Document 0LKeY3pjbXnr7Yb4LVMXmNr2m

i Hertu^tgelsen von , B Fricki vor}-, c^<'-. chs it<- /:.' QM fyla rtrra; A. irade r '"`;:,'y"'* 1 *>; M^24Abbi!dungtn:uwd |3r!J>bellert v Springer-Verlag Berlin Heidelberg New York 1981 Vinyl Chloride-Associated Disease W.K LELBACH and HJ. MARSTELLER 1 1 Introduction......................................................................................................... ; 2 Technoiopcal Details............................................................................................. 2.1 Vinyl Chionde Monomer (VCM)................................................ ............. 2.1.1 History............................................................................................... 2.1.2 Production o>'VCM ......................................................................... 2.2 Production ot Polyvinyl Chloride (PVC)..................................................... 2.2.1 Technology of Polymenzation.......................................................... 2.2.2 Methods of Polymerization............................................................... 2.2.3 Compounding ................................................................................... 2.2.A Sources of Exposure to VCM in PVC Production......................... 2.2.5 The Explosion Hazard...................................................................... 2 2 6 The Odour Threshold _................................................................... 2.2 * VCM as an Anaesthetic Agent......................................................... 2.2 8 Effects of Acute Overexposure in Man................................. ... 2.2-9 Monitoring VCM Concentrations in Worktn| Areas...................... 2.2.10 Exposure to VCM in PVC-Proccssing (Fabricating) Plants.......... 2.2.11 National Standards for the Control of Exposure................... 2.2.12 Exposute to VCMOuside the Woricing Area............................... 4 4 4 5 6 t 7 g g 9 10 10 U |j 15 17 18 2 Toxicology of VCM.............................................................................................. 2 1 Acute Toxicity.............................................................................................. 2.2 Chronic Toxicity............................................................................................ 3.3 Oncogen* Properties..................................................................................... 3.4 Toxicodynaaics............................................................................................ 3.4.1 Uptake end Distribution....................................... 3 4.2 Metabolism....................................................................................... 3.4.2.1 Relation between Chemical Structure. Reactivity and Mutagenic or CarcinogenicEffect................................ 3.4 2.2 Metabolic Pathways............................................................ 21 21 21 22 24 25 26 26 26 4 Clincal Spectrum................................................................................................. 4.1 ThcTnad: Raynaud's Phenomenon. Pseudoecleroderaa and Acroosteolysis............................................................................................... 4.1.1 Familial and Idiopathic Acrooeteolyais........................................... 4.1.2 Epidemiology of Occupational Acrooeteolysii.............................. 4.1 J Clinical and Rocntgenolopcai Features........................................... 4.1.3.1 Occupational Acreofteotysis............................................. 4.IJ.2 Pscudoscicroderma............................................................ 4.1.4 Histology............................................................................................ 4.14.1 Cutaneous Lessons............................................................... 4.1.4.2 Bone Lesions...................................................................... 4 | J Arteriography. Capillaroscopy. Infrared Thermography............... 4.1.6 Immunolopcal Studies...................................................................... 29 31 34 34 36 36 31 39 39 39 40 42 1 Department of Medicine. Director Prof. Dr. IU. Deeper. University of Bonn, FRO * c 'l * 4 W.K. Lelbach and H.J. MarsteHlleer <1.1 7 Pathogrnetic Considerations................................................ d.2 Non-malignant Liver Disease m Vinyl Oiloridc.'Folynnyl Chloride Production Worker*..................................................... .*.................... 4.2.1 Clinical Manifestations of Xonxnalifnant Liver Disease . . 4.2.2 Laboratory Findings............................................................. 4.2.3 Gross Inspection of the Liver and Spleen............................ 4.2.4 Histology.......... .................................................................. 4.2.4.1 Hepatic Fibrosis..................................................... 4.2.4.2 Sinusoidal Lining Cells......................................... 4.2.4 J Hepatocytcs................................................... ... 4.2.4.4 Histology of the Spleen......................................... 4 2.5 Pathophysiology of Portal Hypertension............................ 4.2.6 Followup of Non-malignant VCM-induced Liver Disease . 4 J Angiosarcoma of the Liver................................................................ .4.3.1 Epidemiology....,................................................................ 4.3.2 Clinical Manifestations........................................................ 4.3J Peritoneoscopy....................................................................... 4 J 4 Gross and Histological Morphology...................................... 4 J J Therapy.................................................................................... 4.3.6 Risk Assessment..................................................................... 4.3.7 Mortality and Cancer Morbidity Studies............................ 4 .4 Miscellaneous Aspects....................................................................... 4.4 1 Thrombocytopenia and Platelet Function Tests.............. 4 4.2 Central and Peripheral Nervous System............................... 4 4.3 Pulmonary Changes................................................................ 4.4.4 Genetic Effects of VCM........................................................ 5 Conclusion and Outlook........................................................................... References........................................................................................................ 44 44 45 49 50 51 51 54 2 54 55 57 57 57 74 76 78 10 80 81 a82 84 85 87 88 89 Key words: Aeroosteolysis - Anfosareoma of the Liver - Portal Fibrous anti Portal Hypertension - Pseudosckrodarme - Raynaud's Phenomenon - Vinyl Chloride 1 Introduction The history of vinyl chlonde-assodated disease, its recognition and prophylaxis is a classic example of shutting the stable door after the hone has bolted. It should help to emphasize the need to shift our attention to preventing exposure from occurring rather than to reparative measures. In view of the large number of new and potentially hazard ous chemicals introduced each year into the workplace and the environment, this ac count should again alcn us to the necessity of pretesting chemicals adequately for their potential health effects, even at the risk that technological progress will develop at a more modest rate. Large-scale production of the synthetic resin polyvinyl chloride (PVC), a thermo plastic material suitable for the most widely divetsified industrial use, was begun around 1930 in the United States and in Germany. The monomer, vinyl chloride (VCM), a rather simple aliphatic compound, was believed until the early 1960s to be Vinyl Chlondc-Asso,- one of the least harmf later turned out, had it evaluation of acute eff to reveal its carcinogei. might have continued 1 pbee, considenng that vapour phase under an: reactive double-bond. Today vinyl ehlorid formation and data on cisely a quarter of a eei tributable to this new e with the shocking disci. tion workers hcaviiy e.x ing that the monomer i pound did not alert the in workets engaged in t lithed in 1949 (Tnbuki Ultimately, it was tl curred in workers expo a causal relationship: (l pseudosleroderma: (2) liver. Particularly, the J nancy among a compar alarming experience wl lunp or the gastroint*. the prolonged latency | sarcoma of the liver. r<` these two fatal consequ the conclusion that Vk cancer meeting in Hous to VCM was a very sen It should be stressc, precise,an intermediate mainly in the mammal, menzation products (p' cited from the polymei they contain unreacted PVC (thermal decompo toxicity of pyrolysis pn mainly due to the relea: Abar 1969\Dyer and E and only very small or r (O'Mare et al. 1971 cite Mantikr 44 4$ 49 50 51 51 !i 54 54 55 5" 5? 51 74 76 75 80 0 s: t: s: 34 85 17 SS 89 u. IFcml itr ft -.tub ill -mid help to mini nthcr tiaDy hazard*u. this acncty for ill develop uathennohtfUB 'deride .4601 to be Vinyl OiloiMe-Atvodated Disease 3 one of the lest harmful chlorinated hydrocarbons. Early animal experiments. s it later turned out. had indeed been carried our *ith dosages sufficiently high for the evaluation of acute efTtcts, but chronic exposure had not been of sufficient duration to reveal in carcinogenic properties. On purely theoretical pounds, however, one might have continued to feel uneasy with this compound ar a pollutant of the work place. considering that it is (1) a halogenitcd hydrocarbon which (2) exists in its vapour phase under ambient condiuons finhalauvt exposure) and (3) contains a highly reactive double-bond. Today vinyl chloridc-assodated pathology is well documented. A large body of in formation and data on this topic has been accumulated, notably since 1974, but piecjsely a quarter of a century had to pus before the full nape of symptomatology at* tnbutabic to this new occupational health hazard became recognized in January 1974 with the shocking discovery that haemanposarcoma of tha liver occurred in produc tion workets heavily exposed to PVC. Early and not easily aceeuible reporn suggest ing that the monomer might be an environmental risk for workers handling this com pound did not alert the expens sufficiently. The earliest indication of advene effects in workers enpged in the production and piocessini of PVC, a Russian study pub lished in 1949 {Tribukh et al. 1949), received little attention. Ultimately, it was the exceptional chancier of the three major lesions which oc curred in workers exposed to VCM that contributed most to the final appreciation of a causal relationship: (1) the syndrome of acroosteolysis, Raynaud's phenomenon and pscudoslerodemu: (2) noo<inhooe portal hypertension; and (3) angiosarcoma of the liver. Particularly, the discovery of a duster of four oses of this extremely rare malig nancy among a comparatively small group of workers (Creech et al. 1974*) was an alarming experience which called for immediate action. It can easily be imagined that a connection between VCM and the mote common malignancies, such is cancer of the lunp or the gastrointestinal tract, might still have gone unnoticed. On the other hand, the prolonged latency periods of both non<iRhotic portal hyptrtenson and anposarcoma of the liver, roughly 10 and 20 years respectively, delayed the recognition of these two fatal consequences of chronic exposure to VCM. But one can h*"<1Y tTTtPt the conclusion that viola's discovery of cancer in experimental animals, presented at_a cancer meeting inHotatpn In 1970, w sufficient evidence AO indicate that exposure to VCM wa a very serious pceuptnonal hazard (Pt:en 1976). It should bt suened that the noxious ttent is glely thugonomer, or to be more precise, an intermediate of the monomer's metabolic bioactiviation. which takespiace mainly in the mammalian liver and yields certain highly reactive epoxidei. The poly merization products CPVQ. th miiit .plastic and the plastic consumer goods fabri cated from the polymer, are chemically inert articles which eany.po health risk unless they contain unreacted residual monomer. Even the combustion of articles made from PVC (thermal decentpoBtion in fires) docs not yield free vinyl chloride monomefTthe toxicity of pytolyril products of polyvinyl chloride pdfymen irif/ormuTstions is mainly due to the release ofHydrochloric add and carbon monoxide (Csmrihind Abar \969:PJvtr v\iich \976,Sorrnson 1976 'Mom l976,Colartyn tt al. 1976) andonlyvery imatt'or no quantities bfphdigtne derived /romreridual monomer (Olforv et ai. 1971 dted by Colnrdyn et al. 1976). 1 ii:s ucc 069291 A 2 Technological Details 2.1 Vinyl Chloride Monomer CVCMj W K Lelhach and H.J M-imcIler At standard (ambient) conditions of temperature and pressure, vinyl chloride iCH;* CHCI: ehloroethylene, ehloroethene) is a non-irritating,colourless gas with a faintly sweet odour, inflammable at concentrauons above 3.3% by volume in air. which is only slightly soluble in water, soluble in ethyl alcohol and easily soluble in ether and carbon tetrachloride. VCM is mainly ured 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 Tore (* 101.3 kPa) to a colourless liquid of low viscosity (Lefaux 1966). Its physical properties are listed in Table 1, the most important of which ate its low boiling point, its high specific grav ity (gaseous VCM is 2.15 times heavier than air), its low solubility in water and the half-life in air. ranging from 3 to 20 h. Table 1. Ph> filial properties of VCM Mol. wt.. i.p.: ' F.p.. Flash point' Limits ot flammability: Autoignition temperature: 62303 *-!3.8*C(-l3.7 to-13.9) -IS3.7*C -7g,s*c (Cleveland open cup) 3.8"-29.3% by volume in air above -78.5*C (- 38 000-293 000 ppm) 472*C Vapour pressure: mm Hg 10 100 692 2300 *C -87.5 -55.8 -15.8 20 2660 *25 Vapour density: 2.15 g/litre (calculated at 25*C and 760 mmtlf (air* 1) Sp. gr. of liquid VCM: 0.9121 at -20*C/4*C 0.99 at -:5*C/4*C Sources: Feirhell 1957 Jmh 1963,Zipp 1964;Ltfaux \9tb.Otttrmeytr !9t>7. Roubel 1972. 2.1.1 History The French chemist,/lepMu/r (1835) ares apparently the flist to study systematically the synthesis and analysis of vinyl chloride. Liebig. who had done some earlier prelim inary experiments, encouraged Regnauh to investigate this compound when Regneutr spent several months in Liebig's laboratories. All compounds containing the vinyl group (CHj"CH-) polymerize readily (FeirhaU 1957). Spontaneous polymerization of vinyl chloride to a white opaque solid mass under the influence of sunlight was first described by Baumann in 1872; he also quotes a paper by Sayner and Glinsky (who Vinyl Oil. succeeded izing subst 2.1-2 Prou Large-Kali by employ: 1) Convex CH*CH 2) Convert chloroe: CH,CI' CH,C1- VCM w Thus, any l< ttons in the in the ranc (IARC 19Twhen VCV meyer 196* in commer V.:f>:Osn> In the r conjecture . retrieved Vi yses came* sum of all ii genates), reacted moi in prepolyp the eonctr.' that even 1' methyl chl>: hobutane.ii Terence in p . tml HJ. Mameiler I chloride (CH;* as with a faintly 31 ait. whieh :s lank in ethrr and manufacture ol *vo employed as a usually handled and Tort ( 101 JkPa) properties are listed ii< high specific jrsvin water and the I I hc -TS.J'C ~ 2300 :660 m 20 115 j.i 760 msHf .rmdytr 1967; - study systematically . some tatiier prelim* .and when Rrjruuir iainir.| the vinyl us polymerization of f sunlight was first - and Glintky (who ) Vin> I Ctiiundi--A*oi-i3ttd D:hm succeeded in decomposing vinyl chloride to monodiloreaidehydc with the aid 01* oxid izing *ubstans such as h> pochiorous and. 2.1 Production of VCM Large-scale commercial synthesis ofV'CM with a high yieia was made possible much later by employing two principle methods, the second having now largely replaced the first; 1) Conversion of acetylene to VCM by hydrochlorination: CH*CH HO--CH*<HC1 (catalyst: HgCl. on charcoal) (damn 1974) 2) Conversion ofcthyhre by vapour-phase or liquid-phase oxychJorination to 1 .2-dichloroethane and subsequent pyrolysis (thermal cracking; to VCM {Aibnght 196`aj: CH:"CH: * MO 1/2 O, - CH;a-CHiCl H-.O; CH,a-cH,a 480*C"5I-C > chj-cho *Ha pumice catalyst (pymlysa; thermal cracking,Aujroi 1974). VCM was usually manufactured in dosed systems and stored in outdoor iadlities. Thus, any leakap of the gas was readily diluted in the ambient air. VCM concentra tions in the atmosphere st some distance from manufacturing plants were found to be in the range 1--2 ppm. In dose proximity, the concentration ranged up to SO ppm flARC 1974).. Spontaneous polymerization in light has also been tepeatedly observed when VCM comes into contact with atmosphenc air due to container leakage (Orrenmaytr 1967). A prerequisite for the polymerization process is a high degree of punry in commercially produced VCM. Impurities retard the polymerization proems (Lefmx 1966; Oumngyer 1967). In the early discussion about the cause of vinyl chloride -associated disease it was conjectuted that other compounds or impurities contained m prtpolymenzation or in retrieved VCM might have been the eausstivc a*ent) (Tliieu and Venen 1974). Anal yses carried out by six West German manufacturers of PVC. however, ritowed that the sum of all impunties (such as saturated or unsaturated hydrocarbons and their halo* genares) was 0*015 by volume for prtpolymerization VCM and 0.1% for retrieved unteacted monomer. Only methyl chloride was found in concentrations of 50-300 ppm in prepolymerization VCM and 100-500 ppm in retrieved VCM fin one instance only, the concentration ranged between 1000 and 5000 ppm). But it should be kept in mind that even 1000 ppm methyl chloride in VCM would mean, at 500 ppm VCM in air. a methyl chloride concentration in air of only 0J ppm. AH other impurities (propylene, isobutane. *-butane etc.) would then be in the ppb range. Betides, no significant dif fetence in purity could be found between VCM from acetylene and from ethylene. e c f, 3a 4 VK. Lelbach and HJ. Manteller 2' Production of Polyvinyl Chloride (PVC) 22.1 Technology of Polymerization The following description is meant to serve merely as a rough sketch of the procedures and technological details involved in the production of polyvinyl chloride. Vinyl chloride monomer is polymerized in large autoclaves (reactors) at tempera tures between 40*C and S0*C and pressures of 6-16 (8-12) atmospheres. Th-rc are usually several reactors (up to 10-30) located in one building. The reactivity of the monomer is a function of its double-bond. The second functional site of the vinyl chloride molecule, the chlorine atom, does not react easily. The double-bond of VCM is not only the site from which the polymerization originates but is alto the source of the toxicity and carcinogenicity of this compound when it is being metabolized in the body. The polymerization ofVCM, which is a strongly exothermic reaction {Barnet 1976), is initiated with the aid of compounds soluble in VCM that form free radicals at relatively low temperatures. Initiators are sueh compounds as lauroyl peroxide, isopro pyl percarbonate, azo-bis-isobutytonitride,and others. The free radicals react with the double-bond of the monomer, transforming it in turn into a free radical and thus propapting 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 1966, A Ibnght 1967 a--c pominingliaut 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 weighs of the finished PVC being statistically distributed around a mean value. Commercial PVC polymen have average molecular weighs that vary from about 50 000 to 150 000 daitons (Albright 1967b). Degree and velocity of polymerization, which art influenced by temperature and the concentration of initiaton. determine the specif - type of PVC produced (Frey 1973). During polymerization considerable amouns i f the monomer art 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 tciminsted, depending on the method used, when approximately S0ft-90% of VCM is polymerized. The timing of this termina tion of the process is assential for the physical properties of the resins produced. The heat generated during the exothermic process of polymerization must be removed to keep the temperature of the reaction under control. Mechanical agitation aids in trans ferring the heat across the colloidal system to the cooling jacket of the reactor. During the process of polymerization certain quantities of the polymer adhere to the walls of the reactor and form a slowly thickening continuous film or crust. This polymer erust on the inner surface of the reactor vessel, which contains cavities filled with unreacted monomer, impedes the conductance of hear.it has, therefore, to be cleaned away after termination of the batch process (Bamet 1976). After completion of the polymerization process, the slurry is released from the re actor into a dump tank. Residual unreaeted vinyl chloride monomer is partly solvated in the polymer (about 10$)'; the remainder is dispersed in the water phase or is present Vinyl Chloride-' in the vapour ph. VC monomer is r is then purified b the finished pol> and Must diffuse Raw PVC resin, t (VKE 1975). Ap proximately 500 The slurry fre large enough to h are then pumped wet polymer, a e drying methods, merization, yield fine solid particlt drying tempered polymer. A cycle The solid polyrm storage bins or si dried powder coi 222 Methods i Four different in PVC (Frey 1973 Sutpention Poly which monomer (such as polyvin? conjuction with this method wh; Emulsion Potym was added in the except that large are added. Emul; emulsifiers canrn Bulk (MattI Poh the additon of o The first reactor aecond one is use solid state, to es-. reaches a level oi characterized by good optical clar _JHJ. Manteller ,f the procedure* -wide. ;.) at temperaitem. There arc -aetreuy of the :uf the vinyl .vu-bondof VCM bo the mice of tetabolized in the action (Renter urn free radical* at I peroxide, ssoprorali met with the cal and thua prop 'll. Chain growth i* .-ulvet a reaction *>:Albnfht 1967 h termination ence different de- wtng statistically about poiymtnzat.'n, *,, determine mt conridcrabie it of than it later which b not soli reason dow* the method used, of this terautoas produced. The 4 be removed to ation aids in tnnthe reactor. During ere to the walls of : hit polymer crust led with umtacted cleaned away after -seed from the re* is partly solvated phase or is present r s Vinyl Chlonde-Assodated Disease ? in the vapour phase above the slurry. Wiile a batch is in the dump tank, this unreacted VC monomer is letricvcd by pumping it oft into a VCM storage tank. Retrieved VCM is then purified by subsequent distillation for recycling purposes. Monomersolvatcd_jn die finished polymer cannot easily be extracted since it has a ttrongUTmity for^VC and'must diffuse through the paniclestthisdiffusiondepcnds onumelricftemperature. RiwTVC reun. therefor*, still contains certain quantities of unrctctcd monomer (VK 19TJ). Bantu (19761 reported that the polymer m the slurry still contains ap proximately 500 ppm of vinyi ehlonde. The slurry from the dump tank is pumped into a norap tank (bland tank) which is large enough to hold seven! batches of the product. The contents of the blend tank are then pumped into a centrifuge which separates the wet solids from the water. The wet polymer, a granular mass, is dried cither in rotating tubular dryers or by spraydrying methods, the liner being used mainly for products formed by emulsion poly merization. yielding a polymer which is similar to a very fine white flour. These very flne solid parades are fed directly into a spray-drying column without dewatering. The drying temperature should not exceed 60*C to prevent thermal decomposition of the polymer. A cydon separator at the exit end of the dryers removes coarser panicles. The solid polymer panicles are then sized by multiple-iiyeT screens, air-conveyed to storage bins or silos and finally packaged for shipment (Albright I967d). The resultant dried powder contains about SO ppm of monomer (Bamn 1976). c i : >i i 222 Methods of Polymerization Four different methods of polymerization are used for the commercial production of PVC (Frey 1973), the firs: two now being the most widely used: Suspension Polymcnzsnon. Polymerization is carried out in an aqueous system in which monomer droplets art maintained in suspension by means of protective colloids (such as polyvinyl alcohol, gelatin, substituted celluloses) under heat and pressure in conduction with brisk agitation. Rclativdy large polymer particles can be obtained by this method which `dry blend* well. Emulsion Polymerization is the oldest technique, to which suspension polymerization was added in the 1950s. The process is similar to that in suspension poiymerizauon, except that large amounts of emulsifying agents (such as soaps or other surfactants) ire added. Emulsion polymerization yields resins of a very small particle size. The emulsifier* cannot be completely removed. Bulk (Mass) Polymerization. In this pieces VCM it polymerized in two stages without Ihe additon of other liquids. The two reactors are operated batch-wise and in serin. The first reactor (a `propolymerizeO provides for the initial liquid phase, while the scond one b usd for agitating the slurry, whieh is transformed, through a sticky solid sate, to essentially dry parudes until the conversion from monomer to polymer roaches a level ofabout 7si-SOZ. The rosins obtained by bulk polymerization are characterized by high purity and panicle unifoimity, resulting in an end-product of pood optical clarity. * S W.K. Lclhach and H.J. Marttcllcr Stratum Polymerization. This type of precipitation polymerization is carried out in oiianic solvents such as n-butane or cyclohexane. It accounts for only a small percent- ape of the total amount of all PVC resins produced and it is used for the production of copolymen. Copolymen are mixtures of cumonomen (such as vinyl acetate, vinyl- stearate, vmyiidcne chloride, propylene, acrylonitrile etc.I and vinyl chloride. Hie co- tnononwn tend to improve flexibility and limited solubility of the product in solvents and exert an influence on the temperatures required for compounding. ___ _ 223 Compounding As a next step, depending on the end use, the dried polymer, a whitish powdery or granular product, is then compounded (or dty blended) under pressure at fusion tem perature with the aid of plasticizers (mainly phthalatc or other organic esters) and light and heat stabilizers (heavy metal salts, organotin compounds, and other stabilizers). Lubricants or dyes ean be added. Plasticizers are added for the production of flexible PVC: rigid PVC contains little or no plasticizer. These additives ean 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 (SmolPic 1966; Tola 1975). Compounding is carried out by hot mixing at fusion tem peratures below or within the softening range (i;0C-160*C). Diversified compound ing and processing technologies were developed about 1950. Tire compounded polymers are used for the production of divetse end-products. The final conversion of tire 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 convetsion 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 Ana! fabricated articles contained approximately 5 ppm VCM and those for foodstuff packaging (bottles, fljms. foils) even Jess. 221 Sources of Exposure to VCM in PVC Production Both polymerization of VCM and subsequent processing (centrifuging, drying, screen ing, bagging) are usually earned out in dosed buiidinp. Exceptions can be found in hot climates (Aryanpur 1977). Polymerization is of necessity a batch process that re quires a large number of single operations. Therefore, valves, gaskets, shaftopenings and control gear are subject to heavy wear and thus to leakage. Other sources of pollu tion of the working atmosphere are exchange of parts and repair jobs. Hie degree of pollution also depends to a large extent on the quality and effcctivity of monitoring equipment and special exhaust systems. Opening of autoclave vats for cleaning and control purposes resulted in larger spillover of the tank atmosphere into the work en vironment. Numerous reports of workers with prenarcotic symptoms (dizziness etc.) Vinyl < i permit t! in the p: Ther date va: wails (`p ton. ItaJ degassed and largi were opc cd the fr. non still manly, t! those wi (ctntnfu ties of ventilatii shipmer.' nomer. v ait dnvr Table I ppi- I mg (Pat; I mr'III; I mp.m' I pptn IT- 223 T In the 7.' nanl mo coven (Ltfavx lect as a opened became I UCC 069296 sKnlicr out m ) percent- *etion of vinyl- The jo. solvents ry or ton tern and light 'iicn). - flexible *ourct of MS on its sphere -m ternmpound- -tiucts. nets is nr. ..ion Mimtr -mewed airied .. sereenjnd in that terenmp of polluaeeof noting gand work enetc.) Vuijl Chloridc-4-w.VMted Diwm 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 deaned the auto clave vatt by scraping away or chipping off the *poly met skin' funned on the reactor walls ('pol> cleaners'), and who in the past had to spend several hours inside the reac tors. had been exposed to the highes: concern) ationi of VCM. Although the vats were degassed pr.or to entry', unreacted monomer remained trapped in the polymer skin, and larger amounts of VCM were released when cavities formed in the polymer crust were opened by chipping. The later introduction of automatic cleaning systems reduc ed the frequency of entry into the reacton, bur tome manual deaning of shoner dura tion mil had to be done after every 20th-30th run. (t is, therefore, plausible that, pri marily. the most severe advene effects of exposure to VCM were fully recognized in those workers who had been employed in this job category. But the subsequent steps (centrifuging, drying, screening) also involve the release of some of the letter quanti ties of unreacted residual monomer from the parades to pollute the environment if ventilation. notably of the drying facilities, is inadequate. Finished polymer, ready for shipment or subsequent compounding, still contains small quantities of unreacted mo nomer. which either slowly diffuse out and pollute the bailing areas during storage or are driven out by the high temperatures necessary for compounding. Table 3. Conversion table for concentration of VCM in ambient air f Mol. wt 1 ppm " 1 000 a 34.4J m*/Ut"e *1 24 US x I 000 J me''per litre " Mui.. wr. -- ppm tFeny lOJg) I mf/litre 1 mg:m* I ppm 2Jh ms/rn' I'.' "10 000 ppm 391 ppm 0.391 ppm 0.00256 mr/litre 25.6 mg/litre 22J The Explotion Hazard In the past only the explosion and fire hazard of VCM was thought to be the domi nant monitoring problem in handling gaseous vinyl chloride (/rah 1963). This hezard coven a concentration range of 4S*-22S by volume of air (40 000-220 000 ppm) (Ltfaux 1966). It was observed that VCM, being 2.15 times heavier than air. may col lect as s compact layer at the floor of a polymerization budding after sp&tavet from opened tanks and may catch fire. At lean two instances of disastrous VCM explosions became known: In 1964, a large plant for the polymerization of VCM in the United 10 W.K. Lelbacti and H J. Manteller States was almost eotnpittely destroyed when VCM escaping from a leak detonated {Albright 196*a). Another explosion in one of the two Rumanian factories operating at that time was mentioned by <Surii< et al. (1975). Monitoring of VCM concentrations polluting the work environment was then directed largely towards preventing VCM from reaching the flammability limit. 2.2.6 The Odour Threshold Unfortunately, gaseous VCM has no irritating or unpleasant warning properties. Its mild odour is described as faintly pleasant, sweet or ethereal. Some of the PVC workers we interviewed reported that they had even enjoyed `sniffing the gas', which soon resulted in a feeling of light-headedncis. For the early days of PVC production, when appropriately sensitive monitoring equipment was not yet available, workers' re* - ports about perception of the odour of VCM can be taken as circumstantial evidence for a rough estimate of the actual degree of exposure. It should be kept in mind, how* ever, that in chemical production units the presence of other odoriferous chemicals and the possibility of olfactory fatigue, as well as different levels of individual sensitiv ity, may render it very difficult to determine the factual odour threshold of a certain gaseous substance unless it possesses irritating warning properties. In 1929. Schmidt and Schaumann declared that the faintly tweet gas is practically odourless at concentrations of 5%--10% by volume. Veltman and Lange (1977a, b) assumed an odour threshold of 5 000-10 000 ppm. Volunteers exposed to VCM detected a slight odour at * 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 (fnsh 1963). Cthring ct al. (1979) recently mentioned a threshold of approximately 3500 ppm. Others have claimed that a concenuauon of -*00-500 ppm is the lower limit for detection of VCM by its odour (Banna et al. 1969; Cook et al. 1971 `.Alarko* wit; et al. I972;e/i?w 1975, cited by Hubtet 1975). Banna 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 chimed that they were able to detect the odour, but this was inconstant. Table 3 shows that differences between the various estimates are at least one order of magnitude. The close proximity between the perception of the odour of VCM and incipient CMS symptoms as reported by Inth (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 is 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 216 ppm (Deete and Joyner 1969). 22.7 VCM as an Anaesthetic Agent VCM was once even considered for use as an anaesthetic agent. In 1929. Schmidt and Schaumann speculated about using VCM as a supplementary narcotic at concentra tions of 3%-5% (v/v) ( 30 000-50 000 ppm) in combined nitrogen oxide oxygen Vinyl Chlori Table 3.0d>- Lowerlunii, 5 1)00-10 On 5 0(.' 4 1C 3 51 50- 400-5 0> 4040t anaesthesia be tic and lethal. oxygen; conce however, that eluded. In to10% VCM to ; several hours t commented u; mined about i 33-5 mmol ( mmol (244 0C Otter et al., in cardiotoxicit> man because c like other hale amines (frith ; the past for at: 226 Effects Some individu listed in Table without acute sympt rnssuci adequate warn exposure to hif A 21-yesr-old. 10 mm after et which had bee cardiac enlarge have been acut which oecurre, doubt that hea found dead wii teller detonated operating mcentrations -tingVOl arties. lu PVC ps\ which reduction, .workers' re al evidence aind. how. chemicals Jual wtuitiv>T a certain - practically 1377a. b i - to VCM ippm fot I drepinns -.imately ^^fljrkoi conducted hamber.in tidt they differences : proximity i at reportfJ an be as* ttnet warn:eye and hmdt and centn* oeygtn Vinyl Chlonde-Avtoaartd Disease Table 3. Odour threshold Lower limit of detection 5 000-10 000 ppm 5 000 ppm 4 100 ppm 3 500 ppm 500 ppm 400-500 ppm 400 ppm 400 ppm Author Veltmen and Lent* 1977a. b Violet 9 U frith 1963 Cehnnjtt al 1970 Bertttst'.ti 1949 Lefivrt 197J (cited b\ Hubiet Cook ct al. 1971 Nerkowin et el. 19*; I! anaesthesia because of its potent narcotic action and the wide margin between narco* tic and lethal concentrations. In animals it produced anaesthesia at 7ft-l0ft in air ot oxygen: concentrations above 12ft proved to be dangerous. The authors pointad out. however, that advene late effects of this halogenated hydrocarbon could not be ex cluded. In toxicity studies with guinea pip Party et ah (1930) found concentratons of 10ft VCM to be lethal within 30-60 min. 3% to eauae marked narcosis, and 0.5ft for several hours to be the maximum tolerable exposure without serious effects. They also commented upon the potential use of VCM for surgical anaesthesia but were undeter mined about its practicability. In mice, the minimal anaesthetic ring* was found to be 3.3-5 mmol (85 000--122 000 ppm) for 10 min, the minimal lethal range 10-12 mmol (244 000-293 000 ppm) (People and Leake 1933). It was not until 1947 that Otter et iL. In contrast to Scfmtmenn't earlier assumption (1934) of a relatively low cardiotoxicity, warned against the use of VCM as a potential general anaesthene in man because of serious cardiac irregularities and CG changes observed in dogs. VCM, like other halogenated hydrocarbons, serintires the heart to the effect of catechol amines (frith 1963). W could not ascertain whether VCM has actually been used in die past for anaesthesia in man. 2.2.8 Effects ofAcuta Overexposure in Man Some individual responses of volunteers to increasing concentrations ofVCM arc listed in Table 4. Lem et al. eonduded in 1963 that the maximum concentration without acute effects in man lies between 8 000 and 12 000 ppm for 5 mm. and that symptoms such as diasias.light-headedness and disorientation should be taken as adequate warning sips for imminent acute danger. Two fatalities after occupational exposure to high concentrations ofVCM are reported in the literature (Dotutfer i960). A 21-year-old autodave deancr at a Canadian polymerization plant was found dead 10 min after entry at the bottom of a probably insufllciendy ventilated reactor tank which had been declared safe solely after an explosiometer test. Heart failure cells end cardiac enlargement found at autopsy, however, implied that the cause of death might have been acute functional disturbance in pre-existing heart disease. In the second case which occurred at the same plant, howrver, circumstantial evidence apparently left no doubt that heavy VCM exposure was the cause of death in a J9^cir-oid worker. He was found dead within 20 raia.Iymg in a pit near the opened valve of a recycling pipeline 1 VK. Laibach and HJ. Marstellcr Table 4. Individual response* of volunteers to increasing concentration*. of VCM Cmcentration Duration of Symptoms cvputure Reference 500 ppm 7.5 h (Inconstant odour detection* Burette et al. mild headache, dryness of t I9b9) eyes and throat in 2 of 7 subjects) x.4 000 ppm - Generally accepted odour threshold Iran < 19b5 6 600 ppm 30 min (Distinct odour) dizziness, sleepiness Irah (1963) 8 000 ppm \ 12 000 ppm 1 5 min3 (twice on lb 000 ppm 1 each of 3 succes sive days) 20 000 ppm / 2 of 6 subjects `Slightly heady' 1 of 6 subjects had reeling, swimming head, just like getting gas* 5 of 6 subjects, various degrees of intoxication All 6 subjects had more intense symptoms of acute intoxication than at 16 000 ppm tester et al. (1965) 25 000 ppm 3 min 2 experimenters: dizziness, disonentation. burning sensation in the soles of the feet Petri- et al. (1963) a Exposure to six different concentrations: 0 ppm:4 000 ppm:8 000 ppm: 12 000 ppm: lb 000 ppm: 20 000 ppm through which non-polymerized residual VCM was pumped back into a reserve tank: another man coming to his rescue was himself overcome by the gas and only just escaped. Two nonfatal eases of VCM gassing were reported in Great Britain in 1951 (Spirtas et al. 1975). A maintenance worker experienced acute narcosis wbde repairing a VCM leak, and a worker cleaning a polymerization vat from outside with a water jet sudden ly collapsed across the open manhole. Subsequently he complained about tightness of the chest, nausea, abdominal pain and headache. Occasional loss of consciousness was also reported by Litis et al. (1975) in 14 of 354 workers at Niagara Falls and by Suciu t al. (1963) at a Rumanian plant. VCM-tnduced narcosis, at least on one occasion in the past, had occurred in 46 of 51 workers (793) referred for medical surveillance from one British PVC-ptoducing plant (Went et al. 1976), with a 1003 incidence of narcosis in 28 symptomatic workers (Raynaud's syndrome and/or actoosteolysis). Successful resuscitation after VCManduced narcosis of several hours' duration with out evidenct of permanent damage was mentioned by Rety et al. (1974). Vinyl Ciller- ---.9 Moni> During the |1 *d data on V1 ^*5 directed 3,1 aPparentl* 1 m.Hethc Cronsbej to Russian poly: 0.05-0.08 m centration of Inspectorate. or from the d mg/htre ( 1, mg/litre ( 3- In the cen air ranged fro ppm, which v ventilation. T trationj, sorm pursuit of im[ ment in the vi ic drying facil centrauons oi continued to l nutted concer In a plant the range of 0 ppm (2.93 mg ieation appara remarkable th the liver, althi past have prot Byrin et ai which occunc cated peak ex; between 1962 Rumanian PV< about 120 mg., exposures to \ 300 Rumanian Greek plant wl resulted in higl (Cirsios 1971) of the reactors up to 10 000 p it. UanttUtT i VCM ctencc <:te et siw9) */Ml963) t*.(l63) I { I t nr ct al. **oi ;rv <1 al. 3> 1"ID tm tank: nly just . 1951 {Sptr-Jf airing a VCM er jtt suddent tightness or h<ihmui> and by Suctu occasion in ncillance nctdcnct of luwlysis). taboe with- Vinyl Chionde-Associated Disc3m; 13 2.2.9 Monitoring VCM Concentrations in Working Anas Ouring the lint two decades of PVC production (1930-19501 no publication contain ed data on VCM concentrations in the wnrking environment. Hie mam interest then was directed towards prevention of the explosion hazard. In 195". the observation of an apparently toxic angioneurosis in Russian PVC production worket? (Stnmi/r. 3 \m^\P!nhehiner ct al,, cited in Filatova and Gmmben 195") induced F'.latrj and Gr-jnsbeij to investigate environmental VCM concentrations m various r*ans of a Russian polymerisation plant in Gorxij. Although most readings were in the range of 0.05-03)8 mg/liue ( 20-313 ppm), c4. below the maximum permitted VCM con centration of 1 mg/litre (approximately 400 ppm) as specified by the State Sanitary Inspectorate at that time, escapes of VCM in the reactor areas from detective fittings or from the discharge of operating autodavts resulted in excursions up to 29.5-^1 .4 mg/litre (* 11 500-16 200 ppm) for penods of 5--10 min. One peak reading of J mg'Utte < 34 000 ppm) was recorded. In the cenmfuging and drying area 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 release of residual VCM from wti PVC resin and poor ventilation. The screening and bagging area was cltanctcrixed by high dust concen trations. sometimes exceeding the official upper limits set for non-toxic dusts. In the pursuit of improving industrial hypene, the installation of modem ventilation equip ment in the vicinity of the autodives, substitution of handoperated by semi-automat ic drying fadliues. and avoidance of leakages succeeded in reducing the ambient con centrations of VCM to below 0.05 mg/litre ( 20 ppm), but toxic angioneurosis still continued to be diagnosed. This led the authon to recommend tliat the maximum per mitted concentration of VCM should be reconsidered. In a plant producing VCM, Filatova tt al. (I95S) found lower concentrations in the range of 0.04--1.1 mg/liue (16-430 ppm), with maximum values of about 1200 ppm <2/93 mg/litre), the latter harir.j Seen observed in dose proximity to the rectif ication apparatuses and having result-u from spillage during sample coiltenon. It is remarkable that up to now the Soviet Union has reported no cases of tngiosarcoma of the liver, although production of PVC nuns started early and VC-1 exposures in the past have probably been in the same range as those observed in Western countries. Bytin ct al. (1976) pointed out that during the 1950s episodes of unconsciousness which occurred among workers of the on* Swedish plant operating at that time indi cated peak exposures of at least 10 000-15 000 ppm. Surer et al. (1975) noted that between 1962 and 1972 a reduction of the avenge VCM concentration in the two Rumanian PVC plants had been achieved from 2298 mg/m* (* 900 ppm) in 1962 to about 120 irii'm1 ( 50 ppm) in 1965-1972. In 1969,4njfirilncu tt al. mentioned exposures to VCM concentrations of 112-545 mg/m' (44--213 ppm) for a group of 300 Rumanian workers, eight of whom (2.7%) had Raynaud's phenomenon. At a Creek plant which started operation in 1967. certain stages in the production process resulted in high concentrations of VCM in the work environment (or brief periods (Gitiioj 1971). In air displaced from reactors during addition of water and on opening of the reactors to obtain PVC samples at the end of a reaction cydt, concentrations of up to 10 000 ppm were found. In open wastedrums into which waste polymer scraped s 14 V.K. Lelbach and H.J. Mamelier may from reactor walk during cleaning was placed, concentrations of up to 600 ppm were measured. In the report of a World Health Organization (WHO) working group on vinyl chlor ide (1ARC 1974) it was stated that in a reactor of 15 m* (production of 4-5 tons of PVC per cycle) a crust of 4 kg PVC containing 3%-Sfe VCM can he formed on the inner surface. During the cleaning procedure 305-50H of this VCM content is liber ated. It was calculated that the probable concentration of VCM nothin the reactor after a 1-h cleaning operation was about 2700 ppm, but that it could le reduced to 90 ppm by 30 renewals of air per hour. In the past a polycleaner used to spend 4-5 h,' day inside the teactor but later the introduction of (not fully sufficient) automated cleaning reduced manual cleaning procedures to shorter periods of 10-15 min following every 20th-30th teactor cycle. A Belgian company, where monitoring in the work ing aiea was started in 1967, claimed that measurements at various sites inside a 9000litre autoclave during the manual cleaning operations had shown VCM concentrations varying between 50 and approximately 540 ppm, with a mean of 413 ppm (Hublet et al. 1977). According to data provided by Cook et al. (1971). VCM concentrations within the teacton prior to ventilation were in the otder of 3000 ppm. The rcaetor cleaners usually did not enter the tutodaves until an aeration period of 15-20 min had reduced the VCM concentration to what was considered s*osfactory limits. In the early days, this was tested either by Inifring at the manhole opening* (the lower limit of detection of VCM by its odour having then been accepted as 400 ppm) or by use of a flammable vapour indicator which required a minimum of 400 ppm for positive read ings. equalling 4% of the lower explosive limit of VCM. Later mote sensitive methods such as gas chromatography were said to have shown that VCM concentrations inside the reacton 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 avenge (TWA) concentrations tanged from 10 to 385 ppm during this period (1950-1959), excursions up to 4000 ppm occurred, agreeing with employees' reports of experiencing dizziness while loading or unloading reactors (Ort 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 advetsc effects in animals exposed to 100-500 ppm VCM had become available (Torktl ton ct al. 1961), the Dow Chemical Company introduced a new 50 ppm guideline for the work environment. Excursions and peaks up to 500 ppm did continue. Measure ments of TWA exposures for various specified job categories in two production units of this plant between 1950 and 1966 were presented by On et al. (1975). In 1966 BASF (West Germany) introduced continuous monitoring by infrared absorption spectrophotometry for VCM concentrations well below 500 ppm;in 1974 more sensi tive equipment was installed and concentrations were kept below 25 ppm and later below 10 ppm, with occauonal ceiling values of 70 ppm (Fleif end Thieu 1974). In severe] surreys individual jobs were grouped into three exposure categones ac cording to job classification to evaluate past exposure experiences (Spores et al. 1975; iiWarms et al. 1976;BAmrisi et al. 1978). These exposure indices were: (a) light less Vinyl than : ppm), plants samph t Estim.. more < arerag. Table : atmosp Chemi. 19451955 1960mid-I9 19 19 * Acc> Equ tions in equipm viduaJ e biniiioi (3) The ly spec;; rnent sh peak coi for the. Cun cempnstion dett (Tonoik which cc conditio lag of re: A ca: industry in 19751 .2 2.10 1 Raw PVC unrcaetei MirtietltT -OOppn nyi ehlor* - ons of n the < liber ator ad to Tid 4--5 hi mated *n follow* the work* c a 9000nmuons Uubki et toons reactor 20 min :ts. In the *er Until pv uu of itive readiethodi s 1950 by aiC* ha period *' Itpotu I. In a U occur* tunj ad* : (Tortet!eline for 'taaire**i aniu ms 4ion wemnsi* I later "4). mease* aL 1975; in "Ian Vinyl Chloride-Associated Disease 15 than 50 ppm: (b) medium 50-200 ppmttc) high * 200 ppm and above (up to 1500 ppm;. In the past, however, estimates of exposure concentrations were based in most piano not on continuous monitoring during the entire work shift but at best on sput samples nor necessarily representative of the different phases of a given operation. Estimates of past exposure levels such as those represented in Table S arc, therefore, more or less conjectural. It can be assumed that considerable deviations from these average values have occurred all too often in the past. Table J. Average concentrations of VCM in the working atmosphere of PVC-producini plana*-1 Estimated by Chemical Indusrncs Auomauon Ltd.) 194J-I955 1955-1940 19t>0-1970 miC-1973 1974 197J % 1000 ppm 1400-500 ppm 1300-400 ppra H50 ppm ' i 50 ppm and less v 5 ppm * According to Flttf and Thuu 1974;tames 1976 Equipment for optimal continuous multipoint monitoring of exposure concentra tion! in the working areas should meet certain basic requirements: (1) For stationary equipment strategically placed sample probes should yield data representative of indi vidual exposure levels in the breathing tone of workers, preferably to be used in com* bination with persona! samplers. f2) Analysing methods should have a high selectivity. (3) The limit of detection should be at least one order of magnitude below the current* !y specified standard regulating the permissible upper level of exposure. (4) Measure* mem should be instantaneous (within seconds) to guarantee rapid detection ofcritical peak concentrations. (5) Recording and data processing technique should he 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 ioniia* lion detection, pi chromatography, man spectrometry, combusuon-conductivity Cionoflux-), and personal samplers in combination with gas chromatography, none of which can at present be considered as absolutely satisfactory for all individual plant conditions because they all differ with rtprd to selectivity, limit of detection and time tag of response. A catalogue of the methodologies that have proved to be of value in the control of industrial hygiene and personnel protection regarding exposure to VCM was compiled in 1975 by Rowe 2.2.10 Expoeute to VCM in PVC*Frocaoin| (-Fabricating) Flano Raw FVC powder ready for compounding and fabricating purposes contains nridual unreacted vinyl chloride monomer in varying amounts* In the past, monomer content Ift W.K. Lelt-avh and (I J Marstelltr was reported to have been as high as 6000-7000 ppm (w/w) in some types 01' raw PV'C. but a level of 500-1000 ppm probably was a more representative range (Sitmaaer 1975: VKE 1974:A>nreJr 1976). The monomer slowly escapes into the environment exponentially with time, depending on length of storage period, tempera* tore, sue and porosity of panicles and other physical properties of the polymer and. more recently, on the eiTectivity of special degassing techniques (Pner 1976:Sclmtz and h'oil' 1977). In 1975, the Association of the German Plastics Industry announced that m future only PVC powder with a maximum monomer content of 10 ppm would be put on the market due to the development of special degassing tcchnolopei (VKE 1975) . Analysts of the types of raw PVC, chiefly suspension polymer, which are now used in German plants showed that in most products the content of unreacted mono mer was now less than 20 ppm but in some foreign products it still ranged between 150 and 250 ppm: it also turned out that there may be considerable variation between different batches of the same product tSelnirs and Wolf 1977). Cold and particularly hot mixing or compounding of PVC. a procedure which usu ally precedes fabricating processes, favours the escape of unreacted monomer and. therefore, requires special ventilation equipment. Depending on the content of residual monomer, considerable amounts ofVCM could be set free during the mixing process, as was shown by Snider and Straby 0975). Apart from hot compounding, other ther moplastic operations, such as 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 m 90ft of the readinp mean levels integrated over 1 -h periods now range below 0.1 ppm, numerous short bums with excursions up to 60 ppm during a workshift were recorded in one instance (Schiirz and Wolf 1977). Similarly low concentrations of VCM in breathing zone samples (maximum: 12 ppm) with 60Tr of the values ranging below l ppm had been found in 1974 in nine United States fabricating plants, but source samples had ranged up to 340- 540 ppm (KanrsJt 1976) . These present results, however, do not permit any conclusions ei to past leyels of atmospheric VCM during the years when residual monomer content of PVC resms was high and ventilation insufficient, particularly in compounding and extruding units. Whatever the extent of the nsk might have been in the past, it can be safely assumed that the ambient monomer concentrations in fabricating plants have always been con siderably lower than in PVC*preducing plana. When it was suspected that certain VCM-telated svmptoms might also have afflict ed PVC process workers, this problem was investipted by our group. Although no cases ofaeroosteolysis, pscudosclerodcrma or angiosarcoma of the liver were observed, evidence was presented which demonstrated that minor and inconspicuous lesions such as mild hepatic fibrosis, btomsulphaicin (BSP) retention, thrombocytopenia and slight enlargement of the spleen could be found in 28 process workers who had been em ployed for years in compounding and fabricating units ge tt ai. 1975,1976a: We$mm l975;AfewWferet 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 enutie them to disability compensation under German taw. Although the in* Vinyl' eonspi tpons quanti obterv t progre male F find ar Ar two C. died relation i Tiealth overall record 2.2.11 Industr. of expc tion' o* Indust: zentrati Amem. exceed;lions si basic ar cupati'.(1974, used in are sun: discrep red to t The not a s* should l tently availabf new inf list of M various i Hxiilei tool for ytisoft! In tl: ppm in ) !|J Marsttilvr es of raw range ipes into the wni. tempera* kmer and. W.Sdiut: *v announced ;0 ppm would Uopti (VKE hicharenow -acted mono* i between men between e which mumet and. ;cnt of residual xing process. ;g. other the:- also resulted -ecently contv German integrated -.cunions up rot terete of V f resins was tag units. .Hy asumcd i\been con- i hac afllict* hough no a rre observed, -m lesions such -nia and slight Iboenem5. 1976a: .nticai with mage attnbut* rwmdered sufHough the in- Vinyl ChlontiwAnocialuii Uiwv-c 17 conspicuous character of these lesions agrees well with the assumption of a dose-re sponse telaiionihip of VCMeeiated disorders and the alterations may seem to be. quantitatively, of little importance, they should not be minimized. Nevertheless, an observauon period up to the present of almost 7 years did not reveal any spontaneous profession. In a proportional mortality study for 1970-19TI among roughly 35 000 male PVC fabrication workers in England and Wales. Baxter and Fox (1976) did not find an excess of angiosarcoma or other liver diseases. A recently completed cohort study of 4007 people who had been employed by two German PVC-fabncar.r.g 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 uf Germany, was slightly elevated with respect to the "healthy worker effect'. No angiosarcomas of the liver were observed and no excess in overall cancer mortality was noted, but an excess mortality from brain tumours was recorded in one of the two plants (i?*irif et aL 1978). 2-.11 National Standards for the Control of Exposure Industrial hygienists have used several designations for acceptable or permissible limits of exposure to chemicals at the work place, such as `maximum allowable concentra tion' or maximum acceptable concentration' (MAC), threshold limit value' fTLV). 'industrial hygiene standard* in the United States and as `Maximal* ArbtiuplatUconsensation' (MAX) in West Germany. These empirical standards were defined by the American Standards Association as setting a limiting concentration "for exposures not exceeding 8 hours daily during a 40-hour work week with the understanding that vatulions should fluctuate below this value" Urnh 1065). An extensive discussion of the baste approach to the principles used in setting environmental quality standards for oc cupational respiratriy axpowrc to toxic agents can be found in the paper of ZieUiuu (1974). In tho pap-, die conceptual differences between threshold limit values as med in the United States and maximum allowable concentrations as used in the USSR arc summarized and the differences in approach and emphasis, which may explain past discrepancies between penainible limits, are elucidated. For details the leader is referrad to this paper. The standard is nor an index of relative toxicity, far lea of hazard, and cenamly not a son of `average'. A standard mi a the ceiling level implies that any fluctuations mould be around a median of perhaps half the standard and that it should be compe tently used in fun awarenca of its phyaolugical bass and the limitations of currently available knowledge Urith 1963). The standard will be subject to imuon as toon a new information is available. An essential element of the annually published German tot of MAX values (MAX-Werte) is its preamble, which exhaustively defines (he various modalities for the interpretation of such standards {Ntmchler 197^73). The so-called TWA, an integration over time of fluctuating cenctntrsdoas. will be a uaeful tool for estimating tbe probability of injury only if it represents a comprehensive anal ysis of the normal fluctuation Mew the standard. In the Federal Republic of Germany the standard for VCM (MAX) was set at 500 ppm in 1966- The German Standards Advisory Committee reduced this to 100 ppm 18 W.K. Lelbach and HJ. Marstcller in 1970 In confoimity with the proposal of Torite/soa et at. (1961). which was based * on th> 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 Riehtkonzemrauon) of 50 ppm was instituted (VKE 1975). The Chemical Industries' Liability Insurance Association (Berufsgenosienschaft der Chemischen Industrie) also issued instructions for the prevention of health hazards arising from handling of VCM in July 1974. As of July 1975, a technical guideline (TRK Technische Richtkonzemration) of 5 ppm. defined as annual mean, for PVC-producing and -fabricating plants was instituted, per mitting excursions up to 15 ppm during periods of not more than 1 h. In order to adapt operating plants, a provisional regulation was issued with reduction of the an nual mean concentration to 20 ppm as of July 1975, and to 10 ppm as of July 1976 and peak concentrations over 1-h periods not exceeding 60 or 30 ppm, respectively (Veltman and Lange 1977a). The technical guideline (TRK value) was revised in 1977 (2 ppm annual mean/5 ppm per 1 h). in the United States the threshold limit value for VCM was originally set at 500 ppm in 1947. It was reduced to 50 ppm in April 1974 u a temporary emergency stan dard and finally reduced to 1 ppm/8 h in 1976. Haley (1975) summarized the conflict ing views on vinyl chionde regulations proposed by Government and industry in 1974. Table 6 shows threshold limit values in a number of PVC-producing countnes. 2-.12 Exposure to VCM Outside the Working Area The Environmental Protection Agency estimated that PVC-producing plants in the United States discharged about 90 million kg VCM annually into the environment (4%-8 losses), most of it as air emissions and lesser quantities dissolved in water effluent streams and entrapped in sludge and solid wastes (Schweitzer 1975). In a pioneer study, concentrations of 1-2 ppm VCM were found in the ambient air near such a plant (IARC 1974), 2-3 ppm in the primary water effluent and 100-200 ppm in the sludge at the plant site, but sampling and analysis methods used were later found to have been inadequate to no conclusions were drawn from these figures since they could have been in error by as much as one order of magnitude (Sclmtirzer 1975). For people who live within 5 miles of monomer and polymer production facil ities in the United States an average exposure of 17 ppb during the yean of uncontrol led emissions was calculated {Hieholson 1977). In the past VCM has been widely used as an aerosol propellant, either alone or mix ed with fluorocarbons, hydrocarbons and inert organic gases, in household and cosmet ic products (hair sprays, deodorants, pesticides, room disinfectants, paint sprays, furniture polish and window cleaners). In Germany, VCM was proposed as propellant for aerosols in 1958 (Ouermaycr 1967), in Japan it has been used as a propellant since 1958, in the United States this use was probably introduced after 1962 {Schweitzer 1*175), As an aerosol propellant, VCM has been a possible source of exposure fot the public at large, particularly fot women, the extent and tlie 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 bums (30 s) (Gay n at. 1975), which could persist for several Vinyl Chi. Table 6. T Country Belgium Canada Finland France German D> Republic. Iran Italy Japan Netheriand Rumania Sweden Switzertjn United Kir USA USSR Federal Re, Germany Sources: S'73; IARC R .~bd HJ. Marsreller v which was fcwd : aronopnic prop* His chemical was rerichtkomemmioni ability Insurance tiwcd instructions 1 in July 19*4. As enaction i of f .. -mu instituted, per; 1 h. In order to juction of the anm at of July 1976 ppm.itspecwly was tensed in 1977 ngintily set at 500 raiy emergency sunnariard the conflictutd industry in 19*-. ij countries. m{ plants in the envtronmen t '^Hvrd m water n:*r 19751 In a He ambwnt air near ... and 100-200 ppm . used were later mu these C|ures since ude (Schwtttzcr mer production facil* s* years of uncontrol- i*. cither alone or mixwuathoid and cosmetus. paint sprays, opined as propellant J as a Mopellant since t |V62 (Sehu-rtizrr of eipoeurt for the ratal health impliesJ spaces has been re. in dosed rooms. U persot for several I Viny i Clionde-A>ociaied Disease 19 Table 6. Threshold limit values iTLV) m various countries Country Year Beifium Canada Finland Franc.* German Democratic Republic (DDR) Iran Italy Japan Nethctlanda Rumania !9*5 1975 I97J 1975 1976 1976 1975 (future) 1970 1974 1975 1975 - Sweden Swuaerland United Kinfdom USA USSR * 1975 1976 1975 (future) 1975 October 1975 1947 April 1974 October 1974 1976 TLV ppmi z* *0 10/:; 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/SO 10/30 500 so 25 1/S 1 mg/litre (391 ppm) 30 mg/m* (R 12 ppm) Comment TWa (5 h/U mini TWA (8 h/15 min) TWa '5 It/15 mini TWAiSh) MAC (Sehorttk 1969) (Komttskt et al. I9"S) TWA ( h/1 h) TWaiI h) (TWA A h/15 min) MAC MAC (25 m|/m*) TWA (S h) MAC IfrodM at ai. 1975) TWa (1 h/15 mm) TWA (8 IiM5 min) mac TWa (8 hi TWa (S h/15 min) TWA (pcrsonat/ceiling) MAC (Amer. Conf. Covemm. Industr. Hypcmsts) TWa (8 hi. temporary emergency standard I OSHA) TWa (8 hk. tcmporanly permittad exposure TWa (8 h. 15 min) MAC. provisional ceiling concen tration; State Sanitary Inspec torate. 1957 {Fdatort and Grontbrrj 1957) HAC ISchontk 1969; rrnrr 1975) (Ssmtarnye normy) Federal Republic of Germany l*ft 1*70 June 1974 1975 1977 500 too SO 5/13 2/5 MAK Mak TRK (preliminary technical guideline). Annulment of MAK refutation. TRK (annual mean/I h) TRK (annual mean/1 h> Sources: Smyth 19$6: Ftitrort and G'Obiktrf 1957;StAoneb 1969-.Httuehltr 1971/ 73.1ARC Report 1974;Me/ry I975;Sefce* l975;/Vodcn et al. \9T5:Arytnytir 1977;TcAerr and Wo//l9T7:MAK-Werte-LiSt l77;JC*rwier I97J r c 20 U' K. Lclbach and H.J. MarMcIlti hours alter repealed spraying in smaller-sized room* (lARC I974).//a/n- (1975) pre sented a list of pesticide product* containing VCM a* a propellant and registered for indoor use. whicli were banned in 1974 by the Food and Drug Administration. In Japan, the monomer was also banned as a propellant in l74 (JAMA 1974.229:8551. There is a case on record of a worker who died from noncirrhotic portal hypertension and angiosarcoma of the liver after 14 years' employment at a chemical plant in south ern Germany where he had been engaged in loading such pesticide cans (Rem/ and It'chcr 1974). The report of a female office worker suffering from typical Raynaud's phenomenon, pseudoscleroderma. acroosteolysis and mandibular osteolysis who never had occupational contact with VCM (Meymon and Meier 1972) is apt to make one wonder what influence the frequent indoor use of VCM-propelled spray cans (Bridbcrd ct al. 1975) may have had in this unique case. Sputum samples collected from frequent users of pressurized spray cans who had no respiratory symptoms were found to con tain a significant excess of moderate and marked atypical metaplastic bronchial calls compared with two groups of controls (Good et al. 1975). PVC bottles, films and foils have been used for many yean for packaging food and beverages (cooking oil. margarine, meat, mineral water, fruit squashes and other soft diinks, hard liquor etc.). The content of residual VCM in PVC bottles wax found to have ranged formerly between 5 and 400 ppm (w/w), and in PVC foils up to 800 ppm (ran Etch and ran Logttn 1975). The problem of migration of unrtacted VCM from the PVC containers into the foodstuff became recognized in 1973. Reports of un pleasant tastes in American brands of vodka and whisky which had been stored in PVC bottles led to the discovery that VCM had leaked into the liquors; in some samples levels up to 10-20 ppm (w/w) were found (vanEtch and van Logten 1975: Amirs and Perry 1975). Data available in 1974 to a group of WHO experts revealed that samples of gm and wiiisky 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 oO were found to be in the range of 0.01 -0.08 ppm and Of) 1-0.04 ppm. respectively (lARC 1974). Levels of 0-0.4 ppm found in British PVC-bottled liquids were mentioned by Davies and Pe r-(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 tn liquids w ith a maximum sensitivity down to the 1 ppb level (van Lierop and Stele 1976: Dreaman and McFamn 1977). It was tentatively estimated that even during the yean when PVC-packaged food and beverages had not been heeded as a potential source of contamination, the likely average daily human intake of VCM from this source could have been in the order of 0.1 mg/penon (lARC 1974). Schlatter (1976) calculated that today it would be leu than' OjOI mg/person (equalling 250 mg during a whole life time); in comparison, he calculated that the inhalational intake of VCM in diseased workers who had been exposed to concentrations of 500-1000 ppm during a period of 10-20 years would have amounted to at least 25 kg. The Association of the German Plastics Industry expects that the use of technology available at present for the production of PVC food-packaging materials decreases the VCM content of food stuffs to below 50qg/kg (50 ppb)even after prolonged storage (VKE 1975). Results of carcinogenicity assays in experimental animals after oral administration of VCM are discussed in Sect.3J. Vinyl Chloridc-A<i- 3 Toxicology ol 3.1 Acute Toxicity Dunng the first three the assessment of the concentrations varyut and Leake 1933.Sclu niarrtotiti, 1960;i< anaesthesia, deep narc this range of exposure tivt and haemorrhagic hepatocellular injury inducing substances (s 3.2 Chronic Toxicity Torketson et al. (1961) exposure to conerntra: 4.5-6 months. All spe however, caused an inc histological changes in pigs ami dogs. An mere in rats exposed to 20 0 (1963); no histological Gorlcij Institute weie n exposure of experimen. mils, bradycardia, chan 0OS mg/litre) for 5 mo creased secretion of cat posterior hypothalamus 3500-4000 ppnu9-U of the cortex and the ar comitanr changes in cir, posure of rats and rabbi resorpuve bone changes nervous system dysfum. available evidence for V( VCM should be suspeete statutory maximal allow crane Republic) should! Of particular import: Pioil ct al. 1971) with c full year. It was only afn . Mardeller t.r(l973) pit* tc^istticd lor tration. In ->74.229:355). < hypertension t plant in southiRctnf and ~al Raynaud's lysii who never o make one , (Sai (Bndbofd J trom fieouent round to eonnmchiil cells ' ipni food and .,J theisoft -as found to up to S00 ppm J VCM from -virtt of un it Mured in PVC -me samples ""J.Davits ami ("that samp'-'* k^U\. after n^Pns in iH ppm and in British -townanal; cs U-uneentnfVCM in -nd Srek l"6: ring tht yean rial source <i( source could calculated a whole TM in diseased irrrf a period of the present for sent of food* *7$) Remits -oof vat Vinyl ChlunUc-A*ouatcd Di*axe J Toxicnlojy of VCM 1.1 Acute To*idtv During the first three decades of PVC production, animat exprnmenu were limited to the assessment uf the acute inhalabonal toxicity' of VCM m short-term exposures to concentrations varying between SO 000 and 400 000 ppm (tuny et ai. 1950: A.-p/a and Luka 1953.Schnintaim 19*4, 1938;0ircr et al. 1947.Cc/vet al. |949;.Wnm>Mttticn t al. I960:4*srer et ai. 1963). In mice. rats, guinea-pigs. rabbits and do|s anaesthesia, deep narcosis, cardiac arrhythmias and lethal erTVcis were observed within tins range of exposure but no relevant organ pathology was noted except for conges tive and haemorrhagic changes in lunp. liver and kidneys on fatal outcome. Acute hepatocellular injury was beer found only in animals ptetreated with potent enzymeinducing substances (see Sect. 3.4.2.2). 3.5 areak Toxicity TorkeUon et al. (1961) were the first to describe results of experiments with prolonged exposure ro concentrations ranging from 50 to 500 ppm, 7 h/day. 5 days/wvefc, for *J-6 months. All species tolerated exposure tq 50 ppm for 6 months: 100 ppm, however, caused an increase is fiver weight and 200-500 ppm caused, in addlson, histological changes in the liver and kidneys of rats and raboia, but not in guineaptp and dogs. An increase in liver weight and decrease in spleen weight was also seen ir. rats exposed to 20 000 ppm. 8 h/day, 5 days/week, for 3 months by 4esrer et al. (1963): no histological lesions were found after J months. Soviet investigators at the Gorlcij Institute were mainly interested in neuroendocrine changes after prolonged exposure of experimental animals to various concentrations of VCM. Cardiac anythmus. bradycardia, changes m phonoeardiognm in rats exposed to 12-20 ppm (Oj030.05 tng/iitre) for 5 months wetc reported (Item and Hokhart 1969b) as well as in creased secretion of catecholamines in rabbits and chanps in the biopotential of the posterior hypothalamus (Vssm and flokhevg ] 969a). After a 5 J-month exposure to 3500-4000 ppm (9-10 mg/litrc) changes in the bioelectric activity /EEC recordings) of the cortex and the antenor and posterior hypothalamic nuclei in rabbits with con comitant changes in circulatory functions were teen {Vasot and Pbklw* 1968). Ex posure of rats and rabbits to 0.03-4).04 mg/litrc (12-16 ppm) for 6 months produced rworptive bone changes and osteoporosis in addition to cardiovascular and central nervous system dysfunction (Batabar ai. 1972). In 1969rAorrr* aimmarited 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 lowered. Of particular importance as pioneer work were I'vrle's experiments (1970a, b: Ilob et ai. 197!) with exposure of rats to 30 000 ppm, 4 h/day, 5 dayt/week. for a full year. Ir was only after this length of expotur* that histopaiholopeal examination / ucc 069309 m :tr7'.5 ^ :,V t .7.< 22 . W.K. UlbjLh jnd H.J. Marsidkr iwcalcii lesions limilar to human acroosteoiysis and alio similar to die type of nontumorout liver diseases which wt observed in FVC workers 3 yean later (Menteller et al. 1973). Viob described lesions of the skin, the small arterial vessels, the connective tissue and clastic reticulum of the paws, and periosteal proliferation wuh chondroui nietaplasis of metatarsal bones. Fibrosis ofsmall peripheral nerves and degenerative changes of the grey and white matter of the brain were prominent, w hereas the kid neys were not markedly affected. The liver showed pronounced depnerative lesions with parenchymal necrosu, cytoplasmic and nuclear polymorphism, abnormal prolifer ation of hypertrophic Kupffer cells and intense ftbrosclerouc reactions. 3J Oncogenic Properties The earliest documentation of the carcinopnic action of VCM was Vmk'% preliminary report presented at the 10th International Cancer Congress in Houston, Texas in May 1970a. Of 36 Wistax rats exposed to 30 000 ppm for 13 months 17 developed epider moid carcinoma, mostly in the paraauricular region;6 also developed adenocarcinoma of the iunp and 5 osteochondroma ofmetacarpal and metatarsal regions of all 4 limbs (I'iofir et al. 1971; Viola \914).Maltoniand Ltfemine (1975) later interpreted these paraauricular tumours as arising from the sebaceous glands of the exterior acoiistic duct, also known as Zymbal's glands, the cell matrix of which seems to be the tarpt tis sue of a number of carcinogens. They wen of the opinion that the pulmonary malig nancies wen mciastases from the Zymbal gland tumours. Autoradiograms of sections of whole rats dosed onlly with (,4CH*belled VCM nvealtd a discrete localization of 14C in the paraauricular region (Zymbal gland?) and in the region of salivary glands and Harder's glands (Crren and Hathway 1975). In this contextiVeumewi ct al. (1979). who analysed the peroxidase activity in Zymbal glands of Wjstar rats, proposed the concept that peroxidase-medialed 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 1973,1977-.Maltoni and Leftmine 1974a, b, 1915, Maltoni ct al. 1974a, 1975). Con centrations used in the inhalation experiments were 30 000,10 000.6000,3500,500, 350 and 50 ppm, with langth of exposure ranging up to 52 weeks and observation peri ods up to 143 weeks. Apart from the induction of Zymbal gland carcinoma other ma lignancies developed, notably angiosarcoma of the liver but also extnhepstic angio sarcomas. nephroblastomas, pulmonary tumours and mammary carcinoma, as well as a number of single tumours of other target tissues. Different types of turnouts were found to coexist in the same animal. On orel administration of VCM dissolved in olive oS (5 dsys/week) angiosarcoma of the liver was found after 50 weeks in two animals of the two groups of 80 Sprague-Dewtey rats each of which had been treated with the -highest doses of 50 and 16.65 mg,leg body wt. {Maltoni ct al. 1975).Maltoni (1977) succeeded in demonstrating that the route of administration of this dearly multipo- Vinyl Chic tential care study of or solved in so 6 dsys/weei ratio only s tion not Heplaced the i the no-toxii angiosarcon Sprague-Da' proved to h genic in rat: be carcmog 10.5 and 1 1979). Ano the dose-rcl exposure lr histological the liver am the induetic posure to !( al. 1974b; I, endothelial pcrplasia an even in the: was scanty: doses. In iht fibrosis was of ossifying feet was sug ffspring of mine 1975). posed to VC ed from Cm it was seen t maturity of to 2000 pprr foci fhepa; Holmber week, for 52 spleen chang mals expose, cutaneous at ppm group 3 Set also i Timelier non' .-ter et uectrw Jroid * tfve - kid* rions ' proiirer- -fijninary in May - cpiderranoma 'a limbi i these " bllw urpt us* .taligoctjoni -'ion of .stilbene .uii, ite a ,-jCUre ation, ' itrvni <). Con- tno. 500. -non penihcrmaanpoi well u <1 were J in olive animals * with the tnrr) dtipo Vim I Chlundt'AiKKiittil Dueam tential carcinogen may significantly vary the ty pe of neoplastic response. In a subacute study of oral VCM to.xicuy. lasting only 13 weeks, in which rats were given VCM dis solved in soya bean oil by lavage in daily doses of 30.100 and 300 mg/kg body wt.. I days week.Fmn e: al.(14'5) found a significant increase in liver-;o-bouy 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. Arrow ct ai. placed the oral no-toxicoffest levtl at 30 mg VCM-'k; body wx./day and suigettcd that the no-toxic-etTect level may actually be even higher. Zymbal gland carcinoma, hepatic angiosarcomas and nephroblastomas had never occurred spontaneously in the breed of Sprague-Cawley rats used at the Bolopa Institute. The neoplastic response to VCM prosed to base a direct Jose-time relationship. Even levels of 50 ppm were carcino genic in no and mice. Later Mahout (1977) found exposure to 25 ppm VCM also to be carcinogenic in rats, whereas no earenogtmc effect was observed at lower levels of 10.5 and I ppm in a study which, however, is still incomplete (quoted from Crieuie 19*9). Another American study designed to complement Maltont'i results confirmed the dose-related induction of liver angiosarcoma and mammary eareinoma In mice at exposure levels of 2500,200 and 50 ppm (Arp/foger et al. 1975). On reexamining histological slides of his pest experiments. Viak later also detected angiosarcomas of the liver and other malignancies of skin, lung and intestine in his rats; he also reported the induction of skin acanthomas and pulmonary adenocarcinomas ir. rabbits after ex posure to 10 000 ppm VCM,4 h/day.5 days/week, for at least 15 months (Maltom et al. 1974b: IARC 1974). Mtltoni and Lejtmme (1975) considered the effect of VCM on endothelial tissue to be a systemic oat since they found dilatation of blood spaces, hy perplasia and atypia of endothelial ceils also in organs and tissues other than the Urer. even in tht absence of angiosarcomas or benign sngiomas. Evidence of hepatic fibrosis was scanty and inconstant m their animals and was more likely to occur at tiw lower doses. In the spleen of treated rats and mice fibroangioblastic proliferation undergoing fibrosa was frequently obaemd. No 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 offspnng of breeding animals exposed for 7 days during pregnancy (.Uaitoni and Leftminr 2975). Later, .Ualtoni (1976) detected angiosarcoma in the offspring of rats ex posed to VCM during the period between the 12th and 18th day of pregnancy (quot ed from Cnciuu 1979). Hepatocellular carcinoma wts not found in adult animals but it was seen to develop readily in newborn animals, possibly In connection with the im maturity of their bioactivttion pathway* (MaUoni 19^7). Exposure of newborn rats to 2000 ppm VCM, 8 h/day, 5 diyr/wetic, for at least 4 weeks elicited preneoplastic foci of hepatocellular ATPaie deficiency, notably in female animals (Ltib et al. 1979). Hotmbcrj et al. (1976) expored mice to 50 and 500 ppm VCM, 6 h/day, 5 days/ week, for 52 and 26 weeki respectively. They* did not observe hepatic fibrosa or spleen changes, but multiple benign atoologenic adenomas developed in 18 of 24 ani mals exposed to 50 ppm and in ail 24 animals exposed to 500 ppm'. In addition, sub cutaneous and/or subperitoncal iuemangiosarcoma developed in 14 animals of the 50ppm group and in 8 of tht 503-ppra poup. Only one hacmangrosarcoma of the liverI I Set alsn WimtB et aL (1976) u W.K. Lclbj.ii and H.J. Mjrelle: was found in an animal exposed to 500 ppm. A few mammary adenocarcinomas, one rhabdomyosarcoma and one renal haemangiosarcoma were also seen. From their ex periments Holmbaj et al. concluded that a lower exposure over a longer period may intensify the eancerogenic response and that an inserted 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 $2 months was pub lished by Feron ct al. f 1979a, b;Finvn and A><*i |9?9j in an eventually fruitless at tempt to elaborate suitable parameters for early detection of VCM-disease in man. Ear ly effects were a shortening of blood clotting time and the occurrence of swollen and malformed hepatocytic mitochondria. At a later stage progessive tubulonephrotic changes in the kidneys, foci of celular alterations in the liver with reduced glucose-6phosphatase activity in hcpatocytes, 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 norma! and atypical sinusoidal cells, multiccntnc hepatic an giosarcoma and Zymbal gland carcinoma occurred. Ftron 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 VCM* induced alterations of hcpatocytes and sinusoidal cells has yet to be elucidated. 34 Toxicodynamics Prior to 1974 very little information was available about the fate and the toxicodynantics of VCM in the mammalian organism, but the discovery of VCM-imluctd angio sarcoma of the liver in humans and expenmenta! animals provoked a large number of studies which resulted in a Hood of publications on the metabolism of VCM. In 1934 Schmtmann reported that in mammals unchanged VCM was excreted via the lungs after inhalational administration;the pulmonary route is the-main excretory route of nonmctaboUzed VCM (Green and Hathnvy 1975). Blocking of nonprotein sulphydryl groups in the blood of vinyl chloride operatives, less pronounced after dis continuous contact, was observed as early as 1964 by Gabor et al. and indicated deple tion of the glutathione pool, which has since also been found in exposed rats (Hefner et al. 1975s). Hepatic glutathione plays a fundamental role in protecting tissues against attack by alkylating agents. The appearance of monochioroacetic add ui the urine of workers expored to VCM was reported in 1966 by Grigoreteu and Toba. indicating that a polar excreuble metabolite of VCM had been formed (Vamio 1978). Toxicodynamic studies have revealed that VCM par te is net 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 Oilom lived but higb mutagenic an cretable prod; 1975). The t< tire velocities tio* of its res nation ofVC! so that above following a it, cordana with 34.1 Uptake Pulmonary up in the arumii'1 with the pool shown by com Bolrttal.(19* as albumin, ar>. pound goes in t After oral ingchas to be cons: is excreted via 1976c). This c able process. P body wt. adm. vesugauon ot . lavage in dosefound a sigmii. plasmic reuculbut only mini rats on a diet c almost all the' testinal tract, h in this way. Percutanet keys following 800 ppm of141 was negligible < Studies of that the liver (p polar metaboli t spleen.lungs an kidneys, spleen of irreversibly j irreversibly bon 4.1 HJ. Marettiler ercinomas. one from their exper period may '-etweeti dose !y been observed pertinent with .mths was pubijy fruitless atcase in man. Ear of swollen and ionephrotic iced glucose-oline phosphatase Jta were observ* aiaution of sinusntrie hepatic anh | sito observed i of very maiig- olfactory-epi: before in con. developed an.hyrea Tlie in;*ded those of t* berween \ CM1 ed. rhet mcodvlandueed angio- irpt number of i VCM. * excreted via main excretory *f nonprotein -unced after disI indicated depied rats (Hefner ng tissues against m the umt of V bidicatmi 79). himate toxin or m) of VCM, that yields short- Vin\! ChionUv-Attociateil Dimm Shed but highly rttettre alkylatmf intemteJurej which are responsible for tire toxic, mutagenic and oncogenic effects. VCM is metabolized rapidly to polar nonvolatile *.\cretable proJucu (Hefner et al. I9"5a: ranDuurtn WS.ftjJuan and Hemehhtr 19"5). The toxicity of VCM teems to be largely determined by the rauo of rite rela tive velocities of both biotraniformation of the compound unu protective detoxifica tion of its reactive intermediates (Hcwchler 1977a). The capacity for metabolic elimi nation of VCM in rats is saturable at an atmospheric concentration of 200-150 ppm. so that above this concentration VCM is metabolized at a constant maximal velocity following a zerororticr kinetic, whereas below 200-250 ppm it a metabolized tn ac cordance with fintrder tite kinetics (Hefner tt al. 1975a; Belt et al. 1977). 3.4.1 Uptake and Distribution Pulmonary uptake of VCM from the atmosphere depends on the nte of its metabolism in the animal's organism. The atmospheric concentration of the compound equilibrates with the pool of unmetaboJizcd VCM distributed in the animal's tittues, as has been shown by complete inhibition of microsomal oxidative metabolism (Bolt et al. 1977a). Bolt et al. (1977a) also concluded that lipids or liccpretcins, nther than proteins such as albumin, are the vehicles that transport VCM m 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 inpstion and absorption from the gastrointestinal tract, a Hist pass effect' has to be considered, but an incresmgly substantial percentage of unmetabolized VCM is excreted via the lunp in direct relation to the dose administered (Wataneb* tt al. 1976c). This confirms the finding that VCM metabolism is a dotedependem and satur- able process. Pulmonary elimination of over 927: withir. 4 h of a dose of 3C0 mg kg body wt. administered orally to rets was alto reported by feron et al. (1975) in an in vestigation of the subacute toxicity of VCM incorporated in toys bean.03 and fed by gavage in doses of 30.100 and 300 mg/kg daily. 6 days/week, for 13 weeks. They found a significant increase in liver-to^ody weight ratio and hypertrophy of the endo plasmic reticulum of hepaiocytes 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 conoining 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. ftrcutaneous absorption was studied by Hefner et al. (1975b) in male Rhesus mon keys following whole-body exposure (head excluded) to concentrations of 7000 and 100 ppm of1 * C4abelled VCM for 2-2.5 h. The quantity absorbed via the intact skin was negligible (D.027(-O.O35) and most ofit waa expired. Studies of the distribution of (1 V^M hi the body dearly revealed that die liver (predominant tire of metabofism) and the kidneys ftite of excretion of polar metabolites) contain the highest eonctntntions of ,4C activity, followed by spleen, iunp and small intestine (Watenabe et al. 1976c(Bolt tt al. 1976a. b). Liver, kidneys.spleen,Jung and small intestine (tn this order) also contain the largest amounts of irreversibly prouin-bound metabolites (Bolt et al. 1976a). Only minor amounts of irreversibly bound metabolises of VCM were found in muscle, adipose tissue and brain. 26 W.K. Lelbach and HJ Mameller Toul radioactivity 48 h after a tingle expoiure 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 timt.Bucluer et al. (1977) also showed that unmetabolized VCM potMsset 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 betw een Chemical Structure, Reactivity and Mutagenic or Carcinogenic Effect Before discussing the metabolic pathways of VCM (monochloroethylene) and its pre sumptive toxic intermediates two features of the chemical structure of this compound should be mentioned. Vinyl chloride is a monohalogenated ethylene and its chlorine substitution is asymmetric. Chlorination of alkenes (olefinic compounds), in general, tends to stabilize the double bond by exerting an electron withdrawal effect on the carbon atom involved. Thus, the chemical reactivity of alkenes decreases with increas ing degree of chlorine substitution, as was shown in 1968 by Williamson and Cvttanovid for reaction rates with ozone. Vinyl chloride, as a monohaiogenated alkene, is the least stable compound with the highest reaction rate in the series of chlorinated ethylenes and ranks next to unsubstituted ethylene. Secondly, the first step in the oxidative metabolism of all chlorinated alkenes is a transformation to epoxides (oxiranes) which arc short-lived, highly reactive electro philic intermediates (Bonse et al. 1975 .Henschlcr 1977b). Such chlorinated epondes may react, by alkylation, with essenoal cellular constituents, a mechanism which Rannug et al. (1974), Bartsch et al. (1975a, b) and Mataveille et al. (1975) claimed to be responsible for the carcinogenic and mutagenic effects of VCM and vinylidene chloride. Epoxides resulting from biotransfotmation of asymmetrically substituted ethylenes, such as VCM, vinylidene chloride and trichloroethylene, seem to be particu larly unstable with increased elcctrophilicity and thus enhanced alkylating effect. Their mutagenicity and, inversely, the nonmutagenicity of oxiranes of symmetrically chlorine-substituted ethvlenei was indicated by the studies of Creim et al. (1975, 1977). 3.4.23 Metabolic Pathway* From 1974 onwards the fate of VCM has been studied extensively in vitro with rat liver microtomes in the presence of a NADPH-gencnting system (Kappus et al. 1975, 1976;5rrsc/i et al. 1975b, 19"I6,Mataveille ti al. 1975:Bolt at al. 1976*:Pejsayre it al. 1979), with the aid of isolated perfused liver preparations (Radu-an and Hensch Ur 1975,Bonse et al. \975,Radwen 1977: Henschlcr 1977a) and in vivo {Hefner et al. 1975a: Wetanabe it al. 1976d. 1978a. b.Boh et al. 1977a, b) in both control animals and animals preueated 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 doublc4>ond of VCM by the hepatic Vin> I Chlor; microsomal i ly highly rca. via the form;-, bon monoxi1 preeisfale rok in vitro an ar> systems and i 1976a). The. iCV Fig- 1. Metabr metabolized tacetic add are methylene oxj protein sulph\ ***.'(1977). Si {Norpoth et a! 5<arboxymet: add) (Hensch! identified in tl J Mamehrr hem orpni. of its -hoacnvity unmctabtetaboiites. anditspret compound m chlorine in general, it on the ith inertas J Oersnonc a. is the less: : rthv:ent* Iktttes a a electro- .d epoxidiu m iJV*- lt> .l;,,ene iMUtuted i he pirt!cu rtfleet. metrically .11973, with rat etal. 1975, '.PeBMTrt and HensehIHefner et al. ttol animals wenhibitmg the predoy the hcpauc Vin;-! Chlonde-Arsociated Oi'icuw V> microsomal mixed-function oxidase system, forming ehbrotthylenc oxtde. a chemical ly highly reactive epoxide (Fi|. 1). A negligible amount of VCM can be metabolized via the fonnauon of peroxides, very unstable compounds decomposing rapidly to car bon monoxide. HG and formaldehyde which, however, do not seem to play any ap preciable role in the toxicity of VCM ificnschltr 1977b). It has also been shown that In vitro an artifical superoxide fOH generating system can replace rat liver mierosomal systems and transform VCM to the active intermediate (Kanpm et al. 1973;flo/r et al. 19*6a) The epoxide rearranges spontaneously to chlorsacetaldchydc. which is rapidly Cmjlvm KnUing lo vi-!l.-br macmMCli.'.'uk-' laik> Ultun > i ,M N'll If 1/ OviJaaV \ VDPH. 0 fTiA-ffn-Mi- free Oriu*' i\( SI povui(> Tiiermal rrarranyi-mcr!: ChtonwcctalJrmUv Fi|. I. Metabolic pathways. Adapted from #enaeb/er( 1977b) 27 W.K. Lclhjch and HJ. MniMcIL-r level of hepatic nonprotein sulphydryl content has been observed in rau alter expo sure to*VCM in concentrations from 150 to 2000 ppm for 2-7 h. No depression was seen after 10 ppm and a concentration of 50 ppm caused only an inconsistent reduc tion (Wannabe et al. 1976b). Protein-bound hepatic suiphydryl content remained unaffected. Hepatic microsomal cytochrome P41. the eoenzyme of microsomal monooxigenases. also decreases linearly with time in animals exposed to VCM tReynolds et al. 1975b). This destruction of cytochrome P4 l0 may prevent further metabolism and toxicity of VCM (Pauyre et al. 1979). Another mode of deactivation of the primary reactive intermediate, the epoxide, is its transfoimstion to the inactive dihydrodioi by the inducible microsomal enzyme epoxide hydrase. The reactive metabolite ofVCM, chlorocthylene oxide, is a powerful alkylating agent which covalently binds to various cellular raacromolecuks, notably vital proteins and nucleic adds. By binding to cellular ONA and RNA or critical proteins the metab olite may alter vital functions and the genetic information of the eell and thus exert its hcpatotoxic,mutagenic and carcinogenic effect.Eventually, however, the only fraction of the formed epoxide that binds to macromolecules is the on* that is not detoxified by protective scavenging mechanisms such as conjugation with cytosolic glutathione or inactivation by epoxide hydrase. Simultaneous presence of other xenobiotics whieh have to be detoxified will impair the effectiveness of the detoxification mechanisms. In ~ assessing the risk of exposure to VCM, Henxhter( 1977a) concluded that there might be a greater risk in intermittent peak exposures over brief periods than might be expected from simple integration over time and that the chances for effective detoxifica tion are greater in long-term exposure to relatively low levels. It was shown by Wannabe et al. (1978a) that repeated exposures of rats to VCM do not appear to induce its biotransformation, but significantly augment the binding of the reactive metabolite with hepatic macromolecules and may thus enhance the po tential toxicity of VCM. On single exposures of rats to increasing concentrations of labelled VCM ranging from 1 ppm to 5000 ppm, the amount of radioactivity covalent ly bound to hepatic macromolecules did not increase proportionately to the increase in concentration but followed a sigmoid curve with low and high inflection points be low 50 ppm and above 250 ppm. respectively, when binding was plotted as a function of the log of the exposure concentration (Wannabe et al. 1978b). This correlates well with Mallow's report (1975) of a linear percentage induction of hepatic angiosarcoma in rats between 50 ppm and 500 ppm when expressed as the log of the exposure con centration. Metabolites or VCM can alkylate nucleic acids, a commonly accepted meehanism for carcinogenesis. Covalent binding to the adenosine {Barbm et al. 1975;cib and Boll 1977), cyodine (Laib and Bolt 1978). and guanine moiety of nucleic adds (Osierman-Colkar et al. 1977) has been described. But the degree of covalent binding of electrophilic metabolites of labelled VCM to hepatic nudeic acids seems to be very snail (Waunaben al. 1978b;I*ib and Bolt 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 nudeic acids after exposure to radioactive VCM. Wannabe et al. (1978b) condudtd 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 < above all. i This a work will I . endoplasmtable to VC phologicall mixed fun*, lobular, mi. found (Jai . 1978). Sec< endothelia! At pres, cesses aret' the hepsto. some metal(5) Meehan tissues othe rant cell rep 1978b). An eqiu nonneoplasRaynaud's' drome was i man. Beside liver lesion* bioactivatic portal flbn ment of the direct or ir tic nervous, lining cells o tion) or wh. 4 Clinica During the r might prove : presented in marked the y pational haz.  Maretelicr it expoaion was -:ttreducuined inal cionoptokis *t ^atomand epoxide. is .nxyme yiating ij proteins he metabUneven ns tiy fraction letoxified itathione or x which .hawrms. In :hcrc mifiii ii be exJetoxifiea- i .it the po ntons of t> covalent* eisnease ooints be- 4 function -elates well lannetcoma xwure con- echanism i jib end tdds (Oi/cr-ndmj of be wy nrarnttd he deterter exposure l| to -< does not V.nvi Chiomie-Ar-ociau-d Dut-aw exclude the possibility of other.more subtle interactions which may impair the control of cellular replication. Alkylation of nudeic acids, however, cannot at present he ex cluded as the mechanism for VCManduced carcinogenesis after repeated exposure and. above aU. in the target ceils 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 hrpatocytc. the liver ceil itself is not particularly suscep tible to VCMmJuctd toxicity Acute hepatocellular injury has not been observed morphologxafly after exposure to VCM unless pretreatraent with potent inducen of the nuxed function oxidase system had preceded the cxposure;in preireated rats centrelobular, mtdzonal and panlobular hepatocellular vacuolization and even necrosis was found (/erger et ai. 197-1.1975.1977:Reynoldi et al. 1975a. \976:Connlly et al. 19*8). Secondly, the site of carcihofenieity in the liver is not the hepatocyte but the endothelial cell of the hepatic sinuses. At present it ean only be speculated which of the foDowini four most likely pro cesses are effective, either singly or in conjunction: (1) The active metabolite leaves the hepatocyte and is conveyed to the endothelial ceil. (2) The endothelium itself has some metabolic capacity (Bolt 1978), as may tissues of organs other than the liver, fJ) 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 ceil replication are less effective than they are in the hepatocyte (Wgttnebe et al. _1978b). An equally puzzling problem is the role of VCM in the pathogenesis of the distal nonneoplastic vascular lesions which an responsible for the development of the read. Raynaud's phenomenon.sclerodermoid skin indurations and acreosteolysis. This svnJromc w as the earliest indication of adverse effects of chronic exposure to VCM in man. Besides.its latency period wai considerably shorter than eithet the nonmalignani liver lesions or angioiareeRU of the liver. Whereas it is now established that hepaoc bioactivation of VCM plays the central pan in the pathogenesis ofboth noncmhouc portal fibrosis and angiosarcoma of the liver, it a not at all dear whether the develop ment of the acre] 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, (c) smooth muscle ceils of the media of anenoles, fd) endothelial lining cells of small aneties (with Gbrobiast transformation and endothelial prolifera tion) or whether (e) the action is mediated by the formation of immune complexes. 4 Clinical Spectrum Duiing the mid-1950s it began to emerge that ehronic occupational exposure to VCM mi|ht prove to be not quite as harmless as had been claimed. The historical synopsis presented in Table 7 summarizes thow dinicai studies from rite world literature that marked the gradual recognition of the full spectrum of damage due to this new occu pational hazard. 30 W.K. Lclbjch and H.J. Mar-teller Table 7. Gradual emergence of evidence for VCM-associated pathology Year Reference Findings 1949 Trtbukh et al. Hepatomegaly. more nr lo-- marked 'anicteric hepatitis*, 'chronic gastnti-'. hype*ten*ion. anaemia, skin lesion* 1954 1957 1957 1960 Smirnnva Filatov* and Gronsberj Kubota Danxifer Toxic angtoneurosi* Toxic ansroneurosis Symptoms similar to Raynaud's phenomenon Two cases of accidental fatal poisoning by VCM. 1 nonfatal acute overexposure 1961 Smirnova Reversible osteolytic lesions of distal phalanges Pscudociubbing, thickening of skin nn volar side of forearms, slight haemolysis and reticulecytosis 196? 5uciu et al. CHS. prenarcotic symptoms tdizziness, euphoria, somnolence), nervousness, insomnia, blunting of memory, general asthenia, headache Vascular: Raynaud's syndrome Dermatol: pruritus. reversible sclerodermalike skin induration, chemical and allergic dermatitis Durst, tymptomt: anorexia, nausea, fullness, hepatomegaly without hyperbilirubinacmta. splenomegaly Cndocrinc: hypothyroidism 1966 Conlitr et al. Raynaud's syndrome, sclerodermalike -kin changes, acroosteolysis. pscudociubbing. joint pain, tiredness, steep reversal. Z episodes of acute overexposure (loss of consciousness* 1967 Harm and Adams Acroosteolysis, skin lesions. Raynaud'* phenom enon. pseudoclubbing, involvement of sacroiliac joints and patella, hepatomegaly with persistent ly raised scrum bilirubin. Skin biopsy 1967 1967 Benou Wilton et al. Arteriography. Skin and bone biopsy Occupational acroosteolysis' with Raynaud's symptoms, sclerodermslike skin changes, pseudociubbtng 1968 1971 Antonyuzhenko Dinman et al. Mentions thrombocytopenia Prevalence of acroosteolysis and Raynaud's phenomenon 1971 1972 Dodson eta). Krtmtr and MuucMIer Vascular lesions preceding the bone lesions Increased BSP retention and raised icterus index related to degree of exposure Vinyl Chlon Table 7 (con Year R< 1972 r Al 19'T2 jm 1973 AL |974/i) Cr 4.1 The Tri. A first indies plant ptoduc non (Toxic a; in detail in he personnel wl hourly sampL drome was a! (Kubota 19? morefulauon and CNS sym (1954) alio n durations on there was evu fred cells, u evidence of d< acroosteolyju operators) aft junction with was found tn lesions to be c reversible chs vibration trau the full ranfe cupational ac; In 1963 5/ analysis of th. Ucc 069318 MU Marsteller -1 amcrenc 'ihunsun. henomenon mini by VCM al phjanges m on volar m and reticulo- ncit. euphoria, tma. blunting - idache crodermaJik ` HU* dermatitis -.'a, tutintss. rubmaemi. tubbing, jemt episodes ol bMMiMieii) naud's phenom-ent of sacroiliac with pemsientw>py h Raynaud's chants. Raynaud's me leriont .il icterus index Vin> | Chtonde-Awociawd Disease 31 Table 71 continued i Year I0-; Reference .UbHrnwsre cl ai. June and Linft 1973 Manteiltr ft al. 1974/a) Cnveh et al. Findings Progressive thickening ot hands and forearm*. arthralgia. Blanching upon exposure to cold with cyanosis of hands accompanied by severe pain. 5km biopsy 1-t German report ot 7 workers -nth sclerodermalike skin lesions. Raynaud's syndrome, and acrousreolyus. Tests showed abnormal liver in I. occlusion of digital arteries ui 1 worker Noncirrhotic portal fibrosis with portai hyper tension and splenomegaly 4 cases of anposarcoma of the liver 4.1 The Triad: Raynmid's Phenomenon. Pscudotcleroderma and Acreotteolytis A first indication of advene etftea due to chronic VCM exposure arose in workers at a plant ptudueni VCM who presented with symptoms similar to Raynaud's phenome non (toxic angioncuroris*). This was reported by Snumoec in 1954 and later desenbed in detail in her thesis (1959). The syndrome was found predominantly in laboratory personnel who had intermittently been exposed to hi|h concentrations of VCM during hourly sampling for chemical analysis (punty of the product). In 1954 Raynaud's syn drome was also observed among several workers at a Japanese PVC producing plant (Kubota 1957)- Apart from i painful vasospastic disorder of the hands, impaired ther moregulation. acrocyanosis raeiuvt cold test, capillarescoptc alterations, panesthesias, and CNS symptoms sudt as headache, blunting of memory and sleep reversal,.Smirnors (1954) alsc mentioned swelling of fingers and development of circumscribed skin in durations on the volarride of the forearms in those most severely affected. In addition, there was evidence of mild haemolysis (borderline ansemta. decreased osmotic fragility' of red cells, urobilinuria,and reticulocytosisi. In 1961 Smirnova described radiographic evidence of destructive bone lesions of terminal phalanges in the hands identical with aeroosteolysis in three workers at a FVC^roduong plant (one fitter, two centrifuge operators) after exposure for 3-9 yean. Since these bone lesions developed in con junction with *toxic angioneurosis' and sine* complete recaleification of the defects was found in two woricen 3 yean after removal from exposure.Smirnova believed the lesions to be characteristic of chronic VCM intoxication. She pointed out that their reversible character might serve to distinguish the Mens from similar defects seen in vibration trauma. In retrospect, Smsmove's observations ate the earliest descriptions of the full range ofsymptoms which much later became known as the syndrome of oc cupational acrcosteoiyaii'. In 1963 Suobi et al. (see aim 1967 and 1975) published the Tint comprehensive analysis of their obstvption of a multiform symptomatology in subactut and chronic a / I * i r I I ! | 5 \ i [V W.K, Lvlbji.li jmJ II.) Mjf<ilv: 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 daisic paper, the authors described in detail the various cen tral nervous, digestive, angioneurotic and cutaneous symptoms (listed here in their order of manifestation). Acroosteolvsts. however, was not mentioned. Episodes of acute overexposure (usually occurring at the end of a batch tun. during retrieval of unrcacted monomer, or at repair jobs) rapidly resulted in a state of light-headedness and transient euphoria similar to a mild degree of inebriety and were accompanied by a feeling of heaviness in the legs and disturbed locomotor coordination. Several workers claimed to have been able to identify escaping monomer by its faint but agreeable odour. Apparently during periods of particularly high ambient concentrations, workers repeatedly noticed formication in the lower limbs and a general feeling of boddy 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 :.somc workers noticed insomnia or sleep reversal. A reappraisal of these nonspecific complaints (see also Vale et al. 1976) 6 yean later. after improvement in industrial hygiene, revealed that the frequency of their oc currence had considerably decreased (Suciu ct al. 1975). Following a prolonged period of repeated overexposure, vague nonspecific digestive symptoms also developed, such as anorexia with ensuing weight loss, nausea, fullness, upper abdominal discomfort, bloating and epigastric pains. Enlargement of the liver was found in 51 workcre (30Tc); in 6~ there was also splenomegaly. Classic Raynaud's phenomenon was found in 6 but a tenfold higher percentage of the total work force showed evidence of vasospastic alterations on plethysmography (Rancher et al., cited by Suctu et al. 1975). Pruritus of the hands, forearms and face was an early complaint followed later by what was theought to be (allergic?) `contact dermatitis'; finally.nodular and scleroderma- or scleroedema-like cutaneous lesions developed in some workers, involving the dorsal surface of the hands, the volar side of wnsts and forearms and the face, with iirm thickening of subcutaneous tissue or formation of whitish papular or slightly elevated plaquelike indurauons. The cutaneous manifestations largely disappeared after removal from the work place. In addition, mention was nude of features of hypothyroidism in a few workers. Also, transient lost of libido in 24% was recorded, with return to nor mal after a break from work or during holidays. With the exception of acrooneolvsis and the two most alanning late sequelae -- nonbrrliotic portal hypertension and hepatic inposarcDtna - Suem'% early documen tation of the prevalence of disease in PVC production workers encompassed a com paratively complete description of the various aspects of chronic VCM intoxication. Later publications supplemented the spectrum of knowledge mainly by providing ad ditional information on epidemiological, rocntgtnolopeal. thermograpliic. angiograph ic, and histomorpholopcal aspects of the lesions encountered in subjects chronically exposed to VCM. Vinyl Chlon The disa two Belgian: classifiable d. marked the n syndrome w: year a numb : United State1 cases of OAC the various pi end of 1979. vascular phen symptoms ih begin with illthe fingers an tips on hard s to cold accon are likewise a ance of painf. osteolytic pK with stnation Table 8. Publ. Year 1966 1967 1967 1967 1967 1969 1969 1971 1972 1972/J973 1973 1974 1974 1975 1975 1976 197! 1979 a One 01 : U Mar-**lltr women :floycd in now ceni the:: Jet of evil of Jcdnei; panted by i al uorkers eeable ?t. workers sdily `eakages. months of MSient a the work 'nlity. .-a workers years ' their ocntJ pir.od .wd.iuch ;U ifi 6". j-itpattic f-'runtut at was :IWOI Jonal i firm elevated ter removal ntidom in <n to nor- tuelaa Jocumeilacoredcation. riding adrnp graphmmtcally Vinyl Chl<`nde-Aca'.ed Disease 33 The discovery f unusual osteolytic defects in the distal phalanges of the hands of two Belgian autoclave cleaners who had suffered from Raynaud's phenomenon and uclassifiable degenerative lesions of the dermal connective tissue iCunJier ei al. 1466) marked the resoptuon of this new occupauonal disease in the Western World. The syndrome was termed `occupational acroostenlyvis'iOAOLi.and during the following } ear a number of additional cases were reported from France, Great Britain and the Limed States. Later Lcfirrc f 19^2) who together with Conner described ute first two cases of OaOL. reported that a subsequent investigation revtaied another '*n cases tn the various plants affiliated to the dim corporation m Spam. Italy and Brazil. By the end of 197Q, a total number of 126 cases had been published in detail (Table 8). The vascular phenomena preceding or accompanying OAOL comprise a broader range of symptoms than those characteristic of Raynaud's syndrome. The conditions seems to begin with ill-deftned pains in Angers, wrists and also large joints fshouldcrs. knees): the fingers are numb and tinfling, tender on palpation, handgrip and upping finger tips on hard surfaces is painful; there is increasing sensitivity of the hands and fingers to cold accompanied by a tendency to cyanoue discolouration, tn some cases, the toes are likewise affected. Later, classic Raynaud's phenomenon develops (sudden appear ance of painful, sharply demarcated blanching) and. concomitant with the onset of osteolyac processes, there is a shortening and broadening of the terminal phalange with nnation of nails (pseudodubbtng). Tsble S. Publications on Occupational Arroosteotysis* since 1966 Y<-sr 1906 I9r*7 9o? (On 7 t9*7 1969 `.969 197| 197: 1972/1973 1973 197S 197a 1975 !973 1976 197# 1979 Country Number Authors of eases Belgium France France United Kingdom USA Rumania Yugoslavia USA USA Fed Republic of Germany Japan France USA USA United Kingdom United Kingdom m4 5 3 4m 31 m4 S 41 4w 6 1 4 1 4 1 4 Brazil Israel s 1 12b Cnrdltr tt ai. Srnoit; Gtattlam and Muntlon toumehon (cited by iteon et al. 1967) Harm and Adams Wilson et al. Anfhtleseu et al. JTorefet al. Dinman et al. Jferfcowtic et al. Jiht and Valtman: Strut et ai. (a. b) Takrucht and Mabuehi 3 Moulin et al. Trapf et al. litis et at. Sttwart t al. Prtston et ai.: Wetter; ititchtU Johnston f 1971) Cama and Meira Hahn at al. 3 One of 2 clear caws, ui addition, 4g suspected caves isct SalcaPr 19751 3* W.K. Laibach and H.J. MarsicHer 4.1.1 Familial and Idiopathic Acroosteolyais Acroosteolysis it a very ran dlwate. The aetiology* and pathogenesis of this condition it still obscure. Osteolytic bone changes in late stages of so<alled Raynaud's disease (accompanied by necrosis and gangrene), characteristically presenting as loss of pan or of an entire distal phalanx of one or more fingers and fclso of toes, hare been mention ed in the literature since 1921 (Atsmann 1921 \Monahan 1926:Bonk \921\Komblum 1929). Kombium attributed the lytic bone defects to reteular abnormalities and noted that he had found identical lesions in early stages of scleroderma and in leprosy. The term aaoostcoiysis was first introduced by Lervcht and Hochftld (1948), who held a neuroendocrine syndrome responsible for the lesions. Independently Hanuuch (1949) reported another case of symmetrical idiopathic acroosteolysis, particularly involving the terminal phalanges of the fingers with preservation of tufts, progressive dubbing and shortening, and ill-defined symptoms of disturbed peripheral circulation. By 1952 Giacti mentioned that 68 cases of the familial type of acroosteolysis and 33 cases of the nonfamilial, idiopathic form had been reported in the medical literature. He added another five eases, but his case reports pertain almost exdusively to mutilating proces ses involving only the feet, with recurrent ulceration and discharge of bone fragments (see also Hormi 1954). In 1957 Lib>rt and Gama listed 16 observations of idiopathic acroosteolysis and commented extensively upon these lesions; the whole ranp of dif ferential diagnosis (various congenital, neurogenic and endocrine osteolytic diseases, leprosy, arthritis mutilans, progressive systemic sclerosis, ainhum etc.) was considered in their study and could be rejected with reasonable certainty. In a later review, Cheney (1965), who added another four cases of the familial type, stated that this variety and the nonfamilial idiopathic type may actually belong to the same disease entity and may be part of a degenerative bone process more generalized than the term implies. It was the puzzling character and the rarity of this peculiar bone lesion that captured the attention of site medieal personnel and industrial hygienists when in November 1963 the condition was detected in two Belgian autoclave cleaners (Lefb re 1972). 4.1.2 Epidemiology of Occupational Acroosteolysis Attempts at assessing the prevalence of OAOL among personnel involved in VCM manufacture and polymerization revealed that in general this occupational type of osteolytic bone lesion was found in only l%-3$ of the work population at risk. tfubler 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. Wilton et si. (1967) observed 31 cases among 3000 employees of one large company. In 1971 Dinimn et al. conducted a survey* in 32 plants belonging to 19 corporations throughout the United States and Canada. The details of this elaborate epidemiologi cal study, comprising a tout of 5011 employees, illustrates the difficulties and limita tions encountered in a retrospective study of this dimension. AH of these 5011 workers had been engaged in various stages of VCM and PVC manufacturing, but 1257 of them were workers who only handled finished.PVC polymer. Five of the 32 plants worked Vinyl Chioi exclusively only 25 clea defined as c cnon;18 of with experic drome were jobs, both rr (1 case pet 7 appeared no was detectei use for react entry into th Table 9. Pre * Country France USA . United Kingdom Fed. Rep Germany United Kingdom ' 1 Total More con related symp Lanjc and I , ologcal cheti pathological. were affected cold, 15 wori morbidity ws found classic numbness ant 8.7% and invr Allen test ind people with p pseudodubbi finding that n duration of p. :HJ Mime;ler this condition aud'i disease <t ios of pan or : been mention* 1027: A'omblum dines and noted ileprosy. The Ml, who held a '.tmeseh (19491 lUriy involving *tive dubbing ; tuon. 3y 1952 id 33 cases of attire. He added nilating ptoeesone fragments ; of idiopathic k range of difIvuc diseases, xas considered *T review, :.-d that this disease ^Hui the term rc lesion that w when tn haner* (Lejhre edinVCM oral type of -mat (iik. ';> had been OAOL and facton. 'arse company. ' rorpotaaons .* epidemiologi* ' and limiu* < SOU workers r 1257 of them Hants worked Vir.yi Chloride*Associated Disease 35 exclusively with the finished PVC-derived consumer productii Dintnan et al. found only 25 clear-cut cases of OAOL among the 5011 employees lmein age: 35.S years), defined as characteristic X-ray Aim abnormalities combined with Raynaud's phenom enon: IS of them had been reactor deaners at some time: another 16 individuals <10 with expcnence in reactor cleaning) with early stage! ormintmal degrees of the syn drome were suspected of suffering from OAOL. It emerged that the two lowest-paid jobs, both reactor cleaning and bagging-packing, had a strong association with OAOL i.l case per 72. or $6 workers at risk, respective:}-1. 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-pitssurt water lances or solvents had been in use for reactor cleaning. Funhtrmort.it seemed that the extent of degassing pnor to entry into the autoclaves conelaud with the manifestation of the disease. Table 9. Prevalence of acral disease in VCMwxposed populations Number of eases Country Size of Classical Severe Sclero group - Raynaud's sensitivity dermoid at nsk OAOL phenomenon to cold skin lesions References France 130 USA 354 United 3* Kingdom Fed. Rep. too Oemianv United 104 Kingdom Total 725 5 4 1 9 1 20 12 IS 5 20 63 ' 23 5 4 9 33 10 25 1 711'N-Kr'l im-ci6-> 4M'.6T-i Benoit 1967 Lbis ti al. 1975 Walker 1976 Lange and X'tltnxtn 1977 Maneq et al. I97S More commonly seen than OAOL were Raynaud's phenomenon (see Table 9) and related symptoms of abnormal peripheral circulttioo (Benoit 1967;Lilis et al. 1975: ianfe and I'elrman 1977). Benoit pointed out that a complete medical and roentgenoiogical check-up of all 528 employees at a French FVC-produang plant retailed pathological manifestations only among the group of 130 reactor cleaners of whore 32 were affected (OAOL. 5: Raynaud's phenomenon without OAOL 12: sensitivity to cold. 15 workers). He stressed the fact that in this group of workers at risk the overall morbidity was almost 257*. Similar results west obtained by Libs et al. (1975). who found classic Raynaud's phenomenon in 5j6% of 354 heavily exposed PVC workers, numbness and tingling in 24%, excessive senntmty to cold in 1 8%. pseudodubbing in S.77p and involvement of the toes in T%. Besides, in 26.6% of tht total an abnormal Alien test indicated Impaired peripheral arterial circulation. It was noted that in tome people with past exposure Raynaud's phenomenon had gradually faded, whereas pseudodubbing persisted or even progressed. Mon important, however, was Uk:' finding that the prevalence of all them abnormalities increased significantly with the duiauon of past exposure to VCM. r e; .1 :' i- ? 4* ,g* 36 W.K. Lelbach and H.J MarMclle: Occupational acroosteolysis is a condition predominantly observed in younger workers. The age range was 20--45 yean and half of all eases reported fell in tite 50-59 yean age-group. Duration of VCM exposure prior to onset of Raynaud's phenomenon ranged from 1 to 25 months (DoJson ct *1.1971). For OAOL the latency period was at least 12 months {Wilton ct a!. 1967): m most eases. OAOL developed insidiously within 2 to 4 -6 yean. There is at least one patient on reeord in whom OAOL was first 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 penist {Williams andMcLachkn 1976). Stein et al. (1973a, b) reported partial healing with restitution of tufts but progressive lysis of the proximal portion of terminal phalanges 3 yean after termination of exposure. Although OAOL developed predominantly in PVC production woricen 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 cany a sub stantially lower risk of exposure. Trapp ct al. (1974) reponed a 31-vear-old white male suffering from Raynaud's phenomenon, clubbing of the flngen and typical bilateral aeroosteolysis, in whom specific inquiry revealed that his employment by an industrial chemical company had included daily handling of small concentrations of vinyl chlo ride (no details given). Typical OAOL was also observed in a worker after 6 yean' em ployment as spray dryer/bagger, pre-mix operator, recovery and charging operator who had never cleaned autoclave vats (Sten-art et al. 1975). According to routine plant monitoring of VCM levels in the past and as measured in 1973 by gas chromatography of grab samples, his average exposure had been within the threshold limit values of the day (200 ppm). Radiographs taken in 1966 at the end of his first year during an earlier survey of OAOL were normal: in 1972 he presented with Raynaud's phenom enon, pseudoclubbing, typical OAOL and dermal thickening of hands and wrists. Ar teriography demonstrated narrowing of most digital arteries, even in flngen 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 transdermal - Dinman ct al. 1971 -.Stewart 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 docs not seem likely, however, that repeated physical microtrauma dunng 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 ct al. (1967). 4.1 J Clinical and Roentgenological Features 41.31 OccupationalAcrootttolysu In the majority of cases osteolytic lesions are confined to the hands. Involvement of the feet was observed only rarely in OAOL. Wilton et al. (1967) believe that OAOL differs from familial or idiopathic acroosteolysis in several respects. Although the bone Vinyl Ch defects in osteopon skull, des* shortenin' r nonoccur genologK UHr one or mu 2) Ini tufts, or a 3) The tufts togei defects (se fbandlike Fig. 2. Oct. ereosteol' year-old au 4) In tland broadr fragments and increas Sodium tnineraiizai multaneoui - sad HJ. 'lawe^r *td in younger fell in the 30--39 aid's phenomenon 'tteney period was 'sped insidiously torn OAOL was first Lonptudmal studies :*ecnve itsntunon. ears alter removal rsioni may persist rtial heaiing with terminal phalanges workers who had at has also seen obil to cany a subyear-old white male J typical bilateral mt by an industrial terns of vinyl chlor after 6 years" enarsing operates who ;routine plant jt chromatography values of r dur.ni an Is phenomub and wrists. Ar il fingers without i of deformed isdcrmaJ -- Dinman ptlbility or idio-iopment of the syn* -.totrauma during t chiselling) was a culated by Mlton *. Involvement of Km* that OaOL . Although the bone V;n>! CUIur.du-Associated Dixjm; J7 defects in the distal phalanges are similar in both conditions, other features, such as osteoporotic compression fractures oi the spine, basilar impression fracture or the skull, destruction of mid-phalanges or osteosclerotic changes of wrists and hand bones, shortening of aeracarpais and conical thickening of the shafts of long bones seen in the nonoccupational type have never been found m OAOL. Wilson et al. worked out roent genological catena for the diagnosis of OAOL: 1) Tiie earliest changes in OAOL are marginal defects and lots of cortex in tufts of one or more of the terminal phalanges of the hands. -) fa the next stage this is foDowed by small Italf-moon' cuts in the cortex of the tufts, or a so-called slice-effect along one or mote tufts. 3) The advanced stage of destruction is eharacmiteed by either a complete loss of tufts together with a portion of the shaft or there may be transverse or oblique bone defects (sec Fig. 2) cutting off the sham from the remaining distal rim of the tufts Cbandiike acroosteoiytu"). r Fig. 2. Occupational acroosteolysu. Transverse or oblique bone defects <*bandlike aeroosteolysis') or partial loss of terminal phalanges in all fingers of both hands. (33ycaroid autoclave claancr: duration of espoeure 2 1/2 years) 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 bone fragments. Finprtips remain short and plump with persistent dubbing of soft tissues and increased lateral and lonprodinal curvature of finprtips. Sodium Auoride 1 *F scintiscan data of affected bof.es suggested that acute de mineralization (rcsorptive; and retninenlizaton (reparative) processes may occur si multaneously even in the same hand (JDotison et aL 1971). In some cues, bones of c 96 W.K. Lribach and H.J Marxtellcr other body regions were also involved. Erosive and sclerotic changes in tlw tacro-iliac jointt and circumscribed resorptive dtfecu(cortical erosions) in patella, clavicle, man dible. humerus, styloid process of ulna, femoral condyles, os calcis, cuneiform and metatarsal bones have repeatedly been observed iConlier et al. 1966.//cm* and Adams \9B~ .Dodson et aJ. 1971;//if etal. l974\Lante et al. 1974a;PirJttvi et al. 1976: Jayson et al. !976a:Lrje and Veltman 1977). 4.1.3.2 Pseudosclcmderme Concomitant with the manifestation of paraesthesias, pain, tenderness of the fingers and Raynaud's phenomenon, cutaneous lesions similar to stigmata seen in progressive scle roderma develop with thickening of the skin of fingers, hands and forearms, sometimes accompanied by swelling or puffiness and coarsening of the skin of the face (mostly on the forehead and cheeks). Raised, ivory-coloured, firm nodules or elevated, sharply de lineated plaquelike skin indurations ate 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 aeroosteolysi* < Raynaud's phenomenon, sclerodermoid skin changes. AOL) / progressive scleroderma with (tare) osteolytic lesions Occupational AOL Progressive scleroderma Sex ratio Hands Exclusively Clubbing and shortening of finger tips; hyperhidrosis: no ulceration t 1:2 Atrophy and tapenng off of fingertips: anhydrosis: ulcerative lesions Penonl puckering of skin Skin appendages Telangiectases Shortening of frenulum Subcutaneous deposits of calcium salts Dysphagia < oesophageal involvement! Renal, cardiac and intestinal involvement Occupational hmoty Prognosis Not observed Preserved Not observed Not observed Not observed Not observed Not observed Obligatory Favourable (skin and bone lesions tend to heal after removal from exposure) Common Loss of skin appendages Common Early symptom Common Common (Common) Usually spontaneous progression Vinyl Chloride- izing sclerosis o tional syndromreadily than the 4.1.4 Histolo*. 4.1,4.1 Cutaiu Several investig: disease (Cordter al. l972;a/ig<. we found only c 1967;,!ibrtrt et; neural changes' who suffered `rr> Darnel chen mis with disone broad interiacin faintly stained n Schiff (PAS). A. histiocytes was: The most notab of elastic fibres, full thickness w. sue. Skin appen Welker (1976) f noi exceeding t. some fibrous th; Vascular lc t capillaries were and pericapillar thelial cells with tionoflurwna ' myocytes, was to narrowing or Degenerative (Benoit 196* ;.i, hyaiinosis of :!iMeusner, Pacini 4.1.4.: Bond. The most stnkn worker with OA ening and hyaln most layer. Sup Jf UCC 069326 Sftsstfarrai RJ. Mjmtiltr the sacio-iliac i. davicls. man-wiforni and mi ami AJams till. 1976. of the fingen and orogressive sclevm. sometimes : lace (mostly on ned. sharply denpen and hands unaoon of Ray* th for other -Tidrome of diffuse immobil- .eW(Rj\13ud'i r.na with 'tarei titroderma jr < upeniti otf P anhydrous: k -t*ns kin appendages .nptom -ronuncous U0R Vin>! Chk>nti)>AnMiiud Disease 39 tang sclerosis of the skin with tapering off of fingertips was never seen ui the occupattonal ryndrome. After cessation of exposure the skin lesions seem to regress more readily than the osteolytic changes. 4.1.4 Histology -* i.J. I Cutaneous Lesions Several investigators described the hmomorphology of skin lesions in vinyl ciiionde disease iConlier et al. \966.Hams and^Janu 1967;,t/nn et ai. 1967,.Wrttc>iwr et al. 19-Z.Ungi e: al. 1974a: Vtltman et al. 1975. hWler 1976.Hahn et al. I9~o>. but we found only one descnption of bone histology in OAOL in the literature (Btnott 1967,Marin et al. 1967). Skin biopsies showed various degrees of dermal, vascular and neural changes which were essentially identical in pauents showing OaOL and in those who suffered `merely' from Raynaud's phenomenon. Dermal changes consisted of hyperkeratosis and pronounced thickening of the der mis with disonentation. swelling and nonilbrillary eosinophilic homogenisation of broad interlacing coDagen bundles. There was some degree of interstitial oedema which faintly stained mctachromatically with toiuidine blue, alcian blue and penodtc add* SclufT (PAS). An inflammatory reaction with infiltration of lymphocytes and a few histiocytes was scanty and, if present at all. of predominantly perivascular distribution. The most notable feature was marked disorganization, fragmentation and rarefication of clastic fibres. In areas corresponding to nodular or plaqucljlce skin inductions, the full thickness of the denial consisted of an accilular. partly hyaiir.ized collagenous tis sue. Skin appendages wen preserved. In 15 apparently les severtly affected workers. Walker (1976) found only some destruction of elastic tissue of tit* dermis, probably not exceeding normal age changes: in one worker with severe Raynaud's phenomenon some fibrous thickening of the media of dermal arterial was seen. Vascular lesions affected capillaries and small dermal arteries. Numerous dilated capillaries wets seen in the subepideraal papillae with swelling of endothelial eclis and perieapdlar oedema. Capillaries of the cutis showed cufflikc hyperplasia of pentheiial ceils with fibroblast transformation, hyilinoiu of vessel wails and final oblitera tion of lumina. Marked medial thickening of dermal arterioles, due to hypertrophy of myocytes, was accompanied by parietal fibrosis and hyalinosis. which ultimately led to narrowing or even complete oeduaon of the lumen. Degenerative lesions of small Jemsal nerves were mentioned by French investigators (Ben nt 1967-.Mam et al. 1967.Oiarelain andMorilhn 1967). They found sclerosing hyaiinosa of the perineurium with atrophy of neutofibrils. Tactile corpuscles (WagnerMeissner, Pacni) were unaffected. Bone Latov The man striking featuie in a biopsy specimen of the bone, obtained from a French worker with OAOL (ease 4 of both Benoit 1967.Mann et al. 1967) was marked thick ening and hyalinization of the periosteum with chondroid metaplasia of the inner most layer. Supplying capillaries and arterioles showed occlusive changes identical with  *31 40 W.K Lclbaclt mil II.J. Marsieller those observed in the demus. The bone matrix pet le m barely affected. There was minimal thinning or cortex, normal spongy bone and only mild fibrosis of the bone marrow. Experience with hisiomorpliwlogy of bone lesions in the familial and idiopathic type of acroosteolysis is limited, in the few cases where biopsy material could be ob tained, there was replacement of bone by nonspecific fibrous tissue, but inflammatory and degenerative changes or osteoid formation were not found (Dnpas et al. 1936: lsun and Buntstein 19J4; Greenberg and Street 1957; Sehwanwctler 1957). In this context, it should be kept in mind that Viola succeeded in reproducing dermal, vascular, neusal and skeletal lesions in the skin of the paws and in small meta tarsal bones of experimental animals which were very similar to those observed in ntan. Viola exposed nts to 30 000 ppm VCM.4 h/day. 5 days/week, for 12 months and de scribed the histology of these lesions in detail (1970b). 4.1 J Arteriography, Capillaroscopy, Infrared Thermography Arteriographic evaluation of the vascular tree of the hands revealed patency of the large arteries in all eases examined. The vascular lesions were almost invariably con fined to the small digital arteries, although the superficial and deep palmar arterial arch may occasionally show some narrowing and a paucity of side-branches (Lange et al. 1974a;.Moulin et al. 1974). The most prominent arteriographic features were ir regularities and segmental stenosis of digital arteries, ranging from localized or diffuse narrowing to subtotal or even total occlusion with development of collateral vessels. Besides, a conspicuous retardation of flow of contrast medium was noted, and peculiar tortuosities of patent digital arteries were found. Circumscribed hypervascularity of the terminal tufts and in the region of the wrists was noted in some cases (Benoit 1967.Lange et al. 1974a: Veltman et al. 1975-.fretton et al. 1976: J/cuorr et al. 1975: Gama and Men 1978). Angiographic findings in a larger group of 19 symp tomatic PVC workers with either Raynaud's phenomenon and/or acroosteolysis (5 19f> were recently described in detail by Koisehwit: et al. (1980). Raynaud's phenomenon had been observed to persist in these patients for prolonged periods after termination of exposure and even after roentgenological evidence of healing of ftsorptive bone defects in those who had formerly suffered from acroosteolysis. In addition to vary ing degrees of stenosis or occlusion of digital arteries with reopening of small collat eral vessels, acral hypervascularity and considerable retardation of perfusion in spite of premedication with tolazoline (Priscoline. t'nited States), the most conspicuous features observed in the majority of these patients (14/19) were circumscribed elonga tions and tortuosities of digital arteries resembling cirsoid aneurysms. An example is shown in Fig. 3 of generalized tortuosity and elongation of digital arteries in a 54year-old patient who started to complain of severe sensitivity to cold 3 yean after cessation of VCM exposure (about 1 year prior to death from both angiosarcoma of the liver and hepatocellular carcinoma). The pathogenesis of there 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. 1963.19o7). Vinyl i w Set it I!: 7 mb uce 069328  I Manreller There* as he bone Mipaihte J 1 be obilammatory i. 1936. slucing mull netsved in man. thi end de- v of the mly conjrtenal ti . were tr' or Ji.Tuse >1 vessels. Jl. -ymp* .*15/191 KMuncnon t.T'ination .'* bone * in vary* -oil collat-i in spue pCUQUS ilred eionp* vample is naSd"e after t.oma of - vucular diw lo de< of digital Vinyl Chionde-Assowuted Discjsc II ri*.3.i iMivpit'iit'ki* tomtom * and *lunfj(u*n >ii di^iul arteries Studies of microvascular changes by widc-ficld npiltery micmscopy (direct obser vations complemented by photography) of selected skin sites - such as nail folds, Gr.gcrpids. donum of phalanges and of proximal us terphaiangea! joints - demonstrat ed a vanety of capillary abnormalities, in. dilated or giant capillary loops, pale avascu lar anas, capillary and subungual haemorrhages. The abnormalities were similar to those seen in scleroderma but were usually les conspicuous, less numerous and of dif ferent distribution. In a survey of a group of 152 Amcr&an PVC workers, these capillaroscopic finding! proved to be significantly more prevalent than in 50 nonexposed control subjects (.Merer? tt al. 1976). Then was also a statistically significant differ ence in the prevalence of these abnormalities between symptomatic and asymptomatic PVC workers. Tie alterations were not only found in workers with clinical symptoms of disturbed acral circulation but also In 6 nonsymptomadc males with either VCMinduced angiosarcoma of the liver (2) or spitnomegalic portal hepatic fibrosa (4). A similar survey was later undertaken in an unselected sample of 129 employees of a PVC-produeing chemical plant in England with 26 employees of a non-PVC-produeng chemical plant serving as controls (.Marie? el al. 1978). The prevalence of capillary ab normalities found in these British workers, which wen of the same type and degree, was comparable to that in the American sample, although the latter included a larger number of more severely affected symptomatic patiena with greater mean length of employment (I S yean n )3 yean). In the authors' opinion, this suggested that VCMKitted disease may develop independently of differenen in manufacturing procedures. It also suggested that this easily detectable type of microvascular lesion may precede more senous VCM-indueed disorders. In a small subgroup of If clinically affected 42 W.K. Laibach and IIJ. Marstellcr British workers who were examined 6-24 montiis 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 was considered to be too small. The same type of capillaroscopic changes was also obKtved 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 Lajigmier-Lewowteka 1974). tnfnrvd thermography, another non-invasive method, used by Rivr et al. (1974) for the study of acral circulation, revealed abnormalities of surface temperature rang ing from marked hypothermia of terminal phalanges (which are normally warmer than the rest of the fingers) to "complete terminal amputation" in four PVC workers suf fering from OAOL. In one of them vascular disturbances as evidenced by infrared thermography persisted in spite of complete healing ofOAOL Stemn et al. (1975) demonstrated uneven blood flow in the fingers and patchy hyperthermia in the distal part of the OAOL-affccted left index and middle finger of their atypical case. Local ized acral hyperthermia seen on 1R thermography corresponded to the anpographic finding of circumscribed abnormal collections of small vessels (compensatory collat erals?) in the pulps of the affected fingen. Using IR thermography in a survey involv ing 143 PVC production worken and 56 controls, Williams et al. (1977) assessed the time needed Cot heat return after immersion of one hand for 10 s in a water bail) kept at 19*C; however, no difference between VCMvxposed subjects and controls and be tween groups within the exposed population was noted. 4.1.6 Immunological Studies Early experience with the syndrome ofoccupational acroosteolysis suggested certain similarities between this disorder and corresponding lesions seen in progressive systemic sclerosis (diffuse scleroderma). Differential diagnosis of these two unrelated conditions is now well established fTable 10). Such similarities stimulated the search for other manifestations of a sy/mic collagen disease, notably immunological features, as pro posed by Marin et al. in 1967. Warri et al. (1976a, b) carried out immunological studies in 58 worken from a British polymerization plant who were referred to them out of a total past and present work force of 320. Mean duration of exposure to VCM was 39 montiis (6-75 months). Of these 58 worken, 28 were symptomatic (Raynaud's phen omenon^: scleroderma of hands or feet. 6: OAOL, 2; sensitivity to cold, excessive fatigue,limb pain.panesthcsias). Sighthvperimmunoglobulinaemia.usually igC. the presence of mixed cyroglobulins. and in vivo convenion of both Cj and C were found in 19 patients in the symptomatic group, with additional evidence of reduced T<ell population and incteased B-cetl 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-titre antinuclear antibodies (IgC 1/20-1/50) in eight of the nine patients wtth Raynaud's phenomenon. Aggreptes of IgC, C4. C*, and fibrinogen/fibrin were reveal ed by direct immunofluorescence in the lumen of vessels, adherent to vascular endo thelium. Aggreprcs were similarly seen in the media and subintimai regions of small Vinyl Chi. and medic lung (1 ea: The au and bone i rbolic inter plasma pro which stirr cular occlt as s mult aton of tis to further Jayson et i suffering f; than in no ride dueiv Inane bi four Pol decrease in ever, Lang, alter Seph; 6 together agglutinins were obser iponsei pi: (1974a) an dcnce of at tion of rhe ttrminitio! immunoflu were later; creases in it taken up a d to sugge hyperpmr with far id three patie. with Rsyn; degrees of. runs were f ranp:TEi! scleroderm of which is In sunu autoimmun establish tli in VCM-ind IHJ. Manic!!;.* .it (termination i that amont ; condition, ipfllaroscopic n.2 fitters) for 2-5 years etal.(l?"4> Venture rang|y wanner than * workers tuf'f mt'rared etai.(l975) *>* m the distal 4 case. Localanpopaphic atory eollaisumy mvolv. '> assessed the aier bath kepi mrols ani be- * <nvcs>'su..n; *-d condiituns > for othei lures, as pro-4opcal siu iiei - `hem out oi a - VQt was ynaud'i phmid. excessive -ually 1|C. the C* were e of reduced i. in vivo con* evidence for ~ demonstrated --menu with in were reveal-ucularendo. ma of small Vi\| ChlonJe-Xssociated Oncaw 4 and medium-sited anciioies in biopsy specimens of the skin f 10 eases >. muscle and lungt I case each). Hie authors proposed as explanation for the induction and pathogenesis of skin and bone changes ai VCM-induced disease a theoretical model based on reactive meta bolic intermediates ofVCM formed during biotransfotmatmn binding covalently to plasma proteins. These may act as anugens tas a result of a structurally abnormal protein > which stimulate B<eil proliferation and antibody response Platelet aggregation, vas cular occlusion and ischaemia were thought to be secondary to complement activation as a result of formation of immune complexes which were implicated as possible medi ators of tissue injury. Ischaemia, U) turn, by leading to collagen synthesis, was believed to further activate the eompiemem pathway and thus to recycle the mechanism. Jayson et at. (1976b), who earned out collagen studies in a skin biopsy of one patient suffering from OAOL found the rate of collagen synthesis to be considerably higher than in normal controls. The pathogenesis of exerts collagen formsnon in vinyl chlo ride disease has not been ftaSy elucidated. In an earlier study no ayogiobulinaemia 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 {fiyeskowtka and Lengmiei'Xewowirte 1974). Later, how. ew.Lsngjuer~lewou.ieka et a!. (19*6) observed latent cr/oglobulinacmia, detectable titer Sephadex G-200 filtration, in IS of 22 workers with Raynaud's phenomenon (in 6 together with aeroosteolysis and sclerodermaiike changes). Again, then were no cold agglutinins delectable, but in five patients marginal to slight elevations of IgC levels were observed The authors suggested that a pathological alteration of immune re sponses plays a key role in the pathogenesis of vinyl chloride disease. Lunge et al. (1074a) and I'elman et al. (191!) concluded from their results that convincing evidense of autoimmune disease was lacking. Immunological studies including determina tion of rheumatoid factor (latex agglutination ten), quantitative immunoglobulin de termination (Mansni radial diffuaon technique) and autoanabody screening (indirect immunofluorescence) were initially introduced in our first series of 50 pahena but were later abandoned because of mostly neptivt results, except for occasional in creases in immunoglobulin levels Qlanrelier et aL 1975a). These studies were laser taken up again with an additional 43 pantos engaged in PVC production but still fail ed to suggest mote than an erratic connection (unpublished dau). W did not observe hypergammaglobulinaemia (see comment in Wrrf et al. 1976a) except in a few paueno with far advanced portal fibrosis and portal hypertension and in the terminal phase of three patients who died from angiosarcoma of the liver. In a group of IS PVC workers with Raynaud's phenomenon in whom arteriography of the hands disclosed various degrees of occlusion of digital arteries, autoantibodies, cryoglobulins and cold aggluti* oms were found in nonc;a moderately increased IgC level (1.93-3.68 g/Iitre;normal (ange; las* GJ-1 J g/litre) was teen in five patients who suffered from OAOL and sclerodermoid skin changes (unpublished 4au). Banin antibody litres (the specificity of which is doubtful) were negative. In summary, currently available evidence docs not seem sufficient to suggest an autoimmune disease as a pathogenetic mechanism. Further studies will be needed to establish the true significance of the pusibly transient immunologtcaJ abnormalities hi VCMenduccd duoiders. gj w r g! w jt ji.i 111ju tw j q p .i jM i w ia t !w /^!r 9 f i i > n m i L i r fw .g T u *'u i y , 1 u uh 44 W.K. Laibach and 11J. Mantclier Vinyl Chlonde-A> 4.1.7 Pathogenetic Considerations The clinical sympr many as ISSoftJi Raynaud's phenomenon as a premonitory clinical symptom, histomorphology in man survey was describe and experimental animals and angiologicai experience suggest that the common de developing chronic nominator in the pathophysiology of both skin and bone lesions in chronic VCM in character of nonm:* toxication is probably to be sought in the local impairment of blood circulation in In 1$"2 Kmm 9i peripheral regions, as Benoit pointed out as long ago as 1967. By reason of their vas had been routinely. l culature. the distal phalanges are the skeletal segments which may be most suscepuble time-weighted aver:*, to impairment of blood supply. particularly to disturbances of microcirculation {Gama environmental data i and Meira 1978). Yet the answer to the next question, the pathogenesis of peripheral vascular injury in vinyl chloride disease, is unknown. It still remains largely a matter of conjecture how a volatile toxic compound that is taken up via inhalation, distributed wise multiple linear tion and. to a lesser level of past exposu* * throughout the systemic circulation and metabolized (bioactivated) in the liver, can i the individuals stud r bring about, apparently only in a small number of predisposed individuals, after a van- j TWA levels of300 p t able period of latency* severe vascular injury and (probably secondary) damage to peri in clinical laboretor. pheral tissue. Some conceivable mechanisms are briefly listed in a previous chapter (see ed BSP retention w: Sect. 3.0J). but no conclusion can be drawn as to their relative significance. case (Marsieller et a. In West Ccrmar- dermatologists in Bi 4.2 Non-malignanr Liver Disease in Vinyl Chloride/Polyvinyl Chloride At first sight, the s> Production Workers derma. This provoke Progressive systemic a first group of 13 p. Long before Raynaud's phenomenon or osteolytic lesions were observed in PVC pro from a nearby PVC-- duction workers. Tnbukh ct al. (1949) studied environmental conditions in a Russian from either 0A0L< plant where polyvinyl chloride resins were produced and compounded. Without going phageaJ varices due i into detail, the authors pointed out that moderate nontender hepatomegaly was found a group of 20 relativ in a target porportion of a group of 73 workers (4S males. 25 females) mostly engaged in PVC compounding; *anictcric hepatitis' was diagnosed in 21 of them (15 d. 6 9). Al previous lirer disease Medical Depanmen t though the authors knew about the narcotic action of high concentrations of VCM patient and revealed (75-250 mg/Iitre 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 Capa 'sfibrosis of ly, marked ponai h> al. 1973). It wv now d compounds desired from halogenated aromatic hydrocarbons (such as chlorinated naphthalenes and diphenyls) used as plasticizers responsible for the systemic toxicity. encompassed a large Hence JUte et al. (ly t They urged, however, that strict monitoring of the health of these workers should be In retrospect, th; t introduced to prevent the development of severe lirer damage, and they suggested the installation of ventilation fadlitiei of sufficient capacity. Nonictcric hepatomegaly was again recorded by Sucw et al. (1963) 14 yean later spleen alterations in t the long latency peril*disease which is acco:t in almost one-third of the total work population (51 of 168 employees) of two Rum anian FVC-produdng plants, including 10 cases with additional splenomegaly. Liver hepatic parenchymal Only 3 months !.> biopsy in two of there workers revealed chronic hepatitis. Studying the prevalence of was surpassed by the. temporary disablement due to liver disease among 350 employees of the Sverdlovsk lit er, an exceedingly r i plastics industry,hahm (1965) found the highest morbidity among employees of the PVC production unit, compared with other units engaged in the production of non- workforce of274emr ican plant {Creech et * t] PVC plastic materials; 170 workers of ancillary industries served as control subjects. upper gastrointestinal o HJ. Manteiler Vtoiogy in man rommon deonic VOt inuculauon in it of their vaion susceptible :rcubaon i.Gama i, of peripheral -ye!y a matter of ni. distributed the liver, on tab, after a vanjamage to peri wig chapter Viet -tiicance. J in PVC proi a Russian ^inui going v war found mostly engaged ,U5d.*5). Al ums of vr\1 Sey explicitly the powdery ther volatile chlorinated -teraic toxicity, iken should be > sufpsted the 114 yean later t) of two Rumuggaiy. Liver c pttvalene* f lie Sverdlovsk mpkjyw of the >etion of non itral subjects. Vinvl C!iind*'AkVUti.J DiwJM' ai The clinical symptomatology' of - typically nonictene - liver disease observed in as many as I 5" of tlte current work louc of the PVC production unit during a 3-year survey was described as having been consistent wish the diagnosis of an insidiously developing chronic hepatitis. No histological data wen available, however, and the true character of nonmalignam liver disease found in these workers remained obscure. In 1972 Kramer and Murehler examined a group of 98 healthy male workers who had been routinely exposed to VCM for periods up to 25 years and for whom career rime-weighted average exposure estimates were available, in an attempt to correlate environmental data and tesults of a medical surveillance programme by means of step wise multiple linear regression analysis, it emerged that bromsulphthalcm (BSP) reten tion and. to a lesser Jejree. the icterus index were significantly correlated with the level of pair exposure to VCM. Although no overt dinical disease was found in any of the individuals studied.AT/muer and.\tutchUr concluded that exposure to VCM at TWA levels of 300 ppm or mote for s working lifetime could result in certain changes in clinical laboratory parameters. As it later turned out. slightly to moderately increas ed BSP intention was the most consistently pathological test for VCM-inductd liver dis ease t.\fanteller e: al. 1975a). In West Germany the first cases of occupational OAOL were observed in 1972 by deraatoJojisri in Bonn (Ju!>c and Leuft 19~l:Juht ei al. 1973;Stem et al. 1973a. b). At first sight, the symptomatology appeared to resemble atypical progressive sclero derma. This provoked a thorough search for manifestations of visceral involvement. Progressive systemic sclerosis, however, could be excluded. On medical examination of a first group of 13 polyclearers who wen referred to the Department of Dermatology from a nearby PVC-producmf 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 (Julie et al. 1973). Further invtsugadon of a group of 20 relatively young PVC production workers fmean age:40 yeas), in whom previous liver disease could be excluded, was carried out in collaboration with the Medical Department. Peritoneoscopy and guided liver biopsy were performed in each patient and revealed varying degrees of nonetrrliorie poml pemunnoUal end subconsular jibrosis ofthe liter, with splenomegaly, thrombocytopenia and, less frequent ly. marked portal hypertension, but stnkingly Uttle hepatic dysfunction (Mantelier ct al. 1973). It was now realised that the disease spectrum in VCM-cxposcJ individuals encompassed a larger scope of injuries and, in fact, suggested a systemic toxie effect. Hence Juite et al. (1973) proposed the term "vinyl chloride disease'. In retrospect, this comparatively late recognition of the true nature of liver and spleen alteration; in chronic VCM intoxication can be attributed, at leas; in part, to the long latency penod as well as the intidious onset and count of this type of liver disease which is accompanied, even far into the advanced stages, by only minimal hepatic parenchymal dysfunction. Only 3 months later, however, in February 1974 the significance of this discovery was surpassed by the alarming announcement that four cases ofonpcsarcvma of the brer, an exceedingly rare malignant tumour, had been found among a comparatively small work force of 274 employees of the FVC polymerization section of a large North Amer ican plant (Creech al. 1974a). Two of these four patients had first presented with upper gastrointestinal bleeding due to portal hypertension between 1964 and 1970. /j T I i i: 46 W.K Lelbsi'h and H.J. Marstelier There is no longer any doubt that chronic exposure to vinyl chloride monomer can produce two different types of liver disease in man as well as in experimental animals: 1) Noncmhotic portal hypertension 2) Angiosarcoma of the liver. The two conditions have one feature in common: they ate both rare disorders which are not easily recognized dunng life. Nondrrhotic portal hypertension and (often inconspicuous) portal fibrosis are not pathognomonic. Primary splenic enlargement and gastroocsophagea) haemorrhage due to marked portal hypertension in the absence of. or preceding, the development of cirrhosis was first described by Banti in 1894. As `Band's syndrome', this symptom complex and its aetiology and pathogenesis have continued to be a matter of debate. Under the designation Idiopathic', or 'primary, portal hypertension' the syndrome has been observed notably in India and other Southeast Asian regions (Ramahngaswami et al. 1962, Imanafa et al. 1962;Basu et al. 1967a, b:Bo,veret si. 1967:5ew0 et al. 1971), It has been seen only sporadically in the Western World (Roussclot 1940: Ravenna I940;7ude/cet al. 1959;/bto/i et al. 1962. Stillerand Brandt ]962,Stderys and I `elltos 1964:Mlkkehen et al. 1965;/6er 1970: Eseartin Marin et al. 1974; MenJenftell et al. 1974; Grwmis 1975; Villencuve et al. 1976). Iber (1969) estimated that "centers throughout the world reviewing their experience with portal hyperten sion encounter 3 to 5$ of patients w'ho 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 noncirrhottc portal fibrosis observed in India.unknown toxins contained in indigenous drugs, herbal medicines or adulterated food might hive been responsible for the condition (Soma et 1.1971). Vitteneuve et al. (1976) suggested that, apart from VCM and inorganic atsenicals, other still unidentified toxins could be the cause of this syndrome. Idio pathic portal hypertension has also been observed to occur in association with known hepatotoxic agents, their common link with VCM being, so far with the exception of vitamin A, the induction of angiosarcoma of the liver. These agents art: 1 a) Inorganic enenicals (Zccfen et al. 1970-.Seale and Azzopanli 1971. Knolle et al. 1974; Morris et el. 1974, Huer et al. 1975; Villencuve et al. 1976; Cbu/u/ww et al. 1979); b) Hyperritaminom A (Muentertt al. 1971 ,Russell et al. 1973,1974; Hruban et al. 1974;Arteretal. 1977); and c) Recently,copper sulphate in Portuguese vineyard workers (Pimentel ind.Vnerw 1977). Arsenical preparations (usually prescribed as Fowler's solution - potassium anenite) have in the past been used as a tonic in neurasthenia, as an adjunct to iron therapy for anaemia, as antiepileptic drop and weD into the 1950s for the treatment of psoriasis. In this context, Bantf's remark in his original paper (1898) that anaemia accompanying primary splenomegaly responded best to arsenical preparations is of note. In a renowned German pharmacology textbook of this period OVot/tnafrl and Rossbaelt 1880) Fowler's solution is also listed as a traditional antimaianal drug of r and HJ Marsteller itoridt monomer can perimental anmuit: tare disorders rnsl fibrosis art not al haemorrhage due development ot '. this symptom . nutter of debate. hi* the syndrome has 16":Senu et aJ. jittfot l WO: '.tndt !962:Stitns reial. 19W; r (1969) estimated h portal nypertencategory of ctrrhosis U that in nonciniiotie genous drugs heroal adition iSame et tnorerni: eyr.dromt Idio. ,,tion an h known .h the exes- non of we: i9?l:A*aiteetal. Lt/w/ii/ww et al. *3. \974-.Hmhan et rimenitl and Menaet -i - potassium an adjunct to iron Ot for tht treatment IB9B) that anaemia ' reparations is of ltd INothntqel and mnaianai drug of Vinyl Chloride-Associated Disease 47 long standing. Guinurmti and Vimtueatti (1979) ttcemly implicated an indigenous Thai medicine contanin g arsenic as a possible aatiologicai factor in a case of idiopathic portal hypertension. Darn et al. 1197Q) found significantly elevated levels of arsenic in liver tasue specimens of four of nine Indian patients with idiopathic porta! hyperten sion resulting from chronic arsenic intoxication i contaminated dnnting water, use of Ayurvedic medicines). Typically.liver disease in these eases occurs in conjunction with other evidence of chronic arsenic intoxication, such as skin pigmentation, palmar and plantar hyperkeratosis, skin cancer and semetimes carcinoma m* other sues. However, neither histological nor radiolopcal or haemodynamic criteria permit a dear distinc tion between Idiopathic' portal hypertension and nondrriionc portal hypertension caused by chronic arsenic tcxification or chrome exposure to VCM, as was demon strated by ViUtneuvt et al. (1976) in a study of five patients. After prolonged treatment with excessively high doses of vitamin A (psoriasis, ichthyosis and other dermatological conditions, adjuvant cancer therapy and in health faddism) chronic intoxication has been seen to cause hepatic fibrosis and cirrhosis (Muentar et al. l971;/Zcc/rmen et al. 1977,Kdtier et al. l9";/tusif// et al. 1973. 1974). Storage of vitamin A in hepatocytes and one type of fat storing, nonphagocytic pensinusoidai ceils [lto cells (/to and -Vemoro 1952)] could be demonstrated by fluo rescence microscopy. Stimulation and proliferation of (to cells, wlueh as probably fibroblast precursors (Popper and Vdenfrtcnd 1970, Schnack et al. 157). provokes an inertas* in basement-membrane-Ukt matenal and collagen within the pensinusoidai space and leads to pensinusoidai fibrosis with partial obliteration of Disse's spaces and the sinusoidal lumen (Hrubon et al. 1974). The recognition of idiopathic portal hypertension, hepatic fibrosis, cirrhosis and angiosarcoma of the liver coexistent with excessively abundant hepatic deposition of copper (besides evidence of 'vineyard sprayer's lung*) in a group of 30 vineyard workers in Portugal is. to our knowledge, the first report in which chronic copper intoxication is implicated as the attiological agent For periods varying from 3 to 45 yean, these workers had been engaged in spraying vineyards with a mixture containing copper sulphate on 15-100 days per year. The authors noted a daw morphological resem blance of the lesions to those resulting from exposure to inorganic arscnicals and to vinyl chloride (Pimentel and Mcnezn 1977). Although extrinsic chronic copper intoxi cation is virtually unknown in man. potential htpatotoxicity of long-continued uptake of copper was discussed by Blomtield et al. in 1971 in connection with recurrent haemodialysis. Although nonmalignant liver disease seems to b* a more common lesion in PVC production workers than angiosarcoma, it lias received less attention than the spectac ular discovery of tnt rare hepatic neoplasm. In continuation of our first two surveys (Afenretlcr et al. 1973.1975a. b), we have now (end of I9$0 observed 17 patients (ad members of a total work force of approximately I BO polymerization workers) in whom clinical and morphological examination, including peritoneoscopy and guided liver biopsy, revealed advanced portal hypertension (Table 11). A larger proportion of them first presented with symptoms ofunheralded gastrointestinal bleeding. On follow up. we strongly suspected that anposreoma was developing in four of them but were unable to prove it during life. Only post-mortem examination finally confirmed the diagnosis. In s smaller tones of seven patients with noncurhotic portal fibrosis and s r W.K. Leibach and H.J. Manteller Table 11.1' PVC workers with advanced portal iiypertcnion i marked oesophageal varices. episodes of upper CI bleeding, splenomegaly t Age at diagnosis Duration of exposure rtntoncuseopic and Vo, (years) /years* months) histological diagnosis i 30 31 3 32 4 35 5 35 6 39 7 39 8 41 94 41 104 47 11 50 i: ;i 13 52 14 52 15 54 16 * 58 17s 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 fibrosis Xoncirrhotic fibrosis Noncirr!' otic fibrosis Noncirrhoiu fibrosis Noncirrhotic fibrosis Xoncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis * On follow-up patients 5.9.10. 16 and I' subsequently developed angiosarcoma of the liver and died 3-6 years after diagnosis of portal hypertension. Patients 6 and 14 are at present 11981) under observation for suspected development of angio sarcoma of the liver, 6 and 11 years after pentoneoscoptc diagnosis of portal fi brosis associated ponaJ hypertension,Smith 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-induced hepatic fibrosis per se is probably not a premalignant lesion. 4.2.1 Oinical Manifestations of Non-malignant Liver Disease Kiysical examination is usually disappointing. In the more advanced stages of VCMinduced nonmalignant liver disease, palpable splenomegaly and a slightly to moderate ly enlarged liver may be the only physical signs. On palpation, we found hepatomegaly in 31 and splenomegaly in 16 of 50 selected PVC production workers who had been heavily exposed in the past (Manteller et al. 1975a). UUs et al. (1975) reported hepa tomegaly in 15% and splenomegaly in 3.4% of 354 consecutively examined employees (267 currently employed, 87 former workers) of one PVC polymerization plant in New York State, USA, a number which included vfnuaHy the entire current produc tion work fore*. A significantly higher prevalence of hepatomegaly was found in those Vinyl Chlorv exposed for r *plenomega!> In contra.ment of heps wwet.gynanot seen. Eve plialopathy d workers only It is pu2zli preceded adv. only one caie development 4.2.2 Labor: Owing to the not the target value for the l This makes it' 1974;Creec/t thrombocytof logical bioche; the levels of s. quent (Mantc (ICC: 0.5 and liver function workers of a (Tamburro et progressively of abnormal S there was ovei phosphatase I alkaline phosp megaiy and/c Exeept for and Vettmen i the reticuiocy parameters us' presenting f*a' Sion (Smith et be dealt with - Assessment malic workers facture ofPVl coproporphyn IJ Mar*ieller v.oric and 44 iiufno'i' -uv 11bruin w fibrous uc fibrous ..tic fibroin me fibrosis ime fibroin mic f|bro*H - -tie fibroin .uc cirrhosis ' an fibrom tie fibroin i >tw fibroin me fibroin ne fibroin i.hic fibroin *i.* eirrb.O'ii -lie fibrein t-arcorr.s ot menu 0 and -an^io- p.irtai fi- .-.Hein oi rdxnesw * idualiiuMhi- % to de!op >hly not a |-re* oiiofVCNly to moderate: ncpatomegaly .ho had been .-.ported hepatcj employees * piam in irent producfound in those Vi.i>! CUondc-AMMiatcd DivCa-* 49 exposed for more than 5 yean, whereas the JilVerence in tire prevalence oi paipabie splenomegaly was not si|mticant. In contrast to cirrhosis of the liver, clinical symptoms indicating tenous impairmeni of hcoauc function sueii as jaundice, vascular spiden. palmar erythema, teiar.^iectases. jynaceomastia. peripheral oedema and asr.tes or hepatic encephalopathy are not seen. Even alter massive bleedini from oesophageal vances portosystemic cneephaiepathy does not ieveiop. Ascites and hepatic coma hare been observed m there workers only in terminal stages of anporarcoma of the lirer. It is pualing that aeroosteolysis and sclerodermoid skin induration have only rarely preceded advanced stages of VCNUnduced lirer disease. To our knowledge there is only one care of anposarcona of the liver on record which was associated with prior development of acroostcolyw (Roche et al. 1978). 4_T_; Laboratory Findinp Owing to the fact that hepatocytes. although being the primary site of metabolism, are not the target of toxicity, standard biochemical lirer function tests ate only of limited value for the detection ofliver disease in populations at risk (Williams et al. I97fb). This makes it very difficult to devise adequate screening programmes (Martin ct al. 197-t. Cratch and.UWd. 1975; hVerr ct al. 1975,Berk at al. 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 alkaline phosphatase. SCOT and SCPT were considerably less fre quent {Montciler ct al. 1975a). Another dye-removal test, indocyanine green clearance fICC: OS and 5.0 mg.'kg), also proved to be more reliable than standard biochemical live: function tests in correctly iden-.i/ing early hepatic injury in 1200 vinyl chloride workers or s chemical plant in Louisvute, Kentucky, during a 4-ycar screening penod (Tamburro et al. 1971b). Tie expos- ;c rank was found to be closely correlated with progressively increasing frequency of abnormal ICC dearance. whereas the frequency of abnormal SCOT, and alkaline phosphatase only increased in late stages, often when there was oven clinical disease. In the survey conducted by Lilia tt at. (1975), alkaline phospliataie levels were elevated in 16.67- of the 554 workers examined. In their senes, alkaline phosphatase was also closely correlated with the clinical symptom of hepato megaly and/or splenomegaly. Except for thrombocytopenia (1**> than 150 x 10* platelets/Iitte) which Lange and I'ctmon (1977) found to be present in 76 of 100 workers, and a slight increase in the reticulocyte count (in 35 of 79 workers,c/ig* and Veitnun 1977), haematoiogiea! parameters usually do not contribute to the diagnosis. Thrombocytopenia was also the presenting feature in two of seven British worked with nondrehotic portal hyperten sion (Smith et al. 1976a). Thrombocytopenia and abnormal platelet function tests will be dealt with separately in Sect. 44.1. Assessment of urinary excretion of porphyrins and porphyrin precursor! in sympto matic workers who had been enpgtd in the production of PVC (n * 23) or the manu facture of PVC artides (n 17) revealed varying but mostly mild degrees of secondary copropotphyrmuria in the majority of them (Lange et al. 1976b). Die significance of i 7 so W.JC- Lelbachand H.J. Manteller these findings as an indication of toxic liver damage is not clear and the relation to previous exposure to VCM remains to be determined. 4.23 Cross Inspection of the Liver and Spleen The gross appearance of the liver, as assessed by peritoneoscopy (.Marstclkr et al. 1975a. b.Monrellcr and Lelbach \9Ti,Lelbach and MarsteUcr 1977) or at exploratory laparotomy, is that of a normal-sued 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 sli^ttly uneven with shallow indentations, but it may be finely granular, trabeeulated or have a peau d'orange-like appearance. At most, there are micronodular changes but the diffuse coarse nodularity of cirrhosis is only rarely seen. Progression to frank cirrhosis with severe derangement of hepatic lobular architecture was observed by Smith and Williams (1974), and also in two of our recent cases in combination with development of angiosarcoma. On palpation (dirtet or by pentoneoscopic probe), the texture of the liver is normal or only slightly firmer than usual. Indirect peiitoneoscopic evidence of portal hyper tension is presented by increased vascularity of the falciform ligament and the intes tinal serosa or numerous dilated tortuous vessels in adhesions draining to the abdomi nal wall. Even in advanced stages, symptoms of pronounced portal hypertension often Fig. 4. PcritoncoKopic view of left hepatic lobe in noncirrhotic portal hypertension (January 1979). Blunted anterior edge, smooth to finely granular surface, conspicuous patch) capsular fibrosu. (aT-year-old autoclave cleaner. VCM exposure 196J-74. I97J thrombocytopenia as first sips. From 1974 to 1979, marked progression of portal hypertension with splenomegaly and one episode of bleeding from oesophageal varices.I See also Fig. 5 (patient 6 in Table 11) Vmyt Chi contras: peetedly s is a focal w opacities.' tstellate sc: ing (\lant> tissue in C extending nective tis: processes i: or more dn - are seen in 4.2.4 Hist Histologic/ is general]> Sts, strikin'fibrosis are (Fig. 5a-di reactions. . throughout fibrosis. Su tological er 1975). Deper.ji date of bic; nant liver o ject to mark ations is sc. Thomas IV* 1976). but (iPopper ti u 4.2.4. J Hl. In its fully J of dense, pj> bile ducts a. with format! central and of connects with enlarge pensinusoiJ. oidal walls.: Muller et al. '! J Marsteilcr elation to ..ret il. t exploratory tipn with mcoscopy aiso l>Kk tt al. i with shallow !'orange-like mt nodutinty ierangerntn it, and also :oma. liver is normal oral hyperi tne iniesthe abdomi'tension ofier. > rertension conspicuous 'bJ-74. .*wun of ii wiptuptii Vinyl l "blonde-Aociated Disease 51 contrast sharply not only with minimal alterations of the surface but also with unex pectedly scanty histological evidence of hepatic fibrosis. The most conspicuous feature is a focal or diffuse capsular fibrosis of varying pattern (Fig. A), presenting as whitish opacities. Tlie degree of capsular involvement ranges from diffuse tiny commalike or stellate scan to coarsely reticular and irregularly patchy milk-white capsular thicken ing {Mjrtreller et al. 1975a). Hisiolop showed that this focal increase of connective tissue in Ciisson's capsule may extend into the parenchyma and connect with septa extending from entirpng fibrosed portal tracts lPopper and Ti-omos 1 75). The con nective tissue capsule of the enlarged spleen also seems to be sensitive to VCM-induced processes that have taken place in the underlying tissue so that focal white thickening or more diffuse opacities together with circumscribed subcapsuiar haemorrhagic cysts are seen in eases with marked splenomegaly. 4.2.4 Histology Histological examination of biopsy specimens shows that normal lobular architecture is generally maintained, but varying patterns of portal and, in some cases, septal fibro sis. sinking intralobular perisinusoids) fibrosis, and focal capsular and subcapsuiar fibrosis arc found in combination with peculiar alterations of sinusoidal lining cells (Fig. 5a--d). Hepatocellular changes usually play negligible role and inflammatory reactions, if present at all, are insignificant. Tlie lesions ate distributed quite irregularly ihrougnout the liver and may vary from minor inconspicuous degrees to quite striking fibrous. Surgical wedge biopsy of sufficient depth appears to be more suitable for histolopca. evaluation than needle biopsy specimens (SnurH ct al. 1976a: Blendis ct al. 1978). Depending on length and degree of exposure, interval between last exposure and date of biopsy, as well as individual factors, histopathology of VCM-induced nonroalignant liver disease is represented by the following features whox manifestation is sub ject to marked interindividual and topical variation: the same variability of tissue aiterauons is seen in the nontumorous anas of the liver in angiosarcoma (Popper and Thomas 1975. Prows etal. 1975 ifier* tt al. 19"6:Gfrr* et al. 1975: Weinbrtn 1976). but in these eases the nontumorous lesions may be even more conspicuous (Popper et al. 1978). tJJ.I Hepatic Fibrosis In its fully developed form, minimal to marked enlargement of portal tracts by excess of dense, paucicellular connective tissue, which in advanced cases contains proliferated bile ducts and some periductular inflammation,may in ran instances be combined with formation of periportal septa tinting portal tracts or. even more ranly, connect central and portal canals. Other portal anas appear almost normal. Focal accumulation of connective tissue in the thickened CUsson's capsule may be connected by septa with enlatged inftacapsutir portal tracts. A more striking featun is an intralobular pcnsinusoidal 'netlike' fibrosis with more or less prominent coDagenization of sinus oidal walls, in some anas even progressing to frank capdtinzation (CeJifk ct al. 1975: .4(tiller et al. 1975). The focal intnsinusoidal fibrosis nay be subtle and in some earn W.K. Laibach jnJ H.J, Mjrifeller Mantel ler ..4' **1r.,C.?1". ' 3'VjS. v Vin>l Chlcrsdt-\*tocutcd Di-os* 5? ## : *i a ` *% *v*,lr *i w `V *, rt*roii H4E, *aet toand * T5T ' .b *? F>o i?- TSfv . ~ . :* *v * Fig. Sc Focal penal fibrosis (left upper corner; and reticulated perisinusoidal fibrous with activated proliferating and pleomorphic sinusoidal lining cells. Trichromc (Goldnerl *tarn, blue filter, a 150. d Conspicuous focal dilatation of sinusoids. Activation and moderate polymorphism of proliferated hypeirhromatie sinusoidal lining cells. Enlarged hcpatocytcs with iiypc.-phromauc nuclei, some of them binuclear. t Potential precursor stage of jngiesarcome*) Courtesy of Professor Miiller-Wallrat. Institute of Patnology. Amberg. H A E. a 4Q0 54 W.K. kelbach and H J Mareiciler may be recognized only in connective tissue stains. Trkhe et al. (10751 pointed out that in one worker with seven actoostcolysis but normal hepatic function and essen tial])' normal liver histology on light microscopy (except for a minimal and easily over looked increase of perisintisoidal collagen in occasional lobules), electron microscopy revealed a striking cenuilobuter innease in collagen between hepatocytes and in Disses spaces together with proliferation and hyperplasia of sinusoidal lining cells (see also Kurokawa et al. 1977). The same ultrastmctutal deposition of peritinusoidal collagen was observed by Schsacnberj 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 histones not mentioned) (Sommenchild and Kluft 1971 ,Klugt et al. 1970; Tandem et al. 1970). 4,2.4.2 Sinusoidal Lining Calls .Marked focal proliferation and hyperplasia of sinusoidal lining cells with nuclear poly morphism and hyperehromisia art the most impressive features of the mesenchymal lesion. The hyperchromatic nuclei of these cells may show a bizarre shape or resemble short pep, and are often amnpd in a chainlike fashion (Ctdigk et al. 1975). These pensinusoidal and sinusoidal cells indude three types: (1) normal endothelial cells, (2) lipocytes (Ito cells), considered to be precursors of fibroblasts and (3) plump cells with spindle-shaped nuelei and PAS-positive cytoplasm. Formation of excess rettculin suggests fibroblastic activity of tome 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 sup. 42.4.3 Hepatocym Unimpressive, nonspecific, depnerativt and adaptive lesions (such as minor degrees of fatty degeneration, cloudy swelling, ballooning or vacuolar depneration, increase of lipofusdn pigment and proliferation of smooth endoplasmatic reticulum of hepato cytes in focal areas without inflammatory reactions), can be seen to disappear gradual ly with increasing intervals between the test exposure and the date of biopsy, in con trast to the apparently irreversible damage to mesenchymal structures (Ctdigk et al. 1975,1977,Muller et al. 1975). In poorly demarcated areas there is hyperplasia and hypertrophy of hepatocytes with polyploidy and increased number of binuclcated cells. Two types of focal hepatocytic proliferation associated with varying degrees of sinusoidal cell alterations were recently described and are thought to play some as yet undefined role in the precursor sup of angiosarcoma (Popper et al. 1973). 4.24.4 Histology Oftht Spittn Unless splenectomy is carried out in vinyl chloride disease, tissue specimens of the spleen are less easily obtainable than liver biopsy material. Popper and Tltomas (1975) Vinyl Chlonde and Thonm et. to be chancteri pneous red pul follicles with mi endothelial cells occasional fresh spicuous fibrosis In ten cases* Htustmenn and terial, together v splcnectomy. TIi process. Excess a tive tissue, notai: and white pulp. There was scanu meshwork and n and diameter of. of the pulp cord: formation of bir collapn fibrils, b the reticular com volume with pars matron of capilla found within the thrombocytes by hineed pooling o help to explain m suges of vinyl chi and Heusermaiw < VCM-induced spk of the liver or ex: in the spleen in vj dieate a primary . port correlating c: tients is being pre. the spleen in nom b!t for company *22 Pathophysi The pathophysiol' unresolved problei to splenoportograi of intrahepatic vai venous radicles (fi end a normal, or o ucc 069342 IHJ Mamtllfr pointed out jn and ttttnmd easily ovr* -l microscopy n and in Disie* :0s (set also tidal collagen we could ob*ges (enlarge* and ttsuiuni ^physiology n a number of rnnal histones -den at al. nuclear poly* nesenchymal -pc or resemble 1073). These helial cells. Oj plump cells -scesj reticalin ds. nnt duh reason to be* S*- Hktr degrees of tt. increase of nofhcpato* appear gradual* Mtpsy, in con* '*difk et al. rwrpiisi* and 'mudeated mg degrees of ly some as yet >- cm of the /homer (197J) Vinyl Chlonde-Assodated Disease JS and Thomas et al. (1975) found the cut surface ofsurgically removed enlarged spleens to be channelized 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, dilauuon of red pulp sinuses luted by endothelial cells ofvariable, often cubotdal shape, thickening of the pulp cords with occasional fresh haemorrhages, and in one cate Candy-Gamna bodies, but only incon spicuous fibrosa of the red pulp. In ten eases we obtained needle biopsy specimens of spleen tissue ar peritoneoscopy'. Htuicrmttm and Stum f1977b) and Sturt and Htutermann (1978) studied this ma terial. together with spleen tissue specimens available from three spleens obtained at splenectomy. They found evidence for an involvement of the spleen in the fibrous process. Exsms amounts of needy formed extracellular elements of reticular connec tive tissue, notably collagen. produced by stimulation of fibroblastic ceils of the red Aid white pulp, particularly in perifollicular and subcapsular areas, were observed. There was scamng of pcrianenal lymphatic sheaths, obliteration of the piEp cord methwork and reduction of pulp cord volume, in addition to an increase in number and diameter of sinuses. The reticular connective tissue of the walls of the sinuses and of the pulp cords showed marked alterations with thickening of reticular fibres and formation of boane platellkc amorphous structures containing irregularly dismbuted collagen fibnls. Nanowing of the labyrinthine cords! tissue with marked increase of the reticular connective tissue caused s reduction of microcircuittory sequestration volume with parallel decrease of the number of pulp cord macrophages and approxi mation of capillaries and sinuses. Frequently, focal accumulation of platelea was found within the narrowed pulp cordbed in addition to increased phagocytosis of thrombocytes by residual macrophages. This lends support to the hypothesis of en hanced pooling of pisteleu in the rpieen (fftustrmann and Stunt 1977a), and may help to explain the pathogenesis of thrombocytopenia often seen even in the eariy stages of nnyt chloride disease. By structural analysis of histomctrical results.5rtirrr and Heusetmann {1911) outlined certain diagnostic criteria for the differentiation of VCM^nduced splenic alterations from those seen in portal hypertension due to cirrhosis of the liver or extnhcpatic portal vein oedusoh. They concluded that fibronc changes in the spleen in vinyl chloride disease an not the result of portal hypertension but in dicate a primary acaon of VCM or its metabolites on the spleen. A comprehensive report correlating dinical and morphological dan gathered from this group of 13 pa tients is being prepared for publication at present. Results of histometricai studies of the spleen in noncinhoric portal hypertension of unknown aetiology are now nail able for comparison (Sett 1965; Yamamoto 1978,1979). *2J Pathophysolop of Portal Hypertension The pathophysiology of portal hypertension in VCM-induced liver disease is v yet an unresolved problem. Patency of the portal vein was demonstrated in all eases subjected to splenoportography. Portography usually showed no or only minimal derangement of intnhepatic vascular pattern such as tapering or `cut-ofT of small peripheral portal venous radicles (Bltudis et al. 1978; VUtenewte et al. 1976). High intrasplenic pressure and a normal, or only slightly raised, wedged hepatic vein pressure indicate that the / '< V1i IV r r i 'f jF. t - i lr ; t.* I J 5 6 5 W.K. Ulbach anj HJ Marxiclicr portal flo it obstructed at the tinusoiJal or presinusoidal level. In a group of five PVC workers selected for haemodynamic studies. Blendts et al. (1978) could not demon strate a direct relationship between the de^ec 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 al. (1975) that the increased splenic and hepatic blood flow as a result of decreased splenic resistance in splenomegaly cannot proper!) 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 peruinusoulal fibrosis. Bkiuiis et al. (197$) found no correlation between spleen or estimated liver blood Vinyl flow c veiled r 4.2.6 In 19' tic fib could tests;; biopsy of bnC the fib cytesf ingee! follow massii exposi sareo/r or less terrain oped {.- Lie detenu (BMHF after h. and toi aid of the reu inertas PVCp. sack ei fit. da. b. Progression of noncinhotic portal hypertension despite termination of ex posure. Oesophageal varices. (Autoclave cleaner, age at diapiosis: 35 yean. VCM-ex- P0MK,,I962-1972. 1972 Raynaud's phenomenon, sklerodermotd skin indurations, thrombocytopenia, splenomegaly, and grade I oesophageal vances Gradual progression of p nal hypertension. Sudden death from ruptured anaplastic angiosarcoma of the liver in June 1971. Hist logically only mild pcristnusoidal fibrosis in nontumorous, areas) IJCC 069344 4J Ai 43.1 I Primary (angioh haeman cell sarc sarcoma vasculai one at e hood (ft the num - Laibach and HJ. Mamelier ' level. In a group of five FVC (1978) could not demonnbresis in needle biopsy specmd that the distribution of wggested by Poppa- and J splenic and hepatic blood ,$aly cannot property be ac cent at adaptive distension d peasinusoidal fibrosis. or estimated liver blood * despite termination of exipteeu: 3$ years. VCM<xNkrmoid skin indurations. I vances. Gradual ptoftesston -iaslic angiosarcoma of the l fibrosis in nontumorous Vinyl Chlonde-A*<oc:atfd t)eaw ' J7 flow and the portal pressure. However, they point out that this itlationslup may be veiled by the amount of blood bypassing the liver via a collateral circulation. 0.6 Follow-up of Non-maiignam VCM-inductd Liver Disease In 197s Manin et al. fsee also Berk et at. 1975) pointed out that VCM-associated hepa tic fibrosis, once established, may progress even after cessauon of exposure. They could demonstrate tins progression despite nomuiitauon of ail routine liver function tests in a 27-yearold worker on a follow-up examination including pcmoneoscopy and biopsy 2 1/2 yean alter cessation of exposure. Progression of flbrosts and appearance of bodging between portal and central veins were indicative of persisting scanty of the fibroblastic process, whereas the previously observed activation of both hepstocytes (marked variation of cell size and numerous binucitated cellsand sinusoidal lin ing ceils had disappeared. 5ince 1973 wt have observed a number of worken who on follow-up sliowed evidence of progressing portal hypertension with development of massive oesophageal varices and subsequent bleeding episodes despite removal from exposure (Fig. 6). In five (77) of these patients with progressing portal hypertension angio sarcoma of the liver finally developed. In this contcxt.it is of interest to note that more or less conspicuous hepauc fibrosis (or rare progression to cirrhosis) was the parental terrain ir. 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-bromomercury-hydroxyprepane (BMHP) labelled artificially damaged red cells, and sequential per/itsion semagnms after bolus injection of *'mTe-pertechnetate ham been found useful in the diagnosis and follow-up of nonmalignant fiver disease in PVC-polymerization workers. With the aid of theie noninvaaive methods, inhomogeneous uptake of labelled sulphur colloid in the icticuiocndothtliai system of the liver and enhanced uptake in the spleen, gradual increase in spleen size and (eduction of portal venous perfusion have been observed in FVC polymerization workers developing portal fibrosis and portal hypenentioo (Biersort et al. 1975a. b, 1977a. b). 4J Angiosarcoma of the LKer 4J.1 Epidemiology Primary angicarcoma of the fiver (ASL) is described under a variety of synonyms (angioblastic sarcoma, angioblastle reticulosarcoma. endothelioma. endothelioblastoraa. haeaangioblastoma. harmangiocndothelioma, hacmangiocndothefiai sarcoma. KupfTer call sarcoma, malignant barmanpoma. metastasizing haemangioma, reticuloendothelial nreotna, primary sarcoma of the fiver). It is an exceedingly rare malignancy, arising from vascular lining ceils. It occurs spontaneously with two peaks in the age distribution: one at early infancy (infantile haemangiotndothelioma) and the other in late adult hood (fourth to sxth decade). The numerous synonyms render it difficult to estimate the number of reported cases and to determine its true incidence. In a recent review 58 W.K. Lelbach and H J. Marsteller of the literature.A frerign (1975) listed 165 published cases of primary angiosarcoma of the liver in adults. In the six autopsy series collected by Ab-cnga. ASL constituted only 1 Xk (091--2.7%) of all primary malignant tumours of the liver, which of them selves are rare ftndinfs in the Western World. Autopsy statistics show, that the incidence of ASL tinfed from 2 lo 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 0.0 14 in 100 000 inhabitants or 25-30 cases per year for the entire United States. Table 12. Incidence of angiosarcoma of the liver (ASL) in autopsy series Authors Observation No. of No. of eases Year period autopsies of ASL Region Simpson et al. 1955 1914-1953 24 196 1 Mayo Clinic, Rochester, Minn.. USA Edmondson 1958 1918-1954 $2 000 MecS* rtn et al. 1973 1900-1969 _ a 1 3 Los Angeies. County Hosp.. USA Western Infirmary Glasgow, UK. Alrtnta 1975 1951-1973 39 700 6 Cook County Hosp. Chicago. USA Rtsn and Huth 1975 1954-1974 30 079 By*(n and Holmbtrf 1975 1958-1969 _b 4 (6) c Dtisscldorf. Fed.Rep. Germany 12 Sweden (adult cases) Daldrrup 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-year period, h Among 8 million inhabitants. c a Angiosarcomas, 1 hacmangioendothtlioma. 1 malignant hacmangiopencytoma Accordingly .the identification of 4 eases of ASL among approximately 270 em ployees of the vinyl chloride polymerization section at a B-F. Goodrich plant near Louisville,Kentucky.between September 1967 and December 1973 was duly recog nized as an alarming situation indicative of a serious new occupational hazard (Cnech et al. 1974*-.Creech and Johnson 1974). Until 1974, only two carcinogenic agents were known to be associated with the development of ASL in man.i*. the administration of a radioactive eollotdal prepara ucc 089346 Vinyl < tion of inorgai. dioxide tern am Thoi contras' ingevid teportei been th. had bee and.'./o. A speci; caused I thorotr from a I ASL (ft Dev, man vin tensive!) 1950--i tion revt of multi: approve, occurred but nota produce, Haustnit (37,-5 Roth (11 18.6-1 Fowler's Gioh haemangj tension h woman v, ride) dun had i hie: manifests The p: be eiicttc, period 18 history el Among tn observed other han 391 auto; .'d.Mantelier Jotareoma constituted ch of themthe inaier.es iih a ntan U9?5)itwas : is 0.014 m `lime. er.Minn.. Hmp.. USA i Infirman - UK. Ho<r l SA Fed Re;- nd' iMffl. Million) iicn ounne .ncytoma lyZTOemSant near hily tecognd (Cratch J with the dal prepare- Vinyl r*ilond-AiMx*U!id Disease 59 lion of thorium dioxide (thoratnsti for diagnostic purposes, and chronic exposure to htvrfMtt menteals. Both substances arc noted mainly in the liver: injected thorium dioxide panicles are rapidly taken up by phagocytic cells of the reticuloendothelial sys* tern and arc permanently tciamcd: arsemcais are oniy slowly rtleasetl from the liver. 7tnotrssi came into use in I 928 and as internationally employed as an injectable contrast medium until the mid-1950s, when its use was abandoned because of mountin; evidence of the caranogtnie anion of thonum dioxide deposits..Mac Motion et al. reported the first case of thonum dioxide-Hiduccd .ASL in 194?. Since then ASL has been the type of liver tumour which occurred most frequently among patients who had been given thorotnst injections in the past (da Siha Horn 1967: Ja Silva Hona and.Uorra 1967 ;b'cffnr etal. 1971;/iir/i and Rixkc 1974;Jehnfcr and Kojf 1975). A special type of progressive portal and subcapsular hepatic fibrosis was another lesion caused by thonum dioxide retained in the liver, da Silva Horta (1967) considered this nhorotrast fibrosis' to be deariy distinguishable from true cirrhosis. Gamma radiation from a lost radium needle has also been implicated as a cauntivc agent in one case of ASL (Ross 1932). Development of ASL a* a late complication of chronic trunk intoxication in Ger man vineyard workers was first described by Liebetott (1949,1952) and has been ex tensively documented by Roth (1956,195"a, b. 1959). During the 10-ycit ptnod. 1950-1959, autopsies of 82 Moselle vintners suffering from chronic aisemc intoxica tion revealed ASL in 8 cases among * total of 61 individuals (74ft), with cancer often of multiple sues (Roth 1959). In 1925. atsenic insecticide sprays and dusts had been approved fbr use in German vineyards but they were banned by law in 1942. Exposure occurred not only via inhalation during spray periods (approximately 30 days/year) but notably by daily consumption of quantities of cheap grape wine CHaustrunk'). produced from a second pressing of the grape stun residue by addition of water. Thu Haustrunk, an allowance in kind to the vineyard workers, had a low alcohol content (35-5% v/v) but contained high levels of residual arsenic (0,2--6.9 mg As-Oi/litrc). Roth (1956) calculated the mean total ingestion of AstOj te have been 53.7 g (range: 18-6-88J g) for a 12-ycar period. ASL was also seen after long-term treatment with Fowler's solution for psonasis (ReftIson et al. l963:LjnJcr et al. 1975). Pwdury et al. (1977) reported an anecdotal case of apparently benign diffuse haemangioendotheliomatosis of the liver with considerable fibrosis and portal hyper tension but normal liver function. This condition was found in a middle-aged black woman who had been exposed to various chemical fumes (including carbon tetrachlo ride) during 20 years in a drycleaning establishment, though it must be noted that she had a high alcohol consumption. The possibility that these symptoms could have been manifestations in later life of congenital disease cannot be ruled out. The proportion of patients with ASLin whom a pertinent history of exposure could be elicited has varied considerably. In an earlier survey of the literature covering the period 1875-1960, won Becker end Bissehtr (1961) listed ! 2 of 54 adult eases with a history of exposure to either thorium dioxide (7) or atienieals (5 ofRorh't cam). Among mote than IS 000 autopsies performed in Bonn during 1950-1959, all 8 eases observed were found exclusively in vintners exposed to anenicais (Roth 1959). On the other hand,.rchm*r and Ryu (1976) recently observed a duster of 4 cases among 391 autopsies during a 29-month period at a hospitai in rural central Wisconsin serving bO W k. Lelbach and H.J. Mantellcr Table 1 3 Personal data of 68 pnlyvinyl chloride production worker with ansiosarcoma el the liver reported to NIOSH up to August 19?S {Spinas and Kaminski |9'31 Birth date No Country* (m/d/))b Date of death lm/d.y) A| ai death 1 Bll) 01.12.13 * CNDil) 12.15.13 3 CND (2) 03.06.14 4 CND (3) 08.26.19 5 CND (4) 04.05.19' 6 CND IS) 05.07.il 7 CND (6) 12.15.19 8 CND 17) 11.09.19 9 CND (8) 05.13.20 10 CND 19) 07.19.21 II CND 110) 05.16.15 06.29.76 09.02.55 12.21.57 03-22.62 01.21.08 07.05.68 04.10.71 12.24.72 06.12.73 09.04.74 04.00.77 63 41 43 42 48 56 51 52 53 53 61 1: fSRtl) 00.00.28 13 CSR 12) 00.00.26 12.00.73 00.00.66 (647) 45 40 (37?) Total years ftp. ' 17 II 14 20 5 23 25 5 26 14 16 15 (14?) Job classification'' 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 Din 15 DC) 16 D(4) 17 D (5) 18 DO 19 D<8) :o D (9) :i D (10) D(l!> zl DU2) z* F (1) 25 F{2) 26 F|3) 27 F{4) 28 F 15) 29 F (6) 30 F (7) 31 F (81 32 F (9j 33 F 110) 34 CB (1) 35 CB (3) 06.04.30 07.26.31 09.04JO OI.OU2 09.29.26 10,19.17 12.13J4 07.23.29 12.29.36 06.14J8 04 15.24 06.03.11 01.06.20 01.27.27 01.29J8 04.I4J4 00.00.27 04.01 J4 10.08 14 05.24.19 04.20.01 06.02J7 01.25.69 12.14.71 11.25.74 01.09.75 11.13.75 12.25.75 03.24.78 06.28.77 03-07.77 10.07.77 02.19.67 01.24.75 06.26.75 01.03.76 05.13.76 09.12.76 07.02.76 01.30.77 12.25.77 01.20.78 12.03.72 12.24.74 38 39 44 43 49 58 42 47 41 39 43 63 55 49 38 42 49 42 62 58 71 37 12 * 11 * 17 12 2.4.5 12 11.(1) 21 m*1*5* io 10 16 10 61 19 1.2 12 29 *m 26 2.6 II 1.2 13 6.7 *m 19 * *** 28 21 * ** 8 41 3 1/2?) 36 1(2) 37 1(3) 11.13.29 03.14.20 12.27.72 07.10.75 43 55 62 21 38 3(1) 39 JO 40 Nil) 08.01.22 08.02.29 12.23.15 I0J4.75 08.10.76 01.04.72 52 37 56 * 13 21 ucc 069348 Vin> Tabic ___ r No 41 42 43 44 45 46 47 48 49 50 51 52 S3 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 * 8. CM) CSR D. F. CB b 00. d C 1.41 2.at. 3.pr 4. p-' 5, fe: 6. Tt! 7Y 8. pr 9. chi (Tablet 1 referent. VjntcJJcr .ttjurconu tication'1 1:. 13 M l ;. i3. is . |7 it i* K Vinyl Chlottdc-Atsociattd Di*cae 61 Table 13 <continued! Birth date No Country* invd,'y*> 41 Sill a; 5 01 43 5*4) 06.23.2? 06.10.10 II.16.14 44 USA 111 1017 23 45 USA (3) 08.19 33 46 USA f3) 05.25.15 47 USA 14) 01.15.24 43 USA 15) 01.25.12 49 USA 16) 11.23.23 50 USA It) 05.03.22 51 52 USA (3) USA (9) 05.06.20 11.08.31 53 USAUOl OS.16.13 54 USA (11) 05.27.09 55 USA 112) II.17.IB 56 USA (13) 12.01.21 57 USA (16) 11.04 27 53 USA 117) 05.06.31 59 USA (18) 04 22.23 60 USA (19) 00.00.15 61 USA CO) 08.31.17 62 USai21 i 09.02.09 63 USA (22) 1002.23 64 USA (23) 00.00.22 65 USA C4) 05.07.17 66 USA 123) 03.07.10 67 USA (26) 7(1978) 68 YU f 1) 04.05.14 Oat* of death (m/d'y) 10.20.70 03 19.76 05.12.77 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) Ape at death 43 65 62 49 37 58 43 52 46 45 41 43 55 61 50 52 4] 43 46 60 58 67 s: 50 60 67 7(1978) Tula! ycatv exp IS 21 31 Job. clarification* 2 21 13 28 15 20 12 17 15 24 17 23 19 28 4 19 It 22 21 2) 28 14 26 20 7(1978) 9 9 10 10 10 10 9(1) 08.04.73 59 20 * B. Belgium CND. Canada. CSR. Chechoslovakia D. Wot Germany F. France GB. Greai Bntain b 00. data not available. c 1. autoclave cleaner 2. autoclave operator. 3. pipe fitter 4. polytncascr 5. foreman 6. Tiltreur' 7. prtpanteur de solution' 1, process worker 9. chemical operator I. Italy J. Japan N, Norway S, Sweden USA, United State* of America YU, Yugoslavia. 10, polymtnzation worker 11. technical amistent 12. maintenance worker 13. millwiiiht 14. water cooEng unit IS, teeter 16. furnace operator 17, machine shop worker (Tables 13-15 ire compiled with the aid of information contamed in ilt literature; reference* tec Table 15) >- u -\ ** " 61 W.K. Lelbach and H.J. Marjtellrr 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 A5L The other three may have had nondocumentcd exposure to arsenical pesticides, which were used for many years in this te|ion, 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 A5L (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 eases not mentioned on the death certificates were detected by a panel of specialists (Baxter et al. 1977). In reassessing 36 of these 47 patients for whom histological sec tions were available, the panel of hisiopathoiogists unanimously agreed on the diagno sis in only 14 cases (7 doubtful, 3 undsssifiible, 12 non-ASL). For 13 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 fust three eases ofASL among vinyl chloride polymerization workerr in the United States had come to the attention of the National Institute for Occupational Safety and Health (N105H) in January 1974 (Lloyd 1974), this institution continued to collect information on additional cases reported to them from nations with an im portant PVC industry (Lloyd 197S.Spirtaz and Kamintki 1977). As of August 1978. data had been presented on a total of 68 cases of ASL among polymerization workers (Spirter and Kamintki 1978, pen. eomm.); another eight cases had been observed among nonpolymerization workers exposed to VCM in various jobs. On the basis of this data collection communicated to us in 1978 - for which wt wish to thank Dts. R. KarwnzkiandR. Spirtat, NIOSH. Cincinnati, USA - wt attempted to trace these cases and their individual symptomatology as well as other relevant information pub lished in the literature up to 1979 (see Tables 13-18). The ten Canadian cases of VCM-induced ASL (cases 2-11) are dealt with summarily in the papers published by Delorme (1978a) and Delorme and Makk (1975): seven of them were described in more detail by Makk et al.(1976). Cases 19 and 23 were observed at our clinic in 1 jnn but details have only been published for case 19 (E.U. in Lclboeh and Menteller 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 Gewerbcant, Diineldorf (Rtml 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 occuned in 1955 in a Canadian polymerization worker. For the 67 VCM polymeriza tion workers for whom details were available, tout yean of exposure ranted from 4 to 31 years (mean and median 18 and 19 yean, respectively), tn comparison, mem 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 penod (yean from first exposure to diagnosis of ASL) ranged from 9 to 38 yean (mem and median: 21 yean). The avenge age at diagnosis of ASL was 50 yean (range: 37-71 yean). ; ' ' t 069350 y g a S, 3 3 -|S nmliia = sl|| ill I aZ s* ff k Km a TaMt 14. nWual m4 motphulorical alala m 44 Hyif*|r| (hliWHk IFVT| pnidKlIm worker* wllli anyhiaarcimia ot ihc livci rcprttlcrf in NIOSII hr A(ml 1971 < llepaloM* merahr 3fleea II |2900|> j\ Atrophic, rtighily In (totaled i 4 ) < t 110*0- . Nr* detail* available 9 10 M Onifkafirf lk|ihi' vjikei liktmit Thrombicylopcnu !) NoncMihultc ! pcrhutiiiutilal A cafinrlar Capnrlaf Capratar, purlat, pcruiiinuiulal SefcttMlf nf wall uf |htrial rtw Capratar, portal, pciisiuHsurilat t Capnrlar, portal, perinnmhlj| Capmlar, portal, peiuiiurMirdal Portal, pcrninuwiMal Capral.ii, portal, pcriiiumoriljl pcmmiNHiU / Aurailciityi)i * No delaih a*ailal4e NijrawiTi (themmu'non Hclnliw 0 ft 9 3 fr ?u o 6 !E I *: mulli|rfv.' mlnlnn (h*|, pleura, pciuauliMiu, ileum, toilm. I ntneys. hell aitreuall I rare: mcrliavlmal lymph noile I ran'1 pariltmeal *pteail I r ater local %|oeail 9*i i r\ /* Table MIcoMltnwed) lltfUnNo. mecaly Spleen 11 Moderately (7100(1 enlarged IS (2750(1 * 14 SplenoDK|alr IS Sttphtiy enlarged Ocsofilugcal Itcpalk vjfkci fthrnsii (i (Cirrhosis!, fibrosis (Cirrhosis) Tt 7 Tlimmboeylopcnta * * * * 16 Spfcmr- (2650(1 meItaly (610(1 Capsular. portal, septal (71000. 65 000) 17 Spleno megaly II T Templtnilh * 1 (114 000, 66 000) IT (1 Spleno (1450 (1 megaly l-HKIgl (*1 Progressire perisinusoidal, 1 SO 000, porlal and 47 000, septal tinInrat 10 000) 70 f t * y 21 Spleno y (1900(1 megaly Aeronslenlysb 0 0 f 0 0 0 0 0 y 0 Raynaud's phenomenon MeIasi mi 0 0 l,eft lun( 0 4lh lefl rib 00 0 hi Itioraek eeriebra 0 Brain Jril Imphav wtlclira 0 0 y? 00 o OJ GO GO G*1 II Spleno megaly t 21 Spleno 0 (7700(1 megaly (455 (> 6 * * Capsular, f porlal, per ismu si tidal Coca! perttimrsr tidal 1 T 00 00 t* . 0 n 0 4- ^ n l SfX X 2a. A i n-* < 5 21 * Spfcoo- (1900(1 mc(jlr * 22 Splcoometal? T Capswlat, portal. pCKsinMUHtlal P 2) Sptemi- 0 (3200(1 metal? (455 (I Focal penfttftmi Hital 2 P24 1 1 T t l.wal H'ltJil lo i aval trio 25 Spfcoo- (1610(1 K(ll| (450(1 Portal, pcikfcnrtoMal (60000, (ihnitit (0 0001 26 * t f * OminIcm.iI wall 22 * Spbioo- Mellcoiakul f (2230(1 mctat? captnlat Month, (400(1 MKtimottiiUi clnhwii Portal, pert- 41b anil 2ib Ihntactc Me(a*]r ttmuoolal. |H0 0001 vcilclwa, tlh kll iili, (650(1 capvolat Month kll ailrvnat 24 34o4tficalkittt ff Sbfhl portal 0 * if (1250(1 Min- (ttifiKii cimtcilive' 0 20 P P Minimal 11 niwKh Small infinline )l * Splennmetal? f ? 2 Paiaamlal lymph links (3000(1 (220(| 32 t t* (10000, 40 0001 33 t n rapmlai, fl initial titmiMl 0 TM 14 (continned) Hepato Oeiophiecjl Hepatic No. megaly Spleen varices fibrosis / 34 Slight 0 0 (26211| splenomegaly Tliromhoeylnpenia 4 (10 0001 Atmitsleidytis 4 Haynatrd's filrenomenon Melaslases 0 If 31 4 emptied, 4 (3240 g) firm (200 g| Nooclrrholk 1 fibrosis 4 44 4)( 4 T 4 y 9 i Local ipreail lo abdominal wall and cobhi; lymph noilc i 37 3 39 40 41 4 Splenomegaly V y y y y 42 t t y t T y y y 43 4 444 4 Splenomegaly 4 Stikifwlii 4 4 ml postal fibrosis 43 4 Spleno megaly 4 Markedly 4 thickened capsule; marked libimh 4t p 46 4 Spleno (1B60 g) megaly ? Pnrlal fibrosis f 4i Spread In diNHlcnnm W.K. L* Ibach and H.J Marsuller ucc 069354 47 4 4* Splennmegaty ? 7 T Pnrlal d / S|iKl lii didfiliragm anil libntih (II 000> lullinnimI wall Slipbi (mal 7 n rf I wins. Imre nut \m all ucc 069355 iXi, i Hi***.* i 4) 4 Spleno megaly Jpfclllf (1140(1 niccaly 4? * SptcBUnwpilr 40 IS MO (I Normal || | Ikirib uni pnMKhcO SI t (IllOt) SS 54 55 s* 57 SI so 40 y ftetalti uni paMhlwl 41 42 4) 44 45 44 47 41 V in y l C hloni!**A <sodattd Disease lliAtiNt thick cneil marlctl lilirnvls Pi Mill fill rods ' Portal lilnmh iisonoi Slight local hepatitis I 'mlakiil hcpatilh'l Capsular ami T pot I at lihiosf* Peculiar ? portal fihrash, miHitiaIt cirrhosis Spread to ihiiHkaum /f Spitail In itiaphiapm ami alHlnnimal wall i l.mift. lafpc and onall IhiwcI, pleura, pcricantmm myoranlmm, knhieys, Iclt ailitHal lliaphrapm. Ktiranl, retropettitine.il amt mcihaslMal lymph runlet, Imp, ailitoal (lanih, ccltlicllom IHaphtapm. yaIWwlilcr. icpimiat lymph mules, timyi, scalp, rAutt MSI 0001 \ : H J. Manteller r is 68 * W.K. Lelbach and H J Mantellcr Table 15, Publications on the 68 cases of angiosarcoma of the liver listed in Tables 15 and 14 No References Additional relevant information i Hubiti et al. (1977) ^* \i 31 4 1 Dtlormt and Makk 5 f 11975) * \ Makk et al. (1976) 7 / Dtlormt (1978a, b) 8 1 Dtlormt and 9 J Thtnault (1978) 10 I 11 ) Hypertrophic, hyperchromatic and jt> picul endothe lial ceils in the glomeruli; foci it haematopoctic cells in liver and spleen Case no. 7; A5L associated with hepatocellular carcinoma (Dtlormt 1978b) (AU cases from one plant in Shawinigan. district Trots Rivtdres. Quebec) ::) Schmidt and Baton (1976) At the same plant: 4 cases of VCM-induccd cirrhosis of the liver plus 1 case of cirrhosis and {rne.-jliKd tcticulosarcoma and 4 cases of carcinoma of the Cl tract or lunp 141 Langt et at. (1974b) Ctdigk ci al (1975) See also Rtinl and Wtbtr (1974) See also Rtinl and Wtbtr (1974) 16 Coktl et al. (1976) Foci of haematopocsts within the tumour areas 17 A mann(1975) Riibtamtn (1976) 1974 portoeeva! anastomosis: cholecystectomy Hypertrophic, hyperchromatic and markedly atypical endothelial cells in the glomeruli and in the capillaries of the lungj 18 Rtinl et al. (1976) 19 (Observed in Bonn) Moderate hepatic siderosis: chronic fibrosinf penertanrit: tubular and interstitial fibrosis of the rearer 30 Rtinl axil (1976) 31 Rtinl et al. (1977) 23 Arm/etal. (1977) 23 (Observed in Bonn) Focal interstitial fibrosis of the panertat 24 Rovitr et al. (1975) See also Jerrod et al. (1978) 25 Aochestal.(197|) 1942 fastrretomy. 1974 splenectomy, right hepatic lobectomy (6401). See also Roche (1977): Rutch et 1.(1977):joiuieron et al.f 1975. 1977);Mtrrod et aid 971) 26 Rtry et at. (1976) No autopsy (see also Btrrod et al. 1978) ucc 069356 Vinyl ChiTable I5u No. Rei 37 A,' 38 Rux 29 Roi 3 \ 31 I 33 33 )(1 Bti 34 Lt 35 36 Mi 37 38 39 - 40 - 41 By 43 By' 43 - 44 Bl. (C3' 45 Bio (ca 46 BU . (CJ.' tiler \-s 13 lOtliecells rhosis '10 - CW picoJ nilbnei im rt* t-patic ret { -ed et Vinyl Chloride-Assoeuicd Disease 69 Table 15`continued* No. Reference* Additional relevant information :? Rer/if eial.U97S) :s Koch* et al. (1978) Chronic alcoholic. Sec also Rncht 11977): hitch at at. (1977): Btrrod et al. (19"8) First symptom: vertebral and costal meustases Right hepatic lobectomy. See also Roche 1?*'): Rutth et ai. (197*); Filxhowjki e: al. i J 979); Cjudr'c tt ai. (1976).Btrrod c: al. (I97S) 29 Koch* et ai. (1978) 1960 se/erodermelike skin induration (hands), swellins of i4cc. upper extremities and feet. 197| bilateral acrooittolynl. Tumour penetration of the abdominal wail (Fistula). Severe interstitial fibrosis of ttttti: fibrosis of interstitial wall.slight mesangial fibrosis of glomtrulL Vamble but generally slight tibronyalinosts of antnal and venous vessel walla (skin. bean, lunp, intestine. testes) 3 ) j: ( Btrrod et al. 11978) 33 ! 34 Let and Harry (1974) 3! Smith et al. (1976b) Latency penod (1st exposure - death) only 8 yean face also Fox and Collier 1977) 36 MaJtont f 1974) 37 - 38 39 ^ * - 40 41 Brrrn and Holmbeij (j 975) 43 Byrin et al. (1976) 43 - 44 Block (1974) (caac 3) 45 Block (1974) (case 2) 1965 portacaval shunt. 1970 cholecystectomy. See also /allot aL (,1974s) (case 4); tohtlan tt al. (1976) (case 1) No autopsy. See also Ottth and'Johwon (1974); FmIk et al. (1974a) (case 3): Melon et al. (1976) (cam IV.iUkk tt al. (1976) (case 6) 46 /<*( 1974) lease 4) Set also Ftlk et aL (1974a) (cam S):.Uei* et al. f 197$) feast 10) i j t r- bvyi ucc 069357 r 70 Table 15 (continued) No. Relettnces 47 Hock 11974) (use 1) 48 Flock (1974) (case 5) 49 Flock U 974) (case 6) 50 51 * 52 Whelan et al.(1976) (use 3) 53-67 - 68 Fence et al. (1975) W.K lelbach and HJ Man-teller Additional relevant information See also Falk et al. (1974a) (caw 2);.Veit et al. (1976) (case 4) See also Folk et al. < 1974a > (case D.Mukk et al (1976) (case 2) See also Falk et al. (I974a)icac 6): Whelan et al. (1976) (case 4):.Vkk et al (1976) (case |4> Chronic alcoholic. See also .Vekk et al (1976) icne 13>;Ff'*cral. (19761 (case 2) Among a work force of 180 (120. PVC polymeriza tion: 60. production of VCM) employed at this plant. 15 died of mslimint disease (2 ASl. 5 bronehogtmc carcinomas. 1 case each ol carcinoma oi the larynx, tib, mamma, spermatic cord: g/ioma. meianotarcoma. leukaemia. Hodckm's disease) Fitst exposure to VCM Tor these 67 cases of A5L dated baek to the period 193*9-- 1966 (median: 1951). Twentyohe years later. i.t. from 197; onwards, a gradual inereas; in the number of new eases diagnosed and reported to N10SH can be observed (Fig. 7). The onset of this gradual increase coincides with the calculated mean latency periv ' of 21 yean (Spttas and Kaminski 1977). Spirits and Kaminski also suggested that -n hmtre cases the age at diagnosis and the length of the latency period may increase 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 A5L for which morphological details arc available varying degrees of associat ed hepatic fibrosis in nontumorous areas of the liver were mentioned. Less often, evi dence of portal hypertension and splenomeply were noted. Metastasis of angiosarco ma to distant sites was observed in approximately half the published cases. It is of note that actootteolyds and cutaneous stigmata of scleroderma have been observed m only 1 of these 76 patients, a French FVC worker who had apparently not been engaged in reactor cleaning (case 29;Rocht et al. 1978), Another noteworthy picee of informadm is that strikingly atypical endothelial cells with hypertrophic and hypcrchromatic nuclei have also been found in organs other than the liver (kidneys, lungs) in autopsy material from two patients (cases 1 and 17et al-1977;Rubsamen 1976). Hubltt et al. (1977) abo found such cells in the myocardium and in the adipose tissue enveloping the adrenals. All this may land support to the idea that the effect of VCM metabolites is not restricted to the vascular endothelium of the liver and spleen. Angio- ucc 069358 t , : t 9 f. i, n d 'lameller ll al. .I al. -t (cut menupunt whopmc uryflx. -atcoma. m"3-- 'sal in* - v rved -i latency &*ested nay in* oi (he - assoaat'tcn.evi/iosarco* t of note I in only nppd -finfotmahremauc autopsy *76). tv< tissue of VCM on. Anpo- Vinyl Chlonde-Aesociated Disease Table It. Personal data on eitht casts of anposartoms of the liver among VCM*\poeed personnel not cmplovetl in PVC production ta* reported to NIOSH bv August 1978>a Date of Birth dare death No Country imi.'yl1 im/d;yi Total Aft at yean death exp Job classification A D(3> OT.lO.'O 10.10'.' 43 14 Loading pesticide cans wits VCM propellant B Dt6> 05.09J6 12.16.74 38 3J Assistant factory chemist r GBi:) 09.08. U 12.00.70 55 11 Fourini PVC oil mix ture onto fabnc bases * D till 06.15 JA 04.16.71 36 3 Fabrication of PVC sacks ami wrappings (extrusion al tempera tures of 120* G E SCI 11.27.11 08.16.71 61 23 Assistant factory ehem- Hi (production of VCM) F USA (15) 00 00.25 02.15.73 47 * Accountant st plant producing PVC fabnc G YU (2) 11.15 J1 07.12.73 42 18 Production of VCM H YUiJl 12.21 Jl 01 11.76 45 Production of VCM * Update of NIOSH itpeter. August 1978. piepaitd by Kaminski as in Table IS. b 00. data not available sarcoma arisini from the kidneys or other types of malignant renal neoplasms, how. ever, have not been described in VCM*xposed individuals, although malignant nephro blastoma has been induced in experimental animals. The extremely ran coincidence of angiosarcoma and hepatocellular carcinoma was found in three instances (case 7,Dtb*nt 1978b: case E,Syrin and tfotmberj 1975, and a case not included in the 1978 NIOSH update Tombums tt al. 1978a). In the ease reported by Tsmburre et al. chronic alcoholism may have played a cofactor role in the development ofliver cancer. We can now add a fourth case obarved in 1978 at the Department of Medicine in Bonn (see Sect. d.1.5 and Fi|. 3). This patient (paoent 9 in Table 11), a FVC-polymerization worker (total penod of exposuie: 18 yean) teas flnt admitted to our department in February 1975 and was found to tufTer from atyp ical etnhoss of the liver with portal hypertension, splenomegaly and Raynaud's phe nomenon. During followup AJL was clinically suspected but could not be confirmed during life, despite exploratory laparotomy and generous surgical biopsies. The patient < 4 Table IT. (Taferi anil morphidogteal data on eight nwi of w{inviKnm.i of Ilie liver among VI'M-<ipini'.l|wivi.iiHi:l not empfoycil in fVC pntymemalion ii llcpatnNo. megjfg Spleen OtfWfthafc;il Hepatic vjriici lilitosis liuonibo. cylopenia Acronslcolysh Raynaud's phenomenon Melailasm A Spleno >noog) megaly forlal fil>rnsM 00 Diaphragm, gastric mwma, abdominal lymph node* B Splcno- t (36JO gf megafy (43J g) l-'ocaf capsular 0 litHom, pnrlal and ccnlioh dollar filirosis 00 Diaphragm. pleura, abdominal lymph males C t> ( Nol enlarged 0 f ? 0 0 Lungs, peiieaidmm I i- * * 1 * 0t y (103 000) F <; Splenomegaly f * t 0 4 Dma, cranium 3 T. \ 1 ii iT. r 3' 3t- C5 C <> of) a> o ?c O< 5f* 5-i si ^ n Xsic^ 3o 2, 3 < ^ D * t> ".ns 3 rt m < 5 arsteller Vinyl Chiondc-Usociated Disease Table I >. Publication* on the eight cases ot angiosarcoma of the liver lined m Tablet 16 and 17 No. References Additional relevant information A R;/anJ t eier 1 17U) I9n7idi `.patr.ic portal iijpertensian: portacaval shunt B Zimmtrmann and ck |97J right hemmcphrectomy for umlate'al hydro- 19711 nephrosis allocated with bilateral double kidr.tv Rtsni 11975) Foci of Hacmatopoetic cells in spleen and kidney. Fibrosis of the pancreas. Slight fibrosis of testes and of the smalt intestinal <crosa c 0 Maitom 1107ui Autopsy- angiomatous epulis. Angiosarcoma involv ing liver, lungs and pericardium The pericardium might have been the primary site! E Byrin and Holmberj Probable eoexistence of a hepatocellular cancer of <1975) both low and high grade differentiation P G Zoriea el al. (1975) H - died on * August 1978. alter a massive haemorrhage from oew'owgeal vsnees. Autop sy revealed both multicentnc metastasizing angiosarcoma and hepatocellular carcino ma of the liver as well as slight fibrosis of the pancreas (to be pubiahed in detail). It is still unexplained why hepatocytes art generally exam? -ri from the carcino genic effect of VCM metabolites but. aa ptcdicud by PoFper in 1975. three anecdotal cases of hepatocellular carcinoma, one German (Coke! ct ai. 1976) and two British PVC workers (Fox and Collier j 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 the Province of Quebec covering the penod 1969-1971 showed a preponderance of adult male cases in urban areas clustered in the district of Trois-Riviere in congru ence with the distribution of the plastics industry, a coincidence which calls for further investigation of a possible exposure to industrial carcinogens (Jacob and Thenmtlt 1975). . Sot included in the NIOSH register arc several anecdoal cases of A5L, capillary and cavernous angiosarcoma of the liver and hacmangioiarcsmatosis of sites other than the liver, for which a relation to occupational or tven possibly residential exposure to VCM has been discussed (Nona et al. 1977;Bndy er aL 1971:Dor ct aL 1975; Mtll- no/'er and Zuinagl 1977). Although of undetermined relevance, it should finally be mentioned that, in addi tion to hepatic fibrosis, varying degrees of intemitial fibrosis of the panneas were noted at autopsy in fourCemtan workers (eases 19,23. B and the above-mentioned 7J W,K Lelbach and H.J. Marstdler patient with both angiosarcoma end hepatocellular carcinoma). Fibrosis of the testes was observed in three cases (19,29,8), and Roche et al. (1978) also reported fibrosis/ hyalinosis in vessels of skin, heart, lungs and intestinal wall. CUMULATIVE N> OF CASES REPORTED TO NIOSH \ o h. at fc r P' u P' V 31 If be arm> su tic *, de an In na no wa Fig ? . Cumulative number of cases of ASL amonf PVC production workers reported to NIOSH up to August 1978. arranged sccording to year of diagnosis (data from Sptrtat and kemuitki 1977,1978) 0.2 Clinical Manifestations The clinical symptomatology of usually multicentric ASL is unspecific. Gradually dedinin| general health and Ion of weight combined with Qldefined upper abdominal discomfort and slight epigastric or right upper quadrant pain are usually the first symptoms. Recurrent bleedinp from oesophageal varices may hare been antecedent vena in patientt with portal hypertension who otherwise felt fairly well. In a number ucc 069362 r k t. I Fit the Uni larsteiler testes fibrosis/ Vinyl Chlonde-Aawciated Disease *! of cases, the tumour first came to attention with massive, often fatal, intnpemoneal haemorrhage. Important tender hepatomegaly (hcpatosplenomegaly), slight jaundice and occasionally development of moderate ascites and oedema were observed. Except for mild to moderate hyperbilirubinaemia.some elevation of strum levels of alkaline phospnatasc and jammaglutamyl tnnspepndase and only slightly abnormal levels of serum transaminases, the speetntm of biochemical tests ts hardly revealing. Alpha-fetoprotein determination has not been helpful in the diagnosis. Ultrasonography, scinti graphy, hepatic angiography and. notably, computer tomognphy of the upper abdomen ate the diaanosuc procedures of choice if ASL is suspected. A technetium-*9" -liver scan visualizes inttahepatic tumour defects (Bitnack et ai. 197Tb) together with abnormal splenic fixation, but peripheral defects of uptake may be difficult to interptet (Widen et aL 1976). Characteristic features of angiography art s normal-sized hepatic artery with possible displacement caused by tumour enlarge ment. a certain degree of central hypervasculariry of the tumour, a peripheral tumour statn, and puddling of contrast medium persisting into the late venous phase. In addi tion. varying degrees of peiiosu hepttis may be observed in some eases. However, even repeated hepaoc angiography may fail to confirm the suspected diagnosis, as was evi dent in one case reported by Roeht et al. (1978). The example of a 5d*year-old polymerization worker who died of metastasizing anposareoma of the liver in February 1980 may serve to illustrate the clinical course. In 1971'75. after an exposure of 18 years' dunuon, we found him to suffer from Ray naud's phenomenon and nonanhotie portal fibrosis and portal hypertension with sple nomegaly and moderate thrombocytopenia. Despite termination of exposure, there was progressive splenomegaly and development of massive oesophageal and gastric .-potted Tom <a4ly deitminal im Client a umber Fig. 8. Computer tomogmhy showing a large, irregular, hypodense enpmarcoma of the liver involving both loba. Courtesy of Professor Thum. Department of Radiology, University of Bonn t . 76 VK. Ltlbach jnd H.J.'Unicller varices during the following yean with repeated episodes of bleeding which required (successful) sclerosing therapy (major surgery was declined by the patient). In August 1979 he presented again with recurrent eptstixis and slight but permanent epigastric and upper right quadrant pain, but declared that he felt otherwise fairly well. He com plained about a sharp localised epigastric pain on sneezing There was marked spleno megaly, and an ill-defined Itard mass was palpable in the eptgjstrium. Apert from mod erate elevation of alkaline phosphatase and borderline hyperbihrubmaemia, biochem istry was normal. Computer tomography showed a large irregular hypodense tumour mass in the liver, involving both right and left lobes (Fig. 8). which became practically isodense after intravenous injection of contrast medium. A liver scan corroborated the tumour defect. Shortly after this there was mounting evidence of brain involvement end rapid deterioration. Computer tomography now revealed multiple brain metastises (Fig. 9). Autopsy confirmed the tentative diagnosis of metastasizing angiosarcoma of the liver (Fig. 10). \ r ? * i ' Fig. 9. Computer tomography showing multiple brain metastases of angiosarcoma of the liver. Sec text. Courtesy of Professor Thum. Department of Radiology. University of Bonn 4J J Peritoneoscopy little information is available in the litentute concerning the peritoneoteopie aspect of VCM-induced ASL (Roe/te ct al. 1978). It may be impossible to make a diagnosis of the initial phase of ASL in VCM-exposed workers by peritoneoscopy and needle biop sy f the liver, is documented in one of our patients who died of multicentric ASL ucc 069364 i % * ** i r \ Fh Cu l*T*tcller aired August jitnc ' (: eora;?lcno'To mod-ehem':::iDur *ucily ited the ment vtastases .ana of Vinyl Ciil0ride*A**Otaaied Disease 77 t t 4.'- * ** y, >*tu of reentry ; aspect paous of .lie btop ASL r.|. 10. Multiple brain metastaics of angiosarcoma of the liver. Courtesy of Professor Cuiiotta. Institute of Neuropathology. Unreemry of loan It VK. Ltlbji'li and H.J. Marsielier 11 months after peritoneoscopic diagnosis of severe hepatic fibrosis fcasc 19: see also Leibach and Slanttiler 1977). In addition to the findings described in connection with hepatic fibrous, these may be hypervascularized or cynic 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 hen that needle biopsy is absolutely contraindicated if then is any suspi cion of ASL. 04 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 cystic tumour masses; a multinodular form with numerous, sometimes umbilicated nodules, is less often encountend. Extensive haemorrhagic and necrotic anas or solid and spongy por tions of tumour tissue nplacc much of the liver pannehyma. Ruptun 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 diffennt por tions even of the same tumour and appear to npresent 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 hypertrophie and hyperplastic sarcoma cells with plcomorphie, elonpted, hypejchromatic and often bi2ane nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells of varying differen tiation envelop liver cel! 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 eelk results in laiger and more irregular blood-filled vascular spaces, into which loose papillary strands of surviving hepatic cords on an axis of connective tissue project, lined by sarcomatous cells (IVeinbrtn 1976). Even larger blood-filled spaces tic seen in the cavernous type, where they may be surrounded by thick fibrotic walls. In a smaller percentage of cases.solid areas or nodules ofanaplastic sarcoma are found, resembling solid spindle-cell sarcoma, or even suggesting an epithelial type of tumour. Cedigk et al. (1975) also observed a leticulosarcomalike 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 at al. 197g). In tumour-free portions of liven with angiosarcoma widely varying degrees of ex cess formation of fibrous connective tissue are usually observed, analogous to that wen in contumorous liven of heavily exposed penons. Fibrosis of enlarged portal tracts with modest proliferation of bile ductules, mostly only scanty* infiltration of lympho cytes and occasional formation of perilobular wpta or thin connective-tissue wpta ex tending into the lobular parenchyma can be found. A more or less conspicuous intra lobular, perisinusoid*! fibrosis b often detected only by special staining methods lor collagen or rrticuiin fibres. As a rule, irregular focal or nodular fibrotic thickening of \ r * %. %i V* Fif liw nu. pet In- of i>Th, rc liti t oid. plii incr itti. eyu def ied- erea m a,*** UCC 069366 _ .-JCiywewwwi--OpffOj 111 i mnwgiyuvii Manteller 19: see also nncction with non visible on j hepatic melinr. It should is any suspt- ;ed from 1600 to ranee of angionc tumour luies, is less md spongy por4" large cavern- rnir basic devellifTerent por=tve evolution: of transition rums cells with lerize the vmj differen- tracts, sc orns stro spans, inint.ci.ttve tissue lUled spaces . nbrotic walls. .mu are found, . pe of tumour, -itferenoation of wlial lining call cically. vinyl 'i other setiol- Jegrecs of exws to that seen portal tracts :.m oflympho'issue septa exTieuous mtrsmethods for thickening of Vinyl Chlonde-Asiociated Disease 79 Fig. 11. Angiosarcoma of the liver (upper peer of photomicrograph) invading adjacent liver parenchyma (case 14 Dl;see Table 13). Note hyperplastic and hypcrehromatic nuclei of proliferating neoplastic lining cells enveloping hepatic cords. Reproduced by permission. Ann NY Acad Sei 346.378-315 (1975). Courtesy of Professor Gcdigk. Institute of Pathology. University of Bonn. H A . x 350 of Clisson's capsule is present: these fib robe capsular areas may extend into the underlying parenchyma and may connect with adjacent enlarged subcapsuiar portal tracts. Tlit cellular and nuclear size of hepatocytes may vary widely; groups of binudeated or even multintidear parenchymal cells with abundant cytoplasm arc 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 hyperplastic precursor lesions were described by Pepptr et aL (1978): I) Poorly circumscribed fod of hyperplastic, often binudeated hepatocytes with increased number of various sinusoidal lining cells and only insgruficant increase of reticulum framework. 3) Almost nodular areas of conspicuously hyperplastic and hypertrophic hepato cytes with more pronounced variation of markedly increased sinusoidal cells without degeneration or necrosis of liver parenchyma, but accompanied by excess formation of reticulum framework and compression of surrounding parenchyma. The transition of sinusoidal lining cells to angiosarcoma cells is characterized by in creasing atypia and anaplasia of these proliferating endothelial ceils accompanied either i" t? I i & I % l s y a t V SO U'.K. Lclbjch and H.J. Marsteller by formation of excess connective tissue or by accentuation of sinusoidal dilatation leading to pnmary peliosis. Involvement of ponaJ areas in the evolution of angiosarcoms tesuiti in considerable fibroplasia and formation of hyalinized collagen together with proliferation of bile ductules. In occasional cases connective tissue bridging be tween portal tracts or between porta! tracts and central veins with subdivision of lobu les followed by rearrangement of hepatocytic plates may lead to a cirrhosislike picture. 4.3.5 Therapy The multicentric development of ASL (Thomas and Popper 1975) as well as the dif fuse spread of the tumour usually encountered by the time of diagnosis preeludes ef fective surgical or radiation therapy in the majonty of cases. A survival period of two years after surgery (Berrod et al. 1978) or chemotherapy (Dannaher et al. 1979) is a rare exception. Resulu of systemic chemotherapy studied in a small group of five pa tients showed that, at best, quality and duration of survival may improve to a very limited extent (Dannaher et al. 1979). At present, no generally accepted guidelines for chemotherapy arc available. 4.3.6 Risk Assessment When in the United States 13 white male cases of ASL had been detected from 1961 to May 1974, among an estimated total population of VCM polymerization workers of roughly 20 000. a risk ratio (ratio of observed to expected cases) for this population of at least 400:1 was calculated (Heath et al. 1975). This calculation was based on data from the National Cancer Institute's Third National Cancer Survey (1969-1971), which expected for the total United States population an annual incidence of this tu mour in the order of0.014/100 000. This would have meant only about 0.03 cases per 20 000 polymerization workers within a 10-year period. Dose-response and attendant biotransforma' :n data on experimental animals have since been used to elaborate sev. era! 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 (SehneHennan et al. 1975: Gthring et al. 1979,1978: Woods 1979). Gehring et al. (1979) consider a probit percent model to be a reliable tool for risk prediction,which works without the assump tion of a threshold. They predicted a cancer risk of IS cases of ASL in 100 000 000 workers on exposure to the current National Standard in the United 5tatcs of 1 ppm VCM 8 h/day, 5 days/week, for a 35-year working life, an incidence which does not significantly deviate from the spontaneous incidence rate. A linear model modified by adjustments for differences in the rate of inhalation, distribution, metabolism, cell proliferation and tumour latency times between rats and humans was described by Woods (1979). This model arrives at an incidence of 3.9 cases per 100 000 000 workers after a lifetime exposure to 1 ppm. Much controversy, however, about the validity of risk extrapolation from animal experiments to man and from high- to low-level expo sure and the problem of threshold doses has been voiced (Mangh 1971. Hooper et al. 1979: SchnckJcrman 1979; Weigcrt \979:Rvitz etal. 1979). ucc 069368 Vinj R (exd ASL This r the l confi had i the re polyr was o viron ceede lesser Risen ting,: milbe vinyl mode the es groun 4J.7 For a hazar. the cr studiisure t. the lu al. 19 IMr.vu of Bn: 1976. posed et al. ' voice:1 Berry empL and cj but ru 1976) In (1974 epidcr (1978 facto r i 'teller ion -arcoher her lobuicture. -dif* .1 ef-ftwo iisa e paT> ws for 1*61 vers of tion of -vs per mlant uc sev.-nce to ; es tate i>- et al. iprobit <*sump1000 I ppm not tied by tx-fl !by workers iity of ! expo*et al. Vinyl Chlonde-Aasociated Disease 31 Results of a recent survey by Bndy et at. (1*77) indicated that for New York State (excluding New York City), a highly industrialized area, the annual incidence rate of ASL during the 6-year period from 1970 through 1975 was 0.25 per million residents. Tltis 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 wert found in the study area from 15S to 1975. and 7 of these had had documented long-term exposure to either As. ThQ; or VCM. Five (all femalei of the remaining 19 patients lived at a distance of 500--1500 feet from VC tabneatton or polymerizauon facilities for long penuds. No pertinent exposure or residential history was obtained from the other 14 pauents. Discharge of unrtacted monomer into the en vironment as result of losses in the PVC production process was estimated to have ex ceeded 200 million pounds annually, most of which escaped into the atmosphere with lesser amounts dissolved in water effluent (Schwarzer 1975). Concerning the order of `magnitude of ambient exposure beyond the work plan. 1*. outside the industrial set ting. an average annual exposure connntrauon of 17 ppb was estimated for the 4.6 million persons throughout the United States who resided within a 5nfic radius of vinyl chloride emission sources (Kuzmaek and MeGeughy 1975). If the nsk assessment mode! elaborated by Wdods (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 .7 Mortality and Cancer Morbidity Studies For a tumour disease as rare as angiosarcoma of the liver even quite small increases in ^hazard o* background levels should be detectable (Doll 1975). The situation with the common types of cancer is far more difficult. Since 1974 a number of mortality studies of VCM^xposed populations have suggested that in humans long-term expo sure to VCM may also bt 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; Tabenhew and Geffcy l97*.Nichotson et aL 1975; Wagoner at al. 1*76: U'axw-R7er et al. \9^b\Niclwison l9T7;Mu/jflerti aL 1979). Epidemiological studies of British workers failed to confirm this suggestion (Duck et al. 1975:Duck and Carter 19"6;Fb.T and CoUitr 1976,1977). as did a prospective study of a VCM/PVCxposed cohort of 1613 employees of s West German chemical plant (Frtnrzel-Beymt et t' 1973). Criticism of design and interpretation of soma of the studies has been voiced (Folk et al. 1974b,Runhese and Williamson 1974;Rrfr \9Tl\Dekiewp 1975: Berry and Rossuer 1976). A follow-up of all VOU.xposed persons (750 traced) ever employed at the one Swedish factory, which started operation in 1945. for mortality and cancer morbidity patterns revealed a fourfouid tins of pancreasAWtr tumours but no deviation in the number of brain tumours from the expected level (Syren ct al. 1976). In addition to the three extenrive mortality studies of Tabenhew end Gaffey (1974). Waxwcilcr et al. (1976), and Fox and Collier (1977), a fourth comprehensive epidemiological study (Reinl and Weber 1976) was completed in 1977 by Rebil et al. (1973). widcii included three study populations from 11 VCM- and PVC-produdng lactones in the Federal Republic of Germany, covering the period from before 1959 L ?- W.K Lelhach and H.J. Marsteiler through 1974: (a) 7021 worker* enpged in the production of VCM end PVC;(b) 4910 chemical workers from the same plana not exposed to VCM: and (c) 4007 workers enpgtd in PVC manufacture. Not included were non-German workers of Mediterranean origin. This German study permits comparison not only with the mor tality ratio of the total male population but also with a comparable occupational group exposed to VCM. With reprd to the liealthy worker effect* (McMtchael et al. 1975). overall mortality was elevated for the VCM-exposed population (group aV but not tot the other chemical workers (group b). Apart from the markedly elevated stan dardized mortality ratio (SMR) for malignant liver tumours (1523). which proved to have been closely itlated to the duration of exposure, a significantly elevated SMR was found for tumours of the lymphatic and haenutopoctic system (214). The group of chemical workets 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 penod 1970 through 1974. about 40ft of deaths having occurred in tx-PVC workers. A recalculation of the available data would have been necessary for the evaluation of a conceivable influence of VCM on vigilance. As an addendum it may be noted that determination of plasma carcinoembryonic antigen litre (CEA) in 200 Canadian PVC production workets (mean duration of em ployment: 10 yean) showed a mote than threefold higher frequency of levels above 10 ng/ml than in a normal healthy population (1.7ft vs. 0.5ft) (Pafc et al. 1976). Levels of CEA were also determined in 1363 worfcen of five different VCM polymeri zation (3) and PVC processing (extrusion) plants (2) in the Uniied States (AwJenoti t< al. 1978). After removal of possible confusing facton (smoking, alcohol intake, past medical history), it emerged that the distribution of CEA titres among the polymeriza tion worken was significantly different from that in the extrusion plant group and in a nonexpose d reference group. Significant differences were also found for two of six job categones examined (polymerization and maintenance) compared with extrusion workers and the reference group. However, the usefulness of the CEA litre as a predic tive indicator of possible increased risk seems doubtful. 4.4 Miscellaneous Aspects 4.4.1 Thrombocytopenia and Ratelet Function Tests Thrombocytopenia in chronic VCM intoxication was Tint mentioned - rather paren thetically and without further comment - in a paper published by Antomuzhtnko in 1968. Later Jiihe et al. (1973) noticed that each of the first 13 autoclave cleaners re fereed to them during 1972 from a West German plant because of suspected skin and UCC 069370 Vi bo B>< tio ce; Op we ot. th. det ph ot!, fab b. ' uphar re: 1o cou of 1 in al. i c> or > *>r T;. w.. tlr. A B C D a pea pielitri linu Fix The teller mor* :al. >. but ' stanJ to IR W3J pot ' the .in- n isin one wind. the out v data lm me -Kn ot et MU < tuaJ in fix twn predic- ia*en-*o in l> te rn and Vint I Chlonde-Assoaaud Dimate 83 bom lesions presented with mj!J to marked thrombocytopenia f30-119 V 1(T* litreV Bone marrow aspirates in 6 patients permitted exclusion of disturbed platelet forma tion or osteomyeioiibtoiis/Kleroin. but in 12 of them splenomegaly was found. Ex cept for slight rettculocytous in 8 and leucopenta in 5 of the workers, other haematolopcal tests were negative. The reduction of the number of leucocytes and platelets as well as reticulocytosis appeared to be attributable to splenomegaly, but further studies on the nature of thrombocytopenia were thought necessary, and it was suggested by the authon that a decrease in the number of platelets might serve as an early and easily detectable symptom. Tire high prevalence of thrombocytopenia (as determined by phase-contrast microscopy) found later on detailed analysis of platelet funeuon and other parameters of blood coagulation in she total cohort of PVC production (and also fabrication) workers from this plant strengthened this suggestion (Bodmer ct at. 1974a. b. 1975a, b. \9~6.Sthn-Bodmer and Eire/1977). Wtjman (1975) also commented upon abnormal platelet couns in 13 of 37 PVC fabricating workers who had only handled PVC powder which, however, might have contained substantial amounts of residue monomer. In contrast.lifts 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 Sthrt*Bachntr and Etui (1977). the mean platelet count in a cohort of 132 PVC polymerization (and processing) workers was significantly lower than that in a nonexposed control group of 150 healthy men. As could be expected, Boduttr et al. (1975b) also demonstrated a positive correlation between the degree of thrombo cytopenia and the prevalence of an enlargement of the spleen (palpable splenomegaly or spleen size determined by selective scintigraphy with l*'-Hg-bromo-mercury-hydroxypropancdabelled red cells) is 70 PVC polymenzauon workers (see Table 19). It ap* Table 19. Prevalence of enlargement of the sp'wn* among 70 PVC-poly merization workers in rviannn to increasing degrees of ihromt ocyropenia (deeAlter et al. I975a> Croup No. of workers examined Flic*leu (* 10'*/Lire) Range Mean Enlargement of the spleen A 14 B 24 C 25 D7 > 130 100-130 70- 99 < 70 168 117 $7 44 * As determined by palpation or by selecuvc spleen scintigraphy. 3 '21*) 11146<:) 19(767r) 6(86") peats, however, that the development of thrombocytopenia is not dependent on the presence of splenomegaly since we observed mild thrombocytopenia (100-120 x 10**/ litre) in a small number of workers in whom spleen size waj definitely within normal traits on selective spleen scintigraphy (MflzUchctundax <4J x KT1 according to Fischer and Wolf 1963). Thrombocytopenia was accompanied by abnormalities in platelet function tests. There was an increase in the number of large (> 10 pa) `juvenile' platelets (increased M W.k- U-lbjih anj H.J. Marsieller Vi platelet spreading), enhanced response (platelet aggregation) to addition of ADP and tal: collagen t Bom test) and increased availability of phospholipid-containing platelet fac en tor 3 (Bactuier et al. 1975a). This pattern was thought to be compatible with the no ati. tion of an increased turnover rate due to derangement of microcirculation (CDIC) in ciu liver and spleen and defective reticuloendothelial system (RES) clearance of activated r vin- dotting factors (5flc/iicret al. 1974b). Wend (1976) and h'jn/ et al. (1976) suggested 1 that thrombocytopenia could be construed as confirmatory evidence of an immune dai sib. complex disorder. Hc-jtcmann and Siutte (1977a) noted untuual focal aggregation of I platelets in klauch preparations of spleen tissue and increased platelet pooling (plate I 1 lets trapped within the subsinusoidai meshwork of pulp cords) in the ltd pulp of the spleen on electron microscopy as well as phagocytosis of thrombocytes by sinusoidal 4.4 macrophages. Schaffncr et al. (1976) found platelet thrombi in and around hepatic Tin sinusoids in mice after exposure to VCM. A direct toxic action of VCM (or metabo FV< lites) on the bone marrow has not been demonstrated so far. a pi Although the pathogenesis of thrombocytopenia in VCM-mduced disease is not fully thn understood, it seems at present most likely that it is caused by increased turnover and dur consumption of platelets within the abnormal vsscular spaces of the liver and spleen. we: A similar type of consumpuon coagulopathy was described as complication of spon deft taneous haemangiosarcoma of the liver by Tntel! et al. (1975). A haemostatic defect lime more complex than mere pooling and destruction of platelets in the enlarged spleen vioi has also been commented upon in the paper by Gtmn et al. 11974) in connection with exp splenomegaly of various nonctrrhotic ongm. foui pos; 4.42 Central and Peripheral Nervous System C, for Miscellaneous nonspecific ind somewhst indefinite symptoms have been described in connection with chronic inhalational exposure to VCM in PVC-producuon workers, ere: vale wi< such as dizziness, disorientiuon, blurring of vision and memory, headache, imtability, Tin excessive fatigue and somnolence, sleep reversal or insomnia and other pscudoneur- Mar. vthemc symptoms (Sum et al. 1963,l975:Selionek 1969:LHii et al. 1975 and others). This prenarcotic syndrome was interpreted as a manifestation of a potentially altlbrot Rvetsiblc acute toxic encephalopathy. Its danger to the individual was thought to lie icai mainly in resultant inadequate reactions to critical situations (Schotttk 1969). How t ever, Vtie et al. (1976) reported that several individuals in a group of 95 comparatively tion young ex-workers, the majority of whom hid no other symptoms, complained of fa tmo tigue, headache. listiessncss and depression, with onset of symptoms having been de to it lved as long as 2 years after cessation of employment. With reference to such pseudoneurasthenic complaints', which may be interpreted at the mildest degree of a toxic encephalopathy, fenei et al. (1975) examined a group of 21 autoclave deanets at varying intervals after cessation of exposure, all of whom presented with other (cutaneous, angioneurotic, hepatic) manifestations of vinyl chlo ride disease. Clinical symptoms of a more or less distinct encephalopathy (including cerebellar ataxia in 4) were found in all but one of them. EEC recordinp were normal bi only five of these patients; in the others, parenrbythmla, dysenrhythmia or a socalled subvigil electroencephalogram was observed. Evidence of distal polyneuropathy, A re thoi. ings to a nect VO resp 17o. R found in 19 patients, was attributed in the fint piece to an abnormal peripheral circu- toP' ucc 069372 Jjffuller UP and clet facihe noniC) in cuvated ggested imunt puon oi' .((piste* of the msoidal cpauc i.-iabo- ; not fully ver and i spleen, fspon- Jelect <pteen non with ohcd in ken. ability, -.wursnd ndally to lie . HowTatatively .1 of fa-m de- terpreted I a group whom yl dtlo htdint -c normal a so* -nopathy. al emu Vinyl ChltMidc-Afttociated Disease 85 lation with resultant hypoxic damage. Tlie pathogenesis ofa possibly VCM-imluced encephalopathy is not clear. It would be conceivable that clinical and bioelectric alter ations found in some patients,in whom portosystemic encephalopathy couid be ex cluded. may have been due to toxic or hypoxic brain damagt. However, no'other con vincing evidence has so far emceed to indicate that chronic irreversible cerebretoxic damage may have resulted from prolonged exposure to VCM. notwuluianding the pos sibility of an induction of brain tumours. 4.4 J Pulmonary Changes The suspected development of nonmalignant pulmonary changes due to VCM and/or PVC dust exposure is still a matter of controversy. Soon after VCM was recognized as a potent carcinogen, duet groups of employees (n 290.250,445. respectively i from three large North Amtncan FVC-ptoduong plants (A, B, C). characterized by different duration and levels of past environmental exposure to VCM as well as to PVC dust, were studied with respect to chest x-ay film abnormalities and pulmonary function defects is assessed by spirometry and determination of maximum expiratory flow vol ume (Miller 1975.Miller et al. 1975;liiu ct al. 1975.1976,1977). All cases with pre vious exposure to asbestos, silica or coal dun had been excluded in these studies. Un expected linear, reticular and. less often, rounded opadues 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 those from plant C. with the lowest exposute level. The ptcvalenee of these radiological abnormalities, for which no pathogrneuc explanation was available, was found to be significantly in creased with longer durauon of VCM-PVC exposure (more than 10 yean), but the pre valence of a positive history of smoking, although identical in both groups A and B, was also found to be significantly higher in workers with abnormal chest x-ray plates. The overall pievalence of a positive history of chronic bronchitis (British Medical Re search Council criteria) was 20.45in group A (highest exposure) and 16.05 in group B. although group B was significantly older. The somewhat higher prevalence of chronic bronchitis in worken 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 since both smoking and age were related to chanps in pulmonary function, it appeared difficult to isolate potential specific effects of occupational exposure to VCM and PVC dust. A restrictive pattern was found in 9 of group A and in only 2 of group B, al though group A was significantly younger. In conclusion, this extensive study, indudfal a total of 985 workers exposed in the past to VCM u well as PVC dun. may point to a potential multiple factor effect of smoking and VCM-PVC exposure. In this con nection, it is of interest to note that according to a cohort study of mortality among VCM polymerization worken the SMRs for respiratory cancer as well as for 'other respiratory disease' were found to have been in excess of expected figures (156 and 176, respectively) (Waxwtiier et ah 1976). Bronchopulmonary changes thought to be due to long-continued, intense exposure to PVC dust were obxmti by several authors (Fanntjpani and Satti \9S5, Broussard 86 W.K. Lclbach and H.J. Manieller 1969:Szende eta). 1970; Vertkin and Mamontov 1970: Frongia et al. 1974: Dari,f 1976:Amaud et al. 197$). Considerable exposure to VPCdust is the rule in the drying, bagging and storage areas of FVC^rodudng plants. Photographs contained in A'antodi'i paper 0976) 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 at long ago as 1955 by Pameggieni and SassL In 1969 Bmuaard mentioned the possibil ity of development of chronic bronchitis caused by the inhalation of PVC dust. The insoluble and inactive dust particles were thought to accumulate in the lungs blocking alveolar spaces and being taken up by alveolar cells. This could lead to elimination of these cells via lymph veseb 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 pregiessive respiratory insufficiency. Sztnde et al. (1970) reported the case of a 31-year-old worker who presented with severe dyspnoea;a chest x-ray examination revealed diffuse micronodular pulmonary lesions. He had been engaged for only 1 year in shovelling PVC powder at a processing factory. Lung biopsy* revealed moderate diffuse fibrosis and small focal granulomatous lesions containing ovoid or polygonal birefnngent foreign matenal which could be eluted by treatment with a known solvent of PVC. Microscopic examination of PVC dust panicles collected at the patient's plaee of work showed, them to be morphologic ally identical with the panicles found in the patient's lungs. Another anecdotil case of pneumoconiosis after 33 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 U VCM-exposed British workers, who complained of breathlessness, revealed focal alveo lar wall thickening with macrophages in alveolar spaces and increased rcticulin and col lagen on electron microscopy (Darke 1976). Although chest x-ray appearances were normal and routine respiratory function tests showed only slightly impaired COj dif fusion in six individuals, perfusion and ventilation scans revealed strikingly abnormal pictures, including marked perfusion defects of upper lobes. Darke pointed out that aome of the men worst affected had been engaged in the polymerization of 'plastisol', a very fine PVC powder with panicle size around 0J tan. Selikoff(1976) called attention to results obtained by Fronpa et al. (1974), who observed significant histopathologicil changes in the lunp 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. Vtrtkw and Mamontov (1970) who examined 96 workers engaged in the manu facture of articles made from PVC powder, also found a considerable proportion of them were suffering from functional and morphological alterations of the broncho pulmonary system, which they ascribed to their exposure to PVC dust. They quoted results of earlier animal experiments conducted in 1963 by GotovtQvk and later by Shtyakhenkti These last authors had apparently shown that exposure of animals to PVC dtst may lead to the development of chronic pneumonia and eventually to a son of mild fibrosis of the lungs. onesreeBiJu m'w*--i -- ucc 069374 \. su bl ah W' ov of 6) er. of de *Pl 4- Th m. im ti> Of ter Ah mi I* co* re: P 1 an fat* Jo ha* h> of an ms pb 19 of VC i Jmjjfi jteller *4;0anke m the drying. I in Karstadr i -nu of tht reported is the possibildust. Tht np blocking miniuon of nent of At *iout hilar lesented with i pulmonary i processing -enulomatous could bt ion of PVC morpholofic- cni in a PV'C * and granu'.i-niic et al.. n 1 of 14 i ;,vai aivto^^nd nHrwere I to.* dif* - abnormal ; nut that *piasttsol'. tvM), who and rau ex* ifging area, rophage re* of foreign hwnatoui lire manuvtftton of brondio!y quoted no later by animals to dly to a ton Vinyl Chloride-Anotiateii Disease 87 Certain type of PVC dim (one of two samples tested) were found to exhibit a strong haemolytic poteneal due to tht presence of an undetermined but readily solu ble surface-associated agent which was not VCM (Richards et ai. 1975). These authors also studied the effect of the haemolytic sample ofFVC dust on lung fibroblast cul tures, but they did not obtain any significant results. Contrary to earlier indications (Longe 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 Mottoni et al. (1974b) reported a high prevalence of pathological changes of respiratory epithelium (squamous metaplasia, squamous dysplasia, typical and atypical adenomatous proliferation) in sputum samples from employees of Italian VOI-PVC factories. Nevertheless, contrary to the now wed*sublished role of VCM in the production of nonmaiignant lesions of bone, skin, small vessels, liver and spleen, rt is still open to debste precisely what importance can he asenbed to pulmonary changes within tht spectrum of VCMnndueed discssc. 4.4.4 Genetic EfTccta ofVCM The discovery of the carcinogenic properties of VCM also stimulated interest in its muug:nie potential. A number of studies have been carried out that demonstrated a mutagenic response to VCM or its metabolites in microbial rest systems. Point muta tions due to base-pair substitution have been produced in various strains of Salmonella typhimurium by VCM in the presence of animal and human liver microtomes as a sys tem of metabolic activation (~annuf et al. 1974, l976;5emc/< et al. 1975a, 1976 : McCann et at. 1975 ;MalaretSe et al. 1975: Cam et al. 1976). Mutagenicity of VCM metabolites was also demons,rt red in yeast strains (lopneno et ai. 1976,1977;S/ioiun 1976) and in mammalian cel: i.'lubtrman et al. 1975). In comparison to nonexposed controls, a significantly bight, incidence of duomoaoRBl aberrations (fragmentation, rearrangement) in lymphocytes of workers occupationally exposed to VCM was re ported by Dueatman et al. (1975), Funes-Crwrioto et al. (1975), Purchase et al. (1975. 1976), and Fomenko et al. (1976). Fitif and Thiess (1974) had failed to demonstrate an increased rate of chromosomal abemtions in six chemical engineers and four PVC fabrication workers. As to the influence on germ cells, Purchase et al. reported that no dominant lethal effects were seen in fetuses of female mice mated with males which had been exposed to 3000,10 000 and 30 000 ppm VCM for 5 consecutive days. Thu, however, docs not absolutely exdudc genetic effects on human gonads. The outcome of pregnancy among wives of VCM-polymerization workers as against wives of rubber and PVC-fabrication workers (Inform et al. 1976a, b) and rates of congenital malfor mation pat 1000 resident live births in three Ohio communities with PVC production plants have also been studied (fnfenrt 1976). As part of a larger survey of workers' health, interview questionnaires (Infante 1976a. b) showed that after paternal age adjustment a significantly higher inadcncc of fetal mortality subsequent to paternal exposure was recorded among the wives of VCMexposed workers. This tread was found to be maintained after elimination of *9 / `l- o t *V W'fT*V*t-* dV; -S- r;-v @r Bjes I fit W.K. Lelbach and H.J. NUrstellcr pregnancies in women who had more than two abortions. The findings of this study raised the question of possible genetic risks of VCM to man and led to the suggestion that germ-cell damage in the father through direct VCM exposure might be a possible explanation. No clear-cut linkage of PVC production and increased occurrence of congenital malformations (primarily CN'S malformations) emerged from preliminary studies in three Ohio communities with PVC production plants. But the need for further study of possible conrributary 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 plants 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 necessary to arrive at tne full recognition of the nr.ge of pathology associated with occupational exposure to vinyl chloride. It can only be hoped that the lesson from the vinyl chloride problem may help to bring about an increased awareness of the risks and hazards which an inevitably the consequence of an ever-expanding technology. The importance of this lesson lies in its exemplary nature. A single substance of rather simple chemical structure, which was long held to be a comparatively safe com pound.even by experts, turned out after all to be a carcinogen with a very long latency penod for those who were heavily exposed to it. But its carcinogenic properties would most probably still have gone unnoticed if the resulting malignancy had been any can cer other than of an exceptionally rare type. Animal experiments in the early days later proved to have been broken off before the oncogenicity of this chemical com pound eould have been detected. The lesson to be learned is that in future any new chemical which is to be widely introduced into the environment should be scrutinized closely, for a sufficient length of time, and with the aid of all available methods for the detection of potential car cinogenic effects. In addition, we should keep in mind that in industrial surroundings we almost never deal with a single compound, but with a very complex occupational environment whose carcinogenic potential is still a completely unresolved problem. If currently adopted guidelines for industnal hygiene are strictly adhered to, there is reason to hope that initiation of new cases of VCM-inductd angiosarcoma of the liver can be effectively prevented- Unfortunately, however, it can be expected that in view of the long latency period for tumour promotion additional cases will appear dur ing the next decade. Considering the ever-increasing complexity of environmental influences, future re search will be faced with almost insurmountable obstacles in its endeavour to establish "safe* levels for potentially hazardous chemicals. Promising areas for further studies m the field of vinyl chloride and allied compounds may be the problem of the interaction ucc 069376 Vinyl Chlor.-' between preJ tissue such as short exposu; will cany the t References AIbnfht LF i Albright LF < . AIbnfht LF t' AJbnght LF ( polyvinyl c Albnght LF t processes. Alrenga DP (1 198-203 Amann R (19 der Leber ' Anderson H x CEA unoi: 1560--156' Andrews AW properties Anghelescu F V(1969)r employees 473-481 Annual Repu London. C, Antonyuiheiiaian text). Antweilcr H i Perspecr I" Amaud A, Po. ride pneurr Aryanpur J t; Iran. J Occi Assmann H (1 Austin CT l1u 17-89 Bichner U. fcund ttsopti. 2409-24K Bachner U. Ft. Befunde br Jahresbenr Centner, S: Bachner U. Mu 1000 patter Bachner U.Et/ und Osoph. Blutunfen . U Maretellcr this study sufsrttion ,, a possible mjcnital -Judies in thsr study .< cf ;r.t par. had cvtr <d within at the full m to vinyl 'Mem may .re inevitably ranee of 1^ eorr. fl^^tencv :mcs would .11 any :rv ?l, dsys n-al com- he widely -i nr length .-ntial caritroundinp cupatioiul : problem. cd to, then ns of the cted that in li appear dur- -s. future rer to establish -r studies m e inttraetion Vinyl Chinnde-Aisocuicd Disease 89 between predominantly bepatocytic metabolism and oncogenic effect on mesenchymal tissue such as vascular endothelium, and also the question of whether intermittent short exposures at high concentrations or connnuous exposure at a low concentration will cart:.* the greater lisle. References Albright LF(1967a) Vinyl Chloride processes. Chem Eng 74:123--130 Albnght LF < 1967b) Manufacture of vinyl chlonde. Chem Eng 74:2)9-224 Albngnt LF 1196?ci Poly mentation of vinyl chlonde. 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Wxw. nsk Mamctlcr .ion* m vinyl - the inluli* tulditurr ul -resumably J.rectior. - -i.rde a causal i'apcr prenf the Liver. - givtn clearance .^presented to Annual Mee:- wrni Ultra.i.ension. Cut liver tngio<o ttnmars results c 'iver and mren ..Vjn>ls- nf vinyl tiduccJ jnfio- . .:ng ejuu.drura' * . ,> title dviermim-4 *4- tn| ' I Mi StJte **<! and Ijum. vinyl .ucrural wiplicated a: . mutagenicity "ting m woilttn Ittotuc expo- Vinyl Chlonde-A^ociatcd Disease 109 Vaztn AN. Plokhova ET (1969a) Changes in adienalindike substances in rabbit blood folia* :ng .hrrmc exposune to vinyl chloride vapour. Ci{ Tr Prof Zabol 13 46 -47 (Russian text I Vazin AN. Plokhova ET (1969b) Chances of cardiac activity in rats followint chronic exposure to vinyl chlor.oc vapour. Fannakol Tok*ikol 32.220-222 i Russian text i VKE11974. 1975) VC/PVC: Beor-iel eater Problemlosung. Hrrausjtfcben vom Ver* band Jer kunstitortcrzeugenben Industrie e.V. iVK). Frankturt) Veltman G. 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