Document O3Z6mjba22ZJmQRwd0BJRZJBQ

4/ 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 23Tabellen /<?? Springer-Verlag " ~~~~---------- --------- -- Berlin Heidelberg New York 1981 Ylnvl Chloride-Associated Disease W.K. LELBACH and HJ. MARSTELLER 1 1 Introduction........................................................................................................... 2 2 Technological Details.............................................................................................. 2.1 Vinyl Chlonde Monomer (VCM).................................................................. 2.1.1 Hijtory................................................................................................. 2.1.2 Production oi VCM .......................................................................... 2.2 Production ot Polymyl Chlonde i PVC)...................................................... 2.2.1 Technology of Polymerization........................................................... 2.2.2 Method* of Polymerization................................................................ 2.2.3 Compounding ..................................................................................... 2.2.4 Source* of Exposure to VCM in PVC Production .......................... 2.2.5 The Explosion Hazard....................................................................... 2 2 6 The Odour Threshold '...................................................................... 2.2.7 VCM a* an Anaesthetic Agent........................................................... 2.2.8 Effects of Acute Overexposure in Man........................................... 2.2.9 Momtonng VCM Concentration* in Working Areas....................... 2.2.10 Exposure to VCM in PVCFroeessing (-Fabricating) Plants .......... 2.2.11 National Standards for the Control of Exposure.................. 2.2 12 Exposure to VCM Outside the Working Area................................ 4 4 4 5 6 6 7 8 S 9 JO 10 (I 13 jf 17 IS 3 Toxicology of VCM................................................................................................ 3 1 Acute Toxicity................................................................................................ 3.2 Chronic Toxicity.............................................................................................. 3J Onco^nte Properties...................................................................................... 3.4 Toxicodynarnics....................... `.................................... ............................... 3 4.1 Uptake and Distribution..................................... 3 *.2 Metabolism........................................................................................ 3.4.2.1 Relation between Chemical Structure. Rraeuvity and Mutagenic or Carcinogenic Effect............................... 3.4 2.2 Metabolic Pathways............................................................. 21 21 21 22 24 25 26 26 26 4 Clinical Spectrum................................................................................................... 4.1 The Triad: Raynaud's Phenomenon. Pseudoscleroderma and Acroosteoiysis................................................................................................. 4.1.1 Familial and Idiopathic AcroostcolyyU............................................ 4.1.2 Epidemiology of Occupational ActooeteolysU............................... 4.1 J Clinical and Roentgenological Features............................................ 4.1.3.1 Occupational Acroosceotysis.............................................. 4.1.3 2 Pseudoscleroderma.............................................................. 4.1.4 Histology............................................................................................. 4.14.1 Cutaneous Lessons............................................. 4.1.4.2 Bone Lesions....................................................................... 4. U Arteriography. Capillaroscopy. Infrared Thermography............... 4.1.6 Immunological Studies....................................................................... 29 31 34 34 38 36 38 39 39 39 40 42 1 Department of Medicine. Director. Prof. Dr. H J. Dcngler. University of Bonn. i-'RG * W K. Lelbach and H.J. Marstellur 4 1 7 Pathogenetic Considerations.......................................................... a - Non-malignant Liver Disease m Vinyl Chloride,'Polyvinyl Chloride Production Workers...................................................... 4 2.1 Clinical Mamlestations of Non-malignant Liver Disease ............ 4.2.2 Laboratory Findings........................................................................ 4.2.3 Gross Inspection oi the Liver and Spleen....................................... 4.2.4 Histology.......... 4.2.4, l Hepatic Fibrosis................................................................ 4.2.4.2 Sinusoidal Lining Cells...................................................... 4.2.4J Hepatocytes........................................................................ 4.2.4 4 Histology of the Spleen.................................................... 4.2.5 Pathophysiology of Portal Hypertension .................. 4.2.6 Follow-up of Non-malignant VCM-induced Liver Disease.......... 4.3 Angiosarcoma of the Liver........................................................................... 4.3.1 Epidemiology....,........................................................................... 4.3.2 Clinical Manifestations...................................................................... 4.3.3 Peritoneoscopy.................................................................................. 4.3 4 Gross and Histological Morphology................................................ 4.3J Therapy............................................................................................... 4.3 6 Risk Assessment................................................................................ 4.3.7 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......................................... 4.4.3 Pulmonary Changes........................................................................... 4.4.4 Genetic Effects of VCM...................................... 5 Conclusion and Outlook....................................... References.................................................................................................................... 44 44 43 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: Acroosreotysis - Angiosarcoma of the Liver - Portal Fibrous and Portal Hypertension - Pscudosclerodtrme - Raynaud s Phenomenon - Vinyl Otbhde 1 Introduction The history of vinyl chlonde-assodated disease, its 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 lhould 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 more modest rate. 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 chlonde (VCM), a rather simple aliphatic compound, was believed until the early 1960s to be Vmyl Chlonde-Assow one of the least harmf later turned out, had evaluation of acute eff to reveal its carcinoget. might have continued place, considering that vapour phase under an: reactive double-bond. Today vinyl chlorid formation and data on cisely a quarter of a cei tnbutabie to this new c with the shocking disci uon workers heavily ex ing that the monomer i pound did not alert the in workers engaged in t lished in 1949 (Tnbuki Ultimately, it was tl cuffed in workers expo a causal relationship: (I pseudosleroderma;(2) liver. Particularly, the d nancy among a compar alarming experience wl a connection between ' lunp or the gastrointe. the prolonged latency j sarcoma of the liver, ro these two fatal consequ the conclusion that V-, cancer meeting in Hous to VCM was a very sen It should be stress*, precise, an intermediate mainly in the mammiL merization products (P' cated from the polymet they contain unreacted PVC (thermal decompo toxicity of pyrolysis pn mainly due to the relear Abar 1969, Dyer andf and only very small or r (OMara et ai. 1971 cite Mareteller 44 44 44 49 50 51 SI *4 54 54 55 57 5? 57 74 76 78 SO SO 81 r s: S4 85 87 38 8<> T.IPartai / taxis is a uld help to 'mng rather liaDy hazardnt. this actcly for .iU develop >, a thermo* heftto itondc l>G0itobe Vinyl CiilonJe-Ai'ocuted Disease 3 one of the least harmful chlorinated hydrocarbons. Early animal experiments, as it later turned out. had indeed been earned out with dosages sufficiently high for the evaluation of acute effects, but chronic exposure had not been of sufficient duration to reveal its carcinogenic properties. On purely theoretical grounds, however, one might have continued to feel uneasy wuh this compound as a pollutant or* the work place, considering that itis (I) a halogenated hydrocarbon which (1) exists in us vapour phase under ambient conditions finlialauve exposure1 and (31 contains a highly reactive double-bond. Today vinyl chloride-associated pathology is well documented. A large body of in formation and data on this topic has been accumulated, notably sine* 1974, but pre cisely a quarter of a centuty had to pass before the full range of symptomatology at tributable to this new occupational health hazard became recognized is January 1974 with the shocking discovery that hacmangiosarcoma of the liver occurred in produc tion workers heavily exposed to PVC. Early and not easily 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 eviitst indication of advene effects in workers engaged in the production and processing of PVC, a Russian study pub lished in 1949 (Tribukh et al. 1949), received little attention. Ultimately, it was the exceptional chancier of tht three major lesions which oc curred in woricen exposed to VCM that contributed most to the final appreciation of a causal relationship: (1) the syndrome of acroosteolysia, Raynaud's phenomenon and pseudoslerederma: (2) non-cirrhotic portal hypertension; and (3) angiosarcoma of the liver. Particularly, the discovery of a duster of four cases of this extremely rare malig nancy among a comparatively small group of workers (Cretch et ai. 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, such as cancer of the lungs or the gastrointestinal tract, might still have gone unnoticed. On the other hand, the prolonged latency periods of both non<iRhotic portal hypertension and anposarcoma of the liver, roughly 10 and 20 yean respectively, delayed the recognition of these two fatal consequences of chronic exposure to VCM. But one can hardly escape the conclusion that Viola's discovery of cancer in experimental animate, presented at a cancer meeting in Houston in 1970, was sufficient evidence to indicate that exposure to VCM ws a very serioua occupational hazard (Ptttrs 1976), It should be stressed that the noxious agent is solely the monomer, or to be mote precise, an intermediate of the monomer's metabolic biosctiviation, which takes place mainly in the mammalian Uver and yields certain highly reactive epoxides. The poly merization products (PVC), i-e, the solid plastic and the plastic consumer goods fabri cated from the polymer, are chemically inert articles which carry no health risk unless they contain uni*acted residual monomer. Even the combustion of articles nude from PVC (thermal decomposition in Arcs) docs not yield free vinyl chloride monomer; the toxicity of pyrolysis products of polyvinyl chloride polymen and formulations Is mainly due to the release of hydrochloric add and carbon monoxide (Cornish and Abar 1969-.flyer andfscA 1976;5o/wuoff 1976t.Voser 1976;Coferfyn et al. 1976) and only very small or no quantities of phosgene derived from residual monomer (O'Man et ai. 1971 dted by Colatdyn et al. 1976). I #3 i&t 3?ss .1 2 Technological Details 2.1 Vinyl Chloride Monomer (VCM) w K. Lelhach and H.J Martfeller At standard (ambient) conditions of temperature and pressure, vinyl ddonJe (CH;" CHC1: chloroethylene, chloroethene) is a non-irritating, colourless gas with a faintly sweet odour, inflammable at concentrations above 3.37o by volume in air. winch 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 also employed as a propellant for aerosoles. It is easily liquefied under pressure and is usually handled and shipped as a liquid. Gaseous VCM condenses at -13.8C and 760 Tort ( 101.3 kPa) to a colourless liquid of low viscosity (Lefaux 1966). Its physical properties are listed in Table 1, the most important of which arc its low boiling point, its high specific grat ify (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. Pli\\ical properties of VCM Mol. wt.: Bp.: F.p.: Flash point: Limits ot flammability: Autoignition temperature: 62.303 '-13.8'C (-13.7 to -13.9) -- I53.78C -78.5*C (Cleveland open cup) 3.8" -29.3*7. by volume in air above -78.59C (- 38 000-293 000 ppm) 472*C Vapour pressure: mm Hg *C 10 100 692 2300 -87.5 -55.8 -15.8 20 2b60 *25 Vapour density: 2.15 g/litre (calculated at 25*C and 760 mmllg (air 1) Sp. gr. of liquid VCM: 0.9121 at -20*C/4*C 0.99 at --2S*C/4*C Sources: Fairhatt 1951, Irish 1963'.Zapp I964;e/aux 19b6:Osttrmartr |9n7, Roubal 1972. 2.1.1 Histoiy The French chemist, Regnault (1835) wu apparently the first to study systematically the synthesis and analysis of vinyl chloride. Liebig, who had done some earlier prelim* inary experiments, encouraged Regnault to investigate this compound when Regnault spent several months in Liebig's laboratories. All compounds containing the vinyl group (CHi*CH-) polymerize readily (Fairholl 1957). Spontaneous polymerization of vinyl chloride to a white opaque solid mass under the influence of sunlight was first described by Baumann in 1872; he also quotes a paper by Saytsev and Glinsky (who Vinyl Oil. succeed*.! izmg subst 2.1.2 Prou Large-jcaf by employ 1) Convert CH^CH 2) Convertchloroe: CHj-CI' CHjCl- VCM w Thus, any li tiom in the in the rang (IARC 19' when VCV mayor 196* in commer. l'J6; Osta In the c conjecrure.. retrieved Vi yses camew sum of all ii genates) w reacted moi in prepolyr the concern that even H methyl chic isobutane./, ference in p mil H.J. MjrMuiief I chlonde fCH;* ms with a faintly :n air. which :i Ijnla in ether and manufacture of 'to employed as a usually handled and rort ( 101.3 kPal ;roperti:s are listed i> high specific cravm water and the we -7S.J*C 1300 20 3660 t:s .i.J 760 mmHg rmtytr 1967; study systematically some earlier prelim* . lund whets Rtpault 'laming th* einyl .me polymerisation of f sunlight was fim - and Glinsky (who Vinvl Ciiofnic-AiiOtiJird Di-ca* succeeded hi decomposing vinyl chlonde to monodiiorouidehyde with the aid of oxid izing substances such as h> pochiorous acid. 3.1.3 Production of VCM Large-scale commercial synthesis of VCM with a high yieio was made possible much later by empio;-ing two principle methods, the second having now largely replaced the first: l) Conversion of acetylene to VCM by hydrochlorination: CHCH HC1-CH:<HCI (catalyn: HgCl. on charcoal) (Ausnn 1974) 3) Conversion of ethylene by vapour-phase or liquid-phase oxychlorination to 1,3-dichloroethane and subsequent pyrolysis (thermal cracking) to VCM (Albnght 196Ta;: CH;<H. -:HCJM'2 0- - CHjCl-CHjCIfHjO: CHjCI-CHjCI *8-C~i-'C - CH;-CHCI * HO pumice catalyst (pyrolysis; thermal cracking,>4usnn 1974). VCM was usually manufactured in dosed systems and stored in outdoor tacilities. 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 range 1-3 ppm. in dost proximity, the concentration ranged up to 50 ppm MARC 1974). Spontaneous polymerization in light has also been repeatedly observed when VCM comes into contact with atmospheric air due to container leakage (Ottermayer 1967). A prerequisite for the polymerization process is a high degree of putity in commercially produced VCM. Impurities retard the polymerization process (Lefitux 1966: Ottemayer 1967). (n the early discussion about the cause of vinyl chloride-associated disease it was conjectured that other compounds or impunries contained in prepolymenzation or in retrieved VCM might have been the causative agentfs) (Titten and 1`crsen 1974). Anal yses earned out by six West German manufacturers of PVC, however, showed that the sum of all impurities (such as saturated or unsaturated hydrocarbons and their halogenatet) was 0.015 by volume for prepolymenzation VCM and 0.1% for retrieved unreacted monomer. Only methyl chlonde was found in concentrations of 50-300 ppm in prepolymenzation VCM and 100-500 ppm in retrieved VCM (in one instance only, the 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 of only 0J ppm. All other impurities (propylene, isobutene,/>-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. c 6 W K. Lelbach and HJ. Marsteller 2.2 Production of Polyvinyl Chloride (PVC) 2.2.1 Technology of Polymerization The following description is meant to serve merely as a rough sketch of the procedures and technological details involved in the production of polyvinyl chloride. Vinyl chloride monomer is polymerized in large autoclaves (reactors) at tempera tures between 40*C and 80*C and pressures of 6--16 (8--12) atmospheres. Tiv-re are usually several reacton (up to 10-30) located in one building. The reactivity of the monomer is a function of its double-bond. The second functional site of the vinyl chlonde molecule, the chlorine atom, does 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 the body. The polymerization of VCM, 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 lauroyl peroxide, isopro pyl percarbonate, azo-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 (Malten and Zitlhuii 1964\Lefeux \966\Albright 1967 s--Q-Vomininghaus 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 polymenzauon. 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 50 000 to 150 000 daltons (Albright 1967b). Degree and velocity of polymenzauon, which are influenced by temperature and the concentration of initiators, determine the specif - type of PVC produced (Frey 1973). During polymerization considerable amounts of the monomer are 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 towardsthe end of the reaction.lt is terminated, depending on the method used, when approximately 80%-90% of VCM is polymerized. The timing of this termina tion of the process is essential for the physical properties of the resins produced. The heat generated during the exothermic proces of polymerization must be removed to keep the temperature of the reaction under control. Mechanical agitation aids in trans ferring the heat across the 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 slowly thickening continuous Him or crust. This polymer crust on the inner surface of the reactor vessel, which contains cavities filled with unreacted monomer, impedes the conductance of heat; it has, therefore, to be cleaned away after termination of the batch process (Barnet 1976). After completion of the polymerization process, the sluny is released from the re actor into a dump tank. Residual unreacted vinyl chloride monomer is partly solvated in the polymer (about 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 proximately 500 The sluny fre large enough to h axe then pumped wet polymer, a r drying methods, merization, yield fine solid particle drying temperau polymer. A eyde The solid polymi storage bins or si dried powder cot 2-2-2 Methods i Four different in PVC (Frey 1973 Suspension Poly> which monomer (such as polyvim conjuction with this method whi. Emulsion Polym was added in the except that large are added. Emul: emulsifiers canm Bulk (Mass> Pol\ the additon of o? The first reactor second one is use solid state, to ess reaches a level of characterized by good optical ciar H.J. Marsteller <1* the procedures >nde. >rs) at temperalitres. There are .acuriiy of the : of the vinyl lie-bond of YCM Iso the source of letabolized in the action (Barnes on free radicals at ! peroxide, isoproals ream with the .cal and thus prop-il. Chain growth is olves a reaction 4:Albrrpir 1967 li termination cnee different dehewg stausiically Jtam about pmerizaron, 777i. determine on considcrabie t>st of this it later which is not sot* ration slows the method used, of this tetmirans produced. The -t be removed to jtion aids in trans ire reactor. During ire to the walls of i his polymer crust >cd with umtaeted cleaned away after ased from the re* - is partly solvated phase or is present Vinyl Oilonde-Associated Disease 7 in the vapout phase above the slurry. Wliile a batch is in the dump tank, this unreacted VC monomer is retrieved by pumping it off into a VCM storage tank. Retrieved VCM is then puntied by subsequent distillation for 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: tius diffusion depends on time and temperature. Raw PVC resin, therefore, still contains certain quantities of unreacted monomer (VKE 1975 V Barnes 119761 reported that die polymer in the slurry- still contains ap proximately 500 ppm of vinyi chloride. The slurry from the dump tank is pumped into a storage unk (blend tank) which is large enough to hold several batches of the product. The contents of the blend tank are then pumped into a centnfuge which separates the wet solids from the water. The wet polymer, a granular mass, is dned either in routing tubular dryers or by spraydrying methods, the latter being used mainly for products formed by emulsion poly merization. yielding a polymer which is similar to a very fine white flour. These very fine solid particles ate fed directly into a spray-drying column without dewatering. The diving temperature should not exceed 60*C to prevent thermal decomposition of the polymer. A eyclon separator at the exit end of the dryers removes coarser particles. The solid polymer panicles are then sized by multiple-layer screens, air-conveyed to storage bins or silos and finally packaged for shipment (Albnfiu 1967d). The resultant dried powder contains about 50 ppm of monomer (Barnes 1976). 2.1.2 Methods of Polymerization 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 (such as polyvinyl alcohol, gelatin, substituted celluloses) under heat and pressure in conduction with brisk agitation. Relatively large polymer panicles can be obtained by this method which 'dry blend' well. Emulsion Polymerization is the older technique, to which suspension polymerization was added in the 1950s. The proces is simile to that in suspension polymerization, except that large amounts of emulsifying agents (such as soaps or other surfactants) are added. Emulsion polymerization yields resins of a very small particle size. The mulsifien cannot be completely removed. Bulk (Mass! Polymerization. In this process VCM is polymerized In two stages without the additon of other liquids. The two reactoa are operated batch-wise and in series. The first reactor (a `prepolytncrizcO provides for the initial liquid phase, while the second one is used for agitating the slurry, which is transformed, through s tricky solid state, to essentially dry particles uadi the conversion from monomer to polymer reaches a level of about 7555--305. The resins obtained by bulk polymerization are characterized by high purity and panicle uniformity, resulting in an end-product of good optical clarity. S W.K. Lcllui.li anJ fl J. \|jr=tiiL-r Suhitum PolymcnzattoH. This type of precipitation polymerization is carried out in organic solvents such as /t-butanc or cyclohexane. It accounts for only a small percent age of the total amount of all PVC resins produced and it is used for the production of copul} mere. Copolymers arc mixtures of comonomers (such as vinyl acetate, vinylstearate. vmylidcne chloride, propylene, acrylonitrile etc.) and vinyl chloride. The co monomers tend to improve flexibility and limited solubility of the product in solvents and exert an influence on the temperatures required for compounding. 2.2.3 Compounding As a next step, depending on the end use, the dried polymer, a whitish powdery or granular product, is then compounded (or dry blended) under pressure at fusion tem perature with the aid of plasticizers (mainly phthalate or other organic esters) and light and heat stabilizers (heavy metal salts, organoun compounds, and other stabilizers). Lubricants or dyes can be added. Plasticizets are added for the production of flexible PVC; ngid 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<ontaming stabilizers may also pollute the working atmosphere (Smuttic 1966; Tola 1975). Compounding is earned out by hot mixing at fusion tem peratures below or within the softening range (120C-160SC). Diversified compound ing and processing technologies were developed about 1950. The compounded polymers are used for the production of diverse end-products. The final conversion of the thermoplastic PVC resins into consumer end-products is accomplished by such procedures as extruding, calendering, injection or compression moulding, blow moulding, dipping (coating) and hot spraying. Temperatures used m these processes range from 100C 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 otT part of the small concentrations of residual monomer still contained in the polymer. Bamcs (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 of Exposure to VCM in PVC Production Both polymerization of VCM and subsequent processing (centrifuging, drying, screen ing, bagging) are usually earned out in dosed buildings. Exceptions can be found in hoi climates fAryanpur 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 arc exchangi of parts and repair jobs. Die degree of pollution also depends to a large extent on the quality and effectively of monitoring equipment and special exhaust systems. Opening of autoclave vats for cleaning and control purposes resulted in larger spillover of the tank atmosphere into the work en vironment. Numerous reports of workers with prenarcotic symptoms (dizziness etc.) Vinyl ( i permit t' in the p: Ther clave \ a: walls f`p tots, iuJ degassed and lar-.'i were opc ed the ft. tion still manly, t! those wi (centnfu ties of ;. ventilatu shipmer,' nomer. v are dnvc Table 2 I ppt* I mg fflrr; 1 mg/liti 1 mg, m' l ppm lri- 22S T In the nant mo> covers (Leftiux lect as a opened became) uCc- 044226 '.I-irsteller jut m 1 percent' >ction of -invl- fhe co,olvents r> or tan tern'i end light Vers), flexible Hiurce of ngon its sphere in tern* mipound- ducu. nets is m. ..ion in ii*. -if , ncammer -iiMincU i lined Vi'*) .screenand in that recnings id pollucrecof ttoring ; and work enaetc.) Vin> I C!iIcndc-4--ccuted Di<-ea* pennit the conclusion that episodes of acute overexposure to VCM were not rare events in the past. There is no doubt, however, that those workers who manually cleaned the auto clave vats by scraping away or chipping off the `poly mer skin' formed on the reactor walls ("pol> cleaners'). and who in the past haJ to spend several hours inside the reac tors. had been exposed to the highest concemtitions of VCM. Although the vau were degassed pr.or to entry, unreactea monomer remained trapped in rhe polymer skin, and larger amounts of VCM were released when cavities formed m the polymer crust were opened by chipping. The later introduction of automatic cleaning systems reduc ed the frequency of entry into the reactors, but some manual cleaning of shorter dura tion still had to be done after every 20th-30ih run. It is. therefore, plausible that, pri marily, the most severe adverse effects of exposure to VCM were fully recognized in those workers who had been employed in this job category. But the subsequent steps (centnfupng. drying, screening) also involve the release of some of the lesser quanti ties of unrtactcd residual monomer from the panicles 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 either slowiv 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. l ppm ; I 000 x 2a.a5 mg/litre 24.45 x 1 000 l mg per litre Mol. wt. ppm t/errr 1658) I mg/litre 1 mg/m* 1 prm * 2Jr> mg/m* r; sio ooo ppm J9J ppm 0.391 ppm 0.00256 mg,'litre 2S.6 mg'litn: Z2J The Explosion Hazard In the pst only' the explosion and fire hazard of VCM eras thought to be the domi nant monitoring problem in handling gaseous vinyl chloride (Irish 1963). This hazard coven a concentration range of 455-223 by volume of air (40 000-220 000 ppm) (Lefaux 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 budding 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 i ucc 04422'? A 10 W.K. Lelbach and H.J. Mantellcr States was almost completely destroyed when VCM escaping from a leak detonated (Albright 1967a). Another explosion in one of the two Rumanian factories operating at that time was mentioned bySuciu et al.(1975). Monitoring of VCM concentrations polluting the work environment was then directed largely towards preventing VCM from reaching the flammability limit. 1.2.6 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 was 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 of exposure. It should be kept in nund, how ever, that in chemical production units the presence of other odoriferous chemicals and the possibility of olfactory fatigue, as well as different levels of individual sensitiv ity, may render it very difficult to determine the factual odour threshold of a certain gaseous substance unless it possesses irritating warning properties. In 1929, Schmidt andSchaumam declared that the faintly sweet gas is practically odourless at concentrations of 5ft-10'S by volume. Veltman and Lange (1977a, b) assumed an odour threshold of 5 000-10000 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). Ctitring et al. (1979) recently mentioned a threshold of approximately 3500 ppm. Others have claimed that a concentrauon of 400-500 ppm is the lower limit for detection of VCM by its odour (Baretm et al. 1969; Cook et al. 1971 .Marko witz tt al. 197Z.Lcfcvrt 1975, cited by Hubtct 1975).Baretta et al. (1969) 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 21-6 ppm {Dtest 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 Sc/unonann speculated about using VCM 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. Od.. Lower limit i 5 000-10 00 5 00 4 10 3 50 5G` 400-50! 40. 40. anaesthesia be tic and lethal. oxygen; concc however, that eluded. In to' 10ft VCM to; several hours t commented u: mined about i, 3 J-5 mmol ( mmol (244 00 Oster et al., in cardiotoxicit> man because c like other hale amines (Irish i the past for ait 22A Effects Some individu listed in Table without acute symptoms sucl adequate warn exposure to hi; A 21-year-old. 10 min after et which had bee cardiac enlarge have been acut which occurs doubt that hea found dead wit  l.J. Mameller detonated * 1 operating nctntftttoni ling VCM ;nies. lu PVC gas*, which 'induction. . workers' re* al evidence . mind, howchemicals dual sensittv* f a certain < practically 15*7a. b t to VCM ppm for I sleepiness -.imately he lower l: Ujrk'Q[inducted lumber, in nut they differences : proximity * as reported on be as* inct warn* :eyt and t a concen- hmtdt and centra* oxygen Vinyl Chlonde-Avsoinated Disease Table 3. Odour threshold Lower limit ot detection i 000-10 000 ppm 000 ppm s ICO ppm 3 00 ppm 00 ppm 400-500 ppm 400 ppm 400 ppm Author felt-nan and Lanjt 1977a. b Viola 19 "4 /m/i 1963 Gehr.nf et jl 1979 Barttts t: ii 1969 ie/tvre 197J icitsd b\ Mubin 1973) Cook et al. 1971 Markout t: er al. 197; 11 anaesthesia because of its potent nareotic action and the wide margin between narco* tic and lethal concentrations. In animals it produced anaesthesia at 75-10% in air or oxygen: concentrations above 12% proved to be dangerous. The authors poinud out, however, that advene late effects of this halogenated hydrocarbon could not be ex cluded. In toxidty studies with guinea pip Patty et al. (1930) found concentrator of 10% VCM to be lethal within 30--60 min, 5% to cause marked narcosis, and 0.5% for several hours to be the maximum tolerable exposure without senous effects. They also commented upon the potential use of VCM for surgical anaesthesia but were 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) (Peaplct and Ltakt 1933). It was not until 1947 that Oster et al- in contrast to Sehmtmnn't earlier assumption (1934) of s relatively low cardiotoxicity, warned against the use of VCM as a potential general anaesthetic in man because of serious cardiac irregularities and ECG changes observed in dogs. VCM, like other halogenated hydrocarbons, sensitizes the heart to the tffect of catechol amines (Irish 1963). We could not ascertain whether VCM has actually been used in the put for anaesthesia in nun. 2--J Effects of Acute Overexposure in Man Some individual responses of volunteers to increasing concentrations of VCM are listed in Table 4. Leittr et tl. concluded in 1963 that the maximum concentration without acute effects in man lies betwsen 8 000 and 12 000 ppm for 5 min, and that symptoms such u dizziness, light-htadednes and disorientation should be taken u adequate warning signs for imminent acute danger. Two fatalities after occupational exposure to high concentrations ofVCM are reported in the literature (Dmtiger 1960). A 21-yesr-old autoclave cleaner 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 explosiometer test. Heart failure cells and cardiac enlargement found at autopsy, however, implied that the cause of death might have been acute functional disturbance in preexisting hem disease. In the second case which occurred at the same plant, however, circumstantial evidence apparently left no doubt that heavy VCM exposure was the cause of death in a 39-year-otd worker. He was found dead within 20 min, lying in a pit near the opened valve of a recycling pipeline i: W.K. Leibach anti HJ. Marsteilcr Table 4 Individual responses of volunteers to increasing concentration* of VCM Concentration 5 00 ppm Duration of Symptoms exposure Reference 7.5 h (Inconstant odour detection) Buretia et al. mild headache, dryness of 1I9b9l eyes and throat in 2 of 7 subjects 1 n.4 000 ppm 6 600 ppm 30 min Generally accepted odour threshold (Distinct odour) dizziness, sleepiness insi, i 196.-1 Insh i 19b3) 8 000 ppm \ 12 000 ppm J 5 min3 (twice on lb 000 ppm 1 each of 3 succes sive days) 20 000 ppm / 2 of 6 subjects `slightly heady' 1 of 6 subjects had reeling, swimming head, 'just like getting gas' 5 of 6 subjects, vanous degrees of intoxication All 6 subjects had more intense symptoms of acute intoxication than at 16 000 ppm Lester et al. (1963) 25 000 ppm 3 min 2 experimenters: dizziness, disonentation. burning sensation in the soles of the feet Pam et al. (1963) 3 Exposure to six different concentrations: 0 ppm: 4 000 ppm:8 000 ppni: I? 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 escaped. Two non-fatal cases of VCM gassing were reported in Great Britain in 1951 (Spinas et al. 1975). A maintenance worker experienced acute narcosis whde repairing a VCM leak, and a worker cleaning a polymerization vat from outside 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 Litis ct al. (1975) in 14 of 354 workers at Niagara Falls and by Sueiu et 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 (Waul et al. 1976), with a 100% incidence of narcosis in 28 symptomatic workers (Raynaud's syndrome and/or aeroosteolysis). Successful resuscitation after VCM-induced narcosis of several hours' duration with out evidence of permanent damage was mentioned by Rety et al. (1974). Vinyl ClUof- 2.2.9 Mont- During the fi ed data on V1 was directed an apparently 1954 .Pieshc Gronsberg to Russian poly: O.Q5-O.08 m centration of Inspectorate. or from the d mg/litre (* 1 i mg/htre (* 3- In the cet' air ranged fro ppm, which ventilauon. T trauons, sorm pursuit of imj meni in the vi ic drying facil centrauons oi continued to 1 nutted concer In a plant the range of 0 ppm (2.93 mg ication apparu remarkable th. the liver, althi past have prob Byrin et ai which occurrc cated peak exp between 1962 Rumanian PV< ab ut 120 mg> exposures to V 300 Rumanian Greek plant wl resulted in higl (Gitstos 1971). of the reactors up to 10 000 p J, Murscelirr VCM -jrcnte - ,;m <! si. *o9> it y ;96i> */i.(l963> >ur ft al. ;tv ft si. '03) we tank: iily just . 1951 {Spiral miring a vr%l >cr jet suddtnt tightness or u-utness was .md by Sueui occasion in rvciilauce ucidcnce of leolysa). ration with- Vinyl ChJonde-AiiiXuted Diseav: 13 2.2.9 Monitoring VCM Concentrations in Working Areas During the first two decades of PVC production (1930-1950) no publication contain ed data on VCM concentrations in the working environment. The main interest then was directed towards prevention of the explosion hazard. In 1957. the observation of an apparently toxic angioneurosis in Russian PVC production workers {Smirnova 19!*:P!cihe!iirscr et al,, cited in Fihtova and Grrmibcr? 195") induced F'hrovj and Gftnsbert to investigate environmental VCM concentrations in various yarn of a Russian poiymer.aauon plant in Gor'kij. Although most readings were m the range of 0.05-0.08 mg/Litri (> 20-313 ppm), e^. below the maximum permitted VCM con centration of 1 mg/litre (approximately 400 ppm) as specified by the State Sanitary Inspectorate at that time, escapes of VCM in the reactor areas from defective fittings or from the discharge of operating autoclaves resulted in excursions up to 29.5--A l .4 mg/Iitref* 11 500-16 200 ppm) lor penodsof 5-10 min. One peak reading of 87.3 mg/iitre (* 34 000 ppm) was recorded. fn the centrifuging and diving area of this plant the VCM content of the ambient ait ranged from 4 ppm to 3 100 ppm with most readings between 2Q ppm and 195 ppm. which was attributed to release of residual VCM from wet 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 diytng facilities, and avoidance ofleakages succeeded in reducing the ambient con centrations of VCM to below 0.05 mg/litre ( 20 ppm), but toxic angioneurosis still continued to be diagnosed. This led the authors to recommend tliat tiie maximum per mitted concentration of VCM should be reconsidered. [n a plant producing VCM, Filatov ct it. (1953) 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 result.u from spillage during sample collection. It is remarkable that up to now the Soviet Union has reported no cases of angiosarcoma of the liver, although production of PVC rccins started early and VCM exposures in the past have probably been in the same range as those observed in Western countries. Byrtn 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. Suciu ct ai. (1975) noted that between 1962 and 1972 a reduction of the avenge VCM concentration in the two Rumanian PVC plants had been achieved from 2298 rag/m1 ( 900 ppm) in 1962 to about 120 mg/mJ ( 50 ppm) in 1965-1972. In 1969, Ajrjf:elncu et al. mentioned exposures to VCM concentrations of 112-54} mg/ra* (44--213 Fpm) for a group of 300 Rumanian worfctn, eight of whom (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 (Ginios 1971). in air displaced from reactors 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 ppm were found. In open waste-drums into which waste polymer scraped ijrstetier -00 ppm ivl chlor.ons of n the liber-aor ' ;d to :id 4-5 hi mated ii followthe work- V a 9000- M muons ,'lubUt et itions motor !0 nun :tv In the er limit i'v use of Hive read* iiethods I* inside M releis'Pn ^50 by tie* lus period .'reports ). in a 11 occur* runs ad: (Torktl L-line for 'ensure* it units 1968 'iOO uestnsiMater T4). nes se al. 197S; ht*lcss * Vinyl Chloride-Associated Disease 1J than 50 ppm: (b) medium * 50-200 ppm: ic) high 200 ppm and above fup to 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 ar best on spot samples not necessarily representative of the different phases of a given operation. Estimates of past exposure leveis such as those represented in Tabie 5 are, therefore, more or less conjectural. It can be aasumed that considerable deviations from these average values have occurred all too often in the past. Table I. Average concentrations of VCM in the working atmosphere of PVC-producing plants4.! Estimated by Chemical Industries Assoeiauon Ltd.) 1945-1955 I9J5-1960 1960-1970 mid-1973 1974 1975 i- 1000 ppm '.400-500 ppm 1,200-400 ppm 1-150 ppm v 50 ppm and lea i- 5 ppm 4 According to Fltif and Thttu 1974\Bamts 1976 Equipment for optimal continuous multipoint monitoring of exposure concentra tions in the working areas should meet certain basic requirements: (1) For stanonary equipment strategically placed sample probes should yield data representative of indi vidual exposure levels in the breathing zone of workers, preferably to be used in com bination with personal samplers- (2) Analysing methods should have a high selectivity. (3) The limit of detection should be at least one order of magnitude below the current ly specified standard regulating the permissible upper level 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 of ambient VCM concentration comprise such analytical tools as long-path infrared spectrophotometry, flame ioniza tion detection, gas chromatography, mass spectrometry, eombustion<onductivfty ('ionoflux'), and personal samplen in combination with gas chromatography, none of which can at present be considered as abtolutaiy satisfactory for all individual plant conditions because they all differ with regard to selectivity, limit of detection 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 compiled in 1975 by Row*. 2.2.10 Exposure to VCM in FVC-Procmtiag (-Fabricating) Rants Raw PVC powder ready for compounding and fabricating purposes contains residual unreacted vinyl chloride monomer in varying amounts. In the past, monomer content i* 1(1 W.K. lelt'.K'h ami 11J Mjrstelier was reported to have been as high as 6000-7000 ppm (w/w) in some types oi` raw PVC, but a level of 500-1000 ppm probably was a more representative range (Sthwcirzcr 1975: VKE 1974:AaarcJr 1976). The monomer slowly escapes into the environment exponentially with time. depending on length of storage period, tempera* cure, size and porosity of particles and other physical properties of the polymer and. more recently, on the effectivity of special degassing techniques (Ptvcr 1976; Schut: and Wolf 1977). In 1975, the Association of the German Plastics Industry' announced that m 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 lest 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 \ Schut; 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 Bmdcr and Straby (1975). Apart from hot compounding, other ther moplastic operations, such as extruding, calendenng and welding of tiles, also resulted in release of unreacted monomer into the work environment. Although recently eonducted 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 1 -li periods now range below 0.1 ppm, numerous shon bunts with excursions up to 60 ppm during a w-orkshift were recorded in one instance (Schiir: and Wolf 1977). Similarly low concentrations of VCM in breathing zone samples (maximum: 12 ppm) with 60Tr of the values ranging below l ppm had been found in 1974 in nine United States fabricating plants, but source samples had ranged up to 340- 540 ppm (KantaJi 1976) . These present results, however, do not permit any conclusions :s to past leyeis of atmosphenc 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 siderably lower than in PVC-producing plants. When it was suspected that certain VCM-reiated symptoms might also have afflict ed PVC process workers, this problem was investigated by our group. Although no cases of acroosteoiysis, pseudoscleroderma 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 yean in compounding and fabricating units (Zwnge et al. 1975,1976a: Wcpmn 1975; Mantalter 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 worken was not considered suf ficient to entitle them to disability compensation under German law. Although the irv- Vinyl1 conspi spons quanti obsen progre male F find ar At twoG. died re' lation <. "health overall record. 2J2.1I 'X'C Manrcller vs of nw nnge ipes into-the , i4. tempera- ilymer and. -'76 :Sdwt: -v announced ; 0 ppm would ilogies tVKE iiich an now acted mono4 between 11 ion between - e which usu* <>mer and, rnt of residual '\mg process. c. other ther- also resulted acentJy coni\ German Is integrated -.cursions up Aolf 1977V 12 ppnu united *iKanu-Jt an levels of ' f mins was ling units. ,-!y assumed \been con- have afflict* 'hough no i -re observed, its lesions such -nis and slight I been era5.1976a: .-ntical with wage attributinsidered juf- hough the in- V'in>! Chlomls;-A*sociatcd Ui;ej'C I" conspicuous character of these lesions agrees well with the assumption of; dose-re sponse relationship of VCM-reiated disorders and the alterations may seem to be. quantitatively, oflittle importance, they should not be minimized. Nevertheless, an observauon period up to the present of almost 7 years did not reveal any spontaneous progression. In a proportional mortality study for 197Q~19T2 among roughly 35 000 male PVC fabrication workers in England and Wales. Baxter and Fb.v (19761 did not And an excess of angiosarcoma or other liver diseases. A recently completed cohort study of 4007 peopie who had been employed by two German PVC-fabncattr.g plants between 193d 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 tumours was recorded in one of the two plants (Reml et ai. 1973). 2.2.11 National Standards for the Control of Exposure Industrial hygienists have used several designauons for acceptable or permissible limits of exposure to chemicals at the work place, such as `maximum allowable concentra tion' or 'maximum acceptable concentrauon' (MAC), "threshold limit value' fTLV). "industrial hygiene standard* in the United States and as `Maximalt Arbetuplatxkon* zentrauon' (MaK) in West Germany. These empirical standards were defined by the Amencan Standards Association as setting a limiting concentrauon "for exposures not exceeding 3 hours daily during a 40-hour work week with the understanding that varia tions should fluctuate below this value" (Iroh I9o3). .An extensive discussion of the baste approach to the principles used in setting environmental quality standards for oc cupational respiratory exposure to toxic agents can be found in the paper of Zieihuis (1974). in this pip'v the conceptual differences between threshold limit values as used in the United States and maximum allowable concentrations as used in the USSR are summarised and the differences in 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 not an index of relative toxicity, far less of hazard, and certainly not a son of "average*. A standard tet as the ceiling level implies that any fluctuations should be around a median of perhaps half the standard and that it should be compe tently used in full awareness of its physiological basis and the limitations of currently available knowledge {Irish 1963). The standard will be subject to revision as soon as new information is available. An essential dement of the annually published German list of MAK values (MAK-Werte) is its preamble, which exhaustively defines the various modalities for the interpretation of such standards (Hensekler 1972/73). The swelled TWA, an integration over 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 teiow the standard. * In the Federal Republic of Germany the standard for VCM (MAK) was set at 500 ppm in 1966. The German Standards Advisory Gsmminee reduced this to 100 ppm X ; ** ( ucc 04423- IS W.K. Leibach and H.J. Marsteller in 1970 in conformity with the proposal ofTorkclson et al. (I960, which was based on the results of their animal expenments. In June 1974, when the carcinogenic prop erties of VCM had been well established, the MAK regulation for this chemical was re pealed and instead a preliminary technical guideline (Technische Richtkonzentration) of SO ppm was instituted (VKE 1975). The Chemical Industries' Liability Insurance Association (Berufsgenossenschaft der Chemischen Industrie) also issued instructions for the prevention of health hazards arising from handling of VCM in July 1Q74 As of July 1975, a technical guideline (TRK * Technische Rtciukonzer.nation) of 5 ppm. defined as annual mean, for PVC-producing and -fabricating plants was instituted, per mitting excursions up to 15 ppm during periods of not more than 1 h. In order to adapt operating plants, 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 (Vetunan 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 m 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 threshold limit values in a number of PVC-producing countries. 2-2.12 Exposure to VCM Outside the Working Area The Environmental Protection Agency estimated that PVC-ptoducing plants in the United States discharged about 90 million kg VCM annually into the environment (4^--S% 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 (IARC 1974). 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 live within 5 miles of monomer and polymer production facil ities in the United States an average exposure of 17 ppb during the yean of uncontrol led emissions was calculated (Nicholson 1977). In the past VCM has been widely used as an aerosol propellant, either alone or mix ed with fluorocarbons, hydrocarbons and inert organic gases, in household and cosmet ic products (hair sprays, deodorants, pesticides, room disinfectants, paint sprays, furniture polish and window cleaners). In Germany, VCM was proposed as propellant for aerosols in 1958 (Ouemayer 1967), in Japan it has been used as a propellant since 1958, in the United States this use was probably introduced after 1962 (Schweitzer 19751. Ax an aerosol propellant, VCM has been a possible source of exposure for the public al large, particularly lot women, the extent and the potential health implica tions of which arc unknown. Use of aerosol products in confined spaces has been re ported to result in air concentrations of VCM of up to 400 ppm in closed rooms, even after only short bums (30 s) (Gay et al. 1975). which could persist for several Vinyl Chi' Table 6. T Country Belgium Canada Finland France German D< Republic' Iran Italy Japan Netherland Rumania Sweden Switzerljn United Kii* USA USSR Federal Re; Germany Sources: S 73; (ARC R - md H.J. Matstsi.'er , which was based ; carcinogenic prop olis chemical was re.chikonientranoni lability Insurance 'ssued instructions 1 in July 19?*, As ntration I of 5 ppm. was instituted, per: t h. In order to Juction of the anmas of July 19?6 ppm. respectively ) as revised in 197? igjnally set at 500 nry emergency sun* mtarixed the conflictltid industry in 19"A, ! countries. mg plants in the the environment ^^>lved in water 19751 In a ^Kmbtent air near m and 100-200 ppm used were later >m these figures since side (Sc/rweirrer mer production facd* years of uncontrol* '.eitheralone or mixhousehold and eosmet>m, paint sprays, oposed as propellant "i as a propellant sine* r 1962 (Schueirzer of exposure for the 'iiial health implica1 spaces has been re in closed rooms. '-I persist for scvani I Vin>i Gilonde-Aj>ocuteJ Disease 19 Table 6. Threshold limit values iTLVV m various countries Country Year TLV ' ppmi Comment Belgium Canada Finland France German Democratic Republic (DDR) Iran Italy Japan Netherlands Rumania jd-; 1975 1975 1975 -- 1976 1976 1975 (future) 1970 1974 1975 1975 - Sweden Switzerland United Kingdom USA 1975 19?6 1975 (future) 1975 October 1975 19*7 April 1974 October 197* 1976 25 50 10/25 S' 10 25 200 * 12 25/50 50 125/50) 500 200 *10 10 100 mg,m* (40 ppm) 5/20 1/5 100 10 25/50 10/30 500 50 25 1/5 TWa 15 h/J5 mmt nVA (3 h/I5 min) TWAiS li;!J mint TWA 18 h/ MAC (Schotrtk 1969) IKonttzke et al. 197$) TWA <8 h/J h) TWA 18 h) (TWa 5 h. 15 min) MAC MAC (25 mg/m*) TWA (8 h) MAC (Prodan etii. 1975) TWA (8 h/15 mm) TWA (8 l'l5 min) MAC TWA (8 to TWAIS hf 13 min) TWA (penonal/ceiling) MAC (Amer. Conf. Govemm. Industr. Hygienists) TWA <$ hi. temporary emergen cy standard (OSHA) TWA (8 h). temporarily permit ted exposure TWAiS h,15 min) US5R 1 mg/litre (391 ppm) 30 rag/m* (* 12 ppm) MAC. provisional ceiling concen tration: State Sanitary inspec torate. 1957 (Filateta and Gronzbtrj 1957) MAC ISchortfk 1969; Ktttntr I97J) (Sanitarnyt normy) Federal Republic of Germany 1966 1970 June 1974 1975 1977 500 100 50 5/15 2/5 UAK MAK TRK (preliminary technical guideline). Annulment of MAK regulation. TRK (annual mean/1 h) TRK (annual mean/I hi Sources: Smyth \9Sb\Filerot* and G/ootOwrf 1957\Sckotrtk 1969: Heiuchler 1972/ 73;lARC Report 197Hatty I9?5;5fcb* l97J:frorf er al. 1975;Ar7tfpr Wf-.Sciiutz and Wolf 1977; MAK-Werte-Liste 19?7:/Termer I97S C :o 'V K. Lclbaclt and H J Mar\iclli.r Vinji Chloride-A^,. hours alter repeated spraying in snuller-sized rooms (IARC 1974), Haley (1975) pre c sented a list of pesticide products containing VCM as a propellant and registered for indoor use, which were banned in 1974 by the Food and Drug Administration. In Japan, the monomer was also banned as a propeilaut its |074 (JAMA 1974.229:S55). 3 Toxicology ol 3.1 Acute Toxicity There is a ease on record of a worker who died from uoncirrhotic portal hypertension and angiosarcoma of the liver after 14 years' employment at a chemical plant m south Dunng the first three ern Germany where he had been engaged in loading such pesticide cans (Rani and the assessment of the Weber 1974). The report of a female office worker suffering from typical Raynaud's concentrations varym phenomenon, pseudoscleroderma. acroosteolysis and mandibular osteolysis who never and I.eake l933.Sc/u had occupational contact with VCM (Mcyerson and Meter 1972) is apt to make one mattto etal. I960; Lt wonder what influence the frequent indoor use of VCM-propelled spray cans (Bridbcrd anaesthesia, deep narc et al. 1975) may have had in this unique case. Sputum samples collected from frequent this range of exposure users of pressurized spray cans who had no respiratory symptoms were found to con tive and haemorrhagic tain a significant excess of moderate and marked atypical metaplastic bronchial cells hepatocellular injury compared with twp groups of controls (Good et al. 1975). inducing substances (s 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 dnnks, hard liquor etc.). The content of residual VCM in PVC bottles was found to 3.2 Chronic Toxicity have ranged formerly between 5 and 400 ppm (w/w), and in PVC foils up to 800 ppm (nw; Exh and van Logttn 1975). The problem of migration of unreacted 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 m 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 xh and van Logrcn 1975: Davtci and Perry 1975). Data available in 1974 to a group of WHO expens revealed that samples of gin and wltisky had contained 0.57 and 0.62 ppm (w/w) of VCM respectively, after storage in miniature PVC bottles for periods up to 3 years; VCM concentrations in orange squash and cooking oil were found to be in the range of 0.01 -04)8 ppm and 001-0.04 ppm. respectively (IARC 1974). Levels of 0-0.4 ppm found in British PVC-bottled liquids were mentioned by Davies and Pern- (1975): in their own analyses of samples of PVT-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 I ppb level (van Lienp and Sick 1976: Drctzman and McFarreit 1977). It waa 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 ofO.l mg/person (IARC 1974). Schlatter(1976) calculated that today tt would be leu than 04)1 mg/person (equalling 250 mg during a whole life time); in comparison, he calculated that the inhaiational intake of VCM in diseased workers who had been exposed to concentrations of 500-1000 ppm during a period of 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 ptesent for the production of PVC food-packaging materials decreases the VCM content of food stuffs to below 50 ug/kg (50 ppb) even after prolonged storage (VKE 1975). Results of carcinogenicity assays in experimental animals after oral administration of VCM are discussed in Sect. 3 J. Torkelson et al. (1961) exposure to concenua: 4.5-6 months. All spc. however, caused an me histological changes in pigs and dogs. An incrc in rats exposed to 20 0` (1963); no histological Gor'kij Institute were n exposure ofexperimenmias. bradycardia, chan 04)5 mg/litre) for 5 mo creased secretion of cat posterior hypothalamus 3500-4000 ppm t9- 1C of the cortex and the ar comitant changes in cir, posure of rats and rabbi resorptive bone changes nervous system dysfunc; available evidence fot Vi VCM should be suspecte statutory maximal ailow critic Republic) should i Of particular import: Viola et al. 1971) with c. full year. It was only al'u II J. Maruelfer ^(1975) pre- rostered for iration .Jn 174.229:355). 1 hypertension plant m south* \Rcil and :al Raynaud's lysis who never 40 make one can* (Bndbont I trom freousnt found to con* ronchial cells iging Tood and J other soft as found to ,tp to S00 ppm J VCM from ' irts of un* stored in PVC re samples '*5.Dawes and Tihat samp'rs vvrively, after ns m m and ;:i British r own anal;, es i .uncentra*fVCM in mI3tc* 1076: ring the years al sourpe of Mure* could calculated '4 a whole .'M in diseased nj a period tsfthe present for tent of food* '75). Results n of VCM Vinyl CUIuniic-AKiicutcd Di'eaw 3 Toxicology of VCM 3.1 Acute Toxicity Z! Dunn; the first three decades of PVC production, animal experiments were limited to the assessment of the acute inhaiational toxicity of VCM .n short-tenn exposures to concentrations varying between JO 000 and -00 000 prm f/V.v. et ai. 1930.Peoples and Leak* 1953:Sdtaumaiui 1934.1938;Oi:cr et al. 1947, Cam et ai. 1949:Mastromncn et al. l960:esrer et ai. 1963). In mice. rats.guinea-pigs, rabbits and dugs anaesthesia, deep narcosis, cardiac arrhyrhmias and lethal effects were observed within this range of exposure but no relevant utpn pathology was noted except for conges tive and haemontugie changes in lungs, liver and kidneys on fatal outcome. Acute hepatocellular injury w-as later found only in animals pretrtated with potent enzymeinducing substances (see Sect. 3.4.2.2>. 3.2 Chronic Toxicity Torkelson 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 4 months. All species tolerated exposure to 50 ppm for 6 months: 100 ppm. however, caused an increase in liver weight and 200-500 ppm caused, m add:non, 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 Lester et al. (1963): no histological lesions were found after 3 months. Soviet investigators at the Cor'kij Institute were mainly interested in neuroendocrine changes after prolonged exposure of experimental animals to various concentrations of VCM. Cardiac anyth* mias. bradyaardia, changes in phonocardiognm in no exposed to 12-20 ppm (03230335 mg/litre) for 5 months were reported (Term and Pfokltava 1969b) as well as in creased secretion of eateeholanunes in rabbits and changes in the biopotential of the posterior hypothalamus (Vam and Phkhova 1969a). After a 5 Jmonth exposure to 3500-4000 ppm (9-10 mg/litrt) changes in the bioelectric activity (EEC recordings) of the cortex and the amenor and posterior hypothalamic nuclei in rabbits with con comitant changes in circulatory functions were seen (farm and Pbktwa 1968). Ex posure of rats and rabbits to 03)3-03)4 mg/litrt (12-16 ppm) for 6 months produced resorptive bone changes and osteoporosis in addition to cardiovascular and central nerraus system dysfunction (8atalatr et al. 1972). In 1969 Schontk summarized available evidence for VCM toxicity and warned urgently that chronic exposure to VCM should be suspected of causing toxic liver damage. He moved that the currently statutory maximal aiiowible concentration of 200 ppm (MAC value. German Demo cratic Republic) should be lowered. Of particular importance as pioneer work were llnla't experiments (1970a, b: IToto et ai. 1971) with exposure of rare to 30 000 ppm, 4 h/day, 5 days/week, for a full year. It was only after this length of exposure that Itistopatholugical examination UCC 044239 21 . W,K. Leibjch anti H i. Martteller revealed lesions similar to human acroosteolysu and also similar 10 the type of nontumorous liver diseases which we observed m PVC workers 3 years later {Manteller et al. 1973). Viola described lesions of the skin, the small arterial vessels, the connective tissue and elastic reticulum of the paws, and periosteal proliferation with chondroid metaplasia of metatarsal bones. Fibrosis of small peripheral nerves and degenerative changes of the grey and white matter of the brain were prominent, w hereas 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 fibrosclerotic reactions. 33 Oncogenic Properties The earliest documentation of the carcinogenic action of VCM was Viola't preliminary report presented 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 epider moid earemoma, mostly in the paraauricular region; 6 also developed adenocarcinoma of the lungs and 5 osteochondroma of metacarpal and metatarsal regions of all 4 limbs (Viola et al. 1971; Viola 1974).Maltoni and Lefemine (1975) later interpreted these paraauricular tumours is arising from the sebaceous glands of the exterior acoustic duct, also known as Zymbal's 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 metastases from the Zymbal gland tumours. Autoradiograms of sections of whole rats dosed orally with [t4C]-labeiled VCM revealed a discrete localization of 1 *C in the paraauricular region (Zymbal gland?) and in the region of salivary glands and Harder's glands (iGreen and ffatltway 1975). In this contextAeumarm et al. (1979). who analysed the peroxidase activity in Zymbal glands of Wistar rats, proposed the concept that peroxidase-mediated bioactivation of carcinogens (in their study: stiibene derivatives) might offer an explanation for these tissue-specific effects. At the end of 1970 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 bioassay designed to study the effects of chronic exposure to VCM in relation to various experimental factors such as route of administration, dose level, length of treatment, and species, strain, sex and age of animals (Maltoni 1973, 1977'.Maltoni and Lefemine 1974a, b, 197$ ;Maltoni 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 ma lignancies developed, notably angiosarcoma of the liver but also extrahepatic 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 of VCM dissolved in olive oil (5 days/week) angiosarcoma of the liver was found after 50 weeks in two animals of the two groups of 80 Sprague-Dawley rats each of which had been treated with the highest doses of 50 and 16.65 mg/kg body wt. (Maltoni et al. 1975). Maltoni (1977) succeeded in demonstrating that the route of administration of this dearly multipo- Vinyl Chlo ten tial care study of or solved in so 6 days/wee: ratio only a tion not ne, placed the i the no-toxii angiosarcon Sprague-Daproved to h genic in rat.be carcinog 10,5 and 1 1979). Ano the dose-rel exposure lehistological the liver am the inducric posure to 1( al. 1974b; 1, endothelial pcrplasia an even in the: was scanty: doses. In thi fibrosis was of ossifying feet was sug, offspring of mine 1975). posed to VC ed from Grit it was seen i. maturity of to 2000 pprr foci of hepa; Holmber week, for 52 spleen chang mils expose, cutaneous at ppm group a i See also l< 1^*1 mem in ucc 044240 ; irtieiler lertt lii-'cuve Jroid itrve kid''-ions oroiiier* limmary in May cpiderrcinoma 4 limbs ! these -tic target us- .iiJig.-cnons `'ion of :.U979). --sit. * te a ,.>sure aiion. `rttttni '<). Con** tno. J00. -non pen* ther ma* angioi watt as -s were J in olive animals 1 with tht it^TT) -iliipo* V'inv I Chlonde-AssociateJ Disease tenuai carcinogen may significantly vary the type of neoplastic response. In a subacute study of oral VCM toxicity, lasting only 13 weeks, in which rats were given VCM dis solved in soya bean oil by gavage in daily doses of 30.100 and 300 me,`kg body wi.. 6 days week, fzron <: al. (19~5) found a significant increase in liver-to-bouy weigiit 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 et al. placed the oral no-toxic<ffect level at 30 mg VCM/kg body wt./day and suggested that the r.o-ioxic<iTect level may actually be even higher. Zymbal gland carcinoma, hepatic angiosarcomas and nephroblastomas had never occurred spontaneously in the breed of Sprague-Dawley rats used ai the Bologna Institute. The neoplastic response to VCM proved to have a direct Jose-ume relationship. Even levels of 50 ppm were carcino genic in rats and mice. LaterMaUoni (1977) found exposure to 25 ppm VCM also to be carcinogenic in rats, whereas no carcinogenic effect was observed at lower levels of 10.5 and 1 ppm in a study which, however, is still incomplete (quoted from Gncmte 1979V Another American study designed to complement.Wafrow's results confirmed the dose-related induction of liver angiosarcoma and mammary carcinoma in mice at exposure levels of 2500,200 and 50 ppm (Ktplinger et al. 1975). On reexamining histological slides of his past experiments. 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, 4 h/day. 5 days/week, for at least 15 months (MaUoni et al. 1974b; IARC 1974V MaUoni and Leftmint (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 of endothelial ceils also in organs and tissues other than the liver, even in tht absence of angiosarcomas or benign angiomas. Evidence of hepatic fibrosis was scanty and inconstant in their animals and was more likely to occur at the lower doses. In the spleen of treated rats and mice fibreanpoblastic proliferation undergoing fibrosis was frequently observed. No acroosteolytic lesions were found, but a few cases of ossifying angiosarcoma were observed. A potential transplacental carcinogenic ef fect was suggested in 19^5 by the development of subcutaneous angiosarcomas in the offspring of breeding animals exposed for 7 days during pregnancy (MaUoni and Leftmint 1975). Later, MaUoni (1976) detected angiosarcoma in the offspring of rats ex posed to VCM during the period between the 12th and lSth day of pregnanes' (quot ed from Griciutt 1979). Hepatocellular carcinoma was not found in seult animals but it was seen to develop readily in newborn animals, possibly In connection with the im maturity of their bioactivation pathways 0MaUoni 19'T7V Exposure of newborn rats to 2000 ppm VCM, 8 h/day, 5 dayj/wesk, for at least 4 weeks elicited prencoplastic foes of hepatocellular ATPase deficiency, notably in female animals (Laid et al. 1979). Hatmbcrg et al. (1976) exposed mice to 50 end 500 ppm VCM, 6 h/day, 5 days/ week, for 52 and 26 weeks respectively. The)* did not observe hepatic fibrosis or spleen changes, but multiple benign alveoloftnic adenomas developed in 13 of 24 inimals exposed to SO ppm and in ail 24 animals exposed to 500 ppm*. in addition, subcutsneois and/or subperitoneal ivaemangiosarcoma developed in 14 animals of the 50ppm group and in 8 of the 503-ppm group. Only one haemangiosarcoma of the liver I See alsn WintU et al. (1976) K lclb.u:i juJ H.J Mjr'Wils was found in an animal exposed to 500 ppm. A few mammae adenocarcinomas, one rhabdomyosarcoma and one renal haemangiosurcoma were also seen. From their ex periments Holmbcrj et al. concluded that a lower exposure over a longer period may intensify the cancerogenic response and that an inverted relationship between dose level and latency time seems 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 YVistar rats to 5000 ppm. 7 h/'day. 5 days/week, for 52 months was pub lished by Fcron et ai. (1979a, b.Fcron and A>oes 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, foci of celular alterations in the liver with reduced glucose-6phosphatase 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, muiticentnc 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 waj noted, which had not been reported before in con nection with VCM. Marked hepatic fibrosis 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 of hepatocytes and sinusoidal cells has yet to be elucidated. 3.4 Toxicodynamics Prior to 1974 very little ii.formation was available about the fate and the toxicodynamics of VCM in the mammalian organism, but the discovery of VCM-induced angio sarcoma of the liver in humans and experimental animals provoked a large number of studies which resulted in a flood of publications on the metabolism of VCM. In 1934 Schaumann reported that in mammals unchanged VCM was excreted via the lunp after inhalational administration; the pulmonary route is the-main excretory route of nonmetabolized VCM (Green and Hathway 1975). Blocking of nonprotein sulphydtyl groups in the blood of vinyl chloride operatives, leu pronounced after dis continuous contact, was observed as early a* 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 plays a fundamental role in protecting tissues against attack by alkylating agents. The appearance of monochloroacetic acid in the urine of workers exposed to VCM was reported in 1966 by Grigorexu and Toba. indicating that a polar excretable metabolite of VCM had been formed (Vainio 19781. Toxicodynamic studies have revealed that KCV per se is net the ultimate toxin or carcinogenic. It is the process of biotransfomtation (metabolic activarion) of VCM. primarily by hepatic microsomal enzymes (mixed function oxidases) that yields short ^ inyl Oilom lived but high mutagenic an. cretable prod; 1975). The t. tive velocities tion of its rea nation of VC' to that above following a it cordance with 3.4.1 Uptake Pulmonary upin the animal'; with the pool > shown by com Bolt et al.(19* as albumin, aa pound goes in t After oral ingc* has to be cons; is excreted via 1976c). This c able process. Pbody wt. adm. vestigation oi. gavage in dose; found a sigmik plasmic reticub but only niinn rats on a diet c almost all the testinal tram, h in this way. Pbrcutanec keys following 800 ppm of14. was negligible! Studies of that the liver (p polar metabolit spleen, lungs an kidneys, spleen, of irreversibly r irreversibly bon J. MarvrMcr srcincmas. one from their :xrtr period'may 'etween dose \ been observed rernier.t with nnths was pubily fruitless jtease in man. Ear- of swollen and lonephrotic iced glucose-oine phosphatase .Us were observilaution of imus* nmc hepatic an") also observed i of very malig- olfactory-epi' before in con developed an.liyma. The in.adcd those of p between k CM1 ctdated. ;lte toxieodyi-induced angio- irge number of -VCM. ts excreted via main excretory >f nonprotein uneed after dist indicated depie<d rate {Hefner mg Tissues against i in the utinc of indicating Ittraate toxin or ion) of VCM. lut yields short* Vpn\! Chioniic-Amiciateii Dimij-v lived but highly reactive jlkylannf mrcmtediatei uiuch are responsible tor the toxic, mutagenic and oncogenic effects. VCM is metabolized rapidly to polar nonvolatile e.\cretable products {Hefner et ll. 19"5a; van Duurcn X^l-.RjJwan and Henjchlcr 19~5V The toxicity of VCM seems to be latgily determined by the ratio of the rela tive velocities of both biotranifomation of the compound anu protective detoxifica tion of its reactive intermediates (//cusdi/er 19'?a). The capacity for metabolic elimi nation of VCM in rats is saturable at an atmospheric concentration of 200-250 ppr.i, so that above this concentration VCM is metabolized at a constant maximal velocity following a zero-order kinetic, whereas below 200-250 ppm it is metabolized in ac cordance wuh first-order rate kinetic: (Hefner et al. 1975a;5o/r 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 of unmetabolized VCM distributed in the animal's tissues, as has been shown by complete inhibition of microsomal oxidative metabolism (Bolt et al. 1977a). Boil et al. (1977) also concluded that lipids or iiaapretetns. rather than proteins such as albumin, are the veltides that transport VCM hie 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 'first 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 (Wannabe et al. 1976c). This confirms the finding that VCM metabolism is a dose-dependent and satur able process. Pulmonary elimination of over 92T; within 4 h of a dose of SCO mg kg body wt. administered orally to rats was also reported by Feron et al. (1975) in an in vestigation of the subacute toxicity of VCM incorporated in soya beanaid and fed by gavage in doses of 30.100 and 300 mg/kg daily, 6 days/week, for 13 weeks. They found a significant increase in liver-to-body weight ratio and hypertrophy of the endo plasmic reticulum of hepatocytes 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 the PVC powder during passage through the in testinal 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. (197Jb) in male Ritesua mon keys following whole-body exposure (head excluded) to concentrations of 7000 and 800 ppm of "C-Ubelltd VCM for 2-2S h. The quantity absorbed via the intact skin was negligible (0027-0035l) and most of it was expired. Studies of the distribution of (l<2-,*C]4ab#il*d VCM in the body dearly revealed that die liver (predominant sire of metabolism) and the kidneys (site of excretion of polar metabolites) contain the highest concentrations of ,4C activity, followed by spleen,lungs and small istestinefMris/rabe et al. 1976c;A>/r et al. 1976a. b). Liver, kidneys.ipicen.lur.g 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 of VCM were found in muscle, adipose tissue and brain. : !: ; ii t nr . * *> :6 W.JC. Lelbach and HJ. MarsttHer Total radioactivity 43 h after a single exposure decreased considerably in these organs, in accordance with the relatively rapid metabolization of VCM and excreuon of its polar metabolites. In contrast, the amount of irreversibly protein-bound radioactivity remained constant during this time. Buchter 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. 34.2 Metabolism 3.4.2.1 Relation betw een Chemical Structure. Reactivity and Mutagenic or Carcinogenic Effect Before discussing the metabolic pathways of VCM (monochloroethylene) and its presumpuve toxic intermediates two features of the chemical structure of this compound should be menuoned. Vinyl chlonde is a monohalogcnatcd ethylene and its chlorine substituuon is asymmetric. Chlorination of alkenes (olefimc 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 IWilliamson and Cvetanovic for reaction rates with ozone. Vinyl chloride, as a monohalogenxted alkene, is the least stable compound with the highest reaction rate in the senes 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. \975-.Henschler 1977b). Such chlorinated epoxides may react, by alkylation, with essential cellular constituents, a mechanism which Rannug et al. (1974), Barrsch et al. (1975a, b) and Malaveillc et al. (1975) claimed to be responsible for the carcinogenic and mutagenic effects of VCM and vinyiidene chloride. Epoxides resulting from biotransfomiation of asymmetrically substituted ethylenes, such as VCM, vinyiidene 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 ethvlenes was indicated by the studies of Creim et al. (1975, 1977). 3.4.23 Metabolic Pathways From 1974 onwards the fate of VCM has been studied extensively in vitro with rat liver microsomes in the presence of a NADPH-generating system (Kappas et al. 1975. 1976,Barrsch et al. 1975b, 1976,Malaveille et al. 1975'.Bolt et al. \976%\Pcssayre et al. 1979), with the aid of isolated perfused liver preparations (Radwan and Hensch ter 1975;Bonse et al. 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 ( 1 j I ' Vinjl Chlor: microsomal i ly highly rea. via the form;; bon monoxj-1 preciable rok in vitro an an systems and ; 1976a). The. '"'H rev Fig. I. Metabr metabolized t< acetic add are roethylene oxi protein sulph> way (1977). St (Norpoth et a! S-carboxymetl add) (Hensch! identified in tl Marsteller T5KSTse organs. <n of it* iioactivity umnctabictaboittes. ir ind its pre compound s chlorine in general. ;t on the ith increas1 CfCrironc .-.is the least ethyienes lker.es ts a - electrod epoxides viucit ed to icuted > he pirncu: efiect. nnetncally 11975. with rat et al. 1975, .PesujTt and Htnsch{Hefner nil. itrol animals *-inhibiting rhepredoy the hepatic Vin;.! Chior.de-Ajjoaated Dt-eaic -* microsomal mixed-function oxidase system. forming clilowet/iylenc ox'Jc. a chemical!> highly reactive epoxide (Fig. 1). A negligible amount of VCM can be metabolized via the formation of peroxides, very unsrahlc compounds decomposing rapidly to car bon monoxide. HC and formaldehyde which, however, do not seem to play any ap preciable role tn the toxicity of VCM (Hcmchier 19"b). It has aiso been shown that m vitro an armlcal superoxide iOD generating system can replace rat liver microsomal systems and rrar.sform VCM to the active intermediate (Kapyus et al. 1975; 8oU et al. I9"6a) The epoxide rearranges spontaneously to chloroacttalJchydc. wmch is rapidly Cmalcm *-imiir.f (o MUfefrv flick-uk* fjiktUlioiit 1 'V^<Hi'N( v s'TM OmJ-hv il*^ Nl WDPH. 0- II ICW C'tlttrrn tlt i /i-rf o riui* i VCM iT>\ulc> Tiiemial rjamnyemert Comufjtion wit)? wiipln Jn I ffettr* <ftuutluon. k-yucinct HyJrols <i> icprxulc lit time' OH OH II Cl--< ---- H II II H H Clilonutt'falJem dc Fig. 1. Metabolic pathways. Adapted from HtntthUr f 1977b) metabolized to monochloroacetic add. Both ehloroacataldehyde and monochioroacetic add am also metabolites which are chemically reactive but less potent than chlo* methylene oxide. AH three intermediates can be detoxified by conjugation with non* protein sulphydryl compounds (glutathione, cysteine) as described by Green and Hath' way (1517) Sulphurcontaining excretable metabolites such asSdiydtoxyethylcysteue fMorpotit et al. 1976). Nccetyl-S<2 chloro)-ethyi-cysteine (Green and Hathwav 1975), Scarboxymethylcysiein* (Wetanabe at al. 1976a), and thiodigiycuiic acid (thiodiacetic aadl (Hcmchicr {577%\MiiUer et al. 1976.1978 i.Viiffcr and Xorpoth 1975) liave been identified in the urine of exposed women and animals. A progressive depression of the ucc 044245 :s W.K. LcHiji.il jtul H.J. Morncllcr level 01'hepatic noaprotem suiphydryl content has been observed in rats alter expo sure to VCM in concentrations from 150 to 2000 ppm for 2-7 h. No depression was seen after 10 ppm anil a concentration of 50 ppm caused only an inconsistent reduc tion (Watanabe et al. 1976b). Protein-bound hepatic suiphydryl content remained, unaffected. Hepatic microsomal cytochrome P4 jo, the coeuzyme of microsomal monooxigenases, also decreases linearly with time in animals exposed to VCM [Reynolds et al. 1975b). This destruction or cytochrome Pj t0 may prevent further metabolism and toxicity of VCM (Pessayre et al. 1979). Anodter 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 of VCM, chluroethylene oxide, is a powerful alkylating agent which covalently binds to various cellular macromolecules, notably vital proteins and nucleic acids. 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 hepaiotoxic,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, Henxhlcr( 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 effecuve detoxifica tion are greater in long-term exposure to relatively low levels. It was shown by Watottobe ct al. (1978a) that repeated exposures of rats to VCM do not appear to induce iu 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 (Watmabt et al. 1978b). This correlates well with MaltonCi 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 careinogenesu. Covalent binding to the adenosine (Barbui et al. 1975 \Latb and Bolt 1977), eytidine (Laib and Bolt 1978), and guanine moiety of nucleic acids (Ottertmnn-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 (Watanabe et al. 1978b;ii& and Bolt \9T!).Laib and Bolt (1977) presented evidence showing that the alkylating potency of VCM metabolites cannot be deter* mined solely by measuring the incorporation of label into nucleic acids after exposure to radioactive VCM. Watanabe et al. (1978b) concluded that covalent binding to nucleic acids is not the preferential reaction, but they pointed out that this does not Vinyl Chi. exclude th of cellular eluded as t above all. i This a> work will 1. endoplasnv tible to VC phologicall' mixed fwu lobular, mi. found (Jat. 1978). Sec endothelial At pres, cesses are t' the hepator some metaH (3) Meehan: tissues othe rant cell rep 1978b). Anequa nonneoplasT Raynaud'sr drome was t man. Besidelivr lesion., bioactivatto: portal fibriment of the a direct or ir tic nervous > lining cells o tion) or win 4 Clinica1 During the r might prove: presented in marked the p pational haz. WW1 6cc 1*4246  MjT'tiflilT ;sion it reduce .lined nial mono* riwlds et :*olisn anti epoxide. is nzyme ylating id proteins he merib* : us exert its dy fraction .'etoxified uthione or s which .hanirms. In there migiU in be exJetoxifica- V to VCM s binding ^tthe po* ^Buof rrcosjlent* * increase oginis be4 'unction -elates well rritnatcoma -oturt con* icchanism > jib and trids (Osrerndkig of be very '.'resented he deter* tr exposure inf to <* docs not V.nyi CliionJs^AM.KuiwJ D^wjx exclude the possibility of other.morr subtle interactions which may impair the control or cellular replication. Alkylation of nucleic acids, however, cannot at present he ex cluded as the mechanism for VCM*induced carcinogenesis after repeated exposure and. above all. in the target cells rather than the nepatocytes. Tins aspect carries on to an unresolved problem on which future experimental work will have to focus. Although the site of formation of the active metabolite is the endoplasmic reticulum of the hepaioeyte. the liver cell itself is not particular!) suscep tible to v'CMmauctd 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;m pretreated rats centra* lobular, mtdzonai and panlobular hepatocellular vacuolization and even necrosis was found (/leper et al. 1974.1975. [977:Reynolds et al. 1975a. [976: Conolly et al. 1973V Secondly, the site of carcinogenicity in the liver is not die 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 m conjunction! f 1) The active metabolite leaves the hepatocyte and is conveyed to the endothelial ctil. (2) The endothelium itself has some metabolic capacity (Bolt 1978), as may tissues of organs other than the liver. (5) Mechanisms for the detoxification of the senve metabolitesI are insufficient in tissues other than the hepatocytes. (4) Repair mechanisms for the correction of aber rant cell replication are less effective than they ste in the hepatocyte (Waumbe et al. 1978b). An equally puzzling problem is the rale of VCM in the pathogenesis of the distal nomieopiasttc vascular lesions which ate responsible for the development of the tnad, Raynaud's phenomenon, sclerodermoid skin indurations and actoosteolysis. This syn drome was the earliest indication of advene etTects of chronic exposure to VCM in man. Besides, its latency period was considerably shorter than either the nonmaiignant liver lesions or angiosarcoma of the liver. Whereas it is now established that hepaoc bioactivauon of VCM plays the cantnl part in the pathogenesis of both noncirrhotic portal fibrosis and angiosarcoma of the liver, it is not at all dear 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 fa) medullary vasomotor centres, fb) the sympathe tic nervous system, (c) smooth musde cells of the media of arterioles, fd) endothelial lining cells of small arteries (with fibroblast transformation and endothelial prolifera tion) or whether (r) the action is mediated by the formation of immune complexes. 4 Ginical Spectrum During the mid-1950s it began to emerge that chronic occupational exposure to VCM might prove to be not quite as harmless as had been claimed. The historical synopsis pmented in Table 7 summarizes those clinical studies from the world literature that marked rite gradual recognition of the full spectrum of damage due to this new occu pational hazard. tJSfSin \ivbiS 30 W.K. Lelbjch and H.J. Mar-teller Table 7. Gradual emergence of evidence for VCM-associated pathology Year Reference Findings 1949 Tnbukh et al. ilepatomecjlv. more or lc" nurkcd `anicteric hepatitis', `chronic gastritis', hypotension, anaemia, skin lesions 1954 1957 1937 1960 Smirnova Filatova and Cronsberg Kubota Dansiftr Toxic angtoneurosis Toxic angioneurosis Symptoms similar to Rjynaud'i phenomenon Two cases of accidental fatal poisoning by YC.M. 1 nonfatal acute overexposure 1961 Smirnova Reversible osteolytic lesions of distal phalanges. Pseudoclubbing, thickening of skin on volar side of forearms, slight haemolysis and rcticulocytosis 196? Suciu et al. CVS; 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 Ditest, symptoms: anorexia, nausea, fullness, hepatomegaly without hypcrbiiirubtnaemts, splenomegaly Endocrine: hypothyroidism 1966 Cordier et al. Raynaud's syndrome, sclerodermalike <kin 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 tl. Arteriography. Skin and bone biopsy 'Occupational acroosteolysis' with Raynaud's symptoms, sclerodermalike skin changes, pseudoclubbing 1968 1971 1971 1972 Antonyushenko Dinman et al. Dodson et al. Kramer and Mutschler Mentions thrombocytopenia Prevalence of acroosteolysis and Raynaud's phenomenon 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 Mi 19': Jii> 1973 Mi. 1974(a) Cr 4.1 TheTn. A first indica plant product non (toxic at in detail in ht personnel wh houriy sampb drome was al(Kubota 195 moreguiation and CNS sym (1954) also rr durations on there wag eviw of red cells, u: evidence of d< acroosteolysis operators) aft junction with was found in > lesions to be c reversible cha vibration trau the full range cupational acr In 1963 Si analysis of tin uoo 044248 JI.J Marstciler I amcrertc 'tension. henomenon ning by VCM -.al phJanges ;n on volar ii anil reticulo- neis euphoria, mia. blunting idache croderm alike -rgic dermatitis v'a. tininess, rubmaemia kin if. joint es 01 piousness! naud's phenomrent of sacroiliac with persistent'op*/ W h Raynaud's < cbengrs. Raynaud's nc lesions d icterus index Vm\ I Chlcnde-Associated Disease Table 7 i continued i Year ia-; Reference Markpm r: el ji. i Jiihc and L-nft 1973 Marsteller et al. L97j<^ Cratch et al. Findings Progressive thickening ot hand* and forearm*, jrthralgia. Blanching upon exposure to cold wuh .yanosis of hands accompanied by severe pain. Skin biopsy 1 -t German report ot ~ worker* with scleroderma^ like sk.rt lesion*. Raynaud's syndrome, and aeroosteolysu. Tests showed abnormal liver m I. occlusion of digital arte.-.es in I worker Noncirrhotic portal fibrosis with portal hyper tension and splenomegaly 4 cases of angiosarcoma of the liver 4.1 The Triad: Raynaud's Phenomenon. Pseudosclcrodenna and Acreosteolyjis A first indication of advene effects due to chronic VCM exposure arose in workers at a plant produeng VCM who presented with symptoms similar to Raynaud's phenome non (`toxic angioneurosis'). This was reported by Smirnova in 1954 and later described in detail in her thesis 11959). The syndrome vs found predominantly in laboratory personnel who had intermittently been exposed to high concentrations of VCM during hourly sampling for chemicd analysis (punty of the product). In 1954 Raynaud's syn drome was also observed arrrong several workers at a Japanese PVC producing plant (Kubota 1957). Apart from a painful vasospastic disorder of the hands, impaired ther moregulation, acrocyanosis,; asitive cold test, capiilaroscapic alterations, paraesthesias. and CNS symptoms such as headache, blunting of memory and sleep reversal,Smirnova (1954) also mentioned swelling of lingers and development of cireumsenbed skin in durations on the volar side of the forearms in those most severely affected. In addition, then was evidence of mild haemolysis (borderline anaemia, decreased osmotic fragility of red cells, urobdinuria.and reticulocytosisr. In 1961 Smirnova described radiographic evidence of detractive bone lesions of terminal phalange in the hands identical with aeroosteolysis in three workers at a PVC-producing plant (one fitter, two centrifuge operators) after exposure for 5-9 yean. Since these bone lesions developed in con junction with toxic angioneurosis' and sine complete recaiciflcadon of the defects was found in two wotlcen 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 sere* to distinguish the lesions from similar defects seen in vibration trauma. In retrospect, Smimova't observations are the earliest descriptions of the full range ofsymptoms which much later became known as the syndrome of oc cupational acreosteolyiis'. In 1963 Sudu at al. (see also 1967 and 1975) published the fust comprehensive analysis of their obrereation of a multiform symptomatology in subactue and chronic UCC^ 0442^9 * - ****..* & 32 W.K. Lclbavli jnd H.J Mjr.icilc: VCM intoxication. During a 4-year period, they examined 163 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 liclu-headedness and transient euphona 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 genera] feeling of bodily wamtth. Six subjects had experienced loss of consciousness when repairing leakages, but recovered rapidly after being carried out into the open air. 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 steep reversal. A reappraisal of these nonspecific complaints (see also Vale et al. 1976) 6 yean later, after improvement in industrial hygiene, revealed that the frequency of their oc currence had considerably decreased (Sucru et al. 1975). Following a prolonged penod of repeated overexposure, vague nonspecific digestive symptoms also developed, such as anorexia with ensuing weight toss, nausea, fullness, upper abdominal discomfort, bloating and epigastric pains. Enlargement of the liver was found in 51 workers (30%); in 6" 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 (Raucher et al., cited by Sueni et al. 1975). Pruritus of the hands, forearms and face was an early complaint followed later by what was thcought 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 pltqueiike 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 34% was recorded, with return to nor mal after a break from work or during holidays. With the exception of acroosteoiysis and the two most alarming late sequelae nondrrliohc portal hypertension and hepatic angiosarcoma - Suciu's 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. Vinjl Chlon The disev iwo Belgian; classifiable d. marked the r. syndrome wc year a numb'. United State' cases of OAO the vanous pi end of 1979. vascular pheu symptoms th begin with illthe fingers ar, tips on hard > to cold accon are likewise a ance of painft osteolytic pri with striation Table 8. Pub!, Year 1966 1967 1967 1967 1967 1969 1969 1971 1973 1972/1973 1973 1974 1974 1975 1975 1976 1978 1979 One o! 2 cl. ucc 044250 ellsr ; worccrs od in >:oui cen* i the:; >ies of ,'val of l edr.es; ranied b> <jl workers :eable s. workers xiily .altages. -ninths of >i$tem t the work 'iliiy, .e workers > yean ' their ocred period vd.such nnfort. .h3(T): .<^Btic Hi^mus at was <ia- or dorsal i firm > elevated tor removal nudism ut n to nor* ,nelaa documen* I acorn* -iication, vidinf ad* ngtographronically Vin\! Chlxndc-A-oociated Disca**: 33 Tli* discovery- of unusual osteolytic defects in the distal phalanges of the hands of two Belgian autoclave cleaners who had suffered from Raynaud's phenomenon and unclassifiable degenerative lesions of the dermal connective tissue (CunJier et al. 1^66) marked the recognition of this new occupational disease in the Western World. The s> narotne was termed `occupational aeroosieolysis' (O.AOLl. and during the foHou tng > ear a number of additional cases were reported from France. Great Britain and the L'nitcd States. Larer Lcjim il9T2) who together with Cornier described tne first two cases of OAQL. reported that a subsequent investigation revealed another `tn cases in the various plants affiliated to the same corporation in Spam. Italy and Brazil. By the end of 197Q. 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 lingers, wrists and also large joints (shoulders, knees): the fingen are numb and tingling, tender on palpation, handgnp and tapping fmcer tips on hard surfaces is painful: there is increasing sensitivity of the hands and fingers to cold accompanied by a tendency to cyanouc discolouration. In some cases, the toes ate likewise affected. Later, classic Raynaud's phenomenon develops (sudden appear ance of painful, sharply demarcated blanching) and. concomitant with the onset qf osteolyae processes, there ts a shortening and broadening of the terminal phalange with stnauon of nails (pseudodubbing). Table S. Publications on 'Occupational Acroosteolysis' since 1966 Veer Country Number Authors of cases I9f 1967 !9o7 1967 1967 t969 1969 197) 1972 1972/197? 1973 1974 1974 J97J 1975 1976 1978 1979 Belgium Franc* France United Kingdom USA Rumania Yugoslavia USA USA Fed. Republic of Germany Japan France USA USA United Kingdom United Kingdom n m 5 5 * 31 * * 8 41 6 l 4 I 4 l 4 Brazil Israel S 2 126 Conifer et ai. Benoit; Giatelam and Mnnlhm Boumchon (cited bv Mann et al. 1967) Harm and AJamt Wilton et al. Angheleteu et al. Korafet al. Dinman et al. Merkouna et al. Jiikt and Valtman; Stain et al. i a. b) Takauehi and Mabuehi 3 Moulin et aL Trapp et al. Ulit et al. Stewart et al. Bratton et ai.: Walker; MitehtU Johnston (1978) Gama and Mtira Hahn et al. 3 One of 2 clear cases, in addition. 48 suspected cases isec Sakjb* 19751 i r-e*k i ucc 044251 u 4.1.1 Familial and Idio pathic Acroosteolysis W.K. Lilb3i.li and H.J MariWller Acroosteolysis is a very rare disease. Hie aetiology and pathogenesis of this condition is still obscure. Osteolytic bone changes in late stages of so<alled 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 1921:Monahan \9Z6\Bonk 1927;Kcmblum 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 first introduced by Laroche and Hochfeld (1948), who held a neuroendocrine syndrome responsible for the lesions. Independently Harnawh (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 1952 Giacci mentioned that 68 cases of the familial type of acroosteolysis and 33 cases of the nonfamtliaJ, 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/furntj 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, ainhurn 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, stated 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 of site medical personnel and industrial hygienists when in November 1963 the condition was detected in two Belgian autoclave cleaners (Le/b-re 1972). 4.12 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 l%-3% 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. lw/m et al. (1967) observed 31 cases among 3000 employees of one targe 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 tout 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 FVC polymer. Five of the 32 plants worked Vinyl Chiot exclusively only 25 dec defined as c enen: 18 of with expenc drome were jobs, both re (1 case per 7 appeared no was detected use for react entry into tf Table 9. Pre Country France USA United Kinidom Fed. Rep Germany United Kingdom Total More con related symp Lange and l \ ological ehecl pathological: were affected c Id, 15 worl morbidity wa found classic numbness am 8.7% and inv< Allen test iml people with p pseudociubbii finding that tl duration of p- ucc 044252 m .H.J Marsteiler - this condition -aud's diseisc s loss of pan or : been mention\a27:Kornbltiri -lines and noted i leprosy The IS). who held a 'match (19491 daily involving "iive clubbing ' ition. 3y 1953 nd 33 cases of ature. He added mining procssone fragments of idiopathic !e range of diflytic diseases, -'-as considered r review, ;.'d that this same disease i than the term ^ttuion that ^^hen in icaiten (Lejhre ed in VCM >nal type of - >n at risk. ' had been tm OAOL and <1 facton. '.vg* company. 1 corporations epidemiologf 'ties and limiuat 5011 workers it 1157 of them ylants worked ''init C'lic-ndc-Associated Disease 03 exclusively with the finished PVC-derived consumer products. Di"ian et al. found only ;5 clear-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: 13 of them had been reactor cleaners at some time; another 16 individuals 110 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 tobs, both reactor cleaning and bagging-pad-ting, had a strong association with OAOL 1.1 case per 7;. or 86 workers at risk, respectively i. Manipulation of the finished polymer appeared not to be associated with a risk of contracting OAOL. Only 1 case of OAOL wu detected in those plants where high-pressure water lances or solvents had been in use for reactor cleaning. Furthermore, i: seemed that the extent of degassing pnor to entry' into the autoclaves correlated with the manifestation of the disease. Table 9. Prevalence of acral disease in VCM-exposed population* Number of eases Country Size of group at risk OAOL Classical Severe Sclero Raynaud's sensitivity dermoid phenomenon to cold skin lesion* References France (30 USA 354 Cm ted 37 Kingdom Fed. Rep. too Germany Untied 104 Kingdom 5 4 I 9 1 \a +* 20 S 9 23 13 63 ' 8 33 " 5 23 4 10 1 Benoit 1967 LUiset al. 1975 Walker 1976 Lan%* and I'.'Union 1977 Mancq et al. 1978 Total 723 :o(%3,3) TUMO^t 119(^16") 43<-.6<7t More commonly seen than OAOL were Raynaud's phenomenon (see Table 9) and related symptoms of abnormal peripheral circulation (.Benoit 196?;Ii7jj et al. 1975; Lanfc and Veltman 1977). Benoit pointed out that a complete medical and roentgen ological check-up of all 528 employees at a French PVC-otoducing 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 worken). He stressed the fact that in this group of workers at risk the overall morbidity was almost 2553. Similar results were obtained by LilU et al. (1975), who found classic Raynaud's phenomenon in 5-63- of 354 heavily exposed PVC worken. numbness and tingling in 243, excessive senritivtty to cold in 183, pseudodubbmg in 8.73 and involvement of the toes la 73. Besides, in 26.63 of the total an abnormal Allen test indicated impaired peripheral arterial circulation. It was noted that in some people with past exposure Raynaud's phenomenon had gradually faded, whereas pseadoclubbing persisted or even progressed. Most important, however, was Lifts' finding that the prevalence of all these abnormalities increased significantly with the duration of past exposure to VOl. ip ;% t ucc 044253 i * Occupational acroosteoiysis is a condition predominantly observed in > ounger workers. The age range was 20-45 years and hall'of all cases reported fell in the 50-59 years age-group. Duration of VCM exposure prior to onset of Raynaud's phenomenon ranged from 1 to 23 months (DoJson et 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 first discovered two yean after termination of exposure (Benoit 1967). Longitudinal studies of the bone lesions demonstrated partial or complete bur mostly detective restitution, resulting in shortened and deformed distal phalanges, within 2-5 years after removal from VCM exposure, but Raynaud's phenomenon and cutaneous lesions may penist (Williams andMcLxhkn 1976}.Stein et al. (1975a, 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 fingers and typical bilateral acroosteoiysis, 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, pre-mix operator, recovery and charging operator who had never cleaned autoclave vats(Stewart 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 first year during an earlier survey of OAOL were normal; in 1972 he presented with Raynaud's phenom enon. pseudoclubbing, 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 ocelusion. Apart from the chemical insult by inhalational (rather than transdcrmal - Dinrnan et al. 1971;Stewan et al. 1975) exposure to VCM, individual susceptibility or idio syncrasy appean to have played some (undefined) rale in the development of the syn drome. It does not seem likely, however, that repeated physical microtrauma during cleaning operations (removal of polymer erusts by hand scraping or chiselling) was a decisive factor in the pathogenesis of the condition as had been speculated by Wilson etal.(1967). 4.12 Clinical and Roentgenological Features 4.1.3.1 OccupationalAcroosnolysa In the majority of cases osteolytic lesions are confined to the hands. Involvement of the feet was observed only rarely in OAOL. Wilton et al. (1967) believe that OAOL diffets from familial or idiopathic acroosteoiysis in several respects. Although the bone defects m osteopcm skull, des' shortens nonoccuf genologK 1)T1k one or mo 2) In t tufts, or a 3) The tufts toget defects (se ('bandlikc Fi*. 2. Oco acroosteoh year-old au 4) In th and broadr fragments, and increas Sodium mineraiizat multaneous  jnd H.J. Marteller in younger d fell in the 30-39 cud's phenomenon 'tteney period was ' >ped insidiously ,ora OAOL was firs; longitudinal studies ,'tecnve restitution, ears alter removal .lions may persist rtial healing with terminal phalanges 'workers who had at lias also been obti to carry a sub- -year-old white male J typical bilateral :nt by an industrial ions of vinyl chio- rafter 6 yean' em* urging operator who > routine piam a: chromatoerscliy 11 limit values of st year dunna an inaud's phenom- )d wnsis. Ar sen without - of deformed vdermal - Dinman ptibility or idio* lopment of the syn* orotrauma during f chiselling) was a culaied by Wilson tnnsivement of lieve that OAOL Although the bone V:n>! Clilor.da-AsiiikUteJ Oise-i'C detects m the distal phalanges art similar in both conditions, other features, such as osteoporotic compression fractures of the spine, basilar impression fracture of the skull, destruction of mid-phalanges or osteosclerotic changes of wnsis and hand bones, shortening of metauarpais and cortical thickening of the shafts of long bones seen in the nonoccuparional type have never been found in OAOL. Wilson e: al. worked out roent genological criteria for tiie diagnosis of OAOL: If Tiie earliest changes in OAOL are marginal defects and l<vs of cortex m tu:;s of one or more of the terminal phalanges of the hands. 2) In the next stage this is followed by small 'half-moon' cuts in the cortex of the tufts, or 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 defects (see Fig. 2) cutting off the shafts from the remaining distal nm of the tufts ('bandlike acroosteolysis'). Fig. 2. Occupational acroosteolysis. Transverse or oblique bone defects i'bandlike acroosteolyitif or partial loss oi terminal phalanges in all fingers of both hands. (33year-old autodavt cleaner: duration of exposure 3 1/2 years) 4) In tlit healing stage there may be either complete bony union with shortening and broadening of the residual parts of the end phalanx or a fibrous union of bone fragments. Fingertips remain short and plump with persistent clubbing of soft tissues and increased lateral and latitudinal curvature of fingertips. Sodium fluoride ` * F scintiscan data of afTected bores suggested that active de mineralization (rcsorptivej and renuneraiizacon (reparative) processes may occur simuitaneously even in the same hand {Dodson ct al. 1971). In some cases, bones of 35 W.K. Lelbacli jnU H.J Marstsllcr other body regions were also involved. Erosive and sclerotic changes in the sjcro-ihac joints and circumscnbcd resorptive defects (cortical erosions) in patella, clavicle, man' dible. humerus, styloid process of ulna, femoral condyles, os caicis, cuneiform and metatarsal bones have repeatedly been observed iConiicr et al. 1966.Hams and Adana 1967.Dodson et al. l97\:Juhe et al. 1974;,a;ige et al. \974a: Preston er al. 1976; Jayson et al. l976a;Laiige and I'cltman 1977). A, 1.3.2 Pteudoscleroderma Concomitant with the manifestation of paracsthesias. pain, tenderness of the fingers ana Raynaud's phenomenon, cutaneous lesions similar ro stigmata seen in progressive scle roderma develop with thickening of the skin of fingers, hands and forearms, sometimes accompanied by swelling or pufTtness and coarsening of the skin of the face (mostly on the forehead and cheeks). Raised, ivory-coloured, firm nodules or elevated, sharply de lineated plaquelike skin indurations are seen on the dorsal surface of fingers and hands and on the volar side of the wnsts 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 clearly distinguished (Table 10). Notably, the diffuse immobil- Table 10. Differential diagnosis; syndrome of occupational acroosteolysis I Raynaud's phenomenon, sclerodermoid skin changes, AOL) / progressive scleroderma with (rare) osteolytic lesions Occupational AOL Progressive scleroderma Sex ratio Exclusively i d>9 - 1:2 Hands Clubbing and shortening of finger tips; hyperhidrosis: no ulceration Atrophy and tapenng off of fingertips; anhydrosis; ulcerative lesions Penoral puckering of skin Skin appendages Telangiectases Shortening of frenulum Subcutaneous deposits of calcium salts Dysphagia t oesophageal invoivementi 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 HiStOlOe. 4.1.4.1 Cutaiu Several investige disease (Condter al. l972;Laugc we found only c 1967, Marin et. neural changes \ who suffered `m Dermal chan mis with disone broad interlacm faintly stained n Schiff (PAS). Ai histiocytes was: The most notab of elastic fibres, full thickness u: sue. Skin appen. Walker (1976) f not exceeding t. some fibrous tin Vascular le t capillaries were and pencapillar thelial cells with tion of lumina.' myocytes, was. to narrowing or Degenerative (Benoit 1967;.ii hyaiinosis of :hMeissner, Pacini 4.1.4.2 Bone 1. The most strtku worker with OA ening and hyaJu most layer. Sup. .1. M^rsteiler f B sicro-diac i. clavicle, man* leitorrn and :rm and Adams et al. !<976. of the finger? and progressive icle* amis, sometimes face (mostly on tied. sharply deveers and hands -.mauon of Raydi for other mirome of diffuse lmmobil- . ?i? i Rav laud 's r.na with i rare i o .vltrodeima Mapenng olf "P anhydrosis: I* M*U* tin appendages i nptom n) ronuneous '4on \ Inv! Chl-.<nd*-A*sociated Disease 59 izing sclerosis of the skin with tapenng off of fingertips was never seen in the occupa tional sy ndrome. After cessation of exposure the skin lesions seem to regress more readily than the osteolytic changes. 4 1,4 Histology a / 4 l Cutaneous Lesions Several investigators described the hutomorphology of skin lesions m vinyl chloride disease (Conifer et ai. 1966; Harris and Adams 1967:.Vann et al. 196 7; Markowitz et al. l9"ZiLange e: al. 1974a; t airman et al. 1975, Walker 1976:Hului et al. 1970). but we found only one desenption of bone histology in QAOL. in the literature (Benoit 196':.Vann et al. 1967). Skin biopsies showed various degrees of dermal, 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 disonentation. swelling and nonfibnlLiry eosinophilic homogenization of broad interlacing collagen bundles. There was some degree of intemmai oedema which faintly stained metachromatically with toiuidine blue, alcian blue and periodic acidScluff (PAS). An inflammatory reaction with infiltration of lymphocytes and a few histiocytes was scanty and, if present at all, of predominantly perivascular distribution. The most notable feature was marked disorganization, fragmentation and rarefication of elastic fibres. In areas corresponding to nodular or plaqueiike skin inductions, the full thickness of the dermis consisted of an aceilular. partly hyalintzed collagenous tis sue. Skin appendages were preserved. In 15 apparently less severely affected workers, h'a/Jfccr (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 artenes. Numerous dilated capillaries were seen in the subepidetmal papillae with swelling of endothelial cells and pericapdlar oedema. Capillaries of the cutis showed cuftlike hyperplasia of pertthelial ceils with fibroblast transformation, hyalinosu of vessel walls and final oblitera tion of lutnina. 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 oceiuaon of the lumen. Degenerative lesions of small dtnnal nerves were mentioned by French investigators (Ben-nt 1967.Mann et al. 1967: Charelaut andMotilhn 1967). They found sclerosing hyalinosis of the penneunum with atrophy of ncurefibrtls. Tactile corpuscles (WagnerMeissncr, Pacni) were unaffected. 4.1.4.2 Bone Lesions The mast striking feature in a biopsy specimen of the bone, obtained from a French worker with OAOL (ease 4 of both Benoit \967:.Vann et al. 1967) was marked thickening and hyalinization of the periosteum with chondroid metaplasia of the inner most layer. Supplying capillaries and arterioles showed occlusive changes iuentieal with i : 40 W.K Lclbach jiul II.J. MaisKllcr those observed in tlte dennis. The bone matrix per sc was barely affected. There was minimal thinning of cortex, normal spongy bone and only mild fibrosis of the bone marrow. Experience with histomorpliolugy of bone lesions in the familial and idiopathic type of aeroosteolysis is limited. In the few cases 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 (Dnpas et al. 1*336; Elion and Burmtein 1954, Crc'ciiberr and Street I957;5c/iwnrcwi:i/i7 \957), In this context, it should be kept m 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 anunais which were very similar to those observed in man. Viola exposed rats to 30 000 ppm VCM. 4 h/day. 5 davs/week. for 12 months and de scribed the histology of these lesions in detail (1970b). 4.1.5 Arteriography, Capillaroscopy, Infrared Thermography Arteriographic evaluation of the vascular tree of the hands revealed patency of the large arteries in all cases examined. The 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;,Uyi///;i 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 hypervasculartty of the terminal tufts and in the region of the wrists was noted in some eases <Benoit 1967:Lange et al. 1974a; Veltman et ai. 1975;Preston et al. 1976\Ste\vart et al. 1975: Game ini Mein 1978). Angiographic findings in a larger group of 19 symp tomatic PVC workers with either Raynaud's phenomenon and/or aeroosteolysis (519) were recently described in detail by Koiscltwirr et al. (I960). 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 resorptivc bone defects in those who had formerly suffered from aeroosteolysis. 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. I'nited 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 t year prior to death from both angiosarcoma of the liver and hepatocellular carcinoma)- The pathogenesis of there peculiar vascular alterations is not clear, but the possibility presents itself that they may be due to de struction of elastic fibres in the vessel walls in analogy to similar alterations of digital arteries seen in rheumatoid arthritis ILawt et ai. 1963.1967). Vinyl i Stu> vations fingerp. ed a var lar area' those vferent t! larosco. control ence in PVCw. of distu induces A si. iPVC-y chcmicr notmali was con number employ related It also s more sc M jntfllef t nere was he bone mpaihi; Si be obilammatory i. 1936. *1. Jucing -mall nets-ved in man. .(its and de* y of the inly conarrernl et were ;r' ot diffuse >1 vessels, 'il peculiar mt\ of ' *H<5/19| cnomenon . i initiation * bone - to varyall collar, '*i in spite I'ICUOUS ihed elonp* varnpie is m a 54* "t after Mcoma of vascular due to de* * of digital Vinyl CliIor.de-Assoi-iateiJ Disease -t Fig. j.t oiispieuou.% turluoiilies and eiuni-itn'ii >! Jieiul arteries Studies of microvascular changes by wide-field eapiUan micmscopv (direct obser vations complemented by photography) of selected skin sites - such as nad folds, Gngerpads. dorsum of phalanges and of proximal interphalaneeal joints - demonstrat ed a variety of capillary abnormalities, it. dilated or glam capillary loops, pale avascu lar areas, capillary and subungual haemorrhages. The abnormalities were similar to those seen in scleroderma but wen usually less conspicuous, less numerous and of dif ferent uiatributioo. In a survey of a group of 152 American PVC workers, these capil* laroscoptc findings proved to be significantly more prevalent than in 50 nonexposed control subjects (Maricq ct ai. 1976). There was also a statistically significant differ* ence in the prevalence of these abnormalities between symptomatic and asymptomatic PVC worked. Tire alterations were not only found in workers with clinical symptoms of disturbed acnl circulation but also in 6 nonsymptomadc males with either VCM* induced angiosarcoma of the liver (2) or splcnomtgalic portal hepatic fibrosis (4). A similar survey ws later undertaken in an unselected sample of 129 employees of a PVC-producing chemical plant in England with 26 employees of a non-PVC*produdng chemical plant serving as controls (Marieq et al. 1978). Hie prevalence of capillary ab normalities found in these British worked, which were of the same type and degree, ws comparable to that in the American sample, although the latter included a larger number of more severely affected symptomatic patients with greater mean length of employment (15 years vs 3 S yean). In the authod' opinion, this suggested that VCMrelated disease may develop independently of differences in manufacturing procedures. It also suggested that this easily detectable type of mtcrovascuiar lesion may precede more senous VCM-induced disorders. In a small subgroup of 15 clinically affected W.K Lelbjch and il J. Mjrstellcr British workers who were examined 6-24 months alter leaving the plant (termination of exposure), the prevalence of capillary abnormalities was not less titan 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 capillaroscopic changes was also observed in three of 4 Polish workers (2 reactor cleaners, 2 fitters) who were found to suffer from Raynaud's phenomenon after exposure for 2-5 years (Brczkowika and Langauer-Lewowicka 1974). Infran-d thermography, another nonmvasive method, used by Rc:y et al. (1974) for the study of acni circulation, revealed abnormalities of surface temperature rang ing from marked hypothermia of terminal phalanges (which are normally warmer than the rest of the fingers) to "complete terminal amputation" in four PVC workers suf fering from OAOL. In one of them vascular disturbances as evidenced by infrared thermography persisted in spite of complete healing of OAOL Stewart et al. (1975) demonstrated uneven blood flow in the fingers and patchy hyperthermia in the distal part of the OAOL-afTected left index and middle finger of their atypical case. Local ized acral hyperthermia seen on tR 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 involving 143 PVC production workers and 56 controls, Wiliams 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. 4.1.6 Immunological Studies Early experience with the syndrome of occupational acreosteolysis 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 sy- .-Tiuc 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: sderoderma of hands or feet, 6: OAOL, 2; sensitivity to cold, excessive fatigue,limb pain, panesthesias). Slight hyperimmunoglobuiinaemia, usually IgG, the presence of mixed cyroglobulins. and in vivo conversion of both C j and Cj 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 C} or C were taken as evidence for the presence of circulating immune complexes. Autoantibody screening demonstrated tow-titre antinuclear antibodies (IgG 1/20-1/50) in eight of the nine patients with Raynaud's phenomenon. Aggregates of IgG, C4.Cs, and fibrinogen/fibrin 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 Chi. and medic lung (1 ca: The au and bone 1 bolic inter plasma pru which surr cular occli as a result ators of tis to further Jayson et; suffering f; than in no ride diseav In an e in four Pol decrease in evet, Lang, titer Seph: 6 together agglutinins were obser sponses pla (1974a) an dence of at tion of rhe terminatioi immunofiu were later. creases in ii taken up at ed to sugge hypetgamr with far ad three patici with Raym degrees of i runs were f. range: x t* sclerodemv of which is In sunu utoimmun establish th in VCM-ind ii (termination < that among condition, lpillaroscopic n, 2 fitters) for 2-5 yean it al. (l"4) prrature ringly warmer than workers iufy infrared ret al.(l975) a m the distal l com. Localangiographic atory collaisurvey rnvolv. "i assessed the iter bath kept iitrois ana be- -regLcsrta'-' jiTcondittons ! for other i urea, as pro* logical sm iiej 'hem out ot a vat was 3*> ivnaud's phi.iiid. excessive ually lgC. the 1 C4 were : of reduced i. in vivo eonevidence for - demonstrated tients with i in were revealocular endoxms of small \ i:n I CltlonJs- \soc:ateil Direjsc and medium-sited anenoles in biopsy specimens of the skin f 10 cases), muscle and lung 11 case each). The authors proposed as explanation lor the induction and pathogenesis of skin and bone changes ;n VCM-induced disease a tiieoretical model based on reactive meta bolic intermediates of VCM formed dunn; biotransformation binding covalently to plasma proteins- These may act as antigens las a resuit of a structurally abnormal protein which stimulate B-ceil proliferation ami antibody response Platelet aggregation, vas cular occlusion and ischaemia were though: to be secondary to complement activation as a result of formation of immune complexes which were implicated as possible medi ators of tissue injury. Ischaemia, in turn, by leading to collagen synthesis, was believed to further activate the complement pathway and thus to recycle the mechanism. Jayson et ai. (1976b), who earned out collagen studies m 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 formation in vmyl chlo ride disease has not been fuily elucidated. In in earlier study no cryoglobulinaemia or presence of cold agglutinins was found in four Polish workers with severe Raynaud's phenomenon: in two of them a slight decrease in lgC was noted (Byeskowska and Lanfaucr-Lewwicka 1974). Later, how ever. Langjucr-Lewowcka et ai. (1976) observed latent cryoglobulinaemia, detectable after Sephadex G-200 nitration.in 18 of 22 workers with Raynaud's phenomenon tin 6 together with acroosieuiysis and scierodemulike changes). Again, there were no coid agglutinins detectable, but in five patients marginal to slight elevations of IgG levels were observed The authors suggested that a pathological alteration of immune re sponses plays a key role in tire pathogenesis of vinyl chloride disease. Lattfa et al. n<J74a) and t'eltman et al. (19'75) 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 autoanobody screening (indirect immunofluorescence) were initially introduced in our first senes of 50 patients but were later abandoned because of mostly neptive results, except for occasional in creases in immunoglobulin levels (ManttUer 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 enauc connection (unpublished data). We did not observe hypergammaglobulineemia (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 occluson 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: x a s 01--1 g/litre) was seen In five patients who suffered from OAOL and sclerodermoid skin changes (unpublished data). Elastin antibody dues (the specificity of which is doubtful) were neptive. 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-induccd disorders. ucc 044261 Ires. m f 44 W.K Lelbaiih jnii U J MjimcIUt Vinyl Chlonde-A- 4,1.7 Pathogenetic Considerations Tne clinical sympt Raynaud's phenomenon as a premonitory clinical symptom, histomorpholocy in man and expenmental animals and analogical expcnence suggest that the common denominator 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 penpheral 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 (Coma ini Metro 1978). Yet the answer to the next question, the pathogenesis of penpheral 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, distnbuted throughout the systemic circulation and metabolized (bioactivated) in the liver, can many as 15"- of th survey was descnbi developing chrome character of nonim In 19*2 Krann had been routinely time-weighted aver:, environmental data wise multiple linear tton and, to a lesser level of past exposu re individuals stud bring about, apparently only in a small number of predisposed individuals, after a vari TWA levels of 300 p able period of latency severe vascular injury and (probably secondary) damage to peri in clinical laborator pheral tissue. Some conceivable mechanisms are briefly listed in a previous chapter (see ed BSP retention wc Sect. 3.4.2.2). but no conclusion can be drawn as to their relative significance. ease (Manteller eta. In West German- dermatologists in Bv 4.2 Non-malignani Liver Disease in Vinyl Chloride/Polyvinyl Chloride At first sight, the s> Production Workers derma. This provoke Progressive systemic a first group of 13 p> Long before Raynaud's phenomenon or osteolytic lesions were observed in PVC pro from a nearby PVC- duction workers. Tribukh et al. (1949) studied environmental conditions in a Russian from either OAOL * plant where polyvinyl chloride resins were produced and compounded. Without going phageal varices due t into detail, the authors pointed out that moderate nontender hepatomegaly was found a group of 20 relattv in a larger porportion of a group of 73 workers (48 males. 25 females) mostly engaged previous liver disease in PVC compounding; `anicteric hepatitis' was diagnosed in 21 of them (IS d, 6 9). Al Medical Department though tlte authors knew about the narcotic action of high concentrations of VCM patient and revealed (75-250 mg/litre 30 000-98 000 ppm) from the literature, which they explicitly capo. 'jfibrosisof:- tt mention, and also knew about the release of unreacted monomer from the powdery ly, marked portal h> PVC resins during thermoplastic compounding, they apparently held other volatile al. 1973). It was nou compounds derived from halogenated aromatic hydrocarbons (such as chlorinated encompassed a large naphthalenes and diphenyls) used as piasticizets 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 Hence Julie et al. (ly In retrospect, thi spleen alterations in c installation of ventilation facilities of sufficient capacity. Nonicteric hepatomegaly was again recorded by Suciu et al, (1963) 14 years later the long latency perildisease which is accon in almost one-third of the total work population (51 of 168 employees) of two Rum hepatic parenchymal * anian PVC-produdng plants, including 10 cases with additional splenomegaly. Liver Only 3 months Lc biopsy in two of these workers revealed chronic hepatitis. Studying the prevalence of was surpassed by the: temporary disablement due to liver disease among 350 employees of the Sverdlovsk liver, an exceedingly r plastics industry,Ptuhin (1965) found the highest morbidity among employees of the workforce of274em; PVC production unit, compared with other units engaged in the production of non- ican plant (Creech et - PVC plastic materials; 170 workers of ancillary industries served as control subjects. upper gastrointestinal 044262 j H.J. Maweiler t'lology in man ommon Je>wiic VCM inmutation in i> of their vaaost suscspnclf reflation tCjma ijot'peripheral !y a matter of 'ii, distnbuted he liver, can nil. after a vandamage to peri* uiua chapter (tee iiieance. J in PVC pro* m m a Russian Without going -aly was found jy engaged Al- uiiu of VCM 'icy expiicitiy the powdery ther volatile .hlormated lemic toxicity, -ken ahouid be y suggested the > 14 yean later 0 of two Rum* iiKgaiy. Urn >e prevalence of lie Swdlonk titpioyces of the ictign of non* itrol tubjeett. Vm>! Oi!nniie-Ao^:a!i- DU-:.im' The clinical symptomatology of - typically nonictenc - live,- disease observed :n 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 m these worker; remained obscure. In 1<JT: Kramer and Mutcli'cr examined a group of 98 healthy male workers who !ud been routinely exposed to VCM for periods up to ZS years and for whom career time-weighted average exposure estimates were available. In an attempt to correlate environmental data ana results of a medical surveillance programme by means of step wise multiple linear regression analysis, it emerged that brurmulphthalein (BSP) reten* tion and. to a lesser degree, the icterus index were significantly correlated with the level of past exposure to VCM. Although no overt clinical disease was found in any of the individuals studied. Kramer and Mutchltr concluded 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 retenuon was the most consistently pathological test for VCM-induced liver dis ease (ManteHer e: al. 1973a). In West Germany the first cases of occupational OAOL. were observed in 1972 by dermatologists in Bonn (Juiie and Laiiye 19'Z.Juhe et al. 19?3:5ren et al. I9?3a. b). At first sight, the symptomatology appeared to resemble atypical progressive sclere dema. 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 polycleanen who were referred to the Department ot Dermatology from a nearby PVC-preducing plant it emerged that 3 of diem, who did not suffer from either OAOL ot scleroderma, had a history* of unheralded bleeding from oeso phageal varices due to portal hypertension (Ju/te et al. 1973). Further investigation of a group of 30 relatively young PVC production workers fmean aee:40 yean), 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 noncorlioric penal. pcrisimtsokJal and sub* capsular fibrosis of rltt Uvtr. with splenomegaly, thrombocytopenia and, leu frequent ly. marked portal hypertension, but stnkingly little hepatic dysfunction (MursteUcr et al. 1973). It was now realizad that the disease spectrum in VCM-exposed individuals encompassed a larger scope of injuries and. in fact, suggested a systemic toxic effect. Hence Julie et al. (1973) proposed the term vinyl chloride disease'. In retrospect, this comparatively late recognition of the true nature of Uver and spleen alteration; in chronic VCM intoxication can be attributed, at leas: 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 tills discovery* was surpassed by the alarming announcement that four cases of angiosarcoma ofthe User, an exceedingly rare malignant tumour, had been found among a comparatively small work force of 274 employees of the PVC polymerization section of a large North Amer ican plant (Creech et al. 1974a). Two of these four petiena had first presented with upper gastrointestinal bleeding due to portal hypertension between 1964 and 1970. I UCC 044263 d* 46 W K Lelbach and H.J. Marsteller There is no longer any doubt that chronic exposure to vinyl chlonde monomer can produce two different types of liver disease in man as well as in experimental animals: 1) Noncirrhotic 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 desenbed 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 (Ramahngaswamt et al. 1962;/manage tt tl. 1962,Bastt et al. 1967a, bitfoyerei al, 1967; Saw et a], 1971). It has been seen only sporadically in the Western World (Roussclot 1940; Ravenna 1940; Tisdale et al. [959,Polish et al. 1962'.Stiller and Brandt \962;Siderys and I'etlios 1964-.Mikkelscn et al. 1965;Iber 1970:Escartm Marin et al. 1974, Mendenhall et al. 1974; Crannis 1975; Vdlencuve et al. 1976). Iber (1969) estimated that "centers throughout the world reviewing their experience with portal hyperten sion encounter 3 to S% 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 noncirThotic portal fibrosis observed in India, unknown toxins contained in indigenous drugs, herbal medicines or adulterated food might have been responsible for the condition (Soma et al. 1971). Vllltneuve et al, (1976) suggested that, apart from VCM and inorganic arsenical*, other still unidentified toxins could be the cause of this syndrome. Idio pathic portal hypertension has also been observed to occur in association 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 arc: 1 a)Inorganic anenicals (Zeegen et al. 1970:;Ve/e and Azzopanii 1971; Knolle et al. 1974;A/oms et al. 1974;Huet et al. 1975; VUleneuve el al. 1976; Cowlishaw et al. 1979); b)HypcrvitaminosisA (Muenter et al. 197l;Russcif et al. 1973, \91A,Hruban et al. l974,Aur/eret al. 1977): and c) Recently,copper sulphate in Portuguese vineyard workers (Pimentel and Menezes 1977). Arsenical preparations (usually prescribed as Fowler's solution - potassium anenite) 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 penod (Nothnagel and Rossbaeh 1880) Fowler's solution is also listed as a traditional antimaianai drug of .and H.J. Marsteller boride monomer can ;'cr.mental animais: '1 rare disorders rial fibrosis ar: not .d haemorrhage due . development of tc\ this symptom i matter of debate. n` the syndrome has v iRjinaiiiifcS'.Jnu I6r:5arrtii ft al. 'Liiseht 1940'. ' and: 1962;Ji'Jem i er al. 197-1; r (1969) estimated li portal hyperten;ate:ory of cirrhosis d that m nonctrrhotic ^enous drugs, heroal condition iSoma et I and inorganic syndrome IdioJion .vi:h known The excc; non or' . are: ' 19*1: Knollc et al. .^wto/icw ft al. '3, l$~4:Hnihan et i'imentel and.Woierci i - potassium an adjunct to iron H for the treatment 1898) that anaemia preparations is of ni (iVor/i/ingef and uinaiahal drug of Vinyl Clilonde-VssocutcU Ducase 47 long standing. Chaimtvan and l'imnurarn( 19^9) recently implicated an indigenous Thai medicine contanin; arsenic as a possible aetiolopcai factor in a case of idiopathic portal hypertension. Dana et a). 1|970) found significantly elevated levels of arsenic in liver tissue specimens of four of nine Indian patients with idiopathic portal hyperten sion resulting from chronic arsenic intoxication icontcmmated drinking water, use of Ayurvedic medicines). Typically, iiver 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 semetimes carcinoma of other sites. However, neither histological nor radiological or haemodynamic criteria permit a clear distinc tion between `idiopathic' portal hypertension and noncirrhoiie portal hypertension caused by chronic arsenic tcxificanon or chronic exposure to VCM, as was demon strated by ViUencuvt et al. (1976) in a study of five patients. After prolonged treatment with excessively lugh doses of viramin A (psonasis. ichthyosis and other dermatological conditions, adjuvant cancer therapy and ;n health faddism) chronic intoxication has been seen to cause hepatic fibrosis and cirrhosis (Muenter et al. 197I;F7crrc/wnn et al. 197?;A*ur/efet al. 19";RuuelI et al. 1973. 1974). Storage of vitamin A in hepatoevtes and one type of fat storing, nonphagocytic pensinusoidal ceils (Ito cells (fro and .Vemoro 1952)] could be demonstrated by fluo rescence microscopy. Stimulation and proliferation of Ito cells, which arc probably fibroblast precursors (Popper and Vdenfricnd 19^0;Schnack et al. 1967). provokes an increase in basement-membrane-like material and collagen within the pensinusoidal space and leads to pensinusoidal fibrosis with partial obliteration of Disse's spaces and the sinusoidal lumen (Hntban et al. 1974). The recognition of idiopathic porta; hypertension, hepatic fibrosis, cirrhosis and angiosarcoma of the liver coexistent with excessively abundant hepatic deposition of copper (besides evidence of `vineyard sprayer's lur.g') in a group of 50 vineyard workers in Portugal is. to our knowledge, the first report in which chronic capper intoxication is implicated as the attioloficai agent. For periods varying from 3 to 45 yean, these workers had been engaged in spraying vineyards with a mixture containing copper sulphate on 15-100 days per year. The authors noted a clow morphological resem blance of the lesions to those resulting from exposure to inorganic anecueals and to vinyl chlonde {Pimentel and Mcnezn 1977). Although extrinsie chronic copper intoxi cation is virtually unknown in man. potential hepatotoxicity of long-conunued uptake of copper wn discussed by BiomtieU 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 lias received less attention than the spectac ular discovery of me rare hepatic neoplum. In continuation of our first two surveys {Manteiler et al. 1973, 1975a, b), we have now (end of 1980) observed 17 patients (all members of a total work force 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 prewnted 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 senes of seven patients with noncirrhotic portal fibrosis and 48 W.K. Lelbach jnd H.J, Marsreller Table 11.1' PVC workers with advanced portal hypertension I marked uc-oplugeal varicc.'. epi'OiieS of upper Gl bleeding, splenomegaly l Age at diagnosis Duration of exposure Perttoneoseopie and Vo. (years) (year*'months) histological diagnosis i 30 31 3 32 4 35 5 1 35 6 39 7 39 8 41 94 41 10 J 47 11 50 12 51 13 52 14 52 15 54 16 4 58 !7a 61 5 5/9 3/6 4 9 10/6 13/6 7 18 18 6/6 17 15/3 11 6/6 21 13 N'lneirrhore fibrosis Noncirrhotie fibrous Noneirrh emc fibrosis Noneirrhotii fibrosis Noneirrftotie fibrosis Noneirrhotic fibrosis Noncirrhotie fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis Noncirrhotie fibrosis Noneirrhotic fibrosis Noncirrhotie fibrosis Noneirrhotic fibrosis Noneirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotie fibrosis a On follow-up patients 5.9,10, 16 and IT subsequently developed angiosarcoma of the liver and died 3-6 yean 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 11 yean after pentoneoscopic diagnosis of portal fi brosis associated portal hypertension,Smith et al. (1976a) observed later development ot' angiosarcoma in one of them. If a rough estimate based on these two small senes 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 nonmaiignant liver disease, palpable splenomegaly and a slightly to moderately enlarged liver may be the only physical signs. On palpation, we found hepatomegaly in 31 and splenomegaly in 16 of 50 selected PVC production workers who had been heavily exposed in the past (AtarueUcr et al. 1975a). Lila al. (1975) reported hepa tomegaly in 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 of hepatomegaly was found in those vin>l Chlon- exposed for r splenomegaly In contra.' mem ofhepa ectases. gyna. not seen. Eve phalopathy d workers only It is push preceded adv. only one ease development 4.2.2 Labor: Owing to the not the target value for the L This makes it 1974; Creech thrombocytof logical bioche: the levels of s. quent (Afonrc (ICC; Oi and liver function workers of a < (Tamburro et progressively of abnormal S there was over phosphatase ( alkaline phosp megaiy and/c Except for and Veltman i the reticulocy parametets usi presenting feat sion (.Smith et be dealt with r Assessment matic workers facture ofPV( coproporphyri i \UfMiller J "'ophaftil -.OC'.-* mb 'i aijgno*" uc iibrusis ':c fibrosis uc hbrosi .tic fibrosis nc fibrosis ftK fibroin >'ic fibrrwit nc fibroin ire cirrftoiii ut fibrosis '(it fibrosis i 'tie fibrosis ' >tit fibrosis "'jc fibrosis nic fibrosu >'i.* eirrriOMs ui fibresf- -'.ircoma ot inents b and " ill OfllflO- p.irtii fi- ltftlt 01 u senes w e idualssutsct* ,w uevelop >.ihly not a i re* wsofVCM* to moderate* : Hepatomegaly ho had been i .`ported heps* mod employee! n plant in i rent produc* iiNind in those Vi.iv! C!tionJf*A'isc>e:Jieil Oiieu'C 9 exposed for more than 5 yean, whereas ihc difference in tiie prevalence of palpable splei'.omepl) was not significant. In contrast to cirrhosis of the liver, clinical symptoms indicating serious imoair* ment of hepatic function such as jaundice, vascular spiders, palmar erythema, telangi ectases. gyrtaccomasria. peripheral oecema and asettes or hepatic encephalopathy are not seen. Even after massive bleeding from oesophageal vances portosystemic ence phalopathy does not develop. Atcites and hepatic coma have been observed in these workers only m terminal stages of angiosarcoma of site liver. It is puzzling chat actoosteolysis and sclerodermoid skin induration have only rarely preceded advanced stages of VCNUnduced liver disease. To our knowledge there is only one case of angiosarcoma of the liver on record which was associated with pnoc development of acroosteolysis (Roche et al. 1978). i lZ Laboratory Findings Owing to tite fact that hepatocytes. although being the primary site of metabolism, are not the target of toxieiry, standard biochemical liver function tests are only of limited value for the detection of liver disease in populations at risk (hW/ioms et al. 1975b). This makes it very difficult to devise adequate screening programmes (Martin et al. 197U. Creec/i andMakk 1975; HVorr et al. l9~S,Bcrk et al. 1975,1976). Apart from thrombocytopenia, we found 45*min BSP retention to be the most consistently patho* logical biochemical test: usually minimal hyperbtiirubtnaemia and minor elevation of the levels of scrum alkaline phosphatase. SCOT and SCPT were considerably less fre* quent (Marsteiicret al. ^Ja). Another dye-removal test.indoeyamne green clearance fICC: OS and 5.0 mg/kg), also proved to be mote reliable titan standard biochemical liver function tests in correctly idenuf/ing early hepatic injury in 1 ZOO vinyl chloride workers of a chemical plant in Louisville, Kentucky, during a 4-year screening period (Tamburro tt al. 1978b). The expos*.: rank was found to be closely correlated with progressively increasing frequency o' 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 Lilia et al. 0975), alkaline phosphatase levels were elevated in 16.677. of the 354 workers examined. In their scries, alkaline phosphatase was also closely correlated with the clinical symptom of hepato* megaly and/or splenomegaly. Except for thrombocytopenia (less than 150 x 10* platelets/litre) which Lange and feltman (1977) found to be present in 76 of 100 workers, and a slight increase in the reticulocyte count (in 35 of 79 workers,doi/igr and feltman 1977), hiematologicai parameters usually do not contribute to the diagnosis. Thrombocytopenia was also the presenting feature in two of seven British workers with nonctrrhotic portal hyperten sion (Smith et al. I976t). Thrombocytopenia and abnormal platelet function teats will be dealt with separately in Sect.4.4.1. Assessment of urinary excretion of porphyrins and porphyrin precursors in sympto matic workers who had been enpged in the production of PVC (n 23) or the manu facture of PVC articles (n 17) revealed varying but mostly mild degrees of secondary coproporpnynnuria in the majority of them (Lange et at. 1976b). The significance of 50 W.K Lelbach and H.J. Mameller 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 Cross Inspection of the Liver and Spleen The gross appearance of the liver, as assessed by peritoneoscopy (\fanu:Uer et al. 1975a. b.Marstcller and Lelbach 1977;Lelbach and Marsteltcr 1977) or at exploratory laparotomy, is that of a normal-sized 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-iike appearance. At most, there are micronodular changes but the diffuse coarse nodulantv of cirrhosis is only rarely seen. Progression to frank cirrhosis with severe derangement of hepatic lobular architecture was observed by Smith and Wiliams (1974), and also in two of our recent cases in combination with development of angiosarcoma. On palpation (direct or by pentoneoscopic probe), the texture of the liver is normal or only slightly firmer than usual. Indirect pentoneoscopic 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. Pentoneoscopic view of left hepatic lobe in noncirrhotic portal hypertension (January 1979). Blunted antenor edge, smooth to finely granular surface, conspicuous patchy capsular fibrosis. (47-year-old autoclave cleaner. VCM exposure 1963-74. 1973 thrombocytopenia as first sign. From 1974 to 1979, marked progression of porui hypertension with splenomegaly and one episode of bleeding from oesophageal vanccs.) See also Fig. 5 (patient 6 in Table ID Vmyl Chi contras: >> pectedly s is a focal opacities.` stellate sc: ing (Marsh tissue in C extending neetive tiss processes h or more dt> are seen in 4.2.4 His' Histologic. is generally sis, strikin'* fibrosis are (Fig. 5a-d> reactions. throughout fibrosis. Sntological tu 1978). Depend date of bie; nant liver u ject to mark ations is sc. Thomas 19" 1976). but (Popper et a 4.2.4. i Hu In its fully <1 of dense, pm bile ducts a: with format! central and i of connecm with enlarge pensinusoiil. oidal walls, i Muller et ai. Mirsistlvr Elation to ..ret al. >t exploratory tigan with neoscopy aiso '<tek et al. ' with shallow x !`onnge-like rtf nodularity lsrangimert 11, and also roma. liver is normal 'urtaj hyper1 me mtesthe abvlomi'tension otter, \ pertension -. conspicuous 'H3-U. . tilun of it rvoptiafral Vinyl ('hlonde-Aooitiated Diseax 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. Tlx degree of capsular involvement ranees from diffuse uny commalike or stellate scars to coarsely reticular ami irregularly patchy milk-*nite capsular thicken ing (Mjntelkr et al. 1975a). Histology showed that tins focal increase of connective tissue in Giisson's capsule may extend into the parenchyma and connect with septa extending from enlarging fibrosed portal tracts \Poppcr md T><onm l75). Tlx con nective tissue capsule of the enlarged spleen also seems to be sensitive to VCM-induc:d processes that have taken place in the underlying tissue so that focal white thickening or more diffuse opacities together with circumscnbed subcapsuiar haemorrhagic cysts ate seen in cases with marked splenomegaly. 4.C.4 Histology Histological examination of biopsy- specimens shows tint normal lobular architecture is generally maintained, but varying patterns of portal and. in some cases, septal fibro sis. striking intralobular pehsinusoidal 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 present at all, are insignificant. The lesions ate 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 hisioIoqcx evaluation chan needle biopsv specimens (Smith at al. 1976a: Blendis et al. 1978). Depending on iengrh and degree of exposure, interval between last exposure and date of biopsy, as well as individual factors.histopathology of VCM-induced nonmalignam liver disease is represented by the following features whose manifestation is sub ject to marked intetindividual and topical variation: the tame variability of tissue alter ations is seen in the nontumorous areas of the liver in angiosarcoma (Popper and Ttfjnm l9?5:77iomesft al. 1975: Jerk t al. 1976, Gtdigk et al. 197J; Weinbnn 1976). but in these cases the nontumorous lesions may be even more conspicuous (Popper et al. 1973). d-2.4.; Hepatic Ftbmm In its fully developed form, minimal to marked enlargement of portal tracts by excess of dense, pauciceliular connective tissue, which in advanced cases contains proliferated bile duets and some pehductular inflammation. may in nr* instances be combined with formation of periportal septa 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 Gisson's capsule may be connected by septa with enlarged infneapsular portal tracts. A more striking feature is an intralobular pensinusoidal `netlike* fibrosis with more or less prominent eollagenization of sinus oidal wails, in some ares even progressing to frank capillarization (GeUigk et al. 1975: Stutter st al. 1975). The focal intrasinusoidal fibrosis may be subtle and in some cases ucc 044269 5S& s*r* Vr.K. Ldbach and H J, MaiMtriler Vin .i 'V.i. ", * / % t'-f, *v.* *.r -,* * .-.f *- * *- * * ?.*.*,.* V'*** . * *. % r. \ ;:-a , -* v .*'*v :<;.* Fig. 5a. Needle biopsy specimen of the liver shown in Fig. 4. Enlargement and fibrosis of portal tracts. Moderately large droplet steatosis. Focal dilatation of sinusoids H &E. x 80. b Close-up of Fig. Sa. Indistinct border of enlarged and fibrosed portal tract to wards parenchyma fitft). Proliferation of capillaries (> <) with polymorphism and hyperchromasia of endothelial cells. PAS, x 400 IJCC 044270 "arsieller V:rnl C!ilcrtd9-Aj`i.'CMtcd Di'Ca^ *> ff* ;^i i,#' 'v ' v "** " *#* *. *^ a **/ ^*v., * . t- tHr.v- /: ihfOilJ . H&E, r3Cf to- and Fif. 5c. Focal portal fibrous /Itft upper comer) and reticulated perisinutoidal fibrosis with activated proliferating and pleomorphic sinusoidal lining eells. Trichrome (Goldnr) *tam. blue filter, x 250. d Conspicuous focal dilataiion of sinusoids. Activation and moderate polymorphism of proliferated hyperohromatic sinusoidal lining cells. Enlarged hepatocytcs with iiyperthrematic nuclei, some of them bmuclear. 'Potential precursor stage of anposarcoma') Courtesy of Professor Miiller-Wallraf. Institute of Patnolosy, Amber*. H A E. * JOO ucc `*T 044271 54 W.K. Lelbach and H J Mjrvieller may be recognized only in connective tissue stains. Triclw et al. 11 *>75) pointed out that in one worker with severe acroosteoiysis but nonnal hepatic function and essen tially normal liver histology on light microscopy (except for a minimal and easily over looked increase of pensinusoidai collagen in occasional lobules), electron microscopy revealed a striking centrilobular increase in collagen between hepatoeytes and m Disses spaces together with proliferation and hyperplasia of sinusoidal lining cells (see also Kurokawa et al. 1977). The same ultrastructural deposition of pensinusoidai 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 sinusotdal 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) {Summcnchild and Kluge [911 , Kluge et al. 1970; Tendon et al. 1970). i.2.4.2 Sinusoidal Lining Cells 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 ate often arranged in a chainiike fashion (Cedigk et al. 197$). These pensinusoidai and sinusoidal cells include three types: (1) nonnal endothelial cells, (2) lipocytes (Ito cells), considered to be precursors of fibroblasts and (3) plump cells with spindle-shaped nuclei and PA5-positive cytoplasm. Formation of excess rencuiin suggests fibroblastic activity of some of these cells. Focal dilatation of sinusoids, not explained by passive congestion, is another peculiar feature usually associated with particularly pronounced alterations of these mesenchymal cells.- There is reason to be lieve that this combination of changes may represent a premalignant stage. 42.4.3 Hepatoeytes Unimpressive, nonspecific, degenerative and adaptive lesions (such as minor degrees of fatty degeneration, cloudy swelling, ballooning or vacuolar degeneration, increase of lipofuscin pigment and proliferation of smooth endopiasmatic reticulum of hepatocytes in focal areas without inflammatory reactions), can be seen to disappear gradual ly with increasing intervals between the last exposure and the date of biopsy, in con trast to the apparently irreversible damage to mesenchymal structures (Cedigk et al. 197$, 1977;Muller et al. 1975). In poorly demarcated areas there is hyperplasia and hypertrophy of hepatoeytes 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 undtflned role in the precursor stage of angiosarcoma (Popper et al. 1973). 4.2.4.4Histology ofthe Spleen Unless splenectomy is carried out in vinyl chlotide 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 follicles with mi endothelial cells occasional fresh spicuous fibrosis In ten cases w Heusermann and terial. together v splenectomy, Th process. Excess a five tissue.notit and white pulp. There was scamr meshwork and re and diameter of of the pulp cord.1 formation of biz. collagen fibrils, h the reticular com volume with pais mation of capilla found within the thrombocytes by hanced pooling o help to explain tn stages of vinyl chi and Heusermann < VOl-induced spit of the liver or ex'. in the spleen in vi dicate a primary . port correlating ci tients is being pre; the spleen in none able for comparisi 4.2.5 Pathophyst The pathophyiioli unresolved probiei to splenoponograr of intrahepatic va* venous radicles (Bi and a nonnal, or o ucc 044272 a JJ Marstelltr pointed out .m and essenmd easily over* i microscopy -s and tn Dint's 11s (see also .tidal collagen w* could ob* 'gel (enlarger and resulting oohysiatogy n a number ot wial histones tan et *1. I nuclear poly-nesenehymal .pc or resemble ,075). These - i-^lial cells, >3) plump cells seess reticulm 'iiusoids, not with ^Jbn to be* "<tor degrees of m, increase of i of hepato* ippear gnduai* >psy, in con* rtdigk tt al. iwrplasU and ''nucleated nj degrees of iy some as yet *8). cus of the ritumaj (1975) Vinyl Chloride-Associated Disease and Thomas et al. (1975) found the cut surface of surgically removed enlarged spleens to be characterized by conspicuously hyperplastic Malpighian follicles in a beefy homo geneous red pulp. Histologically, they noted lam germinal centres of the Malpighian follicles with merging of perifollicular zones, dilatation of red puip sinuses lined by endothelial ceils of vanable. often cuboidal shape, thickening of the pulp cords with occasional fresh haemorrhages, and in one case Candy*Cantna bodies, but only incon spicuous fibrosis of the red pulp. In ten cases we obtained needle biopsy specimens of spleen tissue a* peritoneoscopy. Heusermam and Smite (1977b) and Stutte and Heitsermann < 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 fibrous process. Excess amounts of newly formed extracellular elements of reticular connec tive tissue, notably collagen, produced by stimulation of fibroblastic ceils of the red and white pulp. particularly in perifollicular and subcapsular areas, were observed. There was scamng of penartenal lymphatic sheaths, obliteration of the pulp cord meshwork 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 platelike amorphous structures containing irregularly distributed collagen fibnla. Narrowing of the labyrinthine eordal tissue with marked increase of the reticular connective tissue caused a reduction of microdtculatoty 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 eordbed in addition to increased phagocytosis of thrombocytes by residual macrophages. This lends support to the hypothesis of en hanced pooling of plateleta in the spleen (Heustmann and Smite 1977*), and may help to explain the pathogenesis of thrombocytopenia often seen even in the early stages of vinyl chloride disease. By structural analysis of histomemnl results. Stunt and Heusermann (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 at extrahepadc portal vein occlusion. They concluded that libtotic changes in the spleen in vinyl chloride disease are not the result of portal hypertension but in* dicate s primary action of VCM or its metabolites on the spleen. A comprehensive re port correlating clinical 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 nondnhotic portal hypertension of unknown aetiology are now avail* able for comparison (Seki 1965; Yamamoto 1978,1979). 42J Pathophysiology of Portal Hypertension The pathophysiology of portal hypertenrioa in VCM-induced liver disease is as yet an unresolved problem. Patency of the portal vein was demonstrated in ail cases subjected to splenoportography. Portography usually showed no or only minimal derangement of intrahepatic vascular pattern such as apering or `cut-ofT of small peripheral portal venous radicles (Blendis et al. 1978; t'Uknetne et al. 1976). High intrasplenic pressure and a normal, or only slightly raised, wedged hepatic vein pressure indicate that the ucc 044273 WJ m* a portil flow is obstructed at the sinusoiJa) or presmusoidal level. In a group or rive PVC workers selected for haemodynamic studies. Blcndis et al. f 1978) could not demon strate a direct relationship between the decree 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 has also been suggested by Pnppcr 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 properl) 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 perutnusoida! fibrosis. Blendis et al. (1975) found no correlation between spleen or estimated liver blood b Fit- 6a. b. Progression of noncitThotic portal hypertension despite termination of ex posure. Oesophageal varices. (Autoclave cleaner, age at diagnosis: 35 yean. VCM<xposune.1962-1972.1972 Raynaud's phenomenon, sklerodermoid skin indurations, thrombocytopenia, splenomegaly, and grade 1 oesophageal vanccs. Gradual progression of portal hypertension. Sudden death from ruptured anaplastic angiosarcoma of the liver in June 1978. Histologically only mild perisinusoidai fibrosis in nontumorous areas) flow : veiled 4.2.6 In 19tic fib could tests :l biopsv of bnd the fib cytes ( ing cel follow massiv expose sarcorr. or less terrain oped (: Lav determ (BMHP after h> and toi aid of < the reu incrcas. PVC psack et 43 Ai 43.1 1 Primary (angiob' haemaii ceilsarc sarcoma vascular one at e hood (ft the num cibach and H.J. Marsrelier ' lev*!. In a group of five PVC i IQ78) could not Jemoniibtosts in' needle bioos;. spec* :nd that the distribution of njecested bv Fopscr and J splenic and hepatic blood aaly cannot properly be ac cent of adaptive distension d pensmusoidal fibrosis. or estimated liver blood despite termination of ex* ptosis: 35 yean. VCM-ex dermoid skin indurations. 'I varices. Gradual progression tastic angiosarcoma of the i fibrous in nontumorous Vinyi C'.iljnde'AiOc:ated Diseaw ' 57 flow and the portal pressure. However, they point out that this relationship may be veiled by rhe amount of blood bypassing the liver via a collateral circulation. 4.2.6 Follow-up of Non-maiignani VCM-mduced Liver Disease In 19"4.t/um et al. (see also Berk et al. 1975) pointed out that VCM-associated hepa tic liorosis. once established, may progress even after cessation of exposure. They could demonstrate tins progression despite normalization of all routine liver function tests m a 2".year-old worker on a follow-up examination including peritoneoscopy and biopsy 2 1/2 years after cassation of exposure. Progression of fibrosis and appearance of bridging between portal and central veins were indicative of persisting activity of the fibroblastic process, w hereas the previously observed activation of both hepato* cytes (marked venation of cell size and numerous binucleated cells) and sinusoidal lin ing ceils had disappeared. Since 1973 we have observed a number of workers who on follow-up allowed evidence of progressing portal hypertension with deveiopment of massive oesophageal varices and subsequent bleeding episodes despite removal from exposure (Fig. 6). In five (7?) of these patients with progressing porta! hypertension angio sarcoma of the liver finally developed. !n this context.it is of interest to note that more or less conspicuous hepatte 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 (sec Tables 13~18). Liver and spleen scans with Wm technetium-labcIIcd sulphur colloid, quanutated determination of spleen xi2e with the aid of l,THg-bromomercury-hydroxypropane (BMHP) labelled artificially damaged red cells, and sequential perfusion scintigrams after bolus injection of "Tc-pcrtechnetate have been found useful in the diagnosis and follow-up of nonmaiignant liver disease in PVC-poiytnerizatioa workers. With the aid of these noninvasive 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 fibrosis and portal hypertension iBiertack et al. 1975a, b, 1977a. b). 4 J Angiosarcoma of the Liver 4J.1 Epidemiology Primary angiosarcoma of the liver (A5L) is described under a variety of synonyms (angioblastic sarcoma,angioblastic reticuloiaicoma. endothelioma, emiothelioblastoma. haemangiotlastotna. haemangioendotheliorna, haemangioendothelial sarcoma. KupfTer cell sarcoma, malignant haemangioma, metastasizing haemangioma, reticuloendothelial sarcoma, primary sarcoma of the liver). It is in exceedingly rare malignancy, arising from vascular lining cells. It occun spontaneously with two peaks in the age distribution: one at cariy infancy (infantile haemangioendotheUoma) 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 jSSfeS f3s$ c" ' 5S#I Jp MSfe* 4& 5gfe> 53 W.K, Lelbach and H.J. Mursteller ot` the literature.^ ire/rga (1975) lilted 165 published cases of primary angiosarcoma of the liver in adults. In the six autopsy senes collected by Alrcnga. ASL constituted only 1 SHe (0.9^--' .7%) of 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 ringed 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. Tsble 12. Incidence of angiosarcoma of the liver (ASL) in autopsy senes Authors Year Observation No. of No. of cases 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 MacSween et al. 1973 1900-1969 _ a I 3 Los Angeies. County Hosp.. USA Western Infirmary Glasgow, U.K. A Irenfa 1975 1951-1973 39 700 6 Cook County Hosp. Chicago, USA Rein and Huth 1975 1954-1974 30 079 Byren and Hotmbert 1975 1958-1969 _ b 4<6)c Dii-iscldorf. Fed.Rep. Germany 12 Sweden (adult eases) Dalderup et a). 1976 1960-1975 At least 40 000 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, I malignant hacmangiopencytoma Accordingly, the identification of 4 cases of ASL among approximately 270 em ployees of the vinyl chloride polymerization section at a BI. 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 et al. 1974a; Creech and Johnson 1974). Until 1974, only two carcinogenic agents were known to be associated with the development of ASL in man, ie. the administration of a radioactive colloidal prepara- Vinyl ( tion of inorgai. dioxide tern am Thoi contras ing evid reponei been th< had bee and Mo, A speci; caused 1 rihorotr from a 1 ASL (R* Devt man vin tensivel) 1950-1 tion rev* of multi; approve occurred but nota produce* Haustrui (35-5'. ' Roth{\<18.6-t: Fowler > Chow haemang! tension h woman w ride) duri had a hici manifests The pr be elicitci period 18 history ot Among m observed other han 391 auto; vcc - tis Marsteller ..iosareoma lonsuiuted -"ch of themlie incidence ith a ntan 11975) it was : isQ.Ql-1 m 'lime. 'er.Minn.. ivies. Hosp.. L'SA i Iniiman. . L'.K. 'nntv Ho<c. ISA ft Fed Rv(., ids I mil. nillion) ties Sunns .neyfoma ty 270 em-iant star luiy recog-wd (Ciredi I with tht iJal prepara- Vinjl C!ilonde-As<-ociatcd Disease 50 non of rhomnn dioxide (thorotrast) for diagnostic purposes, and chronic exposure 10 inorganic am-ntcals 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 pemianendy retained: arsemcais are only slowly released from the liver. Thvmtrcst came into use in 1973 and u as internationally employed as an injectable contrast medium until the mid-1950s, when trs use was abandoned because of mount ing evidence of ihe carcinogenic action of ;honum dioxide deposits..'/ac.'/u/io" er al. reported the first case of thortum -iioxide-'uduced ASL m 1947. Since then ASL has been the type of liver tumour which occurred most frequently among patients uno had been given thorotrast injections in the past (da Siha Horta 196": da SHrj Horn and Morra 1967; Wegener et al. 1971 ;fur/i and Pinke 1974;Selingcr and Kujf 1975). A special type of progressive portal and subeapsular hepatic fibrosis was another lesion caused by thorium dioxide retained in die liver, da Sih a Horta (1967) considered this thorotrast fibrosis' to be clearly distinguishable from true cirrhosis. Gamma radiation from a lost radium needle has also been implicated as a causative agent in one case of ASL (floss 1932). Development of ASL as a late complication of chronic ancntc intoxication in Ger man vineyard workers was first described by Liebcgott (1949,1952) and has been ex tensively documented by Roth (1956,195"a, b. 1959). During the 10-year period. 1950-1959. autopsies of 82 Moselle vintners suffering from chrome 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. arsenic insecucide sprays and dusts had been approved for use in German vineyards but they were banned by law in 1942. Exposure occurred not only via inhalauon dunng 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. Tins Haustrunk, an allowance m kind to the vineyard workers, had a low alcohol content (3%-5% r/v) but contained high levels of residual arsenic (0.2-& .9 mg As-Oj/Utre). Roth (1956) calculated the mean total ingestion of AatOj te have been 53.7 g (range; 18.6-88.8 g) for a 12-year period. ASL was also seen after long-term treatment with Fowler s solution for psonasis (Rcgelson et al. 1963;LrnJcret al. 1975). Otowduty et al. (1977) reported an anecdotal case of apparently benign diffuse hacmangioendotheilORiatosis 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 dry-cleaning 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, ron Bteka' and Bitscher (1961) listed 12 of 54 adult cases with a history of exposure to either thorium dioxide (7) or anenicals (f of Roth's cases). Among more than 15 000 autopsies performed in Bonn duisig 1950-1959, all 8 eases observed were found exclusively in vintners exposed to arsenicals (Roth 1959). On the other hand, Fiechmer and fli es (1976) recently observed a cluster of 4 cases among 391 autopsies during a 29-month period at a hospitai in rural central Wisconsin serving I ucc 044277 M3 W K.. Lelbath and H.J. Mantellcr Table 1 3. Personal data of 68 oolvvinyl chloride production workers with anEiO'jrcoma Ol the luer reported to NIOSH up tu August 197$ tSpirtas and Kaminski |97ji Birth date No Country3 (m/d/y)15 1 Bill 01.12.13 * CNDtl) 12.15.13 3 CND12) 03.06.14 4 CND (3) 08.26.19 5 CND (4) 04.05.19- 6 CND (5) 05.07 1| 7 CND (6) 12.15.19 8 CND 17) 11.09.19 9 CND (3) 05.13.20 10 CND 19) 07.19.21 11 CND < 10) 05.16.15 Date of death (m/U.v) 06.29.76 09.02.55 12.21.57 03.22.62 Ol.2l.b8 07.05.68 04.10.7! 12.24.72 06.12.73 09.04.74 04.00.77 Age at death 63 41 43 42 48 56 51 52 53 53 61 Tofjl >car\ e\p. ` 17 11 14 20 5 23 25 5 26 14 Job classitivation1- 1.2 1.2 2.3. 12. 13 2.5 1.2.5. 14 1. 14 1. 12. 13. 15 1.9. 17 1. 12. 17 3. 12. 16 2. 16 i: fSR f1J 13 C5R 12) 00.00.28 00 00.26 12.00.73 00,00.66 (647) 45 40 (37?) 16 15 (14?) 1 l 14 D (1) 13 D(2) 16 D(4) 17 DC) 18 DC) 19 Dig) :o D (9) :i D < 10) DUD :S D (12) 06.04.30 07.26.31 09.04 JO 01.01.32 09.29.26 10.19.17 12.13.34 07.23.29 12.29.36 06.14J8 01.25.69 12.14.71 11.25.74 01.09.75 11.13.75 12.25.75 03.24.78 06.28.77 03.07,77 10.07.77 38 39 44 43 49 58 42 47 4| 39 12 11 17 12 2.4,5 12 11.(I) 21 15 To 10 16 10 61 14 F(l) 23 F (2) 26 F (3) 27 F (4) 28 F (5) 29 F (6) 30 F (7) 31 F (8) 32 F (9) 33 F (10) 34 C.B(I) 35 CB (3) 04.15.24 06.03.11 01.06.20 01.27.27 01.29.38 04.14J4 00.00.27 04.01J4 10.08.14 05.24,19 04.20.01 06.02J7 02.19.67 01.24.75 06.26.75 01.03.76 05.13.76 09.12.76 07.02.76 01.30.77 12.25.77 01.20.78 12.03.72 12.24.74 43 63 55 49 38 42 49 42 62 58 71 37 19 1.2 12 29 y 26 2.6 11 1. 2 13 6.7 *m 19 28 21 8 41 *3 1/2?) 36 1(2) 37 1(3) 38 3(1) 39 3(2) 40 N(|) 11.13.29 03.14.20 08.01.22 08.02.29 12.23.15 12.27.72 07.10.75 10.24.75 08.10.76 01.04.72 43 55 52 37 56 6* 21 13 21 Vinv Tabic -- No. 41 42 43 44 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. NI) CSK D. F. GB b 00. d c t.Jl 2,31* 3. pi* 4, p.' 5. fo: 6, `fit * r* 8. pr 9. chi (Table* ! itferem. arsteller :iuiif;onu 'cation Vinyl Chlonde-Aaioetaied Diitj'C Tabic 13'continued) Birth date No Country-1 tm/d/v)** 41 SHi a; 5 < 3) 4? 5 <41 06.33.37 36.10.10 11.16.14 44 USAi I) 10 1733 45 usa <:) 08.19 33 46 USA (3) 05.35.13 47 USA |4) 01.15.34 43 USA (5) 01.35.13 49 USA 16) 11.23.28 50 USA (7) 05.03.:: 51 USA(8) 05.06.30 5* USA (9) 11.08.31 53 USA 110) 03.16.13 54 USAUl) 05.27.09 55 USA . 13) 11.17 18 56 USA (13) 13.01.31 57 USA 1 16) 11.04,37 53 USA i 1 7) 05.06.31 59 USA 118) 04.23.:s 60 USA (19) 00.00.15 61 USA CO) 08.31.17 6: usa.:d 09.03.09 63 usa a:) 10.03.33 64 USA (33) 00.00.33 65 USA 134) 05.07.17 66 USA(33) 08.07.10 67 USA (36) :<197S> 61 YU(I) 04.05.14 Date ol death (m/d'y) 10.30.70 05 19.*6 05.13.77 Age at death 43 65 63 Totjl jearv e\o 13 31 31 Joh, * 03.03.73 09.37.71 12.19.73 01.07.68 04.09.64 07 24.75 03.33.68 08.38.61 03.00.75 05.10.68 03.16.70 05.03.69 07.04.74 03.37.69 1978 alive 11.02.75 04.06.76 01.30.77 01.0177 12.04.76 04.06.73 05.37 77 C3.10.77 ?(1978) 49 37 53 43 53 46 45 41 43 55 61 50 53 41 43 46 60 58 67 53 50 60 67 7(197S) 31 13 38 15 30 13 17 IS 34 17 33 19 38 4 19 11 23 21 21 38 14 36 20 7(1978) 9 9 10 10 10 10 9(1) 08.04.73 59 30 1,3.5 a B. Belgium ND, Canada. CSR. Czechoslovakia 0. West Germany F, France CB, Great Britain ^ 00. data not available. c 1. autoclave cleaner 2. autoclave operator. 3. pipe fitter 4. polymenzer 5, foreman 6.*flltrvur 7. 'preparateur de solution' S.procts* worker 9. c hemtcjl owra tor I. Italy J. Japan N. Norway S, Sweden USA, United States of America YU, Yugoslavia. 10, polymerization worker 11, technical asistent 12. maintenance worker 13. millwright 14. water cooling unit 15, rtager 16, furnace operator 17. machine shop worker (Tables 13 -1S tic compiled with the aid of information contained in the literature; references see Table 15) uec 044279 L'le.-i 6! W.K. Lelbadi and H.J. Marsteller 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 nondoeumented 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 pehods 1963-1973 in England and Wales and 1965-1973 in Scotland recorded 41 cases of ASL (1-9 cases per year: mean: 4 cases per year). An unexplained peak was observed in 1963/1969 (Baxter and Fox 19",5). 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 unciassifiable, 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 of ASL among vuiyt chloride polymerization 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 1975; Spirtas and Kaminski 1977). As of August 1978. data had been presented on a total of 68 cases of ASL among polymenzation workers (Spirtas and Kaminski 1978, pen. comm.); another eight cases had been observed among nonpoiymerization workers exposed to VCM in various jobs. On the basis of this data collection communicated to us in 1978 - for which we w ish to thank Drs. R Kamtnski andR. 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 papen published by Delorme (1978a) and Delorme and Makk (1975); seven of them were described in more detail by Makk et *1.(1976). Cases 19 and 23 were observed at our clinic in i jnn but details have only been published for case 19 (E.U. in Lclbaclt and Marsteller 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 Staatlieher Gewerbearzt, Diisseidorf (Rein/ 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 17 th 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 polymenzation worker. For the 67 VCM polymeriza tion workers for whom details were available, tout 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 103/4 yean (range: 3 1/2-21 yean). The latency period (yean from fust 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). d H.J. M iftteiier a * r o' S " 5jj ^ ec r s ;|s0 * fclzr fr ?i rlt tonr. 2Mg|3|aa's"?---?sO:'' ^r2^|3.=|r`av<*=, 1r25<1t:i2a"o=M no9^o- ^aa9-i. E2oS^g3 = SP-g2Q ?!!1 &* B o. ^ 0 CD o- 31 ??. S^' "-* 5d Scs 3g 3*- \ b. iL =: 5. h ix io. 2, oEoWSg Ig ? -g 5 " (* r .m t3 n * oS"e3&-S .'C*O*h* ^ Sno cCh ^t " a s- g. 5 |z 3 O; 3" *U i3fJUs<Ti *n"* U5a 3aU_*<> O*nowC1 'V inyl Chlonda-Associated Disease TM M. Clinic*! w! wmpliotofkJ tlili <*o bt polyvinyl chlornlc ll*VC) pruducliim winters with ineniuriiiiiu til lire Itm iciitirlctl in NIOSII by Aupoil 1971 llcpa Io Nu. nicpaly Spleen 1 Alropbic, (2900() tliphlfr imlunlcil ll Ocn|i|u|tij| llepalK VJfii.CS lihiooi Tlironibocylopcnia ( Nunciiihotii.* ? perkuimsoidal A opailnr Capiulai ' Acroosleolysis O' It aynami's plietimm:mm Mclaslaset 00 ) ('ipMiUr, potlal, pcminiiuiitljl 4 5 6 7iam: L (-* 1 r (1160*200*1 a l Ha delailf * avertable 10 Sclcioat of wall of portal vein Capsular. trial, pillsihHMHlM t Captolar, pojlel, > penaaamtilil Capsular. portal, perisinusoid al forlal. pcminuvudal Capsular. potlal, pcrisinusoidal No detail* available 1 one: mnlliptc idclaslnscs (lung. pleura, peiicarrtiiiiu, ileum, cull id. tiilneyi. Jell jilienall c 1 i-ativ mcilinslmat lyn>|t|i nihle 1 run" perilnueal spread 11 mi l local spread H i Capsular. ptiilal. perisiioisoiil.it ) ; rs {WO?BB3g W.K. Lelbach and H J. Marsteiler Tabk 14 (continued) Hepato No. megaly Spleen Oesophageal Hepatic varices (thrusts 1 lirornhoeytopciua n* Moderately m (7300*1 enlarged (Cirrhosisl, fibrosis 1 13 t (2750g) ? 14 Spleno megaly 7 (Cirrhosis) * ? IS Slightly V y V enlarged 16 + Spleno (2650(1 megaly (830(1 Capsular. portal, septal (72 000, 65 0001 17 Spleno *? megaly 18 7 Perisplenitis V 7 t (134 000. 68 000) 19 <> Spleno 11450 g) megaly (400 (I 20 * 7 () 1 Progressive perisinusoidal, (80 000, portal ami 47 000, septal cm In isc. 30 000) 1 * 21 * Spleno * * (I900(| megaly Aeroosteolysis P P P P P P P P J P Itaynaud's phenomenon Metastases +9 P I.eN lime P 4 Hi lell rib PP P 1st thoracic vertebra P Drain t 3rd hiiphjr vertebra PP 1 f PP 22 + Splcnume(.ily * 2J S pie no- 0 (2700(1 megaly (455 g) * Capsular, portal, pertsinusttidal Cocal perisinusoiilal 7 PPP P 09 Vinyl Chlnr 20 t * 21 Sptenu- 11900(1 me|aly I l.tl. at-caiiQ p.tic!?oi*.Y.?puo|i|j 22 Splcnumt|al|r T 22 Splcmi- 0 (2700 b) meBaly 1422 |l 24 4 7 2S 4 Spkao- (1610b) willy (410 B| T i 26 4 1 27 4 Spfcno- (2230 g) w|ily (400 b) 9 f 21 6 Splcaow|4y (610 Bl 4 29 9`Motlificalinni (I7S0 f) flbfn- ctingeiitive* 20 4 9 21 4 Splcnimtcfaly T (3000 b) (370 b) 32 4 t 32 I ? Capuilai. * piirlJl. lwiKkiniiwHil.il l:iwal penliunwijtl.il ? l*oflal, * periilnuwiiJJ 160000. fibrmii BO 000) Heikulalcil ! npuibi lilxmu, iuicitinotliil.il clirhowi Fwltl, peri- linusoiilal. f BO 000) capinln lilirmii Sliptil puilal ft IiIiiikii 9 9 9 Minimal flbltlMS 4 (aoooo, 40 000) Cjpvulai. 0 pmlal lilmnii 9 9 t 9 9 9 9 9 l.ot'ill >|lfLMit III I ;u4l U'i| 9 Diiotlcn.il wall 9 4lli ami 7||| llmiacic vcilclii.t, 51ti Icll uli, Icll .iilu n.il Small iiilckiinc .............. lal lymjili iiihIo 9 Table 14 (continued) llepaloNo. tnegaly Spleen Oesophageal Hepatic varices fibrosis Thrombocytupenia 34 Slight fi 0 * (2623 ) splenomegaly (40 000) 33 + Congested, (3240 g) firm (200 g) Nonciriholic 7 fibrosis 36 1 ? ? Acruosteolysis If 0 0 37 39 39 40 41 * 42 7 43 44 * Splenomegaly ? 77 Splenomegaly + 43 * S pie nomegaly * 46 t Spleno- (I960 g) niegaly T 7* 7t Suhcapsular and portal fibrosis Markedly t thickened capsule; marked librosis I'urtal fibrosis 7 7 7 0 0 0 Kaynaud's phenomenon Melaslaves 00 Ch Ok 00 0 Local spread lo abdominal wall and colon; lymph nudes W ,K. Lelbach and H.J. M arsteller ?7 77 00 PP 0 Spread lo duodenum 47 44 Spleno megaly 7 7 T forlal fibrosis u* s oont / Sprejil In <li.iplir,i|!in ami ulMluauiti.il wall 45 Spleno megaly 46 t Splenw- (IC60|) mctily 47 Spleno megaly 4 t f IS 300 s) 49 Normal SO I jl j fielatbnotpttMMieil s: 1 53 54 55 56 57 sa so 60 ftetafb uni published 61 62 62 64 65 66 67 66 Ua Hhit) W ciaiiptMmilic: lilillcil lilirmis hnlal lil> rusts / i* i i Spread In duodenum FwIjI filimsis ositmi) Slight focal Itcpjtriis I `minimal hepatitis*) fitpsnbi and 7 portal fibrosis }* P IVciilijf ? portal fibrosis, moderate cirrhosis ^ i Spicad In ili.ipliiagm and alnliniiiit.il wall l-Miif.s. I.if|!e and mii.iII lrwcl, plenra. pericardium intiH'.iidnini. Sidneys, Icll adienal lli.iplii.imu. reginiial. fetrn|ienliinc al anil ilicihaslinal lymph nodes. lunys, adiciial 1'l.iniK, I'caeltellmti 11 i apliragm. y.iI Ihl.iddcr. regional tyniph nodes, longs. scalp, ;.k till Vinyl Chloride-Associated Disease M CM <8 68 W K. Lelbach and HJ MarMcllcr Tabic 15. Publications on (he 68 cases of angiosarcoma of the liver listed in Tables 13 and 14 No References Additional relevant information l Hubkt et al. 11977) 1\ 3I 4 / Dtlormt and Makk 5 | 11975) 6 V Makk et al. (1976) 7 / Dtlormt (1978a, b) 8 1 Dtlormt and 9 1 Thtnault (1978) 1 I 11 / Hypertrophic, hyperchromatic and jt> pical endothe lial cells m the glomeruli; foci ot haematopoctic cells in liver and spleen Case no. 7: ASL associated with hepatocellular carcinoma (Dtlormt 1978b) (All cases from one plant in Shawinigan. district Trois Rivieres. Quebec) Schmidt and Bitora "I) (1976) 14 1 Langt et al. (1974b) 15 ) Cedigk et al. (1975) 16 Goktl et al. (1976) 17 Amann (1975) Riibsamtn (1976) At the same plant: 4 cases of VCM-mduccd cirrhosis of the liver plus 1 case of cirrhosis and penerahred reticulosarcoma and 4 cases of carcinoma of the Cl tract or lungs See also Rtml and Weber (1974) Set also Rtinl and IVtbtr (1974) Foci of haematopoesis within the tumour areas 1974 portocaval anastomosis: cholecystectomy Hypertrophic, hyperchromatic and markedly atypical endothelial cells in the glomeruli and in (he capillaries of the fungi 18 Rtml etal. (1976) 19 (Observed in Bonn) Moderate hepatic siderosis; chronic fibrosing panertatitu: tubular and interstitial fibrosis of the ttttts 20 Rtinl et al. (1976) 21 Rtml et al. (1977) 22 Rtml etal. (1977) 23 (Observed in Bonn) 24 Ravitr et al. (1975) 23 Roeht et al. (1978) 26 Rtty et al. (1976) Focal interstitial fibrosis of the panertas See also Btrrod et al. (1978) 1942 gastrectomy. 1974 splenectomy, right hepatic lobectomy (640 g). See also Roeht (1977); Puteh et 1.(1977y.Bonntton et al.f 1975. 1977),Btrrod et al.( 1978) No autopsy (see also Btrrod et al. 1978) Vinyl Chi' Table 15 t. No. Rei / Rn 28 Ruk 29 Rot 3 v Si Btr 33 ) 34 Li 35 Sm. 36 Me: 37 - 38 _ 39 40 41 By. 42 Byr, 43 44 Bb (n> 45 Bio (ca- 46 St*:* (ca> KllJ m UCC 044286 tiler otlie* veils V ! rhovs : 01 ical pillanes tncrea*' cpatie ech et '>d er Vinyl Chloride-Associated Disease b<* Table 15 i continued! No. References *7 Rocht et a). 11978) Additional relevant uitormation Chronic akoholu. See also Rnche i I7?): Butch et al. (l97~):errod et al. (I978) :s Roche et al. (1978) First symptom: vertebral and wOstal metxstises. Right hepatie lobectomy. See also Roche < 1 y"r).Puech et al. 1197"); p-.hchowiki e: al. 11979); Coude'c et al. (l9~6).Berrod e: al. (I97S) 29 Roche eral.M97S) 51 1 3: ( Berrod et al. i I97S) 33 ' 1960 tclerodtrmaiikc skin induration (hands), swell* ingot' face, upper extremities and icet. 1971 bilateral acrooueotym. Tumour penetration of the abdominal wall (fistula). Severe interstitial fibrosis of rearer; fibrosis of interstitial wall, slight mesangial fibrosis of flomtmli. Variable but generally slight fibronyalmosis of arsenal and venous vessel walls (skin, heart. lungs, intestine, testes) - 34 Lee and Harry (1974) 35 Smith et al. (1976b) Latency penod (Ut exposure -- death) only 8 yean (see also fox and Collitr 1977) 36 Matron (1974) 37 - 38 39 _ V * 40 41 Byren and Holmberj (1975) 42 Byrin et al. (1976) 43 - 44 Block (1974) (cat* 3) 43 Block (1974) (cat* 2) 46 Block (1974) (caa< 4) 1965 portocavai shunt. 1970 cholecystectomy. See also Falk et aL (,1974a) (case 4); Whelan et al. (1976) (case 1) No autopsy. See also Creech and`Johnxon (1974); Folk et al. (1974a) (case 3): Whelan et aU 1976) (case 2Y,Makk et aL (1976) (case 6) Sec also Folk et aL (1974a) (case SY.Makk et al. f 1976) tease 10) 70 Table 15 (continued) No. References 47 Block (1974) (case 1) 48 Block (1974) (case 5) 49 Block (1974) (case 6) 50 51 52 Whelan et al. (1976) (case 3) 53-67 - 68 Zones et al. (1975) W.K Lelbjch and HJ MarMeller Additional relevant information See also Falk et al. i I974j) uase 2). Makk et al. 119"6) (case 4) See also Falk et al. (1974a) tease 1 ):Mukk et al (1976) (case 2) See also Falk et al. 11974a) tease 6): Whelan et al. (1976) (case 4); Makk et al. 11976) (case I4> * Chronic alcoholic. See also Makk et al (1976) i case 13);fieri: et al. (1976) (case 2) Among a work force of 180 < 1 20. PVC polymeriza tion; 60. production of VCM) employed at this plant. 15 died of malignant disease (2 ASL. 5 bronchogenic carcinomas. 1 case each ot carcinoma of the iarynv. nb. mamma, spermatic cord: glioma, meUnosarcoma. leukaemia. Hodekm's disease) Fint exposure to VCM for these 67 cases of ASL dated back to the period 19391966 (median; 1951). Twenty^ne years later, j.e. from 1972 onwards, a gradual in crease in the number of new cases diagnosed and reported to N10SH can be observed (Fig. 7). The onset of this gradual increase coincides with the calculated mean latency peril'' of 21 years (Sp&tas and Kaminski 1977). Sp&tas and Kaminski also suggested that >n future cases the age at diagnosis and the length of the latency penod 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 of ASL for which morphological details are available varying degrees of associat ed hepatic fibrosis in nontumorous areas of the liver were mentioned. Less often, evi dence of portal hypertension and splenomegaly were noted. Metastasis of angiosarco ma to distant sites was observed in approximately half the published cases. It is of note that aeroosteolysis and cutaneous stigmata of scleroderma have been observed in only 1 of these 76 patients, a French PVC worker who had apparently not been engaged in reactor cleaning (case 29;Roeht 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 (kidneys, lungs) in autopsy material from two patients (cases 1 and 17, Hubltt et al. l977\Riibsamcn 1976). Hubltt 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- A* stores UCC 044238 teller ai Jl, .-1 il . < f ease1 *neriZ3` punt. Jiogrmc urvn\. ircoma. ^^hred i latency -c.-ested nay in- ui the auociat'ten. evi4 losarco i of note I m only staged f infotmi* Hromatic autopsy *76). iix tissue of VCM an. Anpo- Vinvl Chloride-Associated Disease Table 16. Personal data on eight cases ot angiosarcoma of tlx User among VCM-e\- poed personnel not emploved in PVC production us reported to NIOSH by August 197SW Date ot Birth dare death No Country l-i 1,'yl5 i m/J >' A 0(3) 07 lb.50 10.10.7 5 Total Age at years death exp. 43 14 lob classification Loading pesticiue cans with VCM propella.-.t B D (6) 05.09.36 1Z.16.74 r GB l Z) 09.08.U 12.00.70 38 55 3.5 Assistant factory chemist n Pouring PVC oil mix- ture onto fabric bases ' '* D lit) 06.15.34 04.16.71 36 3 Fabrication of PVC sacks and wrappings (extrusion at temperatures of 120* O E s t; ii.:7.n 08.16.71 61 23 Assistant factory chem- ist (production of VCM) F USA f 1 5) 00.00.25 02.15.73 47 * Accountant at plant producing PVC fabnc G YUC) II. 15.31 07.12.73 42 18 Production of VCM H YUiJ) i:.:i.3i 01.11.76 45 Production of VCM * Update of NIOSH register, August 1978. prepared by Kaminski as in Table 13. b 00. data not available sarcoma arising from the kidneys or other types of malignant renal neoplasms, how ever, have not been described in VCM-exposed individuals, although malignant nephro blastoma has betn induced in experimental animals. The extremely rare coincidence of engiosarcoma and hepatocellular carcinoma was found in three instances (cast 7, Dtbrme 1978b: case E, Byrin and Holmbtrj 1975, and a case not included in the 1978 NIOSH update Tambum ct si. 1973a). In the case reported by Tambum ct ai. chronic alcoholism may have played a cofactor role in the development of liver cancer. Wt can now add a fourth case observed in 1978 at the Department of Medicine in Bonn (see Sect. 4.1 J and Fig. 3). This patient (patient 9 in Table 11), a PVC-poiymerization wodeer (total period of exposure: 1$ yean) was first admitted to our department in February 1975 and was found to suffer from atyp ical einhoss of the Uver with porul hypertension, splenomegaly and Raynaud's phe nomenon. During followup ASL was clinically suspected but could not be confirmed during life, despite exploratory laparotomy and generous surgical biopsies. The patient sirar V i. ~ *; ** * Table 17. Uinicil and niorph<4oekal Jala *m eight aw of aiigiosjri:iiin:i of llu- |jnr umune Vl'M^xpowi pcrv incl mil citi|i|uyt*cl m FVC (lotymcHulton 4 i'J llcpjlftNo. inccjly A+ (6000 f) a (J6S0*I c Spleen Oewoplioiical llcpjlic varive* ll>r(i%is Thromhocylo|icnia SplunnKfily fibrosis * Spk-nn- mcgaly (42S |) Focal u|niihr fS fibrosis, jidiIjI and cent mbdollar litirosis i-.lcnly-.i-i 0 0 It jy Hand's 1 > lie nnrncnon Mclaslascs 0 l>iaplirai;in. gastric mucosa, abdominal lyni|ili node* 0 Diaphragm. pleura, abdominal iyinpli itodc-i i) ( 1: No| cnLiFycd 0 t 1 1 0 0 Lungs, pericardium +00 * f 104 000) F C+ Spk*nomc(uiy f 1 * 0 4 Dm a, cranium II I ij | -jr j\ f n pur iprqi?-] U,A Is I ^<ss--s! 3g'32.s<^ars 3 -9 & I i n i m Q ., 5- a s ? s 5 ^ ? 3 ? * I on -|?| O*. *o* sutler Vm> I ChionJe-Wociated Disease < Tabic IS. Publications on the eight cases of angiosarcoma of tltc liver listed m Tables It) and I 7 No References Additional relevant information a Rt :nl and iVeavr 1|0?U| l?n" iUirpail-.lv portal ;iy pertension. portacaval shunt a Zimmermann and Eck l"? ngnt hcmmephrectomy for jn:!are-:l hydro* i1975) nephrosis associated with bilateral Jcuble kidney Rttnl (1975) Foci ot haematopoetic cells in spleen and kidney. Fibrosis of the pancreas. Slight fibrosis of testes and of the small intestinal serosa r 0 Mjltont < l C7at Autopsy angiomatous epulis. Angiosarcoma involv ing liver, lungs and pericardium The pericardium might have been the primary sue! Bvrin and Holmbtrf Probable coexistence of a hepatocellular cancer of (197J) both low and high grade differentiation F G Zorica et al. (1975) H * died on 7 August 1978, alter a massive haemorrhage from oescpr.sgeal varices. Autop sy revealed both muiucentnc meustasuing angiosarcoma and hepatocellular carcino ma of the liver as well as slight fibrosis of the pancreas (to be put! shed in detail). It is still unexplained why hepitocytes art generally exemg from the carcino genic effect of VCM metabolites but. as predicted by ?opper in 1975. three anecdotal cases of hepatocellular carcinoma, on* German (Gokeltt al. 1976) and two British PVC workers (Fox and Collier 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 tltc Province of Quebec covering the period 1969-1972 showed a preponderance of adult male cases in urban areas clustered in the district of Trois-Riviere in congru ence with the distribution of the plastics industry, a coincidence which calls for further investigation of a possible exposure to industrial carcinogens (Jacob and Theriault 1975). . Sot included in the NIOSH register are several anecdotal cases of ASU capillary and cavernous angiosarcoma of the liver and haemangiosarcomatosis of sites other than the liver, for which a relation to occupational or even posibiy residential exposure to VCM has been discussed (Soria et aL 1977; Brody tt al. 1977;Air et aL 1975; Wattnrifer and Zinnagl 1977). Although of undetermined 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 fcases 19,23, B and the above-mentioned raesq UCC 044291 n W.K. Lelbacli ind H.J. Marstdler patient with both angiosarcoma and hepatocellular carcinoma I. Fibrosis of the testes was observed in three cases (19,29, B), and Roche et al. (1978) also reported fibrosis/ hyaiinosis in vessels of skin, heart, lungs and intestinal wall. CUMULATIVE N OF CASES REPORTED TO NIOSH 1955 I960 1965 1970 1975 1978 year of diagnosis 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 t data from Spirtas and Kaminski 1977, 1978) 4.3.2 Clinical Manifestations The clinical symptomatology of usually multicentric ASL is unspecinc. Gradually de clining general health and Ion of weight combined with Hi-defined 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 felt fairly well. In a number alter testes rlbron!/ Vinyl Chionae-Asioouteil Disease 75 of cases, the tumour fust came to attennon with massive, often fatal, intrapentoneal haemorrhage. Important tender hepatomegaly (hepatosplenomegaly), sliest jaundice and occasionally development of moderate ascites and oedema were observed. Except for mild to moderate hyperfeilirubtnaemia. some elevation of serum levels of alkaline phospnatase and ganmaglutamyl transpeptidase and only slightly abnormal levels of serum transaminases, the spectrum of biochemical tests :s hardly revealing. Alpha-feto protein determination has not been helpful in the diagnosis. Ultrasonography, scinti graphy, hepatic angiography and, notably, computer tomography of the upper abdomen are the diagnostic procedures of choice if ASL is suspected. A technetium-99TM -liver scan visualizes intrahepauc tumour defects (Bitnack et al. 1977b) together with abnormal splenic fixation, but peripheral defects of uptake may be difficult to interpret (IVhekn et al. 1976). Characteristic features of angiography art a normal-sized hepatic artery with possible displacement caused by tumour enlarge ment. a certain degree of central hypervascularity of the tumour, a peripheral tumour stain, ana puddling of contrast medium persisting into the late venous phase. In addi tion. varying degrees of peiiosis hepetis may be observed in some eases. However, even repeated hepatic angiography may fail to confirm the suspected diagnosis, as was evi dent in one ease reported by Roche et al. (1978). The example of s Jd-year-old polymerization worker who died of metastasizing angiosarcoma of the liver m February 1980 may serve to illustrate the clinical course. In 197:.'?3. after an exposure of 18 years' duration, we found him to suffer from Ray naud's phenomenon and nonarrhodc portal fibrosis and portal hypertension with sple nomegaly and moderate thrombocytopenia. Despite termination of exposure, there was progressive splenomegaly and development of massive oesophageal and gastne - ported rum oily deofninal int cedent s number Fig. 8. Computer tomognohy showing a large, irregular, hypodense angiosarcoma of the liver involving both lobes. Courtesy of Professor Thum, Department of Radiology, University of Bonn ---*-s$ i To W.K. Lelbacli and H J. Mjrstcller 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 lelt 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. Apart from mod erate elevation of alkaline phosphatase and borderline hyperbihrubinaemia, biochem istry was normal. Computer tomography showed a large irregular hypodense tumour mass in the liver, involving both right and left lobes (Fig. 8). winch 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), ra* **- * . .sr 'i \ f r Fi|. 9. Computer tomography showing multiple brain metastaies of angiosarcoma of the liver. Sec text. Courtesy of Professor Thum, Department of Radiology. University of Bonn Little information is ivailable in the literature concerning the peritoneoseopic aspect of VCMdnduced ASL (Hoche et al. 1978). It may be impossible to make s diagnosis of the initial phase of ASL in VCM-exposed workers by peritoneoscopy and needle biop sy of the liver, as documented in one of our patients who died of multicentric ASL fe R '8 W K. Lelbjkli jnd H.J Mjrstcller 11 months after peritoneoscopic diagnosis of severe hepatic fibrosis (case 19; see also Lelbach and Marsteller 1977). In addition to the findings described in connection with hepauc fibrosis, there may be hypervasculanzed or cyjtic tumour formation visible on the surface of a nodular, quasi-cirrhotic liver, or a gross aspect resembling hepatic me* tastases 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. 4J.4 Cross and Histological Morphology 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 of angio sarcoma of the live, 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 and Popper (1975) distinguished four basic developmentai patterns of histomorphology 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, hype;chromatic and often bizarre nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells of varying differen tiation envelop liver cell plates and may invade enlarged and fibrosed portal tracts, ac companied by proliferation of bile ductules (Fig. 11). In papillary angiosarcoma atro phy of liver cells results in larger and more irregular blood-filled vascular spaces, into which loose papillary strands of surviving hepatic cords on an axis of connective tissue project, lined by sarcomatous cells (Weinbren 1976). Even larger blood-filled spaces an seen in the cavernous type, where they may be surrounded by thick fibroin walls. In a smaller percentage of cascs.solid areas or nodules of anaplastic sarcoma are found, resembling solid spindle-cell sarcoma, or even suggesting an epithelial type of tumour. Gedigk et al. (1975) also observed a roticulosareomalike pattern. The differennation of the tumour cells varies widely: it ranges from the inconspicuous endothelial lining cell type to irregularly shaped, grossly distorted giant-cell forms. Morphologically, vinyl chloride-related ASL cannot be distinguished from ASL associated with other aeuological factors or from the cryptogenic type (Popper et al. 1978). In tumour-free portions of livers with angiosarcoma widely varying degrees of ex cess formation of fibrous connective tissue are usually observed, analogous to that seen in nontumorous liven of heavily exposed penons. Fibrosis of enlarged portal tracts with modest proliferation of bile ductules, mostly only scanty infiltration oflymphocytes 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, perisinusoidai fibrosis is often detected only by special staining methods for collagen or reticuiin fibres. As a rule, irregular focal or nodular fibrotic thickening of wm*, mtm 7 W K. Lelbjcli and H.J. Mjrstclitfr 11 months after peritoneoscopic diagnosis of severe hepatic fibrosis Cease 19 . see also Lelbach and Marsttller 1977). In addition to the findings described in connection with hepatic fibrosis, there may be hypervascularized or cystic tumour formation visible on the surface of a 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. 4 J .4 Cross and Histological Morphology The liver is usually markedly enlarged. Liver weight in cases of ASL ranged from 1600 to 7300 g (Thomas and Popper 1975 :Roclte et aJ. 1978). The gross appearance of angio sarcoma of the live, 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 intrapehtoneal haemorrhage. Thomas et al. (1975) and Thomas and Popper (1975) distinguished four basic devel opmental patterns of histomorphology 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, hypejehromatie and often bizarre nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells of varying differen tiation envelop liver cell plates and may invade enlarged and fibrosed portal tracts, ac companied by proliferation of bile ductules (Fig. 11). In papillary angiosarcoma atro phy of liver cells results in larger and more irregular blood-filled vascular spaces, into which loose papillary strands of surviving hepatic cords on an axis of connective tissue project, lined by sarcomatous cells (Weinbren 1976). Even larger blood-filled spaces are seen in the cavernous type, where they may be surrounded by thick flbrotic walls. In a smaller percentage'of cases, solid areas or nodules of anaplastic sarcoma are found, resembling solid spindle-cell sarcoma, or even suggesting an epithelial type of tumour. Gtdifk et al. (1975) also observed a reticulosarcomalikc pattern. The differentiation of the tumour cells varies widely; it ranges from the inconspicuous endothelial lining cell type to irregularly shaped, grossly distorted giant-cell forms. Morphologically, vinyl chloride-related ASL cannot be distinguished from ASL associated with other aeuological factors or from the cryptogenic type (Popper et al. 1978). In tumour-free portions of liven with angiosarcoma widely varying degrees of ex cess formation of fibrous connective tissue are usually observed, analogous to that seen In nontumorous livers of heavily exposed persons. Fibrosis of enlarged portal tracts with modest proliferation of bile ductules, mostly only scant)* infiltration oflymphocytes 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, perisinusoida! fibrosis is often detected only by special staining methods for collagen or reticulin fibres. As a rule, irregular focal or nodular fibrotic thickening of pias crea a Marsteiler T9:see also nnection with lion visible on : hepatic meliver. It should is any rospi- T?d from 1600 :o 'inct of angjo'uc tumour luiei, is less ind spongy porflarge cavern- "ur basic devetliffertnt porvvt evolution: of transition oma cells with fenie the ''tng differeniMktacts, ac^J|ma itto spares, mt" ni.eelive tissue 'Died spaces fihrooc walls. ><na arc found, pe of tumour, uferennauon of dial lining ceil heady, vinyl '> other aetioi- Jegreesofex* ms to that seen portal tracts `Mi oflympho'isrje septa ex* viataut intramethods for thickening of Fig. 11. Angiosarcoma of the liver (upper pare of photomicrograph! invading adjacent liver parenchyma (case U"DI;et Table 13). Note hyperplastic and hyperehromanc nuclei of proliferating neoplastic lining cells enveloptng hepatic cords. Reproduced by permission. Ann NY Acad Sci 2*6:278-285 (1975). Courtesy of Professor Cedigk, insnrute of Pathology, University of Bonn. H l E. x 250 of GUsson's capsule is present: these fibradc capsular areas may extend into the under lying parenchyma and may connect with adjacent enlarged xubcapsuiar portal tracts. Hi* cellular and nuclear size of hepatoevtes may vary widely; groups of binudeated or even multinudear parenchymal cells with abundant cytoplasm are seen. Focai pro* lifention of sinusoidal lining cells may be encountered, especially within foci of sinus oidal dilatation. In connection with conspicuous sinusoidal dilatation, two rypes of focal hyper plastic precursor lesions were described by Popper et aL (1978): 1) Poorly circumscribed foci of hyperplastic, often binudeated hepatocytes with inettased number of various sinusoidal lining eclls and only insignificant increase of rerieuium framework. 2) Almost nodular areas of conspicuously hyperplastic and hypertrophic hepato cytes with more pronounced variation of markedly increased sinusoidal ceils without degeneration or necrosis ofliver parenchyma, but accompanied by excess formation of reticulum framework and compression of surrounding parenchyma. The transition of sinusoidal lining cells to angiosarcoma cells is characterized by in creasing atypta and anaplasia of these proliferating endothelial ceils accompanied either ucc 044298 80- W.K. Lclbjtli and H.J. Mji'K'ilcr by formation of excess connective tissue or by accentuation of sinusoidal dilatation leading to pnmary peliosis. Involvement of portal areas in the evolution of aneiourco* ma results in considerable fibroplasia and formation of hyalinized collagen together with proliferation of bile 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 rearrangement of hepatocytic plates may lead to a cirrhosislike picture. 4Ji 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 precludes ef fective surgical or radiation therapy in the majonty of cases. A survival period of two years after surgery (Berrod 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 are available. 4J.6 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 of VCM polvmenzation 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 expected for the total United States population an annual incidence of this tu mour in the orderof0.014/100 000. This would have meant only about 0.03 cases per 20 000 polyme: nation workers within a 10-year period. Dose-response and attendant biotransformar : n 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 of a person exposed (Schncklennan et al. 1975: Gehring et al. 1979,1978: Woods 1979). Gthring et al. (1979) consider a probit percent model to be a reliable tool for risk prediction, which works without the assump tion of a threshold. They predicted a cancer risk of 1J 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 of inhalation, distribution, metabolism, cell proliferation and tumour latency times between rats and humans was described by Woods (l 979). This model arrives at an incidence of 3S 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 man and from high- to low-level expo sure and the problem of threshold doses has been voiced (Maugh i 9 78: Hooper et al. 1979.SchneUennan 1979; Weigert 1979:Reitz et al. 1979). Vin\ R. (exc; ASL Thisthe C con ft had d the re polyr waso viron: ceede lesser magn ting.; millic vinyl mode the es grour. 4J.7 Fora hazar. the cr studiisure t-. the lu al. 19` ftfavw of Bn: 1976; posed et al. I voice*1 Berry emplo and ca but nc 1976) In (1974 cpiden (1978 facion `teller -arcoher her lobu* icture. dif:i ett'two is a c pary >ici for 1961 vers of nion of law ' ?. * (U- r uc sev.nee to ex safe /* et al. i probit 'xsump- `lOOO I ppm t not tied by .nil :by workers iity of i expo* et al. Vmyl Clilondtf-Assocuted Disease 31 Results of a recent survey by fircdr tt al. (1977) indicated tliat for New York State (excluding New York City), a lughiy industrialized area, the annual incidence rate of ASL daring the 6-vear period from 1970 through 1975 was 0.25 per million residents. Tliis considerably exceeded the national avert.;r rate of 0.1-- per million per year in the L'mted States. In a concomitant case-con irol study. 26 patients with histologically confirmed ASL were found in the study area from l5S to lq7J. and 7 of these had had documented long-term exposure to either .As. ThO; or VCM. Five tall female of the remaining 19 patients lived at a distance of SCO--1500 feet from VC iabn:ai:on or polymerization facilities for long periods. No pertinent exposure or residential history was obtained from the other 14 patients. Discharge of unreacted monomer tnto the en vironment as result of losses 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 (Sclnvetrzer 1975). Concerning the order of magnitude of ambient exposure beyond the work place. i.e. outside the industrial set ting, an average annual exposure concentration of 17 ppb was estimated for the 4.6 million persons throughout the United States who resided within a 5-mile radius of vinyl chloride emission sources (Kuzrmck and McCaughy 1975). If the risk assessment mode! elaborated by Woods (1979) is applied to this population of 4.6 million people, ihe estimated incidence of angiosarcoma per year would not be above expected back ground levels. 4 J .7 Mortality and Cancer Morbidity Studies for a tumour disease as rare as angiosarcoma of the liver even quite small increases in -hazard o1 background levels should be detectable (Do// 1975). The situation with the common types of cancer is far more difficult. Since 1974 a number of mortality studies of VCM-e.xposed populations have suggested that in humans long-term expo sure to VCM may also be associated with cancer of sitei other than the liver, notably the lungs, and the lymphatic and central nervous system (Manson et aL 1974: Ott et al. 1975; Tabenhgw and Coffey l97*;Nieholson et al. 1975; Wagoner et al. 1976: Waxweder et al. I976;iVtc/to/ro 1977;Buffer e\ aL 1979). Epidemiological studies of British workers failed to confirm this suggestion (Duck et al. 1975 : Duck and Carter 1976; Fox and Collier 1976,1977). as did a prospective study of a VCM/PVC-tx* posed cohort of 1613 employees of a West German chemical plant (Frenrzel-Beyme et al. 1973). Criticism of deign and interpretation of some of the studies has been voiced (Falk et al. 1974b:/W/ieic and Williamson l97i;Rrger \977;Daklerup 1975; Berry 2nd Rysurer 1976). A follow-up of aS VCM-exposed persons (750 traced) ever employed at the one Swedish factory, which starred operation in 1945, for mortality and cancer morbidity patterns revealed a fourfould execs of pancreas/livtr tumours but no deviation in the number of brain tumoua from the expected level (B\ren et al. 1976). In addition to the three extensive mortality studies of Tabenhaw and Caffey (1974). tVaxivei/crei al. (1976), and Fox and Collier (1977), a fourth comprehensive epidemiological study (Reinl and Weber 1976) was completed in 1977 by Reinl et aL (1973). wiiicii included three study populations from 11 VCM- and PVC-ptoduting facior.es in the Federal Republic of Germany, covering the period from before 1959 S; W.K. LelhaJi and HJ MarstcMer through 1974: (a) 7021 workers encaged in the production of VCM and PVC;fb) 4910 chemical worker) from the same plants not exposed to VCM: and fcj 4007 workers engaged in PVC manufacture. Not included were non-German workers of Mediterranean ongin. This German study permits comparison not only with the mortality ratio of the total male population but also with a comparable occupational group exposed to VCM. With regard to the "healthy worker effect1 (McMichael 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 sun- dardized mortality ratio (5MR) for malignant liver tumours (1523). which proved to have been closely related to the duration of exposure, a significantly elevated 5.MR 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 signify cantly increased risk was found concerning tumours of the central nervous system or the respiratory tract. It has already been mentioned (Sect. 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 penod 1970 through 1974, about 40ft 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 carcinoembryomc antigen litre (CEA) in 200 Canadian PVC production workers (mean duration of em* ployment: 10 yean) showed a more than threefold higher frequency of levels above 10 ng/ml than in a normal healthy population {1.1% vs. 0.5ft) (Page et al. 1976). Levels of CEA were also determined in 1363 workers of five different VCM polymeri- xation (3) and PVC processing (extrusion) plants (2) in the United States (Andenon et al. 1978). After removal of possible contusing factors (smoking, alcohol intake, past medical histoty), it emerged that the distribution of CEA litres among the polymenzation workers was signifleandy different from that in the extrusion plant group and in a nonexposed reference group. Significant differences were also found for two of six job categones examined (polymerization and maintenance) compared with extrusion workers and the reference group. However, the usefulness of the CEA litre as a predicdire indicator of possible increased risk seems doubtful. 4.4 Miscellaneous Aspects 4.4.1 Thrombocytopenia and Platelet Function Tests Thrombocytopenia in chronic VCM intoxication was first mentioned - rather parenthetically and without further comment - in a paper published by AntonyuzUtnko in 1968. Later/u/ie et al. (1973) noticed that each of the first 13 autoclave cleaners referred to them during 1972 from a West German piant because of suspected skin and V< bo b>' tio ce; of we oi. the det pk. oil. fab b.' up har rer10 cou 01 *n **1 c>' or " X>T Ta (;f(. __ * B C P a ^ JiUc _. tSi. -- filer nor* : jl. but ' `tmJ to (R was pot the .inn .tin one ound. the out , data i in MIC ;m- \ISl i- ft/a* din six jiredie-. 'areniko in rs re<< and Vinvl Chloride-Associated Disease 33 bone lesions presented with mild to marked thrombocytopenia (30-119 Y 10** litreV Bone marrow aspirates in 6 patients permitted exclusion of disturbed platelet forma tion or osteomyelofibrosis/sclerosis. but in 12 of them splenomegaly was found. Ex cept for slight reticulocytosis in 3 and leucopenta in 3 of the workers, other haematological tests were negative. The reduction of the number of leucocytes and platelets as well as reticulocytosis appeared to be attnbutable 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 analysts of platelet funcuon and other parameters of blood coagulation in the total cohort of PVC production (and also fabneanon) workers from this plant strengthened this suggestion (Baehncr et ai. 197-ta, b. 1975a. b, 1976;Sthrt-Bachner and Erztl 1977). It'egman (1975) also commented upon abnormal platelet courts in 13 of 37 ?VC fabricating workers who had only handled PVC powder which, however, might have contained substantial amounts of residual monomer. In contrast, mis et al. (1975) detected thrombocytopenia in only 1 of 354 polymentation workers, but an electronic cell counter was used for platelet counts (personal communication). According to Sehn-Saehntr and Etztl (1977). the mean platelet count in a cohort of 132 PVC polymentation (and processing) workers was significantly lower than that in a nonexposed control group of ISO healthy men. As could be expected, Bachncr 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 orspieen site determined by selective scintigraphy with 1 *'-Hg-bromo-mercury-hydroxypropanc-labeiled red cells) in 70 PVC polymenzation workers (see Table 19). It ap- Tablt 19. Prevalence of enlargement of the spleen2 among 70 PVC-polymentation worker* in rvijimn to increasing degrees of thrombocytopenia (Baehntm al. l97Ja> Croup No. of workers examined Platelets (x 10*'/litre) Range Mean Enlargement of the spleen A 14 B 24 C 23 D7 > 130 100--130 70- 99 < 70 168 117 87 44 3f2ID 11 (46ft) 19 (7617) 6(86") * As determined by palpation or by selective spleen scintigraphy. pears, however, that the development of thrombocytopenia is not dependent on the presence of splenomegaly since we observed mild thrombocytopenia (100-120 x 10**/ litre) in a small number of workers in whom spleen site was definitely within normal limits on selective spleen scintigraphy (MflzflJt&etundex <<J x I0r* according to Fitehtr ana Wolf 1963). Thrombocytopenia was accompanied by abnormalities in platelet function tens. There was an increase in the number of large (> 10 pn) 'juvenile' platelets (increased 84 W'.K. Lclb-uh and H.J. Manteller platelet spreading), enhanced response (platelet aggregation) to addition of AD? and collagen l Bom test) and increased availability of phospholipid-containing platelet fac tor 3 (Bachncr 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 (Baciuwr et al. 1974b). IW(1976) and h'jnc/et ai.( 1976)suggested that thrombocytopenia could be construed as confirmatory evidence of an immune complex disorder. Hcuscrmaim and Su/rrc (1977a) noted unusual focal aggregation of platelets in klaisch preparations of spleen tissue and increased platelet pooling (plate lets trapped within the subsin usoidal meshwork of pulp cords) in the red pulp of the spleen on electron microscopy as well as phagocytosis of thrombocytes by sinusoidal macrophages. Schaffncr et 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 marrow has not been demonstrated so far. Although the pathogenesis of thrombocytopenia in VCM-induced disease is not fully undeniood.it seems at ptesent 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 of consumption coagulopathy was described as complication of spon taneous haemangiosareoma of the liver by Tructt et al. (1975). A haemosrauc defect more complex than mere pooling and destruction of platelets in the enlatged spleen has also been commented upon m the paper by Ctmti et al. (1974) in connection with splenomegaly of various noncirrhotic origin. . 4.4.2 Central and Peripheral Nervous System Miscellaneous nonspecific and somewhat indefinite symptoms have been described in connection with chronic inhalational exposure to VCM in PVC-production workers, such as dizziness, disorientation, blurring of vision and memory, headache, irritability, excessive fatigue and somnolence, sleep reversal or insomnia and other pseudoneurasthenic symptoms (Suciti et al. 1963, \97S.Schotttk l969;C<fis et al. 1975 and others). This prenareotic syndrome was interpreted as a manifestation of a potentially reversible acute toxic encephalopathy. Its danger to the individual was thought to lie mainly in resultant inadequate reactions to critical situations (Schonek 1969). How ever. Vale et al. (1976) reported that several individuals in a group of 95 comparatively young ex-workers, the majority of whom had no other symptoms, complained of fa tigue, headache, listlessncss and depression, with onset of symptoms having been de layed as long as 2 years after cessation of employment. With reference to such *pseudoneurasthenic complaints', which may be interpreted as the mildest degree of a toxic encephalopathy, Benin et al. (1975) examined a group of 21 autodav* cleaners at varying intervals after cessation of exposure, all of whom presented with other (cutaneous, angioneurotic, hepatic) manifestations of vinyl chlo ride disease. 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, dysenrhythmia or a socalled subvigil electroencephalogram was observed. Evidence of distal polyneuropathy, found in 19 patients, was attributed in the first place to an abnormal peripheral circu lar en. ati< clu vin. dan sib. 4.4 Tin PV< a pi thrv dur wer defi umc vioi exp foui pos> C.v for crea vale was Tlie sear: aitl. broi* icai- t lion smo to is A re thou tag; to a nect VC.\ respi 17t. r tor teller UP and ulet fac-_ the noniC) in -tivited iggested nnune ration of >e (plate; of the t'.isoidal patic 'aibo- j not fully ver and > spleen, f spon- defea spleen non with `lability, icur:nd n dally * to lie How;'iratively l of fa-m de- izrpretcd 1 a group whom nyl chloluding -n rmal - asoropathy, a! circa- Vinyl CUanJe-A^iOLined Disease 85 lauon with resultant hypoxic damage. Hie pathogenesis of a possibly VCM-induced encephalopathy is not clear. It would be conceivable that clinical and bioelectric alter ations found in some patients, in whom portosy sternic encephalopathy could be ex cluded. may have been due to toxic or hypoxic brain damage. However, no'other con vincing evidence has so far emerged to indicate that chronic irreversible cerebroto.xic damage may have resulted from prolonged exposure to VCM. notwithstanding the pos sibility of an induction of brain tumours. 4.4 J Pulmonary Changes Hie suspected development of nonmalignant pulmonary changes due to VCM and/or PVC dust exposure is still a matter of controversy. Soon after VCM was recognized is a potent carcinogen, three groups of employees fn * 290.250,445. respecnvelv i from three large North American PVC-ptoduang plants (A, B, C). characterized by different dunnon and levels of past environmental exposure to VCM as well as to PVC dust, wete studied with respect to chest x-ray film abnormalities and pulmonary function defects as assessed by spirometry and determination of maximum expiratory flow vol ume (Miller 1975,Miller et ai. 1975.Lilis et al. 1975, 1976, 1977). All cases 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 of employees from plants A (highest ex posure) and B (22.7ft, and 1S.375, respectively), but in only 4Jft of those from plant C, with the lowest exposure level. Hie prevalence of these radiological abnormalities, for which no pathogenetic explanation was available, was found to be significantly in creased with longer duration of VCM-PVC exposure (more than 10 yean), but the pre valence of a positive history- of smoking, although identical in both groups A and B, was also found to be significantly higher in workets with abnormal chest x-ray plates. Hi* overall prevalence of a positive history of chronic bronchitis (British Medical Re search Council criteria) was 20.4ft in group A (highest exposure) and 16.0ft in group B. although group B was significantly older. The somewhat higher prevalence of ehronic bronchitis In workers with abnormal chest x-ray plates did not attain statistical signif icance. On the other hand, age did not appear to be an important factor. Pulmonary func tion tests showed a strikingly high prevalence of obstructive changts, but since both smoking ind age were related to changes in pulmonary function, it appeared difficult to isolate potential specific effects of occupational exposure to VCM and PVC dust. A restrictive pattern was found in 9 Jft of group A and in only 2Jft of group B, al though group A was significantly younger. In conclusion, this extensive study, includ ing a total of 9S5 workers exposed in the pest to VCM as well aa PVC dust, may point to a potential multiple factor effect of smoking and VCM-PVC exposure. In this con nection, it is of interest to note that aceoiding to a cohort study of mortality among VCM polymerization workers the SMRs for respiratory cancer as well as for *othcr respiratory disease' were found to have been in excess of expected figures (156 and 176, respectively) (Waxweiler t aL 1976). Bronchopulmonary changes thought to be due to long-continued, intense exposure to PVC dust were observed by several authors (Pamejpani and Saui l9S$;Brvuaard W^"isrdrijf -,m rSiik 86 W.K. Lelbacli and H J Marsrcller 1969:Szende et al. 1970; Vertkin and Mamontov 1970-. Frnngia et aJ. 1974.Darke \916,Arnaudet al. 1978). Considerable exposure to VPCdust is the rule in the drying, bagging and storage areas of PVC-producing plants. Photographs contained in Fanradt's paper (1976) give a general idea of the potential dust exposure. Measurements of the concentration of PVC dust at various sites of the bagging operations were reported as long ago as 1955 by Pamiegpani and Sassi. In 1969 Broussard mentioned the possibil ity of development of chronic bronchitis caused by the inhalation of PVC 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 of interstitial 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 1 year in shovelling PVC powder at a processing factory. Lung biopsy revealed moderate diffuse fibrosis and small focal granulomatous lesions containing ovoid or polygonal birefnngent foreign matenal which couid be eluted by treatment with a known solvent of PVC. Microscopic examination of PVC dust panicles collected at the patient's place of work showed, them to be morphologic ally identical with the panicles found in the patient's lungs. Another anecdotal case of pneumoconiosis after 23 yean of employment in a PVC bagging area, with radiological.evidence of diffuse micronodular infiltrates and granu lomatous lesions found in a lung biopsy identical with those recorded by Szende et al., was published by Amaud et al. in 1978. Histology of open lung biopsies in 1 of 14 VCM-exposed British workers, who complained of breathlessness, revealed focal alveo lar wall thickening with macrophages in alveolar spaces and increased reticuiin 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, including marked perfusion defects of upper lobes. Darke pointed out that some of the men wont affected had been engaged in the polymerization of 'plastisol', a very fine PVC powder with particle size around 0J pm. Selikoff (1976) called attention to results obtained by Frongia et al. (1974), who observed significant histopathological changes in the lungs of guinea-pigs 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 of exposure (alveolar histiocyte-microphage re actions); they proved to be fairly marked after 4 months, with appearance of foreign body giant cells, and proceeded to development of Urge interstitial granulomatous fod. Vertkin and 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 motphologicai alterations of the broncho pulmonary system, which they ascribed to their exposure to PVC dust. They quoted results of earlier animal experiments conducted in 1963 by Golovatyuk and later by ShlyakhetskiL These last authors had apparently shown that exposure of animals to PVC dust may lead to the development of chronic pneumonia and eventually to a sort of mild fibrosis of the lungs. m ucc 044305 fMjnteller y, Darke iti the drying. I in Ranroars i-nts of the reported as the posstbil* Just. The ngs blocking mmatton of nent of the hour hilar tesented with i pulmonary 1 a processing anulomatous could be ion ofPVC morphologic- mi in a PVC i and granu- ende et al., 1 of 14 i \vai aiveotlin and col- . abnormal t! <mt that -i "plastisor. i -.* 14), who md rats cxeging area, rophage re- of foreign lomatous the menuortion of bronchohey quoted nd later by jnimals to illy to a son Vinyl Chloriue-Assoeiated Disease 87 Certain types ofPVC dust (one of two samples tested) were found to exhibit a strong haemolytic potennai due to the presence of an undetermined but readily solu ble surface-associated agent which was not VCM (Richards et al. 19*5). These authors also studied the effect of the haemolytic sample ofPVC dust on lung fibroblast cul tures, but they did not obtain any significant results. Contrary to earlier indications (Lanpe et al. 1974a) and despite continued efforts we faded to deteet any significant restrictive changes of pulmonary function in the overwhelming majority of patients we had occasion to examine. It may be of interest to note that Maltoni 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 well-established role of VCM in the production of nonmalignant lesions of bone, skin, small vessels. liver and spleen, it is still open to debate precisely what importance can be asenbed to pulmonary changes within the spectrum of VCM-induced disease. 4.4.4 Genetic Effects of VCM The discovery of the carcinogenic properties of VCM also stimulated interest in its mutagenic potential. A number of studies hate 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 strains of Salmonella typhimunum by VCM in the presence of animal and human liver microsomes as a sys tem of metabolic activation ("j/wuf et al. 1974,19~6, Rarrsch et al. 1975a, 1976: McCann et al, \975\Malareiile et al. 1975:fow et al. 1976). Mutagenicity of VCM metabolites was also demons.:):*d in yeast strains (Lopneno et ai. 1976,1977;S/iohm 1976) and in mammalian eel; i'luberman et al. 1975). In comparison to nonexposed controls, a significantly higher incidence of chromosomal aberrations (fragmentation, rearrangement) in lymphocytes of workers occupationally exposed to VCM was re ported by Ducatman et ai. (1975),Funes-Oavioto et al. (1975),Purchase et ai. (1975, 1976), and Fomenko et al. (1976). Fletg and Thiess (1974) had faded to demonstrate an increased rate of chromosomal 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 fetuses of female mice mated with males which had been exposed to 3000,10 000 and 30 000 ppm VCM for 5 consecutive days. This, however, does not absolutely cxdude genetic effects on human gonads. The outcome of pregnancy among wives of VCM-polymenzation workers as against wives of rubber and PVC-fabriciuon workers (Infante et ai. 1976a, b) and rates of congenital malfor mation per 1000 resident live births in three Ohio communities with PVC production plants have also been studied (Infante 1976). As part of a larger survey of workers' health, interview questionnaires (Infante 1976a. b) showed that after paternal age adjustment a significantly higher inadence of fetal mortality subsequent to paternal exposure was recorded among the wives of VCM^xposed workers. This trend was found to be maintained after elimination of S3 W.K. Lelba^h and H.J. Mursteller pregnancies in women who had more than two abortions. The findings of this study raised the question of possible 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 dear-cut linkage of PVC production and increased occurrence of congenital malformations (pnmarily CNS malformations) emerged from preliminary studies tn three Ohio communities with PVC production plants. But the need for further study of possible conmbutary factors was indicated (Infante 1976). In fact, none of the par ents of affected children in Painsville, one of the three Ohio communities, had ever worked at either of the two PVC polymerization plants in Painsville or lived wuhin two miles of these plants (Edmonds et al. 1975). 5 Conclusion and Outlook The combined efforts of multiple disciplines have been necessary to arrive at tne full recognition of the range of pathology associated with occupational exposure to vtnyl 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 of an 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 sull have gone unnoticed if the resulting malignancy had been any can cer other than of an 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 industnal hygiene are strictly adhered to, there is reason to hope that initiation of new cases of VCM-induced angiosarcoma of the liver can be effectively prevented. Unfortunately, however, it can 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 of environmental 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 of vinyl chloride and allied compounds may be the problem of the interaction Vin>| Clilor. between preJ tissue such as short exposu, will carry the References Albnght LF t Albnght LF i . Albnght LF t' Albnght LF ( polyvinyl c Albnght LF t processes. Alrtnga DP t *. 198-203 Amann R (19 der Leber ' Anderson H V CEA amor. 1560-156' Andrews AW, properties Anghelescu F V(1969>r employees 473-482 Annual Repu London. Ci Antonyuzhett'Sian text). * Antweiler H > i Perepect 1' Amaud A, Po;. ride pneurr Aryanpur J 11 Iran, i Ocvi As*minn H(1 Austin GT (1 87-89 Bachner U. E und Osoph.i 2409-24If Baehner U, Ft. Befundt be JahresbericGentner, S: Bachner U. Mu 1000 patier Bachner U.Ei/ und Osoph: Blutungen - Mantellcr this study suggestion a possible r.gsmtal Judies in ther study t of the par. had ever ed within at the full ire to vinyl 'letn may -re inevitably ranee of !v sate comtig latency ^Mses would ^|^ny :anI, days H-al com- <* widely - ' nt length -ntiai car* ttroundings cupattonal : problem, red to, there na of the cted that in l| appear dot* ..'.future rer to establish -r studies in e interaction Vinyl Chlnnde-Asiociatcd Disease 39 betw een predominantly hepatocy tic metabolism and oncogenic effect on mesenchy mal tissue such as vascular endothelium, and also the question of whether intermittent short exposures at high concentrations or continuous exposure at a low concentration will carry the greater nsk. References Albright LF( 1967a) Vinyl Chloride processes. Chem Eng 74:123-130 Albnght LF (1967b) Manutacture of vinyl chloride. Chem Eng 74 219-224 Alhngni LF 11967c) Polymerization of vinyl chlonde. Chem Eng 74- IJ l -158 Albnght LF (I967d) Vinyl chlonde polymerization by suspension processes yields polyvinyl chlonde resins. Chem Eng 74 145-152 Albnght LF f 1967e) Vinyl chlonde polymerization by emuision. bulk and solution processes. Chem Eng 74.85 -92 Alrenga OP (1975) Primary angiosarcoma of the liver. Review article. Int Surg 60: 198-203 Amann R (197J) Beitrag rur Vinylchlorid-Krankheit. - Ein Fall von Angiosarkom der Leber. Dissertation. Umversitat Freiburg Anderson HA. Snyder S, Lewmson T. Woo C. Ldis R, Selifcoff IJ (1978) Levels of CEA among vmyl chlonde and polyvinyl chlonde exposed workers. Cancer 42: 1560-1567 Andrews aW, Zawistowski ES. Valentine CR (1976) A companion of the mutagenic properties of vinyl chlonde and methyl chlonde. Mutat Res 40:273-276 Angheiescu F. Otoru M, Oobnnescu E, Hagi-Paraschiv-Oostios L. Dobnnescu G, Canea V11969) Clinico-pathogenetic considerations on Raynaud's phenomenon among employees of the polyvinyl chlonde industry. (Rumanian text) Med Interna 21: 473-482 Annual Report of the Giief Inspector of Factones for the Year 1931 (1953) HMSO London. Cmd 8772 Antonyuzhenko VA (1968) On the occupational vinyl chloride intoxication. (Rus sian text).GigTr Prof Zabol 12: 50-52 Antweiler H (1976) Studies on the metabolism of vinyl chlonde. Environ Health Petspcct 17:217-219 Areaud A. Pommier de Santi P, Garbe L. Payan H, Charpin J (1978) Polyvinyl chlo ride pneumoconiosis. Thorax 33:19--23 Aryanpur J (1977) Vinyl chloride: its impact on occupational madicine practice in Iran. J Occup Med 19:689-692 Asiminn H (1921) Die Rdntgendiignostik der inneren Eritnnkungen. Vogel, Leipzig Austin GT (1974) IndustnaUy significant organic chemicals, part 3. Chem Eng 81: 87-89 Bachner U, Etzel F, Lsnge CE, Mantellcr HJ. Veltman G (1974a) Hlmostisebefunde und Osophagusvanzen bai Vinylchlorid-Krankheit. Dtsch Med Wochenschr 99: 2409-2410 Bachner U, Etzel F, Lange CE, Juhe S, Veltman G (1974b) Gerinnungsphysiolofische Befundc bet Vinyleftloridkrarkheit. In: Lehnert C, Szadkowski D, Weber Hi (cds) Jahresbericht der 14. Jahrestagung der Dtutschen GeseUschaft fQr Arbeitimedizin. Centner, Stuttgart, pp 27J-280 Bachner L'. Muller R. Egii H (197$a) Clinical relevance of platelet function tests in 1000 patients with hemorrhagic diathesis. Thromb Res 6:139-149 Bachner U. Etzel F. Lange CE. Mantellcr HJ, Veitmen G (1975b) Himostasebefundc und dsoshagusvanzen bei Vinylchlorid-Krankheit. In: Marx R. Thics HA (eds) Blurungen des Gastreintcstinaltraktes. Schattauer. Stuttgart New York, pp 67-73 ucc 0443OS m 90 W.K. Lelbach and H J Marsteller Bachner U, Etxel F. Muller N, Lange CE, Egli H 11976) Prineoplastische und kolUgenisierer.de Verandeningen der Leber und Hiimosiasebefunde bei PVC-Arbeuern. In: GastparH(ed)Onkohamo*taseologie. Schatrauer, Stuttgart New York, pp 319-326 Bantt C (1898) Splenomegaiie mu Leberxirrhose, Bettr Pathol Anat All? Tathol 24 21-33 Barb:n A. Bresil H. Crony A. Jacquignon P, Malaveille C. Montesano R Bartsch H (1975) Liver-microtome mediated formation of alkylating agents from vinyl bro mide and vmyl chionde. Biochem Biophys Res Commun 67:596-603 Baretta ED. Stewart RD, Mutchler JE (1969) Monitoring exposures to vinyl chionde vapor breath analysts and continuous air sampling. Am InJ Hvg Assoc J 30:537544 Bames AW (1976) Vinyl chloride and the production of PVC. Proc R Soc Med 69: 277-231 Bartsch H. Malaveille C, Montesano R.Tomatis L (1975a) Tissue-mediated mutagenic ity of vinyltdene chionde and 2-chlorobutadiene in Salmonella typhimunum. Nature 255:641-643 Bartsch H, Malaveille C, Montesano R (1975b) Human, rat. and mouse liver mediated mutagenicity of vinyl chloride in S typhimunum strains. Int J Cancer 15/3.429437 Bartsch H, Malaveille C, Barbm A. Bresil H. Tomatis L, Montesano R (1976) Mutagen icity and metabolism of vinyl chionde and related compounds. Environ Health Per* spect 17.192-198 Basalaev AV, Vazin AN, Kosetkov AG (1972) On the pathogenesis of changes develop ing due to long-term exposure to the effects of vinyl chionde. Gig Tr Prof Zabol 16:24--27 (Russian text) Basu AK. Boyer J, Bhaitacharya R. Basu Mallik KC. Sen Gupta KP (1967a) Noncirrhone portal fibrosis with portal hypertension; a new syndrome. I. Clinical and function studies and results of operations. Indian J Med Res 55:336-350 Basu Mallik KC, Sen Gupta KP, Basu AK. Biswas SK, Pal NC, Boyer J (1967b) Noncirrhotic portal fibrosis with portal hypertension: a new syndrome. II. Histopathologieal studies. Indian J Med Res 55:351-359 Baumann E (1372) Obercinige Vinylverbindungen. Liebigs Ann Phann 163:308-322 Baxter PJ (1976) Epidemiological studies of PVC manufactures and fabricators, and primary angiosarcoma of the liver. Proc R Soc Med 69:297-299 Baxter Pi, Fox AJ (1975) Angiosarcoma of the liver as the certified cause rf death 1963-1973. Lancet 11:27-28 Baxter PJ, Fox AJ (1976) Angiosarcoma of the liver in P.V.C. fabricators. Lancet 1:245 . Baxter, PJ, Anthony PP. McSween RNM, Scheuer PJ (1977) Angiosarcoma of the liver in Great Britain. 1963-1973. Br Med J 11:919-921 Becker V, Busschtr K (1961) t)ber das Himangioendotheliom der Leber. Acta KepatoSplenoi 8:356-379 Benoit J-P (1967) L'acro-osteolyse d'orifine profcssionelle. Thise, University of Lyon Berk PD, Martin JF, Waggoner JG (1975) Petsistence of vinyl chionde induced liver injury after cessation of exposure. Ann NY Acad Sci 246:70-77 Berk PD. Martin JF, Young RS. Creech J. Selikoff IJ, Falk H. Watanabe P. Popper H. Thomas L (1976) Vinyl chloride-associated liver disease. Ann Intern Med 84: 717-731 Betrod JL, Laxard P. Pierre C. Puech A, Ravier E, Rety J, Smagghc G (1978) A Propos de 10 observations d'angiosareome* hipatiques survenua chet des ouvners expos6s au ehlorure de vinyle. Paper presented at the 19th International Congress of Occupational Medicine, Dubrovnik, 25-30 September. 1978 Berry G, Rossiter CE (1976) Vinyl chloride and mortality? Lancet 11:416--417 BenifsgenosxenschartlicheGnindsiitze fur arheitsmedizmische Vonorgeuntersuchungen. Gefahrdung durch Vinylchlorid. Fassung Juli 1974. Arbeitsmed SozialmeU Praevenuvmed 9:226-229 Vinyl Chlo; Biersack HJ szintigrai restagun-r 3 10. (Bn: Biersack HJ C(1975b ten mit \ Biersack HJ. graphy o. (Stuttg) 2 Biersack HJ schiden I Vmylchlo 88 Blendis LM. sion in vir 75:206-1 Block JB 119 229 53-5 Blomfield J, current he Bolt HM (19' HM, Bann England, r Bolt HM. Kar 1:1425 Bolt HM. Kar of '*C vm Bolt HM. K-| in the rut Bolt HM, Lai: in the rat. Bolt HM. Kar lite. In: G,. ehlond-Kr.. Bonneton G.' de rupture rure de vin; Bonneton G. < Marty F. F leurs du ch. Bonse G, Urb* oxinne tor perfused ra Bonk J (192" Neurol Ps>i Border EA, W, oxide and . Interact 17 Boyer JL. Sen (1967) Idir cirrhosis an Brady J, Liber Polan A, Vi Natl Cancer iazsteller nd Lollagem-etiern. In: *>p 319-326 ' jiltol 24 r rtsch H vinyl bro* . i chloride J 30.5j*- Med 69: .. fnuugemcmum. .mediated 15/3.429- "M Mutagen. Health Per- develop-f Zabol < i Vm:mcai and 50 *h| NonHtstopathol 4ty of Lyon luced liver ", Popper H, d 84: ;S APropos vnexpoji* reef -417 u-r-uchungtn. tied Vinyl Chlonde-Aisociated Disease 91 Btenack HJ. Lange CE. Velrman G. Winkler Ci l97Jai Bedeutung der Lrrrr- und Milz- szmagraphie tur die Diagnose der Vinykhlond-Krankheit. Bencht uber die 15. Jahrestagungdcr Deutschen Gesctlschaft fur Arbeitsmedizin. 24,-26.4.1975. pp 505510 i Brenner W. Rohmcrt W, Rurcnfranz J. eds C-iner Stutriari Bieruck HJ. Lange CE. Ebmger H. Marereller HJ. Le:baa;i WK. Veltman '. Winkler C i l97Jbi Sequenzszintigraomsche lintctvtchungrn von Leber und Milz bei Patten'en m;t Vinyichlor.d-Krankiien. Dtsch Med Wochenschr 100 615-617 Biersaak HJ. San Luis T Jr. Lange CE. Thekn M. Veltrnan G, Winkler C (197"a) Se;nugnohy or I.ver jnd spleen m vinyl chl-.mde workers. \;:a Hfpato G istroenieroi (Sturtgi 24 55^-561 Biersack HJ. Ebinger H. Winkler C < 1977b) Leber-Milz-Szmcgramm bet Vinylchlondschiden In. Gutaeker HW, Lelbach WK (eds) Leberschaden dutch Vinvkhior.d Vinyichlond-Krankheit. Witxstrock. Baden-Baden Brussel K31n New York, pp 8488 Blendii L.M. Smith PM. Lawrie BW. Stephens MR. Evans WQ {1978) Portal hyperten sion in vinyl chloride monomer workers. A hemodynamic studv Gastroenterology 75:206-211 Block JB 11974) Angiosarcoma of the liver following v-nv|-chloride exposure. JAMA 229:55-54 Blomfield J, Dixon SR. McCredie DA 11971) Potential hepatotoxtcity of copper in re current hemodialyns. Arch Intern Med 128:555-560 Balt HM 11973) Metabolic activation of halogenated ethylene. In: Remmcr H.'Bolt HM. Bannasch P. Popper H (edi) Primary liver turnon. MTP Press. Lancaster/ England, pp 285-294 Bolt HM. Kappus H. Buchter A, Bolt W (1975) Metabolism of vinyl chloride. Lancet l:U2S Bolt HM. Kappus H. Kaufmann R. Appel KE. Buchter A. Bolt W (1976a) Metabolism of "C vinyl chloride in vitro and in vivo. 1NSERM Symp Ser 52:151-164 Bolt HM. Kappus H. Buchter A. 8olt W f 1976b) Disposition of 11 Clvinyl chloride in the rat. Arch Toxicol 55:155-162 Bolt HM, Laib RJ. Kappus H. Buchter A (1977a) Pharmacokinetics of vinyl chloride in the nt. Toxicoiogy 7:179-188 Bolt HM. Kappus H, Bueh rr A. Bolt W (1977b) ReaktivitSt der Vinylchiortdmetabo* lite. In: Gutaeker HW, Lribaeh WK (eds) Leberschiden dutch Vinylchlorid - Vinyl- ehlorid-Knnkheit. Witas-ock. Baden-Baden Brussel K&ln New York, pp 32-55 Bonneton G. Champcticr J. Sotto J, Guidicelli G. Letoublon C, Panh M (1973) Un cas de rupture ipontanee d'angosarcome htpatique chcz un travailleur expose au chiorure de rnyle. Chinirgi* 101:936-942 Bonneton G.Charapener J, Foumct J,Guidicelli H. Legrand J. Dupri A, Hostetn M. Marty F. Panh M (1977) Angtosarcomc h<pauque ct fibrose portal* chea Its travailleun du ehiorute de vinyle. Nouv Presse Med 6:735-742 Bonse G. Urban T, Reichert D. Heasehier D (1975) Chemical reactivity, metabolic oxirane formation and biological reactivity of chlorinated ethylcnes in the isolated perfused rat liver preparation. Biochem Pharmacol 24:1829-1834 Borak J (1927) Zur Pathogencse und Therapte der Raynaud'schcn Krankheit. Z Gcs Neurol Psychiatr 3:1-16 Boeder A. Webster I (1977) The effect of vinyl chloride monomer, chloroethylenc oxide and chloiaceuldehydt on DNA synthesis in regenerating rat liver. Chcm Biol Interact r:239-247 Boyer JL. Sen Gupta KP. Biswre SK. Pal NC, Basu Mallik KC. tber FL. Bans AK (1967) Idiopathic portal hypertennon. Companion with the portal hypertension of cirrhosis and extnhepatic portal vein obstruction. Ann Intern Med 66:41-68 BraJy J. Liberator* F. Harper P,Greenwald P. Burnett W, Davies JNP, Bishop M. Poian A. Vimna N (1977) Angiosarcoma of the liver, an tpidemiologic survey. J Nau Cancer Inst 59:1383-1383 ucc 044311 Q ' W.K. Lelbach and H.J. Marstcller Bmlbord K. Brubaker PE. Cay B. French JG (19751 Exposure to halogenared hydro carbons in the indoor environment. Environ Health Perspect 11.215--220 Brontenma;er S. Schatfner F. Popper H (1966) Fat-stonng cells (lipocytes) in human liter. Arch Pathol 82 447-453 Broussard G (196V) Patologiu da resinc poliviniliche. Met! Bull (Naples) 52:102-108 Bruder U. Straby A 11975) Exposure to vinyl chlonde in PVC processing induimes. - Report TK 176 on j survey in collaboration with the Swedish Plastics Industry and the Agency for the Protection of Workers. Stockholm.February 1975 (Swedish text) Buchter A. Bolt HM. Kappus H. Bolt W (1977) Die Gewebsverteilung vo.i 1.2-'*CVinylchlond bei der Ratre. Int Arch Oceup Environ Health 39 27 -32 Buffler PA. Wood S. Suarez L, Kilian DJ (1979) Mortality experience ot workers in a vinyl chlonde monomer production plant. J Occup Med 21:195-203 Byczkowska Z. Langauer-Lewowicka H (1974) Raynaud's syndrome in workers em ployed in production of polyvinyl chloride (Polish text). Pol Ty| Lek 29:14611464 Byren D, Holmberg B (1975) Two possible cases of angiosarcoma of the liver in a group of Swedish vinyl chlonde-polyvmy! chlonde workers. Ann NY Acad Su 246. 249-250 Byrfn D. Engholm G. Englund A. Westerholm P (1976) Mortality and cancer morbid ity in a group of Swedish VCM and PVC production workers. Environ Health Per spect 17-167-170 Carr J. Burgmson RM. Viteha JF. Krantz JC (1949) Anesthesia XXIV. Chemical con stitution of hydrocarbons and cardiac automaticity. J Pharmacol Exp Ther 97- ] Chainuvati T, Viranuvatti V (1979) Idiopathic portal hypertension and chrome arsenic poisoning. Report of a case. Am J Dig Dis 24:70-73 Chatelain A, MotiUon P (1967) Un syndrome d'acro-ostcoiyse d'ongine professionnelle et de constatation nouveile cn France, J Radiol Elecrrol Med Nud 48:277-280 Cheney WD (1965) Acro-osteolysis. Am J Roentgenol 94:595-607 Chowdhury AR. Black M, Lorber SH. Chty WY (1977) Haemangiocndotheliomatosis of the liver. A I2year followup. Gastroenterology 72:157-160 Colardyn F. van der Straeten M. Lamont H. van Peteghem T (1976) Acute inhalation- intoxication by combustion of polyvinylchloride. Int Arch Occup Environ Health 38:121-127 Conolly RB. Jaeger RJ; Szabo S (1978) Acute hepatotoxiciry of ethylene, vinyl fluo ride, vinyl chlonde and vutyl bromide after aroelor 1254 pretreatment. Exp .Viol Pathol 23:25-33 Cook WA, Giever PM, Dinman BD, Magnuson HJ (1971) Occupational acroosteolysu. II. An industrial hygiene study. Arch Environ Health 22:74-82 - Corbett TH (1975) Inhalation anesthetics - more vinyl chloride? Environ Res 9:2 II214 Cordicr JM. Fievez C. Leftvre MJ, Scvrin A (1966) Acroostiolyse et lesions cutanfes chez deux ouvriers affectfs au nettoyage d'iutoclavet. Cah Med Tra 4:14, 3-39 Cornish HH, Abar EL (1969) Toxicity of pyrolysis products of vinyl plastics. Arch Environ Health 19:15-21 Coudere P, Panh MH, Pasquier B, Pasquier D. N'Golet A, Faure H (1976) Anglosarcome osseuse revilateur d'une tumeur hepatique chez un travailleur expose au chloruie de vinyle. Sem H6p Paris 52:1721-1722 Cowlishaw JL. Pollard EJ, Cowen AE, Powell LW < 1979) Liver disease associated with chronic arsenic ingestion. Aust NZ J Med 9:310-313 Creech JL, Johnson MN (1974) Angiosarcoma of the liver in the manufacture of poly vinyl chlonde. J Occup Med 16:150-151 Creech JL, Makk L (1975) Liver disease among polyvinyl chloride production workers. Ann NY Acad Sci 266:88-94 Creech JL. Johnson MN, Block A (1974a) Epidemiologic notes and reports. Angio sarcoma of the liver among polyvinyl chloride workers. Morbid Mortal Weekly Rep 23:49-50 Vinyl Clilondi Creech JL. M. vmyl ehlorv Gastroentet Djlderup LM 17:285-28 Dalderup LM Lancet 1:24 Dannaher C, Y coma chem. May 16-29 Danziger H (l0 Med Assoc Darke CS(I97< tion of PVC Datta DV. Mtt: toxication a cirrhotic po Davies IW, per: Environ Pol! Deese DE, Joyr Ind Hyg Ass Delorme F (19: chlorure de Delorme F (19: ouvrier du c` Delorme F. Ms* tact prolong. Union Med' Delorme F.TiiQuebec. J O- Devignevielle i poiyvmyUqu Dinman BD.Ctional acro<- Dod'on VN. Du tional acroo* Doll R( 1975) l Dominmghaus i: -- Anwendui Dor JK. Arlauu (1975) Anpi rune de poly Oressman RC, v. mtnation of s Sci 15:69 Du JT. Tambun chlonde expo Ducatman A. Hi. chromosome Duck BW (197* i Duck BWU976307--309 Duck BW, CarteDuck BW, Cartechloride prod 1. Marsteller Ted lud.-o- ::o i tn human :.io:-:o3 mdustr.es- I-.dustry ami t Swedish text) i. workers in a otters em29:1461- `ivcrin a \cad Set 246. .i-.tr mordid. Health Per- icmteal conTiier 9": i Mrv>niw arttmc r ifessioftncile 2*7-230 'wlioniat'isis - inhalationi Health ^royl fluo* - Kxp Mol n-nteolysii. Res 9:211 ns cutanecs 14. J-J9 iui. Arch \npovxpose au -iciated with tun of poly* turn workers. is, Anpio* Weekly Rep Vinyl Chloride-Associated Disease 9? C:ecch JL. Makk L. Whelan JC Jr.Tamburro CH 11974bl Hepatotoxiciry among poly vinyl chloride (I*VO production workers dunng tint year of surveillance propram Gastroenterology 67.786 Dalderup LM i i9"Si V'mvl chloride and haemanposareoma ot the liver. J Qceup Med 17,235-286 Dalderup LM. Freni SC. Bras G. Sronck.hont FB (19761 Angiosarcoma of the liver. Lancet I.24p Djnnaiier C. Vam LT, Tamburro C (19791 Vinyl chloride associated hepatic anposar- coma chemotherapy. American Association tor Cancer Research. Inc.. Meettnp May 16-29. 1979. New Orleans. Louisiana Danzicer H (1960) Accidental poisoning by vinyl chloride. Report of two cases. Can Med Assoc J 82:323-830 Darke CS < i 976) Discussion remark to: A.W games: Vinyl chloride and the produc tion of PVC. Proc R Soc Med 69' 280--291 Darta DV, Mitra SK. Chhuttam PN. Chakravarti RN (1979) Chronic oral arsenic in toxication as a possible aetiological factor m idiopathic portal hypertension (noncirrhotic portal fibrosis) m India. Gut 20:3*8-384 Davies IW. Petty R (1975) Vinyl chlonde monomer's effect on liquids in PVC bottles. Environ Pollut Manage 5:22-23 Deese DE. Joyner RE f 1969) Vinyl acetate: a study of chronic human exposure. Am Ind Hyg Assoc J 30:449--157 Delorme F < 1978a) 10 cax eanadiens d'anpoxarcomes du foie chcz des ouvriers du chlorine de vtnyle. Ann Anat Pathol (Pans) 23.97-104 Delorme F (1973b) Association d'un angiosarcome du foie et d'un hfpatome. chez un ouvrier du chlorure de vmyle. Ann Anat Pathol (Pahs) 23:105-114 Delorme F. Makk L (1975) Angiosarcoma du foie chez des ouvriers ayant hi tn con tact prolong* avec le chlomne de vinyle: description morpholopque des lesions. Union Med Can 104:1336-1844 Delorme F. Theriault G (1973) Ten cases of angiosarcoma of the liver in Shawinipan. Quebec. J Occup Med 20:338-340 Devignevielle D. Flueher AM < 1953) Etude tostcologique experimental* des mines polyvinyliques. Service Midicalc des Manufactures de Saint-Marccl. Vernon Dinman BD. Cook wa, Whitehouse WM. Magnuson HJ. Ditcheck T (1971) Occupa tional aeroosteolysis. 1. An cpidemiolugicai study. Arch Environ Health 22:61-73 Dodson VN. Dinman BD. Whitehouse WM, Nasr ANM, Magnuson HJ (1971) Occupa tional acreosteolysis. III. A'clinical study. Arch Environ Health 22:33-9! Doll R (1975) Discussion paper. Ann NY Acad Sci 246:320-321 Domintnghaus H (1972) Kunststoffe. I. Aufbau und Eigenschaften - Kunststoffsortcn - Anwendungen. 2nd ed. VDI-Veriag. Dusseldorf Dor JF. Artaud J. Coste C. Faure F, Kasbarian M. Lebreuil G. Padovani J. Mongin M 11975) Anpome capillaire et cavemeux dit'/us du foie, chez un travailleur du chlorute de polyvinyle. Merseille Med 1 12:709--720 Drcssman RC. McFarrcn EF (1977) A sample-bottle purging method for the deter mination of vinyl chloride in water at submicrognrn per liter levels. 2 Chromatogr Sci 15:69-72 Du JT. Tamburro CH (1976) Decreased glucose^-phosphatase activity in liver in vinyl chloride exposed rets. Fed Proc 33:1422 Ducatman A. Hirsehhom K. Selikoff U (1975) Vinyl chloride exposure and human chromosome aberrations. Mutat Res 31/3:163-168 Duck BW1197$) Vinyl chloride carcinogenesis. Br J Cancer 32:260-261 Duck BW (1976) Medical surveillance of vinyl chloride workers. Proc R Soc Med 69: 307-309 Duck BW. Carter JT( 1976) Letter to the editor. Lancer 11:195 Duck BW. Carter JT. Combes EJ (1975) Mortality study of workers in a polyvinyl chloride production plant. Lancet II: 1197-1199 -r.\ r UCC 044312 94 W.K. Lelbach anti H.J. Marsiciler Dugeis P. Amblard P. de Bignicourt B, Legnnd J (1972) Acropathie polyvinylique profesionnellc. Bull Soc Fr Dermatol Syphiligr 79. 197-198 Dupa* J. Badclon P, Daydf G (1936) Osteolvse essentiellc progressive de la main gauche J'ongine indetermine'e. Mem Acad Chir 62:148-153 van Duuren L (1975) On the possible mechanism of carcinogenic action of vinyl chlo ride. Ann NY Acad Sci 246.258-267 Dyer RF. Esch HV (1976) Polyvinyl chlonde toxicity in fires. Hydrogen chloride tox icity m fire fighters. JAMA 236:393-397 Edmonds LD. Fait H, Nissin JE (1975) Congenital malformation* and vinyl chlonde. Lancet 11.1098 Edmondson HA (1958) Tumours of the liver and intrahepatic bile ducts. In. Edmond son HA (ed) Atlas of tumor pathology, sect VII. fare 25. Published by Armed Forces Institute of Pathology, Washington, pp 1-216 Elmore JD, Wong JL, Laumbaeh AD, Streipx UN (1976) Vinyl chloride mutagenicity via the metabolites chloro-oxirane and chloroacetaldehyde monomer hydrate. Biochem Biophys Acta 442:405-4)9 Ebon L, Burnstem N (1954) Idiopathic afrophy of bones of feet with typical "neuro trophic" changes. Am J Med 16.909-914 Escartin Mann P, Alvarez Bustos G, Garcia Plaza A. Fernandez Corugedo A. Arenas Mirave 1. Chantar Barnos C (1974) Hipertensidn porta idiopattca. Rev Clm Esp 133:255-262 van Esch GJ. van Logten MH (1975) Vinyl chloride: a report of a European assess ment. Toxicology 4:1 -4 Fairhail LT (1957) Industnal toxicology, 2nd ed. Williams & Wilkins, Baltimore Falk H. Waxweiler RJ (1976) Epidemiological studies of vinyl chlonde health effects in the United States. Proc R Soc Med 69 303 -306 Falk H. Creech JL Jr, Heath CW Jr. Johnson MN, Key MM (1974a) Hepatic disease among workers at a vinyl chloride polymerization plant. JAMA 230:59-63 Falk H. Heath CW Jr, Carter CD, Wagoner JK. Waxweiler RJ. Stringer WT (1974b) Mortality among vinyl chlonde workers. Lancet 11:784 Feron VJ, Kroes R (1979) One-year time sequence inhalation toxicity study of vinyl chlonde in rats. II. Morphological changes in rhe respiratory tract, ceruminous glands, brain, kidneys, heart, and spleen. Toxicology' 13:131-14] Feron VJ, Speek AJ, Willems Ml. van Battum D. de Groot AP (1975) Observations on the oral administration and toxicity of viny. chlonde in rats. Food Cosmet Toxicol 13:633-638 Feron VJ. kruysse A, Til HP (1979a) One-year time sequence inhalation toxicity study of vinyl chloride in rets. I. Growth, mortality, haematology , clinical chem istry and organ weights. Toxicology 13:25-28 Feron VJ, Spit BJ, Immei HR, Kroes R (1979b) One-year time sequence inhalation toxicity study of vinyl chloride in rau. III. Morphological changes in the liver. Toxicology 13:143-154 Fiechuier JJ, Reyes CN Jr f 1976) Angiosarcoma of the liver in a rural population. Four eases diagnosed in a 29-month period. JAMA 236:1704-1706 Filatova VS. Babochkina MS (1964) Hygienic assessment of some types of equipment employed for drying and screening of polyvinyl chloride resins. Gig Tr Prof Zabol 8:9-13 (Russian text) Filatova VS, Gronsberg ES (1957) Hygienic working conditions in the production of polyvinyl chlonde resins and measures for improvement. GigSanit 1:38-42 (Russian text) Filatova VS, Balakhonova LI. Gronsberg ES (1958) Hygienic characteristics of vinyl chlonde production. Gig Tr Prof Zabol 2:6-9 (Russian text) Filatova VS. Blagodatin VM. Coffman FE (1964) The efficacy of health measures in the production of polyvinyl chlonde resins. Gig Tr Prof Zabol 8:3-6 (Russian text) Fischer J, Wolf R (1963) Die quantitative Abschatzung der Milzgrolie mu Hilfe der Scintigraphic. DtscK Med Wochenschr 88:1430-1437 Vinyl Fisc !u (10 Fleig I AriFleisci Hosior WoFeme:of t` poU Fox A. Fox AJ sele. Fox AJ moi 34 1 Frentz. Arb. Soz Frey H ham A-? Frongi. Zion FunesA Goll Lam Futh l tion Gaboi Apr. *i p. Gama' 86 Garre. effe. Gay BV ride Gedigk vmy 278 Gedigk bet Leb< Yor! Gehrim forApp Gehnm Co vi 15- Gcrrits with Giaccai 29 H.J. Mjnteller ifyvinyliqut Je la main n ol vinyl cliio- ?n chloride rox- i vinyl chloride. .ti In Edmondl by Armed l mutagenicity icr hydrate i typical "neuio- . lio A. Arena* Rev Cm Esp ropean assess- . Baltimore Is health etfetts 'pat:e d:sea*e 0 59-63 WT(19"4hi -tudy of - -.y i fc.-utr.mous "servanui.- on 11'mmet Toxicol ii-.n toxicity - linical chtm- .nee inhalation s in the liver ii population. 06 pea of equipment Tr Prof Zabol :c production of ui :;J8 --*2 (Russian tcnstics of vinyl alth measures in * 6 (Russian text) mit Hilfe der Vinyl Cilonde-Associated Diicase 95 Fischer J. Mundwhenk H. Wolf R 1 1965) Milzszinugraphie mit l-3romomercun I 197FUi-2-iiydro\i propan I BMHri. ROEFO 103.3--9 --366 Flop I. Thicss AM (1974) Chromoiomen-Cntersuchungen bei Vinylchlond-Exposition. Arbeitsmcd Sozialmed Praeventivmed 9280-283 Fleiichtr.ann R. Schlote W. Schomerus H. Wol'ourg H. Castntlon-Oberndorier WL. Hoensch H i I9?-) IC.'emknotipe Leberzirrhose mit au|erni|ter portaler Hyperten sion au Folge einer Vitamm-A-Intoxikatton bei Psonasif-Senandlung Otsch Med W'ochtnschr 102.1637-1640 Fomenko VN. Katosova LD, Pavlento 011 -,76) C> togtneiii. an.nl> sis of lympr.ocytei of the peripheral bleed tram worker- employed m the process of '.myl chlon-le polymerization. Gig Tr Prof Zabol 20:46-50 (Russian text) Fox Ai (1976) Vinyl chlonde and mortality? Lancet 11.41? Fox AJ, Collier PF (19?5) Low mortality rates in industrial cohort studies due to selection for woric and survival in the industry. Br J Prev Soc Med 30:215 -230 Fox AJ, Collier PF 1197?) Mortality expenenct of workers exposed to vinyl chlonde monomer m the manufacture of potvvinvl chlonde in Great Britain. Br J tnd Mca 54 | -|0 Frennel-Beyme R. Schmitz T. Thiess AM (1978) Mortalitiitjstudie bei VC-'PVCArbenem der BASF Aknengesellschaft. Ludwigshafen am Rhem. Arbe:timed Sozuimed Praeventivmed 13.218-228 Frey HE (1973) Vinyl chlonde and polyvinyl chlonde resins, tn: Chemical economics handbook Stanford Research Instirute (SRI). Menlo Park. California, pp 580.188 1 A-5S0 1885 B Fronpa N. Spinaiiola A. Bucarelii A (19?4) Lcsioni polmonari ipenmentali da inalazione proluneata di poWen di PVC in ambiente di lavoro. Med Lav 65:321-342 Funes-Cravioto F, Lambert B. Lindsten J, Ehrenberg L, Nararaian AT, Osterman* Golkar S (1975) Chromosome aberrations in workers exposed to vinyl chlonde. Lancet 1:459 Futh U, Pietzke HU (1974) Hamangioendotheliom dcr Leber naeh Thorotrast-Applikation vor 30 Jahren. ROEFO 1 21:398 -399 Gabor S. Radu M,Preda N, Abrudean S, Ivanof L. Anca Z. Valaczkay C (1964) Aprecten asupra unor modifican Hjochimtce la muncitohi din mdustha sintezeik si polimenzati chloruru dc vimi. Igitna (Bucharest) 13:409--*18 Gama C. Mem JBB (1978) Occupational acro-osteoly'sis. J Bone Joint Surf (Am) 60: 86-90 Garre AJ. Guttenplan JB, Milvy P (1976) Vinyl chloride dependent mutagenesis: effects of liver extracts and free radicals. Mu tat Res 38:81 -88 Gay BW, Lonnemin WA, Bridbord K. Moran JB (1975) Measurements of vinyl chlo nde from aerosol sprays. Ann NY Acad Sd 246:286-29$ Gedigk P. MOiler R, Bcchtelshetmer H (1975) Morphology of liver damage among poly vinyl chloride production workers. A report of 51 cases. Ann NY Acad Sci 246: 278-28S Gedigk P. Muller R, Schattenbetg PJ. Totonf V (1977) Morphologic der Leberechiden bei chronisclter Vinylehlorid-lntoxikation. In: Gutacker HW, Leibaeh WK (cds) Leberechiden dureh Vinylchlond. Witzstrock, Baden-Baden. Bnissei Kflln New York, pp 43-S2 Gehring PJ. Wjtanabe PC. Park CN (1978) Resolution of dose response toxicity data for chemicals requiring metabolic activation: example - vinyl chlonde. Toxicol Appl Pharmacol 44:$a 1-591 Gchnng PJ. Wjtanabe PG. Park CN f 1979) Risk of angiosarcoma in workers exposed to vinyl chloride as predicted from studies in rets. Toxicoi Appl Pharmacol 49: tJ-21 Gcrrits WBJ, van Aken WG. van der Meer J, Vreekcn J (1974) Splenomegaly associated with chronic consumption coagulopathy. Acta Med Scand 195:425-430 Giaccai L (1952) Familial and sporadic neurogenic aeroosteolysis. Acta Radiol 38:17- tat i i r-- W.K, Leibach and HJ. Marstelier Gi:;i>n CT < 1 7! i Aero-ostculy <is in PVC worker* Med Bull Stand Oil Co 3 I ah - it Gokel JM. Liel'czeit E, EJer Nl (I97q) Hemangiosarcunia and hepatocellular urononw of the trier following'inyl chlonde exposure. Virchows Arch (Pathol Anat) 372 105 --205 Good WO. Eilison C. Archer VE (1975) Sputum cytology among frequent u*er' ot pressurized spray cans Cancer Res 55.Zlb --ZZI Gordon DE. Thomas LB. (Cent G. Calandra J. Bahu R. Popper H I 19^4) Hepatic angiosarcoma m man and rodents following prolonged exposure to vinyl chlonde Gastro enterology 67,794 Grannis FW 11975) Guido Banti's hypothesis and its impact on the understanding and treatment of portal hypertension. Mayo Clin Proc 50:41--47 Green T. Hathwav DE (1975) The biological fate in rats of vinyl chloride in relation to its oncogenicity. Chem Biol Interact 11:545-562 Green T, Hathway DE (1977) The chemistry and biogenesis of the S-containg metabo lites of vinyl chloride in rats. Chem Biol Invest 17:137-150 Green T. Hathaway DE (1978) Interactions of vinyl chloride with rat liver DNA in vivo. Chem Biol Interact 22.211 -224 Greenberg BE. Street DM (1957) Idiopathic oon-faniilial acro-osteolysis. Radiology 69:259-262 Gretm H. Bonse G, Radwan Z. Reichert D. Henschler D (1975) Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylene* as a function of metabolic oxtrane formation. Biochem Pharmacol 24:2013-2017 Greim H, Bonse G. Henschler D (1977) Mutagenitiit von Vinylchlorid und anderen chlorierten Athyienen. In: Gutacker HW, Leibach WK (eds) Leberechaden Jurch Vinylchlorid. Witistrock, Baden-Baden &riissel K6In New York, pp 36-40 Gnciute L (1979) The carcinogenicity of vinyl chlonde. IARC Sci Publ 22:3-11 Gngorescu I.TobaG (1966) Clornra di vinyl. Aspecte de toxicologie tnduitnale. Rev Chim (Bucharest) 17:499 Hahn E. Aderka D. Suprun H, Slttamler B (1979) Occupational acroosteolysis in vinyl chloride workers in Israel. Isr J Med Sci 15 218-222 Haley TJ (1975) Vinyl chlonde: how manv unknown problems? J Toxicol Environ Health 1.47-73 Harms I (1954) Cber die familiire Aktoosteolyse. ROEFO 50.727-732 Hamasch H (1949/50) die Akroosteolysts. ein neues Krankheitsbtld. ROEFO 72: 352-359 Harns DK. Adams WGF (1967) Acro-osteolysis occurring in men engaged in the poly merization of vinyl chloride. Br Med J 111:712-714 Heath CW, Falk H. Creech JL (1975) Characteristics of cases of angiosarcoma of the - liver among vinyl chloride workers in the United States. Ann NY Acad Sci 246: 231-236 Hefner RE Jr. Watanabe PG, GehringPJ (1975a) Preliminary studies of the fate of inhaled vinyl chloride monomer in rats. Ann NY Acad Sci 246:135-148 Hefner RE Jr, Watanabe PG. GehringPJ (1975b) Percutaneous absorption of vinyl chlonde. Toxicol Appl Pharmacol 34:529-532 Henschler D (d) (1972/73) Gesundheitsschidliche Arbcitsstoffe. Vcriag Chemie. Wcinheim Henschler D (1977a) Metabolismus von Vinylchlorid. In: Gutacker HW. Leibach WK (eds) lebtrschiiden dutch Vinylchlorid. Witzstrock, Baden-Baden Briissel K&ln New York, pp 27-31 Henschler D (1977b) Metabolism and mutagenicity of haiogenated olefins - a com parison of structure and activity. Environ Health Perspcct 21:61-64 Henschler D (1977c) Mechanismen dcr Aktiviening chlorierter aliphatischer Verbtndungen - expenmen telle ZugSnge und klinische Bedeutung. Areneim Forsch 27: 1827-1832 Vinyl Chloride- Heu*ermann U. chlond-Kran Heusermann U. itrukturelle l Arcli (Pathol Holmbtrg B. Kr mice Acra V Hooper NK. H41 603 Hruban Z. Russt in liven of tw Huberman E. Ba cells by two * hyde. Int J C Hublet P(1975) Belg Med See Hublet P. Left*r sarcome du ft vinyle monor Huet PM, Guilla sinusoidal po Gastroentero Hussain S.Oster vinyl chlonde IARC (1974) In vinvi chloride Iber FL(1969) ( tension. Ann Iber FL( 1970) I NY Acad Sci Imanaga H, Yam tension a.cor. Infante PF (i97t ride prod uc'11 Infante PF, j, of vinyl-c;..on Infante PF. Wag. of vinyl<hlor Irish DO (1963) Toxicology-. V pp 241 fO Ito T. Nemoto M len" (fat-ston Okajima Folia Wanetich KM. A> hepatic micro 74:1411-141 Jacob PJ.Thiriji province of 0 Jaeger RJ (1975) action with 1. Jaeger RJ. Reym injury by viny 726 Jaeger RJ.Conol ated hydrocar d H J Marstrlier il Oil Co 3 I 49-56 lucellular car-moma Pathol Anatl 3*2, :.x:queni uses oi :9"4i Hepatic angio,'iyl ahlonde Gastro- . ur.Uemasiir.f jrJ Jilonde in relation to c $<ontauig metabo- *Sl liver DNA in -otysis. Radtology tutagenwiry in vitro ktion of metabolic rid and amieren l'rsc!iader! darcli pp 3b-40 . Puoi i c.e industnaie. Rev osteolysis tn vinyl miTicol I' iwron J?: 'U. ROEFO ngapid in 'he poly* i giosarcoma of the V Acad Sei 246: -.'v of the fate of 133-148 '*>orptton of vinyl . Vcriag Chcmie. cr HW, Leibaeh WK Jen Brussel Kdln d olefins - a com bi-64 :>|iharischer Verhin* \rzncim Forach 27: V'iny! Ciilonde-Asiociated Disca'e 9" Hcusermann U. Stutte HJ i |9?7ji Zur AtioUigte der Thrombozytopeme bei der Vmvl- chlond-KrunUteit. Blut 35.317-322 Heuscrmann U. Stutte HJ i 1977b nz\ mhisioehetnuthe. Iititomctnjohe und ultrastruktunrlls Cntsrmehunpen vor. Milirn be: der V.-; Ichlond-Krankheit. Virabows Arch iPatnol Anatt 3r5 303-3 1 * Holmberg B. Kronevt T. '.V'ineil M t |0To) Th* parnciogy ot vm>t chlonde fxpo-ed mice, Acta Vet scand 17.238-342 Hooper NR, Harm RH. Ames BN 11979) Chemical carcinogenesis. Science 203.t>02603 Hruban Z. Russell RM. Boyer JL. Giagov S. Baghen SA (i 974: L'ltrastructural changes m liven of two patients with hypemtamtnosii A. Am J Parltol 76:451 -462 Huberman E. Bartscn H. Sachs L (1975) Mutation inducuon m Chinese hamster V79 ceiU by two vinyl ciilomie metabolites, chloroethyiene oxide and 2<hloroaeetildehyde. Int J Cancer 16:639-644 Hublet P 1 1975) Expose des nuisances industnelles dues au chlorure de vmyle. Arch Belg.Med Soc33.73-89 Hubiet P. Let'ivteMJ. DecuyperL. Hamn C. Hamels J. Fievez M (1977) Un cas d'angiosarcome du foie chez un travatlleur avar.t fic4 longuement expose au chlorure de vmyle monomire. Arch Belg Med Soe 35:601-622 Huet PM, Guillaume E, Cote J, Legate A, Lavoie P, Viallet A 11975) NoncitThottc prestnusoidai portal hypertension associated with chrome arsenical intoxication. Gastroenterology 68' 1270-1277 Hussain S, Osterman-Golkar 5 (1976) Comment on the mutagenic effectiveness of vinyl chlonde metabolites. Chem Biol Interact 12:265-267 lARC (19T4) Internal Technical Report no. 74/005. Report of a working group on vinyl chlonde. Lyon 24-25 June 1974, pp i -55 I her FL f 1969) Obliterative portal venopathy of the liver and idiopathic portal hyper tension. Ann Intern Med 71:660-661 Ibtr FL (1970) Portal hypertension tn the presence of normal liver morphology. Ann NY Acad Sci 170:115-126 Imanaga H. Yamamoto S. Kuroywtagj Y (1962) Surgical treatment of portal hyper tension according ro state of intrahepattc circulation. Ann Surg 155.42-50 Infante PF (1976) Oncogenic and mutagenic risks in communities with polyvinyl chlo ride production facilities. Ann NY Acad Sci 271:49-57 Infante PF. Wagoner JK. McMichael AJ. Waxwctler RJ. Falk H f 1976a) Genetic risks of vtnyK-hlondc. Lancet 1:734-733 Infante PF. Wagoner JK. McMichael AJ. Waxwefler RJ. Falk H (1976b) Genetic tisks of vinyhihloride. Letter to the editor. Lancet 1:1239-1290 Irish OD (1963) Haiogenated hydrocarbons: I. Aliphatic. In: Fasset OW, Irish DD(eds) Toxicology. Wiley, New York London (Industrial hygiene and toxicology, vol II. pp 241 fO lto T. Nemoto M (1932) Die Kupfferschcn StcntzcUcn und die "Fcmpeieherunpztllen" (fat-storing cells) in der BlutkapiUarenwand in der menscftlichen Leber. Okajima Folia Anat Jpn 24:243-238 Ivancttch KM. Aronson I. Katz 1011977) The interaction of vinyl chloride with rat hepatic microsomal cytochrome p-450 in vitro. Biochem Biophys Res Cotnmun 74:1411-14)8 Jacob PJ, Thtriault GP (1975) Distribution of primary cancers of the liver in the province of Quebec. Can Med Assoc J 112:305-307 Jaeger RJ (1975) Vinyl chloride monomer comments on its hepatotoxicity and inter action with l.i. dichioroethylene. Ann NY Acad Sci 246:150-151 Jaeger RJ. Reynolds ES. Conolly RB. Mostcn MT. Murphy SO (1974) Acute hepatic injury by vinyl chlonde in mts pretreated with phenobarbital. Nature 252:714726 Jaeger RJ. Conolly B8. Murphy SO (1975) Short-term inhalation toxicity of haiogen ated hydrocarbons. Arch Environ Health 30:26-31 c 98 W.K. Lelbaeh and H J Marsteller Jaeger RJ. Murphy SD. Reynolds ES. Szabo S. Moslen MT (1977) Chemical modiii-jtion of acute hepatotoxicity of vinyl chloride monomer in rats. Toxicol Appl Pharmacol 41:597--607 Jayson M1V, Lloyd-JonesK. Berry DC, Bromige M < 1976a) Resorption oi the mandible in vinyl chlonde acrooxteolysi*. Arthntis Rheum 19:971 Javson MlV, Bailey AJ, Black C, Jones KL (1976b) Collagen studies in acroosteoivsis. Proc R Soc Med 69:295-297 Johnson MN, Creech JL Jr (1974) Angiosarcoma of liver in the manufacture of poly vinyl chlonde J Occup Med 16:150-151 Juhc S, Lance CE (1972) Sklerodermieartige Hautveranderungen. Raynaud-Syndrom und Akroosteolysen bei Arbeitem der PVC-hentellenden Industrie. Dtsch Med Wochenschr 97:1922-1923 Jiihe S, Vcltman G (1972) Zur Klinik der sopnannten Vinylchlondkrankheit. (Sklerodemiie-ahnliche Verinderungen bei Arbeitem der PVC-herstellenden Industrie.) 1. Internationales Symposium der Werksarete der chemischen Industrie. Ludwigshafen. 27.-29.4 1972. pp 267-276 Jiihe S, Lange CE, Stein G, Veltman G (1973) Uber die sogenannte VinyichlondKrankheit. Dtsch Med Wochenschr 98:2034-2037 Jiihe S, Lange CE. Stem G, Veltman G f 1974) Uber die sogenannte VinyichlondKrankheit. Berutsdermitosen 22:4-22 Kappus H, Bolt HM, Buchter A, Bolt W (1975) Rat liver microsomes catalyse covalent binding of "C-vinyichlonde to macromolecules. Nature 257.134-135 Kappus H. Bolt HM, Buchter A. Bolt W (1976) Liver microsomal uptake of "C vinyl chlonde and transformation to protein alkylating metabolites in vitro. Toxicol Appl Pharmacol 3 7:461 -471 Karstadt M (1976) PVC. Health implications and production trends. Environ Health Perspect 17; 107-115 Keplinger ML, Goode JW Gordon DE. Calandra JC (1975) Intenm results of exposure of rats, hamsters, and mice to vinyl chlonde. Ann NY Acad $ci 246:219-220 Kettner H (1975) Umweltschutz in der Sowjetunion. III. Maximale Arbeitsplats-Konzentrationen (MAK-Werte) von Schadstoffen und ihre Normierung. In. Benchte des Osteuropa-Instituts. Heft 108. Freie Univereitat, Berlin JCistler HJ. PlOer S, Dickenmann W, Pirozynski W (1977) Portale Hypertonic ohne Leb r-`iThosc bei ehroniacher Vitamin-A-Intoxikation. Schweiz Med Wochenschr 107-8^-832 Kluge T, Sommenchild H, Flatmark A (1970) Sinusoidal portal hypertension. Surgerv 68:294-300 Knolle J. FSrster E. Roessncr A,Thcmann H, Hdhn P, Meyer zum BOschcnfelde KH (1974) Die nichtziirhousche portale Fibrose (hepatoportale Ski*rose! nach chronischtr Areenvcrgiftung. DUch Med Wochenschr 99:903-908 Koischwitz D, Marsteller HJ, Lackner K, Brecht G. Brecht T( 1980) Verinderungen der Hand-und Fingerartenen bei der Vinylchlondkrankheit. ROEFO 132:62-68 Konetzke G, Bittersohl G. Grand W, Schramm T, Teichmann B, Zschunke E (1978) Uber die Bedcutung des Vinylchlorids als Schadstoff aus der Sicht der Arbeitsme- dizin, expenmentel'.en Onkologie und Industrictoxikologie. Z ges Hyg 24:501 -507 Komblum K (1929) Bone changes in Raynaud's disease. Am J Roentgenol 21:448- 452 KovaE A. Kunjica L. JuriE-Ruzie D, ParaE B (1969) Acropathia extrtnutamm in polymerizatione nnyi-chlondi - nova profesionalna bolest. LijeE Vjesn 91:5--17 Kramer CG. Mutehler JE (1972) The correlation of clinical and environmental mea surements for workers exposed to vinyl chloride. Am Ind Hyg Assoc J 33:19-30 Kubota J (1957) Occupational diseases in synthetic resin and fibre industries. (Japanese text). J $ci Labour 33:1 -22 Kurokawa S, Inagaki T, Okuyama S (1977) Electron microscopic observation of the liver in portal hypertension following chronic exposure to vinyl chlonde monomer. Gastroenterol Jpn tJ.64-69 Vinyl Ohio Kuzmack A posure ti Laib RJ. Bt and m v Laib RJ. B- vinyl chi Laib RJ. St parattve Congres* Laib RJ. St parauve . 463 Laib RJ, St> compartzymt dt: Lander JJ. b the liver Langauer-L. aemia m : Health .* Lange CE. \ Gutacker Baden-B.i. Lange CE, J. heit - eir; Lange CE. J1 Leber be. 99:1S<>8 Lanp CE J product!, Lanp CE. I' Veltmau heit bei ache und tisch E,v 16. Jahrv Lanp CE. b worker- 1 Pans Ln; Laroche ( neurtxi. Lassiter DV 176-17.' Laws JW, L: tts and <>t Laws JW. digital an Lee FI.Har 1:1316Lec FI, Har chloride Lefaux R < t Lefevrc MJ * In tern.,11 27.-29 4 __H J Marsteller liemicai modiiicaJXlCOl Appl n of the mandible m acroosteolysis. macture 01 poly- .lyr.aud-Syndrom \\ Dtsch Med krankheit. (Sklera"len Industrie.) . lustnc, Ludwigs- Vinylchlond- Vinylchlond- i catalvse covalent i 13* ike of "C -inyl vitro. Toxieol Environ Health 'ilti of exposure i.. 219-22 \rbeitsntai/-*Con- In. eru;;:e Jes otiu oh tie ad Wochenschr % --ension. Surgery Kchenfeldr KH ts<) nach chroni* Verinderungcn i:fois:;6:-68 hunke E (19781 r der Arbeitsme* ' Hy 24:501--SO? itpnol 21:448- 1 rcmitatum in poly* sn 91:5-17 ironmcntai mta* noeJ 33:19-30 industries. Jwervation of the hlonde monomer. Vinyl Chloride-Associated Disease 99 Kuzmack AM. McGaupiy RE (I9"5) Quantitative risk assessment tor community ex posure to vinyl chlonde. U.S. EPA/ORD Raport. December 19*5 Laib RJ. Bolt HM (1977) Alkylation of RNA by vinyl chlonde metabolites in vitro and in vivo: formation of l-N*<rheno-adenosine. Toxicology 8.18!-195 Lath RJ. Bolt H.M (I*>?S1 Formation of 3-N4*theno^:ytidine moieties in R.N'A by vinxi chlonde metabolites in vitro and in vivo. Arch Toxicol J9-235 Laic RJ. Sidcklc G. Bolt HM i 1973) Induction of premalifnant hepatic lesions com parative effects of vinyl chlonde and tnc.ilcroethylene. Paper presented at the 20th Congress or European Society of To\:cciogy, Berlin (Wi*;', June 25 --22,19"3 Laib RJ. Stdekle G. Bolt HM (19791 Induction of premalifnant hepatic lesions com parative effects of vinyl chlonde and trichloroethylene. Arch Toxicol < Suppl) 2. 463 Laib RJ.Stdekle G, Bolt HM. Kunt \V (19791 Vinyl chlonde and trichloroethylene- comparison of alkylating effects of metabolites and induction of preneoplustic en zyme deficiencies in rat liver. Cancer Res Clin Oncol 94:139-147 Lander JJ. Stanley RJ, Summer HW. Boswell DC, Aach RD (197J1 Angiosarcoma of the liver associated with Fowler's solution. Gastroenterology 68:15S2 -- 1536 Langauer-Lewowteka H. Dudziak Z. Byczkowsky Z. Marks J (19761 Cryoglobulin* aamia in Raynaud's phenomenon due to vinyl chlonde. Int Arch Occup Environ Health 36:197-207 Lange CE. Veltman G (1977) Dermatologiiche Aspekte der Vjnylchloridschaden. In; Gutacker HW. Lelbach \VK fedsi Leberschaden durch Vinylchlond. IVitzstrock. Baden-Baden Brussel Kdln New York, pp S5-68 Lange CE, Juhe S. Stein G, Veltman G (1974a) Die sogenannte Vinylehlorid-Krank- heit - erne beniisbedingte Systemsklerost? Int Arch Arbeitsmed 32:1-32 Lange CE. Juhe S. Veltman G (1974b) Uber das Auftreten von Anposarkomen der Leber bei zwei Arbeitem der PVC-hemellenden Industrie. Duch Med Wochenschr 99:1598 -- 1599 Lange CE, Juhe S, Stein G. Veltman G (197S) Further result) in polyvinyl chlonde production workers. Ann NY Acad Sci 246:18-21 Lange CE. Bloch H. Biereaek HJ. Sehrt U. Etzel F, Mareteller HJ. Lelbach WK. Veltman G (1976a) Chromsch-toxisehe Schaden im Sinne der Vinylchlond-ICrank* ht bei Arbeitem in PVC*weitervenrbeitcnden Berneben. Xlinische. laborchemi* sehe und szmtjgnphische Untcnuchdnpbcfundc. In: Bolt W. Buchter A. Reben* usch E. Worth D feds) Jahresbencht der Dcutschen Gesellschaft fBr Arbeitsmedizin. 16. Jahrestagunf. Kdln J.-8 J I976. Centner. Stuttgart, pp 195-200 Lange CE. Bloch H, Veltman G, Doss M (1976b) Urinary porphynne among PVC- workers. In: Dos M (ed) Porphynns in human disease). Karger, Basel Munchen Paris London New York Sidney, pp 352-355 Laroche G. Hoehfeld M (1948) Un cas d'acro-ostlolyse aisocil a un syndrome osteo- neuro-endocrinien eomplexe. Scm H6p Pans 24:984--991 Lassiter DV (1976) Vinyl chlonde - best available technology. Ann NY Acad Sci 271: 176-178 Laws JW, Lillie JG, Scott JT (1963) Artenognphie appearances in rheumatoid arthn* tia and other disorders. Br J Radiol 36:477-493 Laws JW, El Sallab RA, Scon JT (1967) An ancriographic and histoiopcai study of digital arttnts. Br J Radiol 40:740--747 Lee Ft. Harry DS (1974) Anpoiarcoma of the liver in a vinyl chloride worker. Lancet 1:1316-1318 Lee FI. Harry DS. Adams WGF. Litchfield M (1977) Screening for liver in vinyl chlonde workers. Br J Ind Med 34:142-147 Lcfaux R (1966; Chemie und Toxikolope der Kunststoffe. Krauaskopf, Mains Lefevre MJ (1972) Akroosteolyse m Zusammenhang out der PVC-Hentellung. In: Intemaoonales Sympoaon der Werksdrzte derCUemiaehen Industrie. Ludwigshafcn 27.-I9.4.1972, pp 69-79 Lelbacli W'K. Marsteilcr HJ (1977) Das Japaroskopische Bitd der VjnyLhlorid-Kranklicit In. Lindner H ted) Fortschritte der gastroenterologischen Endoskopie. vol S Witzstroek. Baden-Baden Brussel. pp 37--10 Lester D. Greenberg LA. Adams \VR (1963) Effects of single and repeated exposure ol humans and rats to vinyl chlonde. Am Ind Hyg Assoc J 1+ 265-2"5 Liebegot: G (I9d9) Pathologische Anatomic der uhromschen Arsenvergittung. Dtc:i Med Woehenschr 74.855-856 Liebegott G (1952) Ober die Bezieliungen zwischen ehroniseher Arsenvergittung und malignen Neubildungen. Zcntralbl Arbeitsmed Arbeit'scl.utz Prophvl 2 15 -- 16 van Lierop JBH, Stek W ( 1976) Analysis of vinyl chloride in food simulants at low parts per billion levels by mass fragmentography. J Cluomatogr 123:183-187 Liivre JA, Gama G (1957) L'acroosteolyse. Bull Mem Soe Med Hop 73.109-120 Lilis R, Anderson H, Nicholson WJ, Daum S, Fishbein AS. Selikoff IJ (1975) Preval ence of disease among vinyl chlonde and polyvinyl chlonde workers. Ann NY Acad Sci 246:22-11 Lilis R. Anderson H. Miller A. Selikoff U f 1976) Pulmonary changes among vinyl chlonde polymenzation workers. Chest 69:299-303 Lilis R, Anderson H. Miller A. Selikoff IJ 11977) Modifications pulmonaires et exposi tion au chlorure et polychlorune de vmyle. Med Hyg 35:1542-1545 Lloyd JW (1974) Angiosarcoma of the liver in vinyl chlonde/polyvmyl chlonde workers. J Occup Med 16.809 Lloyd JW (1975) Angiosarcoma of the liver in vinyl chlonde/polyvinyl chlonde workers. J Oceup Med 17:333-334 Lopneno N, Birale R. Baroncelli S. Bauer C. Bronzetn G. Cummeliini A. Cercignani G. Corsi C. Gervasi G. Leponm C, Nien R, Rossi AM. Street! G, Turchi G (1976) Eval uation of the genetic effects induced by vinyl chloride monomer (VCM) under mammalian metabolic activation: studies in vitro and in vivo. Mutat Res 40:85-96 Lopneno N, Barale R. Baroncelli S. Bartsch H. Bronzettt G. Camineilmi A. Coni C. Freza D. Nien R*. Leporim C. Rosellmi D. Rossi AM < 1977) Induction of gene mu tations and gene convenions by vinyl chlonde metabolites in yeast. Cancer Res 36:253-257 MacSween RNM. Vetters JM. Ross SL. Ferguson J, Johnstone J.V. Sandison AT11973) Haemangio-endothelial sarcoma of the liver. J Pathol 109.39-44. MAK-Werte (1975) Umwcltschutz in der Sowjctunion. 111. Maxi.nale Arbeitsplatz* Konzentrationen (MAK-Werte) von Schadstoffen und ihte N* .--nierung. In. Benchte des Osteuropa-Instituts, Heft 108, Freie Univetsitit. Berlin, p 67 Makk L, Creech JL. Whelan JG Jr. Johnson MN (1974) Liver damage and angiosarco ma in vinyl chloride workers. JAMA 230:64-68 Makk L. Delorme F, Creech JL (1975) Angiosartomcs du foie chez des ouvners ay ant tie en contact prolonge avee Ic chlorure de vinyie: epidemiologic et programme de recherches chez let ouvners. Union Med Can 104:1833-1835 Makk L, Delorme F. Creech JL Jr. Ogden II LL. Fadell EH. Songster CL. Ganton J. Johnson MN. Christofferson WM (1976) Clinical and morphologic features of hepatic angiosarcoma in vinyl chloride workers. Cancer 37:149-163 Malaveille C. Bartsch H, Barbin A. Camus AM. Montesano R. Croisy A. Jacquignon P (1975) Mutagenicity of vinyl chloride, chloroethyleneoxide, chloroacetaldehvde end chlorocthanol. Biochem Biophys Res Commun 63:363-370 Malten KE, Zielhuis RL (1964) Industrial toxicology and dermatology in the produc tion and processing of plastics. Elsevier. Amsterdam London New York Maltoni C (1973) Occupational carcinogenesis. Excerpta Mcdica Int Congr Ser 322: 19-26 Maltoni C (1974) Angiosarcoma cpatico in operai esposti a eloruro di vinile. Rexo* conto dei primi due casi riscontrati in Italia. Med Lav 65:445-450 Maltoni C f 1975) The value of predictive experimental environmental carcinogenesis. Ambio 4:18-23 Manteller c.nd-Krankjpie. voi 8. J exposure of King. Dtsch --tiling und : ! 5 - I to i, re it low '33-137 !O-i:0 >*? Preval- \nn NV Acad ong vinyl : et exposi- hionde .hlonae ' Ci-cignam G . i i3*0' Evai*11 ur.cer ::.i AO. 55-a6 A. Coni r. - .'f eerie mu1 Res AT U073) hetuplating. in: Berichte 'I anposuft.i- ciivners ayant -nijramme de Clanton J. irures of Jaequignon P cetaldehyde .n the produc:fc nff Scr 322: .ml*. Rtso- xrvmogenesis. Vinyl Chloride-Associated Disease 101 Maltoni C 11976) Occupational chemical carcinogenesis, new fjets. priorities, and perspectives. I.ARC Sc; Publ SI: 117-Ida Mjltoni C (1977) Recent findings on the carcinogenicity of chlonnated olefins. Environ Health Penpeet 21.1 --5 Mjltoni C. Lefemme G 1197uj) Carcinogenicity bioassays or vmyl chloride. I. Research pian anaeariy resuns. Environ Res 7-3S7-405 Maitom C, Lelemine G i 19"4b) La potenaiaiita dei saggi specimen tali nella preJicic-..- dei nschi oncogem arabienrali L'n esempio II cloruro di vmile. Academia National* dei Lircst. Estratto dai Rendiconti della Classe di Scienze :i i-he. matematiche e naturah. Set VIII. vol LVl. fas 3 Maitom C. Lefemme G (1975) Carcmopnicity bioassays of vinyl chiondc: current results. Ann NY Acad Sci 2-*6* 195--218 Maitom C.Crespi M, Burch PI feds) (19731 n International Symposium on Cancer Detection and Prevention. E.scerpta Medica Int Congr Ser 175:1-137 Maltoni C. Lefetmne G, Chieco P. Carretti D (1974a) La caneerogenesi ambientale e professional: Nuove prospettive alia luce della cancerogenesi da cloruro di vintle. Osp Vita 166 Maitom C. Lefemme G. Chieco P. Carretti D (1974b) Vinyl chiondc carcinogenesis: current results and perspectives. Med Lav 65:421--444 Maltoni G.Cilibert: A. Gianni L, Chieco P (1975) Insorgenza di angiosarcomi in rattt. in seguito a sommimstrazione per via orale di doturo di vmile. Osp Vita 2:65 -66 Marieq HR. Johnson MN. Whetstone CL. LtRoy EC (1976) Capillary abnormalities in polyvinyl chloride production workers. JAMA 236:1568-1371 Mancq HR. Darke CS. Archibald R McL. LeRoy EC (1978) In vivo observaoons of skin capillaries in workers exposed to vinyl chloride. An English-Amencan compari son. Br J Ind Med 35:1--7 Marin A. Strauss J. Michels R. Benoit JP. Baltic R. Pierre C (1967) Acro-ostiolys* d'origine professionnelle. Rev Rhum Mai Osteoartic 34:340-351 Markowitz SS, McDonald CH. Fethiere W, Kenner MS U972) Occupational aeroosteolysis. Arch Dermatol 106:219-223 Marleau D, Villtneuve JP. Huet PM. Coti J. Lafortune M. Legare A. Lavoie P. ViaUct A (197a, Noncirrhooc idiopathic portal hypertension (OPH): Radiological and hemo dynamic evaluation of 4 cases by combined hepane and umbtiicoportal catheteriza tion. Gastroenterology 67:813 Manic.1-:r HJ. Ltlbach WK (1977) Das intemmedizinisch* Bild bei Vinylchlond* schadcn. In: Gutacker HW. Ltlbach WK (e^s) Lebenchiden durch Vinylchlond Vinykhlond-Krankheit. Wjtzstrock, Baden-Baden Brdssel KSln New York, pp 6983 Manteller HJ. Lelbach WK. Muller R. Juhe S. Lange CE. Rohner HG, Veltman G (1975) ChromsctKuxische Lebenchiden bet Arbcttem m der PVC-Produkuon. Dtsch Med Wochcnschr 98:2311-2314 Manteller HJ. Ltlbach WK. MQUcr R.Gedigk P (1975a) Unusual sptenomegalic liver disease is evidenced by peritoneoscopy ind guided liver biopsy among polyvinyl chloride production workers. Ann NY Acad Sci 246:95-134 Manteller HJ, Lelbach WK. Miller R. Gedigk P, Lange CE (1975) Klinischt und laparoskopuchc Aipekte der Lebenchiden bet Chemiearbcitem in dcr Vinylehlond-Polyracrisahon. Leber Magen Dans 5:196--202 Manteller HJ, Lelbach WK. Lange CE. Veltman G f 1976) Chromseh-toxisehe Schiden im Slnne der Vinylchlorid-Knnkheit bei Arbcitcm in PVC-wcitervcrarbcitcnden Betricbcn. In: Bolt W, Buchter A, Rcbentisch, E. Worth D (edi) Verhandlungen der Deutschen Gtsellsehaft fir Arbeiumedizin. 16. Jahrestagung. Centner, Stuttgart, pp 201-207 Martin JF. Waggoner JG. Berk PD (1974) Persistence of vinyl chloride (VO induced liver injury after cessation of exposure. Gastroenterology 67:8(4 l :fe- TV hr & i Mastromarteo E, Fisher AM. Chnjtie H. Danziger H (1960) Acute inhalation to\ic;:> of vmyl chlonde to laboratory animals. Am Ind Hyg Assoc J 5:394-398 Maugh TH II (1978) Chemical carcinogens: how dangerous are low doses? Science 202.37-41 McCann J. Simmon V, Streitwieser D. Ames BN (1975) Mutagenicity of chloroacet- aldehyde. a possible metabolic product of 1,2-dichIoroethar.e (e:liy lene dn-ldo.-id-'i. chloroethanol (ethylene chlorohydnn), vinyl chlonde. and cyclophosphamide Pri.c Natl Acad Sci 72.3190-3193 McMichael AJ, Haynes SO. Tyroler HA (1975) Observation on the (.valuation of occu pational mortality data. J Occup Med 17:123 -- 131 Mendenhall CL. Sherman J. Chedid A (197-4) Intermittent idiopathic portal hyperten sion. Gastroenterology 67:142-148 Meyerson LB. Meier GC (1972) Cutaneous lesions in acroosteolysis. Arch Dermatol 106:224-227 Mikkelsen WP. Edmondson HA. Peters RL. Redeker AG, Reynolds TB (1965) Extra- and intrahepatic portal hypertension without cirrhosis fhepatoporral sclerosis) Am Surg 162:602-620 Miller A (1975) Pulmonary function defects in nonsmoking vinyl chlonde workers Environ Health Penpcct 1 1:247-256 Miller A, Tcirstem AS, Chuang M. Sehkoff U, Wmhaw R (1975) Changes in pulmo nary function in workers exposed to vinyl chlonde and poiyvinvl chloride. Ann NY Acad Sci 246:42-52 Miller MC. Brandt JL (1962) Portal hypertension in the absence of both liver disease and vascular obstruction. Am J Dig Dis 7:442-448 Mitchell Johnston EN(1978) Vinyl chlonde disease. Br J Dermatol (Suppl 16)99 45--48 Monahan JJ (1926) Raynaud's disease; limitations of classical picture as a guide to diagnosis; report of a case showing extensive bone involvement. Am J Med Sci 171:346-358 Monson RR. Peters JM, Johnson MN (1974) Proportional mortality among vmylchlonde workers. Lancet 11:397-398 Moms JS. Schmid M. Newman S. Scheuer PJ, Sherlock S < 1974) Arsenic and noncirrhotie portal hypertension. Gastroenterology 66:86-94 Moser KM (1976) Meat wrapper's asthma. JAMA 236:2846-2847 Moulin O. Rely J. Palliard P. Vouillon G. Guttin G (1974) Aspects sderodermiques de 1'acro-osteolyse professionnelle. Ann Dermatol Syphiligr 101:33-44 Muller G, Norpoth K (1975) Bestimmung zweier Unnmetabolite dcs Vinylchlonds. Naturwissenschaftcn 62:541 Muller G. Norpoth K. Eckard R (1976) Identification of two urine metabolites of vinyl chlonde by GC-MS4nvestigations. Int Arch Occup Environ Health 38.69-75 MOllerG. Norpoth K, Kusters E, HerwegK. Venin E (1978) Determination of thioUi- glycolic acid in unne specimens of vinyl chloride expoied worken. Int Arch Occup Environ Health 41; 199-205 Muller R. Gedigk P. Bechtelsheimer H (1974) Neuere morphologaschc Befunde in der menschlichen Leber nach Vinylchlohd-Exposiuon. In: Lehnert G. Szadkowski D, Weber HJ (eds) 14. Jahresberich: der Dcutschcn Gesellschaft fur Arbeitsmedizin. 17.-19.10.1974, Hamburg- Centner. Stuttgart, pp 267-269 Mailer R. Beehtelsheimer H. Gedigk P. Mameller HJ, Leibach WK (1975) Das morphologische Bild der Lebenchadigung nach chronischer Vinylchlorid-Exposaion. Leber Magen Darm 5 :204-208 Mailer W. Baida BB (1975) Polymnylchlorid-Krankhelt unter dem Bild einer Akrosklerodermie. Hautatzt 26:387 Muemer MD, Perry HO. Ludwig J (1971) Chronic vitamin A intoxication in adults. Am J Med 50:129-136 Myers SA. Quinn IIJ. Zook WC0 975) Determination of vinyl chloride monomer at the sub ppnt level using a personal monitor. Am Ind Hyg Assoc J 36:332 337 Neale (: h>F` Neuma ana here Nichols chlv Nichol> coh> 230 Nona D expr Path. Norpot! Qber latte. Arbc Nothnai Hits. Oster R Ane- Osterm. Wadchloi Osterm. teehi Ott MG tnal Page M wo; Panh M by i Parmec laviv Patty ! dn Patty r new 19o- Pcnin 1' troe Bren Detu Stu. Peoples Exp Pessayr and Pha: Peters - sepv. Pillicho cost; Pimem Gav. il H.J Marsteller son roxuitv 598 ci? Science I chioroacetlane dtvhionde i. 'phsmuie Proe uation or occu- i.rtal hyperfen- <cn Dermatol (196$) Extra.4-citrous) Am iJe workers. its in pulmo* ; >nde. Ann NY 4 liver disease I'pl 16)0 45 --43 - .1 guide to 'lei Sell ng vtnylch.u- and non- tuque- .L- .tehkmds i iitci ot vinyl 9--75 on of thiovli;i i Arch Occup - funde in der -.Jkuwski D. usmedizin, ' i Das morphoosition. Leber ncr Akro- n in adults. nonomer at `52-337 Vinyl Clilonde-Associated Disease V 03 Neale G. Azzopardt JG (1971) Chronic arsenical poisoning and non-cirrhotic portal hypertension - a case for diagnosis. Br Med J 11:725 -730 Neumann HG. Osborne JC. Metzler M < 1979) Peroxidase activity in rat Zymbal'j gland and its possible role tor the metabolic activation of carcinogens. N'aunyn Schm-.cie- berp Arch Pharmacol t Suppl) 307, R15 Nicholson WJ 11977) Cancer following occupational exposure to asbestos and vinyl chloride. Cancer 39 I"52-1801 Nicholson WJ. Hammond EC. Seidman H. Selikoff IJ (1975) Mortality experience o; a cohort of vinc| chloride - polvvir.vt chloride workers A.in NY Acad Sc: 246-225 - 230 Nona DF, Ritchie S. Silver MD (1977) Angiosarcoma of the liver after vinyl chloride exposure: report of a case and review of the literature. International Academy of Pathology ,66th Annual Meeting. Toronto. Abstracts of Papers 56.361 Norpoth K. Miiller G. Witting U. Gottschalk D. Gottschalk J (1976) Untersuchungen tiber den Stoffwechsel des Vinylchlonds und liber Wirkungen der Vinylchlofidinha* lafion auf Regulationsmechamsmen des Leberstoffwechsels. Verb Dtsch Ges Arbettsmed 16:137 Nothnagei H. Rossbach MJ (1580) Handbuch der AraneimitteUehre. d. Autlage. Htrschwaid, Berlin Oster RR. Cirr CJ. Kranct JC11947) Anesthesia XXVII, Narcosis with vinyl chlonde Anesthesiology 8:359-361 Osterman-Golkar S. Hultmark D. Segerback D. Caileman CJ. GSthe R. Ehrenberg L. Wachimeister CA (1977) Alkylation of DNA and proteins in mice exposed to vinyl ' chlonde. Siochem Biophys Res Commun 76:259-266 Ostermayer H (1967) Vinylchlond. In: Foem W fed) Utlmanns Encvklopadie der technischen Chemie. vol 16. Urban Sehwarzenberg. Miinchen. pp 87-94 Ott MG, Langner RR. Holder BB (197S) Vinyl chlonde exposure in a controlled Industnal environment Arch Environ Health 30:333-339 Pag* M. Thenauil L. Delorme F (1976) Elevated CEA levels in polyvinyl chloride workers. Biomedeeine 1976:279 Panh Meng H, Faure H. Pasquier D. Couderc P (1977) Liver angiosarcoma occasioned by exposition to vinyl chloride. Acta Pharmacol Toxicol (Kbhi (Suppli 41.331 Parmeggiani L, Sasst C(1955) Rischi e patologia professionals nella produxiont e nclU tavorazione di alcunc match* plastichc. Med Lav 4<: 14-24 Patty FA fed! (1958) Industrial-hygiene and toxicology, vol 1: General principles. 2nd tdn. Intencience Publishers. New York Patty FA, Yant WP, Waite C7 (1930) Acute response of guinea pip to vapors of some new commercial organic compounds. V. Vinyl chlonde. Public Health Rep *5: 1963-1971 Penin H. Sargar G, Lanp CE. Veitman G (1975) Neurolupsch-psychiatrische und elektrocnztphiiegraphische Befundt bei Patienten mit Vinylchlorid-Krankheit. In: BrennerW. Rohmert W, Rutenfranx J (eds) Bench! uher die IS. Jahrextagung der Deutschen Gesellschaft fur Arbeitsmedizin. Munches 24.-26.4.1975. Centner. Stuttgart, pp 299-304 Peoples AS, Leake CD (1933) The anesthetic action of vinyl chlonde. J Pharmacol Exp Ther 48:284 Pessayrc D.WandscheerJC.Dcscatoire V. Artigou JY.Bcnhamou JP (1979) Formation end inacuvauon of e chemically reactive metabolite of vinyl chloride. Toxicol Appl rhermacol 49:505 -515 Peters JM (1976) Public-Health rounds at the Harvard School of Public Health Persepetives. N Engl J Med 294:653-657 FiUichowski P, Faure C. Aubert M, Pahn M. Latrcille R. Barrie J (1979) Angiosarcome costal lie i une intoxication au chlorure de polyvinyl. Nouv Pressc Med 8:2485 Pimentel Cortez i. Menezes Peixoto A < 1977) Liver disease in vineyard sprayers. Gastroenterology 72:275-283 ( \ \CO -044322 104 W.K. Lelbjch and H.J Mars teller Piier WT (I9'n) Diffusion ot' residual monomer in polvmer resins. Environ Health Per- sped 17.227-236 Polish E. Chnstte J.Cohen A, Sullivan B I 1962) Idiopathic presinuvoidal portal li>per- tension < Batui's syndrome). Ann Intern McJ 56:624-627 Pols vm> 1 ehlonde banned in Japan (1974) JAMA 229:855 Popper H (19751 The heuristic importance oi'environmental pathology Lessons from the vinyl ehlonde problem. Arch Pathol 99.69-71 Popper H. Thomas LB (1975) Alterations of liver and spleen among workers exposed to vinyl ehlonde. Ann NY Acad Sei 246.172-193 Popper H. L'denincnd S (1970) Hepatic fibrosis. Correlation of bioshemu.; and mor phologic investigations. Am J Med 49:707-721 Popper H, Thomas LB. Falk H, Berk PD, Selikoff I (1974) Banti syndrome followed by hepatic angiosarcoma in vinyl ehlonde exposure. Paper presented at the Sixth Meeting of the International Association for the Study of the Liver. Acapulco. Mexico. Oct. 20-22. 1974 Popper H,Thomas LB. Telles NC, Falk H. Selikoff IJ (1978) Development of hepatic angiosarcoma in man induced bv vinyl ehlonde. thorotrast, and arsenic. Am J Pathol 92:349-370 Preston BJ. Jones KL. Grainger RG (1976) Clinical aspects of vinyl chloride disease. Proc R Soe Med 69 284-286 Prodan L. Suciu I. PTslam V. Ilea E, Pascu L (1975) Expenmental acute toxicity of vinyl ehlonde (monochloroethene) Ann NY AcadSci 246:154-163 Puech AM, Foumet A, Laulhere L, Faurt J, Cau G. Mallion JM (1977) Etude des lesions hepatique* observes chez 5 sujets exposes au chlorure de vmyle dont 3 cas d'angiosarcome hepatique Arch Mai Prof 38:787-795 Purchase LFH. Williamson KS (1974) Proportional mortality among vmyt-chlonde workers. Lancet 11:591-592 Purchase LFH. Richardson CR. Anderson D (1975) Chromosomal and dominant lethal effects of vinyl chloride. Lancet 11:410-411 Purchase LFH. Richardson C. Anderson D (1976) Chromosomal effects in penpheral lymphocytes. Proc R Soc Med 69:290-292 Pushin GA (1965) On lesions of the liver and the biliary tract in workers engaged in the production of some types of plastics. Sov Med 2S: 132-135 (Russian text) Radwan Z (1977) Uptake and rate of metat-Lism of vinyl ehlonde by the isolated per fused rat liver preparation. Int Arch Occ Environ Health 40:101-110 RadwanZ.HenschlerD (1975) Uptake and metabolism of vinyl ehlonde m the isolated perfused rat Uver preparation. Naunyn Schraiedcbergs Arch Pharmacol (Suppl) 287.R100 Ramalingaswami V, Wig KL, Sama SK (1962) Cirrhosis of the liver in northern India a clinicopatholopcal study. Arch Intern Med 110:350-358 Rannug U. Johansson A. Ramel C. Wachtmeister CA (1974) The mutagenicity of vinyl ehlonde after metabolic activation. Ambio 3/5:194-197 Rannug U, Gdthe R, Wachtmeister CA (1976) The mutagenicity of chloroerhylene oxide, chloroacetaldehyde, 2<hloroethanol and chloroacetic acid, conceivable metabolites of vinyl ehlonde. Chcm Biol Interact 12:251 -263 Ravenna P (1940) Banti syndrome (fibrecongestive splenomegaly). Definition, classi fication and pathogenesis. Arch Intern Med 66:879-892 Ravey M. Klopstock J (1975) Tract analysis of vinyl chloride in PVC and in the atmo sphere. J Chromatogr Sci 13:552-553 Ravier E, Diter JM, Pialat J (1975) Un cas d'angiosarcome hepatique chez un ouvner expos* au chlonitc de vinyle monomire. Arch Mai Prof 36:171-177 Regclson W, Kim U, Ospina J, Holland JF (1968) Hemangioendothelial sarcoma of liver from chronic arsenic intoxication by Fowler's solution. Cancer 21:514-522 Reger RB (1977) Vinyl chloride and the polymers. J Occup Med 16:772-773 Vmyl Ch. Regnauh olbiidi Rem FR. Kollek Reinl W ( des L_ Reinl W. ' Gewer Reinl W. nd-iv r,. Reinl W. der Ge Reinl W. v derGe Reinl W. vder Gc Reitz RH. ing the Rety J, Lc superv. Arch M Rety J, Sa tique . Reynolds ' vinyl cl Reynold-1 ation o dase Reynold* vinyl cl I8:3n Richards > Nature Roche J.' tions k Roche J. 1 hcpa:i< 2:669 Rots JM * Bacter. Roth F (1 BeriicV Roth F (1 468-< Roth F 11 Dtsch ` Roth F11 Pathoi Roubal J Encycl Roussclot with hi etioloe portal1 h and H J, Mcf'itellc: ins. Environ Health i'sr- .sinusoidal portal h\ pt- .'Jthoiogy Lesions irom intor.p workers expired >t biochemical and siuf- ,nti syncrome followed presented at the S:\th 'he Liver. Acapulco. Development of hepatic . and arsenic. Am J vinyl chionde disease. . ntal acute toxicitv of 15*-ioJ M 1197-1 Etude dev are de vmyle dont 3 civ nong vinyl-chlonde rnal and dominant lethal ml effect* ..i peripheral pricer* `npajed in '(Rus-un teat) rule by the isolated per *0:101-110 . I chionde in the isolated Pharmacol (Suppi) liver in northern India - rhe mutagenicity of vinyl tty of ehloroethylenc ic acid, conceivable 263 Italy). Definition, classi- in PVC and in the atmo- I'atfque chez un ouvner ifi-m iidothelial sarcoma of n. Cancer 21:314--322 Jed 16:771-773 Vinyl Chlonde-Associuted Di'eave iQS Regnault V 11835; Cber die Zusamniensetzung dc* Ciilorkonlcnivasserstotis 'Oel des dlhildenden Gives) Liebigs Ann Pharm I* 22-38 Rem FR. Huth F (197$) Scchs vpontane pnmiire malignc GeriligesehwuKie m eincm Kollektiv von 30.000 Ohduktionen. list Arch Arbeit*med 3* 237-1*6 R,,*:n: W 11975) trkrankunpen durch V'inylehli'rtd. Janresbertcnt der Ge'.verpeaittstcSi des Landes Nordrhem-iVestfalen. PP 290-3 16 Re-.m W tteber III I97*i Erkrankuncen aurcli Vmyichior.d Jahresbcncht der Gewerbcaufsicht aes Landes Nordrhein-tVevtralen, FT 21" -252 Reini 'V. Weber H i 197t>) Stand der epidetr.iolofi*c,'cn F^rvcliuitj ubcr d:e V-.nyichio- nd*K;ankhen. Zentralbl Arhe::<med 26.97-10* Reinl tv. Weber H. Gieiser E 11976) Erkrankungen durch Vinvlchlond. Jahresbencht der Ge'verbeaufsicht des Landes Nordrhein-Westfalen. pp 287-29J Reinl W. 'Veber H. Greiser E f 1977) Erkrankunyen durch Vinjichlond. Jahresbencht derGewerbeaufsicht des Landes Nordrhem-Weitialen. pp 305-32* Reinl W. Weber H. Greiser E 11973) Erkrankunyen durch Vinylchlond. Jahresbencht derGewerbeaufsicht de? Landes Nordrhein-Westfalen. pp 3*7-377 Reitz RH. Quast JF. Wjtanabe PG. Gehrtng PJ11979) Chemical carcinogens: Estimat ing the risk. Science 205:1206-1208 Rety J. Lazard P. Berrod J. Schmitt M 1197*) Infrared thermography in diagnosis and supervision ot morciditv in workers dealing with vinyl chlor.de polymerisation. Arch Mai Prof 35:733-738 Rety J.Sauvage.Tuaillon. Habrari A (1976) Le 3e cas fran^ais d'angiosarcome hepatique chez un ouvner du chlorure de vmyle. Arch Mai Prof 3* 55 i -j j J Reynolds ES, Moslen MT Szabo S, Jaeger RJ. Murphy SD (1975a) Hepatotoxictty of vinyl chionde and I .trichloroethylene. Am J Pathol 81:219-236 Reynolds ES. Moslen MT. Szabo S. Jaeger RJ 11975b) Vinyl chloride-induced deactiv ation of cytochrome P-J50 and other components of the liver mixed function oxi dase system: in in vivo study. Res. Comm Chem Pathol Pharmacol 12:685-69* Reynolds ES. Moslen MT. Szabo S, Jaeger RJ (1976) Modulanon of halo thane and vinyl chionde induced acute injury to liver endopiastic reticulum. Panminerva Med 18:367-374 Richards RJ. Desai R. Hcxt PM. Rose FA (1975) Biological reactmtv of PVC dust. Nature 256:66*--665 Roche J (1977) Affections hepatiques ft chlorure de vmyle. A propos de 5 observa tions. Revue genlralt de littfrature. These. University of Grenoble Roche J, Foumct J. Hostein J. Panh M. Bcnnet-Eyrnard J (1978) Angiosarcoma hipadqut du au chlorure de vinyle. Presentation de * cas. Gastroenterol Gin Biol 2:669-678 Ross JM (1932) A ease illustrating the effeet of prolonged action of radium. J Pathol Bactenol 35:399-912 Roth F (1956) Obcr die chronischc Anenvergiftung der Moselwinzer mir besonderer Beriicksiehtigung des Arsenkrebscs. Z Krebsforsch 61:287-319 Roth F (1957a) Arsen, Leber. Tumoren (Himangioendothetiom). Z Krebsforsch 61: *68-503 Roth F (1957b) Cber die Spltfolgen des chronischen Arsenismus der Mpselwinzer. Dtseh Med Wochcnschr 82:211 -217 Roth F (1959) Zur Pathologic dcr chronischen Anenvergiftung. Zentralbl Allg Pathol Pathol Anat 100:329-530 Roubal J (1972) Vinyl polyvinyl chloride. In: I.L.O. (Internation Labor Organization) Encyclopaedia of occupational health and safety, vot II. Geneva, pp 1*67-1*68 Rousseiot LM (19*0) The late phase of congestive splenomegily (Band's syndrome) with hemsttmesis but without cirrhosis of the liver. Further observations on the etiology of Band's syndrome and the effect on prognosis of certain variations in the portal venous pattern. Surgery S:3*-*2 106 W.K. Lelbaeli and H.J. Marsteller Rowe VK 11975) Experience in industrial exposure control. Ann \'Y \ead Sci 246 306-310 Riibsamen H (1976) Vinylchlondkrankhcit (VC-Krankheit). Z. Allger.wtnmcd 52: 1551-1555 Russell RM. Bagheri SA. Boyer JL (1973) The hepatic lesion of hypcrvitanun-Kis A a unique pattern of hepatic fibrosis with portal hypertension and ascites. Gasiroenteroloiy 65:568 Russeil RM. Boyer JL. Bagheri SA. Hruban Z (1974) Hepatic injurs from chronic hypervttaminosis A resulting in portal hypertension and ascites N Engl J Med 291. 435-440 Sakabe H (1975) Bone lesions among polyvinyl chloride production workers in Japan Ann NY Acad Set 246:78-79 Sama SK. Bhargava S.Gopi Nath N.Tilwar JR, Nayak NC. Tandon BN. Wig KLi 1971) Noncirrhotic portal fibrosis. Am J Med 51:160-169 Saric M, KulSar Z. Zorica M, Geli 1 (1976) Malignant tumors of the liver and lungs >.n an area with a PVC industry. Environ Health Penpect 17:189-192 Schaffner F, Popper H, Selikolf IJ (1976) Initial features of vmvl chloride I VC) hepa tic injury. Gastroenterology 71:928 Schattenberg PJ, Totovi V, Gedtgk P. Marsteller HJ (1977) Die Ultrastruktur der Lebenchddigung bet der chronischen Vjnylchlond-lntoxikatton. Virchows Archiv (Pathol Anat) 273:233-247 Schaumann O (1934) Uber die Herzwirkungeiniger Inhalationsnarkotika. Med Chem (Leverkusen Ger) 2:139-147 Schaumann O (1938) Monochlonithylen. In: Lehmann KB. Fluty F (eds) Toxikologie und Hygiene der techntschen Ldsungsmittcl. Sprinpr. Berlin, pp 130-131 Schlatter C (1976) Gefahrdung von Konsument und PVC-Arbeitem durch Vinylchlotid. Schweiz Med Wochenschr 106:647-650 Schmidt H. Schaumann O (1929) Uber kombinierte Gasnarkose Dtsch Z Chtr 216. 149-157 Schmidt K. Baton J (1976) Vorkommen des Leberhdmangioendothelioms bei Arbeitern, die lang dauemd dem Vinylchiond ausgesetzt waren. Z aerztl Fortbild 70. 1020-1022 Schnack H, Stocktnger L. Wewalka F (1967) Adventitious connective tissue cells in the space of Disse and their relation to fibre formation. Rev Int Hepatol 17:855-860 Schneiderman MA (1979) Chemical carcinogens. Science 203:603 Schneiderman MA. Mantel N. Brown CC (1975) From mouse to man - or how to get from the Laboratory to Park Avenue and 59th street, Ann NY Acad Set 246:237248 Schottek W (1969) Zur Toxikologie des Vinylehloiid*. Chem Techn (Leipzig) 21: 708-711 Schiitz A. Wolf D (1977) Gefihrdung durch Vinylchiond bei der PVC-Weiterverarbei- tung. Bcnsfigenossenschaften 1:7-13 Schwarzweiier F (1957) Verlaufsuntcrsuchungen bei cinem osteolytischcn Krankheits- bild. ZOrthop 88:404-413 Schweitzer GE (1975) Environmental concerns beyond the workplace. Presentation to the Working Group on Toxicity of Vinyl Chlohde-Polyvinyl Chloride. Ann NY Acad Sci 246:296-302 Sehrt-Bachner U, Etzel F (1977) Haemostastologische Befunde bei Vinylchtondschaden- In: Gutacker HW. Lelbach WK (eds) Lcbenchdden dutch Vinylchlorid. Witzstrock. Baden-Baden Bnissel KSIn New York, pp 89-91 Seki K (1965) Histometrical studies of the spleen in Banti's syndrome with refereii.e to clinieo-pathologic correlations. Tohoku J Exp Med 87:222-243 Selikoff IJ (1976) Discussion remark to Barnes: Vinyl chloride and the production of PVC. Free R Soc Med 69:281 Vin>! Selin l 79' Severen-. A<- Shafii the Sherh of . Sidery stn Da Sii effi Da Si. Por Simp. r Slater Smim 19: Smim- Di< Smim ole Smith Smith chi Smith pr<Smith ml. Smolc for Smyt.. 17 Somn.. Sv a Suren. Spirt;* ch>. 424 Spirt-.* rid i Stem < ph.. Stein < nar Sit*rid. Stutt? all* Suciu I cl. Suciu I Me 3 Mcrsteller ;jd Sci 24'i nmed 52: i.iin.i'is A :tvi Gustro- chronic pi J Med 191 ken in Japan. Wig KLI197)) er and lungs in ile i VC) liepa- lukinr der IlOWS AfChlV .a. Med Client Tavikolote <*131 -h Vinyl- l CH:r 2)6 I- hei Xr^eiibud 1 ceils in :!ls I 17:855-*0 or how to pet 1 Sci 246;2.' 7 - -put) >1 '* vitervetarbei- len Krankhetts- Presen ration nde. Ann NY nylchloridsehl. Ichlorid. with referet.-e . production of Vm> I Chlond-Assooiated Disease 107 Seltr.gcr M. Kotf RS (1975) Thorut.*at and the liver: a reminder. Gastroenre.-oMgy hi -oo.303 Severs LW. Skory LK 11975) Monitoring personnel exposure to vinyl chloride, vtnylidene chloride and methyl chlonde ir. an industrial work environment. Am Ind Hyp Assoc J 3* o6?-o76 Si-.ahm MM i I9'e) The non-mutajenicity and -recombinogemoity of vinyl chiotide m ;he absence of metabolic activation. Mutat Res 40 2o9-Z",2 Sherlock S. Feldman CA. Moran B. Scheuer PJ (19661 Partial nodular transformation 01 the liver with portal hypertension Am / Med 40 )'-3C3 Sidery s H. Vellios F i 1964) P.artal hypertension without cirrhosis or txtrahepanc ob struction. Am 3 5ur| 10S:7SS -789 Da Silva Horta J(1967) Late effects of thorotrast on the liver and spleen, and their efferent lymph nodes. Ann NY Acad Sci 14J 676-499 Da Sdva Horta J. da Motta LC (1967) Follow-up study of thonum dioxide patients .n Portugal. Ann NY Acad Sci 145:830-842 Simpson HM. Baggenstost AH. Stauffer MH (1955) Primary sarcoma of the liver- a report of three cases. South Med 3 48:11"TT--1182 Slater TF 1 1972) Free radical mechanisms in tissue injury. Pton. London Smirnova NA (1954) Paper presented at the conference ot young scientists. Cor k::. 1954. pp 10-11 (Russian text) Smirnova NA (1959) Clinics of chronic intoxication by olefins and vinyl chloride. Dissertation Cor'kiitRussian text) Smirnova NA( 1961) On the question of bone lesions due to chrome intoxication by olefins and vinyl chlonde. Vestn Rentgenol Radiol 36:63-66 (Russian text) Smith PM. Williams DM3 11974) Vinyl chlonde and cirrhosis. Digestion 10:321 Smith PM. Williams DM3. Crossley IR (1975) Portal hypertension induced by vmyl chlonde. Cut 16:4Q2^S03 Smith PM. Crossley IR. Williams DM3 (1976a) Portal hypertension in vinyl chlonde production workers. Lancet U.602-604 Smith PM. Williams DM3. Evans DMD (1976b) Hepatic angiosarcoma in a vinyl chlo ride worker. Bull NY Acad Med 52.447-452 Smoldid V 11966) Assessment of lead exposure in PVC manufactones an-1 suggestion-. for control measures. Arh Hig RadaToksikol 17:30** 316 (Serbo-Croatian text) Smyth HF 3r( 1956) Hygienic standards for daily inhalation. Am lnd Hvt. Assoc 3 17:129-183 Sommenchild H. Kluge T (1971) Some observations on hepatic sinusoids. Acta Our Scand 137:257-263 Sorenson WR (1976) Polyvinyl chlonde in fires. 3 AM A 236:1449 Spirtas R. Kammski R (1977) Angiosarcoma of the liver in vinyl chlonde/polyvinvl chlonde workers. - 1977 Update on the NTOSH Register. 3 Oceup Med 20:427429 Spirtas R. McMichaet A3. Gamble J. van Ert M (1975) The association of vinyl chlonde exposures with morbidity symptoms. Am Ind Hyg Assoc J 36:779-789 Stein G. Jtihe S. Lange CE. Veitman G (1973a) Bandfdmuge Osteolysch in den Endphalangen dei Handskeietts. ROEFO 118:60-63 Stein G. fche S. Lange CE. Veitman G (1973b) Skeiettvcrdnderungen bet der sogenannten Vinylchlondkrankheit. Rocntgenblactter 26:350-335 Stewart 3D. Williams DM3. McLaehtan MSF (1975) Acro-asteolysis in a polyvinyl chlo ride worker with an atypical industrial history. 3 Soc Occup Med 25:103-109 Stuttc H3, Heusermann U (1978) Die Mill bet der Vinylchlond-Krankhett. Zentralbt alls Pathol Pathol Anat 122:234 Suciu I. Drejman 1. Valatkai M (1963) Contribu(ii la studiul TmbolnSvirilor produse de donna de noil. Med Intern!' 15:967-978 Suciu 1. Drejman 1. Vaiaskai M (1967) Etude des maladies dues au chlorurc de vinyle. Med Lav 58:261-271 103 . W.K. Lclbach and H.J. Marstellcr Suciu I, Prodan L, Ilea E. Paduraru A. Pasco L (1975) Clinical manifestations in vinyl chloride poisoning. Ann NY Acad So I4o.5 3 -69 Szende B. Lapis K. Nemes A. Pinter A (1970) Pneumoconiosis caused by the tnlialj- non of polyvinylchloride dust. Med Ljv 61 433-436 Tabetshaw IR, Gaffey WR (1974) Mortality study of workers in the manutaeture of vinyl chlonde and its polymers. J Occup Med 16:509-5 IS Takeuchi Y, Mabuchi C (1973) A case ot occupational acroosteolysis. presumably caused by vinyl chloride. Jpn J Ind Health 15:385-394 Tamburro CH (I97S) The hepatic role in the carcinogenesis and in early detection - the vinyl chloride model. Yale J Biol Med 51:67-30 Tamburro CH. Creech JL, Makk L. Whelan JG (1978a) Alcohol vinyl chloride, a causal relationship in the development of primary hepatocellular carcinoma. Paper pre- sented at the Meeting of the International Association for the Study of the Liver. Fuengirola. Spain, October 30-21. 1978 Tamburro CH. Creech JL, Davts A, Greenberg RA(197Sb) Indocyanine green clearance as the prospective indicator of hepatocellular chemical toxicity. Paper presented to the American Association for the Study of Liver Diseases at the 29th Annual Meet- ing, Chicago. Ill, Nov 6--8, 1978 Tandon BN. Lakshmmarayanan R, Bhargava S. Nayak NC. Sama SK (1970) Ultra- structure of the liver in non<irrhotic portal fibrosis with portal hypertension. Gut 11:905-910 t Tassignon JP (1979) Log normal distribution of the incubation period of liver angto- sarcoma in vinyl chloride polymenzation workers. J Occup Med 21:10 Taylor KJW, Barrett JJ, Williams DMJ, Smith PM. Duck BW (1976) Preliminary results of grey-scale ultrasonography in the detection of vinyl chloride related liver and spleen disease. Proc R Soc Med 69:292-295 Thiess AM, Versen P (1974) Arbettsmedizintsche Gedanken zursogenannten ..Vinyl- chloriderkrankung". Arbeitsmcd Sozialmed Praeventivmed 9:146-148 Thomas LB, Popper H (197J) Pathology of angiosarcoma of the liver among vinyl chloride - polyvinyl chloride workers. Ann NY Acad Sci 246:268-277 Thomas LB, Popper H, Berk PD.Selikoff I, Falk II (1975) Vinyl-chloride-induced liver disease. From idiopathie portal hypertension (Banti's syndrome) to angio- sarcomas. N bngt J Med 292:17-22 Tisdale WA, Klatskin G, Glenn WWL (1959) Portal hypertension and bleeding eso* phageal varie * Their occurrence in the absence of both intrahepatic and extrahe- patic obstruct wn of the portal vein. N Engl J Med 261:209-218 Tola S ( 1975) Occupational lead exposure in Finland. IV. The polyvinyl chloride plastic industry. Scand J Work Environ Health 1:173-177 Torfcelson TR.Oyen F, Rowe VK (1961) The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Am Ind Hyg Assoc J 22:354-361 Trapp JT, Lummus FL, Hilbun BM (1974) Aero-osteolysis: a ease report. J Miss State Med Assoc 15:246-248 Tribukh SL. Tikhomirova NP, Levina SV. Kozlov LA (1949) Conditions of work and measures of industrial hygiene in the production of. and manufacture from, vinyl chloride plastics. Gig Sanit 10:38--44 (Russian text) Triche T, Nanba K, lshak K. Wolkoff A. Berk PD (1975) Hepatic ultrastructural changes in vinyl chloride (VC) workers. Clin Res 23:259A Truell JE, Peck SD, Reiquam CW(I973) Hcmangiosareoma of the liver complicated by disseminated intravascular coagulation. Gastroenterology 65:936-942 Vainio H (1978) Vinyl chloride and vinyl benzene (styrene)-mctabolism, mutagenicity and. carcinogenicity. Chem Biol Interact 22:117-124 Vale FT, Kipling MD, Walker AE (1976) Miscellaneous symptoms occurring in workers cnpged in the manufacture of PVC. J Soc Occup Med 26:95-97 Vazin AN, Plokhova ET (1968) On the pathogenesis of disease due to chronic expo- sure to vinyl chloride. Farmakol Toksikol 3:369-372 (Russian text) Viny: Vazin t;)| (R>. Vazin ex VKE ban Veltm ge Veltm in. chi Veltm con Veltm 197 Vertk:' in v 29- Villem Via; Viola 1 Viola 1' Viola T Viola 1 to s Wagon 1 Walkc: e:n Walkr. 341Walkc- 2&r Walln-. Me Ward . PrWard ' not Watan;' sib:. Watan ridWatan hep anWatu>. sine Watan nu,, 391 Water bin. Waxw. risk .H J Mjrvu-llcr -ii-ui* in nil) l the mtulu* luijvtur: l>( 'ssumably J.rectior. - f -..ride a causal . I'aper prenf the Liver. green clearance . r presented to Annual Meet- ''Oi I'ltn* ,i.cniion. Gut liver artgio- unman results a uver and m'en ..Vinyl%- ng vinyl tiduced Ljngio- Sp esuu.4eetra` . .H<ntle Vtermim-ii 4. 3*| I Mis State v.'rtr and Irum. vm\l vuctun! rtmpiicated 942 >. mutagenicity -ting in workers ironic expo- Vinyl Chlnnde-Avocuted Disease 109 Vaitn AN. Plokhova ET11969a) Changes in adrenalin-like substances m rabbit blooU following .hronic exposure to unsl chloride vapour. Gig Tr Prof Zabol 13 46 -47 I Russian text) Vann AN. Plokhova ET I I69b) Ounces of cardiac activity in rats following chronic expi.sjurt to vmyi chlortoe vapour. Farmakol Tok-ikoi 52.220-222 iRussian text) VfiEi 19*4. |975> VCPVC: Beisniel etner Problemlosune. Herausgegcben vom Ver- band der kunstitotterreujinden Industrie e.V i VKE). Frankfurt) Veltmin G. Large CE 119"7i) A;l;citrniediiimsche Aspekte der Viny Ichlondscliader.. Bemisacmiatosen 25 6" *7 Veltnan G. Lar.ce CEl -*>rivit<incdiz:ntsche Aspects Jcr V-ny'chlondschiden. In- Gutacker H\V. Lelbav.li WR ie;lsi Lebersehaden Jurch Vinvlchlorid - Vinyl- chlond-Krankheit Witistrock. Baden-Baden Bousel Koln New York, pp 95-101 Veltman G, Lange CE. lithe S. Stein G. Baehner U H75) Clinical manifestations and course of vinyl chlonde disease. Ann NY Acad Sci 246 6-17 Veltman G, Lange CE. Stein G (1973) Die Vinylchlorid-Krankheit. Hautarzt 29: 1977-1982 Vertkin YI. Mamontov YR 11970) On the condition of the broncho-pulmonary system in workers employed in the manufacture of PVC articles. Cug Tr Prof Zabol J4. 29-32 (Russian text) ViUencuvc JP, Huet PM. Joly JG. Marleau 0, Cote J. Legate A. Lafortune M, Lavoie P. Viallet A (1976) Idiopathic portal hypertension. Am J Med 61.4J9--464 Viola PL 11970a) Cancerogentc effect of vinyl chlonde. Int Cancer Congr, Abstr 29 Viola PL i 1970b) Pathology of vinyl chlonde. Med Lav 61:174-180 Viola PL( 1974) La malattia dacloruro di vmde.Med Lav 65.31-99 Viola PL, Sigotti A. Caputo A (1971) Oncogenic response of rat skin. lungs, and bones to vinyl chlonde. Cancer Res 31:516-519 Wagoner JK, Infante PF, Saracci R (1976) Vinyl chlonde and mortality? Lancet II: 194-195 Walker aE (1974) A preliminary report of a vascular abnormality occurring in men engaged in the manufacture of polyvinyl chlonde. Br 5 Dermatol 1974? 22-23 Walker A (1975) Occupational aero-osteolysis (two cases). Proc R Soc Med 68:343- 346 Walker AE fl 976) Clinical aspects of vinyl chlonde disease: Skin. Proc R Soc Med 69: 256-289 Walindfer H, Zinnagl N (1977) Himsngiourkomatos* naeh Polyunylchloridexposition. Med Klin 72:410-413 Ward AM (1976) Evidence of an immune complex disorder in vinyl chloride workers. Proc R Soc Med 68:289-290 Ward M, Udnoon S, Watkins J. Walker AE, Darke CS (1976) Immunological mecha nisms in the pathogenesis of vinyl chloride disease. Br Med J 1:936-938 Watanabc PC, Gehring Pi (1976) Dow-dependent fate of vinyl chlonde and its pos sible relationship to oncogenicity in rets. Environ Health Perspect 17:145-152 Watanabc PG. McGowan GR. Madnd EO, Gehring PJ (1976a) Fate of1 *C-vtnylchlo- ride following inhalation exposure in rats. Toxicol Appi Pharmacol 37:49-59 Watanabc PG, Hefner RE Jr, Gehring Pi (1976b) Vinyl chloride-induced depression of hepatic non-protein sulfhydryl content and effects on bromosulphaiein (BSP) clear ance in rets. Toxicology 6:1-8 Watanabc PG, McGowan GR, Gthrini PJ (1976c) Fate of "C vinyl chlonde after single oral administration in rats. Toxicol Appt Pharmacol 36:359-352 Watanabc PG, Zcmpei JA, Gehring Pi (1978a) Comparison of the fate of vinyl chlo ride following single and repeated exposure in rats. Toxicol Appl Pharmacol 44: 391-399 Watanabc PG. Zempel JA, Pegg DG. Gehring PJ (1978b) Hepatic maeromolecular binding following exposure to vinyl chlonde. Toxicol Appl Pharmacol 44;<71-J79 Waxweiler RJ, Stringer W, Wagoner JK, Jones J, Falk H. Carter C11976) Neoplastic risk among workers exposed to vinyl chlonde. Ann NY Acad Sci 271: 40-43 rm .-- v. ucc 044323 rm 110 W.K. Lelbach anil H.J. Marsteller: Vinv! CMonde-Assotiated Diwase W.-gcnrr K. Wc'J: H; Kainpiumi trastose naeii Jia&iostischer Ail -iC* Wrgman DH > |9_ri(Diseu;yii>tt rei.. 'V-gmanDH > 1`. V\Publik.*IIeal:!i ricti.'ulpcnd'vihelialcx Sv icm und TlioroMed Wodictivchr *6' 1977- 198; ' ) ,\tnz.\ 5ei 246'2fl-2I it Han A.I School o; Public Health NFnf!T'Maj':>ai6',-i s. ' * Wricrrt FJ t 15*4' O'-'.-.icj! car .scie:- ; TO? P03 W*in*sren K I I *> i Hi 1 i -M If 'icf'-'in J'--ateil ith exposure in vws I hlunle itv> . J f u - 'SJ' JT 1 7 .i '1 Mi-I.m J( J' < e *. J r.w/ . m r;\ len-tiC' >1 ` ir j;, ' i. . I ..*- -f ' >-i ' i -mi. > 1 t ' u v. -ke- It ' -g'. i i' *-**-' > J- i, , Williams DMJ. MiCachlhN <fM. 11 >' ; Heahut o) I'ly.lanc^al defects m aero-osteolysix. J Soc Occui' MV;: 2o.98--.j9 , ", V > - * ' Williams DMJ. Taylor KJW: 'H'jiSit'.h PM U975a) Screening vinyl chloride monomer workers for liv.'. unease Gut !> *39, WilliamsOMJ,TaylorKJW (^aylev IR.-S---fliPM. Duck BWU975b) Pre-symptomanc detection of liver changf. ;n Vinyl chlonde monomer workers. Digestion 12:362 Williams DMJ. Smith PM, Taylor KJW, Crossley IR (1976) Momtonng liver disorders in vinvl chlonde monomer worked i4lnc greyscale ultrasonographv. Br J lnd Med 33152 -- 157 , |r Williams DMJ, Roberts E. Evans KT (I'lf'7) An assessment of hand thermography tn vinyl chlonde workers. J Soc Occup ^led 27.S7-62 Williamson DG. Cvetanovic RJ (1963) Rates of reactions of ozone with chlorinated and conjugated olefines. J Am Chem>Soc 90.4248 Wilson RH, McCormick WE. Tatum CF.Creech JL (1967) Occupational acroosteolysis. Report of 31 cases. JAMA 201:577-581 W'inell M. Holmberg B. Kronevi T(1976) Biological effects of vinyl chlohile: an ex penmen til study Environ Health Perspect 17:211--216 Woods JS (1979) Epidemiologic considerations'fh the design of toxicologic studies: an approach to risk assessment in humans. Fed True 38' 1891-1896 Wyatt RH, Kotchen JM. Hnchstrasser DL. Buch'iian JW Jr. Campbell DR. Slaughter JC, Doll AH U 9,75) An epidemiologic study M blood screening tests and illness histories among chemical workers involved in the manufacture of polyvinyl chloride Ann NY Acad Sci 246:80-87 Yamamoto K (I9iS) Morphological studies of t.ic spleen in splcnomegatic liver cirrho sis comparing with the spleen in idiopathic pprtai hypertension (so-called Banti's syndrome witlix.V liver cirrhosis). Acta Patiicl Jpn 28:891-905 Yamamoto K (1979) Morptologtcai studies of the spleen in idiopathic portal hyper tension (so-called Banu's ndromt without liver cirrhosis) using light microscopy, scanning electron fnicroscopv and hutometr5`.*Acta Pathol Jpn 29:1-19 ZappJA(l964) Vinyl chlonde. Am lnd HygAssocJ 25:421-423 Zecgcn R. Stansield AG. Dawson AM, Hunt AH.f 1970) Prolonged survival after poru1 decompression of patients with non<ttrhuticantrahepatic portal hypertension. Gut 11:610-617 Ziclhuis RL (1974) Perrifissiblc limits for occupational exposure to toxic agents A discussion in approach between US and USSR. Int Arch Arheitsnted 33.1-13 Zimmermann H. Eck H (1975) Zur Pathologischen Anatomic der Vinylchlond-Krankhett. Virchows Arch (Pathol Anat) 368:51 -59 Zorica M. Sant M. Ko'nstantinovit M. Koea? I (1975) Two cases of angiosarcoma of the liver following exposure to vinyl chlonde. Arch Hig Rada Toksikol 26:275-231 Serbo-Croatian text) Die f M.W1ES 1 Einieit 2 Gesch 3 Alice:- 3.1 P 32 I 3,3 D 34 D 3.5 D. 3 3; 3' 4 Marian 4.1 B 4.2 O' 4 4 43 M 4 .4 C> 4.5 M 4.6 M 5 Klim*. 5.1 t. 5 .2 P 5 5 Herrn I 1 Median renstra