Document YrDRy4vMKQ8jLjXQMBQZ14eOD

i.' 4^"' 4; vc ft ^ ^ Ergebnisse der Jnneren Medizin und Kinderheilkunde Advances in fjfu**c* internal Medicine and Pediatrics So C/J Neue Folge Herausgegeben von P Frick G.-A.von Harnack K.Kochsiek G.A. Martini A. Prader Mit 24 Abbildungen und 23Tabellen :Kj Berlin Heidelberg New York 1981 * rK .V v\* (r*fKi V s/- Vinyl Chloride-Associated Disease , *i W.K. LELBACH and HJ. MARSTELIER 1 ~ * --,r,> |--rant 1 Introduction ........................................................................................................ 2 2 Technological Details........................................................................................... 2.1 Vinyl Chloride Monomer(VCM)................................................................ 2.1.1 History.............................................................................................. 2.1.2 Production or' VCM................................................................ . 2.2JJjgilyttosus/Polyv>nvl Chloride l PVC).................................................... 2.2.1 Technology of Polymerization......................................................... Methods of Polymerization.............................................................. Compounding............................................................................... Sources of Exposure to VCM in PVC Production ......................... The Explosion Hazard..................................................................... The Odour Threshold 1..................................................................... VCM as an Anaesthetic Agent......................................................... Effects of Acute Overexposure ...................................... Monitoring VCM Concentrations m WorkingAreas....................... 2.2.10 Exposure to VCM in PVC-Processing (-Fabricating) Plants.......... 2.2.11 National Standards for the Control of Exposure........................... 2.2.12 Exposure to VCM Outside theWorking Area................................. 4 4 4 ; 6 6 7 8 8 9 10 10 11 13 13 17 18 3 Toxicology of VCM.............................................................................................. 3.1 Acute Toxtcity.............................................................................................. 3.2 Chronie Toxicity........................................................................................... 3 .3 Oneogemc Properties.................................................................................... 3.4 Toxicodynamics........................ 3.4.1 Uptake and Distribution.................................................................. 3.4.2 Metabolism...................................................................................... 3.4.2.1 Relation between Chemical Structure. Reactivity and Mutagenic or CarcinogenicEffect............................... 3.4.2.2 Metabolic Pathways........................................................... 21 21 21 22 24 25 26 26 26 4 Clinical Spectrum................................................................................................ 4 I Tlie Triad; Raynaud's Phenomenon. Pscudoscleroderma and Acroosteolysis.............................................................................................. 4.1.1 Familial and Idiopathic Acroosteolysis........................................... 4 1.2 Epidemiology of Occupational Acroosteolysis............................... 4 1 3 Clinical and Roentgenological Features.......................................... 4.1.3.1 Occupational Acroosteolysis............................................ 4.1.3.2 Pseudoscleroderma........................................................... 4.1.4 Histology............................................................................................ 4.1 4.1 Cutaneous Lesions.............................................................. 4.1.4 2 Bone Lesions............................. ..... ............................ 4 1.5 Arteriography. Capillaroscopy, Inlrared Thermography............... 4 I 6 Immunological Studies................................................................... 29 31 34 34 36 36 38 39 39 39 40 42 Department ol Medicine, Director; Prof. Dr. II J. Dcngler, L'nKersity ol Borin. I-'RG ***** . '*" I ( W.K. Lelbach and H.J. Marsteller 4.1.7 Pathogenetic Considerations......................................................... 4.2 Non-malignant Liver Disease in Vinyl Chloride/Polyvinyl Chloride Production Workers.................................................................................... 4.2.1 Clinical Manifestations of Non-malignant Liver Disease............... 4.2.2 Laboratory Findings.............................................................. 4.2.3 Gross Inspection of the Liver and Spleen..................................... 4.2.4 Histology....................................... 4.2.4.1 Hepatic Fibrosis.............................................................. 4.2.4.2 Sinusoidal Lining Cells.................................................... 4.2.4.3 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............................................... 4.3.5 Therapy............................................................................................ 4.3.6 RM- Axseasmenf............................................................................. 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 Generic Effects jif VCM_.............................................................. 5 Conclusion and Outlook.................................................................................... References............................................................................................................. , 44 44 48 49 50 51 51 54 54 54 55 57 57 57 .74 76 78 80 80 81 82 82 84 85 87 88 89 Key words: Acroostcolysis - Angiosarcomajof^ the Liver - Portal Fibrosis and^ortal^ Hypertension - Pseudoscleroderma - Haynauii's Phenomenon - v inyrOtioride 1 1 Introduction The history of vinyl chloride-associated disease, its recognition and prophylaxis is a classic example of shutting the stable door after the horse 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, tliis ac count should again alert us to the necessity of pretesting chemicals adequately for their potential health effects, even at the risk that technological progress will develop at a 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 chloride (VCM),a rather simple aliphatic compound, was believed until the early 1960s to be Vinyl Chloride-Assix; one of the least harmf later turned out, had n evaluation of acute eff to reveal its carcinogei might have continued ; place, considering that vapour phase under am reactive double-bond. Today vinyl chloric formation and data on cisely a quarter of a ce; tributable to this new <. with the shocking disci tion workers heavily ex ing that the monomer i pound did not alert the in workers engaged in t lished in 1949 (Tribuki. Ultimately.it was ti cuned in workers expo a causal relationship; (! pseudosleroderma; (2) liver. Particularly, the u nancy among a compa.*. alarming experience wn a connection between \ lungs or the gastroime the prolonged latency r sarcoma of the liver, re these two fatal consequ the conclusion that Vi, cancer meeting in Hous to VCM was a very sen It should be stresse,. precise, an intermediate mainly in the mammaL merization products (P\ cated from the polymer, they contain unreacted PVC (thermal decompotoxicity of pyrolysis pre mainly due to the relear A bar 1969`.Dyer and E`and only very' small or n (O'Mara et al. 1971 cite R&s 005029 Marstellor 44 / Portal londe laxis is a <>uld help to irring rather ially hazard;t. this ac utely for ill develop i, a thermobegun Monde ''60s to be Vinvl Chloride-Associated Disease one of the least harmful chlorinated hydrocarbons. Early animal experiments, as it later turned out, had indeed been carried 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 with this compound as a pollutant of the work place, considering that it is (1) a halogenated hydrocarbon which (2) exists in its vapour phase under ambient conditions (inhalative exposure) and (3) 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 since 1974, but pre cisely a quarter of a century had to pass before the full range of symptomatology at tributable to this new occupational health hazard became recognized in January 1974 with the shocking discovery that haemangiosarcoma 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 earliest indication of adverse 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 character of the three major lesions which oc curred in workers exposed to VCM that contributed most to the final appreciation of a causal relationship: (1) the syndrome of acroosteolysis, Raynaud's phenomenon and pseudosleroderraa: (2) non-cirrhotic portal hypertension; and (3) angiosarcoma of the liver. Particularly, the discovery of a cluster of four cases of this extremely rare malig nancy among a comparatively small group of workers (Creech et al. 1974a) was an alarming experience which called for immediate action. It can easily be imagined that a connection between VCM and the more 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-cirrhotic portal hypertension and angio sarcoma of the liver, roughly 10 and 20 years 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 animals, presented at a cancer meeting in Houston in 1970. was sufficient evidence to indicate that exposure to VCM was a very serious occupational hazard {Peters 1976). It should be stressed th3t the noxious agent is solely the monomer, or to be more precise, an intermediate of the monomer's metabolic bioactiviation, which takes place mainly in the mammalian liver 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 unreacted residual monomer. Even the combustion of articles made from PVC (thermal decomposition in fires) does not yield free vinyl chloride monomer; the toxicity of pyrolysis products of polyvinyl chloride polymers and formulations is mainly due to the release of hydrochloric acid and carbon monoxide {Cornish and Abar I969:Z) ver andrc/t 1976;.Sorenson 1976;/V/oser 1976: Colardyn et al. 1976) and only very' small or no quantities of phosgene derived from residual monomer {O'Mara et al, 1971 cited by Colardyn et al. 1976). *^jp fW. 4 2 Technological Details 2.1 Vinyl Chloride Monomer (VCM) W.K. Lclbach and H.J. Marsteller At standard (ambient) conditions of temperature and pressure, vinyl cltloride (CH: = CHC1: chloroethylene, chloroethene) is a non-irritating, colourless gas with a faintly sweet odour, inflammable at concentrations above 3.8% by volume in air. which is only slightly soluble in water, soluble in ethyl alcohol and easily soluble in ether and carbon tetrachloride. VCM is mainly used as an intermediate in the manufacture of plastics, as a refrigerant and in organic synthesis. It was formerly 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 Torr (= 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 are its low boiling point, its high specific grav ity (gaseous VCM is 2.15 times heavier than air), its low solubility in water and the half-life in air, ranging from 3 to 20 h. Table 1. Physical properties of VCM Mol. wt.: B.p.: F.p.: Flash point: Limits of flammability: Autoignition temperature: 62.503 -13.85C (-13.7 to -13.9) -153.7C --78.5aC (Cleveland open cup) a 3.8%-29.3% by volume in air above -78.5aC (= 38 000-293 000 ppm) 472C Vapour pressure: mm Hg 10 100 692 2300 C -87.5 -55.8 -15.8 + 20 2660 + 25 Vapour density: 2.15 g/litre (calculated at 25SC and 760 minllg (air = 1) Sp. gr. of liquid VCM: 0.9121 at -:0SC/4C 0.99 at -25C/48C Sources: Fairiialt 1957,Irish 1962 ;Zapp 1964;Lefaux 19b6; Ostennayer 1967: Roubat 1972. 2.1.1 History The French chemist,Regnault (1835) was 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 (CH2 =CH-) polymerize readily (Fairltall 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 Savrsev and Glinsky (who 37 C/3 hi. O O UJ cn . O tbsr. CO o Prod Large-scale by employ" 1) Convent CH^CH 2) Conversi chloroe: CH2 =cr CH,C1-: VCM w Thus, any tions in the in the rang (IARC 19\ when VCM mayer 196' in commer 1966; Osta In the e conjecture., retrieved V' yses carrier sum of all ii genates) u. reacted mor in prepolyp the concern that even 10 methyl chlo isobutane, nference in p R&S 005031 md H.J. Mursteller yl chloride (CH; = :.is with a faintly : in air, whicii is luble in ether and manufacture of 'so employed as a usually handled and forr( 101.3 kPa) voperties are.listed us high specific grav- in water and the i i l we -78.5C : 2300 8 + 20 3660 + 25 :..l 760 mmHg rrmayer 1967: study systematically ' some earlier prelimuttnd when Regnault taining the vinyl us polymerization of f sunlight was first and Glinsky (who Vinyl Chloride-Associated Disej>e 5 succeeded in decomposing vinyl chloride to monochlomaldehyde with the aid of oxid izing substances such as hypochloruws acid. 2.1.: Production of VCM Large-scale commercial synthesis of VCM with ahigii yield was made possible much later by employing two principle methods, the second having now largely replaced the first: 1) Conversion of acetylene to VCM by hydrochlonnation: CH-CH + HC1 -* CH:.=CHC1 (catalyst: HgCU on charcoal) (Austin 1974) 2) Conversion of ethylene by vapour-phase or liquid-phase oxyctilorination to 1,2-dichloroethane and subsequent pyrolysis (thermal cracking) to VCM (Albright 1967a): CHj-CHj+2HCl + l/2 0: - CH,C1-CH;C1 + H30; CHjCl-CHiCl --80 C-~10 pumice catalyst CH;=CHC1 + HC1 (pyrolysis; thermal cracking, Austin 1974). _ VCM was usually manufactured in closed 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 -2 ppm. In close proximity, the concentration ranged up to 50 ppm (IARC 1974). Spontaneous polymerization in light has also been repeatedly observed when VCM comes into contact with atmospheric air due to container leakage (Osrerntayer 1967). A prerequisite'for the polymerization process is a high degree of purity in commercially produced VCM. Impurities retard the polymerization process (Lcfaux 1966 :Ostcnnaycr 1967). In the early discussion about the cause of vinyl chloride-associated disease it was conjectured that other compounds or impurities contained in prepolymerization or in retrieved VCM might have been the causative agent(s) (Thicss and I'crscn 1974). Anal yses carried out by six West German manufacturers of PVC. however, showed that the sum of all impurities (such as saturated or unsaturated hydrocarbons and their halosenates) was Q.Olff by volume for prepoiymerization VCM and O.lfT- for retrieved un reacted monomer. Only methyl cldoride was found in concentrations of 50-300 ppm in prepoiymerization VCM and 100-500 ppm in retrieved VCM fin 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 0.5 ppm. All other impurities (propylene, isobutane, n-butane etc.) would then be in the ppb range. Besides, no significant dif ference in purity could be found between VCM from acetylene and from ethylene. 6 W.K. Lelbaeh jnd H.J. 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 40C and 80C and pressures of 6-16 (8-12) atmospheres. There are usually several reactors (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 chloride 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 Zielhuis 1964; Lefaux 1966; Albright 1967 a--epomininghaus \917;Slater 1972). The random character of such termination steps accounts for the production of chains of different length and hence different de grees of polymerization, with molecular weights of the finished PVC being statistically distributed around a mean value. Commercial PVC polymers have average molecular weights that vary from about SO 000 to ISO 000 daitons (Albright 1967b). Degree and velocity of polymerization, which are influenced by temperature and the concentration of initiators, determine , the specific type of PVC produced (Frey 1973), During polymerization considerable amounts of the monomer 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 towards the 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 process 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 film 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 (Barnes 1976). After completion of the polymerization process, the slurry 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 hloride-.' 30 ^ 'Pur ph. omer is r ^ urified h Ui ted poly 3 diffuse Is3 ! resin, t i 75). Bar j ;ly 500 me slurry fre Urge enough to h are then pumped wet polymer, a gr drying methods, i merization, yieldi fine solid particle drying temperatu polymer. A cyclo The solid polyme. storage bins or sil dried powder con 222.2 Methods o Four different in. PVC (Frey 19Vi - Suspension Polya which monomer . (such as po!yvin> conjuction with h this method whi. Emulsion Polymwas added in the except that large. are added. Emuhemulsifiers cannm Bulk (Massl Pol\ the additon of oii The first reactor' second one is use. solid state, to ess<reaches a level of characterized by ' good optical clan R&S 005033 iJ H.J, Marsteller of the procedures oride. tors) at temperaheres. There are ^activity of the ; of the vinyl 1`--d of VCM .ource of ted in the [Bamez : radicals at ide, isoproct with the J thus propiin growth is a reaction right 1967 h termination unce different de1 heing statistically ar\ from about polymerization, t'-r-, determine on considerable lost of this is later which is not soli ization slows the method used, of this termimns produced. The ,t be removed to ttion aids in translie reactor. During .re to the walls of i his polymer crust led with unreacted cleaned away after .ised from the re is partly solvated phase or is present Vinyl Chloride-Associated Disease 7 in the vapour phase above the slurry. VVlule 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 purified 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 particles: this diffusion depends on time and temperature. Raw PVC resin, therefore, still contains certain quantities of unreacted monomer (VRE 1975). Barites (1976) reported that the polymer in the slurry still contains ap proximately 500 ppm of vinyl chloride. The slurry from the dump tank is pumped into a storage tank (blend tank) which is large enough to hold several batches of the product. The contents of the blend tank are then pumped into a centrifuge which separates the wet solids from the water. The wet polymer, a granular mass, is dried either in rotating tubular dryers or by spray drying methods, the latter being used mainly for products formed by emulsion poly merization, yielding a potymer which is similar to a very fine white flour. These very fine solid particles are fed directly into a spray-drying column without dewatering. The drying temperature should not exceed 60SC to prevent thermal decomposition of the polymer. A cyclon separator at the exit end of the dryers removes coarser panicles. The solid polymer panicles are then sized by multiple-layer screens, air-conveyed to storage bins or silos and finally packaged for shipment (Albright 1967d). The resultant dried powder contains about 50 ppm of monomer (Bames 1976). 2.2,2 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 conjuction with brisk agitation. Relatively large polymer panicles can be obtained by this method which `dry blend* well. Emulsion Polymerization is the oldest technique, to which suspension polymerization was added in the 1950s, The process is similar to that in suspension polymerization, except that large amounts of emulsifying agents (such as soaps or other surfactants) arc added. Emulsion polymerization yields resins of a very small particle size. The emulsifiers cannot be completely removed. Bulk IMcssj Polymerization. In this process VCM is polymerized in two stages without the additon of other liquids. The two reactors are operated batch-wise and in senes. The first reactor (a `prepolymerizer') provides for the initial liquid phase, while the second one is used for agitating the slurry, which is transformed, through a sticky solid state, to essentially dry particles until the conversion from monomer to polymer reaches a level of about 757t.-807o. The resins obtained by bulk polymerization are characterized by high purity and particle uniformity, resulting in an end-product of good optical clarity. i it I* if J*V 3 W.K.. Lelbach and H.J. Marstvller Solution Polymerization. This type of precipitation polymerization is carried out in organic solvents such as n-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 copolymers. Copolymers arc mixtures of comonomers (such as vinyl acetate, vinylstearate, vinylidene 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. 2.23 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, organotin compounds, and other stabilizers). Lubricants or dyes can be added. Plasticizers are added for the production of flexible PVC: rigid PVC contains little or no plasticizer. These additives can also be a source of toxicity. The plasticizers may slowly diffuse out of the final product depending on its compatibility. Lead-containing stabilizers may also pollute the working atmosphere (Smoltic 1966; Tola 1975). Compounding is carried out by hot mixing at fusion tem peratures below or within the softening range (120C-I60SC). 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 in these processes range from 100aC to 3009C. 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 containedin the polymer. Barnes (1976) calculated that the final fabricated articles contained approximately 5 ppm VCM and those for foodstuff packaging (bottles, films, foils) even less. 2.2.4 .Sources of Exposure to VCM in PVC Production Both polymerization of VCM and subsequent processing (centrifuging, drying, screen ing, bagging) are usually carried out in closed buildings. Exceptions can be found in hot climates (Arvanpur 1977), Polymerization is of necessity a batch process that re quires a large number of single operations. Therefore, valves, gaskets, shaft-openings and control gear are subject to heavy wear and thus to leakage. Other sources of pollu tion of the working atmosphere are exchange of parts and repair jobs. The degree of pollution also depends to a large extent on the quality and effectivity of monitoring equipment and special exhaust systems. Opening of autoclave vats for cleaning and control purposes resulted in larger spill-over of the tank atmosphere into the work en vironment. Numerous repons of workers with prenarcotic symptoms (dizziness etc.) Vinyl ( i permit t' in the pa Ther clave va;walls ('p tors, had degassed and large were ope ed the fr. tion still manly, t! those wi> (centrifuties of t:ventilatii shipmem nomer, v. are drive- Table 2. I pp> 33 r; CO o o t: tn o co 2.23 T In the pj nam mon covers :> (Lefaux 1 lect as a i opened . became k '.larsteller out in ! percent'etion of vinyl- The cosolvents ry or :on temi and light lizers). ' flexible source of ingon its sphere ion tern* mpound* ducts, nets is nr.-sion tsed in It* I of luurtca* sunier ' uuined otined 33 9f> CO o o en o oa CM Vinyl Chloride-Associated Disease 9 permit 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 'polymer skin" formed on the reactor walls ('polydeaners'), and who in the past had to spend several hours inside the reac tors, had been exposed to the highest concetnrations of VCM. Although the vats were degassed prior to entry, unreacted monomer remained trapped in the polymer skin, and larger amounts of VCM were released when cavities formed in 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--30th 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 (centrifuging, drying, screening) also involve the release of some of the lesser quanti ties of unreacted 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. wlucli either slowly diffuse out and pollute the bagging areas during storage or are driven out by the high temperatures necessary' for compounding. Table 2. Conversion table for concentration of VCM in ambient air Mol. wt. lpPn,= TOOOT' 24A5 ' nlS/Iita' 24.45 x I 000 l mg per litre = Mol. wt. ppm \Fanv l5S) 1 mg/ii'trc = I me/m' = I ppm = 2.5(i mg/mJ I "' =10000 ppm 391 ppm 0 591 ppm 0.00256 me,litre 25.6 me,'litre 22.5 The Explosion Hazard In the past only the explosion and fire hazard of VCM was thought to be the domi nant monitoring problem in handling gaseous vinyl chloride (Irish 1963). This hazard covers a concentration range of 493-22To by volume of air (40 000-220 000 ppm) (ie/'aux 1966). it was observed that VCM. being 2,15 times heavier titan air. may col lect as a compact layer at the floor of a polymerization building after spill-over from opened tanks and may catch fire. At least two instances of disastrous VCM explosions became known: lit 1964, a large plant for the polymerization of VCM in the United 10 W'.K. Lelbach and H.J. Marstsllcr 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 by Sudu et al. (1975). Monitoring of VCM concentrations polluting the work environment was then directed largely towards preventing VCM from reaching the flammability limit. 2.2.6 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 mind, 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 and Schaumann declared that the faintly sweet gas is practically odourless at concentrations of 5%-10% by volume. Veltman and Lange (1977a, b) assumed an odour threshold of 5 000-10 000 ppm. Volunteers exposed to VCM detected a slight odour at 4 100 ppm; a distinct odour was noted at 6 600 ppm for 30 min and this was accompanied by subjective symptoms of dizziness and sleepiness {Irish 1963). Gehring et al. (1979) recently mentioned a threshold of approximately 3500 ppm. Others have claimed that a concentration of 400-500 ppm is the lower limit for detection of VCM by its odour {Baretta et al. 1969; Cook et al. 1971; Marko witz et al. \912\Lefcvre 1975, cited by Hublct 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 ail test subjects at a concen tration of 21.6 ppm {Deese and Joyner 1969). 2.2.7 VCM as an Anaesthetic Agent VCM was once even considered for use as an anaesthetic agent. In 1929. Schmidt and Schaumann 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 73 99 'hloriCO o Od.- o as O mit. 03 03 ) Of- ot ic J St- 50 400 5 Ot 40 4Q> anaesthesia be tic and lethal oxygen; conct however, that eluded. In to10% VCM to! several hours t commented u: mined about i 3.5-5 mmol (mmol (244 00 Oster et al., in cardio toxicity man because r like other hair, amines {Irish the past for an 2.2.8 Effects Some individulisted in Table without acute. symptoms sue! adequate warm exposure to hie A 21-year-old; 10 min after en which had bee cardiac enlargehave been acut. which occurred doubt that heafound dead wit, ! I..J. Marsteller detonated ''s operating ncentrations ling VCM erties. Its r* -- s >r 30 8 O) a ;| o o cl .1 tfl o 03 -4 1 e- V* yi s y 1077a, b) ! to-VCM 1 ppm for 1 sleepiness .-\imately lie lower '771 \Marko'I conducted lumber, in i.,at they differences : proximity as reported m be as- met wami; eye and I a concen- hmidt and centraoxygen Vinyl Chloride-Associated Disease Table 3. Odour threshold Lower limit of detection 5 000-10 000 ppm 5 000 ppm 4 100 ppm 3 500 ppm 500-ppm 400-500 ppm 400 ppm 400 ppm Author Veltman and Lange 1977a. b Viola 19 74 Irish 1963 Gehring et al. 1979 Baretta et al. 1969 Letevre 1975 (cited by Huhlet 1975; Cook et al. 1971 Markowitz et al. 1972 11 anaesthesia because of its potent narcotic action and the wide margin between narco tic and lethal concentrations. In animals it produced anaesthesia at 77a-10% in air or oxygen: concentrations above 12% proved to be dangerous. The authors pointed out, however, that adverse late effects of this halogenated hydrocarbon could not be ex cluded. In toxicity studies with guinea pigs Patty et al. (1930) found concentratons of 107 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 serious 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) (Peoples and Leake 1933). It was not until 1947 that Ostcr et al,, in contrast to Schaumann's earlier assumption (1934) of a 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 effect of catechol amines (Irish 1963). We could not ascertain whether VCM has actually been used in the past for anaesthesia in man. 2.2.8 Effects of Acute Overexposure in Man Some individual responses of volunteers to increasing concentrations of VCM are listed in Table 4. Lester et al. concluded in 1963 that the maximum concentration without acute effects in man lies between 8 000 and 12 000 ppm for 5 min, and that symptoms such as dizziness, light-headedness and disorientation should be taken as adequate warning signs for imminent acute danger. Two fatalities after occupational exposure to high concentrations of VCM are reported in the literature (Danzigcr 1960). A 21 -year-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 pre-existing heart disease. In the second case which occurred at the same plant, however, circumstantial evidence apparently left no doubt that heavy VCM exposure was the cause of death in a 39-year-old worker. He was found dead within 20 min, lying in a pit near the opened valve of a recycling pipeline 12 W.K. Lelbach and H.J. Marstellvr Table 4. Individual responds of volunteers to increasing concentrations ol' VCM Concentration Duration of Symptoms exposure- Relerencc 500 ppm 7.5 h (Inconstant odour detection! Baretta et al. mild headache, dryness of (1969) eyes and throat in 2 of 7 subjectsli -V4 000 ppin - Generally accepted odour threshold Irish (1963) 6 600 ppm 30 min (Distinct odour) dizziness, sleepiness Irish (1963) 8 000 ppm \ 12 000 ppm I 5 min3 (twice on 16 000 ppm | 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, various degrees of intoxication AH 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, disorientation, burning sensation in the soles of the feet Pattv et al. (1963) 3 Exposure to six different concentrations: 0 ppm: 4 000 ppm: 8 000 ppm: 12 000 ppm: 16 000 ppm; 20 000 ppm through which non-polymerized residual VCM was pumped back into a reserve tank: another man coming to his rescue was himself overcome by the gas and only just escaped. Two non-fatal cases of VCM gassing were reported in Great Britain in 1951 (Sptrtas et al. 1975). A maintenance worker experienced acute narcosis while 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 et al. (1975) in 14 of 354 workers at Niagara Falls and by Suciu 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-producing plant (Ward et al, 1976), with a 100% incidence of narcosis in 28 symptomatic workers (Raynaud's syndrome and/or acroosteolysis). Successful resuscitation after VCM-induced narcosis of several hours' duration with out evidence of permanent damage was mentioned by Rcty et al. (1974). Vinyl Chlon 2.2,9 Monit During the li ed data on V' was directed an apparently \9S4\Pleshc Gronsberg to Russian polyi 0.05--0.08 m; centration of Inspectorate or from the d mg/litre (= I i mg/litre (= 34 In the cen air ranged fro: ppm, which w ventilation. T1 trations, sonic pursuit of imp ment in the vi- ic drying facih cen trations--' atinued to i 33 ted concen In a plant CO range of 0. o i (2.93 mg o on on apparai rkable the co cs ver, althi. lave prob. reit et al. --i occurred cated peak exp- between 1962. Rumanian PVC about 120 mg.-r exposures to V: 300 Rumanian Greek plant wli resulted in high (Gitsios 1971). of the reactors ; up to 10 000 p, I.J. Marsteiler I VCM Irenes -etta et al. >69) -It (1963) r//,(l963) 'ter et al. 463) ttv et al. '>63> ,v.\. 12 000 | i serve tank; ;ily just .1951 {Spir n airing a VCM Vt jet suddent tightness of lousness was and by Suciv occasion in Tvcillauce ucidence of t i 33 9P (/) o 0 01 o w to h- Vin>l Chloride-Associated Disease 1.1 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, (n 1957. the observation of an apparently toxic angioneurosis in Russian PVC production workers (Smirnova \9S9: Pleslidutscr et ah, cited in Filatova and Gronsber% 1957) induced Filatova and Gronsbarg to investigate environmental VCM concentrations in various parts of a Russian polymerization plant in Gor'kij. Although most readings were in the range of 0.05-0.08 mg/litre (= 20-313 ppm),e.g. below the maximum permitted VCM concentration 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 29.5-41.4 mg/litre f= 11 500--16 200 ppm) for periods of 5 --10 min. One peak reading of 87.3 mg/iitre (= 34 000 ppm) was recorded. In the centrifuging and drying area of this plant the VCM content of the ambient air ranged from 4 ppm to 3 100 ppm with most readings between 20 ppm and 195 ppm, wltich was attributed to release of residual VCM from wet PVC resin and poor ventilation. The screening and bagging area was characterized by high dust concern trations. sometimes exceeding the official upper limits set for non-toxic dusts. In the pursuit of improving industrial hygiene, the installation of modern ventilation equipment in the vicinity of the autoclaves, substitution of hand-operated by semi-automat ic drying facilities, and avoidance of leakages succeeded in reducing the ambient con centrations of VCM to below 0.05 mg/litre (= 20 ppm), but toxic angioneurosis still continued to be diagnosed. This led the authors to recommend that the maximum permitted concentration of VCM should be reconsidered. In a plant producing VCM, Filatova et al. (195S) found lower concentrations in the range of 0.04--1.1 ntg/litre (16-430 ppm), with maximum values of about 1200 ppm (2.93 mg/litre), the latter having beemobserved in close proximity to the rectification apparatuses and having resulted 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 resins started early and VCM exposures in the past have probably been in the same range as those observed in Western countries. Byrht et al. (1976) pointed out that during the 1950s episodes of unconsciousness wltfch occurred among workers of the one Swedish plant operating at that time indi cated peak exposures of at least 10 000-15 000 ppm. Arm et al.(l975) noted that between 1962 and 1972 a reduction of the average VCM concentration in the two Rumanian PVC plants had been achieved from 2298 mg/mJ (= 900 ppm) in 1962 to about 120 mg/m3 (= 50 ppm) in 1965--1972. In l969,Aug/icIcscii et al. mentioned exposures to VCM concentrations of 112-545 mg/m3 (44--213 ppm) for a group of 300 Rumanian workers, 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 (Gitsios 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 cycle, concentrations of up to 10 000 ppm were found. In open waste-drums into which waste polymer scraped X 14 W.K. Lelbach and H.J. Marsceller away from reactor walls during cleaning was placed, concentrations of up to 600 ppm were measured. In the report of a World Health Organization (WHO) working group on vinyl chlor ide (IARC 1974) it was stated that in a reactor of 15 m3 (production of 4-5 tons of PVC per cycle) a crust of 4 kg PVC containing 3%~5% VCM can be formed on the inner surface. During the cleaning procedure 30%--50% of this VCM content is liber ated. It was calculated that the probable concentration of VCM within the reactor after a 1-h cleaning operation was about 2700 ppm, but that it could be reduced to 90 ppm by 30 renewals of air per hour. In the past a polycleaner used to spend 4-5 h/ day inside the reactor but later the introduction of (not fully sufficient) automated cleaning reduced manual cleaning procedures to shorter periods of 10-15 min follow ing every 20th--30th reactor cycle. A Belgian company, where monitoring in the work ing area was started in 1967, claimed that measurements at various sites inside a 9000litre autoclave during the manual cleaning operations had shown VCM'concentrations varying between 50 and approximately 540 ppm, with a mean of 413 ppm (Hublet et al. 1977). According to data provided by Cook et al. (1971), VCM concentrations within the reactors prior to ventilation were in the order of 3000 ppm. The reactor cleaners usually did not enter the autoclaves until an aeration period of 15-20 min had reduced the VCM concentration to what was considered satisfactory limits. In the early days, this was tested either by `sniffing at the manhole opening' (the lower limit of detection of VCM by its odour having then been accepted as 400 ppm) or by use of a flammable vapour indicator which required a minimum of 400 ppm for positive read ings, equalling 4% of the lower explosive limit of VCM. Later more sensitive methods such as g3S chromatography were said to have shown that VCM concentrations inside the reactors tended to be below 100 ppm during cleaning operations, but VCM releas ed from the residue during scraping resulted in concentrations of 600-1000 ppm measured close to the hand. The Dow Chemical Company started monitoring the work environment in 1950 by means of grab samples; continuous monitoring was installed in 1959. While timeweighted average (TWA) concentrations ranged from 10 to 385 ppm during this period (1950-1959), excursions up to 4000 ppm occurred, agreeing with employees' reports of experiencing dizziness while loading or unloading reactors (Ott et al. 1975). In a second unit with modernized equipment excursions up to 600-1300 ppm still occur red during the period of 1953-1959. In 1959, when toxicological data indicating ad verse effects in animals exposed to 100-500 ppm VCM had become available (Torkclson et al. 1961), the Dow Chemical Company introduced a new 50 ppm guideline for the work environment. Excursions and peaks up to 500 ppm did continue. Measure ments of TWA exposures for various specified job categories in two production units of this plant between 1950 and 1966 were presented by Ott et al. (1975). In 1968 BASF (West Germany) introduced continuous monitoring by infrared absorption spectrophotometry for VCM concentrations well below 500 ppm; in, 1974 more sensi tive equipment was installed and concentrations were kept below 25 ppm and later below 10 ppm, with occasional ceiling values of 70 ppm (Fleig and Thiess 1974). In several surveys individual jobs were grouped into three exposure categones ac cording to job classification to evaluate past exposure experiences (Spirtas et al. 1975: Williams et al. 1976;Btendis et al. 1978), These exposure indices were: (a) light = less averag. Table f atmosp Che mi. Acco Equ: tions in equiprru viduai ebination (3) Thr 1 ly speci'' ment sin peak con for the d Cum compris. tion dete (`ionotlu which cai conditio: lag of res: A cat industrial in 1975 b 2.2.10 E Raw PVC unreacted i-t-Lr*?-rftu. -7 Marsteller eOQ ppm ;nyl chlor' ions of m the is liber;actor eed to h/ 20 k- O VI :t o -U, the vvct ,.mit by use of itive readmethods ns inside M releasipm i 1950 by I1L-ius period reports I. In a II occurttmg ad: (Torkeleline for teasure>n units l68 non ire sensiilater 74). ries acal, 1975; lit = less Vinyl Chloride-Associated Disease 15 than 50 ppm; (b) medium s 50-200 ppm:fc) high = 200 ppm and above (up 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 at best on spot samples not necessarily representative of the different phases of a given operation. Estimates of past exposure levels such as those represented in Table 5 are, therefore, more or less conjectural. It can be assumed that considerable deviations from these average values have occurred all too often in the past. Table 5. Average concentrations of VCM in tlie working atmosphere of PVC-producing plants-1. (Estimated by Chemical Industries Association Ltd.) 1945-1955 1955 -1960 1960-1970 mid-1973 1974 1975 "o 1000 ppm ^.400-500 ppm ^200--100 ppm v 150 ppm 50 ppm and less o 5 ppm According to Fleig and Thiess \974\Barnes 1976 Equipment for optimal continuous multipoint monitoring of exposure concentra tions in the working areas should meet certain basic requirements; (1) For stationary equipment strategically placed sample probes should yield data representative 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 of TWA 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, combustion-conductivity ('ionoflux'). and personal samplers in combination with gas chromatography, none of which can at present be considered as absolutely 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 Rowe. 2.2.10 Exposure to VCM in PVC-Processing (-Fabricating) Plants Raw PVC powder ready for compounding and fabricating purposes contains residual unreacted vinyl chloride monomer in varying amounts. In the past, monomer content 7.***'3 .V*Vai?- 7 taJi, 16 W.K. Lelhach ami H J. MarsreHer was reported to have been as high as 6000--7000 ppm (w./w) in some types of raw PV'C. but a level of 500--1000 ppm probably was a more representative range (Schweitzer 1975; VfCE \914-\Karstadt 1976). Tiie monomer slowly escapes into the environment exponentially with time, depending on length of storage period, tempera ture. size and porosity of particles and other physical properties of the polymer and. more recently,on the effectivity of special degassing techniques (Piver [916:Sch:itz and Wolf 1977). In 1975, the Association of the German Plastics Industry announced that in future only PVC powder with a maximum monomer content of 10 ppm would be put on the market due to the development of special degassing technologies (VKE 1975) . Analyses of the types of raw PVC, chiefly suspension polymer, which are now used in German plants showed that in most products the content of unreacted mono mer was now less 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 (Schiit: and Wolf 1977). Cold and particularly hot mixing or compounding of PVC, a procedure which usu ally precedes fabricating processes, favours the escape of unreacted monomer and, therefore, requires special ventilation equipment. Depending on the content of residual monomer, considerable amounts of VCM could be set free during the mixing process, as was shown by Bruder and Scraby (1975). Apart from hot compounding, other ther moplastic operations, such as extruding, calendering and welding of tiles, also resuited in release of unreacted monomer into the work environment. Although recently con ducted measurements of the concentration of VCM in working areas of six German PVC fabricating plants have shown that in 90% of the readings mean levels integrated over 1 -It periods now range below 0.1 ppm, numerous short bursts with excursions up to 60 ppm during a workshift were recorded in one instance (Schiitz and Wolf 1977). Similarly low concentrations of VCM in breathing zone samples (maximum: 12 ppm) with 60% of the values ranging below 1 ppm had been found in 1974 in nine United States fabricating plants, but source samples had ranged up to 340-540 ppm (Karzrcdt 1976). These present results, however, do not permit any conclusions as to past levels of atmospheric VCM during the years 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 titan in PVC-producing plants. When it was suspected that certain VCM-related svmptoms might also have afflict ed PVC process workers, this problem was investigated by our group. Although no cases of acroosteolysis, 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 years in compounding and fabricating units (Lange et al. 1975, 1976a; Wcgman \915\Mantetler et al. 1976). In principle, these lesions were identical with those seen after heavy exposure as we will describe, but the degree of damage attribut able to occupational VCM exposure observed in these workers was not considered suf ficient to entitle them to disability compensation under German law. Although the in- Vinyl conspi sponsquanu obser. progre male F find ar Ar two Gdied re* lation < `health, overall record. 2.2.11 Industn of expo tion' o' indust; 00 Co to o o cn o i ro v. r The not a st should t tently avails blnew mi dst of ,v various; SO-caller tool for ysis oft1 In tl: ppm in ! ! I J Marsteller :-vs of raw : nnge ipes into the Tod, tempera'olymer and, ''>~6:Schiit: ry announced ! 0 ppm would ologies (VKE liich are now racted monoJ between at ion between .';e which usu>>tner and, .cut of residual cxing process, ig, other ther. also resulted -eeently conix German !; integrated `.xatrstons up .IW/1970. n- 12 ppm; United i'ptn (Kant.;Jt ast levels of ^ f resins uas Img units. !y assumed i> 3 been con- i Inve aftlictno served. Qo ns such W ' slight o m* o oOn *si:t,h Jp? tnbut- d sufhe in- Vniyl Chloride-Associated Disease 17 conspicuous character of these lesions agrees well with the assumption of a dose-re sponse relationship of VCM-related disorders and the alterations may seem to be. quantitatively, of little importance, they should not be minimized. Nevertheless, an observation period up to the present of almost 7 years did not reveal any spontaneous progression. In a proportional mortality study for 1970-19~2 among roughly 35 000 male PVC fabrication workers in England and Wales, Baxter and Fox (1976) did not find an excess of angiosarcoma or other liver diseases. A recently completed cohort study of 4007 people who had been employed by two German PVC-fabricatmg plants between 1934 and 1974 and of whom 360 had died revealed that overall mortality, although marginally below that of the male popu lation of the Federal Republic of Germany, was slightly elevated with respect to the `healthy worker effect'. No angiosarcomas of the liver were observed and no excess in overall cancer mortality was noted, but an e.xcess mortality from brain tumours was recorded in one of the two plants (Rein! et al. 1973). 2.2.11 National Standards for the Control of Exposure Industrial hygienists have used several designations for acceptable or permissible limits of exposure to chemicals at the work place, such as `mxcimum allowable concentra tion' or "maximum acceptable concentration' (MAC), `threshold limit value' (TLV). `industrial hygiene standard' in the United States and as `Maximale Arbeitsplatzkonzentration' (MAK) in West Germany. These empirical standards were defined by the .American Standards Association as setting a limiting concentration "for exposures not exceeding 8 hours daily during a 40-hour work week with the understanding that varia tions should fluctuate below this value" Uns/i 1963). .An extensive discussion of the basic 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 Zielltttis fl974). in this paper, the conceptual differences between threshold limit values as used in the United States and maximum allowable concentrations as used in the USSR are summarized and the differences 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 sort of `average', A standard set as the ceiling level implies that any fluctuations should he around a median of perhaps half the standard and that it should be compe tently used in full awareness of its physiological basis jnd the limitations of currently available knowledge (/m/i 1963). The standard will be subject to revision as soon as new information is available. An essential element of the annually published German list of MAK values (MAK-Werte) is its preamble, which exhaustively defines rhe various modalities for the interpretation of such standards fHenschlcr l972/'3). The so-called 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 tile normal fluctuation below the standard. ' In tiie Federal Republic of Germany the standard for VCM (MAK) was set at 500 ppm in i966. The German Standards Advisory Committee reduced tin's to 100 ppm X Vvi IS W.K. Lelbach and H.J. Marsteller in 1970 in conformity with the proposal of Torkdson et al. (1961). which was based on the results of their animal experiments. 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 (Techuische Richtkonzentration) of 50 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 1974. As of July 1975, a technical guideline (TRK = Technische Richtkonzentration) 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 l*h periods not exceeding 60 or 30 ppm. respectively (Veltman and Lange 1977a). The technical guideline (TRK value) was revised in 1977 (2 ppm annual mean/5 ppm per 1 h). In the United States the threshold limit value for VCM was originally set at 500 ppm in 1947. It was reduced to 50 ppm in April 1974 as a temporary emergency stan dard and finally reduced to 1 ppm/8 h in 1976. Haley (1975) summarized the conflict ing views on vinyl chloride regulations proposed by Government and industry in 1974. Table 6 shows 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-producing plants in the United States discharged about 90 million kg VCM annually into the environment (4%--8% 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 years 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 (Ostcnnaycr 1967), in Japan it has been used as a propellant since 1958, in the United States this use was probably introduced after 1962 (Schweitzer 1^75). As an aerosol propellant, VCM has been a possible source of exposure for the public al huge, particularly for women, the extent and the potential health implica tions of which are unknown. Use of aerosol products in confined spaces has been re ported to result in air concentrations of VCM of up to 400 ppm in closed rooms, even after only short bursts (30 s) (Gay et al. 1975). which could persist for several Vinyl ChiTable 6. 1 Country Belgium Canada Finland France German D: Republic Iran Italy Japan Nether! anc Rumania Sweden Switzerlan United K.- USA USSR Federal Re, 13 CO --o s< o R&S 005045 J.J. Marstelltfr :h was based nogenic prop;micaJ was reonzentratton) .y Insurance i instructions tly 1974. As tion) of 5 ppnt. UJ instituted, per' I h. In order to duction of the anmi as of July 1976 ppm, respectively ) was revised in 1977 iipnally set at 500 rary emergency stannmarized the conflictind industry in 1974. mi* countries. mg plants in the the environment "b>lved in water veer 1975) In a he ambient air near '< and 100- 200 ppm used were iatcr in these figures since ide (Schweitzer itier production facili>e years of uncontrol- it. either aione or mixhousehold and cosmet ic. paint sprays. oposed as propellant I as a propellant since r 1962 {Schweitzer of exposure for the Uial health implica-.1 spaces has been rc: in closed rooms. :.l persist for several ^ inyl Chloride-Associated Disease 19 Table 6. Threshold limit values (TLV) m various countries Country Vear TLV (ppm) Comment Belgium Canada Finland France German Democratic Republic (DDR) Iran Italy Japan Netherlands Rumania 1975 1975 1975 1975 - 1976 1976 1975 (future) 1970 1974 1975 1975 Sweden Switzerland United Kingdom USA USSR 1975 1976 1975 (future) 1975 October 1975 1947 April 1974 October 1974 1976 Federal Republic ot Germany 1966 1970 June 1974 1975 1977 25/50 10/25 5/10 25 200 - 12 25/50 50 (25*/50) 500 200 -10 10 100 mg/m1 (40 ppm) 5/20 1/5 100 10 25/50 10/30 500 50 1/5 1 mg/litre (391 ppm) 30 mg/m1 (= 12 ppm) 500 100 50 5/15 2/5 TWA 13 h/15 min) TWA (S h/15 min) TWA (3 h/15 min) TWA (8 h) MAC (Schottek I960) 1 Konetzke et al. I97S) TWA (8 li/l h) TWA (3 h) (TWA 8 h/15 min) MAC MAC (25 mg/m1) TWA (8 h) MAC (Prodan et al. 1975) TWA (8 h/15 min) TWA (8 IU15 min) MAC TWA (8 h> TWA (8 h/15 min) TWA (personal/ceiling) MAC (Amer. Conf. Governm. Inaustr. Hygienists) TWA (8 hi. temporary emergen cy standard (OSHA) TWA (8 h). temporarily permit ted exposure TWAlSh'15 min) MAC. provisional ceiling concen tration: State Sanitary Inspec torate. 195 7 (Filatova and Gronsberj 1957) MAC (Schottek 1969: Kettner 1975) (Sanitarnye normy) MAK MAK TRK (preliminary technical guideline). Annulment of MAK regulation. TRK (annuat mean/1 h) TRK (annual tnean/l It) Sources: Smyth ISSb:Filatova and Gronsbcrg 1957; 5t/turret ISM; Henschlcr 19721 73;IARC Report 197<l\Haley \9T5\Sckabe 1975 : Prodan et al. \915\Aryanpur 1 977;Schut: and Wolf 1977: MAK-Werte-Liste 1977; Kenner 197? y ` -t 20 W.K. Lelbacli and II.J. Manuellcr hours after repeated spraying in smaller-sized rooms (1ARC 1974). Haley (1975) pre sented a list of pesticide products containing VCM as a propellant and registered for indoor use, which were banned in 1974 by the Food and Drug Administration. In Japan, the monomer was also banned as a propellant in 1974 (JAMA 1974. 229:855). There is a case on record of a worker who died from noncirrhotic portal hypertension and angiosarcoma of the liver after 14 years' employment at a chemical plant in south ern Germany where he had been engaged in loading such pesticide cans (Rein! and IVcbcr 1974). The report of a female office worker suffering from typical Raynaud's phenomenon, pseudoscleroderma.acroosteolysis and mandibular osteolysis who never had occupational contact with VCM (Aleyerson and Meier 1972) is apt to make one wonder what influence the frequent indoor use of VCM-propelled spray cans (Bridhord et al. 1975) may have had in this unique case. Sputum samples collected from frequent users of pressurized spray cans who had no respiratory symptoms were found to con tain a significant excess of moderate and marked atypical metaplastic bronchial cells compared with two groups of controls {Good et al. 1975). PVC bottles, films and foils have been used for many years for packaging food and beverages (cooking oil, margarine, meat, mineral water, fruit squashes and other soft drinks, hard liquor etc.). The content of residual VCM in PVC bottles was found to have ranged formerly between 5 and 400 ppm (w/w), and in PVC foils up to 800 ppm (van Esch and van Logten 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 in PVC bottles led to the discovery that VCM had leaked into the liquors; in some samples levels up to 10-20 ppm (w/w) were found (van Esch and van Logten \91S:Davies and Perry 1975). Data available in 1974 to a group of WHO experts revealed that samples of gin and whisky 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 0.01-0.08 ppm and 0.01-0.04 ppm, respectively (IARC 1974). Levels of 0-0.4 ppm found in British PVC-bottled liquids were mentioned by Davies and Perry (1975): in their own analyses of samples of PVC-bottlcd spirits supplied by British Airways they found concentra tions of 0-0.25 ppm (w/w). Methods were developed for the detection of VCM in liquids with a maximum sensitivity down to the 1 ppb level (ren Lierop and Stek 1976: Dressman and McFarrcn 1977). It was tentatively estimated that even during the years when PVC-packaged food and beverages had not been heeded as a potential source of contamination, the likely average daily human intake of VCM from this source could have been in the order ofO.I mg/person (IARC 1974). Schlatter (1976) calculated that today it would be less than 0.01 mg/person (equalling 250 mg during a whole life time); in comparison, he calculated that the inhalational intake of VCM in diseased workers who had been exposed to concentrations of 500-1000 ppm during a period of 10-20 years would have amounted to at least 25 kg. The Association of the German Plastics Industry expects that the use of technology available at present for the production of PVC food-packaging materials decreases the VCM content of food stuffs to below 50 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. 3.3. Vinyl Chloride-Assi3 Toxicology oi 3.1 Acute Toxicity Dunng the first threv the assessment of the concentrations varyir and Leake t ntatteo 50:1 anaesth tliis ran; Ro live and ^ t narv asurt tagk hepatoo o inducing o ury es (s O) 3.2 Chr. city Torkelson et al. (1961, exposure to concenua4.5--6 months. All spe however, caused an ir.r histological changes i., pigs and dogs. An incr. in rats exposed to 20 V (1963); no histologies: Gor'kij Institute were t exposure of experimen. mias, bradycardia, chan 0.05 mg/litre) for 5 mo creased secretion of cat. posterior hypothalamus 5500--4000 ppm (9-1C of the cortex and the an comitant changes in ex posure of rats and rabbit resorptive bone changes nervous system dysfunvt available evidence for VC VCM should be suspectei statutory maximal allow? cratic Republic) should b Of particular imports Viola et al. 1971) with e> full year. It was only afte J tl J. Marsleller sy (1975) p reregistered for lration. In T74. 229:855). ! hypertension < plant in south(Rcinl and cal Raynaud's 'lysis who never to make one cans (Bridbord d from frequent found to conronchial cells ' iging food and iid other soft . as found to ap to 800 ppm d VCM from l- pvc 3J fio s (/> s and o p'-'S o ifter CJ1 o i ^4 id 1>. es i ,.`a'f VCM in nd Stek I <*76: ting the years tia! source ot source could calculated ; a whole CM in diseased i-sg a period of the present for lent of food75). Results n of VCM Vinyl Chluritlc-As-iOciuted Disca-w 3 Toxicology of VCM 3.1 Acute Toxicity During the first three decades of PVC production, animal experiments were limited to the assessmentof the acute inhaiational toxicity of VCM in short-term exposures to concentrations varying between 50 000 and 400 000 ppm (Putty et al. 1930:/'>/>/ and Leake 1933:Schautnann 1934.1938;O.vrcr et al. 1947-.Ce/ret al. 1949:Mastromattco et al. 196Q:Lestcr et al. 1963). In mice, rats, guinea-pigs, rabbits and dogs anaesthesia, deep narcosis, cardiac arrhythmias and lethal effects were observed within this range of exposure but no relevant organ pathology was noted except for conges tive and haemorrhagic changes in lungs. liver and kidneys on fatal outcome. Acute hepatocellular injury was later found only in animals pretreated with potent enzymeinducing substances (sec 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/dav, 5 days/week, for 4.5-6 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, in addition, histological changes in the liver and kidneys of rats and rabbits, but not in guineapigs and dogs. An increase in liver weight and decrease in spleen weight was also seen in rats exposed to 20 000 ppm, 8 h/day, 5 days/week, for 3 months by Lester et al. 119631; no histological lesions were found after 3 months. Soviet investigators at the Gor'kij Institute were mainly interested in neuroendocrine changes after prolonged exposure of experimental animals to various concentrations of VCM. Cardiac arrythinias, bradycardia, changes in phonocardiogram in rats exposed to 12-20 ppm (0.03 -- 0.05 mg/litre) for 5 months were reported {Vasin and Phkhova 1969b) as well as in creased secretion of catecholamines in rabbits and changes in the biopotential cf the posterior hypothalamus (Vcstn and Phkhova 1969a). After a 5.5-month exposure to 3500-4000 ppm (9-10 mg/litre) changes in the bioelectric activity (EEG recordings) of the cortex and the anterior and posterior hypothalamic nuclei in rabbits with con comitant changes in circulatory functions were seen (Vasin and Phkhova 196S). Ex posure of rats and rabbits to 0.03-0.04 mg/litre (12-16 ppm) for 6 months produced resorptive bone changes and osteoporosis in addition to cardiovascular and central nervous system dysfunction (Basalaev et al. 1972). In 1*569 Schottek 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 allowable concentration of 200 ppm (MAC value. German Demo cratic Republic) should be iowered. Of particular importance as pioneer work were Viola's experiments (1970a. b; Viola et al. 1971) with exposure of rats to 30 000 ppm, 4 h/day, 5 days/week, for a full year. It was only after this length of exposure that histopathological examination -i -i \V.K. Lelbach and H.J. M.irsteller revealed lesions similar to human acroosteolysis and also similar to the type of nontumorous liver diseases which we observed in PVC workers 3 years later (Marsteller 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, whereas the kid neys were not markedly affected. The liver showed pronounced degenerative lesions with parenchymal necrosis, cytoplasmic and nuclear polymorphism, abnormal prolifer ation of hypertrophic Kupffer cells and intense fibrosclerotic reactions. 33 Oncogenic Properties The earliest documentation of the carcinogenic action of VCM was Viola's 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 carcinoma, 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 nn&Lefemine (1975) later interpreted these paraauricular tumours as 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 metasrases from the Zymbai gland tumours'. Autoradiograms of sections of whole rats dosed orally with [|4C]-labelled VCM revealed a discrete localization of 1 *C in the paraauricular region (Zymbai gland?) and in the region of salivary glands and Harder's glands (Green and Hathway 1975), In this contextiVeirmmui et al. (1979). who analysed the peroxidase activity in Zymbai glands of Wistar rats, proposed the concept that peroxidase-mediated bioactivation of carcinogens (in their study: stilbene derivatives) might offer an explanation for these tissue-specific effects. At the end of l910Maltoni 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, [91S\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 tire induction of Zymbai 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 tumours 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 clearly multipo Vinyl Chic tential care study of or solved in s^ 6 days/wee ratio only: tion not ne placed the i the no-toxi- angiosarcon Sprague-Da- proved to h genic in rah be carcinoc 10, 5 and 1 1979). Ano- the dose-rel. exposure le\ histological the liver anc the inductio posure to 1C al. 1974b; 1/ endothelial: perplasia am even in the t was scanty a doses. In tin fibrosis was of ossifying: feet was sugp offspring of i mine 1975). posed to VC ed from Gnc it was seen n ma t to 3J fo to t; il:r\ wo SI o tn no 12 c CO an- F ? 31 I See . l-SO tl I irsteller noni-Her et nective droid ttive kid1 -sions ' prolifer- liminary in May epiderireinoma `l 4 limbs .1 these ".Stic - target tis naligections <tion of `lands 1.(1979), the . stilbene lull, nre a ...isure ation, ' 'Iruui 5). Con;no. 500, non peri tlier ma.nizio. `veil as h were I in olive inimals ' with the (19771 Virul Chloride-Associated Disease tential carcinogen may significandy 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 nig/kg body wt., 6 days/week, Feron et al, (1975) found a significant increase in liver-to-body weight ratio only at the highest dose level. This was interpreted as a merely nonspecific reac tion not necessarily indicative of a toxic response. Based on these results. Feron et al. placed the oral no-toxic-effect level at 30 mg VCM/kg body wt./day and suggested that the no-toxic-effect 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 at the Bologna Institute. The neoplastic response to VCM proved to have a direct dose-time relationship. Even levels of 50 ppm were carcino genic in rats and mice. Later.Maltoni (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 Uon\ Qriciute 1979). Another American study designed to complement Maltonfs results confirmed the dose-related induction of liver angiosarcoma and mammary carcinoma in mice at exposure levels of 2500,200 and 50 ppm (A'eplingcr 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 (Maltoni et al. 1974b; I ARC 1974). Maltoni and Lef'emine (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 cells also in organs and tissues other than the liver, even in the 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 fibroangioblastic 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 1975 by the development of subcutaneous angiosarcomas in the offspring of breeding animals exposed for 7 days during pregnancy {Maltoni and Lcfemine 1975). Later, Maltoni (1976) detected angiosarcoma in the offspring of rats ex posed to VCM during the period between the 12th and 18th day of pregnancy (quot ed from Griciute 1979). Hepatocellular carcinoma was not found in aduit animals but it was seen to develop readily in newborn animals, possibly in connection with the im maturity of their bioactivation pathways (Maltoni 1977). Exposure of newborn rats to 2000 ppm VCM, 8 h/day, 5 davs/week, for at least 4 weeks elicited preneoplastic foci of hepatocellular ATPase deficiency, notably in female animais (Laib et al, 1979). Holmbcrg et al. (1976) exposed mice to 50 and 500 ppm VCM. 6 h/day. 5 days/ week, for 52 and 26 weeks respectively. They did not observe hepatic fibrosis or spleen changes, but multiple benign alveologenic adenomas developed in IS of 24 ani mals exposed to 50 ppm and in ail 24 animals exposed to 500 ppm1. In addition, sub cutaneous and/or subperitoneal haemangiosarcorna developed in 14 animals of the 50ppm group and in S of the 500-ppm group. Only one haemangiosarcorna of the liver mm ^`.VS 24 W.K. Lelbaeli and H.J. Mjrsteller was found in an animal exposed to 500 ppm. A few mammary adenocarcinomas, one rhabdomyosarcoma and one renal haemangiosarcoma were also seen. From their ex periments Holmberg 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 Wistar rats to 5000 ppm. 7 h/day, 5 days/week, for 52 months was pub lished by Feron et al. (1979a, b; Fcrtm and A'roes 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, multicentric hepatic an giosarcoma and Zymbal gland carcinoma occurred. Feron et al, (1979b) also observed hepatocellular carcinoma in three animals.Surprisingly, the induction of very malig nant metastasizing carcinomas of the nasal cavity originating from the olfactory epi thelium and Bowman's gland was noted, which had not been reported before in con nection with VCM. Marked hepatic fibrosis was only seen within fully developed an giosarcoma or as a reaction to extensive necrosis of the hepatic parenchyma. Tire 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 VCM* induced alterations of hepatocytes and sinusoidal cells has yet to be elucidated. 3.4 Toxicodynamics Prior to 1974 very little information was available about the fate and the toxicody namics 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 lungs after inhalational administration; the pulmonary route is the main excretory route of nonmetabolized VCM (Green and Hathway 1975). Blocking of nonprotein sulphydryl groups in the blood of vinyl chloride operatives, less pronounced after dis continuous contact, was observed as early as 1964 by Gabor et al. and indicated deple tion of the glutathione pool, which has since also been found in exposed rats (Hefner et al. 1975a). Hepatic glutathione plays a fundamental role in protecting tissues against attack by alkylating agents. The appearance of monocnioroacetic acid in the urine of workers exposed to VCM was reported in 1966 by Grigorescu and Toba. indicating that a polar excretable metabolite of VCM had been formed (Vainio 1978). Toxicodynamic studies have revealed that VCM per sc is nor the ultimate toxin or carcinogenic. It is the process of biotransformatton (metabolic activation) of VCM, primarily by hepatic microsomal enzymes (mixed function oxidases) that yields short- 33 C ChlomCO Oo ut high :nic an> o : prod: cn o The ti icities ts rea- ....ufvc: so that above following a ze cordance with 3.4.1 Uptake Pulmonary up1 in the animal'* with the pool shown by com Bolt et al. (19* as albumin, arc pound goes int After oral ingc has to be cons: is excreted vi;1976c). This . able process. 1' body wt. adi/ivestigation ol . gavage in dose: found a signiti. plasmic reticub but only mini! rats on a diet c almost all the ' testinal tract, 1in this way. Percutanec keys following 800 ppm of ' Ji was negligible i- Studies of'-' that the liver (p polar metaboli* spleen,lungs ai< kidneys, spleen, of irreversibly irreversibly bon. ul H.J. Marsteiler arcinomas. one Prom their exter period may 'lerween dose observed t with g is pub(/) less atnan. EarO len and 0 otic CJi cose-6sphatase observi of sinusntric hepatic an'b)also observed <i of very malig. olfactory-epi1 before in con. developed anvhyma, The intcded those of p between VCM' cidated. flic toxicody' 1-induced angio irge number of f VCM. as excreted via main excretory if nonprotein unced after dis* I indicated deple t'd rats fHefner tig tissues against l in the urine of itf, indicating i78). Itimate toxin or ion) of VCM, that yields short Vinyl Chlonde-Associated Disease 25 lived but highly reactive alkylating intermediates which are responsible for the toxic., mutagenic and oncogenic effects. VCM is metabolized rapidly to polar nonvolatile e.xcretable products (Hefner et al. 1975a: van Dintrcn \97S'.Rudwan and Henschtcr 1975). The toxicity of VCM seems to be largely determined by the ratio of the rela tive velocities of both biotransformation of the compound and protective detoxifica tion of its reactive intermediates (Hcnschlcr 1977a). The capacity for metabolic elimi nation of VCM in rats is saturable at an atmospheric concentration of 200-250 ppm, so that above this concentration VCM is metabolized at a constant maximal velocity following a zero-order kinetic, whereas below 200-250 ppm it is metabolized in ac cordance with first-order rate kinetics (Hefner et al, \915a\Bolt 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 inliibition of microsomal oxidative metabolism (Bolt et al. 1977a). Bolt et al. (1977a) also concluded that lipids or lipoproteins, rather than proteins such as aibumin. are the vehicles that transport VCM in the blood and from which the com pound goes into the adipose tissue or is taken up by the liver for metabolic conversion. After oral ingestion and absorption from the gastrointestinal tract, a `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 (Watanabe et al. 1976c). This confirms the finding that VCM metabolism is a dose-dependent and satur able process. Pulmonary elimination of over 925s witltin 4 h of a dose of 300 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 bean.oil 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 w-as 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. (1975b) in male Rhesus mon keys following whole-body exposure (head excluded) to concentrations of 7000 and S00 ppm of 1 "C-labelled VCM for 2 -2.5 h. The quantity absorbed via the intact skin was negligible (0.0257--0.037?) and most of it was expired. Studies of the distribution of [l,2-14C]-labeiled VCM in the body clearly revealed nat the liver (predominant site of metabolism) and the kidneys (site of excretion of polar metabolites) contain the highest concentrations of 14C activity, followed by spleen, lungs and small intestine (Watanabe et al. l976c\Bolt et al. 1976a, b). Liver, kidneys,spleen,lung and small intestine (in this order) also contain the largest amounts of irreversibly protein-bound metabolites (Boit et al. 1976a). Only minor amounts of irreversibly bound metabolites of VCM were found in muscle, adipose tissue and brain. r ;l .i :* i" V t 1 * ; 26 W.K. Lelbach and H.J. Marsteller Total radioactivity 4S h after a single exposure decreased considerably in these organs, in accordance with the relatively rapid metabolization of VCM and excretion of its polar metabolites. In contrast, the amount of irreversibly protein-bound radioactivity remained constant during this time. Buchteret al. (1977) also showed that unmetab olized VCM possesses a great affinity for adipose tissue, in contrast to its metabolites, which are concentrated primarily in liver and kidneys. 3.4.2 Metabolism 3.4.2.1 Relation between Chemical Structure. Reactivity and Mutagenic or Carcinogenic Effect Before discussing the metabolic pathways of VCM (monochloroethylene) and its pre sumptive toxic intermediates two features of the chemical structure of this compound should be mentioned. Vinyl chloride is a monohalogenatcd ethylene and its chlorine substitution is asymmetric. Chlorination of alkenes (olefinic compounds), in general, tends to stabilize the double bond by exerting an electron withdrawal effect on the carbon atom involved. Thus, the chemical reactivity of alkenes decreases with increas ing degree of chlorine substitution, as was shown in 1968 by Williamson and Cveranovic for reaction rates with ozone. Vinyl chloride, as a monohalogenated alkene, is the least stable compound with the highest reaction rate in the series of chlorinated ethylenes and ranks next to unsubstituted ethylene. Secondly, the first step in the oxidative metabolism of all chlorinated alkenes is a transformation to epoxides (oxiranes) which are short-lived, highly reactive electro philic intermediates (Bonse et al. \97S\Henschler 1977b). Such chlorinated epoxides may react, by alkylation, with essential cellular constituents, a mechanism which Rannug et al. (1974),i?awc7i et al. (1975a, b) and Malaveille et al, (1975) claimed to be responsible for the carcinogenic and mutagenic effects of VCM and vinylidene chloride. Epoxides resulting from biotransformation of asymmetrically substituted ethylenes, such as VCM, vinylidene chloride and trichloroethylene, seem to be particu larly unstable with increased electroplulicity and thus enhanced alkylating effect. Their mutagenicity and, inversely, the nonmutagenicity of oxiranes of symmetrically chlorine-substituted ethylenes was indicated by the studies of Greim et al. (1975. 1977). 3.4.2.2 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 (Kappus et al. 1975, \976\Bartsch et al. 1975b, \916\Malaveille et al. 1975',Bolt et al. 19763.'.Pcssayre et al, 1979), with the aid of isolated perfused liver preparations (Radwan and Henschler 197S'.Bonse et al. 1975 \ Radwan \977: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 Vinyl Chlon microsomal i ly highly rea-. via the form;, bon monoxii' preciable roll, in vitro an an systems and i 1976a). The; Cl H 'X-C H' JO Bo CO o o 07 o 07 to Fig, I. Meta-v metabolized tacetic acid are roethylene oxi protein sulph;. way (1977). Sc (Norpoth et a.'. S-carboxymeti. acid) (Henschi identified in ti. J. Marsteller hose organs, on of Us '.lioactivity unmetabicrabolites. and its pre compound is chlorine in general, ct on the vith increasid Cvetanovic is the least ! ethylenes dkenes is a a electro.d epoxides i which ) claimed to ylidene iisiituied o be particueffect. !v 33 C/) o o . cn o s' at .. co ai i(A tl. mol animals (^-inhibiting the predoy the hepatic Vinyl Chloride-Associated Disease microsomal mixed-function oxidase system, forming chloroethyknc oxide, a chemical ly highly reactive epoxide fFig. 1). A negligible amount of VCM can be metabolized via the formation of peroxides, very unstable compounds decomposing rapidly to car bon monoxide, HC1 and formaldehyde which, however, do not seem to play any ap preciable role in the toxicity of VCM {Henschler 1977b). It has also been shosvn that in vitro an artifical superoxide (Of) generating system can replace rat liver microsomal systems and transform VCM to the active intermediate (Kappus et ai. 1975:Bot{ et al, 1976a). The epoxide rearranges spontaneously to chioroacetalJehyde. which is rapidly C(v.jk-n( I'linlir.c in cellular ni-uTumolcculcs ialli\ latiou i i tl ;r=<.r H Nl mi OmiI.uc NADPH. 0- H'1 'H Chtnmvthvh'ne Ov/uV (VCM epoxule i Coniueutiuit with -=ulV>n\. dry I yroupx i glutathione. cy'temci Thermal rcarraiicemenr H coI I H 'll lly xlroly -ix iepoxide hydrasci Oil Oil C|--(--C -- H !I il ll C'hloroaeetjMelw Je Fig. 1, Metabolic pathways. Adapted from Henschler { | 977b > metabolized to monochloroacetic acid. Both cliloroacetaldehyde and monocldoroacetic acid are also metabolites which are chemically reactive but less potent than chloroethylene oxide. All three intermediates can be detoxified by conjugation with nonprotein sulphydryl compounds (glutathione, cysteine) as described by Green and Hathway (1977),Sulphur-containing excretable metabolites such asS-hydroxvethylcysteine (Norpoth et al. 1976), M-acetyl-S-(2 chloro)-ethyl-cysteine (Green and !lathway 1975), S-carboxymethylcysteine (Watanabc et ai. 1976a), and thiodiglycolie acid fthiodiacetic acid) (Henschler 1911 Muller et al. 1976, l918:Mullcr and Norpoth 1975) have been identified in the urine of exposed workers and animals. A progressive depression of the :s W.K. Lclbach and H.J. Marstellcr level of hepatic nonprotein sulphydryl content has been observed in rats after expo sure to VCM in concentrations from 150 to 2000 ppm for 2-7 h. No depression was seen after 10 ppm and a concentration of 50 ppm caused only an inconsistent reduc tion {Watanabe et al. 1976b). Protein-bound hepatic sulphydryl content remained unaffected. Hepatic microsomal cytochrome P4 50, the coenzyme of microsomal monooxigenases, also decreases linearly with time in animals exposed to VCM (Reynolds et al. 1975b). This destruction of cytochrome P450 may prevent further metabolism and toxicity of VCM (Ressavre et al. 1979). Another mode of deactivation of the primary reactive intermediate, the epoxide, is its transformation to the inactive dihydrodiol by the inducible microsomal enzyme epoxide hydrase. The reactive metabolite of VCM, chloroethylene 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 hepatotoxic,mutagenic and carcinogenic effect. Eventually, however, the only fraction of the formed epoxide that binds to macromolecules is the one that is not detoxified by protective scavenging mechanisms such as conjugation with cytosolic glutathione or inactivation by epoxide hydrase. Simultaneous presence of other xenobiotics which have to be detoxified will impair the effectiveness of the detoxification mechanisms. In assessing the risk of exposure to VCM, Hensdtler (1977a) concluded that there might be a greater risk in intermittent peak exposures over brief periods than might be ex pected from simple integration over time and that the chances for effective detoxifica tion are greater in long-term exposure to relatively low levels. It was shown by Watanabe et al. (1978a) that repeated exposures of rats to VCM do not appear to induce its biotransformation, but significantly augment the binding of the reactive metabolite with hepatic macromolecules and may thus enhance the po tential toxicity of VCM. On single exposures of rats to increasing concentrations of labelled VCM ranging from 1 ppm to 5000 ppm, the amount of radioactivity covalent ly bound to hepatic macromolecules did not increase proportionately to the increase in concentration but followed a sigmoid curve with low and high inflection points be low 50 ppm and above 250 ppm. respectively, when binding was plotted as a function of the log of the exposure concentration (Watanabe et al. 197Sb). This correlates well with Malront's report (1975) of a linear percentage induction of hepatic angiosarcoma in tats between 50 ppm and 500 ppm when expressed as the log of the exposure con centration. Metabolites of VCM can alkylate nucleic acids, a commonly accepted mechanism for carcinogenesis. Covalent binding to the adenosine (Barbin et al, 1975 \ Laib and Bolt 1977), cytidine {Laib and Bolt 1978), and guanine moiety of nucleic acids (Osrcrmann-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\Laib and Bolt 1977). Laib and Bolt (1977) presented evidence showing that the alkylating potency of VCM metabolites cannot be deter mined soiely 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 i above all. i This as. work will 1-. endoplasmtible to VC phologicalh mixed fum. lobular, mi. found (Jac. 1978). Sec. endothehV At prescesses are t" the hepatoc some metah (3) Mechani tissues othe. rant cell rep 1978b). An equa nonneoplasRaynaud's drome war man. Besid.liver lesion* bioactivatio. portal fibnment of the a direct or ir tic nervous. lining cells o tion) or win. 4 Clinical Duri miel 37 ~ fio Prer CO mai pat o in i Marsteller expo ;sion was nt reduc* nained mal mono* :ynolds et i'olism and epoxide, is enzyme :ylating tal proteins the me tab* bus exert its nly fraction detoxified ntathione or cs which chartisms. In ihere might iit be ex detoxifica- s to VCM >e binding ;.:e the po ntons of t. covalent* e increase i points be- a function -dates well uiiosarcoma -osure con- icchanism / jib and .icids (Qstermding of < be very presented be deterrer exposure ling to s does not Vinyl Chloride-Associated Disease exclude tlie possibility of other, more subtle interactions which may impair the control of 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 hepatocytes. This 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 Itepacocvte, the liver cell itself is not particularly suscep tible to VCM-induced toxicity. Acute hepatocellular injury has not been observed mor phologically after exposure to VCM unless pretreatment with potent inducers of the mixed function oxidase system had preceded the exposure;in pretreated rats centrolobular, midzonal and panlobular hepatocellular vacuolization and even necrosis was found (Jaeger et al. 1974,1975. 1977'.Reynolds et al. 1975a. l976:Connlty et ai. 19781. Secondly, the site of carcinogenicity in the liver is not the hepatocyte but the endothelial cell of the hepatic sinuses. At present it can only be speculated which of the following four most likely pro cesses are effective, either singly or in conjunction: (1) The active metabolite leaves the hepatocyte and is conveyed to the endothelial cell. (2) The endothelium itself lias some metabolic capacity (Bolt 1978), as may tissues of organs other than the liver. (3) Mechanisms for the detoxification of the active metabolitefs) are insufficient in tissues other than the hepatocytes. (4) Repair mechanisms for the correction of aber rant cell replication are less effective than they are in the hepatocyte (Watanabe et ai. 1978b). An equally puzzling problem is the role of VCM in the pathogenesis of the distal nonneoplastic vascular lesions which are responsible for the development of the triad. Raynaud's phenomenon, sclerodermoid skin indurations and acroosteolysis. This syn drome was the earliest indication of adverse effects of chronic exposure to VCM in man. Besides, its latency period was considerably shorter than either the nonmalignant liver lesions or angiosarcoma of the liver. Whereas it is now established that hepatic bioactivation of VCM plays the central part in the pathogenesis of both noncirrhotic portal fibrosis and angiosarcoma of the liver. i is not at all clear whether the develop ment of the acral lesions is due to VCM itself or to active metabolites which may exert a direct or indirect toxic action on (a) medullary vasomotor centres, (b) the sympathe tic nervous system, fc) smooth muscle cells of the media of arterioles, fd) endothelial lining cells of small arteries (with fibroblast transformation and endothelial prolifera tion) or whether (e) the action is mediated by the formation of immune complexes. 4 Clinical Spectrum During the mid-1950s it began to emerge that chronic occupations] exposure to VCM might prove to be not quite as harmless as had been claimed. The historical synopsis presented in Table 7 summarizes those clinical studies from the world literature that marked the gradual recognition of the full spectrum of damage due to this new occu pational hazard. 30 W.K. Lelbach and H.J, Marsteller Table 7. Gradual emergence of evidence for VCM-associated pathology Year Reference Findings 1949 Tribukh et al. Hepatomegaly, more or less marked `anicteric hepatitis', `chronic gastritis", hypotension, anaemia, skin lesions 1954 1957 1957 1960 Smirnova Filatova and Gronsberg Kubota Danziger Toxic angioneurosis Toxic angioneurosis Symptoms similar to Raynaud's phenomenon Two cases of accidental fatal poisoning by VCM. . 1 nonfatal acute overexposure 1961 Smirnova Reversible osteolytic lesions of distal phalanges. Pseudoclubbing, thickening of skin'on volar side of forearms, slight haemolysis and reticulocytosis 1963 5uciu et al. CNS; prenarcotic symptoms (dizziness, euphoria, somnolence), nervousness, insomnia, blunting of memory, general asthenia, headache Vascular: Raynaud's syndrome Dermatol.: pruritus, reversible sclerodermalike skin induration, chemical and allergic dermatitis Digest, symptoms: anorexia, nausea, fullness, hepatomegaly without hyperbilirubinaemia. splenomegaly Endocrine: hypothyroidism 1966 Cordier et al. Raynaud's syndrome, sclerodermalike skin changes, acroosteolvsis, pseudoclubbing, joint pain, tiredness, sleep reversal: 2 episodes of acute overexposure (loss of consciousness) 1967 Harris and Adams Acroosteolvsis. skin lesions, Raynaud's phenom enon, pseudoclubbing, involvement of sacroiliac joints and patella, hepatomegaly with persistent ly raised serum bilirubin. Skin biopsy 1967 1967 Benoit Wilson et al. Arteriography. Skin and bone biopsy "Occupational acroosteolvsis" with Raynaud's symptoms, sclerodermalike skin changes, pseudoclubbing 1968 1971 1971 1972 Antonyuzhenko Dinman et al. Dodson et al. Kramer and Mutschler Mentions thrombocytopenia Prevalence of acroosteolvsis and Raynaud's phenomenon Vascular lesions preceding the bone lesions Increased BSP retention and raised icterus index related to degree of exposure V 33 Ti (/) Yt o o 19 cn o CJ1 O) m rr il f fc 19', l 1973 Ma 1974(a) Ca 4.1 The Trie A first indicat plant produc'dnon (`toxic atin detail in hr personnel wlhourly sampli. drome was aN (Kubota 195' moregulation. and CNS sym(1954) also m. durations on there was evic of red cells, u: evidence of dc acroosteolysis operators) aft* junction with was found in i lesions to be c, reversible cha: vibration trau the full range i cupational acr In 1963 Sianalysis of th. R&S 005057 I H.J. Marsteller d `anicteric intension. lenon .y VCM. tlanees. olar eticulo- jphoria. mting adache crodermalike tcrgic dermatitis aj. fullness, rubinaemia. like skin lubbing. joint episodes o( -ciousness) uaud's phenoment of sacroiliac with persisient'inpsy psv h Raynaud's changes. Raynaud's >ne lesions cd icterus index Vinyl Chloride-Associated Disease 31 Table 7 I continued) Year Reference 1972 Markowitz et al. sO - j~ Ij Jilhe and Lange 1973 Marsteller et al. 1974(a) Creech et al. Findings Progressive thickening of hands and forearms, arthralgia. Blanching upon exposure to cold with cyanosis ot hands accompanied by severe pain. Skin biopsy 1st German report of 7 workers with sclerodermalike skin lesions. Raynaud's syndrome, and acroosteolysis. Tests showed abnormal liver in 2. occlusion of digital arteries 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, Pseudoscleroderma and Acroosteolysis A first indication of adverse effects due to chronic VCM exposure arose in workers at a plant producing 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 (1959). The syndrome was found predominantly in laboratory personnel who had intermittently been exposed to high concentrations of VCM during hourly sampling for chemical analysis (purity of the product). In 1954 Raynaud's syn drome was also observed among several workers at a Japanese PVC producing plant {Kubota 1957). Apart from a painful vasospastic disorder of the hands, impaired ther moregulation, acrocyanosis, positive cold test, capillaroscopic alterations, paraesthesias. andCNS symptoms such as headache, blunting of memory and sleep reversal.Smirnova (1954) also mentioned swelling of fingers and development of circumscribed skin in durations on the volar side of the forearms in those most severely affected. In addition, there was evidence of mild haemolysis (borderline anaemia, decreased osmotic fragility of red cells, urobilinuria,and reticulocytosis). In 1961 Smirnova described radiographic evidence of destructive bone lesions of terminal phalanges in the hands identical with acroosteolysis in three workers at a PVC-producing plant (one fitter, two centrifuge operators) after exposure for 3-9 years. Since these bone lesions developed in con junction with 'toxic angioneurosis' and since complete recalcification of tire defects was found in two workers 3 years after removal from exposure, Smirnova believed the lesions to be characteristic of chronic VCM intoxication. She pointed out that their reversible characrer might serve to distinguish the lesions from similar defects seen in vibration trauma. In retrospect,Smirnova's observations are the earliest descriptions of the full range of symptoms which much later became known as `the syndrome of oc cupational acroosteolysis'. In 1963 Suciu et al. (see also 1967 ami 1975) published the first comprehensive analysis of their observation of a multiform symptomatology in subactue and chronic s % 32 W.K. Lelb.ich ami H.J. MarMellcr Vinyl Chlor. VCM intoxication. During a 4-year period, they examined 168 mostly young workers The disci from two Rumanian PVC-producing plants who had not previously been employed in two Belgian other industries. In their classic paper, the authors described in detail the various cen classifiable d tral nervous, digestive, angioneurotic and cutaneous symptoms flisted here in their marked the r order of manifestation). Acroosteolysis. however, was not mentioned. Episodes of syndrome w: acute overexposure (usually occurring at the end of a batch run. during retrieval of year a numb- unreacted monomer, or at repair jobs) rapidly resulted in a state of light-headedness United State and transient euphoria similar to a mild degree of inebriety and were accompanied by cases of OAC a feeling of heaviness in the legs and disturbed locomotor coordination. Several workers the various p claimed to have been able to identify escaping monomer by its faint but agreeable end of 1979. odour. Apparently during periods of particularly high ambient concentrations, workers vascular pher. repeatedly noticed formication in the lower limbs and a general feeling of bodily symptoms th warmth. Six subjects had experienced loss of consciousness when repairing leakages, begin with ill but recovered rapidly after being carried out into the open air. After a few,months of the fingers ar 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 tips on hard to cold accot; are likewise a ance of painf noticed insomnia or sleep reversal. A reappraisal of these nonspecific complaints (see also Vale et al. 1976) 6 years osteolytic pn. with striation later, after improvement in industrial hygiene, revealed that the frequency of their oc -rsa currence had considerably decreased (Sticiu et al. 1975). Following a prolonged period of repeated overexposure, vague nonspecific digestive symptoms also developed, such as anorexia with ensuing weight loss, nausea, fullness, upper abdominal discomfort, . Pub! 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 (Rancher et al., cited by Sitciu et al. 1975). Pruritus of the hands, forearms and face tvas an early complaint followed later by what was theought to be (allergic?) 'contact dermatitis'; finally, nodular and scleroderma- or scleroedema-like cutaneous lesions developed in some workers, involving the dorsai 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 plaquelika indurations. The cutaneous manifestations largely disappeared alter removal from the work place. In addition, mention was made of features of hypothyroidism in 1971 1972 1972/197: a few workers. Also, transient loss of libido in 24% was recorded, with return to nor mal after a break from work or during holidays. With the exception of acroosteolysis and the two most alarming late sequelae - noncirrhotic 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 1978 1979 ic, and histomorphological aspects of the lesions encountered in subjects chronically exposed to VCM, One of 2 t; $ -J** f# Marsteller g workers iployed in rious cen'i their lies of oval of dedness panied by ral workers oeable ms, workers jdily k'akages. months of sistent it the work ability, ne workers ' years I their occed period ped. such mifort, .is(3(T): id in 6"-. ..n-ispastic Pruritus 30 J(/2> cn ID i I a comsication. viding admgiographronically Vinyl Chloride-Associated Disease Tlte discovery of unusual osteolytic detects in the distal phalanges of the hands of two Belgian autoclave cleaners who had suffered front Raynaud's phenomenon and undassifiable degenerative lesions of the dermal connective tissue {Cordicr et al. ]%6) marked the recognition of this new occupational disease in the Western World. Tlte syndrome was termed 'occupational acroosteolysis' (OAOL), and during the following year a number of additional cases were reported from France. Great Britain and the United States. Later Lcfevre 0972) who together with Cordicr described the first two cases of OAOL. reported that a subsequent investigation revealed another 'en cases in the various plants affiliated to the same corporation in Spain, Italy and Brazil. By the end of 1979, a total number of 126 cases had been published in detail (Table 8). The vascular phenomena preceding or accompanying OAOL comprise a broader range of symptoms than those characteristic of Raynaud's syndrome. The conditions seems to begin with ill-defined pains in fingers, wrists and also large joints (shoulders, knees): the fingers are numb and tingling, tender on palpation, handgrip and tapping finger tips on hard surfaces is painful; there is increasing sensitivity of the hands and fingers to cold accompanied by a tendency to cyanotic discolouration. In some cases, the toes are likewise affected. Later, classic Raynaud's phenomenon develops (sudden appear ance of painful, sharply demarcated blanching) and, concomitant with the onset of osteolytic processes, there is a shortening and broadening of the terminal phalange with striation of nails (pseudodubbing). Table 8. Publications on `Occupational Acroosteolysis' since |066 Ve.ir Country Number Authors of cases 1906 1967 1967 1967 1967 1969 1969 1971 1972 i 972/1977 1973 1974 1974 1975 1975 1976 1978 1979 Belgium France France United Kinedom USA Rumania Yucoslavia USA USA Fed. Repubbe of Germany Japan France USA USA United Kingdom United Kingdom 5 5 s 31 a 8 41 -1 6 l 4 1 4 1 4 Brazil Israel 5 a 126 Cordier et al. Benoit: Chatelaiit and Mottlhm Bourrtchon (cited by Marin e! al. 1967) darns and Adams Wilson et al. Anghelescu et al. ATorflc et al. Dintnan et al. Markowitz et al. Jtihe and Veltman: Stein et al. ta. bl Takeuchi and Mabuchi 3 Moulin et al. Trapp et al, /.ills et al. Stewart et al. Preston et al,: Walker; Mitchell Johnston (1978) Gama and Meira dahn et al. 3 One of 2 clear cases, in addition. 48 suspeeted cases isee Sakabe |9?5) 34 W.K. Lelbaclt and H.J. Marsteiler 4.1.1 Familial and Idiopathic Acroosteolysis Acroosteolysis is a very rare disease. The aetiology and pathogenesis of this condition is still obscure. Osteolytic bone changes in late stages of so-called Raynaud's disease (accompanied by necrosis and gangrene), characteristically presenting as loss of part or of an entire distal phalanx of one or more fingers and also of toes, have been mention ed in the literature since 1921 (Assmann 1921 \ Monahan 1926', Borak 1927; Kornblum 1929).Kombtum attributed the lytic bone defects to vascular abnormalities and noted that he had found identical lesions in early stages of scleroderma and in leprosy. Tire term acroosteolysis was first introduced by Laroche and Hochfeld (1948), who held a neuroendocrine syndrome responsible for the lesions. Independently Harnasch (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 nonfamilial, idiopathic form had been reported in the medical literature. He added another five cases, but his case reports pertain almost exclusively to mutilating proces ses involving only the feet, with recurrent ulceration and discharge of bone fragments (see also Harms 1954). In 1957 Liivre and Gama listed 16 observations of idiopathic acroosteolysis and commented extensively upon these lesions; the whole range of dif ferential diagnosis (various congenital, neurogenic and endocrine osteolytic diseases, leprosy, arthritis mutilans, progressive systemic sclerosis, ainhum etc.) was considered in their study and could be rejected with reasonable certainty. In a later review, Cheney (1965), who added another four cases of the familial type, 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 (Leftvre 1972). 4.1.2 Epidemiology of Occupational Acroosteolysis Attempts at assessing the prevalence of OAOL among personnel involved in VCM manufacture and polymerization revealed that in general this occupational type of osteolytic bone lesion was found in only I%--3% of the work population at risk. Hublei et al. (1977) considered the fact that only 2% of all workers who had been engaged in manual cleaning of autoclaves at a Belgian plant suffered from OAOL and Raynaud's phenomenon to be indicative of the importance of individual factors. Wilson et al. (1967) observed 31 cases among 3000 employees of one large company. In 197) Dinrmn et al. conducted a survey in 32 plants belonging to 19 corporations throughout the United States and Canada. The details of this elaborate epidemiologi cal study, comprising a total of 5011 employees, illustrates the difficulties and limita tions encountered in a retrospective study of this dimension. All of these 5011 workers had been engaged in various stages of VCM and PVC manufactunng, but 1257 of them were workers who only handled finished PVC polymer. Five of the 32 plants worked Vinyl Chlor exclusively only 25 clea defined as c enon;18 of with expene drome were jobs, both re (1 case per 7 appeared no was detectcc use for react entry into th Table 9. Prei Country France USA United Kingdom Fed. Rep. Germany United Kingdom Total More con related svmp Lange and f. ological cheepathological: were affected cold, 15 work morbidity wa found classic numbness am. 8.7% and invc Allen test inJ people with p pseudoclubbn that ti 20 i of p. R&S 005061 I H.J. Marsteller andition disease of part or mentionKomblum and noted asy. The 'ho held a 'ttmasch (1949) 'larly involving ssive clubbing lation. By 1952 nd 33 cases of ature. He added dilating proces')one fragments : of idiopathic .le range of difIvtic diseases. was considered r review, ted that this same disease 1 lhan the term uc lesion that -ts when in loaners (Lefhre ed in VCM -mal type of >n at risk, m had been im OAOL and i! factors. 'urge company. 1 corporations epidemiologi'ties and limitac 5011 workers it 1257 of them plants worked Vinyl Chloride-Associated Disease 3j exclusively with the finished PVC-derived consumer products. Dinman et al. found only 25 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: 18 of them had been reactor cleaners at some time; another 16 individuals (10 with experience in reactor cleaning) with early stages or minimal degrees of the syn drome were suspected of suffering from OAOL. It emerged that the two lowest-paid jobs, both reactor cleaning and bagging/packing, had a strong association with OAOL 1,1 case per 72. or 86 workers at risk, respectively). Manipulation of the finished polymer appeared not to be associated with a risk of contracting OAOL. Only 1 case of OAOL was detected in those plants where high-pressure water lances or solvents had been in use for reactor cleaning. Furthermore, it seemed that the extent of degassing prior to entry into the autoclaves correlated with the manifestation of the disease. Table 9. Prevalence of acral disease in VCM-exposed populations Country Number of cases Size of group at risk OAOL Classical Severe Sclero Raynaud's sensitivity dermoid phenomenon to cold skin lesions References France 130 USA 354 United 37 Kinadom Fed. Rep. 100 Germany United 104 Kingdom Total 725 5 12 4 20 15 99 I 25 15 5 63 23 84 33 10 --1 20 K3*3) 7 IK 10%) 119K 16%) 43(^6^) Benoit 1967 Lilis et al. 1975 Walker 1976 Lange and Veltman 1977 Maricq et al. 1978 More commonly seen than OAOL were Raynaud's phenomenon (see Table 9) and related symptoms of abnormal peripheral circulation (Benoit 1967;/,iVfj et al. 1975: Lange and I'eltman 1977). Benoit pointed out that a complete medical and roentgen ological check-up of all 528 employees at a French PVC-producing 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 workers). He stressed the fact that in this group of workers at risk the overall morbidity was almost 25%. Similar results were obtained by Lilts et al. (1975), who found classic Raynaud's phenomenon in 5.6% of 354 heavily exposed PVC workers, numbness and tingling in 24%, excessive sensitivity to cold in 18%. pseudoclubbing in 8.7% and involvement of the toes in 7%. Besides, in 26.6% 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 pseudoclubbing persisted or even progressed. Most important, however, was Ltlis' finding that the prevalence of all these abnormalities increased significantly with the duration of past exposure to VCM. i :i !1 tu- r :-6 W.R. Lelbaeh and H.J. Marstcller Occupational acroosteolysis is a condition predominantly observed in younger workers. The age range was 20--t5 years and hall'of all cases reported fell in the 30--29 years age-group. Duration of VCM exposure prior to onset of Raynaud's phenomenon ranged from 1 to 23 months (Dodson ct al. 1971). For OAOL the latency period was at least 12 months (Wilson et al. 1967): in most cases, OAOL developed insidiously within 2 to 4-6 years. There is at least one patient on record in whom OAOL was first discovered two years after termination of exposure (Benoit 1967). Longitudinal studies of the bone lesions demonstrated partial or complete but mostly defective restitution, resulting in shortened and deformed distal phalanges, within 2-3 years after removal from VCM exposure, but Raynaud's phenomenon and cutaneous lesions may persist (Williams and.lfcZ.ac/iiin 1976). Stein et al. (1973a, b) reported partial healing with restitution of tufts but progressive lysis of the proximal portion of terminal phalanges 3 years 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 acroosteolysis, in whom specific inquiry revealed that his employment by an industrial chemical company had included daily handling of small concentrations of vinyl chlo ride (no details given). Typical OAOL was also observed in a worker after 6 years' em ployment as spray dryer/bagger, pre-mix operator, recovery and charging operator who had never cleaned autoclave vats (Srewarr 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 occlusion. Apart from the chemical insult by iahaiational ("rather than transdermal - Dinman et al. 197l;5reH'arr et al, 1975) exposure to VCM, individual susceptibility or idio syncrasy appears to have played some (undefined) role in the development of the syn drome. It does not seem likely, however, that repeated physical microtrauma during cleaning operations (removal of polymer crusts by hand scraping or chiselling) was a decisive factor in the pathogenesis of the condition as had been speculated by Wilson et al. (1967). 4.1.3 Clinical and Roentgenological Features 4.1.3.1 Occupational Acroosteolysis In the majority of cases osteolytic lesions are confined to the hands. Involvement of the feet was observed only rarely in OAOL. Wilson et al. (1967) believe that OAOL differs from familial or idiopathic acroosteolysis in several respects. Although the bone Vinyl Ch defects in osteopori skull, desshortening nonoccup genologic. 1) The one or mo 2) In t: tufts, ora 3) The tufts toget defects (se (`bandlike Fig. 2. Occ acroosteoh year-old au 4) In tli and broade fragments.; and increas. Sodium mineralizati muitaneous i arui H.J. Marsteller :vcd in younger ;d fell in the 30-39 aud's phenomenon latency period was liiped insidiously horn OAOL was first Longitudinal studies elective restitution, ears after removal esions may persist irtial healing with ' terminal phalanges workers who had at has also been ob;d to carry a sub' -year-old white male d typical bilateral ent by an industrial ions of vinyl chlor after 6 years' enl arging operator who ni routine plant as chromatography 1 limit values of st year during an ijnaud's phenomids and wrists. Ar al lingers without of deformed sdermal -- Dinrnan ptibtltty or idio- lent of the synauma during ^ eliing) was a ^ ed by Wilson o o cr 0 01 CP ement of Hcve that OAOL Although the bone Vinyl Chloride-Associated Disease defects in the distal phalanges are similar in both conditions, other features, such as osteoporotic compression fraetures of the spine, basilar impression fracture of the skull, destruction of mid-phalanges or osteosclerotic changes of wrists and hand bones, shortening of metaearpals and cortical thickening of the shafts of long bones seen in the nonoccupational type have never been found in OAOL. Wilson et al. worked out roent genological criteria for the diagnosis of OAOL: 1) The earliest changes in OAOL are marginal defects and loss of cortex in tufts of one or more of the terminal phalanges of tire 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 rim of the tufts (`bandlike acroosteolysis'). Fig. 2. Occupational acroosteolysis. Transverse or oblique bone defects ('bandlike acroosteolysis') or partial loss of terminal phalanges in all fingers of both hands. 133year-old autoclave cleaner: duration of exposure 3 1/2 years) 9) In the healing stage there may be either complete bony union with shortening and broadening of the residuaj 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 longitudinal curvature of fingertips. Sodium fluoride 11F scintiscan data of affected bones suggested that active de mineralization (resorptive) and remineralization (reparative) processes may occur st muitaneously even in tiie same hand (Dodson er al. 1971). In some cases, bones of \V,K. Lelbach and H.J. Marsteller other body regions were also involved. Erosive and sclerotic changes in the sacro-iliac joints and circumscribed resorptive delects (cortical erosions) in patella, clavicle, mandible, humerus, styloid process of ulna, femoral condyles, os calcis. cuneiform and metatarsal bones have repeatedly been observed (Contier et al. l966://ams and Adams \961-.Dodson et al. 1971 \Jiihe et al. 1974;ia/r^-e et al. l974a:Prcston et al. 1976; /arson et al, 1976a\Lange and I'chman 1977). 4.1.3.2 Pseudoscleroderma Concomitant with the manifestation of paracsthesias, pain, tenderness of the fingers and Raynaud's phenomenon, cutaneous lesions similar to stigmata seen in progressive scle roderma develop with thickening of the skin of fingers, hands and forearms, sometimes accompanied by swelling or puffiness and coarsening of the skin of the face (mostly on the forehead and cheeks). Raised, ivory-coloured, firm nodules or elevated, sharply de lineated piaquelike skin indurations are seen on the dorsal surface of fingers and hands and on the volar side of the wrists and lower forearms. It was this combination of Ray naud's phenomenon and cutaneous lesions which first prompted a search for other symptoms of progressive systemic sclerosis in affected workers. The syndrome of OAOL, however, can be clearly distinguished (Table 10). Notably, the diffuse immobil- Table 10. Differential diagnosis; syndrome of occupational acroosteolysis ( Raynaud's phenomenon, sclerodermoid skin changes. AOL) / progressive scleroderma with (rare) osteolytic lesions Sex ratio Occupational AOL Exclusively i Progressive scleroderma <s:9 = 1:2 Hands Clubbing and shortening of finger tips; hyperliidrosis: no ulceration Atrophy and tapering off of fingertips; anhydrosis; ulcerative lesions Perioral puckering of skin Skin appendages Telangiectases Shortening of frenulum Subcutaneous deposits of calcium salts Dysphagia (oesophageal involvement) Renal, cardiac and intestinal involvement Occupational history Prognosis Not observed Preserved Not observed Not observed Not observed Not observed Not observed Obligatory Favourable fskin 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 l tional syndrom readilv than th-. 4.1.4 Histoloi 4.1.4.1 Cutan. Several investia disease (Cord:. al. 1972; Lange we found only \961;Marin et neural changes who suffered V Dermal cha. mis with disorie broad interlacm faintly stained: Schiff (PAS). A histiocytes was The most notab of elastic fibres full thickness r, sue. Skin appv,, Walker (1976) t not exceeding i. some fibrous th Vascular k capillaries were and pericapiilar thelial ceils with tion of lumina. myocytes, was. to narrowing or Degenerative (Benoit 1967;.) hyaiinosis of :!: Meissner, Pacim 4.1.4 2 Bone l. H.J. Marsteller i I iliac i. man- ' r, (j) d Jams >o o cn o O) tn 6: o ers and pi scle- 'arms, sometimes lace (mostly on ated, sharply demgers and hands ibmation of Rav- rch for other ndrome of diffuse immobil- ysis <Raynaud's rma with (rare) vc 'deroderma ar. I tapering off up anhydrosis: li ' mns kin appendages nptom i nl -pontaneous 'ion Vinyl Chlonde-Assoeiated Disease 39 izing sclerosis of the skin with tapering off of fingertips was never seen in the occupa tional syndrome. After cessation of exposure the skin lesions seem to regress more readily than the osteolytic changes. 4.1.4 Histology 4.1.4.1 Cutaneous Lesions Several investigators described the histomorphology of skin lesions in vinyl cldoride disease (Cordieret al. \966\Harris and Adams 1967\ Marin et al. 1967;Markowitz et al. 1972;Lange et al. 1974a: Vcltman et al. 1975; Walker 1976\Hahn et al. 1979), but we found only one description of bone histology in OAOL in the literature [Benoit 1967;.lfenn 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 tliickening of the der mis with disorientation, swelling and nonfibriliary eosinophilic homogenization of broad interlacing collagen bundles. There was some degree of interstitial oedema which faintly stained metachromatically with toluidine blue, alcian blue and periodic acidSchiff (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 plaquelike skin indurations, the full thickness of the dermis consisted of an acellular, partly hyalinized collagenous tis sue. Skin appendages were preserved. In 15 apparently less severely affected workers. Walker (1976) found only some destruction of elastic tissue of the dermis, probably not exceeding normal age changes; in one worker with severe Raynaud's phenomenon some fibrous thickening of the media of dermal arterial was seen. Vascular lesions affected capillaries and small dermal arteries. Numerous dilated capillaries were seen in the subepidermal papillae with swelling of endothelial cells and pericapillar oedema. Capillaries of the cutis showed cufflike hyperplasia of peritheiial cells with fibroblast transformation, hyalinosis of vessel walls and final oblitera tion of lumina. Marked medial thickening of dermal arterioles, due to hypertrophy of myocytes, was accompanied by parietal fibrosis and hyalinosis. which ultimately led to narrowing or even complete occlusion of the lumen. Degenerative lesions of small dermal nerves were mentioned by French investigators (Beii'itt 1967\Marin et al. 1967;Qmelain zndMotillon 1967). They found sclerosing hyalinosis of the perineurium with atrophy of neurofibrils. Tactile corpuscles (WagnerMeissner. Pacini) were unaffected. -t./.d.J Bone Lesions The most striking feature in a biopsy specimen of the bone, obtained from a French worker with OAOL (case 4 of both Benoit \967\Marin et al. 1967) was marked thick ening and hyalinization cf the periosteum with chondroid metaplasia of the inner most layer. Supplying capillaries and arterioles showed occlusive changes identical with . i ;! Vf I* :l \f 1iI . ! fj t: * l `Y . fr 40 W.K. Lelbach uml II.i, Mjrsielter those observed in the dermis. The bone matrix per se was barely affected. There was minimal thinning of cortex, normal spongy bone and only mild fibrosis of the bone marrow. Experience with histomorphulogy of bone lesions in the familial and idiopathic type of acroosteolysis 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 (Dupas et al. 1936: Elson and Bitmstein 1954;Greenberg and Street 1957 ;Schwar:wciltr 1957). In this context, it should be kept in mind that Viola succeeded in reproducing dermal, vascular, neural and skeletal lesions in the skin of the paws and in small meta tarsal bones of experimental animals which were very' similar to those observed in man. Viola exposed rats to 30 000 ppm VCM.4 h/day. 5 days/week, for 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;Moulin et al. 1974). Die most prominent arteriographic features were ir regularities and segmental stenosis of digital arteries, ranging from localized or diffuse narrowing to subtotal or even total occlusion with development of collateral vessels. Besides, a conspicuous retardation of flow of contrast medium was noted, and peculiar tortuosities of patent digital arteries were found. Circumscribed hypervascularity of the terminal tufts and in the region of the wrists was noted in some cases (Benoit I967',lange et al. 1974a; Vcitman et al. \97$; Preston et al. 1976;i'rt'U'fl/'f et al. \91S\Gama and Metro 1973). Angiographic findings in a larger group of 19 symp tomatic PVC workers with either Raynaud's phenomenon and/or acroosteolysis (5/19) were recently described in detail by Eoischwit: et al. (1980). Raynaud's phenomenon had been observed to persist in these patients for prolonged periods after termination of exposure and even after roentgenological evidence of healing of resorptive bone defects in those who had formerly suffered from acroosteolysis. In addition to vary ing degrees of stenosis or occlusion of digital arteries with reopening of small collat eral vessels, acral hypervascularity and considerable retardation of perfusion in spite of premedication with tolazoline (Priscoline. United States), the most conspicuous features observed in the majority of these patients (14/19) were circumscribed elonga tions and tortuosities of digital arteries resembling cirsoid aneurysms. An example is shown in Fig. 3 of generalized tortuosity and elongation of digital arteries in a 54year-old patient who started to complain of severe sensitivity to cold 3 years after cessation of VCM exposure (about 1 year prior to death from botli angiosarcoma of the liver and hepatocellular carcinoma). The pathogenesis of these 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 (Ami's et al. 1963. 1967), Vinyl t Stuf vations fmgerp-.i ed a var lar area those s, ferent J larosco, control ence in : PVC wof distir induce,; A Si: a PVC-p chemicr. normal: was con number entplo> related i It also s more sc: ' I. Marsteller There was 'he bone liopathic aid be obilammatory il. 1936: 7). iducing small metarved in man. iths and de- y of the 3J nhly con- (/) arterial 'iLunge were ir* or diffu oil vessels O oCJ1 oO-4) "'d pecu. irity of '"unit ' al. ' .ymp- -is (5/191 cuomenon 'urination :> bone to vary- ill collat- " in spite peuous ri'ed elonga- '.imple is "i a 54- after i-oma of vascular -.hie to de- - of digital Vinyl Chloride-Associated Disease 41 Fig. 3. Conspicuous tortuosities and elongation ot digital arteries Studies of microvascular changes by wide-field capillary microscopy (direct obser vations complemented by photography) of selected skin sites - such as nail folds, ftngerpads. dorsum of phalanges and of proximal interphalanceal joints - demonstrat ed z variety of capillary abnormalities, i.e. dilated or giant capillary loops, pale avascu lar areas, capillary and subungual haemorrhages. The abnormalities were similar to those seen in scleroderma but were usually less conspicuous, less numerous and of dif ferent. distribution. In a survey of a group of 152 American PVC workers, these captllaroscopic findings proved to be significantly more prevalent than in 50 nonexposed control subjects (Maricq et al. 1976). There was also a statistically significant differ ence in the prevalence of these abnormalities between symptomatic and asymptomatic PVC workers. The alterations were not only found in workers with clinical symptoms of disturbed acrai circulation but also in 6 nonsymptomatic males with either VCMinduced angiosarcoma of the liver (2) or spienomegalic portal hepatic fibrosis (4). A similar survey was later undertaken in an unselected sample of 129 employees of a PVC-prcducmg chemical plant in England with 26employees of a non-PVC-producing chemical plan: serving as controls (Maricq et al. 1978). The prevalence of capdlary ab normalities found in these British workers, which were of tltc same type and degree, was 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 fl5 years vs 3.5 years). In the authors' opinion, this suggested that VCMrelated disease may develop independendy of differences in manufacturing procedures. It also suggested that this easily detectable type of microvascuiar lesion may precede more so no us VCM-induccd disorders. In a small subgroup of 15 clinically affected 42 W.K. Lelbach and 1I.J. Marsteller British workers who were examined 6--24 months after leaving the plant (termination of exposure), the prevalence of capillary abnormalities was not less than that among those who continued work. For an evaluation of the reversibility of this condition, however, the group was considered to be too small. The same type of capillaroscopic changes was also observed in three of4 Polish workers (2 reactor cleaners. 2 fitters) who were found to suffer from Raynaud's phenomenon after exposure for 2-5 years (Byczkowska and Langauer-Lewowicka 1974). Infrared tltennography, another non-invasive method, used by Rc;y et al. (1974) for the study of acral circulation, revealed abnormalities of surface temperature rang ing from marked hypothermia of terminal phalanges (which are normally warmer than the rest of the fingers) to "complete terminal amputation" in four PVC workers suf fering from QAOL. 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-affected left index and middle finger of their atypical case. Local ized acral hyperthermia seen on IR thermography corresponded to the angiographic finding of circumscribed abnormal collections of small vessels (compensatory collat erals?) in the pulps of the affected fingers. Using IR thermography in a survey involv ing 143 PVC production workers and 56 controls, Williams et al. (1977) assessed the time needed for heat return after immersion of one hand for 10 s in a water bath kept at 19C: however, no difference between VCM-exposed subjects and controls and be tween groups within the exposed population was noted, 4.1.6 Immunological Studies Early experience with the syndrome of occupational acroosteolysis suggested certain similarities between this disorder and corresponding lesions seen in progressive systemic sclerosis (diffuse scleroderma). Differential diagnosis of these two unrelated conditions is now well established (Table 10), Such similarities stimulated the search for other manifestations of a systemic collagen disease, notably immunological features, as pro posed by Marin et al. in 1967. Ward et al. (1976a, b) carried out immunological studies in 58 workers from a British polymerization plant who were referred to them out of a total past and present work force of 320. Mean duration of exposure to VCM was 39 months f6--75 months). Of these 58 workers, 23 were symptomatic (Raynaud's phen omenon..9: scleroderma of hands or feet, 6: OAOL, 2; sensitivity to cold, excessive fatigue,limb pain,paraesthesias). Slight hyperimmunoglobulinaemia. usually IgG. the presence of mixed cyroglobulins, and in vivo conversion of both Cj and C4 were found in 19 patients in the symptomatic group, with additional evidence of reduced T-cell population and increased B-cell proliferation. Mixed cryoglobulins, in vivo con version of complement and depressed values for Cj or C4 were taken as evidence for the presence of circulating immune complexes. Autoantibody screening demonstrated low-titre antinuclear antibodies (IgG 1/20--1/50) in eight of the nine patients with Raynaud's phenomenon. Aggregates of IgG, C4, C3,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 Chin- and mediun lung (1 case The auti and bone c: bolic intern plasma pro; which stimv cuiar occlus as a result o ators of tiss to further a4 Jayson et al suffering frr than in non: ride disease In an ear in four Polls decrease in I ever, Langan after Sephai 6 together v agglutinins c ..... . " *'-en ala\ DO an*. 'au* U) it a o o tn ion n:hi' o o r a; 00 \ it". ay gc;> hypergamn. with far ads three patic; with Raynav degrees of < nins were t\j range: x s sclerodermo of which is, In sumtr autoimmune establish the in VCM-indi *I'.1rv wiVr ` >1 cV i H.J. Marstellcr .it (termination i that among ; condition, apillaroscopic rs, 2 fitters) lor 2-5 years et al, (1974) tperature rang'ly warmer than '' workers sufhy infrared ' et al. (1975) h in the distal .<1 case. Localangiographic `^tory collatsurvey involv" > assessed the ater bath kept ntrols and be- cited certain " ssjve systemic '. ed conditions li for other lures, as pro'ological sto lies 'hem out oi a VCM was 3 lynaud's plKn| M. excessive ually IgG. the Vinyl Chloride-Associated Disease 43 and medium-sized arterioles in biopsy specimens of the skin (10 cases), muscle and lung (1 case each). The authors proposed as explanation for the induction and pachogenesis of skin and bone changes in VCM-induced disease a theoretical model based on reactive meta bolic intermediates of VCM formed during biotransformation binding covalently to plasma proteins. These may act as antigens (as a result of a structurally abnormal protein) which stimulate B-cell proliferation and antibody response. Platelet aggregation, vas cular occlusion and ischaemia were thought 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 al. (1976b), who carried out collagen studies in a skin biopsy of one patient suffering from OAOL found the rate of collagen synthesis to be considerably higher than in normal controls. The pathogenesis of excess collagen formation in vinyl cldoride disease has not been fully elucidated. In an 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 IgG was noted (Byczkowska and Langatier-Lewowicka 1974). Later, however. Langaucr-Lewowicka et al. (1976) observed latent cryoglobulinaemia, detectable after Sephade.x G-200 filtration, in 18 of 22 workers with Raynaud's phenomenon (in 6 together with acroosteolysis and sclerodermalike changes). Again, there were no cold 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 the pathogenesis of vinyl cltloride disease. Lange et al. (1974a) and Velrman et al. (1975) concluded from their results that convincing evi dence of autoimmune disease was lacking. Immunological studies including determina tion of rheumatoid factor (latex agglutination test), quantitative immunoglobulin de termination (Manzini radial diffusion technique) and autoantibody screening (indirect immunofluorescence) were initially introduced in our first series of 50 patients but were later abandoned because of mostly negative results, except for occasional in creases in immunoglobulin levels (Marstellcr et al. 1575a). These studies were later taken up again with an additional 43 patients engaged in PVC production but still fail ed to suggest more than an erratic connection (unpublished data). We did not observe hypergammaglobulinaemia (see comment in Ward et ai. 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 13 PVC workers with Raynaud's phenomenon in whom arteriography of the hands disclosed various degrees of occlusion of digital arteries, autoantibodies, cryoglobulins and cold aggluti nins were found in none:a moderately increased IgG level (1.93-3.6S g/Iitre;normal range: x s = 0.3-1.8 g/litre) was seen in five patients who suffered from OAOL and sclerodermoid skin changes (unpublished data). Elastin antibody titres (the specificity of which is doubtful) were negative. In summary, currently available evidence does not seem sufficient to suggest an autoimmune disease as a pathogenetic mechanism. Further studies will be needed to establish the true significance of the possibly transient immunological abnormalities in VCM-induced disorders. * 44 W.K. Lelbaeh and II.J. M.irstel!er Vinyl Chlorids-A' 4.1.7 Pathogenetic Considerations Tne clinical sympt Raynaud's phenomenon as a premonitory clinical symptom, histomorphology in man and experimental animals and angiological experience suggest that the common de nominator in the pathophysiology of both skin and bone lesions in chronic VCM in toxication is probably to be sought in the local impairment of blood circulation in peripheral regions, as Benoit pointed out as long ago as 1967. By reason of their vas culature, the distal phalanges are the skeletal segments which may be most susceptible to impairment of blood supply, particularly to disturbances of microcirculation (Gama and Meira 1978), Yet the answer to the next question, the pathogenesis of peripheral many as 153 of th survey was describdeveloping chronic character of nonm. In 1972 Kramc had been routinely time-weighted aver environmental data wise multiple linear vascular injury in vinyl chloride disease, is unknown. It still remains largely a matter of tion and, to a lesse: conjecture how a volatile toxic compound that is taken up via inhalation, distributed level of past exposu throughout the systemic circulation and metabolized (bioactivated) in the liver, can the individuals stud bring about, apparently only in a small number of predisposed individuals, after a vari TWa levels of 300 : able period oflatency 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 w: : `J Sect. 3.4.2.2). but no conclusion can be drawn as to their relative significance. ease (Manteller et a In West German dermatologists in Bi 4.2 Non-malignant Liver Disease in Vinyl Chloride/Polyvinyl Chloride At first sight, the s> Production Workers derma. This provokv j Progressive systenu'c 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 i plant where polyvinyl chloride resins were produced and compounded. Without going phazeai varices due t I: into detail, the authors pointed out that moderate nontender hepatomegaly was found a group of 20 relativ i in a larger porportion of a group of 73 workers (48 males. 25 females) mostly engaged in PVC compounding; `anicteric hepatitis' was diagnosed in 21 of them (15 o', 6 9). Al previous liver disease Medical Department though the 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 capsular fibrosis of':- 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 U compounds derived from halogenatcd aromatic hydrocarbons (such as chlorinated naphthalenes and diphenyls) used as plasticizers responsible for the systemic toxicity. encompassed a large Hence Jiihe et al. (19 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 In retrospect, th; installation of ventilation facilities of sufficient capacity. spleen alterations in l the long latency perie- Nonicteric hepatomegaly was again recorded by Suciu et al. (1963) 14 years later disease wlu'ch is accon in almost one-third of the total work population (51 of 168 employees) of two Rum hepatic parenchymal anian PVC-producing plants, including 10 cases with additional splenomegaly. Liver Oniy 3 months Lt ii biopsy in two of these workers revealed chronic hepatitis. Studying the prevalence of temporary disablement due to liver disease among 350 employees of the Sverdlovsk was surpassed by the ; liver, an exceedingly r plastics industry, Pushin (1965) found the highest morbidity among employees of the work force of 274 emr PVC production unit, compared with other units engaged in the production of non- ican plant (Creech et i PVC plastic materials; 170 workers of ancillary industries served as control subjects. upper gastrointestinal arsfeiler 8 W O o WJ n man o, -4 de- M ini in r vas* most susceptible ifculation {Gama is of peripheral 'gely a matter of nn, distributed the liver, can ials, after a vari; damage to peri lous chapter (see Ulcance. :J in PVC pro ms in a Russian , Without going galy was found ; mostly engaged .<155,6 ^.Al ums of VCM hey explicitly i the powdery titer volatile chlorinated -temic toxicity, ikers should be v suggested tiie ) 14 yean later s) of iwc Rummegaly. Liver e prevalence of lie Sverdlovsk mployees of the iction of non itrol subjects. Vinci Chloride-Associated Disease 5 Tire clinical symptomatology of - typically nonieteric - liver disease observed in as many as IS?' of the current work force of the PVC production unit during a 3-year survey was described as having been consistent with the diagnosis of an insidiously developing chronic hepatitis. No histological data were available, however, and the true character of nonmalignant liver disease found in these workers remained obscure. In 1973 Kramer and Mutdiler examined a group of 98 healthy male workers who had been routinely exposed to VCM for periods up to 25 years and for whom career time-weighted average exposure estimates were available. In an attempt to correlate environmental data and results of a medical surveillance programme by means of step wise multiple linear regression analysis, it emerged that bromsulphthalein (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 Mutdiler 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 retention was the most consistently pathological test for VCM-induced liver dis ease (Marsteller et al. 1975a). In West Germany the first cases of occupational OAOL were observed in 1972 by dermatologists in Bonn {Julie and Lange \912:Jiihe et al. I973:Srein et al. 1973a, b). At first sight, the symptomatology appeared to resemble atypical progressive sclero derma, This provoked a thorough search for manifestations of visceral involvement. Progressive systemic sclerosis, however, could be excluded. On medical examination of a first group of 13 polycleaners who were referred to the Department of Dermatology from a nearby PVC-producing plant it emerged that 3 of them, who did not suffer from either OAOL or scleroderma, had a history of unheralded bleeding from oeso phageal varices due to portal hypertension (Jiihe et al. 1973). Further investigation of a group of 20 relatively young PVC production workers (mean age:40 years), in whom previous liver disease could be excluded, was carried out in collaboration with the Medical Department. Peritoneoscopy and guided liver biopsy were performed in each patient and revealed varying degrees of noncirrhotic portal. pcrisimtsoidaland subcapsular fibrosis of the liver, with splenomegaly, thrombocytopenia and, less frequent ly. marked portal hypertension, but strikingly little hepatic dysfunction (Marsteller et al. 1973). It was now realized that the disease spectrum in VCM-exposed individuals encompassed a larger scope ofinjuries ana, in fact, suggested a systemic toxic effect. Hence Jiihe et al. (1973) proposed the term `vinyl chloride disease'. In retrospect, this comparatively late recognition of the true nature of liver and spleen alterations in chronic VCM intoxication can be attributed, at least in part, to the long latency period as well as the insidious onset and course of this type of liver disease wtueh is accompanied, even far into the advanced stages, by only minimal hepatic parenchymal dysfunction. Only 3 months later, however, in February 1974 the significance of this discovery was surpassed by the alarming announcement that four cases of angiosarcoma of the liver, an exceedingly rare malignant tumour, had been found among a comparatively small work force c.f 274 employees of the PVC polymerization section of a large North Amer ican plant (Creech et al. 1974a). Two of these four patients had first presented with upper gastrointestinal bleeding due to portal hypertension between 1964 and 1970. r & S 005072 46 W.K. Lelbach and H,J. Marsteller There is no longer any doubt that chronic exposure to vinyl chloride monomer can produce two different types of liver disease in man as well as in experimental animals: 1) 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 described by Band in 1894. As `Band's syndrome', tin's 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 (Ramalingaswarni etal. I962;7ma/iaga et al. 1962\Basu et al. 1967a, b:Boyer et al. 1967:5<rm<7 et al. 1971). It has been seen only sporadically in the Western World (Roussclot 1940: Ravenna 1940; Tisdale et al. \959\Polish et al, 1962', 4filler and Brandt 1962;Siderys and Vellios l96A\Mikkclsen et al. 1965;/her 1970\Escartin Marin et al. 1974; Mendenhall et al. 1974; Grannis 1975; ViUencuve et al. 1976). Iber (1969) estimated that "centers throughout the world reviewing their experience with portal hyperten sion encounter 3 to 5% of patients who do not clearly fit into the category of cirrhosis or blockage of the portal vein." In the absence of an identifiable aetiology it has been speculated that in noncirrhotic portal fibrosis observed in India,unknown toxins contained in indigenous drugs, herbal medicines or adulterated food might have been responsible for the condition (Santa et al. 1971), Villeneuve et al. (1976) suggested that, apart from VCM and inorganic arsenicals, other still unidentified toxins could be the cause of this syndrome. Idio pathic portal hypertension has also been observed to occur in 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 are: a) Inorganic arsenicals {Zeegen et al. l970:A'ee/c and ,4zzopardi 1971; Knolle et al. 1974;3/om's et al. \974\Httec et al. 1975; Villencuve et al. 1976:Cou7/s/imv et al. 1979); b) Hypen-iraminosis A {Muchter et al. 1971 \Russell et al. 1973,1974\Hntban et al. l974\Kistler et al. 1977): and c) Recently, copper sulphate in Portuguese vineyard workers {Pimentel ani Menczes 1977). Arsenical preparations (usually prescribed as Fowler's solution - potassium arsenite) have in the past been used as a tome in neurasthenia, as an adjunct to iron therapy for anaemia, as antiepdeptic drugs and well into the 1950s for the treatment of psoriasis. In this context, Band's remark in his original paper (189S) that anaemia accompanying primary splenomegaly responded best to arsenical preparations is of note. In a renowned German pharmacology textbook of this period (iXot/inagcl and Rossbach 1880) Fowler's solution is also listed as a traditional antimalarial drug of ! and H.J. Marstelier iloride monomer can perimental animals: h rare disorders irtal fibrosis are not :al haemorrhage due development of ne', this symptom a matter of debate, m' the syndrome has 'i (RamalingasMtnti . 1967\Santa et al. ; msselor 1940: Brandt \962:Siderys et al. 1974; it (1969) estimated .th portal hyperten- category' of cirrhosis .-d that .igenou. condi pJU 1 and ii O) svndt o outior o ill the CJ1 o . are: CO 197 CowIt. rhotic erbal ta et >awn i of et al. 1. ''3, 1974\Hmhan et Pimentel and Menem i - potassium an adjunct to iron Os for the treatment 1398) that anaemia ' preparations is ot I'd (Nothnagc! and limalanal drug ot Vinyl Chlonde-Associated Disease 47 long standing, Chainuvati and Viramivatti (1979) recently implicated an indigenous Thai medicine contaning arsenic as a possible aetiological factor in a case of idiopathic portal hypertension. Datta et al. (1979) found significantly elevated levels of arsenic in liver tissue specimens of four of nine Indian patients with idiopatliic portal hyperten sion resulting from chronic arsenic intoxication (contaminated drinking water, use of Ayurvedic medicines). Typically, liver disease in these cases occurs in conjunction with other evidence of chronic arsenic intoxication, such as skin pigmentation, palmar and plantar hyperkeratosis, skin cancer and sometimes carcinoma of other sites. However, neither histological nor radiological or haemodynamic criteria permit a clear distinc tion between 'idiopathic' portal hypertension and noncirrhotic portal hypertension caused by chronic arsenic toxification or chronic exposure to VCM, as was demon strated by ViUeneuve et al. (1976) in a study of five patients. After prolonged treatment with excessively high doses of vitamin A (psoriasis, ichthyosis and other dermatological conditions, adjuvant cancer therapy and in health faddism) chronic intoxication has been seen to cause hepatic fibrosis and cirrhosis (Muenter et al. 197 \\Fkhchtnann et al. 1977; Kistler et al. 1977; Russell et al. 1973, 1974). Storage of vitamin A in hepatocytes and one type of fat storing, nonphagocytic perisinusoidal cells [Ito cells (Ito and Ncmoto 1952)] could be demonstrated by fluo rescence microscopy. Stimulation and proliferation of Ito cells, which are probably fibroblast precursors (Popper and Udenfricnd 1970\Schnack et al. 1967), provokes an increase in basement-membrane-like material and collagen within the perisinusoidal space and leads to perisinusoidal fibrosis with partial obliteration of Disse's spaces and the sinusoidal lumen (Hntban et al. 1974). The recognition of idiopathic portal hypertension, hepatic fibrosis, cirrhosis and angiosarcoma of the liver coexistent with excessively abundant hepatic deposition of copper (besides evidence of'vineyard sprayer's lung') in a group of 30 vineyard workers in Portugal is, to our knowledge, the first report in wliich chronic copper intoxication is implicated as the aetiological agent. For periods varying from 3 to 45 years, fhese workers had been engaged in spraying vineyards with a mixture containing copper sulphate on 15 -- 100 days per year. The authors noted a close morphological resem blance of the lesions to those resulting from exposure to inorganic arsenicals and to vinyl chloride (Pimentel and Mcnezes 1977). Although extrinsic chronic copper intoxi cation is virtually unknown in man, potential hepatotoxicity of long-continued uptake of copper was discussed by Blomtield 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 has received loss attention than the spectac ular discovery of the rare hepatic neoplasm. In continuation of our first two surveys (Marztellcr et al. 1973, 1975a, b). we have now fend of I c,80) 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 presented with symptoms of unheralded 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 scries of seven patients with noncirrhotic portal fibrosis and 48 W.K. Lelbach and H.J. Marsteller Table 11. IT PVC workers with advanced portal hypertension (marked oesophageal sarices. episodes of upper Gl bleeding, splenomegaly) Age at diagnosis Duration of exposure Peritoneoscopic and No. (years) (years/ months) histological diagnosis 1 30 n 31 3 32 4 35 5 4 35 6 39 7 39 8 41 9 a 41 104 47 11 50 12 51 13 52 14 52 15 54 16 4 58 17 a 61 5 5/9 3/6 4 9 10/6 13/6 7 18 18 616 17 15/3 11 616 21 13 Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis Noncirrhotic.fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis 3 On follow-up patients 5,9. 10, I6and 17 subsequently developed angiosarcoma of the liver and died 3-6 years after diagnosis of portal hypertension. Patients 6 and 14 are at present (1981) under observation for suspected development of angio sarcoma of the liver, 6 and 11 years after peritoneoscopic diagnosis of portal fi brosis associated portal hypertension. Smith et al. (1976a) observed later development of angiosarcoma in one of them. If a rough estimate based on these two small series were acceptable.it would appear that approximately one of five to seven individuals suffer ing from advanced VCM-induced portal hypertension might be expected to develop angiosarcoma later, although PVC-inducea hepatic fibrosis per s< is probably not a premalignant lesion. 4.2.1 Clinical Manifestations of Non-malignant Liver Disease Physical examination is usually disappointing. In the more advanced stages of VCMinduced nonmalignant liver disease, palpable splenomegaly and a slightly to moderate ly enlarged liver may be the only physical signs. On palpation, we found hepatomegaly in 31 and splenomegaly in 16 of 50 selected PVC production workers who had been heavily exposed in the past {Mantcllcr et al. 1975a). Lilis et 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 winch included virtually the entire current produc tion work force. A significantly higher prevalence of hepatomegaly was found in those Vinyl Chlorv' exposed for n splenomegah In contras ment of hepa: ectases, gynav not seen. Evephalopathy ch workers only It is puzzli preceded adv. only one case development 4,2.2 Labor? Owing to the . not the target value for the d This makes it \ 1974; Creech. thrombocytop logical bioche; the levels of s. quent (Manrc(ICC; 0.5 and liver function workers of a t (Tamburro et progressively of abnormal S there was ovei phosphatase Ialkaline phosp' megaly and/'c Except foi and Vcltman i the reticulocv parameters us' presenting fea; rli et vith 2D ;ment C/) rkers o fPV( 0 ,-phyn: 01 teller X al U) O 0 id 01 0 >sis M 01 sis sis 1 >sis i..,,.___ >sis Vitic fibrosis hotic fibrosis otic fibrosis iutie fibrosis otic cirrhosis 'otic fibrosis hotic fibrosis lotic fibrosis Hitic fibrosis hotic fibrosis hotic fibrosis :'Stic cirrhosis ioric fibrosis .;:0>arcoma of "juents 6 and of angio ! portal fi* .iiient of ;li scries w e ' iduals sutteio develop ':ih(y not a |-rc- cjsofVCMy to moderate, iiepatomegaly .ho had been .ported hepa n.'d employees on plant in rent producfound in those Vinyl Chloride-Associated Disease 49 exposed for more than 5 years, whereas the difference in the prevalence of palpable splenomegaly was not significant. In contrast to cirrhosis of the liver, clinical symptoms indicating serious impair ment of hepatic function such as jaundice, vascular spiders, palmar erythema, telangi ectases; gynaecomastia, peripheral oedema and ascites or hepatic encephalopathy are not seen. Even after massive bleeding from oesophageal varices portosystemic ence phalopathy does not develop. Ascites and hepatic coma have been observed in these workers only in terminal stages of angiosarcoma of the liver. It is puzzling that acroosteolysis and sclerodermoid skin induration have only rarely preceded advanced stages of VCM-induced liver disease. To our knowledge there is only one case of angiosarcoma of the liver on record which was associated with prior development of acroosteolysis (Roche et al. 1978). 4.2.2 Laboratory Findings Owing to the fact that hepatocytes, although being the primary site of metabolism, are not the target of toxicity, standard biochemical liver function tests are only of limited value for the detection of liver disease in populations at risk (Williams et al. 1975b). This makes it very difficult to devise adequate screening programmes (Martin et al. 1974;G-eec/i andMakk 1975; Wyatt et al. [915 \ Berk et al. 1975,1976). Apart from thrombocytopenia, we found 45-min BSP retention to be the most consistently patho logical biochemical test: usually minimal hyperbilirubinaemia and minor elevation of the levels of serum alkaline phosphatase, SGOT and SGPT were considerably less fre quent (Marsrcller et al. 1975a). Another dye-removal test, indocyanine green clearance (ICG; 0.5 and 5.0 mg/kg), also proved to be more reliable than standard biochemical liver function tests in correctly identifying early hepatic injury in 1200 vinyl chloride workers of a chemical plant in Louisville, Kentucky, during a 4-year screening period (Tambtirro et al. 1978b). The exposure rank was found to be closely correlated with progressively increasing frequency of abnormal ICG clearance, whereas the frequency of abnormal SGOT, and alkaline phosphatase only increased in late stages, often when there was overt clinical disease. In the survey conducted by Lilis et al. (1975), alkaline phospiiaiase levels were elevated in 16.6^> of the 354 workers examined. In their series, alkaline phosphatase was also closely correlated with the clinical symptom of hepato megaly and/or splenomegaly. Except for thrombocytopenia fiess than 150 x 10' platelets/litre) which Lange and Veltman (1977) found to be present in 76 of 100 workers, and a slight increase in the reticulocyte count (in 35 of 79 workers,lunge and Veltman 1977). haematological parameters usually do not contribute to the diagnosis. Thrombocytopenia was also the presenting feature in two of seven British workers with noncirrhotic portal hyperten sion (Smith et al. 1976a). Thrombocytopenia and abnormal platelet function tests will be dealt with separately in Sect. 4.4.1. Assessment of urinary excretion of porphyrins and porphyrin precursors in sympto matic1 workers who had been engaged in the production of PVC (n = 23) or the manu facture ot PVC articles (n = 17) revealed varying but mostly miid degrees of secondary coproporphyriuuria in the majority of them (Lange et al. 1976b). The significance of i ti I I 50 W.K. Lelbach and H.J. Marsteller these findings as an indication of toxic liver damage is not clear and tire relation to previous exposure to VCM remains to be determined. 4.23 Gross Inspection of the Liver and Spleen The gross appearance of the liver, as assessed by peritoneoscopy [Marsteller et al. 1975a, b`.Marsteller and Lelbach 1977; Lelbach and Marstellcr 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-like appearance. At most, there are micronodular changes but the diffuse coarse nodularity of cirrhosis is only rarely seen. Progression to frank cirrhosis with severe derangement of hepatic lobular architecture was observed by Smith and Williams (1974), and also in two of our recent cases in combination with development of angiosarcoma. On palpation (direct or by peritoneoscopic probe), tire texture of the liver is normal or only slightly firmer than usual. Indirect peritoneoscopic evidence of portal hyper tension is presented by increased vascularity of the falciform ligament and the intes tinal serosa or numerous dilated tortuous vessels in adhesions draining to the abdomi nal wall. Even in advanced stages, symptoms of pronounced portal hypertension often Fig. 4. Peritoneoscopic view of left hepatic lobe in noncirrhotic portal hypertension (January 1979). Blunted anterior edge, smooth to finely granular surface, conspicuous patchy capsular fibrosis. (42-year-old autoclave cleaner. VCM exposure 1965 -74. 19/5 thrombocytopenia as first sign. From 1974 to 1979, marked progression of portal hypertension with splenomegaly and one eptsodc of blecdme from oesophageal varices.) See also Fig. 5 (patient 6 in fable 1 !) Vinyl Chi contras: si' pectedly s is a focal ,, opacities.' stellate scr ing {Marsh tissue in G: extending nective tiss processes or more dii are seen in 4.2.4 Hist- ologicu! 33 nerally itrikinr /> )ris are O . Sa--d> 0 01 tions. o ughout ~-4 O) >sis. Su lcal t' S). Depen.-. date of bio; nant liver u ject to mark ations is sc. Thomas 19" 1976). but [Popper et a 4.2.4.1 Hi: (n its fully 5 of dense, pu^ bile ducts a. with format! central and : of connects with enlarge perisinusoid, oidal walls, n Mtiller ei al. !I J. Marsteller relation to U r et al. at exploratory organ with oneoscopy also lock et al. a with shallow J'orange-like irse nodularity derangement ' '4), and also coma. liver is normal portal hyper'd the intes' the abdomirtension often 33 (/) o ocn o ~sl -4 \ pertension conspicuous 't>3-74. evsion of i -eMiphageal Vinyl ChlondeAssoeuied Disease 5I contrast sharply not only with minimal alterations of the surface but also with unex pectedly scanty liistological evidence of hepatic fibrosis. The most conspicuous feature is a focal or diffuse capsular fibrosis of varying pattern (Fig. 4), presenting as whitish opacities. The degree of capsular involvement ranges from diffuse tiny commaiike or stellate scars to coarsely reticular and irregularly patchy milk-white capsular thicken ing (Marsteller ei al. 1975a). Histology showed that this focal increase of connective tissue in Glisson's capsule may extend into the parenchyma and connect with septa extending from enlarging fibrosed portal tracts (Popper and Thomas I ^75). The con nective tissue capsule of the enlarged spleen also seems to be sensitive to VCM-induced processes that have taken place in the underlying tissue so that focal white thickening or more diffuse opacities together with circumscribed subcapsular haemorrhagic cysts are seen in cases with marked splenomegaly. 4.2.4 Histology Histological examination of biopsy specimens shows that normal lobular architecture is generally maintained, but varying patterns of portal and, in some cases, septal fibro sis. striking intralobular perisinusoidal fibrosis, and focal capsular and subcapsular 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 are distributed quite irregularly throughout the liver and may vary from minor inconspicuous degrees to quite striking fibrosis. Surgical wedge biopsy of sufficient depth appears to be more suitable for his tological evaluation than needle biopsy specimens (Smith et al. 1976a: Blcndis et a). 1978). Depending on length and degree of exposure, interval between last exposure and date of biopsy, as well as individual factors, histopathology of VCM-induced nonmalignant liver disease is represented by the following features whose manifestation is sub ject to marked interindividual and topical variation: the same variability of tissue alter ations is seen in the nontumorous areas of the liver in angiosarcoma (Popper and Thomas 1975: Thomas et al. 1975-.Berk et al. 1976:Gedigk et al. 1975: Weinbren 1976). but in these cases the nontumorous lesions may be even more conspicuous (Popper et al. 1978). -1.2.-1.1 Hepatic Fibrosis In its fully developed form, minimal to marked enlargement of portal tracts by excess of dense, paucicellular connective tissue, which in advanced cases contains proliferated bile ducts and some periductular inflammation, may in rare instances be combined with formation of periportal septa linking portal tracts or. even more rarely, connect central and porta! canals. Other portal areas appear almost normal. Focal accumulation of connective tissue in the thickened Glisson's capsule may be connected by septa with enlarged infracapsular porta! tracts. A more striking feature is an intralobular perisinusoidal 'netlike' fibrosis with more or less prominent collagenization of sinus oidal walls, in some areas even progressing to frank capillanzation (Gedigk et al. 1975; y.iiilc' et ai. 1975). The focal intrasinusoidal fibrosis may be subtle and in some cases R&S 005079 Vinyl Chloride-Associated Disease ; * * T* ` 1 . '-'v-u.: -$3$: *< 1 /. ft a.' w "ihroMS H&E. act fo und > ? .? $f}* =T $?> oj-y;^i5rsv5. * v, V' > SsC* - ' ' ^*0 &~i Fig. 5c. Focal portal fibrosis (lejt upper corner! and reticulated perisinusoidai fibrosis with activated proliferating and pleomorphic sinusoidal lining cells. Trichrome I Goldner) stain. blue Filter, x 250. d Conspicuous focal dilatation of sinusoids. Activation and moderate polymorphism of proliferated hypcrchromatic sinusoidal lining cells. Enlarged hepatocytes with hypcrchromatic nuclei, some of them binuclear. i Potential precursor siacc of angiosarcoma?) Courtesy of Professor Muller-Wallraf. Institute of Pathology. Amberg. H &. E, x 400 WH&m 54 W.K. Lelbach and H J Marstcller Vinyl Chloride may be recognized only in connective tissue stains. Trichc et al. (1975) pointed out and Thomas et. that in one worker with severe acroosteolvsis but normal hepatic function and essen tially normal liver histology on light microscopy (except for a minimal and easily over looked increase of perisinusoidal collagen in occasional lobules), electron microscopy revealed a striking centrilobular increase in collagen between hepatocytes and in Disses spaces together with proliferation and hyperplasia of sinusoidal lining cells (see also Kurokasva et al. 1977). The same ultrastructural deposition of perisinusoidal collagen was observed by Schattenberg et al.(1977) in 15 PVC workers in whom we could ob tain liver tissue for electron microscopy at peritoneoscopy. Similar changes (enlarge ment of Kupffer cells, abundant deposits of collagen in the Disse's space and resulting reduction of sinusoidal diameter suggesting a possible factor in the pathophysiology of `sinusoidal* portal hypertension) were seen on electron microscopy-in a number of cases of idiopathic portal hypertension of unknown aetiology (occupational histories to be character!.' geneous red pul; follicles with me endothelial cells occasional fresh spici >sis It u Hew. gg md teria So 7 spier 0 Tli proc o is a tive i ^ tab not mentioned) (Sommerschild and Kluge 1971; Kluge et al. 1970; Tandon et al. 1970). and' 03 Ther p,r rrin 4.2.4.2 Sinusoidal Lining Cells mesh and c l re. of s. of the puip cords Marked focal proliferation and hyperplasia of sinusoidal lining cells with nuclear poly formation of biza morphism and hyperchromasia are the most impressive features of the mesenchymal collagen fibrils. N lesion. The hyperchromatic nuclei of these cells may show a bizarre shape or resemble the reticular conn short p.egs, and are often arranged in a chainlike fashion (Gedigk et al. 1975). These volume with parai perisinusoidal and sinusoidal cells include three types; (1) normal endothelial cells, mation of capillar (2) lipocytes (Ito cells), considered to be precursors of fibroblasts and (3) plump cells found within the | with spindle-shaped nuclei and PAS-positive cytoplasm. Formation of excess reticulin suggests fibroblastic activity of some of these cells. Focal dilatation of sinusoids, not explained by passive congestion, is another peculiar feature usually associated with thrombocytes by: hanced pooling o' help to explain tn : vl particularly pronounced alterations of these mesenchymal cells. There is reason to be stages of vinyl chi- lieve that this combination of changes may represent a premalignant stage. and Heusermann t 4.2.4.3 Hepatocytes VCM-inducedspI; of the liver or ex;- \.f< Unimpressive, nonspecific, degenerative and adaptive lesions (such as minor degrees of in the spleen in vn fatty degeneration, cloudy swelling, ballooning or vacuolar degeneration, increase of dicate a primary . lipofuscin pigment and proliferation of smooth endoplasmatic reticulum of hepato port correlating cn cytes in focal areas without inflammatory reactions), can be seen to disappear gradual tients is being prep ly with increasing intervals between the last exposure and the date of biopsy, in con die spleen in none trast to the apparently irreversible damage to mesenchymal structures (Gedigk et al. able for comparisc 1975, 1977-.Miillcr et al. 1975). In poorly demarcated areas there is hyperplasia and .j3? hypertrophy of hepatocytes with polyploidy and increased number of binudeated 4.2.5 Pathophysi- cells. Two types of focal hepatocytic proliferation associated with varying degrees of sinusoidal cell alterations were recently described and are thought to play some as yet undefined role in the precursor stage of angiosarcoma (Popper et al. 19'S). Tne pathophysiolu unresolved proble: 4.2.4.4 Histology of the Spleen to splenoportograp' of intrahepatic vas Unless splenectomy is earned out in vinyl cliloride disease, tissue specimens of the spleen are less easily obtainable than liver biopsy material. Popper and Thomas (1975) venous radicles (Bi< and a normal, or oi :rstel!er 3d out CO ssen- o o y over Ul copy o 00 Disse^ dso lagen lob- lfcllldrg~ e and resulting ^physiology ii a number of onal histories Ion et al. 'i nuclear poly* mesenchymal pc or resemble i ^75). These kelial cells, 13) plump cells xcess reticulin -musoids, not -dated with - reason to be- nor degrees of ii. increase of .1 of hepatoippear graduai">psy, in con icdigk et al. nerplasia and '(nucleated ug degrees of iy some as yet b ..'ns of the Y'lutnas (1975) Vinyl Chloride-Associated Disease 55 and Thomas et al. (1975) found the cut surface of surgically removed enlarged spleens to be characterized by conspicuously hyperplastic Malpighian follicles in a beefy homo geneous red pulp. Histologically, they noted large germinal centres of the Malpighian follicles with merging of perifollicular zones, dilatation of red pulp sinuses lined by endothelial cells of variable, often cuboidal shape, thickening of the pulp cords with occasional fresh haemorrhages, and in one case Gandy-Gamna bodies, but only incon spicuous fibrosis of the red pulp. In ten cases we obtained needle biopsy specimens of spleen tissue at peritoneoscopy. Heusennann and Stutte (1977b) and Stutte and Heusermann (197S) studied this ma terial. together with spleen tissue specimens available from three spleens obtained at splenectomy. They found evidence for an involvement of the spleen in the fibrosis process. Excess amounts of newly formed extracellular elements of reticular connec tive tissue, notably collagen, produced by stimulation of fibroblastic cells of the red and white pulp, particularly in perifollicular and subcapsular areas, were observed. There was scarring of periarterial 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 fibrils. Narrowing of the labyrinthine cordal tissue with marked increase of the reticular connective tissue caused a reduction of microcirculatory sequestration volume with parallel decrease of the number of pulp cord macrophages and approxi mation of capillaries and sinuses. Frequently, focal accumulation of platelets was found within the narrowed pulp cordbed in addition to increased phagocytosis of thrombocytes by residual macrophages. This lends support to the hypothesis of en hanced pooling of platelets in the spleen (Heusermann and Stutte 1977a), and may help to explain the pathogenesis of thrombocytopenia often seen even in the early stages of vinyl chloride disease. By structural analysis of histometrical results, Stutte 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 or extrahepatic portal vein occlusion. They concluded that fibrotic changes in the spleen in vinyl chloride disease are not the result of portal hypertension but in dicate a 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 noncirrhotic portal hypertension of unknown aetiology are now avail able for comparison (Seki 1965: Yamamoto 1978, 1979). 4.2.5 Pathophysiology of Portal Hypertension The pathophysiology of portal hypertension in VCM-induced liver disease is as yet an unresolved problem. Patency of the portal vein was demonstrated in all cases subjected to splenoportography. Portography usually showed no or only minimal derangement of intrahepatic vascular pattern such as tapering or `cut-off of small peripheral portal venous radicles (Blendis et al. 1978: 1 illeneuvs et al. 1976). High intrasplenic pressure and a normal, or only slightly raised, wedged hepatic vein pressure indicate that the i 4.' $ 5 6 9c : % y`. W.K. Lelbach jikI H.J. Marstelicr portal flow is obstructed at tlie sinusoidal or presinusoidal level. In a group of five PVC workers selected for haemodynamic studies, Blendis et at. (1978) could not demon strate a direct relationship between the degree of hepatic fibrosis in needle biopsy spec imens and portal hypertension. But it should be kept in mind that the distribution of fibrosis in these workers is quite irregular. It has also been suggested by Popper and Thomas (1975) and Thomas et al. (1975) that the increased splenic and hepatic blood flow, as a result of decreased splenic resistance in splenomegaly cannot properly be ac comodated in the hepatic portal vein bed owing to impairment of adaptive distension of portal veins and sinusoids by the subcapsular, portal and perisinusoidal fibrosis. Blendis et al. (1978) found no correlation between spleen or estimated liver blood Vinyl flow: veiled 4.2.6 Fig. 6a. b. Progression of noncirrhotic portal hypertension despite termination of ex posure. Oesophageal varices. (Autoclave cleaner, age at diagnosis: 35 years. VCM-exposure. 1962-1972. 1972 Raynaud's phenomenon, sklerodermoid skin indurations, thrombocytopenia, splenomegaly, and grade I oesophageal varices. Gradual progression of portal hypertension. Sudden death from ruptured anaplastic angiosarcoma of the liver in June 1978. Histologically only mild perisinusoidal fibrosis in nontumorous areas) Primary (angiob haemau. cell sarc sarcoma vascular one at c hood (k the num I*. -T^ ** . Lelbach and H.J. Marsreller i level. In a group of five PVC (1978) could nor demoniibrosis in needle biopsy specand that the distribution of suggested by Popper and d splenic and hepatic blood .'galy cannot properly be acrnent of adaptive distension d perisinusoidal fibrosis. ! or estimated liver blood v- i > despite termination of exlenosis: 35 years. VCM-e.x"dormoid skin indurations, ' sances. Gradual progression lustie angiosarcoma of the librosis in nontumorous Vinyl Chloride-Associated Disease 57 flow and the portal pressure. However, they point out that this relationship may be veiled by the amount of blood bypassing the liver via a collateral circulation. 4.3,6 Follow-up of Non-mahguant VCM-induced Liver Disease In 1974 Martin et al. (see also Berk et al. 1975) pointed out that VCM-associated hepa'tic fibrosis, once established, may progress even after cessation of exposure. They could demonstrate this progression despite normalization of all routine liver function tests in a 27-year-old worker on a follow-up examination including peritoneoscopy and biopsy 2 1/2 years after cessation of exposure. Progression of fibrosis and appearance of bridging between portal and central veins were indicative of persisting activity of the fibroblastic process, whereas the previously observed activation of both hepatocytes (marked variation of cell size and numerous binucleated cells) and sinusoidal lin ing cells had disappeared. Since 1973 we have observed a number of workers who on follow-up showed evidence of progressing portal hypertension with development of massive oesophageal varices and subsequent bleeding episodes despite removal from exposure (Fig. 6). In five (7?) of these patients widi progressing portal hypertension angio sarcoma of the liver finally developed. In this context.it is of interest to note that more or less conspicuous hepatic fibrosis (or rare progression to cirrhosis) was the parental terrain in wluch the majority of cases of VCM-induced angiosarcoma of the liver devel oped (see Tables 13-18). Liver and spleen scans with 99m technetium-labelled sulphur colloid, quantitated determination of spleen size with the aid of 197Hg-bromomercury-hydroxvpropane (BMHP) labelled artificially damaged red cells, and sequential perfusion scintigrams after bolus injection of "mTc-pertechnetate have been found useful in the diagnosis and follow-up of nonmalignant liver disease in PVC-polymerization 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 (Biersack et al. 1975a. b, 1977a, b).. 4.3 Angiosarcoma of the Liver 4.3.1 Epidemiology' Frimary angiosarcoma of the liver (ASL) is described under a variety of synonyms (angioblastic sarcoma,angioblastic reticulosarcoma. endothelioma, endothelioblastoma. haemangioblastoma, haemangioeudotheiioma. haemangioendothelial sarcoma, Kupffer cell sarcoma, malignant haemangioma, metastasizing haemangioma, reticuloendothelial sarcoma, primary sarcoma of the liver). It is an exceedingly rare maiignancy, arising from vascular lining ceils. It occurs spontaneously .wkh two peaks in the age distribution: one at early infancy (infantiie haemangioendothelioma) 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 58 VV.K. Lelbach and H.J. Marsteller of the literature. Alrenga (1975) listed 165 published cases of primary angiosarcoma of the liver in adults. In the six autopsy series collected by Alrenga. ASL constituted only 1.8% (0.9fo--2.7%) 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 ranged from 2 to 20/100 000 autopsies during different periods with a mean incidence of 12/100 000 autopsies (Table 12). According to Heath et al. (1975) it was estimated that in the United States the expected annual incidence of ASL is 0.014 in 100 000 inhabitants or 25--30 cases per year for the entire United States. Table 12. Incidence of angiosarcoma of the liver (ASL) in autopsy scries Authors Observation No. of No. of cases Year period autopsies of ASL Region Simpson et al. 1955 1914 --1~9S3 24 196 1 Mayo Clinic. Rochester, Minn., USA Edmondson 1958 1918-1954 52 000 MacSween et al. 1973 1900-1969 _ a 1 3 Los Angeles, County Hosp.. USA Western Infirmary Glasgow. U.K. Alrenga 1975 1951-1973 39 700- 6 Cook County Hosp. Chicago. USA Rein and Huch 1975 1954-1974 30 079 By ran and Holmberg 1975 1958-1969 _ b 4 (6) c Diisseldorf, Fed,Rep, Germany 12 Sweden (adult eases) Dalderup et al. 1976 1960-1975 At least 40 000 S Netherlands (population: 10- 14 million) a Among 120 cases of pnmary malignant liver tumours studied post mortem during this 70-year period, b Among 8 million inhabitants. c 4 Angiosarcomas. 1 haemangioendothelioma. 1 malignant haemangiopericytomj Accordingly, the identification of 4 cases of ASL among approximately 270 em ployees of the vinyl chlonde polymerization section at a B.F. 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,i.e. the administration of a radioactive colloidal prepara- Vinyl C tion of inorgai- dioxid-: tern an Tho contras ing evic reporte been th had bee and Mo A sped: caused < `thorc n from a i ASL(f? Dew man vin tensiveh 1950-1 tion revt of multi approve occurred but no' produce Haustru (3%-5-. Roth (1< 18.6--SS Fowler's CW 33 taemanc ension v CO oman * o ie) dun o cn d a hue 00o '.nifest: The p: ilicitei od 18 __ ory o: Among m observed other han 391 auto; ! J. Marsteller xiosarcoma constituted i'ch of themthe incidence v ith a mean (1975) it was is 0.014 in ' "linic. -er. Minn.. ceies. . Hosp., USA n. Infirmarv v U.K. minty Hosp. . (. SA rf. Fed.Rey linn. itillinn) ifem during ricytoma Iv 270 emiant near duly recog- > ch 33 O) i- o o o0n 03 01 Vinyl Chloride-Associated Disease 59 tion of thorium dioxide (tltorotrast) for diagnostic purposes, and chronic exposure to inorganic arsenicals. Both substances are stored mainly in the liver: injected thorium dioxide particles are rapidly taken up by phagocytic cells of the reticuloendothelial sys tem and are permanently retained: arsenicals are only slowly released from the liver. Tltorotrast came into use in 192S and was internationally employed as an injectable contrast medium until the mid-1950s, when its use was abandoned because of mount ing evidence of the carcinogenic action of thorium dioxide deposits..dacMahon et al. reported the first case of thorium dioxide-induced ASL in 1947. Since then ASL has been the type of liver tumour which occurred most frequently among patients who had been given tltorotrast injections in the past (daSilva Harm \961\da Sih-a Horta andMotta 1967; Wegener et al. 1971;fi<r/i and Pitzke 1974-Salinger and Koff 1975). A special type of progressive portal and subcapsular hepatic fibrosis was another lesion caused by thorium dioxide retained in the liver, da Silva Horta (1967) considered this `tltorotrast 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 (flow 1932). Development of ASL as a late complication of chrome arsenic intoxication in Ger man vineyard workers was first described by Liebegott (1949,1952) and has been ex tensively documented by Roth (1956,1957a, b, 1939). During the 10-year period, 1950-1959, autopsies of 82 Moselle vintners suffering from chronic arsenic intoxica tion revealed ASL in 8 cases among a total of 61 individuals (74C), with cancer often of multiple sites (Roth 1959). In 1925. arsenic insecticide sprays and dusts had been approved for use in German vineyards but they were banned by law in 1942. Exposure occurred not only via inhalation during spray periods (approximately 30 davs/year) but notably by daily consumption of quantities of cheap grape wine (`Haustrunk'), produced from a second pressing of the grape skin residue by addition of water. This Haustrunk. an allowance in kind to the vineyard workers, had a low alcohol content (3"-55e v/v) but contained high levels of residual arsenic (0.2-8.9 mg As;Oj/jitre), Roth (1956) calculated the mean total ingestion of .As:03 to have been 53.7 g (range: 18.6-33.8 g) for a 12-year period. ASL was also seen after long-term treatment with Fowler's solution for psoriasis (Regclson et al. 1968:Lander et al. 1975). Chu\vdur\: et al. (1977) reported an anecdotal case of apparently benign diffuse haemangioendothcliomatosis 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 years 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, von Becker and BUsschcr (1961) listed 12 of 54 adult cases with a liistory of exposure to either thorium dioxide (7) or arsenicals (5 of Roth's cases). .Among more than 15 000 autopsies performed in Bonn during 1950-1959, all 8 eases observed were found exclusively in vintners exposed to arsenicals I Roth 1959). On the other hand. Ficchtner and Ryes (1976) recently observed a cluster of 4 cases among 391 autopsies during a 29-month period at a hospital in rural central Wisconsin serving y-.TM-* frQ WX, Lelbudi and HJ. Marstdler Table 1 3. Personal data of 68 polyvinyl chloride production workers with angiosarcoma ot the liver reported to NIOSH up to August I97S (Spinas and Kaminski 19781 Birth date No. Country1 (m/d/y)'3 Date of death (m/d/y) Age a t death Total years e.sp. Job classification1" . i B (1) 01.12.13 a CND(1) 12.15.13 3 CND (2) 03.06.14 4 CND (3) 08.26.19 5 CND (4) 04.05.19- 6 CND 15) 05.07.11 7 CND (6) 12.15.19 8 CND (7) 1 1.09,19 9 CND 18) 05.13.20 10 CND (9) 07.19.21 1 1 CND (10) 05.16.15 06.29.76 09.02.55 12.21.57 03.22.62 01.21.68 07.05.68 04.10.71 12.24.72 06.12.73 09.04.74 04.00.77 63 41 43 42 48 56 51 52 53 53 61 17 11 14 20 5 23 25 5' 26 14 1. 2 1.2 2,3. 12. 13 2.5 1.2, 5. 14 1. 14 l. 12. 13. 15 1.9. 17 1. 12. 17 3. 12. 16 2. 16 12 CSR (1) 13 CSR (2) 00.00.28 00.00.26 14 DU) 15 D(2) 16 D (4) 17 0(5) 18 D (7) 19 D (8) 20 D (9) 21 DUO) -I"! D (1 1) 23 D (I 2) 24 F (1) 25 F (2) 26 F (3) 27 F (4) 23 F (5) 29 F (6) 30 F(7) 31 F(S) 3 2 F(9) 33 F (10) 34 CBM) 35 GB(3) 06.04.30 07.26.31 09.04.30 01.01.32 09.29.26 10.19.17 12.13.34 07.23.29 12.29.36 06.14.38 04.15.24 06.03.1 l 01.06.20 01.27.27 01.29.38 04.14.34 00.00.27 04.01.34 10.08.14 05.24.19 04.20.01 06.02.37 12.00.73 00.00.66 (647) 45 40 (37?) 01.25.69 12.14.71 1 1.25.74 01.09.75 1 1.13.75 12.25.75 03.24.78 06.28.77 03.07.77 10.07.77 38 39 44 43 49 58 42 47 41 39 02.19.67 01.24.75 06.26.75 01.03.76 05.13.76 09.12.76 07.02.76 01.30.77 1 2.25.77 01.20.73 43 63 55 49 38 42 49 42 62 58 12.03.72 12.24.74 71 37 16 15 (14?) 12 11 17 12 12 21 15 22 16 6 l 1 n 2,4,5 -11 1,(1) 10 10 10 1 19 1.2 12 -% 29 2 26 2.6 1 i 1.2 13 6. 7 19 ? 28 T 21 T *1 S 4I (3 1/27) 36 K2) 37 1 (3) 38 HI) 39 J (2) 40 Nil) I 1.13.29 03.14.20 08.01.22 03.02.29 12.23.15 1 2.27 72 07.10.75 ro.24,75 08.10.76 01.04.72 43 55 52 37 56 6 21 T1 13 21 3D CO Vin> o 0 01 o Table 03 at 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 1 B. CND CSK D. F. GB b 00.. C I. ji 2. ai. 3. pi 4. p. 5. fc` 6. `h7.T 8. pr 9. ch, (Tables ` referem R&S 005087 Marsreller .ousarcorua '8) >n 3 15 (7 16 Vinyl Chloride-Associated Disease M Table 13 (continued) Birth date No. Country'1 I m/d/y 41 5(1) 42 5(3) 43 5(4) 06.23.27 06.10.10 11.16.14 Date of death (m/d/y) 10.20.70 03.19.76 05.12.77 44 USA (1) 10.17.23 03.03.73 45 USA 12) 08.19.33 09.27.71 46 USA (3) 05.25.15 12.19.73 47 USA (4) 01.15.24 01.07.68 48 USA (5) 01.25.12 04.09.64 49 USA (6) 11.23.23 07.24.7 5 50 USA (7) 05.03.22 03.23.68 51 USA (8) 05.06.20 08.23.61 52 USA (9) 11.08.31 03.00.75 53 USA (10) 08.16.13 05.10.68 54 USA (11) 05.27.09 03.16.70 55 USA (1 2) 1 1.17.18 05.02.69 56 USA (13) 12.01.21 07.04.74 D / USA (16) 1 1.04.27 03.27.69 58 USA ( 1 7) 05.06.3 1 19"8 alive 59 USA (18) 04.22.28 1 1.02.75 60 USA (19) 00.00.15 04.06.76 61 USA (20) 08.31.17 01.30.77 62 USA (21) 09.02.09 01.02.77 63 USA (22) 10.02.23 12.04.76 64 USA (23) 00.00.23 04.06.73 65 USA (24) 05.07.17 . 05.27.77 66 USA (25) 08.07.10 03.10.77 67 USA (26) 7(1978) ?(1978) 68 YU (I) 04.05.14 08.04.73 Age at JcuLh 43 65 62 49 37 58 43 52 46 45 41 43 55 61 50 52 41 43 46 60 58 67 52 50 60 67 ?(I97S) 59 Total years e.\p. 13 21 31 Job classification1' 2 21 13 28 15 20 12 17 15 24 17 23 19 23 4 19 11 1 21 21 28 14 26 20 ? (1 978) 9 9 10 10 10 10 9(1) 20 1. 2. 5 a B. Belgium CN'D, Canada C5R, Czechoslovakia D, West Germany F. France GB, Great Britain l. Italv J. Jaoan N. Norwav S, Sweden USA, United States of America YU. Yugoslavia. 00. data not available. c 1, autoclave cleaner 2. autoclave operator. 3. pipe fitter 4. polymerizer 5. foreman 6. Tdtreur' 7, "preparateur de solution' 8. process worker 9, chemical operator 10. polymerization worker 1 1. technical assistent 12. maintenance worker 13. millwright 14, water cooling unit la.reager 16. furnace operator 1 7, machine siiop worker (Tables 13-15 arc compiled with the aid of information contained in the literature; references see Table 15) ,454 ft '=ag t-iiSfeV 62 W.K. Lelbach 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 nondocumented exposure to arsenical pesticides, which were used for many years in this region, but such conjectural deliberations must await further investigation for confirmation. Death certificates for the periods 1963-1973 in England and Wales and 1965-1973 in Scotland recorded 41 cases of ASL (1-9 cases per year; mean: 4 cases per year). An unexplained peak was observed in 1968/1969 (Baxter and Fox 1975). Six additional cases not mentioned on the death certificates were detected by a panel of specialists (Baxter et al. 1977). In reassessing 36 of these 47 patients for whom histological sec tions were available, the panel of histopathologists unanimously agreed on the diagno sis in only 14 cases (7 doubtful, 3 unclassifiable, 12 non-ASL). For 12 of these 14 cases occupational and residential histories were obtained which revealed one un doubtedly VCM-induced case, two cases with possible exposure to (low levels of?) VCM and one case attributable to thorium dioxide. After the first three cases of ASL among vinyl 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 \97S\Spirtas and Kaminski 1977). As of August 1978, data had been presented on a total of 68 cases of ASL among polymerization workers (iSpirtas and Kaminski 1978, pers. comm.); another eight cases had been observed among nonpolymerization workers exposed to VCM in various jobs. On the basis of this data collection communicated to us in 1978 - for which we wish to thank Drs. R. Kaminski and R. Spirtas. NIOSH, Cincinnati, USA - we attempted to trace these cases and their individual symptomatology as well as other relevant information pub lished in the literature up to 1979 (see Tables 13-18). The ten Canadian cases of VCM-induced ASL (cases 2--11) are dealt with summarily in the papers published by Delorme (1978a) and Deiorme and Makk (1975): seven of them were described in more detail by Makk et al. (1976). Cases 19 and 23 were observed at our clinic in Bonn but details have only been published for case 19 (E.U. in Lelbaeh and Marstcllcr 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 Staatlichcr Cewerbearzt, Diisseldorf (Reinl et al. 1978), the number of deaths from VCM-induced ASL in the Federal Republic of Germany had increased to 16 by the end of 1978, to which we now add a 17th case (Figs. 8 and 9). In retrospect, it was discovered that the first case of VCM-induced ASL had already occurred in 1955 in a Canadian polymerization worker. For the 67 VCM polymeriza tion workers for whom details were available, total years of exposure ranged from 4 to 31 years (mean and median 18 and 19 yean, respectively). In comparison, mean dura tion of exposure in our group of 17 individuals with advanced nonmalignant liver dis ease (see Table 11) was 10 3/4 years (range: 3 1/2-21 years). The latency period (years from first exposure to diagnosis of ASL) ranged from 9 to 38 years (mean and median: 21 years). The average age 3t diagnosis of ASL was 50 years (range: 37-71 years). Vinyl oS-v O s OC 30 *33 (/> o o >o cn o 00 oo *,> c. and H.J. M arsteller X aX g ? f*. ^ -3oo-uon. 5 ~ 5_g V---'I il U3(3j OD. 2< a. ^^Qcr. CL *f p < c_ 9- >C/> *i3 r . et a. E. 'C<L 0x0| 0 < En3?" Srt> nrt CL 0>0 n 50* cft. $ ft O' fCtJ N _ C- *V/> U S3 ' <k 3. "i CL 0x| C> C O 5` 0* C0O 3 CL Vfr>t* tA Tc3 cr ft 21 * CL 7C 5" CL cc/*ri EL *_ L* A ' 3 OP 3 P nL4 o' 3 3C cr ' rc,. O *UO1 ft fmftt 3P37T* a os P" o " JT a* 2 o'>"*"> D. 5 2, a. e o <3 3K ?Sftr >-0-00j 3. 3trt s 5tr* 33ri ^ ft 3Q. ^O 3o nO 2g S "a 5Crt` R o' - 3 r 5O. * o: S(* M 3 --- ii -- n* -- 3 !-^i r, Sf<s<t ' oeft.. o it;-* t *' 680S00 c ft 4L P *o S'Sti 3 2- rt X30 3p V in y l Chloride-Associated Disease Table 14. OJinic.il and til 1 >x[>Iitlojitcal data on (18 polyvinyl chloride U`VC) production workers with angiosarcoma ol the liver reported to NIOSII hy August l`J78 1 lepato- No. megaly Spleen 1+ Atrophic, (29UO $} slightly inchi rated 2> \ Oesophageal Hepatic varices (ihrosis Tlirombocylopenia (+j Noncirrliolic ? pcrisinnsoidal A capsular (.'apsular ^ Acroosleolysis Cf Raynaud's phenomenon Metaslases ft 0 3 4 5 C, 7 cases: v (+) - * 7 ? (1 8<jO 5 3 Of) g) 1 No details ' availahle H > Capsular, portal, pcrisinnsoidal Sclerosis of wall of portal vein Capsular, portal, perisimistmlal > Capsular, portal, pertsmusoidal \ / (.'apsular, portal, perisiiiusnidnl I'ortal, pcrisinnsoidal No details available i case: multiple metaslases flung, pleura, pericardium, ileum, colon, kidneys, left adrenal) \ / case: mediastinal lymph node l iw: perilone.il spread 3 cases: local spic.ul 1(1 11 __/ > Capsular, porlal, pcrisinnsoidal (`apsular, porlal, pcrisinusoidul / j .*e*i tpIfAJiMlT HWWiMWWifta utMirfii *5&&& W.K. Lelbach and H.J. Marsteller pSgSfl J*S0sc4tiriKT*vu7T.iJtT-.^*V'*; PErr' j n ,Vl taSSS* ' **'."t>** V ;^ava- 060S00 S'Sy Table 14 (conjoined) No 12 13 14 IS 1 lepalotnegaly Spleen + &)(7300 Moderately enlarged + H7sn g) 7 + Spleno megaly + Slightly enlarged Ocsoptuigcu! v;j nccs 1 lepatic fibrosis (+i (Cj rrliosis), lilmisis + (Cirrhosis) j 7 77 Thrornhoey topenia 7 7 7 7 l(i + Spleno (2650 tO megaly (8.10 g) + Capsular. portal, septal + (72 000, 65 000) 17 + 18 7 Spleno megaly 1`erisplenitis + t ')1 (+) Spleno (HSOg) megaly ( I DO g} 20 7 7 21 + Spleno (MJOOg) megaly (*) 7 + -t- 7 7+ 0 34 000, 68 000) I'rogressive + perisinusoidal. (80 000, portal and 47 000, septal cirrhosis 30 000) 77 +7 Aeroosteolysis 0 0 P 0 0 0 0 P 7 0 Raynaud's phenomenon Me las tases +0 0 l.el't lung 0 4th left rib 00 0 1st thoracic vertebra 0 Drain + 3rd lumbar vertebra 00 77 00 22 t Spleno megaly 7 21 + Spleno 0 (2700 g) megaly (455 g) I Capsular, portal, perisinusoidal bocal pertsinusoidal 7 000 0 0P Vinyl Chlon y t + (1900 K) Splcnomeguly 7 + Splenomegaly 7 + (270Ug) + Spleno- 0 megaly (-J 55 g) f 7 + (16 t 0 g) Spleno- megaly <4 50 g) + ? + (2 230S) Spleno- megaly (4011 i-) pr 7 + Spleno- i megaly ((.50 g) + (1750 ii) 'Mndilicatiom Iil.rofinigir'.ttvi: ` -L ft P + (3000 s) + Splenomegaly 7 CHOg) V P P PCapsular, + portal, peiisimisoid .il 9 9I;olm! peri- 7 it sinusoidal 0 1`orlal, + perisinusoid al (60 000, fibrosis 80 0001 P 4 > if Local spread lo caval v ff p? ? ff llitodenal wall P PKeliculaled 7 if capsular fibrosis, mjcroriodutar cirrhosis 1`orlal, peri- r sinusoidal, (80 000) capsular fibrosis t 4tli and 7th thoracic verlchra. 5th lull rib, Iclt adrenal Slight jioi lal )f fibrosis ) if pMinimal ff 9 Small mleslitie fibrosis P? ? if I'aiaaortal lymph node f* (HO 000, 40 000) Capsular, portal fibrosis P P 9 ff 9P Table 14 (continued) Hepato No. megaly Spleen Oesophageal Hepatic varices fibrosis Thrombo cytopenia 34 + Slight 0 (2625 g) splenomegaly fi + (80 000) 35 + Congested. ^ (3240 g) firm (200 g> Noncirrbotie ? fibrosis 36 + > + 7 7 37 38 39 40 41 + 42 7 43 44 * Splenomegaly ? V? Splenomegaly + 45 Spleno- + megaly 46 + Spleno- (1 860 g) megaly ? 7 > 77 Stihcapsular and portal fibrosis t Markedly t thickened capsule; marked fibrosis 1`ortal fibrosis Acroosteolysis tf fi P 7 7 P * * Raynaud's phenomenon Mcta^tascs * ff t Local spread lo abdominal wall and colon; lymph nodes 77 77 iP *P i Spread to duodenum W.K. Lelbach and H.J. Marsteller 260900 ssy 47 + S|ilcnomegaly 7 I'orlal fibrosis + (35 000) * i Spread lo diaphragm and abdominal wall i H.J. Marsteller V inyl Chloride-Associated Disease 68 W.K. Lelbach and H.J. Mar'teller Table 1 5. Publications on the 68 cases of angiosarcoma of the liver listed in Tables 13 and I 4 No. References Additional relevant information 1 Hublet et al. (1977) , Nk Hypertrophic, hyperchromatic and jt> picul endothe lial cells in the glomeruli: foci oi haematopoetie cells in liver and spleen 4' 5 6i 7f 8 9 10 11 t Delorme and Makk (1975) Makk et al. (1976) Delorme (1978a, b) Delorme and Theriault (1978) > = Schmidt and Batora ' (1976) 13 14 i Lange et al. (1974b) 1 15 | Gedigk et al. (1975) 16 Gokel et al. ( 1976) 17 A maim (1975) Riibsamen (1976) 18 Reint et al. (1 976) 19 (Observed in Bonn) 20 Reinl et al. (1 976) 21 Reinl et al. (1977) 22 Reinl et al..(1977) 23 (Observed in Bonn) 24 Ravier et al. (1975) 25 Roche et al. (1978) 26 Rety et al. (1 976) Case no. 7: ASL associated with hepatocellular carcinoma (Delorme 1978b) (All cases from one plant in Shawmigun, district Trois Rivieres. Quebec) At the same plant: 4 cases of VCM-induccd cirrhosis of the liver plus 1 case of cirrhosis and generalized reticulosarcoma and 4 cases of carcinoma of the GI tract or lungs See also Reini and Weber (1974) See also Reinl and Weber (1974) Foci of haentatopoesis within the tumour areas 1974 portocaval anastomosis: cholecystectomy. Hypertrophic, hyperchromatic and markedly atypical endothelial cells in the glomeruli and in the capillaries of the lungs Moderate hepatic siderosis; chronic fibrosing pancrea titis: tubular and interstitial fibrosis of the testes Focal interstitial fibrosis of the pancreas See also Berrod e t al. ( 1978) 1942 gastrectomy. 1974 splenectomy, right hepatic lobectomy (640 g). See also Roche (1 9li).Puech et al. (1977); Bonne ton e t al, (1 975. 1977); Berrod et al. t 1 978) No autopsy (see also Berrod et al. 1 978) Vinyl ChiTable I 5 (i No. Rei 27 28 Ro. 29 Roi 30 ) 31 { ' Ber 33 / 34 Le 35 Sn. 36 Me37 38 39 40 41 By 42 By-'43 44 Bl. (ca- 45 Bio (ca- 46 BL (ca* Is i>viK.vr..' r. IT/. ..tc||sr :s 13 -- lothecells l rllOsiS /t:d e GI '} pical I'lllaries i/ti sea- pa tic ch et id et Vinyl Chloride-Associated Disease 69 Table 1 5 I continued) No. References 27 Roche et al. 1 1 978) 28 Roche et al. (1978) 29 Roche et al. (1 978) 30 31 i) 33 ) Berrod et al. (1978) Additional relevant information Chronic alcoholic. See also Roche i 1 477); Puech et al. (1977); Berrod et al. (197S) First symptom, vertebral and costal inetastases. Right hepatic lobectomy. See also/?oc/ie( 1977); Puech et al. (1977); Pilichow'ski et al. (1979): Ccniderc et al. (1 916)'. Berrod et al. (1978) 1960 sclerodermaiike skin induration I hands), swell ing of face, upper extremities and feet. 1971 bilateral acroosteolysis. Tumour penetration of the abdominal wall (fistula). 5evere interstitial fibrosis of testes: fibrosis of interstitial wall; slight mesangial fibrosis of glomeruli. Variable but generally slight fibrohyalinosis of arterial and venous vessel walls (skin, heart, lungs, intestine, testes) 34 Lee and Harry ( 1 974) . 35 Smith et al. ( I 976b) Latency period ( 1st exposure -* death) only 8 years (see also Fox and Collier 1977) 36 Maltont ( 1 974) 37 38 39 - 40 _ 41 Byren and Holmbcrg (;1975) 42 Byren et al. (1 976) 43 - 44 Block (1 974) 1 case 5) 1965 portocaval shunt. 1970 cholecystectomy. See also Folkst al 1.1974a) (case 4); Whelan et al. 1 1976) (case 1) j>5 Block (1974) (case 2) 46 Block 1 1974) (case 4) No autopsy. See also Creech and'Johnson (1974); Falk et al. (1974a) (case 3): Whelan et al. (1976) (case 2)\Makk et al. 11976) (case 6) See also Falk ct al. (1974a) (case 5): Makk et al. ( 1 976) (case 10) R&S 005096 70 Table 15 (continued) Mo, 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 Zonca et al. 11975) W.L, Lelbech and H.J. Marsteller Additional relevant information See also Falk et al. 11974a) (case 2):Makl: et al. (1976) tease 4) See also Falk et al. (1974a) lease 1 )\Makk et al. (1976) (case 2) See also Falk et al. (1974a) (case 6): Whelan et al. (1976) (case 4)-,Makk et al. 11976) (case 14) Chronic alcoholic. See also Makk et al. (1976) lease 13); Berk et al. (1976) lease 2) Among a work force of 18011 20. PVC polymeriza tion; 60, production of VCM) employed at this plant, 15 died of malignant disease ( 2 ASL, 5 bronchogeniccarcinomas. 1 case each of carcinoma of the larynx, rib, mamma, spermatic cord;glioma, melanosarcoma, leukaemia, Hodgkin's disease) First exposure to VCM for these 67 cases of ASL dated back to the period 19391966 (median: 1951). Twenty-one years later, i.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 period of 21 years (Spinas and Kaminski 1977). Spinas and Kaminski also suggested that in future Cases the age at diagnosis and the length of the latency period may in crease as a result of the later reduction in levels of exposure. From the synopsis in Table 13-18 it can be seen that in about two-thirds of the cases 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 acroosteolysis and cutaneous stigmata of scleroderma have been observed in only l of these 76 patients, a French PVC worker who had apparently not been engaged in reactor cleaning (case 19 \ Roche et al. 1978). Another noteworthy piece of informa tion is that strikingly atypical endothelial cells with liypertropltic and hyperchromatic nuclei have also been found in organs other than the liver (kidneys, lungs) in autopsy material from two patients (cases 1 and 1 l,Hublet et al. 1977-,Rubsamen 1976). Hublet 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 tint the effect of VCM metabolites is not restricted to the vascular endothelium of the liver and spleen. Angio- m lyi 'lars teller ; al 3l, -t al. <) (case meriza his plant chogenic larynx, 'jrcoma, ! la bial in v-rved t latency zested nay in- >ii the jssociat'',n. eviiosarco i of note 1 in only gaged f informahromatic mtopsy 76). ">se tissue of VCM .'n. Angio- Vinyl Chloride-Associated Disease 71 Table 16. Personal data on eight eases of angiosarcoma of the liver among VCM-exposed personnel not employed in PVC production las reported to NIOSH by August 197SW Birth date No. Country (m/d/y ip Date of death (m/d/y) Total Age at years death exp. Job classification A D (3) 07.16.30 10.10.73 43 14 Loading pesticide cans with VCM propellant B D (6) 05,09.36 12.16.74 38 3.5 Assistant factory chemist r GB (2) 09.08.14 12.00.70 55 11 Pouring PVC oil mix ture onto fabnc bases D 1(1) 06.15.34 04.16.71 36 3 Fabrication of PVC sacks and wrappings (extrusion at tempera tures of 1 20' C) E SC) 1 1.27.1 1 08.16.71 61 23 Assistant factory chem ist (production of VCM) F USA (15) 00.00.25 02.15.73 47 Accountant at plant producing PVC fabric G YUC) 1 1.15.31 07.12.73 42 IS Production of VCM H YU (3) 12.21.31 01.1 1.76 45 1 Production of VCM 3 Update of NIOSH register. August 1978. prepared by Kaminski as in Table 13. ^ 00. datj 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 been induced in experimental animals. The extremely rare coincidence of angiosarcoma and hepatocellular carcinoma was found in three instances (case 1 .Delorme 1978b: case E,Byron andHolmbcrg 1975. and a case not included in the 1978 NIOSH update Tamburro et al. 1978a). In the case reported by Tamburro et al. chronic alcoholism may have played a cofactor role in the development of liver cancer. We can now add a fourth case observed in 1973 at the Department of Medicine in Bonn (see Sect. 4.1.5 and Fig. 3). This patient (patient 9 in Table l), a PVC-polymerization worker (total period of exposure: 13 years) was first admitted to our department in February 1975 and was found to suffer from atyp ical cirrhosis of the liver with portal hypertension, splenomegaly and Raynaud's phe nomenon . During follow-up ASL was clinically suspected but could not be confirmed during life,despite exploratory laparotomy and generous surgical biopsies. The patient .A, v i *- T* - . 4s. TaMe I 7. Clinical and morplmhigicul iLiiu on cighl cases of angiosarcoma ut llie liver among VCM-e.\pme<i personnel noi employed m l*VC polyincrizuijnn ^ * 1 [epaloNn megaly A+ 16000 g) Spleen Splunnmcg.ily Oesophageal Hepatic varives fibrosis + I'oital fibrosis Thromhocytopcnia + Aeroosteolysis 0 Raynaud's , phenomenon MetasCases 0 Diaphragm, gastric mucosa, abdominal lymph nodes fl Splenu- t 0650 g) muyaly (-125 g) (; Local capsular ,0 libmsis, portal and centrolobnSar lilmisis 00 Diaphragm, pleura, abdominal lymph nodes !) <+) !: f j Nut enlarged )S 77 V 7 07 0 Lungs, pericardium H 0 0 *) (104 0001 (; + u Spit;iimiicyaly ? ) 0i 0 Dura, cranium : W.K. Lelbach and H.J. Marsteller ~ c c' n n. ^ tj S. ? 2 3 O 2 ,' ?5??1 3CJ 860S00 S$H DO O- | --0\ H* Vm R&S 005099 Marsteiler Vinyl Chlonde-Associated Disease 73 Table IS. Publications on the eight cases of angiosarcoma of the liver listed in Tables 16 and 17 No. References Additional relevant information A Reinl and Weber (1974) 1967 idiopathic portal hypertension; portocaval shunt 8 Zimmermann and Eck 1973 right heminephrcctomy for unilateral hydro- (19751 nephrosis associated with bilateral double kidney. Reinl (I 975) Foci of haematopoetic cells in spleen and kidney. Fibrosis of the pancreas. Slight fibrosis of testes and of the small intestinal serosa c D Maltoni ( 1974) Autopsy: angiomatous epulis. Angiosarcoma involv ing liver, lungs and pericardium. The pericardium might have been the primary" site! E Byren and Holmherg Probable coexistence of a hepatocellular cancer of l 1975) both low and high grade differentiation P G Zorica et al. (1975) H diet! on 7 August 1978, after a massive haemorrhage from oesophageal varices. Autop sy revealed both multicentric metastasizing angiosarcoma and hepatocellular carcino ma of the liver as well as slight fibrosis of the pancreas (to be published in detail). It is still unexplained why hepatocytes are generally exempted from the carcino genic effect of VCM metabolites but. as predicted by Popper in 1975, three anecdotal cases of hepatocellular carcinoma, one German (Gokel et al. 1976) and two British FVC 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 the Province of Quebec covering the period 1969-1972 showed a preponderance of adult mate 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). . Not included in the NIOSH register are several anecdotal cases of ASL, capillary and cavernous angiosarcoma of the liver and haemangiosarcomatosis of sites other than the liver, for which a relation to occupational or even possibly residential exposure to VCM has been discussed (Aorta et al. 1977.Brady et al. l977:Dor et al. 1975; Wallr.bfer and Zinna%l 1977). Although of undetermined relevance, it should finally be mentioned that, in addi tion to hepatic fibrosis, varying degrees of interstitial fibrosis of tire pancreas were noted at autopsy in four German workers leases 19. 23, 8 and the above-mentioned 7-1 W.K. Lelbaeh and H.J, Marsteller patient with both angiosarcoma and hepatocellular carcinoma). Fibrosis of tire testes was observed in three cases (19, 29. B). and Roche et al. (1978) also reported fibrosis/ hyalinosis in vessels of skin, heart, lungs and intestinal wall. CUMULATIVE N* OF CASES REPORTED TO NIOSH 70 IzT -135 J_l! : ..ill -i_i_ _____ --------- : l--Jja--1~ I 1 5 1 i" T-r-HW3*-- -1- -- - *" 1955 1960 1965 1970 yeor of diagnosis 1975 1978 Fig. 7. Cumulative number of cases of ASL among PVC production workers reported to NIOSH up to August I 978. arranged according to year of diagnosis < data from Spirias and Kaminski 1977, 1978) 4.3,2 Clinical Manifestations The clinical symptomatology of usually multicentric ASL is unspecific. Gradually de clining general health and loss of weight combined with ill-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 R&S 005101 l.trsteller testes fibrosis/ Vinyl Chloride-Associated Disease 75 ot'cases, tite tumour first came to attention with massive, often fatal, intraperitoneaj haemorrhage. Important tender hepatomegaly (hepatosplenomegaiy), slight jaundice and occasionally development of moderate ascites and oedema were observed. Except for mild to moderate hyperbilirubinaemia, some elevation of serum levels of alkaline phosphatase and gammaglutamy! transpeptidase and only slightly abnormal levels of serum transaminases, the spectrum of biochemical tests is hardly revealing. AJpha-fetoprotein 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 intrahepatic tumour defects (Bienack et al, 1977b) together with abnormal splenic fixation, but peripheral defects of uptake may be difficult to interpret {Whelan et al. 1976). Characteristic features of angiography are a normal-sized hepatic artery with possible displacement caused by tumour enlarge ment, a certain degree of central hypervascuiarity of the tumour, a peripheral tumour stain, and puddling of contrast medium persisting into the late venous phase. In addi tion. varying degrees of peliosis hepatis may be observed in some cases. However, even repealed hepatic angiography may fail to confirm the suspected diagnosis, as was evi dent in one case reported by Roche et al. (1978), The example of a 54-year-old polymerization worker who died of metastasizing angiosarcoma of the liver in February 1980 may serve to illustrate the clinical course. In 1972/73, after an exposure of 18 years' duration, we found him to suffer from Ray naud's phenomenon and noncirrhotic 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 gastric ported rnm tally de1'ininaJ 'irst cedent i number Fig. 8. Computer tomography showing a large, irregular, hypodense angiosarcoma of the liver involving hoth lobes. Courtesy of Professor Thum, Department of Radiology. University ol Bonn & u W.K. Lelbuch and H.J. Marseille;r varices during the following years with repeated episodes of bleeding which required (successful) sclerosing therapy (major surgery was decli'ned by the patient). In August 1979 he presented again with recurrent epistaxjs and slight but permanent epigastric and upper right quadrant pain, but declared that he felt otherwise fairly well. He com plained about a sharp localized epigastric pain on sneezing. There was marked spleno megaly, and an ill-defined hard mass was palpable in the epigastrium. Apart from moeferate elevation of alkaline phosphatase and borderline hyperbilirubinaemia, biochem istry was normal. Computer tomography showed a large irregular hypodense tumour mass in the liver, involving both right and left lobes (Fig. 8), which became practically isodense after intravenous injection of contrast medium. A liver scan corroborated the tumour defect. Shortly after this there was mounting evidence of brain involvement and rapid deterioration. Computer tomography now revealed multiple brain metastases (Fig. 9). Autopsy confirmed the tentative diagnosis of metastasizing angiosarcoma of the liver (Fig. 10). R&S 005102 sis mTLfi m m Fig. 9. Computer tomography showing multiple brain metastases of angiosarcoma of the liver. See text. Courtesy of Professor Thum. Department of Radiology. University of Bonn 4JJ Peritoneoscopy Little information is available in the literature concerning the peritoneoscopic aspect of VCM-induced ASL(Roche et al, 1978). It may be impossible to make a diagnosis of the initial phase of ASL in VCM-exposed workers by peritoneoscopy and needle biop sy of the liver, as documented in one of our patients who died of multicentric ASL W iiuired August jstric lie com'pleno>tn modidism utnour ictically a ted the oment vtastases oma of Vinyl Chloride-Associated Disease 77 Fig. 10. Multiple brain metastases of angiosarcoma of the liver. Courtesy of Professor Gullotta, Institute of Neuropathology, University of Bonn mg w mM f* Flgi itSSJGf-f3 78 W.K. Lelbat'li and H.J, Marstdler 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 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 inetastases 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. 4.3.4 Gross and Histological Morphology The liver is usually markedly enlarged. Liver weight in cases of ASL ranged from 1600 to 7300 g (Thomas and Popper l97S;Roche et al. 1978). The gross appearance of angio sarcoma of the liver is mostly that of large bulky, irregularly shaped cystic tumour masses; a multinodular form with numerous, sometimes umbiiicated 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 Copper (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, hypejchromatic 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 typo, where they may be surrounded by thick fibrotic 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. Gedigk et al. (1975) also observed a reticulosarcomalike 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 aetiological 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 livers of heavily exposed persons. Fibrosis of enlarged portal tracts with modest proliferation of bile ductules, mostly only scanty infiltration of lympho cytes and occasional formation of perilobular septa or thin connective-tissue septa ex tending into the lobular parenchyma can be found. A more or less conspicuous intra lobular. perisinusoidal fibrosis is often detected only by special staining methods for collagen or reticulin fibres. As a rule, irregular focal or nodular fibrotic thickening of r. - m* *. f /4 * ,, V' Fi* Liw run po In oi * Thv or : lift:; oid, pla*: me; rem cyidecc retK r &S 005105 larsteller ee also on with ible on ic me- should uspi- ted from 1600 to mnce of angioric tumour lutes, is less md spongy pot'f large cavern- nur basic devel* lifferent porlive evolution: of transition coma cells with terize the ring differen cial tracts, ac .arcorna atro spaces, int" m.ective tissue 'tiled spaces tlbroric wails, mia are found, pe of tumour. :!fcrentiation ot -dial lining cell dually, vinyl other aetiol- ilezrees of ex tus to that seen portal tracts on oflymphorissue septa expicuous intra methods for thickening of Vinyl Chloride-Associated Disease 79 Fig. 11. Angiosarcoma of the liver (upper part of photomicrograph) invading adjacent liver parenchyma (case 14 = D1 ;see Table 13). Note hyperplastic and hyperchroma tic nuclei of proliferating neoplastic lining cells enveloping hepatic cords. Reproduced by permission. Ann NY Acad Sci 346:378-385 (1975). Courtesy of Professor Ged.gk, institute of Pathology. University of Bonn. H & E, x 350 of Glisson's capsule is present: these fibrotic capsular areas may extend into the under lying parenchyma and may connect with adjacent enlarged subcapsuiar portal tracts. The cellular and nuclear size of hepatoevtes may vary widely: groups of binucleated or even multinuclear parenchymal cells with abundant cytoplasm are seen. Focal pro liferation of sinusoidal lining ceils may be encountered, especially within foci of sinus oidal dilatation. In connection with conspicuous sinusoidal dilatation, two types of focal hyper plastic precursor lesions were described by Popper et al. (1978): 1) Poorly circumscribed foci of hyperplastic, often binucleated hepatoevtes with increased number of various sinusoidal lining cells and only insignificant increase of reticulum framework. 3) .Almost nodular areas of conspicuously hyperplastic and hypertrophic hepatocytes with more pronounced variation of markedly increased sinusoidal cells without degeneration or necrosis of liver 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 atypia and anaplasia of these proliferating endothelial cells accompanied either so W.K. Laibach and H.J. Marsteller by formation of excess connective tissue or by accentuation of sinusoidal dilatation leading to primary peliosis. Involvement of portal areas in the evolution of angiosarco 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 hepatocy tic plates may lead to a cirrhosislike picture. 43.5 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 majority of cases. A survival period of two years after surgery (Berrod et al. 1978) or chemotherapy (Danuahcr et ai. 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. 43.6 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 polymerization workers of roughly 20 000, a risk ratio (ratio of observed to expected cases) for this population of at least 400:1 was calculated (Heath et al. 1975). This calculation was based on data from the National Cancer Institute's Third National Cancer Survey (1969-1971). which expected for the total United States population an annual incidence of this tu mour in the order of 0.014/100 000. This would have meant only about 0.03 cases per 20 000 polymerization workers within a 10-year period. Dose-response and attendant biotransfonnation 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 (Schneiderman et al. \915:Gehring et al. 1979, 1978 .Woods 1979). Gehring 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 1.5 cases of ASL in 100 000 000 workers on exposure to the current National Standard in the United States of 1 ppm VCM 8 h/day, 5 days/week, for a 35-vear 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 (1979),This model arrives at an incidence of 3.9 cases per 100 000 000 workers after a lifetime exposure to 1 ppm. Much controversy, however, about the validity of risk extrapolation from animal experiments to man and from high- to low-level expo sure and the problem of threshold doses has been voiced {.Waugh [91$: Hooper et al. 1979\Schneidermau 1979: Weigert \979:Rcii: et al. 1979). Vin> R; (excl ASL This, the ont'r 33 ad c 9 le re </> slyr o is o-' o C--J*l o on; de< o> er ;nr IIUIUOI vinyl e model the est groun 43.7 For a hazard the ci studk sure ti the lu: al. 19" Mv.vuof Bn; 1976.. posed et al. 1 voiced Berry ; employ and cj' but no 1976), In . (1974i epidem (19781 factoin ^teller ion sarcoher beT lobuieture. difcs eff two i is a c pat n 30 C/3 O ocn 1 o I 'si 4 (U- -es per tflant i;e sev.nee to : e\<afe et al. i probit <ssump- <1000 1 ppm < not icd by ell : byworkers iity of ! cxpo- et al. Vinyl Chlonde-Associated Disease 81 Results of a recent survey by Brady et al. 0*377) indicated that for New Vork State (excluding New York City), a highly industrialized area, the annual incidence rate of ASL during the 6-year period from 1970 through 1975 was 0.25 per million residents. This considerably exceeded the national average rate of 0.14 per million per year in the United States. In a concomitant case-control study, 26 patients with Itistologically confirmed ASL were found in the study area from 1958 to 1975. and 7 of these had had documented long-term exposure to either As. ThO; or VCM. Five (all female) of the remaining 19 patients lived at a distance of 500--1500 feet from VC lubrication or polymerization facilities for long periods. No pertinent exposure or residential history was obtained from the other 14 patients. Discharge of unreacted monomer into the en vironment as result 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 (Schweitzer 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-ntile radius of vinyl chloride emission sources (Kuzniack and McGaughy 1975). If the risk assessment model elaborated by Woods (1979) is applied to this population of 4.6 million people, the estimated incidence of angiosarcoma per year would not be above expected back ground levels. 43.7 Mortality and Cancer Morbidity Studies For a tumour disease as rare as angiosarcoma of the liver even quite small increases in hazard over background levels should be detectable (Doll 1975). The situation with the common types of cancer is far more difficult. Since 1974 a number of mortality studies of VCM-exposed populations have suggested that in humans long-term expo sure to VCM may also be associated with cancer of sites other than the liver, notably the lungs, and the lymphatic and central nervous system (Monson et al. 1974; Otr et al. 1975: Tahershaw and Gaffcy \91A\Nicholson et al. 1975: Wagoner et al. 1976: IVaxwet/eret al. 1976.Nicholson \911\BufJler et al. 1979). Epidemiological studies of British workers failed to confirm this suggestion (Duck et al. \91S\Dnck and Carter 1976;Fo.\ and Collier 1976, 1977), as did a prospective study of a VCM/PVC-ex posed cohort of 1618 employees of a West German chemical plant (Frcntcel-Beymc et al. 1978). Criticism of design and interpretation of some of the studies has been voiced (Falk et al. 1974b:Purchase and Williamson \9~d .Reger \911\Daldentp 1975: Berry and Rosutcr 1976). A follow-up of all VCM-exposed persons (750 traced) ever employed at the one Swedish factory, which started operation in 1945. for mortality and cancer morbidity patterns revealed a fourfould excess of pancreas,liver tumours but no deviation in the number of brain tumours from the expected level (Bvren et al. 1976). '- In addition to the three extensive mortality studies of Tahershaw and Gaffcy (1974), Waxwcilcr et al. (1976), arid Fox and Collier ([917). a fourth comprehensive epidemiological study (Rein! and Weber 1976) was completed in 1977 by Rcinl et al. (1978). winch included three study populations from 11 VCM* and PVC-producing lactones in the Federal Republic of Germany, covering the period from before 1959 s; W.K. Lelbach and H.J. Marsteller ' through 1974: (a) 7021 workers engaged in the production of VCM and PVC; (b) b- 4910 chemical workers from the same plants not exposed to VCM: and (c) 4007 B workers engaged in PVC manufacture. Not included were non-German workers of u Mediterranean origin. This German study permits comparison not only with the mor Ct tality ratio of the total male population but also with a comparable occupational O: group exposed to VCM, With regard to the 'healthy worker effect1 (McMic/iacI et al/ 'I 1975), overall mortality was elevated for the VCM-exposed population (group a), but W O' not for the other chemical workers (group b). Apart from the markedly elevated stan ti. dardized mortality ratio (SMR) for malignant liver tumours (1523). which proved to di I have been closely related to the duration of exposure, a significantly elevated SMR was found for tumours of the lymphatic and haematopoetic system (214). The group of P' ot chemical workers not exposed to VCM (b) also showed a significant elevation of the fa I SMR for liver tumours (401), a result that deserves further investigation. No signifi cantly increased risk was found concerning tumours of the central nervous system b. ur or the respiratory tract. he It has already been mentioned (Sect. 2.2.10) that an excess mortality from brain II 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. re 1 cc At present, there is no explanation for the increased SMR for accidents found in the VCM-exposed population, particularly during the period 1970 through 1974, about 40% of deaths having occurred in ex-PVC workers. A recalculation of the available data would have been necessary for the evaluation of a conceivable influence of VCM on vigilance. As an addendum it may be noted that determination of plasma carcinoembryonic ot in al c> or antigen titre (CEA) in 200 Canadian PVC production workers (mean duration of em ;\ ployment: 10 years) showed a more than threefold higher frequency of levels above 10 ng/nil than in a normal healthy population (1.7% vs, 0.5%) (Page et al. 1976). Levels of CEA were also determined in 1363 workers of five different VCM polymeri- 33 Ti zation (3) and PVC processing (extrusion) plants (2) in the United States (Aiidenon et ^ w, al. 1978). After removal of possible confusing factors (smoking, alcohol intake, past medical history), it emerged that the distribution of CEA titres among the polymerization workers was significantly different from that in the extrusion plant group and in Cn Gr a nonexposed reference group. Significant differences were also found for two of six job categories examined (polymerization and maintenance) compared with extrusion workers and the reference group. However, the usefulness of the CEA titre as a predic tive indicator of possible increased risk seems doubtful. o 00 A B C D 4.4 Miscellaneous Aspects 4.4.1 Thrombocytopenia and Platelet Function Tests Thrombocytopenia in chronic VCM intoxication was first mentioned - rather paren thetically and without further comment -- in a paper published by Antonyuihenko in 1968. Later Julie et al. (1973) noticed that each of the first 13 autoclave cleaners re ferred to them during 1972 from a West German plant because of suspected skin and pe: pre litr lim FiY Till  feller I' :iior- ( al. but ! stanJ to IR was p of the tifi- 11 i tin .1' one lound. i the out 'c data I '.in nic -Tll- meri"i et MSt I- o/a >J in . six ""lOll 'redic- 33 cn o o Ml (J| r* (D Vinyl Chloride-Associated Disease S3 bone lesions presented with mild to marked thrombocytopenia (30-119 X 10'*,'litre). 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 8 and leucopenia in 5 of the workers, other haematol* ogical tests were negative. The reduction of the number of leucocytes and platelets as well as reticulocytosis appeared to be attributable to splenomegaly, but further studies on the nature of thrombocytopenia were thought necessary, and it was suggested by the authors that a decrease in the number of platelets might serve as an early and easily detectable symptom. The high prevalence of thrombocytopenia (as determined by phase-contrast microscopy) found later on detailed analysis of platelet function and other parameters of blood coagulation in the total cohort of PVC production (and also fabrication) workers from this plant strengthened this suggestion (Bachneret al. 1974a, b, 1975a, b, \976\Sehrt-Backncr and Eszel 1977). Wepnan (1975) also commented upon abnormal platelet counts in 13 of 37 PVC fabricating workers who had only handled PVC powder which, however, might have contained substantial amounts of residual monomer. In contrast, Lilis et al. (1975) detected thrombocytopenia in only 1 of 354 polymerization workers, but an electronic cell counter was used for platelet counts (personal communication). According to Sehn-Bachner and Etzel (1977), the mean platelet count in a cohort of 132 PVC polymerization (and processing) workers was significantly lower than that in a nonexposed control group of 150 healthy men. As could be expected, Bachner et al. (1975b) also demonstrated a positive correlation between the degree of thrombo cytopenia and the prevalence of an enlargement of the spleen (palpable splenomegaly or spleen size determined by selective scintigraphy with 19"'-Hg-bromo-mercury-hydroxypropanedabelled red cells) in 70 PVC polymerization workers (see Table 19). It ap- Table 19. Prevalence of enlargement of the spleen3 among 70 PVC-polytnerization workers in rcijiion to increasing degrees of thrombocytopenia (Bachner et al. 1975a) Group No. of workers examined Platelets (x 10'* /litre) Range Mean Enlargement of the spleen A 14 B 24 C 25 D7 > 130 100-130 70- 99 < 70 168 117 S7 -U 3(21') 1 1 (46!') I9(76'-) 6 (86") 3 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 10'9/ litre) in a small number of workers in whom spleen size was definitely within normal limits on selective spleen scintigraphy (Milzrlacheninde.x <4.5 x 10"3 according to Fischer and Wolf 1963). Thrombocytopenia was accompanied by abnormalities in platelet function tests. There was an increase in the number of large (> 10 pm) `juvenile' platelets (increased (* '84 W.K. Lelbach and H.J. Marsteller platelet spreading), enhanced response (platelet aggregation) to addition of ADP and collagen (Bom test) and increased availability of phospholipid-containing platelet fac tor 3 (Bac/mcr et al. 1975a). This pattern was thought to be compatible with the no tion of an increased turnover rate due to derangement of microcirculation (CDIC) in liver and spleen and defective reticuloendothelial system (RH5) clearance of activated clotting factors (Bachncrtt al. 1974b). Ward (1976) and Ward et al. f 1976) suggested that thrombocytopenia could be construed as confirmatory evidence of an immune complex disorder.Hcusermann and Stum (1977a) noted unusual focal aggregation of platelets in klatsch preparations of spleen tissue and increased platelet pooling (plate lets trapped within the subsinusoidal mesluvork of pulp cords) in the red pulp of the spleen on electron microscopy as well as phagocytosis of thrombocytes by sinusoidal macrophages.Schaf'fneret 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 understood.it seems at present most likely that it is caused by increased turnover and consumption of platelets within the abnormal vascular spaces of the liver and spleen. A similar type of consumption coagulopathy was described as complication of spon taneous haemangiosarcoma of the liver by Tmdl et al, (1973). A haemostatic defect more complex than mere pooling and destruction of platelets in the enlarged spleen has also been commented upon in the paper by Cerrits et al. 11974) 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 pseudoneur asthenic symptoms (Sucitt et al. 1963, \91S\Schottek l969:/.dis et al. 1975 and others). This prenarcotic 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 (Schottck 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, lisdessness 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. Penin et al. (1975) examined a group of 21 autoclave 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 (including 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.dysenrhyihmia 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- Vi: 4.4. mm* Ma DO DF oh U) ill O 01 S in 'g opiate- ,) of the lusoidal epatic ictabo- s not fully niver and I spleen. I'spon- defect 1 spleen ..tion with nbed in 'leers, lability, teur,nd utialiy i to lie i. Howaratively I of fa;n de- icrpreted a group whom >yl chloluding . normal a 5o'ropathy. ml circu- Vin> 1 Chloride-Associated Disease 85 lation with resultant hypoxic damage. The pathogenesis of a possibly VCM-induced encephalopathy is not dear. It would be conceivable that clinical and bioelectric alter ations found in some patients, in whom portosystemic encephalopathy could be ex cluded. may have been due to toxic or hypoxic brain damage. However, no other con vincing evidence has so far emerged to indicate that chronic irreversible cerebrotoxic damage may have resulted from prolonged exposure to VCM. notwithstanding the pos* sibility of an induction of brain tumours. 4.4.3 Fhtlmonary Changes Tlte suspected development of nonmalignam pulmonary changes due to VCM and/or PVC dust exposure is still a matter of controversy. Soon after VCM was recognized as a potent carcinogen, three groups of employees (n = 290, 250,445, respectively) from three large North .American PVC-producing plants (A, B, C), characterized by different duration and levels of past environmental exposure to VCM as well as to PVC dust, were studied with respect to chest x-ray film abnormalities and pulmonary' function defects as assessed by spirometry and determination of maximum expiratory flow vol ume (Miller \915,Miller et al. 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 (22.7%, and 18.8%, respectively), but in only 4 j% of those from plant C, with the lowest exposure level. The prevalence of these radiological abnormalities, for which no pathogenetic explanation was available, was found to be significantly in creased with longer durarion of VCM-PVC exposure (more than 10 years), 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 workers with abnormal chest x-ray plates. The overall prevalence of a positive history of chronic bronchitis (British Medical Re search Council criteria) was 20.4% in group A (highest exposure) and 16.0% in group B. although group B was significantly older. The somewhat higher prevalence of chronic 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 liigh prevalence of obstructive changes, but since both smoking and 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 9.3% of group A and in only 2.3% of group B. al though group A was significantly younger. In conclusion, this extensive study, includ ing a total of 985 workers exposed in the past to VCM as well as 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 according to a cohort study of mortality among VCM polymerization workers the SMFli for respiratory cancer as well as for `other respiratory disease' were found to have been in excess of expected figures (156 and 176, respectively) (Waxweikr et al. 1976). Bronchopulmonary changes thought to be due to long-continued, intense exposure to PVC dust were observed by several authors (I'anneggicni and Sassi 1955; Broussard fN 36 W.K. Lelbach and H.J. Marsteller 1969 :S;endeet al. 1970; Vertkin and Mamontov \970: Frongia et al. 1974 :Darke \976: Arnaudet al. 1978). Considerable exposure to VPCdust is the rule in the drying, bagging and storage areas of PVC-producing plants. Photographs contained in Kantadt'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 Panncggiani 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 birefringent foreign material which could be eluted by treatment with a known solvent of PVC. Microscopic examination of PVC dust particles collected at the patient's place of work showed them to be morphologic ally identical with the particles found in the patient's lungs. Another anecdotal case of pneumoconiosis after 23 years 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 Arnaud 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 reticulin and col lagen on electron microscopy (Darke 1976). Although chest x-ray appearances were normal and routine respiratory function tests showed only slightly impaired CO: 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 worst affected had been engaged in the polymerization of `plastisoT, a very fine PVC powder with particle size around 0.5 ^m. Selikoff{\916) 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-macrophage re actions); they proved to be fairly marked after 4 months, with appearance of foreign body giant cells, and proceeded to development of large interstitial granulomatous foci. 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 morphological alterations of the broncho pulmonary system, which they ascribed to their exposure to PVC dust. They quoted results of earlier animal experimenta conducted in 1963 by Golovatyuk and later by Shlvakhetskii. These last authors had apparendy 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. \I to 4.-1 pie m I J. Marsteller '4 \ Darke m the drying. I in Karscade's tents of the reported as the possibil' dust. The ngs blocking mination of nent of the 'thout hilar lesented with i pulmonary i a processing nnulomatous could be ion of1""' morph 33 ,:ntin * s and g 'teitde i 1 of 1 (Ji * -al ^ iltn an w if ces wi ICO; abnormal u nut that ! `plastisol'. i .< /4), who md rats exigging area, lophage re of foreign loinat ous > the mnmi irtion of bronchohey quoted nd later by animals to illy to a sort Vinyl Chloride-Associated Disease S7 Certain types of PVC dust (one of two samples tested) were found to exhibit a strong haemolytic potential due to the presence of an undetermined but readily solu ble surface-associated agent which was not VCM (Richards et al. 1975). These authors also studied the effect of the haemolytic sample of PVC dust on lung fibroblast cul tures, but they did not obtain any significant results. Contrary to earlier indications {Lange et al. 1974a) and despite continued efforts we failed to detect any significant restrictive changes of pulmonary function in the overwhelming majority of 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 ascribed 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 have been carried out that demonstrated a mutagenic response to VCM or its metabolites in microbial test systems. Point muta tions due to base-pair substitution have been produced in various strains of Salmonella typhinmritim by VCM in the presence of animal and human liver microsomes as a sys tem of metabolic activation (Ranrntg et al. 1974,1976\Bartsch et al. 1975a, 1976: McCann et al. 1975; 3/a/aveiV/e et al, \915\Gano et al. 1976). Mutagenicity of VCM metabolites was also demonstrated in yeast strains (Lopricno et al. 1976, \971\Shahin 1976) and in mammalian ceils (Huberman 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 al. (\915), Fnncs-Cravioto et al. (1975), Purchase et al. (1975, 1976). and Fomenko et al. (1976). Fletg and TTi/ess (1974) had failed 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 exclude genetic effects on human gonads. The outcome of pregnancy among wives of VCM-polyinerization workers as against wives of rubber and PVC-fabrication workers (Infante et aJ. 1976a, b) and rates of congenital malfor mation per 1000 resident live births in three Ohio communities with FVC 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 patemai age adjustment a significantly higher incidence of fetal mortality subsequent to patemai exposure was recorded among the wives of VCM-exposcd workers. This trend was found to be maintained after elimination of S3 W.K. Lelbadt and H.J. Marsteller pregnancies in women who had more than two abortions. The findings of this study raised the question of possible genetic risks of V'CM to man and led to the suggestion that germ-cell damage in the father through direct VCM exposure might be a possible explanation. No clear-cut linkage,of PVC production and increased occurrence of congenital malformations (primarily CNS malformations) emerged from preliminary studies in three Ohio communities with PVC production plants. But the need for further study of possible contributary 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 within two miles of these plants (Edmonds et al. 1975). 5 Conclusion and Outlook Tlie combined efforts of multiple disciplines have been necessary to arrive at the full recognition of the range of pathology associated with occupational exposure to vinyl chloride. It can only be hoped that the lesson from the vinyl chloride problem may help to bring about an increased awareness of the risks and hazards which are inevitably the. consequence 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 still 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 industrial 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 w-ill 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 Vinyl Chlor,- between preJ tissue such as short exposui will carry the References Albright LF.t - Albright LF (1 Albright LF f ` Albright LF (: polyvinyl v Albright LF (' processes. Alrenga DP 11 198--203 Amann R (19' der Leber. 1 Anderson HA. CEA amor,. 1560-156' Andrews AW,. properties Anahelescu F. V (1969) employee. 473-482 Annual Repo. London. Ci Antonyuzheu- sian text;. Antweiler H i ! Perspect 1 ' Arnaud A, Po.: ride pneun' Aryanpur J I 1 Iran. J Occi Assmann H (1 Austin GT (10 37-89 Bachner U. E'. und Osoph.i 2409-24 ir- Bachner U, Fi. Befunde be Jahresberic: GG Bad ii' 1 33 Bad oo t/ u cn r. I 30 9f> t </) o dler 1 e 11 tn ie......... rar. had ever ed within at the full ire to vinyl `'lem may are inevitably ' . ;ance of Iv safe com bing latency rties would n any can 't; days cal com- lie widely : nt length -ntial carirroundings cupational : problem, led to. there na of the ted that in II appear dur- .s. future re* r to establish :r studies in he interaction Vinyl Chloride-Associated Disease Sb between predominantly hepatocytic metabolism and oncogenic effect on mesenchymal 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 risk. References Aibnght LF (1967a) Vinyl Chloride processes. Chetn Eng 74:123-130 Albright LF (1967b) Manufacture of vinyl chloride. Chem Eng 74:219-224 Albright LF (1967c) Polymerization of vinyl chloride. Chem Eng 74:15 I -158 Albright LF (I967d) Vinyl chloride polymerization by suspension processes yields polyvinyl chloride resins. Chem Eng 74:145 -152 Albnght LF (1967e) Vinyl chloride polymerization by emulsion, bulk and solution processes. Chem Eng 74:S5 -92 Alrenga DP f 1975) Primarv aneiosarcoma of the liver. Review article, int Surg 60: 198-203 Amann R (1975) Beitrag zur Vinylchlorid-Krankheit. - Ein Fall von Angiosarkom der Leber. Dissertation. Universitat Freiburg Anderson HA, Snyder S, Lewinson T, Woo C, Lilis R. Selikoff IJ (1978) Levels of CEA among vinyl chloride and polyvinyl chloride exposed workers. Cancer 42: 1560-1567 Andrews AW, Zawistowski ES, Valentine CR (1976) A comparison of the mutagenic properties of vinyl chloride and methyl chloride, Mutat Res 40:273-276 Anghelescu F, Otoju M, Dobrinescu E, Hagi-Paraschiv-Dossios L. Dobrinescu G. Ganea V (1969) Clinico-parhogenetic considerations on Raynaud's phenomenon among employees of the polyvinyl chloride industry, f Rumanian text) Med Interna 21: 473-482 Annual Report of the Chief Inspector of Factories for the Year 195 1 (1953) HMSO London. Cmd 8772 Antonyuzhenko VA (1968) On the occupational vinyl chloride intoxication. (Rus sian text). Gig Tr Prof Zabol 12: 50-52 Antweiicr H (1976) Studies on the metabolism of vinyl chlonde. Environ Health Perspect 17:217-219 Arnaud A, Pommier de Santi P, Garbe L. Payan H, Charpin J (1978) Polyvinyl chlo nde pneumoconiosis. Thorax 33:19-25 Arvanpur J (1977) Vinyl chloride: its impact on occupational medicine practice in Iran. J Occup Med 19:689-692 Assmanri H (1921) Die Rontgendiagnostik derinneren Erkrankungen. Vogel, Leipzig Austin GT f 1974) Industrially significant organic chemicals, part 3. Chem Eng 8 1; 87-89 Baehner U, Etzel F, Lange CE. Marsteller HJ. Veitman G 11974a) Hiimostasebefunde und Osophagusvarizen bei Vinylchlorid-Krankheit. Dtsch Med Wochenschr 99: 2409-2410 Baehner U. Etzel F. Lange CE, Jiihe S, Veitman G (1974b) Gennnungsphysiologische Befunde bei Vinylchloridkrankheit. In: Lehnert G. Szadkowski D, Weber HJ (eds) Jahresbericht der 1 4. Jahrestagung der Deutschen Gesellschaft fur Arbeitsmedizin, Gentner. Stuttgart, pp 275-280 Baehner U, Muller R. Egli H (1975a) Clinical relevance of platelet function tests in 1000 patients with hemorrhagic diathesis. Thromb Res 6:139-149 Baehner U, Etzel F, Lange CE. Marsteller HJ. Veitman G (1975b) Hiimostasebefunde und Osophagusvarizen bei Vinylchlorid-Krankheit. In: Marx R.Thic* HA teds) Bluutngen des Gastrointestinaltraktes. Schattauer, Stuttgart f'-ow York, pp 67-73 90 W.K. Lelbach and H.J. Marsteller Bachner U, Etzel F, Muller N, Lange CE, Egli H (1976) Priineoplastische und kollagenisierende Verandenmgen der Leber und Humostasebefunde bei PVC-Arbeitern. In: Gastpar H(ed) Onkohamostaseologie. Schattauer, Stuttgart New York, pp 319-326 Band G (1898) Splenomegalie mit Leberzirrhose, Beitr Pathol Anat Alle Pathol 24: 21-33 Barbin A, Bresil H, Croisy A, lacquignon P. Malaveille C. Montesano R. Bartseh H (1975) Liver-microsome mediated formation of alkylating agents from vinyl bro mide and vinyl chloride. Biochem Biophys Res Commun 67:596-603 Baretta ED, Stewart RD, Mutchler JE (1969) Monitoring exposures to vinyl chlortde vapor: breath analysis and continuous air sampling. Am Ind Hyg Assoc J 30:537544 Bames AW (1976) Vinyl chloride and the production of PVC. Proc R Soc Med 69: 277-281 Bartseh H, Malaveille C, Montesano R, Tomatis L (1975a) Tissue-mediated mutagenic ity of vinylidene chloride and 2-chlorobutadiene in Salmonella typhimurium. Nature 255:641-643 Bartseh H, Malaveille C, Montesano R (1975b) Human, rat. and mouse liver mediated mutagenicity of vinyl chloride in S. typhimurium strains. Int I Cancer 15/3:429437 Bartseh H, Malaveille C, Barbin A, Bresil H, Tomatis L, Montesano R (1976) Mutagen icity and metabolism of vinyl chloride and related compounds. Environ Health Perspect 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 chloride. Gig Tr Prof Zabol 16:24-27 (Russian text) Basu AK, Boyer J, Bhattacharya R, Basu Mallik KC, Sen Gupta KP (1967a) Noncirrhotic 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. Histopathological studies. Indian I Med Res 55:351 -359 Baumann (1872) Ober einige Vinylverbindungen. Liebigs Ann Pharm 163:308-322 Baxter PI (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 of death 1963-1973. Lancet 11:27-28 Baxter PI, Fox Al (1976) Angiosarcoma of the liver in P.V.C. fabricators. Lancet 1:245 Baxter, PI, Anthony PP, McSween RNM, Scheuer PI (1977) Aneiosarcoma of the liver in Great Britain. 1963-1973. Br Med I 11:919-921 Becker V, Busscher K (1961) Ober das Hamangioendotheliom der Leber. Acta Hepato- Splenol 8:356-379 Benoit I-P (1967) L'acro-osteolyse d'origine professionelle. Thse. University of Lyon Berk PD, Martin IF, Waggoner IG (1975) Persistence of vinyl chloride induced liver injury after cessation of exposure. Ann NY Acad Sci 246:70-77 Berk PD. Martin IF, Young RS, Creech I. Selikoff II, Falk H. Watanabe P. Popper H. Thomas L f 1976) Vinyl chlonde-associated liver disease. Ann Intern Med 84; 717-731 Berrod IL. Lazard P. Pierre C, Puech A. Ravjer E, Rety I. Smagghe G (1978) A Propos de 1 0 observations d'angiosarcomes hepatiques survenus chez des ouvriers exposes au chlorure de vinyle. Paper presented at the 19th International Congress of Occupational Medicine, Dubrovnik, 25-30 September. 1978 Berry C<. Rossi ter CE (1976) Vinyl chloride and mortality? Lancet 11:416--117 BerufsgenossenschaftlicheGrundsatzc fur arbeitsmedizinische. Vorsorgeuntcrsuchungen. Gefahrdung durch Vinylchlorid. Fassung luli 1974. Arbeitsmed Sozialmed Praeventivmed 9:226-229 Vinyl Chlo; Biersack HJ. szintigrat restagunc 3 10. (Brv Biersack HI. C (1975b ten mit V Biersack HI. graphy o; (Stuttg) 2 Biersack HI. schaden.i Vinyichlo 88 Blendis LM, .sion in vin 75:206-2 Block IB (19" 229:53-5- Blomfieid I.. current he: Bolt HM (197 HM, Bonn, and. p 1, Kap 3J 25 1. Ka. CD C vin- O I. Kj| o : rat CJI I, La:1' : rat. cn . Kap n: G . d-Kr., . .-n G, > de rupturv rure de vinBonneton G.' Marty F, p leurs du ch. Bonse G, Urhoxirane tot. perfused ra' Borak I (192' Neurol Psy, Border A, \\\ oxide and , Interact 1 7 Boyer IL, Sen (1967) ldi. . cirrhosis an. Brady I, Liber. Polan A, Vi Natl Cancer R&S 005117 ' J Marsteller Md kollagenieitern. In: "P 319-326 : atliol 24: irtsch H vinyl bro- ,v I chloride J 30:537- Med 69: i mutagenic1'irium. . r mediated 15/3:429- Y>) MutagenHealth Per- nges developri;f Zabol i) Non -|,nical and '50 >7h) Non- llistopathol -322 md :h : live i pato .yon er '. Popper H, : -d 84: `.It A Propos icrs exposes jss of 417 :.:rsuchungen. ited Vinyl Chloride-Associated Disease 91 Biersack HJ. Lange CE. Veltman G, Winkler C f 1975a) Bedeutung der Leber- und Milz* szintigraphie fur die Diagnose der Vinvlchlorid-Krankheit. Bericht fiber die 15. Jahrestagung der Deutschen Gesellschaft fur Arbeitsmedizin. 24.-26.4,1975. pp 305 -- 3 10.1 Brenner \V. Rohmert W, Rutenfranz J, eds), Centner. Stuttgart Biersack HJ. Lange CE. Ebinger H, Marsteller HJ. Lelbach WK. Veltman G. Winkler C (1975b) Sequenzszintigraphische Untersuchungen von Leber und Milz bei Pattenten mic Vinylchlond-Krankheit. Dtsch Med Wochenschr 100:615-617 Biersack HJ. San Luis T Jr. Lange CE. Thelen M. Veltman G, Winkler C (1977a) Scinti graphy of liver and spleen in vinyl chloride workers. Acta Hepato Gastroenterol (Stuttg) 24:357-361 Biersack HJ, Ebinger H, Winkler C /1977b) Leber-Milz-Szinttgramm bei Vinylchloridschaden. In: Gutacker HW. Lelbach WK (eds) Leberschaden durch Vinylehlorid Vinylchlorid-Krankheit. Witzstrock. Baden-Baden Brussel Koln New York, pp 8488 Blendis LM, Smith PM. Lawrie BW, Stephens MR. Evans WD (1978) Portal hyperten sion in vinyl chloride monomer workers. A hemodvnamic study. Gastroenterology 75:206-211 Block JB (1974) Angiosarcoma of the liver following vinyl-chloride exposure. JAMA 229:53-54 Blomfield J, Dixon SR. McCredie DA (1971) Potential hepatotoxicity of copper in re current hemodialysis. Arch Intern Med 128:555-560 Bolt HM (1978) Metabolic activation of halogenated ethylene. In: Remmer H. Bolt HM, Bannasch P, Popper H (eds) Primary liver tumors. MTP Press. Lancaster/ England, pp 285-294 Bolt HM. Kappus H, Buchter A, Bolt W (1975) Metabolism of vinyl chloride. Lancet 1:1425 Bolt HM. Kappus H. Kaufmann R. Appel KE, Buchter A. Bolt W (1976a) Metabolism of14 C vinyl chloride in vitro and in vivo. INSERM Symp Ser 52:151 -164 Bolt H.M. Kappus H, Buchter A. Bolt W (1976b) Disposition of | l.2-|4C|vinyl chloride in the rat. Arch Toxicol 35:153-162 Bolt HM. Laib RJ, Kappus H, Buchter A (1977a) Pharmacokinetics of vinyl chloride in the rat. Toxicology 7:179-188 Bolt HM. Kappus H, Buchter A. Bolt W f 1977b) Reaktivitiit der Vinylchloridmetabolite. In: Gutacker HW. Lelbach WK (eds) Leberschaden durch Vinylehlorid - Vinyl chlorid-Krankheit. Witzstrock, Baden-Baden Brussel Koln New York, pp 32-35 Bonneton G, Champetier J, Sotto J. Guidicelli G. Letoubion C. Panh M (1975) Un cas de rupture spontanee d'angiosarcome hepatique chez un travailleur expose au chlorure de vinyie. Chirurgie 101:936-942 Bonneton G, Champetier J, Foumet J, Guidicelli H. Legrand J. Dupre A. Hostein M, Marty F, Panh M f 1977) Angiosarcome hipatique et fibrose portale chez les travatlleurs du chlorure de vinyie. Nouv Presse Med 6:735-742 Bonse G. Urban T, Reichert D, Henschler D (1975) Chemical reactivity, metabolic oxirane formation and biological reactivity of chlorinated ethylenes in the isolated perfused rat live: preparation. Biochem Pharmacol 24:1829-1834 Borak J (1927) Zur Pathogenese tind Therapie der Raynaud'schen Krankheit, Z Ges Neurol Psychiatr 3:1 -16 Border EA, Webster I (1977) The effect of vinyl chloride monomer, chloroethylene oxide and chloracetaidehyde on DNA synthesis in regenerating rat liver, Chem Biol Interact 1 7:239-247 Boyer JL. Sen Gupta KP, Biswas SK, Pal NC, Basu Mallik KC. Iber FL. Basu AK (1967) Idiopathic portal hypertension. Comparison with the portal hypertension of cirrhosis and extrahepatic portal vein obstruction. Ann Intern Med 66:4 1 -68 Brady J. Liberatore F. Harper P. Greenwald P. Burnett W. Davies JNP. Bishop M, Polan A, Vianna N (I 977) Angiosarcoma of the liver: an epidemiologic survey. J Natl Cancer Inst 59:1383-1355 92 W.K. Lelbach and H.J. Marsteller Bridbord K. Brubaker PE, Gay B, French JG d 975) Exposure to halogenated hydro carbons in the indoor environment. Environ Health Perspect 11:215-220 Bronfenmajer S, Schaffner F, Popper H (1966) Fat-storing cells (lipocytes) in human liver. Arch Pathol 82:447-453 Broussard G (1969) Patologia da resine poliviiiiliche. Med Bull (Naples) 52:102-108 Bruder U, Straby A ( 1975) Exposure to vinyl chloride in PVC processing industries. - Report TK 176 on a survey in collaboration with the Swedish Plasties 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 vou 1.2*'4 CVinylchlorid bei der Ratte. Int Arch Occup Environ Health 39:27-32 Buffler PA, Wood S, Suarez L, Kilian DJ (1979) Mortality experience of workers in a vinyl chloride monomer production plant. J Occup Med 21:195-203 Byczkowska Z, Langauer-Lewowieka H (1974) Raynaud's syndrome in workers em ployed in production of polyvinyl chloride. (Polish text). Pol Tyg Lek 29:1461 1464 Byren D, Holmberg B (1975) Two possible cases of angiosarcoma of the liver in a group of Swedish vinyl chloride-polyvinvl chloride workers. Ann NY Acad'Sci 246: 249-250 Byren 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. Burginson RM. Vitcha JF, Krantz JC (1949) Anesthesia. XXIV. Chemical con stitution of hydrocarbons and cardiac automaticity. J Pharmacol Exp Ther 97:1 Chainuvati T, Viranuvatti V (1979) Idiopathic portal hypertension and chronic arsenic poisoning. Report of a case. Am J Dig Dis 24:70-73 Chatelain A, Motillon P (1967) Un syndrome d'acro-osteolyse d'origine professionnelle et de constatation nouveile en France. J Radiol Electrol Med Nucl 48:277-280 Cheney WD (1965) Acro-osteolysis. Am J Roentgenol 94:595-607 Chowdhury AR. Black M. Lorber SH. Chey WY (1 977) Haemangioendotheliomatosis of the liver. A 12,year follow-up. 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 hepatotoxicitv of ethylene, vinyl fluo ride. vinyl chloride and vinyl bromide after aroclor 1254 pretreatment. Exp Moi Pathol 23:25-33 Cook WA, Giever PM, Dinman BD, Magnuson HJ (1971) Occupational acroosteolysis. II. An industrial hygiene study. Arch Environ Health 22:74-82 Corbett TH (1975) Inhalation anesthetics - more vinyl chloride? Environ Res 9:211 214 Cordier JM. Fievez C. Lefevre MJ. Sevrin A f 1966) Acroosteolyse et lesions eutanees chez deux ouvners affectes au nettoyage d'autoclaves. Cali Med Tra 4:14. 3-39 Cornish HH. Abar EL (1 969) Toxicity of pyrolysis products of vinyl plastics. Arch Environ Health 19:15-21 Couderc P, Panh MH, Pasquier B. Pasquier D. N'GoIet A, Faure H (1976) Angiosareome osseuse revelateur d'une tumeur hepatique chez un travailleur expose au chlorure de vinyle. Sem Hop Paris 52:1721 -1 722 Cowlishaw JL, Pollard EJ, Cowen AE, Powell LW (' 1 979) Liver disease associated with chronic arsenic ingestion. Aust NZ J Med 9:3 10-3 13 Creecli JL, Johnson MN (1974) Angiosarcoma of the liver in the manufacture of poly vinyl chloride. J Occup Med 16:150-15 1 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 Wceklv Rep 23:49-50 Vil 33 id; fio Cr< cn o o cn Da St a on. tei Mi Da 00 28. M. :24 Da . Y. Utt4U .enn May 16-29 Danziger H (1 Med Assoc J Darke CS (197. tion of PVC Datta DV. Mitr. toxica tion a- cirrhotic pc> Davies IW, Pen. Environ Poll Deese DE, Joyr Ind Hyg Ass- Delorme F (197 chlorure de Delorme F (197 ouvrier du c1- Delorme F, Mar. tact prolong-.- Union Med Delorme F, Th Quebec. J O. Devignevielle I.' polyvinyhq. Dinman BD, C tional aero.- Dodson VN. Di: tional acroo- Doll R ( 1975) ; Domininghaus i- - Anwendi : Dor JF. Arlauu (1975) Angi. rure de poly Dressman RC, ,\: minatton of \ Sci 15:69 Du IT. Tambur; chlonde exp- Ducatman A. Hi. chromosome Duck BW ( 1975 i Duck BW (1976' 307-309 Duck BW, Carte Duck BW, Carte chloride prop- t ), Marsteller ated hydro- 220 J i id ext) , --* CD ta n- liver in a \cad Sci 246: :icer morbid. Health Per- hemical conl'her 97:1 hronie arsenic "mfessionnelte 277-280 liehomatosis c inhalation ton Health . vinyl fluolixp Mol '< *> isteolysis. . Res 9:211 ns eutanees 14.3-39 >;as. Arch > \ngio \pose au ..iciated with ture of poly- don workers. i' Angio' Weekly Rep Vinyl Chloride-Associated Disease 93 Creech JL, Makk L. Whelan JC Jr. Tamburro CH ( 1974b) Hepatotoxicity among poly vinyl chloride (PVC) production workers during first yearot surveillance program. Gastroenterology 67:786 Dalderup LM ( 1975) Vinyl chloride and haemanciosarcoma of the liver. J Ocoup Med 17:285-256 Dalderup LM. Freni SC. BrasG, Bronekhorst FB (1976) Angiosarcoma of the tiver. Lancet 1:246 Dannaher C. Yam LT. Tamburro C 11979) Vinyl chloride associated hepatic angiosar coma chemotherapy. American Association for Cancer Research, Inc.. Meeting May 16-29, 1979. Mew Orleans. Louisiana Danziger H (1960) Accidental poisonimz bv vinyl chloride. Report of two cases. Can Med Assoc J 82:828-830 Darke CS (1976) Discussion remark to: AAV. Barnes: Vinyl chloride and the produc tion of PVC. Proc R Soc Med 69:230-281 Datta DV, Mitra SK. Chhuttani PN, Chakravarti RN (1979) Chronic oral arsenic in toxication as a possible aetiological factor in idiopathic portal hypertension (noncirrhotic portal Fibrosis) in India. Gut 20:378-384 Davies IW. Perry R (1975) Vinyl chloride monomer's effect on liquids in PVC bottles. Environ Pollut Manage 5:22-23 Deese DE. Joyner RE (1969) Vinyl acetate: a study of chronic human exposure. Ant Ind Hyg Assoc J 30:449-457 Delorme F f 1978a) 10 cas canadiens d'angiosarcomes du foie chez des ouvriers du chlorure de vjnyle. Ann Anat Pathol (Paris) 23:97-104 Delorme F (1978b) Association d'un angiosarcoma du foieet d'un h6patome. chez un ouvrier du chlorure de vinyle. Ann Anat Pathol (Paris) 23:105-114 Delorme F, Makk L (1975) Angiosarcoma du foie chez des ouvriers ayant et5 en con tact prolonge avec le chlorure de vinyle: description morphologique des lesions. Union Med Can 104:1836-1844 Delorme F. Theriault G (1978) Ten cases of angiosarcoma of the liver in Shawinigan. Quebec. J Occup Med 20:338-340 Devigneviolle D. Flucher AM f 1953) Etude toxicologique expOrimentale des resines polyvinyliques. Service Medicate des Manufactures de Saint-Marcel. Vernon Dinman BD. Cook WA. Whitehouse WM. Magnuson HJ. Ditcheck T (1971) Occupa tional acroosteolysis. 1. An epidemiological study. Arch Environ Health 22:61-73 Dodson VN. Dinman BD. Whitehouse WM, Nasr ANM, Magnuson HJ (1971) Occupa tional acroosteolysis. III. A clinical study. Arch Environ Health 22:83-91 Doll R ( 1975) Discussion paper, Ann NY Acad Sci 246:320--321 Doniininghaus H (1972) Kunststoffe, I. Aufbau und Eigensehaften - Kunstst'offsorten - Anwendungen. 2nd ed. VDt-Verlag. Dijsseldorf Dor JF, Arlaud J, Coste C, Faure F. Kasbarian M. Lebreui! G. Padovani J. Monain M ( 1975) Angjome capillaire et caverneux diffus du foie, chez un travailleur du clilo,rure de polyvinyle. Marseille Med 112:709--720 Dressman RC, McFarren EF ( 1977) A sample-bottle purging method for the deter mination of vinvl chloride in water at submicroeram per liter levels. J Chromatocr Sci 15:69-72 Du JT. Tamburro CH (1976) Decreased glucose-6-ohosphata.se activity in liver in vinyl chloride exposed rats. Fed Proc 35:1422 Ducatman A. Hirschhom K. Selikoff IJ (1975) Vinyl chloride exposure and human chromosome aberrations. Mutat Res 3 1/3:163- 16S Duck BW ( 1975) Vinyl chloride carcinogenesis. Br j Cancer 32:260-26 1 Duck BW (1976) Medical surveillance of vtnyl chloride workers. Froc R Soc Med 69: 307-309 Duck BW. Carter JT 1976) Letter to the editor. Lancet II: 195 Duck BW. Carter JT, Combes EJ (. 1975) Mortality study of workers in a polyvinyl chloride production plant. Lancet 11:1197-1 199 94 W.K. Lelbach and H.J. Marsteller Dugois P, Amblard P, de Bignicourt B. Legrand J (1972) Acropathic polyvmylique profesionnelle. Bull Soc Fr Dermatol Syphiligr 79. 197-198 Dupas J. Badelon P, Davde G (1936) Osteolyse essentielle progressive de la main gauche d'origine indetermine'e. Mem Acad Chir 6 2:148-158 van Duuren L ( 1975) On the possible mechanism of carcinogenic action of vinvl chlo ride. Ann NY Acad Sci 246:258-267 Dyer RF. Esch HV 61976) Polyvinylchloride toxicity in fires. Hydrogen chloride tox icity in fire fighters. JAMA 236:393 -397 Edmonds LD, Falk H, Nissin JE (1975) Congenital malformations and vinyl chloride. Lancet II: 1098 Edmondson HA (1958) Tumours of the liver and intrahepatic bile ducts. In: Edmond son HA (ed) Atlas of tumor pathology, sect VII. fasc 25. Published by Armed Forces Institute of Pathology, Washington, pp I -216 Elmore JD, Wong JL, Laumbach AD, Streips UN (1976) Vinyl chloride mutagenicity via the metabolites chloro-oxirane and chloroacetaldehyde monomer hydrate. Biochem Biophys Acta 442:405-4 19 Elson L, Burnstein N (1954) Idiopathic atrophy of bones of feet with typical "neuro trophic" changes. Am J Med 16:909-914 Escartin Marin P, Alvarez Bustos G, Garcia Plaza A. Fernandez Corugedo A. Arenas Mirave I. Chantar Barrios C f 1974) Hipertension porta idiopatica. Rev Clin Esp 133:255-262 van Esch GJ. van Logten MH (1975) Vinyl chloride; a report of a European assess ment. Toxicology 4:1 --l Fairhall LT (1957) Industrial toxicology. 2nd ed. Williams &. Wilkins, Baltimore Falk H, Waxweiler RJ (1976) Epidemiological studies of vinyl chloride 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 chloride workers. Lancet 11:784 Feron VJ, Kroes R (1979) One-year time sequence inhalation toxicity study of vinyl chloride in rats. II, Morphological changes in the respiratory tract, ceruminous glands, brain, kidneys, heart, and spleen. Toxicology 13:131-141 Feron VJ, Speek AJ. Willems MI. van Battum D. de Grool AP (1975) Observations on the oral administration and toxicitv of vinyl chloride 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 rats. I. Growth, mortality, haematology, clinical chem istry and organ weights. Toxicology' 13:25-23 Feron VJ, Spit BJ, Immel HR, Kroes R (1 979b) One-year time sequence inhalation toxicity study of vinyl chloride in rats. III. Morphological changes in the liver. Toxicology 13:]43-|54 Fiechtner J J. Reyes CN Jri 1976) Angiosarcoma of the liver in a rural population. Four cases 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 E5 ( 1957) Hygienic working conditions in the production of polyvinyl chlor.de resins and measures for improvement. Gig Sanit 1:38 --)2 l Russian text) Filatova VS. Balakhonova LI. Gronsberg ES (1958) Hygienic characteristics of vinyl chloride production. Gig Tr Prof Zabol 2:6-9 (Russian text) Filatova VS, Blagodatin VM. Goffman FE (1964) The efficacy of health measures in the production of polyvinyl chloride resins. Gig Tr Prof Zabol 8:3-6 (Russian text) Fischer J. Wolf R (1963) Die quantitative Abschatzung der Milzgrolse mit Hilfe der Scintigraphie. Dtscit Med Wochenschr 83:1430-1437 Vin vi Fisc he (19 Fleig 1 aV Fleisci Hoi sior Wo. P-mei: ft sh 33 4. U CO e. oj or CJ1 to O A-.' Frongm zion ' Funes-f Go!). L.` Futh i tion ' 'Gabor Apr-, si p. Gama 1 86 Garro A effei Gay BU nde Gedigk vin\ : 278 Gedigk bei . LebYori Gehnni for . App. Gehnr.,. to V| 15Gernts ' with Giaccai 29 J H.J. Marstelle -ilyvinylique Je la mam >n of vinyl chlo- een chloride tox- I vinyl chloride. In: Edmondi by Armed lie mutagenicity icr hydrate. :i typical "neuro- ;do A. Arenas Rev Clin Esp ssess- 33 re 99 effects c/> o sease , o* UI 74b) -a. ro -a. f v.nyl DUS :iot.* on ! ( osmet Toxicol inm toxicity . linical chem- .uce inhaljcion in the liver il population. 06 pex of equipment c Tr Prof Zabol :e production of mi 1:38--i- (Russian ' ristics of vinyl jlth measures in : 6 (Russian text! *- mit Hilfe der Vinyl Chloride-Associated Disease 95 Fischer J. Mundschcnk H. Wolf R i 1 5> Milzszintigraphie mit I-Broniotnercun I 19 7Hg 1-2-hydroxy propan I BMHP). ROEFO 103:349-366 Fleic I, Thiess AM ( 1974) Chromosomen-Untersuchungen bei Vinylchlond-Exposition. Arbeitsmed Sozialmed Praeventumed 9:230-233 Fleischmann R. Schlote W, Schomerus H, Wolburg H. Castrilion-Oberndorfer WL. Hoenscli H f 1977) Kleinknotige Leberzirrhose mit ausgepriigter portaler Hvperten-^ sion als Folge einer Vitantin-A-Into.xtkation bei Psoriasis-Behandlung Dtsch Med Wochenschr 102:1637-1640 Fomenko VN, Katosova LD. Pavlenko GI (1976) Cytogenetic analysis of lymphocytes of the peripheral blood from workers employed in the process of vinyl chloride polymerization. Gig Tr Prof Zabol 20:48-50 (Russian text) Fox AJ (1976) Vinyl chloride and mortality? Lancet 11:417 Fox AJ. Collier PF (1976) Low mortality rates in industrial cohort studies due to selection for work and survival in the industry. Br J Prev Soc Med 30.225-230 Fox Aj. Collier PF (1 977) Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of polvvinyl chloride in Great Britain. Br J Ind Med 34-1-10 Frentzel-Beyme R. Schmitz T, Thiess AM (197S) Mortalitiitsstudie bei VC-/PVCArbeitern der BASF Aktiengeseilschaft. Ludwigshafen am Rhein. Arbeitsmed Sozialmed Praeventivmed 13:218-228 Frey HE ( 1973) Vinyl chlonde and polyvinyl chloride resins. In: Chemical economics handbook, Stanford Research Institute (SRI), Menlo Park, California, pp 580.1881 A-580.1885 B Frongia N. Spinazzola A, Bucarelli A (1974) Lesioni polmonari spenmentali da inalazione prolungata di polveri di PVC in ambiente di lavoro. Med Lav 65:321-342 Funes-Cravioto F. Lambert B. Lindsten J, Ehrenberg L, Natamian AT, OstermanGolkar S (1975) Chromosome aberrations in workers exposed to vinyl chloride. Lancet 1:459 Futh (J, Pietzke HU (1974) Hiimangioendotheliom der Leber nach Thorotrast-Apphkation vor 30 Jahren. ROEFO 1 2 1:398 -399 Gabor S. Radu M. Preda N, Abrudean S, Ivanof L, Anca Z. Valaczkay C (1964) Aprecieri asupra unor modificari hiochimice la muncitorii din industria sintezeik si polimerizati chloruni de vinil. Igiena (Bucharest) 13:409--)IS Gama C. Meira JBB (1978) Occupational acro-osteolvsis. J Bone Joint Surg (Am) 60: 86-90 Garro AJ. Guttenplan JB. Milvy P (I 976) Vinyl chlonde dependent mutagenesis: effects of liver extracts and free radicals. Mutat Res 38:8 1 -SS Gay BW. Lonneman WA, Bridbord K. Moran JB (1975) Measurements of vinyl chlo ride from aerosol sprays. Ann NY Acad Sci 246:236-2^5 Gedigk P, Muller R, Bechtelsheimer H f 1975) Morphology of liver damage among poly vinyl chloride production workers. A report of 5 1 cases. Ann NY Acad Sci 246: 273-285 Gedigk P, Muller R, Schattenberg PJ. Totovic V (1 977) Morphologic der Lsberschaden bei chronischer Vinylchlorid-intoxikation. In: Gutacker HW, Lelbach W'K ieds) Leberschiiden durch Vinylchlond. W'itzstrock. Baden-Baden, Brussel Koln New York, pp 43-52 Gehring PJ. Watanabe PG. Park CN (1978) Resolution of dose response toxicity data for chemicals requiring metabolic activation: example - vinyl chlonde. Toxicol Appl Pharmacol 44:58*I -591 Gehring PJ. Watanabe PG, Park CN (1979) Risk of angiosarcoma in workers exposed to vinyl chlonde as predicted from studies in rats. Toxicol Appl Pharmacol 49: 15-21 Gernts WBJ. van Ake.n WG. van der Mcer J, Vreeken J f 1974) Splenomegaly associated with chronic consumption coagulopathy. Acta Med Scand 195:425---30 Giaccai L f! 952) Familial and sporadic neurogenic acroosteolvsis. Acta Radiol '38:1729 r 1 f f' i' a E: r. ies if S : t 9V * 1 Ji v; H i l1 I ^6 W.K. Lelbach and H.J Marsteller Gitsios CT ( 19T | j Aero-osteolysis in PVC workers. Med Bull Stand Oil Co 3 1:49 -- 56 Gokel JM, Lit'hezeit E, Eder M (1976) Heinangiosarcoma jnd hepatocellular carcinoma of the liver following vinvl chloride exposure. Virchows Arch (Pathol Anati 372: 195-203 Good WO, Ellison C. Archer VE (1975) Sputum cytology among frequent users of pressurized spray cans. Cancer Res 35:2 16-221 Gordon DE. Thomas LB, Kent G, Calandra J, Bahu R. Popper H (1974) Hepatic angio sarcoma in man and rodents following prolonged exposure to vinyl chloride. Gastro enterology 67:794 ' Grannis FW (1975) Guido Banti's hypothesis and its impact on the understanding and treatment of portal hypertension. Mayo Clin Proc 50:41-47 Green T, Hathway DE (1975) The biological fate in rats of vinyl chloride in relation to its oncogenicity. Chem Biol Interact 1 1:545-562 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 DMA in vivo. Chem Biol Interact 22:21 1 --224 Greenberg BE. Street DM (1957) Idiopathic non-familial aero-osteolysis. Radioloey 69:259-262 Greim H, Bonse G, Radwan Z, Reichert D.Henschler D (1975) Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxirane formation. Biochem Pharmacol 24:2013-2017 Greim H. Bonse G, Henschler D (1977) Mutagenitat von Vinylchlorid und anderen chlorierten Xthylenen. In: Gutacker HW, Lelbach WK (eds) Leberschaden durch Vinylchlorid. Witzstrock. Baden-Baden Briissel Koln New York, pp 36-40 Griciute L f 1979) The carcinogenicity of vinyl chloride. IARC Sci Publ 22:3-1 I Grigorescu I, Toba G (1966) Clorura di vinyl. Aspecte de toxicologie industrialc. Rev Chim (Bucharest) 17:499 Hahn E, Aderka D, Suprun H, Shtamler B (1979) Occupational acroosteolysis in vinyl chloride workers in Israel. Isr J Med Sci 15:218--222 Haley TJ (1975) Vinyl chloride: how many unknown problems? J Toxicol Environ Health 1:47-73 Harms I (1954) Ober die familiare Akroosteolyse. ROEFO 80:727-732 Harnasch H (1949/50) die Akroosteolysis. ein neues Krankheitsbild. ROEFO 72: 352-359 Harris DK. Adams WGF (1967) Aero-osteolysis occurring in men engaged in the poly merization of vinyl chloride. Br Med J 111:712-7)4 Heath CW, Falk H, Creech JL (I9755 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, Gehnng PJ (1 975a) 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 chloride. Toxicol AppI Pharmacol 34:529-532 Henschler D (ed) (1972/73) Gesundheitsschiidiiche Arbeitsstoffe, Verlag Chemie, Weinheim Henschler D (1977a) Metabolismus von Vinylchlorid. In: Gutacker HW. Lelbach WK (eds) Leberschaden durch Vinylchlorid, Witzstrock, Baden-Baden Briissel Koln New York, pp 27-3 1 Henschler D (1977b) Metabolism and mutagenicity of halogenated olefins - a com parison of structure and activity. Environ Health Perspeet 21:61 -64 Henschler D (1977c) Mechanismen der Aktivierung chlorierter aliphatischer Verbindungen - experimentelle Zugange und klinische Bedeutung. Arzneim Forsch 27: 1827-1832 Vinyl Chloride-,' Heusermann U. chlorid-Kran- Heusermann U, strukturelle l Arch (Pathol Holmberg B, Kr- mice. Acta V\ Hooper NK, Har 603 Hruban Z, Russe in livers of tw Huberman E. Bai cells by two v- hyde. Int J C- Hublet P (1975/ Belg Med Soc Hublet P, Lefts r,, sarcome du fo vinyie monom Huet PM, Guillau sinusoidal por Gastroenterol- Hussain S, Osterr vinyl chloride [ARC (1974) Ini vinyl chloride Iber FL (1969) O tension. Anr. *. Iber FL( 1970 NY Acad Sci ' Imanaga H, Yam. tension accorv Infante PF (197t ride product!:- Infante PF. Wag-- of vinyl-chlon Infante PF. Wjg, of vinyl-chlon- Irish DD (1963) Toxicology, w f) l to 30 ito M ston; Folia Ivai W 4. A, ! o Jacc tpnS P Jaeg ttoo icro 14 I ; eriai .f Qu '75) ai Jaegi in l1 . ync ins i 726 Jaeger RJ, Conoll- ated hydrocari h and H.J. Marsteller d Oil Co 31:49-56 loecllular carcinoma I'athol Anat) 372: :ruquent users of 1974) Hepatic angioi'lyl chloride. Castro- ic understanding and chloride in relation to c S-containg metabo- 'i -at liver DNA in ,-olysis. Radiology lutagenicity in vicro ction of metabolic lurid und anderen :-herschaden durcli pp 36--10 . Publ 22:3 -11 <ie industrials. Rev . .osteolysis tn vinyl I Toxicol 1- iviron 732 id. ROEFO '2. ngagcd in `he poiy- .ciosarcoma of the V Acad Sci 246: i.. < of the fate of 135-148 "sorption of vinyl . Verlag Chcmic, cr HW. Lslbach WK len Brussel Koln I olefins -- a comM -64 lijdutischcr Verhin\rzneim Forsch. 27' Vinyl Chloride-Associated Disease 97 Hcusermann U, Stutte HJ f |97"j) Zur Atiologie dcr Tlironibiv.ytnpenie bei der Vinylchlond-Krankheit. Blut 35:317-322 Heuscnuann (J. Stutte HJ t 1977b) Enzymlnstocheinischc. histomctrisclie und ultra* strukturelle Untersuchungen von Milzen bei der Vinylehlorid-Krankheit, Virchows Arch (Pathol Anat) 375:303-317 Hohuberg B, Kronevi T. Winell M (1976) The pathology ot vinyl chloride exposed, mice. Acta Vet scand 17:238-342 Hooper NK. Harris RH. Ames BN ( 1979) Chemical carcinoecnesis. Science 203:602603 Hruban Z. Russell RM, Boyer JL.Glacov S. Bagheri SA 11974) Ultrustruetural changes in livers of two patients with hypervitaminosis A. Am J Pathol 76:451 -462 Huberman E. Bartsch H, Sachs L ( 1975) Mutation induction in Chinese hamster V79 cells by two vinyl chlonde metabolites, chloroethylene oxide and 2-chlaroaeetaldehyde. Int J Cancer 16:639-644 Hublet P (1975) Expose des nuisances industriclles dues au chlorure de vjnvle. Arch Belg Med Soc 33:73-89 Hublet P. Leflvre MJ, Decuyper L, Hanin C, Hamels J. Fievez M (1977) Un cas d'angiosarcome du foie chez un travailieur ayant tfi longuement expose au chlorure de vinyle monomre. Arch Belg Med Soc 35:601 -622 Huet PM, Guillaume E.Cote J. Legate A, Lavoie P, Viallet A (1975) Noncirrltotic presinusoidal portal hypertension associated with chronic arsenical intoxication. Gastroenterology 68:1270-1277 Hussain S, Osterman-Golkar S (1976) Comment on the mutagenic effectiveness of vinyl chloride metabolites. Chem Biol Interact 12:265-267 1ARC (1974) Internal Technical Report no. 74/005. Report of a working group on vinyl chloride. Lyon 24-25 June 1974, pp. 1 -55 Iber FL(1969) Obliterative portal venopathy of the liver and idiopathic portal hyper tension. Ann Intern Med 71:660-661 Iber FL (1970) Portal hypertension in the presence of normal liver morphology. Ann NY Acad Sci 170:1 15-126 Imanaga H, Yamamoto S, Kurovanagi Y (1962) Surgical treatment of portal hyper tension according to state of intrahepatic 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, Waxweiler RJ, Falk H 11976a) Genetic risks of vjnyl-chloride. Lancet 1:734-735 Infante PF, Wagoner JK. McMichael AJ, Waxweiler RJ. Falk H ( 1976b) Genetic risks of vinyl-chloride. Letter to the editor. Lancet f: 1 289- 1 290 Irish DD 11963) Halogcnated hydrocarbons: 1. Aliphatic. In: Fasset DW. Irish DD(eds) Toxicology. Wiley, New York London (Industrial hvgiene and toxicology, vol II. pp 241 ff) Ito T. Nemoto M (1952) Die Kupfferschen Sternzellen und die "Fectspeichefungsze!len" (fat-storing cells) in der Blutkapillarenwand in der menschlichen Leber. Okajima Folia Anat Jpn 24:243--258 Ivanetich KM, Aronson l. Katz ID f 1977) The interaction ot vinyl chloride with rat hepatic microsomal cytochrome p450 in vitro, Biochem Biophys Res Commun 74:1411-1418 Jacob PJ. Theriault GP ( 1975) Distribution of primary cancers of the liver in the province of Quebec. Can Med Assoc J 1 12:305-307 Jaeger RJ (1975) Vinyl chloride monomer: comments on us hepatotoxieity and inter action with 1.1. dichloroethylcne. Am NY Acad Sci 246:150-15 1 Jaeger RJ. Reynolds ES, Conolly RB. Moslen MT, Murphy SD (I 974) Acute hepatic injury by vinyl chloride in rats pretreated with phenobarbital. Nature 252:724 726 Jaeger RJ. Conolly BB. Murphy SD f 1975) Short-term inhalation toxicity of halogenated hydrocarbons. Arch Environ Health 30:26-31 - >**** 98 W.K. Lelbach ami H.J. Marsteller Jaeger RJ. Murphy SD. Reynolds ES, Szabo S. Moslen MT (1977) Chemical modifica tion of acute hepatotoxicity of vinyl chloride monomer in rats. Toxicol Appl Pharmacol 4 1:597 --607 Jayson MI V, Lloyd-Jones K. Berry DC. Bromiee M (1976a) Resorption of the mandible in vinyl chloride acroosteolysis. Arthritis Rheum 19:971 Javson MIV. Bailey AJ, Black C. Jones KL (1976b) Collacen studies in acroosteolysis. Proc R Soc Med 69:295-297 Johnson MN, Creech JL Jr (1974) Angiosarcoma of liver in the manufacture of poly vinyl chloride, j Occup Med 16:150-151 Jiihe S, Lange CE (1972) Sklerodermieartige Hautveriinderungen, Raynaud-Svndrom und Akroosteolysen bei Arbeitern der PVC-herstellenden Industrie. Dtsch Med Wochenschr 97:1922-1923 Jiihe S, Veltman G (1972) Zur Klinik der sogenannten Vinylchloridkrankheit. (Sklerodermie-Shnliche Veninderungen bei ATbeitem der PVC-herstellenden Industrie.) 1. Internationales Symposium der Werksarzte der chemischen Industrie. Ludwieshafen, 27.-29.4.1972. pp 267-276 Jiihe S. Lange CE, Stein G. Veltman G (1973) Ober die sogenannte VjnylchloridKrankheit. Dtsch Med Wochenschr 98:2034--2037 Jiihe S. Lange CE. Stein G, Veltman C> f 1974) Ober die sogenannte VinylchioridKrankheit. Berufsdermatosen 22:4-22 Kappus H, Bolt HM, Buchter A, Bolt W (1975) Rat liver mierosomcs catalyse covalent binding of1 *C-vinylchloride to macromolecules. Nature 257:134-135 Kappus H, Bolt HM, Buchter A. Bolt W (1976) Liver microsomal uptake of l4C vinyl chloride and transformation to protein alkylating metabolites in vitro. Toxicol Appl Pharmacol 37:461 -47 I Karstadt M (1976) PVC: Health implications and production trends. Environ Health Perspect 17:107-115 Keplinger ML, Goode JW Gordon DE, Calandra JC (1975) Interim results of exposure of rats, hamsters, and mice to vinyl chloride. Ann NY Acad Sci 246:219-220 Kettner H (1975) Umweltschutz in der Sowjetunion. III. .Maximale Arbeitsplatz-Konzentrationen (MAK-Werte) von Schadstoffen und ihre Normierung. In: Berichte des Osteuropa-Instituts. Heft 108. Freie Universitiit. Berlin Kistler HJ, Pliier S, Dickenmann W, Pirozynski W (1977) Portale Hypertonie ohne Leberzirrhose bei chronischer Vitamin-A-lntoxikation. Schweiz Med Wochenschr 107:825-832 Kluge T, Sommerschild H, Flatmark A (1970) Sinusoidal portal hvpertenston. Surgery 68:294-300 Knolle J. Forster E, Roessner A, Themann H, Hohn P. Meyer zum Biischcnfelde KH (1974) Die nichtzirrhotische portale Fibrose (hepatoportale Sklerose) nach chroni scher Arsenvergiftung. Dtsch Med Wochenschr 99:903-908 Koischwjtz D. Marsteller HJ, Lackner K, Brecht G, Brecht T (1980) Vcranderungen der Hand- und Fingerarterien bei der Vinylchloridkrankheit. ROEFO 1 32:62-68 Konetzke G, Bittersohl G, Grund W. Schramm T. Teichmann B. Zschunke E (1978) Ober die Bedeutung des Vinylchlorids als Schadstoff aus der Sicht der Arbeitsme- dizin, experimentellen Onkologie und Industnetoxikologie, Z ges Hyg 24:501 -507 Komblum K (1 929) Bone chanaes in Ravnaud's disease. Am J Roentgenol 2 1 ;448- 452 Kovac A, Kurajica L. Juric-Ruzic D, Parac B C1969) Acropathia extremitatum in poly- merizattone vinyl-chloridi - nova profesionalna bolest. LijeZ" Vjesn 91:5-17 Kramer CG, Mutchler 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 Sci Labour 33:1 -22 Kurokawa 5. Inagaki T, Okuyama S (1977) Electron microscopic observation of the liver in portal hypertension following chronic exposure to vinyl chloride monomer Gastroenterol Jpn 1^:64-69 20 Co hlo (n O ,ck A cOn ure i- tJ. B. to J in v RJ. Blvl chi RJ, St rarative Congress Laib RJ, Si parativ.. 463 Laib RJ, T-t. comparizyme de' Lander JJ.v the liver Langauer-L. aemia in Health 3Lange CE. \ Gutacker Baden-8:Lange CE. J heit - ei: Lange CE. J Leber be 99:150Lange CF ' produeti Lange CE, P Veltm-v heit bei sche unit tisch E,' 16. Jahn. Lange CE. h workers Paris Lev. Laroche G neuro-ei. Lassiter DV 176-17Laws JW, L: tis and < Laws JW. F; digital arLee Ft, Har 1:1316 Lee FI, Har: chloride Lefaux R (: Lefevre MJ Intern,,! 27.-29 s R&S 005125 .mil H.J. Marsteller liemieal modificaoxicol Appl f the mandible icroosteolysis. :ture of poly- md-Syndrom )tsch Med .kheit, (SkleroIndustrie.) rie, Ludwigs- Vinylchlorid- Vinylchlond- < catalyse covalent 1 -135 ptake of l4C vinyl vitro. Toxicol Environ Health *->iIts of exposure ' ii>.219-22'"' \rbeitsplata-KonIn: Berichte des .wrtonie ohne .J Wochenschr 'fension. Surgery " Kchenfeldr KH i>e) nach chroni- Veranderuncen liFO 132:62-68 hunke E(1978) ut der Arbeitsme- Hyg 24:501 -507 ntgenol 21:448- remitatum in poly>n 91:5-17 ironmental mea.s-,oc J 33:19-30 ' industries. i'servation of the chloride monomer. Vinyl Chloride-Associated Disease 99 Kuzmack AM. McGaueliy RE ( 1975) Quantitative risk assessment for community ex posure to vinyl chloride. U S. EPA.'ORD Report. December 1975 Laib RJ. Bolt HM (1977) Alkylation of RNA by vinyl chloride metabolites in vitro and in vivo: formation of I -N*-etheno-adenosine. Toxicology 8. 185-195 Laib RJ. Bolt HM (1978) Formation of 3-N4-etheno-cytidine moieties in RN'A by vinyl chloride metabolites in vitro and in vivo. Arch Toxicol 39:235 Laib RJ. Strickle G. Bolt HM (1978) Induction of premalignant hepatic lesions: com parative effects of vinyl chloride and trichloroethylene. Paper presented at the 20th Congress of European Society of Toxicology, Berlin (West). June 25-23, 1973 Laib RJ, Strickle G. Bolt HM (1979) Induction of premalignant hepatic lesions: com parative effects of vinyl chloride and trichloroethvlene. Arch Toxicol (Suppl) 2: 463 Laib RJ, Strickle G, Bolt HM, Kunz W (1979) Vinyl chloride and trichloroethylene: comparison of alkylating effects of metabolites and induction of preneoplastic en zyme deficiencies in rat liver. Cancer Res Clin Oncol 94:139-147 Lander JJ. Stanley RJ, Summer HW, Boswell DC. Aach RD (1975) Angiosarcoma of the liver associated with Fowler's solution. Gastroenterology.68:1582-1536 Langauer-Lewowicka H. Dudziak Z. Byczkowsky Z. Marks J f 1976) Cryoglobulinaemia in Ravnaud's phenomenon due to vjnvl chloride. Int Arch Occup Environ Health 36:197-207 Lange CE, Veltman G (1977) Dermatologische Aspekte der Vinylchloridschiiden. In: Gutacker HW. Lelbach WK (eds) Leberschaden durch Vinylchlorid. Witzstrock, Baden-Baden Brussel Kriln New York, pp 55-68 Lange CE, Jiihe S, Stein G, Veltman G (1974a) Die sogenannte Vinylchlorid-Krankheit - eine berufsbedingte Systemsklerose? Int Arch Arbeitsmed 32:1 -32 Lange CE, Jiihe S. Veltman G f 1974b) liber das Auftreten von Angiosarkomen der Leber bei zwei Arbeitem der PVC-herstellenden Industrie. Dtsch Med Wochenschr 99:1598-1599 Lange CE, Jiihe S, Stein G, Veltman G (1975) Further results in polyvinyl chloride production workers. Ann NY Acad Sci 246:18-21 Lange CE, Bloch H, Biersack HJ. Sehrt U. Etzel F, Marsteller HJ. Lelbach WK. Veltman G (1976a) Chronisch-toxische Schiiden im Sinne der Vinylchlorid-Krankheit bei Arbeitem in PVC-weiterverarbeitenden Betrieben. Klinische, laborchemische und szintigraphische Untersuchungsbefunde, In: Bolt W. Buchter A. Reben* tisch E. Worth D feds) Jahresbericht der Deutschen Gesellschaft fur Arbeitsmedizin. 16. Jahrestagung, Kriin 5 -8.5.1976. Gentner. Stuttgart, pp 195-200 Lange CE, Bloch H. Veltman G. Doss M (1976b) Urinary porphyrine among PVCworkers. In: Doss M (ed) Porphyrins in human diseases. Karger. Basel Miinchen Paris London New York Sidney, pp 352-35 5 Laroche G. Hochfeld M (1948) Un cas d'acro-osteolyse associtf a un syndrome osteoncuro-endocrinien complexe. Sem Hrip Paris 24:984-991 Lassiter DV (1976) Vinyl chloride - best available technology. Ann NY Acad Sci 271: 176-178 Laws JW. Lillie JG, Scott JT (1963.) Arteriographic appearances in rheumatoid arthri tis and other disorders. Br J Radiol 36:477--193 Laws JW, El Sallab RA, Scott JT (1967) An arteriographic and histological study of digital arteries. Br J Radiol 40:740--747 Lee FI. Harry DS (1974) Angaosarcoma of the liver in a vinvl chloride worker. Lancet 1:13 16-13 iS Lee FI. Harry DS. Adams WGF. Litchfield M (1 977) Screening for liver disease in vinyl chionde workers. Br J Ind Med 34:142-147 Lefaux R (1966) Chemie und Toxikologie der Kunststoffe. Krausskopf. Mainz Lefevre MJ (1972) Akroosteolyse in Zusammenhang mit der PVC-HerStellung. In: Internationales Symposion der Werksarzte der Chemisciien Industrie. Ludwigshafen 27.-29.4.1972,pp69-79 * R&S 005126 100 W.K. Lelbach and H J. Marsteller Lelbach WK. Marsteller HJ ( 1977) Das laparoskopische Biid dcr Vinylehlorid-Krunk* heii. In: Lindner H (ed) Fortschritte dcr gastroenterologischen Endoskopic, vo! 8. Witzstrock, Baden-Baden Brussel, pp 37-40 Lester D. Greenberg LA, Adams \VR (1963) Effects of single and repeated exposure of humans and rats to vinyl chloride. Am Ind Hyg Assoc J 24:265-275 Liebegott G (1949) Pathologische Anatomie der chronischen Arsenvergir'tung. Dtscit Med Wochenschr 74:855-856 Liebegott G (1952) Uber die Beziehungen zwischen ehronischer Arsenvergiftting nnd maiignen Neubildungen. Zentralbl Arbeitsmed Arbeitssckutz Prophyl 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 Chromatogr 128:183-187 Lifevre JA.Gama G (1957) L'acroosteolyse. Bull Mem Soc Med Hop 73.109--120 Lilis R, Anderson H, Nicholson WJ, Daum S, Fishbein AS. Selikoff IJ (1975) Preval ence of disease among vinyl chloride and polyvinyl chloride workers. Ann NY Acad Sci 246:22-41 Lilis R. Anderson H, Miller A. Selikoff IJ f 1976) Pulmonary changes among vmyl chloride polymerization workers. Chest 69:299-303 Lilis R, Anderson H, Miller A. Selikoff U (1977) Modifications pulmonaires et exposi tion au chlorure et polychlorure de vinyle. Med Hyg 35:1542-1545 Lloyd JW (1974) Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. J Occup Med 16:809 Lloyd JW (1975) Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. J Occup Med 17:333-334 Loprieno N, Barale R. Baroncelli S. Bauer C, Bronzetti G. Cantmellini A, Cercignani G. Corsi C, Gervasi G, Leporini C, Nieri R, Rossi AM. Stretti 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 Loprieno N, Barale R. Baroncelli S. Bartsch H. Bronzetti G. Catnmellini A. Corsi C. Freza D, Nieri R, Leporini C, Roscllini D. Rossi AM ( 1977) Induction of gene mu tations and gene conversions bv vinyi chloride metabolites in yeast. Cancer Res 36:253-257 MacSween RNM, Vetters JM. Ross SL. Ferguson J, Johnstone JM, Sandison AT(1973) Haemangio-endothelial sarcoma of the liver. J Pathol 109:39-44 MAK-Werte (1975) Umweltschutz in der Sowjetunion. III. Maximale ArbeitsplatzKonzenUacionen (MAK-Werte) von Schadstoffen und litre Normierung. In: Benchte des Osteuropa-Instituts. Heft 108, Freie Universitiit. Berlin, p 67 Makk L. Creech JL, Whelan JG Jr. Johnson MN (1974) Liver damage and angiosarco ma in vinyl chloride workers. JAMA 230:64-63 Makk L. Delorme F, Creech JL (1975) Angiosarcomes du foie cheZ des ouvriers ayant ete en contact prolonge uvec le chlorure de vinyle: epidemiologic et programme de recherches chez les ouvriers. Union Med Can 104:1833-1835 Makk L. Delorme F, Creech JL Jr, Ogden (I LL. Faded EH. Songster CL. Clanton 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. Jacquiznon P (1975) Mutagenicity of vinyl chloride, chloroethyleneoxide. chloroacetaldehyde and chloroethanol. Bioehem Biophvs Res Comraun 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 Maltom C (1973) Occupational carcinogenesis. Excerpta Medica Int Coner Ser 322: 19-26 Maltoni C (1974) Angiosarcoma epatico in operai esposti a cloruro di viniie. Resoconto dei primi due casi riscontruti in Italia. Med Lav 65:445 -450 Maltoni C (1975) The value of predictive experimental en v iron men tjl carcinogenesis. Ambio 4:18-23 II.J. .Marsteller lorid-Rrankkopie, vol 8. J exposure of Hing. Dtseh rgiftunz und 2.15-16 mrs at low 183-187 109--120 ' 0751 Preval* Ann NY Asad ong vinyl res et expost* hloride ..hloride , Cereignani G. G, f 1976) EvalM) under Res 40:85-96 A. Corsi C. n of gene nuti `jiKer Res i- n AT ll<>73) beitsplatz* ma. In: Berichte 30 C :W rcu- sent ,'e de O t J. Ul ho an P de >duc :k lgr Ser 322: mle. Reso* in. mogenesis. Vinyl Cliioride-Assoeiated Disease 101 .Maltoni C (1976) Occupational chemical carcinogenesis: new facts, priorities, and perspectives. IARC Sci Publ 52:1 27-134 Maltoni C f 1977) Recent findings on the carcinogenicity of chlorinated olefins. Environ Health Perspect 21:1-5 Maltoni C. Lefemine G (1974a) Carcinogenicity bioassays of vinyl chloride. I. Research plan and early results. Environ Res 7:387-405 Maltoni C. Lefemine G ( 1974b) La potenzialita dei sjegi speriitientali nella predizione dei rischi oncogeni ambientali. Uti esempio: II cloruro di vjnilc. Academia Nazionale dei Lincei. Estratto dai Rendiconti della Classe di Seienze tisiche. matematiche e naturali. Ser VIII, vol LV1. fas 3 Maltoni C, Lefemine G (1975) Carcinogenicity bioassays of vinyl chloride: current results. Ann NY Acad Sci 246:195-218 Maltoni C.Crespi M, Burch PJ (eds) ( 1973) II. International Symposium on Cancer Detection and Prevention. Excerpta Medica lnt Congr Ser 275:1 -137 Maltoni C, Lefemine G. Chieco P, Carretti D (1974a) La cancerogenesi ambientale e professionale: Nuove prospettive alia luce della cancerogenesi da cloruro di vinile. Osp Vita 1:66 Maltoni C. Lefemine G. Chieco P, Carretti D (1 974b) Vinyl chloride carcinogenesis: current results and perspectives. Med Lav 65:421 -444 Maltoni G. Ciliberti A. Gianni L. Chieco P (1975) Insorgenza di angiosarcomi in ratti. in seguito a somministrazione per via orale di cloruro di vmile. Osp Vita 2:65 -66 Maricq HR. Johnson MN, Whetstone CL, LeRoy EC (1976) Capillary abnormalities in polyvinyl chloride production workers. JAMA 236:1368-1371 Maricq HR, Darke CS, Archibald R McL, LeRoy EC < 1978) In vivo observations 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. Baltie R. Pierre C (1967) Acro-osteolyse d'origine professionnelle. Rev Rhum Mai Osteoartic 34:340-35 1 Markowitz SS. McDonald CH. Fethiere W, Rerzner MS f 1972) Occupational acroosteolysis. Arch Dermatol 106:219-223 Marleau D. Villeneuve JP, Huet PM. Cote J. Lafortune M, Legare A, Lavoie P. Viallet A (1974) Noncirrhotic idiopathic portal hypertension (OPH): Radiological and hemo dynamic evaluation of 4 cases by combined hepatic and umbilicoportal catheteriza tion. Gastroenterology 67:8 13 Marsteller HJ, Lelbach WR (1977) Das internmedizinische Bild bei Vinylchloridschiiden. In: GutackerHW, Lelbach WR (eds) Leberschiiden durch Vinylchlond Vinylchlorid-Krankheit. Witzstrock. Baden-Baden Brussel Roin New York, pp 6983 Marsteller HJ, Lelbach WK. Miiller R, Jiihe S. Lange CE. Rohner HG, Veitman G (1973) Chronisch-toxische Leberschiiden bei Arbeitem in der PVC-Produktion. Dtsch Med Wochenschr 98:23 1 1 -23 14 Marsteller HJ, Lelbach WR, Muller R. Gedigk P (1975a) Unusual spienomegalic liver disease as evidenced bv peritoneoscopy and guided liver biopsy among polyvinyl chloride production workers, Ann NY Acad Sci 246:95-134 Marsteller HJ. Lelbach WR. Muller R. Gedigk P, Lange CE (1975) Klinische und laparoskopische Aspekte der Leberschiiden bei Chemiearbeitem in der Vinylchlorid-Polymerisation. Leber Magen Darm 5:196-202 Marsteller HJ. Lelbach WR. Lange CE. Veitman G ( 1976) Chronisch-toxische Schiiden im Sinne der Vinylchlorid-Rrankheit bei Arbeitem in PVC-weiterverarbeuenden Betrieben. In: Bolt W, Buchter A. Rebenusch, E, Worth D (eds) Verhandlungen der Deutschen Gesellschaft fiir Arbeitsmedizin. 16. Jahrestaeung. Gentner, Stuttzart, pp 201-207 Martin JF. Waggoner JG, Berk PD (1974) Persistence of vinyl chloride (VC) induced liver injury after cessation of exposure. Gastroenterology 67.814 M M 102 W.K. Lelbach and H.J. Marsteller Mastromatteo E. Fisher AM, Christie H. Dunziger H (1960) Acute inhalation toxicity of vinyl chloride to laboratory animals. Am Ind Hyg Assoc J 5:394-398 Maueh TH II (1978) Chemical carcinogens: how dangerous are low doses? Science 202:27-4 l McCann J, Simmon V, Streitwieser D, Ames BN (1*775) Mutagenicity of chloroacetaldehyde.a possible metabolic product of 1,2-dichloroethane fetltylene dichloridel. chloroethanol (ethylene chlorohydrin), vinyl chloride, and cyclophosphamide. Pruc Natl Acad Sci 72:3190-3193 McMichael AJ,-Haynes SO, Tyroler HA (1975) Observation on the evaluation of occu pational mortality data, J Occup Med I 7:1 28-13 l Mendenhall CL, Sherman J, Chedid A (1974) 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) Extraand intrahepatic portal hypertension without cirrhosis (hepatoportal sclerosis). Ann Surg 162:602-620 Miller A (1975) Pulmonary function defects in nonsmoking vinyl chloride workers. Environ Health Perspect 1 1:247-256 Miller A, Teirstein AS. Chuang M, Selikoff IJ, Warshaw R (1975) Changes in pulmo nary function in workers exposed to vinvl chloride and polyvinvl 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 chloride disease. Br J Dermatol (Suppl 16) 99:45 --IS 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 vinylchioride workers. Lancet 11:397-398 Morris JS. Schmid M, Newman S, Scheuer PJ. Sherlock S (1974) Arsenic and non cirrhotic portal hypertension. Gastroenterology 66:36-94 Moser KM (1976) Meat wrapper's asthma. JAMA 236:2846-2847 Moulin O, Rety J. Pailiard P, Vouillon G. Guttin G (1974) Aspects sclerodcrmiques de l'acro-osteolyse professionnelle, Ann Dermatol Syphiligr 101:33-44 Muller G. Norpoth K (1975) Bestimmung zweier Urinmetabolite des Vinylchlorids. Naturwissenschaften 62:541 Muller G. Norpoth K. Eckard R (1976) Identification of two urine metabolites of vinyl chloride by GC-MS-investigations. Int Arch Occup Environ Health 3S 69-75 Muller G. Norpoth K, Kustcrs E. Herweg K. Versin E (1978) Determination of thiodiglyeolic acid in unne specimens of vinyl chloride exposed workers. Int Arch Occup Environ Healtli 4 | : 1 99-205 Miiller R. Gedigk P. Bechtelsheimer H f I 974) Neuere morpholoeische Befunde in Jer menschlichen Leber nach Vinvlchlorid-Exposition. In: Lelmert G. Szadkowski D. Weber HJ (eds) 14. Jahresbericht der Deutschen Gesellschaft fur Arbeitsmedizm. 17.-19.10.1974. Hamburg. Centner. Stuttgart, pp 267-269 Muller R. Bechtelsheimer H. Gedigk P, Marsteller HJ, Lelbaeh WK ( 1975) Das morphologische Bild der Leberschiidigung nach chronischer Vinylchlond-E.xposition. Leber Magen Darm 5:204-208 Miiller W, Baida BB (1975) Polyvinylchlorid-Krankheit unter dem Bild einer Akrosklerodermie. Hautarzt 26:387 Muenter MD, Perry HO. Ludwig J (1971) Chronic vitamin A intoxication in adults Am J Med 50:129-136 Myers SA. Quinn IIJ. Zook WC f 1975) Determination of vinyl chloride monomer at the sub ppm level using a personal monitor. Am lnd live Assoc J 36 332 337 Vinyl C Neale G hyp; Neuma' and berg Nichols chlu Nichols cohi 230 Noria D expo Patln Norpotl uber latio Arbe Nothna;. Hits, Oster R Ane- Osternu Wadchlot Osterm.. tech: Ott MG trial Page M wo;. Panh M by i Parnu'i lavo: Patti 1 edn Patty T new 196.- Penin 1' troe B re it Den' Suit People1 Exp Pessax r and d H.}, Marsteller xicit\ 33 (n io oU1 !i N> <> ce cetonde). :. Proc OCCU- irten- *c of ' 0965) Extra I 'derosis). Ann ide workers. ees in pulmo'iride. Ann NY h liver disease j'pl 16)99:45-43 - a guide to ' Med Sci ng vinylcldii- and non- 'dermique- da ylchlorids 1 ilites of vinyl i>9 -75 ion of thiodi- 4rch Oeeup funde in der .idkowski D, itsmedizin. `1 Das morpho'osition. Leber ner Akro- i in adults. 'innorncr at ; 3 2 -- 3 37 Vinyl Chloride-Associated Disease 103 Neale G. Azzopardi JG (1971) Chronic arsenical poisoning and non-cirrhotic portal hypertension - a case for diagnosis. Br Med J 11:725-730 Neumann HG, Osborne JC. Metzlcr M ( 1979) Peroxidase activity in rat Zymbal's gland and its possible role for the metabolic activation of carcinogens. Naunyn Schmiedebergs Arch Pharmacol (Suppl) 307: R15 Nicholson WJ {1977) Cancer following occupational exposure to asbestos and vinyl chloride. Cancer 39:1792-1801 Nicholson WJ, Hammond EC. Seidman H. Selikoff IJ (1975) Mortality experience of a cohort of vinyl chloride - polyvinyl chloride workers. Ann NY Acad Sci 246:225230 Noria 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 36:361 Norpoth K, Muller G, Witting U. Goctschalk D. Gottschalk J (1976) Untersuchungen iiber den Stoffwechsel des Vinylehlorids und uber Wirkungen der Vjnylchloridinhalation auf Regulationsmeehanismcn des Leberstoffwechsels. Verh Dtsch Ges Arbeitsmed 16:187 Nothnagel H. Rossbach MJ (1880) Handbuch der Arzneimittellehre. 4. Auflage. Hirscitwald, Berlin Oster RR, Carr CJ, Krantz JC (1947) Anesthesia XXVII, Narcosis with vinyl chloride. Anesthesiology 8:359-361 Osterman-Golkar S, Hultmark D, Segerback D. Calleman CJ, Gothe R, Ehrenberg L. Wachtmeister CA (1977) Alkylation of DNA and proteins in mice exposed to vinyl chloride, Biochem Biophys Res Commun 76:259-266 Ostermayer H (1967) Vinylchlorid. in: Foerst W (ed) Ullmanns Encyklopadie der technischen Chemie. vol 16, Urban <& Schwarzenberg, Miinchen, pp 87-94 Ott MG, Langner RR. Holder BB f 1975; Vinyl chloride exposure in a controlled indus trial environment. Arch Environ Health 30:333-339 Page M. Theriault L. Delorme F (1976) Elevated CEA levels in polyvinyl chloride workers. Biomedecine 1976:279 Panh Meng H, Faure H, Pasquier D. Couderc P (1977) Liver angiosarcoma occasioned by exposition to vinyl chloride. Acta Pharmacol Toxicol (Kbh) (Suppl) 4-1:331 Parmegciani L. Sassi C (1955) Rischi e patologia professionale neila produzione e nella lavorazione di alcune materie plastiche, Med Lav 46:14-24 Patty FA(ed)(I958) Industrial hygiene and toxicology, vol I: General principles, 2nd edn. Interscience Publishers. New York Patty FA. Yant WP, Waite CP (1930) Acute response of guinea pigs to vapors of some new commercial organic compounds. V, Vinyl chloride. Public Health Rep 45: 1963-1971 Penin H, Sargar G. Lange CE, Veltman G (1975) Neurologisch-psychiatrische und elektroenzephalographische Befunde bci Patienten mit Vinylchlorid-Krankheit. In: Brenner W, Rohmert W. Rutenfranz J feds) Bericht iiber die 15. Jahrestagung der Deutschen Gesellschaft fur Arbettsmedizm. Miinchen 24.-26.4.1975. Gentner. Stuttgart, pp 299-304 Peoples AS. Leake CD < 1933) The anesthetic action of vinyl chloride. J Pharmacol Exp Ther 48:284 Pessayre D. Wandscheer JC. Descatoire V. Artigou JY, Bcnhamou JP (1979) Formation and inactivation of a chemically reactive metabolite of vinyl chloride. Toxicol Appl Pharmacol 49:505-5 15 Peters JM (1976) Public-Health rounds at the Harvard School of Public Health Persepctives. N Engl J Med 294:653 -657 Pillichowski P, Faure C, Aubert M, Pahn M, Latreille R. Barrie J (1979) Angiosarcome costal lie a une intoxication au chlorure de polyvinyl. Nouv Presse Med 3:2485 Pimentel Cortez J. Menszes Peixoto A 1 1977) Liver disease in vineyard sprayers. Gastroenterology 72:275-283 104 W.K. Lelbuch and H.J. Marsteller Vinyl Ch. Piver WT (1976) Diffusion of residual monomer in polymer resins, t'nviron Health Per- Regnault XJ sped 17:227 -236 olbildv Polish E. Christie J. Cohen A, Sullivan B ( 1962) Idiopathic presinusoidj! portal hyper Rein FR. tension iBanti's syndrome). Ann Intern Med 56:624-627 Kollek Polyvinyl chloride banned in Japan (1974) JAMA 229:855 Reinl W l Popper H ( 1975) The heuristic importance of environmental pathology. Lessons from des L-- the vinyl chloride problem. Arch Pathol 99:69-7 l Rein! W.\ Popper H. Thomas LB (1975) Alterations of liver and spleen among workers exposed Geweri to vinyl chloride. Ann NY Acad Sci 246:172-193 Reinl W. ' Popper H. Udenfriend S (1970) Hepatic fibrosis. Correlation of biochemical and mor phologic investigations. Am J Med 49:707-721 rid-Kra Reinl W.' Popper H, Thomas LB, Falk H. Berk PD, Selikoff I (1974) Banti syndrome followed der Gc by hepatic angiosarcoma in vinyl chloride 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 f 1978) Development of hepatic angiosarcoma in man induced bv vinyl chlonde, thorotrast, and arsenic..Am J Pathol 92:349-370 Preston BJ, Jones KL, Grainger RG (1976) Clinical aspects of vinyl chloride disease. Proc R Soc Med 69:284-236 Prodan L, Suciu I. PTslaru V, Ilea E, Pascu L f 1975) Experimental acute toxicity of vinyl chloride (monochloroethene), Ann NY Acad Sci 246:154-163 Puech AM, Foumet A, Laulhere L, Faure J. Cau G. Mallion JM (1977) Etude des lesions hepatiques observees chez 5 sujets exposes au chlorure de vinyle dont 3 cas d'angiosarcome hepatique. Arch Mai Prof 38:787-795 Purchase LFH, Williamson KS (1974) Proportional mortality among vinyl-chloride workers. Lancet 11:591-592 Reinl W. v der Ge Reinl W. v der Ge- RH. he 30 L. rvi CD i M Sc o o CJ1 Is -a CO o 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 (I 976) Chromosomal effects in peripheral 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 28:13 2-135 1 Russian text) Radwan Z f 1977) Uptake and rate of metabolism of vinyl chloride by the isolated per fused rat liver preparation. Int Arch Occup Environ Health 40:101-1 10 Radwan Z, Henschler D (1975) Uptake and metabolism of vinyl chloride in the isolated perfused rat liver preparation. Naunvn Schmiedeberzs Arch Pharmacol fSuppI) 287:R100 vinyl d 18:36Richards i Natui. Roche J tions. IRoche J. I hepaii2:669 Ramalingaswami V, Wig KL. Sama SK (1962) Cirrhosis of the liver in northern India Ross JM i a clinicopathological study. Arch Intern Med I 10:350-353 Bacter. Rannug U, Johansson A. Ramel C. Wjchtmeistcr CA f 1 974) The mutagenicity of vinyl chloride after metabolic activation. Ambio 3/5:194-197 Roth F (I Berne) Rannug U. Gothe R, Wachtmeister CA (1976) The mutagenicity of chloroethylene Roth F (1 oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable 468 metabolites of vinyl chloride. Chem Biol Interact 12:25 I -263 Roth F : ! Ravenna P (1940) Banti syndrome (fibrocongestive splenomegaly). Definition, classi fication and pathogenesis. Arch Intern Med 66:879-892 Dtsch Rotil F (I Ravey M. Klopstock J ( 1975) Trace analysis of vinyl chloride in PVC and in the atmo Pathui sphere. J Chromatogr Sci 13:552-553 Roubal J - Ravier E, Diter JM. Pialat J (1975) Un cas d'angiosarcome hepatique chez un ouvrier expose au chlorure de vinyle monom^re. Arch Mai Prof 36:171-177 Regelson W. Kim U, Ospina J, Holland JF (1968) Hemangioendothelia! sarcoma of liver from chronic arsenic intoxication by Fowler's solution. Cancer 21:514-522 Reger RB (I 977) Vinylchiorideand the polymers. J Occup Med 16:772-773 Encyci Rousselut with hi ctioloe portal ilbiich and H.J. Marsteller .`unx. Environ Health Perc.sinusoidal portjl hsper- pathology. Lessons from among workers exposed of biochemical and mor- .nti syndrome followed presented at the Sixth the Liver. Acapulco. Development of hepatic 1. and arsenic. Am J ' vinyl chloride disease. ntal acute toxicitv of -.154-163 '1(1977) Etude des tire de vinyle dont 3 cas niong vinyl-chloride -mal and dominant lethal .ul effects :.i peripheral .n workers engaged in 135 (Rushan text; tide by the isolated per 40:101-110 i (rJ t^e iso|ateJ ol (Suppi) JO arthern India - 'W r o o ' in CO enicity of vinyl iroethylene mceivable inition. classi- id in the atmo- patique chez un ouvrier -171-177 .idothelial sarcoma of n. Cancer 2 1:5 14-522 led 16:772-773 Vinyl Chloride-Associated Disease 105 Regnuult V i 1835) Uber die Zusammeiiseizung des Chlorkohlenwasserstofts (Oel des olbildenden Gases) Liebigs Ann Pharm 14:22-38 Rein FR. Huth F ( 1975; Sechs spoiltane pnmare maligne GefaL-geschwiilite in einem Kollektiv von 30.000 Obduktionen. Ini Arch Arbeirimed 34: 237 -24n Reinl W (1975) Erkrankungen durch Vinylchlorid. Jahresbericlu der Gewerbeaufsicht des Landes Nordrhein-Westfalen, pp 299-316 Reinl W, Weber II (1974) trkrankungen durch Vinylchlorid. Jahresbericlu der Gewerbeaufsicht des Landes Nordrhein-Westfalen, pp 217-25 2 Reinl W. Weber H ( I 976) Stand der epidemiologiscl-on Forschung uber die Vinylohlo* rid-Krankheit. Zentralbl Arbeitsmed 26:97-104 Reinl W, Weber H. Greiser E (1976) Erkrankungen durch Vinylchlorid, Jahresbericht der Gewerbeaufsicht des Landes Nordrhein-Westfalen, pp 287-295 Reinl W, Weber H, Greiser E (1977) Erkrankungen durch Vinylchlorid. Jahresbericht der Gewerbeaufsicht des Landes Nordrhein-Westfalen, pp 305-324 Reinl W, Weber H, Greiser E ( 1978) Erkrankungen durch Vinylchlorid. Jahresbericht der Gewerbeaufsicht des Landes Nordrhein-Westfalen, pp 347-377 Reitz RH. Quast JF. Watanabe PG. Gehring PJ ( 1979) Qiemica! carcinogens: Estimat ing the risk. Science 205:1 206- 1 208 Rety J, Lazard P, Berrod J. Schmitt M (1974) Infrared thermography in diagnosis and supervision of morbidity in workers dealine with vinyl chloride polymerisation. Arch Mal Prof 35:733-738 Rety J. Sauvage, Tuaillon. Habrard A (1976) Le 3e cas frangais d'angiosarcome hepatique chez un ouvrier du chlorure de vinyle. Arch Mal Prof 37:55 1 -555 Reynolds ES, Moslen MT. Szabo S. Jaeger RJ. Murphy SD (1975a) Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene. Am J Pathol 8 1:219-236 Reynolds ES, Moslen MT, Szabo S. Jaeger RJ (. 1975b) Vinyl chloride-induced deactiv ation of cytochrome P-450 and other components of the liver mixed function oxi dase system: an in vivo study. Res. Comm Chem Pathol Pharmacol 12:685 -694 Reynolds ES, Moslen MT, Szabo S, Jaeger RJ (1976) Modulation of halothane and vinyl chloride induced acute injurv to liver endoplastic reticulum. Panminerva Med 18:367-374 Richards RJ. Desai R, Hext PM. Rose FA (1975) Biological reactivity of PVC dust. Nature 256:664-665 Roche J (1977) Affections hepatiques et chlorure de vinyle. A propos de 5 observa tions. Revue generate de litterature. These. University of Grenoble Roche J, Foumet J, Hostein J. Panh M. Bonnet-Evmard J (1978) Angiosarcome hepatique du au chlorure de vinyle. Presentation de 4 cas. Gastroenterol Clin Biol 2:669-678 Ross JM (1932) A case illustrating the effect of proloneed action of radium. J Pathol Bactenoi 35:899-912 Roth F (1956) Uber die chronische Arsenvergiftung der Moselwinzer mit besonderer Beriicksichtigung des Arsenkrebses. Z Krebsforsch 6 1:287-3 19 Roth F ( 1957a) Arsen, Leber, Tumoren (Hiimaneioendotheliom). Z Krebsforsch 6 1: 468-503 Roth F ( 1957b) Uber die Spatfolgen des chronischen Arsenismus der Moselwinzer. Dtsch Med Wochenschr 82:211-217 Roth F (1 959) Zur Patholoeie der chronischen Arsenvergiftung. Zentralbl AHz Pathol Pathol Anat 100:529-530 Roubal J (1972) Vinyl, polyvinyl chloride. In: l.L.O. (Internation Labor Organization) Encyclopaedia of occupational health and safety, vol II. Geneva, pp 1467-1468 Rousselot LM (1940) The late phase of congestive splenomegaly (Banti's syndrome) with hematemesis but without cirrhosis of the liver. Further observations on the etiology of Banti's syndrome and the effect on prognosis of certain variations in the portal venous pattern. Surgery 8:34-42 ,3 JSSS 106 W.K. Lelbach and H.J. Marsteller Rowe VK ( 1975) Experience in industrial exposure control. Ann NY Acad Sci '46: 306-310 Riibsamen H (1976) Vinylchloridkrankhcit ( VC-Krankheit). Z. Allgemeinmeil 5 3: 1551-1555 Russell RM. Bagheri SA. Boyer JL (1973) The hepatic lesion of Mypervitammosis A a unique pattern of hepatic fibrosis with portal hypertension and ascites. Gastro enterology 65:568 Russell RM. Boyer JL. Bagheri SA. Hruban Z (1974) Hepatic injury from chronic hypervitaminosis A resulting in portal hvpertension and ascites. N Enel J Med 29 1: 435-440 Sakabe H (1975) Bone lesions among polyvinv! chloride production workers in Japan. Ann NY Acad Sci 246:78-79 Sama SK, Bhargava S, Gopi Nath N. Talwar JR, Nayak NC, Tandon BN, Wig KL (1971) Noncirrhotic portal fibrosis. Am J Med 51:160-169 Saric M, Kular 2, Zorica M, Gelif I (19761 Malignant tumors of the liver and lungs in an area with a PVC industry. Environ Health Perspect 17:189-192 Sohat'fner F, Popper H, Selikoff IJ f 1 976) Initial features of vinyl chloride (VC) hepa tic injury. Gastroenterology 71:928 Schattenberg PJ, Totovic V, Gedigk P, Marsteller HJ ( 1977) Die Ultrastruktur der Leberschadiaung bei der chromschen Vinylchlorid-Intoxikation. Virchows Archiv (Pathol Anat) 273:233-247 Schaumann O (1934) Ober die Herzwirkung einiger Inhalationsnarkotika. Med Client (Leverkusen Ger) 2:139-147 Schaumann 0(1938) Monochlorathylen. In: Lehmann KB. Flury F (eds) Toxikologie und Hygiene der technischen Losungsmittel. Springer, Berlin, pp 130-131 Schlatter C (1976) Gefahrdung von Konsument und PVC-Arbeitern dutch Vinylchlorid. Schweiz Med Wochenschr 106:647-650 Schmidt H. Schaumann O (1929) Ober kombinierte Gasnarko.se, Dtsch Z Chir 216: 149-157 Schmidt K, Batora J (1976) Vorkommen des Leberhamangioendothelioms bei Arbeitem. die lang dauemd detn Vinylchlorid ausgesetzt waren. Z aerztl Fortbild 70: 1020-1022 Schnack H, Stockinger L, Wewalka F (1967) Adventitious connective tissue cells in the space of Disse and their relation to fibre formation. Rev Int Hepatol 1 7:855-860 Schneiderman MA (1979) Chemical carcinogens. Science 203:603 Schnetderman 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 Sci 246:237248 Schottek W (1969) Zur Toxikologie des Vinylehlorids. Chem Techn (Leipzig) 21: 708-711 Schiitz A, Wolf D (i 977) Gefahrdung dutch Vinylchlorid bei der PVC-Weiterverarbeitung. Berufsgenossenschaften 1:7-13 Schwarzweiler F (1957) Verlaufsuntersuchungen bet einem osteolytischen Krankheitsbild. Z Orthop 88:404--U3 Schweitzer GE (1975) Environmental concerns beyond the workplace. Presentation to the Working Group on Toxicitv of Vinvl Chlonde-Polwinvl Chloride. Ann NY Acad Sci 246:296-302 Sehrt-Bachner U. Etzel F (1977) Haemostaseologtsche Befunde bei Vinylchloridsehaden. In: GutackerHW, Lelbach WK (eds) Leberschaden durch Vinylchlorid. Witzstrock. Baden-Baden Brussel Koln New York, pp 89-9 I Seki K (1965) Histometrical studies of the spleen in Banti's syndrome with reference to clinico-pathologic correlations. Tohoku J Exp Med 87:222 -243 Selikoff (J f 1976) Discussion remark to Barnes: Vinyl chloride and the production of PVC. Proc R Soc Med 69:28 1 Vine: Selinv 79' Severeiv. As- Shahi the Sherh of ` Siders stn Da Sir effc Da SiiPor Simpv rep Slater Smirn. 19: Smirm Dis Smirn ole: Smith Smith chiSmitli pr.Smith rid. Smok' tor Smvi.. 17- Soimt-. Sc:. Soren Spir'r chi 4 "Hi Spirted ndi Stem ( ph. Stein ' nar Stew., mb ttc 3] dltc :iu I C/3 in 1 O ocn Me. CJ to 1 H J. 3) cad Sc U> mmed O . 'idinc Otn ites. G; 03 03 chroi igl J Me r rfcers in Japan. .. W,s KLf 197 1) er and lungs in ide (VC) hepa- Muktur der chows Arcluv ka. Med Chem . .i Toxikologie 0-131 I'.'h Vinyl- l Chir 216: ,i' bei Arbei1 "rtbild 7m I'Mie cells in the I 17:835 AiiO iir how to get ! Sci 246:2.'7 .ipzic) 2 1. A riterverarbei- ;ien Kranklieus- I'resentation 'tide. Ann NY uylehloridschaIchlond. with reference production of Vinyl Chiorid-Associated Disease 107 Selinger M. Koff RS (1975) Thorotrast and the liver: a reminder. Gastroenterology 68' 799 803 Severs LW. Skory LK 11975) Monitoring personnel exposure to vinyl chloride. vtnyliJene chloride and methyl chloride ir, an industrial work environment. Am Ind Hyg Assoc J 36:669-676 Shahin MM (1976) The non-mutagenicity and -recoinbinogemcity of vinyl chloride in the absence of metabolic activation. Mutat Res 40: 269-272 Sherlock S. Feldman C.A. Moran B. Scheuer PJ (1966) Partial nodular transformation of the liver with portal hypertension. Am J Med 40:195 -203 Siderys M. Vellios F {1964) Portal hypertension without cirrhosis or extrahepatic ob struction. Am J Sure 108,785-789 Da Silva Horta J (1967) Late effects of thorotrast on the liver and spleen, and their efferent lymph nodes. Ann NY Acad Sci 145:676-699 Da Silva Horta J. da Motta LC (1967) Follow-up study of thorium dioxide patients ;n Portugal. Ann NY Acad Sci 145:830-842 Simpson HM. Baggenstoss AH. Stauffer MH (I 955) Primary sarcoma of the liver: a report.of three cases. South Med J 48:1177-1 182 Slater TF (1972) Free radical mechanisms in tissue injury. Pion. London Smirnova NA (1954) Paper presented at the conference of young scientists. Gor'kii. 1954. pp 10-11 (Russian text) Smirnova NA (1959) Clinics of chronic intoxication by olefins and vinyl chloride. Dissertation Gor'kii (Russian text) Smirnova NA (1961) On the question of bone lesions due to chronic intoxication by olefins and vinyl chloride. Vestn Rentgenol Radiol 36:63-66 (Russian text) Smith PM, Williams DMJ (1974) Vinyl chloride and cirrhosis. Digestion 10:321 Smith PM. Williams DMJ, Crossley IR (1975) Portal hypertension induced by vinyl chloride. Gut 16:402-403 Smith PM, Crossley IR, Williams DMJ (1976a) Portal hypertension in vinyl chloride production workers. Lancet 11:602-604 Smith PM. Williams DMJ. Evans DMD (I 976b) Hepatic jngiosareoma in a vinyl chlo ride worker. Bull NY Acad Med 52:447-452 Smolfid V ( 1966) Assessment of lead exposure in PVC manufactories and suggestions for control measures. Arh Hig Rada Toksikol 1 7'30`t- 3 1 6 (Serbo-Croatian text) Smyth HF Jrt 1956) Hvzienic standards for daily inhalation. Am Ind Hyg Assoc J 17:129-185 Sommerschild H. Kluge T (1971) Some observations on hepatic sinusoids. Acta Chir Scand 137:257-263 Sorenson WR (1976) Polyvinyl clilonde in fires. JAMA 236:1 449 Spirtas R. Kaminski R (1977) Angiosarcoma of the liver in vinyl ehloride/polyvmyl chloride workers. - 1977 Update on the NIOSH Register. J Occup Med 20:427429 Spirtas R. McMichael AJ. Gamble J. van Ert M (1975) The association of vinyl chlo ride exposures with morbidity symptoms. Am Ind Hyg Assoc J 36:779-789 Stein G. Jiihe S. Lange CE. Veltman G (1975a) Bandformige Osteolysen in den Endphalangen des Handskeletts. ROEFO 1 18:60-63 Stein G, Julie S, Lange CE, Veltinan G (1973b) Skelettveranderungen bei der soge* nannten Vinylchloridkrankheit. Roentgenbiaetter 26:350-355 Stewart JD, Williams DMJ. McLachian MSF ( 1975) Acro-osteoi> sis in a polyvinyl chlo ride worker with an atypical industrial history. J Soc Occup Med 25:103 -109 Siutte HJ. Heusermann U ( 1978) Die Milz bei der Vinylchlond-Krankhcit, Zentralbl allg Pathol Pathol Anat I 22:284 Suciu I, Drejman I, Valaskai M (19631 Contribujii la studiul tmbolnavirilor produse de clorura de vinil. Med InterniT 15:967-978 Suciu I. Dreiman 1, Valaskai M ( I 967) Etude des maladies dues au chlorure de vinyle. Med Lav'58.:bl -271 r.* 1- 108 W.K. Lelbach and H.J. Marsteller Suciu I, Prodan L. Ilea E. Paduraru A. Pyscu L (I 975) Clinical manifestations in vinyl chloride poisoning. Ann NY Acad Sei 24(5:53-69 Szende B. Lapis K. Nemos A, Pinter A ( 1970) Pneumoconiosis caused by the inlialu- tion of polyvinylchloride dust. Med Lav 61:433--136 Tabershaw IR, Gaffey WR (1974) Mortality study of workers in the manufacture of vinyl chloride and its polymers. J Occup Med 16:509-513 Takeuchi Y, Mabuchi C (1973) A case of occupational acroosteolysis, presumably caused by vinyl chloride. Jpn J Ind Health 15:385-394 Tamburro CH (1973) The hepatic role in the carcinogenesis and in early detection - the vinyl chloride model. Yale J Biol Med 51:67-80 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 20-21, 1978 * Tamburro CH. Creech JL, Davis A. Greenberg RA (1978b) 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, Lakshminarayanan R. Bhargava S. Nayak NC, Sama SK (1970) Ultra- structure of the liver in non-cirrhotic portal fibrosis with portal hypertension. Gut 11:905-910 . Tassignon JP (1979) Log "normal distribution of the incubation period of liver angio- sarcoma in vinyl chloride polymerization 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) Arbeitsmedizinische Gedanken zur sogenannten ,,Vinyl- chloriderkrankung". Arbeitsmed Sozialmed Praeventivmed 9:146-148 Thomas LB, Popper H (1975) 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. Seltkoff I, Falk H (1975) Vinyl-chloride-induced liver disease. From idiopathic portal hypertension (Banti's syndrome) to angio- sarcomas. N Engl J Med 292:17-22 Tisdale WA, Klatskin G, Glenn WWL (1959) Portal hypertension and bleeding eso- phageaj varices. Their occurrence in the absence of both intrahepatic and exirahe- patic obstruction 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 Torkelson TR, Oyen F, Rowe VK (1961) The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Am Ind Hyg Assoc J 22:354-36 I Trapp JT. Lummus FL, Hilbun BM (1974) Acro-osteolysis: a case 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 chlonde 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 (1973) Hemangiosarcoma of the liver complicated by disseminated intravascular coagulation. Gastroenterology 65:936-942 Vainio H (1978) Vinyl chloride and vinyl benzene (styrene)-metabolism. mutagenicity and.carcinogenicity, Chem Biol Interact 22:1 17-124 Vale PT, Kipling MD. Walker AE (1976) Miscellaneous symptoms occurring in workers engaged 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 chlonde. Farmakol Toksikol 3:369-372 (Russian text) ^ Vinyl Vazm t^' (R' Vazir. ex r 30 t fi : (/> Q o: in w` -9 Villen Vi; Viola Viola Viola Viola t0 l*" Walkc e:|* Walkr 3 `- Wail-r 23- Walln Me Ward Pri Ward ` ni>* Watan sir. Watan nd- Watan hep an. Wata.. sm: Watan nc. 39: Water bir,. Waxw-.  H.J Murstcller .ions in vinyl the inhaia- iiufucture of resumably detection iiuride: a causal i. I'aper preof the Liver, green clearance rr presented to : Annual Meet* 770> Ultra. i.ension. Gut liver angioi0 ntninary results c liver and mten ,,Vinyl1 a- mg vinyl iiup ?! it,d e W ..oin. viin I ' .uctural implicated 942 mutagenicity 'ling in workers 'ironic expo- Vinvl Chloride-Associated Disease 109 Vazin AN, Plokhova ET I 1969a) Changes in adrenalin-like substances in rabbit blood following chronic exposure to vinyl chloride vapour. Gig Tr Prof Zabol 13 46 47 ( Russian text) Vazin AN. Plokhova ET (1969b) Changes of cardiac activity in rats following chronic exposure to vinyl chloride vapour. Farmakol Toksikol 32: 220-222 I Russian text) VKE I 1974. 1975) VC/PVC: Beisjnel einer Problemldsung, Herausgegeben vom Verband der kunststofferzeugenden Industrie e.V. (VKE). Frankfurt) Veltman G, Lange CE 11977a) A/l^citsniedizinisehe Aspekte der Vinylchloridschaden. * Berufsdcrmatosen 25:67- ,'7 Veltman G. Lange CE f 1977b> Arbeitsmcdizinische Aspekte der Vinylchloridschaden. In: Gutacker HW, Lelbach WK leds) Leberschiiden durch Vinylchlorid - Vinyl* chlorid-Krankheit. Witzstrock, Baden-Baden Brussel Kdln New York, pp 95-101 Veltman G, Lange CE. Jiihe S. Stein G, Bachner U (1975) Clinical manifestations and course of vinyl chloride disease. Ann NY Acad Sci 246:6-17 Veltman G. Lange CE, Stein G (1978) Die Vinylchlorid-Krankheit. Hautarzt 29: 1977-1982 Vertkin YI, Mamontov YR (1970) On the condition of the bronchp-pulmonary system in workers employed in the manufacture of PVC articles. Gig Tr Prof Zabol 14: 29-32 (Russian text) ViUeneuve JP, Huet PM. Joly JG. Marleau D. Cote J. Legare A. Lafortune M, Lavoie P. Viallet A (1976) Idiopathic portal hypertension. Am J Med 61:459-464 Viola PL (1970a) Cancerogenic effect of vinyl chloride, lnt Cancer Congr, Abstr 29 Viola PL (1970b) Pathology of vinyl chloride. Med Lav 61:174-180 Viola PL (1974) La malattia da cloruro di viniie.Med Lav 65:81 -99 Viola PL, Bigotti A. Caputo A (1971) Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31:516-519 Wasoner JK. Infante PF. Saracci R (1976) Vinyl chloride 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 chloride, Br J Dermatol 1974: 22-23 Walker AE (1975) Occupational acro-osteolysis (two cases). Proc R Soc Med 68:343 - 346 Walker AE (1976) Clinical aspects of vinvl chloride disease: Skin. Proc R Soc Med 69: 286-289 Wallnofer H, Zinnael N ( 1977) Hamangiosarkomatose nach Polyiinvlchloridexposition. Med Klin 72:410-413 Ward AM (1976) Evidence of an immune complex disorder in vinyl chloride workers. Proc R Soc Med 69:289-290 Ward M. Udnoon S. Watkins J, Walker AE. Darke CS (1 976) Immunological mecha nisms in the pathogenesis of vinyl chloride disease. Br Med J 1:936-938 Watanabe PG. Gehring PJ (1976) Dose-dependent fate of vinyl chloride and its pos sible relationship to oncogenicity in rats. Environ Health Perspect 17:145-152 Watanabe PG, McGowan GR, Madrid EO, Gehring PJ f 1976a) Fate of IJC-vinylchlonde following inhalation exposure in rats. Toxicol Appl Pharmacol 37:49-59 Watanabe PG, Hefner RE Jr. Gehring PJ (1976b) Vinyl chlonde-induced depression of hepatic non-protein sulfhydryl content and effects on bromosulphalein (BSP) clear ance in rats. Toxicology 6:1 -8 Watanabe PG. McGowan GR. Gehring PJ f 1976cI Fate of 1 *C vinyl chloride alter single oral administration in rats. Toxicol Appl Pharmacol 36:339-352 Watanabe PG, Zempel JA, Gehring PJ (1978a) Comparison of the fate of vinyl chlo ride following single and repeated exposure in rats. Toxicol Appl Pharmacol 44: . 391-399 Watanabe PG, Zempel JA, Pegs DG, Gehring PJ (1 978b) Hepatic macromolecular binding following exposure to vinyl chloride. Toxicol Appl Pharmacol 44:571-579 Waxweiler RJ. Stringer W, Wagoner JK. Jones J, Falk H. Carter C (1976) Neoplastic- risk among workers exposed to vinyl chloride. Ann NY Acad Sci 27 1:4Q-48 10 W,K, Lelbach and H.J. Marsteller: Vinyl Chloride-Associated Disease Wegener k\ Wev.li H; Ramf-uann M. f ! 0^ 11 ITottculoendotheliales System und Thoro- trastose nach ^1 *.1^71 ostisui 1.-_r .sir "iCfTi.- Med Woehettsehr 6' 1977- 198! Wegman DH 1 197?) tDiscirphnn rei.: .1; V AiaTJ Sci 246:20-21 Wecmaa.PHt i VrIaJPublierHealth nm:';./ it the Harv/d School 01 Public Health. N EngltJ^Med J9-. 6pC.' .;/ Weigerr FJ 1 l970| ^lla/.itc-^I car- .Scieo' j 703:603 Wvin'ven K ( 1 ) IIwf !^:l' I .7--pi If - icF'mi' j<si".rated with exposure to vinyl blonde tt'.'.-'r ; u. Si. -.;J L '.? ' d ' W hel.nl J( Jr. ('.i t 1. J I7. 1 \ >..|indi ,( , !i ,1 -.. . tcnslics.'l 1,* iriy, v t j , 1. < \ 'w-rkc:- K -i:y i i ' 549-557 . 1 ' :> Williams DMJ. MdtjchhtW.'rtS'.' 11 V;.*; Hcalitri o51dv.lantv.1l defects in acro-osteolysis. J Soc Occur Med 36:98-4?? . \ >' Williams DMJ. Tayfor KJW.'/^fC.Jvj; [fef'yjjjirih p>( (1975a) Screening vinyl chloride monomer workers for liver disease. Gut !6:*39 .-7 ' Williams DMJ. Taylor KJW, f^j.rdev IR :7i I'M. Duck BW (| 975h> 1'^symptomatic detection of liver changes m vinyl chloride monomer workers. Digestion 12:362 Williams DMJ, Smith PMi Taylor KJW. Crossley IR (1976) Monitoring liver disorders in vinyl chloride monomer worked* urme erevseale ultrasonography. Br J Ind Med 33:152-157 , i Williams DMJ, Roberts E, Evans KT (19P7) An assessment of hand thermography in vinyl chloride workers. J Soc Occup fyed 27:57-62 Williamson DG. Cvetanovic RJ (1968) 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 3 I cases. JAMA 201:5 77-581 <4, W'inell M, Holmberg B. Kronevi T (1976) Biological effects of vinyl chloride: an ex perimental study.Environ Health Perspect 17:211-216 Woods JS f 1979) Epidemiologic considerations'fn the design of toxicologic studies: an approach to risk assessment in humans. Fed l'roc 38:1891-1896 Wyatt RH. Kotchen JM, Hochstrasser DL, Buchild.an JW Jr. Campbell DR. Slaughter JC. Doll AH 1 1975) An epidemiologic study Ut hlood screening tests and illness histories among chemical workers involved in the manufacture of polyvinyl chloride Ann NY Acad Sci 246:80-87 Yamamoto K f 1918) Morphological studies of the spleen in splenomegalic liver cirrho sis comparing wjth the spleen in idiopathic pprtal hypertension (so-called Banti's syndrome with^A liver cirrhosis). Acta Patliil Jpn 28:891 -905 Yamamoto K ( 1979) Morptological studies of the spleen in idiopathic portal hyper tension (so-called Banti's.*'ndrome without liver cirrhosis) using light microscopy, scanning electron Inicroscopy and lnstometryvActa Pathol Jpn 29-1-19 Zapp JA (1964) Viny l chloride. Am Ind Hyg Assoc J 25:421 --)23 Zeegen R, Stansfeld AG, Dawson AM. Hunt AH.t 1970) Prolonged survival after portM decompression 01 patients with non-cirrhotic-mtrahepatic portal hvpertension. Gut 11:610-617 Zielhuis RL (1974) Permissible limits for occupational exposure to toxic agents. A discussion in approach between US and USSR. Int Arch Arhcitsmed 3 3 1-13 Zimmermann H. Eck H f 1975) Zur Pathologischen Anatomic der Vinylchlond-Krank- heit. Virchows Arch fPathol Anat) 368:5 1 -59 Zonca M. Saric M. KoYistantinovic M. Kovaf I f I 975) Two cases of angiosarcoma of the liver following exposure to vinyl chloride. Arch Hig Rada Toksikol 26:275-231 1 Serbo-Croatian text) Die C JO CO O 0 01 CO eit 09 ch P j._ t3.3 D3.4 D 3.5 D. 3. 3 3 4 Manon 4.1 B. \ 4 4.2 O' 4 4 4.3 M 4.4 Li 4.5 M4.6 M5 Klintw 5.1 t. 5.2 P * Herrn I I Median.