Document jmnKKrvZq76KZb4XQXRggYee5

Ergebnisse der Inneren Medizin und Kinderheilkunde Advances in Internal Medicine and Pediatrics Neue Foige Herausgegeben von P Frick G.-A.von Harnack K.Kochsiek G. A. Martini A. Prader Mit24 Abbiidungen und 23Tebellen Springer-Verlag Berlin Heidelberg New York 1981 Vinyl Chloride-Associated Disease W.K. LELBACH and HJ. MARSTEU-ER ' 1 Introduction............................................ ; 2 Teclutolopcal Details................................................................................................ 2.1 VmylChloride Monomer (VCM).................................................................... 2.1.1 History................................................................................................... 2.1.2 Production ot'VCM.............................................................................. 2.2 Production of PolyvinylQtlortde iPVC)........................................................ 2.2.1 Technology of Polymerization............................................................ 2.2.2 Method* of Polymerization................................................................. 2.2.3 Compounding........................................................... 2.2.4 Sources of Exposure to VCM in PVC Production .......................... 2.2.5 The Explosion Hazard......................................................................... 2.2 6 The Odour Threshold '......................................................................... 2.2.7 VCM as an Anaesthetic Agent............................................................ 2.2.8 Effects of Acute Overexposure in Man ....................................... .. . 2.2.9 Monitoring VCM Concentrations in Working Areas........................ 2.2.10 Exposure to VCM in PVGProcessing (-fabricating) Plants........... 2.2.11 National Standards fof the Control of Exposure.................... . 2.2.12 Exposure to VCM Outside the Working Area.................................. 4 4 a 5 6 6 7 g 8 9 10 10 M 13 j5 17 18 3 Toxicology of VCM................................................................................................... 21 3.1 Acute Toxicity................................................................................................... 2t 3.2 Chronic Toxicity................................................................................................. 21 3 3 Oncogenic Properties................... 22 3 .4 loxicadyntmtcs........................ '24 3.4.1 Uptake and Distribution..................................... 25 3 4.2 Metabolism.......................................................................................... 26 3.4.2.1 Relation between Chemical Structure. Reactivity tad Mutagenic or Carcinogenic Effect................................ 26 3 4.2.2 Metabolic Pathways............................................................... 26 4 Clinical Spectrum...................................................................................................... 4.1 The Triad: Raytimid's Phenomenon. PseudoacJerodetma and Actoosttolysu................................................................................................... 4.1.1 Familial and Idiopathic Acroosicaiyss....................... 4.1.2 Epidemiology of Occupational Acrooataoiysis................................ 4.1 J Clinical and Roentgenological Features............................................. 4.1.3.1 Occupational AcrooaMotyss............................................... 4.1J.2 Paeudoaderodcrma............................................................... 4.1.4 Kbto&fy................................................................................................. 4.1.4.1 Cutaneous Lesions.................................................................. 4.1.4.2 Bone Lesions......................................................................... 4.1.5 Arteriography. CaplUaroscopy. Infrared Thermography ................ 4.1.6 Imaunotogseal Studies......................................................................... 29 Jl 34 J4 3d 36 38 38 39 39 40 42 I Department of Medicine. Director Prof. Dr. HJ. Dangler. University of Bonn. KRG W K Lelbuch and H.J Manteller 4 1 7 Pathogenetic Considerations............................................................ 4.2 Non-malignant Liver Disease in Vinyl Chloride/Poiyvmyl Chloride Production Workers.......................................................... ............................... 4 2 1 Clinical Manifestations oi Noiwnalignant 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....................................................... 4.2.4J Hepatocytes.......................................................................... 4.2.4 4 Histology of the Spleen..................................................... 4.2.5 Pathophysiology of Portal Hypertension .................................. 4.2.6 FolJow-yp of Non-malignant VCM-induced Liver Disease........... 4.3 Angiosarcoma of the Liver............................................................................. 4.3.1 Epidemiology....................................................................................... 4.3 .2 Clinical Manifestations....................................................................... 4.3.3 Peritoneoscopy..................................................................................... 4.3 4 Gross and Histological Morphology.................................................. 4.3 S Therapy................................................................................................. 4 3 6 Risk Assessment.................................................................................. 4.3.7 Mortality and Cancer Morbidity Studies........................................ 4 4 Miscellaneous Aspects......................................................................... 4.4] Thrombocytopenia and Platelet Function Tests.......................... 4 4.2 Central and Peripheral Nervous System.......................................... 443 Pulmonary Changes............................................................................ 4 4 4 Genetic Effects of VCM.................................................................... 5 Conclusion and Outlook ....................................................................................... References....................................................................................................................... 44 44 48 49 50 51 51 54 54 54 55 57 $7 57 74 76 78 80 80 81 82 82 84 85 87 86 89 Key words: Acroosteolysis - Angiosarcoma of the Liver - Portal Fibrosis and Portal Hypertension - Pseudosckrodarma - Raynaud's Phenomenon - Vinyl Chloride 1 Introduction The history of vinyl chloride-wodated disease, its recognition and prophylaxis i* a classic example of shutting the stable door after the hone has bolted. It titould help to emphasize the need to shift our attention to preventing exposure from occurring rather than to reparative measures. In view of the iaiye number of new and potentially hazard ous chemicals introduced each year into the workplace and the environment, this ac count should again alert us to the necessity of pretesting chemicals adequately for their potential health effects, even at tbs risk that technological program will develop at a more modest rate. Large-acalc production of the synthetic retin polyvinyl chloride (PVC), a thermo plastic material suitable for the most widely diversified Industrial use, was begun around 1930 in the United States end in Germany. The monomer, vinyl chloride (VCM), a rather timple aliphatic compound, was believed until the early 1960s to be Vinyl Chlonde-Assov one of the least harm I' later turned out, had r evaluation of acute eft to reveal its carcinogei might have continued place. considering that vapour phase under an- reactive double-bond. Today vinyl chloric formation and data on cisely a quarter of a cei tributable to this new ^ with the shocking disc., tion workers heavily e.x inf that the monomer t pound did not alert the in workers engaged in : lished in 1949 {Tnbuki Ultimately, it was tl cuned in workers expo s causaJ relationship: (1 pseudoslerodemu: f2) liver. Particular J nancy among a C alarming exper a connection b ^ \ lungs or the ga -* the prolonged oj f sarcoma of the these tw6 fatal j the conclusion cancer meeting in Hous. to VCM was a very sen It should be stresse,. precise, an intermediate mainly in the mammal merization products (P\ cated from the polymer, they contain unieacted PVC (thermal decompo- toxicity of pyrolysis pro mainly due to the relea* A bar 1969 .Dyer and v and only very small or n {QMero et al. 1971 cite t Marsttlkr 44 43 49 50 51 51 54 55 5" 5* 5? 74 76 76 SO 80 81 *: s: 84 85 S" S3 89 I tonal Umda .laxisisa *mld help to tiring rather tiaQy haardnt.tUtaC' uly for . develop t.a thermobegun loride <>60ttobe Vinyl Oilonue-Ai^ociJteiJ Disease one of the leas; harmful chlorinated hydrocarbons. Early ammai experiments, as it later turned out, had indeed been carried out with dosages sufficiently high for the evaluation of acute effects, but chronic exposure had not been of sufficient duration to reveal its carcinogenic properties. On purely theoretical grounds, however, one might have continued to fee] uneasy wh this compound as a pollutant of the work place. considering that it is (II a halogenated hydrocarbon which (3) exists in its vapour phase under ambient conditions finhalauve exposure) and *3) contains a highly reactive double-bond. Today vinyl chloride-associated pathology is well documented. A large body of in formation and data on this topic has been accumulated, notably since 1974, but pre cisely a quarter of a century had to pass before the full range of symptomatology at tributable to this new occupational health hazard became recognized in January 1974 with the shocking discovery that haemangiosarcoma of the liver occurred in produc tion workers heavily exposed to PVC. Early and not easily accessible reports suggest ing that the monomer rrught be an environmental risk for workers handling this com pound did not alert the experts sufficiently. The earliest indication of advene effects in workers cnpged in the production and processing of PVC, a Russian study pub lished in 1949 (Tfibukh et al. 1949), received little attention. Ultimately, it was the exceptional character of the three major lesions which oc curred in workers exposed to VCM that contributed most to the final appreciation of a causal relationship: (1) the syndrome of acroosteolysis, Raynaud's phenomenon and pscudosleroderma: (2) non-cirrhotic portal hypertension; and (3) angiosarcoma of the liver. Particularly, the discovery of a chmer of four cases of this extremely ran malig nancy among a comparatively small group of workers (Cnrch et al. 1974a) was an alarming experience which called for immediate action. It can easily be imagined that a connection between VCM and the more common malignancies, such as cancer of the lungs or the gastrointestinal tract, might still have gone unnoticed- On the other hand, the prolonged latency periods ofboth noo<inhotie portal hypertension and angio sarcoma of the liver, roughly 10 and 20 yean respectively, delayed the recognition of these two fatal consequences of chronic exposure to VCM. But me can hardly escape the concluson that Viola's discovety ofcancer in experimental animals, presented at a cancer meeting in Houston in 1970, ws sufficient evidence to indicate that exposure to VCM was i very serious occupational hazard (Perm 1976). it should be stressed that the noxious agent is solely the monomer, or to be more precise, an intermediate of the monomer's metabolic bioacriviattoa, which takes place mainly in the mammalian liver and yields certain highly reactive epoxides. The poly merization products (PVC), La,, the solid plastic and the plastic consumer goods fabri cated from the polymer, are chemically inert articles which carry no health risk units they contain orueacted reridual aoootmr. Even the combustion of strides mode from PVC (thermal decomposition in /ties) dots nor yield free vinyl chloride monomer; the toxicity ofpyiotyris products of polyvinyl chloride polymers and formulations is mainly due to the release of hydiodrioric add and carbon monoxide (ComtiJt and Abar 1969:Dyer and *e* 1976;<&*** 1976;ifa*r l976;Goleftf.i7T et $L 1976) and only-very small or no quantities of pho^ane derived from residual monomer (OMan et al. 1971 died by Cokrdyn et al. 1976). URL 12154 4 2 Technological Details 2.1 Vinyl Chloride Monomer (VCM> W.K. Lelbach and H.J Murstc'.ler At standard (ambient) conditions of temperature and pressure, vinyl chloride <CH:* CHCl; chloroethylene. chloroethene) is a non-irritating, colourless gas with a faintly sweet odour, inflammable at concentrations above 3.8% by volume m jir. which is only slightly soluble in water, soluble in ethyl alcohol and easily soluble m ether and carbon tetrachloride. VCM is mainly used as an intermediate in the manufacture of plastics, as a refrigerant and in organic synthesis. It was formerly also employed as a propellant for aerosoles. It is easily liquefied under pressure and is usually handled and shipped as a liquid. Caseous VCM condenses at --13.B*C and 760 Torr ( 101J kPa) to a colourless liquid oflow viscosity {Ltfaux 1966). Its physical properties are listed in Table 1, the most important of which are its low boiling point, its high specific gra\ ity (gaseous VCM is 2.15 times heavier than air), its low solubility in water and the half-life in air. ranging from 3 to 20 h. Table 1. Physical properties of VCM Mol wt.; B.p.: F.p.. Flash point: Limits of flammability: Autoignition temperature: 62.503 -I3.8C 1-13.7 to-13.9) -IS3.7*C --78.5*C (Cleveland open cup) 3.8%-29.3% by volume in air above -7g.5*C f* 38 000-293 000 ppm) 472-C Vapour pressure: mm H| #C 10 100 692 2300 -87.5 -55.8 -15.8 + 20 2660 + 25 Vapour density: 2.IS g/litrc (calculated at 25*C and 760mmflg (air* 1) Sp. gr. of liquid VCM: 0.9121 at --20*C,'4*C 0.99 at --25*C/4*C Sources: FtirheR 19S1-,Irish !963;Zepp J964^1r/eu.r 19&6:Orrermeyrr L9o7. Route! 1972. 2.1,1 History The French chemist, RegrtmiU (163$) was apparently the first to study systematically the synthesis and anatyris of vinyl chloride.lirbqr who had done some earlier prelim inary experiments, encouraged Repwtir to investigate this compound when Rtpiault spent several months in Liebig's laboratories. All compounds containing the vinyl group (CH3*CH-) polymerize readily (Fi&hail 1957). Spontaneous polymerization of vinyl chloride to white opaque solid mass under the influence ofsunlight was first described by Bmmmn in 1872;healeo^osesn paper by Sayner and Glinsky (who Vinyl Oil' succeeded izing subs: 2.1.2 PtOw Large-seal by employ 1) Convers CH=CH 2) Convers chloroe: CHs *cr CHjCl-- VCM w Thus, at tioru ir c in the (JARf when ^ "*> in c 19f # conjecture . retneved Vi yses carne sum of all ii genates) w,, reacted mor in prepolyp the concer.' that even lo methyl chi.: isobutane. n ference in p ind H.J. Murstritr 1 chloride CCK;* ns with a fainth ;n air. which :s iynle in ether and manufacture of *V3 employed as a usually handled and Torr (* 101.3 kPa> -roperaes are listed :< high specific grav: m water and the .v -7S.5C : 2300 m +20 2660 25 ,i.J 760mmHg rmaytr 1967: wudy systematically : some earlier preiim.ttad when Rtgnault 'tabling the vinyl .ms polymerization of i smUght was first - and GSntky (who Vins I CiiIonde-Asot-i;ied Dr-caw 5 succeeded in decomposing vinyl chionde co monodilorouideiivde wish the aid oi'oxidnine substances such as hypodiioruus acui. 2.1.2 Production of VCM Large-scale commercial synthesis of VCM with a high yield was made possible much later b> employing two principle methods, the second having now largely replaced the first: 1) Conversion of acetylene to VCM by hydrochiorinauon: CH*CH * HQ " CH$*CHCI (catalyst: HgCl* on charcoal) (Austin 1974) 2) Conversion of ethylene by vapour-phase or liquid-phase oxychlorination to 1.2-dichloroethane and subsequent pyrolysis (thermal cracking) to VCM (Albright 1967a): CH:CHs + 2HG * 1/2 Oa - CH2Cl-CHjCI+HjO; CH-Cl-CH-CI _<m*r 3W u CH:CHQ +HC pumice catalyst (pyrolysis; thermal cracking, Austin 1974). VCM was usually manufactured in dosed systems and stored in outdoor facilities. Thus, any leakage of the gas was readily diluted in the ambient air. VCM concentra tions in the atmosphere at some distance from manufacturing plants were found to be in the range 1 -2 ppm. In close proximity, the concentration ranged up to SO ppm 11ARC 1974). Spontaneous polymerization in light has also been repeatedly observed when VCM comes into contact with atmospheric air due to container leakage (Osttrmerer 1967). A preiequiate for the polymerization process is a high degree of purity in commercially produced VCM. Impurities retard the polymerization process (Lefatx l966:Ostermm,er 1967). (n the early discussion about the cause of vinyl chloride-associated disease it was conjectured that ocher compounds or impurities contained in prepolymerization or in retrieved VCM might have been the causative agenda) (Thies and Venn 1974). Anal yses carried out by six West German manufacturers of PVC. however, showed that the sum of all impurities (such as saturated or unsaturated hydrocarbons and their halogenaies) was 0-015- by volume for pitpolymerization VCM and 0.1% for retrieved un reacted monomer. Only methyl chloride was found in concentrations of 50-300 ppm in prepolymerization VCM and 100-500 ppm la retrieved VCM (in one instance only, the concentration rangrt between 1000 and 3000 ppm). But it should be kept in mind that even 1000 ppm methyl chloride in VCM would men, at 500 ppm VCM in air. a methyl chloride concentration in air ofonly 0J ppm. AD other imparities (propylene, bobutsne, fl-baane etc.) would then be in the ppb range. Besides, so significant dif ference in purity could be found between VCM from acetylene and from ethylene. URL 12156 - ir 6 W.K. Lelbaoh and H.J. Mar<tei!cr 2.2 Production of Polyvinyl Chloride (PVQ 2.2.1 Technology of Polymerization The following description is meant to serve merely as a rough sketch of the procedures and technological details involved in the production of polyvinyl chloride. Vinyl chloride monomer is polymerized in large autoclaves (reactors) at tempera tures between 40*C and S0*C and pressures of 6-16 (8-12) atmospheres. Tlv-re are usually several reactors (up to 10-30) located in one building. The reactivity of the monomer is a function of its double-bond. The second functional site of the vinyl chloride molecule, the chlorine atom, does not react easily. The double-bond of VCM is not only the site from which the polymerization originates but is also the source of the toxicity and carcinogenicity of this compound when it is being metabolized in the body. The polymerization ofVCM, which is a strongly exothermic reaction (Barnes 1976), is initiated with the aid of compounds soluble in VCM that form free radicals at relatively low temperatures. Initiators are such compounds as lauroyl peroxide, isopro pyl percarbonate, azo-bis-isobutyionitride, and others. The free radicals react with the double-bond of the monomer, transforming it in turn into a free radical and thus prop agating the growth of a chain of molecules with a terminal free radical. Chain growth is interrupted by saturation of the terminal free radical which often involves a reaction between two growing chains (Molten and Zitlhuis 1964;Z.e/our l966,Albnght 1967 i-c&omitwifhaus 1972,5later 1972). The random character of such termination steps accounts for the production of chains of different length and hence different de grees of polymerization, with molecular weights of the finished PVC being statistically distributed around a mean value. Commercial PVC polymers have average molecular weights that vary from about SO 000 to ISO 000 dtitons {Afbrifht 1967b). Degree and velocity of polymerization, which are influenced by temperature and the concentration of initiators, determine the specific type of PVC produced {Fny 1973). During polymerization considerable amounts of the monomer are at first dissolved in the polymer, but most of this is later also transformed to PVC as polymerization progresses. The polymer which is not sol uble in the liquid monomer precipitates out. The proeesi of polymerization slows down towards the end of the reaction. It is terminated, depending on the method used, when approximately 6096-9016 ofVCM is polymerized. The tinting of this termina tion of the process is esential for the phytical properties of the resins produced. The heat generated during the exothermic process of polymerization mist be removed to keep the temperature of the reaction under control. Mechanical agitation aids in trans ferring the host acroa tils coOoidsI system to the cooBngjacket of the reactor. During the process of polymerization certain quantities of the potymer adhere to the walls of the reactor and form a slowly thickening continuous film or crust. This polymer crust wi the inner surface of the reactor vessel, which contains cavities filled with unreseted monomer, impedes the conductance ofheat; It has, therefore* to be cleaned away after termination of the batch procam (Acmes 1976). After completion of the polymerisation process, the slurry h rekased from the re actor into a dump tank. Retidual unreacted vinyl chloride monomer is partly solvated In the polymer (about 1096); the remainder Is dispersed in the water phase or is present Vjnyl Chlonde-' in the vapour ph VC monomer is r is then purified v the finished poi> and must diffuse * Raw PVC resin, r <VKE 1975). 8a proximately 500 The slurry fre large enough to h are then pumped wet polymer, a er drying methods, i merization, yield1 fine solid particle drying temperatu. polymer. A eycio The solid polymet storage bins or sil dried powder con 2.2.2 M*hods o Four i ig . in, PVC l r- 73' Suspi whic (sucl conj this olyr X] ner vin\1 rith h wh;. Emulsion Polym-. was added in the except that large. are added. Emu!?emulsifiers canno* Bulk /MassI Poly theadditon of oil The first reactor < second one is use. solid state, to es*reaches a level of characterized by 1 good optical dan .j H.J. Mars teller ->f the procedures mde. on) at temperaiieres. There are ^activity of the : of the vinyl ile-bond of VCM iso the source of letaboUzed in the 'action (Bomes *rm free radicals at I peroxide, isopro- react with the ,cal and thus prop* *ti. Chain growth is -oh*es a reaction ^.Albnghr 196" h termination cnee different de nying statistically jn from about poiyroerizat'.m, f-r%, determine mm considerable of this is later which is not soli izadon slows the nethod used, of this terminins produced. The -4 be removed to ation aids in tnns* lie reactor. During ere to the wails of i his polymer oust >cd with uareacted dewed away after ased from the re* is partly solvated phase or is present V/" '* ^ * Vinyl Chloride-Assocuied Disease in the vapour phase above the slurry. While a batch is in the dump tank, this unreacted VC monomer is retrieved by pumping it off into a VCM storage tank. Retrieved VCM is then purified by subsequent distillation for recycling purposes. Monomer solvated in the finished polymer cannot easily be extracted since it has a strong affinity for PVC and must diffuse through the particles: this diffusion depends on time and temperature. Raw PVC resin, therefore, still contains certain quantities of unreacied monomer (VKE 1975 i. Bernes (1976) reported that the polymer m the slurry still contains ap proximately 500 ppm of vinyl chionde. The slurry from the dump tank is pumped into a storage tank (blend tank) which is large enough to hold several batches of the product. The contents of the blend tank , are then pumped into a centrifuge which separates the wet solids from the water. The wet polymer, a granular mass, is dried either in rotating tubular dryers or by spray* drying methods, the liner being used mainly for products formed by emulsion polymenzaoon. yielding a polymer which is similar to a very fine white Hour. These very* fine solid parades art fed directly into a ipny-drymg column without dewatering. The drying temperature should not exceed 60*C to prevent thermal decomposition of the polymer. A cyclon separator at the exit end of the dryers removes coarser panicles. The solid polymer particles are then sized by multiple-layer screens, air-conveyed to stonge bins or silos and finally packaged for shipment {Albnght 1967d). The resultant dried powder contains about 50 ppm of monomer {Barnes 1976). 2.2.2 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 Poiymcnzation. Polymerization is carried out in an aqueous system in which monomer droplets are maintained in suspennoa by means of protective colloids (such as polyvinyl alcohol, gelatin, substituted celluloses) under heat and pressure in conduction with brisk agitation. Relatively targe polymer parades 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 suspention polymerization, except that large amounts of emulsifying agents (such as soaps or other surfactants) arc added. Emulsion polymerization yields resins ofa very nail particle size. The emulsifiers cannot be completely removed. Bulk (Monl Pofymertzetion. In this process VCM is polymerized In two stages without the addttOQ ofother liquids. The two reactors are operated betch-wise and is series. The first reactor (a ptepalymetUer') provides Car the Initial liquid phase, whfle the second one Is used for agitating the shiny, whieh is transformed, through a sticky solid state. to earatiaSy dry panidcs until the conversion from monomer to polymer reaches a level of about 75%-dOSJ. The resins obtained by bulk polymerization are characterized by high purity and particle uniformity, resulting in an end-product of good optical darity. ipeo ! I [ [ I !j :, 'j : :[ 1! ;J 'i .1 !i T> CO s W.K Lclbjch and H.J Manuiler Solution Polymerization. This type of precipitation polymerization is carried out in organic solvents such as -buunc or cyclohexane. It accounts for only a small percent* age of the total amount of all PVC resins produced and it is used for the production of copolymers. Copolymen arc mixtures of comonomers (such as vinyl acetate. vinylstearate, vinylidene chloride, propylene, acrylonitrile etc.I and vinyl chloride. The co monomers tend to improve flexibility and limited solubility of the product in solvents and exert an influence on the temperatures required for compounding. 2.2.3 Compounding As a next step, depending on the end use, the dried polymer, a whitish powdery or granular product, is then compounded (or dry blended) under pressure at fusion tem perature with the aid of plasticizers (mainly phthalate or other organic esters) and light and heat stabilizers (heavy metal salts, organotin compounds, and other stabilizers). Lubricants or dye* can be added. Plasticizers are added for the production of flexible PVC. rigid PVC contains little or no plasticizer. These additives can also be a source of toxicity. The plasticizers may slowly diffuse out of the final produet depending on its compatibility Lead-containing stabilizers may also pollute the working atmosphere (Smolctc 1966: Tola 1975). Compounding is carried out by hot mixing at fusion tem peratures below or within the softening range (120C-I60*C). Diversified compound ing and processing technologies were developed about 1950. The compounded polymers are used for the production of diverse end-producu. The final conversion of the thermoplastic PVC resins into consumer end-products is accomplished by such procedures as extruding, calendering, injection or compression moulding, blow moulding, dipping (coating) and hot spraying. Temperatures used in these processes range from 100*C to 300*C. End-products include a vast number of articles used in almost every sphere of daily life. The temperatures during the fabrica tion operations (compounding and conversion of compound polymer into consumer articles) drive ofT pan of the small concentrations of residual monomer still contained in the polymer. Bamcs (1976) calculated that the final fabricated articles contained approximately 5 ppm VCM and those for foodstuff packaging (bottles, films, foils) even less. 2.2.4 Sources of Exposure to VCM in PVC Production Both polymerization of VCM and subsequent processing (centrifuging, drying, screen ing, bagging) are usually carried out in dosed buildings. Exceptions can be found in hot dimates (Arympur 1977). Polymerization is of necessity a batch process that re quires a large number ofsingle 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 tie exchange of parts and repair jobs. The degree of pollution also depends to a large extent on the quality and effectivity of monitoring equipment and special exhaust systems. Opening of autodeve vats for cleaning and control purposes resulted in larger spill-over of the tank atmosphere into else work en vironment. Numerous reports of worker*with prenarcotic symptoms (dizziness etc.) Vinyl < i permit i< in the p: Thet clave va. walls (`p tors. ha-, degassed and la::'were opc ed the fr. tion still manly, ti those wi (centrifu ties of.. ven til at) i shipmer' nomer, v. are dnve- Table : ID 1 ppr pvj <*n <o I m*: , (Pat: 1 my'lii; 1 mf, l ppm 1^ 2.2.5 T In the tv nant mon coven .. (Lefau.\ ] lect as a. opened became K 'jntelltr out in l percent' 'Ction of -iny The covilvems r> ot :jn tern> and light `tiers), tlexibie source of ttg on its sphere ->n temnpourd- UUCtS. nets is ''won cd in ih- ){ rica<Mtmer rained . sereenvui in that re* *entnp n| potlu aree of muring gand work, enss etc.) Vinji Chlomk'-A-oOcuied Disease permit the conclusion that episodes of acute overexposure to VCM were not rare events in the past. There is no doubt, however, that those workers who manually cleaned the auto clave vats by scraping away or chipping off the 'polymer skin' formed on the reactor wails (*poi> cleaners'), and who in the past had to spend several hours inside the reac tors, had been exposed to the highest concent muons of VOl. 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, but some manual cleaning of shorter dura tion still had to be done after even 20th-30th run. It is. therefore, plausible that, pri marily. Use most severe advene effects of exposure to VOl 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 tenet quanti ties of unreacted residual monomer from the particles to pollute the environment if ventilation, notably of the drying facilities, is inadequate. Finished polymer, ready for shipment ot subsequent compounding, still contains small quantities of unreacted mo* nomer, which either slowly diffuse out and pollute the bagging areas during storage or arc driven out by the high temperatures necessary for compounding. Table 2. Conversion cable for concentration of VCM in ambient air Mol. wt. ` r000~~4~ I mg/litre ! mg/m* J ppm 23n mg/m* r; * ioooo ppm URL 12160 10 W.K. Lelbach and HJ Marstelier Stales was almost completely destroyed when VCM escaping from a leak detonated {Albright 1967a). Another explosion in one of the two Rumanian factories operating at that time was mentioned by Suciu et si. (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-hcadedness. 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 olfectory fatigue, is 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 andSehaumann declared that the faintly sweet gas is practically odourless at concentrations of 5%-- 10% by volume. VtItman and Lange (1977a. b) assumed an odour threshold of 5 000-10 000 ppm. Volunteers exposed to VCM detected a slight odour at 4 100 ppm; a distinct odour was noted at 6 600 ppm for 30 min and this was accompanied by subjective symptoms of dizziness and sleepiness (Irish 1963). Gthring et al. (1979) recently mentioned a threshold of approximately 3500 ppm. Others have claimed that a concentration of400-500 ppm is the lower limit for detection of VCM by its odour {Bartrta et al. 1969; Cook et al. 1971 .Marko witz et al. WIZ'.Lefevrt 1975, cited by Hublet 1975).Bantu et al.(1969) conducted experiments with concentrations of 50,250 and 500 ppm in an exposure chamber, in which 13 volunteers participated. At 500 ppm only some of them claimed that they were able to detect the odour, but this was inconstant. Table 3 shows that differences between the various estimates are at least one order of magnitude. The close proximity between the perception of the odour of VCM and incipient CNS symptom as reported by Irish (1963), however, makes it likely that the actual odour threshold ean 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 aa low as 0.4 ppm; eye and throat irritation begin upward of 5 ppm and are noted by all test subjects at a concen tration of 21 b ppm {Dm and Joyner 1969). 2.2.7 VCM as an Anaesthetic Agent VCM was once even coftridmd for use as an anaesthetic agent. In 1929, Schmidt and Scfmtmenn speculated about using VCM as a supplementary narcotic at concentra tions of 35fc-5% (v/v) ( 30 000--50 000 ppm) in combined nitrogen oxide oxygen Vinyl Chior. Ttbie 3. Od Lower limit 5 000-10 O' 5 O' 4K 3 5t N* 400-50 4G 40' anaesthesia be lie snd lethal oxygen; cone.; however, that eluded. In to' 10% VCM to: several hours t commented u- mined about > 3.5--5 mmol ( mmol (244 0C c al., in c a ticitv R to OD r_~* use c hale ar ro ish i th >r an. 2- sets Some individu listed in Table without acute . symptoms sue! adequate warm exposure to hip A 21-year-old . 10 rein after en which had bee cardiac enlarge have been acut. which occurred doubt that her found dead wit; l.J. Marateiler detonated '* operating 'octntmioru ting VCM jrties. Its PVC jas\ which iroduction. . workers' re al evidence mind, how* chemicals .luai sensitivf a certain practically J '|77a, b) to VCM ppm for 1 sleepiness '.imately lw iowet *71 :.\krko- i conducted lumber, in they' differences . proximity as reporteJ an be as* ^nctwani<: eye and hrmdt sad centra* oxygen Vtnyi Chlonde-Aisocured Disease Table 3. Odour threshold Lower limit of detection :* 000-10 000 ppm 5 000 ppm 4 ] 00 ppm 3 500 ppm 500 ppm 400-500 ppm 400 ppm 400 ppm Author Veirman and Lange !*77a, b Viola i 9 Irish 1963 Gehnng et si 1979 Barman ji !?69 Lefevre 197? tens* b\-Huble; i97?, Cook et al. 1971 Markawitt et si. 1972 u anaesthesia because of iu potent narcotic action and the wide margin between narco* tic and lethal concentrations. In ammais it produced anaesthesia at 75-10% in air or oxy gen: concentrations above 13% proved to be dangerous. The authors pointed out. however, that advene law effects of this halogenawd hydrocarbon could not be ex* cluded. In toxicity studies with guinea pip Patty et al. (1930) found concentrator of 10% VCM to be lethal within 30-60 min. 5% to cause marked narcosis, and 0.5% for several hours to be the maximum tolerable exposure without serious effects. They also commented upon the powntiai use of VCM for surgical anaesthesia but were undeter* mined about its practicability, in mice, the minimal anaesthetic ranp was found to be 3.5-5 mmol (85 000--123 000 ppm) for 10 min. the minimal lethal ranp 10-12 mmol (244 000--293 000 ppm) (Peoples and Ltakt 1933). It was not until 1947 that Osttr et al., in contrast to Sehmtmann'% earlier assumption (1934) of a relatively low cardiotoxicity, warned against the use of VCM as a potential general anaesthetic in man because of serious cardiac irregularities and ECC changes observed in dop. VCM, like other halopnated hydrocarbons, sensitizes the heart to the effect of catechol amines (Irish 1963). We could not ascertain whether VCM has actually been used in the past foranaesthesia in man. 2.2.8 Effects ofAcute Overexposure in Man Some individual responses of volunteers to increasing concentrations ofVCM are listed in Table 4. Lester et al. concluded in 1963 that the maximum concentration without scuts effects in man ties between 8 000 and 12 000 ppm for 5 min, and that symptom* such ss dizziness, Ught-headednea and disorientation should be taken as adequate warning signs for imminent acute danger. Two fatalities after occupational exposure to Ugh concentrations ofVCM an reported in the ttonnue (Denxifer i960). A 21*year*old sutodm deeper at a Canadian polymerization plent wet found dead IQ ntin after envy at the bottom of a probably insufficiently ventilated reactor tank which had been declared safe solely after an exptaftooieter test. Heart Failure cells and cardiac enlargement found at antopey, however* tanptted that the cams of death might have bean acuta functional disturbance in preexisting heart disease, la the second case which occurred at the same plant* however, ctrcumstantial evidence apparently left no doubt diet hcevy VCM expose<e was the cause ofdeath in a 39*ye*r-oid worker. He was found dead within 20 mht, lying in a pit aearthe opened vafte ofa recycling pipeline URL 12162 1 2 W.K. Lelbacii and H J. Marstelkr Table 4. Individual re<portM.-si of volunteers to increasing concentrations of VCM Concentration Duration of Symptoms exposure Reference 500 ppm 7.5 h (inconstant odour detection' Burcrra et al mild headache, dryness of (]9b9i eyes and throat in 2 of 7 subject-::i V4 000 pptn - Generally accepted odour threshold Inst- i l9e.' i 6 600 ppm 30 min (Distinct odour) dizziness. sleepiness Insh (19b3) J8 000 ppm \ 12 000 ppm 1 5 min* (twice on 16 000 ppm ( each of 3 succes sive days) 20 000 ppm / 2 of 6 subjects 'slightly heady* 1 of 6 subjects had reeling, swimming head, just like getting gas' 5 of 6 subjects, various degrees of intoxication Ail 6 subjects had more intense symptoms of acute intoxication than at 16 000 ppm Lester i at. 11963) 25 000 ppm 3 mm 2 expenmenten. dizziness. disonentation. burning sensation in the soles of the feet Pern- et al. (1963) 2 Exposure to six different concentrations: 0 ppm; 4 000 ppm: 8 000 ppm: 1.000 ppm; 16 000 ppm; 20 000 ppm through which non-polymerized residual VCM was pumped back into a reserve tank: another man coining to his rescue was himself overcome by the gas and only just escaped. Two non-fatal eases of VCM gassing were reported in Great Britain hi 1931 (Spinas et al. 1975). A maintenance worker experienced acute narcosis while repairing a VCM leak, and a worker cleaning a polymerization vat from outside with a water jet sudden ly collapsed across the open manhole. Subsequently he complained about tightness of rite chest, nausea, abdominal pain and headache. Occasional lorn of consciousness was also reported by LiUs et al. (1975) in 14 of 354 workers at Niagara Falls and by 5ucfu et al. (1963) at a Rumanian frtont. VCM-induced narcosis, at toast on one occarion in the past, had occurred in 46 of 58 workers (79%) referred for medical surveillance from ooe British PVC-producing plant (Ward et al. 1976), with a 100% incidence of narcosis in 28 symptomatic workers (Raynaud's syndrome and/or acroosteolysis). Successful resuscitation after VCMnnducvd narcosis of several hours' duration with out evidence of permanent damage was mentioned by Raty ct al. (1974). Vmyl Chiop 2.2.9 Morn* During the f; ed data on V< was directed an apparent]; 195A :f/es/ic Cronsberg to Russian poly: 0.05-0.08 m centration of Inspectorate.. or from the d mg,'litre (* ). mg/litre (* 5- In the cei: air ranged fro; ppm, which w ventilation. Tl unions, some pursuit of imp merit in the vs, ic drying fact!: centrations oi \ied to h -- concen Zi--D . plant, geof0.< PO .93 mg' cn W appardi able th- r, lithe 'e prob *> rin et ai. which oceurrco cated peak exp between 1962. Rumanian PVC about J20mg>r exposures to Vt 300 Rumanian Greek plant wh resulted in high (Ciisios 1971). of the reactors i up to 10 000 Pi 9 i J NURtel!r i VCM fence *:te : al. 'o9 ' : | I93: -.6.(1963) vf t al. rv <: al. *3) '2 rme tank, nly just . 1951 (Spiral rririnf VCM Vi jtt suddcnt tightness of lousncss was and by Sucut - nccason in irvedlauce netdence of -iindysis). ratios with* \-.r.y! Cliionde-Assoctated Disease 13 2.2.9 Monitoring VCM Concentrations m Working Areas During the first two decades of PVC production (1930-1950) no publication contain ed data on VCM concentrations in the working environment. The mam interest then was directed towards prevention of the explosion hazard. In 195". the observation of an apparently toxic angioneurosis in Russian PVC production workers {Sonnws i^S-i-.PIcshchtnerti al., cited in FUatora and Gronsocff 195") mdneed F'far^vj and Gion^-.-rj to investigate environmental VCM concentrations in various yarts of a Russian pol. menzation plant in Gorkij. Although most readings were in the range of 0.05-0.08 mg/Uue ( 20--313 ppm), .g. below the maximum permitted VCM con centration of 1 mg/litre (approximately 400 ppm) as specified by the State Sanitary Inspectorate at that time, escapes of VCM in the reactor areas from defective fittings or from the discharge of operating autoclaves resulted in excursions up to 29.5-41.4 mg/litre (* 1! 500-16 200 ppm) for periods of 5-10 min. One peak reading of 87.3 me/litre ( 34 000 ppm) was recorded. In the centrifuging and drying area of this plant the VCM content of the ambient air ranged from 4 ppm to 3 100 ppm with most readings between 20 ppm and 195 ppm. which was attributed to release of residual VCM from wet PVC resin and poor ventilation. The screening and bagging area was characterized by high dust eoncen* (rations, sometimes exceeding the official upper limits set for non*toxic dusts. In the pursuit of improving industrial hygiene, the installation of modem ventilation equip ment in the vicinity of the autoclaves, substitution of hand^perated by semi-automat ic drying facilities, and avoidance of leakages succeeded in reducing the ambient con centrations of VCM to below 0.05 mg/Utre (* 20 ppm), but toxic angioneurosis still continued to be diagnosed. This led the authors to recommend that the maximum per mitted concentration of VCM should be reconsidered. In a plant producing VCM, Filatovs et al. (1958) found lower concentrations in the range of 0.04--1.1 mg/Utre (16-430 ppm), with maximum values of about 1200 ppm (2.93 mg/Utre), the latter having been observed in dost proximity to the rectif ication apparatuses and having resulted from spillage during sample collection. It is remarkable that up to now the Soviet Union has reported no cases of angiosarcoma of the liver, although production of PVC reams started early and VCM exposures in the past have probably been in the same range as those observed In Western countries. Byfin et ai. (1976) pointed out that during the 1950s episodes of unconsciousness which occurred among workers of the one Swedish plant operating at that time indi cated peak exposures of at least 10 000-15 000 ppm. Sudu 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/mJ ( 900 ppm) in 1962 to about 120 mg/mJ ( 50 ppm) in 1965--1972. In 1969.AngMneu et al. mentioned exposures to VCM concentrations of 112-545 mg/m* (44--213 ppm) for a group of 300 Rumanian workers, eight ofwhoa (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 for briefperiods (Girsios 197|). In air displaced from reacton during addition of water and on opening of the reactors to obtain PVC samples at the end of a reaction cyde, concentrations of up to 10 000 ppm were found. In open waste^rums into which waste polymer scraped URL 12164 14 W.JC. Lelbach and H.J. MantelJer away from reactor walls during cleaning was placed, concentrations of up to 600 ppm were measured. In the report of a World Health Organization (WHO) working group on vinyl chlor ide (IARC 1974) it was stated that in a reactor oflSm1 (production of 4-5 tons of PVC per cycle) a crust of 4 kg PVC containing 3%-5*> VCM can be formed on the inner surface. During the cleaning procedure 30^-50% of this VCM content is liber ated. It was calculated that the probable concentration of VCM within the reactor after a l-h cleaning operation was about 2700 ppm, but that it could bt reduced to 90 ppm by 30 renewals of air per hour. In the past a polycleaner used to spend 4-5 h/ day inside the reactor but later the introduction of(not fully sufficient) automated cleaning reduced manual cleaning procedures to Sorter periods of 10-15 min follow ing every 20th-30th reactor cycle. A Belgian company, where monitoring in the work ing area was started in 1967, claimed that measurements at various sites inside s 9000litre autoclave during the manual cleaning operations had shown VCM concentrations varying between 50 and approximately 540 ppm, with a mean of 413 ppm (Hubltt et 1.1977). According to data provided by Cook et al. (1971), VCM concentrations within the reacton prior to ventilation were in the otder of3000 ppm. The reactor deaners usually did not enter the autodtves until an aeration period of 15-20 min had reduced the VCM concentration to what was considered satisfactory limits. In the early days, this was tested either by ^miffing at the manhole opening' (the lower limit of detection of VCM by its odour having then been accepted as 400 ppm) or by use of a flammable vapour indicator which required a minimum of400 ppm for positive readinp, equalling 4% of the lower explosive limit of VCM. Later more sensitive methods such as gas chromatography were said to have shown that VCM concentrations inside the reacton tended to be below 100 ppm during cleaning operations, but VCM releas ed from the residue during scraping resulted in concentrations of600-1000 ppm measured dose to the hand. The Dow Chemical Company started monitoring the work environment in 1950 by means of grab samples; continuous monitoring was insulted in 1959. While timeweighted average (TWA) concentrations ranged from 10 to 385 ppm during this period (1950-1959), excursions up to 4000 ppm occurred, agreeing with employees' reports of experiencing dizziness while loading or unloading reactors (Ott et al. 1975). In a second unit with modernized equipment excursions up to 600-1300 ppm still occur red during the period of 1953-1959. In 1959, when toxicological data indicating ad verse effects in animals exposed to 100-500 ppm VCM had become available (Torktlton et at. 1961), the Dow Chemical Company introduced e new 50 ppm guideline for the work environment Excursions and peaks up to 500 ppm did continue. Measure ments ofTWA exposures for various specified job categories in two production units of this plant between 1950 and 1966 were presented by Ott et al. (1975). In 1968 BASF (West Germany) introduced continuous monitoring by infrared absorption spectrophotometry for VCM concentrations wcQ below 500 ppm; in 1974 mote sensi tive equipment wre installed and concentrations were kept below 25 ppm and later below 10 ppm, with occasional ceiling values of 70 ppm (FlrJr and Tltiets 1974). In several surveys individual jobs were grouped into three exposure categories ac cording to job classification to evaluate past exposure experiences (Spinas et el. 1975; WUliems etal. 1976;filendtsetal. 1978). These exposure Indices were: (a) light * less Vin>! than f ppm), plants SSJTtpk Esrim. more i averag. Table atmosfChemu 1945 -! 1955 1960mid-19' 19" 19* a Acc. Equ: **s in _ pm. Jr~D al e' tioii ro Hie i 05 wcji" t $hi : cor he i Cum compris. tion dete Oonoflt which cai conditig- lag of re&; A cat: industrial in 1975 b 2.2.10 t Raw PVC unreacteJ `ijrsteller *00 ppm nyl chlorons of n the libcr- -ctor id to id 4--5 n. mated 'rt followtheworkiv 19000n nations UubUt ti mons factor *0 min ,tt. fa the Aer limit oy use of itive read, methods i< inside M rateas* 'pm 11950 by iw Ins period s'report i. in a II occur* iun$ ad- {TorktU dine for 'asuren units t<*S tiob mrensti later 4). nesicaL 1975; -lit* Mm Vinyl Cliionde-Assooiated Disote 15 than 50 ppm: (b) medium * 50-200 ppnv.tcl high* 200 ppm and above (up to 1500 ppm)- In the past, however, estimates of exposure concentrations were based in most plants not on continuous monitoring during the entire work shift but at best on spot simples not necessarily representative of ihe different phases of a given operation. Estimates of past exposure levels such as those represented m Table 5 are. therefore, more or less conjectural. It can be assumed that considerable deviations from these average values have occurred ail too often in the past. Table 5. Average concentrations of VCM in the working atmosphere of PVC-producing plan aJ < Estimated by Chemical Industries Association Ltd.) 1945-1955 1955-I960 1960-1970 mid*l9?3 1974 1975 % 1000 ppm -`>.400-500 ppm v 200--400 ppm %1J0 ppm % 50 ppm and ten v 5 ppm a According to Fleif and Tfutss 1974-.Bernes 1976 Equipment for optimal continuous multipoint monitoring of exposure conctntra* tions in the working areas should meet certain basic requirements: (1) For stationary equipment strategically placed sample probes should yield data representative of indi vidual exposure levels in the breathing zone of workers, preferably to be used in com. bination with personal samplers. (2) Analysing methods should have a high selectivity. (5) The limit of detection should be at least one order of magnitude below the currently specified standard regulating the permissible upper level of exposure. (4) Measure* ment should be instantaneous (within seconds) to guarantee rapid detection of critical peak concentrations. (5) Recording and data processing techniques should be provided for the daily estimation ofTWa exposure during the whole work shift. Currently available methods for the determination of ambient VCM concentration comprise such analytical tools as long*path infrared spectrophotometry, flame ioniza tion detection, gas chromatography, mass spectrometry, combustion<ooductivity (ionoflux*), and personal samplers in combination with gas chromatography, none of which can at present be considered as absolutely satisfactory for all individual plant conditions because they all differ with regard to selectivity, limit ofdetection and time lag of responre. A catalogue of the methodologies that have proved to be ofvalue fat the control of industrial hygiene and personnel protection regarding exposure to VCM was compiled in 1975 by Rowe. 2.2.10 Exposure to VCM fat FVC*Frocmsfai| (Fabricating) Plants Raw PVC powder ready for compounding and fabricating purposes contains raridual unreacted vinyl chloride monomer in varying amounts. In the past, monomer content a g U .n tW If W.K. Lelhach and H.J Mjrsielkr was reported to have been as high as 6000-7000 ppm (w/w) in some types or raw PVC. but a level of 500-1000 ppm probably was a more representative range (ScVmetrrer I975:VKE \974:Kantcdt 1976). The monomer slowly escapes into the environment exponentially with time. depending on length of storage period, tempera- | turr.srze and porosity of partieles and other physcal properties of the polymer and. more recently, on the etTectivity of special degassing techniques {Ptrer l916:Scl>ui: _ and Wolf 1977). In 1975, the Association of die German Plastics Industry announced that in future only PVC powder with a maximum monomer content of 10 ppm would be put on the market due to the development of special degassing technologies (VKE 1975) . Analyses of the types of raw PVC, chiefly suspension polymer, which are now used in German plants showed that in most products the content of unreacted mono mer was now less than 20 ppm but in some foreign products it still ranged between 150 and 250 ppm; it also turned out that there may be considerable variation between different batches of the same product iSchurz and Wolf 1977). .~ Cold and particularly hot mixing or compounding of PVC. a procedure which usu ally precedes fabricating processes, favours the escape of unreacted monomer and, therefore. requires special ventilation equipment. Depending on the content of residual monomer, considerable amounts of VCM could be set free during the mixing process, as was shown by Bntder and Straby (1975). Apart from hot compounding, other ther moplastic operations, such as extruding, calendering and welding of tiles, also resulted in release of unreined monomer into the work environment. Although recently con ducted measurements of the concentration of VCM In working areas of six German PVC fabricating plants have shown that in 90% of the readings mean levels integrated over i -h periods now range below 0.1 ppm, numerous short bunts with excursions up to 60 ppm during a workshift were recorded in one instance (Sclairz and Wolf 1977). Similarly low concentrations of VCM in breathing zone samples (maximum: 12 ppm.) with 60% of the values ranging below 1 ppm had been found in 1974 in nine United Statfs fabricating plants, but source samples had ranged up to 340-540 ppm {Kantad: 1976) . These present results, however, do not permit any coodusioas as to past leveb of atmospheric VCM during the yean when residual monomer content of PVC resins was high and ventilation Insufficient, particularly in compounding and extruding units. Whatever the extent of the risk might have been in the past. It can be safely assumed that the ambient monomer concentrations in fabricating plants have always been con siderably lower than in PVC-productng plants. When it was suspected that certain VCM-related symptoms might also have afflict ed PVC process workers, this problem was investigated by our group. Although no cases of acroosteolyau, pseudosclcroderma or angiosarcoma of the liver were observed, evidence was presented which demonstrated that minor and inconspicuous lesions such as mild hepatic fibrosis, brommlphakin (BSP) retention, thrombocytopenia and slight enlargement of Che spleen could be found in 28 ptoces workers who had been em ployed for years in compounding and fabricating units (mtfc et al. 1975.1976a; Wtgmam 1975 MamaBtr et al. 1976). In principle, these lessons were identical with those seen after heavy 'exposure as we wfl] describe, but the degree of damage attribut able to occupational VCM exposure observed in these workers was not considered suf ficient to entitle them to disability compensation under German law. Although the in- VinM conspi sports quant i oosen Jjrogre male F find ar Ai two G. died re lation health overall record 2.2.11 Indust, of exp tion`or indust: zentrai' Amen i exceed C D tions Si nsic ap UpStJv CO 1974) ed in ? sun. crep J to ; The - not a s. should i tently availabl new ini list of M various i sootier tool for ysis of tl In tl: ppm in I m !R 'I J. Marsieiler *.-s of raw ; arvft ti into the iiud. tempera* ilymer and. `*76; Scftura 'v announced : D ppm would iopes (.VKE hich are now -acted mono* J between juon between ' e which usu* imer and. cnt oi residual >\ing process. .a. other the:* j!so resulted ,'cemJy con! \ German 'i integrated .cuoions u? Mitf 1977V tv I 2 ppm I United .pm [fonuJi sat level* of C resins was :mg units. .*{y assumed been con* * haft afflict* hough bo m observed, Hts leaioas such -iiia and slight i been *m5.1976*: cntieai with magi anxibut* <i*intaretl suf- iough the in Vinyl ChloO(Ju*Astociau;d 13hea>c conspicuous character of these lesions agrees well with the assumption of a dose-re* spouse relationship of VCM-reJated disorders and the alterations may seem to be. quantitatively. of little importance, they should not be minimized. Nevertheless, an obsenauon period up to the present of almost 7 years did not reveal any spontaneous progression. In a proportional mortality study for 1970-197; among roughly 35 000 male PVC fabrication workers in England and Wales. Baxrer and fox (19761 did not find an excess of angiosarcoma or other liver diseases. A recently completed cohort study of 4007 people who had been employee t* two German PYC-fabricacir.e plants between 1934 and 1974 and of whom 360 had died revealed that overall mortality. although marginally below- that of the male populauon of the Federal Republic of Germany, was slightly elevated with respect to the "healthy worker effect'. No angiosarcomas of the Ihrcr were observed and no excess in overall cancer mortality was noted, but an excess mortality from brain tumours was recoidcd in one of the two plants (Reutf et ai. 1973). 3.3.11 National Standards for the Control of Exposure Industrial hygienists have used several designations for acceptable or permissible limits of exposure to chemicals at the work place, such as "maximum allowable concentre* tion' or "maximum acceptable concentration" (MAC), "threshold limit value* (TLVV "industrial hygiene standard* in the United States and as "Muimale Arbeitsplatzkan* sanitation" (MAK) in West Germany. These empirical standards wen defined by the American Standards Association as setting a limiting concentration **for exposures not exceeding 3 hours daQy during a 40-hour work week with the undemanding that varia tions should fluctuate below this value" (/raft 19631. An extensive discussion of the basic approach to the principles used in setting environmental quality standards for oc cupational respiratory exposure to toxic agents can be found in the paper ofZittituis (1974). In this paper, die conceptual differences between threshold limit values as used in the United States and maximum allowable concentrations as used In the USSR arc summarised and the differences in approach and emphasis, which may explain past discrepandes between pcoafesfbfc limits, are elucidated. For details the reader is refer red to this paper. Tit* standard is not an index of relative toxicity, far leas ofhazard, and certainly not a son of "average*. A standard set as the ceiling level implies that any fluctuations should be around a median of perhaps half the standard and that it should be compe tently used to fiifl awareness ofit physiological basil end the (imitations of currently tvaibbie knowledge (/rrsft 1963). The standard wfll be subject to mehion at soon as new information is available. A* snential dement of the annually published German list ofMAX values (MAK-Werte) is in preamble, which ixhauiiiveiy defines the vaiiofo modafltics for the teterpratstion of such standards (/touchier 1973/73). The sootted TWA, as femgndoa over thne of fluctuating concentrations, will be a useful molYor estimating the probability ofinjury only if it represents a comprehensive andyds of the aormd fluctuation Mow the standard. * In the Federal Republic of Germany the standard for VCM (MAK) was set at 500 ppm in 1966. The German Standards Advisory Committee reduced this to 100 ppm -i , Ki el DD O) 00 1 W.K. Lelbach and HJ. Mameller in 1970 in conformity with the proposal of 7br*ctoita].(1961). which was based on the results of their animal experiments. In June 1974, when the carcinogenic prop erties of VCM had been well established, the MAK regulation for this chemical was re pealed and instead a preliminary technical guideline (Teciinische Richtkonzentration) of 50 ppm was instituted (VKE 1975). The Chemical Industries' Liability Insurance Association {Berufigenossenschaft der Chemischen Industrie! also issued instructions for the prevention of health hazards arising from handling of VCM in July 197a. As of July 1975. a technical guideline (TRK * Technische Richtkonzeiuraiionl of 5 ppm. defined as annual mean, for PVC-produring and -fabricating plants was instituted, per mitting excursions up to 1 $ 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 50 ppm, respectively (Veltman and Lanft 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 ici at 500 ppm in 1947. It was reduced to 50 ppm in April 1974 as a temporary emergency stan dard and finally reduced to 1 ppm/8 h in 1976./fia/ey (1975) summarized the conflict ing views on viny] chloride regulations proposed by Government and industry in 1974. Table 6 shows threshold limit values in a number of PVC-producing countries. 2.2.12 Exposure to VCM Outside the Working Area The Environmental Protection Agency estimated that PVC-producjng plants in the United States discharged about 90 million kg VCM annually into tl-e environment (47^--g7f losses), most of it as air emissions and lesser quantities dissolved in water effluent streams and entrapped in sludge and solid wastes (Schweitzer 2 975). In a pioneer study, concentrations of 1 -2 ppm VCM were found in the ambient air near such a plant (1ARC1974), 2--3 ppm in the primary water effluent and 100-200 ppm in rite sludge at the plant site, but sampling and analysis methods used were later found to have been inadequate so no conclusions were drawn from these figures since they could hive been in error by as much as one order of magnitude (Schweitzer 1975). For people who live within 5 miles of monomer and polymer production facil ities in the United Sates an average exposure of 17 ppfc during the years of uncontrol led emissions n calculated (flkhobon 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 potish and window deanen). in Germany, VCM was proposed as propellant for aerosols in 1958 (Osrerotejer 1967), to Japan h has been used as s propellant since 19S8, in Ac Untied States this nee wa probably fatrodueed after 1962 (Schweitzer 1975k As an aerosol propellent. VCM has been a pesribh source ofexposure for the public at large.particubriy for women, the extent and the potential health implica tions of which are unknown. Use of aerosol products in confined spaces has been re ported to result in air concentrations ofVCM of op to 400 ppm in dosed rooms, even after only titetr busts (30 s) (Gey et at. 1975), which could persist for several Vinyl Chi. Table 6.1 Country Belgium Canada Finland Prince German D> Republic . Iran Italy Japan N'elherlami Rumania n r? .-rljn ro d cr* te USSR Federal Rc, Germany Sources: Sr 73;1ARC R 1977;Schu i md H.J. MarsteHer '.which was bawd .* cartiaofenic prop* his chemical was re' ichtkonzemration) lability Insurance issued instructions t us iulv 1974 As nutation) of 5 ppm. - was instituted, per: l fa. In order to iuction of the an-mas ofJuly 1976 ppm. respectively was revised in 1977 nanally set at 500 raty emeijencyttanimarized the conflictid industry in 19"A. 13 countries. inf plants in the the environment -jived in water aztr 19751 In a ' ambient air near u and 100-200 ppm . used were later in these figures since tide (Sckwtttzer mer production facl' tie yearn of uncootrol- n. either alone or mixmuaehold and costnetus* pent sprays, opoesd as propellant *d as a propellant since t 1962 (Schweftrcr * niexposure for the >uiel health impliesU spaces hat been re m dostd rooms. <J petsfct for several v<n>i Chloride-Associated Disease 19 Table 6, Threshold limit values TLVi m various countries Country Year TLV ppm Comment Belgium Canada Finidnd Franca German Democratic Republic (DDR) Iran Italy Japan Netherlands Rumania I O'** 1975 1975 1975 1976 1976 1975 (furure) 1970 1974 1975 1975 - Sweden Switzerland United Kinfdom USA USSR 1975 1976 1975 (future) 1975 October 197s 1947 April 1974 October 1074 1976 -- Federal Republic of Germany 1966 1970 farm 1974 1975 1977 25/50 10/25 5*'10 25 200 *12 25/50 SO 125/50) 500 200 *10 10 100 mj/m* (40 ppm) 5/20 1/S 100 10 25/SO 10/50 500 50 25 1/5 1 mg/litrv (591 ppm) 50 as/m1 (* 12 ppm) 500 100 50 s/ts 2/5 TWA tS h>lS mini TWa (8 h/15 mini TWA * S I* 15 min* TWAig hi MAC (Seftotuk 1969) (Xonetffcc ei at. \9"S) TWAlBb/lJi) TWA(Sh) (TWa B h/15 min) MAC MAC (23 mf/m*) TWA ( hi MAC iProdan cl al. 1975) TWa (8 h/15 min) TWA (8 li/l $ min) MAC TWa (B hi TWA (8 hUS min) TWa (peraonal/eeilinp) MAC (Amer. Conf. Govern* Industr. Hypetusts) TWA (I fa). temporary emergen cy standard (OSHA) TWA <8 h). temporarily permit ted exposure TWA (8 h/15 mia> MAC. provisional eettinc concen tration: State Sanitary Inspec torate. 1951 (FUarare and Otonsbtrt 1957} MAC (Scftonefc l969;Xcrmtr 1975) (Saniceraye oocmy) MAX MAX TEX (preliminary tecbnieai piMettne). Annulment of MAX repulsrion. TEX (annual mean/1 h> TEX (annua) mean/1 hi Soorcet: Smytk l936:Fderora and Oromsttrg 1957.Schomk l99\H*tucUer 1972/ 73 .IAXC Mport |974;lMi7 197S;Je*fae 1975:Prodaw el al. l975;Arypur I977;5c*ira and Wolf 1977;MAXWeru-Ustt t9T7:JCermcr 1975 URL 12110 :o " K. Lclbach and HJ. Mjr\ijlki hours alter repealed spraying in smaller-sized rooms (IARC 1974). Haley M975) pre sen led a Kst of pesticide products containing VCM as a propellant and registered for indoor use, which were banned in 1974 by the Food and Drug Administration. In Japan, the monomer was also banned as a propellant in 1974 (JAMA 1974. 229:655) There is a case on record of a worker who died front noncirrhotic portal hypertension and angiosarcoma of the liver after |4 yean* employment at a chemical plant in south ern Germany where he had been engaged in loading such pesticide cans (Retnf and Weber 1974). The report of a female office worker suffering from typical Raynaud's phenomenon, pseudoscleroderma, aeroosteoiysts and mandibular osteolysis who never had occupational contact with VCM (Mcymon and Meter 1972) is apt to nuke one wonder what influence the frequent indoor use ofVCM-propelled spray cans (Bridbord et al. 1975) may have had in this unique ease. Sputum samples collected from frequent users of pressurized spray cans who had no respiratory symptoms were found to con tain a significant excess of moderate and marked atypical meuplastic bronchial cells compared with two groups ofcontrols (Good et al. 1975). PVC bottles, films and foils have been used for many yean for packaging food and beverages (cooking oQ. margarine, meat. mineral water, fruit squashes and other soft drinks, hard liquor etc.). The content of residual VCM in PVC bottles was found to have ranged formerly between 5 and 400 ppm (w/w). and in PV'C foils up to 600 ppm (ij Etch and van Loften 1975). The problem of migration of unreacted VCM from the PVC containers into the foodstuffs became recognized in 1973. Reports of un pleasant tastes in American brands of vodka and whisky which had been stored in PVC bottles led to the discovery that VCM had leaked into the liquon .in some samples levels up to 10-20 ppm (w/w) were found (sen seh and sen Loften 1975;Dories and Perry 1975). Dau available in 1974 to a group of WHO experts revealed that samples of gin and whisky had contained 0.57 and 0.62 ppm (w/w) of VCM respectively, after storage in miniature PVC bottles for periods up to 3 yean: VCM concentrations in orange squash and cooking oQ were found to be in the range of 0.01 -0.08 ppm and 0.01 -0XU ppm, respectively (IARC 1974). Levels of 0-0.4 ppm found in British PVC-bottled liquids were mentioned by Aeries and Perry (1975): in their own analyses of samples of PVC4iottied spirits supplied by British Airways they found concentra tions et 0-0.25 ppm (w/w). Methods were developed for the detection ofVCM in liquids with a maximum sensitivity down to the ] ppb level (mi Lterop and Sick 1976: Oressman and MeFarren 1977). It was tentatively estimated that even during the yean when PVC^aekaged food and beverages had not been heeded as a potential source of contamination, the likely average daily human intake ofVCM from this source could have been in the order of0.1 mg/persoo (IARC 1974). Schkrrer (1976) calculated that today it would be less than OJOl mg/perton (equalling 250 mg during a witok life thne);in comparison, he calculated that the Mutational hitake of VCM indieemed workers who had been exposed to concentrations of 500-1000 ppm during a period of 10-20 yeas would have amounted to at least 25 kg. The Amotiatiow of the German ftetics Indusry expects that the use of technology mliMi at present for the production ofPVC food-packaging materials dtcreatts the VCM content of food stuffs to bektw30x/kg(50 ppb)even after ptotonged storage (VICE 1975). Results of carcinogenicity assays in experimental animals after oral administration of VCM are ditoiwed In Sect. 3J. V:nyl Chlondv-Ab<> 3 Toxicology ol 3.1 Acute Toxicirv Dunng the first three the assessment of tht concentrations varym and Leake 1933 :Sc/u meneo et al. !960:t anaesthesia, deep nar. tills range of exposure ttve and haemorrhagi, hepatocelluiar injury inducing substances ($, 3.2 Chronic Toxicitv Torkelson et al. (19611 exposure to concentrat. 4 J--6 **hs. AD spc. howe- edaninci histof runges in r pigs: .. Anincrc. in ra ^ ed to 20 01 (196 ^ isiologcal ` Gor -* rule were rr exp experimeu. mu cardia.chan.. OAi ,, .re) for 5 mo- creased secretion of cat . posterior hypothalamus - 3 500-4000 ppm *9-1C of the cortex and the an> comitant changes in cir.- posure of rau and rabbit resorptivc bone changes nervous system dysfum t available evidence for VC VCM should be suspected statutory maximal allows cratie Republic) should b Of particular imports? Viola et al. 1971) with c> full year. It was only alt,-. S fiJ. Maruellvr -.'(197J) picgatemd foi traiion, In >74.229:855V hypertension plant in south{Rein/ and -cal Raynaud's fyjit u<ho never o make one cans (Bridbo/ti >i 1RMT7 freauenr found to conronchial cells 'Sflg tood and "J other soft 33 found to <*P to 8QQ ppm 3 VCM from * rtj ofun" stored in PVC w tamples 'y.Oniesifltl f ihat samp'rs *vW*eiy. after rations in * ppm am,' s 8nush ownanalr es ) .uecemra* rfVCMin -ndSiefc 1*76; Wf the year* rial mince f Atorer could `afetfUted 'sf 4 whole TMJo diseased * period of the Qi**atfCT tent offood'51 Remits of VCM Viny I Chi^riUcvWrcauiJ 3 Toxicology of VCM 3.1 Acute Toxicity :i During the first three Jccadcs ofPVC production, animal rxpenmenu were limited to the assessment of the acute inhalations! toxicity of VCM in short-term exposures to concentrations varying between 50 000 am! 400 000 ppm /Aw. et al. i93Q;fv'pA.:s and Leake 1933-.$eheumann I9M, 1938:Osieret al. I94T.Carpet al. 1949..Uisfrontatteo et al. J 960: Lester et al. 1963). In mice. tats, guinea-pigs. rabbm and dogs anaesthesia, deep narcosu. cardiac arrhythmias and lethal effects were observed within this range ofexposure but no relevant organ pathology was noted except for conges* uve and haemorrhagic changes in lungs, liver and kidneys on fatal outcome. .Acute hepatocellular injury was later found only in animals pretreaud with potent enzymeinducing substances (see Sect. 3.4.2-2V 3.2 Cbione Toxicity Torkeison et al. (1961) were the first to describe results of experiments with prolonged exposure to concentrations ranging from SO to S00 ppm, 7 h/day. 5 days/week, for 4.5-6 months. All species tolerated exposure to 50 ppm for 6 months: 100 ppm. however, caused an increase in liver weight and 200-500 ppm caused, in addition, histological changes in the liver and kidneys of rats and rabbits, but not in guineapigs and dogs. An increase in liver weight and decrease in spleen weight was also seen in rats exposed to 20 000 ppm. 8 hfday, 5 days/week, for 3 months by Lester et al. (1963): no histological lesions were found after 3 months. Soviet investigators at the Gorki; Institute were mainly interested in neuroendocrine changes after prolonged exposure of experimental animals to various concentrations ofVCM. Cardiac arrythmtas. bradycardia, changes in phoaocanUofnm In rats exposed to 12-20 ppm (003OJ05 rag/litre) for S months were repotted (I'erti and Pbkkttva 1969b) as well as in creased secretion ofcatcchoiarames in rabbits sad changes in the biopotential of the posterior hypothalamus (Fasot cad ftskhoM 1969a). After s 5 -S-month exposure to 5500-4000 ppm <9-10 mg/litre)changes in the bioelectric activity (EEG recordings) of the cortex and rite anterior and posterior hypothalamic nudei in rabbits with con comitant changes la oreuterory functions were seen (Ftem and Rhkiiora 1968). Ex posure of mu and rabbits to 03-0-04 mg/tine (12-16 ppm) for 6 months produced tesotptive bona changes end osteoporosis in addition to cardiovascular and central nervous system dysfunction (ftmai--r et al. 1972). In 1969Sekottak summarized avsQabk evidence for VOI toxicity and warned urgently that chronic exposure to VCM riaauld be suspeemd ofcanring Untie tiver daresgs. He moved that the cunenriy statutory maximal aflowabk concamratiow of 200 ppm (MAC whie. German Demo cratic lUpohflc) ritould be lowed. Ofparticular hnpottance as pioneer erotic wete HMs't experiments (1970a. b; llok et al. 1971) with cxpouc of tarn to 30 000 ppm, 4 hfdsy. S daysfweek. for a full year. It wm only after thfc length ofcxpomm thK-MnopatholMgicai examination W.K. Lelhjch jrul HJ. Marstelkf revealed lesioai > to human acncneolytu and also similar to dte type of non* tumorous liver diseases which we observed in PVC workers 3 yean later (Manrtihr *i ai. 1973). Hok described lesom of the skin. the small arterial vessels, the connective tissue and elastic reticulum of the paws, and periosteal proliferation with chondroiu me uptasis ofmetatarsal bones. Fibrosis of small peripheral nerves and degenerative changes of the grey and white matter of the brain were prominent, whereas the kid* neyt were not markedly affected. The liver showed pronounced degenerative lesions with parenchymal necrosis, cytoplasmic and nuclear polymorphism, abnormal prolifer* ation of hypertrophic Kupffer cells and intense fibrosdcrooc reactions. 33 Oncogenic Properties The earliest documentation of the carcinogenic action ofVCM was Viola's preliminary report presented at the 10th International Cancer Congress in Houston. Texas in May 1970a. Of 26 Wistar rats exposed to 30 000 ppm for 12 months 17 developed epider moid carcinoma, mostly in the paraturicular region; 6 also developed adenocarcinoma of the lunp and 5 osteochondroma of metacarpal and metatarsal regions of all 4 limbs (Viola et al. 1971; Viola l974).3fe/ro#u md Lefemine (197$) later interpreted these paraauricular tumours as arising from the sebaceous glands of the exterior acoustic duct, also known as Zymbal's glands, the cell matrix of which seems to be the target tis sue of a number of carcinogens. They were of the opinion that the pulmonary malig nancies were metanases from the Zymbal gland tumours. Autoradiograms of sections of whole rats dosed orally with [>4C]4tbeUed VCM revealed a discrete localization of 1 'C in the paraauricular region (Zymbal gland?) and in the region of salivary glands and Harder's glands (Green and Hathway 197$). In this concexuVeumcnn ct il. (1979). who analysed the peroxidase activity in Zymbal glands of Wistar rats, proposed the concept thatperoxidaseenedialed bloactivauon of carcinogens (in their study: stilbenc derivatives) might offer an explanation for these tissue-specific effects. At the end of 1970Maltoni and his group, with the support of Italian, British, Belgian and French chemical companies, started to plan and subsequently execute a luge-scale cucinogenidty bioassay downed 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 spedes.strata. sex and age of animals (Meironi 1973, \977:Mttioni snd Ltftmint 1974a, b, 1975;MUimriet al. 1974a. 197$). Con centrations used in the inhalation experiments were 30 000.10 000,6000,2500,500, 2$0 and 50 ppm, with length of exposure ranging up to 52 weeks and observation peri ods up to 143 weeks. Apart from the induction of Zymbal gland carcinoma other maUgnandes developed, notably angiosarcoma of the bvr but also extrahcpatic angjosarcomm. nephroblastomas, pulmonary tumours and mammary cartinoma. as well as a number ofsingk turnouts ofother target tissues. Different types oftumours were found to coexist in the game animal. On oral adminiuittioo of VCM dissolved in olive oA (5 days/week) angiosarcoma of the Urn was fouod after 50 weeks In two animals of the two groups of80 Sprague-Dswiey rats each of which had been treated with the highest doses of50 end 16.65 mg/kg body wt. (Metam et al. \975). AMtoni (1977) succeeded in demonstrating that the route* of administration of this dearly muitipo* Vinyl Chic itnuu cue study of or solved in 6 days/wee! ratio only 2 tion not ne>. placed the 1 the no-toxiangiosarcor Sprague-Da proved to li. genic in rats be carcinogi 10. $ and 1 1979). Anoi (he dose-re!, exposure !e\ histological the liver and the inductio: posure to 10 al. 1974b: lA endothelial : perplasia and ev 3w CT ,-a d * the f /as; ing CO sufc; ~ ig of i- 975). 1 to VC ed trom Cm> it was seen u maturity of : to 2000 ppm foci of hepa:< Holmbcn week, for $2 spleen ehing mals exposed cutaneous ani ppm group ar i See also ' ! iT^teilef tion>kr et xtfctive Jroid MWe kid'fions Droiiier- limmary :t May epiderrcinoma *' * limbs i these *' >tc target tis- .itd'.g.-ctions non of jnds .(1979). he . stiibene it* a :>jcure jtion. 'Hroni *5). Con* no. 500, non peri* ihermaanglo;weQas som ,1m olive antmah ` with the 11977) tltipo V`;nvl ChluniU.AsfOciatcd Disease tential carcinogen ma;- significantly vary the typo of neoplastic response. In a subacute study of oral VCM toxicity, lasting only 13 weeks, in which rats were given VCM dis solved in soya bean oil by savage in daily doses of 30.100 and 300 nig/kg body t.. 6 days, week.Ftron et al. (1*5) found a significant increase in liver-to*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. Ftron et al. placed the oral no-toxic-eiTect level at 30 mg VCM/ka body wt./day and suggested that the no*toxic-effect level may actually be even higher. Zymba! eland carcinoma, hepatic angiosarcomas anj nephroblastomas had never occurred spontaneously tn the breed of Sprague-Dawiey rats used at the Bologna institute. The neoplastic response to VCM proved to have a direct dose-time relationship. Even levels of 50 ppm were carcmogenic in rats and mice. LiterMaitoni (1977) found exposure to 25 ppm VCM also to be carcinogenic in rats, whereas no carcinogenic effect was observed at lower levels of 10.5 and 1 ppm in a study which, however, is still incomplete (quoted from Gnciutc 1 979). Another American study designed to complement Maitoni \ results confirmed the dose-related induction of liver angiosarcoma and mammary carcinoma in mice at exposure levels of 25X, 200 and 50 ppm (AVptirifer et al. 1975). On reexamining histological slides of his past experiments. Viota Utet-also detected angiosarcomas of the liver and other malignancies of skin, lung and inteshn^n hit rats: he also reported the induction of skin acanthomas and pulmonary adenocarcinomas in rabbits after ex posure to 10 000 ppm VCM.* h/day. 5 dayi/weckfTbTit least 15 months {Maitoni et al. 1974b: IARC 1974). Maitoni and Ltfemine (1975) considered the effect ofVCM on endothelial tissue to be a systemic one since they found dilatation of blood spaces, hy perplasia and atypia ofendothelial ceils also in organs and tissues other than the liver, even in (he absence of angiosarcomas or benign angiomas. Evidence of hepatic fibrosis was scanty and inconstant in their animals and was more likely to occur at the lower doses, tn the soietn of treated rats and mice fibroangiobiastie proliferation undergoing fibrosis was frequently observed. No scroosteolyttc lesions were found, but a few cases of ossifying angiosarcoma were observed. A potential transplacental carcinogenic ef fect was suQtsted in 1975 by the development ofsubcutaneous angiosarcomas in the offspring of breeding animals exposed for 7 days during pregnancy {MaUont and Leftmint 1975). Later,.Uafrom (1976) detected angiosarcoma tn the offspring of rats ex posed to VCM during the period between me 12th and 18th day of pregnancy (quot ed from Gndutt 1979). Hepatocellular carcinoma ws not found in adult animats but it was seen to develop readily in newborn animals, possibly in connection with the im maturity of their bieacthration pathways (Maitoni 1977). Exposure of newborn rau to 2000 ppm VCM, 6 h/day, 5 days/week, for at least * weeks elicited preneoplastic foct of hepatocellular ATPasc deficiency, notably in female animals (Laib et ai. 1979). Hotmberj et al. (1976) exposed mice to 50 and 500 ppm VCM, S h/day, S days/ week, for 52 and 26 weeks respectively. They* did not observe hepatic fibrosis or spleen changes, but multiple benign ahuotopnJc adenomas developed m 18 of 2* ani mals exposed to 50 ppm and in ail 2* animals expnmd to 500 ppm1. tn addition, sub cutaneous and/or subperitoneai haemangioaaicowia developed in 1* animals of the 50ppm group and In 8 ofthe SOQ-ppm group.Only ooe haemiigimennmi of the liver I See also WUutt et al. (1976) U'.K. Lclbach anJ H.J Mameller was found in an animal exposed to 500 ppm. a few mammary adenocarcinoma*, one rhabdomyosarcoma and one renal haemangiosarcoma were alv* wen. From their ex* periments Holmberg et al. concluded that a lower exposure over a longer period may intensify the cancerogenic 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 stiU another animal experiment with exposure of Wistar rats to 5000 ppm. 7 h/day. 5 days/weck. for 52 months was pub lished by Feron et al. (1979a, b: Faron and Krors 1979) in an eventually fruitless at tempt to elaborate suitable parameters for early detection of VCM-disease in man. Ear ly effects were a shortening of blood clotting time and the occurrence of swollen and malformed hepatocytic mitochondria. At a later stage progessivc tubulonepluotic changes in the kidneys, fod of celular alterations in the liver with reduced glucose-6* phosphatase activity in hepatocytes. strong sinusoidal activity of alkaline phosphatase and increase of smooth endoplasmic reticulum in parenchymal liver cells were observ ed. In the final stage ireas of necrosis in the liver parenchyma, focal dilatation of sinus oids and proliferation of normal and atypical sinusoidal cells, multicentnc hepatic an giosarcoma and Zymbal gland carcinoma occurred, feron et al. (1979b) also observeda hepatocellular carcinoma in three animals.-Surprisingly, the induction of very rtulig turn metastasizing carcinomas of the nasal cavity originating from the olfactory epi 0*thelium and Bowman's gland was noted, which had not been reported before in con iwction 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 liepatic stroma, but they stressed the fact that the true relationship between VCM* induced alterations of hepatocytes and sinusoidal cells has yet to be elucidated. 3.4 Toxkodynamics Prior to 1974 very little information was available about the fate and the toxieodynamics of VCM in the mammalian organism, but the discovery of VCM-induced angio sarcoma of the liver in humans and experimental animals provoked a large number of studies which resulted in a flood of publications on the metabolism of VCM. In 1934 Schaimenn reported that in mammals unchanged VCM was excreted via the lungs after inhalational administration; the pulmonary route is themain excretory route of nonraetabotized VCM (Green and Harkway 1975). Blocking of nonprotein sulphydryl groups in the blood of vinyl chloride operatives. Its pronounced after dis continuous contact, ws observed as early a* 1964 by Gabor et al. and indicated depic tion of the glutathione pool, which has since also bean found in exposed rats {Htfncr et al. 1975a). Hepatic glutathione plays a fundamental role in protecting tissues against attack by aOcytating agents. Tha appearance of aonochlotoacetie add in the urine of workers exposed to VCM was reported in 1966 by Grigortacu and Toba. indicating that a polar exoatabla metabolite ofVCM had been formed (KbMo 1978). Toxfcodyaarnie studies have revetted that tZMpar se knot the ultimate toxin or caicinogsnic.lt b the process of btotransfoimation (metabolic activation) of VCM. primarily by hepatic microsomal enzymes (mixed function oxidases) that yields short- Vinyl Chloru lived but high mutagenic an cretable prod 1975). The ilive velocities tion of its rea nation of VC` so that above following a u cordance with 3.4.1 Uptake Pulmonary' up in the animal'with the pool > shown by com Bolt et ai. (19" as albumin, ar- goesin< ral ingc Ji--D e cons: :ed via - |SJ --1 1. l t This k cess. P . adm. an ot . 1 dose L sigmiK piasmie reticut1 but only mini; rats on a diet c almost all the ' trstinal tract, b- in this way. Percutanec keys following 800 ppm of1 * i wa negligible i Studies of >: that the liver (p polar metabolir spleen,lungs at. kidneys.tpleen. of irreversibly p irreversibly boi: .] HJ. Memelier -ardnomas. one from their exter period may ''erween dose iy been observed pertinent wiih mths was pubJJy fruitless atease in man. Ear of swollen and tonephrotic iced glucose-6:ine phosphatase ^ils were observliatation of sinusntric hepatic innj also observed of very malig olfactoryepi! before in con developed an.hvma. The in*ded those of t between VCM1 existed. thetoideody1-induced angio use number of fVCM. as excreted *ia main excretory f nonprotein unced after disI indicated deple-ed f*l (Jiifiier mgtissuo against i in the mine of 4*. ImUnrini 78). Ithnste toxin or *rtq)of VCM. 'hat yield* short v'">l Chionde-Associated Di'cav; >< lived but highly reactire aikylarwg intermediates wiiich are responsible lor the toxic, mutagenic and oncogenic effects. VCM is metabohxed rapidly to polar nonvolatile excretabk products {Htjner et al* I9"'5a: vanDuurcit \^i-.Rajwomnd Hcmchivr I9"5). The toxicity of VCM seems to be largely determined by the ratio of the rela tive velocities of both biotransfotmaoon of the compound and protective detoxifica tion of its reactive intermediates (Hcnschkr 1977a). The capacity for metabolic elimi nation ofVCM in rats is saturable at an atmospheric concantration of 200-250 ppm. so :hat above this concentration VCM is metabolized at a constant maximal velocity following a zero-order kinetic, whereas below 200-250 ppm tt is metabolized in ac cordance with ftmorder rate kinetics (Hefner et ai. l975a:ofr et al. 1977). 3.d.l Uptake and Distribution Pulmonary uptake ofVCM from the atmosphere depends on the rate of its metabolism in the animal's organism. The atmospheric concentration of the compound equilibrates with the pool ofumnetaboUzed VCM distributed in the animal's tissues, as has been shown by complete inhibition of microsomal oxidanve metabolism {Bolt et al. 1977a). Bolt et al. (1977a) also concluded that liptds or lipopioteins. rather than proreins such as albumin, are the vehicles that transport VCM in the blood and from which the com pound goes into the adipose tissue or is taken up by the liver for metabolic conversion. After oral Ingestion and absorption from the gastromte?unal tract, a lust pass effect' has to be considered, but an increasingly substantial percentags of umnetaboUzed VCM is excreted via the lungs in direct relation to the dote administered fWoamabt et al. 1976c). This confirms the finding that VCM metabolism is a dose^ependent and satur able process. Pulmonary elimination of over 925; within Ah ofdose of 300 mg.leg body wt. administered orally to rats was also reported by F*n et al. (1975) in an in vestigation of the subacute toxicity of VCM incorporated in so> a beanzril and fed by lavage in doses of 30.100 and 300 mg/kg daily. 6 days/week, for 13 weeks. They found a significant increase in Uver-to-body weight ratio and hypertrophy of the gndo* ptasmic reticulum of hepatocytes as indications of s toxic effect at tire highest dose but only mhtimal histological changes In the Uver. In a second experiment, they fed rats on a diet containing PVC powder with e high monomer consent and observed that almost all the VCM was released from the PVC powder during pareage through the in testinal tract, but only about 10 mg VCM/kg body wt. per day could be administered in this way. Percutaneous absorption was studied by Htfrttr et aL (1975b) in raals Rhesus mon keys following whole-body exposure (head excluded) to concentrations of 7000 tod 900 ppm of "Cdebefled VCM for 2-25 h. The quantity aborted via the Intact skin was negligible <0429-039) wd most ofit u expired. Studio ofthe distribution of [U-,4C}-t*befled VCM in the body dearly revealed that the Mere (pradomin wt rite ofmetibolnn) and the kidneys (sire ofexcretion of poire metabolites) conrete the highest concentrations of **C activity, fettowed by pu-- tMf--nun--w-- faa i -- iQ7fcMm***t 1976a.b).Liver, kidneys,urieen,lung and small tesextet (la thfeoctier) also conttin the largest amounts ofirreversibly pcotetobound metabolites (Mr et al. 1976a). Only minor amounts of hreveiaibiy bound metabolites of VCM were found in muscle, adipose time and brain. URL 1217$ f \ . 26 W-K. Lelbach and H J. Mantelier Toul radioactivity 43 h after a single exposure decreased considerably in these organs, in accordance with the relatively rapid metabohzation of VCM and excretion of its polar metabolites. In contrast, the amount of irreversibly protein-bound radioactivity remained constant during this time.Buchter et al. (1977) also showed that unmetab* olixed VCM possesses a great affinity fot adipose tissue, in contrast to its metabolites, which are concentrated primarily in liver and kidneys. 3.4.2 Metabolism 3 4.2.1 Relation between ChemicalStructure, Reacth'ity andMutagenic or Carcinogenic Effect Before dismissing the metabolic pathways of VCM (monochioroethyiene) and its pre sumptive toxic Intermediates two features of the chemical structure of this compound should be mentioned. Vinyl chloride is a monohalogenoted ethylene and its chlorine substitution is asymmetric. Chlorination of alkenes (oiefinic 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 l96Sby Williamson and Cvetanovii for reaction rates with ozone. Vinyl chloride, as a monohalogenated alkenc, is the least stable compound with the highest reaction rate in the series of chlorinated ethylenes and ranks next to unsubstituted ethylene. Secondly, the first step in the oxidative metabolism of all chlorinated alkenes is a transformation to epoxides (oxiranes) which are short-lived, highly reactive electro philic intermediates {Bonse et al. 197S;ffeiJc/iler 1977b). Such chlorinated epoxides may react, by alky*ation, with essential cellular constituents, a mechanism which Rannug et al. (l974),Semcft et al. (1975a, b) and Malaveille et al. (1975) claimed to be responsible for the carcinogenic and mutagenic effects of VCM and vinylidene chloride. Epoxides resulting from biotransformation ofasymmetrically substituted ethylenes, such as VCM, vinylidene chloride and trichloroethylene, seem to be particu larly unstable with increased electrophilidty and thus enhanced alkylating effect. Their mutagenicity and, inversely, the nonmutagemdty of oxiranes of symmetrically chlorine-eubstttuted ethylenes was indicated by the studies of Greim et al. (1975, 1977). 3.4.2.2 Metabolic Pathways From 1974 onwards the fate ofVCM has been studied extensively in vitro with rat liver mlcrosomcs fat the presence ofa NADPH-fencnting system (Kappus et al. 1975, 1976;Samc/i at al. 1975b, 1976;.tMeriBr at al. 1975;JMr at al. 1976a;Hsseyre et al. 1979), with die aid of isolated pestered ttver preparations (Redwan and Hensch<er 1975;Jonse at aL l975;Andwen 1977:JjfataeMer 1977a) and in vhro (figfnern al. 1975a; htoawabe at al. 1976d, 1973a, b;Bolt at al. 1977a, b) fat both control animals and animals pratreated with various types ofenzyme-inducing and enzymednhftiting Present biochemical knowledge strongly suggests that the first step of the predo minant metabolic pathway is the oxidation of the double-bond of VCM by the hepatic Vinyl Chlor; microsomal > ly highly rea, via the form.; bon monoxh' preciable rol, in vitro at: systems and < ]9?6a). The (I H pr-c. H c: jo ro --j Fig. 1. Metab metabolized ( acetic acid are methylene oxj protein sulphy wen-(1977). Si. (Norpoth et a!. S<arboxyme<; acid) {Hcnschl identified in tl. J Mameiler ;-u organs, n of its aoacnvity anmetab;cuboiiies. jnd its pre compound ichionne in general. ;t on the ith increas 1 Cvcuwtc -.isthe least -thyienes Irenes is a ^ electro.d epoxides -.vhich claimed to .iitiene oiuruted I he particueffect, nnetrically <1975. with rat etal. 1975, andHtnsch* iHcfntrtxti. itrol inttnih wdnttbiting thepradoy the hepatic ^tnt.'Chionde-AttOuactd Dhea^c 2? microsomal mixed-function oxidase system, forming chforoeittvlvnc oxide, a chemical ly highly reactive epoxide (Fig. 1). A negligible amount of VCM can be metabolized via the formation of peroxides, very unstable compounds decomposing rapidly to car bon monoxide. HO and formaldehyde which, however, do not seem to play any ap preciable role in the toxicity of VOl (Hcnschler J97"b). h has also been shown that in vitro an anitical superoxide (07") generating system can replace rat liver microsomal systems and transform VCM to the active intermediate (Keppusti al. \915.Bolt et al. 19"6a). The epoxide rearranges spontaneously to chJoroaceuldchyJc. which is rapidly Cmjlcnt Hmliry u> ..clh.ur nu.romck'^uli'' uiy<>Ljliun> 1 H H' M uM QmJjx1 X\DPH. 0: ('{{/rrn'thi Zoic 0rwV itCM eposulo Tivcmul rearrangement CnrnufrJlio" HilltuiHh uy group* tfluutliiene. cvMetnc ll}Jroi\rt rpo'uit: !i) JraMTi on oh ii O--t --<--H II it (1tloriKKXfeilleh> .hr Fig. 1. Metabolic pathways. Adapted from Htnachltr ft 977b) metabolized to monodtiotoacetic add. Both chloroacttaldchyda and monochloioacetic add an also mttabolitas which an chtmicafly tmactive bat lass potent than chloroethykne oxida. AM three intennediatei can be detoxified by conjugation with nonprotein mlpfcydryt compound! (gtumhioae, cytttfee) is described by Grttn and HathHurr (l9T7).Sulphar-contabling astcntabla ntttaboBm sach aaS-hydroxytthylcysteiac (Noepth ataL197<).N acstyl g (2 driotofrethyl-cywaint (Otew and fiotkwty 1975), S<arboxymathyicyiteine (Msmanbe et al. I97fie). and dtiodglycuiic acid (thindsaceric aod>(Hewchkr l977a;iWWteret al. 1976. l979:AGtter and tVorpoth 1975) have been UentiAad hi the tutae of exposed workers and -**>* A progressive depression of the :s W.K. Lclhjch and H J -Marvcllcr level ofhepatic nonprotein sulphyUryl conten (has been observeJ in rats after expo* sure to VCM in concentrations from 150 to 2000 ppm for 2-7 h. No depression was seen after 10 ppm and a concentration of 50 ppm caused only an inconsistent rcduc* tion (li'erenebc et al. 1976b). Protein-bound hepatic sulphydryl content remained unaffected. Hepatic microsomal cytochrome P4S0. the coenzymc of microsomal monooxijenases. also decreases linearly with time in animals exposed to VCM {Reynolds et ai. 1975b). This destruction of cytochrome J0 may prevent further metabolism and toxicity of VCM (Pcssayn et al. 1970). Another mode of deactivation of die primary reactive intermediate, the epoxide, is its transformation to the inactive dihydrodioi by the inducible microsomal enzyme epoxide hydrase. The reactive metabolite of VCM.chluroethytcne oxide,is a powerful alkylating agent which covalently binds to various cellular macromolecules, notably vital proteins and nudetc adds. By binding to cellular DNA and RNA or critical proteins the metab olite may alter vital functions and the genetic information of the cell and thus exert its hepatotoxic.muiafcnic and carcinogenic eflect.Evcntually, however, the only fraction of the formed epoxide that binds to miCTomoiecules is the one that is not detoxified by protective scavenging mechanisms such as conjugation with cytosolic glutathione or inactivation by epoxide hydrase. Simultaneous presence of other xenobiotics which have to be detoxified will impair the effectiveness of the detoxification mechanisms. In assessing the risk of exposure to VCM, Henxlilcr (1977a) concluded that there might be a greater risk in intermittent peak exposures over brief periods than might be ex pected from simple integration over time and that the dunces for effective detoxifica tion are greater in long-term exposure to relatively low levels. It was shown by Wetanabe et al. (1976a) that repeated exposures of rats to VCM do not appear to induee 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 I ppm to $000 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 (kfemnebeet al. 1976b). This correlates well with MahonCs report (1975) of a linear percentage induction ofhepatic angiosarcoma in rats between 50 ppm and 500 ppm when expressed as the log of the exposure con centration. Metabolites of VCM can alkylate nuckic adds, a commonly accepted mechanism for carcinogenesis. Covalent binding to the adenosine (0er*m ct al. 1975 .Ltib and Bolt 1977),cytidiftc(#tri and Soli 1978). and guanine moiety of nucleic adds (Qucr. mtntbGoB&r et iL 1977) has been described. But the degree of covalent binding of electrophilic metabotitts oflabelled VCM to hepadc nucleic acids seems to be very mall (Wusnafre et at 1978b;Ld& and tfori 1977).& and Bolt (1977) pteaanted . evidence showing that the afleyiatmg poseocy of VCM metabolites cannot be deter mined solely by measuring the Incorporation of label into nucleic adds after exposure to radioactive VCM. Htotenebe et al. (1978b) coodudcd that covalent binding to nudete adds is not the preferential reaction, but they pointed out that this does nor Vjn> I Chi- exclude tti of cellular eluded as i above all. i This is work will ] endoplasn: lible to Vl cesses are t the hepato. metal fechaj )-- es othe ^ cell rep - !b)(0 Xft cqila neoplav naud's' me was man. Besideliver lesion* bioactivatic: portal fibn ment of the a direct or it* tic nervous * lining cells o tion)orwhi 4 Clinics' During trier might prove : presented in marked the y pational haz.  MartulUT .r expowon was .[ reducjined ;tul monoynokis et :*olism and epoxide. is QZ>'ITW ylating jl proteins he merab;iatn its ily fraction :<tOXiftd itathione or s which .hanirms. In there mtgiu .u be exJetoxjfica- s to VCM f binding the po ntons ot t;. covalent, sttcnae . oafeits bea function -dates well ekwaicoma resure con* wdtanism '.riband idds {Over*oding of be very .Manned he detrrtr exponue img to k does not ^inyl Chi>ndc*A.'-ociati*d Dutt-iv exclude the possibility of other.more subtle interactions which may impair the control ot cellular replication. Alkylation of nucleic acids, however, cannot at present be ex cluded as the mechanism for VCM-induced carcinogenesis after repeated exposure and. lbove all. in the target cells rather than the iiepaiocytes. Tins aspect carnes on to an unresolved problem on which future experimental work will have to focus. Although the site ot tormatton of the active metabolite is the endoplasmic reticulum of the hepatoevte. the liver cell itself is not particularly suscep tible to VCMinduced toxicity. Acute hepatocellular injur;' has not been observed mor phologically after exposure to VCM unless pretreatment with potent inducers of the mixed function oxidase system had pteetded the exposure:in pretreated rats centre* lobular, midzonai and panlobular hepatocellular vacuolization and even necrosis was found Uaefertt ai. 1974.1975, i977:Rejrttoids et al. 1975a. \Q76:CoitolIy et al1978). Secondly, the site of carcinogenicity in the liver is not the hepatoeyte but the endothelial ceil of the hepatic sinuses. At present it can only be speculated which of the following four most likely pro cesses are effective, either singly or in conjunction: (1) The active metabolite leaves the hepatoey te and is conveyed to the endothelial cell. (2) The endothelium itself has some metabolic capacity fBolt 1978). as may tissues of organs other than the liver. (3) Mechanisms for the detoxification of the active metabolitefs) are insufficient in tissues other than the hepatocytes- (4) Repair mechanisms for the correction of aber rant cell replication are less effective than they are in the hepatoeyte (, Wacanabe et ai. 1978b). An equally pusling problem is the role ofVCM in the pathogenesis of the distal numieoplasiic vascular lesions which an responsible for the development of the triad. Raynaud's phenomenon, sclerodermoid akin indurations and acroosteoivsb. This syn drome was the earliest indication of advene effects of chronic exposure to VCM in man. Besides, its latency period was cornderably shorter than either the noomalignant liver lesions or angiosarcoma of the liver. Whereas It is now established that hepatic btoaotivation of VCM plays the central part in the pathogenesis of both nondrrhotic portal fibrosis and angiosarcoma of the liver. is not at ail dear whether the develop ment of the acid lesions is doe to VCM itself or to active metabolites which may exert a direct or indirect toxic action on (a) medullary vasomotor centres, (b) die sympathe tic nervous system, (c) smooch muscle cslb of die media of arterioles, fd) endothelial lining ccOs ofsmall arteries (with fibroblast transformation and endothelial prolifera tion) orwhethcr (e) the action is mediated by the formation ofImmune complexes. 4 Ginical 5pectmm During the nrid-I9S0s H began to emerge that chronic occupational exposure to VCM aright prove to be not qette tc hinnies as had been daimed The historical synopsis presented in TaMe 7 summarizes those dinfeel studies from the woddfeemure that merited the gradual ecnpririon of the foO spectrum of dmagi due to this new occu pational heard. . r5 -s li- ; W: '-rT; " ' - -'V yi : . VJ-' X J M - 30 W,K. Lclhj.'h and M.J. \lj:*teilcr Table 7. Gradual emergence of evidence for VCMa*sociated pathology Year 19-19 Reference Tnbukh a al. Findings HepaiomegaiN. more or lo* marked 'anicteric hepatitis', 'chronic gastritis', hypotension, anaemia, skin lesions 1954 1957 1957 1960 Smirnova Filatova and Gronsberg Kubota Danzigtr Toxic anfioneurosi* Toxic angioneurosis Symptoms similar to Raynaud's phenomenon Two cases of accidental fatal poisoning by VCM. 1 nonfatal acute overexposure 1961 Smirnova 1963 Suctti et al. Reversible moeolytic lesions of distal phalanges. PscudoclaiUbHg. thickening of skin on volar hdr dtf forearms. slight kaematysis and reticulo cyte** CfO - prenarcotic symptoms 1 dizziness, euphoria, somnolence), nervousness, insontsict, blunting of ireanory, general asthenia.headache Vascular; Raynaud's svndranc Dermatol.. pruritus, reversible sdferotlermalike skin i^unlion.Remlcal and altafic dermatitis Giftsi. \ymptomr. anorexia. aausex. fullness, hepartreegaiy without hyperhilirdbinacrma. spiesomega^f Endoerimt: liipre.hyroidism 1966 Conher et al. Raynaud's syndrome. sclerodennalifce 'kin rheum acroo^ceolyn. presidedubbing.joint pam. tiredness, sleep mrerecL. episodes of acute overexpoeure (loss ofconsciousnessI 1967 Harris and Adams AcrooMMfysis.akin tesions. 'Raynaud's phenom enon. peeudoclebbtnf. involvement of sacroiliac jointsand patella, hepatomegaly with persistent ly raised serum bilirubin. Skin biopsy 1967 1967 Benoit Wilson ettl. Amriognphy- Ska and base biopsy `Occupational acroosttolys" with Raynaud's symptoms. tderodermeUke akin changes, pmudodubbing 1968 1971 ^ffrofiyuzAnlto JMeme* et al. Mentions thrembocytopenia Prevalence of acroeeteotysis and Raynaud's phenomenon 1971 1972 Dodsonetal. Kramer and Muachler Vascular leaioM preceding the bone lesions Increased BSP retention and raised icterus index related to degree of exposure Vinyl Chlon Table 7 (con Year R< I9': Mo J9''; Jl' 1973 AL 1974(a) Cr. 4.1 The Tru; A first indicat producii toxic a> 30 r~ lil in hc- . _j. inel w'. rs> sampl; oo was si ze 195 slation. ' -- IS synv t,tvo4) also in durations on there was evic of red cells.u: evidence of d* aeroosteolysis operators) afi junction with was found in i lesions to be c. reversible cha; vibration trau the full range - cupational aer In 1963 Sr analysis of th. MIJ Mameller 1 anicteric -"wn.'ion. henomenon 'nin| by VCM. -.ai phalanges. .n on volar 4* and rciKuJo- <nes. euphoria. mu. blunting idache .;rodennalike rfic dermatitis ,'a. :uiine&5. -rubuuemu hk 'km tabbing. jvnt .pBOtUs 01 UauNfi) piwnom* ent of sacroiliac with p*rm>entupay W h Raynaud * -changes. Raynaud's .d icterus index 1 Chioride-A*ocij[eii Discs'* 31 Table " (continued) Year Reference |9*2 .Weri.^wirr et ji. I9"- Siifu and Lsngc 1973 Martteiler tt ai. 1974(4) Cntch et al. Findinp Progressive thickening ot hand* and forearms, arthralgia. Blanching upon exposure to cold with cyanosis of hands accompanied by severs pam. Skin biopsy ] *t German report oi " workers %ith ci<:oJeroalike sk;n lesions. Raynaud's syndrome, and acroosteoiysis. Tests showed abnormal liver in 2. occlusion of digital arteries in 1 worker Noncirriiotic portal fibrosis with portal hyper tension and splenomegaly 4 cases of angiosaruoma of the liver 4.1 The Triad: Raynaud's Phenomenon. Pseudoscieroderma and Acroosteoiysis A fust indication of advene effects due to chronic VCM exposure arose in workers at a plant produemg VCM who presented with symptoms similar to Raynaud's phenome non (toxic anponeurosu*). This was reported by Smimora in 1954 and later described in detail in her thesis (1959). The syndrome wet found predominantly in laboratory personnel who had intermittently been exposed to high concentrations of VCM during hourly sampling for chemical anilyw (purity of the product). In 19$4 Raynaud's syn drome was also observed among several workers at a Japanese PVC producing plant (Kubota 1957). Apart from a painful vasospastic disorder of the hands, impaired ther moregulation, aerocymous, positive cold test. eapiUaroscopic alterations, parsesthesias. and CNS symptoms such as headache, blunting of memory and sleep teversal,5miniova (1954) the mentioned swelling of fingers and demlopmen: of circumscribed skin in durations on the volarride of the forearms in those most severely affected. In addition, there was evidence of mfid haemolysis (borderline anaemia, decreased osmotic fragility of red cans.uroMUnuria.vd rcticuiocytosisj. In 1961 Smvnota described radiographic evidence of destructive bone lesions of terminal phalanges in the hands identical with aeroosteolysis in thine workers at a PVC-ptodudng plant (one fitter, two centrifuge operators) after exposure for 3-9 yean. Since these bone lesions developed in con junction with "toxic an^ooturoris' and since complete recalcificaUon of the defects wts found in two wotfcen 3 years after removal from exposure, Smirnov* believed the lesions to be characteristic ofchronic VOd Intoxication. She pointed out that thsir reversible might serve to dritingukh the leriooa from similar defects saen m ribmrion trauma. In retrospect. Sminom'% observations art the earliest descriptions of the Ml rangi ofsymptoms which much later becanu knoam as the syndrome ofoc- ouperioori actoosteotysu'. / In 1963 SucteetaL (aae also 1967 and 1975) published the first comprehensive analysis oftheir ohmtvarion ofa multiform symptomaiotofy in subactua and chronic n c ID ro 00 NJ ii . 3; %-K. Lclbuclt jnJ H ) Mar^ieilcr VCM intoxication. During a 4-year period, they examined 168 mostly young workers Irom two Rumanian PVC-producing plants who had not previously been employcJ in other industries. In their classic paper, live authors described in detail the various cen tral nervous, digestive, angioneurotic and cutaneous symptoms (listed here in their order of manifestation). Acroosttoiysis, however, was not mentioned. Episodes of acute overexposuit (usually occurring at the end of a batch run. during retrieval of unreacted monomer, or at repair jobs) rapidly resulted in a state of Ught-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 Umbs and a general feeling of bodily warmth. Six subjects had experienced loss of consciousness when repairing leakages, but recovered rapidly after being carried out into the open air. After a few months of work, unusual fatigrie 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- paiaesthesias, and general weakness were reported: some workers noticed insomnia or sleep reversal. A reappraisal of these nonspecific complaints (see also Vale et ah 1976) 6 years later, after improvement in industrial hygiene, revealed that the frequency of their oc currence had considerably decreased (Suctu et si. 197S). 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 worl ers (30t); in 6^ there was also splenomegaly. Classic Raynaud's phenomenon was fou id in 6ff. but a tenfold higher percentage of the total work force showed evidence of vasospastic alterations on plethysmography (Raucher et al,, cited by Suciu etal. 1975). Pruritus of the hands, forearms and face was an early complaint followed later by wliat was theought to be (allergic?) `contact dermatitis': Anally, nodular and scleroderma- or scleroedema-tike cutaneous lesions developed in some workers, involving the dorsal surface of the hands, the volar side of wrists and forearms and the face, with firm thickening of subcutaneous tissue or formation of whitish papular or slightly elevated plaquelike indurations. The cutaneous manifestations largely disappeared after removal from the work place. In addition, mention was made of features of hypothyroidism in a few workers. Also, trenaent loss of libido in 24% was recorded, with return to nor mal after a break from work or during holidays. With the exception of acrooneolyris and the two most alarming late sequelae nondiThotic portal hypertension and hepatic angkMarooma Swciu's early documen tation of the prevalence ofdisease in PVC production workers encompassed a com paratively complete description ofthe various aspects of chronic VCM intoxication. Later publications supplemented the spectrum ofknowledge mainly by providing ad ditional information on epidemiological, roentgenological, thermographic, angiograph ic, and histomorpholofical aspects of the lesions encountered in subjects chronically exposed to VCM. Vinyl Chlon The disci two Belgian . classifiable d marked the r. syndrome w: year a numb'. United States cases of OAO the various pi end of 1979. vascular pheiv symptoms tfr begin with til- the fingers arc tips on hard > to cold accorv are likewise a; ance of pain it. osteolytic pro Xi with striation NO CO CO Table 8. Publ.. Year I960 1967 1967 1967 19671969 1969 197] 1972 1972/197? 197? 1974 1974 1975 1975 1976 1978 1979 a One of 2 ci. Marneller ; workers rployed in nous cen* : the:; les of aval of Redness anted by >ul workers .-table s. workers tdily -okages, months of xstent i the work 'titty, .e workers ' yean f their ocstd period .Ktl. such <mfi>rt. iMJOT): :J m 6". ..^spastic Pruritus at was iiu-or dorsal i firm elevated tar removal ruidism in n to nor* .uelaa Jocumen! a coradcatton. vidfeg ad* ngwgnphmonacaHy Vin>l Chl-mdc-Wocuted Discjw ,31.J" The discovery of unusual osteolytic delects in the distal phalanges of the hands of tu-o Belgian autoclave cleaners who had sutfcrcJ from Raynaud's phenomenon and undassifiable degenerative lesions of the dermal connective tissue (ConJicr ei al. I**66) marked the recognition of this new occupational disease in the Western World. The svrtdrome was termed 'occupational acroosteolysis' iOAOLi. ami during rtie following year j number of additional cases were reported irom Francs. Great Britain and the United States. Later Lcfirrc (19^2) who together with Coruicr described the first t o cases oi OAOL. reported that a subsequent investigation revealed another 'en cases in the various plants affiliated to the same corporation in Spam. Italy and Brazil. By the end of 197Q. a total number of 126 cases had been published in detail (Table 8). The vascular phenomena preceding or accompanying OAOL comprise a broader range of symptoms than those cnaraccerisuc of Raynaud's syndrome. The conditions seems to begin with ill-defined pains in fingers, wrists and also large joins (shoulders, knees): the lingers are numb and tingling, tender on paipauon. handgrip and tapping finger ups on hard surfaces is painful; there is increasing serwuvity of the hands and Angers to cold accompanied by a tendency to cyanotic discolouration. In some eases, the toes are likewise affected. Later, classic Raynaud's phenomenon develops (sudden appear ance of painful, sharply demarcated blanching) and. concomitant with the onset of osteolytic processes, there is a shortening and broadening of the terminal phalange with stnauon of nails (pseudodubbing). Table S. Publications on Occupational Aeroosteolysu' since 1*66 ) e.ir 1|99h^76 I9p7 |9h7 19*7 1969 1969 5971 1971 1972/1973 1973 1974 1974 1975 !975 i9"6 1978 1979 Coun try Number Authors of cases Belgium France France United Kingdom USA Rumania Yugoslavia USA USA Fed. Republic of Germany Japan France USA USA United Kingdom United Kingdom re 5 5 3*l 8 412 6 1 4 1 4 l 4 Brazil Israel 5 ^^2^ 126 Cnrdi, r (jj. Benoit; Giateiain and Motillnn Boumchon (cited by Man* ei al. 1967) Hotfix and Adams Wilson ct al. Angheiescu ei alKomtet al. Dinman et al. Markowitz etal. Jake and Valtman; Stein et al. 1 a. b) Tekaueki and Mabuchi 3 Moulin et al. Trapp et al. IMiset al. Stewart et al. Preston et ai.: Walker; MitchellJohnston (1978) Gama and Maim Hahn et aL a One oi 2 dear cases. m addition. 48 suspected cases I tee Sakabe >97? URL 1218-4 14 W.K. Leibach and HJ Mameller 4.1.1 Familial and Idiopathic Acroosteolysis Acroosiedytis is a very rue disease. The aetiology and pathogenesis of this condition is still obscure. Osteolytic bone changes in late stages of so-called Raynaud's disease (accompanied by necrosis and gangrene), characteristically presenting as loss of part or of an entire distal phalanx of one or more fingers and also of toes, have been mention ed in the literature since 1921 (Asstnann \9Z\-Monahan 1926:Bora* \921\Komblum 1929). Komblum attributed the lytic bone defects to vascular abnormalities and noted that he had found identical lesions in early stages of scleroderma and in leprosy. The term aeroosteolysis was first introduced by Laroche u\d Hochfeld (1946), who held a neuroendocrine syndrome responsible for the lesions. Independently Hamasch (1949) reported another case of symmetrical idiopathic aeroosteolym, particularly involving the terminal phalanges of the fingers with preservation of tufts, progressive clubbing and shortening, and ill-defined symptoms of disturbed peripheral circulation. By 1952 Giacci mentioned that 66 cases of the familial type of acroosteolysis and 33 cases of the aonfamilial, idiopathic form had been reported in the medical literature. He added another five cues, but his case reports pertain almost exclusively to mutilating proces ses involving only the feet, with recurrent ulceration and discharge of bone fragments (see also Harms 1954). In 1957 Lib>n and Gama listed 16 observations of idiopathic acroosteolysis and commented extensively upon these lesions: the whole range of dif ferential diagnosis (various congenital, neurogenic and endocrine osteolytic diseases, leprosy, arthritis mutilans, progressive systemic sclerosis, ainhum etc.) was considered in their study and could be rejected with reasonable certainty. In a later review. Cheney (1965), who added another four cases of the familial type, stated that this variety and the nonfamiliai idiopathic type may actually belong to the same disease entity and may be pan of a degenerative bone process more generalized than the term implies. Jt was the puzzling character and the rarity of this peculiar bone lesion that captured the attention of site medical personnel and industrial hygienists when in November 1963 the condition was detected in two Belgian autoclave cleaners (Ltfbrre 1972). 4.1.2 Epidemiology of Occupational Acroostcolysts Attempts at assessing the prevalence ofOAOL among personnel involved in VCM manufacture and polymerization revealed that in general this occupational type of osteolytic bone lesion was found in only !%-3% of the work population at risk. Hubkt et al. (1977) cormdcred the fact that only 3% of aO workers who had been engaged in "**"*1 cleaning of autoclaves at a Belgian plant suffered from OAOL and Raynaud's phenomenon to be indicative of the importance ofindividual factors. Wilson et si. (1967) observed 31 cases among 3000 employees of one large company, la 1971 Dtmmn et aL conducted a survey in 32 plants belonging to 19 corporations throughout the United States and Canada. The details of this elaborate epidemiologi cal study, comprising a total of 5011 employees, flhntiates the difficulties and limita tions encountered In a retrospective study of this dimension. All of these SOU 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 Vjnyl Chioi exclusively v only 25 clea defined as clenon;18 oi with experic drome were jobs, both re (I case per 7 appeared nci was detected use for react> entry into th Table 9. Prt. c Country prance SA nited r= Kingdom ---`ed.Rep. ' Germany co United i <L-n Kingdom Total More con' related symp' Lange and I, ological ched pathological: were affected cold, 15 work morbidity wa found classic ' numbness and 6.7% and invr Allen test inJ people with p pseudodubbit finding that ti duration of p.' :HJ Marsteller ' this condition laud's disease s loss of pan or : been mentionl27:A'0m6/u"i .lines and noted - leprosy. The VS who held a rimajdr 11949) iUrty involving xiive clubbing 'nion. 3y 1952 <d 33 cases of ature. He added itilating procesone fragments ; of idiopathic ie range of dif'ytic diseases. '.js considered t review, -.'d that this same disease I than the term tc lesion that ts when in icanrn {Lefbrrt edia VCM *nal type of hi at risk. 1 had been *n OAOL and factors. 9|i roipofittOM tpiotniotofi* 'uesandUnata^ SOU workers it 1357 of them pbius worked ^iny[ Chlcriiic-Asociated Disease exclusively with the finished PVC-dcrivfd consumer products. Dir/nan er al. found only 25 elcar-cut eases of OAOL among the 5011 employees (mean age: 35.B yean), defined as characteristic X-ray tilm abnormalities combined with Raynaud's phenom enon; IS of them had been reactor cleaners at some time;ancrlier Id individuals 110 with expenertce in reactor cleaning) with early stages or minimal degrees of the syn drome were suspected of suffering from OAOL. It emerged that the two lowest-paid jobs, both reactor cleaning and bagging/packing, had a strong association with OAOL 1.1 case per "2. or 86 workers at risk, respectively}. Manipulation of the finished polymer appeared not us be iscotiaccd with a risk of contracting OAOL. Only 1 case of OAOL was detected in those plants where high-pressure water lances or solvents had been in use for reactor cleaning. Furthermore, it seemed that the extent of degassing prior to entry into the autoclaves correlated with the manifestation of the disease. Table 9. Prevalence of acral disease in VCM^xposed populations Number of cases Country Sire of group at risk OAOL Classical Severe Sclero Raynaud's sensitivity dermoid phenomenon to cold skin lesions References France 130 USA 35-) United 37 Kingdom Fed. Rep. too Oermanv United 10-i Kingdom 5 4 I 9 1 s: :o 5 9 25 15 63 ' 8 35 5 23 4 10 l Btnou 1967 Lilian al. 1975 Walker 1976 Lanft and VtUntan I9T? Mahcq et al. 1978 Total 725 ;o(`v3'=> TK-vUTel 119(^16^1 43(%6S> More commonly seta than OAOL were Raynaud's phenomenon (see Table 9) and related symptoms of abnotmal peripheral drcnltttoo (Jewofr 1967; Lifts etal. 1975: Cans* and Vdtman 1977). Btnoit pointed out that a complete medical and roentgen* otogical checkup of all 528 employees at a French FVCproducing plant revealed pathological manifestations only among the group of 130 reactor deanen of whom 52 were affected (OAOL. 5: Raynaud's phenomenon without OAOL, 12; sensitivity to cold. 15 workers). He snused the fact that m this group of workers at risk the overall morbidity was almost 25ft. Similar results were obtained by Lifts et aL (1975), who found dasric Raynaud's phenomenon hi SJft of 354 heavRy exposed PVC workers, numbaew and tingling in 20%, excessive watitivicy to cold hi 18ft, pecudodubbing in 8.7ft id iavelwmaut of the torn m 7ft. lislilii, In 2fc6ft ofthe total an aboormal Alien ten indfcawd impaired peripheral arterial circulation. h was noted that in some people with pmt expoausc Rayaend's phenomenon had gradually faded, whereas paeudodubbing persisted or even psopisasd. Most important, however. was Liiit' finding that the prevalence of ad ttaeaa abnormalities iucreaaed significantly with the duration of past expoaue to VCM, I r .{ I :I r A I33 i ocno r- ! IV >*. J M y x3 W.K. Lethach and H.J Marticller Occupational acroosteolysis is a condition predominantly observed in younger workers. The age range was 20-45 years and half of all cases reported fell in die 50-59 years age-group. Duration of VCM exposure prior to onset of Raynaud's phenomenon ranged from 1 to 25 mondufZWso/i ct al. 1971). For OAOL the latency period was at least 12 months (Wilson et al. 1967): in most cases. OAOL developed insidiously within 2 to 4 -6 years. There is at least one patient on record in whom OAOL was first discovered two 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 years after removal from VCM exposure, but Raynaud's phenomenon and cutaneous lesions may persist {Williams wdMcLachlait 1976). Stem et al. (1973a, b) reported partial healing with restitution of tufts but progressive lysis of the proximal portion of terminal phalanges 3 years after termination of exposure. Although OAOL developed predominantly m PVC production workers who had at least for some time been engaged in reactor cleaning, the syndrome has also been ob served in association with other job assignments which were believed to carry a sub stantially lower risk of exposure. Trapp et al. (1974) reported a 31-year-old white male suffering from Raynaud's phenomenon, dubbing of the Angers and typical bilateral acroosteolysis, in whom specific inquiry revealed that his employment by an industrial chemical company had induded daily handling of small concentrations of vinyl chlo ride (no details given). Typical OAOL was also observed in a worker after 6 years' em ployment as spray dryer/bagger, pre-mix operator, recovery and charging operator who had never cleaned autoclave vats (Sfrwerr 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 ofOAOL were normal; in 1972 he presented with Raynaud's phenom enon, pseudodubbing, typical OAOL and dermal thickening ofhands and wrists. Ar teriography demonstrated narrowing of most digital arteries, even in fingers without bone defeats, and abnormal collections ofsmall vessels in the pulps of deformed finger tips, but no vascular oeduaon. Apart from the chemical insult by inhalational (rather than transdermal - Dinman et al. l971;ftfHwr et al. 1975) exposure to VCM, individual susceptibility or idio syncrasy appears to have played some (undefined) role in the development of the syn drome. It does not seem likely .however, that repeated physical microtrauma during cleaning operations (removal of polymer crusts by hand scraping or chiselling) was a decisive factor in the pathogenesis of the condition as had been speculated by Wilson ct al.(1967). 4.1 J Clinieal and Roemgenotogtcal Features 4.1.3.1 OccupetioimlAcrvoueoiysis In the majority ofcams osteolytic lesions are coofihcd to the hands. Involvement of the feet wn observed only rarely In OAOL. Mbm et al. (1967) believe that OAOL differs from famflial or idiopathic acroosteolysis in several respects. Although the bone Vinyl Cli defects in osteopon skull, des' shortenin', nonoccufgenologu 1)TK one or mo 2) In l: tufts, or a 3) The tufts toget defects (sc. (`bandlike Fig. 2. Oci acroosteoK year-old au 4) In th and broad*" fragments, i and incteas. Sodium minenlizat) multaneous ' jsU HJ. MameKir vrd in younger -:d fell m the 30--3? i -aud's phenomenon 'itency period was ' iped insidiously <om OAOL was first Longitudinal studies .-`ective restitution, ears after removal .*sions may persist rtial healing with terminal phalanges .vorfcers who had at - lias also been ob<i to cany a sub* year-old white male J typical bilateral ,-nt'bv an industrial inns ofvinyl chlor after 6 yean' err,urging operator who n routine plant m chromatography < limit values of st year during an ynaud's phenomiil* and wnsu. Ati ftngtn without . of deformed sdetmal --Dinman ptiWUty or idio* H^prsant of the synutotnuma dunng - chjeeOinf) was a ctdated by Wilson *. tawlniwat of here that OAOL . Although the bone Ciitordii'Assouated Diseu;* 3^ defects in the distal phalanges are similar in both conditions, other features, such as osteoporotic compression fractures of the spine, basilar impression fracrure of the skull, destruction of mid-phalanges or osteosclerotic changes of wrists and hand bones, shortening of metacarpals and cunicai thickening of the shafts of long bones seen in the nonoccuparional type have never been found in OAOL. Wilson e: al. worked out roent genological catena for the diagnosis of OAOL: i i The earliest changes in OaOL are marginal defects and lo:s of cortex in tufts of one or more of the terminal phalanges of the hands. In the next stage this is followed by small "half-moon' cuts in the cortex of the tufts, or a so-called slice-effect along one or more tufts. 3) The advanced stage of destruction is characterized by either a complete loss of tufts together with a portion of the shaft or there may be transverse ot oblique bone detects (see Fig. 2) cutting ofT the shafts from the remaining distal rim of the tufts < 'bandlike aeroosteolysti'). Fig. 2. Occupational scroovteoiyfls. Transverse or oblique bone defects < *bindUkc acroosteoiysu') or partial loss of terminal phalanges in aD fingers of both bands. (33ycar-old autoclave cleaner: duration of exposure 2 1/2 years) 4) In the healing stage there may be either complete bony union with shortening and broadening of the residual pants of the end or a fibrous union of bone fragments. Fingertips remain short and plump with petalstent dubbing of soft tissues and increased lateral and longitudinal curvature offingertips. Sodium fiootide14 F scintiscan data of afleesed bones suggested that active dendnetalizstioo (tesoeptire) and remmeiillaaiton (reparative) processes may occur si* muhaatouriy even in the same hand (Dodson et aL 1971). In some cases, bones of 88UVW I r r r i 38 W.K. Lelbach and H.J. Marvellcr other body regions were also involved. Erosive and sclerotic changes in the sacro-iliac joints and circumscribed resorptive defects (cortical erosions) in patella, clavicle, man dible, humerus, styloid process of ulna, femoral condyles, os calcis. cuneiform and metatarsal bones have repeatedly been observed [Conlicrtx al. l966://crm and Adams \96~.Dodson et al. \97\ :Jiihe et al. 1974; Lange et al. l974r.Prcsron et al. 1976; Jayson et al. !976a;Ldnge and I'cltmen 1977). 4.1.3.2 Psendoscleroderma 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 puffines and coarsening of the skin of the face (mostly on the forehead and cheela). Raised, ivory-coloured, firm nodules or elevated, sharply de lineated plaquelike skin indurations axe seen on Use dorsal surface of fingers and hands and on the volar side of the wrists and lower forearms. It was this combination of Ray naud's phenomenon and cutaneous lesions which first prompted a search for other symptoms of progressive systemic sclerosis in affected workers. The syndrome of OAOL. however, can be clearly distinguished (Table 10). Notably, the diffuse immobil- Tabic 10. Differential diagnosis; syndrome of occupational acroosteolysis (Raynaud's phenomenon, sclerodermoid skin changes, AOL) / progressive scleroderma with (rare) osteolytic lesions Occupational AOL Progressive scleroderma Sex rau.t Exclusively t e-t 1:2 Hands Dubbing and shortening of finger tips: hyperhidrosis: no ulceration Atrophy and tapering off of fingertips: anhydrosis: ulcerative lesions Perioral puckering of skin Skin appendages Telangiectases Shortening of frenulum Subcutaneous deposits of calcium salts Dysplugia < oesophageal involvement) Renal, cardiac and intestinal involvement Occupational history Prognosis Not observed Preserved Not observed Not observed Not observed Not observed Not observed Obligatory Favourable (skin and booe lesions tend to heal after removal from exposure) Common Loss of skin appendages Common Early symptom Common Common (Common) Usually spontaneous progression Vinyl Chlondc- izing sclerosis o tional syndrom, readily than th. 4.1.4 HistoJo- 4.1.4 1 Cutam Several investicdisease (Cordici al. \912\Unga we found only c 1967;,Vfcnn el j neural changes v who suffered *m Dermal chan mis with dlsorie broad interlacin', faintly stained n SchifF(PAS). Ar histiocytes was The most notabt of elastic fibres, full thickness u. sue. Skin appen --'>r(l976)f tceedingr. 3D Ibroustlu ^ tcular lc rc ies were ao~icapil!ar 10 *Us with 'umina * ts.was ^ ..--owing or Degenerative (Benoir 1967;.1/ hyalinosis of*hMeissner, Pacini 4.1.4.2 Bonet The most strikii worker with OA ening and hyaJn most layer. Sup; 1HJ. Mameiler ' the sacro-diac l clavicle, maneiform and rnt and Adams et al. 1976. of die fingers and progressive sde* inns, sometimes . face ( mostly on aied, sharply de nser* and hands `unaoon of Ray* ch for other ndrome of diffuse immobii- . sis i Raynaud's r.na with <rare> o vlsroderma jr I tapering off - P anhydrous; l *n* kin appendages i nptom 0 -ron umoiu MOO .. V:nv! Chk-nde-Associated Disease 59 izing sclerosis of the shin with upenng off of fingertips was never seen in the occupa tional syndrome. After cessation of exposure the skin lesions seem to regress more readdy than the osteolytic changes. *. 1.4 Histology i'.JJ Cutaneous Lesions Several investigators described the histomorphology of skin lesions in vinyl clilor.de disease {Conifer et al. 1966;/farm and Adorns \961:Mantt et al. l96T,Morkowitz et al. l^ZiLangc et al. 1974a; 1`elnnan ct al. 1975. Walker I976;ftr/r et al. 1979). but we found only one description of bone histology in OAOL in the literature (Benoir 1967;.tfervr et al. 1967). Skin biopsies showed various degrees of dermal, vascular and neural changes which were essentially identical in patients showing OAOL and in those who suffered 'merely' from Raynaud's phenomenon. Dermal changes consisted of hyperkeratosis and pronounced thickening of the der mis with disorientation, swelling and nonfibrillary eosinopnilic homogenization of broad interlacing coDagen bundles. There was some degree of interstitial oedema which family stained meuchromatically with toluidine blue, alcion blue and periodic addScruff (PAS). An inflammatory reaction with infiltration of lymphocytes and a few lustiocytes was scanty and, if present at all. of predominantly perivascular distribution. The most notable feature was marked disorganization, fragmentation and rarefication of elastic fibres. In areas corresponding to nodular or plaqueiike skin inductions, the full thickness of the dermis consisted of an acellular, partly hyalinized collagenous tis sue. Skin appendages were preserved. In 15 apparently less severely affected workers, Walker (1976) found only some destruction of elastic tissu*- of the dermis, probably not exceeding normal age changes: in one worker with seve e Raynaud's phenomenon some fibrous thickening of the media of dermal arterial vu seen. Vascular lesions affected capillaries arid small dermal arteries. Numerous dilated capillaries were seen in the subcpidermal papillae with swelling of endothelial cells and pericapillar oedema. Capillaries of the cutis showed cuffiike hyperpiaria of peri* thelial cells with fibroblast transformation, hyalinosis of vessel walls and final oblitera tion of iumina. Marked medial thickening of dermal arterioles, due to hypertrophy of myocytes, was accompanied by parietal fibrosis and hyalinosis, which ultimately led to narrowing or even complete oedusion of the lumen. Degenerative lesions of small dermal nerves were mentioned by French investigators (Ben-tit t967:.tferinet al. 1967; Qtarelain and Motillott 1967). They found sclerosing hyalinosts of the perineurium with atrophy of neurofibrils. Tactile corpuscles (WagnerMeissner. Pacini) were unaffected. dj.tj Bone Lesions Tire mass striking feature in a Mopiy t--" of the bone, obtained from a French worker with OAOL (ease 4 of both Benoit l967\Mdrm et al. 1967) was marked thick ening and hyriintealion of the periosteum with chondroid metaplasia of the inner most layer. Supplying capillaries and arterioles showed occlusive changes identical with URL 12190 t I ;i * ;l , 40 W.K. Lclbucli jmi H J. Manidlvr those observed in the dermis. The bone matrix per se was barely affected. There was minimal thinning of cortex, normal spongy bone and only mild fibrosis of the bone marrow. Experience with histomorpliolugy ul bone lesions in the familial and idiopathic type of aeroosteolysis is limited. In the tew 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 {D'/pas et al. 1936: Elson and Bunistein l9S4:Grccnber% 2nd Street 19S7.Sch\iarzu <:thr 195"'). In this context, it should be kept in mind that Viola succeeded in reproducing dermal, vascular, neural and skeletal lesions in the skin of the paw? and in small meta tarsal bones of experimental animals which were very similar to those observed in man. Viola exposed rats to 30 000 ppm VCM. 4 h/dav. 3 days/week, for 12 months and de scribed the histology of these lesons in detail (1970b). 4.1.5 Arteriography, Capillaroscopy, Infrared Thermography Aneriographic evaluation of the vascular tree of the hands revealed patency of the large arteries in ail cases examined. The vascular lesions were almost invariably con fined to the small digital arteries, although the superficial and deep palmar arterial arch may occasionally show some narrowing and a paucity of side-branches [Lange et al. 1974a;,thf//m 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 lortuosries of patent digital arteries were found. Circumscribed hypervascularity of the tent inal tufts and in the region of the wrists was noted in some cases (Benoit 1967:Lange et al. 1974a; Veftman et ai. 197S ;Preuott etal. l9?6:5/*nvrr etal. 1975: Game end Mein 1978). Angiographic findinp in a larger group of Asymp tomatic PVC workers with either Raynaud's phenomenon and/or aeroosteolysis (5'19) were recently described in detail by Koischwitr et al.(!980). Raynaud's phenomenon had been observed to persist in these patients for prolonged periods after termination ofexposure and even after roentgenological evidence of healing of resorptive bone defects in those who had formerly suffered from acroosteoiysis. 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 tolizoline (Priscoline. United States), the most conspicuous features observed in the majority of these patients (14/19) were circumscribed elonga tions and tortuosities of digital arteries resembling cirsoid aneurysms. An example is shown in Fig. 3 of generalized tortuosity and elongation of digital arteries in a 54yearold patient who started to complain of severe sensitivity to cold 3 yean after cessation of VCM exposure (about 1 year prior to death from both angiosarcoma of the liver and hepatocellular carcinoma). The pathogenesis of these peculiar vascular alterations Is not dear, but the possibility presents itself that they may be due to de struction of elastic fibres in the vessel walls In analogy to similar alterations of digital arteries seen in rheumatoid arthritis (Laws et al. 1963.1967). Vinyl t x\ __ ,,IX. control ence in r PVCw. of distir induce. A si. aPVC-r chemica normali was con number employ: related It also s more so I Mjjv.sller Tltere was 'he bone spathic aid be obilammaiory * 1956; Jucmg >truQ raeta"fd in man. tiu and de- > of the .oly conarterial 1 l.j>\p: si *-ete r1 or diiTase 'I vessels. i peculijj my of >tr il. ' -ymp -is (5/I9i i**: aomenon tarnation - .* bone * to varycollati in spite I'lttlOUS ;^ed elongaarapk is m a 54taftfl nidmof macular duetode* of digital ^ *nyl ChJor.de-Assovuied Di Fig. 3. I'oiv-picuou* loraioHiea and cionj[i><n '! dittiiat artenex m'mS? +Tj Studies of microvascular chances by wide-field capillary micmtcopy (direct obser vations complemented by phetoinphy) ofselected skin sites - such as nail toids, Sugetpads, dorsum of phalanges and of proximal interphaUngul >otnts - demonstrat ed a variety of capdiary abnormalities, ie. dilated or giam capillary loops, pale avascu lar areas, capillary and subungual haemorrhages. The abnormalities were similar to those seen in scleroderma but were usually km conspicuous, kss numerous and of dif ferent attribution. In a survey of a group of 152 American PVC workers, these capil- taracepic findings proved to be significantly mote prevalent than in 50 nonexposed control subjects 0Uerin? et al. 1976). There was also a statistically significant differ ence in the prevalence ofthese abnormalities between symptomatic and asymptomatic PVC workea. The alterations were not only found in workers with dinicai symptoms of disturbed acral circulation but also In 6 nonsymptomadc males with either VCM- tnduced angiosarcoma of the liver (2) or spknomegatie portal hepatic fibrosis (4). A similar survey was later undertaken in an uttselected sample ofl 29 employees of a PVC^rodudngchemical plant in England with 26employees of a non-PVC-producmg chemical plant serving as controls (Ataricq et al. 1978). The prevalence ofcapillary ab normalities found in time British workers, which were of the same type and degree, was comparable to that hi the American sampk, although the lauer included a Larger number ofmore severely affected patients vrtth greater mean length of employment (IS years vs 3J years). In the authors' opinion, this riprrtiil that VCM- rtkted dlaaaia may develop independently of differences in manufacturing procedures. It also aigpntJ that thh easily detectable type ofaticrovascular lesion may precede mom serious VCMinduced disorders. In a small subgroup of 15 clinically affected W.K. Lelbaeh and HJ. Marstelkr British workers who were examined 6--24 months alter leaving the plant (termination of exposure), the prevalence of capillary abnormalities was not less than that among those who continued work. For an evaluation of the reversibility of this condition, however, the group was considered to be too small. The same type of capillaroscopic changes was also observed in three of 4 Polish workers (2 reactor cleaners, 2 fitters) who were found to suffer from Raynaud's phenomenon after exposure for 2-5 years {Byctkowska and Langauer-Lesvowieka 1974). Infrared thermography, another nonnnvasive method, used by Rt;y et al. (1974) for the study of acral circulation, revealed abnormalities of surface temperature rang ing from marked hypothermia of terminal phalanges (which are normally warmer than the rest of the fingers) to "complete terminal amputation" in four PVC workers si/ fering from OAOL. In one of them vascular disturbances as evidenced by infrared thermography persisted in spite of complete healing ofOAOL. Stewart et al. (1975) demonstrated uneven blood flow in the fingers and patchy hyperthermia in the distal part of the OAOL-tffected (eft index and middle finger of their atypical case. Local ized acral hyperthermia seen on IR thermography corresponded to the angiographic finding ofcircumscribed abnormal collections of small vessels (compensatory collat erals?) in the pulps of the affected fingers. Using !R thermography in a survey involv ing 143 PVC production workers and 56 controls. Williams et al.( 1977) assessed the time needed for heat return after immersion of one hand for 10 s in a water bath kept at 19C; however, no difference between VCM-exposed subjects and controls and be tween groups within the exposed population was noted. 4.1.6 Immunological Studies Early experience with the syndrome of occupational scroosteolysis suggested certain similarities between this disorder and corresponding lesions seen in progressive systemic sclerosis (diffuse scleroderma). Differential diagnosis of these two unrelated conditions is now well established (Table 10). Such similarities stimulated the search for other manifestations of a systemic collagen disease, notably iramunotoficai features, as pro posed by .Marin et al.in 1967. Word et al. (1976a, b) carried out immunological studies in 58 workers from a British polymerization plant who were referred to tltem out of a total past and present work force of 320. Mean duration ofexposure to VCM was 39 months (6--75 months). Of these S3 workers, 28 were symptomatic (Raynaud's phen omenon.9: scleroderma ofhands or feet* 6; OAOL, 2; sensitivity to cold, excessive fatigue, limb pan, paiaesthesias). Slight hyperfntmunofiobuUnaeniia, usually lgC, the presence of mixed cyiogtobulins, and in vivo conversion of both Cj and C4 were found in 19 patients In the symptomatic group, with additional evidence of reduced T<eU population and increased B<e& proliferation. Mixed cryoglobulins, m vivo con version ofcomplement and depressed values for C> or C were taken as evidence for the presence ofcirculating immune coraplexas. Autoantibody screening demonstrated low-titrt andaudear antibodies (IgG 1/20--1/50) in eight of the nine patients with Raynaud's phenomenon. Aggregstes of IgG, C*, C*., and fibrinogen/fibrin were reveal ed by direct Immunofluorescence in the lumen of vessels, adherent to vascular endo thelium. Aggregates were similarly seen in the media and subintimil regions of small Vinyl Chl^ and mediui lung(l case The aut< and bone c: bolic interv. plasma pro: wluch sum: cular occlui as a result o aton of tiss to further a Jayson et al suffering fn- than in non: ride disease In an ea; in four Pol; decrease in ? t\ts,Langu:` after Seph&6 together v agglutinins >. we-- *1 ( < c IX--) n. la-. jn. aur ro heu '& tior. CO jfiU' ter . -- , inir up ay ed tosuggo1 hypergamr. with far ad\ three patici with Rayna*: degrees of nins were range:x t s sderodermn of which is. In sunur autoimmune establish tlu in VCM-indt i HJ, Mantel!:.' it (termination * that among condition, ipillaroscopic rj, 2 fitters) ;`or 2--5 yean etal.(l9"4) perature rangly warmer than workers sufy infrared ct ai. f 1975) a in the distal 1 case. Localangiographic -latory coilatsurvey involv* *i assessed the arer bath kept itrois and oe- ,ied certa:* wive jys;..,\ .-U conditions >i for other tares, as pro* `logical stu iies - 'hem out ot a VCM was jo tynaud's plu.iiid. excessive uaDy IgC. the *C4 were : of reduced s.ia vivo con* evidence for - demonstrated clients with in were reveal* .ocular endo* os of small ^inylO)londe*\ssoc:ated Di4* J-' and medium-sited artenoies m biopsy specimens ot the skin f 10 cases), muscle and lung \ l case each). The authors prooosed as explanation lor the induction and pathogenesis of skin and bone changes tn VCM-indaced disease a Uieoretical model based on reactive meta bolic intermediates of VCM formed during biotransformation binding covalently to plasma proteins.These may act as antigens (as a result of a structurally abnormal protein) wSuclt 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, in turn, by leading to collagen synthesis, was believed to further activate the complement pathway and thus to recycle Use mechanism. Jayson et tl. (1976b). who carried out collagen studies in a skin biopsy of one patient suffering from QAOL found the rue of collagen synthesis to be considerably higher than in normal controls. The pathogenesis of excess collagen formation in vinyl chlo ride disease has not been fully elucidated. In an earlier study no cryoglobulinaemia or presence of cold agglutinins was found in four Polish workers with severe Raynaud's phenomenon: in two of them a slight decrease in IgC was noted (ByezJcovske and Langatior-Lewowtcka 1974). Later, how ever. Langaucr-Lewowicka et al. (1976) observed latent cryogiobulinaemia, detectable after Sephadex G-200 filtration, in 18 of 22 workers with Raynaud's phenomenon (in 6 together with acroosteolysis and sclerodermalike changes). Again, there were no cold agglutinins detectable, but in five patients marginal to slight elevations of IgC levels were observed The authors suggested that a pathological alteration of immune re sponses plays a key rale in the pathogenesis of vinyl chloride disease. Lange et al. (1974a) and i'etrman et al. (!?7$) concluded from their results that convincing evi dence of autoimmune disease was tacking. Immunological studies including determina tion of rheumatoid factor (latex agglutination test), quantitative immunoglobulin de termination (Manzini radial diffuson technique) and autoantibody screening (indirect immunofluotescance) were initially introduced in our flm series of 50 patients but were later abandoned because of mostly negative results.except for occasional in creases in immunoglobulin levels (.1tanteSer et al. 1975a). These studies were later taken up again with an additional 43 patients engaged in PVC production but still fail ed to suggest more than an erratic connection (unpubttshed data). We did not observe hypcrgammaglobulinaeata (see comment in Ward et aL 1976a) except in a few patients with far advanced portal fibrosis and portal hypertension and in the terminal phase of three patients who died from angiosarcoma of the liver. In a group of 18 PVC workers with Raynaud's phenomenon in whom arteriography of the hands disclosed various degrees of occlusion of digital arteries, autoantibodies, cryoglobulins and cold aggluti nins were found in none;a moderately moused IfG level (I.93-J.68 g/ttoe;normal range: Its* 0J--14 g/Utre) ws teen in five patients who suffered from OAOL and sclerodermoid skin changes (unpublished data). Bastin antibody titres (the specificity of which is doubtful) wen negative. In summary, cuwtntiy sviilaMs evidenca does not seem sufficient to suggest an autoimmune disease ss t pathogenetic mechanism. Farther studies wfi] be needed to establish die true rigntfidance of the possibly transient immunoiogieat abnormalities i VCMdnduced disorders. r f r ;> it :f , i. J :i t * r' 72 : r. t l1 r ! \ f, x 4J W.K. lelbach and H.J. Mjrstcikr Vinyl Chloride-A- 4.1.7 Pathogenetic Considerations The clinical sympt- many as 15S of th Raynaud's phenomenon as a premonitory clinical symptom, histomorpliolocy in man survey was describe and experimental animals and angiologtcal experience suggest that the common de developing chrome nominator in the pathophysiology of both skin and bone lesions in chronic VCM in character of norim:' toxication is probably to be sought in the local impairment of blood circulation in In 1972 Krann }; - peripheral regions, at Lenoir pointed out as long ago as 1967. By reason of their vas culature. the distal phalanges are the skeletal segments which may be most susceptible to impairment of blood supply, particularly to disturbances of microcirculation (Gama had been routinely time-weighted at err. environmental data and Meira 1978). Yet the answer to the next question, the pathogenesis of peripheral wise multiple linear vascular injury in vinyl chloride disease, is unknown. It still remains largely a matter of tion and. to a lesser conjecture how a volatile toxic compound that is taken up via inhalation, distributed level of past exposu throughout the systemic circulation and metabolized (bioactivated) in the liver, can the individuals stud t bring about, apparently only in a small number of predisposed individuals, after a vari TWA levels of 300 t < able period of latency severe vascular injury and (probably secondary) damage to peri in clinical laborator pheral tissue. Some conceivable mechanisms are briefly listed in a previous chapter (see ed BSP retention w: Sect. 3.0.2), but no conclusion can be drawn as to their relative significance. ease (Varste/Ier et a. t In West Germandermatologists in Bi 42 Non-maiignant Liver Disease in Vinyl Chloride/Polyviayl Chloride At first sight, the s> Production Workers derma. This provoke \ Progressive systemic a first gr*'-- ^f 13 p- Long before Raynaud's phenomenon or osteolytic lesions were observed in PVC pro from a PVC- > duction workers. Tribukh et al. (1949) studied environmental conditions in a Russian from ei ^ OL i- V plant where polyvinyl chloride resins were produced and compounded. Without going phagea r- due into detail, the authors pointed out that moderate nontender hepatomegaly was found agrour ^ slauv I in a larger porportion of a group of 73 workers (48 males. 25 females) mostly engaged in PVC compounding; "anicteric hepatitis' was diagnosed in 21 of them (15 4,6 9). Al previoi iseasc Medical ^ ment though the authon knew about the narcotic action of high concentrations of VCM (75-250 mg/Utrc 30 000-98 000 ppm) from the literature, which they explicitly mention, and also knew about the release of unreacted monomer from the powdery PVC resins during thermoplastic compounding, they apparently held other volatile compounds derived from halogensted aromatic hydrocarbons (such as chlorinated naphthalenes and diphenyls) used as plasticizers responsible for the systemic toxicity. They urged, however, that strict monitoring of the health of these workers should be introduced to prevent the development of seven liver damage, and they suggested the installation of ventilation facilities ofsufficient capacity. Nonicteric hepatomegaly was again recorded by Sucfci et al. (1963) 14 years later in almost one-third of the total work population (51 of 168 employees) of two Rum anian FVCpreducing plants, including 10 cases with additional splenomegaly. Liver patient saled capsuiai ly.mark : of.al h> al. 1973). It was now encompassed a large Hence JUtc et al. (IV ' In retrospect, th; spleen alterations in v the long latency peril ' disease which is acco:i hepatic parenchymal Only 3 months !- ! biopsy in two of them worked revealed chronic hepatitis. Studying the prevalence of temporary dhablament due to liver disease among 350 employees of the Sverdlovsk plastics industry,Arsftin (1965) found the highest morbidity among employtai ofthe was surpassed by the : liver, an exceedingly r work force of 274 emr PVC production unit, compared with other units engaged in the production of non- ican plant (Creech et; i PVC plastic materials: 170 workers of ancillary industries served as control subjects. upper gastrointestinal * 5 i HJ. Mjrsreiler 'ology in man .ommon de-.mie VCM in* ;culauon in ii of their vu.osi susceptible rcuUiion ioj/hj 3 oi peripheral -selva matter or m. distributed he liver. can lals, after a vandamage to peri lous chapter (see dieance. :J in PVC pro:i in a Russian Without going oly was found mostly engaged < 15 d.6 ?). AJins of VTM hey explicitly i the powdery -ther volatile chlorinated -teuric toxicity, tkentiiouid be > suggested the 114 yens later 0 of two Rum* -uwgaly. Liver < prevalence of lie Seeidhre* mptoyees of the >ictkxi ofnon* mci subjects. Vinjl OiJonde-AssO'.istcJ Di'caw aj The dinted symptomatology oi - typically nonicienc - liver disease observed in as many as IJ': of the current work forv.5 ot the PVC production unit during a 3-year survey was described as having been consistent with the diagnosis of an insidiously developing chronic hepatitis. No histological data were available, however, and the true chancer or nonmaiignant liver disease found m these worker: rsmamed obscure. Jr. | QT Kramer and Murchtcr examined a group of 98 healthy male workers who had been routinely exposed to VCM for penods uo to -5 years ,v:J for whom career time-weighted average exposure estimates were available. In an attempt to correlate environmental data and results of a medical surveillance programme by means of step wise multiple linear regression analysis. it emerged that brumsulphthalein (BSP) reten tion and. to a lesser degree, the icterus index were significantly correlated with the level of past exposure to VCM. Although no overt clinical disease was found in any of the individuals studied, Kramer and Mutchkr concluded that exposure to VCM at TWA levels of 300 ppm or more for a working lifetime could result in certain changes in clinical laboratory parameter!. As it later turned out. slightly to moderately increas ed BSP retention was the most consistently pathological test for VCM-ind'\ced Liver dis ease iManreHer et a|. 19?5a). In West Germany the first cases of occupational QAOL were observed in 1972 by dermatologists in Bonn (June and tenge \9~Z.Juhe et ai. \9~j -.Steui ti al. 1973a. b). At first sight, the symptomatology appeared to resemble atypical progressive sclero derma. This provoked a thorough March for manifestations of visceral involvement. Progressive systemic sclerosis, however, could be excluded. On medical examination of a dm group of 13 polycleaners who were referred to the Department of Dermatology from a nearby PVC-producmg plant it emerged that 3 of them, who did not suffer from either OaOL or scleroderma, had a history ofunheralded bleeding fre m oesophageal varices due to portal hypertension (Julie et al. 1973). Further invest igation of a group of 20 relatively young PVC production workers (mean ege;40 years). in whom previous liver disease could be excluded, we* carried out in collaboration with the Medical Department. Peritoneoscopy and guided liver biopsy were performed in etch patient and revealed varying degrees of rtoncvritoric ponal. pertsimtsoidol and subcapoilarjlbrosis ofr*eliter, with splenomegaly, thrombocytopenia and* less frequent ly. marked ponal hypertension, but strikingly tittle hepatic dysfunction (AlarsteUef et al. 1973). It was now realised that the disease spectrum In VCM<xposed individuals encompassed a larger scope of injuries and. In fact, suggested a systemic toxic tfTect. Hence Mte et al. (1973) propoeed the term "vinyl chloride diseaje'. In retrospect, this comparatively fare recognition of the true nature of Um and spleen alterations in chronic VCM intoxication can be attributed, at least in part, to the tong latency period es well as (he Midiow onset and count of this type ofliver dlseeae which is accompanied, even far into the advanced stages, by only mtnimai hepaik parenchymal dysfunction. Only 3 months later,however,hi February ITT1 the rignlflrmre nf ihk discovery n sutparesd by the afaxmfag ennounemest that four ernes ofmgjlamaaem ofthe ifrg-.anewidlngly aw --tignant tumour,hud been found among > ccapaatfniy unail workforce of 274emptoywi ofthe FVCpolysrizatiourectiou ofa large North Amerlean ptaut (Creech et al. 1974a). Two of them four patkno had first presented with upper gastrolnuniniil bleeding due to portal hypertenrion between 1964 and 1970. ~j5 ^ ro yo 05 46 w.K- Lelbach and H.J. MameUe? There is no louger any doubt that chronic exposure to vinyl chloride monomer can produce two different types ofliver disease in man as well as in experimental animals: 1) Nondnrhodc portal hypertension 2) Angiosarcoma of the liver. The two conditions have one feature in common: they are both tare disorders which are not easily recognized during life. Noncirrhotic portal hypertension and (often inconspicuous) ponal'fibrosis are not pathognomonic. Primary splenic enlargement and gastroocsoplugea) haemorrhage due to marked portal hypertension in the absence of. or preceding, the development of cirrhosis was first described by Banri in 1894. As `Banti's syndrome', this symptom complex and its aetiology and pathogenesis have continued to be a matter of debate. Under the designation `idiopathic',or `primary, portal hypertension' the syndrome has been observed notably in India and other South-East Asian regions (Rameiingeswami et at 1962;/ma*dfo et al. 1962;Beat et ai. 1967a, b;Boyer et al. 1967:5emeet al. 1971). It has been seen only sporadically in the Western World (Rousscloi 1940: Revenue 1940; T-sdaic et al. \959\Polish et al. 1962:MMer and Brandt }962,Skiers and VeUtos 1964 Mikkctsen et al. 1965;/ber \97Q. Escartin Marin et ai. 1974; Mendenhall et al. 1974; GnawriJ 1975; Vitttneuve et al. 1976). Iber (1969) estimated that "centers throughout the world reviewing their experience with portal hyperten sion encounter 3 to 556 of patients who do not clearly fit into the category of cirrhosis or blockage of the portal vein." In the absence of an identifiable aetiology it has been speculated that in noncirrhotic portal fibrosis observed in India, unknown toxins contained in indigenous drugs, herbal medicines or adulterated food might have been responsible for the condition (Satie et ai. 1971). Villettaveei al.(1976)suggested that, apart from VCM and inorganic arsenical*, other st-U unidentified toxins could be the cause of this syndrome. Idio pathic portal hypertension has also been observed to occur in association with -mown bepaiotoxic agents, their common link with VCM being, so far with the exception of vitamin A, the induction of angiosarcoma of the liver. These agents are: (.e u n a n a) Inorjenic anenkats (Zeegen et al. 1970;Neale and Azzoperdi 1971; Knollc et al. I9?4;4fomiet al. 1974;//uef et al. 1975; Vittenewe et al. 1976'.Cowluhaw et ai. 1979); b) Hyperviuminosts A (Mueitter et al. 197Russell ex al. 1973,1974 ;Hn/ban et al. 1974;jCarteret ai. 1977): and c) Recently,copper sulphate in Portuguese vineyard workers (Pimentel tndMenezes 1977). ._ Arsenicalprepaarions (usually prescribed as Fowler's solution - potassium amnit*) ban in the pvt been used as a tonic in neurasthenia, as an adjunct to iron therapy far anaemia, as anticpgepdc drags and wall into the 1950s for the treatment of pioriash fas this context, Band'll remark to his original paper (1898) that anaemia accompanying primary splenomegaly responded bast to arsenical preparations is of note. In a renowned German pharmacology textbook of this period (Nothnagei and Rossbach 1880) Fowkr's solution is also listed as a traditional antimalariai drug of ! andH.J.Marr.illcr t4orkle monomer can perimental animals: n rare disorders * ml fibrosis arr noi il haemorrhage due . development of -<e`, symptom a matter of debate. "t* the syndrome has ' (Ramathifaswami l67:^ernj et ai. u/tsefcr l WO: rarrdt \962:SUerys i ctal. 1974; (1969) estimated h portal hypertencategory' of cirrhosis d that in noncirrhotic tVenous drugs neroaJ condition xSj'na et I and inorcr.mc syndrome. Idio. nation with known :h theexet; non of are: - WH.KitolIc et al. et al. *3.1974;/fn<6an et rimtnttl and Mcncces i - potassium an adjunct to iron Is for the treatment 189S) that anaemia preparations is of h! (Nothnagei and nmalarial drug of v iny! Chloride-Associated Disease 4? long standing. Otcinurati and Virsnuratti (1979) recently implicated an indigenous Thai mediant conuning arsenic as a possible aetiotogical factor in a case of idiopathic ponal hypertension. Delta et al. i 1970) found significantly elevated levels of arsenic in liver tissue specimens of four of nine Indian patients with idiopathic porta! hyperten sion resuiting from chronic arsenic intoxication fcontaminated drinking water, use of Ayurvedic medicines). Typically.liver disease in these cases occurs in conjunction with other evidence of chronic arsenic intoxication, such as skin pigmentation, palmar anJ plantar hyperkeratosis, skin cancer and sometimes carcinoma other sites. However, neither histological nor radiological or haemodynamic criteria permit a clear distinc tion between idiopathic* portal hypertention and nondrriioac portal hypertension caused by chronic arsenic tcxification or chronic exposure to VCM, as was demon- stmedby ViUencuve et al. (1976) in a study of five pariens. v After prolonged treatment with excessively high doses of vitamin A (psoriasis, ichthyosis and other dermatological conditions, adjuvant cancer therapy and in health faddlsm) chronic intoxication has been seen to cause hepatic fibrosis and cirrhosis (Mumttr et ai. 1971 iFkachmann et al. l9TJ:JCbderct al. \971,RusstU et al. 1973. 1974). Storage of vitamin A in hepatoeytes and one type of fat storing, nonphagocytic pertsinusoidal cells {(to cells (fro and Nemoto 1952)] could be demonstrated by fluo rescence microscopy'. Stimulation and proliferation of (to cells, which ate probably fibroblast precursors (Popper and Udenfriend 1970; Schnack et al. 1967). provokes an increase in basement-mrmbrane-iike material and collagen within the perisinusoidal space and leads to perisinusoidal fibrosis with partial obliteration of Disse s.ipaces and the sinusoidal lumen (Hntben et al. 1974). The recognition of idiopathic portal hypertension, hepatic fibrosis, cirrhosis and angiosarcoma of the liver coexistent with excessively ebundant hepatic depostion of copper (besides evidence of `vineyard sprayer's lung") in a group of 30 vineyard workers in Portugal is. to our knowledge, the Ant report in which chronic copper intoxication is implicated as the aetiolo^cal agent. For periods varying from 3 to 45 years, these workers had been engaged in spraying vineyards with a mixture containing copper sulphate on 15-100 days per year. The authors noted e dose morphological resem blance of the lesions to those resulting from exposure to inorganic arsenicals and to vfayl chloride (Pimentel and.Uencrs 1977). Although extrinsic chronic copper intoxi cation is virtually unknown in man, potential bepitotoxicity oflong<ontinued uptake ofcopper was discussed by Biomfiebi et al. in 1971 in connection with recurrent haemodialysis. Although nonmalignant liver disease seems to be a more common lesion in PVC production workers than angiosarcoma, it lias received less attention than the spectac ular discovery of me rare hepatic neoplasm. Is continuation of our first two surveys QfanteBer et al. 1973,I97Ja. b), wo have now (end of t9b0)obaerwd 17 patients (all members of a total work force ofapproximately ISO polymerisation workers) in whom cfiaicsl and morphological exidnarton, jmChadhtg petitomoscopy and guided Over biopsy, reviled advanced portal hypertension (Table 11)-A larger proportion of them tat prerenred with symproae ofwhenMed furobiteitinal Warding. On follow, up wi mingf) nifiertert thir niomirnmi im derelnping In four of them but were unaWe to prov it during Ufc. Only pore-mottem examination finally confirmed the diagnosis. In a smaller series ofseven patients with noodrrhotic portal fibrosis and URL 12198 r f r r r i r T W.K- Lelbach anti H.J. Mameller Table 11. [? PVC workers with adMinced portji hypcrten-ion <marked oesophageal i*nis/>di!t i)l utinvrrM ku^<i:.. i Age at diagnosis Duration of exposure I'emoneoscopic and No. (years! (yean.'months! histological diagnosis I 30 31 3 32 4 35 5 a 35 6 39 7 39 8 41 9 a 41 10 > 47 n 50 i: 5 l 13 5; 14 52 15 54 16 a 58 l?a 61 5 5/9 3/6 4 9 10/6 13/6 7 18 18 6/6 17 15/3 11 6/6 :i 13 Noncirrhotie fibrosis Noncirrhotie fibroMS Noncirrhotie fibrosis Noncirrhotiw fibrosis Noncirrhotie fibrosis Noncirrhotie fibrosis Noncirrhotic fibrosis Noncirrhotie fibrosis Postnecrotic cirrhosis Noncirrhotie fibrosis Noncirrhotie fibrosis Noncirrhotie fibrosis Noncirrhotie fibrosis Nonurrh-nic fibrosis Noncirrhotie fibrosis Postnecrotic cirrhosis Noncirrhotie fibrosis On follow-up patients 5.9,10.16 and I 7 subsequently developed angiosarcoma of the liver and died 3-6 years after diagnosis of portal hypertension. Patients 6 and W are at present <1981) under observation for suspected development of angio sarcoma of the liver, 6 and 11 years after pcnroaeoscopic diagnosis of portal fi brosis associated portal hypertenaon,5mrr/i et al. (1976a) observed later development of angiosarcoma in one of them. If a rough estimate based on these two small series were acceptable, it would appear that approximately one of five to seven individuals suffer ing from advanced VCMenduced portal hypertension might be expected to develop angiosarcoma later, although PVCenduced hepatic fibrosis per se is probably not a premalignant lesion. Clinical Manifestations of Non-malignani Liver Disease Physical examination is usually disappointing. In the more advanced stages of VCMinduced nonmalignant Uver disease, palpable splenomegaly and a slightly to moderate ly enlarged liver may be the only physical signs. On palpation, we found hepatomegaly in 31 and splenomegaly in 16 of SO selected PVC production workers who had been heavily exposed in the past {MerutBer et al. 197Sa). UBs et al. (1975) reported hepa tomegaly in 15% and splenomegaly in 3.4% of 354 consecutively examined employees (267 currently employed, 87 former workers) ofone PVC polymerization plant in New York State, USA, a number which included virtually the entire current produc tion work force. A significantly higher prevalence of hepatomegaly was found in those Vinyl Chlorv exposed for r splenomegaly In contra.ment ofhepa ectases, gyna. not seen. Eve phalopeihy d workers only It is puzzli preceded adv. only one case development 4.2.2 Labor: Owing to the not the target value for the J This makes it ' 1974 ;Gw/r . thrombocytop logical biochei th- ''Is of s. i __ iarstc X> 5 and etion - ro of a > U3 to et to ively -- rtnal S is ovei , ause! alkaline phospmegaly and/c- Except foi and Veltman < the reticulocy parameters uspresenting fea' sion {Smith et be dealt with * Assessment tnatic workers facture of pvt coproporphyn :J.J. Marstellcr -Miphageal x.ocL` and 4i dijJTO'l' uv tibrusi* *ie fibrosis uc fibrosis ti: fibrosis - >tic fibrosis .< .tic fibrosis ic fibrtwn ' -(ic fibrosis <ic cirrhosis "(ic fibrosis -.lie fibrosis i xic fibrosis ' me fibrosis - 'Uc fibrosis i.>uc fibrosis *i_- cirrhosis tie ubresis veircorns ot nrtnts b end " "1 4f1iO- p.Ttii fi> .`.nciit ol 4 series w e . limit !'>. ' g develop ably notayre- SMofVCMy to moderate: hepatomegaly -ho had been sported hepatticJ tmpioytcs ra plain in rent producioond in those vinj i Chloride-Associated Dwc^c 49 exposed for more than 5 years, whereas the difference in the prevalence of palpable splenomegaly was not significant. In contrast to cirrhosis of the liver, clinical symptoms indicating serious impair ment of hepatic function such as jaundice, vascular spiders, palmar erythema, teianaeetases. gynaecomastia. peripheral oedema and ascites or hepatic encephalopathy are not seen. Even after massive bleeding from oesophageal varices portosystemic ence phalopathy does nor develop. Ascites and hepatic coma have been observed in these workers only in terminal stages of angiosarcoma of the liver. It is t-usling that acroosteolysis and sclerodermoid skin induration have only rarely preceded advanced stages of VCMnnduced liver disease. To our knowledge there is only one case of angiosarcoma of the liver on record which was associated with prior development of acroosteolysis (Roche et al. 197g). 4.2.1 Laboratory Findings Owing to the fact that hepatocytes. although being the primary- site of metabolism, are not the target of toxicity, standard biochemical liver function tests are only of limited value for the detection of liver disease in populations at risk (Widiami et ai. 1975b). This makes it very difficult to devise adequate screening programmes (Martin et al. 19*4. Creech itbiMakk 1975; Wyart et al. I975;Serifc *tal. 1975, 1976). Apart ftom thrombocytopenia, we found 45-min BSP retention to be the most consistently patho logical biochemical test: usually minimal hyperbilirubinaemia and minor elevation of the levels ofserum alkaline phosphatase. SCOT and SOFT were considerably less fre quent [Mantcllcr et al. 1975a). Another dy*-removal test, indocyanine green clearance fICG:0i and 5.0 mg/kg), also proved to be more reliable than standard biochemical liver function tests in correctly identifying early hepatic injury in 1200 vinyl ehloride workers of a chemical plant in Louisville, Kentucky, during a 4-year screening period (Temburro et al. 1978b). TIte exposure rank was found to be closely correlated with progmnvcfy increasing frequency ofabnormal ICC clearance, whereas the frequency of abnormal SCOT, and alkaline phosphatase only increased in late stages, often when there was overt dmical disease, in the survey conducted by idles et al. (1975), alkaline phosphatase levels were elevated in 16-6*3 of the 354 workers examined. In their series, alkaline phosphatase was also closely correlated with the dinieal symptom of hepato megaly and/or splenomegaly. Except for thrombocytopenia (less than 150 x 10' pbteiets/liire) which Lange and I'dman (1977) found to be present in 76 of 100 workers, and a slight increase in the reticulocyte count (in 35 of 79 workersand Vdtman 1977), haaaatological parameters uaially do not contribute to the diagnosis. Thrombocytopenia was also the presenting feature in two of sewn British workers with noorintotic portal hyperten sion (Smiti et aL 1976a). Thrombocytopenia and abnormal platelet function tests will be dealt with separately in Sect. 4.4.1. Aisimmint ofurinary excrationof porphyrins and porphyrin precursors in sympto matic workers who had boon engaged in the production ofFVC (a 23) or the manu facture ofFVC artides (n * 17) revealed varying but meetly mAd degrees of secondary coproporphyrinuria in the m^ority of them (Lange et aL 1976b). The significance of I [ F r <j ; C 30 ro ro o o * hl f. 50 W.K. Letbach and H.J. Marsteller these findings as an indication of toxic liver damage is not clear and the relation to previous exposure to VCM remains to be determined. 4.2 .3 Cross Inspection of the Liver and Spleen The gross appearance of the liver, as assessed by peritoneoscopy (Mantcllcr et al. 1975a. b:Mantclicr and Lelbach \9T7;lelbach uui Marsteller 1977; or at exploratory laparotomy, is that or a normal-sized or slightly to moderately enlarged organ with often blunted and irregular anterior edge. Inspection of the liver at peritoneoscopy also permits exclusion of partial nodular transformation as described by Sherlock et al. (1966). In most cases, the surface of the liver is smooth or slightly uneven with shallow indentations, but it may be finely granular, trabcculated 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 Wiliams (1974), and also in two of our recent cases in combination with development of angiosarcoma. On palpation (direct or by peritoneoscopic probe), the texture of the liver is normal or only slightly firmer than usual. Indirect peritoneoscopic evidence of portal hyper tension is presented by increased vascularity of the falciform ligament and the intes tinal serosa or numerous dilated tortuous vessels in adhesions draining to the abdomi nal wall. Even in advanced stages, symptoms of pronounced portal hypertension often Vinyl Chi contrast sipectedly % is a focal ^ opacities, stellate sc: ing (.Want, tissue in C extending nective tis< processes t' or more di< are seen in Histologic/ is generallv sis. striking fibrosis are (Fi" r i) re; thi C" fib r~ toh -19: NJ ro o dati nan ject* .... ations is sc. Thomas 19" 1976). bu; (Popper ei j- In its fully d of dense, pji bile ducts twith formau central and r of connects with enlarge, perisinusoid, oidal walls.: Muller et al. !J Mantelirr Priori to ..^et al. u expiorator> *;gan with 'otoscopy aiso lock ei al. with shallow Vonnse-like to nodularity iemrrmeni ' l). and aiso :oma. - liver is normal 'nrtal hyperi tne imes:he abdomi'tension oiler. .>p*nttuion conspicuous njr74. c-^iun of si -opiupsa) \ :nvl ChloriUr-Ao<;i3tc<l Disci** contrast sharply not onlv with ntintrnal alterations of the surface but also with unex pectedly scanty histological evidence 01 hepatic fibrosis. The most conspicuous feature is a focal or diffuse capsular fibrosis ot varying pattern (Fig. 4). presenting as whitish opacities. The degree of capsular involvement ranges from diffuse tmy comrnaJike or stellate scan to coarsely reticular and irregularly patchy milk-white capsular thicken ing (Marsttllcr ci al. 1975a). Histology showed that this focal increase of connective tissue in Glisson's capsule may extend into the parenchyma and connect with septa extending from enlarging fibrosed portal tracts iPopper and Thomas 1 ?5). The con nective tissue capsule of the enlarged spleen also seems to be sensitive to VCM-mductd processes that have taken place in the underlying tissue so that focal white thickening or mote diffuse opacities together with circumscribed subeapsuiar haemorrhagic cysts are seen in cases with marked splenomegaly. 4.2.4 Histology Histological examination of biopsy specimens shows that normal lobular architecture is generally maintained, but varying patterns of portal and, in some cases, septal fibro sis. striking intralobular perisinusoids! fibrosis, and focal capsular and subeapsuiar fibrosis are found in combination with peculiar alterations of sinusoidal lining cells (Fig. 5a-d). Hepatocellular changes usually play a negligible role and inflammatory reactions, if present at all, ait insignificant. The lesions are distributed quite irregularly throughout the liver and may vary from minor inconspicuous degrees to quite striking fibrosis. Sutgical wedge biopsy ofsufficient depth appeals to be more suitable for his tological evaluation than needle biopsy specimens (Smirii et al. 1976a: Blendisex al. 1978). Depending on length and degree of exposote. interval between last exposure and date of biopsy, as weO as individual factors, hatopathotogy of VCMnoduced oonmalignant liver disease is represented by the Mowing feature! whose manifestation is sub ject to marked iaterindhridual and topical variation: the sum variability of tissue alter ations is seen in the nontumorous areas of the fiver in angiosarcoma (Popper end Thomas 1975: Thome* et al. 1975;Jc/t et aL 1976; Getffr* et ai. 1975: Wevtbmt 1976). but in these cases the nootumorous lesions may be even more conspicuous (Popper at al. 1978). 4^4.1 In its fully developed form, <<-- to marked enlargement of portal tracts by excess ofdense, paodcdiular connective (hue, which in advanced cam contains pcofifetaced Me ducts end some pcriductular inflammation, may in ram instances be combined with fprmerion of periportal septa finking portal ttaca or, even more rarely, connect central and portal canris. Other portal aieas appear afamet normal. Foci accumulation of connective rime In Ac thickened CBnm'i cepnile my be connects d by septa with enlarged tnftacapmlar portal tracts. A more striktng feature is an intralobular perisinuaoidai *netllke* fibrosis with more or less prominent eoBagenkarion ofsinus oidal watts, in some areas men programing to frank caplfarixarion (Getlifk et al. 197$: MUkr et al. 1975). The focal inuasimtsoidal fibrosis may be subtle end in some i % % fH a W rP P ff^ V p s iiig ^ O f r r W.K. Lelbach and H.J. Marsteller Vitr .or * e* .'.j. ' t * ' K. * <= & T3 & ro m ; * o, w *. Fig. Sa* Needle biopsy specimen of the liver shown in Fif. 4. Enlarpement end fibrosis of portel trsets. Moderately larfe droplet steatosis. Focal dilatation of sinusoids. H&E. x 80. k Gossip of Fig. $e. Indistinct border of enlaried and fibrosed portal tract to* wards parenchyma (kft). frobferation of capittaiies(> <) with polymorphism and hyporchromeoa of endothelial cells. FAS, x 400 i-- i0 V a i Fit with ner> and : Enlar prec.. Pam. Mar<(eJler .t. m *J It -* m 54 W.K. Lelbach and H.J MaMicHer may be recognized only In connective tissue stains. Trtchc et al. 119751 pointed out that in one worker with severe icroosteoiysis but normal hepatic function and essen tially normal liver histology on light microscopy (except for a minimal and easily over looked increase of perisinusoidal collagen in occasional lobules), electron microscopy revealed a Striking centrilobular increase in collagen between hepatocytes and in DisWs spaces together with proliferation and hyperplasia of sinusoidal lining cells (see also Kurokawa et al. 1977). The same ultrastructural deposition of perisinusoiclal collagen was observed by Schartenberg 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 Kupfler cells, abundant deposits of collagen in the Disse's space and resulting reduction of sinusoidal diameter suggesting a possible factor in the pathophysiology of `sinusoidal* portal hypertension) were seen on electron microscopy in a number of cases of idiopathic portal hypertension of unknown aetiology (occupational histories not mentioned) (Sommenchild and Kluge 1971,Kluge et al. 1970: Tandon et al. 1970). 4.2.4.2 Sinusoidal Lifting Cells Marked focal proliferation and hyperplasia of sinusoidal lining cells with nuclear poly morphism and hyperchromasia are the most impressive features of the mesenchymal lesion. The hyperehiomatic nuclei of these cells may show a bizarre shape or resemble short pegs, and are often arranged in a chaintike fashion {Cedigk et al. 1975). These pensinusoidaJ and sinusoidal cells include three types: (1) normal endothelial cells. (2) lipocytes (Ito cells), considered to be precuison of fibroblasts and (3) plump cells with spindle-shaped nuclei and PAS-positive cytoplasm. Formation of excess reticulin suggests fibroblastic activity of some of these cells. Focal dilatation of sinusoids, not explained by passive congestion, is another peculiar feature usually associated with particularly pronounced alterations of these mesenchymal cells. There is reason to be lieve that Hus combination of changes may represent a premalignant stage. 4J.4J Hepatocytes Unimpressive, nonspecific, degenerative and adaptive lesions (such as minor degrees of fatty degeneration, cloudy swelling, ballooning or vacuolar degeneration, increase of lipofusdn pigment and proliferation of smooth endoptasmatic reticulum of hepetocytes in focal areas without inflammatory reactions), can be seen to disappear gradual ly with increasing intervals between the last exposure and the date of biopsy, in con trast to the apparendy irreversible damage to mesenchymal structures {Cedigk et al. 1975, \n\MiNcr ti al. 1975). [n poorly demarcated areas there is hyperplasia and hypertrophy of hepatocytes with polyploidy and increased number of bmueleated cells. Two types of focal hepatocytk proliferation anodised with varying degrees of sinusoidal ceS alterations were recently described and are thought to play some as yet undefined rote in the precursor stage of angiosarcoma {Popper et al. 1978). Vinyl Chloride and HiOfnus et. to be characten. geneous red pul; follicles with mi endothelial cells occasional Tresh spicuous fibrosis In ten cases w Htusermann and terial, together v. splenectomy. TV process. Excess a tive tissue, notab and white pulp, > There was scarrin. meshwork and re and diameter of s> of the pulp cords formation of bi2j 'gen fibrils. N eticularcom. ^5 me with paia> --* ion of capillar nd within the ^ jmbocytes by i iced pooling o' p to explain tr> ges of vinyl ch< and Heusermann < VCM-inducedspU of the liver or ex', in the spleen in vn dicate a primary . port correlating cj> tients is being pre; the spleen in none able for company 4.2.5 Pathophysi The pathophyaoli* unresolved probiei to splenoponogiap of intrahepatic va> venous radicles (/< and a normal, or o; l HJ Manil!<i - pointed out jn aid essen* irul easily over-i microscopy s and m Disse* Us (see also 'iidal collagen we could obges (enlarge? and resulting ("physiology i a number of onal histories Sonet al. `i nuclear poly, nesenchymal re or resemble i*>75). These f-.elial cells. ' 3) piump ceils 'teen rericuiin muaoids, nm dated with . reason to be* F*. -*nov degrees of -i. increase of -i of bepetoppear gradual* upsy, in eon* fttUgk et al. TWtpiasia and 'nucleated ng degrees of ay some as yet '8). 'CRSOf ttW /homes (1975) viny| ChloridC'Assooiaicd Di-w*** 55 and Htorrur et al. (1975) found the cut surface of surgically removed enlarged spleens to be characterized by conspicuously hyperplastic Malpighian follicles in a beefy homo* geneous red pulp. Histologically, they noted large germinal centres of the Malpighian follicles with merging of perifoiUcular zones, dilatation of red pulp sinuses lined by endothelial cells of variable, often cuboidal shape, thickening of the pulp cords with occasional fresh haemorrhages, and in one case Gandy-Gamna bodies, but only incon spicuous fibrosis of the red pulp. In ten eases we obtained needle biopsy specimens of spleen tissue a? peritoneoscopy. Hcuicrmann miSnitre (1977b) vi&Sturte and Heusermarm (1978) studied this ma terial, together with spleen tissue specimens available from three spleens obtained at splenectomy. They found evidence for an invoivetoam of the spleen in the fibrosis process. Esteem amounts of newly formed extracellular elements of reticular connec tive tissue, notably collagen, produced by stimulation of fibroblastic cells of the red and white pulp, particularly in perifollicular and subcapsular areas, were observed. There was scarring of periarterial lymphatic sheaths, obliteration of the pulp cord meshwork and reduction of pulp cord volume, in addition to an increase in number and diameter of sinuses. The reticular connective tissue of the walls of the sinuses and of the pulp cords showed marked alterations with thickening of reticular fibres and formation of bizarre plaulike amorphous structures containing irregularly distributed collagen fibnls. Narrowing of the labyrinthine eordal tissue with marked increase of the reticular connective tissue caused a reduction of itncrodiculatory sequestration volume with parallel decrease of the number of pulp cord macrophages and approxi mation of capillaries and tinuses. Frequently. fool accumulation of platelets was found within the narrowed pulp cordbed in addition to increased phagocytosis of thrombocytes by residual macrophages. This lends support to the hypothesis of en hanced pooling of platelets in the spleen (ffatumuiin and Stune 1977a), and may help to explain the pathogenesis of thrombocytopenia often seen even in the early stages of vinyl chloride disease. By structural analysis of histometrical results. Sturtt vn&Heutermatw (1978) outlined certain diagnostic criteria for the differentiation of VCM-induced splenic alterations from those seen in portal hypertension due to cirrhosis of the liver or extrabepatie portal vein oedustoo. They concluded that fibrotic changes in the spleen in vinyl chloride disease ere not the result of portal hypertension but in dicate a primary action ofVCM or its metabolites on the spleen. A comprehensive re port correlating dirtied and morphological data gathered bom this group of 13 pa tients is being prepared for publication et present. Remits ofhistometrical studies of the spleen in noadnhotic portal hypertension of untaown aetiology are now avail able for comparison {Stki 1965; Yamamoto 1978,1979). 4U Pathophyriology ofBanal Hypenewrioa The pathopfeyriotoc' of portal hypertension in VOI lodumd Hvsr diwtae Is a yet an utusaohud probtem. Patency of tb* portal vein was demonstrated in aO cases subjected to iplmoponofmpby. Portography tmtatty rimmed no or only miaimal derangement of intnhepetic vvcular pastern such as tapering or `catofT ofand peripheral portal venom mdlekt (Bkndtt et at 1978: Plfienenvc et iL 1976). ffigfa fcitraspienic pressure and e normal, or only riightfy railed, wedged hepatic vain pleasure indicate that the c: X3 r~ rsj c=> Cti i W.K. Lclbach and HJ. Martc!lcr portal flow is obstructed at the sinusoidal or presinusoidal level. In a croup of live PVC workers selected for haemodynamic studies.Blcndis et al. (1978) could not demon* stratc a direct relationship between the degree of hepatic fibrosis in needle biopsy spec imens and portal hypertension. But it should be kept in mind that the distribution ot fibrosis in these workers is quite irregular, it has also been suggested by Pepper and 77ioi (1975) and Thomas et al. (1975) that the increased splenic and hepatic blood flow as a result of decreased splenic resistance in splenomegaly cannot properly b< ac comodated in the hepatic porta] vein bed owing to impairmen t of adjptive distension of portal veins and sinusoids by the subcapsutar, porta] and perisinusoidal fibrosis. Blcndis et al. (1978) found no correlation between spleen or estimated liver blood W&jgg*' - Vinyl flow 1! veiled in 19tic fib: could tests :: biops) of b rid the flb' eytes ( ing cell followmassiv. exposu sarcom or less , terrain : oped (. Uv: detemn (BMHP after b. and to.: aid ofr* the reu increas PVC p.. sack et  Laibach and HJ. Marvelier ? level. In a group of five PVC I 1978) could nor demonibross in needle biopsy specwid that the distribution oi suggested by Popper and d splenic and hepatic blood zaiy cannot properly be a<neiit of adaptive Jistension J perisinusoids! fibrosis. or estimated liver blood i Oopite termination of exHpasfc: 35 years. vcit^x* -dermoid akin induration*. 'I varices. Gradual profession . lassie MfiOMfeoau of the < ffhrotif in nontumorous vinyi C'.tlonUe-As<ocMte<l Disease '57 flow and the portal pressure. However, they point out that this relationship may be veiled by the amount of blood bypassing the liver via a collateral circulation. 4.2.6 Follow-up of Non-maiignart V'CM-imiuced Liver Disease In 19-4 Martin et al. (see also Berk et al. 1975) pointed out that VCM-associated hepa tic fibrosis, once established, may progress even after cessation of exposure. They could demonstrate this progression despite nonuaiizauou of all routine liver function tests in a 2?-year<ld worker on a follow-up examination including peritoneoscopy and biopsy 2 1 /2 yean after cessation of exposure. Progression of fibrosis and appearance of bridging between portal and central veins were indicative of persisting activityof the fibroblastic process, whereas the previously observed activation of both hepatocytes (marked variation of c*U size and numerous binudeated cells) and sinusoidal lin ing ceils had disappeared. Since 1973 we have observed a number of workers who on folloW-up showed evidence of progressing portal hypertension with development of massive oesophageal varices and subsequent bleeding episodes despite removal from exposure (Fig. 6). In five ( 7?)ofthese patients with progressing portal hypertension angio sarcoma of the liver finally developed. In this context.it is ofinterest to note that more or less conspicuous hepatic fibrosis (or ran progression to cirrhosis) was the parental terrain in which (he majority of cases of VCMnnduced angiosarcoma of (he 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 I97Hg-bromomercury4iydroxypropane (BMHP) labelled artificially damaged red cells, and sequential perfusion scintigrams after bolus injection of ""Tc-perteehnetate have been found useful in the diagnosis and follow-up of nonmalignant fiver disease In PVCpoiynifixation workers. With (he aid of these noninvisive methods, inhomogeneous uptake oflabelled sulphur colloid in the reticuloendothelial system oftiu liver and enhanced uptake In the spiesn. gradual increase in spleen size and redaction of portal venous perfiisioo have been observed in PVC polymerization workers developing portal fibrosis and portal hypertension (Bierseek et al. 1975a, b, 1977a. b). C r= ^ co 43 iVinineeirnmi nf rhs I jrtr 4J.1 Epidemiology Primary angtomreoms of the fiver (A$L) is described under a variety of synonyms (sngtoMastic sarcoma,iftabtonlc itticatoetiCQmaueadothoHorm.endotheliobiastoroa. ^mlww4wrtMiel BIWM gupff#r eolZ sarcoma, mafiprant hatmaagiomt, metastasiziBg hsemaagiofiia, reticuloendothelial sarcoma, primery --tar-- of the fiver). It h an exceedingly ran msUgnmcy. tririag from vascular ttrrieg ceffla. It occurs ipnnfuuriy with two peaks in the age distribution: oat at early infancy (infantile h--iwngloiiidodieltou) and (hr other in late adult hood (fourth to sixth decade). Use swastua synonyms render it difficult to estimate the number of reported cases and to desennme its true incidence. In a recent review 58 W.K. Lcll'jch and HJ. Mameller of the literature.,4/reflgB (1975) listed 165 published esses of primary angiosarcoma of the liver in adults. In the six autopsy series collected by Alrcnga. ASL constituted only I (0-9^-2.756) ofall primary malignant tumours of the liver, which of them selves are rare findings in the Western World. Autopsy statistics show that the incidence of ASL ranged from 2 to 20/100 000 autopsies during different periods with a mean incidence of 12/100000 autopsies (Table 12). According to Heath et al. (1975) it was estimated that in the United States the expected annual incidence of ASL is 0.014 in 100 000 inhabitants or 25-30 cases per year for the entire United Stares. Table 12. Incidence of angiosarcoma of the liver (ASL) in a-itopsy scries Authors Observation No. of No. of case* Year period autopsies Of ASL Region Simpson et al. . 1955 1914--1953 24 196 1 Mavo Clinic. Rochester.Minn-. USA Edmondson 1958 1918-1954 52 000 MacSe*n ex al. 1973 1900-1969 _ a 1 3 Lo* Angeles. County Hosp.. USA Western Infirmary Glasgow, U.K. A trengo 1975 1951-1973 39 700 6 Cook County Hosp Chicago. USA Rein and Hitch 1975 Syren and Holmberg Daidrrup et al. 1975 1976 1954-1974 30 079 1958-1969 _ b I960-I97S At least 40 000 4<6)c Diiitseldorf. Fed.Rep Germany 12 Sweden (adult cases) 8 Netherlands f population: 10- M million) * Among 120 cases of primary malignant liver tumours studied post mortem during this 70year period, b Among 8 million inhabitants. c 4 Angiosarcomas, l haemangioendotheltoma, 1 malignant haemangiopericytoma Accordingly, the identification of4 ernes of ASL among approximately 270 em ployees of the vinyl chloride polymerization section at a B.F. Goodrich plant near LonMBe, Kentucky, between September 1967 and December 1973 was duly recog nized as an alainting situation indicative ofa serious new occupational hazard (Orer/r ttal. 1974a; Ouecft andJoAnjofi 1974). Until 1974, only two carcinogenic agents were known to be associated with the development of ASL in man, i. rite administration of a radioactive colloidal prepara- Vinyl C tion of / inorgom dioxide i tem ami Thor contras! ingewdi. reported been the had been and Mot. A special thorotra from a h< ASL (*. Devei man vine tensive!) 1950-K tion reve., of multip: approved C occurred . X but notaf produced no Hausrrun' o CO (3^-5: Roth (|Q- 18.6-8b -fowler's > OlQ\\ haemangt* tension hi; woman u ride) dun. had a high manifest a The pr be elicited period 18 history- of Among nv observed > other han 391 auto; mmf mm .1 J. Marsteller :-Warcoma wOnstituied "ch of themdie inodencf tth a mean 11975) it was is 0.014 in 'lime. 'er.Minn.. Hoip.. USA i Infirnur. k UK. Minty Hosp t SA i Fed Rep id1turnmtlion) cm during fheytoma ly170 TO"iast >hity rvcogafd(Oweeft iwMfthe kUI prepare ^ inyi rhionde-Ajvociaied Disea* 5 tion of thorium dioxide (thorotrast) for diagnostic purposes, and chronic exposure to uors&iic ancNieali. Both substances are stored mainly in the liter: injected thorium dioxide particles are rapidly taken up by phajocytic cells of the reticuloendothelial sys tem and are permanently retained: arsenicals are only slowly released from the liver. Tiiorotrsj: came into use in 19-8 and w as internationally employed as an injectable contrast medium until the mid-1950s, when in use was abandoned because of mount- ms evidence of the carcinogenic action ot thorium dioxide deposits. MacMaiion ei al. reported the tint case ofthorium dioxide-induced ASl in 194?. Since then A5L has ' been the type of liver tumour which occurred most frequently among patients who had been given thorotrast injections in the past (da Siti-a Horta 196?: da Silva Horta andMotta 1967;4'egeerttai. andPitzkt 1974,Scii/igcr and Ko}f 1975). A special type of progressive portal and subcapsular hepatic fibrosis was another lesion caused by thorium dioxide retained in the liver, da Silva Horta (1967) considered (his "thorotrast fibrosis' to be dearly distinguishable from true cirrhosis. Gamma radiation from a lost radium needle has also been implicated as a causative agent in one case of ASL (Rob 1932). Development of ASL as a late complication ofchronic anetnc intoxication in Ger man vineyard workers was first described by Liebegott (1949.1952) and has been ex tensively documented by Roth (1956,1957a. b, 1959). During the 10-year period. 1950--1959. autopsies of 82 Moselle vintners suffering from chronic arsenic intoxica tion revealed ASL in 8 eases among a total of 61 individuals (74ft), with eancer often of multiple sites (Roth 19S9). In 1925. arsenic insecticide sprays and dusts had been approved for use in German vineyards but they were banned by law in 1942. Exposure occurred not only via inhalation during spray periods (approximately 30 daysfyear) but notably by dally consumption ofquantities ofcheap grape wine ('Haustrunk'). produced from a second pressing of the grape skin residue by adc ition of water. This Haustrunk. aa allowance in kind to the vineyard workers, had a Imv alcohol content (35-5ft v/v) but contained high levels of residual arsenic (0---89 mg Ai;Oi/Utre). Audi (1956) calculated the mean total ingestion of ASjO to have been 53.7 g (range: 18.6-88.8 g) for a 12-year period. ASL eras also seen after long-term treatment with Fowler's solution fot psoriasis (Rotation et al. 1968;Landert al. 1975). Chowdury et al. (1977) reported an anecdotal case ofapparently benign diffuse harmangtoendothetiomarosis of the liver with cootidenble fibrosis and portal hyper tension but normal Uver function. This condition was found in a middle-egad black woman who had been exposed to various chemical fumes (including carbon tetrachlo ride) during 20 yean in a ory<leanisf establishment, though it must be noted that she had a high alcohol consumption. The possibility (hat these symptoms could have been manifestations in laser life of congenital disease cannot be ruled out. The proportion of patients with ASLin whom a pertinent history of exposure could be efitited has varied conriderably. In an earlier survey of the Steranue coveting the period 1875.1960, non See**- and Bixxher (1961) listed 12 of 54 adult earn with a history ofexposure to either thorium dioxide (7) or aneninh (5 ofRodCft cam). ilmnag Tin rtisri nfnnunrnpiiffi^rmil1? ftrr ifn^gl"** T*** -***------ obeenwd were found exdutively in wtntnea expoeed to arsenical! (Roth 1959). On the other hand,Ascfcimr and Ayes (1976) recently observed a duster of 4 can among 391 mopries during a 29<noath period at a hospital in rural central Wisconsin serving \r c: -o_ ro ro M) W.K. Lelbaeh and H.J. MamelJcr Table I 3. Personal data of 68 polyvinyl chloride production workers with inipiosuconia of the li\ct reported to NIOSH up to Augui 1978 tSputat and Kwnski I97g> Birth date No. Country3 <m/d/y>b 1 B ( ti 01.12.13 Date of death t m/d/y) 06.29.76 Age at death 63 Total years exp 17 Job classilication1' 1.2 CNDtl) 12.15.13 3 CND C) 03.06.14 4 CND (3) 08.26.19 5 CND (4) 04.05.19' 6 CND (5) 05.07.11 7 CND (6) 12.15.19 8 CND 17) 11.09.19 9 CND (8) 05.13.20 10 CND<9) 07.19.21 M CND MO) 05.16.15 09.02.55 12.21.S7 03-22.62 01.21.66 07.05.68 04.10.71 12.24.72 06.J2,73 09.04.74 04.00.77 41 43 42 48 56 51 52 53 53 6) 11 i.: 14 2.3. 12. 13 20 2.5 1. 2.5. 14 5 1 *!4 23 l. 12.13. 15 25 1.9. 17 j 1.12. 17 26 3. 12. 16 14 2. 16 i: dSRll) 00.00.28 13 tSR (2) 00.00.26 M DU) IS DC) lo D 14) 17 D(S) 18 D (7) 19 D (8) 20 D (9) 21 DUO) D (11) 23 D(12) 06.04.30 07.26.31 09.04 JO 01.01 32 09.29.26 10.19.17 12.13J4 07.23.29 12.29 J6 06.14J8 12.00.73 00.00.66 (64-*) 01.25.69 12.14.71 11.25.74 01.09.75 1113.75 12.25.75 03.24.78 06.28.77 03.07.77 10.07.77 45 40 (37?) 38 39 44 43 49 58 42 47 41 39 16 15 (14") 12 11 17 12 12 21 IS 16 6 1 1 : 2.4. 5 II. (1) I To 10 10 i 24 F(l)t 25 F(2) 26 F(3) 27 F (4) 28 F<5) 29 F (6) 30 F (7) 31 F(8> 32 F (9) 33 F (10) 04.15.24 06.03.11 01.06.20 01.27.27 01.29J8 04.14J4 00.00.27 04.01J4 10.08.14 05.24.19 02.19.67 01.24.75 06.26.75 01.03.76 05.13.76 09.12.76 07.02.76 01J0.77 12.25.77 01.20.78 43 63 55 49 38 42 49 42 62 58 19 1.2 12 29 26 2.6 n 1. 2 13 6.7 * 19 * 28 * 21 * 34 GB (1) 35 GB (3) 04.20.0! 06.02J7 12.03.72 12.24.74 71 37 8 4l f3 1/2?) 36 1(2) 37 1(3) 11.13.29 03.14.20 12.27.72 07.10.75 43 55 6 21 38 Id) 39 5(2) 08.01.22 08.02.29 (0.24.75 08.10.76 52 37 22 13 40 N (1) 12.23.15 01.04.72 56 21 Vin> Tabic No. 42 43 44 45 46 47 48 49 SO 51 52 53 54 55 56 57 58 59 60 61 62 63 C 64 65 66 r_< 67 68 -- 3 B. CSK D. F. GB b 00. d c I.Jl 2. at. 3.pi 4. p.-: 5. fo: 6. *f?i 7 *p8. pr 9. eh. (Tables 1 refereni MjrsteJIer .'tuurcoma "Si nation' 12. 13 !4 i 13. is 17 ' !7 16 Vinyl Chlond*A*sociated Disease e1 Table 13 uontsnuedl Birth date No Country-* invd/ytb 4| Mi j; S/3t 43 S .41 06.23.2? 06.10.10 1 l.lo.l J 44 USAID 10.17.23 45 USA (2) 08.19 33 46 USA (3) 05.25,15 47 USA 14) 01.15.24 45 USA (5) 01.25.12 49 USA (6) 11.23.28 50 USA (7) 05.03.22 51 USA (8) 05.06.20 52 USA (9) 11.08.31 53 USA < 10) 08.16.13 54 USA (11) 05.27.09 55 USA< 1 2) 11.17 18 56 USA 113) 12.01.21 2 USA 116) 11.04.27 58 USA 117) 05.06 Jl 59 USAllS) 04.22.28 60 USA 119) 00.00.15 61 USA (201 08.31.17 6: usa <:i> 09.02.09 63 USA (::) 10.02.23 64 USA (23) 00.00.25 65 USA (24) 05.07.1? 66 USA 125) 08.07.10 67 USA (26) ?(1978) 68 YU (1) 04.05.14 Date ol death (m/d/yl 10.20.70 05.I9.-6 05.1 2.7* Ape at death 43 65 62 Total > earexp IS 21 31 Joli ciasMltcjtiOn' > 03-03.73 09.27.71 12.19.73 01.07.68 04.09.64 07.24.75 03.23.66 06.26.61 03 00.75 05.10.66 03.16-70 05 02.69 07.04.74 03.27.69 1978 alive 1 1.02,75 04.06.76 01.30.77 01.02.77 12.04.76 04.06.73 05.27.77 C3.10.77 7(1978) 49 37 58 43 52 46 45 41 43 55 61 50 s: 4| 43 46 60 58 67 52 50 60 67 ? (1978) 21 9 13 9 28 10 15 10 20 10 12 10 17 15 24 9(1) 17 23 19 28 4 19 11 21 21 :s 14 26 20 7(1978) 08.04.73 39 20 1.2. S a B. Belgium ND, Canada. SR. Czechoslovakia D. West Germany F. France GB, Great Britain l. Italy 1. Japan N, Norway S, Sweden USA, United States of America YU, Yugoslavia. b 00. dau not available. c l. autodave dtaner 2. autoclave operator, 3.pipe fitter 4. potytMrtter 5.fonwa 6. fUtreur' 7. `piipareteurde solution' 8. process worker 9. chemical operator lO.potymenzadon worker I l.redwdral amistent IX. nsktrasaa worker 13. millwright 14. wamr coo&agunit 15. rw Id, furnace opentor 17. machine shop worker (Tables 13-15 are compBed with the aid of information contained in the liiereture; references see Table IS) URL 12212 62 W K. Lelbith and H.J. Marste'.lrr a population of 130 000. One of the four had a history of occupational exposure to polyvinyl acetate, which has hitherto not been related to ASL. Use other three may have had nondocumented exposure to arsenical pesticides, which were used for many years in this region, but such conjectural deliberations must await further investigation for confirmation. Death certificates for the periods 1963--1973 in England and Wales and 1965-1973 in Scotland recorded 41 cases of ASL (1-9 cases per year: mean: 4 cases per year). An unexplained peak was observed in 1968/1969 {Baxter and Fox 1975V Six additional cases not mentioned on the death certificates were detected by a panel of specialists {Baxter et al. 1977). In reassessing 36 of these 47 patients for whom histological sec tions were available, the panel of histopathologists unanimously agreed on the diagno sis in only 14 cases (7 doubtful. 3 unclassifiable, 12non-ASL). For 12 of these 14 cases occupational and residential histories were obtained which revealed one un doubtedly VCM-induced case, two cases with possible exposure to (low levels of?) VCM and one case attributable to thorium dioxide. After the first three cases ofASL among vinyl chloride polymerization workerj in the United States had come to the attention of the National Institute for Occupational Safety and Health (NIOSH) in January 1974 {Lloyd 1974), this institution continued to collect information on additional cases reported to them from nations with an im portant PVC industry {Lloyd 1975-.Spirtas and Kaminski 1977). As of August 1978. data had been presented on a total of 68 cases of ASL among polymerization workers {Spirtas and Kaminski 1978, pen. comm.); another eight cases had been observed among nonpolymerization workers exposed to VCM in various jobs. On the basis of this data collection communicated to us in 1978 -- for which we wish to thank Drs. R. Kaminski and R. Spirtas, NtOSH. Cincinnati. USA - we attempted to trace these cases and their individual symptomatology as well as other relevant information pub lished in the literature up to 1979 (see Tables 13-18). The ten Canadian cases of VCM-induced ASL (cases 2--11) are dealt with summarily in rite papers published by Delorme (1978a) and Delorme and Makk (1975); seven of them were described in more detail by Ala** et al. (1976). Cases 19 and 23 were observed at our clinic in Bonn but details have only been published for case 19 (E.U. in Lelbaeh and Mamelier 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 Staariicher Gcwerbeatzt, Diisseldorf (Reinl et al. 1978), the number of deaths from VCM-induced ASL in the Federal Republic of Germany had increased to 16 by the end of 1978, to which we now add a 17th ease (Figs. 8 and 9). In retrospect, it was discovered that the first case ofVCM-induced ASL had already occurred in 1955 in a Canadian polymerization worker. For the 67 VCM polymeriza tion workers for whom details were available, total yean ofexposure ranged from 4 to 31 years (mean and median 18 and 19 yean, respectively). In comparison, mean dura tion of exposure in our group of 17 individuals with advanced notunalignam liver dis ease (see Table 11) was 10 3/4 years (range: 3 1/2-2! yean). The latency period (years from first exposure to of ASL) ranged from 9 to 38 yean (mean and median: 21 yean). The average age at diagnosis ofASL was 50 yean (range: 37-71 years). et z z n u n Tabic 14. Clinical and morphological data on nH polyvinyl chlomlc <1*VC) production workers with angiosarcoma <<l (he liver reported to NIOSII by August 1978 V'iny md HJ. Marsteiler mal exposure co other three may re used for many urlier investigation n and 1965-1?"? cases per year). An Six additional nei of specialists u histological sec;sd on the diagno12 of these 14 . fakd one un* t low levels of?) 'zanon worker? in te for Occupational xtitudon continued itionj with an im > of August 1973. icnzation workers been observed .. On the basis of >li to thank Drs. * cd to trace these .formation pub* dun cases <f . rs published by described in our clinic in Bonn td Mentttter 1977). <1,53-67 and i Oewerbeam. luccd ASL in the 078, w which we v*d ASL had already VCM poiymerizaat imped from 4 to nanaoa,mcm dun* msdfnant Uivt dislatency period l8 ytaa (mean and f*(<Ufe: 37-71 'inyi Chlondt-AHociated Disease ] V1 j 1| 1 V u t>i 2 22 5 y is A5 '2 9 V c 4 35 a 55 9 5* A aV 9 ye 59 >A TP Sv " a <1 1 t* il 2 fV 3 Z m =* S . |II|| Z55 si** s 1S n*- i! H Cs 9-- 6. S *0 ~tx f + Spleno 0 <2700 g) nicgaly MSS g) Focal perisinusoidal Vjn-vJ ChJor. W.K. Lelbawh jnJ H.J. Mai'.ieller ' J. Mantel let Vn.yl rMonds-Aisociau'd Dtsea-c 65 m a rtcii flltrm h (51 000) 68 W-K. Lelbach and HJ Mjr<iellvr Tabic IS. Publication* on the 63 cases of angiosarcoma of the liver lifted in Tables 1 3 and 14 No Reference* Hubiet et al. (19771 Additional relevant information Hypertrophic, hyperchromatic and ji\ pical endothe lial cells in the glomeruli; toci ol haematopoctic cells in liver and spleen Delorme and Makk 0975) Makk el al. (1976) Delorme ( 1978a. b) Delorme and Theriault (1978) Case no. 7: ASL associated with hepatocellular carcinoma {Delorme 1978b) (All eases from one plant in Shawinigan. district Trois Rivieres. Quebec) Schmidt and B&tora 0 976) 141 Lange et al (1974b) is ii Cedigk et al. (1975) 16 Gokel et al. (1976) 17 Amann 0975) Riibtamen 0976) 18 Reinl et al. (1976) 19 (Observed in Bonn) :o Reinl et al. 0 976) :i Reinl etal. (1977) 22 Reinl et al. (1977) 23 (Observed in Bonn) 24 Rarier et al. (1975) 25 Roche et *1.(1978) 26 Rely ct al. (1976) At the same plant: 4 cases of VCM^nduced cirrhosis of the liver plus 1 case of cirrhosis and generalized reticiilosareoma and 4 cases of carcinoma of the Cl tract or lunes See also Reinl and Weber {1974) See also Reinl and Weber (1974) Foci of haematopoesis within the tumour areas 1974 portocav^J anastomosis: cholecystectomy Hypenropluc. hyperchromatic and markedly atypical end .'ihelial cells in the glomeruli and in the capillaries of the lungs Moderate hepatic siderosis: chronic fibrosing pancrea titis: tubular and interstitial fibrosis of the testes Focal interstitial fibrosis of the pancreas See also Berrod etal. (1978) 1942 gastrectomy. 1974 splenectomy, right hepatic lobectomy (640 g). See also Roche (1977): Butch et al.(1977);9Riief9ft et al. # 1975. !9??);4errorf et al. (1978) No autopsy (see also Berrod et al. 1978) Vinyl Chi Table IS u No. Re> R :8 Ro. 29 Ro 30 \ 3312 1i' Bet 33 ) 34 33 35 Le Srr. no ro 36 37 38 39 40 41 42 Ms - ByByr. 43 - 44 ! (ca-- 45 Bio (ca . 46 Sir. (ca  -'filer :i IJt -- iotlie(.'fils i TllOSIJ f 01 ; pical (UUines Mirto - n-patie *tck ct * td et VinylChlori4e>A*S0cuied Disease 69 Table 15 'continued! No. References n Roche tx al t 1978) :s Roche erjl. (1978) 29 /toerie et al. (1978) Additional relevant iniormaiion Chronic alcoholic. See also Roche i 1977): Puech ei 41. n977>:aerroJe: al. (1978) First symptom vertebral and costal metastases Rifft? hepatic lobectomy. See also Roche < 15'~).Puech et al (1977). Piiiehowski et al. 119791; Coudere e: al. (1976).BerroJ et al. (.1978) 1960 sclerodermaiike skin induration (hands), swell ing of face. upper extremities and test. 1971 bilateral ecrootttolyas. Tumour penetration of the abdominal wall (fistula). Severe interstitial fibrosis of testet: fibrous of interstitial wall; slight mesangial fibrosis of glomeruli. Variable but generally slight fibrohyalinosis of arterial and venous vessel walls (skin, heart, lungs, intestine, testes) 31 s: 1( Berrod el al. i 1978) 33 ? 34 Lee and Herry (1974) 35 Smith et at. (1976b) Latency period (1st exposure -- death) only 8 years (see also Fox and Collier 1977) 56 Mutant f 1974) 37 38 39 - 40 41 Syren and Holmberg (1975) 42 Syren et al. (1976) 43 44 Block (1974) (cate 3) 45 toc*<1974) (CM 2) 46 *tec*(1974) (CM 4) 1965 portoeaval shunt. 1970 cholecystectomy. See also Folk 4t aL (.1974a) (cam 4); Whelm etai-tl 976) (CM l) No autopsy. See also Owe* end'Johnson (1974); Aft ct cL (1974a) (cm 3); Whelm et aL (1976) (cm 2);Jfc** ct aL (1976) (cm 6) Set also Falk ct at (1974a) (cm S); Mekk et al. 119?6) fCM 10) 70 Table 15 (continued) No. References 47 Block i\ 974) (case 1) 46 Block (1974) (case 5) 49 Block(1974) (case 6) 50 51 - 52 ktte(anetal.(l976) (case 3) 53-67 68 Zonca et al. (1975) W.K. Lelbjch and H J Marxteller Additional relevant information See also Fa/* et al. < I974ji tease 2 );Makk et jl. (1976) (case 4) See also Falk et al. (1974a) (cave 1): Makk et al (1976)(case 2) See also Falk et ai. t 1974j) cac 6): Whelan et al. (1976) (case 4>; Makk et al. M9?6) (case 14) V Chronic alcoholic. See also Makk et al. (1976) (case 13); Berk et al. (1976) (case 2) Among a work force of 18011 20. PVC polymeriza tion; 60, production of VCM) employed at this plant. 15 died of malignant disease (2 ASL. 5 bronchogenic carcinomas. 1 case each of carcinoma of the larynx, rib, mamma, spermatic cord; glioma, melanosareoma. leukaemia. Hodckin's disease) First exposure to VCM for these 67 cases of ASL dated back to the period ] 9391966 (median: 1951).Twenty<ne yean later, i.e. from 1973 onwards, a gradual in crease in the number of new cases diagnosed and reported to NI05H can be observed (Fig. 7). the onset ofthis gradual increase coincides with the calculated mean latency period of 21 yean (Spinas and Kaminski l971).Spirtas and Kaminski also suggested that in future cases the age at diagnosis and the length of the latency period may in crease as a result of the later reduction in levels of exposure. From the synopsis in Table 13-16 it can be seen that in about two-thirds of (he cues of ASL for which morphological details are available varying degrees of associat ed hepatic fibrosis in nontumorous areas ofthe liver were mentioned. Less often, evi dence of portal hypertension and splenomegaly were noted. Metastasis of angiosarco ma to distant sites was observed in approximately half the published cases. It n of note that acroosteolysis and cutaneous stigmata ofscleroderma have been observed in only 1 of those 76 patients, a French PVC worker who had apparently not been engaged in reactor attaining (care 29;&ocht at al. 1978). Another noteworthy piece of informa tion is that strikingly atypical endothehal caSa with hypertrophic and hyperchromatic nudd have also been found in organa other then the Uver (Iddneys, lungs) in autopsy material from two patients (cases 1 and 17,/fuWrr et al. 1977\Ribsemen 1976). Hubkt et at (1977) also found such ceQs in tha myocardium and in the adipose tissue enveloping the adrenals. All this may lend support to the idea that the effect of VCM metabolites is not restricted to the vascular endothelium of the liver and spleen. Angio- xzzi ion i 9 n k nu 'Ianteller a! al. -t al. o lew nema`m piant -itogemc . jryn.x. arcoma, 11030uai m- vrrd 1 latency *fi*sted oay in- wt die - assodat'cn.evi- esarco1 of note i in only nppd .rinforniahromatic autopsy 76). -tv* tissue ofVCM cn.Angio- Vinyl Chloride-Associated Disease Table 16. Personal data on eight eases ol angiosarcoma of the liver among VCM-exposed personnel nor employed in PVC production (a* reported to NIOSH bv August Date ot Birth dale death No Country fm.d im/d-y) A Dl3) OT.16.30 10.10.73 8 D<6> 05.09J6 12.16.74 r GB (2) 09.08.U 12.00.70 D 111) 06.15.J4 04.16.71 E SC) 11.27.11 08.16.71 F USA (IS) 00.00.2S 02.13.73 C, Vl'C) 11.15.31 07.12.73 H YU Cl 12.21.31 01.11.76 Total Act at years death exp a3 1 4 38 3.5 55 11 36 3 61 23 47 * 42 18 45 ioh classification Loading pesticide cans with VCM propellant Assistant factory chemist Pouring PVC oil mix ture onto fabric bases Fabrication of PVC fades and wrappings (extrusion at temperaturn of 120*0 Assistant factory chem ist (production ofVCM) Accountant at plant producing PVC fabric Production of VCM Production of VCM a Update of NIOSH register, August 19T8. prepared by Ktmbuki as in Table 13. * 00. dau not available sarcoma arising from the kidneys or other types ofmalignact renal neoplasms, how ever, have not been described in VCMwxpoeed individuals, although malignant nephro blastoma has been induced in experimental animals. The extremely rare coincidence of angiosarcoma and hepatocellular carcinoma was found in Uuee instances (case 7,Debrme 1978b: case Z,Syria ud/foimberj 197S, and a case not included in the 1978 NIOSH update Tamtnirro ct al. 1978a). In the am reported by Ttmbvmo et aL chronic alcohodun may have played a cofactor role h> the development ofliver cancer. We can now add a fourth cam observed in 1978 at the Department of Medicine in Bonn (see Sect. 4.14 and Fig. 3). This patient (patient 9 in TabH Ilk a PVC-pofrmetttarioo worker (total period of exposure: 18 yean) was ftm admitted to our department in February 1973 and w fowl to suffer from atyp ical cinhorif ofthe fiver with portal hypertension, gplannmply and Raynaud's phe nomenon. During follow-up ASL eras dfcucafiy suspected but could not be confirmed during life,despite exploratory laparotomy ind generous surgteai bioprics. The patient Munu-IJcr Vinyl CliionUc-.-Wiocured Disease Table 18. Publication* on the eight case* or jngiosjrcoma or' the liver listed m Tables 16 and 17 So References Additional relevant information A RtirtJ and h'eber l|9?4) 196 7 idiopathic portal hypertension iporcocaval shunt 3 Zmuntrmann and ek |9"3 right hemtnephreccotny for un-date-sl hydro i19"Si nephrosis associated with bilateral double kidney Rttnl 1197$) Foci oi hacmatopoetic cells in spleen and kidney Fibrosis of the pancreas. Slight fibrosis of testes and of the small intestinal serosa C 0 .1taltom (1974) Autopsy angiomatous epulis. Angiosarcoma involv ing liver. lungs and pericardium. The pericardium might have been the primary site! E Byrin and ffolmberg Probable coexistence of a hepatocellular cancer of t1975) both low and high grade differentiation G Zones et al. f 197S) H - died on 7 August 1978. alter a massive haemorrhage from oesophageal varices. Autop sy revealed both multicentric metastasizing angiosarcoma and hepatocellular carcino ma of the liver as well as slight fibrosis of the pancreas (to be published in detail). It is stfll unexplained why bepatocytes an generally exempted from the carcino genic effect of VCM metabolites but. as predicted by Popper in 1975. three anecdotal cases of hepatocellular carcinoma, one German (Gokeiei al. 1976) and two British PVC workers (Fox and GoBier 1977), have now also been observed after exposure to VCM. It may be mentioned that a review of the distribution of primary liver cancer in the Province of Quebec covering the period 1969--1972 showed a preponderance of adult male cases in urban areas clustered in the district ofTrots-Ririere in congru ence with die distribution of the plastics industry, a coincidence which ealls for further investigation of a posibk exposure to industrial carcinogens (Jacob and Thehatiit 1975). . Sot Included in the NIOSH register an several aneedotal cases of ASU capGUry and cavernous angiosarcoma of the liver and hetmanyjosatcomatoeis ofsites other than the liver, for which a relation to occupational or even possibly reddentill exposure to VCM has been dlscumcd (Mw* et aL 1977;M> et aL 1977;Ubr aL t97S; fctefr nd/iar and Zbtmfi 1977). Although ofundetermined reievsice. It should flnafly be mentioned that, in addi tion to hepatic fibrosis, varying degrees of tnttmitiaJ fibrosis of the pancreas were noted at autopsy in four German workns (cases 19,23, B sod the aboveenentioned w z z n a ft 74 W.K. Lelbach and H.J. Manteller patient with both angiosarcoma and hepatocellular carcinoma). Fibrosis of the testes was observed in three cases (19.29, B), and Roche et al. (1978) also reported fibrosis/ hyalinosis in vessels of skin, heart, lungs and intestinal wall. CUMULATIVE N* OF CASES REPORTED TO N10SH O' h. ar fo P: $e Pr gr ar. 19 be an me st. tio re;det aru In na1 no: Wi' C DO ro rv vi Fig. 7. Cumulative number of cases of ASL among PVC production workers reported to NIOSH up to August 1978, arranged according to year of diagnosis I data from Sptms tad Xemiruki 1977, 1978) 43.2 Clinical Manifestations The clinical symptomatology ofusually multicentric ASL is unspecific. Gradually dedintag general health end loss ofweight combined with fll-defined upper abdominal discomfort and slight epigastric or right upper quadrant pain an usually the first symptoms. Recurrent bleedings from oesophageal varices may have been antecedent events in patients with portal hypertension who otherwise felt fairly well, (n a number **.=* -*CWy* 11 timteller ' testes fibrous. Vir.j I Chlonde-Ass^-iaied Disease *5 ot cases, the tumour tint came to sttenoon with massive, often fatal, intraperitonei! haemorrhage. Important tender hepatomegaly fhepatosplenomegaly), slight jaundice and occasionally development of moderate ascites and oedema wn observed. Except tor mild to moderate hyperbilinibinaemia. some elevation of serum levels of alkaline phosphatase and jmmaelutamyl aanspeptidase and only slightly abnormal levels of serum transaminases, the spectrum of biochemical tests is hardly revealing. Aipha-fetoprorein determination has not been helpful in the diagnosis. Ultrasonography, scinti graphy, hepatic angiography and, notably, computer tomography of the upper abdomen are the diagnostic procedures of choice if ASL is suspected. A technetium-"1* -liver scan visualizes intrahepatic tumour defects (fiienack et al. 1977b) together with abnormal splenic fixation, but peripheral defects of uptake may be difficult to interpret (Mieiart et al. 1976). Characteristic features of angiography ate a normal-sized hepatic artery with possible displacement caused by tumour enlarv ment. e cenain degree of central hypervescularity of the tumour, a peripheral tumour stain, and puddling ofcontrast medium pernsring into the late venous phase. In addi tion, varying degrees of peiiosi! hepatis may be obmrved in some cases. However, even repeated hepatic angiography may fail to confirm the suspected diagnosis, as was evi dent in one case reported by Roche et al. (1978). The example of a 54-year-old polymerization worker who died of metastasizing angiosarcoma of the liver in February 1960 may serve to illustrate the clinical course. In 1972/73. after an exposure of 18 years' duration, wc found him to suffer from Ray naud's phenomenon and noncirrhotic portal fibrosis and portal hypertension with sple nomegaly and moderate thrombocytopenia. Despite texnanstion of exposure, there was progressive splenomegaly and development of massive oesophageal and gastric i W.K. Lelbuch and H.J. MarsMUr 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 widt recurrent eptsuxis and slight but permanent epigastr.c and upper right quadrant pain, but declared that he felt otherwise fairly well. He com plained about a sharp localized epigastric pain on sneezing. There was marked spleno megaly, and an ill-defined hard mass was palpable in the epigastrium. Apart from mod erate elevation of alkaline phosphatase and borderline hyperbilirubinaemia, biochem istry was normal. Computer tomography showed a large irregular hypodense tumour mass in the Liver, involving both right and left lobes (Fig. 8). which became practically isodense after intravenous injection of contrast medium. A liver scan corroborated the tumour defect. Shortly after this there was mounting evidence of brain involvement and rapid deterioration. Computer tomography now revealed multiple brain metastases (Fig. 9). Autopsy confirmed the tentative diagnosis of metastasizing angiourconu of llu.. /C: 1 m 78 W K. Lelbacli and H.J Marstcller 11 months after peritoneoscopic diagnosis of severe hepatic fibrosis (case 19: see also Leibach and ManteUer 1977). In addition to the findings described in connection with hepatic fibrosis, there may be hypervascularized or cystic tumour formation risible on the surface ofa nodular, qimi-drrhotic liver, or a gross aspect resembling hepatic metastases if the vascular malignancy involves the superficial regions of the liver. It should be stressed here that needle biopsy is absolutely contraindicated if there is any suspidon of ASL. 4.3.4 Gross and Histological Morphology The liver Is usually markedly enlarged. Liver weight in cases of ASL ranged from 1600 to 7300 g (77iomej and Popper 197S;Jtocfeeet al. 1978). The gross appearance of angio sarcoma of the liver is mostly that of large bulky, irregularly duped cystic tumour masses; a multinodular form with numerous, sometunes umbiUcated nodules, is less often encountered. Extensive haemorrhagic and necrotic areas or solid and spongy por tions of tumour tissue replace much of the liver parenchyma. Rupture of large cavern ous cysts mey cause fatal Intrapetiioneal haemorrhage. Thome* et al. (197S) and Thomas and Popper (1975) distinguished four basic devel opmental patterns ofhistomorphology of ASL, which can be found in different por tions even of the same tumour and appear to represent stages of progressive evolution: sinusoidal, papillary, cavernous and anaplastic patterns. Indistinct areas of transition and merging of patterns can be observed. Dilated sinusoidal spaces lined by hypertrophic and hyperplastic sarcoma cells with pleomorphic,elongated, hypejchromatic and often bizarre nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells of varying differentiation envelop liver cell plates and may invade enlarged and fibrosed portal tracts, accompanied by proliferation of bile ductules (Fig. 11). In papillary angiosarcoma atrophy ofliver cells results in larger and more irregular Mood-filled vascular spaces, into which loose papillary strands of surviving hepatic cords on an axis of connective tissue project, lined by sarcomatous cells (Weinbrvn 1976). Even larger blood-filled spaces are seen in the cavernous type, where they may be surrounded by thick fibrotic walls. In a smaller percentage of cases,solid areas or nodules oCanepksric sarcoma are found, resembling solid spindle-cell sarcoma, or even suggesting an epithelial type of tumour. Gedigk et al. (1975) also observed a reticuloaarcoiiialike pattern. The differentiation of the tumour cells varies widely: it ranges from the inconspicuous endothelial lining cell type to irregularly shaped, grosriy distorted giant<eD forms. Morphologically, vinyl chloride-related ASL cannot be distinguished from ASL associated with ocher aetiol ogies] (acton or from the cryptogenic type {Popper et al. 1978). In tumour-free portions of Uven with angloureoraa widely varying degrees of ex ecs formation of fibrous connective tissue are usually observed, analogous to that seen tat nontumorous liver* ofheavily exposed persona. Fibrosis of enlarged portal tracts with modest proliferation of bfle ductules, mostly only scanty infiltration of lympho cytes and occasional formation of perilobular septa or thin connective-tissue septa ex tending into the lobular parenchyma can be found. A more or less conspicuous intra lobular, perisinusoidal fibrosis is often detected only by special staining methods for collagen or reticulin fibres. As a rule, irregular focal or nodular fibrotic thickening of C r\j co * J* * ^ 4>' *. >' * Fit U*< nu. pci In- of < !>.; Thv or <: lifer old* i plait incr retu cyu? degcretR r crea> 'i; Mameiler ' 19: set also nnccOon with I non visible on hepatic me* liver. It should a any suspi- from 1600 to met of angioric tumour iuies, is less md spongy pot* flarge cavern* itor basic devel* lifferent por* mv* evolution: of transition -yma cells with teriae the ving differen cial tracts, acarcotna atro* > spaces, int-* -qiactive tissue tilled spaces . Abiotic walls. Mna art found, pe of tumour, -ttferenelation of KiUal lining cell rically, vinyl ' other aetiol* degrees of *x nato that seen portal tracts v>m oflympho* rinse septa ex* picoooe httra* : methods for ihickening of Vinyl Chlondc-Ajsociated Disease 70 Fig. 11. Angiosarcoma of the liver (upper pvt of photomicrograph) invading adjacent Uvr parenchyma (case l*)Dl ;seeTWe 13). Note hyperplastic andhyperchromatic nuclei of proliferating neoplastic lining calls enveloping hepatic cords. Reproduced by permission. Ann NY Acad Set 2-*6:37S-ZB5 (1075).Courtesy of Professor Gedigk, institute of Pathology. University of Bonn. fUE.x 250 of CUason's capsule is present: these fibrode capsular areas may extend into the under lying parenchyma and may connect with adjacent enlarged subcapsular portal tracts. The cefiular and nudesr rize ofhepttocytes may vary widely; groups ofbinodeared or even oultfaiudear parenchymal cells with abundant eytopiaara are seen. Focal pro* mention ofsinusoidal tining eeils may be encountered, --p***ty within foci of sinus* oidal dftatahoa. In connection with conspicuous sinusoidal dilatation, two types of focal hyper* plasdc precursor lessons were described by Popper et aL <1978): 1) Poorly circumscribed foci of hyperplastic, often binudeated hepatocytes with increased number ofvarious sinusoidal Hiring cells and only butgnificant increase of reticuhim framework. 2) Almost nodular areas ofcorupicuoutiy hyperplastic and hypertrophic hepatocytes with more pronounced variation ofmarkedly Increased rinuaotdal cells without defineration nr nocturia ofttver parenchyma, but gecompenied by emra formation of lericuhta fhumwork md completion ofsurroundiag parenchyma. The tranktion of sinusoidal (hung cells to angiosarcoma calls is characterized by in creasing etypia and anaplasia of chase proliferating endothelial calls accompanied either c: n ro ro u> o so W.K. Lclbach and H J. Mar<teller by formation of excess connective tissue or by accentuation of sinusoidal dilatation leading to primary petiosis. Involvement of portal areas in die evolution of angiosarco ma results in considerable fibroplasia and formation ofhyalinized collagen together with proliferation of bile ductules. In occasional cases connective tissue bridging be tween portal tracts or between portal tracts and central veins with subdivision of lobu les followed by rearrangement of hepatocytic plates may kad to a cirrhosislike picture 4 J .5 Therapy The multicentric development of ASL {Thorns and Popper 1975) as well as $e dif fuse spread of the tumour usually encountered by the tune of diagnosis precludes ef fective surgical or radiation therapy in the majority ofcases. A survival period of two yean after surgery {Berrod et al. 1978) or chemotherapy {Daiinaher et al. 1979) is a rare exception. Results of systemic chemotherapy studied in a small group of five pa tients showed that, at best, quality and duration of survival may improve to a very limited extent (Dannahcr et al. 1979). At present, no generally accepted guidelines for chemotherapy are availabk. 4J.6 Risk Assessment When in the United States 13 white male cases of ASL had been detected from 1961 to May 1974, among an estimated total population of VCM 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 of03)14/100 000. This would have meant only about 03)3 cases per 20 000 polymerization workers within a 10-yeir period. Dose-response and attendant biotransformation data on experimental animals luve since beet used to elaborate sev eral different models ofextrapolation to man. These were calculated with reference to relative body surface areas, for estimating the risk of ASL in human populations ex posed to VCM and for establishing guidelines to assist the research for Realistic safe doses' that do not affect the average lifespan of a person exposed (Schneiderman et al. 1975; Gehrtnt et al. 1979,1978: Woods 1979). Cekrittf et al. (1979) consider a probit percent model to be areliabktoo! for risk prediction, which works without the assump tion of a threshold. They predicted a cancer risk of 1.5 cases of ASL in 100 000 000 wotken on exposure to the currant National Standard in the United States of 1 ppm VCM 8 h/day, 5 days/week, for a 35-year working life, an incidence which does not significantly deviate from the spontaneous incidence rate. A linear model modified by adjustments for differences in the rate of inhalation, flistribuoon. metabolism, cell proliferation and tumour latency times between rats and humans was described by Woods 0979).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 Mima! experiments to man and from high- to low-level expo sure and the problem of threshold doses has been voiced {Almtg/i 1978 -.Hooper et cl. 1979:c/inei/ennafi 1979: Weigcrt 1979:Rcirretal. 1979). Vin> R. (exci ASL This the l conii had d the rv polyr was o viron: ceede lesser magnr ting.: millior vinyl c model the esi grour 4J.7 For a ' hazarJ jP the cc Jtudk *urc t . w thclual. 19ftfo.vuof Bn: 1976.: posed et al. I voiced Berry . empk and cj1 but no 1976) In . (1974. epideni (1978) facton- teUer ion -arcoher hr lobuicture. dif;s ert'two i is a ip*O ilia for 1061 \ers of non of data ' i. iU-ci per mlant ue sev.-nee to t exraft cet al. t probit slump* -0 000 I ppm < not fed by <v9 (by waiken iity pf 1expo-ct eL >'inyl Chloride-Associated Disease $1 Results of a recent survey by Brady *t al. (197?) indicated that for New York State (excluding N'w York City), a liigiiiy industrialized area, the annual incidence rate of ASL during the 6year period from 1970 through 19*5 was 0.25 per million residents. This considerably exceeded the national average rate of 0.14 per million per year m the United States. In a concomitant caseoontroi study. 26 patients with histologically confirmed ASL were found in the study area from 15S to 1975. and 7 of these had had documented long-term exposure to either .As. ThO; or VCM. Five (all female r of the remaining 19 patients lived at a distance of 500--4500 feet from VC tabrisation or poiymenuuon facilities for long periods. No pertinent exposure or residential history was obtained from the other 14 patients. Discharge of unreacted monomer into the en vironment as result of losses in the PVC production process was estimated to have ex ceeded 200 million pounds annually, most of which escaped into the atmosphere with lesser amounts dissolved in water effluent (Schreiner ] 975). Concerning the order of 'magnitude of ambient exposure beyond the work place. Le. outside the industrial set ting, an average annual exposure concentration of 17 ppb was estimated for the 4.6 million persons throughout the United States who resided wttlun a 5-mfle radius of vinyl chloride emission sources (Kuvnack and McGaufhy 1975). If the risk assessment model elaborated by (foods (1979) is applied to this population of* million people, the estimated incidence of angiosarcoma per year would not be above expected back ground levels. -i 2.7 Mortality and Cancer Morbidity Studies For a tumour disease as rare as angiosarcoma of the liver even quite small increases is hazard over background levels should be detectable (DoB1975). The situation with the common types of cancer is fur more difficult. Since 1*974 a number of mortality studies of VCMexposcd populations have suggested that in humans long-term expo sure to VCM may also be associated with cancer ofates other than the Uver. notably the lungs, and the lymphmfc md central nervom system (Moruon at aL 1974: On ft at. 1975: Ttbenkgw mi Omffey 1974-^Metee at aL 1975; Watontr tt aL 1976: WexweOer*t al. \9H\Nthobax l9T?\BuffkrnaL 1979). Epidemiological studies *~~ ofBritish workers failed to confirm this sugginlon (Dock ct aL 1973:ftoe* and Carter 1976;fox and CoKtr 1976,1977). as did a prospective study of a VQ1/PVC-ex pand cohort of 1618 employees of a Vest German ehemieal plant (FrtnncLBermt at al. 1978). Criticism ofdesign and Interpretation ofsome ofthe sauries has been voiced (Fatk at al. 1974h;Amehese and MBleoisorr 1974;Aryr 1977;De4/erop 1975: Berry and Rentier 1976). A follow-up of aS VCM-exposed persons (750 traced) ever employed at the ooeSwedbh factory, which started operation in 1945* for mortality and cancer morbidity patterns revealed a fotafouid excess of panaeas/Dver tumours but no deviation in the number ofbrain from the sxpectad level (Byrin at al. 1976). In addtion to the three extrusive,mortafity attdias ofThboshaw and Gtffey (1974). htorwriferet L (1976), and /bur and CotBtr (1977), a fourth comprehentive epidemiological study ifttml and Weber 1976) was completed in 1977 by Rttni *L (1978). which tndudod three study populations from 11 VCM* and FVC-produdag factories in the Federal Republic ofGermany* covering the period from before 1959 URL 12232 91 W.K. Lelbach and H.J Marctelfer through 1974: (a) 7021 workers engaged in the production of VCM and PVC; (b) 4910 chemical workers from the same plana not exposed to VCM; and (c) 4007 workers engaged in PVC manufacture. Not included were non-German workers of Mediterranean origin. This German study permits comparison not only with the mor tality ratio of the total male population but also with a comparable occupational group exposed to VCM. With regard to the *healthy worker effect* (MeMidiael et al. 197$), overall mortality was elevated for the VCM-exposed population (group a), but not for the other chemical workers (group b). Apart from the markedly elevated stan dardized mortality ratio (SMR) for malignant liver tumours (J 523). which proved to have been closely related to the duration of exposure, a significantly elevated SMR was found for tumours of the lymphatic and haematopoetic system (214). The group of chemical workers not expoaed to VCM (b) also showed a significant elevation of the SMR for liver tumours (401), a result that deserves further investigation. No signifi cantly meremed 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 plana: in the second plant in elevated SMR (434) for fiver tumours was found. At present, there is no explanation for the increased SMR for accidents found in the VCM-exposed population, particularly during the period 1970 through 1974, about 40% of deaths having occurred in ex-PVC workers. A recalcufatjon 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 ezreinembryonic antigen litre (CEA) in 200 Canadian PVC production workers (mean duration of em ployment: 10 yean) showed a more than thKcioid higher frequency of levels above 10 ng/ml than in a normal healthy population (1.7% vs. 0.55) (Page et al. 1976). Levels of CEA were also determined in 1363 workers of five Afferent VCM polymeri zation (3) aad PVC processing (extrurion) plana (2) in the ttated States (Andtnoii et al. 1978). After removal of possible confusing factors (smoking, alcohol intake, past medical history), it emerged thet the distribution of CEA litres among the polymeriza tion workers was significantly different from that in the extrusion plant group and in a nonexposed reference group. Significant differences woe also found for two of six job categories examined (polymerization and jothtenance) compared with extrusion workers and the reference group. However, Ibe usefulness ofrite CEA titre as a predic tive indicator of possible increased risk seems doubtful. 44 Miscellaneous Aspeca 44.1 Thrombocytopenia and Ratelet Function Tcsas Thrombocytopenia in chronic VCM intoxication was first mentioned - rather paren thetically aad without further comment -- in a paper pnbllriirrl by AHton%ttzheko in 1968. Liter JSht et al. (1973) noticed thet each of the first 13 autoclave deaners re ferred to them during 1972 from a West German plant because of suspected skin and v, b<' Bo tio ce; or we oi. th. dei ph. ou. fab b. Up. har re: 1 o; cou C 3D N3 fsJ OJ lO Of I, in f al. i` cvi or . xyr. Tj w. tin- A B C O a peaprelitre limi FU< The