Document 4Je9n7BGV3oYn4y7njM32BgYR

* * t r Ergebnisse der Inneren Medizin und Kinderheilkunde 4/ Advances in Internal Medicine and Pediatrics Neue Folge Herausgegeben von P Frick G.-A.von Harnack K.Kochsiek G. A. Martini A. Prader Mit 24 Abbildungen und 23TabHen Springer-Verlag Berlin Heidelberg New York 1981 ucc krj 046873 Vinyl Chloride-Associated Disease W.K. LELSaCH and HJ. MARSTELLER 1 1 introduction...............................................................,....................................... ; 2 Technoiopcal Details............................................................................................ 2.1 Vinyl Chlonde Monomer (VCM)................................... ,........................... 2.1.1 History............................................................................................... 2-1.2 Production oi VCM............................................................................ 2-2 Producoon of Polyvinyl Cliionde i PVO..................................................... 2.2.1 Technology of Polymerization.......................................................... 2 2 2 Methods of Polymerization................................................................ 2 2J Compounding ................................................................................... 2.2.a Sources of Exposure to VCM is PVC Production.......................... 2 2 5 The Explosion Hazard....................................................................... 2 2.6 The Odour Threshold \.................................................................... 2.2.7 VCM as an Anaesthetic Apnt.......................................................... 2-2.8 Effects of Acute Overexposure is Man............................................ 2.2.9 Monitoring VCM Concentrations in Working Areas.................. . 2 2.10 Exposuie to VOi in PVC-Proccssingl-Fabncatingl Plants.......... 2.2.11 National Standards for the Control of Exposure................... 2.2-12 Exposure to VCM Outside the Working Area................................ 4 4 4 j s 6 ^ g 3 9 io 10 |l 13 15 17 18 3 Toxicology of VCM............................................................................................... 3 I Acute Toxicity.............................................................................................. 3.2 Chronic Toxicity............................................................................................. 3 J Oncopme Properties.................................................................................... 3.* Toxicodynamics ......................... 3.4.1 Uptake and Distribution................................... .*............................. 3 4.2 Metabolism....................................................................................... J.4.2.1 Rclaaon between Ciemical Structure. Reactivity and Mutapnie or Carcinogenic Effect.............................. 3.4 2.2 Meubolic Pathways............................................................ 21 21 21 22 24 25 26 26 26 4 Clinical Spectrum.................................................................................................. 4.1 The Triad: Raynaud's Phenomenon. Pscudaaclerodemu and Acroosteolysis ............................................................................................... 4.1.1 Familial and Idiopathic Acrooetcolytis........................................... 4.1.2 Epidemiology of Occupational Acroomotysia.............................. 4.1J Clinical and Roentgenological Feature*.......................................... 4.1 J.l Occupational Acrooateotysis............................................. 4.132 Psrudoscierodcrma............................................................ 4.1.4 Hatotogy............................................................................................ 4.1 4.1 Cutaneous Lesions............................................................... 4 1.4.2 lone Lesions...................................................................... 4|J Artenography. Capiiiaroscopy. Infrared Thermography.............. 4.1.6 Immunolopeil Studies..................................................................... 29 31 34 34 36 36 31 39 39 39 40 42 I Department of Medicine. Director: Prof. Dr. IIJ. Dcngier. University os' Bonn. FRO \ t c X. W.K, Lelbach and HJ. Mantelkr 4 | 7 Pathogenetic Considerations.......................................................... Non-malitnant Liver Disease in Vinyl Chloride,Tolywiyl Chloride Production Workers......................................................,*.............................. 4 2.1 Clinical Manifestations of Xon^nalignant Liver Disease............ 4.2.2 Laboratory Findings....................................................................... 4.2.3 Gross Inspection oi the Liver and Spleen...................................... 4.2.4 Histoloiy.......... ............................................................................ 4.2.4.1 Hepatic Fibrous............................................................... 4.2.4.2 Sinusoidal Lininc Cells..................................................... 4.2.4J Hepstocytcs....................................................................... 4.2.4.4 Histoloiy of the Spleen................................................... 4.2.5 Pathophysiology of Portal Hypertension...................................... 4.2.6 Followup of Non-malignant VCM-induced Liver Disease.......... 4J Angiosarcoma of the Liver......................................................................... .4.3.1 Epidemiology................................................................................... 4.3.2 Clinical Manifestations........................................................ .... 4.3 J Peritoneoscopy................................................................................. 4.3 4 Gros and Histological Morphology................................................ 4JJ Therapy............................................................................................. 4J6 Risk Assessment............................................................................... 4.3.7 Mortality and Cancer Morbidity Studies...................................... 4,4 Miscellaneous Aspects...................................................................... 4.4 1 Thrombocytopenia and Platelet Function Tests......................... 4.4.2 Central and Peripheral Nervous System......................................... 4 4,3 Pulmonary Changes......................................................................... 4.4.4 Genetic Effects of VCM.................................................................. 5 Conclusion and Outlook..................................................................................... References.................................................................................................................. 44 44 43 49 jn 31 jl <4 34 $4 53 J7 57 57 74 73 78 $0 10 81 82 82 84 85 87 88 89 Key words: Aeroosteolym - Ang-osareoma of the Later - Portal Fibrous and Portal Hypertension - Pscudosckrodtrmo - Raynaud's Phenomenon - Vinyl Oilonde 1 Introduction The history of vinyl chlonde-assodated disease, its recognition and prophylaxis is a classic example of shutting the stable door after the hone has bolted. It should help to emphasize the need to shift our attention to preventing exposure from occurring rather than to reparative measures. In view of the large number of new and potentially hazard* ous chemicals introduced each year into the workplace and the environment, this ac count should again alert us to the necessity of pretesting chemicals adequately for their potential health effects, even at the risk that technological progress will develop at a more modest rate. Large-scale production of the synthetic resin polyvinyl chloride (PVC), a thermo plastic material suitable for the most widely diversified industrial use, was begun around 1930 in the United States and in Germany. The monomer, vinyl chloride (VCM), a rather simple aliphatic compound, was believed until the early 1960s to be Vinyl Chlonde-Asso. one of the least harm later turned out, had evaluation of acute ef to reveal its carrinoge might have continued place, considering tha: vapour phase under ar reactive double-bond. Today vinyl chlon formation and data or cisely a quarter of ace tributable to this new with the shocking disc uon workers heavily e ing that the monomer pound did not alert th in workers enpged in lished in 1949 (Trtbuk Ultimately, it was curTed in workers expt a causal relationship: ( pseudosleroderma; (2) liver. Particularly, the > nancy among a compa. alarming experience wi a connection between lunp or the gastrointe. the prolonged latency . sarcoma of the liver. r>* these two fatal conseqt the conclusion that Vi. cancer meeting in Hoit to VCM was a very sen It should be stress*, precise, an intermedia!! mainly in the mammal, menzation products (P cited from the polyme they contain unreicted PVC (thermal decompc toxicity of pyrolysis pr mainly due to the releaAbor 1969;flyer and and only very small or r (O 'Mare ct al. 1971 cite JCC 0458:30 i Manteller 44 4 49 50 51 SI *4 34 S4 S3 j: 37 57 74 76 76 30 0 s: t: s: Si 7 ss 89 u. I Penal im It .tads is a <<uid help to irring rather ilaQy hazard* nt. this acusly for .ill develop Vinyl OilonJe-Aivodaud Disease 3 one of tltt least harmful chlorinated hydrocarbons. Early animal experiments, as it later turned out. had indeed been earned out with doages sufficiently hi|h for the evaluation of acute effects, but chrome exposure had not been of sufficient duration to reveal its carcinogenic properties. On purely theotencal grounds, however, one might have continued to feel uneasy with this compound as a pollutant of the work* place, considering that it is (1) a halogensied hydrocarbon which (2) exists in its vapour phase under smbtent condtuons finhalauve exposure) and (3) contains a highly inactive doublebond. Today rinyl chloride-associated pathology is well documented. A large body of in* formation and data on this topic has been accumulated, notably sines 1974, but pre* duly a quarter of a century had to pass befote the full nap of syrnptpinstoiocy at* tnbutabk to this new occupational health hoard became recognised in January 1974 wuh the shodring discovery that haemangioiarcoina of the liver oecuned in produc tion workers heavily expoud to PVC. Early and not easily accessible reports suggest ing that the monomer might be an environmental risk for workers handling this com pound did not alert the expens sufficiently. The earliest indication of adeem effects in worken engaged in the production and proctsing of PVC, s Russian study pub lished in 1949 (Tnbukh ct al. 1949), received little attention. Ultimately, it was the exceptional character of the three major lemons which oc curred in worken expoud to VCM that contnbuted most to the final appieaaoon of a causal relationship: f 1) the syndrome of acroosteolysis, Raynaud's phenomenon and pscudosleroderma: (2) non<inbouc portal hyptnension; and (3) angioarcoma of the Uver. Particularly, the discovery of a duster of four cases of this extremaly rate malig nancy among a comparatively small group of workers (Cmch et al. 1974a) was an alarming experience which called for immediate action. It can easily be imagined that a connection between VCM and the mote common malignancies, such as cancer of the lunp or the gastrointestinal tract, might sull have gone unnoticed. On the other hand, the prolonged latency periods of both aon<inhotie portal hypertension and angio sarcoma of the Uver, roughly 10 and 20 yean respectively, delayed the recognition of these two fatal consequences of chronic exposure to VCM. But one " hM<|Y ^f1 the conclusion that viola's discovery of cancer in experimental animals, presented at a cancer meeting in Houston in 1970, was sufficient evidenceiQ indicate that expowise to VCM wa a my serious occupational hdtard f/ererx 1976). It should be stressed that the noxious stent is muiyrh* rponpmtr. or to be more precise, an intannediate of the monomer's tnetaboUc bioaetteiatioa. which takeToUce mainly in tht mimmaiian lives and yields certain hifhly reictrir epqxrdes7Tlit_pqlymtriaation products flpVQj-v-, timniiri piie jnd.the plastic consumer goods fabri cated from the polymer, are chemically hurt articles which cartyno health risk unless they contain unreacted residual monomer. Even the combustion of snides made from PVC (thermal dfeomporirion in flits) does mt yield free vinylchlortdi monomer the toxicity ofpyrolysh products oTpoiyvtnyi chloride polymers ind fonBuTtoonsls siainty due to the"f*lew ofEydrochJQric add and carboomonoxidc (Gomtth and Abar 1969:D}]tr and Eick \916\Sortmo* 19?6:.tfoser 1976; Cbkrtf)vtetaLl976) and only very snajTqr hoquanuGes bfpfiostcilifdtrivtd fromraadual monomer (Onfaro ct al. 1971 dted by Coludyn et ai. 1976). ucc 046881 2 Technological Details 2.1 Vinyl Chloride Monomer (VCM) W-K. Lelbach and H.J Marvtc!ler * At standard (ambient) conditions of temperature and pressure, vinyl chloride (CH:" CHC1: chloroethylene, chloroethene) is a non-imtating. colourless gas with a faintly sweet odour, inflammable at concentrauons above 3.3% by volume in air. which is only slightly soluble in water, soluble in ethyl alcohol and easily soluble in ether and carbon tetrachloride. VCM is mainly used as an intermediate in the manufacture of plastics, as a refrigerant and in organic synthesis. It was formerly also employed as a propellant for aerosoles. It is easily liquefied under pressure and is usually handled and shipped as a liquid. Caseous VCM condenses at -13.8*C and 760 Ton (* 101-3 ItPa) to a colourless liquid of low viscosity (Ltfaux 1966). Its physical propemes are listed in Table 1, the most important of which are its low boiling point, its high specific grav ity (gaseous VCM is 2.15 times heavier than air), its iow solubility in water and the half-life in air. ranging from 3 to 20 h. Vinyl CJi. succeeds izing subs i.U Pro Large-seal by empiov 1) Conver CH*CH 2) Conver. chloroe CHjC CHjCl- VCM w Thus, any. tioni in the in the ranc (IARC 197 when VCV. maytr 196 in eommer i::6; Cret in the e conjecture. retrieved V yses camew sum of alii, genates) reacted mo in prepoivr the conctr. that even I1 methyl chL bobutanc.j ferencc m p . imJ H.J. Mantel ler I chloride fCH;* `.is with a faintly :n air. which is luhts in ethst and manufacture of 'so employed as a usually handled and Toref-101.3 kPa) ropentes are listed us hijh specific env oi water and the ve --TS.J*C : 3300 *30 3660 *35 j.J 760 mmHg .rmtytr 1967: ' study systematically .* some earlier prelim.iund when Rrfrwult lainini the vinyl .his polymerization of f sunlight was first - and Glintky (who Vinvl Ciiondc-AiiOi'ijtjU Di'caie succeeded in decomposing vinyl ehlunde to nionodtloroaidehyde with the aid of ovidiztng substances such as h> podiiorou* acid. 3.1.3 Production of VCM Large-scale commercial synthesis of VCM with a high yieid was made possible much later by employing two principle metiiods. the second having now largely replaced the first: 1) Conversion of acetylene to VO! by hydrochlorination: CHCH HC1 - CH-H3HG (catalyst: HfCIj on charcoal) (Ausnn 1974) 3) Conversion of ethylene by vapour-phase or liquid-phase oxychlorination to I.3-dichioroethane and subsequent pyrolysis (thermal cracking; to VO! (Albnfnt 1967a;: CH-^H * ZHO 1/2 Oj - CH-Cl-CHiCH-H-.O; C^a-CHjG -80*C~5!?--* CH:*CHG *HC1 pumice catalyst (pyrolysis; thermal crocking,Austin 1974). VOl was usually manufactured in dosed systems and stored tn outdoor lactlities. Thus, any leakage of the gas was readily diluted in the ambient air. VCM concentra tions in the atmosphere at some distance from manufacturing plants were found to be in the range 1-3 ppm. In dose proximity, the concentration ranged up to 50 ppm ilARC 1974). Spontaneous polymerization in light has also been repeatedly observed when VCM comes into contact with atmotphene air due to container leakage (Osrmmerer 1967). A prerequisite for the polymerization process is a high degtee of punty in commercially produced VCM. Impumtcs retard the polymerization proems (Lefrux l966:Osrcnrwi`cr 1967). - In the early discussion about the cause of vinyl chloride-associated disease it was conjectured that other compounds or impurities contained in prepolymerization or in retrieved VCM might have been the causative agentts; (Tinea and I'cncn 1974), Anal yses carried out by six Wen German manufacturers of PVC, however, showed that the sura of all impurities (such as saturated or unsaturated hydrocarbons and their halogenates) was 0.015 by volume for prepolymerization 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 in retrieved VCM fin one instance only, the concentration ranged between 1000 and 3000 ppm). But it should be kept in mind that even 1000 ppm methyl chloride in VCM would mean, at 500 ppm VCM in air. a methyl chloride concennation in air of only 0J ppm. All other impurities (propylene, isobutane, si-butane etc.) would then be in the ppb range. Besides, no significant dif ference in purity could be found between VCM from acetylene and from ethylene. J 1 c r c 6 22 Production of Polyvinyl Chloride (PVC) W.K. Laibach and H.J. Marsieller 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 temperaturns between 40*C and 80*C and pressures of 6-16 (8-12) atmospheres. Tlvrc 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, docs not react easily. The double-bond of VCM is not only the site from which the polymerization originates but is also the source of the toxicity and carcinogenicity of this compound when it is being metabolized in the body. The polymerization of VCM, which is a strongly exothermic reaction <[Bamcs 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, axo-bis-isobutyromtride, 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 (Maltcn and ZieUmis 1964;Ie/jux 1966, Albnfltr 1967 t-c'Domirtmgliaus 1972;SIater 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 1 SO 000 daltons (Albrifht 1967b). Degree and velocity of polymerization, which are influenced by temperature and the concentration of initiators, determine the specif ` type of PVC produced (Frty 1973). During polymerization considerable amounts of the monomer are at first dissolved in the polymer, but most of this is later also transformed to PVC as polymerization progresses. The polymer which is not sol uble in the liquid monomer precipitates out. The process of polymerization slows down towardsthe end of the reaction.lt is terminated, depending on the method used, when approximately 80ft-90% of VCM is polymerized. The timing of this termina tion of the process is essential for the physical properties of the resins produced. The heat generated during the exothermic process of polymerization must be removed to keep the temperature of the reaction under control. Mechanical agitation aids in trans ferring the heat acres the colloidal system to the cooling jacket of the reactor. During the process of polymerization certain quantities of the polymer adhere to the walls of the reactor and form a slowly thickening continuous film or crust. This polymer crust on the inner surface of the reactor vessel, which contains cavities filled with unreacted monomer, impedes the conductance of heat; it has, therefore, to be cleaned away after termination of the batch process (Bamts 1976). After completion of the polymerization proccs, the slurry is released from the re actor into a dump tank. Residualjinreacted vinyl chloride monomer is partly solvated in the polymer (about 10%7; the remainder is dispersed in the water phase or is present Vinyl Chlonde- in the vapour ph. VC monomer is r is then purified b the finished pol> and trfust diffuse Raw PVC resin, t (VKE 1975). Bar proxunately 500 The slurry fre Urge enough to h are then pumped wet polymer, a gdrying methods, merization, yield fine solid particle drying tempenu polymer, A cycle The solid polymt storage bins or si dried powder coi 222 Methods i Four different in PVC (Frey 1973 Suspension Polyi which monomer (such as poly%in> conjuetion with this method wh;. Emulsion Polym was added in the except that large are added. Emul: emulsifiers cann< Bulk (Mass) Poh the additon of o The first reactor second one is usi solid state, to ese reaches a level ol characterized by good optical clar 048384 Manrcllcr f the procedures -tridc. :on) it temperaiwrts. There art .-acuity of the : f the vinyl .iU^ondofVCM too the rourct of waboiized in the action (Bames <nn free radicals at I peroxide, isopro* ?als react with the cal and thus prepii. Chain growth is tdves a reaction t-.Albnfnt 196" h termination once different dt- being statistically m from about poiymerizatMn, etemune nridcrable ->t of this is later which la not sol* i nation slows the method used, of this tetnuna* ns produced. The 4 be removed to ation aids in inns* he reactor. During eta to the walk of 1 lib polymer crust >cd with unmeted chancd away after -amd from the tt* * is partly solvated phex or is present r Vinyl Chloride-Associated Disease 7 in the vapour phase above the sluny. Wlifle a batch is in the dump tank, this unreaeted V`C monomer is retrieved by pumping it off into a VCM Stonge tank. Retrieved VCM is then purified by subsequent distiilauon for recycling purposes. Monomersolvatedjn the finished polymer cannot easily be extracted since it has a strongTfTmity for ?\rC antTmust diffuse through the panicles: this diffusion depends oh time ansftemperature. RawTVCTesut, therefore, still contains cenarn quantities of unreaeted monomer (VKE 1975). Barnes (19761 reported that the polymer in the slurry still contains ap proximately 500 ppm of vinyi chloride. The sluny 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 tht blend tank are then pumped into a centrifuge which separates the wet solids from the water. The wet polymer, a granular mass, is dried cither in rotating tubuiar dryen or by spray* drying methods, the latter being used mainly for products formed by emulsion poly merization. yielding s polymer which is similar to a very fine white flour. These very fine solid panicles are fed directly into a ipray-drying column without dewatering. The drying temperature should not exceed 60*C to prevent thermal decomposition of the polymer. A eydon separator at the exit end of the dryen removes eoaner parades. The solid polymer particles ate then sized by multiple-layer screens, air<onvtyed to storage bins or aios and finally packaged for shipment (Albright 1967d). The resultant dried powder contains about SO ppm of monomer (Bamet 1976). ~~ 2.2.2 Methods of Polymerization Four different methods of polymerization art used for the commercial production of PVC (Frey-1973), the fin: two now being tht most widely used: Suspension Polymerization. Polymerization is carried out in an aqueous system in which monomer droplets art maintained in suspension by means of protective colloids (such as polyvinyl alcohol, gelatin, substituted celluloses) under heat and pressure in conduction with brisk tgitation. Relatively large polymer panicles can be obtained by this method which 'dry blend* well. Emulsion Polymerization is the oldest technique, to which suspension polymerization ras added in the 1950s. The process is similar to that in suspension polymerization, except that large amounts of emulsifying agents (such as soaps or other surfsetants) ate added. Emulsion polymerization yields resins of a very small particle size. The emulsifiers cannot be completely removed. Bulk (Mass) Polymerization. In this process VCM is polymerized in two itaget without the additon of other liquids. The two reaeton are operated batch-wise and in series. The first reactor (a prepolymerizer*) provides for the initial liquid phase, while the second one is used for agitating the sluny, which is transformed, through s sticky solid sate, to essentially dry panicles until the conversion from monomer to polymer reaches a level ofabout 753-40%. The resins obtained by bulk polymerization are characterized by high purity and panicle uniformity, resulting in an end-product of good optical darity. \ A >t T .-`'SK5P S W.K. Lclbach and H.J. Marttvllcr Solution Polymerization. This type of precipitation poiymenzation is carried out in organic solvents such as n-touunc or cyclohexane. It accounts for only a small percent age oftlie total amount of all PVC resins produced and it is used for the production of copolymers. Copolymers arc mixtures of comonomers (such as vinyl acctaic. vinyl- stearate, vinylidene chloride, propylene,acrylonitrile etc.)and vinyl chloride. The co monomers tend to improve flexibility and limited solubility of the product in solvents and exert an influence on the temperatutes required for compounding. ____ 2-2J 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, organotm compounds, and other stabilizers). Lubricants or dyes can be added. Plasticizers ate added for the production of flexible FVC:rigid PVC contains little or no plasticizer. These additives can also be a source of toxicity. The plasticizers may slowly diffuse out of the final product depending on its compatibility. Lead-containing stabilizers may also pollute the working atmosphere (Smultic 1966: Tola 1975). Compounding is carried out by hot mixing at fusion tem peratures below or within the softening range (120*C-160*C). Diversified compound ing and processing technologies were developed about 1950. The compounded polymers are used for the production of diverse end-products. The final conversion of the thermoplastic PVC resins into consumer end-products is accomplished by such procedures as extruding, calendering, injection or compression moulding, blow moulding, dipping (coating) and hot spraying. Temperatures used in these processes range from 100*C to 300*C. End-products include a vast number of articles used in almost every sphere of daily life. The temperatures during the fabrica tion operations (compounding and conversion of compound polymer into consumer articles) drive off part of the small concentrations of residual monomer still contained in the polymer. Barnes (1976) calculated that the final fabricated articles contained approximately 5 ppm VCM and those for foodstuffpackaging (bottles, films, foils) even less. Z2A Sources of Exposure to VCM in PVC Production Both polymerization of VCM and subsequent processing (centrifuging, dry ing, screen ing, bagging) are usually earned out in dosed buildings. Exceptions can be found in hot climates (Arj'anpur 1977). Polymerization u of necessity a bateh process that re quires a large number of single operations. Therefore, valves, gaskets, sliaft-openings and control gear are subject to heavy wear and thus to leakage. Other sources of pollu tion of the working atmosphere are exchange of parts and repair jobs. The degree of pollution also depends to a large extent on the quality and effectively of monitoring equipment and special exhaust systems. Opening of autoclave vats for cleaning and control purposes resulted in larger spill-over of the tank atmosphere into the work en vironment. Numerous reports of workers with prenarcotie symptoms (dizziness etc.) O'' *> v w *.w Vinyl < i permit t! in the p: Th clave va; walls f'p tots. ItaJ degassed and largi were opc ed the fr. tion still manly, t! those wi (eentnfu ties of vemdatn shipmer.' nomer. v are dnvr Table I ppi- I me (Pm: I mg tin 1 mg,m' 1 ppin 1* 2.2.5 T in the rv nant mo; coven (Lefdu.x lect as a opened became ) ucc 046886 -4ursteller ! *etion of tnylThc co-** solvents ry or :oo temi and light u<*m. ' tkxible source of Hg on its <phm n ternmpound- siuctJ. ucts is nr, ,ion ieU in it*: f U :nca* ^mcr ^Bncd -.scrttnjmlin that re* -citings of polluerne of tuning I and worien etc.) t`in) I Chlcmlc-A.scvuted Dr-ea-e 9 permit the conclusion that episodes of acute overexposure to VCM were not rare events in the past. There is no doubt, however, that those workers who manually cleaned the auto clave vats by scraping away or chipping off the `poly mer skin' formed on rise reactor walk (`poly cleaners ), and who in the past had to spend several hours inside the reac tors. had been exposed to the highest concenttations of VCM. Although the vats were degassed pr.or to entry, unreacted monomer remained trapped in the polymer skin, and large: amounts cf VCM were released when cavities formed m the polymer crust were opened by chipping. The later introduction of automanc cleaning systems reduc ed the frequency of entry into the reactors, but some manual cleaning of shorter dura tion still had to be done after every 20th-30th run. (t is. therefore, plausible that, pri marily. the most severe adverse cfTects of exposure to VCM were fully recognized in those workers who had been employed in this job category. But the subsequent steps (centrifuging, drying, screening) also involve the release of some of the lesser quanti ties of unteacted residual monomer from the parades to pollute the environment if ventilation, notably of the drying facilities, is inadequate. Finisiied polymer, ready for shipment or subsequent compounding, still contains small quantities of unreacted mo nomer, which either slowly diffuse out and pollute the bagging areas during stonge or art driven out by the high temperatures necessary- for compounding. Table 2. Conversion table for concentration of VCM in ambient air Mol. wt. lppB," Tooo'x :a.ui m</Utne 24 JS a I 000 1 mg per litre ---- ------- ppm t/errr !9jg> I mg/litr* 391 ppm I mg:m* 0.391 ppm 1 ppm 2-5h mg/m* 0.00256 mg/litr* l'______ 10 000 ppm 25.6 mg/litre 2-2.5 Tltc Explosion Hazard In the past only the explosion and fire hazard of VCM was thought to be tht domi nant monitoring problem m handling gaseous vinyl chloride (/nth 1963). This hazard coven a concentration range of 45&-22S by volume of air (40 000-220 000 ppm) (Ltfmu 1966). It was observed that VCM, being 2.15 times heavier than air, may col lect as a compact layer at the floor of a polymerization building after spill-over from opened tanks and may catch Are. At lean two instances of disastrous VCM explosions became known: (n 1964, a large plant for the poiymenzadon of VCM in the United 10 W.K. Laibach and H J. Marsteller Suttt was almost completely destroyed when VCM escapinf from a leak detonated (Albnght 196'a). Another explosion in one of the two Rumanian factoncs operating at that time was mentioned by 5uriu et al. (1975). Monitoring of VCM concentrations polluting the work environment was then directed largely towards preventing VCM from reaching the flammability limit. 2.2.6 The Odour Threshold Unfortunately, gaseous VCM has no irritating or unpleasant warning properties. Its mild odour is described as faintly pleasant, sweet or ethereal. Some of the PVC workers we interviewed reported that they had even enjoyed *snifflng the gas', which soon resulted in a feeling of light-headedncu. For the early days of PVC production, when appropriately sensitive monitoring equipment was not yet available, workers' re* * poru about perception of the odour of VCM can be taken as circumstantial evidence for a rough estimate of the actual degree of exposure. It should be kept in mind, how* ever, that in chemical production units the presence of other odoriferous chemicals and the possibility of olfactory fatigue, as well as different levels of individual sensitiv* Ity, may render it very difficult to determine the factual odour threshold of a certain gaseous substance unless it possesses irritating warning properties. In 1929,5c/im/dr andSehaumonn declared that the faintly sweet gas is practically odourless at concentrations of 5%--10% by volume. Veltman and Lange (1977a, b) assumed an odour threshold of 5 000-10000 ppm. Volunteers exposed to VCN1 detected a slight odour at * 100 ppm; a distinct odour was noted at 6 600 ppm for 30 min and this was accompanied by subjective symptoms of dizziness and sleepiness (Irish 1963). Gehring 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 (Banna et al. 1969; Cook et al. 1971,Marko witz et al. 1972;c/cwe 1975, cited by Hubkt 1975). Banna et al. (1969) conducted experiments with concentrations of 50,250 and 500 ppm in an exposure chamber, in which 13 volunteers participated. At 500 ppm only some of them 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 petccpuon of the odour of VCM and incipient CNS symptoms as reported by Irish (1963), however, makes it likely that the actual odour threshold can be as* sumed at or above 4000 ppm. In contrast to VCM, the comonomer vinyl acetate, for instance, has distinct warn* ing properties and can be detected by its odour at a level as low as 0.4 ppm; eye and throat irritation begin upward of 5 ppm and are noted by all test subjects at a concen tration of 21.6 ppm (Dtese tad Joyner 1969). 2.2.7 VCM as an Anaesthetic Agent VCM was once even conadeted for use as an anaesthetic agent. In 1929. Schmidt and Schautnann speculated about using VCM as a supplementary narcotic at concentra tions of 3%-5% (v/v) ( 30 000-50 000 ppm) in combined nitrogen oxide oxygen Vinyl ChJori Table 3. Od.- Lower limn * 5 1)00-10 On J oe 4 1C 3 St 50- 400-5 O' 4040' anaesthesia be tic and lethal. oxygen; conec however, that eluded. In to' 10% VCM to; several hours i commented u; mined about i. 3-5--5 mmol ( mmol (244 OC Oster et al., in eardiotoxicit) nun because c like other hale amines (Irish i the past for an 223 Effects Some individu listed in Table without acute symptoms sud adequate warn exposure to hi; A 21*year-old. 10 min after et which had bee cardiac enlarge have been aeut which occurred doubt that hea found dead wii >M. Mameller id Rating neemniions ling VDI .stitt. Ita PVC gas". which 'reduction, .workers' re* sl evidence mind, howchemicals Jnal icnntiv* f a certain -* ptaencaUy <9T7a,bl to VCM ppm for 1 sleepiness .imitely lower 'VM..UM-0- i>-u they itUTeiencei - .* proximity i v reporteJ be sa tinet wan* : eye and hmdt and centraoxygen Vinyl Chlonde-Avtocisred Discs* Table 3. Odour threshold Lower limit of detection 5 000-10 000 ppm 5 000 ppm z 100 ppm 3 500 ppm 500 ppm 400-500 ppm 400 ppm 400 ppm Author Celtman and Lang* 1977a. b Viola 19'J Irish 1963 Gthrngtl j! 1979 Bartrts it si 1969 Ltftvrt 197* (cited by Hubitt i97*i Cook et al. 1971 .Verrtrwrr eral. 1972 II anaesthesia becum of it* potent narcotic action and the wide margin between narco tic and lethal concentrations, (n animals it produced anaesthesia at 7T#--IOC* in air or oxygen; concentrations above 125 proved to be dangerous. The authors pointed out, however, that advene hi* t(Tecta of this haiogenated hydrocarbon could not be ex cluded. In toxidty studies with guinea pip tony et aL (1930) found conctntratons of 105 VCM to be lethal within 30-60 min, S% to cause marked narcosis, and 0J5 for several hours' to be the maximum tolerable exposure without senous effects. They also commented upon the potential use of VCM for surgical anaesthesia but were undeter, mined about its practicability. In tract, the minimal anaesthetic ring* was found to b* 3.5-5 mmol (85 000-122 000 ppm) for 10 min, the minimal lethal ring* 10-12 mmol (26S 000-293 000 ppm) (ftopicr and Ltokt 1933). It was not until 1947 that Otter et aL in contrast to Schoumenn't earlier assumption (1934) of a relatively low cardiotoxicity, warned against the use of VCM as a potential general anaesthetic in man because of senous cardiac irregularities and ECC changes observed in dogs. VCM. like other haiogenated hydrocarbons, sensitizes the heart to the efTem of catechol amines (Irish 1963). We could not ascertain whether VCM has actually been used in the past foranaesthrua in man. J Effect* ofAcute Overexposure in Man Some individual responses of volunteers to increasing concentrations of VCM arc listed in Table 4. Later et aL concluded in 1963 that the maximum concentration without acute effects in man lies between 8 000 and 12 000 ppm for 5 min. and that symptoms sudi as dizziness light-headednrs and disorientation should be taken as adequate warning signs for imminent acute danger. Two fatalities after occupational exposure to high concentrations ofVCM arc reported is the literature (fimtiger 1960). A 21 -ytirold autodave deaner at a Canadian polymerization plant w* found dead 10 min after entry at the bottom of a probably insuflleiently ventilated reactor tank which had been declared safe solely after in exploaiotnctfr test. Heart failuse cells and cardiac enlargement found at autopsy, however, implied that the cause of death might have been scut* functional disturbance in pre-existing heart disease. In the second ease which occurred at the same plant, however, circumstantial evidence apparently left no doubt xhat heavy VCM exposure was the cause of death in a 39-y*ir-old worker. He was found dead within 20 min, lying in a pit near the opened vaiva of a recycling pipeline i: W.K. Lelbach <tnil H J. Memellvr Table 4. Individual response* of volunteer* to increasing concentration* of VCM Concentration Duration of Sympiom* exposure- Reference 300 ppm 75 h (Inconstant odour detection* Burette et el. mild headache, dryness of (19o9> yes and throat in 2 of 7 subject <1 000 ppm - Generally accepted odour threshold /mu i 196.-1 6 600 ppm 30 nun (Distinct odour) dizziness, sleepiness trail 11963) 8 000 ppm \ 12 000 ppm 1 5 min1 (twice on 16 000 ppm I each of 3 succes sive days) 20 000 ppm / 3 of 6 subjects Slightly heady* 1 of 6 subjects had reeling, swimming head, lust like getting gas* 5 of 6 subjects, various degrees of intoxication All 6 subjects had more intense symptoms of acute intoxication than at 16 000 ppm Lester et al. (1965) 25 000 ppm 3 min 3 experimenters: dizziness, disonentation. burning sensation in the soles of the feat Bern et al. (1963) 3 Exposure to six different concentrations: 0 ppm: 4 000 ppm; 8 000 ppm: 12 000 ppm; 16 000 ppm: 20 000 ppm through which non-polymerized residual VCM was pumped back into a reserve tank: another man coming to his rescue was himself overcome by the gas and only just escaped. Two non-fatal cases of VCM gassing were reported in Great Britain in 1951 (.Spinas ft al. 1975). A maintenance worker experienced acute narcosis while repairing a VCM leak, and a worker cleaning a polymerization vat from outside with a water jet sudden ly collapsed across the open manhole. Subsequently he complained about tightness of the chest, nausea, abdominal pain and headache. Occasional loss of consciousness was also reported by Lilii et al. (1975) in 14 of 354 worktn at Niagara Falls and by Sudu t al. (1963) at a Rumanian plant. VCM-induced narcosis, at least on one occasion in the past, had occurred in 46 of 58 workers (79ft) referred for medical surveillance from one British PVC-produring plant (Men/ et al. 1976), with a 100ft incidence of narcosis in 38 symptomatic wotkets (Raynaud's syndrome and/or acroosteolysis). Successful resuscitation after VCM-induced narcosis of several hours' duration with out evidence of permanent damage was mentioned by Rety et al. (1974). Vinyl Chip;. -2-9 Monn During the ti ed data on V< directed an apparenth i W.Heshc Cronsberf to Russian poly: 0.05-0.08 m ccntration of Inspectorate . or from the d mg/litre ( J, mg/litre ( 3- ln the cei: air ranged fro ppm, which w venulauon. T trations, sonu pursuit ofimj ment in the vi ic drying facil cemrations ot continued to) milted concer in a plant the range of 0 ppm (2.93 mg ication apparj remarkable th the liver, althi past have profc Byritt et ai which occunc ated peak ex; between 1962 Rumanian PV( about 120 mg. exposures to \ 300 Rumanian Greek plant wl resulted in higl (Cirtios 1971) of the reacton up to 10000 p i i. Manteilrr l ttttUi* <;u et il. *69) h i i 9631 t*.(1963) *rtt jl. OJ) I ! i t i ;tr et il. >63> ..4.1:310 scree tank: nlyjun . 1951 (Jpirjs wiring a VCM <er jet suddenl tightness or was and by Sucnt -nccasoftin mihaiics nodeneeof levlysis). ration with- Vinyl ChlonUe-AssacisteU Disvsm: 13 2--J9 Monitoring VCM Concentrations in Working 4reas Duiini the Ant two litcadct of PVC production <1930-19501 no publication contain ed data on VCM concentration! in tit* wnrking environment. Tltc main interest then was directed toward! prevention of Ate explosion hazard. In 1957. the obtervauor. of an apparently toxic angfoncuroiu in Russian PVC production worker! [Smmutva \o*i:P!ctiichirser et al* cited in Fihtova and Gmntberf 195*1 induced F-lat'ivj and Grjnsberj to investigate environmental VCM concentration! in vanoui r-ans of a Russian polymerization plant in GorTuj, Although moil reading were in the range of 0J05-0O8 mg/liue ( 20-313 ppm), <4. below the maximum permitted VCM con centration of 1 mg/litre (approximately 400 ppm) ai specified by the State Sanitary Inspectorate at that time, escapes of VCM in the reactor areas from defective Atttngs or from the discharge of operating autoclaves resulted in excursions up to 29.5-Al .4 mg/litre f* 11 500-16 200 ppm) lor penods of 5--10 min. One peak reading of 87J mg/litre < 34 000 ppm) was recorded. In the centrifuging and drying area of this plant the VCM content of the ambient air tanged from 4 ppm to 3 100 ppm with most readings between 20 ppm end 195 ppm. which was attributed to release of residual VCM from wet PVC ream and poor ventilation. The screening and bagging area was characterized by high dust concen trations. sometimes exceeding the official upper limits set for non-toxic dusts. In the pursuit of improving industrial hygiene, the installation of modem ventilation equip ment in the vicinity of the autoclaves, substitution ofhandperaied by semiautomat ic drymg fadliuts. and avoidance of leakages succeeded in reducing the ambient con centrations of VCM to below 0,05 mg/iitre ( 20 ppm), but toxic angioneurosa 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, Fikto*a et ai. (1958) found lower concentrations in the range of 004-1.1 mgAiue (16-430 ppm), with maximum values of about 1200 ppm (253 mg/iitre), the latter havir.j been observed in dose proximity to the rectif ication apparatuses and having resuluu from spillage during sample collection. It is remarkable that up to now the Soviet Union has reported no oses of angiosarcoma of the liver, although production of PVC teems started early and VCM exposures in the past have probably been in the same range as those observed in Western countries. Byrtn et al. (1976) pointed out that during the 1950s episodes of unconsciousness which occurred among workers of the one Swedish plant operating at that time indi cated peak expoaires of at least 10 000-15 000 ppm. Suck et aJ. (1975) noted that between 1962 and 1972 a reduction of the avenge VCM concentration in the two Rumanian PVC plans had been achieved from 2298 mg/m' ( 900 ppm) in 1962 to about 120 mg/m1 ( 50 ppm) in 1965-1972. In 1969,4tgf:rfncu et al. mentioned exposures to VCM concentrations of 112-545 mg/ra* (44-213 ppm) for a group of 300 Rumanian workers, eight of whom (2.7%) had Raynaud's phenomenon. At a Creek plant which started operation in 1967. certain stages in the production process resulted in high concentrations of VCM in the work environment for brief periods (Girtiot 1971). In air displaced from reactors during eddition of water and on opening of the reacton to obtain PVC samples at the end of a reaction eydt, concentrations of up to 10 000 ppm were found. In open waste drums into which waste polymer scraped ttl v Y 14 W.K. Lclbach and H i. Mantellcr way from reactor walls during cleaning was placed, concentrations of up to 600 ppm were measured- In the report of a World Health Organization (WHO) working group on vinyl chlor ide (IARC 1974) it was stated that in a reactor of 15 m* (production of 4-5 tons of PVC per cycle) a emit of * kg PVC containing 33-55 VCM can be formed on the inner surface. During the cleaning procedure 305-503 of this VCM content is liber ated. It was calculated that the probable concentration of VCM wnhin the reactor after a 1-h cleaning operation was about 2700 ppm, but that it could be reduced to 90 ppm by 30 renewals of air per hour. In the past a polydeaner used to spend 4-5 h/ day inside the reactor but later the introduction of (not fully sufficient) automated cleaning reduced manual cleaning procedures to shorter periods of 10-15 min follow ing every 20th-30th reactor cycle. A Belgian company, where monitoring in the work ing area was started in 1967, claimed that measuremenu at various sites inside a 9000litre autoclave during the manual cleaning operations had shown VCM concentrations varying between 50 and approximately 540 ppm, with a mean of 413 ppm (Hublet ct al. 1977). According to data provided by Cook et al. (1971), VCM concentrations within the reacton pnor to ventilation were in the order of 3000 ppm. The reactor dcanen usually did not enter the autoclaves until an aeration period of 15-20 min had reduced the VCM concentration to what was considered satisfactory limits. In the early days, this was tested either by `sniffing at the manhole opening' (the lower limit of detection of VCM by iu odour having then been accepted as 400 ppm) or by use of a flammable vapour indicator which required a minimum of 400 ppm for positive readtap, equalling 43 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 reactors tended to be below 100 ppm during cleaning operations, but VCM releas ed from the residue during scraping resulted in concentrations of 600-1000 ppm measured close to the hand. The Dow Chemical Company started monitoring the work environment in 1950 by means of pab samples; continuous monitoring was installed in 1959. While timeweighted ivcragt (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 (Orr et al. 1975). In a second unit with modernized equipment excursions up to 600-1300 ppm still occur red during the period of 1953-1959. In 1959, when toxicological data indicating ad vene effects in animals exposed to 100-500 ppm VCM had become available (Torktlson et al. 1961), the Dow Chemical Company introduced a new 50 ppm guideline for the work environment. Excursions and peaks up to 500 ppm did continue. Measure ments of TWA exposures for various specified job categories in two production units of this plant between 1950 and 1966 were presented by Ott et al. (1975). In 1968 BASF (West Germany) introduced continuous monitoring by infrared absorption spectrophotometry for VCM concentrations well below 500 ppm; in 1974 more sensi tive equipment was installed and concentrations were kept below 25 ppm and later below 10 ppm, with occasonal ceiling values of 70 ppm (Flcig and Thieu 1974). In several surreys individual jobs were grouped into three exposure categones ac cording to job classification to evaluate past exposure experiences (Spinas et al. 1975; Williams et al. l976,BIendis et al, 1978). These exposure indices were; (a) light * less Vinyl than: ppm), plants samplv Estim:. more ^ averag. Ttblt: aimosr Cherm. * Act' Equ tionr in equipm vidual e btaatioi (3) The ly spec;: ment sh peak coi for the. Cun compns. tion dct< (lonotk which cs conditio lag of re: A cat indiums ta 19751 22.10 I Raw PVC unreactei. i * w - ppra nyi chiot 'tilts of n the < Hber* jetor - si to -,d 4-5 h/ reared m follow- - the work* w a 9000titrations Uubkt ct tuons -Victor 20 min ;ts. In the Ar limit i'V use of itivt reidr-tthods i inside M releas-pra '^ Ua period .'reports i. In a U occuriun| id: {Torkel'(.line for 'rasuren units l6l ion rtsensilister '4). net se al. 1975; ht-less Vinyl ChlondcvUsooated Disease IS than 50 ppm; (b) medium * 50-200 ppnr.ict high* 200 ppm and above (up to 1500 ppmJ. In the past, however, estimates of exposure concentrations were based in most plants not on continuous monitonn| during the entire work shift but at best on sput samples not necessarily repmentanve of the 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-produdng plants*. (Estimated by Chemical Industries Association Ltd.) IWJ-I9J5 IMS-i960 !90-l9?0 nud-1973 197a 1975 v 1000 ppm V400-500 ppm *v 200--100 ppm "V150 ppm ` i* 50 ppm and less v 5 ppm * According to Fltif and Thttu 197d; Aemrr 1976 Equipment for optimal continuous multipoint monitoring of exposure concentra tions in the working areas should meet certain basic requirements; (I) For stationary equipment strategically placed sample probe should yield data representative of indi* vidual exposure levels in the breathing zone of workers, preferably to be used in com bination with personal samplers. (2) Analysing methods should have a high selectivity. (3) The limit of detection should be at least one order of magnitude below the current, ly specified standard regulating the permissible upper level of exposure. (4) Measure* * mem should be instantaneous (within seconds) to guarantee rapid detection ofcritical 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 ofambient VCM concentration comprise such analytical tools as long-path infrared spectrophotometry, flame ioniza tion detection, gas chromatography, mass tpectromauy, combustion<onductivity (lonofliuO, and personal samplers in combination with gas chromatography, none of which can at present be consdercd as absolutely satisfactory for all Individual plant conditions because they all differ with regard to selectivity, limit ofdetection and rime lag of response. A catalogue of the methodologies that have proved to be of value in the control of industrial hygiene and personnel protection regarding exposure to VCM was compiled to 1975byitowc 2-2-10 Exposure to VCM to FVC-Frocamtog (-Fabricating) Rants Raw FVC powder ready for compounding and fabricating purposes contains retidual unreacted vinyl chloride monomer in varying amounts. In the past, monomer content f lt W.K. Lelbach ami H J Marttcller was reported to have been as high as 6000-7000 ppm (w/w) in some types ot' raw PVC, but a level of 200-1000 ppm probably was a more representative range (&/maser-1973: VK 1974:Kantedt 1976). The monomer slowly escapes into the environment exponentially with time. Jcpending on length of storage period, tempera ture. sue and porerity of panicles and other physical propenies of the polymer and. more recently, on the etTectivity of special degassing techniques (Ptvcr 1976 and Wolf 1977). In 1975, the Association of die German Plastics Industry announced that m future only PVC powder with a maximum monomer conient of 10 ppm would be put on the market due to the development of special degassing technologies t VKE 1975). Analyses of the types of taw PVC, chiefly suspension polymer, which are now used in German plants showed that in most products the content of unrcacted 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 tScliiit: and Wnlf 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 Bntdcr and Siraby (1975). Apart from hot compounding, other ther moplastic operations, such as extruding, calendering and welding of tiles, also resulted in release of unreactcd 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 903 of the readinp mean levels integrated over 1 -h periods now range below 0.1 ppm, numerous short bums with excursions up to 60 ppm during a workshift were recorded in one instance (Schiirz and Wolf 1977). Similarly low concentrations of VCM in breathing zone samples (maximum: 12 ppm) with 603 of the values ranging below 1 ppm had been found in 1974 in nine United States fabricating plants, but source samples had ranged up to 340- 540 ppm (KantaJt 1976). These present results, however, do not permit any conclusions ~.t to past levels of atmospheric VCM during the yean when residual monomer content of PVC resins was high arid ventilation insufficient, parueulariy in compounding and extruding units. Whatever the extent of the nsk might have been in the past, it can be safely assumed that the ambient monomer concentrations in fabricating plants have always been con siderably lower that in PVC-preducing plana. When it was suspected that certain VCM-relaicd symptoms might also have afflict ed PVC process workers, this problem was investigated by our group. Although no eases of tcroosteolysis, pseudosclerodemu or angiosarcoma of the liver were observed, evidence was presented which demonstrated that minor and inconspicuous lesions such as mild hepatic fibrosis, bromsulphalein (BSP) retention, thrombocytopenia and slight enlargement of the spleen could be found in 28 process workers who had been em ployed for yean in compounding and fabricating units (le/ijv et al. 1975,1976a: Women 197$;Mantcller et al. 1976). In principle, these lesions were identical with thorn seen after heavy exposure as we will describe, but the degree of damage attribut able to occupational VCM exposure otncrvrd in these workers was not considered suf ficient to enutlc them to disability compensation under German law. Although the in- Vinyl conspi tponsquami obsers progre male F find ar Ar twoG. died relation <. Iiealth overall record 2-2.11 IJCC q46S4 'I J -Mametler noge ipes into th* mmI, temperadymer and. '*"6:Sc/tut: *v announced iO ppm would Uogies (VK Hicham now acted mono- ition between e which usu`mar and, mt of residual *\mg precis. ;g. other the:- jlto rouited .ceatly eoniv Ccrman U integrated ".fusions up ,lotf 19T7V n- i; pp:llj I.* United levels of t C mint tas ing unto, rfy asumed i\ been con- i han afflicttough no v -re observed, ns lesions such 'ttia and slight I been cm5.1976a: .-ntical with ipage ittnbut* ntederrd suf`hough the in* Vin>l OtlonUu-AMOciawd Ui<ea*c 17 conspicuous chancier of tiiese lesions agren w*U with the assumption of a dose-re sponse relationship of VCM-edated disorders and the attentions may seem to be. quantitatively, of little importance, they should not be minimized. Nevertheless, an observation period up to the present of almost 7 yean did not reveal any spontaneous progression. In a proportional mortality study for 1970--19"Z among roughly 55 200 male PVC fabrication workers in England and Wales. Baxter and Fox (19761 did not find an excess of angiosarcoma or othar liver diseases. A recently completed cohort study of 4007 people who had been employed by two German PVC-fabricacng plants between 1934 and 1974 and of whom 360 had died revealed that oeni! mortality, although marginally below that of the male popu lation of the Federal Republic vf Germany, was slightly elevated with respect to the healthy worker effect'. No angiosarcomas of the liver were observed and no excess in overall cancer mortality was noted, but an excess mortality from brain tumours was recorded in one of the two plants {Rtiitltt al. 1979). I.M 1 National Standards for the Control of Exposure Industrial hypenisu have used several designauons for acceptable or permissible limits of exposure to chemicals at the work place, such ss 'maximum allowable concentra tion' or maximum acceptable concentration' (MAC), "threshold limit value' fTLV). `industrial hygiene standard* in the United States and as *Maxinulc ArbciupUtzkonsennation' (MAX) in West Germany. These empirical standards were defined by the American Standards Association as setting e limiting concentration "for exposures not exceeding 9 hours daily during a 40-hour work week with the undemanding that varia tions should fluctuate below this value** (Irish 19631. An extensive discussion of the basic approach to the principles used in setting environmental quality standards for oc cupational respiratrn. exposure to toxic agents can be found in the paper of ZieUimt (1974). In this p*p-\ the conceptual differences between threshold limit values as used In the United States and maximum allowable concentrations as used in the USSR an summarized and the differences in approach and emphasis, which may explain past discrepancies between permissible Undo, are elucidated. For details the reader is refer red to this paper. The standard is nor an index of relative toxicity, far lea of hazard, and certainly not a ion of'avenge'.A standard set a the ceiling level implies that any fluctuations should be around a median of perhaps half the standard and that it should be compe tently used in full awareness of in phynolopcai basis and the limitations of currently available knowledge Uriah 1963). The standard will be subject to revision a soon a new* information is available. An essential element of the annually published German tin of MAX values (MAX-Wert*) is in preamble, which exhaustively defines the various modalities for the interpretation of such standards (Htntchltr 1972/73). The so-called TWA, an integration over time of fluctuating concentrations, will be a useful tool for estimating the probability of injury only if it represents a comprehensive anal ysis of the normal fluctuation beiow the standard. * tn the Federal Republic of Germany the standard for VCM (MAX) was set at S00 ppm in 1966. The German Standards Advisory Committee reduced this to 100 ppm 18 W.K. Lelbach anil H.J, Marsieller in 1970 in conformity with the proposal of Torkehon et al. (1961). which was based * on the results of their animal experiments. In dune 1974, when the carcinogenic prop erties of VCM had been well established, the MAK regulation for this chemical was re pealed and instead a preliminary technical guideline (Technische Richtkonzemration) of 50 ppm was instituted (VKE 1975). The Chemical Industries' Liability Insurance Association (Berufsgenossenschaft der Chemischen Industrie) also issued instructions for the prevention of health hazards arising from handling of VCM in July 1974. As of July 1975, a technical guideline (TRK * Technische Richikonzemration) of 5 ppm. defined as annual mean, for PVC-producing and -fabricating plants was insututed, per mitting excursions up to 15 ppm during periods of not more than I h. In order to adapt operating plants, a provisional regulation was issued with reduction of the an nual mean concentration to 20 ppm as of July 1975, and to 10 ppm as of July 1976 and peak concentrations over 1-h periods not exceeding 60 or 30 ppm, respectively (Veltman and Lange 1977a). The technical guideline (TRK value) was revised in 1977 (2 ppm annual mean/5 ppm per 1 h). In the United States the threshold limit value for VCM was originally set at 500 ppm in 1947. It was reduced to 50 ppm in April 1974 as a temporary emergency stan dard and finally reduced to 1 ppm/8 h in 1976. Haley (1975) summarized the conflict ing views on vinyl chloride regulations proposed by Government and industry in 1974. Table 6 shows threshold limit values in a number of PVC-producing countries. 2-2-12 Exposure to VCM Outside the Working Area The Environmental Protection Agency estimated that PVC-producing plants in the United States discharged about 90 million kg VCM annually into the environment (4ft--8ft losses), most of it as air emissions and lesser quantities dissolved in water effluent streams and entrapped in sludge and solid wastes (Schweitzer 1975). In a pioneer study, concentrations of 1-2 ppm VCM were found in the ambient air near such a plant (IARC 1974), 2-3 ppm in the primary water effluent and 100-200 ppm in the sludge at the plant site, but sampling and analysis methods used were later found to have been inadequate so no conclusions were drawn from these figures since they could have been in error by as much as one order of magnitude (Schweitzer 1975). For people who live within 5 miles of monomer and polymer production facil ities in the United States an average exposure of 17 ppb during the yean of uncontrol led emissions was calculated (Nicholson 1977). In the past VCM has been widely used as an aerosol propellant, either alone or mix ed with fluorocarbons, hydrocarbons and inert organic gases, in household and cosmet ic products (hair spnys, deodorants, pesticides, room disinfectants, paint sprays, furniture polish and window cleaners). In Germany, VCM was proposed as propellant for aerosols in 1958 (Ouermayer 1967), in Japan it has been used a* a propellant since 1958, in the United States this use was probably introduced after 1962 (Schweitzer 1975). As an aerosol propellant. VCM has been a possible source of exposure for the public at large, partieularly lor women, the extent and the potential health implica tions of which are unknown. Use of aerosol products m confined spaces has been re ported to result in air concentrations of VCM of up to 400 ppm in closed rooms, even after only short bunts (30 s) (Gay et al. 1975). which could persist for several Vinyl Chi. Table 6. T Country Belgium Canada Finland France German O. Republic. Iran Italy Japan Netherland Rumania Sweden Swiuerljn United Kir USA USSR Federal Re, Germany Sources: Jr 73; IARC K l977;Sr/m, ucc 046896  uid H.J. Marsteiier hich was baled [dnogenic prop.isii chemical was re* ichtkonzemrationi sability Insurance tsaicd instructions 1 in July 1974. As rntration i of 5 was instituted, per* ih. In order to Auction of the anmas of July 1976 ppm. respectively i ms revised in 1977 ^finally set at 500 raty emergency nan-imahzed the confllettnd industry m 19"a. countries. tng plants m the the environment -- dved in water /:*r!9"5t In a j^nbtetenntt atr near d 110000-200 ppm ^Bed were later tit these figures since itde (Schweitzer me? production fad"ie years of uncontrol- n. either alone or mix* household and cosmet* it. paint sprays, -oposed as propellant J as a propellant since r 1962 (Schweitzer f exposure for the rial health implies4 spaces has been re in dosed rooms. U persist for several Vint i Chionde-Atsociated Disease Table 6. Threshold limit values <TIV> in various countries Country Year TJ.V ppmi Comment Belfium Canada Finland France German Democratic Republic (DDR) Inn Italy Japan Netherlands Rumania !9*5 1975 1975 1975 -- 1976 1976 1975 (future) 1970 1974 1975 1975 Sweden Switzerland United Kingdom USA USSR ' 1975 1976 1975 (future) 1975 October 1975 1947 April 1974 October 1974 1976 * 25 50 10/25 5'10 25 200 *12 25(50 50 (25/50) 500 200 *10 10 100 mg.m* (40 ppm) 5/20 l/S too 10 25/50 10/30 500 50 25 1/5 1 mi/litte (391 ppm) 30 ntf/m* (* 12 ppm) TWa (S h/15 mini TWa (3 h/15 min) TWa $ It, !5 mini TWa it h) MAC (Schottek 1969) (Konttzkt et ai. 167$) TWA( h/l h) TWA i8 h) (TWa 5 h/15 mm) MAC MAC (25 mg/m') TWa (> h) MAC (Froden etal. 197J) TWa (8 h/15 min) TWA (6 li'IJ mm) MAC TWA(Sh) TWA (S h/15 min) TWA (penonal/ceiling) MAC (Amer. Conf. Govemm. Industr. Hypenuts) TWa (8 hi. temporary emergen cy standard (OSHA) TWa (8 h). temporarily permit ted exposure TWa (8 h/15 min) MAC. provisional ceiling concen tration: State Sanitary inspec torate. 1957 (Filetora and Growbetf 1957) MAC ISchonek 1969: Kettner 1975) (Sanuarnye normy) Federal Republic of Germany t66 1970 June 1974 1975 1977 500 too 50 5/15 2/5 MAK MAK TRK (preliminary technical guideline). Annulment of MAK regulation. TRK (annual mean/1 h) TRK (annual mean/! h) Sources: Smyth \95b:FiUton and Grontberf mi.Svhottek 1969\HetueMer 197;/ 73;IARC Report IW\Hetty \915.Sekabe l975:Fnm et al. 1975-.Aryenpur l977;Tcne/r and Wolf |977;MAK-Werte-Lisie 1977;/Termer |97J t 20 W K. Lclbjcli and II.J. Maroallcr hours alter repeated spraying in smaller-sized rooms (IARC 1974). Haley (197S) pre sented a list of pesticide products containing VCM as a propellant and registered for indoor use. which were banned in 1974 by the Food and Drug Administration. In Japan, the monomer was also banned as a propellant in 174 (JAMA 1974.229:855). There is a case on record of a worker who died front noncirrhotic portal hypertension and angiosarcoma of the liver after 14 yean* employment at a chemical plant in south ern Germany where he had been enpged in loading such pesticide cans (Rein! and h'rhcr 1974), The report of a female office worker suffering from typical Raynaud's phenomenon, pseudoscleroderma. acroosteolysis and mandibular osteolysis who never had occupational contact with VCM (Meytnon and Meier 1972) is apt to make one wonder what influence the frequent indoor use of VCM-propelled spray cans (BnJbord ct al. 1975) may have had in this unique case. Sputum samples collected from frequent users of pressurized spray cans who had no respiratory symptoms were found to con tain a significant excess of moderate and marked atypical metaplastic bronchial cells compared with tw-Q groups of controls [Good et al. 1975). PVC bottles. Aims and foils have been used for many yean for packaging food and beverages (cooking oil. margarine,meat, mineral water, fruit squashes and other soft drinks, hard liquor etc.). The content of residual VCM in PVC bottles was found to have ranged formerly between 5 and 400 ppm (w/w). and in PVC foils up to 800 ppm (va/f Exit and van Logttn 1975), The problem of migration of unreacted VCM from the PVC containers into the foodstuffs became recognized in 1973. Reports of un pleasant tastes in American brands of vodka and whisky which had been stored in PVC bottles led to the discovery that VCM had leaked into the liquors; in some samples levels up to 10-20 ppm (w/w) were found (ran Etch and ran Logttn 1975; Amies and Perry 1975). Data available in 1974 to a group of WHO experts revealed that samples of gin and wliisky had contained 0.57 and 0.62 ppm (w/w) of VCM respectively, after storage m miniature PVC bottles for periods up to 3 yean; VCM concentrations in orange squash and cooking oil were found to be in the range of 0.01 -0.08 ppm and 001-0.04 ppm. respectively (1ARC 1974), Levels of 0-0.4 ppm found in British PVC-bottled liquids were mentioned by Denes and Pe-r- (1975): in their own tnalyses of samples of PVC-bottled spirits supplied by British Airways they found concentra tions of 0-0.25 ppm (w/w). Methods were developed for the detection of VCM in liquids with a maximum sensitivity down to the I ppb level (van Lienp end Stek 1976; Dresman and McFarren 1977). It was tentatively estimated that even during the yean when PVC-packaged food and beverages had not been heeded as a potential source of contamination, the likely average daily human intake of VCM from this source could have been in the order of 0.1 mg/penon (IARC 1974). Schlatter (1976) calculated that today it would be less than 0D1 mg/penon (equalling 250 mg during a whole life time); in comparison, he calculated that the inhaJational intake of VCM in diseased workere who had been exposed to concentrations of 500-1000 ppm during a period of 10-20 yean would have amounted to at least 25 kg. The Association of the German Plastics Industry expects that the we of technology available at present for the production of PVC food-packaging materials decreases the VCM content of food stuffs to below 50 ug/kg (50 ppb)even after prolonged storage (VKE 1975). Results of carcinogenicity assays in experimental animals after ora] administration of VCM are discussed in Sect. 3 J. Vinjl Chlondc-Assv 3 Toxicology o! 3.1 Acute Toxicity Dunng the fint three the assessment of the concentrations varyut and Leake 1933;Schi nutteo et al. 1960:Z,< anaesthesia, deep natc this range of exposure tive and haemorrhagic hepatocellular injury inducing substances (s 3.2 Chronic Toxicity Torkelson et al. (1961! exposure to conccntra; 4J--6 months. All spc. however, caused an inc histological changes in pigs and dogs. An incrc in rats exposed to 20 0 (1963): no histological Gorlcij Institute were n exposure of experimeu. mias. bradycardia, chan 0D5 mg/litre) for 5 mo creased secretion of cat posterior hypothalamus 3500--4000 ppm (,9- K of the cortex and the ar comitant changes in circ posure of rats and rabbt resorptiv* bone changes nervous system dysfunc available evidence for Vt VCM should be suspecte statutory maximal allow erratic Republic) should! Of particular impon; Viok et al. 1971) with c full year. It was only itu j IIJ, Mintrllr ?75)prtnPRered for ration. In 174.229:855). hypertension plant m south* {Rein/ and sal Raynaud's 'lysis who never to raakt one . (Bridbotd I tfom freouent t'ound to conroacbial cells ' rpng food and ,,J other toft -as found to .ip to 500 ppm J VCM from -i irtt of unnoted in PVC ute samples "*!.Davies and t'thai mn':s vtlively, after i rations in <H ppm and *toh anal'.es i .onaentn-fVCM in -*td 5rc* l*6: <ru>) the years -eta! source f source could calculated 41 whole ,'M in diseased iHf a period of the praent for tent of food 'll Results -n of VCM Vinyl ChlunUc-Avcouauii Disease 3 Toxieolojy of VCM 3.1 Acute Toxicity 1 During the first three decades of PVC production, animal experiments were limited to the assessment of the acute inhaiational toxicity of VCM in short-term exposures to concentrations varying between 50 000 and 400 000 pem f/'err. et si. 1930:Pet<pks m&leok* l9j3:Sdimnwnn 1934.1938;0rrcrt al. 1947.Cc/vet al. 1949,-ltarroww et at. 1960:1 rarer et al. 1963). In mice. rats, guinea-pigs, rabbits and dogs anaesthesia, deep narcosis, cardiac arrhythmias and lethal effects were observed within this range of cxposutt but no relevant organ pathology was noted except for conges tive and haemorrhagic changes in lunp. liver and kidneys on fatal outcome. Acute hepatocellular injury was later found oniy in animals pretreaud with potent enzymeinducing substances (see Sect. 3.4.2-2). 3.2 Chronic Toxicity Torkelso" et al. (1961) were the fust to describe results of experiments with prolonpd exposure to concentrations ranging from 50 to 500 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 m guineapip and dop. An increase in liver weight and decrease in spleen weight was also seen ir rats exposed to 20 000 ppm, 8 h/day. 5 days/week, for 3 months by Letter et al. (1963): no histological lesions w-erc found after 3 months. Soviet investigators at the Gorlcij Institute were mainly interested in neuroendocrine changes after prolonpd exposure of experimental animals to various concentrations of VCM. Cardiac anythmm. bradycardia, changes m phonocardiognm in rats exposed to 12-20 ppm (0.03005 mg/litre) for 5 months were reported (I'etn and Ptokhon 1969b) as well as in creased seertnon of catecholamines in rabbits snd ehanps in the biopotential of the posterior hypothalamus (Vesm snd Plokhma 1969a). After a 53-month exposure to 3500-4000 ppm (9-10 mplitre) changes in the bioelectric activity (EEC recordinp) of the cortex and the anterior and posterior hypothalamic nuclei in rabbits with con comitant changes in circulatory functions were seen (Ccw and PbkHova 1968). Exponire of rats and rabbis to 003-0.04 mg/litre (12-16 ppm) for 6 months produced tetorptive bone chtngcs snd osteoporosis in addition to cardiovascular and central nervous system dysfunction {Besaiair et ai. 1972). In 1969 Schottek summarized available evidence for VCM toxicity and warned urgently that chronic exposure to VCM should be suspected of causing toxic liver damage. He moved that the currently statutory maximal allowable concentration of 200 ppm (.MAC value, German Demo cratic Republic) should be lowered. Of particular importance as pioneer work were Mo/e'i txperimens (1970a, b; Mo/e et al. 197!) with expoaue of ns to 30 000 ppm, 4 h/day, 5 dayi/week. for a full year. It was only after this length of exposure that histopathoiogicai examination / m ucc 046899 22 . W.K. Lelbauh and H,J, Martteller revealed lesions limilar to human acroosteolysis and also similar to the type of nontumorous liver diseases which we observed in PVC workers 3 yean later (Mantellcr et al. 1973). Viola described lesions of the skin, the small arterial vessels, the connective tissue and elastic reticulum of the paws, and periosteal proliferation with chondroid metaplasia of metatarsal bones. Fibrosis of small peripheral nerves and degenerative changes of the grey and white matter of the brain were prominent, whereas the kid neys were not markedly affected. The Urn showed pronounced degenerative lesions with parenchymal necrosis, cytoplasmic and nuclear polymorphism, abnormal prolifer ation of hypertrophic Kupffer cells and intense fibrosderotie reactions. 33 Oncogenic Properties The earliest documentation of the carcinogenic action of VCM was Viola's preliminary report presented at the 10th International Cancer Congress in Houston, Texas in May 1970a. Of 26 Wistar tats exposed to 30 000 ppm for 12 months 17 developed epider moid carcinoma, mostly in the pinauricular region; 6 also developed adenocarcinoma of the lunp and S osteochondroma of metacarpal and metatarsal regions of all 4 limbs (Viola et al. 1971; Viola 1974).Maltoniand Leftmine (1975) later interpreted these paraaurieular tumours as arising from the sebaceous glands of the extenor aeoiutic duct, also imown 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 meiastases from the Zymbal gland tumours. Autoradiograms of lections of whole rats dosed orally with [l4C}-labelled VCM revealed a discrete localization of 14C in the paraaurieular region (Zymbal gland?) and in the region of salivary glands and Harder's glands (Green and Hathway 1975). In this con text,Veumeun et al. (1979), who analysed the peroxidase activity in Zymbal glands of Wistar rats, proposed the concept that peroxidase-medialed bioactivation of carcinogens (in their study: stilbene derivatives) might offer an explanation for these tissut-epedffc effects. At the end of 1970-Ve/to/ir and his group, with the support of Italian, British, Belgian and French chemical companies, started to plan and subsequently execute a large-scale carcinogenicity bioassay designed to study the effects of chronic exposure to VCM in relation to various experimental factors such as route of administration, dose level, length of treatment, and species, strain, sex and age of animals (Maltom 1973,197?;,1/a/row and Leftmine 1974a, b, 191$,Maltoni et al. 1974a, 1975). Con centrations used in the inhalation experiments were 30 000,10 000,6000,2500,500, 250 and 50 ppm, with length of exposure ranging up to 52 weeks and observation peri ods up to 143 weeks. Apart from the induction of Zymbal gland carcinoma other ma lignancies developed, notably angiosarcoma of the liver but also extrahepatic angio sarcomas. nephroblastomas, pulmonary tumours and nummary carcinoma, as well as a number of single tumours of other target tissues. Different types of turnouts were found to coexist in the same animal. On oral administration of VCM dissolved in olive o3 (5 days/week) angiosarcoma of the liver was found after 50 weeks in two animals of the two groups of SO Spngue-Dawicy rats each of which had been treated with the highest doses of 50 and 16.65 mg/kg body wt. (Metroni et al. 1975).Meltoni (1977) succeeded in demonstrating that the route of administration of this dearly multipo- Vinyl Chic ten till care Study of or solved in so 6 days/weei Ratio only a tion not ne> placed the i the no-toxii tngiosareon Sprague-Daproved to h genic in rat, be caranog 10,5 and 1 1979). Ano the dose-eel exposure le< histological the liver anc the inducuc posure to 1( al. 1974b; I, endothelial perplasia an even in the; was scanty: doses. In the fibrosis was of ossifying feet was sug offspring of mine 1975). posed to VC d from Grit it was seen t matunty of to 2000 ppn foci of hepa; Holrnbcr week, for 52 spleen chang mils expose, cutaneous ai ppm group a i Sec also l- 'JCC 046900 4 "`.K. LclbjnJ H J, was found in an animal exposed to 500 ppm. A few mammary adenocarcinomas, one rhabdomyosarcoma and one renal haemangiosarcoma were also seen. Prom their ex periments Holmberg et a), concluded that a lower exposure over a longer period may intensify the eancerogenic response and that an inverted relationship between dose level and latency time seems to exist in the case of VCM. as had already been observed with other carcinogens. Recently the results of still another animal experiment with exposure of Wistar rats to 5000 ppm. 7 h/day. 5 days/weelt. for 52 months was pub lished by Fcron et al. (1979a, biFerjn and Kroei 1979) in an eventually fruitless at tempt to elaborate suitable parameters for early detection of VCM-dtscasc in man. Ear ly effects were a shortening of blood clotting time and the occurrence of swollen and malformed hepatocytic mitochondria. At a later stage progessive tubulonephrotic changes in the kidneys, foci of celular alterations in the liver with reduced glucose-6phosphatase activity in hepatocytes. strong sinusoidal activity of alkaline phosphatase and increase of smooth endoplasmic reticulum in parenchymal liver cells were observ ed. In the final stage areas of necrosis in the liver parenchyma, focal dilatation of sinus oids and proliferation of normal and atypical sinusoidal cells, multicentne hepatic an giosarcoma and Zymbal gland carcinoma occurred, ferorret al. (1979b) also observed hepatocellular carcinoma in three animals. Surprisingly, the induction of very malig nant metastasizing carcinomas of the nasal cavity originating from the olfactory epi thelium and Bowman's gland was noted, which had not been reported before in con nection with VCM. Marked hepatic fibrosis was only seen within fully developed an giosarcoma or as a reaction to extensive necrosis of the hepatic parenchyma. The in vestigators wete of the opinion that hepatic parenchymal changes preceded those of the hepatic stroma, but they stressed the fact that the true relationship between VCMinduced alterations of hepatocytes and sinusoidal cells has yet to be elucidated. 5.4 Toxicodynamies Prior to 1974 very little information was available about the fate and the toxicodynamics of VCM in the mammalian organism, but the discovery of VCM-indueed angio sarcoma of the liver in humans and expenmental animals provoked a large number of studies which resulted in a flood of publications on the metabolism of VCM. In 1954 Schaumann reported that in mammals unchanged VCM was excreted via the iunp after inhalations! administration;the pulmonary route is the-main excretory route of nonmetibolized VCM (Green and Hethwey 1975). Blocking of nonprotein sulphydry! groups in the blood of vinyl chloride operatives, less pronounced after dis continuous contact, was observed as early as 1964 by Gabor ct til. and indicated deple tion of the glutathione pool, which has since also been found in exposed rats (Hefner etal. 1975a). Hepatic glutathione playa a fundamental role in protecting tissues against attack by alkylating agents. The appearance of monochloroacetic acid in the urine of workers exposed to VCM was reported in 1966 by Grigomeu and Toba. indicating that a polar excretable metabolite of VCM had been formed (Vainio 1978). Toxicodynamic studies have reveaied that VCM per te a nor the ultimate toxin or carcinogenic. It is the process ofbiotnnsfonnation (metabolic activation) of VCM, primarily by hepatic microsomal enzymes (mixed function oxidases) tlut yields short- Vinyl Qilorii lived but high mutagenic am cretable prod; 1975). Then tive velocities tiog of its re3 nation of VC I so that above following a i< cordance with 3j4.1 Uptake Pulmonary up in the animal'with the pool > shown by com Bolt et al. (19* as albumin, an pound goes in i After oral ingchas to be cons: is excreted via 1976c). This c able process. R body wt. adm, vestigation ot . gavage in dosefound a sigmii. plasmic reticul' but only mini ms on a diet c almost all the' testinal tract, h in this way. Penutanei keys following 800 ppm of 141 was negligible i Studies of that the liver (.p polar metabolir spleen, lungs an kidneys, spleen, of irreversibly r irreversibly bon 4 HJ. MatxieHer ^^Ksnus. one From their ex* -er period may 'eiween dote \ been observed Terimetst with .intht * pubily fruitless atase in man. Ear of twoiien and Honcphrotic ctd glucose-o:<ne phosphatase jilt were obscrv* nlaiarion of sinusntric hcpttic an* *)also bservea i of wry malig* * olfwtoiy-epi! before in con. developed an.hyma. The inreded those of T between ^ CM1 cidated. the toncody* ' t-indueed ingio* - irge numbet of i'VCM. as excreted vta main excretory f nonptottin tweed after disI indicated depied rats (Hefner mg tissues against < m the urine of **. indicating 73). Ithnate toxin or wo) of VCM, that yields short* Vint! Chiond<r*Ati(>iriated Di-ca-v* lived but highly recerirc alkylannf inrenncJiares which are responsible for the toxic, mutagenic and oncogenic effects. VCM is metabolized rapidly to polar nonvolatile excietable products (Hefner et al. 19"5a::cDuttrcn IQ?$:RaJwan and Hemehkr 19"5). The toxicity of VCM seems to be largely determined by the rauo of the rela tive veloaties of both biotranuomation of the compound ami protective detoxifica tion of its reactive intermediates (Henxhler 1977a). The capacity for metabolic elimi nation of VCM in rats is saturable at an atmospheric concentration of 200-250 ppm. so that above this concentration VCM is metabolized at a constant maximal velocity following a xero<rder kinetic, whereas below 200-250 ppm it is metabolized in ac cordance whh fintorder rate kineties (Hefner at al. 1975a.Bolt et al. 1977). 5.4.1 Uptake and Distribution Pulmonary uptake of VCM from the atmosphere depends on the rate of us metabolism in die animal's organism. The atmospheric concentration of the compound equilibrates with the pool of unmetabolized VCM distributed in the animal's tissues, as has been shown by complete inhibition of microsomal oxidative metabolism (Bolt et ai. 1977a). Bolt et al. (1977a) also concluded that lipids or Ilaaproteins. rather than protsins such as albumin, are the vehicles that transport VCM x. die blood and from which the com pound goes into the adipose tissue or is taken up by the Uver for metabolic conversion. After oral ingestion and absorption from the gastrointestinal tract, a "first pass effect' has to be considered, but an increasingly substantial percentage of unmetibolizcd VCM is excreted via the lunp in direct relation to the dose administered (Wannabe et al. 1976c). This confirms the finding that VCM metabolism is a dose-dependent and satur able process. Pulmonary elimination of over 92?; wuhir. * h ot a dose of 5C0 mg. kg body wt. administered orally to rats was also reported by Fmn et al. (1975) in an in vestigation of the subacute toxicity of VCM incorporated in soya bean0 and fed by gavage in doses of 30.100 and 300 mg/kg daily, 6 days/week, for 15 weeks- They found a significant increase in liver*to4>ody weight ratio and hypertrophy of the endo plasmic reticulum ofhepatocytes as indications of a toxic eiTeet at the highest dose but only minimal histological changes in the Uver. In a second experiment, they fed rats on a diet containing PVC powder with a high monomer content and observed that almost all the VCM was released from the PVC powder during passage through the in testinal tract, but only about 10 mg VCM/kg body wt. per day could be administered In this way. Percutaneous absorption was studied by Hefner et si. (1975b) in male Rhesus mon keys following whole-body exposure (head excluded) to concentrations of 7000 and 300 ppm of "Ciabclied VCM for 2-25 h. The quantity absorbed via the intact skin was negligible (0.027?--0-03?*) end most of it was expired. Studies ofthc distribution of[l,2->4C]dabclled VCM in the body clearly revealed that the liver (predominant site of metabolism) end the kidneys (site of excretion of polar metabolites) contain the highest concentrations of ,4C activity, followed by spleen, lunp and small intestine (Wannabe et al. !976c;So/r et al. 1976a. b). Liver. kidnevs.spieen,lur.g and small intestine (in this order) also contain the largest amounts of irreversibly protein-bound metabolites (Bolt et al. 1976a). Only minor amounts of irreversibly bound metabolites of VCM were found in muscle, adipose tissue and brain. t i dfcp |.r i r - i x ,, ^ Ji . . ^ . t T . M rM i-f* - f ; i n i ~r V rin r W.K. Ltlbach and HJ. Mameller Total radioactivity 48 h after a tingle exposure decreased considerably in these organs, in accordance with the relatively rapid metabolization of VCM and excretion or* its polar metabolites. In contrast, the amount of irreversibly protem-bound radioactivity remained constant during this time. Buchter et al. (1977) also showed that unmetaboiized VCM possesses a great affinity for adipose tissue, in contrast to its metabolites, which are concentrated primarily in Uver and kidneys. Metabolism 3.4.2.1 Relation between Chemical Structure. Reactivity and Mutafenic or Carcinottnie Effect Befoie discussing the metabolic pathways of VCM (monochloroethylene) and its presumpuve toxic intermediates two features of the chemical structure of this compound should be mentioned. Vinyl chloride is a mono/ialofcnatcd ethylene and its chlorine substitution is asymmetric. Chlorination of alkenes (oleftnie compounds), in general, tends to stabilize the double bond by exerting an electron withdrawal effect on the carbon atom involved. Thus, the chemical reactivity of alkenes decreases with increas ing degree of chlorine substitution, as was shown in 1968 by Williamson and Cvetanovic for reaction rates with ozone. Vinyl chloride, as a monohalogenated alkene, is the least stable compound with the highest reaction rate in the series of chlorinated ethylenes and ranks next to unsubstituted ethylene. Secondly, the fust 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. l91S\Henschler 1977b). Such chlonnated eporddes may react, by alkylation, with essential cellular constituents, a mechanism which Rannuf et al. (1914), Bartsch et al. (1975a, b) and Malavtiilc et al. (1975) claimed to be responsible for the carcinogenic and mutagenic effects of VCM snd vinylidene chloride. Epoxides resulting from biotransformation of asymmetrically substituted ethylenes, such as VCM, vinylidene chloride and trichloroethylene, seem to be particu larly unstable with increased eicctrophilieity and thus enhanced alkylating effect. Their mutagenicity and, inversely, the nonmutagenicity of oxiranes of symmetrically chlorine-substituted ethvlenes was indicated by the studies of Crtim et al. (1975, 1977). 3.4,22 Metabolic Pathways From 1974 onwards the fate of VCM has been studied extensively in vitro with rat liver microtomes in the presence of a NADPH-generating system (,Kappui et al. 1975. 1976.Barrsch et al. 1975b, l976,Malaveil!e et al. 1975 .Bolt et al. 1976a; Pcssayre et al. 1979), with the aid of isolated perfused liver preparations (Radwan and Henscfa lor 1975 ,Bonte et al. 191$ ,Radwan \911\HtnscMer 1977*) and in vivo (<Hefner et al. 1975a: Watanabe et al. !976d, 1978*. b-.Bolt et al. 1977a, b) in both control animals and animals pretreated with various types of enzyme-indudng and enzyme-inhibiting substances. Present biochemical knowledge strongly suggests that the first step of the predo minant metabolic pathway is the oxidation of the double-bond of VCM by the hepatic Vin> l Chlor: microsomal i ly highly rea. via the form;; bon monou 1 prociable roK in vitro an an systems and : 1976a). The. Cl H ICV Fi|. I. Metabr metabolized tacetic acid are roethylene oxj protein sulphi w.v(l 977). Si (Norpoth et a! S<arboxymei. acid) (ffensehl identified in tl JCC 046903 J. Matsteller prpns. ffits -iioacti'vity unrnctabwtaboiites. tr and its pit* t compound i chlorine in general. ;i on the ith mcrcjs J Ci-e.weric .-..is the least ethy;enss Iketies is a . electro* .d epoxides ; '.vhlk'h i claimed to .lidene -et'iect-nnetneally U975. with rat etai. 1975, -.Fauyrt and HtnsehUttfntrn il. itMuunah ^-inhibiting thepttdoy the hepatic Vm;! Chlonde-A.-joviaied Dt<ea*: 2* microsomal mixed-function oxidase system. forming chlomethylene oxtde. a chemical ly highly reactive epoxide (Fig. 1). A negligible amount of VCM can be metabolised via the formation of peroxides, very unstable compounds decomposing rapidly to car bon monoxide. HC and formaldehyde which, however, do not seem to play any ap preciable role ui the toxicity of VCM (Hcnschter 197Tb). It has also been shown that in vitro an anitlcal superoxide lOT) generating system can replace rat liver microsomal systems and transform VCM to the active intermediate (Kappus et al. l97J:flo/r ct jj. 19~6a). The epoxide rearranges spontaneously to chloroacetaldchydc. which is rapidly Cmjlcnl ^nilir.j to kdl-Lir macro, molecule' <cU.i U(run k m` Nt If'/ Ovulate X VDPH. 0- n. II n/imn-th* li lt Oritic <V( M t(nvl(i ComuSJi>n Hill; uiiph> Jr) I poiii" ehiuihtont. eywemc > Tiwrmal rramnycinrtt: H 1 >' II) Un>h m ICpptllk It) JraaC I OH OH II Cl--t --<--H II II II H ChloriMixulJcti) Ce Fig. I. Metabolic pathways. Adapted from Htntchler (1977b) metabolised to monochloreacedc add. Both chloroacctaldehyde and monoehioroacetic add are also metabolites which are chemically reactive but less potent than chlo* roethyiene oxide. All three intermediates can he detoxified by conjugation with nonprotein sulphydr/1 compounds (glutathione, cysteine) as describee by Green and Hathwav (1577) Sulphur-containing excretablc metabolites such as 5-hydroxyethylcysteine Qforporit et al. 1976). Nccetyl4<2 chloro)-ethyl-cysteine (Gncn and Hethway 1975), 5<arboxymethylcysieine (Watanobe ct al. 1976a), and thiodiglyculic acid (thimliacetic aad) {Htnxhler 1977a:MuUcrt\ al. 1976.1978-.Muller and Sorpoth 1975) have been identified in the urine of exposed workers and animals. A progressive depression of the :S W.K. Ulhxh and HJ. Mar-rcller level of hepatic nonproiein sulphydryl content has been observed in rats alter expo sure to VCM in concentrations from 150 to 2000 ppm for 2-7 h. No depression was seen after 10 ppm and a concentration of 50 ppm caused only an inconsistent reduc tion (Watanabe et al. 1976b). Protein-bound hepatic sulphydryl content remained unaffected. Hepatic microsomal cytochrome P4 (0. the coeitzyme of microsomal monooxigenases. also decreases linearly with time in animals exposed to VCM (Reynold* et al. 1975b). This destruction of cytochrome P410 may prevent further metabolism and toxicity of VCM (Pctuyrt et ai. 1970). Another mode of deactivation of the primary reactive intermediate, the epoxide, is its transformation to the inactive dihydrodiol by the inducible microsomal enzyme epoxide hydrase. The reactive metabolite of VCM, chloroethyiene oxide, is a powerful alkylating agent which covalently binds to various cellular macromoleculcs, notably vital proteins and nucleic acids. By binding to cellular DNA and RNA or critical proteins the metab olite may alter vital functions and the genetic information of the ceil and thus exert its hepatotoxic,mutagenic and carcinogenic effect.Eventually, however, the only fraction of the formed epoxide that binds to macromoleeules 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, Henschler (1977a) concluded that there might be a greater risk in intermittent peak exposures over brief periods than might be ex pected from simple integrauon over time and that the chances for effecuve detoxifica tion are greater in long-term exposure to relatively low levels. It was shown by Watanabe et al. (1975a) that repeated exposures of tats to VCM do not appear to induce its biotransformation, but significantly augment the binding of the reactive metabolite with hepatic macromoleculcs and may thus enhance the po tential toxicity of VCM. On single exposures of rats to increasing concentrations of labelled VCM ranging from 1 ppm to 5000 ppm, the amount of radioactivity covalent ly bound to hepatic macromoleculcs 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 (Watanabr et al. 1978b). This correlates well with Mehoni'i report (1975) of a linear percentage induction of hepatic angiosarcoma in tats between 50 ppm and 500 ppm when expressed as the log of the exposure con centration. Metabolites of VCM can alkylate nucleic acids, a commonly accepted mechanism for carcinogenesis. Covalent binding to the adenosine (Barbm et al. 19"!5, Laib and Bolt 1977), eytidine (Laib and Bolt 1978), and guanine moiety of nucleic acids (Ottermann-Colkar et al. 1977) has been described. But the degree of covalent binding of electrophilic metabolites of labelled VCM to hepatic nucleic acids seems to be very small (Watunabt et al. 1978b;tb and Bolt 1977). Laib and Bolt (1977) presented evidence showing that the alkylating potency of VCM metabolites cannot be deter mined solely by measuring the incorporation of label into nucleic acids after exposure to radioactive VCM. Watanabt et al. (1978b) concluded that covalent binding to nucleic acids is not the preferential reaction, but they pointed out that this does not Vinyl Chi- exclude th of cellular eluded as i above all. i This a. work will I . endoplasm tible to VC phologicaU mixed funv lobular, mi, found (Jat. 1978). Sec ndotheliai At pres, cesses im' the hepato, some meut(5) Meehan, tissues othe rant cell rep 1978b). An equa nonneoplas: Raynaud's " drome was i man. Beside liver lesion., bioactivauo: portal fibn ment of the a direct or ir tic nervout > lining cells o tion) or whi 4 Clinica During the r might prove ; presented in marked the y pational haz. . Manttlivr < was mt reduc..lined mal monoptulus *t :-aiism and epoxide. is toyme ytating ij| proteins `he merabi.us exert us ity fraction letoxificd itathione or s which .hanisms. in itwre might ;ii be exJetoxu'ca- * to VCM e binding :.cc the po* n,. v .case uoints be- 4 function -elates well lamateoma -ocurc con- edtanism > jib and adds (Orrcrndkig of be eery .wanted he deter* ier exposure fag to does not V.nyl ChtonJr-AfOvuuJ Dimijm.- : exclude the possibility of other, more subtle interactions which may impair the control of cellular replication. Alkylation of nucleic acids, however, cannot at present he ex cluded as the mechanism for VCMenduccd carcinogenesis after repeated exposure and. above all. in the target ceils rather than the nepaiocytes. This aspect carries on to an unresolved problem on which future experimental work will have to focus. Although the sire of formation of the active metabolite is the endoplasmic reticulum of the hepatocyte. the liver cell itself is not particularly suscep tible to vOUnduced toxicity Acute hepatocellular injury has not been observed mor phologically after exposure to VCM unless pretreatment with potent inducers of the imxed function oxidase system had pteeeded the exposure ;w pretreated rats centre* lobular, midzonal and pantobuiar hepatocellular vacuolization and even necrosis was found f/jejer t al. 1974.1975.1977;Rernctfr et al. 1975a. 1976: Cwimf/v et ai. 1978). Secondly, the site of carcinogenicity in the liver ii not the hepatocyte but the endothelial cell of the hepatic sinuses. At present it can only be (peculated which of the following four most likely pro cesses are effective, cither singly or in conjunction: (1) The active metabolite leaves the hepatocyte and is conveyed to the endothelial cell. (2) The endothelium iuelf has some metabolic capaoty fBolt 1978), as may tissues of organs other than the liver, fa) Mechanisms for the detoxification of the active metabohtefs) are insufficient in tissues other than the hepatocytei. (4) Repair mechanisms for the correction of aber* ram cell replication are less effective than they ate in the hepatocyte (Watambe et al. _l978b). An equally puzzling problem is the role of VCM in the pathogenesis of the distal nonneoplasuc vascular lesions which ait responsible for the development of the tnad. Raynaud's phenomenon, sclerodermoid skin indurations and acroosteoiysis. This syn drome was tlit earliest indication of advene effects of chronic exposure to VCM in man. Besides, its latency period was conaderably shorter than either the nonmalignant liver lesions or angiosarcoma of the liver. Whereas it is now established that hepaoc bioactivation of VCM plays the central pan in the pathogenesis of both nonduhotic portal fibrosis and angiosarcoma of the liver, it is not at all clear whether the develop ment of the acral lesions is due to VCM itself or to active metabolites which may exert a direct or indirect toxic action on (a) medullary vasomotor centres, fb) rite sympathe tic nervous system, (c) smooth muscle cells of the media of arterioles, fd) endothelial lining ceils of small artenes (with fibroblast transformation and endothelial prolifera tion) or whether (e) the action is mediated by the fotmanon of immune complexes. 4 Clinical Spectrum During the mid-1950s it began to emerge that chronic occupational exposure to VCM might prove to be not quite u harmless as had been claimed. The historical synepsts presented in Table 7 summarizes those clinical studies from fits world literature that marked the gradual recognition of the full spectrum of damage due to this new occu pational hazard. -f 30 . W.K. LclHa*h anil H.J Mar-ieKcr Table 7. Gradual emergence of evidence for VCM-associated pathology Year Reference Findings 1949 Tribukh et at. llepatnmtfjlv. more nr Iv*- marked 'jnictcrii. hepatitis', 'chronic gastrin*'. hypotension, anaemia, skin lesions 1954 1937 1937 I960 Smimi-e Filatova and Crontberj Kubota Dansiger Toxic anfioneurosis Toxic angioncurosis Symptoms similar to Raynaud's phenomenon Two cases of accidental fatal poisoning by VCM. 1 nonfatal acute overexposure 1961 Smirnova Reversible osteolytic lesions of distal phalanges. Pscudociubbing, thickening of skin nn volar side of forearms, slight haemolysis and reucuiocyrosis 1963 Suctu et al. CSS: prenarcotic symptoms (dizziness, euphoria, somnolence), nervousness, insomnia, blunting of memory, general asthenia, headache Vascular: Raynaud's syndrome Dermatol: pruritus, reversible sclerodermalike skin induration, chemical and allergic dermatitis Digest, symptoms: anorexia, nausea, fullness, hepatomegaly without hypcrbilirubtnxmia. splenomegaly fhdocrtne; hypothyroidism 1966 Coulter et al. Raynaud's syndrome, sclerodermalike skin changes, acroosteolysis. pseudoctubbmg. joint pain, tiredness, sleep reversal; Z episodes of acute overexposure (loss of consciousness) 1967 Harm and Adtmi Acroosteolysis, skin lesions. Raynaud'* phenom enon. pscudoclubbing, involvement of sacroiliac joints and patella, hepatomegaly with penmently raised scrum bilirubin. Skin biopsy 1967 1967 Menotr Wilton et al. Arteriography. Skin and bone biopsy 'Occupational acroosteolysis' with Raynaud's symptoms, scierodtrmalike skin changes, pseudodubbing 1968 1971 Anronyuzhenko Dinman et al. Mentions thrombocytopenia Frevalcnce of acroosteolysis and Raynaud's phenomenon 1971 1972 Dodson et al. Kramer and Muttehler * Vascular lesioni preceding the bone lesions Increased BSP retention and raised icterus index related to degree of exposure Vinyl Chlon Table 7 (eon Year R< 1972 r M. I91: JSi 1973 AL 19741*) Cr. 4.1The Tri -A fust indica plant pioduc: non (`toxic a: tn detail in ht personnel wlhourly sampL drome wai al{Kubota 195 ntoregulation and CN5 tyrr (1954) also ndurations on there was evK of red cells, u: evidence f d. icroosteolysu operators) aft junction with was found in lesions to be c reversible eha vibration trau the full range cupstiona) ae; In 1963 Si analysis of th. ( i inn l II J-Manteller 1 anicteric -tension. henomenon 'isinf by VCM. >al phJanets in on volar as and rvticulo- net*, euphoria, inn. blunting idache croderm alike .rpc demand) Va. laiineii. rubmaemu like `kin lul .j.-mt R 01 mud's phenom-em of sacroiliac with persistent'mpey h Raynaud's changes. Raynaud's mw Itiions U ictents index i Vin)l Chlonde-Asociated Disease 31 Table ?i continued* Year Reference .UerffMi.? <i ji. lot; Jihc end Lange 1973 ManniUr tt al. 19teta> Crttch ei al. Findings Progressive thickening oi hands end forearms. arthralgia. Blanching upo*i exposure to cold with cyanosis of hands accompanied by severe pain. 5km biopsy l`i German report oi * workers with sclerodermalike skm lesions. Raynaud's syndrome, and acroosteolyxu. Tests showed abnormal liver m *. occlusion of digital arteries m 1 worker Noncirrhotie portal fibrosis with portal hyper tension and splenomegaly 4 cases of angiosarcoma of the liver a / r 4.1 The Triad; Raynaud's Phenomenon. Pseudoscierodenna and Aeroosteolysis A first indication or advene etTects due to etuonic VCM exposure arose in workers at a plant produeng VCM who presented with symptoms similar to Raynaud's phenome* non (toxic angtoncuross'). This was reported by Smimora in 1954 and later described in detail in her thesis (1959). The syndrome was found predominantly in laboratory personnel who had intcrmirtently been exposed to high concentrations of VCM during hourly sampling for chemical analysis (punty of the product). In 1954 Raynaud's syn drome was also observed among several workers at a Japanese PVC producing plant (Kuban 1957). Apart from a painful vasospastic disorder of the hands, impaired ther moregulation, acrocyanosis.raiuvt cold test, capillaroscopic alterauons, panesthesias, and CNS symptoms such as headache, blunting of memory and sleep reversal,Jmirnorc (1954) abc mentioned swelling of fingers and development of eircumscriocd skin in durations on the volarade of the forearms in those most severely affected, in addition, there was evidence of mild haemolysis (borderline anaemia, decreased osmotic fragility of red cells, urobilinuns.and reuculocytosis;. In 1961 Smirnova descnbnl radiographic evidence of dcsirucave bone lesions of terminal phalanges in the hands identical with aeroosteolysis in three woricen it a PVC-producing plant (one fitter, two centrifuge operators) after exposure for 3-9 yean. Since these bone lesions developed in con junction with toxic angioneurosis* and since complete recalcification of the defects was found in two workers J yean after removal from exposure, Smirnova believed the lesions to be characteristic of chronic VCM intoxication. She pointed out that their tevenible character might serve to distinguish the lesions from similar defects seen in vferation trauma. In retrospect, Smimora'i observations are the earliest descriptions of the full range ofsymptoms which much later became known as the syndrome of oc cupational acrooiiaofyiu'. In 1963 Tutfe et il. (see abo 1967 and 1975) published the fint comprehensive analysis of their observation of a multiform symptomatology in subactuc and chronic i i * f- 3; W.K. Lt'lbucli jnd H.J Mar-teller VCM intoxication. During a 4-year period. they examined 168 moitly young workers from two Rumanian PVC-producing plants who had not previously been employed in other industries. In their dassie paper. Use authors described in detail the various cen tral nervous, digestive, angioneurotic and cutaneous symptoms (listed here in their order of manifestation). Acroosteolvsis, however, was not mentioned. Episodes of acute overexposute (usually occurring at the end of a batch run. during retneval of unttacted monomer, or at repair jobs) rapidly resulted in a state of light-headedness and transient eupltona similar to a mild degree of inebriety and were accompanied by a feeling of heaviness in the lep and disturbed locomotor coordination. Several workers claimed to have been able to identify escaping monomer by its faint but agreeable odour. Apparently during periods of particularly high ambient concentrations, workers repeatedly noticed formication in the lower limbs and a general feeling of bodily warmth. Six subjects had experienced loss of consciousness when repairing leakages, but recovered rapidly after being carried out into the open air. After a few months of work, unusual fatigue and sleepiness set in. there were complaints about persistent somnolence, even outside the work premises, and a tendency to fall asleep at the work place, particularly during night-shifts. In addition, headache, dizziness, irntability, blunting of memory, paraesthesias, and general weakness were reported;.some workers noticed insomnia or sleep reversal. A reappraisal of these nonspecific complaints (see also I `ale et al. 1976) 6 yean later, after improvement in industrial hygiene, revealed that the frequency of their oc currence had considerably decreased (Suciu ct al. 1975). Following a prolonged period of repeated overexposure, vague nonspecific digestive symptoms also developed, such as anorexia with ensuing weight loss, nausea, fullness, upper abdominal discomfort, bloating and epigastric pains. Enlargement of the liver was found in 51 worken (305); in 6" there was also splenomegaly. Classic Raynaud's phenomenon was found in 65, but a tenfold higher percentage of the total work force showed evidenee of vasospastic alterations on plethysmography (Rouchtr et al- cited by Suciu ct at. 1975). Pruritus of the hands, forearms and face was an early complaint followed later by what was thcoughc to be (allergic?) `contact dermatitis'; Anally, nodular and scleroderma- or scieroedema4ike cutaneous lesions developed in gome worken, involving the dorsal surface of the hands, the volar side of wnsts and forearms and the face, with firm thickening of subcutaneous tissue or formation of whitish papular or slightly elevated plaqueltke indurations. The cutaneous manifestations largely disappeared after removal from the wotk place. In addition, mention was made of features of hypothyroidism in few worken. Also, tranaent lots of libido in 243 was recorded, with return to nor mal after 1 break from work or during holidays. With the exception of icroosteolysis and the two most alarming late sequelae nonrirrhohe ponal hypertension and hepatic angiosarcoma - Sucw't early documen tation of the prevalence of disease in PVC production worken encompassed a com paratively complete description of the various aspects of chronic VCM intoxication. Later publications supplemented the spectrum of knowledge mainly by providing ad ditional information on epidemiological, roentgenological, thermographic, angiograph ic. and histomorphological aspects of the lesions encountered in subjects chronically exposed to VCM. Vinyl Chlon The disa two Belgian: classifiable d. marked the n syndrome ws year a numb.1 United Stater cases of OAC the vinous pi end of 1979. vascular phen symptoms th begin with til th* fingers an tips on hard > to cold accon are likewise a ance of painft osteolytic pn. with striation Table 8. Publ. Year 1966 1967 1967 1967 1967 1969 1969 1971 1972 1972/1973 1973 1974 1974 1975 1975 1976 1978 1979 One 01 2 el. ucc 046909 A 'W \ ,ucrs .7*luyid in nous cen* i the:r In of :vai of Icdnest piflMd by isl worker* .cable it, workers MlHy '.-akagci. tonthi of listen t .1 the work fctlity, .-i workers ivean > their ocetd period uni. such ntfort. im3(Ti: ;J in 6". :<P :iw or . dorsal < firm > elevated i;r removal ruidismm n to non tseiae doormen* I a com<icanon, ndinf ad* rtgiognph* ironically 'f Vinyl Chl"ndi*A**ocij:*d DIwjw 33 The discovery of unusual osteolytic defects in the distal phalanges of the hands of two Belgian autoclave deanets ulus had sutTered from Raynaud's phenomenon and an* classifiable dtgencrauve lesions or* the dermal connective tissue iCorUii-r et al. 1966) marked the resolution of this new occupational disease in the Western World. The sy ndrome was termed `occupational acroosteoly-Ms' lOAOL). and dunn| the following y ear a number of additional cases were reported from Francs. Great Bntarn and the United States. Later Lefirre 119*2) who together with Cornier described the fust two cotes of QaQL. reported that a subsequent investigation revealed another 'en cases in the various piano affiliated to the lame corporation in Spain. Italy and Brazil. By the end of 1970, a total number of 126 cases had been published in detail fTable S). The vascular phenomena preceding or accompanying OAOL comprise a broader range of symptoms than those charaderoue of Raynaud's syndrome. The conditions teems to begin with ill-defined pains in finger*. wrists and also large joints (shoulders, kneesi; the fingers are numb and tingling, tender on paipauon. handgrip and tapping linger ups on hard surfaces is painful; there is increasing sensitivity of the hands and fingers to cold accompanied by a tendency to cyanouc diseolourauon. In some cases, the toes ate likewise affected. Later, dauic Raynaud's phenomenon develops (sudden appear* anct of painful, sharply demarcated blanching) and. concomitant with the onset qf ostcolyac processes, there is a shortening and broadening of the terminal phalange with stnation of nsls (pseudodubbing). Table S. Publication! on Occupational Acroosteolyiis' since 1066 Year Country Number Authors of cases 19*6 1967 1907 1967 1967 1969 1969 197| 1972 1972/1973 1973 1974 1974 1975 1975 1976 I97g 1979 Belgium France France United Kingdom USA Rumania Yugoslavia USA USA Fed. Republic of Germany Japan France USA USA United Kingdom United Kingdom * 5 5 * 31 ** S 41 6 1 4 1 4 1 4 Brazil Israel S 2 126 Coniier et ai. Baton; Giattlam and Unnihm Bournehon (cited by .Venn er al. 1967) Menu and Adams Wilson et al. Angkaltseu et oL Koraf*i al. ffInman et al. Markons: et al. /ike and Veltman: Slain et al. la. b) Takauekl and Mabuehi 3 Moulin et al. Trapp et al. Ulu et al. Siam* at al. Prtsron et ai.: Walkar; MitektU Johnston (1971) Gama and Malta Hahn et al. a One oi 2 clear caws, in addition. 4g suspected caws isee Sakabt 19751 St f*TKR3 uce 04691 '( 34 W.K. Laibach and H.J. Marswllcr 4.1.1 Familial and idiopathic Acroosteolysis Acroosteolysu it a very ran diwaw. The acuoloD' and pathoienesis of this condition it ttill obtcun. Osteolytic bone changes in late stages of so-called Raynaud's disease (accompanied by necrasis and gangrene), characteristically presenting as loss of pan or of an entire distal phalanx of one or mote fingers and 'also of toes, hate been mention ed in the literature since 1921 (Aumann 1921 iMonaiun 1916:Bonk \9Zl:Komblum 1929). Xomblum 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 acraosteolysis was first introduced by Larocht and HoehftU (1948). who htid a neuroendocrine syndrome responsible for the lesions. Independently Hsmaieh (1949) reported another case of symmetrical idiopathic acroosteolysis, particularly involving the terminal phalanges of the fingers with preservation of tufts, progressive clubbing and shortening, and ill-defined symptoms of disturbed peripheral circulation. By 1952 Giacei mentioned that 68 cases of the familial type of acroosteolysis and 33 eases of the nonfamilial, idiopathic form had been reported in the medical literature. He added another five caws, 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>rt 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 cenainty. In a later review, Otcfiey (1965), who added another four cases of the familial type, stated 'Jut this variety and the nonfamilial idiopathic type may actually belong to the same diraase entity and may be pan of a degenerative bone process more generalized than the term implies. It was the pualing 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 dcanen (Lefivn 1972). 4.12 Epidemiology of Occupational Acroosteolysis Attempts at assessing the prevalence of OAOL among personnel involved in VCM manufacture and polymerization revealed that in general this occupational type of osteolytic bone lesion was found in only l%-3% of th work population at risk. tfubler ct al. (1977) considered the fact that only 3% of all workers who had been engaged in manual cleaning of autoclaves at a Belgian plant suffered from OAOL and Raynaud's phenomenon to be indicative of the importance of individual factors. WUson et al. (1967) obstrred 31 caws among 3000 employees of one large company. In 1971 Dinman et al. conducted a survey' in 32 plana belonging to 19 corporations throughout the United States and Canada. The details of this elaborate epidemiologi cal study, comprising a total of 5011 employees, illustrates the difficulties and limita tions encountered in a retrospective study of this dimension. All of these 5011 workers had been engaged in various stages of VCM and PVC manufacturing, but 1257 of them were worken who only handled finished PVC polymer. Fiv* of the 32 pianu worked Vinyl Chloi exclusively only 25 dea defined as c enon;18 of ith experic drome were jobs, both re (1 caw per 7 appeared no was detected use for react entry into th Table 9. Pre Country France USA United Kingdom Fed. Rep. Germany United Kingdom Total More con related symp Laiife and I ', olopcai chei-i pathological. were affected cold, 15 wort morbidity wa found classic numbness an> 8.7% and um Allen test inJ people with p pwudodubbt finding that ti duration of p. 1C * ucc 046911 Mantcilr >hti eondiuon mud's disease t* ion of part or ; bm mtnnon\a27: Komblum .Uties and noted i leprosy. The i*), who held a '.vnescH (1949) tUrty involving -tive dubbing *uion. 3y 1953 'id 33 easts of sturt. He added milling ptocet* one fragments .if idioparhie I* range of dif* lytic diseasei. .-as considered -r review. ::d that this same disease ! than the term w lesion that n^fen in (Lejh're edia VQt nil type of met rut i had been m OAOL and H faeton. 'srgt company. ' imrporanons epidemiologi* 'tics and limits< SOU worken f 1257 of them Hants worked r Vir.ji Chioriile*Asocured Disease 33 exclusively with the finished PVC-Jenved consumer products. Dtnman et al. found only 25 dear-cut cases of OAOL among the 5011 employees (mean age: 35.S years l. defined as characteristic X-ray film abnormalities combined with Raynaud's phenom enon: 15 of them had been reactor cleaners at some time .another 16 individuals 110 with experience ui reactor cfeamnf > with early stages or minimal degrees of the syn drom* were suspected of suiTenng from OAOL. It emerged that the two lowest-paid jobs, both reactor cleaning and bagging'packing, had a strong association with OAOL i.l case per 72. or 86 workers at rsk. resgeemmy i. Manipulation of the finished polymer appeartd not to be associated with a risk of contracting OAOL Only 1 case of OAOL was detected in those plana where high-pressure water lances or solvent! had been m use for reactor cleaning. Furthermore, it seemed that the extent of degassing phot to entry into the autoclaves correlated with the manifestation of the disease. Table 9. Prevalence of acral disease in VCM^xposed populations Number of cases Country Sist of group at risk OAOL Classical Severe Sclera- - Raynaud's sensitivity dermoid phenomenon to cold skin lesions References France 130 USA United 354* 4m* Kingdom Fed. Rep. 100 Germany United 104 Kingtiom Total 725 3 12 4 20 I3 99 1 23 13 63 ` 8 33 5 23 4 10 1 lOC^l 7H-VI05I l I9Tvl6"W 4J(*.6i tenon 1967 lilisti al. 1975 Welker 1976 tenge and t'sltmen 1977 Mencq 11 al. 1978 More eommoniy seen thar. OAOL were Raynaud's phenomenon (sec Table 9) and related symptoms of abnormal peripheral circulation (Benoit \ W,LUit et al. 1975: Lmife and t'elrmm 1971).Benoit pointed out that a complete medical and roentgen ological checkitp of ill 528 employees at a French FVC-orodudng plant revealed pathological manifestations only among the group of 130 reactor deanets of whom 32 were affected (OAOL. 5: Raynaud's phenomenon without OAOL 12: sensitivity to cold. 15 worken). He strened the fact that in this group of worken at risk the overall morbidity was almost 255. Similar results were obtained by Litis et al. (1975), who found classic Raynaud's phenomenon in 5.6ft of 35* heavily exposed PVC worken. numbness and tingling in 24%, excessive sensitivity to eold in 18%, pseudodubbing in 1.75 and involvement of the toes in 75. Besides, in 26.65 of the total an abnormal Allen test indicated Impaired peripheral arterial circulation. It was noted that in some people with past exposure Raynaud's phenomenon had gradually faded, whereas pseudodubbing persisted or even progressed. Mon important, however, was Litis' finding that the prevalence of all these abnormalities inneaxd significantly with the duration of past exposure to vat. r ucc 046912 3 W.K, Lclbach ami H J Mar<lcI!*r Occupational acroosteolysis is a condition predominantly observed in younger workers. The age range was 20--15 yean and hail* of all cases reported fell in the 50-59 yean age-group. Duration of VCM exposure prior to onset of Raynaud's phenomenon ranged from 1 to 25 months (Dodson ct al. 19T1), For OAOL the latency period was at least 12 months (Wilton et al. 1967)-. in most eases. OAOL developed insidiously within 2 to 4 -6 yean. There is at least one patient on record in whom OAOL was first discovered two yean after termination of exposure (Benoit 1967). Longitudinal studies of the bone lesions demonstrated partial or complete but mostly detective restitution, resulting in shortened and deformed distal phalanges, within 2-3 yean after removal from VCM exposure, but Raynaud's phenomenon and cutaneous lesions may persist (Williams andMcLachian 1976). Stein tt ai. (197J*, b) reported partial healing with restitution of tufts but progressive lysis of the proximal portion of terminal phalanges 3 yean after termination of exposure. Although OAOL developed predominantly in PVC production woriten who had at least for some time been engaged in reactor cleaning, the syndrome has also been ob served in asociation with other job assignments which were believed to carry a sub stantially lower risk of exposure. Trapp et al. (1974) rtponed a 31-year-old white male suffering from Raynaud's phenomenon, clubbing of the fingers and typical bilateral acroosteolysis, in whom specific inquiry revealed that his employment by an industrial chemical company had included daily handling of small concentrations of vinyl chlo ride (no details given). Typical OAOL was also observed in a worker after 6 yean' em ployment as spray diyer/bagger, pie-mix operator, recovery and charging operator who had never cleaned autoclave vats (Sten-art et al. 1975). According to routine plant monitoring of VCM levels in the past and as measured in 1973 by gas chromatography of grab samples, his average exposure had been within the threshold limit values of the day (200 ppm). Radiographs taken in 1966 at the end of his fint year during an earlier survey of OAOL were normal; in 1972 he presented with Raynaud's phenom enon. pseudodubbing, typical OAOL and dermal thickening of hands and wrists. Ar teriography demonstrated narrowing of most digital arteries, even In fingers without bone defects, and abaotmal collections of small vessels in the pulps of deformed finger tips, but no vascular occlusion. Apart from the chemical insult by inhalational (rather than transdermal - Dinman et al. 1971 :Sitwan et <1.1975) exposure to VCM, individual susceptibility or idio syncrasy appears to have played some (undefined) role in the development of the syn drome. it docs not seem likely, however, that repeated physical microttauma during cleaning operations (removal of polymer crusts by htnd scraping or chiselling) was a decisive factor in the pathogenesis of the condition as had been speculated by Wilton et ai.(l967), 4.13 Clinical and Roentgenological Features 4.1.3.1 OccupationalAcroosttoiytis In the majority of cases osteolytic lesions ate confined to the hands. Involvement of the feet was observed only rarely in OAOL. Wilson et al. (1967) believe that OAOL differs from familial or idiopathic acroosteolysis in several respects. Although the bone Vinyl Ch defects in ositopon skull, del' shortenin' nonoccup gcnologj*. 1)T1k one or mo 2) In t tufts, or a 3) The tufu toget defects (sc ('bandlike Fig. 2. Ocv aeroosteoi? year-old ao 4) In tland broadr fragments and inereas Sodium rnineraiuai multaneou!  Mil HJ. Mameiier ^^oungcr ... !I in the 30-39 zsmTi phenomenon 'incy period was 'tped mndieinly hnb OAOL was first Langmidmal studies .-feetive restitution, tan alter removal .-siuns may persist rtial healing with terminal phalanfes workers who had at has also betn ooJ to cany a sub* ' -year-old white male J typical bilateral :nt by an industrial -mru of vinyl chlo* alter 6 yean" en* arging operater who routine plant jt chromatography I limit values of st year during an ynaud's phenomulsM^emits. At- wwiiithout fetioorrmtne* d tdermal - Dinman -pdbility or idio* Atpment fthesyn* crotrauma durui| r chiselling) was a culaied by Wilton Involvement of >* that OaOL . Although the b nc r V:n>.' Chl-jr-.dc-AxiOkijtrd J? detects in the distal phalanges are similar in both conditions, other features, such as osteoporotic compression fractures ot the spine, basilar impression fracture of the skull, destruction of mid-phalanges or osteosclerotic changes of wrists and hand bones, shortening of aeiacarpais and corneal thickening of the shafts oi long bones seen in the nonoccupational type have never been found in OAOL. Wilson t: al. worked out roent genological catena for the diagnosis oi OAOL; 1) Tiie earliest changes in OAOL are marginal defects and lots cf cortex in tufts of one or more of the terminal phalanges of the hands. 2) In the next nage this is followed by small 'half-moon' cuts in the cortex of the rufrs. or * so-called sliceeffect along one or more tufts. 3) The advanced stage of destruction ts characterized by either i complete loss of tufts together with a portion of the shaft or there msy be transverse or oblique bone defeett (see Fig. 2) cutting off the shafts from the remaining distal run of the tutu rbandlike aooostcoiyiis*). r Fig. 2. Occupational acroosteolysis. Traruvcne or oblique bone defects rbandlike acroosteoiysu') or partial lots of terminal phalanges in all fingers of both bands. (33yeaKld autodava dtaner: duration of exposure 3 1/2 years! A) In die healing stage there msy be cither complete bony union with shortening and broadening of the residual pans of the end phalanx or a fibrous union of bone fragments. Fingertips remain short and plump with ptnisttnt clubbing of soft tissues and increased latent and lonptudinal curvature of fingertips. Sodium fiuoride 1 *F scintiscan data of affected bores suggested that active de mineralization (rcsorptjvt) end retnineralization (reparative) processes may occur simuitaneouaiy even in the same hand {Dodson at aL 1971). In some cases, bones of c r W.K. Leibawh and H.J Marsteilcr other body regions wen also involved. Erosive and sclerotic changes in tlic sacro-iliac joints and circumscribed resorptive defects fcorticai erosions) in patella, clawcle. man dible. humerus, styloid process of ulna, femoral condyles, os calcis, cuneiform and metauisal bones have repeatedly been observed (Conlier et al. l966;/A/mt and Adams 1967:Dodson et al. 1974,/ijr et al. 1974a:Preston et al. 1476: Jayson et si. I9~6t: Longe and Vcltman 1977). 4.1.3.2 Pxtudoxtcroderma Concomitant with the manifestation of pancsthesias, 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 lingers, hands and forearms, sometimes accompanied by swelling or puffiness and coarsening of the skm of the face (mostly on the forehead and cheeks). Raised, ivoryooloured, firm nodules or elevated, sharply de lineated ptaqueiike skm indurations are seen on the dorsal surface of fingers and hands and on the volar side of the wrists and lower forearms. It was this combination of Ray. naud's phenomenon and cutaneous lesions which fltsi prompted a search for other symptoms of progressive systemic sclerosis in affected workets. The syndrome of OAOL. however, can be dearty distinguished (Table 10). Notably, the diffuse immobil- Tabic 10. Differential diagnosis: syndrome of occupational acroosteoiysis i Raynaud's phenomenon,sclerodermoid skin changes, AOL) / progressive scleroderma with (rare) osteolytic lenonj Sex ratio Hands Occupational AOL Exclusively 4 Clubbing and shortening of finger tips; hyperhidrosis: no ulceration Progressive scleroderma * 1:2 Atrophy and tapenng off of fingertips*, anhydrotu: ulcerative lesions Pcnoral puckering of skin Skin appendages Telangiectases Shortening of frenulum Subcutaneous deposits of calcium salts Dysphagia (oesophageal involvement! Renal, cardiac and intestinal involvement Occupational history Prognosis Not observed Preserved Not observed Not observed Not observed Not observed Not observed Obligatory Favourable (skm and bone lesions tend to heal after removal from exposure) Common Loss of skin appendages Common Earty symptom Common Common (Common) Usually spontaneous progression Vinyl Chloride- izing sclerosis o tional syndrom readily than the 4.1.4 HistolOfc. 4.1.4.1 Cutan. Several investig: disease (Cordier al. i972;mifc we found only c 1967-.Morin et: neural changes' who suffered *tr. Dermal chan mis with disone broad interiaein faintly stained n Schiff (PAS). Ai histiocytes was: The most notab of elastic fibres, full thickness u. sue. Skin appen Walker (1976) f not exceeding i. some fibrous tin Vascular lc! capillaries were and pencapillat thclial cells with tion oflumina.' myocytes, was. to narrowing or Degenerative {Benoit 1967 ;.V hyalinosts of :hMeissner, Pactm 4.1.4.2 Bond. The most stnkn worker with OA ening and hyaln most layer. Sup ( ucc 0469'1c liac i. daviclt. man-reifotm and .-ms and ,4Jjmi etal. 19?6. of the fingers and orogresstv* clarms. sometimes : tan (mostly on rod, sharpy dets and hands `mutton of Raych for other ndromt of - diffuse immobil* ws< Raynaud's r.oa mtsimsi o -.'.ergderma enn* oif ihydrosii: V-H-IIS km appendages notom rontantous Vi:i> I Oik*ml-Aociaud Oiwa** 39 tang sclerosis of the akin with tapering otT of fingertips was never seen tn the occupa tional syndrome. After cessation of exposure the skin lesions seem to regress more readily than the osteolytic changes. a l.a Histology i i, A i Cutaneous Lesions Several investigators described the histomorphology of skin lesions in vinyl chloride disease iConiicr ct al. 1966;/ferns and.4Jams 1967;.tfarwi ct al. Ml,Markowitz et at. 19??;Lu*irc : al. 1974a: Velrman et al. 1975. Walker 1916.Hahn et al. 197). but we found only one description of bone histology in 0A01 in the literature (Benou 1967;.Uerin et al. 1967). Skin biopsies showed various degites of dermal, vascular and neunl changes which were essentially identical in patients showing OAOL and in those who suffered merely* from Raynaud's phenomenon. Dermal changes consisted of hyperkeratosis and pronounced thickening of the der mis with disonentation. swelling and nonfibrillary eosinophilic homogenization of broad interfacing collagen bundles. There wj some degree of interstitial oedema which faintly stained mttachromatically with toiutdine blue, alcian blue and pvnodie acidScluff (PAS). An inflammatory reaction with infiltration of lymphocy tes and a few histiocytes was scanty and, if present at all, of predominantly penvaicuiar distribution. The most notable feature was marked disorganization, fragmentation and rarcficauon of elastic fibres. In areas corresponding to nodular or piaquciilce skin inductions, the full thickness of the dcncis consisted of an acellular, partly hyalinized collagenous tis sue. Skin appendages were preserved. In 15 apparently less severely affected workers. Walker (1976) found only some destruction of elastic tissue of the derma, probably not exceeding normal age changes: in one worker with severe Raynaud's phenomenon some fibrous thickening of the media of dermal arterial was seen. Vascular lesions affected capillaries and small dermal arteries. Numerous dilated capillaries were seen in the subcpidermal papillae with swelling of endothelial ceils and pencapdlar oedema. Capillaries of the cuds showed cufflike hyperplasia of pentheiial cells with fibreblast transformation, hyilinons of vessel walls and final oblitera tion of lumina. Marked medial thickening of dermal arterioles, due to hypertrophy of myocytes, was accompanied by parietal flbrons and hyalinosis. which ultimately led to narrowing or even complete oeduaon of the lumen. Degenerative lesions of small dermal nerves were mentioned by French investigators (Ben hi \961\Marm ct al. 1967:Qiattiain andMotilhn 1967). They found sclerosing hyaiinors of the perfneunum with atrophy of neureflbrils. Tactile corpuscles (WagnerMetsintr. Padni) were unaffected. V.. Bone Lesions The man striking feature in a biopsy specimen of the bone, obtained from a French worker with OAOL (case 4 of both Benoit 1961.Mann *t al. 1967) was marked thick ening and hyatinization of the periosteum with chondreid metaplasia of the inner most layer. Supplying capillaries and arterioles showed occlusive changes identical with / m2& feta! ucc 046916 ' 4-if *i 40 W.K Lclbacli and II.J. Manteller 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 histomorphulugy ufbone lesions in the familial am) idiopathic type of acrooneolysis is limited. In the few cases where biopsy material could be ob tained. there was replacement of bone by nonspecific fibrous tissue, but inflammatory and degenerative changes or osteoid formation were not found (Dnpas et al. 1936: Elton and Bnnistein 1954. Greenberg and Street 1957:Scltn-orzweiler 19J7). In this context, it should be kept in mind that Viola succeeded in reproducing dermal, vascular, neun] and skeletal lesions in the skin of the pawl and in small meta tarsal bones of experimental animals winch were very similar to those observed in man. Viola exposed rats to 30 000 ppm VCM.4 h/day. 5 days/week, for 12 months and de scribed the histology of these Jesons in detail (1970b). 4.1 J Arteriography, Capdlaroscopy, Infrared Thermography Arteriographic evaluation of the vascular tree of the hands revealed patency of the large arteries in all cases examined. The vascular lesions were almost invariably con fined to the small digital arteries, although the superficial and deep palmar arterial arch may occasionally show some narrowing and a paucity of side-branches (Lange et al. 1974a;.l/nn/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 ot even total occlusion with development of collateral vessels. Besides, a conspicuous retardation of flow of contrast medium was noted, and peculiar tortuosities of patent digital arteries were found. Circumscribed hypervascularity of the terminal tufts and in the region of the wrists was noted in some cases (Benoit 1967, Lange et al. 1974a; Veltman et al. l97S\Pretton et al. 1976: J/ruerr et al. 1973; Came and Mem 1978). Angiographic findinp in a larger group of 19 symp tomatic FVC workers with cither Raynaud's phenomenon and/or acroosteolysis ( 519) were recently described in detail by Koiseltwin et al. (1980). Raynaud's phenomenon had been observed to persist in these patients for prolonged periods after termination of exposure and even after roentgenological evidence of healing of resorptive bone defects in those who had formerly suffered from ictoosieolyiis. In addition to vary ing degrees of stenosis or oedusion of digital arteries with reopening of small collat eral vessels, acral hypervascularity and considerable retardation of perfusion in spite of premedication with tolazoline (Prixoline. I'nited States), the most conspicuous features observed in the majority of these patients (14/19) were circumscribed elonga tions and tortuosities of digital arteries resembling cirsoid aneurysms. An example is shown in Fig. 3 of generalized tortuosity and elongation of digital arteries in a 54year-old patient who started to complain of severe sensitivity to cold 3 yean after cessation of VCM exposure (about l year prior to death from both angiosarcoma of the liver and hepatocellular carcinoma). The pathogenesis of there peculiar vascular alterations is not elear. but the possibility presents itself that they may be due to de struction of elastic fibres in the vesxl walls in analogy to similar alterations of digital arteries seen in rheumatoid arthritis ILaut et al. 1963.1967). Vinyl 7 Stu< vations finger? ed a var Ur areathose s. fetent ,! Urotcb. control ence in FVC w. of distu induce,. A si. iPVC-y chcntic: notmaii was con number cmplo) related It also s more sc A ucc 046917 rwraraag-  I teller ..e* w he bent wpaihic J1 be obilammatory i. 1936. "1. Juting rfnaU mttavtd in man. *ths and de- y of the mlv ionarterial iff i . were tr1 or diffuse 'I vessels, tl pecului rit> of -*<3/19 Kiuwntnon r.-mnation bone n varyall rollat-i in spite I'ICUOUS ihed eiongtvarapit is mS4s after nuonaof - vsicuiar due to de of digital V.n>l Chlonde-Aitocuicii Diseaw 41 W f.$9 m -vS* Wit I."?-v Aate it *.. ,\*&4 'JS & 14#* fi.3. Contpicuou* ludiwtiiio and tbn(]ln,n <>l Uiiciijl tflcrin Studies of microvascuiaf changes by wide-field capillary miemteopy (direct obser vations complemented by photography) of selected skin sites - such as nail folds, Gr.p:?ads. dorsum of phalanges and of proximal interphalanpal joints - demonstrat ed a variety of capillary abnormalities, Le. dilated or giam capillary loops, pale avascu lar areas, capillary and subungual haemorrhages. The abnormalities wort similar to those seen in scleroderma but were usually lest conspicuous, less numerous and of dif ferent distribution. In a survey of a group of 152 Arneriban PVC workers, these capillaroscopic findinp proved to be significantly more prevalent than in 30 nonexpos*il control subjects (Merer? et al. 1976). There was also a statistically signiiicant differ ence in the prevalence of these abnormalities between symptomatic and asymptomatic PVC workers. The alterations were not only found in wotkeri with clinical symptoms of disturbed acral circulation but also in 6 nonsymptomanr males with either VCM* induced angiosarcoma of the liver (2) or splenomeiaiic portal hepatic fibrosa (4). A similar survey was later undertaken in an unieiected sample of 129 employees of a PVC-producing chemical plant in England with 26 employees of a noo-PVC-produeiftg chemical plant serving as controls (Maricq et at. 1978). The prevalence of capillary ab normalities found in them British workers, which were of the same type and degree, was comparable to that in the American sample, although the Utter included a larger number of more severely affected symptomatic patients with greater mean length of employment (IS yean vs 3J yean). In the authors' opinion, this suggested that VCMrelated disease may develop independently of differences in manufacturing procedures. It also suggested that this easily detectable type of microvascular lesion may precede more senous VCM-induced disorders. In t small subgroup of 13 clinically affected f 42 W.K Laibach and IIJ. Marstellcr British woriccn who were examined 6-24 montlu alter leaving the plant (termination ofexposure), 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 w considered to be too small. The same type of eapillaroscopie 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 {Byczkwtka and LAiigautr'Lnvowicke 1974). infrared thermography, another non-invasive method, used by Ray et al. (19~4) for the study of acral circulation, revealed abnormalities of surface temperature rang ing from marked hypothermia of terminal phalanges (which are normally warmer than the rest of the flngrrs) to "complete termini] imputation" in four PVC workers suf fering from OAOL. In one of them vascular disturbances as evidenced by infrared thermography persisted in spite of complete healing ofOAOL. Stewart et al. (1975) demonstrated uneven blood flow in the fingers and patchy hyperthermia in the distal part of the OAOL-affeeted left index and middle finger of their atypical case. Local ized acral hyperthermia seen on 1R thermography corresponded to the angiographic finding of circumscribed abnormal collections of small vessels (compensatory collat erals?) in the pulps of the affected fingers. Using 1R thermography in a survey involv ing 143 PVC production workers and 56 controls, Williams <t al. f1977) assessed the time needed for heat tecum after immersion of one hand for 10 s in a water bath kept at 19*C; however, no difference between VCM-exposed subjects and controls and be tween groups within the exposed population was noted. 4.1 j6 Immunological Studies Early experience with the syndrome of occupational aeroosteolysis suggested certain timilamies 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 ty- .-mic collagen disease, notably immunological features, as pro posed by Marin et al. in 1967. Ward et al. (1976a, b) carried out inununoiogicai studies in 58 workers from a British polymerization plant who were referred to them out of a total past and present work force of 320. Mean duration of exposure to VCM was 39 months (6-75 months). Of these 58 wotktn. 28 were symptomatic (Raynaud's phen omenon. 9: scleroderma of hands or feet, 6; OAOL, 2; sensitivity to cold, excessive fatigue,limb pain, paraesthesias). Slight hyptrimmunoglobulinaemia, usually 1(0. the presence of mixed cyroglobulins. and in vivo conversion of both Cj and C4 were found in 19 patients in the symptomatic group, with additional evidence of reduced Tell population and increased B-cell proliferation. Mixed cryoglobulins, in vivo con version of complement and depressed valuas for C] or C* were taken as evidence for the presence of circulating immune complexes. Autoantibody screening demonstrated low-titre antinuclear antibodies (IgC 1/20-1/50) in eight of the nine patients with Raynaud's phenomenon. Aggregates of IgC, C4, Cj. end 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 subintimai regions of small Vinyl Chi* and medic lungf] cat The au and bone <, rbolic inter plasms pro which surr eular occIl as s resuit tors of tis to further Jayton et; suffering f; than in no ride diseu< In an e In four Pol decrease in ever, Lang, titer Seph; 6 together agglutinins were obser tponses pit (1974a) an dencc of at tion of rite tcrminatioi iflununofiu were later ; creases in ii taken up at d to sugge hypcrgami* with far ad three patic: with Raynj degrees of i nins were f range: x i; sderodermof which is In sumi autoimmun establish th in VCM-inu it ucc 04691y H I J^^Ianull.-r Termination -> that amon| . condition, iptilaroscopic rj, 2 fitter*) ;or 2-5 yean *tal. (19"4> penturv rang* ly wanner than ' workers ruf'y infrared etaL(I975) a in the distal I ease. Local* angiographic tatorv collatsurrey involv* *i assessed the ater batii kept titrols and be- .v*d ctrta:ys;-...iu nditiuns jrothei Hires. as pro"logical stu ties - *hem out ot a VCM was 3*t tynaud's phi.iiid.ncesira ually I|C, the *C4 were e of reduced i. in riro con- tridence for - demoniuated -nienti with in were revealucutar endorna of small Vi\l ChlonJu- \esocated Di'vjw 43 and medium-died ancnoles in biops>' specimens of the skin f 10 cases), muscle and lung tl case each). The autliors proposed as explanation lor the induction and pathogenesis of skin and bone changes ;n VCM-induced disease a theoretical model based on reactive meta bolic intermediates of VCM formed dunn; biotransformation binding covalently to plasma proteins. These may act as anugens l as a result of a structurally abnormal protein) which stimulate B*ceil proliferation and anubody response Platelet agyegation. vas cular occlusion and ischaemia were thought to be secondary to complement activation as a result of formation of immune complexes which were implicated as possible medi ators of tissue injury. Ischaemia, in turn, by leading to collagen synthesis, was believed to further activate the complement pathway and thus to recycle the mechanism. Jayson t al. (1976b), who earned out collagen studies in a sfcm biopsy of one patient suffering from OAOL found the rate of collagen synthesis to be considerably higher than in normal controls. The pathogenesis of excess collagen formation in vinyl chlo ride disease has not been fully eluddatea. In an earlier study no cryoglobulina*mia or presence of cold agglutinins wn found in four Polish worker* with severe Raynaud's phenomenon: in two of them a slight decrease in IgC wo noted (Bycskowtka and lanfeuer~Lrvowieka 1974). Ijtcr. how. ever. Linfiuer-Ltwowieka et al. (1976) observed latent cr/oglobulinaenua, detectable after Sephadex G-200 filtration, in 18 of 22 workers with Raynaud's phenomenon (in 6 together with acroosteolym and sclerodcrmalike changes). Again, there wen no cold agglutinins detectable, but in five patients marginal to slight elevations of IgC levels were observed The authors sugpsttd that a pathological alteration of immune re sponses plays a key rote in the pathogenesis of vinyl chloride disease. Lange ct al. f]9?4a) and Veltnun et al. (1975) concluded from their results that convincing evi dence of autoimmune disease was lacking. Immunological studies including determina tion of rheumatoid factor (latex agglutination test), quantitative immunoglobulin de termination (Manani radial diffuson technique) and autoanobody screening (indirect Immunofluorescence) were initially introduced in our first series of 50 patients but were later abandoned because of mostly neptive results, except for occasional in creases in immunoglobulin levels (fUanreiler et aL 1975a). These studies were laser taken up again with an additional 43 patients engaged in FVC production but still fail ed to suggest more than an emuc connection (unpublished data). We did not observe hypcrgammeglobulinaemia (see comment in Ward et al. 1976a) except in e few patients with far advanced portal fibrosis and portal hypertension and in the terminal phase of three patients who died frera 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, autoanubodies, etyoglobulins and cold aggluti nins were found is nonets moderately increased IgC level (1.93-3.68 g/liue;normal range: s:i 0J--1J g/litre) was teen in five patients who suffered from OAOL and sclerodermoid skin changes (unpublished data). Elastis antibody litres (the specificity of which is doubtful) were negative. In summary, currently available evidence does not seem sufficient to suggest an autoimmune disease as a pathogenetic mechanom. Further studies will be needed to establish the true significance of the possibly transient immunological abnormalities in VCM-induced disorders. . t .I I ,f f i l a [ \ : - :t i. r V i. V W.K. Laibach and JiJ. MjntclJcr 4.1.7 Pathogenetic Considerations Raynaud's phenomenon as a premonitory clinical symptom, histomorphologv in man and experimental animals and angiological experience suggest that the common denominator in the pathophysiology of both skin and bone lesions in chronic VCM in* toxieation is probably to be sought in the local impairment of blood circulation in peripheral regions, ts Benoit pointed out is lon| a|0 as 1967. By reason of their vas culature. the distal phalanfes arc the skeletal segments which may be most susceptible to impairment of blood supply, particularly to disturbances of microcirculation [Gatna and Mtin 1978). Yet the answer to the next question, the pathogenesis of peripheral vascular injury in vinyl chloride disease, is unknown. It still remains largely a matter of conjecture how a volatile toxic compound that is taken up via inhalation, distributed throughout the systemic circulation and metabolized (bioactivated) in the liver, can bring about, apparently only in a small number of predisposed individuals, after a vari able period of latency severe vascular injury and (probably secondary) damage to peri pheral tissue. Some conceivable mechanisms are briefly listed in a previous chapter (see Sect. 3.4.2.2). but no conclusion can be drawn as to their relative significance. 42 Non-maiignant Liver Disease in Vinyl Chloride/Polyvinyl Chloride Production Workers Long before Raynaud's phenomenon or osteolytic lesions were observed in PVC pro duction workers. Tribukh et el. (1949) studied environmental conditions in a Russian plant where polyvinyl chloride resins were produced and compounded. Without going into detail, the authors pointed out that moderate nontender hepatomegaly was found in a larger porportion of a group of 73 workers (48 males, 25 females) mostly engaged in PVC compounding; 'anicteric hepatitis* was diagnosed in 21 of them (15 d.6 9). Al though the authors knew about the narcotic action of high concentrations of VCM (75 -250 mg/litre 30 000-98 000 ppm) from the literature, which they explicitly mention, and also knew about the release of unreacted monomer from the powdery PVC resins during thermoplastic compounding, they apparently held other volatile compounds derived fromhalogensted aromatic hydrocarbons (suchas chlorinated naphthalenes and diphenyls) used as plaiticiztri responsible for the systemic toxicity. They urged, however, that strict monitoring of the health of time workers should be introduced to ptevent the development of severe liver damage, and they suggested the installation of ventilation facilities of sufficient capacity. Nonicterie hepatomegaly was again recorded by Suctu et al. (1963) 14 yean later in almost one-third of the total work population (51 of 168 employees) of two Rum anian PVC-produdng piano, including110 eases with additional splenomegaly. Dm biopsy in two of these workers revealed chronic hepatitis. Studying the prevalence of temporary disablement due to liver disease among 350 employees of the Sverdlovsk plastics industry,hahin (1965) found the highest morbidity among employees of the PVC production unit, compared with other units engaged in the production of nonPVC plastic materials; 170 workers of ancillary industries served as control subjects. Vinyl Chlonde-A> The clinical sympr many as J55ofih survey was describe developing chronic character of nonm:- In 1$72 fCranic had been routinely. time-weighted avern environmental data wise multiple linear tion and, to a lesser level of past exposur the individuals stud TWA levels of300 p in clinical laborator. *d BSP retention w; case (Marsteller et a. In West Germandermatolopsts in Be At lint sight, the s> derma. This provoke Progressive systemic a first group of 13 p; from a nearby PVCfrom cither OAOL<. phagcal varices due > a group of 20 relanv pievious liver disease Medical Department patier.t and revealed capii's}ibrowo}`ly, marked portal h> al. 1973). It was now encompassed a large Hence J&he et al. (ly In retrospect, th; spleen altcnuoni in e the long latency peric. disease which is aeeo:i hepatic parenchymal Only 3 months Lt was surpassed by the; /h er. an exceedingly r workforce of 274emr ican plant {Creech et .upper gastrointestinal Lw*4 'J a ucc 046921 Manteller rftolofy in man ommofl Je anic VCM in oculation m ii of thtir vas.on susceptible rtnbuon iOuma u of peripheral -yelv a matter of , distributed the liver, an tab, after a van- Jama|e to pen* tout chapter (tee iiieanee. t :J in PVC pro ne m a Raman Without goinf uiiy was found engaged m 6 3).A1rvm hey explicitly i the powdery trier volatile chlorinated acme toxicity, ikenriiouid be > aoneited the I14 yean later i) of two Rurniiwjaiy. Liver <c prevsienct of lie Sverdlovsk -inpioyees of the coon of nonaoi subjects. V Vm>l Chlunde-AiuviauJ DiMia*- 4J The clinical symptomatology of - typically nonictenc - live.- disease obiened in as many u 15" of the current work forwJ of the PVC production unit during a J-year survey was described as having been consistent with the diagnosis of an insidious!) developing chronic hepatitis. No histological data were available, however, and the true character of nonmalignant liver disease found in these workers remained obscure. In 14*2 AVjmcr and Murchicr txamined a group of 98 healthy male workers who had been rounnety exposed to VCM for periods up to 25 years and for whom career rime-weighted average exposure estimates were available. In an aiien.pt to correlate environmental data and results of a medical surveillance programme by means of stepwise multiple linear regression analysis.it emerged that bronauJphthaitin (BSP) reten tion and. to a lesser degree, the icterus index were significantly correlated with rite level of paR exposure to VCM. Although no oven dinicai disease was found in any of the individuals studied. Kramer and Murchltr eonduded that exposure to VCM at TWa levels of 500 ppm or mote for s working lifetime could result in etnain changes in clinical laboratory parameters. As it later turned out. slightly to moderately increas ed BSP retention was the most consistently pathological test for VCM-induced liver dis ease tMunrcUer e: ai. 1975a). In West Germany the first cases of occupational OAOL were observed in 1972 by dermaioiagxs in Bonn (Jiiiic and Lanfe 1972:Juht et ai. 1973:Stem tt ai. 1975a. b). At tint sight, the sympeomatotor1' appeared to resemble atypical progressive sclere dema. This provoked * thorough search for manifestations of visceral involvement. Progressive systemic sclerosis, however, could be excluded- On medical examination of a first group of 13 polycieancts who wen referred to the Department ot Dermatology from a nearby PVC-preduong plant it emerged that 3 of them, who did not suffer from either OAOL ot scleroderma, had a history of unheralded bleeding from oeso phageal varices due to portal hypertension (Jvhc et al. 1973). Further invciugatton of a group of 20 relatively young PVC production workers (mean sge:40 yeas), in whom previous liver disease could be excluded, was carried out in collaboration with the Medical Department, peritoneoscopy and guided Uver biopsy were performed in each patient and revealed varying degrees of nonarrhotie portal, perttimtoidal and mbcapsular Jihrosis ofthe User. with splenomegaly, thrombocytopenia and. leu frequent ly. marked portal hypertension, but strikingly Unit htparic dysfunction (Manteller et al. 1973). It was now realized that the disease spectrum in VCM-exposed individuals encompassed a larger scope of injuries and. in fact, suggested a systemic toxic effect. Hence Jiihe et al. (1973) prepared the term `vinyl chloride disease'. In retrospect, this comparatively late recognition of the true nature of liver and spleen alteration; in ehronic VCM intoxication can be attributed, at leas; in part, to the long latency period as well as the htsdious onset and course of this type of liver disease which is accompanied, even far into the advanced stages, by only minimal hepatic parenchymal dysfunction. Only 3 months latsr, however, in February 1974 the significance of this discovery was surpassed by the alarming announcement that four eases ofanfiotareoma ofthe Urtr. an exceedingly rare malignant tumour, had been found among a comparatively small work fores of 274 employees of the PVC polymerization section of a large North Amer ican plant (Creech et ai. 1974al. Two of these four patients had tint presented with upper gastrointestinal bleeding due to porui hypertension between 1964 and 1970. * / 46 W.K Lelbach snd H.J. Marsieller There ii no lou|er any doubt that chronic exposure to vinyl chloride monomer can produce two different types of liver disease in man as well as in experimental animals: 1) N'ondrrhotic portal hypertension 2) Angiosarcoma of the liver. The two conditions have one feature in common: they arc both rare disorders which are not easily recognized during life. Nontirrhotic portal hypertension and (often inconspicuous l portal fibrosis are not pathognomonic. Primary splenic enlargement and (astrooesophageal haemorrhage due to marked portal hypertension in the absence of. or preceding, the development of cirrhosis was first desenbed by Bantt in 1894. As 'Band's syndrome', this symptom complex and its aetiology and pathogenesis have continued to be a matter of debate. Under the designation Idiopathic', or `primary, portal hypertension' the syndrome has bean observed notably in India and other South-East Asian regions (Ramahngeswami ct al. 1962;/meege ct al. 1962, Bow et al. 1967a, b;Boyer et al. 1967; Jama et al. 1971). It has been seen only sporadically in the Western World (Roussclot 1940: Ravenna 1940; Tisdale et al. \9S9\Poiish et al. \962`. Miller and Brandt 1962\SUlerys and VtUioi 19A\ Mikkelscn et al. 1965;/bar I970:scerrm Marin et al. 1974; Mendenhall et al. 1974;C/tnti 1975; VtUencwe et al. 1976).Iber (1969) estimated that "centers throughout the worid reviewing their experience with portal hyperten sion encounter 3 to $% of patients who do not dearly fit into the category of cirrhosis or blockage of the portal vein." In the absence of an identifiable aetiology it has been speculated that in noneirrhotic portal fibrosis observed in India.unknown toxins contained in indigenous drugs, herbal medicines or adulterated food might have been responsible for the condition {Soma et al. 1971). ViUeneuve et al. (1976) suggested that, apart from VCM and inorganic arscnicals. other still unidentified toxins could be the cause of this syndrome. Idio pathic portal hypertension has also been observed to occur in association with known hcpatotoxic agents, their common link with VCM being, so far with the exception of vitamin A, the induction of angiosarcoma of the liver. There agents are: * a)Inorjankanenicals (Zeeyen et al. l97Q;.Ve/e and Aziopardi 1971 \KnoUc et al. 1974Morris ct al. 1974-,Huet et al. 1975; VUIcncuve et al. 1976: Cowlishaw ct al. 1979); b) Hypervitaminods A (Muenter et al. 1971 ;RusseU et al. 1973.1974; Hruban et al. 1974;/rr/#r et al. 1977):and e) Recently,copper sulphate in Portuguese vineyard workers (Pimentel tniMeneces 1977). Arsenical preparation] (usually prescribed as Fowler's solution - potassium amnite) have in the past been used as a tonic in neurasthenia, as an adjunct to iron therapy for anaemia, as antiepileptic drop and well Into the 1950s for the treatment of psoriasis. In this context, Band's remark in his original paper (1898) that anaemia accompanying primary splenomegaly responded best to arsenical preparations is of note. In a renowned German pharmacology textbook of this period (Xotlinagcl and Rossbach 1880) Fowler's solution is also listed as a traditional anumalanal drug of d HJ. Marstelle.* le monomer can penmental animats: 'i tar* disorders mat fibroin an not at haemorrhage due : development of \ this symptom .1 matter of debate, o' the syndrome has (Hjmaiinteovjnii l67*.5aww et al. ijuefot 1940: ''andt l962:5tJervj i et at. 1974; r (1969) estimated h portai nypertencategory of cirrhosis d that in non.-irriiotic venous drugs. heroai - condition \Surna et I and inorcr.mc wndrome. Idio- tilon with known e exce; non of W \$"\ :Kttollc et al. luwfit/idM' i*t al. *3. \9~4\Hmhan et rimenttl andMcnczct \ - potassium an adjunct to iron 0* for the treatment 1898) that anaemia ' prvparanons is of d (Nothnafe! and ninalahai drug of Vinyl Chloride-Associated Dimase 47 long standing. Gtaimrrah and I'iranueatti (1979) recently implicated an indigenous Thai medicine eontaring anenic as a possible actioiopcaJ factor m a case of idiopathic portal hypertension. Dana et al. 11979) found significantly elevated levels of anenic m liver ussue specimens of four of nme Indian patients with idiopathie portai hyperten sion resulting from chronic anenic intoxication icontsnmated drinking water, use of Ayurvedic medicines). Typically.liver disease in these eases occurs in conjunction with other evidence of chronic anenic intoxication, such as skin pigmentation, palmar and plantar hyperkeratosis, skin cancer and sometimes carcinoma m* other sties. However, neither histological nor radiolopcal or haemodynanuc criteria permit a clear distinc tion between Idiopathic* portai hypertension and nondnhotic portal hypertension caused by chronic anenic tcxit'ication or chrome exposure to VCM, as was demon strated by VWtnaott at al. (1976) in a study of flv patients. After prolonged treatment with excessively high doses of vitamin A (psoriasis, ichthyosis and other dermatological conditions, adjuvant cancer therapy and in health faddism) chronic intoxication has been seen to cause hepatic fibrosis and cirrhosis (Muenttr et al. \9Tl :Flenchmann etal. 197?; Xistier tt al. \9'~,Ruutll tx al. 1973. 1974). Storage of vitamin A in hepatocytes and one type of fat stonng, nonphagocytie pensinusoidai cells [Ito cells (/ro and .Vcmoro 1953)] could be demonstrated by fluo rescence microscopy. Stimulation and proliferation of {to cells, wluch as probably fibroblast precursors {Popper and Vdvxfricnd \97Q\Schnack et al. 157), provokes an increase in basement-membrane-iike mstenal and collagen within the pensinusoidai space and leads to pensinusoidai fibrosis with partial obliterationof Oisse's spaces and the sinusoidal lumen (Hntban et al. 1974). The recognition of idiopathic portal hypertension, hepatic fibrosis, cirrhosis and angiosarcoma of the liver coexistent with excessively abundant hepatic deposition of copper (besides evidence of `vineyard sprayer's lung*) in a group of 50 vineyard workers in Portugal ;s. to our knowledge, the first report in which chronic copper intoxication a implicated as the astrological agent. For periods varying from 3 to 45 yean, these worktn had been enpged in sptaying vineyards with a mixture containing copper sulphate on 15-100 days per year. The authors noted a close morphological resem blance of the lesions to those resulting from exposure to inorganic anentcals and to vinyl ehlonde (Pimentel and .Wenezes 1977). Although extrinsic chronic copper intoxi cation is virtually unknown m man. potential hepatotoxicity of long<ontinued uptake of copper wb discussed by BlomfieU 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 lus received less attention than the spectac ular discovery of tne rare hepatic neoplasm. In continuation of our first two surveys (Manteiicr et a!. 1973,1975a. b), we have now (end of 1980) observed 17 patients (all members of a total work force of approximately 180 polymerization workers) in whom clinical and morphological examination, including peritoneoscopy and guided liver biopsy, revealed advinced portal hypertension (Table 11). A larger propornon of them Cm presented with symptoms ofunheralded gastrointestinal bleeding. On follow up. we strongly suspected that anpoarcoma was developing in four of them but were unable to prove it during life. Only post-mortem examination finally confirmed the diagnosis. In a smaller scries of seven patients with nonerrhotic portai fibrosis and / r 4g W.K. Lelbach and H.J. .Maisteller Tabic 11.17 PVC workers with advanced portal hypertension i marked ooophagejl vanco. episodes of upper (*l bleeding, splenomegaly i Age at diagnosis Duration of exposure IVntoneoscopic and Vo. (years) (years-months) histological diagnosis 1 30 m 31 3 32 4 35 5 a 35 6 39 7 39 8 41 9a 41 10 a 47 11 50 12 51 13 $2 14 52 15 54 16 * 58 17 a 61 5 5/9 3/6 4 9 10/6 13/6 7 18 18 6/6 17 13/3 II 6/6 21 13 Nnnvirrhotic fibrost* Noncirrhonc fibrosis Voneirr!- jtie fibrosis Noncirrhoiu fibrosis Noncirrhonc fibrosis Noncirrhotic fibrosis Noncirrhonc fibrosis Noncirrhonc fibrosa Postnecrotic cirrhosis Noncirrhonc fibrosa Noncirrhonc fibrosa Noncirrhotie fibrosa Noncirrhonc fibrosa Noncirrhonc fibrosa Noncirrhonc fibrosa Postnecrotic cirrhosis Noncirrhotic fibrosa a On follow-up patients 5. 9,10. lb and l? subsequently developed angiosarcoma of the liver and died 3-6 yean after diagnosis of portal hypertension. Patients 6 and 14 are at present 11981) under observation for suspected development of angio sarcoma of the liver, 6 and 11 yean after peruoncoscopic diagnosis of portal fi brosis associated portal hypertension. Smith et al. (1976a) observed later development of angiosarcoma in one of them, (f a rough estimate based on these two small senes wert acceptable.it would appear that approximately one of five to seven individuals suffer ing from advanced VCM-induced portal hypertension might be expected to develop angiosarcoma later, although PVC-induced hepatic fibrosis per se is probably not a premalignant lesion. 4.2.1 Clinical Manifestations of Non-malignant Liver Disease Physical examination is usually disappointing. In the mote advanced stages ol VCMinduced nonmalignant liver disease, ptlpable splenomegaly and a slightly to moderate ly enlarged liver may be the only physical signs. On palpation, we found hepatomegaly in 3] and splenomegaly in 16 of SO selected PVC production workers who had been heavily exposed in the pan (Manteller et al. 1975a). Lilis et al. (1975) reported hepa tomegaly in 15% and splenomegaly in 3.4% of 354 consecutively examined employees (267 currently employed, 87 former workers) of one PVC polymerization plant in New York State, USA, s number which included virtually the entire current produc tion work force. A significantly higher prevalence of hepatomegaly was found in those Vinyl Chlon- exposed for r splenomeea,') In contra; ntent ofhepa eqtases, gyna. not seen. Eve phalopathy d workers only It is push preceded adv. only one case development 4.2.2 Labor: Owing to the not the targe: value for the c This makes it 1974;Creec/r thrombocytoj logical bioche-. the levels of s. quent (Mantc (ICC; 0.5 anJ liver function workers of a. (Tamburro et progressively of abnormal S there was ovei phosphatase I alkaline phosp megaly and/i- Except for and Veltman i the retieulocy parameters us* presenting fea< Sion (Smith et be dealt with Assessment matie workers factor* of PV( coproporphyn I.J MaiMeiler hageal opic and ci dutno'io *iic nbrusis tc fibrous tic fibrosa .tic fibrous tic fibrosis ,tw fibrosis fibnuii m: fibrosis lie eirrftosis ut fibrosis in. fibrous . >ut fitrosis nit fibrosis --ue fibrosis 'i.suc fibrosis i*i.- cirriiOMs ut fibresu . ..irto~a ot iiicnts 0 Jnd * tntto* p.HlSI fi- III 01 hes w e illllSI lUMCt* u develop ably not a pre- ;of VCMv to moderate* ; Hepatomegaly -ho fud been sported hepauJ employees 'm plant in irtnt produc* found in those Vj,i>! Chlonilc-Attoctaied Distt-t 49 exposed for more than 5 years, whereas the difference in the prevalence of palpable splenomegaly was not significant. (n contrast to cirrhosis of the liver, clinical symptoms indicating serious impair* ment of hepatic function such as jaundice, vascular spiders, palmar erythema. teiar.giectases. jynaccomastia. peripheral oedema and ascites or hepatic encephalopathy are not seen. Even after massive bleeding from oesophageal varices portosy stemic ence phalopathy does not develop. Ascites and hepatic coma have been observed in these workers only in terminal stages of angiosarcoma of the liver. It is pusling that acroosteolysis and sclerodermoid skin induration have only rarely preceded advanced stages of VCNUnduced liver disease. To our knowledge there is only one case of angiosarcoma of the liver on record which was associated with prior development of acroosteolysis (Roche et il. 1978). 4.2.2 Laboratory findings Owing to the fact that htpatocytes. although being the primary site of metabolism, are not the target of toxieity, standard biochemical liver function tests are only of limited value for the detection of liver disease in populations at risk (h'illiams et al. 1975b). This makes it very difficult to devise adequate screening programmes (Martin et al. 1974; Cratch and.lfjU 1975; hVerr et al. 1975;Seri et al* 1975.1976). Apart from thrombocytopenia, we found 4S*min BSP retention to be the most consistently patho logical biochemical test: usually minimal hyperbilirubinaemia and nunor elevation of the levels of serum alkaline phosphatase. SCOT and 5GPT were considerably leu fre quent iMantcUcrtt al. I975a). Another dye-removal test, indocyanine green clearance flCC; Oi and 5.0 mg:kg), also proved to be more reliable than standard biochemical live: function tests in correctly idem;;,.-mg early hepatic injury in 1200 vinyl chloride workers of a chemical plant is Louisville, Kentucky, during a 4-y*ar screening penod iTamburro et al. 1978b). The expos. ;t rank was found to be closely correlated with progressively increasing frequency of abnormal ICC clearance, whereas tht frequency of abnormal SCOT, and alkaline phosphatase only increased in late stages, often when there was oven clinical disease. In the surety conducted by Lilia et al. f1975), alkaline phospliatase levels were elevated in 16.67- of the 354 workers examined. In their tenet. alkaline phosphatase was also closely correlated with the clinical symptom of hepato megaly and/or splenomegaly. Exctpt for thrombocytopenia (less than 150 * 10* plattlets/litre) which Ltmjt and I'clrmen (1977) found to be present in 76 of 100 workers, and a slight increase in the reticulocyte count (in 35 of 79 workers,Lc/ige and Veltman 1977), hatmatoiogical parameters usually do not contribute to the diagnosis. Thrombocytopenia was also the presenting feature in two of seven British workers with nondrrhotic porui hyperten sion (Smith et al. 1976a). Thrombocytopenia and abnormal platelet function tests wtU be dealt with separately in Sect. 44.1. Assessment of urinary excretion of porphyrins and porphyrin precursors in sympto matic workers who had been cnpged in the production of PVC (n 23) or the manu facture of PVC articles (n ! 7) revealed varying but mostly mild degrees of secondary coproporphymuna m the majority of them (Ltiift et al. 1976b). The significance of / r i :l i I r . *f u i . L f i ? i 50 W.K. Lelbach and H J. Manteller these findings as an indication of toxic liver damage is not clear and the relation to previous exposure to VCM remains to be determined. 4.2 J Cross Inspection of the Liver and Spleen The gross appearance of the liver, as assessed by peritoneoscopy (Uarstcllcr et at. 1975a. b : Monteller and Lelbach \9Ti\Lelboch and Mametlcr 1977) or at exploratory laparotomy, is that of a normal-sized or slightly to moderately enlarged organ with often blunted and irregular anterior edge. Inspection of the liver at peritoneoscopy also permits exduaon of partial nodular transformation as described by Sherlock et al. (1966). In most cases, the surface of the liver is smooth or slightly uneven with shallow indentations, but it may be finely granular, trabeculated or have a peau d'orangc-iike appearance. At most, there are micronodular changes but the diffuse coarse nodularity of cirrhosis is only rarely seen. Progression to frank cirrhosis with severe derangement of hepatic lobular architecture was observed by Smith and Williams 11974), and also in two of our recent cases in combination with development of angiosarcoma. On palpation (direct or by pemoneoscopic 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 Fig. 4. Peritoneoscopic view of left hepatic lobe in noneirrhotic portal hypertension (January 1979). Blunted anterior edge, smooth to finely granular surface, conspicuous patchy capsular fibrosis. (42-yearold autoclave cleaner. VCM exposure 1965-74. 1973 thrombocytopenia as first sign. From 1974 to 1979. marked progression of portal hypertension with splenomegaly and one episode of bleeding from oesophageal varices.) See also Fig. 5 (patient 6 in fable 11) Vinyl Chi contras: ipectedly s i* a focal o opacities.' t-ltellate sc: mg (Manti tittue in C extending nective tin processes ii or mote di. are seen in 421.4 His: Histolopc.' is generally sis, strikin'fibrosis are (Fig. 5a-d i reactions, throughout fibrosis. $utoiogicai c 1976). Depend date of bie; rant liver o ject to mark ations is sc: Thomas 19* 1976), but (Popper et j *2.4.1 Hk: In its fully j of dense, pa> bile ducts g. <vith forman central and t of connects wftii enlarge pcruinusoij. oidal wails.: Muller et al. ^L Mameiler cmion to ..ret si. n exploratory ugan with oeoscopv also hick ct al. with shallow !`onnge-like ne nodularity lerangement > i, and also :oma. - liver is normal iirtal hyper* J tne intesthe abdomi'tension otter. > pertension .'.conspicuous 63-74. c*sion of i snoptiagcal Vinyl Chlonde-A^ociated Discs** 51 contrast sharply not only with minimal alterations of the surface but also with unex pectedly scanty histological evidence of hepatic llbrosis. The most conspicuous feature is a focal or diffuse capsular llbrosis of varying pattern (Fig. 4). presenting as whitish opacities. Hie degree of capsular involvement ranges from diffuse tmy commalike or stellate scan to coarsely reticular and irregularly patchy milk-white capsular thicken ing (Marstelkr et al. 1975a). Histology showed that this focal increase of connective tissue in GUsson's capsule may extend into the parenchyma and connect with septa extending from enlaryn; fibrosed portal tracts \Popper and Thomas I 7). The con nective tissue capsule of the enlarged spleen also seems to be sensitive to VCM-tnduced processes that have taken place in the underlying tissue so that focal white thickening ot mote diffuse opacities together with circumscnbed subeapsulir haemorrhagic cysts ait 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 subcapsular fibrosis are found in combination with peculiar aiterauons of sinusoidal lining eells (Fig. 5a-d). Hepatocellular changes usually play i negligible role and inflammatory reactions, if present at ail. ait insignificant. The lesions ate distributed quite irregularly throughout the liver and may vary from minor inconspicuous degrees to quite sinking fibrosii. Surgical wedge biopsy of sufficient depth appears to be more suitable for histoiopca. evaluation than needle biopsy specimens (Smith et al. 1976a:Btendis ct al. 1978). Depending on length and degree of exposure, interval between Ian exposure end date of biopsy, as well as individual factors, lustopathology of VCM-tnduced aonmalignant liver disease is represented by the following features whose manifestation is sub ject to marked interindividual and topical variation: the same variability of tissue alter* auons it seen in iht nontumorous areas of the liver in anposarcoma (Popper and Thomas 1975: Tnomes et al. 1975;Jenfc ct al. 1976; Gedifk et al. 1975; Wtutbrttt 1976). but in these cans the nontumorous lesions may be even more conspicuous (Popper ct al. 1978). 4-2.4./ Htpanc Fibrosis In its fully developed form, minimal to marked enlargement of portal tracts by excess of dense, paucicellular connective tissue, which in advanced cases contains proliferated bile ducts and some periductular inflammation, may in rare instances be combined with formation of periportal septa linking portal tracts or, even more rarely, connect central and portal canals. Other portal areas appear almost normal. Focal accumulation of connective tissue in the thickened Glisson s capsule may he connected by septa with enlarged infrccapsular portal tracts. A more striking feature is an intralobular pensinusoidal `netlikf' fibrosis with more or less prominent coDagenization of sinus oidal walls, in some areas even progressing to ftank capillarization (CeJigk tt al. 1975; Matter et al. 1975). The focal inuasinusoidal fibrosis may be subtle and In some cams I W.K. Lclbach and H.J. MjiMtrllsr stellee L-v-1*. :*._ .. ` % `t~~ `Vv*- * -.ST* `-MVrcv.r-*. Vinyl Chl^n<!*~\*HvuU'd Disease wr . . *u -V &*1 ihrosis H4E. 'act tfr aud Fit- Sc Focal portal fibrosis ftrft upper earner> and reticulated perisiniuoidal fibrosis with activated proliferating and pleomorphic sinusoidal lining cells. Trichrome (Coldneri stain, blue filter. * 2!0. d Conspicuous focal dilatation of sinusoids. Activation and moderate polymorphism of pioliferated hyptrchromauc sinusoidal linuig cells. Enlarged hepatocytes with .lyperchromatic nuclei, some of them bmuciear. < Potential precursor Mage of anposarcoma7) Courtesy of Professor Mfiller-Wallrat. Institute of Patnology. Amberg. HiE,r J00 :i ofcUAVt xm ucc 0469: W 54 W.K. Leibach and H.J Mantcller may be recognized only in connective time stains. Trichc et al. 11975) pointed out that in one worker with severe acroostcolysis 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 ctnuilobular increase in collagen between hepatocytes and in Diaei spaces together with proliferation and hyperplasia of sinusoidal lining cells (see also Kurokawa et al. 1977). The same ultrastnictunl deposition of perisinusoidal collagen was observed by Schsttenberg 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 Kupfter cells, abundant deposits of collagen in the Disse's space and resulting reduction of sinusoidal diameter suggesting a possible factor in the pathophysiology of 'sinusoidal' portal hypertension) were seen on electron microscopy in a number of cases of idiopathic portal hypertension of unknown aetiology (occupational histones not mentioned) {Sommerschild and Kluge 1971;Kluge et al. 1970; Tendon et al. 1970). 4.2.4.2 Sinusoidal Lining Cells Marked focal proliferation and hyperplasia of sinusoidal lining cells with nuclear poly morphism and hyperchromasia are the most impressive features of the mesenchymal lesion. The hyperehroraarie nuclei of these cells may show a bizarre shape or resemble shon pegs, and are often arranged in a ehainlike fashion (Gedigk et al. 1975). Tlicse perisinusoidal and sinusoidal cells indude three types: (1) normal endothelial cells, (2) lipocytes (Ito cells), considered to be precursors of fibroblasts and (5) plump cells with spindle-shaped nuclei and PAS-positive cytoplasm. Formation of excess retieulin suggests fibroblastic activity of some of these cells. Focal dilatation of sinusoids, not explained by passive congestion, is another peculiar feature usually aarodated with particularly pronounced alterations of these mesenchymal cells; There is reason to be lieve that this combination of changes may represent a premaiignant stage. 42.4.3 Hepatocytes Unimpressive,nonspecific, degenerative and adaptive lesions (such as minor degrees of fatty degeneration, cloudy swelling, ballooning or vacuolar degeneration, increase of lipofuscin pigment and proliferation of smooth endoplasmatic reticulum of hepato cytes in focal areas without inflammatory reactions), can be seen to disappear gradual ly with increasing intervals between the last exposute and the date of biopsy, in con trast to the apparently irreversible damage to mesenchymal structures (Gedigk et al. 1975, l977,A/u//er et al. 1975). In poorly demarcated areas there is hyperplasia and hypertrophy of hepatocytes with polyploidy and increased number of binudeated cells. Two types of focal hepitocytic proliferation associated with varying degrees of sinusoidal cell alterations were recently described and are thought to play some as yet undefined role in the precursor stage of angiosarcoma (Popper et al. 1973). 42.4.4 Histology ofthe Spleen Unless splenectomy is carried out in vinyl chloride disease, tissue specimens of the spleen are less easily obtainable than liver biopsy material. Popper and Thomas (1975) Vinyl Chlonde and Thomas ei. to be eharacten geneous red pul follicles with mi endothelial cells occasional fresh spicuous fibrosis In ten cases w Heusemann and terial, together v splenectomy. TIi process. Excess a tive tissue, notab and white pulp, There was icami meshwork and rt and diameter of: of the pulp cord: formation of biz. collagen fibrils. J* the reticular com volume with para matron of eapilia found within the thrombocytes by hanced pooling o help to explain in stages of vinyl chi and Hcusermann < VCM-induced spk of the liver or ex: in the spleen in m dieate a primary . port correlating c: tients is being pre, the spleen in nom able for company 42J Pathophysi The paihophysioit unresolved probiei to splenoponograf of intrahepatic va* venous radicles (Bi and a normal, or o ucc 1 HJ Marsteller fed out no essentnd cosily over* n microscopy i and m Dines :0t (see also <>tdal collagen we could obtgnienla^e and rtsulung xrehyriology i a number of nmal histones -ton ct al. i nudear polv`nesenchytnal .pc or resemble 1075). These helial cells. J) plump cells sees* rencuiin musoids. not -dated with reason to be- *01 depees of -n. mcrease of nofhepato* ppcar gradualttpiy, in con* tdigktttl. twrplatii and 'mudeated *nj depecs of ly seme si yet *8). xnsofthe Hnmm (197J) Vinyl Chlonde-AisociateU Disease Ji and Thomas ct 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. Histolopcally. they noted large germinal centres of the Malpighian follicles with merging of perifollicular zones, dilatation of red puip sinuses lined by endothelial cells of variable, often cuboidal shape, thickening of the pulp cords with occasional fresh haemorrhages, and in one cast Gandy-Gamna bodies, but only incon spicuous fibrosis of the red pulp. In ten eases we obtained needle biopsy specimens of spleen tissue at peritoneoscopy. Htutcrmann and Slum (1977b) and Sttitre and Httntrmann (19TB) studied this ma terial. together with spleen tissue specimens available from three spleens obtained at splenectomy. They found evidence for an involvement of the spleen in the fibrous process. Excess amounts of newly' formed extracellular elements of reticular connec tive tissue, notably collagen, produced by stimulation of fibroblastic ceils of the red and white pulp, particularly m perifollicular and subnpsular areas, were observed. There was scamng of perianenai lymphatic sheaths, obliteration of the pifip 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 coids showed marked alterations with thickening of reticular fibres and formation of bizarre platelike amorphous structures containing irregularly distributed collagen fibrils. Narrowing of the labyrinthine eordal tissue with marked increase of the reticular connective tissue caused a reduction of microcirculatory sequestration volume with parallel decrease of the number of pulp cord macrophages and approxi* matron of capillaries and sinuses. Frequently, focil accumulation of platelea was found within the narrowed pulp cordbed in addition to increased phagocytosis of thrombocytes by residual macrophages. This lends support to ths hypothesis of en hanced pooling of platelets in the spleen (Hnarrmann and Stunt 1977a), and may help to explain the pathogenesis of thrombocytopenia often seen even in the early stager of vinyl chloride disease. By structural analysts of histometneal rttulvs. Stunt and Heusemann (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 extrahepatie portal vein ocdusioif. They concluded that fibtotic changes in the spleen in vinyl chloride disease are not the mult of portal hypertension but in dicate a primary action ofVCM or its metabolites on the spleen. A comprehensive re port correlating clinical and morphological data gathered from this group of 13 pa tients is being prepared tot publication at present. Rcsuta ofhistometricil studies of the spleen in nonanhotic portal hypertension of unknown aetiology are now avail able for comparison (Seki 1965; Yamamoto 1978,1979). 4.2.5 Pathophyriology of Portal Hyptnenrion The pathophyriology of portal hypertenrion in VCM-induced liver disease is as yet an unresolved problem. Patency of the portal vein was demonstrated in ail casts subjected to splenoportography. Portography uaially showed no or only minimal derangement of intrahepatic vascular pattern such as tapering or `eut-ofi* of small peripheral portal venous radicles {Bltndis et al. 1978; Vilknnnt et al. 1976). High intrasplenic pressure and a normal, or only slightly raised, wedged hepatic vein pressure indicate that the / rrfts. s J* W.K. LcIbacJt and H.J. Mjrvtcllcr portal flow is obstructed at the sinusoidal or presinusoidal level. In a group of five PVC workers selected for haemodynamic studies. Blendis et al. (1978) could not demon strate a direct relationship between the decree of hepatic fibrosis in needle biopsy spec imens and portal hypertension- But it should be kept in mind that the distribution of fibrosis in these workers is quite irregular. It has also been suggested by P >ppcr and Thomas (1975) and Thomas et al. (1975) that the increased splenic and hepatic blood flow as a result of decreased splenic resistance in splenomegaly rannot properl) be ac comodated in the hepatic portal vein bed owing to impairment of adaptive distension of portal veins and sinusoids by the subcapsular, portal and pensinusoidal fibrosis. BUndis et al, (1978) found no correlation between spleen or estimated liver blood b Fit. ta. b. Progression of noneirrhotic portal hypertension despite termination of ex posure. Oesophageal varices. (Autodive cleaner, age at diagnosis: 35 yean. VCM ex posure,. 1962-1972.1972 Raynaud's phenomenon, sklerodermoid skin indurations, thrombocytopenia, splenomegaly, and grade 1 oesophageal varices. Gradual progression of portal hypertension. Sudden death from ruptured anaplastic angiosarcoma of the liver in June 1978. Histologically only mild pensinusoidal fibrosis in nontumorous areas! Vinyl flow: veiled 4.2.6 In 19* tic fib couJd tests ;j biopsy of bnd the fib cytesf ing cel follow russu expose sarcorr or less terrain oped (= Liv detemi (BMHF after h, and toi aid of < the reti inertas PVCp, sock et 43 Ai 43.1 I Primary (anpoh haeman cell sarc sarcom,, vascular one at c hood (ft the nun: j40y22 ach and H J. Marerelier * ter*!. In a group of five PVC (!978) could not demon* .ibtotif in needle biopsy spec* ind that the distribution of niggtsted by Popper and d splenic and hepatic blood .galy cannot property be ac:nent of adaptive distension J pertstnusoidal fibrosis. or estimated liver blood f :*V*- 'J'- ii e V*>-. N/"Vm .Ji * . *4 *%^ .r --7.i-. v' . > 1 :`*TJ**fcr<* * l&K&sF -v despite termination of ex* iptoms: 3S yean. VCMadermoid skin indurations. t varices. Gradual progression lustic angiosarcoma of the i nbroits in nontumorous Vinyi Cilonde-Asiociated Oueax: 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 ofNon-malipiam VCM-induced Liver Disease In 1974 Martin et al. fsee also Berk ct al. 19^5) pointed out that VCM-assoctated hepa tic fibrosis, once established, may progress even after cessation of exposure. They could demonstrate this progression despite normalization of all routine liver function tests in a 2"-year-old 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 pemsting activity of the fibroblastic process, wheteas the previously observed activation of both hepatocytes (marked variation of cell size and numerous binucieated cells) and sinusoidal lin ing ceils had disappeared. Since 1973 we iiave observed a number of worken who on follow-up allowed evidence of progressing portal hypertension with development of massive oesophageal varices and subsequent bleeding episodes despite removal from exposure (Fig. 6). In five (7?) of these patients with progressing portal hypertension angio sarcoma of the liver finally developed. In this context.it is of interest to note that more or less conspicuous hepatic fibrosis (ot tare progression to cirrhosis) was the parental terrain in which the majority of cases of VCM-induced angiosarcoma of the liver devel oped (see Tables 13-18). Liver and spleen scans with technetium-labelled sulphur colloid, quantitated determination of spleen size with the aid of 197Hg-bromotnereury-hydroxypropane (BMHP) labelled artificially damaged red cells, and sequential perfusion semngnma after bolus injection of *9n'Te-ptrttchneiate hare been found useful in the diagnosis and follow-up of nonmaiignant liver disease in PVC-polytmtization workers. With the aid of these nonmvastre methods, inhomogeneous uptake of labelled sulphur colloid in the reticuloendothelial system of the liver and enhanced uptake in the spleen, gradual increase in spleen size and reduction of penal venous perfusion hare been observed in PVC polymerization workers developing portal fibrosis and portal hypertension (Biersack et al. 1975a, b, 1977a. b). r c 43 Angiosarcoma of the Urer 43.1 Epidemiology Primary angiosarcoma of the liver (A5L) is described under a variety of synonyms (angioblastic sarcoma, angioblastic reticulosarcoma. endothelioma, endothelioblastoma. haemangioblastoma, haemangiocndothelioma. hacmangioendothelial sarcoma. Kupfler cell sarcoma, malignant haemangioma, metastasizing haemangioma, reticuloendothelial sarcoma, primary sarcoma of the liver). It is an exceedingly rare malignancy, arising from vascular lining cells. It ocoun spontaneously with two peaks in the age distribution: one at early infancy (infantile haemangiocndothelioma) and the other in late adult hood (fourth to sixth decade). The numerous synonyms render it difficult to estimate the number of reported cases and to determine its true incidence. In a recent review 58 . W.K. UIbat.ii and H J Marsteller of the isientute.Alrenpt (1975) lilted 165 published cases of primary angiosarcoma of the liver in adults. In the six autopsy series collected by Airaifa. ASL constituted only 13>% (095-2.7%) of all primary malignant tumours of the liver, which of them* selves are rare findings in the Western World. Autopsy statistics show that the incidence of ASL ranged from 2 to 20/100 000 autopsies during different periods with a mean incidence of 12/100 000 autopsies (Table 12). According to Heath et al. (1975) it was estimated that in the United States the expected annual incidence of ASL is 0.014 in 100 000 inhabitants or 25-30 cases per year for the entire United States. Table 12. Incidence of angiosarcoma of the liver (ASL) in autopsy senes Authors Observation No. of No. of cases Year period utopsies of ASL Region Simpion et al. 1955 1914-1953 24 196 1 Mayo Clinic. Rochester. Minn.. USA Edmondson 1958 1918-1954 52 000 MacS^etn et al. 1973 1900-1969 _ a 1 3 Los Angeies. County Hosp.. USA Western Infirmary Glasgow, U.K. Alrenge 1975 1951-1973 39 700 6 Cook County Hosp. Chicago. USA Rein and Huth 1975 Myrfn and Holmbtrg 1975 1954-1974 30 079 1958-1969 -b 4 (6) c Diiftsvldorf. Fed.Rep. Germany 12 Sweden (adult cases) Daldervp et al. 1976 1960-1975 At least 40 000 8 Netherlands (population 10- 14 million! Among 120 cases of primary malignant liver tumours studied post mortem during this 70-ytsr period, h Among 8 million inhabitants. c 4 Angiosarcomas. 1 haemangioendothelioma. 1 tnalignanr haemangiopcncytoma Accordingly, the identification of A cases of ASL among approximately 270 em ployees of the vinyl chloride polymerization section at a BI. Goodrich plant near Louisville, Kentucky, between September 1967 and December 1973 was duly recog* nized as an alarming situation indicative of a serious new occupational hazard {Creech et al. 1974a; Creech and Johnson 1974). Until 1974, only two carcinogenic agents were known to be associated with the development of ASL in man, i.e. the administration of a radioactive colloidal prepara* Vinyl ( tion of triorgm. dioxide tem am Thot contras: ing evid rcporiet been th, had bee and -'-to, A specu caused I Thorotr from a I ASL (A. Dev, man vin tensiveh 1950-1 tion revt of multi: approve, occurred but nota produce, Kaustrut (35-5 Roth (|t 18.6*4. Fowfcr Oiou haemangj tension h woman w ride) dun had a hie; marines ta The p; be elicire, period 18 history oi Among m observed other han 391 auto; Vbir- * j. Mafittlkf uBLeoma SUBStltUtCd 'eh of themtit* ineder.ee - ith a mean (197$ lit was ' is 0.01 in ' lime. -etMinn.. A-ies. H'isp.. USA i Infirmarv * U.K. Hinp.- Ho<p t S.A i Fed Rf|-. wl lion: .nHIion) neat ounne .-ricyroma ly 270 cm* Hue near duly recoj-wd (Crttch I with the dai prepare* Vinyl ChlonUe-Astoctated Disuse 59 non of thonum dioxide (thototnst > for diagnostic purposes, and chronic exposure to onwyaHic anentcaU Both substances arc stored maini>- in the liver: injected thorium dioxide particles are rapidly taken up by phagocytic cells of the reticuloendothelial systern and are permanently retained: arsemcais are only slowly released from the liver. Tnototrsst came into use in 1928 and was internationally employed as an injectable contrast medium until the mid-1950s, when in use was abandoned because of mount ing evidence of the carcinogenic action of thonum dioxide deposits. MacMuhon et al. reported the lint case of thonum dioxide induced ASl m 19-17. Since then A5L has been the type of liver rumour which occurred most frequently among patients who had been given thototnst injections in the past (daSilva Horta I96":i/a Silva Horn and Mona I967;4'egtwet ai. 1971 ;futh and Pstske 1974; JWtnyrr and Koff 1975). A special type of progressive portal and subcapsular hepauc fibrosis was another lesion caused by thorium dioxide retained in the liver, da Silva Mono (1967) consdered this Ihorotrast fibrosis' to be dearly distinguishable from true cirrhosis. Comma radiation from a lost radium needle has also been implicated as a causative agent in one case of ASL (/loss 1932). Development of ASL as a late complication of chronic arsenic intoxication in Ger man vineyard workers was first described by Liebcfort (1949.1952) and his been ex tensively documented by Roth (1956,1957a. b. 1959). During the 10-year penod. 1950-1959, autopsies of 82 Moselle vintners suffering from chrome arsenic intoxica tion revealed ASL in 8 cases among a total of 61 individuals (74%), with cancer often of multiple sues (Roth 1959). In 1925. atscnic insecticide sprays and dusts had been approved fbr use in German vineyards but they were banned by law in 1942. Exposure occurred not only via inhaiauon during spray periods (approximately 30 days/yesr) but notably by daily consumption of quantities of cheap grape wine ('Haustrunk'). produced from a second pressing of the grape skin residue by addition of water. This Haustrunk. an allowance in kind to the vineyard workers, had a low alcoiioi content (3%-J% v/v) but contained high leveis of residual arsenic (0.2--& .9 mg Ai-Oa/Iitie). Roth (1956) calculated the mean total ingestion of AljOj tc hive been 53.7 g (range: 18.6-88.8 g) for a 12-year period. ASL was also seen after long-term treatment with Fowler's solution for psoriasis (Rcfthon ct al. I W.lJndcr et al. 1975). Chowdury et al. (1977) reported an anecdotal case of apparently benign diffuse haemangioendotheiiomatosis of the liver with considerable fibrous and portal hyper tension but normal liver function. This condition was found in a middle-aged black woman who had been exposed to various chemical fumes (including carbon tetrachlo ride) during 20 yean in a drycleaning establishment, though it must be noted that she had a high alcohol consumption. The possibility that these symptoms could have been manifestations in later life of congenital disease cannot be mild out. The proportion of patients with ASL in whom a pertinent history of exposure could be elicited has varied considerably. In an eaxiier surrey of the literature covering the period 1875-1960, tonBtck& and Bisscher (196 Olisted 12 of 54 adult cases with a history of exposure to either thorium dioxide (?) or anenicaii (5 ofRoth's cases). Among more than 1$ 000 autopsies performed in Bonn dureng 1950-1959, all 8 cases observed were found exclusively in vintners exposed to arsenical* (Roth 1959). On the other hand, Fiechtner and Ryes (1976) recently observed a duster of 4 cases among 391 autoptics during a 29-month period at a hospitai in rural central Wisconsin serving 60 W.k. Lelbavh and H.J. Mantellcr Table ] 3. Personal data of b8 polyvinyl chloride production worker* with anciosareonu pi the liter reported to NIOSH up Ui Aupisi I97S [Spirits and Kaminski I9*3i Date of Birth date dvjtli No Country* (m/d/>)b (m/d,y) Age at death Total years exp. ` Job classification1- I BID 01.12.13 06.29.76 65 17 1.2 CNDil) 12.15.13 j CND t2) 03.06.14 4 CND (3) 08.26.19 s 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 II CND (10) 05.16.15 12 fSR(l) 00.00.28 13 CSR 12) 00.00.26 09.02.55 12.21.57 03.22.62 01.2i.b8 07.05.68 04.10.71 12.24.72 06.12.73 09,04.74 04.00.77 41 43 42 48 56 5! 52 53 53 61 12.00.73 00.00.66 (647) 45 40 (377) 11 14 20 5 23 25 5 26 14 16 15 (147) 1.2 2.3. 12.13 2.5 1.2.5. 14 1. 14 1.12.13.15 1.9. 17 1.12.17 3. 12.16 2.16 1 1 . 14 D (1) 15 D 12) 16 D (4) 17 0(5) 18 D (7) 19 D<8) :o D (9) :i DUO) D<11) 23 DU2) 06.04.30 07.26.31 09.04 JO 01.01.32 09.29.26 1019.17 12.13J4 07.23.29 12.29.36 06.14J8 01.25.69 12.14.71 11.25.74 01.09.75 11.13.75 12.25.75 03.24.78 06.28.77 03.07.77 10.07.77 38 39 44 43 49 58 42 47 4| 39 12 11 17 12 2.4,5 12 11.(1) 21 15 io 10 16 10 6l 24 F (1) 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) 34 CB(I) 35 CB (3) 04.15.24 06.03.11 01.06.20 01.27.27 01.29J8 04.I4J4 00.00.27 04.01 J4 10.08.14 05.24.19 04.20.01 06.02J7 02.19.67 01.24.75 06.26.75 01.03.76 05.13.76 09.12.76 07.02.76 01.30.77 12.25.77 01.20.78 12.03.72 12.24.74 43 63 55 49 38 42 49 42 62 58 71 37 19 1.2 12 29 * 26 2.6 II 1.2 13 6.7 19 . + 28 21 * ** rnm 8 41 (3 1/27) 36 1(2) 37 1(3) 38 1(1) 39 J(2> 40 NIII 11.13.29 03.14.20 08.01.22 08.02.29 12.23.15 12.27.72 07.10.75 10.24.75 08.10.76 01-04.72 43 55 52 37 56 62 21 13 21 \rC: Vin> Tabic .. -- t N0 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 * B. CNI) CSK D. F GB b 00. d * 1.41 2, ai. 3. Pr 4.P-5, fo: 6 .*n7.V 8. pr 9. eh. 'Tablri 1 atelier twurcoma *s> lication1 12.13 14 Vinyl Chlonde*A*iociated Diaes'c bl Table 13 'continued) Birth dare No Country1* w/d.'yb 41 5< II a; S 3> 4? S4 06.23.27 06.10.10 11.16.14 Dale of death im/d'y) 10.20.70 03 19.76 05.12.77 Age at death 43 6* 62 Tout ycart exp. IS 2! 31 Jc'h, v!aiiuJtiorr A 44 USA 11) 1017 23 45 USA (2) 08.1933 46 USA f 31 05.25.15 47 USA 14) 01.15.24 46 USA (5) 01.25.12 49 USA) 6) 1123.28 50 USA (7) 05.03.22 51 USA (8) 05.06.20 s: USA (9) 11.08.31 53 USA (10) 08.16.13 54 USA <11) 05.27.09 55 USA. 12) 11.17.18 56 USA (13) 12.01.21 57 USA(16) 11.04.27 58 USA 117) 05.06.31 59 USA (18) 04.22.28 60 USA (19) 00.00.15 61 USA (20) 08.31.17 6: USA1211 09.02.09 63 USA (22) 10.02.23 64 USA 123) 00.00.23 65 USA (24) 05.07.17 66 USA C5) 03.07.10 67 USA (26) 7(1978) 03.03.73 09.27.71 12.19.73 01.07.68 04.09.64 07 24.7J 03.23.68 08.28.61 03 00.75 05.10.68 03.16.70 05.02.69 07.04.74 03.27.69 1978 alive 11.02.75 04.06.76 01J0.77 01.02.77 12.04.76 04.06.73 05.27,77 03.10.77 7(1978) 49 37 - 58 43 52 46 45 41 43 55 61 50 52 4| 43 46 60 58 67 52 50 60 67 7(197$) 21 13 28 15 20 12 17 15 24 17 23 19 28 4 19 It 22 21 21 23 14 26 20 7(1978) 9 9 10 10 10 10 9(1) 61 YU (1) 04.05.14 08.04.73 59 20 1,2.5 * B. Belgium CN'D, Canada. CSR, Czechotlovakia D. W**t Germany F. France GB. Great Bntain b 00. data not available. e I. autoclave cleaner * autoclave operator. 3. pipe Titter 4. polymerucr 5. foreman 6. Tdtreur' 7. `pit pare teur de rolulion' 8. preces* worker 9. chemical operator I. Italy J. Japan N. Norway S, Sweden USA, United State* of America YU, Yugoslavia. 10, polymerization worker 11, technical aretstent 12. maintenance worker 13. millwright >4. water cooling unit 15,rea|cr 16, furnace operator 17. machine chop worker (Tablet 13 -15 ate compiled with the aid of information contained in the literature; reference* tee Table 15) Srji *' * * SSS 6! W.K. Lelbach and H.J. Marsteller a population of 130 000. One of the four had a history of occupational exposure to polyvinyl acetate, which has hitherto not been related to ASL. The other three may have had nondocumented exposure to arsenical pesticides, which were used for many 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 196S/1969 (Baxter and Fox I9'5). Six additional cases not mentioned on the death certificates were detected by a panel of specialists (Baxter et al. 1977). In reassessing 36 of these 47 patients for whom histological see* tions were available, the panel of histopathoiogists unanimously agreed on the diagno sis in only 14 cases (7 doubtfu!,3 undassifiable, 13 non-ASL). For 12 of these 14 cases occupational and residential histories were obtained which revealed one un doubtedly VCM-induced ease, two cases with possible exposure to (low levels of?) VCM and one case attributable to thorium dioxide. After the first three cases ofASL among vtnyl chloride polymerization worker* in the United States had come to the attention of the National Insutute 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;5>trr and Kamintki 1977). As of August 1978. data had been presented on a total of 68 cases of ASL among polymerization workers (Spirtat and Kamintki 1978, pen. comm.); another eight eases had been observed among nonpolymerization workers exposed to VCM in vanous jobs. On the basis of this data collection communicated to us in 1978 - for which we wish to thank Drs. R Kaminski andR. Spirtat. NIOSH. Cincinnati, USA - we attempted to trace these cases and their individual symptomatology as well as other relevant information pub lished in the literature up to 1979 (see Tables 13-18). The ten Canadian cases of VCM4nduced ASL (eases 2-11) are dealt with summarily in the papers published by Delorme (1978a) and Delorme and Makk (1975); seven of them were desenbed in more detail by Makk et sl.(1976). Cases 19 and 23 were observed at our clinic in 1 -inn but details have only been published for case 19 (E.U. in Lclbaeh and Marsteller 1977). In reviewing the literature we could not trace cases 37-40.43.50.51.53-67 and C, F and H. According to the latest annual report of the Staatlicher Cewerbcarzt, Dihseldorf (Rtml et al. 1978), the number of deaths from VCM-induced ASL in the Federal Republic of Germany had increased to 16 by the end of 1978, to which we now add a 17th case (Figs. 8 and 9). In retrospect, it was discovered that the first case of VCM-indueed ASL had already occurred in 1955 in a Canadian polymerization worker. For the 67 VCM polymenzation workers for whom details were available, total yean of exposure ranged from 4 to 31 yean (mean and median 18 and 19 yean, respectively). In comparison, mean dura tion of exposure in our group of 17 individuals with advanced nonmalignant liver dis ease (see Table 11) was 103/4 yean (range: 3 1/2-21 yean). The latency penod (yean from fust exposure to diagnosis of ASL) ranged from 9 to 38 yean (mean and median: 21 yean). The average age at diagnosis of ASL was 50 yean (range: 37-71 yean). Vinyl U s f ? I I w s '5 I IO "f:n za if w 55 "vC2 3Z i i ,-m_u ".i J3HMS*.WW and HJ. Mannailer 'Vinyl Chionda>Associatad Disease TaMa 14. CNulcal ami morpholok'al data on bl polyvinyl cMotiilc IPVC| productimi workers wilb aMiosaiciima id Ihe tivci reported to NtOSIt by Aapiri 1974 Hepato No megaly Spleen 1 Atrophic, 12*00 (1 slightly In thru led ll ' J vjticcs Hepatic IthrtiMi Thrum In cylopcnia Nuncirrholie T pcibttmsuiiJal Capsular 1 Capsular, portal, pcrtstiuKnttlal Ac ru ns leulysis O' Raynaud** pltenomeitari kUl^Irwi 00 1 . 4 5 6 7 cam: L ! - 7 f <14*01200 |t) a l No Itialh ' available 9 SckfoiH nf wall l portal vcm Capsular, portal, petrsiiotsnrilal T Capsular, portal, perisinusoidal Cipmlar, portal, pcrtstousnidal Porlal. pcmiiiou tidal No details available t ivk: mulli|rfe ntelaslasct ffcntg, pkma. iKiicanlmiN, ileum, coIini. Iuliicy',. Icll xlreirall ^ 1 no*v awtlmlwrl lymph node f oinv peritoneal spread 1 ton local s|*rcail 10 Capsular, |ntrial, pettsimisi liilal II J Capsular. portal, pemiiiutoitljl ) > Tilde Mkonlinucil} llepatoNn, m((jly Spleen Ocwpluccal llcpalie vafites (ihrosi* Thromltticylopema 12 Moderately (> (7300 gl enlarged 13 (2250 g) 4 14 Spleno megaly T ti Slightly enlarged 4 (Cirrhosis!. fibrosis (Cirrhosis) 4 4 4 4 74 16 Spleno (26JO |tl megaly III 30 g) 4 Capsular, portal, seplal (72 000. 6S 000) 17 Spleno 4 4 megaly II 4 Perisplenitis 4 1 (134 000, 68 000) 19 ( Spleno- M4S0g| megaly Id III) el (i Progressive * pertsinnsoidjI.ISO 000, portal and 47 OfHt, seplal cirrhosis 3011001 20 4 4 4 4 4 21 4 Spleno 4 4 (1900 it megaly Acro* tent y sis 0 0 0 f 0 0 0 0 4 f* Kay Hand's phenomenon Metaslaves 49 0 l.efl lung 0 41 li le(l rib 00 0 111 thoracic vertebra 0 Brain 3rd Iniphar vertebra 00 44 00 9 W K. Lelbach and H J, Marsieller 22 Spleno megaly 4 23 Spleno- 0 (2700 g) megaly (45J g| * Capsular, 4 portal, pensinusoidal Pocal peri- T si nnsoidal 00 0 n 0 0' 9 Vmy] IJ. Marv*ll*r JO t 7 II * Spkno- (1900(1 me(jlr ? t > >ll <* * f 000 22 4 Splemt* Mciily f 2) 4 SpleOtt- 0 (3700g> Mt'lily (45S it 34 4 7 I 4 Syk* (IStOg) w|ily MJOg) t 26 4 t 27 4 Spko- (2230 ! mcgaty (400 t (T ! 21 Spfewt- Me|dr <6J0g| 4 29 'MotlirkallmH 0 117JO g) fibrn- cmtgexlive* 30 4 0 0 31 4 Splenomegaly T (3000 r| (270 g) 32 7 7 Capsular. pm Ul. pcnsiniismilal focal peri- 7 IMIlUHilll 0 forlal, 4 pcrklniisnMal (60 000, fibrous 10 0001 44 NdMiliil t npurin fibrous, wikronoilular dnhutii forlal, peri- 4 limtwmlal, (00 0001 cipuilri libnuik Slight prlil 0 libiiRii 0 0 fi 4 0 0 0 Minimal (ibiiKit ? |f 7 0* (SO 000, 40000) Capsular. ft pmlal fibrous 0 0 0 0 00 0H l.iic.il )iiuil Iti i aval vv 00 0 fluoilcHat wall 00 0 4Hi anil 7th 1km atli ve ilcIn.i, 5III tell till, loll aihi-ii.il 0 0 SmijII inlcsliuc 0 faiaamlal lymph mules 00 0M --t--"-- --------------- =*--^-- Vinyl ChlonJe-Aviociated Disease % . il Table 14 <conlinucd) Hepato Nil. megaly Silken Oesophageal Hepatic * antes librmit Thrombo cytopenia 34 Slight 0 0 <1623 s) iplenomcgaly (80 0001 33 4 Cftncnlnl, * <3240(1 firm <200 () Nonclrrholic * fibrihii 36 T * 7 T Armml coty sit ft 4 t* 37 36 39 40 41 41 t 43 44 4 Splenomegaly * *7 Splenomegaly 43 Spleno megaly 46 Spleno (I8601) megaly T 7 77 Suhcaptular ami portal fibroin Markedly 4 thickened capsule; marked fibrosis Portal fibrosis 7 T * t 4 4 Kaynaiid'i pheiiomenon MelasUset 44 o> 44 4 Local spread to abdominal wall and colon; lymph node! 77 77 44 tP *3 n %9(4*. X 4 Spread to dm hIciiiiiii 47 411 * Spleno megaly 7 1 T Portal fibrosis (3$ 0001 SIiflit final 7 i n i if Spread lo di:^liragm and abiloriiinal wall 1 lines. I iicc mil small < a' O cr> o o ' 45 Spleno megaly 46 t Splmu- (1160 g) rnctily 7 47 I Spk>u me(air 41 4 (S200g| T 49 t Normal ? 50 51 } Delaiti no| poMtihed S2 4 t (21101| T 53 \ 54 1 55 1 56 I 57 I SI I 59 I 60 > Iklilb not puMIthcd 61 / 61 I 61 1 64 1 65 I 66 I 67 / 66 4 7 4 llMt 4 I* t P IhlctciKil capsule; nuilcil lilunsis rorlal fibrosis i * Spitfatl lit thiiHlcRum rnrtjl fibrosis 4 05 MH /I )i Spreail In ttiaphtariN amt alHluniinal wait Stifhl focal hcpalilts (`minimal hcpalifis`1 ? t I.ihirs. large ami small bowel, pkiira. iwiicanliinn mviK'aiilmni. liitncin, tell adiciial Capsular Mil 7 porlal fihiosu f ft Diaphragm, legional, relropculoncaf anil kkiImiIiujI lymph maks, lungs, mIil-ii.iI f.lamls, tcicliclliini tVcwNar 7 porlal (ilwnii, moderate ciithnsis ff /I Diaphragm, gallbladder, icpimal lymph ihmIcs, Innpi. sc.ilp, :.l nil 7____________4(51 IMHII jC__________ ji JL_ Vinyl Chionde-Asjocuted Disease HJ. M m teller *8 W.K. Lelbuch and H .J Margie Her Table IS. Publications on the bS cases of angiosarcoma of the liver listed in Tables 15 No. References 1 Hu bitt et al. (1977) n\ 3 4 j Dtlormt and Makk s J 11975) 6 \v Afekfc et al. (1976) 7 /' Dtlormt (1978a, b) 8 ( Dtlormt and 9 || Thtnaulr (1978) 10 U) 12) Schmidt and Bitora 13 1[ (1976) M <| Lanft et al. (1974b) 15 1[ Gtdigk et al. (1975) 16 Coktlti al.(1976) 17 Amannl 1975) Riibumtn (1976) 18 Rtml et al. (1976) 19 (Observed in Bonn) :o Rtinl et al. (1976) 21 Rtml etal. (1977) 22 Rtml etal. (1977) 23 (Observed in Bonn) 24 Rttitr et al. (1975) 23 Roeht et al. (1978) 26 Rtty et al. (1976) Additional relevant information Hypertrophic, hyperchromatic ansi ji\ pical endothe lial cells in the glomeruli; foci ot haematopoctic cells in liver and spleen Case no. 7; ASL associated with hepatocellular carcinoma (Dtlormt 1978b) (AU cases from one plant in Shawinigan. district Trots Rivieres. Quebec) At the same plant: 4 cases of VCMinduccd cirrhosis of the liver plus 1 case of cirrhosis and geneMlired itticulosarcoma and 4 cases of carcinoma of the Cl tract or lunp Sec also Rtml and Wtbtr (1974) See also Rtinl and Wtbtr (1974) Foci of haematopocsis within the tumour areas 1974 portocaval anastomosis:cholecv'tcetomv. Hypertrophic, hyperchromatic and markedly atypical endothelial cells in the glomeruli and in the capillaries of the lungt \ Moderate hepatic siderosis; chronic fibrosing panertanru: tubular and interstitial fibrosis of the ttttts Focal interstitial fibrosis of the pancrtai See also ien-od etal. (197$) 1942 gastrectomy. 1974 splenectomy, right hepatic lobectomy (640 g). See also Roeht (1977); hitch et al. (1977):Bonneron et al. (1975. 1977);Btrrod et al.(l978) No autopsy (sec also Btrrod et al. 1978) Vinyl Chi Table 151> no. KCI 27 fto r :s 29 30 } i31 ' Btr 3323 ) 34 Lt 35 Sm. 36 A/c 37 - 38 39 " 40 41 By42 Byr, 43 44 Bl (ca- 45 Bio (ca 46 Bu > fca.' tiler ii :Otli- vslls t rhosis 'tO nil pical nilUnes 4IUW * cpatic *di tt -id tt Vinyl Chloride-Associated Disease 69 Tabic 15 (continued! No. References n Roche tt al. 11978) Additional relevant information Chronic alcoholic. See also Rne/ir 11977): FurWi tt al. (1977);flfrrod tt al. (1978) :s Roche tt al.( 19781 Fint symptom: vertebral and costal metastasis Right hepatic lobectomy. See also Roche <! 7").Aieclt et al. (197'); Ptficltoniki c: al. 11979); Coude'c et al. (1976). Jfrroc e: al. 1197S) 29 Roc/ieetal. (1978) 3 ) 533= )( Btrrod tt si. (1978) 1960 tcltndermalikt skm induration (hands), swell* inp of tact, upper extremities and ten. 1971 bilateral ecTootttolym. Tumour penetration of the abdominal wall l fistula). Severe interstitial fibrosis of ttitei: fibrosis of interstitial wall; slight mesangial fibrosis of glomeruli. Venable but generally slight tibronyalinoiis of artenal and venous vessel walls (skin, heart, lungs, intestine, testes) 3- Lee and Harry (1974) 35 Smith tt al. (1976b) Latency penod (1st exposure -- death) only 8 yean (sec also Fox and Collier 1977) 36 MtUtont (1974) 37 38 39 _ \ * 40 41 Brrin and Holmberf (1975) 42 Byrdn tt al. (1976) 43 - 44 Block (1974) least 3) 4S Block (1974) (case 2) 46 Block (1974) (case 4) 1965 portocavai shunt. 1970 cholecystectomy. See alto Falk t *L (.1974a) (case 4); Whelan et al. 11976) (ease 1) No autopsy. See also Creech and'Johneon (1974); Folk et al. (1974a) (cast 3): Whelan et aL (1976) (ease lKUakk et al. (1976) (case 6) See also Falk et al. (1974*) (case 5);Makk et al. (1976) (case 10) S j l f 70 Table 15 (continued) No. References 47 Block (1974) (case 1) 48 Block (1974) (case S) 49 Block (1974) (case 6) so SI -- 52 Whelan et al. (1976) (case 3) S3--67 68 Zonca et al. (1975) W.K lelbach and HJ Marsteller Additional relevant information See also Falk et al. (1 9"4a) lease 2):Makk et al. (1976) (case 4) See also Falk et al. (1974a) (case l):Makk et al tl976)(case 2) See alsoFalk et al. < 1974a) (case 6); Whelan et al. (1976) (case 4):Makk et al. 11976) (case 14) Chronic alcoholic. See also Makk et al (1976) <caie 13):Berk et al. (1976) (case 2) Amon| a work force of 180(120. PVC polymemation: 60, production of VCM) employed at this plant. 15 died of malignant disease (2 ASL. 5 bronchogenic carcinoma*. 1 cue each of carcinoma of the larynx, rib,mamma.spermatic cord; glioma, meUnosarcoma. leukaemia. Hodgkin's disease)____________________ Fint exposure to VCM for these 67 cases of ASL dated back to the period 19391966 (median; 1951). Twentycne years later, iae. from 1973 onwards, a gradual inertas: in the number of new cases diagnosed and reported to N105H can be observed (Fig. 7). The onset of this gradual increase coincides with the calculated mean latency peril' * of 21 yean (Spinas and Kaminski 1977). Spirras and Kaminski also suggested that >n future cases the age at diagnosis and the length of the latency penod may in crease as a result of the later reduction in levels of exposure. From the synopsis in Table 13-18 it can be seen that in about two-thirds of the eves of ASL for which morphological details are available varying degrees of associated hepatic fibrosis in nontumoious areas of the liver were mentioned. Less often, evidence of portal hypertension and splenomegaly wen noted. Metastasis of angiosarco ma to distant sites was observed in approximately hair the published cases. It is of note that acmosteolysis and cutaneous stigmata of scleroderma have been observed in only 1 of these 76 patients, a French FVC worker who had apparently not been engaged in reactor cleaning (ease 29;Roche et al. 1978). Another noteworthy piece of informa tion is that strikingly atypical endothelial cells with hypertrophic and hyperchromatic nuclei have also been found in organs other than the liver (kidneys, lungs) in autopsy material from two patients (cases 1 and 17.Hubiet et al. \971 \Rubsamcn 1976). Hubkt et al. (1977) also found such cells in the myocardium and in the adipose tissue enveloping the adrenals. All this may lend support to the idea that the effeet of VCM metabolites is not restricted to the vascular endothelium of the liver and spleen. Angio- Matstcller | al ai. t al. ) feast mema* hix punt, cliogemc .aryn.\. <*rcom3. ---- ! 1030. 'ual in vrred iflcy ted nay tn* ul the - assocuttcn.rri.ioiarco* i of note I ui only ngaged f informahrosutic autopsy *76). iie tissue ofVCM en. Angio* Vinyl Chloride-Associated Disease Table 16. Personal data on eight eases at angiosarcoma of the liver among VCM*\posed personnel not emploved tn PVC production 13s reported to NIOSH by August I9?8) Birth date So. Country 1 m'i.'y\ Date of death l m/d'yi Total Age at vein death exp. Job classification A D(3> 07.lo.S0 10.10.-3 43 14 Loading pestictue cam with VCM propeller, t B D (6) 05.09.36 12.16.74 38 3.5 Assistant factory chemist r CBl2) 09.08.14 12.00.70 S3 11 Touring PVC oil mix* * cure onto fabrie bases '* D 111) 06.I5J4 04.16.71 36 3 Fabrication 01 PVC sacks and wrappings (extrusion it ttmperaturns of 120*0 E SC) 11.27.11 08.16.71 61 23 Assistant factory chem ist (production ofVCM) F USA (IS) 00.00.23 02.15.73 47 Accountant at plant producing TVC fabric G YUC) It.lSJi 07.J2.73 42 18 Production of VCM H YU3) 12.21.31 0111.76 45 *m* Production of VCM a Update of NIOSH rtfuitr, August 1978. prepared by Kaminski as in Tabic 13. * 00. data not available saieoma arising from the kidneys 01 other Types of malignant renal neoplasms, how* ever, have not been described in VCM^xpored indieiduals, although malignant nephro blastoma has been induced in experimental animals. The extremely tart coincidence of angiosarcoma and hepatocellular carcinoma was found in three instances (case 1978b: case E.Byrin and ftolmbcff 197$, and a case not included in the 1978 NIOSH update Tambunv ct al. 1978a). In the case reported by Tambum0 et al. chronic alcoholism may have played a cofactor role In the development of liver cancer. We can now add a fourth case observed in 1978 at the Department of Medicine in Bonn (sec Sect. 4.1.5 and Fig. 3). This patient (patient 9 in Tabic 11), a PVC-polymerization worker (total period of exposure: 18 years) was first admitted to our department in February 197$ and was found to suffer from atyp ical cirrhosis of the Ever with portal hypertension, splenomegaly and Raynaud's phe nomenon. During followAip ASL was clinically suspected but could not be confirmed during life, despite exploratory laparotomy and generous surgical biopsies. The patient .a- 4 17 4Table . Otaicd anti moipHt oBkal lfafawi etfhl caics of angiimvcnma of itiu Hvrr among VrM<ij*ftt\l|>ervi l*VC ptilyrntfriuiion * hoi vmiduycii in llcptlnNo. locejly Spleen Onophap;^ llcpalk varivci lilnosis Tlirombocylopenia A Spkno- (fcOOOgl meItaly fotlal flhtlhil t D Splcno- + (3650m awmljrlCS () Focal capsular 0 Mitosis, pmljl and ccnlriitolmlai Mirosjs Acroostcirfysh 0 0 Raynaud's plicnnmcnon Mclaslases 0 Diaphragm, (tailric mucosa, abdominal lympli nodes 0 Diaphragm. pleura, abdoimnal lympli nodes C l (+> i: 0Not (IlLllptl *t T y * 0 0 Lungs, pericardium -t- 0 0 1 (104 0001 F <; Splcnomeitsly y y f 0 i Dma. cranium ii i* W.K. Lelhjth and M J. MaMcllcr Virv c 5 < S 3?3 3rt<8? g " o => > D * 1 ,, ; 3 n " "On* - _ z r 2 1= o I on v oz rs- jrstdler Vinyl CHionde-.-Wociated Dimiu Table 19. Publications on the eight eases 01 angiosarcoma of the liver listed in Tables 16 ami 17 No. References Additional relevant information A Runt and 'other il7J) I9n" idi-vpaiftic portal ;r. pertension: portacaval shunt S Zimmtrmenn and Eek l7J nglu hcmmephrectomy for'jnilate*al hydro- tl97S\ nephrosis associated with bilateral double kidr.ev Remit 197J) Foci oi hacmatopoetic cells in spleen and kidney. Fibrosis of the pancreas. Slight fibrosis of testes and of the small intestinal <erosa f D Maitom 1107JI Autopsy- angiomatous epulis. Angiosarcoma involv ing liver. lungs and pericardium. The pcncardium might have been the primary site! E Byrin and Holmbtrf Probable coexistence of a hepatocellular cancer of H97J) both low and high grade differentiation r G Zoriea et al. (1975) H * died on * August 1978, alter a massive haemorrhage from oesrpr.sgeai varices. Autopty revealed both nulueentne mttastasmng angiosarcoma and hepatocellular carononu of the liver as well u slifht fibrosis of the pancreas (to be pufei .shed in detail). It is still unexplained why hepaiocytes are generally exemp *;1 from the carano* genic elTect of VCM metabolites but. as predicted by fopper in 1975. three anecdotal eases of hepatocellular carcinoma, one German (Coke! et ai. 1976) and two British PVC workers (Fox and Collier 1977), hare now also been observed after exposure to VCM. It may be mentioned that a review of the distribution of primary tirer cancer in tlie Province of Quebec covering the penod 1969-1972 showed a preponderance of adult male cares in urban areas clustered in the district of Trois-Riviere in congru ence with the distribution of the plastis industry, a coincidence which calls for further investigation of a possible exposure to industrial carcinogens (Jacob and Theriault 1975). . Not included in the N105H register are several anecdotal cases of A5L, capillary and cavernous angiosarcoma of the liver and hacmangiosarconutoais of sites other than the liver, for which a relation to occupational or even poretbly residential exposure to VCM has been discussed (Soria et al. 1977;Brady er al. 1977;lor et aL 1975; Wallnbfer and Zmnagl 1977). Although of undetermined relevance, it should finally be mentioned that, in addi tion to hepatic fibrosis, varying degrees of intemitial fibrosis of the pancreas were noted at autopsy in four Carman workers (cares 19,23, B and the above-mentioned ft V I * *t I t / t W.K. Lelbadi and H.J. Marsteiler 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 ofskin, heart, lungs and intestinal wall. CUMULATIVE N* OF CASES REPORTED TO NIOSH M 4 82 M 54 IS 41 4* 42 40 31 31 34 A---=-------- t=i= 1955 I960 1965 1970 1975 1978 yter of diagnosis Fig. 7. Cumulative number of cases of ASL among PVC production workers reported to NIOSH up to August 1978, arranged according to year of diagnosis tdata from Spines and Kamuiski 1977,1978) 4J.2 Clinical Manifestations The clinical symptomatology of usually multieentric ASL is unspedfic. Gradually dedining general health and loss of weight combined with fll-defined upper abdominal discomfort and slight epigastric or right upper quadrant pain are usually the first symptoms. Recurrent bleedings from oesophageal varices may have been antecedent events in patients with portal hypertension who otherwise felt fairly well. In a number tameller T<rted row usily dinuiul cedent a number Vinyl Chtonoe-A**oo3teil Disease. oi* cases, the tumour first came to attention with massive, often fatal, intrapentoneal haemorrhage. Important tender hepatomegaly fhepatoiplenomegaiy), slight jaundice and occasionally development of moderate ascites and oedema were observed. Except for mild to moderate hyperbilirubinaemia. some elevation of scrum levels of alkaline phospnatase and jammaglutamyl ttanspepndase and only slightly abnormal levels of scrum transaminases, the spectrum of biochemical tests is hardly revealing. Alpha-fetoprotein determination has r.ot been helpful in the diagnosis. Ultrasonography, scinttgraphy, hepatic angiography and, notably, computer tomography of the upper abdomen are the diagnosue procedures of choice if A5L is suspected. A ttehneuum*49TM -liver scan visualizes intrahepatic tumour defects (Bitruck et al. 1977b) together with abnormal splenic fixation, but peripheral defects of uptake may be difficult to interpret (Mitten et aL 1976). Characteristic features of angiography are a normal-sized hepatic artery with possible displacement caused by tumour enlarge ment. a certain degree of central hyperviscuiarity of the tumour, a peripheral tumour statn. and puddling of contrast medium persisting into the late venous phase. In addi tion. varying degrees of peiiosis hepatis may be observed in some cases. However, even repeated hepatic angiography may fail to confirm the suspected diagnosis, as was evt. dent in one case reported by Roche et al. (1978). The example of a Jd-year-old polymerization worker who died of metastasizing anposarcoma of the liver m February 1980 may serve to illustrate the clinical course. In 19";,'73. after an exposure of 18 years* duration, wc found him to suffer from Ray naud's phenomenon and nonatthotic porul fibrosis and portal hypertension with sple nomegaly and moderate thrombocytopenia. Despite termination of exposutt, there was progressive splenomegaly and development of nuiaive oesophageal and gastnc 7^ sS#l M. Ssfe suru."i Z*\ /*? Fig. 8. Compuier tomograohy showing a large, irregular, hypodens* angiosarcoma of the liver involving both lobes. Courtesy of Profesor Thum. Department of Radiology, Umvenity of Bonn CHefS ucc 0469Gr.? 76 U K. Lelbuch and H.J. Marstcller varices dunng the following yean with repeated episodes of bleeding which required (successful) sclerosing therapy (major surgery was declined by the patient), in August 1979 he presented again with recurrent epistixis and slight but permanent epigastric and upper right quadrant pain, but declared that he felt otherwise fairly well. He com* plained about a sharp localised epigastric pain on sneezing. There was marked spleno megaly, and an ill-detined 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 metasuses (Fig. 9). Autopsy confirmed the tentative diagnosis of metastasizing angiosarcoma of the liver (Fig. 10). \ r r ; t; i s r Fig. 9. Computer tomography showing multiple bram metastases of angiosarcoma of the liver. See test. Courtesy of Professor Thum, Department of Radiology, University of Bonn 4JJ Peritoneoscopy Little information is available in the literature concerning the peritoneoscopie aspect of VCM-induced ASL (Roche et al. 1978). It may be impossible to make a diagnosis of the initial phase of ASL in VCM-exposed workers by peritoneoscopy and needle biop sy of the liver, as documented in one of our patients who died of multmntnc ASL Ei Is I# Fi Gu f arsieller fed August .jjtric 'ts com* plcno* 'm mod* *ehemvntour cticily ittd the intent vtastases unaof Vinyl Cilondt-Aitoinstcd Disease I';r.->-fte--VwcitSv1"--* il' 77 I,,' V -? 5< -- .aspect ^ynosa of IW biop* ASL ri|. JO. Multiple brain metasrases of angiosarcoma of the liver. Courtesy of Professor Gallons. Institute of Neutepathoioiy, University of Bonn _ .r* .-i 7fl W.K. Lelbai.ii and H.J. Marstcller 11 months after pcritoneoscopic diagnosis of severe hepatic fibrosis (case 19; see also Letbach ami ManteUtr 1977). In addition to the fiadinp described in connection with hepauc fibrosis, there may be hypervascularized or cystic tumour formation visible on the surface of a nodular, quasi-cinhotic liver, or a gross aspect resembling hepatic metastases if the vascular malignancy involves the superficial regions of the liver. It should be stressed here that needle biopsy is absolutely contraindicated if there is any suspi cion of ASL. 4J.4 Gross and Histological Morphology The liver is usually markedly enlarged. Liver weight in cases of ASL ranged from 1600 to 7300 g (Thomas and Popper 1975 ,Roche ct al. 1978). The gross appearance of angio sarcoma of the live, is mostly that of large bulky, irregularly shaped cystie tumour trusses; a multinodular form with numerous, someumes umbilieated nodules, is less often encountered. Extensive haemorrhagic and necrotic areas or solid and spongy por tions of tumour tissue replace much of the liver parenchyma. Rupture of Urge cavern ous cysts may cause fatal intraperitoneal haemonhage. Thomas et al. (1975) and Thomai and Popper (1975) distinguished four basic devel opmental patterns of histomorphology of ASL, which can be found in different por tions even of the same tumour and appear to represent stages of progressive evolution: sinusoidal, papillary, cavernous and anaplastic patterns. Indistinct areas of transition and merging of patterns can be observed. DiUted sinusoidsl spaces lined by hypertrophic and hyperplastic sarcoma cells with pleomorphic, elonpted, hypejehromatie and often bizarre nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells of varying differen tiation envelop liver cell pUtes and may invade enlarged and fibrosed portal tracts, ac companied by proliferation of bile ductules (Fig. 11). In papillary angiosarcoma atro phy of liver ceils results in Urger ind more irreguUr blood-filled vascular spices, into which loose papilUry strands of surviving hepatic cords on in axis of connective tissue project, lined by sarcomatous cells (IVtinbrtn 1976). Even Urger blood-filled spaces are seen in the cavernous type, where they may be surrounded by thick fibrouc walls. In a smaller percentageof cases,solid areas or nodules ofanaplastic sarcoma are found, resembling solid spindie-cell sarcoma, or even suggesting an epithelial type of tumour. Cedifk ct al. (1975) also observed a reticulosarcomalike pattern. The differentiation of the tumour cells varies widely : it ranges from the inconspicuous endothelial lining cell type to irreguUrly shaped, grossly distorted giant-cell forms. Morphologically, vinyl chloride-related ASL cannot be distinguished from ASL associated with other aeuological factors or from the cryptogenic type (Popper et al. 1978). In tumour-free portions of livers with angiosarcoma widely varying degrees of ex cess formation of fibrous connective tissue are usually observed, analogous to that seen in nonnimorous liven of heavily exposed penons. Fibrosis of enUrged portal tracts with modest proliferation of bile ductules, mostly only scanty' infiltration of lympho cytes and occasional formation of perilobular septa or thin connective-tissue septa ex tending into the lobular parenchyma can be found. A more or less conspicuous intra lobular, perisinusoidai fibrosis is often detected only by special staining methods for collagen or reticulin fibres. As a rule, irregular focal or nodular fibrotic thickening of V: r >r w * > w. v, FIs' liw nu. ln> of< ly.i Thi re lift: id. plas inct reu. cyu defi re tii crea I J Uanuilcr -19: let also -nnection with visible on patic me* liver. It should is any s?i* yd from 1600 :o mice of anyo ne tumour lulei. is less md spongy porf large cavern* <mr basic devel* lifTerent pot* ivive evolution: of transition roma cells with terize the lying differen* ftal tncts, ac* arcoma atro* spaces, mi" nuectivt tissue fflkd spaces walls. jHTare found, - pe of tumour, itfetenbation of wlial lining cell -neatly, vinyl '> other aetiol* degrees of ex* wb to that seen portal tracts `m of lympho* 'issue sepu ex* picuous intra* : methods for thickcnini of Vinyl Chloride-Associated Disease 79 r * Fit. 11. Angiosarcoma of the liver (upper peer of photomicrograph) invading adjacent liver parenchyma (case U D l ;$et Table 13). Note hyperplastic and hypereiiremanc nuclei of proliferating neoplastic lining cells enveloping hepatic cords. Reproduced by permission. Ann NY Acad Set 2Z6:278-28? (197S), Courtesy of Professor Gedigk, Institute of Pathology, University of Bonn. HlE.i 250 of Glisson's capsule is present: these flbtooc capsular areas may extend into the under* lying parenchyma and may connect with adjacent enlarged subcapsuiar portal tracts. Tli* cellular and nuclear size of hepatocytes may vary widely; groups of binudeared or even multinudear parenchymal evils with abundant cytoplasm art seen. Focal pro liferation of sinusoidal lining cells may be encountered, especially within fod of sinus* oidai dilatation. In connection with conspicuous sinusoidal dilatation, two types of focal hyper* plastic precursor Ituons were described by Popptr ft aL (1978): 1) Poorly circumscribed fod of hyperplastic, often binudested hepatocytes with increased number of various sinusoidal lining nils and only inagnificant increase of reticulum framework. 2) Almost nodular areas of conspicuously hyperplastic and hypertrophic hepato cytes with more pronounced variation of markedly increased sinusoidal ceils without degeneration or necrosis of liver parenchyma, but accompanied by execs formation of reticulum framework and compression of surrounding parenchyma. The transition of sinusoidal lining cells to angiosarcoma cells is characterized by in* creasing atypta and anaplasia of these proliferating endothelial cells accompanied either ' i a vr so- U'.K. Lelbach ami H.i. Marttciler by formation of excess connective tissue or by accentuation of sinusoidal dilatation leading to pnmary peliosis. Involvement of portal areas in the evolution of angiosarco ma results in considerable fibroplasia and formation of hyalinized collagen together with proliferation of bile ductules. In occasional cases connective tissue bridging be tween portal tracts or between portal tracts and central veins with subdivision of lobu les followed by rearrangement of hepatocytic plates may lead to a cirrhosislike picture. 4JJ Therapy The multicentric development of ASL (Thomas and Popper 1975) as well as the dif fuse spread of the tumour usually encountered by the time of diagnosis precludes ef fective surgical or radiation therapy in the majonty of cases. A survival period of two yean after surgery (Berrod et al. 1978) or chemotherapy (Dennaher et al. 1979) is a rare exception. Results of systemic chemotherapy studied in a small group of five pa tients showed that, at best, quality and duration of survival may improve to a very limited extent (Dannaher et al. 1979). At ptesent, no generally accepted guidelines for chemotherapy am available. 4.3.6 Risk Assessment When in the United States 13 white male cases of ASL had been detected from 1961 to May 1974,among an estimated total population of VCM polymerization workers of roughly 20 000. a risk ratio (ratio of observed to expected cases) for this population of at least 400:1 was calculated (Heath et al. 1975). This calculation was based on data from the National Cancer Institute's Third National Cancer Survey (1969-1971), which expected for the total United States population an annual incidence of this tu mour in the orderof0.014/100 000. This would have meant only about 0.03 cases per 20 000 polyrer: .ration workers within a 10-year period. Dose-response and attendant biotnruforma- data on experimental animals have since been used to elaborate sev eral different models of extrapolation to man. These were calculated with reference to telative 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 Yealistic safe doses' that do not aiTect the average lifespan of a person exposed (Seluwklermm et al. 1975: Gf/ir)tf et al. 1979,1978: Woods 1979). Cehring et al. (1979) consider a probit percent model to be a reliable tool for risk prediction, which works without the assump tion of s threshold. They predicted a cancer risk of 1J esses of ASL in 100 000 000 workers on exposure to the current National Standard in the United States of 1 ppm VCM 8 h/day, 5 days/week, for a 33-year working life, an incidence whicit does not significantly deviate from the spontaneous incidence rate. A linear model modified by adjustments for differences in the rate of inhalation, distribution, metabolism, cell proliferation and tumour latency times between rats and humans was described by Woods (1979).This model arrives at an incidence of 3.9 cases per 100 000 000 workers after a lifetime exposure to 1 ppm. Much controversy, however, about the validity of risk extrapolation from animal experiments to man and from high- to low-level expo sure and the problem of threshold doses has been voiced (Maugh 197S. Hooper et al. 1979;Schneiicnmn 1979. Wtigen 1979 . Rein elal. 1979). Vinj R. (exci ASL This r the 1 confl had d the re polyr wu o viron. ceede lesser magn ting,: millic vinyl mode the es grour 4J.7 Fora hazar. the er studii sure t . the lu al. 19 hfa.vu Of Bn: 1976. posed et al. i voice i1 Berry empli and cj but nc 1976) In (1974 epiden (1978 facton teller -*S pet it Vinyl Chlondii-Auocuicd Disease Sl Results ofa recent survey by Bredy et al. (l77) indicated that for New York State (excluding New Yurie City), a highly industrialized area, the annual incidence rate or ASL during the 6-year period from 1970 through 1975 was 0.25 per million residents. Tltis considerably exceeded the national ave^;e rate of 0.14 per million per year in the United States. In a concomitant case<ontrol study. 26 patients with histologically continued ASL were found in the study area from 15S to 1975. and 7 of these had had documented long-term exposure to either .As. ThQ; or VCM. Five (all female) of the remaining 19 patients lived at a distance of 500-4500 feet from VC tabneation or polymerization facilities for Jong penods. No pertinent exposure or residcncal history was obtained from the other 14 patients. Discharge of unreaettd monomer into the en vironment as result of losses in the ?VC 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 (Scfneancr 1975). Concerning the order of `magnitude of ambient exposure beyond the work place, ij. outside the industrial set ting. an average annual exposure concentration of 17 ppb was estimated for the 4.6 million persons throughout the United States who resided within a 5-milc radius of vinyl chloride emission sources (Kuznaek and MeGeufhy 1975). If the risk assessment model elaborated by Moods (1979) is applied to this population of * million people, the estimated incidence of anpourcoma per year would not be abovt expected back ground levels. 4.5.7 Mortality and Cancer Morbidity Studies For a tumour disease as rare as angiosarcoma of the liver even quite small increases in ;*hazard o<" background levels should be detectable {Doll 1975). The situation with the common types of cancer is far more difficult. Since 1974 a number of mortality studies of VCM^xposcd populations have suggested that in humans long-term txposuic to VCM may also be associated with cancer of rites other than the liver, notably the lung?, and the lymphatic and central nervous system (Atonson et aL 1974: On ct aL 1975: Ttbmhaw and Goffey \91A,Nicholson et aL 1975; Wagoner et al. 1976: Wexweiler et al. l9">6;Mic/iolson l9T7tBufjfler*i aL 1979). Epidemiological studies of British workets failed to confirm this suggestion (Duck et al. \9H.Duck and Carter 19?6;/b.t and Collier 1976,1977). as did a prospective study of a VCM/FVC-exposed cohort of 16IS employees of s West German chemical pbnt (Frentsel-Beyme et al. 197$). Criticism of design and interpretation of tome of the studies has been voiced {Faik et al. l974b;Ai/r/icic and Williamson 1974;Refer 1977-.DaUenip 1975: Berry and Rosater 1976). A follow-up of aO VCM-exposed persons (750 traced) ever employed it the one Swedish factory, which started operation in 1945, for mortality and cancer morbidity patterns revealed a fourfouid excess of pancreas/Iivtr tumours but no deviation in the number of brain turnouts from the expected level (Byrin et al. 1976). In addition to the three extenrive mortality studies of Tabmhme and Goffey (1974). IVaxwctfcret al. (1976), and Fox and Collier (1977), a fourth comprehensive epidemiological study (Rent/ and IVeher 1976) was completed in 1977 by Rein! et iL (1978), wiuch induded three study populations from 11 VCM- and PVC-produdng lactones in the Federal Republic of Germany, covering the period from before 1959 s- JJ m u*.'-1T cU-1oj lv O 82 W.K. Lelhach and H.J. Marsteiler Vi through 1974: (a) 7021 workers engaged in the production of VCN1 and PVC; (b) bo 4910 chemical workers from the same plants not exposed to VCM; and (c) 4007 Bo workers engaged in PVC manufacture. Not included were non-German workers of Mediterranean origin. This German study permits comparison not only with the mor- tio ce; ulity ratio of the total male population but also with a comparable occupational r op group exposed to VCM. With regard to the Itealthy worker effect* (McMichael et al. we ' 1975), overall mortality was elevated for the VCM-exposed population (group al. but 0r. j no* for the other chemical workers (group b). Apart from the markedly elevated stan- the i dardiied mortality ratio (SMR) for malignant liter turnouts (1523). which proved to det have been closely ttlated to the duration of exposure, a significantly elevated SMR was ph. < found for tumours of the lymphatic and hacmatopoctic system (214). T7ie group of oil. chemical workers not exposed to VCM (b) also showed a significant elevation of the fat I SMR for liver turnouts (401), a result that deserves further investigation. No signifi- b.1 candy increased risk was found concerning tumours of the central nervous system or the respiratory tract. up har It has already been mentioned (Sect. 2.2.10) that an excess mortality from brain ref 1 tumours (SMR 535) was recorded among PVC workers engaged in manufacture at one ' of two plants: in the second plant an elevated SMR (434) for liver tumours was found. 1 '> cou 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 of 1 405 of deaths having occurred in ex-PVC workers. A recalculation of the available data *n would have been necessary for the evaluation of a conceivable influence of VCM on vigilance. *1-1 e>* As an addendum it may be noted that determination of plasma carcinocmbryonic or 1 antigen dtre (CEA) in 200 Canadian PVC production workers (mean durauon of em- *>T plovment: 10 yean) showed a more than threefold higher frequency of levels above 10 ng/'ml than in a normal healthy population (1.75 vs. 0.55) (Page et al. 1976). Levels of CEA were also determined in 1363 workere of five different VCM polymeri- zation (3) and PVC processing (extrusion) plants (2) in the United States {Amitnon 11 al. 1978). After removil of possible confusing facton (smoking, alcohol intake, past Ta. ^ medical history), it emerged that the distribution of CEA titres among the polymenia- t;r,. tion worken was significantly different from that in the extrusion plant group and in a nonexposed reference group. Significant differences were also found for two of six _ A job categories examined (polymenzation and maintenance) compared with extrusion g woiken and the reference group. However, the usefulness of the CEA titre as a predic- C live indicator of possible increased risk seems doubtful. D a 4.4 Miscellaneous Aspects 4.4.1 Thrombocytopenia and Platelet Function Tests Thrombocytopenia in chronic VCM intoxication was first mentioned - rather parenihetjcally and without further comment - in a paper published by Antonyushenko in 1968. Later Juht ct al. (1973) noticed that each of the first 13 autoclave cleaners referred to them during 1972 from a West German piant because of suspected skin and prr j|tri JTM (i\ flier f nor- : al. . but ' stan1 to IR W31 p of ' the .ifi-n ;ain i* one <ound. . the >ut v data im I1IC ;m- MSI r fi/a- ij in six predic- iamritko in n it'x and Vinyl Chioride-Aasociattd Disease 83 bone lesions presented with milJ to marked thrombocytopenia (30-119 V 10"* litre). Bone manow aspirates in 6 patients permitted exclusion of disturbed platelet forma tion or osteomyeloflbrosis/sclerosn. but in 12 of them splenomegaly was found. Ex cept for slight reticulocytosis in 8 and leucopenta in 5 of the woricers. otlter haematological tests were negative. The reduction of the number of leucocytes and platelets as well as reticulocytosis appeared to be attributable to splenomegaly, but further studies on the nature of thrombocytopenia were thought necessary, and it was suggested by the authors that a decrease in the number of platelets ought serve as an early and easily detectable symptom. Tire high prevalence of thrombocytopenia (as determined by phase-contrast microscopy) found later on detailed analysis of platelet function and other parameters of blood coagulation in the total cohort of PVC production (and also fabticanon) workers fnm this plant strengthened this suggestion (Baehncr et al. 1974a, b, 1975a. b, 1976;Sthn-Bachner and Enel 1977). Wegmen (1975) also commented upon abnormal platelet counts in 13 of 37 PVC fabricating workers who had onlyhandled PVC powder which.however, might have contained substantial amounts of residual monomer. In contrast.Litis et ai.(l975) detected thrombocytopenia in only 1 of 354 polymerization workers, but an electronic cell counter was used for platelet counts (personal communication). According to Sthn-Baelmtr and Et:tl (1977). the mean platelet count in a cohort of 132 PVC polymerization (and processing) workers was significantly lower tlian that in a nonexposed control group of ISO healthy men. As could be expected,Baehttr et al. (1975b) also demonstrated s positive correlation between the degree of thrombi cytopcnia and the prevalence of an enlargement of the spleen (palpable splenomegaly or spleen size determined by selective scintigraphy with ,*T-H|-bmmo-mercury-hydroxypropane-Ubcllcd red eells) in 70 PVC polymerization workers (ice Table 19). It ap- Table 19. Prevalence of enlargement of the spleen3 among 70 PVC-poiymeriaation worker* in rrijtinn to increasing degrees of thrombocytopenia <Btchntr et al. 1975a) Croup No. of workers examined Platelets (x IO*\'Ltre) Rang* Mean Enlargement of the spleen A 14 B 24 C 25 D7 > 130 100-130 70- 99 < 70 168 11? 7 44 3 (2 ID 11146*3) 19(763) 6 (86") * As determined by palpation or by selective spleen scintigraphy. peats, however, that the development of thrombocytopenia is not dependent on the presence of splenomegaly since we observed mild thrombocytopenia (100-120 x 10"*/ litre) in a small number of workers in whom spleen size was definitely within normal limits on selective spleen scintigraphy (Mflzflachenindex <45 x tor1 according to Fischtr ana \Votf 1963). Thrombocytopenia was accompanied by abnormalities in platelet function tests. There was an increase in the number of large (> 10 isa) `juvenile' platelets (increased (M IV.K. Lclbjih anj H.J. Marsu'ller platelet spreading), enhanced response (platelet aggregation) to addition of ADP and collagen (Bom test) and increased availability of phospholipid-contaming platelet lactor 3 {Bechner et al. 1975a). This pattern was thought to be compatible with the no* lion of an increased turnover rate due to derangement of microcirculation (CDJC) m liver and spleen and defective reticuloendothelial system (RES) clearance of activated clotting factors (BacJiner et al. 1974b). IW (1976) and h'ard et al, (1976) suggested that thrombocytopenia could be construed as confirmatory evidence of an immune complex disorder. Hcuxmann and Stuttc (1977a) noted unusual focal aggregation of platelets in Uatsch preparations of spleen tissue and increased platelet pooling (plate lets trapped within the substnusoidal meshwork of pulp cords) in the red pulp of the spleen on electron microscopy as well as phagocytosis of thrombocytes by sinusoidal macrophages.Sehaffner et al. (1976) found platelet thrombi in and around hepauc sinusoids in mice after exposure to VCM. A direct toxic action of VCM (or metabo lites) on the bone marrow has not been demonstrated so far. Although the pathogenesis of thrombocytopenia in VCM-induced disease is not fully understood, it seems at present most likely that it is caused by increased turnover and consumption of platelets within the abnormal vascular spaces of the liver and spleen. A similar type of consumpuon coagulopathy was described as complication of spon taneous haemangiosatcoma of the liver by Tntett et al. (1975). A haemostatic defect more complex than mere pooling and destruction of platelets in the enlarged spleen has also been commented upon in the paper by Cerrin et al. (1974) in connection with splenomegaly of various nonarrhotic origin. . 4.4.2 Central and Peripheral Nervous System Miscellaneous nonspecific and somewhat indefinite symptoms have been described in connection with chronic inhaiationa! exposure to VCM in PVC-producuon workers, such as dizziness, disorientation, blurring of vision and memory, headache, irritability, excessive fatigue and somnolence, sleep reversal or insomnia and other pseudoncursthenic symptoms {Sucitt et al. 1963,1975-.Sehotttk 1969\Littt et al. 1975 and others). This prenareotic syndrome was interpreted as a manifestation of a potentially reversible acute toxic encephalopathy. Its danger to the individual was thought to lie mainly in resultant inadequate reactions to critical situations (,Schortck 1969). How ever, Vait et al. (1976) reported that several individuals in a group of 95 comparatively young ex-workers, the majority of whom had no other symptoms, complained of fa tigue, headache, listlesiness and depression, with onset of symptoms having been de layed is long as 1 yean aftei cessation of employment. With reference to such `pseudoneurasthenic complaints', which may be interpreted as the mildest degree of a toxic encephalopathy,/Vmn et al. (1975) examined a group of 21 autodave cleaners at varying intervals after cessation of exposure, all of whom presented with other (cutaneous, angioneurotic, hepatic) manifestations of vinyl chlo ride disease. Clinical symptoms of a more or less distinct encephalopathy (including cerebellar ataxia in 4) were found in ill but one of them. EEC recordings were normal in only five of these patients; in the others, parenrhythmia, dyienrhythmia or a socalled subvigil electroencephalogram was observed. Evidence of distal polyneuropathy, found in 19 patients, was attributed in the first place to an abnormal peripheral circu Vr lar en ati. clu t vin. daii sib. 4.4 Tliv FV( P` thu dur we: defi URU vioi exp foul pos> C.> for ere: vale WI5 The sear. ait). bror icai t tion smo to is A re thou ing: to a nect VO resp. 176. n toP' teller UP and clet facthe nof'lC) in ctivsted tggtsied imune nation 01 >( (plate< of the' tusoidal .-patic i.-tabo- < not fully -vet and ; spleen. -ispon- defect <pleen non with -.nd ndally to lie Howparativeiy of fa-' m de- terpreted 1 a group whom nyl dtlolndin| -? normal a soropathy, >al even- Vinyl Chlonl<>A*cKtawd Disease 55 lation with resultant hypoxic damage. Tlie pathogenesis of a possibly VCM-imluced encephalopathy is not clear. It would be conceivable that clinical and bioelectric alter ations found in some patients, in whom portosystemic encephalopathy could be ex cluded. may have been due to toxic or hypoxic brain damage. However, noother con vincing evidence has so far emerged to indicate that chronic irrevetsiblt cerebrotoxic damage may have resulted from prolonged exposure to VCM. notwithstanding the pos sibility of an induction of brain turnouts. 4.4J Pulmonary Changes The suspected development of nonmalignant pulmonary changes due to VCM asd/or PVC dust exposure is still a matter of controversy. Soon after VCM was recognized as a potent carcinogen, three groups of employees fn 290.250,445. respectively i from three large North Amcncan PVC-produang plana (A. B. C). characterized by different duration and levels of past environmental exposure to VCM as well as to PVC dust, were studied with respect to chest x-riy film abnormalities and pulmonary funenon defects as assessed by spirometry and determination of maximum expiratory flow vol ume (Miller IT!S,Miller ti *1. 1975;IiZu et al. 1975,1976,1977). AH cases with prevtous exposure to asbestos, silica or coal dust had been excluded in these studies. Un expected linear, reticular and, lea often, rounded opacities on chest x-ray films were found in about one-fifth of the two groups of employees from plana A (highest ex posure) and B (22.7%, and 18.3%, respectively), but in only 4 of those from plant C. with the lowest exposure level. The prevalence of these radiological abnormalities, for which no pathogenetic explanation was available, was found to be significantly in creased with longer duration of VCM-PVC exposure (more than 10 yean), but the pre valence of a positive histoiy of smoking, although identical in both groups A and B, was also found to be significantly higher in wotken with abnormal chest x-rey plates. The overall prevalence ofa positive history of chronic bronchitis (British Medical Remreh Coundl criteria) w 20.4% in group A (highest exposure) and 16j0% in group B, although group 8 was significantly older. The somewhat higher prevalence of chronic bronchitis in wotken with abnormal chest x-ray plates did not stum statistical signif icance. On the other hmd, age did not sppear to be an important factor. Pulmonary func tion tests showed a strikingly high prevalence of obstructive changes, but since both smoking and age were related to changes in pulmonary function. it appeared difficult to isolate potential specific tlfeca of occupational exposure to VCM and PVC dust. A restrictive pattern wts found in 9J% of group A and in only 23% of group B, al though group A was significantly younger. In conclusion, this extensive study, mdudIng a total of 915 workers exposed in the pvt to VCM as well a PVC dun. may point to a potential multiple factor effect of smoking and VCM-PVC exposure. In this con nection, it is of interest to note that according to a cohort study of mortality among VCM polymerization workers the SMRs for respiratory cancer as well as for `other respiratory disease' were found to hare been in execs of expected figures (156 and 176, respectively) (Waxwetler t iL 1976). Bronchopulmonary changes thought to be due to long-continued, intense exposure to PVC dust were observed by several authors (Pemetpani tniSasti 1955,Broussard t 86 W.K. Lelbach and H.J. Marnetler \969:S;citde et al. 1970; X'enkin and Mamontov 191Q: Froitfia ei al. 1914 :Darke 1976: Ameud et al. 1978). Considerable exposure to VPCdust is the rule in the drying, bagging and storage areas of PVC-preducing pbnts. Photographs conuineti in Kantadt s paper (1976) give a general idea of the potential dust exposure. Measurements of the concentration of PVC dust at various sites of the bagging operations were reported as long ago as 1955 by Parmezpani and Saui. In 1969 Bmuaard mentioned the possibil ity of development of chronic bronchitis caused by the inhalation of PVC dust. The insoluble and inactive dust particles were thought to accumulate in the lungs blocking alveolar spaces and being taken up by alveolar cells. This could lead to elimination of these cells via lymph vessels to regional lymph nodes, with either enlargement of the hilar region or a micronodular aspect of interstitial pulmonary fibrosis without hilar lymph node enlargement but progressive respiratory insufficiency. Sstnde et al. (1970) reported the case of a 31 year-old worker who presented with severe dyspnoea;a chest x<ay examination revealed diffuse micronodular pulmonary lesions. He had been engaged for only 1 year in shovelling PVC powder at a processing factory. Lung biopsy revealed moderate diffuse fibrosis and small focal granulomatous lesions containing ovoid or polygonal birefringent foreign material which could be eluted by treatment with a known solvent of PVC. Microscopic examination of PVC dust panicles collected at the patient's place of work showed them to be morphologic ally identical with the panicles found in the patient's lungs. Another anecdotal case of pneumoconiosis after 33 yean of employment in a PVC bagging area, with radiological.evidence of diffuse micronodular infiltrates and granu lomatous lesions found in a lung biopsy identical with those recorded by S:e>idc et al., was published by Amaud et al. In 1978. Histology of open lung biopsies in 1 of 14 VCM-exposed British worfcen, who complained of breathlessness, revealed focal alveo lar wall thickening with macrophages in alveolar spaces and increased retieulin and col lagen on electron microscopy {Darke 1976). Although chest x-ray appearances were normal and routine respiratoty function tests showed only slightly impaired C02 dif fusion in six individuals, perfusion and ventilation scans revealed strikingly abnormal pictures, including marked perfusion defects of upper lobes. Darke pointed out that some of the men wont affected had been engaged in the polymerization of 'plastisol', a very fine PVC powder with particle size around 0J m. Sttikoff(1976) called attention to results obtained by Fronpa et al. (1974), who observed significant histopathological changes in the lunp of guinea-pip and tats ex posed for 2-7 months to inhalation of the airborne PVC dust in a PVC bagging area. Lesions began to appear at 3 months of exposure (alveolar histiocyte-tnaerophage re actions); they proved to be fairly marked after 4 months, with appearance of foreign body giant ceils, and proceeded to development of large intenutiil granulomatous fod. Vtrtkin and Mamontov (1970) who examined 96 wotken engaged in the manu facture of articles made from PVC powder, also found a considerable proportion of them were suffering from functional and morphological alterations of the broncho pulmonary system, which they ascribed to their exposure to PVC dust. They quoted results of earlier animal experimenta conducted in 1963 by Gotovaryuk and later by SiUyakhtnkii These last authors had apparently shown that exposure of animals to PVC dust may lead to the development of chronic pneumonia and eventually to a sort of mild fibrosis of the lungs. m(.a111 ttiw liningawiPWRiJpwjiMire Jure1.l \. sti bi ll; tu W*' OV Of iy er.- of de P1 4.- Th nvmv tic Of ter mt I* CO' re; po an fat Jo hat h-> of an pb 19 of VC I j Mjmeller #u, in the drying, i in Rantadi s *m* of the reported as the possibildust. The up blocking minauon of nent of the ^hout hilar resented with i pulmonary 1 a processing anulomatous could be ion of PVC morphologic- cm in a PVC ' and granu'.endc ti aJ.. n 1 of 14 i i.v ji alveoelan and colr:cee were dif^Armai .Itmh that *piaitiior. (* 74), who md rats ex* gging area, rophage re- of foreign Unnatouj the maimwtion of broncho!<ey quoted nd later by animals to "dly to a son Vinyl Chloride-Associated Disease 87 Certain types of PVC dust (one of two samples tested) were found to exhibit a strong haemolytic potential due to the presence of an undetermined but readily solu ble surface-associated agent which was not VCM {Richards ct ai. 1975). These authon alio studied the effect of the haemolytic sample of PVC dust on lung fibroblast cul tures, but they did not obtain any significant results. Contrary to earlier indications (Lange ti al. 1974a) and despite continued effons we failed to detect any significant restrictive changes of pulmonary function in the overwhelming majority of patients we had occasion to examine. It may be of interest to note that Maltoni ct al. (1974b) reported a high prevalence of pathological changes of respiratory epithelium (squamous metaplasia, squamous dysplasia, typical and atypical adenomatous proliferation) in sputum samples from employees of Italian VCM-PVC factories. Nevertheless, contrary to the now well-established role of VCM in the production of nonmalignant lesions of bone, skin, small vessels. liver and spleen, it is still open to debate precisely what importance can be asenbed to pulmonary changes within the spectrum of VCM-induced disease. 4.4.4 Genetic Efftos ofVCM The discovery of the carcinogenic properties of VCM also stimulated interest ui its mutagenic potential. A number of studies have been carried out that demonstrated a mutagenic response to VCM or its metabolites in microbial test systems. Point muta tions due to base-pair substitution have been produced In various strains of Salmonella typhimurium by VCM in the presence of animal and human liver microtomes as a sys tem of metabolic activation fFiamtug et al. 1974,1976\Bamch et al. 1975a, 1976: McCann et al. \97l,,\1akretlle et al. 1975:Gereo et al. 1976). Mutagenicity of VCM metabolites wn also demonstrated in yeast strains (loprieno et ai. 1976,1977,Sltalim 1976) and in mammalian eel; {.'lubeman ct al. 1975). In comparison to nonexposed controls, a significantly hight. incidence of chromosomal abenauons (fragmentation, rearrangement) in lymphocytes of workers occupationally exposed to VCM was re ported by Ducaman et al. (l975),Funes-Oatioto ct al. (1975), futchtse et al. (1975. 1976), and Fomenko et aL (1976). Fteig and Thiess (1974) had failed to demonstrate an increased rate of chromosomal aberrations in six chemical engineers and four PVC fabrication workers. As to the influence on germ cells. Purchase et al. reported that no dominant lethal effects were seen in fetuses of female mice mated with males which had been exposed to 3000,10 000 and 30 000 ppm VCM for 5 consecutive days. This, however, does not ebrohtteiy exclude genetic effects on human gonads. The outcome of pregnancy among wives of VCM-poiymerization workers as against wives of rubber Bid PVC-fabrieation workers (Infante ct al. 1976a, b) and rates of congenital malfor mation per 1000 resident live births in three Ohio communities with PVC production plants have also been studied {Infante 1976). As pan of a larger survey of workers' health, interview questionnaires {Infante 1976a, b) showed that after paternal age adjustment i significantly higher inddence of fetal mortality subsequent to paternal exposure was recorded among the wives of VCM-cxposed workers. This trend was found to be maintained after elimination of gs ucc L4 u y ij*4 88 W.K. Lelbach and H.J. Mareteller pregnancies in women who had more than two abortions- The findings of this study raised the question of possible genetic risks of VCM to man and led to the suggestion that germ-cell damage in the father through direct VCM exposure might be a possible explanation. No clear-cut linkage ofFVC production and increased occurrence of congenital malformations (primarily CX5 malformations) emerged from preliminary studies in three Ohio communities with PVC production plants. But the need for further study of possible contributary factors was indicated (Infante 1976). In fact, none -if the par ents of affected children in Painsville, one of the three Ohio communities, had ever worked at either of the two PV'C polymerization plants in Painsville or lived within two miles of these plants (Edmonds et al. 1975). 5 Conclusion and Outlook The combined efforts of multiple disciplines have been necessary* to arrive at tne full recognition of the range of pathology associated with occupational exposure to vinyl chloride. It can only be hoped that the lesson from the vinyl chloride problem may help to bring about an increased awareness of the risks and hazards which are inevitably the consequence of an ever-expanding technology. The importance of this lesson lies in its exemplary nature. A single substance of mher simple chemical structure, which was long held to be a comparatively safe com pound, even by experts, turned out after all to be a carcinogen with a very long latency period for those who were heavily exposed to it. But its carcinogenic properties would most probably still have gone unnoticed if the resulting malignancy had been any can cer other than of an exceptionally tare type. Animal expentnents in the early days later proved to have been broken off before the oncogenicity of this chemical com pound could have been detected. The lesson to be learned is that in future any new chemical which is to be widely introduced into the environment should be scrutinized closely, for a sufficient length of time, and with the aid of all avarlable methods for the detection of potential car cinogenic effects. In addition, we should keep in mind that in industrial surroundings we almost never deal with a single compound, but with a very complex occupational environment whose carcinogenic potential is still a completely unresolved problem. If currently adopted guidelines for industrial hygiene are strictly adhered to, there is reason to hope that initiation of new cases of VCM-induced angiosarcoma of the liver can be effectively prevented. Unfortunately, however, it pan be expected that in view of the long latency period for tumour promotion additional cases will appear dur ing the next decade. Considering the evtT-increising complexity of environmental influences, future re search will be faced with almost insurmountable obstacles in its endeavour to establish levels for potentially hazardous chemicals. Promising areas for further studies in the field of vinyl chloride and allied compounds may be the problem of Use interaction Vinyl Chlon-' between preJ tissue such as short exposu: will catty the t References Albnght Lf < Albnght LF <. Albnght LF <' Albnght LF (: polyvinyl c Albnght LF i processes. Alrenga DP <! 198-203 Amann R (19 der Leber ' Anderson H \ CEA amoi; 1560-156* Andrews AW properties' Anghelescu F V(1969)r employees 473-48: Annual Repo London. Ci AntonyuzhfiiV sian text). < Antweilcr H < I Perspecr I" Amaud A. Po. ride pneuir Aryanpur J11 Iran. J Oco Assmann H (l Austin GT110 87-89 Bachner U. Iund Gsopli. 2409-24ir Bachner U, Ft. Befunde br Jahresbenc: Centner, 5; Bachner U, Mu 1000 patieBachner U.Ei.1 und Otoph Blurungen . ;j469b5 iTMellet tHrainrcrut dy suggestion ** a possible ir.gsmtal `tudies in thst study t oi the par. had ever id within at the full ire to vinyl 'lent may .re inevitably tance of ly safe eont-mg latency trues would he widely i ntlen|th .ntiaJ ear`irroundinp cupttional ' problem. 'ed to, there m of the cted that in U appear due* future nr to establish r studies in >e interaction Vinyl Chinmie-Associatcd Disease 89 between predominantly hepatocytic metabolism and oncogenic effect on mesenchymal tissue such as vascular endothelium, and also the question of whether intermittent short exposures at high concentrations or continuous exposure at a low concentration will carry* the greater risk. References Albnght LF (1967a) Vinyl Chloride processes. Chtm Eng 74:123-130 Albnght LF (1967b) Manufacture of vinyl chloride. Chem Eng 74 119-224 Alhngnt LF i 1967c) Folymenaation of vinyl chlonde. Chem Eng 74:151-158 Albnght LF (I967d) Vinyl chlonde polymerization by suspension processes yields polyvinyl chlonde resins. Chem Eng 74:145-15? Albnght LF (1967) Vinyl chlonde polymenzanon by emulsion, bulk and solution processes. Chem Eng 74:85 -9? Alrtnga DP M975) Primary angiosarcoma of the liver. 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