-pip and rats ex posed for 2-7 months to inhalation of the airborne PVC dust in a PVC bagging area. Lesions began to appear at 2 months ofexposure (alveolar histiocyte-macrophage re actions); they proved to be fairly marked after 4 months, with appearance of foreign body giant cells, and proceeded to development ofluge interstitial granulomatous fod. Vertkin tni. Mamontov (1970) who examined 96 workers engaged in the manu facture of articles made from PVC powder, also found a considerable proportion of them were suffering from functional and motphological alterations of the broncho pulmonary system, which they ascribed to their exposure to PVC dun. They quoted results ofearlier animal experiments conducted in 1963 by Golovatyuk and later by ShlyekhenkU. These lan authors tad apparently shown that exposure of animals to PVC dun may lead to the development ofchronic pneumonia and eventually to a sort ofmOd fibrosis of the lungs. Vi Sti M. al; tu ov f 4y erv. fdei pc 4.4 Th m; mu tif or ten Ml me |u w re; pO' 1 an fabdo tat h.v of an ms pb . Mannller is of the ported as e possibiian. The (blocking utionof it of the wt hilar sited with ibnonaiy processing uloinatous utd be ofPVC rpholopc- tinaPVC idgranunde ct al., of 14 'al alveo li and col es were piastisol*. r4), who ratsexug area, hage re` foreign atom manuuon of mefaoquoted later by Tiais to to a tort Vinyl Chloiide-Assodated Disease 87 Certain types ofPVC duR (one f two samples tested) were found to exhibit a strong haemolytic potential due to the presence of an undetermined but readily solu ble surface-associated agent which was not VCM (Richards et al. 1975). These authors also studied the effect of the haemolytic sample ofFVC duR on lung fibroblast cul tures. but they did not obtain any significant results. Contrary to earlier indications (Lange et al. 1974a) and despite continued efforts we failed to detect any significant restrictive changes of pulmonary function in the overwhelming majority of patienB we had occasion to examine. It may be ofinterest to note that Malmni et al. (1974b) reported a high prevalence of pathological changes of respiratory epithelium (squamous metaplasia, squamous dysplasia, typical and atypical adenomatous proliferation) in sputum samples from employees of Italian VCM-PVC factories. Nevertheless, contrary to the now wtil-established role ofVCM in the production ofnonmalignant lesions of bone, skin, small vessels, liver and spleen, it is still opes to debate precisely what importance can be ascribed to pulmonary changes within the spectrum ofVCMendueed disease. 4.4.4 Genetic Effects ofVCM The discovery of the carcinogenic properties of VCM also stimulated interest in its mutagenic potential. A number ofstudies have been carried out that demonstrated a mutagenic response to VCM or its metabolites in microbial test systems. Point muta tions due to base-pair substitution have been produced in various Rrains ofSalmoneila typhimurmm by VCM in the presence of animal and human liver microtomes as a sys tem of metabolic activation (Ranrmg et al. 1974,1976;Borsch at al. 1975a, 1976: A/eCannetal. l975;Maiareilie et al. \97$,Cairo et al. 1976). Mutagenicity of VCM metabolites was also demonstrated in yeaR strains (Loprieno et al. 1976.1977;57io/im 1976) and in mammalian cells (Hubeman ct al. 1975). b comparison to nonrxpoted controls, a rignlficfedy higher incidence ofchromosomal aberrations (fiagnMotation, rearrangement) in lymphocytes ofworkers occupationally exposed to VCM was re ported by Duattmm et aL (1975),FuttnGrueiom et al. (1975), Purchase et al. (1975, 1976), and fomenko etaL(197Q.f2e(g and Threw (1974) had failed to demonstrate increased rate ofchromosomal aberrations in six chemical engineers and four PVC fabrication workers. As to the influence on germ cells.Purchase et al. reported that no dominant lethal effects were seen in fetums of female mice mated with males which had been exposed to 3000,10000 and 30 000 ppm VCM for 5 consecutive days. This, however, does not absolutely exdude genetic effects on human gonads. The outcome of pregnancy among wives ofVCM-polymerization workers as against wives of rubber ud PVC&brication workers (Infante et al. 1976a, b) and rates of congenital malfor mation per 1000 resident live births in three Ohio communities with PVC production (dans have also been studied (Infanta 1976). As part ofa larger survey ofworkers' health, interview questionnaires (Infante 1976a. b) showed that after paternal age adjustment a significantly higher incidence of fetal mortality subsequent to paternal exposure was recorded among the wives of VCM^xpased workers. This trend was found to be maintained after elimination of 68 W.K. Lelbach and HJ.Mareteller pregnancies in women who had more than two abortions. The findings of this study raised the question of posible genetic risks of VCM to man and led to the suggestion that germ-cell damage in the father through direct VCM exposure might be a possible explanation. No clear-cut linkage of FVC production and increased occurrence of congenital malformations (primarily CNS malformations) emerged from preliminary studies in three Ohio communities with FVC production plants. But the need for further study of possible contributary factors was indicated (In/ante 1976). In fact, none of the par ents of affected children in Painsvflk, one of the three Ohio communities, had ever worked at either oflhe two FVC polymerization plants in Fainsville or lived within two miles of these plana (Edmondi et tl. 1975). S Conclusion and Outlook The combined efforts of multiple disciplines have been neeessaty to arrive at the full recognition of the range ofpathology associated with occupational exposure to vinyl chloride. It can only be hoped that the lesson from the vinyl chloride problem may help to bring about an increased awareness of the risks and hazards which are inevitably the consequence ofan ever-expanding technology. The importance of this lesson lies in its exemplary nature. A single substance of rather simple chemical structure, which was long held to be a comparatively safe com pound,even by experts, turned out after all to be a carcinogen with a very long latency period for those who were heavily exposed to it. But its carcinogenic properties would most probably still have gone unnoticed if the resulting malignancy had been any can cer other than ofan exceptionally rare type. Animal experiments in the early days later proved to have been broken off before the oncogenicity of this chemical com pound could have been detected. The lesson to be learned is that in future any new chemical which is to be widely introduced into the environment should be scrutinized closely, for a sufficient length of time, and with the aid of all available methods for the detection of potential car cinogenic effects. In addition, we should keep in mind that in industrial surroundings we almost never deal with a single compound, but with a very complex occupational environment whose carcinogenic potential is still a completely unresolved problem. If currently adopted guidelines for industrial hygiene are strictly adhered to, there is reason to hope that initiation ofnew cases of VCM-induced angiosarcoma of the liver can be effectively prevented. Unfortunately, however, it pan be expected that in view of the long latency period for tumour promotion additional cases will appear dur ing the next decade. Considering the ever-increasing complexity ofenvironmental influences, future re search will be faced with almost insurmountable obstacles in its endeavour to establish "safe' levels for potentially hazardous chemicals. Promising areas for further studies in the field ofvinyl chloride and allied compounds may be the problem of the interaction Vinyl Chlorv between pret' tissue suds as short exposu: will carry the References Albright LF11 AJbnght LF <, Albright LF (' Albright LF (: polyvinyl c Albright LFf i- processcs. Alrenga DP (! 198-203 Amann R (IS' der Leber. 1 Anderson H \ CEA amoi; 1560-156' Andrews AW.. properties Anghelescu F.' V(i969) r: empk 473Annual F Londc Antonyu, sian te Antweilet Peispei Amaud A ride pn Aryanpur Iran, i t Assmann F Austin GT1 87-89 Bachner U. 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