Document NEEvQ4y2Vy77jrnr2Q72ekGZE

Ergebnisse der Inneren Medizin und Kinderheilkunde Advances in Internal Medicine and Pediatrics Neue Folge Herausgegeben von P Frick G.-A.von Harnack K.Kochsiek G. A. Martini A. Prader Mit 24 Abbildungen und 23TabelIen Springer-Verlag Berlin Heidelberg New York 1981 Vinyl Chloride-Associated Disease w.K. LELBaCH and HJ. MARSTELLER 1 1 Introduction ........................................................................................................ 2 2 Tcchnoiopcal Details ............................................................................................ :.I Vinyl Chloride Monomer(VCM).................................................................. 2.1.1 History................................................................................................ 2.1.2 Production of VCM .......................................................................... 2.2 Production oi Polyvinyl GtlondePVC)..................................................... 2.2.1 Technology of Polymerization.......................................................... 2.2.2 Methods of Polymerization............................................................... 2.2.3 Compoundini ..................................................................................... 2.2.4 Source* of Exposure to VCM in FVC Production.......................... 2 2.5 Tlie Explosion Hazard...................................................................... 2 2 6 The Odour Threshold .................................................................... 2.27 VCM a* an Anaesthetic Agent......................................................... 2.2 3 Effects of Acute Overexposure in Man................................. ... 2.2.9 Monitoring VCM Concentrations in Wotting Areas....................... 2.2.10 Exposure to VCM in PVC-Proeessing (-Fabricating) Plants.......... 2.2.11 National Standards for the Control of Exposure.................. 2.2.12 Exposure to VCM Outside the Woricin* Area................................ 4 4 4 5 6 6 7 g S 9 10 10 u 13 15 17 IS 3 Toxicology of VCM................................................................................................ 3 1 Acute Toxicity............................................................................................... 3.2 Chronic Toxicity. ........................................................................................... 3 J Oncogen* 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 Carcinogenic Effect............................... 3.4 2.2 Metabolic Pathways............................................................. 21 21 21 22 24 25 26 26 26 4 Clinical Spectrum................................................................................................... 4.1 The Triad: Raynaud's Phenomenon. Pseudaacieroderma and Acroasteolysis................................................................................ 4.1.1 Familial and Idiopathic Acreosteolrsis........................................... 4.1.2 Epidemiology of Occupational Acroosttolytif............................... 4.1 J Clinical andRoentgenological Features............................................. 4.1.3.1 Occupational Acrooswotysia.............................................. 4.1J.2 Pseudoscieroderma............................................................. 4.1.4 Histolosy.............................................................................................. 4.1.4.1 Cutaneous Lesions................................................................ 4.1.4.2 Bone Lesions............................................... 4 15 Arteriography. CapiUarescopy. Infrared Thermography.............. 4.1.6 (mmunolopcal Studies.................. 29 31 34 34 36 36 31 39 39 39 40 42 I Department of Medicine. Director Prof. Dr. IIJ. Dvngler. University of Bonn. I'RG \ c c \V K Lelbach and H.J. MarMellur a I 7 Pathogenetic Consideration!........................................................... a 2 Non-malignant Liver Oisease in Vinyl CJiloride/Polyvinyl Chloride Production Workers...................................................... ............................. aM Clinical Mamiestations of Non-malignant Liver Disease............. 4.2.2 Laboratory Findinp........................................................................ 4.2.3 Cross Inspection of the Liver ami Spleen....................................... 4.2.4 Histology.......... V..................................................................................... 4.2.4.1 Hepatic Fibrosis................................................................ 4 .2 4.2 Sinusoidal Lining Cells...................................................... 4.2.4J Hepttocytei........................................................................ 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.......... a.3 Angiosarcoma of the Liver........................................................................... 43 1 Epidemiology....,........................................................................... 4.3.2 Clinical Manifestations...................................................................... 4.3.3 Peritoneoscopy................................................................................ 4.3 4 Gross and Hisrological Morphology............................................... 4.3 i Therapy.......................................................................................... . 4.3 6 Risk Assessment................................................................................ 4.3.7 Mortality and Cancer Morbidity Studies....................................... 4 4 Miscellaneous Aspects.................................................................................. 4.4 1 Thrombocytopenia and Platelet Function Tests.......................... 4 4.2 Central and Peripheral Nervous System......................................... 4 4.3 Pulmonary Changes........................................................................... 4.4.4 Genetic Effects of VCM ................................................................... 5 Conclusion and Outlook...................................................................................... 44 44 48 49 50 51 51 54 5a 54 55 57 57 57 74 76 78 80 80 81 O. 82 84 85 87 88 89 Key words: Acroosrcolysis - Angiosarcoma of the Liver - Portal Fibrous and Portal Hypertension - Pseudoselemderme - Raynaud's Phenomenon - Vinyl Odorule 1 Introduction The history of vinyl chlonde-asodated disease, its recognition and prophylaxis is a classic example of shutting the stable doot aftet the hone has bolted. It should help to emphasize the need to shift our attention to preventing exposure from occurring rather than to reparative measures. In view of the Urge number of new and potentially hazard ous chemicals introduced each year into the workplace end the environment, this ac count should again alert us to the necessity of pretesting chemicals adequately for their potential health effects, even at the risk that technological progress will develop at a more modest rate. Large-scale production of the synthetic resin polyvinyl chloride (FVC), a thermo plastic material suitable for the most widely dhrenifled industrial use, was begun around 1930 in the United States snd in Germany. The monomer, vinyl chloride (VCM), a rather simple aliphatic compound, wu believed until the early 1960s to be Vinyl Chlonde-Asso,- one of the least harmf later turned out. had ii evaluation of acute eff to reveal its carcinogei. might have continued : place, considering that vapour phase under an: react; -e double-bond. Today vinyl chlorid formation and data on cisely a quarter ofacei tnbutable to this new e 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 (Tribute! Ultimately, it was tl curred in workers expo a causal relationship: (1 pseudosleroderma; (2) liver. Particularly, the d nancy among a eompar alarming experience wt a connection between' lungs or the gastroime. the prolonged latency f sarcoma of the liver, n: these two fatal consequ the conclusion that VU. cancer meeting in Horn to VCM was a very sen It should be stresse. precise, in intermediate mainly in the mammal, mentation products (P' cated from the polymer they contain unreacted PVC (thermal decompo toxicity of pyrolysis pn mainly due to the relta: A bar 1969 : Dyer and and only very small or r (0 Mara et al. 1971 cite Marsteller 44 4$ 49 JO SI Jl ;; 54 J4 55 57 57 57 74 76 78 50 80 a; ; s: S4 85 87 88 89 I Pcrtai !>m ft laxisisi uld help to wring nthcr (tally hazardnt. this sc* uly for iO develop i. a thermobegun 'tlotid* * 960s to bs Vinvl GtlonJ-Aio<iJUd Disease 3 on* of th* least harmful chlorinated hydrocarbons. Early animal experiments, as it later turned out. had indeed been earned out with dosages sufficiently hijh for the evaluation of acute effects, but chronic exposure had not been of sufficient duration to reveal its carcmo|enic properties. On purely theoretical (rounds, however, one might have continued to feci uneasy with this compound as a pollutant of the work* place, considering that it is (I > a halogenated hydrocarbon which (2) exists in its vapour phase under ambient conditions finlialauve 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 nuartcr of a century had to pan before the full nnpt of symptomatology at* tnbutable to this new occupational health hazard became recognized in January 1974 with th* 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 th* experts sufficiently. The earliest indication of advene effects in worken tnpgtd in th* production and procasing of PVC. a Russian study pub lished m 1949 (Tribukh et si. 1949), received Uttit attention. Ultimately, it was the exceptional character of the three major lesions which oc curred m workers exposed to VCM that contributed most to the final appreciation of a causal relationship: (1) the syndrome of acreoneolysis, Raynaud's phenomenon and pscudoilerodermi: (2) non-cirrhotic portal hypertension; and (3) anposarcoma of the liver. Particularly, the discovery of a duster of four cam of this extremely rare malig nancy among a comparatively small group of worken (GreecA et al. 1974a) was an alarming experience which called for immediate action, h can easily be imagined that a connection between VCM and the more common malignancies, such as cancer of me lungs or the gastrointestinal tract, might still have gone unnoticed. On th* other hand, die prolonged latency periods of both non-onhotic portal hypertension and ang sarcoma of the liver, roughly 10 and 20 yean respectively, delayed the recognition of these two fatal consequences of chronic exposure to VCM. But on* can hardly escape th* 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 exponas to VCM was a very serious occupational hazard (Parers 1976). It should be stressed that the noxious agent is solely the monomer, or to be more precis*, an intermediate of th* monomer's metabolic broachstation, which takes place mainly in th* mammalian liver and yields certain highly reactive epoxides. The poly merization products (PVQ, i.*., the solid plastic and the plastic consumer pods fabri cated from the polymer, are chemically inert articles which cany no health risk units they contain unnamed reridual monomer. Even the combustion of articles made from PVC (thermal decomposition in fins) does not yield free vinyl chloride monomer; the toxicity of pyrolyris product! of polyvinyl chloride polymen and formulations b mainly due to the release of hydrochloric add and carbon monoxide (Combh and Abtr 1969:Dvr andficA 1976;3brertsoe 1976;.t/oser 1976; Cohrdyn et aL 1976) and only very small or no quantities of phosgene derived from madual monomer (O'Man et al. 1971 dttd by Colaidyn et ai. 1976). 2 Technological Details :.l Vinyl Chloride Monomer (VCM) At standard (ambient) conditions of temperature and pressure, vinyl cldoriJc iCH;* CHC1: chJoroethylene, chloroethene) is a non-irritating, colourless gas with a faintly sweet odour, inflammable at concentrations above 3.3% by volume hi 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. Caseous VCM condenses at -13.8*C and 760 Torr (* 101J kPa) to a colourless liquid of low viscosity {Lefaux 1966). Its physical properties are listed in Table 1, the most important of which arc its low boiling point, its high specific 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. Tsblt I. Ph\ deal properties of VCM Mol. wt.: B.p.: ' F.p.. Flash point: Limits ot flammability: Autoignition temperature: 62.503 '-13,8*C(-13.7 to -13.9) -153.7*C -78.5*C (Cleveland open cup) 3.8%-29.3l* by volume in air above -7g.5*C (. 38 000-293 000 ppm) 472*C Vapour pressure: mm Hg 10 100 692 2300 *C -87.5 -55.8 -15.8 20 2b60 25 Vapour density: 2.15 g/litra (calculated at 2S*C and 760 mmllf (air* 1) Sp.gr. of liquid VCM: o.9 t:i at -:o*c,'4*c 0.99 at -25*C/4*C Sources: FairhaB 1957;Iruh 1963;Zapp 1964;f/eux \9o6. Os rtrmayor 196'; Roubal 1972. 2.1.1 History The French chemist,Rtgnault (183S) was appatentiy the first to study systematically the synthesis and analyhs of vinyl chlotide. Litbig. who had done some earlier prelim inary experiments, tneouraged Rtgnouh to investipte this compound when Repioult spent several months in Litbig'i laboratories. All compounds containing the vinyl group (CHj"CH-) polymerize readily (Fairhall 1957). Spontaneous polymerization of vinyl chloride to i white opaque solid mass under the influence of sunlight was first described by Baumann in 1872; he also quotes a paper by Saynor and Gliniky (who succeeded iztng subst M.2 Proc Urge-scal< by employ - 1) Convert CH*CH 2) Convert chloroe: CH,-cr CHjCl- VCMw Thus, any li tions in the in the rang (IARC 19* when VCV mayor 196' in commer. r.ce.oua In the c conjeeturc.. retrieved Vi yses earner sum of all ii genates)** reacted moi in prepoiyr the concen' that even If methyl chit; isobutane, n ferenee in p .nj H.J. Mantciier I chlonde fCH;" .u with a faintly :n air. which s I jpL' in ethsr and - manufacture of 'to employed as a usually handled and TofTf-101.3 kPa) ropemet are listed high specific jra';n water and the .i -TS.J'C .i.J 760 raaHi rmtftr 1967; ' study systematically some earlier prelim- iuimI when Rtjruiult -laming the vtnyl >us polymerization of i sunlight was first - and GUntky (who Vint) CuioRdc-AfeOtuted succeeded in decomposing vinyl chlonde to nionociiloroaideityde with the aid of oxid izing substances such as It) podiiorous acid. 3.1.2 Production of VCM Large-scale commercial $> nthesis of VCM w-.th ahigh yieia was made possible much later b\ empioymj two principle metiiods. the second having no largely replaced tite first: 1) Conversion of acetylene to VCM by hydrochiorinetion: CHCH HQ -- CH-KIHG (catalyst: HjCl; on charcoal) (.-Uisrwr 1974) 2) Conversion of tthylent by vapour-phase or liquid-phase oxychlorination to 1.2-dichloroethane and subsequent pyrolysis (thermal cracking) to VCM (Albnfiir 1967a): CH:<H. *aatl/:0. - CH;C1-CH:C1 * H:0: 480*C-S10*C CH;Q-CH,a pumice catalyst CH:-CHa*HQ (pyrolysis; thermal cracking, Austin 1974). VCM was usually manufactured in dosed systems and stored in outdoor laalities. Thus, any leakage of the gas was readily diluted in the ambient air. VCM concentra tions in the atmosphere at some distance from minufactunng piano were found to be in the range 1-2 ppm. In doit proximity, the concentration ranged up to 50 ppm CIARC 1974). Spontaneous polymerization in light has also been repeatedly observed when VCM comes into contact with atmospheric air due to container leakage (Osrrnmerer 1967). A prerequisite for the polymerization process is a high degree of purity in commercially produced VCM. Impurities retard the polymerization process (Lefox 1966: Ottenmycr 1967). In the early discussion about the cause of vinyl chloride-associated disease it eras conjectured that odter compounds or impurities contained in prepolymerizarion or in retrieved VCM might have been the causative agenqs) (Thica and Venen 1974), Anal yses carried out by six West German manufacturers of PVC. however, mowed that the sum of ail impurities (such as saturated or unsaturated hydrocarbons and their halo genares) * 0.01% by volume for piepotymerizarion VCM end 0.1% for retrieved un reacted monomer. Only methyl chloride was found in concentrations of 50-300 ppm in prepolyaerization VCM and 100-500 ppm in retrieved VCM (in one instance only, the concentration ranged between 1000 and 3000 ppm). But it should be kept in mind that even 1000 ppm methyl chloride in VCM would mean, at 500 ppm VCM in air. a methyl chloride concentration in sir of only 0.5 ppm. All other impurities (propylene, isobutane.ii-butane etc.) would then be in the ppb range. Bcridet, no significant dif ference in purity could be found between VCM from acetylene and from ethylene. 6 2.2 Production of Polyvinyl Chloride (PVQ W.K. Lelbiiuh and HJ. Marcteller 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 poly-vinyl chloride. Vinyl chloride monomer is polymerized in large autoclaves (reactors) at tempera tures between 40*C and S0*C and pressures of 6-16 (8-12) atmospheres. Th-re are usually several reactors (up to 10-30) located in one building. The reactivity of tire monomer is a function of its double-bond. The second functional site of the vinyl chlonde molecule, the chlorine atom, does not react easily. The double-bond of VCM is not only the site from which the polymerization originates but is also the source of the toxicity and carcinogenicity of this compound when it is being metabolized in the body. The polymerization of VCM, which is a strongly exothermic reaction (Barnes 1976), is initiated with the aid of compounds soluble in VCM that form free radicals at relatively low temperatures. Initiators an 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 rum into a free radical and thus prop agating the growth of a chain of molecules with a terminal free radical. Chain growth is interrupted by saturation of the terminal free radical which often involves a reaction between two growing chains (Molten and Zielhuis 1964;Ltfaux \9f>6,Albn%ht 1967 s-cDomninghaus 1972 (Slater 1972). The random character of such termination steps accounts for the production of chains of different length and hence different de grees of polymerization, with molecular weights of the finished PVC being statistically distributed around a mean value. Commercial PVC polymers have average molecular weights that vary from about SO 000 to 150 000 diions (Albright 1967b). Degree and velocity of polymerization, which art influenced by temperature and the concentration of initiators. determine the specif - type of PVC produced (Frey 1973). During polymerization considerable amounts of the monomer ate 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%-9Q% of VCM is polymerized. The timing of this termina tion of the process is essential for th* 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 adhete 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 vest*!, which contains cavities filled with unreacted monomer, impedes the conductance of heat; it has, therefore, to be cleaned away after tetmination 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 umtacted vinyl chloride monomer is partly solvated in the polymer (about 10%); the remainder is dispersed in the water phase or is present Vinyl Chlonde- in the vapour ph. VC monomer is r is then purified h the finished pol> and must diffuse Raw PVC resin, t (VKE 1975). Bar proxunately 500 The slurry fre large enough to h are then pumped wet polymer, a edrying methods, menzation, yield fine solid particle drying temperau polymer. A cycle The solid polynu storage bins or si dried powder coi 2.2.2 Methods! Four different tn PVC (Frey 1973 Suspension Poly which monomer (such as polyvim conjucuon with this method whi. Emulsion Pofym was added in the except that large are added. Emul: emulsifiers cann< Bulk (Mass! Pot\ the additon of O' The flnt reactor second one is use solid state, to ess leaches a level of characterized by good optical clar 044224 # .J H.J Marsteller 1'l`the procedure* mde. ore) it temperahere*. There ire ;activity of the : of the vinyl hit-bond of VCM ho the source of leuboUztd in the action (Barnes >rm free radicals at l peroxide, aoproals react with the ,cal and thus propsi. Chain growth is ulves a reaction ^`.Albrjnt 1967 h termination cnee different debeing statistically A from about ymenzat.m, determine -on considerable ost of this is later which is not sol* iixation slows the method used, of this terminins produced. The 4 be removed to ation aids in translie reactor. During .-re to the wills of his polymer crust ted with unreacted cleaned away after reed from the re is partly solvated phi* or s prerent Vmyi Chloride-Associated Disease ? in lire vapour phase above the slurry. Mule a batch is in the dump tank, this unreacted VC monomer is retrieved by pumping it 01Tinto a VCM storage tank. Removed VCM is then puntied by subsequent distinction 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: tins diffusion depends on tune and temperature. Raw PVC resin, therefore, still contains certain quantities of unreteted monomer (VKE 1975). Bams 11976) reported that the polymer m the slurry' still contains ap proximately 500 ppm of vinyl chloride. The slurry from the dump tank is pumped into a Stonge unk (blend tank) which is large enough to hold seven! batches of the product. The contents of the blend tank are then pumped into a centnfuge which separates the wet solids from the water. The wet polymer, a granular mass, is dhed either in rotating tubular dryers or by spreydrying methods, the latter being used mainly for products formed by emulsion poly merization. yielding a polymer which is similar to a vtty fine white flour. There very fine solid particles are fed directly into a spray-drying column without dewatering. The drying tempenture should not exceed 60*C to prevent thermal decomposition of the polymer. A eydon separator at the exit end of the diyen removes coiner pirncits. The solid polymer particles ate then sized by multiple-layer screens, sir-conveyed to storage bins or silos and finally packaged for shipment (Albright 1967d). The resultant dhed powder contains about 50 ppm of monomer (Romes 1976). Z22 Methods of Polymerization Four different method* of polymerization arc used for the commercial production of PVC {Frey 1973), the first two now being the most widely used: Suspension Polymerization. Polymerization is carried out in an aqueous system in which monomer droplets are maintained in suspension by means of protective colloids (such as polyvinyl alcohol, gelatin, substituted celluloses) under heat and pressure in conduction with brisk agitation. Relatively large polymer particles can be obtained by this method which *dty blend* well. Emulsion Polymaitetion {* the oldest technique, to which suspension polymerisation was added in the 19J0s. The process is similar to that in suspension polymerization, except that large amounts of emulsifying ageno (such as soaps or other surfactants) sre added. Emulsion polymerization yields resins of * very smalt particle size. The emulsifies* cannot be completely removed. Bulk {Mass) Potymertohon. in this process VCM is polymerized In two stages without the additon ofother liquids. The two reactors sre operated batch-wise tnd in reties. The first reactor (a ptepolymerfzer-) provides for the initial liquid phase, while the second one ta used for sgitaring the slurry, which 1> transformed, through s sticky solid state, to eisesriiOy dry partides until the conversion from monomer to polymer reaches a level ofabout 7Tit* resins obtained by bulk polymerization are charactcrizad by high purity and particle uniformity, rendting in an end-product of good optical darity. c t :! . I c I sS W.K. Li'lhiK'li ami H J. MjriMler Solution Polymerization. This type of precipitation polymerization is earned out in organic solvents such as n-butane or cyclohexane. It accounts for only a small percent age of the total amount of olJ PVC resins produced and it is used for the production of copolv iners. Copolymers arc mixtures of comonomers (such as vinyl acetate, vinylstearate. vtnylidene 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 piasticizen (mainly phthalatc or other organic esters) and light and heat stabdizers (heavy metal salts, organotin compounds, and other stabilizers). Lubricants or dyes can be added. Piasticizen an added fot 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 (Smolttc 1966: Tola 1975). Compounding is carried out by hot mixing at fusion tem peratures below or within the softening range (120eC-160*C). Diversified compound ing and processing technologies were developed about 1950. The compounded polymen are used for the production of diverse end-producu. The final convenion 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 100"C to 300*C. End-products include a vast number of articles used in almost every sphere of daily life. The temperatures during the fabrica tion operations (compounding and conversion of compound polymer into consumer articles) drive off part of the small concentrations of residual monomer still contained in the polymer. Barnet (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, dry ing, screen ing, bagging) are usually carried out in dosed buildings. Exceptions can be found in hoi climates (Arympur 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 pans and repair jobs. The degree of pollution also depends to a large extent on the quality and effectivity of monitoring equipment and special exhaust systems. Opening of autoclave vats for cleaning and control purposes resulted in larger spill-over of the tank atmosphere into the work en vironment. Numerous reports of workers with ptenarcotic symptoms fdizziness etc.) Vinyl < i permit n in the p: Ther clave va: walls f'p ton. haJ degassed and iargi were ope ed the fr. non still manly, t! those wi (centrifu ties of ventilatii shipmerv nomer, v. are drive Table : I ppn I mp l Pat; I mf/lin 1 mp, m* 1 ppm ir- 223 T In the 7.' nant mo> covers * (Lefitux leet as 3 opened became t VVtA* ucc 044226 Umelltf jut in I percent' tction of -wyl* n>e co* - solvents f> or ran tern* i and light 'icers). flexible source of ngon iu sphere m tern* mpoand* ducts, nets is >' "ion icd in I*. .if U ftC3* "itmer nuintd ; cured VlM .screen* and in that reenings of polluareeof uoring g and work en* 4 etc.) Vm)l Chlcndc-A--cctJied Di^ea-e 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 autoclave vats by scraping away or chipping 01T the *polv mer skin* formed on the reactor walls ( pol> cleaners*), and who in the past had to spend several hours inside the reac tors. hid been exposed to the highest coucennations of VOl. Although the vats were degassed pr.or to entry, tin reacted monomer remained trapped in the polymer skin, and !a;;er amounts of VCM were released when cavities formed in the polymer erust 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 dun* tion still had to be done after every 20th-30th run. It is. therefore, plausible that, pri marily, the most severe advent effects of exposure to VCM were fully recognized in those workers who had been employed in this job category. But the subsequent steps feentrifuging, drying, screening) also involve the release of some of the lesser quanti ties of unitacred residual monomer from the parades to pollute the environment if venulauon. notably of the drying facilities, is inadequate. Finished polymer, reedy for shipment or subsequent compounding, still contains small quantities of unreacted mo nomer. which either slowly diffuse out and poOure the bagging areas during storage or are dir-en out by the high temperatures nectssaty for compounding. Table 2. Conversion table for concentration of VCM in ambient ait Mol wt. ,ppni* 1000 * 24,45 m*/litpe M.J5 x 1 000 1 mg [> litre -- Mu[--- ....... ppm Iftriy I0J8) ! mg/litre l mg/m' 1 ppm * 2 J* mg/m* I'y____ 10 000 ppm 391 ppm 0 391 ppm 0.00256 mg/litre 2J.6 mg/litre 2--J The Explosion Hazard In the peat only the explosion and fire hazard of VCM was thought to be the domi nant monitoring problem in handling gaseous vinyl chloride (frisk 1963). This hazard covets a concentration tangs of by volume of air (40 000-220 000 ppm) (Ltfaux 1966). It was observed that VCM. being 2.15 times heavier than sir, may col lect as a compact layer at the floor of a polymerization budding after spOtavsr from opened tanks and may catch fire. At least two instances of disastrous VCM explosions became known; In 1964, a large plant for the polymerization of VCM in the United 10 W.K. Lelbach and H.J. Marsteller States was almost completely destroyed when VCM escaping from a leak detonated [Albrtgltt 196'a). Another explosion in one of the two Rumanian factories operating at that time was mentioned bySuciu et ml. (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 repotted 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 possibdtty 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 Schaumaitn declared that the faintly sweet gas is practically odourless at concentrations of 5%--10% by volume. Vtltman and Lange (1977a, b) assumed an odour threshold of 5 000-10 000 ppm. Volunteers exposed to VCM detected t 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 (/nth 1963). Cthring et al. (1979) recently mentioned a threshold of approximately 3500 ppm. Others have claimed that a concentration of400-500 ppm is the lower limit for detection of VCM by its odour (Barerta et al. 1969; Cook et al. 1971;,l&rto* wit; etal. 1972;Lefevrt 1975,cited by Hubtet 1975). Barerta 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 wtre 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 dose proximity between the perception of the odour of VCM and incipient CNS symptoms as reported by tmh (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 imtation begin upward of 5 ppm and are noted by all test subjects at a concen tration of 21.6 ppm (Dee* and Joyner 1969). 2.2.7 VCM as an Anaesthetic Agent VCM was once even considered for use is an anaesthetic agent. In 1929. Schmidt and Schautnann speculated about using VCM as a supplementary narcotic at concentra tions of 3%-5% (v/v) ( 30 000-50 000 ppm) in combined nitrogen oxide oxygen vinyl Chlori Teble 3. Odr Lower limil > 5 000-10 00 J 00 4 1C 3 5t 5C` 400-50' 40' 40' anaesthesia be tic and lethal. oxygen; concc however, that eluded. In to10% VCM to ", several hours i commented u: mined about i. 3.5-5 mmol ( mmol (244 oc Otter et al., in cardiotoxicit) man because c like other hale amines (frith ; the past for an 22 Effects Some individu listed in Table without acute symptoms sud adequate warn exposure to hig A 21-year-old. 10 min after er which had bee cardiac enlarge have been scut which occurtt, doubt that hea found dead wii Msrsteller detonated operating ncentriiipns tinf VCM irttes. lu PVC pa', whi-h reduction, worker*' te al evidence inrnd. how* diemicals dual sensiav>f i certain practically '377a, b) to VCM ppm for I sleepinw* -.imattly ;ie lower M; Mjrkor conducted lumber, in not they difference* : proximity ; at reporteJ .*1 be as- `inet warn* ;eyt and t a canon* hmuit and centra* oxygen Vinyl ClilonCc.Aisoctated Disease Table 3 Odour threshold Lower limit of detection 5 000-10 000 ppm 5 000 ppm a 100 ppm 3 500 ppm 500 ppm 400-500 ppm 400 ppm 400 ppm Author Vtlttnan and Langt 1*773, b Viola 19 7a Irish 1963 Cthnnjtiii 1979 Bar;ns a: a 1969 It'h-rt 197; rcited b\ Hubltt 197;* Cook et si. 1971 Markowitz et al. 197; 11 anaesthesia because of its potent narcotic action and the wide margin between narco* tic and lethal concentrations. In animals it produced anaesthesia at 75--105 in air or oxygen; concentrations above 125 proved to be dangerous. The authors pointed out, however, that advene late effects of this halogenated hydrocarbon could not be ex* eluded. In toxieity studies with guinea pip Patty ct aL (1930) found concentratons of 105 VCM to be lethal within 30--60 min, 5% to etuit marked narcosis, and 0.55 for several hours to be the maximum toicrabie exposure without serious tfTeets. 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 (85 000-123 000 ppm) for 10 min, the minimal lethal range 10-12 mmol (244 000-293 000 ppm) (Ptopla and Ltakt 1933). It was not until 1947 that Osttr 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 setious cardiac irregularities and ECG changes observed m dogs. VCM, like other halogenated hydrocarbons, senstiza the heart to the effect of catechol* amines (Irish 1963). We could not ascertain whether VCM hat actually been used in the past for anaesthesia in nun. 2.2*8 Effects of Acute Overexposure in Man Some individual responses of volunteers to increasing concentrations ofVCM are listed in Table 4. Lattr et tl. concluded in 1963 that the maximum concentration without acute effects in men Ues between 8 000 and 12 000 ppm for S min, and that rymptoms such u dlzzmos, tightdieadedncs and disorientation should be taken as adequate warning signs for imminent acute danger. Two fatalities after occupational exposure to high concentrations ofVCM are reported in the literature (Dantiger i960). A 21 -yearold autodave denier 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 explosiomtttr test. Mean failure ceils and cardiac enlargement found at autopsy, however, implied that the cause of death might have been acute functional disturbance in precasting heart disease. In the seeond case which occurred at the same plant, however, cireumstantiai evidence apparently left no doubt tiiat heavy VCM exposure was the cause of death in a 39-year-old worker. He waa found dead within 20 mis, lying in a pit near the opened valve of a recycling pipeline i: W.K. Leibach and H J. Marsteilcr Table 4 Individual responses ut volunteers to increasing concentrations of VCM ConwentMtion Duration of Symptoms exposure Reference 5 f>0 ppm 7.5 h (Inconstant odour detection> Barerfa et al. mild headache, dryness of U9o9> eyes and throat in 2 of 7 sub.ice: <1 v.4 000 ppm - Generally accepted odour threshold trim i 1963 6 600 ppm 30 mm (Distinct odour) dizziness, sleepiness iruix 11963) 8 000 ppm \ 12 000 ppm J 5 min3(twice on lb 000 ppm I each of 3 succes sive days) 20 000 ppm / 2 of 6 subjects `slightly heady' 1 ol 6 subjects had reeling, swimming head, just like getting gas' 5 of 6 subjects, various degrees of intoxication All 6 subjects had more intense symptoms of acute intoxication than at 16 000 ppm Letter et al. (1963) 25 000 ppm 3 min 2 experimenters: dizziness, disonentation. burning sensation in the soles of the feet Patty et al. (1963) 3 Exposure to six different concentrations: 0 pptn: 4 000 ppm: 8 000 ppm: 12 000 ppm: 16 000 ppm; 10 000 ppm through which non-polymerixed 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 (Spirtat 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 5ucni 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 acroostcolysis). Successful resuscitation after VCM-induced narcosis of several hours' duration with out evidence of permanent damage was mentioned by Rety et al. (1974). Vinyl Chior 2.2.9 Monr During the fi ed data on was directed an apparent!; 1954 .Plaits Croniberg to Russian poly: 0.05-0.08 m centrationof Inspectorate . or from the u mg/lure (* 1, mg/htre (* 3~ In the cet> air ranged fro ppm, which ventilauon. T trations, som-. pursuit of imt ment in the vi ie drying fact! cen trations ot continued to I nutted concer in a plant the range of 0 ppm (2.93 mg ication apparu remarkable th the liver, althv past have prot Byrfn et ai which occutTc cated peak ex; between 1962 Rumanian PV( about 120 mg> exposures to V 300 Rumanian Greek plant wl resulted in higl (Cirsios 1971) of the reactors up to 10 000 p i J. Marstellrr i VCM -.rence - .,'M f. ll. o9( il K ;9oJ) ^.(1963) >Mf et ll. >f3) nr et si. iibj) : rm wre tank: niy just . 1951 (Spirjs airing a VCM <it jtt suddeni tightness of wusness was and by Sueat occasion in radiance iictdence of loolyits). ration with* Vinjl CliJoniie-AssocMteil DiscaMt 13 2.2.9 Monitorinf VCM Concentrations in Working Areas Dunng the llrst two decades of PVC production (1930-19501 no publication contain ed data on VCM concentrations in the *n:king environment. The mam interest then was dimmed towards prevention of the explosion hazard. In 195*. the observation of an apparently toxic angioneurosis in Russian PVC production workers (S/ntnnn-3 195c;P'.cthchiner et al., cited in Filatova and Gromocf 195") induced F-ht n j ir.d Gr'jn/ficrj to investigate environmental VCM concentrations m various r*aru of a Russian polymerization plant in Gorki). Although most readings were in the range of 0.05-0.08 mg/litre ( 20-313 ppm), e^. below the maximum permitted VCM con* centration of 1 mg/litre (approximately 400 ppm) as specified by the State Sanitary* Inspectorate at that time, escapee of VCM in the reactor anas from defective fittings or from the discharge of operating autoclaves nsulted in excursions up to 29.5-41.4 mg/litre { 11 500-16 200 ppm) for periods of 5-10 min. One peak reading of 8?J mg/litre ( 34 000 ppm) was recorded. (n the centrifuging and drying ana of This plant the VCM content of the ambient air ranged from 4 ppm to 3 100 ppm with most readinp between 20 ppm and 195 ppm. which was attributed to niease of nsidual VCM from wet PVC nan and poor ventilation. The screening and bagging ana was characterized by high dust concen trations. sometimes exceeding the official upper limits set for non-toxic dusts. In the pursuit of improving industrial hygiene, the installation of modem ventilation equip* ment in the vieinity of the autoclaves, substitution of hand-operated by semi-automat ic drying facilities, and avoidance of leakages succeeded in nducing the ambient con centrations of VCM to below 0.05 mg/litra ( 20 ppm), but toxic angioneurosis still continued to be diagnosed. This led the authors to recommend tlut the maximum per mitted concentration of VCM should be reconsidered. In a plant producing VCM, FUato-a et al. (1958) found lower concentrations in the range of 0.04--1.1 m^liue (16-430 ppm), with mammura values of about 1200 ppm (2.93 mg/litra), tha latter having been observed in dose proximity to the ramif ication apparatuses and having rasuii.t. 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 reams started early and VCM exposures in the past have probably been in the same range as those observed in Western countries. Byrin et al. (1976) pointed out that during the 1950s episodes of unconsciousness which occurred among workers of the one Swedish plant operating at that time indi cated peak exposures of at least 10 000-15 000 ppm. Sucw et al. (1975) 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/m* ( 900 ppm) in 1962 to about 120 mg/m1 ( 50 ppm) in 1965-1972. In 1969,Xng/;rlracu et al. mentioned exposures to VCM concentrations of 112-545 mg/m1 (44--213 ppm) for a group of 300 Rumanian workers, eight of whom (2.7R) hid Raynaud's phenomenon. At a Creek plant which started operation in 1967. certain sages in the production process resulted In high concentrations of VCM in the work environment for brief periods (Gitsiot 1971). In sir displaced from reactsn 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 wastedrums into which waste polymer scraped I l-t W.K. Lelbach jnd H.J Marieller Vinyl Vi away from reactor wall! 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 m1 (production of 4-5 tons of than Ppm). plants samp!-. PVC per cycle) a crust of 4 kg PVC containing 3%-5?i VCM can he formed on the Esiim. innet surface. During the cleaning procedure 30ft-50% of this VCM content is liber more i ated. It was calculated that the probable concentration of VCM within the reactor averag. after a 1 -h cleaning operation was about 3700 ppm, but that it could be reduced to 90 ppm by 30 renewals of air per hour. In the past a polydcaner 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 Table : atmosf Chtmu ing area was started in 1967, claimed that measurements at various sites inside a 9000- litre 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 a). 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 mm had reduced the VCM concentration to what was considered sstisfactory limits. In the Acc< early days, this wss tested either by Iniffing 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 whieh required a minimum of 400 ppm for positive read ings, equalling 4% of the lower explosive limit of VCM. Later mort sensitive methods such as gas 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 dunng this period (1950-1959), excursions up to 4000 ppm occurred, agreeing with employees' reports of experiencing dizziness while lotding or unloading reactors (Orr 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 vene effects in animals exposed to 100-500 ppm VCM hid become available (Torktlson et al. 1961), tha Dow Chemical Company introduced a new SO 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 ware presented by Ott et al. (1975). In 1968 BASF (Wast Germany) introduced continuous monitoring by infrared absotption spectrophotometry for VCM concentrations well balow 500 ppm; in 1974 more sensi Equ lions in equipm vidual e binitioi (3) The ly spec: i ment sh peak eoi for the s. Curr compri*. tion detc (lonofli. which cs conditio lag of re: A cat induatria in 19751 tive equipment was Installed and concentrations ware kept balow 25 ppm and lattr below ]0 ppm, with oecaaonal ceiling values of 70 ppm (flcig and Tliim 1974). 2.2.10 1 In several surveys individual jobs ware grouped into three exposure categories ac cording to job classification to evaluate past exposure experiences (Spares et al. 1975; Raw PVC Williams et al. 1976\Bkndis at al. 1978). These exposure indices were: (s) light less unresctti. occ 044232 flr Mjnietlef '00 ppm nyl ehlor .tins of n the liber-ctor id to :id 4-5 hi mated n followthe work- a 9000(nations HubUt et ttions -eaotor IQ min ;tt. In the .et limit i'y use of Hive readmethods is inside M releas- 1950 by uVe* lus period -* rtporu I. In a ;i occuraims ad: (TorktlVline for 'tassrem units tioo msensiHater s se al 1975; -HtalfSl Vinyl Chloride-Associated Disease t5 than 50 ppm: (b) medium 50-200 ppm:ie) 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 neaessanly representative of the different phases of a given operation. Estimates of past exposure levels such as those represented in Table J are, therefore, more or leu conjectural. Is ean be assumed that considerable deviations from these average values have occurred all too often in the past. Table 5. Average concentrations of VCM in the working atmosphere of PVC-producing plants4.t Estimated by Chemical Industries Association Ltd.) 1941-1955 1955-1960 1960-1970 mid-1973 1974 1975 "v 1000 ppm V400-500 ppm 200-400 ppm % 150 ppm r, 50 ppm and leu v 5 ppm 4 According to Fltif and Threat 1974; Stmts 1976 Equipment for optimal continuous multipoint monitoring of exposure concentra tions in the working areas should meet certain basic requirements; (1) For stationary equipment sttategicaUy placed sample probes should yield data representative of indi vidual exposure levels in the breathing tone of workers, preferably to be used in com bination with personal samplers. (2) Analysing methods should have a high selectivity. 13) The limit of detection should be at least one order of magnitude below the current ly specified standard regulating the permissible upper level of exposure. (4) Measure- * ment should be instantaneous (within seconds) to guarantee rapid detection of critical peak concentrations. (5) Recording and data processing techniques should be provided for the daily estimation ofTWA exposure during the whole work shift. Currently available methods for the determination of ambient VCM concentration comprise such analytical tools as long-path infrared spectrophotometry, flame ioniza tion detection, gas chromatography, man spectrometry, combustion-conductivity Cionoflux"), and personal samplers in combination with gas chromatography, none of which can at present be comidered as absolutely satisfactory for all individual plant conditions because they aO differ with regard to selectivity, limit of'detection and time lag of response. A catalogue of the methodologies that hive proved to be of value in the control of industrial hygiene and personnel protection regarding expoeure to VCM was compiled bt 1975 by Row*. 2.2.10 Expoeure to VCM in FVC-Frocecting (-Fabricating) Plants Raw FVC powder ready for compounding and fabricating purposes contains residual unreacted vinyl chloride monomer in varying amounts, tn the past, monomer content lo W.K. Lelhath and H J Mursielier was reported to have been ai high aj 6000-7000 ppm (w/w) in some types of raw PVC. but a level of 500-1000 ppm probably was a more representative range {Schweitzer 1975: VKE 19?4:Ararcdr 1976), The monomer slowly escapes into the environment exponentially with time. Jcpending on length of storage period, tempera ture. size and porosity of particles and other physical properties of the polymer and. more recently, on the efTectivity of special degassing techniques (Pircr l976:Seli:itz and h'o//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 ate now used in German plants showed that in most products the content of unreacted monomet 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 tSchiir: and Is'nlf 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 amount! of VCM could be set free during the mixing process, us was shown by Bmder and Straby (1975). Apart from hot compounding, other ther moplastic operations, such is extruding, calendering and welding of tiles, also resulted 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 readinp 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 (Schiirz and H'o//1977). Similarly low concentrations of VCM in breathing zone samples (maximum: 12 ppm) with 6QTr 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 {KanrsJt 1976) . These present results, however, do not permit any conclusions :s to past Icyels of atmospheric VCM during the years when residual monomer content of PVC teams was Itigh 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 plana have always been con siderably lower than in PVC-preducing plana. When it was suspected that certain VCM-related svmptoms might also have afflict ed PVC process workers, this problem was invtsiipted by our group. Although no cases of acreosteolysis, pseudoscleroderma or angiosarcoma of the Uver 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 employed for yean in compounding and fabricating units {Laitge t al. 1975,1976a: Wegman 197S\Manteller *i 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- < ! i Vin>l conspi spons quanti obsert pregrr male F find ar Ar two G. died re< lation i "health overall record 2.2.11 Industr. of expc tion' O' Indust; zen tratr Ament, exceed;' tions si basic ar cupatK(1974). used in are sum docrep . red to t The not a st should l tendy availabl' new inf< list of M various i so<allei: tool for yrisofi! In tl: ppm in I 'U Marsteller of raw Mng* pci miff the ;<!. tempera* lymer and. '~6:Sdiut; -v announced i 0 ppm would lopej (VKE itidt it* now 'acted mono* J between iitm between * wfueh mu mmer end, cnt of residual sing ?cess, other theralio resulted acently coniv German '*integrated `juniors up f/V/1977V " I: ppm i United pm itUrvjJt an levels of C mint ** mg units. !> assumed <i been con- > lure afflict* 'hough no v :re observed. lessons wch -nia end slight I been eraS. 1976a; -ntieal with mage atutbut`nadered mf. 'bough the m. Vm>! Chlopdc-Avvociatcd Lli^e-i'C 17 conspicuous character of titese lesions agrees well with the assumption of a dose-respoitsa relationship of VCM-reiated disorders and the alterations may teem to be. (|uanmatively. of little importance, they should not be minimized. Nevertheless, an observauon period up to the present of almost 7 yean did not reveal any spontaneous progression. In a proportional mortality study tor 1970-19" among roughly 35 000 male PVC fabrication workers in England and Wales. Baxter and for (19761 did not find an excess of angiosarcoma or other liver diseases. A recently completed cohort study of4007 people who had been employed by two German PVC-fabnesting 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 0f the liver were observed and no excess in overall cancer mortality was noted, but an excess mortality from brain tumours was recorded in one of the two plana {Reuitti al. 1978), 1.3.11 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 is 'maximum allowable concentra tion' or `maximum acceptable concentration' (MAC), threshold limit vaiue' nXV). industrial hygiene standard* m the United States and as `Maximal* Arbettsplatzkontenmtion' (MAX) in West Germany. These empirical standards were defined by the Amencan Standards Association as setting a limiting concentration "for exposures not exceeding 8 hours daily during a 40-hour work week with the undemanding that varia tions should fluctuate below this value" Umli 1963). .An extensive discussion of the basic approach to the principles used in setting environmental quality standards for oc cupational respiratrri exposure to toxic agents can be found in the paper of ZitUmt 11974). in tha pip-- the conceptual differences between threshold limit values is used in the United States and maximum allowable concentrations as used in the USSR ate summarized and the differences In approach and cmpliasis, which mat' explain past discrepancies between permissible limits, are elucidated. For deads the reader is refer red to tha paper. The standard is nor an index of relative toxicity, far less of hazard, and certainly not a son of `average'. A standard set as the ceiling level implies that any fluctuations should be around a median of perhaps half the standard and that it should be compe tently used in full awareness of its phonological basis and the limitiaotu of currently available knowledge {Irish 1963). The standard win be subject to revision es soon as new information is available. An essential dement of the annually published German list of MAX values (MAX-W*rte) is its preamble, which exhaustively defines the various modalities for the Interpretation of such standards {Htnuhltr 1973/73). The so-called TWA, an integration over time of fluctuating concentrations. wfH be a useful tool for estimating the probability of injury only if it represena a comprehensive anal ysis of the normal fluctuation btiow the standard. In the Federal Republic of Germany the standard for VCM (MAX) was set at S00 ppm in 1966. The German Standards Advisory Commute* reduced this to 100 ppm I 044235 18 W.K. Lelbach and H.J. Mjrsidler in t9?0 in confoimity with the proposal of Tarkclson et al. (I960, 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 (Technische Richtkonzentration) of 50 ppm was instituted (VXE 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 t74. As of July 1975, a technical guideline (TRX * Technische Richtkonzetitrar.on) 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 I h. In order to adapt operating plants, a provisional regulation was issued with reduction of the an nual mean concentrauon to 20 ppm as of July 1975, and to 10 ppm as of July 1976 and peak concentrations over 1-h periods not exceeding 60 or 30 ppm, respectively (I'cltntan 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 Ststes discharged about 90 million kg VCM annually into the environment (4%--8 n 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 s pioneer study. concentrations of 1 -2 ppm VCM wen 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 Stetes an average exposure of 17 ppb during the yean of uncontrol led emissions ws calculated (Nicholson 1977). In the put 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 end window cleaners). In Germany, VCM was proposed as propellant for aerosols in 1958 (Ostermayer 1967), in Japan it has been used as a propellant since 1958, in the United States this use was probably introduced after 1962 (Schweitzer 1075). As an aerosol propellant. VCM has been a possible source of exposure for the public al large, particularly for women, the extent and the potential health implica tions of which are unknown. Use of aerosol products in confined spaces has been re ported to result in air concentrations of VCM of up to 400 ppm in closed rooms, even after only short butstt (30 s) (Gay et al. 1975), which could persist for several Vinyl Chi. Table 6. T Country Belgium Canada Finland Franc* German Di Republic. Iran Italy Japan Netherland Rumania Sweden Switzerijn United Kir USA USSR Federal Re, Germany Sources: Sn 73;IARC R md H.J. Marsiei'.er 1 which was tiled . ,`ironogeme prop;iu chemical was re'.chikonzemncionj lability Insurance isued instructions 1 in July 1974 Ai .titration i of 5 pen. vai instituted. perI ft. In order to Juction of the anmas of July I97fi ppm. respectively i *u revised in 1977 tginally set at 500 -riry emergency nanimarized the conflictnid industry' in 19 "4. t; countries. mg piants in the the environment >* - lived in water -/:*rl975) In a ambient air near i and 100-200 ppm . used were later m tliese figures since mle {Schweitzer mer production facil'<c year* of uncontrol- >'. either alone or mixhousehold and cosmetus. punt sprays, -opened as propellant J as a propellant since r 1962 (Schweitzer * ofexposure for the mial health implies-J spaces ha* been ra in dosed rooms. J persist for several / Vinyi Chlonde-Aitociated Disease Table 6. Threshold limit vaiuts iTLV) various countri** 19 Country Tear TLV <ppmi Comment Belgium Canada Finland FrsnmJ German Democratic Republic (DDR) Iran Italy Japan Netherlands Rumania io*5 197J 1975 1975 1976 1976 1975 (future) 1970 1974 I97J 1975 * Sweden Switzerland United Kingdom USA 1975 1976 1975 (future) 197J October 1975 1947 USSR April 1974 October 1974 1976 25 50 10(25 5-10 25 200 12 25/50 50 (25/50) 500 200 10 10 100 mg,m* (40 ppm) 5/20 1/5 too 10 25/50 10/30 500 50 25 1/5 1 mg/Utn (391 ppm) 30 rag/rn* (b 12 ppm) TV A IS h/15 min) TWA fg h/1 J min) TWA `5 li/!5 mm) TWAigh) MAC (Schottek 1969) (Kottetskt et al. 19Tg) TWAig h/1 h) TWAig h> TWa 9 h. 15 min) MAC MAC (25 mg/m*) TWA (g h) MAC (Frodan et al. 1975) Twa (g h/15 min) TWA(g lifts mm) MAC twa rg h> TWA IS h/lj mitt) TWa I personal/eciiing) MAC (Amer. Conf. Gov*mm. tndustr. Hypenms) TWA If hi. temporary emergen cy standard (OSHA) TWa (8 h), temporarily permit ted expouite TWAllh.IJmin) MaC. provisional ceiling eoncentrauon: State Sanitary Inspec torate. 1957 (FOatore and Cromberf J9J7) MAC tSchortek 1969;/Termer 1975) (Sanitantye sonny) Federal Republic of Germany 1946 1970 June 1974 1975 1977 500 100 SO 5/15 2/5 MAR MAK TRK (preliminary technical guideline). Annulment of MAK regulation. TRK (annual mean/! h) TRK (annual mean/1 hi Sources: Smyth UStifibreN and Ctonthtij l9$7;SiAorrek 1969: Hentchltr 1972/ 73;!ARC Report 1974; Haley 1975;Sakabe 197S.Frodan et si. \STS\Arytnpttr I977;2c*firt and Wolf |977;MAK-Werte*Listt 1977;/Termer 1975 :o w K. Lclbucli and HJ. Marsidlur hours slier repealed spraying in smaller-tiled rooms I!ARC 1974). Haley (1975) pre sented s list ot` 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 us a propellant in I74 (JAMA 1974.229:S531. There is a case on record of a worker who died from uonctrrhotic 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 Weber 197J). 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 (Meyenon and Meier 1972) is apt to make one wonder what influence the frequent indoor use of VCM-propelled spray cans (BriJbcrd et at. 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 meuplastic bronchial cells compared with twp groups of controls (Good et al. 1975). PVC bottles. Aims 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 (rail Exit and van Lofttn 1975). The problem of migration of unreaeted 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 tin some samples levels up to 10-20 ppm (w/w) were found (van Exit and van Logten 197$; Dorics and Perry 1975). Data available in 1974 to a group of WHO experts revealed that samples of gin and wliisky had contained 0.57 and 0.62 ppm (w/w) of VCM respectively, after storage in miniature PVC bottles for periods up to 3 yean; 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 Pc -ry (1975): in their own analyses of samples of PVC-bottled spirits supplied by British Airways they found concentra tions of 0-0.25 ppm (w/w). Methods were developed for the detection of VCM in liquids with a maximum sensitivity down to the 1 ppb level (van Uenp and Stek 1976: Dressman and MeFarren 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.l mg/person (IARC 1974). Schktter(1976) calculated that today it would be less than OOl mg/person (equalling 250 mg during a whole life trine); in comparison, ht 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 Indusity expects that the use of technology available at present for the production ofPVC food-packaging materials decreases the VCM content of food stuffs to below 50 qg/kg (50 ppb) even after prolonged stotage (VKE 1975). Results of carcinogenicity assays in experimental animals after oral administration of VCM are discussed in Sect. 3J. Vinji Chloride-An, 3 Toxicology oI 3.1 Acute Toxicity' During the first three the assessment of the concentrations varyiri and Leake 1933.Sc/n maireo et al. 1960:Z,. anaesthesia, deep nare this range of exposure uve and haemorrhagic hepatocellular injury inducing substances (s 3.2 Chronic Toxicity Torktlsonti al.(1961) exposure to conetntra: 4.5-6 months. All spe. however, caused an me histological changes in pigs ami dogs. An incrc in rats exposed to 20 O' (1963); no histological Gor'kij Institute were n exposure of experimeu. mias. bradycardia, chan 005 mg/litre) for 5 mo creased secretion of cat;, posterior hypothalamus 3500-4000 ppm (9-lt of the cortex and the ar. comitam changes In cir, posure of rats and rabbi resorptive bone changes nervous system dysfunti available evidence f r Vt VCM should be suspecit statutory maximal allow cratic Republic) should I Of particular import: Viola et al. 1971) with c full year. It was only aft.  It J. Mantelier ..i'(!975) pitregistered tor tration.Jn vri.::9:S55v 1 hypertension plant m south- [Rctnl and cal Raynaud's lysis who never io matte one . Ana (Bruiboni l irom freautnt round to eon. 'ronchiai cells ijing food and .,J other soft as found to ,ip to SQO ppm J VCM from i irts of un stored in PVC nc samples "i, Davies and I "that samp'.'s vt lively, after mirations tn ppm and in British town anal- es i .unctnin* *f VCM in *tl Sret 1"6; ring the yean rial source <if source could calculated 4 a whole 7M in diseased tm] a period of the present for lent of food* '?$) Results nofVCM Vinyl Clilundc-A'SOwiiilcd Di*ei' 3 Toxicology of VCM 3.1 Acute Toxicity 2! Dunng the rlrst three decades ot'PVC producuon. animal expsnmenu were limited to the assessment of the acute inhalanonal toxicity of VOI m short-term exposures to concentrations varying between 30 000 and 400 000 pem (fan:, et ai. 1930.Pcopfcs andLeake 1933'.Schmutwm 1934. 193S;0r/ecai. 1947.Cr/**iai. l949:.l/fromanto et ai. I960-.Lester et ai. 1963). hi mice. rats, guinea-pigs. rabbits and dogs anaesthesia, deep narcosis, cardiac arrhythmias and lethal effects were observed within tins range of exposure but no relevant organ pathology was mind except for conges* tive and haemorrhagic changes in lunp. liver and kidneys on fatal outcome. Acute hepatocellular injury was later found only in animals pieireated with potent enzymeinducing substances (tee Sect. 3.4.2.3). 3 2 Chronic Toxicity Torkeison et al. (1961) were the fint to describe results of experiments with prolonpd exposure to concentrations ranging from 50 to 100 ppm, 7 h/day. 3 days/week, for 4J-6 months. All species tolerated exposure tq 50 ppm for 6 months: 100 ppm, however, caused an increase tn liver weight and 200-300 ppm caused, in addition, histological changes in the liver and kidneys of rats and rabbits, but not in guinea, pip and dop. An increase in liver weight and decrease in spleen weight was also seen ir. rats exposed to 20 000 ppm, 8 h/day. 5 days/week. for 3 months by Letter et al. ( 1963): no histological lesions were found after 3 months. Soviet investigators at the GorTcij Institute were mainly interested in neuroendocrine changes after pretonpd exposure of experimental animals to various concentration! of VCM. Cardiac anyth* mias. bradycardia, changes in phonocarriiognm in rats exposed to 12-20 ppm (0.030.03 mg/litre) for 3 months were reported (I'erar and Ptokhan 1969b) as well as in* creased secretion of catecholamines in rabbits and changes in the biopotential of the posterior hypothalamus {Yarn and Pfokltme 1969a). After a 5.5-month exposure to 3$00--1000 ppm (9-10 mg/Utre) changes in the bioelectric activity (EEC tecoedinp) of the cortex and the anterior and posterior hypothalamic nudei in rabbin with conconutant changes in circulatory functions were seen (Yazm and Pbkhon 1968). Ex posure of rats and rabbin to 0-03-0.04 mg/litre (12-16 ppm) for 6 months produced tesorptive bone changes and osteoporosis in addition to cardiovascular and central nervous system dysfunction (ArsoSeer et al. 1972). In 1969 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 loweted. Of particular importance u pioneer work ware t'Snk't experiments (1970a, b: Hob et al. 1971) with exposure of rats to 30 000 ppra.4 h/day, 3 days/week, for a full year. It was only after this length of exposure that histopatholupcai examination ucc 044239 :: . W K. Lelbit.lt and H.J. Marvtellcr revealed lesions similar to human aeroosteolysis and also similar to the type of nontumorous liver diseases which we observed in PVC workers 3 years later (ManttUer 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 metatatsal 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, cytoplasmie and nuclear polymorphism, abnormal prolifer ation of hypertrophic Kupffer cells and intense ftbrosclcrotic reactions. 3 J 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 13 months 17 developed epider moid carcinoma, mostly in the panauricular region; 6 also developed adenocarcinoma of the lunp and 5 osteochondroma of metacarpal and metatarsal regions of all 4 limbs (Viola et al. 1971; Viola 1974).Maltoniand Lefemme (1975) later interpreted these panauricular tumours as arising from the sebaceous glands of the extenor acoustic duct, also (mown as Zymbal's glands, the cell matrix of which seems to be the target tis sue of a number of carcinogens. They were of the opinion that the pulmonary malig nancies were metastases from the Zymbal gland tumours. Autoradiograms of sections of whole rats dosed orally with [|4CJ4abclled VCM revealed a discrete localization of 1 `C in the psnaurieular region (Zymbal gland?) and in the region of salivary glands and Harder's glands (Green and Hallway 1975). In this contextMeumaun et al. (1979). who analysed the peroxidase activity in Zymbal glands of Wistar rats, proposed the concept that peroxidase-mediated bioactivation of carcinogens (in their study: stilbene derivatives) might offer an explanation for these tissue-specific effects. At the end of 1970 Maltoni and his group, with the support of Italian, British, Belgian and French chemical companies, started to plan and subsequently execute a large-scale carcinogenicity bioassay designed to study the effects of chronic exposure to VCM in relation to various experimental factors such as route of administration, dose level, length of treatment, and species, strain, sex and age of animals (Maltoni 1973,1917-.Maltoni and Leftmint 1974a. b, MS,Maltoni at al. 1974a, 1975). Con centrations used in the inhalation experiments were 30 000,10 000.6000,3500,500, 350 and 50 ppm, with length of exposure ranging up to 53 weeks and observation peri ods up to 143 weeks. Apart from the induction of Zymbal gland carcinoma other ma lignancies developed, notably angiosarcoma of the liver but also extrahepatic angio sarcomas. nephroblastomas, pulmonary tumours and mammary carcinoma, as well as a number of single tumours of other target tissues. Different types of 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-Dawlcy rats each of which had been treated with the .highest doses of 50 and 16.65 mg/kg body wt. (Maltoni et al. \975). Maltoni (1977) succeeded in demonstrating that the route of administration of this dearly multipo- Vinyl Chlo tentiai care study of or solved in so 6 days/wee. ratio only: tion not ne. placed the t the no*toxii angiosarcon Sprague-Daproved to li genic in rat: be carcinog10.5 and 1 1979). Ana the dose-re! exposure le' histological the liver ant the inducnc posure to 1( ah 1974b: 1, endothelial perplasia an even in the; was scanty: doses. In thi fibrosis was ofossifying feet was sug offspring of mine 1975). posed to VC ed from Cm it was seen t. maturity of to 3000 ppn fociofhepa; Hobnber week, for 53 spleen ching malt expose, cutaneous ar ppm group a i Sec also l< ucc 044240 $ ; irMflltf non* Her et rectim Iroid aivt kldtiom oroiifer- Mminary in May - epiderrcinoma 11 a limba 1 thtse iic target us.laiif.ctjons "ion of -.ands :.<|979). .n* ttiibcn* .iisU. - it* a ,-aSUie jtion, 'Hroni <). GanTO. 500. iton peri-thermaangio* < well as :|ll Jin olive animals ' with tha M977) Vm. l Chiondt-Asiociated Disease tintial carcinogen may significantly vary the typ-a of neoplastic response. in a subacute study of oral VCM toxicity, lasang only 13 weeks, in wtueh rats were given VCM dis solved in soya bean od by gavsge in daily doses of 30.100 and 300 mg/kg body wt.. 6 days we*k./m>/i t: al. (1 *>~5) found a significant increase in livcr-to-buuy weight ratio only at the highest dose level. This was interpreted as a merely nonspecific reac tion not necessarily indicative of a toxic response. Based on these results. Ftron et al. placed the oral no-toxic-effect level at 30 mg VCM'k; body wt./day and suggested that the r.o-toxiceffect level may actually be even higher. Zymbal gland carcinoma, hepatic angiosarcomas and nephroblastomas had never occurred spontaneously in the breed of Sprague-Ocwley rats used at the Bulopta Institute. The neoplastic response to VCM proved to have j direct Jose-time relationship. Even levels of 50 ppm were carcino genic in rats and mice. Later Maltont (1977) found exposure to 25 ppm VCM also to be carcinogenic in reti. whereas no carcinogenic effect was observed at lower levels of 10.5 and I ppm in a srudy which, however, it still incomplete (quoted from Gnciute 197?). Another American study designed to complement Maitorn't results confirmed the dose-related induction of liver angiosarcoma and mammary carcinoma in mice at exposure levels of 2500,200 and 50 ppm (Ktplinger et al. 197J). 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 rau: he also reported the induction of skin acanthomas and pulmonaiy adenocarcinomas in rabbits after ex posure to lOOQOppra VCM,* h/day,5 days/week, for at least 15 months[Maltoni et al. 1974b: {ARC 1974). Maitom and Ln'mini (1975) considered the effect of VCM on endothelial tiasuc to be a systemic one since they found dilatation of blood spam. 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. So acroosteolytic lesions were found, but a few eases 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 (.t/e/ronf and Leftmm 1975). Later, \Uttom (1976) detected angiosarcoma in the offspring of rats ex posed to VCM during the period between the 12th and IBth day of pregnancy (quot ed from Geidutt 1979). Hepatocellular carcinoma *n not found in acuit animals but it was seen to develop readily in newborn animals, possibly in connection with the im maturity of their bioactivation pathways (MaUoni l9'rTt. Exposure of newborn rati to 2000 ppm VCM. 8 h/day, 5 dayt/wttk, for at least A weeks elicited preneoplastic foci of hepatocellular ATPase deficiency, notably bi female animals (LUb et al. 1979). Holmbcrj et al. (1976) expomd mice to 50 and 500 ppm VCM, 6 h/day, 5 days/ week, for 52 and 26 weeks respectively. They did not obmrre hepatic fibrosis or spleen changes, but muUpi* benign afreoiogtnic adenomas developed in IS of 24 ani mals exposed to 50 ppm and in ail 24 animals exposed to 500 ppm1. In addition, mbcutaneous and/or subperitoneal hsemangiosarcoma developed in 14 animals of the 50ppm group and in 8 of the 500-ppm group. Only one haemangiosarcoma of the liver N K. Iclbach juJ H J Mjr*u*Iler was found in an ammal exposed to 500 ppm. A few mammary adenocarcinomas, one rhabdomyosarcoma and one renal haemangiosarcoma were al>o seen. From their ex periments Holmbcij et al. concluded that a lower exposure over a longer period may intensify the caneerogenic 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; Feron and tiroes 1979) in an eventually fnntless 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, multicentnc 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. The in vestigators were of the opinion that hepatic parenchymal changes preceded those of the hepatic stroma, but they stressed the fact that the true relationship between VCMinduced alterations of hepatocytes and sinusoidal cells has yet to be elucidated. 34 Toxicodynamies Prior to 1974 very little ii.formation was available about the fate and the toxicodynamics of VCM in the mammalian otganism. but the discovery of VCM-induced angio sarcoma of the liver in humans and experimental animals provoked a large number of studies which resulted in a flood of publications on the metabolism of VCM. In 1934 Schaumann reported that in mammals unchanged VCM was excreted via the lunp after inhalational administration; the pulmonary route is thc-main excretory route of nonmetabolized VCM (Green and Harhwev 1975). Blocking of nonprotcin 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 monochloroacetic acid in the urine of workers exposed to VCM waa reported in 1966 by Grigortseu and Toba. indicating that a polar exctetable metabolite of VCM had been formed (Vamio 197$). Toxicodynamic studies have revealed that VCM per it is not the ultimate toxin or carcinogenic. It is the process of biotransformation (metabolic activation) of VCM. primarily by hepatic microsomal enzymes (mixed function oxidases) that yields short- Vinyl Chlaru lived but high mutagenic am cretable prod; 1975). The t. live velocities tion of its rea nation of VC' so that above following a zc cordance with 3.4.1 Uptake Pulmonary up' in the-animal'1 with the pool > shown by com Bolt etal.(19` as albumin, art pound goes in i After oral ingchas to be cons; is excreted via 1976c). This e able process. Pbody wt. adm. vestigation ot. gavage in dose; found a signilk plasmie reticub but only nunn rats on a diet c almost all the testinal tract, b in this way. Permtanec keys following 800 ppm of14' was negligible i Studies of' that the liver (p polar metabolit spleen, lungs ai> kidneys, spleen, of irreversibly r irrcversibly bou UCC 044242 miriffli . 1 HJ. Mafxtr!!cr arcincmas out from their ex-r period nay '-ecween dose \ been observed r-eriment with mths was publy fruitless cr ease in man. Ear of swollen ami 'ionephrotic iced glucose-8^ne phosphatase ells were observilatation of sinusnmc hepatic in i') also observed i of very malig olfactory-epi: eet'ore in con. developed an.hyma. Tie m.adcd those of n between V CM` cidated. the toxicodyt-induetd angio* - irge number of i VCM. v excreted via main excretory if nonprotein -unced after disI indicated depie<d rets (Htfiwr mg tissues against i in the urine of indicating "iVt). Itimate toxin or Mm)of VCM. 'Hat yields short ChionJc-A.-o.-ijtvJ Dt-iJ-O lived but highly rcacmc Mylamg intcrmciimei wiiieh are responsible for the toxic, mutagenic and oncogenic effects. VCM is metabolized rapidly to polar nonvolatile excretable products (Hefner et al. 19"5a: "aw Dutircn 1^5: FjJwau and ficmchkr 19*51, P.ie toxicity of VCM seems to be largely detemined by the ratio of the rela tive velocities of both btotransformatiun of the compound anu protective detoxifica tion of its reactive intermediates {lUnxhkr 197?a), Tie capacity for metabolic elimi nation of VCM m 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 lero-order kinetic, whereas below 200-250 ppm it is metabolized in ac cordance with first-order rstt kinetics (Htfner et al. 1975a.Bolt et al. 1977), 5.O.] 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 unm*tabolized VCM distributed in the animal's tissues, as has been shown by complete inhibition of microsomal oxidative metabolism {.Bolt et al. 1977a). Boi; et el. (1977a) also concluded that lipids or licoprotetnt, rather than proteins such as albumin, are the vehicles that transport VCM at die 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 *fim pass effect' has to be considered, but an increasingly substantial percentage of unmeubolixed VCM is excreted via the lunp in direct relation to the dose administered flVatanabt et al. 1976c). This confirms the finding that VCM metabolism is a dose-dependent and satur able process. Pulmonary elimination of over 927; within a h of a dose of 3CO 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 beanoil and fed by pvagt in doses of 50.100 and 500 mg/kg daily, 6 days/week, for 15 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 Uver. In a second experiment, they fed rats on a diet containing PVC powder with a high monomer content and observed that almost all the VCM was released from the PVC powder during passage through the in testinal tract, but only about 10 mg VCM/kg body wt. per day could be administered in this way. Percutaneous absorption was studied by Htfhwr et al. (1975b) in male Rhesus mon keys following whole-body exposure (head excluded) to concentrations of 7000 and 500 ppm of14 C-Ubelled VCM for 2-2.5 h. The quantity absorbed via the intact skin w as negligible (0.0275--0.057#) and most ofit was expired. Studies of the distribution of [l,2-|4CH*beiIed VCM in the body dearly revealed that die liver (predominant site of metaboUsra) end the kidneys (site of excretion of polar metabolites) contain the highest concentrations of ,4C activity, followed by spleen, lunp and mull intestine (Mmrrofrret si. !976c;Aofr etal. 1976a. b). Liver, luincyvspleen.lur.g and small intestine (In this order) also contain the largest amounts of irreversibly protein-bound metabolites (Bob et al. 1976a). Only minor amounts of irreversibly bound metabolites of VCM were found in muscle, adipose time and brain. > .\ i; . ; ii >* C k ;' - ;6 W.K. Uibach and HJ. Marsieller Total radioactivity 43 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. Buellter et al. (1977) also showed that unmetab olized VCM possesses a great affinity for adipose tissue, in contrast to its metabolites, which are concentrated primarily in liver and kidneys. 3.4.2 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 chlonde it a monohalogenated ethylene and its ehiorine substitution is esi'mmerrfc. 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 Cvttanovii for reaction rates with ozone. Vinyl chlonde, as a monohalogenated alkene, is the least stable compound with the highest reaction rate in the senes of chlorinated ethylenes and ranks next to unsubstituted ethylene. Secondly, the first step in the oxidative metabolism of all chlorinated alkenes is a transformation to epoxides (oxsranes) which are short-lived, highly reactive electro philic intermediates (Bonte et al. \97$\Henschler 1977b). Such chlonnated epondes may react, by alkylation, with essential cellular constituents, a mechanism which Rannug et al. (1974), Bartsch et al. (1975a, b) and Malaveitle et al. (1975) claimed to be responsible for the carcinogenic and mutagenic effects of VCM and vinyhdene chloride. Epoxides resulting from biotransfomiation of asymmetrically substituted ethylenes. such as VCM, vinylidene ehloride and trichloroethylene, seem to be particu larly unstable with increased electrophilicity and thus enhanced alkylating effect. Their mutagenicity and, inversely, the nonmutagenicity of oxirancs 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 microtomes in the presence of a NADPH-generating system (Kappas et al. 1975, 1976:Bartsch et al. 197$b, 1976,Mataveifle et al. 1975;Boh et al. 1976a;Fcsse.vre et al. 1979). with the aid of isolated perfused liver preparations (Radwan and Htnschler 197$,Bonte et al. \97$\Radivan \977,Henschltr 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 Vin>J Chlor: microsomal i ly highly res. via the form;; bon monoxi' preciable rok in vitro an art systems and : 1976a) The. I'Of - Fig. 1. Metabr metabolized t< acetic acid are roethylenc oxi protein sulphy tw?'(1977). St (Norpoth et a! S-carboxymeti acid) (Hentchl identified in tl ucc 044244 i Marstelltr :tc organs. n of its iioaenvuy unmctabtctaboiites. it ind its pre' compound < chlorine in general. ;t on the ith increas- 1 Cmsnovtc is the least ' rtdyieties .ker.es is a . electroJ epoxides winch claimed to liwnt nsutuitd > he particu.e fleet, nnetncally 11975, with rat et al. 1975, :ftotyn and Htnsch[Htfntrnal. trial anirntb wistiubiting the prtdoy the hepatic Vm;.! Chior.de-Asjoviaied Dtseav: * microsomal mixed-function oxidase system. forming i-libnethytenc oxide, a chemical ly highly reactive epoxide (Fig. 1). A negligible amount ofVCM can be metabolised vu the fonnation of peroxides, very unstable compounds decomposing rapidly to car bon monoxide. HC and formaldehyde which, however, do not seem to play any ap. preciable role in the toxicity ofVCM (Hcusehler 19T~b), (t has aiso been shown that in vitro an artitical superoxide (Ofl generating system can replace rat liver microsomal systems and transform VCM to the aetive intermediate (Keppus el al. 1975; Bolt er ai. I9'6a) The epoxide rcarranses spontaneously to chlotoacetaldehydc. winch ii rapidly Ci'wfcfu Nnau-4 M iiUwrrb* mp!:,uiv^ uikvUtioiit 1 w OmuIjk1 n \kophTo;1 Ctikmu'rln tint Ot/uV V ( M Jin l fruttf* *ftwuthioc. vtcifttf i Thermal rttrrrfnyvnirft; H I^ It; Jrob epoiilt iitame) UK Oil II o--<--<-n II II II H OilonweetilJelii Jv Fig. I. Metabolic pathways. Adapted from Htiuehltr < 1977b) metabolized to monochlotoacetic add. Both chioroacetiidehydt and monochloto* acetic add art also matabolites which art chemically tractive but less potent than ehloroethylenc oxidt. AB three intermediates on be detoxified by conjugation with non* protein aulphydtyl compounds (glutathione, cysteine) as describes: by Gram and Hathway (1977) Sulphur-containing exctetabla meubolits* such as S-hydtaxyethylcysteine Warpath at al. 1976). N-cety)&{r chloro)-ethy(<y$teine (Green ami Nathway 1975), S<arboxymethylcysttHi (Watanabe et al. 1976a), and thiodigtycuhc add I ihii>diacttic sadl (HerociUer 1977a:.Vuffer et al. 1976.1978Mutter and Xorpoth 197J) liave been identified in the urine of exposed worisen and animals. A progressive depression of the W,K. Lvlhjch jntl H J Maf'fcIL'r level of hepatic nonprotein sulphydryl content has been observed in rats alter expo sure to "VCM in concentrations from 150 to 2000 ppm for 2-7 h. N'o depression was seen after 10 ppm and a concentration of 50 ppm caused only ait inconsistent reduc tion (Waranabe et al. 1976b). Protein-bound hepatic sulphydryl content remained, unaffected. Hepatic microsomal cytochrome P4lo. the cocnzyme of microsomal monooxigenases, also decreases linearly with time in animals exposed to VCM {Reynold* et al. 1975b). This destruction of cytochrome P4,, may prevent further metabolism and toxicity of VCM (Pemyn 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 macromotecules, 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 hepatotoxie,mutagenic and carcinogenic effect.Eventually, however, the only fraction of the formed epoxide that binds to macromoiecules 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, HenKhltr (1977a) concluded that there might be a greater risk in intermittent peak exposures over brief periods than might be ex pected from simple integrauon over time and that the chances for effecuve 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 macromoiecules 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 macromoiecules 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 (Waianabt et al. 1978b). This correlates well with Mahont'% report (1975) of a linear percentage induction of hepatic angiosarcoma in ran 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 (Barbm et al. \97S\Laib and Boh 1977). cytidine {Laib and Bolt 1978), and guanine moiety of nucleic adds (OsiermannGolkar 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 (ftterenabeet al. 1978b .Laib and Boh 1977). Laib and Boh (1977) presented evidence showing that the alkylating potency of VCM metabolites cannot be deter mined solely by measuring the incorporation of label into nudcic adds after exposure to radioactive VCM. hfatanab* et al. (1978b) conduded that covalent binding to nudeic adds is not the preferential reaction, but they pointed out that this does not Vinyl Chi. exclude th of cellular eluded as t above all, i This a> work will I. endoplasm' tible to VI phologicall mixed funi lobular, mi. found (Jet. 1978). Sec endotheliai At pres, ccises are t` the hepatov some metal(5) Meehan: tissues othe rant cell rep 1978b). An equa nonneoplas* Raynaud's drome was i man. Besideliver lesion., bioactivatio: portal fibn ment of the a direct or ir tic nervous * lining cells o tion) or win 4 Clinical During the rmight prove: presented in marked the y pationai haz. Ucc ^246 9 MjfMeliv: -.r expo:son u it reduci jintd itul nonoynoIds ei !-olism and cpOXldt. is nzyme ylatinf ijJ proteins he mttab* ; us exert its sly Traction ietoxificd itathione or s which .Hirusms. In :!wrt micnt in be exJetoxiilca- v to VCM c binding i the politioiu oT m> covalent increase uotnts be- 4 'unction -elates well icioutcoma osurt con- icchanism i jib and tads (Osierriding of be very .-resented be deter'*r exposure Ung to -does not V.nyi Chionde-Ar-Juaivd Diwjw exclude the possibility of other.mote subtle interactions which may impair the control of cellular replication. .Alkylation oT nucleic acids, however, cannot at present he ex cluded as the mechanism Tor VCM-induccd carcinogenesis after repeated exposure and. above all. in the target cells rather than the uepatocytes. 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 hepatocyte. the liver cell itself is not particularly suscep tible io vCMin Juced lovcity 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 rati centrelobular, midzonal and panlobulat hepatocellular vacuolization and even necrosis was found (Jeefer et al. 1974.19"5.19^7: Reynolds et al. 1975a. 1976; Conntlv et al. 19~S). 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 (fftetivt. either singly or in conjunction: (1) The active metabolite leaves the hepatocy te and is conveyed to the endothelial cell. (2) The endothelium itself has some metabolic capacity (Bolt 1978). as may tissues of or|ins other than the liver, fd) 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 (Watanabr et al. 1978b). An equally puzzling problem is the role of VCM in the pathogenesis of the distal nunneoplastic vascular lesions which are responsible for the development of the triad. Raynaud's phenomenon, sclerodermoid skin indurations and actoosteoiysis. This syn drome was tlit earliest indication of advene 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 ia now established that hepatic bioactivation of VCM plays the central part in the pathogenesis ofboth nonarrhotic portal fibrosis and angiosarcoma of the liver, it is not at all clear whether the develop ment of tht acral lesions is due to VCM itself or to active metabolites which may exert a direct or indirect toxic action on fa) medullary vasomotor centres, fb) die sympathe tic nervous system, (e) smooth muscle ceils of the media of artenoiet, fdl endothelial lining ceils ofsmall 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 occupational exposure to VCM might prore to be not quite as harmless as had been claimed. The historical synopsis presented in Table 7 summarizes those dinleal studies from the world literature that marked the gradual recognition of the full spectrum of damage due to this new occu pational hazard. ucc 044247 30 W.K. U'lhj.-h and H.J Ma.'-ter.c Table 7. Gradual emergence of evidence for VCM-associaied pathology Year Reference Findings 1949 Tnbukh et al- Hepatomegaly. more or Ic** marked 'anicteric hepatitis', `chronic gastritis', hypotension, anaemia, skin lesions 1954 1957 1957 1960 Smini nva Filatova and Gronsberg Kubota Dansiger Toxic angioneurosis Toxic angioneurosis Symptoms similar to Raynaud's phenomenon Two cases of accidental fatal poisoning by VC.M. 1 nonfatal acute overexposure 1961 Smirnova Reversible osteolytic lesions of distal phalanges. Pseudoclubbing, thickening of skm on volar side of forearms, slight haemolysis and reticulocytosis 1963 5uciuetal. CVS: prenarcotic symptoms (dizziness. euphoria, somnolence). nervousness, insomnia. blunting of memory, general asthenia, headache Vascular: Raynaud's syndrome Dermatol.: pruntus, reversible sclerodermalike skin induration, chemical and allergic dermatitis Digest, symptoms: anorexia, nausea, fullness, hepatomegaly without hypcrbilirubinaemia. splenomegaly Endocrine: hypothyroidism 1966 Cordier et al. Raynaud's syndrome, sclerodermalike skin changes, acroosteolysi*. pseudociubbing. joint pain, tiredness, sleep reversal; 2 episodes of acute overexposure (loss of consciousness! 1967 Harris and Adams Acroostcolysis, 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 acroostcolysis' with Raynaud's symptoms, sclcrodermalike skin changes, pseudociubbing 1968 1971 Antonyuthenko Dinman et aL Mentions thrombocytopenia Prevalence of aoooateolysis and Raynaud's phenomenon 1971 1972 Dodson et al. Kramer and MutscMer Vascular lesions preceding the bone lesions Increased BSP retention and raised icterus index related to degree of exposure Vinyl Chlon Ttble 7 (con Year 1972 Rc M. i9'>: Jiii 1973 Ah. 19741a) Cr 4.1 TheTn. A first indica plant ptoduc. non (Toxic ai in detail in he personnel w! hourly sampL drome was a! (Kubota 195 moregulation and CN5 sym (1954) also rr durations on there was evil of red cells, u: evidence of d> acroosteolysii opetitors) aft junction with was found in i lesions to be c reversible cha. vibration trau the full range cupational act In 1963 5i analysis of the  II.J Mameller I anicteric otcnsion. henontenon 'iiing b> VCM -.al phJanfts ,i\ on volar ii and reticulo- ntii. euphoria. <nia. blunting idache croderm alike rgic dermatitis id. .' Juniss, rubmaemic ciike skin Subbing. j<-:nt 'episodes 01 -wiousnesvt ujud's phenoment of sacraUtac with pemvent`i>p*y tvy h Raynaud's cbanprs, - Raynaud's ne taiions -d icttnn index Vinil Chlonde-A'vociJied Disease 31 Table " icontinued! Year Reference i*: Maritowtt: et si. i **: JjilC 4,-lii i.-Uff I97J Mantelltr et ai. 19741a) Crttch et al. FimJinp Progressive tiuckenmg ot hand) and forearm#, jrtliralgu. Blanching upmi exposure to cold with cyanosis of bands accompanied by severe pain. Skin biopsy 1 *t German report or " workers -vith vcieroJermalike sk.ti lesion>. Raynaud's syndrome, and iscroosteoiysi*. Tests showed abnormal liver m 3. occlusion of digital arteries m I worker Nonctrrhotic portal fibrosis with portal hyper tension and splenomegaly 4 cases of angiosarcoma of the liver 4.1 The Triad: Raynaud's Phenomenon. Pseudoscleroderma and AcroosteolysU A tint indication of advene effects due to chronic VCM exposure arose in workers at a plant produong VCM who presented with symptoms similar to Raynaud's phenome non (toxic angoneurosis^. This was reported by Snwwora in 1954 and later desenbed in detail in her thesis 11959). The syndrome was found predominantly in laboratory personnel who had intermittently been exposed to high concentrations of VCM during hourly sampling for chemicd analysis (punty of the product). In 1954 Raynaud's syn drome wes also observed among several workers at a Japanese PVC producing plant (Kubota 1957). Apart from painful vasospastic disorder of the hinds, impaired ther moregulation, acrocyanosis.asitive cold wit. capillaroscopie alterations, paraesthesias. andCNS symptoms such as headache.blunting of memory and sleep reversal,5minwra (1954) also mentioned swelling of lingers 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 ted cells, urobiiinuria,and reticulocytoiisi. In 1961 Smimora desenbed radiographic evidence of destructive bone lesions of terminal phalanges in the hands identical with aeroosteolysis in three workers at a PVC-producing plant (one fitter, two centrifuge operators) after exposure for 3-9 yean. Since these bone lesions developed in con junction with toxic angoneuross' and since complete recaleincanon of the defects eras found in two workers J yean after removal from exposure, Smimora believed the lesions to be characteristic of chronic VCM intoxication. She pointed out that their reversible character might terra to distinguish the lesions from similar defects seen in vibration trauma. In retrospect, Smintota't observations ate the earliest descriptions of the full range ofsymptoms which much later became known as The syndrome of oc cupational acrcoswoiysis*. In 1963 Suebi at at. (let also 1967 and 1975) published the lint comprehensive analysis of their obxrmion of a multiform symptomatology* in subactue and chronic Ucc** 044249 32 W K. Lvlbji.li jmJ H.J tljr-icllc; VCM intoxication. During a 4-year period, they examined 168 mostly young workers from two Rumanian PVC-producing plants who had not previously been employed in other industries. In their classic paper, the authors described in detail the various cen tral nervous, digestive, angioneurotic and cutaneous symptoms (listed litre in their order of`manifestation). Acroosteoiysis. however, was not mentioned. Episodes of acute overexposure (usually occurring at the end of a batch run. during retrieval of unreacted monomer, or at repair jobs) rapidly resulted in a state of licht-headedncss and transient eupiiona similar to a mild degree of inebriety and were accompanied by a feeling of heaviness in the legs and disturbed locomotor coordination. Several workers claimed to have been able to identify escaping monomer by its faint but agreeable odour. Apparently during periods of particularly high ambient concentrations, workers repeatedly noticed formication in the lower limbs and a general feeling of bodily warmth. Six subjects had experienced loss of consciousness when repairing leakages, but recovered rapidly after being carried out into the open air. After a few months of work, unusual fatigue and sleepiness set in, there were complaints about persistent somnolence, even outside the work premises, and a tendency to fall asleep at the work place, particularly during night-shifts. In addition, headache, dizziness, irritability, blunting of memory. paraesthesias. and general weakness were reported :,some workers noticed insomnia or sleep reversal. A reappraisal of these nonspecific complaints (see also I'ale et al. 1976) 6 yean later, after improvement in industrial hygiene, revealed that the frequency of their oc currence had considerably decreased (Stictu et al. 1975). Following a prolonged penod of repeated overexposure, vague nonspecific digestive symptoms also developed, such as anorexia with ensuing weight loss, nausea, fullness, upper abdominal discomfort, bloating and epigastric pains. Enlargement of the liver was found in 51 workers (30ft); in 6" there was also splenomegaly. Classic Raynaud's phenomenon was found in 6ft. but a tenfold higher percentage of the total work force showed evidence of vasospastie alterations on plethysmography (Rmchtr et al.. cited by Suciu et al. 1975). Pruritus of the hands, fottaims and face was 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 dorsal surface of the hands, the volar side of wrists and forearms and the face, with turn thickening of subcutaneous tissue or formation of whitish papular or slightly elevated plaquelike indurations. The cutaneous manifestations largely disappeared after removal from the work place. In addition, mention was made of features of hypothyroidism in a few workers. Also, transient loss of libido in 241 was recorded, with tetum to nor mal after a break from work or during holidays. With the exception of acroosteoiysis and the two most alarming late sequelae nondrrhodc portal hypertension and hepatic angiosarcoma - Such/'t early documen tation of the prevalence of disease in PVC production workers encompassed a com paratively complete description of the various aspects of chronic VCM intoxication. Later publications supplemented the spectrum of knowledge mainly by providing ad ditional infoimation on epidemiological, roentgenological, thermographic, angiograph ic, and hiitomorphological aspects of the lesions encounteted in subjects chronically exposed to VCM. V'in > 1 Chlor The disci, two Belgian : classifiable dmarked the r. syndrome w: year a numb'. United State* cases of OAO the various pi end of 1979. vascular phen symptoms th begin with illthe fingers art tips on hard to cold aceon are likewise a ance of print': osteolytic pu with stnation Table 8. Pub!> Year 1966 1967 1967* 1967 1967 1969 1969 1971 1972 1972/1973 1973 1974 1974 1975 1975 1976 1978 1979 One oi 2 ul. ucc 044250 Mar-'elltr ; women yluycti in iious ceni the:; ies of .'vjJ 01 icdr.esi yarned b> ml worker* .-table >1. workers niily .akages, tonthi of >isien i i the work ''ility, -s workers yn tlteir occed period .vd.sueh >mfort. i-iJITi: in 6". spastic >rruuntus Jl M JS :na- or . dorsal firm t elevated tar removal roidism in n to nor- iiieiae doeumen1 a comticatton. vtding adngiographironically Vm>! Chbrndc-A".cciated Disease 33 Tlte discovery of unusual osteolytic defects m the distal phalanges of the lianas of two Belgian autoclave cleaners who had suffered from Raynaud's phenomenon and unclassifiable degenerative lesions of the dermal connective tissue I Cunjitr et al. 1^66) marked the recognition of tlus new occupational disease in the Western World. The ssnorome was termed 'occupational acroostenlysis'tO.AOLl.and durin| the following \ ear 4 number of additional cases were reported from France. Great Britain and the L'ntted States. later Lefirre f 19,;> who together with Cornier described the first two cases of O.AOl. reported that a subsequent investigation revealed another 'en eases in the various plants affiliated to the same corporation in Spain. Italy and Brazil. By the end of 1970, a total number of 126 cases had been published in detail fTable 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 linger 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 ait likewise affected. Later, dassie 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 stnation of nails (pseudodubbing). Table S. Publications on 'Occupational Acroosteolysts' since 1466 \<^r I9f-6 1967 1967 1967 19*7 1969 1969 1971 197; 1972/1973 1973 1974 1974 1973 97J 1976 1978 1979 Country Number Authors of cases Belgium France France United Kingdom USA Rumania Yugoslavs USA USA Fed. Republic of Germany Japan France USA USA United Kingdom United Kingdom n 5 S * 31 ** 8 41 ** 6 1 4 1 4 I 4 Brazil Israel 5 126 GWler et ai. Benoit: Giaretain and Mnnlhm Boumehon felted bv Mann et al. 1967) //erne and AJamt Vilion et al. Angheltteu et aL Kora?et al. Dinman et al. Markowiti et al. Juke and Veltman: Stain et al. a. b) Takeueht and Mabuehi * Moulin et ah Trapp et al. Utii et al. Sreuart et aL Bratton et as.: Walker; Mitchell Johnston 0978) Gama and Metro Hahn at aL One of 2 clear cases, in addition. *9 suspected cases i see Sabtba 1975) ki yuK; *> vC-s- *5^ > ucc 044251 JJ 4.1.1 Familial and Idiopathic Aerooutolysis W K Leibadi ami H.J Ma.-su-ller Acroosteolysis it a very ran disease. Tlie 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 pan or of an entire distal phalanx of one or mom fingers and also of toes, have been mention ed in the literatus* since 1921 (Assmann 1921 .Monahan 1926: Bonk 1927: Kemblum 1929). Komblum attributed the lytic bone defects to vascular abnormalities and noted that he had found identical lesions in early stages of scleroderma and in leprosy. The term acroosteolysis was fust introduced by Larochi and Hoehfeld (1948), who held a neuroendocrine syndrome responsible for the lesions. Independently Hamaich (1949) reported another case of symmetrical idiopathic acroosteolysis. particularly involving the terminal phalanges of the lingers with preservation of tufts, progressive clubbing and shortening, and ilMefined symptoms of disturbed peripheral circulation. By 19S2 Giacci mentioned that 68 cases of the familial type of acroosteolysis and 33 cases of the nonlamilial, 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 Hams 1954). In 1957 Liivrt 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. Oirney (1965), who added another four cases of the familial type, stated that this variety and the nonfimilial 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 ranty 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 (Lefh/re 1972). 4.1.2 Epidemiology of Occupational AcroostcolysU Attempts at assessing the prevalence of OAOL among personnel involved in VCM manufacture and polymerization revealed that in general this occupational type of osteolytic bone lesion was found in only l%-2% of the work population at risk. Hublet et al. (1977) considered the fact that only 3% of all workers who had been engaged in manual cleaning of autoclaves at a Belgian plant suffered from OaOL and Raynaud's phenomenon to be indicative of the importance of individual factors. Wilson et al. (1967) observed 31 cases among 3000 employees of on* large company. In 1971 Dinman et at. 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 s total of SOU employees, illustrates the difficulties and limita tions encountered in a retrospective study of this dimension. AH of these 5011 workers had been engaged in various stages of VCM and FVC manufacturing, but 1257 of them were workers who only handled finished FVC polymer. Five of the 32 piano worked Vinyl Chloi exclusively only 25 cle: defined as e enen; 18 of with experie drome were jobs, both re (1 case per 7 appeared no was dttectec. use for react entry into tf Table 9. Pre Country France USA . United Kingdom Fed. Rep. Germany United Kingdom 1 Total More con related rymp Lange ini U olopeal chccl pathological: were affected cold, 15 wort morbidity wa found classic numbness am 8.7% and urn Allen test ind people with p pseudodubbifinding that tl duration of p. UCC 044252 ; H.J Marsieiler ' 'hit condition 'aud's disease s loss 01' pan or : been mention\al~\Komolun dities and noted i leprosy. The it), who held a 'imaseh (1949) Uriy inTolling .'live clubbing ttion. 3y 1952 'id 33 cases of ature. He added tulatmg preeesone fragments - of idiopathic It range of diflytic diseases, -as considered r review, i.'tl that this tame disease i than the term ; lesion that s when tn icaners (Le/iire edinVCM nal type of - >n at risk. had been rm OAOL and d factors. `orge company. ' corporations epidemiologi'rtes and litmtac 5011 workers r 1257 of them [Hams worked Vinii Chloride-Associated Disease 35 exclusively with the finished PVC-derived consumer preduetsi Dtuman et al. found only 25 dear-cut cases of OaOL anion; the 5011 employees (mean age: 55.$ years I. 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 efeaningi 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 assocanon with OaOL 11 case per 7:. or 86 workers at rule, 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 m use for reactor cleaning. Furthermore, it seemed that the extent of degassing phot to entry into the autoclaves correlated with the manifestation of the disease. Table 9. Prevalence of acral disease in VCMxposed populations Number of eases Country Site of group at risk OAOL Classical Sever* Sclero Raynaud's sensitivity dermoid phenomenon to cold skin lesions References France 130 USA 354 United 37 Kingdom Fed.Rep. 100 Germany United 104 Kingdom Total 725 S 12 4 20 i5 99 1 25 15 63 ' 8 33 5 13 4 10 1 :o<>.3-) 7if^nr'i 119(1,16") 43i*-6^i Renoir 1967 Ldii et ai. 197} Walktr 1976 Langt and t'.tltnin 1977 .i/cnre et al. 1978 More commonly seen than OAOL were Raynaud's phenomenon (sec Table 9) and related symptoms of abnormal peripheral circulation (Renoir iW.Lilit et ai. 1975; Lattje and Vtlman 1977). Btnoit pointed out that a complete medical and roentgen ological check-up of all 528 employees at a French PVC-preducing 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 worfccts at risk the overall morbidity was almost 255*. Similar results were obtained by LUU et al. (1975), who found classic Raynaud's phenomenon in SJS% of354 heavily exposed WC workers, numbness and tingling in 24%, excessive sensitivity to cold in If*. pseudodubbtng in 1.775 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 tome people with past exposure Raynaud's phenomenon had gradually faded, whereas paeudodubbing persisted or even progressed. Mon important, however, was IMis4 rinding that the prevalence of all them abnormalities increased significantly with the duration of past exposure to VCM. I ucc 044253 Occupational acroosteolysis it a condition predominantly observed in ) oun;er workers. The age range was 20--45 years and hail' of ail cases reported tell in the 30-59 years age-group. Duration of VCM exposure prior to onset of Raynaud's phenomenon ranged from 1 to 23 monilit (Dodson ct *J. 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 fust discovered two yean after termination of exposure (Benoit 1967). Longitudinal studies of the bone lesions demonstrated partial or complete but mostly detective restitution, resulting in shortened and deformed distal phalanges, within 2-3 yean after removal from VCM exposure, but Raynaud's phenomenon and cutaneous lesions may penut (Williams andMcLachlan 1976). Stein et al. (1973a, b) reported partial healing with restitution of tufts but progressive lysis of the proximal portion of terminal phalanges 3 yean after termination of exposure. Although OAOL developed predominantly in FVC production worken 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 w hite 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 chemicai 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 diyer/bagger, pre-mix operator, recovery and charging operator who had never cleaned autoclave vats.Cfrrwarr et al. 1975). According to routine plant monitoring of VCM levels in the past and as measured in 1973 by gas chromatography of grab samples, his average exposure had been within the threshold limit values of the day (200 ppm). Radiographs taken in 1966 at the end of his fust year during an earlier survey of OAOL were normal: in 1972 he presented with Raynaud's phenom enon, pseudodubbing, typical OAOL and dermal thickening of hands and wrists. Ar teriography demonstrated narrowing of most digital arteries, even in fingets 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 inhalational (rather than transdetmal - Dinrmn et al. 1971; Jrewen 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 mierotrauma 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 etaJ.(1967). 4.12 Clinical and Roentgenological Features 4.1.3.1 Occupational AcroosteofysiS In the majority of cases osteolytic lesions are confined to the hands. Involvement of the feet was observed only rarely in OAOL. Wlson et al. (1967) believe that OAOL differs from familial or idiopathic acroosteolysii in several respects. Although the bone defects in osteopon skull, des' shortenir. nonoccup genologu 1)T1k one or mu 2) Int tufts, or a 3) The tufts togei defects (sc (`bandlike Fig. 3. Oc. seroosteoh year-old au 4) In tli and broad? fragments, and increai Sodium mineraiiiai multineoui jnJ H.J. Marvreller ved m younger tl fell in the 30-39 cud's phenomenon itency period was ' <ped insidiously ,om OAOL wu first Longitudinal studies ,-`;cnv* restitution, ears after removal rsions may persist mil heating with terminal phalanges '.voHters who had at has also been ob* J to earry a sub* ' -year-old white male J typical bilateral nf by an industrial inns of vinyl chio- r after 6 years' em erging operator who n routine plant us chromatoeraohy ' I limit values of st year during an ynaud's phenomis and wnsts. Ar flngen without - of deformed sdarmai -- Diitman pdbility or idioh'pmenr of the syncrotnuma during i chiselling) was a culated by WIson Involvement of tieve that OAOL . Although the bone V:nv! Clil'jr.ic-.\iii)vUtrJ D'.xjm: defects in the distal phalanges are similar in both conditions, other features, such as osteoporotic compression fractures 01 the spine, basilar impression fracture of the skull, destruction of mid-phalanges or osteosclerotic changes of wnsts and hand bones, shortening of metacarpals and cortical thickening of the shafts of long bunts seen in the nonoccoganonai type have never been found in OAOL. h'llson et al. worked out roent genological catena for the diagnosis of OAOL: 1) Tiie earliest changes in OAOL are marginal defects and lo. s of cortex in tufts of one or mort of the terminal phalanges of the hands. 21 In the next stage this is followed by small `half-moon' cuts in the cortex of the tufts, or t so-called slice-effect along one or mort tufts. 3) The advanced stage of destruction is characterized by either s complete lost of tufts together with a portion of the shaft or there may be transverse or oblique bone defects (see Fig. 3) cutting off the shafts from the remaining distal rim of the tufts (hindlike actooateolysis'). ATtJ wt? Fig. 2. Occupational aereoiteolyw. Transverse or oblique bane defects (`bandlike acreosteolyiis') or partial loss of terminal phalanges in all fingers of both bands, (33year-old autoclave cleaner: duration of caposute 3 1/2 yean) A) In die healing stage there may be either complete bony union with shortening and broadening of the residual parts of the end phalanx or a fibrous union of bon* fragments. Fingertips remain short and plump with persistent dubbing of soft tissues and increased lateral and lonptudinal curvature of fingertips. Sodium fluoride ' *F ecinriscan data of affteted bones suggested that active de mineralization (resorpovej and renuncralizstion (reparative) processes may occur si multaneously even in the same hand (DoUson et aL 1971). In soma cates, bo--t of c 0*00 044" .55 n W K. Lrlbach and H.J Mjrxiellcr other body regions were also involved. Erosive and sclerotic changes in the sjcro-diuc joints and circumscnbed resorptivt defects (cortical erosions) in patella, clavicle. man dible. humerus, styloid ptocess of ulna, femoral condyles, os calcis, cuneiform and metatarsal bones have repeatedly been observed i Conlicr et al. 1966.//jrm and Adams 196*:Dodson et al. 1971 .Juke et al. 197A:Lange et al. 1974a:^\w et al. 1976: Jayson et al. 1976a.Lange and I\ltman 1977). 41.3.2 Pseudoscleroderma Concomitant with the manifestation of paracsthesias, pain, tenderness of the (infers 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 pufliness and coarsening of the skin of the face (mostly on the forehead and cheeks). Raised, ivorycoloured, firm nodules or elevated, sharply de lineated plaquelike skin indurations are seen on the dorsal surface of fingers and hands and on the volar side of the wrists and lower forearms. It was this combination of Ray naud's phenomenon and cutaneous lesions which first prompted a search for other symptoms of progressive systemic sclerosis in affected workers. The syndrome of OAOL. however, can be dearly distinguished (Table 10). Notably, the diffuse immobil- Table 10. Differential diagnosis; syndrome of occupational aeroosteolysis i Raynaud's phenomenon, sclerodermoid skin changes, AOL) / progressive scleroderma with (rare) osteolytic lesions Occupational AOL Progressive scleroderma Sex ratio Hands Exclusively e Clubbing and shortening of finger tips; hyperhidrosis: no ulceration e> 1:2 Atrophy and tapenng off of fingertips: anhydrous: ulcerative lesions Penoral puckering of skin Skin appendages Telangiectases Shortening of frenulum Subcutaneous deposits of calcium salts Dysphagia (oesophageal involvemen tl Renal, cardiac and intestinal involvement Occupational history Prognosis Not observed Preserved Not observed Not observed Not observed Not observed Not observed Obligatory Favourable (skin and bone lesions tend to heal after removal from exposure! Common Loss of skin appendages Common Early symptom Common Common (Common! Usually spontaneous progression Vinyl Chloride izing sclerosis u tional syndrom^ readily than the 4.1.4 HiitolOp, 4.1.4.1 Cmam Several investig; disease {Cordier al. 1972 ;Lefc we found only c 1967-.Marin et. neural changes' who suffered 'rr. Dermal chan mis with disone broad interlacin faintly stained n Schiff (PAS). A. histioeytes was: The most notab of elastic fibres, full thickness o . sue. Skin appenWalker (1976) f not exceeding t. some fibrous tin Vascular le t capillaries were and pencapillar thelial cells with tion of lumina. ` myocytes, was a to narrowing or Degenerative {Benoit I967;.t; hyalinosis of :hMeissner, Pacini 4.1.4.2 Bone!. The most strikn worker with OA ening and hyaln most layer. Sup 1 ucc 044256 HJ. M.:rst*iler the sscro-iliae t. clavicle. man* leit'orm and :mt 3110 AdJrnS et al. I9`e. of tiie fingers and :>rotressive sdeinns. sometimes ; lice imoitly on ited. sharply det<en and hands -matron of Ray* th for other ndrome of i.ffuse immobil- ,<n i Rjviaud s r.na with i rarei f vleroderma Sr i tapering off p anhydrous: i* >* kin appendages i nptom n) -ron lentous MOa V;n>! Chl..*nde*Associated Diwase 59 ixmg sclerosis of the skin with tapering off of fingertips was never seen in the occupauonal syndrome. After cessation of exposure the skin lesions seem to regress more readily than the osteolytic changes. a 14 Histology a I Cutaneous Lesions Several investigators described the histomorphology of skin lesions in vinyl chloride disease iConiiertt at, I960;/farm and.-tdams I967;.tf*nn et al. \967; Markowitz et al. '.9~2:Lange e: al. 197-la: Vtlnncn et al. 1975. Walker 1976.Helm et al. 1979). but we found only one description of bone histology in OAOL in the literature (Benoit \ 967,Mann et al. 1967). Skin biopsies showed various degrees of dennal. 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 end pronounced thickening of the der mis with disonentanon. swelling end nonfibrillaiy eosinophilic homogenization of broad interlacing collagen bundles. Then ns some degree of interstitial oedema which faintly stained mctachromatically with toiuidine blue, aleian blue and periodic acidSciuff (Pa5). An inflammatory reaction with infiltration oflymphocvtes and a few liistioeytes 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 aceilutar. partly hyaliniced collagenous tis sue. Skin appendages were preserved. In 15 apparently less severely affected workers. Walker (1976) found only some destruction of eiasne 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. t'oscular lesions affected capillaries and small dermal arteries. Numerous dilated capillaries wen seen in the subepidermal papillae with swelling of endothelial calls and pericaptllar oedema. Capillaries of the cutis showed cufflikc hyperplasia of peri thelia! cells with fibroblast transformation, hyalinosia of vessel walla and final oblitera tion of lumina. Marked medial thickening of dermal arterioles, due to hypertrophy of myocytes, was accompanied by parietal fibrosis and hyaiinous, which ultimately led to narrowing or even complete oedusion of the lumen. Degenerative lesions of small dermal nerves were mentioned by Frendi investigators (Ben ht 1967, Marm etal. 1967: Owretoin and Motilhn 1967). They found sclerosing hyaiinotts of the pciineunum with atrophy of neurofibrtls. Tactile corpuscles (WagnerMeissner, hbni) were unaffected. Bone Lesions Tire roost striking feature in a biopsy specimen of the bone, obtained from a French worker with OaOL (ease 4 of both Benoit 1967:.tfnrsw et ai. 1967) was marked thick ening and hyalinization of the periosteum with chondroid metaplasia of the inner most layer. Supplying capillaries and arterioles showed oedustve changes identical with 10 W.K Lelbjch anil 11J Mamdler thou observeJ in the dermu. The bone matrix per se wet barely affected. There was minimal ilunmng of cortex, normal spongy bone and only mild fibrosis of the bone marrow. Experience with histomorphulugy of bone lesions in the familial and idiopathic type of aeroosteolysis is limited. In the few eases where biopsy material could be ob tained, there was replacement of bone by nonspecific fibrous tissue, but inflammatory and degenerative changes or osteoid formation were not found (Dnpas et al. 1936: Elion and Bumstcin 1954; Greenberg and Street 1957: Sehwarzueiler 19J7). In this context, it should be kept m mind that Viola succeeded in reproducing dermal, vascular, neural and skeletal lesions in the skin of the paws and in small meta tarsal bones of expenmental animals which were very similar to thou observed in man. Viola exposed rats to 30 000 ppm VCM, 4 h/day. 5 dayi/week. for 12 months and de scribed the histology of these lesions in detail (1970b). 4.1.5 Arteriography, Capdlaroscopy, 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. 197-ia;Moulin et il. 1974). The most prominent arteriographic features were ir regularities and segmental stenosis of digital arteries, ranging from localized or diffuse narrowing to subtotal or even total occlusion with development of collateral vessels. Besides, a conspicuous retardation of flow of contrast medium was noted, and peculiar tortuosities of patent digital arteries were found. Circumscribed hypervascularity of the terminal tufts and in the region of the wrists was noted in some cases (Benott 1967:e;ifr et al. 1974a: Velrman et al. \91i\Prtston et al. 1976:5rmwr at al. 1975: Gama and Meira 1978). Angiographic fmdinp in a larger group of 19 symp tomatic PVC workers with either Raynaud*s phenomenon and/or aeroosteolysis (519) were recently described in detail by tCoischwin et al. (I960). Raynaud's phenomenon had been observed to persist in these patients for prolonged periods after termination of exposure and even after roentgenological evidence of healing of resorptive bone defects in those who had formerly suffered from aeroosteolysis. In addition to vary ing degrees of stenosis or occlusion of digital arteries with reopening of small collat eral vessels, acral hypervascularity and considerable rttardation of perfusion in spite of premedication with tolazoline (Priscolinc. 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 both angiosarcoma of the liver and hepatocellular carcinoma). The pathogenesis of these peculiar vascular alterations is not dear, but the possibility presents itself that they may be due to de struction of elastic fibres in the vessel walls in analogy to similar alterations of digital arteries seen in rheumatoid arthritis (Laws et al. 1963.1967). Vinyl i Stu> various finger?. ed a var lar area* those ferent i! larosco. control encein . PVCw. of distu induccv. A si. a PVC-)' Cheniic: normali was con number employ related It also s more sc  I Marstillrr (We was 'he bone spathic ..ij be obilimmatory i. 1936. *). Jucing .-mall mete* *vtd in man. .(its end de- y of the Nity eonarterial U j'iti- et . ere ir1 or Jj.'fjse 'I vessels, oeealut nt;. of ` -*(5/19) i<crd>menon - 'initiation bone * in vary* dll collat-n in spite riotous ii'Cd elongavampie is m a 54. "t after Mdotna of vascular due to de< of digital V.nvl ChloftcU-AisocutcU Oim'J Jl Fig. 3. l uii'.picuou). tuMuosUiti and elon^jticn >>i di|tiial iirtvnii Studies of microvascular changes by wide-Held capillary micmtcepy (direct obser vations complemented by photography) of selceted shin sites - such as nail folds. Cnger?ads. dorsum of phalanges and of proximal interphalangcai joints - demonstrat ed a vanety of capillary' abnormalities, U. dilated or giant capillary loops, pale avascu lar areas, capillary and subungual haemorrhages. The abnormalities were similar to those seen in scleroderma but wen usually less conspicuous, less numerous and of dif. ferenr distribution. In a survey of a group of 152 Amerffcan PVC workers, these eapil* laroscopic findinp proved to be significantly mom prevalent than in 50 nonexposed control subjects 0Merited et al. 1976). There was also a statistically significant differcnee 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 acral circulation but alio in 6 nonsymptomatic males with either VCM* induced angiosarcoma of the liver (2) or splcnomtgalie portal hepatic fibrosis (*). A similar survey ws later undertaken in an unsclteted sample of 129 employees of a PVC-producing ehemieal plant in England with 26 employees of a aon-PVC-prtadueng chemical plant serving as controls (Maricq et al. 197$). The prevalence of capillary ab normal!tits found in these British workers, which were of the same type and degree, was comparable to that in the American sample, although the latter included a larger number of mote severely affected symptomatic patients with greater mean length of employment (15 yean vs 35 yean). In the authors' opinion, this suggested that VCMmisted disease may develop independently of differences in manufacturing procedures. It also suggested that this easily detectable type of mtcovascuiar lesion may precede more senous VCM-induced disorders. In a small subgroup of 15 clinically affected 4 'V K Lelbjth and I! J Marstcllur British workers who were examined 6-24 months alter 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 wis considered to be too small. The same type of capillaroscopic changes was also observed in three of 4 Polish workers (2 reactor cleaners, 2 fitters) who were found to suffer from Raynaud's phenomenon after exposure for 2-5 years {Byczkowska and Langautr-Lcwowxka 1974). Infrared thermography, another non-invasive method, used by Rc;y et al. (19*4) 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 imputation" in four PVC workers suf fering from OAOL. In one of them vascular disturbances as evidenced by infrared thermography persisted in spite of complete healing ofOAOL. Stewart et al. (1975) demonstrated uneven blood flow in the fingers and patchy hyperthermia in the distal part of the OAOL-affected left index and middle finger of their atypical case. Local ized acral hyperthermia seen on IR thermography corresponded to the angiographic finding of circumscribed abnormal collections of small vessels (compensatory collat erals?) in the pulps of the affected fingers. Using IR thermography in a survey involv. ing 143 PVC production workers and 56 controls, Williams et al.(L977) assessed the time needed for heat return after immersion of one hand for 10 s in a water bath kept at 19*C; 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 occupations! aeroosteolysis 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 seareh for other manifestations of a sy' .'mic 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 workere from a British polymerization plant who were referred to them out of a tout past and present work force of 320. Mean duration of exposure to VCM was 39 months (6-75 months)- Of these 58 workere, 28 were symptomatic (Raynaud's phen omenon. 9: scleroderma of hands or feet. 6: OAOL, 2; sensitivity to cold. excessive fatigue,limb pain, panesthesias). Slight hyperimmunoglobulinacmia, usually IgC, the presence of mixed eyroglobulini. 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<ell proliferation. Mixed cryoglobulins, in vivo con version of complement and depressed values for Cj or C were taken as evidence for the presence of circulating immune complexes. Autoantibody screening demonstrated low-titie antinudear antibodies (IgC 1/20-1/50) in eight of the nine patients with Raynaud's phenomenon. Aggregates of IgC, C4, C , and flbrinofen/flbrin were reveal ed by direct immunofluorescence in the lumen of vessels, adherent to vascular endo thelium. Aggregates were similarly seen in the media and subintimal regions of small Vinyl Chi. and medic lung(] C3: The au and bone i bolic inter plasma pro which suncuiir occlu as a result aton of tis to further Jayson et; suffenng f. than in no ride discv In an e in four Pol decrease in evet, Lang. after Seph; 6 together agglutinins were obser sponses pis (1974a) an dence of at non of rhe terminatioi immunoflu were later > creases in ii taken up at ed to sugge hypergamr with far ad three patiei with Rayn, degrees of i runs were f range: 1 a sderodenrx of which is In sumi autoimmun establish tit in VCM4nd I H.J. Mirtfil!.' it (termination < that among * condition, lpilbroicopic rs.2 fitters) for 2-5 yean etaJ.(l9"-) yerature rangly wanner than workers suf. -y infrared -et al.(l975) a m the distaj i case. Localangiographic atory coilatsurvey utvolv> aueuei the ater bath kept iitroii ani be- eJ certs;^ivesys:-...uc conditions i for other turn, as pro* -logical sic iies - `hem out ot a VCM was 30 tynaud's phuiId. excessive ually IgC. the 1C* were : of reduced . in vivo con* - vMcnc* for - demonstrated 'tieno with 1 in were reveal* itcular endo* nns of small Vir>>l ChlonJe-Xwocuted Di'Vj'c 4.' and medium-sited artenoles in biopsy specimens of the skin (10 cases), muscle and lung 11 case each). Tlic authors proposed as explanation for the induction and pathogenesis of skin and hone changes in VCM-mduccd disease a theoretical model based on reactive meta bolic intermediates of VCM formed during biotransformatirm binding covalently to plasma proteins.These may act as anugens las a result of a structurally abnormal protein) which stimulate B-ceil proliferauon and anubody response Platelet aggregation. vas cular occlusion and ischaemia were though: to be secondary to complement activation as a result of formation of immune complexes w hich w-ert 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 earned our collagen studies in a start biopsy of one patient suffering from OAOL found the rue of collagen synthesis to be considerably higher than in notmal controls. Tlie pathogenesis of excels collagen formation in vinyl chlo ride disease has not been fully elucidated. In an earlier study no cryoglohuhnaemia or presence of cold agglutinins was found in four Polish workers with severe Raynaud's phenomenon: in two of them a slight decrease in IgC was noted (Byczko^tka and Lang7uer~Le\vowicka 1974). Later, how ever. Lanjiuer'Ltwowicka ct al. (1976) observed latent cr/oglobulinaemia, detectable after Sephadex C-200 filtration, in 18 of 22 workers with Raynaud's phenomenon (in 6 together with acrooiteolyns and sclcrodermalike changes). Again, there were no cold agglutinins detectable, but in live patients marginal to slight elevations of IgC levels were observed The authors suggested that a pathological alteration of immune re sponses plays a key role in the pathogenesis of vinyl chloride disease. Lanft et al. f 197-ia) and I'elrmart et al. (I975) concluded from their results that convincing evi dence of autoimmune disease was lacking. Immunological studies including determina tion of rheumatoid factor (latex agglutination test), quantitauve immunoglobulin de termination (Marumi radial diffusion technique) and autoantibody screening (indirect immunofluorescence) were initially introduced in our first aenes of 30 pattena but wen later abandoned because of mostly neptive results, except for occasional in creases m immunoglobulin levels Qfantrtler et aL 1973a). 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 hypergammaglobuUnaemii face comment in Ward et al. 1976a) except in a few patients with far advanced portal fibrosis and portal hypertension and in the terminal phase of three patiens who died from angiosarcoma of the Urn. In a group of 18 ?VC workers with Raynaud's phenomenon in whom arteriography of the hands disclosed various degrees of oedution of digital arteries, autoantibodies, cryoglobulins and cold aggluti nate were found in none; a moderately increased 1|C level (1.93-3.68 g/btre; normal range: I a 1 01--11 g/liut) was seen in five patients who suffered from OAOL and sclerodermoid skin changes (unpublished data). Elistin antibody titres (the specificity of which is doubtftil) were neptive. In summary, currently available evidence does not seem sufficient to suggest an autoimmune disease as a pathogenetic mechanism. Further studies will be needed to establish the true significance of the possibly transient immunoiogicai abnormalities in VCNUnduced disorders. ucc 044261 44 W.K Lclbach and II J. Mjrvtiillcr 4.1.7 Pathogenetic Considerations Raynaud's phenomenon as a premonitory clinical symptom, histomorphology in man and expenmental animals and angiological exponents 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 tn 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 (Cjwc and Metre 1978), Yet the answer to the next question, the pathogenesis of peripheral vascular injury in vinyl chloride disease, is unknown. It still remains largely a matter of conjecture how a volatile toxic compound that is taken up via inhalation, distributed throughout the systemic circulation and metabolized (bioactivated) in the liver, can bring about, apparently only in a small number of predisposed individuals, sfter s vari able period oflatency severe vascular injury and (probably secondary) damage to peri pheral tissue. Some conceivable mechanisms am briefly listed in a previous chapter (see Sect. 3.4.2.2). but no conclusion can be drawn as to their relative significance. 4.2 Non-malignant Liver Disease in Vinyl Chloride/Polyvinyl Chloride Production Woikeri Long before Raynaud's phenomenon or osteolytic lesions were observed in PVC pro duction workers. Trtbuklt et al. (1949) studied environmental conditions in a Russian plant where polyvinyl chloride resins were produced and compounded. Without going into detail, the authors pointed out that moderate nontender hepatomegaly was found in a larger porportion of a group of 73 workers (48 males. 25 females) mostly engaged in PVC compounding; 'anicteric hepatitis' was diagnosed in 21 of them (IS d. 6 9). Al though the authois knew about the narcotic action of high concentrations of VCM (73 -250 mg/litre * 30 000-98 000 ppm) from the literature, which they explicitly mention, and also knew about the release of unreacted monomer from the powdery PVC resins during thermoplastic compounding, they apparently held other volatile compounds derived from halogenated aromatic hydrocarbons (such as chlorinated naphthalenes and diphenyls) used as plasticizers responsible for the systemic toxicity. They urged, however, that strict monitoring of the health of these wotken should be introduced to prevent the development of severe liver damage, and they suggested the installation of ventilation facilities of sufficient capacity. Nonicteric hepatomegaly was again recorded by Suem et al. (1963) 14 yean later in almost one-third of the total work population (51 of 168 employees) of two Rum anian PVC-producini plants, including 10 cases with additional splenomegaly, liver biopsy in two of these wotken revealed chronic hepatitis. Studying the prevalence of temporary disablement due to liver disease among 350 employees of the Sverdlovsk plasties industry,Bushin (1965) found the highest morbidity among employees of the PVC production unit, compared with other units engaged in the production of nonPVC plastic materials; 170 wotken of sndllary industries served as control subjects. Vinyl Chlondf-A- The clinical rymprmany as 152- of rli survey was describe developing chronic character of nonm;' In 1972 Kranu. had been routinely time-weighted aver: environmental data wise multiple linear tion and. to a lesser level of past exposu: the individuals stud TWA levels of 300 in clinical (aborator ed BSP retention w: ease (Marsteller et a. In West German' dermatologists in Bt At flnt sight, the $> derma. This provoke Progressive systemic a first group of 13 pi from a nearby PVCfrom either OAOL i. phageal varices due t a group of 20 relativ previous liver disease Medical Depanmen t patient and revealed capst'j Jibmsts o/. ly. marked portal h> al. 1973). ft was now encompassed a large Hence /tt/te et al. (IV In retrospect, thi spleen ilterations in c the long latency peril disease which is accon hepatic parenchymal - Only 3 months Lt was surpassed by the; lit er, an exceedingly r workforce of274emr ican plant (Creech et r upper gastrointestinal j HJ. Manreiler ihology in man .ommon de-onie VCM in oculation m -it of their rasost rutce?title rculation (C/jina t of peripheral )!y a matter of '>u. distributed the liver, can ' lak, after a vandamage to penMui chapter (.see itieanct. :J in PVC pro* hi in a Russian Without going Italy was found iwscly engaged HJd.6?). Ai- .onaofvrM hey explicitly i the powdery ther volatile chlorinated tome toxicity, t ken should be > sucgtited the > 14 yean later 0 of two Rum* ungaly. Um < prevalence of he Sverdlovsk inptoyees of the nebon of non* itral subjects. Vini! C!t!i>nde-Auo<.taivd Di-caw The clinical symptomatology of - typically nonieieric - liver disease observed :n as many as 1 S~ 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 insidious!) developing chrome hepatitis. No histological data were available, however, and the true character of nonmalignint liver disease found in these worker: remained obscure. in lb?' AVcwr andMurchkr examined a group of 98 healthy male workers who .had been routinety 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. Krvmer and Mutchltr concluded that exposure to VCM at TWA levels of 300 ppm or more for s working lifetime could result in certain changes in clinical laboratory parameters. As it later turned out. slightly to moderately increas ed BSP retention wis the most consistently ptthologieal test for VCM*inducd liver dis ease {Menteller v. al. l97Ja). In West Germany the first cases of occupational OAOL were observed in 197; by dermatologists in Bonn {Julie and Lanjt \9~2:Juht ct al. 1973:Stem et al. 1973a. b). At tint sight, the symptomatology appeared to resemble atypical progressive sclero derma. This provoked a thorough search for manifestations of visceral involvement. Progressive systemic sclerosis, however, could be excluded. On medical examination of a first group of 13 polycieaners who were referred to the Oepertment of Dermatology from a nearby PVC-preduemg 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 {Juhe et al. 1973). Further investigation of a group of 20 relatively young PVC production workers ('mean ige:40 years), in whom previous liter disease could be excluded, was carried out in collaboration with the Medical Department Pemoneoseapy and guided liver biopsy were performed in each patitnt and revealed varying degrees of mnevrhotk ponel. pensmuteUd and mbcantular jibrosis ofthe brer. with splenomegaly, thrombocytopenia and, lest frequent ly. marked portal hypertension, but strikingly little hepatic dysfunction (Mantellcr c al. 1973). It was now realized that the disease spectrum in VCM-exposed individuals encompassed a larger scope of injuries and, in fact, suggested a systemic toxic effect. Hence Ju/tc et aL (1973) propoeed the term Vinyl chloride disease*. In retrospect, this comparatively late recognition of the true nature of liver and spleen alterations in ebrenie VCM intoxication can be attributed, at teas; in pan. to the long latency period as well as the insidious onset end course of this type of liver disease which is accompanied, even far into the advanced stages, by only minimal hepatic parenchymal dysfunction. Only 3 months later, however, in February 1974 the significance of this discovery was uupaiiad by the alarming announcement that four cases ofengiommma ofthe brer, an exceedingly rate malignant tumour, had ben found among a comparatively matt work force of 274 employees of the PVC polymerization section of a large North Amer ican plant (Creech ct al. 1974s). Two of them four patients had first presented with upper gastrointestinal bleeding due to portal hypertetuioo between 1964 and 1970. I :t I. t iqmeeiy w w e T ucc 04426: 9 46 W.K Ltlbawh and H.J. Marjieller There is no longer any doubt that chrome exposure to vm> 1 chloride monomer can produet two different types of liter disease tn nun as well as m experimental animals: 1) Noncirrhotic portal hypertension 2) Angiosarcoma of the liver. The two conditions have one feature in common: they ate both rare disorders which art not easily recognized during life. Noncirrhotic portal hypertension and (often inconspicuous) portal fibrosis are not pathognomonic. Primary spleme enlargement and gastrooesophageal haemorrhage due to marked portal hypertension in the absence of. or preceding, the development of cirrhosis was first described by Bantt in 1894. As `Band's syndrome', this symptom complex and its aetiology and pathogenesis hew 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 Southeast Asian regions (Ramalmgatwamt ct al. 1962;//neefn et al. 1962, Arm et al. 1967a, b;Boyer tt al. 1967:Soma et al. 1971). It has been seen only sporadically in the Western Worid (Roussclot 1940: Ravenna 1940; Tisdate et al. I959;?o/u/i et al. 1962: Miller and Brandt 1962.Sideryi and Vettiot 1964: Mikkehcn et al. 1965,/her 1970: Escarnn Marin et al. 1974; Mendenhall tt al. 1974; Crannis 1975; Villenante et al. 1976). Iber (1969) estimated that "centers throughout the world reviewing their experience with portal hyperten sion encounter 3 to 5?e of patients who do not dearly fit into the category of cirrhosis or blockage of the portal vein." In the absence of an identifiable aetiology it has been speculated that in noncirthotic portal fibrosis observed in India, unknown toxins contained in indigenous drop, herbal medicines or adulterated food might have been responsible for the condition (Same et al. 1971), Vitteneuve ct al. (1976) suggested that, apart from VCM and inorganic ancnicals, 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 tha liver. These agents are: ` t)Inorganic enenicats (Zeefen et al. 1970;.Vefe wd Azzopardi \9H .Knolle et al. 1974;Afomsctal. 1974: Huet et al. 1975; VUteneuve et al. 1976; Cowlithaw et al. 1979); b)Hypenitaminotit A (Minuter et al. 1971;RutteB et al. 1973. l914:Hmban ct al. \97a,Kittler t\ al. 1977): and e) Rectntly.copper tnlphete in Portuguese vineyird workers (Pimentel tniMenezes 1977). Arunical prtpvetionz (usually prescribed as Fowler's solution - potassium anenite) have in the past been used as a tonic in neurasthenia, as an adjunct to iron therapy for anaemia, as antiepileptic drop and well into the 1950s fot the treatment of psoriasis. In this context. Band's remark in his original paper (1898) that anaemia accompanying primary splenomegaly responded best to anenical preparations is of note. In a renowned German pharmacology textbook of this period (Notlmogel and Rtmbach 1880) Fowler's solution is also listed as a traditional antimalarial drug of ; and H.J. Msrr.eller iioride monomer can I'crimental immiis: 'i rare disorders rta! fibrosis ire not :-J liarmorrhap due . development of ic`. this symptom i matter of debate. .<i` the syndrome has iRjinaiinfsP'.jrtti 16~:Seme et al. nisselot 1940: andt 1962 '.Sultryt i er al. 1974; t (1969) estimated h portal nypenencategory of cirrhosis j that in noncirritotic ^enous drugs heroal condition iSj.na et 1 and inorenmc tyr,creme, Uio. ..tion wr.h known .h the exes; non of are: \91 UKnolle et al, ow/is/iju- I't al. 'J. 1974;Af/w6an et 1`imtnttl iniMenezes i - potassium an adjunct to iron Os for the treatment 1891) that anaemia 1 preparations is of <>d f/Vor/mofe/ and mnalarial dnif of Vinyl CMondt-*\jsocutcd Ducim 47 long standing. Otainuvth and Viranuratti (1979) recently implicated an indigenous Thai medicine contanin; arsenic as a possible aetiolopcal factor in a case of idiopathic portal hypertension. Dana et al. 11970) found significantly elevated levels of arsenic in liver tissue specimens of four of nine Indian patients with idiopatlue portal hyperten- sion resulting from ehronic arsenic intoxication icontammated drinking water, use of Ayurvedic medicines). Typically, liver disease in these cases occurs m conjunction wnh other evidence of chronic arsenic intoxication, such as skin pigmentation, palmar and plantar hyperkeratosis, skin cancer and scmetimes carcinoma v oilier sites. However, neither histological nor radiological or haemodynamic criteria permit a clear distinc tion between Idiopathic' portal hypertension and nonarthotte portal hypertension caused by chronic arsenic tcxiticauon or chronic exposure to VCM, as was demon strated by Viiltncuvt et al. (1976) in a study of live patients. After prolonged treatment with excessively high doses of vitamin A (psoriasis, ichthyosis and other dermatological conditions, adjuvant cancer therapy and :n health faddism) chronic intoxication has been seen to cause hepatic fibrosis and cirrhosis (Muenter et al. 191 UFktschmmn et al. I97?:A*iir/eeetal. 19", Russell ex al. 1973, 1974). Storage of vitamin A in hcpatocytet and one type of fat storing, nonphagocytie pcnsinusoidal cells [Ito cells (fro and .Vemoro 1952)] could be demonstrated by fluo rescence microscopy. Stimulation and proliferation of Ito cells, which are probably fibroblast precunon (Popper and Vdenfricnd \910\Sehnack et al. 147). provokes an increase in basement-membrane-Uke material and collagen within the pcnsinusoidal space and leads to perisinusoidal fibrosis with partial obliteration of Disse's spaces and the sinusoidal lumen (Hrubm 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 50 vineyard workers in Portugal is. to our knowledge, the first report in which chronic copper intoxication is implicated as the aedological agent For periods varying from 2 to *5 yean, these workers had been enpged in spraying vineyards with a mixture containing copper sulphate on 15-100 days per year. The authon noted a dose morphological resem blance of the lesions to those resulting from exposure to inorganic anenicali and to vinyl chloride (Pimentel and Meneset 1977), Although extrinse ehronic eopper intoxi cation is virtually unknown in man. potential hepatotoxicitv of long<ontinued uptake of copper wa discussed by Blom/ltU et ah in 1971 in connection with recurrent haemodialysis. Although nonmalignant liver disease seems to be a more common lesion in PVC production workers than angiosarcoma, it lias received less attention than the spectac ular discovery of tne rare hepatic neoplasm, lit continuation of our first two surveys (Afanreller et ai. 1973,1975a. b), we have now (end of i980) observed 17 patients (all members ofa total work force of approximately 180 polymenzatian workers) in whom ciinicai and morphological examination, including peritoneoscopy and guided Over biopsy, revealed advanced portal hypertension (Table 11). A larger proportion of them Cm presented with symptoms ofunheralded gastrointestinal bleeding. On follow up. we strongly suspected that angioarcoraa 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 teries of seven patients with nonerrhotic portal fibrosis and c i 18 W.K. Lelbach end H.J Mjntdler Table II. 17 PVC workers with advanced porrjl hypertension i marked oesophageal vanto. episodes tit upper (II Weeding, splenomegaly i Age at diagnosis Duration of exposure rcrttoneoscopic and No, (years) (years months) histological diagnosis i 30 i 31 3 32 4 35 5 4 35 6 39 7 39 8 4) 94 41 10 4 47 11 50 12 51 13 52 14 52 15 54 16 1 58 17 1 61 5 5/9 3/6 4 9 10/6 13/6 7 18 18 6/6 17 15/3 11 6/6 21 13 Noncirrhotic fibrosi* Noncirrhotic fibrosis Noncirrh otic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis a On follow-up patients 5.9,10, 16 and IT subsequently developed angiosarcoma of the liver and died 3-6 years after diagnosis of portal hypertension. Patients 6 and 14 arc at present (1981) under observation for suspected development of angio sarcoma of the liver, 6 and 11 yean after pentoneoscopic diagnosis of portal fi brosis associated portal hypertension. 5rn/r/i et al. (1976a) observed later development of angiosarcoma in one of them. If a rough estimate based on these two small senes were acceptable, it would appear that approximately one of five to seven individuals suffer ing from advanced VCM-induced portal hypertension might be expected to develop angiosarcoma later, although PVC-inductd hepatic fibrosis per sc is probably not a premalignant lesion. 4.2.1 Clinical Manifestations of Non-malignant Liver Disease Physical examination is usually disappointing. In the mote 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 worked who had been heavily exposed in the past (Mmtttter et al. 1975a). Lila ct al. (1975) reported hepa tomegaly in 15% and splenomegaly in 3.4% of 354 consecutively examined employees (267 currently employed, 87 former worked) of one PVC polymerization plant in New York State, USA, a number which included virtually the entire current produc tion work force. A significantly higher prevalence of hepatomegaly was found in those Vinyl Chlon- exposed for r splenomegaly In contra.ment ofhepa ectases. gym. r.ot seen. Eve plialopathy ii workers only It is push preceded adv. only one case development 4.2.2 Labor: Owing to the not the target value for the <. This makes it 1974; Creech throrabocytop logical biochei the levels of s. quent (Mantc (ICC. 05 and liver function w orked of a (Tamburm et progressively of abnormal b there was ove> phosphatase 1 alkaline phosp megaly and/r- Except for and Vtitman i the reticulocy parametcd us? presenting feat Sion (Smith et be dealt with r Assessment matic worked factureofPVt coproporphyri :tj Mar-trlier uphagsal and ji ilU|p3'i' lie Ubroiis 'it fibrosis He tlbfOMi tie fibrous tic fibrosis tie fibrosis me :"i''rnr. in; fibrosis lie cirrhons ' 'tie fibrous 'tie fibrosis <ue fibrosis itih fibrosis fibrosis nine fibrosis i; cirrfiQ'is ue fibrcsis -.ircor.a ot menu b and : an^io- p.>rui fi- .-.nciir ot it enes w iduaUsufiii- ^ u develop uhly not a |te- ;is of VCMy to moderate; Hepatomegaly -liohad been .ported hepamaj employees -a plant in i rent produciond in thine Vtn;,! Chlondti'Af'&iXJMtf DiWj-c 49 exposed for more (tun 5 years, whereas the JilVerence 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. gynaeeomastta. peripheral oedema and asettes or hepatti encephalopathy ate not seen. Even after massive bleeding from oesophageal vances portosystemic ence phalopathy does not develop. Asettes and hepatic coma have been observed in these workers only in terminal stages of anposareonta of the liver. It ts pusling that aeroosteolysis and sclerodermoid stun induration have only rarely preceded advanced stages of VCM-induced liver disease. To our knowledge there is only one ease of angiosarcoma of the liver on record which was associated wuh prior development of aeroosteolysis (Roche et al. 19*8). 4.2.2 Laboratory findings Owing to the fact that hcpatocytes. 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 vety difficult to devise adequate screening programmes {Martin t al. 1974.Creecfi and.WcW. 1975. hVeff et *1.1975;fl* etal. 1975,1976). Apart from thrombocytopenia, we found 45-min BSP retention to be the most consistently patho logical biochemical test: usually minimal hyperbdirubinaemia and minor elevation of the levels of serum alkalint phosphatase. SCOT and SGPT were considerably less fre quent OhntcUcr tt al. 1975a). Another dye-removal test, indocyanine green clearance OCCi 0.5 and J.0 mg/kg), also proved to be more reliable than standard biochemical liver function tests in correctly iden-ii/ing early hepatic injury in 1200 vinyl ehloride workers of a chemical plant in Louisville, Kentucky, during a 4-year screening period (Tambum et al. 1978b). The exposi it rank was found to be closely correlated with progressively increasing frequency of abnormal ICC clearance, whereas the frequency of abnormal SCOT, and alkaline phosphatase only increased in late stages, often when there was oven clinical disease. In the surety conducted by Ulis et al. (1975), alkaline phospliatasc levels were elevated in 16.67* of the 354 workers examined. In their scries, alkaline phosphatase was also closely correlated with the clinical symptom of hepato megaly and/or splenomegaly. Except for thrombocytopenia (less than 150 x 10* platelets/litre) which langt and I'dtmm (1977) found to be present in 76 of 100 workers, and a slight increase in the reticulocyte count (in 35 of 79 workers,Lung* and Veltman 1977), haematolo|ical parameters usually do not contribute to the diagnosis. Thrombocytopenia was also the presenting feature in two of seven British wotfcsn with nondnhotic portal hyperten sion {Smith et al. 1976a). Thrombocytopenia and abnormal platelet function testa will be dealt with separately in Sect. 4.4.1. Assessment of urinary excretion of porphyrins and porphyrin precursors in rymptomatic workcti who had been enpged in the production of PVC (n 23) or the manu facture of PVC articles (n 17) revealed varying but mostly mild degrees of secondary coproporphyttnuha in the majority of them {Ungt et al. 1976b). Tlie significance of l i *? S #v 50 W.K Lelbach and H.J. Marveller these findings as an indication of toxic liver damage is not clear and the relation to previous exposure to VCM remains to be determined. 4.2 J Cross Inspection of the Liver and Spleen The gross appearance of the liver, as assessed by peritoneoscopy (.Uann-ller et al. 1975a, b.Manreller and Lelbach 1977.Lelbach andMaizteller 1977) or at exploratory laparotomy, is that oft 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 pcau 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 William (1974), and also in two of our recent cases in combination with development of angiosarcoma. On palpation (direct or by pentoneoscopic probe), the texture of the liver is normal or only slightly firmer than usual. Indirect pentoneoscopic evidence of portal hyper tension is presented by increased vascularity of the falciform ligament and the intes tinal serosa or numerous dilated tortuous vessels in adhesions draining to the abdomi nal wall. Even in advanced stages, symptoms of pronounced portal hypertension often Pig. 4. PeritoMOKOpic view of left hepatic lobe in noacirrhotic portal hypertension (January 1979). Blunted anterior edge, smooth to finely granular surface, conspicuous patchy capsular fibroin. (42-year-old autoclave cleaner. VCM exposure 1963 -74. 197} thrombocytopenia as first sign. Prom 1974 to 1979. marked progression of portal hypertension with splenomegaly and one episode of bleeding from oesophageal varices.l See also Fig. J (patient 6 in Table 11) Vinyl Chi contras: s' peetedlv s is a focal opacities.' Stellate sc: ing (Manh tissue in C extending nective tiss processes \` or more di< are seen in 4.2.4 Hii- Histologies is gencraliv sis. strikin'fibrosis are (Fig. 5a-d) reactions, i. throughout fibrosis. Sir toiogical C'. 1978). Depenjt date of bic; nant liver u jeet to mark ations is sc. Thomai I9` 1976). but {Popper et a 4.2.4.! Hu In its fully 2 of dense, pai bile ducts a. with format) central and i of conneetn with enlarge perisinusoid. Oidal walls.: Muller et al. !J Manteiler .lation to ..ret il. m exploratory igan .viih neoscopy aiso !'<k t ai. with shallow 4I'orange-like nr nodularity leringiment * I, and also :oma. - liver it normal nrtaJ hyper1 tne intesthe abdomi-lension otter. > perteniion 1,'onipK'UOUS 63-74. -<<WD Of i vNootiafsai ''my I Otlondv-A^oclaied Discs** 51 contrast sharply not only with minimal alteration! of the surface but alto with unex pectedly scanty histological evidence or' hepatic fibroin. Hie most conspicuous feature is a focal or diffuse capsular fibrosis of varying pattern (Fig. 4). presenting at whitish opacities. The degree of capsular involvement ranges from diffuse tiny commalikc or Stellate scars to coarsely reticular and irregularly patchy milk-white capsular thicken ing (Mjnttlkr et ai. 1975a). Histology showed that this focal increase of connective tissue in Clisson's capsule may extend into the parenchyma and connect with septa extending from enlarpng fibrosed portal tracts iPopper and Tnomas 1 7). The con nective tissue capsule of the enlarged spleen also seems to be sensitive to VCMtnduced processes that have taken place in the underlying tissue so that focal white thickening or mote diffuse opacities together with circumscribed subcapsuiar haemorrhagic cysts ate seen in easts with marked splenomegaly. a.;.a 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 perismusoidal fibrosis, and focal capsulat and subcapsuiar fibrous are found in eombmauon with peculiar aiterauons of sinusoidal lining cells (Fig. 5a-d). Hepatocellular changes usually play s negligible role and inflammatory reactions, if present at all, tie insignificant. The lesions ate distributed quite irregularly throughout the liver and may vary from minor inconspicuous degrees to quite striking fibrosis. Surgical wedge biopsy of sufficient depth appears to be more suitable for histolopca. evaluation than needle biopsy specimens (Smith et al. 1976a: Blendis et al1978). Depending on length and degree of exposure, interval between lan exposure and date of biopsy. as well as individual factors, hinopathology of VCM-induced sonrealignant liver disease is represented by the following features whose manifestation is sub ject to marked interindividual and topical variation: the same variability of tissue aiter auons is setn in the nontumorous areas of the liver in angiosarcoma (Popper and Thomas \97S: Thomas et al. \97%\Berk tt al. 1976;Gerffpt et al. 19TJ; Weinprtn 1976). but in these cases the nontumorous lesions may be even more conspicuous (Popper tt al. 1978). 0.4./ Htpanc Fibrosis In its fully developed form, minimal to marked enlargement of portal tracts by excess of dense, paudceliular connective tissue, which in advanced cases contains proliferated bile ducts and soma pcriductular inflammation, may in ran instances be combined with formation of periportal septa linking portal tracts or, even more rarely, connect central and portal canals. Other portal areas appear almost normal. Focal accumulation of connective tissue in the thickened Clisson's capsule may be connected by septa with enlarged infhcapailar portal tracts. A more striking feature is an intralobular pensinusoidal 'netlike* fibrosis with more or less prominent coOageniaation of sinus oidal walls, in some areas even progressing to frank capilUnution (GeJigk et ai. 1975: MUtlcr et al. 1975). The focal intrastnusoidal fibrosis may be subtle and in some cases W.K. Ldhach und H J Mjr^reller Vin .e\r *5$?. t 1 .-i *:r#-' * I IE. Fi|, Ja. Needle biopsy specimen of th lier shown in Fig. 4. Enlargement and fibrosis of portal tracts. Moderately latft droplet steatosis. Focal dilatation of sinusoids. HIE. x 50. b Close-up of Fig. 5a. Indistinct border of enlarged and fibrosed portal tract to* wards parenchyma fltft). Proliferation of capillaries (> <) with polymorphism and hyperchromias of endothelial cells. PAS, x 400 `tl Marveller r'-'vitt- - \ 'ii" * 'V\J . i *4W$ sv' *ur r:;^; V;n\l ChL*r..ie-A*ti'CMtcd Di'tase /: . '**' Jl- I* \ . k W ;< ihfont . H4E, 'act toand Fig. Sc Focal portal fibrosis (lift upptr comer,' and reticulatad pcrtsinusoidal fibrosis with activated pwliferacng and pleomorphic sinusoidal lining cell*. Trichrome (Goldnerl turn, blue filter. * 2f 0. d Conspicuous focal dilatation of tinueoids. Activation and moderate poiymotpham of proliferated hyperehromatic tinuaoidai lining ceils. Enlarged hepatocytes with liypcrchromauc nuclei, some of them bmuclcar. i Potential precursor suge of anposarcoma ) Courtesy of Professor Miiilcr-Wallrai. Institute of Pathology. Amberg. HiE.t 400 4 s-i W.K. Lelbach and H J Mjrodler Vinyl Chloride may be rtcocnixtd only in connective tissue stains. Triche et ad. I l7J) pointed out that in one worker with severe icroostcolysis but normal hepatie function and essen tially normal liver histology on tight microscopy (except for a minimal and easily over looked increase of perisinusoids! collagen in occasional lobules), electron microscopy revealed a striking centrilobular increase in collagen between hepatocytcs and in Disses spaces together with proliferation and hyperplasia of sinusoidal lining cells (see also Kurokawa et al. 1977). The same ultrastructutal deposition of perisinusoidal collagen was observed by Schsttenberj et al. (1977) in 15 PVC workers in whom we could ob tain liver tissue for electron microscopy at peritoneoscopy. Similar changes (enlarge ment of Kupffer cells, abundant deposits of collagen in the Disse's space and resulting reduction of sinusoidal diameter suggesting a possible factor in the pathophysiology of 'sinusoidal' portal hypertension) were seen on electron microscopy in a number of cases of idiopathic portal hypertension of unknown aetiology (occupational histories not mentioned) (Sommenchihl and Kluge 1971;JfAige et al. 1970; Tendon et al. 1970). 4.2.4.2 Sinusoidal Lining Cells Marked focal proliferation and hyperplasia of sinusoidal lining cells with nuclear poly morphism and hyperchromasia art the most impressive features of the mesenchymal lesion. The hypcrchromatic nuclei of these cells may show a bizarre shape or resemble short pegs, and art often arranged in t chtinlike fashion (Cedigk et al. 1975). These pensmusoidal and sinusoidal ceils include three types: (1) normal endothelial cells. (2) lipocytes (fto cells), considered to be precursors of fibroblasts and (3) plump cells with spindle-shaped nuclei and PAS-positivt cytoplasm. Formation of excess retieulin suggests fibroblastic activity of some of these cells. Focal dilatation of sinusoids, not explained by passive congestion, is another peculiar feature usually associated with particularly pronounced alterations of these mesenchymal cells.' There is reason to be lieve that this combination of changes may represent a premaiignant stage. *-2.4.3 Hepetoeytes Unimpressive, nonspecific, degenerative and adaptive lesions (sueh as minor degrees of fatty degeneration, cloudy swelling, ballooning or vacuolar degeneration, increase of lipofusdn pigment and proliferation of smooth endopiasmatic reticulum of hepatocytes in focal areas without inflammatory reactions), can be seen to disappear gradual ly with increasing intervals between the last exposure and the date of biopsy, in con trast to the apparently irreversible damage to mesenchymal structures (Cedigk et al. 1975,1977,Multer et al. 1975). In poorly demarcated areaa there is hyperplasia and hypertrophy of hepatocytes with polyploidy and increased number of binudeated cells. Two types of focal hepatocytic proliferation associated with varying degrees of sinusoidal cell alterations were recently described and are thought to play some as yet undefined rok in the precursor stage of angiosarcoma (Popper et al. 1973). 4.2.4A Histok>p> ofthe Spleen Unless splenectomy is carried out in vinyl chloride disease, tissue specimens of the spleen are less easily obtainable than liver biopsy material. Popper and Thames (1975) and 71tonus et. to be character! gensous red pu! follicles with mi endothelial cells occasional fresh sptcuous fibrosis In ten cases v Heustrmann and tcrial, together v splenectomy. Tli process. Excess a tive tissue, notab and white pulp. There was scarrir meshwork and r< and diameter of. of the pulp con formation of biz. collagen fibrils, b the reticular com volume with para nation of capilla found within the thrombocytes by haneed pooling o help to explain in stages of vinyl chi and Heustrmenn VCM-induced spl-. of the liver or ext in the spleen in vt dicate a primary . port correlating ct tients is being pre; the spleen in nom able for comparisi 42J Pathophyst The pathophytiofi unresolved problei to splenoportogram of intrahepatic va venous radicles (Si and a normal, or o I HJ Mststeller pointed out .in ana essen* irtti easily omi microscopy s and m Dines Us (set also oidal collagen we could ob* >ges (enlarge? and resulting ophysiology < a number of /ml histones Ion et tl. n nuclear poly, nesenehymal .pc or resemble These heiial ceils. Oj plump cells ices* rtticulm ntusoids, not fisted with reason to be* `nor degrees of n. increase of :i ofhepatoippear gradual* opey, ia con* `Hfdigk tt al. :<erpUsia and 'nucleated ;ng degrees of ay some is yet eta of the /7iwmes (197J) vinyl Chlonde-Associated DUcas* 55 and Thomas et al. (1975) found rhe cut surface of surgically removed enlarged spleens to be characterized by conspicuously hyperplastic Malpighian follicles in a beefy homo* lentous red pulp. Histologically, they noted large germinal centres of the Malpighian follicles with merging of perifollicular zones, dilatation of red puip sinuses luted by endothelial cells of variable, often cuboidal shape, thickening of the puip eerds "nth occasional fresh haemorrhages, and in one case Gandy-Gimna bodies, but only incon* spteuous fibrosis of the red pulp. In ten eases we obtained needle biopsy specimens of spleen tissue a* peritoneoscopy. Htustmann and Stunt (!977b) and Srtmt and Htustrmann (197$) studied this ma terial, together with spleen tissue specimens available from three spleens obuined at splenectomy. They found evidence for an involvement of the spleen in the flbroeu process. Excess amounts of new!)' 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 subeapsuhr areas, were observed. There was scarring of penartenal lymphatic sheaths, obliteration of the pulp cord meshworic and reduction of pulp cord volume, in addition to an increase in number and diameter of sinuses. The reticular eonnccuve tissue of the walls of the sinuses and of the pulp cords showed marked alterations with thickening of reticular fibres and formation of bizarre platelikc amorphous structures containing irregularly distributed collagen fibnls. Harrowing of the labyrinthine cordai tissue with marked increase of the reticular connective tissue caused a reduction of miciocircuUtory sequestration volume with parallel decrease of the number of pulp cord macrophages and approxi mation of capillaries and sinuses. Frequently, fool accumulation of platelets was found within the narrowed pulp cordbed in addition to increased phagocytosis of thrombocyres by residual macrophages. This lends support to the hypothesis of en hanced pooling of platelets in the spleen (Htustmann and Stunt I97?a), and may help to explain the pathogenesis of thrombocytopenia often seen even in the early stages of vinyl chloride disease. By structural analysis of histomemeal remits. Stunt and Hcutermann (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 fibronc changes in the spleen in riayl chloride disease ire not the result of portal hypertension but in dicate a primary action ofVCM or its metabolites on the spleen. A comprehensive re port correlating clinical and morphological data gathered from this group of 12 pa tients is being prepared for publication at present. Results of histomstrical studies of the spleen in nonciiihotic portal hypertension of unknown aetiology are now avail able for comparison (Stki 1965; Yamamoto 1978,1979). O.S Pathophyriology of Portal Hypcrtenaon The pathophyriology of portal hypertension in VCMAndueed fiver disease is a yet aa unresolved problem. Pstency of the portal vein was demonstrated in aO cases subjected to splenoportography. Portography unufly showed no or only minimal derangement of intrahcpatic macular pattern such a tspenng or 'cut-ofT of small peripheral portal wnou* redieies (Bltndis et al. 197g; Villentute et al. 1976). High intraiplenie pressure and a normal, or only slightly retted, wedged hepatic vein pressure indicate that the ucc 044273 5 W.K. Lulbacli jnJ H.J. Mjittclicr portal flow is obstructed at the sinusoids! or presinusoidallevel. In s group of live PVC workers selected for haemodynamic studies, Bleiidis et al. f 1978) could not demon* strata a direct relationship between the decree of hepatic fibrosis in needle biopsy spec imens and portal hypertension. But it should be kept in mind that the distribution of fibrosis in these workers is quite irregular. It has also been suggested by Pepper and Thomas (1975) and Thomas et at. (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 peruinusoidsl fibrosis. Bltndis et al. (197S) found no correlation between spleen or estimated liver blood b Fig. 4*. b. Progression of noncirrhotic portal hypertension despite termination of expawn. Oesophageal varices. (Autoclave cleaner, age at diagnosis: 35 yean. VCM-exposure,.1962-1972.1972 Raynaud's phenomenon, skleredennoid 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 1971. Histologically only mild perismusoidal fibrosis in nontumorous areas) Vinyl flow ; veiled 4.2.6 In 19* tic fib could tests ;r biopsy of bnC the fib cytesf ing cel follow nusstv e.xpon saieorr, or less terrain oped (= Liv determ (BMHP after h. and toi aid of > the ten increas. PVCp.. sack et 4J Ar 4J.I I Primary (tngioh' haeman ecllsarc sarcoma vvculai one at e hood (f< the num LelbjLh and H.J. Marereiier ' level. In a group of five PVC 11978) could not Jemon.ibrosis in"needle biopsy spec* :nd that the distribution ot digested by Paccar and J splenic and hepatic blood galy cannot properly be ac cent of adaptive distension J perisinusoidal fibrosis. or estimated liver blood ' V/ * o-. Te 5 I'.' >7'* 'i . , *M 1 >:Ur* ;-r* despite termination of expnoeis: 35 yean. VCM-ex- Hkrmoid skin indurations. I vahcei. Gradual profreision Iuntie anpoureoma of the I fibrosu in nonrumorout V:r.yi Chijnde-Auociatfd Disease J7 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. 4.2.6 Followup of Non-maiignant VCM-induced Liver Disease In 19*4 Martin et al. fsce also Berk ft al. 1975) pointed out that VCM-sssoctated hepa tic fibrosis, once established, may progress even sue: cessation of exposure. They could demonstrate this progression despite normalization of all routine liver function tests in a 27-year-old worker on a follow-up examination including peritoneoscopy and biopsy 2 1/2 yean after eeasation of exposure. Progression of fibrosis and appearance of bndpng between portal and central veins were indicative of persisting activity of the fibroblastic process, w hereas the previously observed activation of both hepatocytes (marked variation of cell size and numerous binudeated cells) and sinusoidal lin ing ceils had disappeared. Since 1973 we itave observed a number of worken who on follow-up showed evidence of progressing portal hypertension with development of massive oesophageal varices and subsequent bleeding episodes despite removal from exposure (Fig. 6). In five 17?) of these patients with progressing portsl hypertension angio sarcoma of the liver finally developed. In this context, it is of interest to note that mote or less conspicuous hepatic fibrosis (or rare progression to cirrhosis) was the parental terrain in which the majority of cases of VCM-induced angiosarcoma of the liver devel oped (see Tables 13-18). Liver and spleen scans with technetium-labelled sulphur colloid, quantitated determination of spleen size with the aid of l,7Hg-bromomereuryhydroxypropane (BMHP) labelled artificially damaged red cells, and sequential perfusion scintigrams after bolus injection of WwTc-perteehnetaie have been found useful in the diagnosis and follow-up of nonmalignant Iber discate in PVC-polymefixation workers. With the aid of these nonavasive methods, inhomogeneous uptake of labelled sulphur colloid in the reticuloendothelial system of the liver and enhanced uptake in the spleen, gradual increase in ipiees size and reduction of portal venous perfusion have been observed in PVC polymerization workers developing portal fibrosis and portal hypertension (Biersack n aL 1975a, b, 1977a. b). 4J Angiosarcoma of the Liver 4J.1 Epidemiology Primary angiosarcoma of the liver (A5L) is described under a variety of synonyms (anpobiastic sarcoma, angioblasiic reucuiosarcoma. endothelioma, endothelioblastoma. hacmanpoblastoma, hacmangiocndotheUoms. haamangiocndothelial sarcoma. Kupffer cell sarcoma, malignant haemangioma, metastasizing haemangioma, reticuloendothelial sarcoma, primary sarcoma of the liver). It is an exceedingly rare malignancy, arising from vascular lining ceils. It occur spontaneously with two peaks in the age distribution: one at early infancy (infantile hemangioendothelioma) and the other in late adult hood ffourth to rixth decade). The numerous synonyms tender it difficult to estimate the number of reported cases and to determine its true incidence. In a recent review c Mr? SfeiS me m Ml * ss W.K. Lclbac!i and H.J Mjrsieller of the literature.A/nrwgn (197J) listed 165 published cases of primary angiosarcoma of the liver in adults. In the six autopsy series collected by Alraiga. ASL constituted only 1 J6% (Q9K-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 0.01 J in 100 000 inhabitants or 25-20 cases per year for the entire United States. Table 12. Incidence of angiosarcoma of the liver (ASL) in autopsy senes Authors Obsenation No. of No. of cases Year period autopsies of ASL Region Simpson ct al. 1955 1914-1933 24 196 1 Mayo Clinic. Rochester. Minn.. USA Edmondson 1938 1918-1934 52 000 I Los Angeies. County Hotp.. USA MacSwttn et el. 1973 1900-1969 3 Western Infirmary Glasgow, U.K. Alrtnte 1973 1931-1973 39 700 6 Cook County' Hosp. Chicago. USA Rem and Huth 1975 1954-1974 30 079 Byrin and Holmbeef 1975 1938-1969 _ b 4(6lc Dti*Stfidorf. Fed.Rep. Germany 12 Sweden (adult eases) Daldtmp et al. 1976 1960-1975 At least 40 000 8 Netherlands (population 10- 14 million) * Among 120 cases of primary malignant liver tumours studied post mortem during this 70*ytar period, b Among 8 million inhabitants. e 4 Angiosarcomas. I haemangioendothclioma, I malignant haemangioptneytoraa Accordingly, the identification of 4 cases of ASL among approximately 270 em ployees of the vinyl chloride polymerization section at a BJ. Goodrich plant near Louisville, Kentucky, between September 1967 and December 1973 was duly recog nized as an alarming situation indicative of a serious new occupational hazard (Creech t al. 1974a; Cnech ant Johnson 1974). Until 1974, only two carcinogenic agents were known to be associated with the development of ASL in man. im. the administration of a radioactive colloidal prepara- Vinyl < non of inorfm, dioxide tem am Thoi contras in; evid reports been th. had bee and Mo, A speeu caused I thorotr from a 1 ASL (/l. Devi men vin tensivel) 1950-1 tion revc of multi; approve occurred but nou produce. Hausinit (37.-5' Roth (lc 185-1. Fowler's C7io>* haemang) tension h woman w ride) dun had a htci manifests Thepr be eliciui period 18 history ol Among tn observed other han 391 auto; 'JCC - 0+1276  >} Mameller .csareoma :onstttuted ''ch of them.lit inctder.ci ith 3 niton 11975) it a ' isO.Ql-t in lime. -'er. Minn.. ll'iip., USA i Infirm an.. U K. Hinty Ho*c l SA ii FtJ Rc[- vds lum: mllion) ties Outing ricytoma lv 270 cmiant near duly recogard (Creech .1 with tht tJai prepan* Vin\ I PilonJt-Anovialid Dittaxe ;a non ot' thorium Jinxide (thorotrast) for diagnostic purposes, and chronic exposure to inorswK arsenicais. 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: arsenicais are only slowly released from the liver. Titvrotrcst came into use in 19'Sand was internationally employes as an injectable contrast medium until the mid-1950s, when in use was abandoned because of mount ing evidence of the carcinogenic action of thonum dioxide deposits .'/cc '/j/ioh et a!, reported the first case of thonum Jioxide-Miduced ASL in 19U7. Since then ASL has been the type of liver tumour which occurred most frequently among patients who had been given thorotraat injections in the past (da Siha Mona 196": da SiIra Mono and Motto 1967; Wefentr tt ai. 1971,/ur/i and A/t*e 1974;Selinfar and Kojf 1975). A special type of progressive portal and subeapsular hepatic fibrosis was another lesion caused by thorium dioxide retained in the liver, do Sih a Mona (1967) considered this thorotrast fibrosis' to be clearly distinguishable from true eirrhosts. Camma radiation from a lost radium needle has also been implicated as a causative agent in one ease of A$L (Host 1932). Development of A5L as a late complication of chronic arsenic intoxication in Ger man vineyard workers was first described by Litbttott (1949,1952) and has been ex tensively documented by Roth (1956,195"a. b. 1959). During the 10-year period. 1950-1959, autopsies of 82 Moselle vintnets suifenng from chronic areenic intoxica tion revealed ASL in 8 cases among a total of 61 individuals (743), with cancer often of multiple sites (Roth 1959). In 1925. areenic insecucide sprays and dusts had been approved fbr use in German vineyards but they were banned by taw in 1942. Exposure occurred not only via inhalauon during spray periods (approximately 30 days/vear) but notably by daily consumption of quantities of cheap grape wine ('Haustrunk'). produced from a second pressing of tht grape skin residue by addition of water. This Haustrunk, an allowance in kind to the vineyard workers, had a low alcohol content (35-53 v/v) but contained high levels of residual areenic (0,2--6.9 mg At-Oa/litre). Ruth (1956) calculated the mean total ingestion of AijOj to hare been 53.7 g (range: 18.6-88.8 g) for a 12-ye*r period. ASL was also seen after long-term treatment with Fowler's solution for psoriasis (Reftlson ct al. l963:Lrn</eret al. 1975). Owdury et al. (1977) reported an anecdotal case of apparently benign diffuse haemangioendotheboreatosis of the liver with considerable fibrosis and portal hyper tension but normal liver function. This enndition was found in a middle-aged black woman who had been exposed to various chemical fumes (Including carbon tetrachlo ride) during 20 year* in a ary-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 ASL in whom a pertinent history of exposure could be elicited has varied considerably. In an earlier survey of the literature covering the period 1875-1960,on Backer and Aasrefar(l96I) listed 12 of 54 adult caret with a history of exposure to either thorium dioxide (7) or ancnicals (5 ofRoth'i caret). Among mom than IS 000 autopilot performed in Bonn during 1950-1959, all 8 cases observed were found exclusively in vintners exposed to arsenicais (Roth 1959). On the other hand, Ficrhmcr and Rytt (1976) recently observed a duster of 4 caret tmong 391 antopics during a 29-month period at a hospital in rural central Wbconsvi serving ii - .*- ` * I M) 'V tv. Lelbach and H.J Mantellcr Table 13.Personal data of 68 polyvinyl chloride production worker* with ansiosarconta ot the liver reported to MUSH up to August 197S iSpirias and Kaminski 19781 Birth date No Country (m/J/ylb Data of death ttn/d.y) Age at death Total years evp. ' Job classification1 1 Bill 01.12.13 * CNDil) 12.15.13 3 CND12) 03.06.14 4 CND (3) 08.26.19 5 CND (4) 04.05.19' 6 CND 15) 05.07.1! 7 CND <6) 12.15.19 8 CND 17) 11.09.19 9 CND (8) 05.13.20 10 CND (9) 07.19 21 11 CND HO) 05.16.15 12 fSRtl) 13 fSR t2) 00.00.28 00 00.26 06.29.76 09 02.55 12.21.57 03.22.62 01.21.e8 07.05.68 04 10.71 12.24.72 06.12.73 09.04.74 04.00.77 12.00.73 00.00.66 (64?) 63 41 43 42 48 56 51 52 53 53 61 45 40 1377) 17 11 14 20 5 23 25 5 26 14 16 15 (14?) 1.2 1.2 2.3. 12. 13 2.5 1.2.5. 14 1. 14 1.12.13. 15 1.9. 17 1.12. 17 3. 12. 16 2. 16 1 1 14 Dll) 15 D(2) 16 D(4) 17 D (5) 18 D<7) 19 D (8) :o D (9) 21 DUO) DUD 23 DU2) :4 F(l) 25 F(2) 26 F<3) 27 F(4) 28 F (5) 29 F (6) 30 F (7) 31 F(8> 32 F (9j 33 F (10) 34 OB(l) 35 CB (3) 36 1(2) 37 1(3) 38 J(l) 39 J (2) 40 Nil) 06.04.30 07.26.31 09,04.30 01.01.32 09.29.26 10.19 17 12.1344 07.23.29 12.29.36 06.1448 04.15.24 06.03.11 01.06.20 01.27.27 01.2948 04)4.34 00.00.27 04.0144 10.08.14 05.24.19 04.20.01 06.0247 01.25.69 12.14.71 11.25.74 01.09.75 11.13.73 12.25.75 03.24.78 06.28.77 03.07.77 10.07.77 02.19.67 01.24.75 06 26.75 01.03.76 05.13.76 09.12.76 07.02.76 0140.77 12.25.77 01.20.78 12.03.72 1244.74 38 39 44 43 49 58 42 47 41 39 43 63 55 49 38 42 49 42 62 58 71 37 11.13.29 03.14.20 08.01.22 08.02.29 12.23.15 12.27.72 07.10.75 1044.75 08.10.76 01.04.72 43 55 52 37 56 12 II n 17 * 12 2.4.5 12 II.(I) 21 15 io 10 16 10 6i 19 1.2 12 * 29 * 26 2.6 It 1.2 13 6.7 ** 19 28 21 * ** 8 41 3 1/2?) 62 21 11 13 21 Vin> Tabic No. 41 42 43 44 43 46 47 48 49 JO 31 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 (Table* rtfertm Satf-SUS ucc 044278 Manteller :ius;rcomj *i i,cation Vinyl Chlorde-Aaiociated Di*ea*e 6I Table 13 (continued) Birth dare No Country^ imi'i.'ylO 41 sm i: S*3> 4) 5*41 06.23.27 06.10.10 11.16.14 44 USAiI) 101723 45 USA i2) 08.19 33 46 USA 13) 05.25.15 47 USA 14) 01.15.24 43 USA (5) 01.25.12 49 USA 16) 11.23.23 50 USA (7) 0S.C3.22 51 USA (S) 0S.06.20 USA (9) 11.08.31 h USA 110) 03.16.13 54 USA (11) 05.27.09 55 USA* 12) II 17.18 56 USA (13) 12.01.21 57 USA i i 6) 11.04.27 53 USA 117) 05.06.31 59 USA (18) 04 22.28 60 USA 119) 00.00.15 61 USA (201 08.31.17 6: USA 121) 09.02.09 65 USA! 22) 10.02.23 64 USA (23) 00.00.23 65 USA 124) 05 07.17 66 USA 1 25) 08.07.10 67 USA (26) 7(1978) 68 YUM) 04.05.14 Date of death (m.'tl'y) 10.20.70 03 19.76 05.12.77 At* at death 43 65 62 Toljl jean. e.\p IS 21 31 Jl'K clarolMCJIlon' 9 A 03.03.73 09.27,71 12.19.73 01.07.68 04.09.64 07 24.75 03.23.68 08.28.61 03.00.75 05.10.68 03.16.70 05 02.69 07.04.74 03.27.69 1978 alive 11.02.75 04.06.76 01J0.77 01.02.77 12.04.76 04.06.73 05 27,77 C3.10.77 7(1978) 49 37 58 43 52 46 45 41 43 55 61 50 52 41 43 46 60 58 67 52 50 60 67 7(1971) 21 13 28 15 20 12 17 15 24 17 23 19 28 4 19 II 22 21 21 2S 14 26 20 7(197$) 9 9 10 10 10 to 9(1) 08.04.73 59 20 1.2.5 * B. Belgium CND. Canada. CSR. Chechoslovakia D. West Germany F. France GB, Great Bntain b 00. data not available. e 1. autoclave cleaner 2. autuclava operator, 3. pipe fitter 4. polymerutr ' 5. foramen 6. Yiitraur' 7. `prepareteur de sotution' >. process worker 9. chemical operator I. Italy i. Japan N. Norway S. Sweden USA, United State* of America YU, Yugoriam. 10, polymerization worker 11. technical anittent 12. maintenance worker 13. millwright 14. water cooling unit 15. reegtr 16. furnace operator 17. machine ebop worker (Tables 13--15 ire compiled with the aid or information contained in the literatim; tefttenees set Table IS) ucc 044279 Vi 6! 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 >eats 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 1963/1969 (Baxter and Fox 19*5). Six additional cases not mentioned on the death certificates were detected by a panel of specialists (Baxter ct 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 undassifiable, 12 non-ASL). For 12 of these 14 cases occupational and residential histories were obtained which revealed one un doubtedly VCM-induced case, two cases with possible exposure to (low levels of?) VCM and one case attributable to thorium dioxide. After the first three cases ofASL among vinyl chloride pofymerization workerj in the United States had come to the attention of the National Institute for Occupational Safety and Health (NIOSH) m 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 197$, Spirtas and Kaminski 1977). As of August 1978. data had been presented on a total of 68 eases of ASL among polymerization workers (Spirtas and Kaminski 1978, pen. comm.); another eight cases had been observed among nonpoiymerization worken 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 A. 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) arc dealt with summarily in the papers published by Delorme (1978a) and Delorme and Makk (1975); seven of them were described in more detail by Slakk et al. (1976). Cases 19 and 23 were observed at our clinic in 1 ->nn but details have only been published for case 19 (E.U. in Letbach and Marsteller 1977). In reviewing the literature we could not trace cases 37-40.43,50.51,53-67 and C, F and H. According to the latest annual report of the Staatlicher Cewerbcarzt, Diisseldorf (Remt 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, tout yean of exposure ranged from 4 to 31 yean (mean and median 18 and 19 yean, respectively). In comparison, mean dura tion of exposure in our group of 17 individuals with advanced nonmalignant liver dis ease (see Table 11) was 103/4 yean (range: 3 1/2-21 yean). The latency period (yean from first exposure to diagnosis of ASL) ranged from 9 to 38 yean (mean and median; 21 yean). The average age at diagnosis of ASL was 50 yean (range: 37-71 yean). Vinyl i 5 E0u | tss 1 8 1 > ucc 044280 SjS-fliItiiSlilltligsilsss?::*.-sl'sS??! s 3- 2 | I 5" **! _ cSmO * O < a X T*Ut 14. Cliakal aad mo(|>ki4uck4i d-ili ua b< pulyviayl thhiritic ll*VC| proUutlioa wutkcts will) anpowteimu ! IIk Inci kihiiIcJ lo NIOSII by ApM 1971 Ocui(>liaptfai llcpalK fjikei libmMi ThrumlH)cylopuaia Acramlciilyiit I* Alrorkic, 1*1 (2900|) diflilly laitMuteil Nuacirihirik T pcifeiauMriilal A captutai O' Capmlat ' liyMuil'k pIlCHlMKIUM MclatlJUM 0 ft ) (`ifiMtif, putlal, pcminauiiilal 4 5 l NodalaAt IIUO- variable 5200 pi a 9 10 II Sckniiis <if wad Ilf ptxlal cai Caywlii, portil, pcusiaawHtlal t Caputlat, putlal, ^ pHiiMaMMil CifinUi. putlal, pc ihiuuinitial Potlal. pctniiiiivi tidal Capuil.<i, |Harlal, pctiiiaitiHlal rjpMilar. pmlil, No delaik avarialilc I raw: mulliiik miliklHi.'i (Ilia*, ptciua, peneatdmin, dcum, cullMl. lllllltfk, tell atlieuall t I ini' awtlia\lnial lyMph male I rail" paiiliawal tpical I tatrt. Itital t|Ncal <i rs Table M liMliniKill lie painNn. mecjJy Spleen Oesophageal liepalic varices hbrnst* Th romho' cytopema 13 Moderately i*i 17300 s) enlarged 13 (2750 ) 1 * (Cirrhosis), fibrosis (CMmis) * * H Spleno 7 V t megaly IS SMehlly enlarged ? ? 16 Spleno <2650 (I megaly IBJO p| Capsular, pnflal, septal (72 000, 65 0001 17 * Spleno V megaly IB T ferisplenitti t T (IJ4 000, fill 000) 19 <> Spleno IHSOpI megaly 141*0(1 <1 PruiRuiic peminnsnidal.l BO 000, portal anti 47 OOfl, seplal unliinis JO OIKII 20 v T tt 21 Spleno + V (1900 f) megaly Aero* ovluitysis X t 0 0 0 0 X p v 9 KiynmiTt lilicnnmenon Mctaslaso t9 X l.cfl htn( X 4lli lell rib 09 X 1st lh<Hack vertebra 0 Drain + 3rl ImpKir vcrlchra P 0r *V 00 7t- T* roo*r oZT 30. X 0. l tX W.K. Lcibach and H J. MarsteMer V in y l 22 Splcmtme paly 23 Spleno- 0 O700g) meJuly (455 () Capsular, poll III, + pertsin us< till al l:ocal perisinusoidal 7 X0 0 9 09 1 o l J Martteller I* t <**> 20 t t t 7 7 1 t 21 SpleRO- *' i ft 0 <1900(1 K(4ly V inyl rhlonJe-X viociatcd Disease 22 * Spfeuumetal? 1 2J Spkmt- jf 13700(1 meetly (4SS (1 24 * 7 7 IS * Spfcuo- cuiftgl Mt(aly 1410(1 t 16 t 17 * Spfeao- (2230 g| K4r (400 7 IB Spkuoawtaly (450 (1 19 * VoOrKiilmii/ imo) fikm- nwinlin' 30 / 0 31 SficRi>wc(4ly 7 0000(3 0701) 32 T 7 33 * 7 7 Capsular, * INWlll. pCMSinMMUllal Pucat pen iiwuHil.il 7 07 Portal, ptrhliMMUil (0000, Miiwit 10 0001 t* Netkulalcil 7 Cl|HMbl lilllDiil, mkiuuotlulat iliikmii Portal, peri- t liatlioiiljl, (10 000) capsular (ibmsis 0Slifhl putlal IOnkm Mwumal fibitMK 7 0 7 $* (to 000. 40 000) Capsular. ft poilal NIkiak 0 4 0 0 0 0 0 * 0 0 0 0 00 4V 1 I bk jI ^jirv.iil In i UV4I \ru 44 4 Itumli-nat wall 44 4 4lh ami Tib IIhhhuc witelm, 5lli kli nh. IcM aln-iul t4 0 Small inlcvlim: 0 PaiaaiHlal I> hi|>Ii ihhIcs 04 00 ;-- -"V 'jf* ? T !l.J. M antelltr Vinyl Chloniie-Aaioeiaied Dueax * Spleno megaly Spfeno(IMO|l megaly 1 Ihiekencil ie|>siik-; MllU-ll (lllllnil fml)| lilltUMI > fl Spread In ilumlemun ; I Spleno megaly FwIjI * p /( Spicail l<> di.iplnagni ami lltlllKIl OS ntM alnlinumal wall ? ISttOgl 1 Slight toeal y ? ii l.migs. large ami Milall hepaliln Ihiwel, I'kmi. per*aolniiii 1 `minimal nit*maul nun. Ii<lney>, hepatitis') lell ailleiial yT KinimI 1 Capsular ami fl fl Diaphragm. regional. relro- porlal fihitHH pentmieal anil meilijslinal lyni|>li inulei, lungs. ailu-n.il glamls, eieln'lhiiu Deljib not poMnheil <2*10g| 1 hcain ? portal lihimh, jf fl Diaphragm. jmIHiUiIiIci. regional lyHi|ili mule-., hhIcuIc eHihiKii hiitgv n il|i. iAiiII Delalb nnl poUMml *T 2 O'______________til CUM) ____________ aai 68 W.K Lelbjch and H J Marueller Table IS. Publications on the bS ease* of angiosarcoma of the li\er listed in Tables I? and 14 No References Additional relevant information I Hu bit t et al (1977) \ 31 4 11 Dtlormt and Makk i [ (1975) 6 'l 3fe*ietal.(1976) 7 i Dtlormt (1978a. b) 8 , Dtlormt and 9 Thinauh (1978) 10 I 11 ) Hypertrophic, hypcrchromatic jihI at\ pkel endothe lial cells in the glomtrtth: foci ot haematopoctic cells in liver and spleen Case no. 7: ASL associated with hepatocellular carcinoma (Dtlormt 1978b) (AU cases from one plant in Shawini|an. district Trois Rivieres. Quebec) = )1 Schmidt and Bitort 13 J[ (1976) At the same plant: 4 cai.es of VCM-mduccd cirrhosis of the liver plus I case of cirrhosis and grnerahred rtticulosarcoma and 4 cases of carcinoma of the Cl tract orlunp 14 i| Ltngt et al. (1974b) IS |[ Ctdigk et al. (1975) Set also Rtinl and Wtbtr < 1974) See also Rtinl and Wtbtr (1974) 16 Goktl et al. (1976) Foci of hacmatopocsis within the tumour areas 17 Amtnn (1975) Riibumen (1976) 18 Remf etal. (1976) 1974 portoeaval anastomosis:cholecystectomy. Hypertrophic, hypcrchromatic and markedly atypical endothelial cells in the glomeruli and in the capillaries of the lunfj i 19 (Observed in Bonn) Moderate hepatic siderosis: chronic Rbrosin* ptnertf mu; tubular and inttnutsal fibrosis of the rearer 20 Rtinl et al. (1976) 21 Rtinl et al. (1977) 22 Retnf etal. (1977) 23 (Observed in Bonn) 24 Reefer et al.(1975) Focal interstitial fibrosis of the ptnerrat See also Btrrod et al. (1978) 23 Roche at al.( 1978) 1942 (astreetomy. 1974 splenectomy, right hepatic lobectomy (6401). See also Roeht (1977): Ruteh et al. (1977); Romsero et al.f 1975.1977),Btnod et al. (1978) 26 Rtty et al.f 1976) No autopsy (ms also Btrrod et al. 1978) 'eller S 13 otit*Llilj l rliOsis -L-a : 01 i'ic.tl mlljnti mi ste el vpattc itch et Vinyl Chlonde-Assocuted Disease 09 Table I i icontinuedi No. References 27 Boeht et ai. 11978) Additional relevant uttomution Chrome alcoholic. Set also Riche 11977); Butch et al. (1977): Btrrod et al. 11978) :s Rocht et al. (1978) first symptom; vertebral and costal mctastases Right hepatic lobectomy. See also AoWt* < 1 O'*): Butch et al. (Pihchowskt et al. 11979); Coudt'c et al. (1976).Btrrod e: al. (1973) :9 Roche tt ai. (1978) i960 teltrodtrmalikt skin induration (hands), swell* ing of tact, upper extremities and test. 1971 bilateral tcrooittolytu. Tumour penetration of the abdominal wall (fistula). Severe interstitial fibrosis of titiet: Hbrosis of interstitial wall, slight mesangial fibrosis of tlomtruli Variable but generally slight fibronyaimosis of artenai and venous vessel walls (skin, heart, lungs, intestine, testes) 3 ) 31 1 r- ( 33 * Btrrod t al. 11973) 34 Let and Hirer {1974) 35 Smith et il. (1976b) Latency period (1st exposure * death) only 8 years (see also fa* and Coilitr 1977) 36 Moltom (1974) 37 - 38 39 _ 1 * 40 41 tyrin and Holmbitf (1975) 42 Byfin et at. (1976) 43 - 44 Block (1974) tease 3) 1965 portocaval shunt. 1970 cholecystectomy. See also feiket aL (,1974s) (case 4); Whtlon et al. (1976) (MM I) 45 Block (1974) (mm2) No autopsy. See also Crttch and 'Johnton (1974); Folk et al. (1974a) (eaM 3): Whtlon et aL (1976) (cam 2)\Atckk et aL (1976) (caM 6) 46 Block (1974) (case 4) See also Folk et aL (1974a) (caM S);Mokk et al. (1976) (case 10) 70 Table 15 (continued) No, References 47 Block 11974) (case 1) 48 Block (1974) (case 5) 49 Block (1974) (case 6) SO Jl J2 Whelan et al. (1976) (case 3) J3-67 - 68 Zonea et al. (1975) W.K Lelbach jnd H.J Marstcller Additional relevant information But also Falk et al.t 19"Cjl leave 2);Makk et al. (1976) tease 4) See also Falk et al. (1974a Mease 1). Mukk et al (1976) (case 2) See also Falk et al.t 1974j> tease 6); Whelan et al. (1976) (case 4) Makk et al 11976) (case |4j Chronic alcoholic. See also Makk et al. (1976) lease 13);Berk et al. (1976) (case 2) Among a work force of 1801120, PVC polymerizetion: 60, production of VCM) employed at this plant. 15 died of malignant disease t2 ASL. 5 bronchogenic carcinomas. 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 A5L dated back to the period 19391966 (median; 1951). Twentyne years later, i.e. from 1973 onwards, a gradual in crease in the number of new eases diagnosed and reported to NIOSH can be observed (Fig. 7). The onset of this gradual increase coincides with the calculated mean latency peric ' of 21 yean (Spirtas and Kaminski 1977). Sptrtas and Kaminski also suggested that >n ritture 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 scmosteolysis and eutineous stigmata of scleroderma have been observed in only 1 of these 76 patients, a French PVC worker who had apparently not been engaged in reactor cleaning (case 29\Roeh* at a). 1978). Another noteworthy piece of infomution is that strikingly atypical endothelial cells with hypertrophic and hyperchromatic nuclei have also been found in organs other than the liver (kidneys, lungs) in autopsy material from two patients (casts 1 and 17et al. 1977;Mbtomen 1976). Hubltt et al. (1977) also found such cells in the myocardium and in the adipose tissue enveloping the adrenals. AH this may lend support to the idea that the afreet of VCM metaboiitet is not restricted to the vascular endothelium of the liver and spleen. Angio- Jarcieller * Jl al. , t J. >>,( case' 'leniahn punt, diogemc uryn.x. arcoma. i l30>tal in- - rved i latency g/ested tuy in* -ui the auoaat'tcn.evs* -iosarco* i of note l in only npied f informa* hromatie autopsy 76). tissue ofVCM cn. Angio- Vinyl Chlonde-A>ooiated Disease 1 Table 16. Personal data on tight :aj of anpoxarcoma of tit* iivtr among VCM-ex posed personnel not employed in PVC production (as reported to NIOSH by August 1978>a Date of Birth dale death Vo Country < m d.'yr tm/J.yt Total Age at years death exp. Job classification of t o A D <3> 10.10*3 43 14 Loadu.g ptsticiue cans with vcm propellant B D (6) 05 09.36 12.16.74 x GB 1 :> 09.08. U o1b4 o 38 55 3.5 Assistant factory chemist 11 Pouting FVC oil mix ture onto fabric bases * D 111) 06.IJ.3- 04.16.71 36 3 Fabrication of PVC sacks and wrappings (extrusion at tempera tures of 120*0 E SC) 11.27.11 08.16*1 61 23 Assistant factory chem ist (production ofVCM) F USA 05) 00.00.25 02.15.73 47 * Accountant at plant producing PVC fabric G YUl2) 11.15.31 07.12.73 42 18 Production of VCM H YUiJ) 12.21.31 01.11.76 45 Production of VCM a Update of NIOSH Rimer, August 1978. prepared by Kaminski as in Table Id. b 00. data not available sarcoma ahsin| from the kidneys or other types of malignant renal neoplasms, how* ever, have not been described in VCNUxposed individuals, although malignant nephro blastoma his been induced in experimental animals. The extremely ran coincidence of angiosarcoma and hepatocellular carcinoma was found in three instances (case l.Dtionmt 1978b: cast . Bvrin and Holmbtff 197S, and a case not included in the 1978 NIOSH update Ttmbum ct el. 1978a). In the case reported by Tamburro et al. chronic alcoholism may have played a cofactor role in the development ofliver oncer. We can now add a fourth case observed in 1978 at the Department of Medicine in Bonn (see Sect. 4.1.5 and Fig. 3). This patient (patient 9 in Table 11), a FVC-polymerizirion worker (total period of exposure: 18 yean) was Ant admitted to our department in February 1975 and was found to suffer from ityp ical eirrhods of the liver with portal hypertension, splenomegaly and Raynaud's phe nomenon. During followup ASL was clinically suspected but could not be confirmed during life, despite exploratory laparotomy and generous surgical biopries. The patient A. i-Vi- t V- '! ' " . * 4 - ' './ Table I7. Clinical Mil Morphtdogical data tM eight cases of aiiginsartinna of the liner among VI`M-es posed |>crsi .ntcl mil cin|>lnyci{ in I'Ve pdymeruatiun ` J IkfilnNo. mepijr A <60001> U6S0(1 Spleen Oesophageal Hepatic natives llllMHtS Tlironihocytopcma Splcaomephr fi trial fi brush t- Sfilenn- mcgaly l-IISg) 0I'ncal capsular Mitosis, portal and centrollilnilar fibrosis At to ns Icolysis 0 0 ttayitaud's phenomenon Mclaslascs 0 Diaphragm gaslnc mnetrsa. abdominal lyinpli nodes 0 Diaphragm, pleura, abdominal lymph nodes C 11 C*> * |T ti it Not enlarged 0 ?t Splenomegaly ? ? y f t 0 0 Lungs, peritaidmill IHM 000) 0 fi i 0 fi Dura, ttaninin g e ? i5S a?3 2, = < 2 8 S 3 ? 9; I X Cl II m on I* I"? ? "jl-'U'IIlT Vinyl Chiondc-Aisociated Disease 7 Table IS. Publication on the eight caws or angiosarcoma of the liver listed in Tables lo and I 7 No References Additional relevant information A Rt'.n/jrJ it'estr 11**4) 1 *t)7 idi.-paiKic portal it;, pertensian, portae.-, at shunt 3 Zimmtrmenn and ek 1 *7$ right iieminephrectomy for jntlate'il hydra- 197$) nephrosis associated with bilateral JcuMt kidney Remit I97J) Foci oi haematopoetic cells in spleen and kidney. Fibrosis of the pancreas. Slight fibrosis of testes and of the small lrtttsrmi! *erosa 0 Miltoni ( l *74) Autopsy- angiomatous epulis. Angiosarcoma involv ing liter, lungs and pertcardtum The pericardium mtflu have been the primary site! E Brrin and Holmbtrp Probable coexistence of a hepatocellular cancer of <1975) both low and high grade differentiation r G Zoriea et al. (197$) H died on 7 August 1978. alter a massive haemorrhage from oesca'.xgeal varices. Autop sy revealed both multicentric metastasmng angiosarcoma and hepatocellular carcino ma of the liver as well as slight fibrosis of the pancreas (to be pufcished is detail). It ia still unexplained why hepatocytes are generally exemg-ri from the carcino genic etTect of VO! metabolites but. as predicted by Topper in 1975. three anecdotal roses of hepatocellular carcinoma, one Gentian (Gokti tt al. 1976) and two British PVC workers (Fox and Cottitr ] 977), have now also been observed after exposure to VCM. It may be mentioned that a review of the distribution of primary liver cancer in tilt Province of Quebec covering the period 1969-1972 showed s preponderance of adult male casts in urban areas clustered In the district of Trois-Rivlert in congru ence with the distribution of the plastics mdustty, a coincidence which calk for further investigation of a ponible exposure to industrial carcinogens (Jacob and Theriault 1975). . Not included in the NIOSH register are several anecdotal eases of A5L, capillary and cavernous angiosarcoma of the liver and haemangiotareomitosis of sites other than the liver, for which a relation to occupational or even poesibly residential exposure to VCM has been discussed (Moria et iL 1977;Brady et sL \9Tt.Dor et aL 1975; MtffnSfer and Zinnagl 1977). Although of undetermined relevance, it should Anally be mentioned that, in addi tion to hepatic tlbrosis, varying degrees of interstitial fibrosis of the pancreas were noted at autopsy in four German wotfcere (eaaca 19,23. Band the above-mentioned 40 ucc 044291 74 W.K. Leltudi 411J H.J, Mameller patient with both angiosarcoma and hepatocellular carcinoma). Fibrosis of the tenet was observed in three cases (19,29, B), and Roche et a). (1978) also reported fibrosis/ hyalinosis in vessels of skin, heart, lunfs and intestinal wall. CUMULATIVE N> OF CASES REPORTED TO NIOSH -H- IS TT T 1955 1960 1965 1970 1975 1978 yeor of diagnosis Fig. 7. Cumulative number of cases of A5L among PVC production workers reported to NIOSH up to August 1978, arranged according to year of diagnosisdata from Spinet and Ktmtnski 1977, 1978) 4 J.2 Clinical Manifestations The clinical symptomatology of usually multicentric ASL is unspecific. Gradually de clining general health and Ion of wei8ht combined with Hi-defined upper abdominal discomfort and slight epigastric or right upper quadrant pain art usually the first symptoms. Recurrent bleedinp from oesophageal varices may have been antecedent events in patients with portal hypertension who otherwise felt fairly well. In a number ucc 044292 s Ijnteller testes fibrous.' Vir\ 1 Chlonor-Aiiodateil Disease *t of cues, the tumour tint came to attention with massive, often fatal, intraperitoneal haemorrhif*. Important tender hepatomegaly fhepatosplenomejaly), slight jaundice and occasionally development of moderate ascites and oedema were observed. Except for mild to moderate hypertilirubinaemia, some elevation of scmm levels of alkaline phospnetaae and gammaglutamyl trantpepudase and only slightly abnormal levels of serum transaminases, the spectrum of biochemical tests ;s hardly revealing. Aipha-feto* protein determination hu not been helpful in the diagnosis. Ultrasonography, scinttfraphy.hspaue angiography and, notably, computer tomography of the upper abdomen ate the diagnostic procedures of choice if ASL is suspected. A technetium-*9TM -liver scan visualizes intrahepatie tumour defects (Sienack et al. 197Tb) together with abnormal splenic fixation, but peripheral defects of uptake may be difficult to interpret (Mtfieri et aL 197$). Characteristic features of angiography are i normal-sized hepatic artery with possible displacement caused by tumour enlarge ment. a certain degree of central hypervascularity of the tumour, a peripheral rumour stain, ana puddling of contrast medium persisting into the late venous phase, in addi tion, varying degreca of peiioss hepatis may be observed in some eases. However, even repeated hepatic angiography may fail to confirm the suspected diagnosis, as was evi dent m 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 count. In 19*;,'73, after an exposure of 18 years* duration, wc found him to suffer from Ray naud's phenomenon and nondrrhodc portal fibrosis and portal hypertension with sple nomegaly and moderate thrombocytopenia. Despitt termination of exposure, there was progressive splenomegaly and development of massive oesophageal and gastric !f i S v * ffc.tJ*w***vPjt* .ported rom daily de* uminal im cedent a nienber 7b W.K. Leltudi and H.J. Mjrsroller vances during the following yean with repeated episodes of bleeding which required (.successful) sclerosing therapy (major surgery was declined by the patient). In August 1979 he presented again with recurrent epistaxis and slight but permanent epigastric plained about a sharp localized epigastric pain on sneezing There was marked spitno* megaly, and an ill-defined hard mass was palpable in the epigastrium. Apart from mod erate elevation of alkaline phosphatase and borderline hyperbilirubinaemia, biochem istry was normal. Computer tomography showed a large irregular hypodense tumour mass in the liver, involving both right and left lobes (Fig. 8). which became practically isodense after intravenous injection of contrast medium. A liver scan corroborated the 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). hr'ieller ;uired August _ jitrie : It cum* plcno* 'm mod-chem;tour cticily ited the .'mer.t vtai:a*e$ >miof Vinyl GiIonde-AMOuiaicd Disease $m3r \ 9 W K. Lelbj.il jnd H.J Mantclier 11 months after peritoneoscopic diagnosis of severe hepatic fibrosis (ease 19; sec also Lelbach and MarstelUr 1977). In addition to the findings described in connection with hepatic fibrosis, there may be hypervaseularized or cyjtie tumour formation visible on the surface of a nodular, quasi-cirrhotic liver, or a gross aspect resembling hepatic metastases if the vascular malignancy involves the superficial regions of the liver. It should be stressed here that needle biopsy is absolutely contraindicated if there is any suspi cion of A5L. 0.4 Cross and Histological Morphology The liver is usually markedly enlarged. Liver weight in cases of ASL ranged from 1600 to 7300 g (Thomas and Popper 1975 -.Roche et al. 1978). The gross appearance of angio sarcoma of the live, is mostly that of large bulky, irregularly shaped cysuc tumour masses;a multinodular form with numerous, sometimes umbilicated nodules, is less often encountered. Extensive haemorrhagic and necrotic areas or solid and spongy por tions of tumour tissue replace much of the liver parenchyma. Rupture of targe cavern ous cysts may cause fatal intraperitoneal haemorrhage. Thomas et al. (1975) and Thomas and Popper (1975) distinguished four basic devel opmental patterns of histomorphology of ASL, which can be found in different por tions even of the same tumour and appear to represent stages of progressive evolution; sinusoidal, papillary, cavernous and anaplastic patterns. Indistinct areas of transition and merging of patterns can be observed. Dilated sinusoidal spaces lined by hypertrophic and hyperplastic sarcoma cells with pleomorphic, elonpted. hypejehromatie and often bizarre nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells of varying differen tiation envelop liver cell plates and may invade enlarged and fibrosed portal tracts, ac companied by proliferation of bile ductules (Fig. 11). In papillary angiosarcoma atro phy of liver cells results in larger and more irregular blood-filled vascular spaees, into which loose papillary strands of surviving hepatic cords on an axis of connective tissue project, lined by sarcomatous cells (Wtinbnn 1976). Even larger blood-filled spaces are seen in the cavernous type, where they may be surrounded by thick fibrutic walls. In a smaller percentage of cases,solid areas or nodules ofanaplastic sarcoma are found, resembling solid spindle-cell sarcoma, or wen suggesting an epithelial type of tumour. Gedifk 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 rumour-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 bOe 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. perisinusoids! fibrosis is often detected only by special staining methods for collagen or reticulin fibres. As a rule, irregular focal or nodular fibrotie thickening of \. *< f. . Fig livi nu. per in- on lyw Th, or liici oidi ( plav met retu eyti: dege retiv erta- Tfl WK. Lelb41.l1 jnd H.J Mjrsieller 11 month* after peritoneoscopic diagnosis of severe hepatic fibrosis fcase 19: see also Lclbaeh ami Marsttlltr 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 grass aspect resembling hepatic metastases if the vascular malignancy involves the superficial regions of the liver. It should be stressed here that needle biopsy is absolutely contraindicated if there is any suspi cion of ASL. 4.3.4 Cross and Histological Morphology The liver is usually markedly enlarged. Liver weight in cases of ASL ranged from 1600 to 7300 g (Thomas and Popper l975:Rochett al. 1978). The grass appearance of angio sarcoma of the live, is mostly that of large bulky, irregularly shaped cystic tumour masses; a multinodular form with numerous, sometimes umbilieated nodules, is less often encountered. Extensive haemorrhagic and necrotic areas or solid and spongy por tions of tumour tissue replace much of the liver parenchyma. Rupture of large cavern ous cysts may cause fatal intraperitoneal haemorrhage. Thomas et al. (1975) and Thomas and Popper (1975) distinguished four basic 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, hype;chromatic and often bizarre nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells of varying differen tiation envelop liver cell plates and may invade enlarged and fibrosed portal tracts, ac companied by proliferation of bile ductules (Fig. 11). In papillary angiosarcoma atro phy ofliver cells results in larger and more irregular blood-filled vascular spaces, into whieh loose papillary strands of surviving hepatic cords on an axis of connective tissue project, lined by sarcomatous cells (Weinbrcn 1976). Even larger blood-filled spaces are seen in the cavernous type, where they may be surrounded by thick Qbrotic walls. In a smaller percentage of cascs.solid areas or nodules ofanaplastic sarcoma are found, tesembling solid spindie-cell sarcoma, or even suggesting an epithelial type of tumour. Gadifk et al. (1975) also observed a reticulosartomalike 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 aetiol ogies] factors or from the cryptogenic type (Popper et al. 1978). In tumour-fret 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. Fibres!* 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 inuslobular, perisinusoids! fibrosis is often detected only by special staining methods for collagen or reticulin fibres. As a rule, irregular focal or nodular fibrotic thickening of u K w v *. t. Tit livi nu. per lo op lyu Thi ore lifer oid. plas incr ten. eyti degv rttu ci?a 044297 f: I M i Marsteiler -19: tee also tnection with tion visible on ; hepatic meliver. It should is any rutpi- -.4 from 1600 to r'mce of 'tic tumour lulea, u lea md tpongy porflarje cavern- nur basic devel* lifferent pot;vive evolution: of transition otna cells with teriie the vms differen cial tract*. c- jcotta atrorspates. ait>nt.et.tive tissue tilled space* . Jlbrooe wall*, iifu an found, pe of tumour11 ferendatton of Hjlial lining call hcally, vinyl *i othar ictiol- Jepees of*xws to that seen nurtal tracts inn oflympho* risrja septa ex.nicuous hurtmethods for thiekcnmg of Vinyl Chionde-Associated Disease 79 Fig. 11. Anpoumoma of the \i*tt {upper pert of photomicrograph* invading adjscent liver parenchyma (case UDl.i*eTable 13). Note hyperplastic and hyperehroraauc nuclei of proliferating neoplastic limni cells enveloping hepatic sards. Reproduced by permission. Ann NY Acad Set ;ud:27J-:i5 (197J). Courtesy of Professor Gcdigk, institute of Pathology. University of Bonn. HIE. 1 2S0 of Clisson's capsule is present; these flbtodc capsular areas may extend into the underlvtn| parenchyma and may connect with adjacent entitled tubapiuiar portal tracts. The cellular and nuclear die of hepatocytes may vary widely', poupa of btnudaated or even multinudeir parenchymal ceQa with abundant cytoplasm art seen. Focal pro liferation of sinusoidal lining cells may be encountered, especially within fod of sinus oidal dilatation. In connection with conspicuous sinusoidal dilatation, two types of focal hyperpiastre precursor Ituom ware desenbed by Popper et aL (197J): 1) Foody circumscribed fod of hyperplastic, often binudeated hepatocytes with increased number of various sinusoidal linm| sails and only insigni/lcant increase of reticulum framework. 2) Almost nodular areas ofconspicuously hyperplastic and hypertrophic hepato cytes with more pronounced variation of markedly increased sinusoidal cells without degeneration or neemtis ofliver parenchyma, but accompanied by execs formation of leticohun fnmewoik and compression of surrounding parenchyma. The transition ofsinusoidal lining cells to angiosarcoma cells is characterized by in creasing ttypia and anaplasia of them proliferating endothelial cells accompanied either ucc 044298 30 W.K Lclbath and H.J. Mar*telier by formation of excess connective tissue or by accentuation of sinusoidal dilatation leadinj to primary peliosis. Involvement of portal areas in the evolution of angiosarcoma results in considerable fibroplasia and formation of hyalinized collagen together with proliferation of bde ductules. In occasional cases connective tissue bndging be tween portal tracts or between portal tracts and central veins with subdivision of lobu les followed by tfarrangement of hepatocytic plates may lead to a cirrhosiilike picture. iJJ Therapy The multicentrie development of ASL (77iomer 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 (Delimiter et al. 1979) it 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 (Dennaher et al. 1979). At ptesent, no generally accepted guidelines for chemotherapy are available. 4.3.6 Risk Assessment When in the United States 13 white male eases 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. 197$). 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 orderof0014/100 000. This would have meant only about 0.03 eases per 20 000 polyme.-.ration workers within a 10-year period. Dose-response and attendant biotnnsformar ; n data on experimental animals have since been used to elaborate sev eral different models of extrapolation to man. These were calculated with reference to relative body surface areas, for estimating the risk of ASL in human populations ex posed to VCM and for establishing guidelines to assist the research for *realistic safe doses' that do not affect the average lifespan of a person exposed (ScImeUermtn et al. 1975: Gehringtx al. 1979,1978: Woods 1979). Gehring et al. (1979) consider a probit percent model to be e reliable tool for risk prediction, which works without the assump tion of a threshold. They predicted a cancer risk of 1B cases of ASL In 100 000 000 workers on exposuie to the current National Standard in the United States of 1 ppm VCM 8 h/day, 5 days/week, for a 3S-yar working life,an incidence which does not significandy 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 rimes between ran and humans was described by Moods (1979). This model arrives at an incidence of IS eases pet 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 197t. Hooper ct al. \979\SehneUerman 1979: Weigert 1979: Reitz tial, 1979). Viru R. (ex cl ASL Thu. the l confi had d the re potyr was o viron, eeedc lesser magn ting.: millio vinyl mode the es grour 4J.7 Fora hazar. the cc studiv sure . the iu el. 19 Wornof Bn: 1976; posed etal. 1 voicct! Berry emplu and a but nc 1976) In (1974 epiden (1978 facton teller ion -1TCO(ter heT lobuicturt. dif-i et* r' two jua e pa- r> >tei for 1*561 <ers of mon of lata t. t ;uvipet riant iic sev. nee to 5 tv afe et at. i prebit -xstimpD000 I ppm t not tied by xHI !by workers lity of ! cxpo*ctJ. Vin> 1 Chloride-Associated Disease SI Result! of a recent survey by Brady et ai. (167?) indicated that for New York Slate (excluding New York City), a lugi'Jy industrialized area, the annual incidence rate of ASL during the 6-year period from 19?0 through 19?$ was 0.25 per million residents. Tlus 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 histologically confirmed ASL were found in the study area from 1JS to 1975. and 7 of these had had documented !ong-term exposure to either As. ThO; or VCM. Five (all female> of the remaining 19 patients lived at a distance of 5C0--tJOO feet from VC labncation cr polymerization facilities for long penods. No pertinent exposure or residentiai history was obtained from the other 14 patients. Discharge of umtacted monomer into the en vironment as result of losses in tht PVC production process was estimated to hate ex ceeded 200 million pounds annually, most of which escaped into the atmosphere with lesser amounts dissolved in water effluent (Sclruarzcr 1975). Concerning the order of 'magnitude of ambient exposure beyond the work place. U. outside the industrial setting, an average annual exposure concentration of 17 ppb was estimated for the 4.6 million persons throughout the United States who resided within a 5-mile radius of vinyl ehionde emission sources (Kuzmoek and MeCaufhy 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. 4 J.? Mortality and Cancer Morbidity Studies For a tumour disease as rare as angiosarcoma of the Over even quite small increases in ..hazard c ' background ltvtls should be detectable (Doll 1975). The situation with the common types of caneer is Car mom difficult. Since 1974 a number of mortality studies of VCM-exposed populations have suggested that in humans long-tctm exposuit to VCM may siso be associated with cancer of sites other than the liver, notably the lungs, and the lymphatic and central nervous system (Monton et aL 1974: On et al. 1975: Tobershow and Coffey \97O.Nicholton et aL 1975; Wejoner et at. 1976: ifatu et/cf et al. 19^6 ;Michobon 1977, Bufflem aL 1979). Epidemiological studies of British workers filled to confirm this suggestion (Duck et al. 1975. Duck and Carer \916;Fox and Collier 1976,1977). as did a prospective study of a VCM/PVC-exposed cohort of 1613 employees of a West German chemical plant (FrenisebBeyme et si. 1973). Criticism of design and interpretation of some of the studies has been voiced (Falk et al. \97M>, Puretunc and Wittienuon \97*;Reger \977\DoUemp 1975: Berry and Rosnttr 1976). A follow-up of all VCM-exposed petsons (750 traced) ever employed at the one Swedish fsetoty, which started operation in 1945, for mortality and cancer morbidity patterns revealed a fouifould excess of pancreas/Uvtr tumours but no deviation in the number of brain turnouts from the expected level (Byrwn et al. 1976). In addition to the three extenave mortality studies of Toben/me and Coffey (1974). Wweilcrei al. (1976), tad Fox and Cottier (1977), a fourth comprehensive epidemiological study (Rem! and Weber 1976) was completed in 1977 by ReM et aL (1973). witicli included three study populations from 11 VCM- and PVC-produdng lactones in the Federal Republic of Germany, covering the period from before 1959 9 S2 W.K. Lelbach and H.J. Marsieller through 1974: (a) 7021 workers engaged in the production of VCM and PVC; (b) 4910 chemical workers from the same plana not exposed to VCM: and (e) 4007 workers enpged in PVC manufacture. Not included were non-German workers of Mediterranean origin. Thu German study permits comparison not only with the mor tality ratio of the total male population but also with a comparable occupational group exposed to VCM. With regard to the liealthy worker effect* (McMichael et al. 1975), overall mortality was elevated for the VCM-exposed population (group a), but not for the other chemieal workers (group b). Apart from the markedly elevated stan dardized mortality ratio (SMR) for malignant liver tumours (1523). which proved to have been closely related to the duration of exposure, a significantly elevated SMR was found for tumours of the lymphatic and haematopoetic system (214). The group of chemical workers not exposed to VCM (b) also showed a significant elevation of the SMR for liver tumours (401), a result that deserves further investigation. No signifi cantly increased risk was found concerning tumours of the central nervous system or the respiratory tract. It has already been mentioned (Sect. 2-2.10) that an excess mortality from brain tumours (SMR 535) was recorded among PVC workers engaged in manufacture at one of two plants: in the second plant an elevated SMR (434) for liver tumours was found. At present, there is no explanation for the increased SMR for accidents found in the VCM-exposed population, particularly during the period 1970 through 1974, about 4QG 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 determinauon of plasma carcmoembryonic 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/ml than in a normal healthy population (1.7% vs. 0.5?e) (Page et al. 1976). Levels of CEA wen also determined in 1363 workers of five different VCM polymeri zation (3) and PVC processing (extrusion) plana (2) in the United States (AnJenon et al. 1978). After removal of possible confusing factors (smoking, alcohol intake, past medical history), it emerged that the distribution of CEA titres among the polymeriza tion workers was significantly different from that in tha extrusion plant group and in a nonexposed reference group. Significant differences were also found for two of six job categones examined (polymerization and maintenance) compared with extrusion workers and the reference group. However, the usefulness of the CEA titre as a predic tive indicator of possible increased risk seems doubtful. 4.4 Miscellaneous Aspeca 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 Anton^tahtttko in 1968. Later JiUtt et al. (1973) noticed that each of the first 13 autodave cleaners re ferred to them during 1972 from a West German plant because of suspected skin and bo Bo tio ; op we oi. th. dei ph. oti. fat b.' Uf har re: 1o cou of; in al. i C>T or. xv r Ta. w,. pea prelitre lirru Fix. teller unr- : i). but ' `tanJ to 1R was p oi' the \ifin -.tin ; one ound. . the out . data i >n me rm- n:n tt MU r flZ3\ in tin won predie- '*CT.iko in n re* -ii and Vin> I Chlunde-Aisoaattd Disease S3 bone lesions presented with mild to marked thrombocytopenia (30-119 v 10** lit:*). Bone matraw 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 tli|ht reticulocytosis in S and leueapema in 5 of the workers, other haematolopeal tests were negative. Tlte reduction of the number or* leucocytes and platelets as well as reticulocytosis appeared to be attributable to splenomegaly, but further studies on the nature of thrombocytopenia were thou|ht necessary, and it was suggested by tht authors that a decrease in the number of platelets might serve is an early and easily detectable symptom. The high prevalence of thrombocytopenia (as determined by phase-contrast microscopy) found later on detailed analysts 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 (Baehncr et ai. 1974*. b, 1975a. b, l9~6\Sthn-Bachner and Etztl 1977). h'tjman (1975) also commented upon abnormal platelet eouns in 13 of 37 PVC fabricating workers who had onlyhandled PVC powder which, however, might have contained substantial amounts of residual monomer. In contrast. Litis 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 Sehrt^Badmtr and Etui (1977). the mean platelet count in a cohort of 132 PVC polymerization (and processing) workers was significantly lower titan that in a nonexpoied control group of 150 healthy men. As could be expected. Bachner et al. (1975b) also demonstrated a positive eomlation between the degree of thrombo cytopenia and the piwalcDce of an enlargement of the spleen (palpable splenomegaly or spieeti size determined by selective scintigraphy with l*T-H|-bremo-fflercury-hydroxypropane4abeiIcd ted ceils) in 70 PVC polymenzadon workers (set Table 19). It ap* Table 19. Prevalence of enlargement of tht spleen3 among 70 PVC-polymentation worker* in rtijttnn to increasing degrees of thrombocytopenia (RecAnrr at al. 1973a) Croup No. of workers examined Platelets (a 1 O'*/Ltre) Range Mean Enlargement of the spleen A 14 B 24 C 23 D7 > 130 100-130 70- 99 < 70 161 117 7 44 3(213) 11 (463) 19(763) 6(16") * As determined by palpation or by selective spleen scinugraphy. pears, however, that the development of thrombocytopenia is not dependent on the presence of splenomegaly since we obsetved mild thrombocytopenia (100-120 x 10**/ litre) in a small number of workers in whom spleen size wit definitely within normal Emits on selective spleen sdnogrephy (MfizfUchimndex < 4J x 1<T1 according to Fuchtr anc Wolf 1963). Thrombocytopenia was accompanied by abnormalities in platelet function tests. There was an increase in the number of large (> 10 ran) `juvenile' platelets (increased 84 tV.K. Lclbjih and H.J. MarMvIler platelet spreading), enhanced response (platelet aggregation) to addition of ADP and collagen (Bom test) and increased avadabdity of phospholipid-containing platelet fac tor 3 (Bodmer et at. 1973a). 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 reuculoendothelia! system (RES) clearance of activated dotting factors (Bodmer et al. 1974b). tiW (1976) and blind et al. (1976) suggested that thrombocytopenia could be construed as confirmatory evidence of an immune complex disorder. Hcusermawi and Stutte (1977a) noted unusual focal aggregation of platelets in tdatsch preparations of spleen tissue and increased platelet pooling (plate lets trapped within the subsinusoidal meshvvork of pulp cords) in the red pulp of the spleen on electron microscopy as well as phagocytosis of thrombocytes by sinusoidal macrophages. Sdia/fner et al. (1976) found platelet thrombi in and around hepatic sinusoids in mice after exposure to VCM. A direct toxic action of VCM (or metabo lites) on the bone marrow has not been demonstrated so far. Although the pathogenesis of thrombocytopenia in VCM-induced disease is not fully understood, it seems at present most likely that it is caused by increased tumovtr 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 TrudI 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 Garin et al. 11974) in connection with splenomegaly of various noncurhotic origin. 4.4.2 Central and Peripheral Nervous System Miscellaneous nonspecific and somewhat indefinite symptoms have been described in connection with chtonic inhalational exposure to VCM in PVC-producuon workers, such as doziness, disorientation, blurring of vision and memory, headache, irritability, excessive fatigue and somnolence, sleep reversal or insomnia and other pseudoncurasthenic symptoms (Sucitt et al. 1963,l97S:Sdwtttk 1969:1/hs et al. 1473 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 (Schonck 1969). How ever, Vait et al.(1976) repotted that several individuals in a group of 95 comparatively young ex^'orken. the minority of whom had no other symptoms, complained of fa tigue, headache, listieisnets and depression, with onset of symptoms having been de layed as long as 3 yean after cessation of employment. With reference to such 'pseudoneurasthenic complaints', which may be interpreted as the mildest degree of a toxic encephalopathy, A/rin et al. (1975) examined a group of 31 autoclave cleaners at varying intervals afttr cessation of exposure, all of whom presented with other (cutaneous, angioneurotic, hepatic) manifestations of vinyl chlo ride disease. Clinical symptoms of more or lev 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: tat the others, perenriiythmia, dyaenrhythmia or a socalled tubrigi! electroencephalogram was observed. Evidence of distal polyneuropathy, found in 19 patients, wet attributed in the first place to an abnotmal peripheral circu- 4.4 Occ 044303 **) c `l.inteller UP wd wlct fac-_ i lie noi-.|C) m ,,-uvited Bested nnune ration of etplateof the fisoidal paiie -.tabo- ; not fully ver and i spittn. ftpon- defect <pleen non with iied in ken. lability, tcuf;nd n dally * to lit *. How;arativeiy I of fa-m de- erpreted I a group whom *tyi chloludini -a normal a toropathy, altirco- Vinyl Chlonde-A.tc'tiated Disease 3< lation with resultant hypoxic damage. The pathogenesis of a possibly VCM-induced encephalopathy is not clear. It would be conceivable that clinical and bioelectric alter* ations found in some patients, in whom portosystemic encephalopathy could be ex* eluded, may have been due to toxic or hypoxic brain damage- However, no'otlter eonanting evidence has so far emerged to indicate that chronic irreversible eerebrotoxic damage may have resulted from prolonged exposure to VCN1. notwitltstanding the pos* sibilitv of an induction of brew tumours. 4.4 J Pulmonary Changes The suspected development of nonmaliinant pulmonary changet 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 i from three large North Axnencan PVC-pieduong plants (A, B. C). characterized by different duration and levels of past anvirontnantal 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 spirometty and detarmination of maximum expiratory flow vol ume (.ttiller 1975 .Miller et ai. 1975;Itiis at al. 1975.1976. 1977). All cases with pre vious exposure to asbestos, silica or coal dust had been excluded in these studies. Unexpected linear, retieular and. lass often, rounded opatiues 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 (.22.75, and 18.85, respectively), but in only 4J5 of thou from plant C. with the lowest exposure level. The prevalence of these radiological abnormalities, for which no pathogenetie explanation was available, was found to be significantly in creased with longer duration of VCM-PVC exposure (more than 10 yean), but the pre valence of a positive history of smoking, although idantical in both groups A and B, was also found to be significantly higher in workers with abnormal chut x-ray pistes. The overall prevalence of a positive history of chronic bronchitis (British Medical Re search Council criteria) was 20.45 in group A (highest exposure) and 16.05 in group B, although group B was significantly oldat. 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 high prevalence of obstructive changes, but snee both smoking and age ware related to changes in pulmonary function, it appeared difficult to isolate potential specific effects of occupational txpoiuit to VCM and PVC dust. A restrictive partem was found ia 9.35 of group A and in only 2J5 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 pan to VCM at well at PVC dun. may point to a potential multiple factor effect of smoking and VCM-PVC exposure. In thto con nection. it is of interest to nott that according to a cohort study of mortality among VCM polymerization workets the SMRs for respiratory cancer at well at for *other respiratory disease' were found to have been in exeta of expected figures (156 and 176, respectively) {Waxweiter et aL 1976). Bronchopulmonary changes thought to be due to long-continued, intense exposure to PVC duat ware observed by several authors (Parmejjvmi and Sassi 1955; Broussard So W.K. Lclbach and H J. Mjntdler l969:S:oidetial. 1970; Vertkin and Mamontov 19*0.Fronpa et aJ. 1974 -.Parke 1976.Arnaud ct al. 1978). Considerable exposure to VPCdust is the rule m the drying, bagging and storage areas of PVC-produdng plants. Photographs contained in Karuadn 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 Pamieggrdni and Sassi. In 1969 Bmuaard mentioned the possibil ity of development of chronic bronchitis caused by the inhalation of PVC dust The insoluble and inactive dust panicles 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 vewte 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. Sztndt 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 yean of employment in a PVC bagging area, with radiological evidence of diffuse micronodular infiltrates and granu lomatous lesions found in a lung biopsy identical with those recorded by Sztnde et al., was published by Ammd 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 rctieulin and col lagen on electron microscopy {Deritt 1976). Although chest x-ray appearances were normal and routine respiratory function tests showed only slightly impaired COt dif fusion in six individuals, perfusion and ventilation scans revealed strikingly abnormal pictures, including marked perfusion defects of upper lobes. Darke pointed out that some of the men wont affected had been engaged in the polymerisation of 'plastisol', a very fine PVC powder with particle size around 0J ton. StUkoff (1976) called attention to results obtained by Frongia et al. (1974), who observed significant histopsthoiogicai changes in the lungs of guinea-pip and rats ex posed for 2-7 months to inhalation of the airborne PVC dust in a PVC bagging area. Lesions began to appear at 2 months 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 fod. Vmkin and Mamonto* (1970) who examined 96 workers enpged 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 Gokumryuk and later by ShlyakhtrtkiL These last authors had apparently shown that exposure of animals to PVC dust may lead to the development of chronic pneumonia and eventually to a son of mild fibrosis of the lunp. \, St! bi ll; tu W-' OV of dy tr. of de *Pl 4.~ Th mmu tit m ter ,1/c me coi re: P 10 an fatdo ha< h-v of an me pb 19 of VC ' J Marsteller "i-.Darke .n the drying, i in Kamadr'i "*nti of the reported as the possibtldust. The ip blocking minauon of nent of the hout hilar icsented with pulmonary ' a processing anulomatous could be ion ofPVC morphologic- :m in a PVC < ind granu'.ittdc et al.. n I of 14 < \v jl alveo'iim and eolu'lces were f-i CO, dif. abnormal out that -i `plastisol*. i 74), who ir.d tats exigging area, tophage re of foreign lumatous the manuunion of broncho!iey quoted (id later by animals to illy to a sort Vinyl Chlondt-Associated Disease 87 Certain types ofPVC dust (one of two samples tested) were found to exhibit a strong haemolytic potennal due to the presence of an undetermined but readily solu ble surface-associated agent which was not VCM (Richards et al. 19*5). These authors also studied the effect of the haemolytic sample of ?VC 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 prolifenoon) 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 aacnbed to pulmonary changes within the spectrum of VCM-induced disease. 4.4.4 Genetic EfTerts ofVCM The discovery of the carcinogenic properties of VCM also stimulated interest in its mutagenic potential. A number of studies have been earned out that demonstrated a mutagenie 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 lyphimumm by VCM in the presence of animal and human liver microsomes as a sys tem of metabolic activation (P.jnnuf et al. 1974,19*6;Bamch et al. 1975a, 1976: McCann et al. 1975;MelareiIle et al-197S: Gam t aL 1976). Mutagenicity of VCM metabolites was also demons.;*:ed in yean strains (Loprieno et ai. 1976,1977;Shahin 1976) and in mammalian eel; i/Iuberman et al. 1975). In comparison to nonexposed controls, a significantly high*: incidence of duomosomal aberrations (fragmentation, rearrangement) in lymphocytes of workers occupationally exposed to VCM was reported by Ducarman et al. (1975), Funet'Oweioto et al. (1975), Fueehase et al. (1975, 1976), and Fomenko et al. (1976). Fleig and Ttuess (1974) had failed to demonstrate an increased rat* of chromosomal aberrations in six chemical engineers and four PVC fabrication workers. As to the influence on gems cells, Purchase et al. reported that no dominant lethal efftets 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, docs not absolutely cxdude genetic efTects on human gonads. The outcome of pregnancy among wives of VCM-polymerization workers as against wives of rubber and PVC-fabrication workers (Infante et al. 1976c. b) and rates of congenital malfor mation per 1000 resident live births in three Ohio communities with PVC production plants have alio been studied (Infante 1976). As part of a larger surrey of workers' health, interview questionnaires (Infante 1976a, b) showed that after paternal age adjustment a significantly higher incidence of fetal mortality submquent to paternal expocurt was recorded among the wives of VCM-exposed workers. This trend was found to be maintained after elimination of f S3 W.K. Lelba.h and H.J Manteller pregnancies in women who had mort than two abortions. The findings of (his study raised the question of possible genetic risks of VCM to man and led to the suggestion that germ-cell damage in the father through direct VCM exposure might be a possible explanation. No dear-cut linkage of PVC production and increased occurrence of congenita] malformations (primarily CNS malformations) emerged from preliminary studies in three Ohio communities with PVC production plants. But the need for further study of possible contnbutary factors was indicated (Infante 1976). In fact, none the par ents of affected children in Painsville, one of the three Ohio communities, had ever worked at either of the two PVC polymerization piano in Painsville or lived within two miles of these plants (Edmondt ct al. 1975). 5 Conclusion and Outlook The combined efforts of multiple disciplines have been neeessary to arrive at ute full recognition of the range of pathology associated with occupational exposure to vinyl chloride. U 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 art 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, whieh 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 tare type. Animal experiments in the eariy days later proved to have bean broken off before the oncogenicity of this chemical com pound could have been detected. The lesson to be learned is that in future any new chemical which is to be widely introduced into the environment should be scrutinized closely, for a sufficient length of time, and with the aid of all available methods for the detection of potential car cinogenic effects. In addition, we should keep in mind that in industrial surroundings we almost never deal with a single compound, but with a very complex occupational environment whose carcinogenic potential is still a completely unresolved problem. If currently adopted guidelines for industrial hygiene are strictly adhered to, there is reason to hope that initiation ofnew cases of VCM-inducad 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 tht next decade. Considering the ever-inercasing complexity ofenvironmental influences, future re search will be faced with almost insurmountable obstacles in its endeavour to establish "safe' levels for potentially hazardous chemicals. Promising areas for further studies in the field of vinyl chloride and allied compounds may be the problem of the interaction between preJ tissue such a* shon exposu. will carry the References Albnght IF t i Albnghi LF < , Albnght LF i' Albnght LF l' polyvinyl e Albnght LF < processes.. Alienga OP I 198-203 Amann R (19 der Leber ' Anderson H X CEA amoi; 1560-156' Andrews AW. properties Anghelescu F. 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