Document vVrYMmYoVBZNGoQEaJjY5yQXY

R&S 133968 k- 17// -C:cc) Ergebnisse der Inneren Medizin und Kinderheilkunde Advances in Internal Medicine and Pediatrics Neue Folge Herausgegeben von P Frick G.-A.von Harnack K.Kochsiek G.A. Martini A. Prader Mit 24 Abbildungen und 23Tabellen Springer-Verlag Berlin Heidelberg New York 1981 Vinyl Chloride-Associated Disease W.K. LELBACH and H J. MARSTELLER 1 1 Introduction ........................................................................................................... 2 2 Technological Details.............................................................................................. 2.1 Vinyl Chloride Monomer (VCM).................................................................. 2.1.1 History................................................... 2.1.2 Production of VCM............................................................................ 2.2 Production of Polyvinyl Chloride (PVC)..................................................... 2.2.1 Technology of Polymerization.......................................................... 2.2.2 Methods of Polymerization................................................................ 2.2.3 Compounding.................................................................................... 2.2.4 Sources of Exposure to VCM in PVC Production ......................... 2.2.5 The Explosion Hazard....................................................................... 2.2.6 The Odour Threshold '....................................................................... 2.2.7 VCM as an Anaesthetic Agent.......................................................... 2.2.8 Effects of Acute Overexposure in Man........................................... 2.2.9 Monitoring VCM Concentrations in Working Areas....................... 2.2.10 Exposure to VCM in PVC-Proccssing (-Fabricating) Plants.......... 2.2.11 National Standards for the Control of Exposure............................ 2.2.12 Exposure to VCM Outside the Working Area................................. 4 4 4 5 g 6 7 8 8 9 )0 to n )3 |f 17 18 3 Toxicology of VCM................................................................................................. 3.1 Acute Toxicity................................................................................................. 3.2 Chronic Toxicity.............................................................................................. 3.3 Oncogenic Properties...................................................................................... 3.4 Toxicodynamics.......................'..................................................................... 3.4.1 Uptake and Distribution..................................................................... 3.4.2 Metabolism......................................................................................... 3.4.2.1 Relation between Chemical Structure, Reactivity and Mutagenic or Carcinogenic Effect.............................. 3.4.2.2 Metabolic Pathways............................................................. 21 21 21 22 24 25 26 26 26 4 Clinical Spectrum......................................................................................................'29 4.1 The Triad: Raynaud's Phenomenon. Pseudoscleroderma and Acroosteolvsis................................................................................................. 31 4.1.1 Familial and Idiopathic Acroosteolysis........................................... 34 4.1.2 Epidemiology of Occupational Acroosteolysis............................... 34 4.1.3 Clinical and Roentgenological Features........................................... 36 4.1.3.1 Occupational Acroosteolysis.............................................. 36 4.1.3.2 Pseudoscleroderma............................................................. 38 4.1.4 Histology.............................................................................................. 39 4.1.4.1 Cutaneous Lesions......................'........................................ 39 4.1.4.2 Bone Lesions....................................................................... 39 4.1.5 Arteriography. Capillaroscopy, Infrared Thermography............... 40 4.1.6 Immunological Studies....................................................................... 42 I Department of Medicine, Director: Prof. Dr. ILL Dengler, University of Bonn, ERG W.K. Lelbach and H.J. Marsteller Viny! Chloride-Asso.. 4.1.7 Pathogenetic Considerations............................................................... 44 one of the least harm! 4.2 Non-malignant Liver Disease in Vinyl Chloridc/Polyvinyl Chloride Production Workers.......................................................................................... 4.2.1 Clinical Manifestations of Non-malignantLiver Disease.................... 4.2.2 Laboratory'Findings........................................................................... 4.2.3 Gross Inspection of the Liver and Spleen.......................................... 44 4g 49 50 later turned out, had i evaluation of acute eft to reveal its carcinoge; might have continued 4.2.4 Histology............................................................................................. 51 place, considering tha; 4.2.4.1 Hepatic Fibrosis................................................................... 51 vapour phase under ar ; : 4.2.4.2 Sinusoidal Lining Cells........................................................... 4.2.4.3 Hepatocytes............................................................................. 54 54 reactive double-bond. 4.2.4.4 Histology of the Spleen......................................................... 54 Today vinyl chlori ] 4.2.5 Pathophysiology of Portal Hypertension........................................... 55 formation and data on 4.2.6 Follow-up of Non-malignant VCM-inducedLiver Disease............. 57 cisely a quarter of a ce 4.3 Angiosarcoma of the Liver..................................................... :................ 57 tributable to this new ; 4.3.1 Epidemiology........................................................................................ 4.3.2 Clinical Manifestations......................................................................... 57 74 with the shocking disc 4.3.3 Peritoneoscopy....................................................................................... 76 tion workers heavily e- : 4.3.4 Gross and Histological Morphology..................................................... 78 ing that the monomer 4.3.5 Therapy.................................................................................................. 80 pound did not alert th 4.3.6 Risk Assessment................................................................................... 4.3.7 Mortality and Cancer Morbidity Studies.......................................... 4.4 Miscellaneous Aspects..................................................................................... 4.4.1 Thrombocytopenia and Platelet Function Tests............................. 4.4.2 Central and Peripheral Nervous System............................................. 80 81 82 82 84 in workers engaged in lished in 1949 (Tribuk Ultimately, it was i curred in workers expi 4.4.3 Pulmonary Changes.............................................................................. 85 a causal relationship: ( 4.4.4 Genetic Effects of VCM...................................................................... 87 pseudosleroderma; (2) . 5 Conclusion and Outlook.......................................................................................... 88 liver. Particularly, the. nancy among a compa References...................................................................................................................... 89 alarming experience w a connection between Key words: Acroosteolysis - Angiosarcoma of the Liver - Portal Fibrosis and Portal Hypertension - Pscudosclcroderma - Raynaud's Phenomenon - Vinyl Chloride lungs or the gastroinu the prolonged latency sarcoma of the liver, n these two fatal conseq the conclusion that Vi 1 Introduction cancer meeting in Hou to VCM was a very ser It should be stress*, The history' of vinyl chloride-associated disease, its recognition and prophylaxis is a classic example of shutting the stable door after the horse has bolted. It should help to emphasize the need to shift our attention to preventing exposure from occurring rather than to reparative measures. In view of the large number of new and potentially hazard ous chemicals introduced each year into the workplace and the environment, tliis ac count should again alert us to the necessity of pretesting chemicals adequately for their potential health effects, even at the risk that technological progress will develop at a more modest rate. Large-scale production of the synthetic resin polyvinyl chloride (PVC), a thermo plastic material suitable for the most widely diversified industrial use, was begun around 1930 in the United States and in Germany. The monomer, vinyl chloride (VCM), a rather simple aliphatic compound, was believed until the early 1960s to be precise, an intermedia! mainly in the mammal merization products (F cated from the polymcthey contain unreactec PVC (thermal decompi toxicity of pyrolysis pi mainly due to th* rplea A bar 1969 ;Dy and only very s (O `Mara et al. i go to -a CO CO CO -4 o Marsteller JO G W w u> CD -4 57 57 74 76 78 80 80 81 82 82 84 85 87 88 89 :../r .7 bride~ laxis is a 'uld help to irring rather ially hazardu. this actelv for ill develop . a thermobegun loride Vinyl Chloride-Associated Disease 5 one of the least harmful chlorinated hydrocarbons. Early animal experiments, as it later turned out. had indeed been carried out with dosages sufficiently high for the evaluation of acute effects, but chronic exposure had not been of sufficient duration to reveal its carcinogenic properties. On purely theoretical grounds, however, one might have continued to feel uneasy with this compound as a pollutant of the work place, considering that it is (1) a halogenated hydrocarbon which (2) exists in its vapour phase under ambient conditions (inhalative exposure) and (3) contains a highly reactive double-bond. Today vinyl chloride-associated pathology is well documented. A large body of in formation and data on this topic has been accumulated, notably since 1974, but pre cisely a quarter of a century had to pass before the full range of symptomatology at tributable to this new occupational health hazard became recognized in January 1974 with the shocking discovery that haemangiosarcoma of the liver occurred in produc tion workers heavily exposed to PVC. Early and not easily accessible reports suggest ing that the monomer might be an environmental risk for workers handling this com pound did not alert the experts sufficiently. The earliest indication of adverse effects in workers engaged in the production and processing of PVC, a Russian study pub lished in 1949 (Tribukh et al, 1949), received little attention. Ultimately, it was the exceptional character of the three major lesions which oc curred in workers exposed to VCM that contributed most to the final appreciation of a causa] relationship: (1) the syndrome of acroosteolysis, Raynaud's phenomenon and pseudosleroderma: (2) non-cirrhotic portal hypertension; and (3) angiosarcoma of the liver. Particularly, the discovery of a duster of four cases of this extremely rare malig nancy among a comparatively small group of workers (Creech et al. 1974a) was an alarming experience which called for immediate action. It can easily be imagined that a connection between VCM and the more common malignancies, such as cancer of the lungs or the gastrointestinal tract, might still have gone unnoticed. On the other hand, the prolonged latency periods of both non-cirrhotic portal hypertension and angio sarcoma of the liver, roughly 10 and 20 years respectively, delayed the recognition of these two fatal consequences of chronic exposure to VCM. But one can hardly escape the conclusion that Viola's discovery of cancer in experimental animals, presented at a cancer meeting in Houston in 1970, was sufficient evidence to indicate that exposure to VCM was a very serious occupational hazard (.Peters 1976). It should be stressed that the noxious agent is solely the monomer, or to be more precise, an intermediate of the monomer's metabolic bioactiviation, which takes place mainly in the mammalian liver and yields certain highly reactive epoxides. The poly merization products (PVC), i.e., the solid plastic and the plastic consumer goods fabri cated from the polymer, are chemically inert articles which carry no health risk unless they contain unreacted residual monomer. Even the combustion of articles made from PVC (thermal decomposition in fires) does not yield free vinyl chloride monomer; the toxicity of pyrolysis products of polyvinyl chloride polymers and formulations is mainly due to the release of hydrochloric acid and carbon monoxide (Cornish and Abar \969\Dyer andEsch \916\Sorenson \916\Moser \916\Colardyn et al. 1976) and only very' small or no quantities of phosgene derived'from residual monomer (OMara et al. 197] cited by Colardyn et al. 1976). 4 2 Technological Details 2.1 Vinyl Chloride Monomer (VCM) W.K. Lelbach and H.J. Marsteller At standard (ambient) conditions of temperature and pressure, vinyl cldoride (CH; = CHC1: chloroetbylene, chloroethene) is a non-irritating, colourless gas with a faintly sweet odour, inflammable at concentrations above 3.8% by volume in air, which is only slightly soluble in water, soluble in ethyl alcohol and easily soluble in ether and carbon tetrachloride. VCM is mainly used as an intermediate in the manufacture of plastics, as a refrigerant and in organic synthesis. It was formerly also employed as a propellant for aerosoles. It is easily liquefied under pressure and is usually handled and shipped as a liquid. Gaseous VCM condenses at --13.8C and 760 Torr (= 101.3 kPa) to a colourless liquid of low viscosity (Lefaux 1966). Its physical properties arc listed in Table 1, the most important of which are its low boiling point, its high specific grav ity (gaseous VCM is 2.15 times heavier than air), its low solubility in water and the half-life in air, ranging from 3 to 20 h. Table 1. Physical properties of VCM Mol. wt.: B. p.: F.p.: Flash point: Limits of flammability: Autoignition temperature: 62.503 -13.8C (-13.7 to -13.9) -153.7C -78.5C (Cleveland open cup) 3.8%--29.3%-by volume in air above -78.5C (= 38 000-293 000 ppm) 472C Vapour pressure: mm Hg C 10 100 692 --87.5 -55.8 -15.8 2300 + 20 2660 +25 Vapour density: 2.15 g/litre (calculated at 25C and 760 mfnllg (air = 1) Sp. gr. of liquid VCM: 0.9121 at --20C/4C 0.99 at --25C/4C Sources: Fairhall \9Sl\lnsh \963\Zapp 1964\Lefaux 1966: Ostennaver 1967: .Roubal 1972. 2.1.1 History The French chemist, Regnault (1835) was apparently the first to study systematically the synthesis and analysis of vinyl chloride. Liebig, who had done some earlier prelim inary experiments, encouraged Regnault to investigate this compound when Regnault spent several months in Liebig's laboratories. All compounds containing the vinyl group (CH,=CH-) polymerize readily (Fairhall 1957), Spontaneous polymerization of vinyl chloride to a white opaque solid mass under the influence of sunlight was first described by Baumann in 1872; he also quotes a paper by Saytsev and Glinsky (who Vinyl Chi- succeeded izing subsi 2.1.2 Pro, Large-scab by emplos 1) Conver.' "HCH 33 avers C/> rroe; =CI oa w to to K 'J nus. any Itions in the in the rang II ARC 197when VCM mayer 19b` in commer 1966: Oslo In the c conjecture', retrieved V* yses carrie,. sum of all i: genates) ,, reacted mo. in prepolyn the concery that even l1 methyl chh isobutane, / ference in p , .md H.J. Marsteller Vjnyl Chloride-Associated Disease 5 succeeded in decomposing vinyl chloride to monochloroaldehyde with the aid of o.\id'--izinc substances such as hypochlorons acid. yl chloride (CH: = :as with a faintly : in air, which is duble in ether and ' manufacture of 'so employed as a usually handled and Torr (=101.3 kPa) 'roperties are listed its high specific gravin water and the 2.1,2 Production of VCM Large-scale commercial synthesis of VCM with a high yield was made possible much later by employing two principle methods, the second having now largely replaced the first: 1) Conversion of acetylene to VCM by hydrochlorination: CHsCH + HC1 -- CH:=CHC1 (catalyst: HgCl2 on charcoal) (Austin 1974) 2) Conversion of ethylene by vapour-phase or liquid-phase oxydilorination to 1,2-dichloroethane and subsequent pyrolysis (thermal cracking) to VCM (Albright 1967a): CH:=CH; +2HC1 + 1/2 0: -* CH2C1~CH:C1 + H:0; CH:C1-CH:C1 480 C~51 C > CH,=CHCI + HCI 1 pumice catalyst (pyrolysis; thermal cracking, Austin 1974). i VCM was usually manufactured in closed systems and stored in outdoor facilities. Thus, any leakage of the gas was readily diluted in the ambient air. VCM concentra tions in the atmosphere at some distance from manufacturing plants were found to be ose --78.5C in the range 1--2 ppm. In close proximity, the concentration ranged up to 50 ppm flARC 1974). Spontaneous polymerization in light has also been repeatedly observed when VCM comes into contact with atmospheric air due to container leakage (Oster `00 8 Vjo 2660 + 25 mayer 1967). A prerequisite for the polymerization process is a high degree of purity in commercially produced VCM. Impurities retard the polymerization process (Lefaux 1966\Ostcrmaycr 1967). ,ii,l 760 mmHg In the early discussion about the cause of vinyl chloride-associated disease it was conjectured that other compounds or impurities contained in prepolymerization or in retrieved VCM might have been the causative agent(s) (Thiess and Vcrscn 1974). Anal 33 99 if) --1. w 00 CD -4 W 1967; yses carried out by six West German manufacturers of PVC, however, showed that the sum of all impurities (such as saturated or unsaturated hydrocarbons and their halocenates) was 0.01% by volume for prepolymerization VCM and 0.1% for retrieved un reacted monomer. Only methyl cliloride was found in concentrations of 50--300 ppm in prepolymerization VCM and 100-500 ppm in retrieved VCM (in one instance only, the concentration ranged between 1000 and 3000 ppm). But it should be kept in mind that even 1000 ppm methyl chloride in VCM would mean, at 500 ppm VCM in air, a si imatically ` s ...er prelimound when Regnault methyl chloride concentration in air of only 0.5 ppnt. All other impurities (propylene, isobutane, n-butane etc.) would then be in the ppb range. Besides, no significant dif ference in purity could be found between VCM from acetylene and from ethylene. taining the vinyl j ous polymerization of j f sunlight was first j and Glinsky (who ; 6 W.K. Lelbach and H.J. Marsteller 2.2Production of Polyvinyl Chloride (PVC) 2.2.1 Technology of Polymerization The following description is meant to serve merely as a rough sketch of the procedures and technological details involved in the production of polyvinyl chloride. Vinyl chloride monomer is polymerized in large autoclaves (reactors) at tempera tures between 40C and 80C and pressures of 6-16 (8-12) atmospheres. There are usually several reactors (up to 10--30) located in one building. The reactivity of the monomer is a function of its double-bond. The second functional site of the vinyl chloride molecule, the chlorine atom, does not react easily. The double-bond of VCM is not only the site from which the polymerization originates but is also the source of the toxicity and carcinogenicity of this compound when it is being metabolized in the body. The polymerization of VCM, which is a strongly exothermic reaction (Barnes 1976), is initiated with the aid of compounds soluble in VCM that form free radicals at relatively low temperatures. Initiators are such compounds as lauroyl peroxide, isopro pyl percarbonate, azo-bis-isobutyronitride, and others. The free radicals react with the double-bond of the monomer, transforming it in turn into a free radical and thus prop agating the growth of a chain of molecules with a terminal free radical. Chain growth is interrupted by saturation of the terminal free radical which often involves a reaction between two growing chains (Malten and Zielliuis l964\Lefaux 1966;Albright 1967 z--c'J)ommmghaus \ 912\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 50 000 to 150 000 daltons (.Albright 1967b). Degree and velocity of polymerization, which are influenced by temperature and the concentration of initiators, determine the specific type of PVC produced {Frey 1973), During polymerization considerable amounts of the monomer arc at first dissolved in the polymer, but most of this is later .also transformed to PVC as polymerization progresses. The polymer which is not sol uble in the liquid monomer precipitates out. The process of polymerization slows down towards the end of the reaction.lt is terminated, depending on the method used, when approximately 80%-90% of VCM is polymerized. The timing of this termina tion of the process is essential for the physical properties of the resins produced. The heat generated during the exothermic process of polymerization must be removed to keep the temperature of the reaction under control. Mechanical agitation aids in trans ferring the heat across the colloidal system to the cooling jacket of the reactor. During the process of polymerization certain quantities of the polymer adhere to the walls of the reactor and form a slowly thickening continuous film or crust. This polymer crust on the inner surface of the reactor vessel, which contains cavities filled with unreacted monomer, impedes the conductance of heat; it has, therefore, to be cleaned away after termination of the batch process (Bames 1976). After completion of the polymerization process, the slurry is released from the re actor into a dump tank. Residual unreacted vinyl chloride monomer is partly solvated in the polymer (about 10%); the remainder is dispersed in the water phase or is present Vinyl Chloride-.' in the vapour ph VC monomer is is then purified I the finished pol\ and must diffuse Raw PVC resin, (VKE \91S).Ba, proximately 500 The slurry fr< large enough to 1 are then pumped wet polymer, a g drying methods, merization, yielc fine solid particl. drying temperati polymer. A cycli The solid polymstorage bins or si dried powder co 2 2.2 Four i 30 fio PVC ( CO 11 Susp< --i CO fi whic CO ler (sucl <o V! rim conj -b ith this wh; Emulsion tolym was added in the except that large are added. Emul emulsifiers cann> Bulk (Mass) Poh the additon of o' Tire first reactor second one is usi solid state, to es^ reaches a level ol characterized by good optical clai id H.J. Marsteller of the procedures unde.' tors) at temperaheres. There are ^activity of the a of the vinyl 'ble-bond of VCM dso the source of netabolized in the eaction (Barnes oirn free radicals at t peroxide, isoprocals react with the leal and thus prop el. Chain growth is solves a reaction $\ Albright 1967 h termination -cnee different de' being statistically jp, from about polymerization, Mr'.f, }rmine ion considerable iost of this is later which is not solnzation slows the method used, of this termina ls produced. The :-t be removed to ation aids in trans ire reactor. During ere to the walls of his polymer crust e ireacted c _ vay after 30 : 00 Co CO vl cn the resolvated is present Vinyl Chloride-Associated Disease 7 in the vapour phase above the slurry. While a batch is in the dump tank, this unreacted VC monomer is retrieved by pumping it off into a VCM storage tank. Retrieved VCM is then purified by subsequent distillation for recycling purposes. Monomer solvated in the finished polymer cannot easily be extracted since it has a strong affinity for PVC and must diffuse through the particles; this diffusion depends on time and temperature. Raw PVC resin, therefore, still contains certain quantities of unreacted monomer (VKE 1975). Barnes (1976) reported that the polymer in the slurry still contains ap proximately 500 ppm of vinyl chloride. The slurry from the dump tank is pumped into a storage tank (blend tank) which is large enough to hold several batches of the product. The contents of the blend tank are then pumped into a centrifuge which separates the wet solids from the water. The wet polymer, a granular mass, is dried either in rotating tubular dryers or by spraydrying methods, the latter being used mainly for products formed by emulsion poly merization, yielding a polymer which is similar to a very fine white flour. These very fine solid particles are fed directly into a spray-drying column without dewatering. The drying temperature should not exceed 60C to prevent thermal decomposition of the polymer. A cyclon separator at the exit end of the dryers removes coarser particles. The solid polymer particles are then sized by multiple-layer screens, air-conveyed to storage bins or silos and finally packaged for shipment (.Albright 1967d). The resultant dried powder contains about 50 ppm of monomer (Barnes 1976). 2.2.2 Methods of Polymerization Four different methods of polymerization are used for the commercial production of PVC (Frey 1973), the first two now being the most widely used: Suspension Polymerization. Polymerizationis carried out in an aqueous system in which monomer droplets are maintained in suspension by means of protective colloids (such as polyvinyl alcohol, gelatin, substituted celluloses) under heat and pressure in conjuction with brisk agitation. Relatively large polymer particles can be obtained by this method which `dry blend' well. Emulsion Polymerization is the oldest technique, to which suspension polymerization was added in the 1950s. The process is similar to that in suspension polymerization, except that large amounts of emulsifying agents (such as soaps or other surfactants) are added. Emulsion polymerization yields resins of a very small particle size. The emulsifiers cannot be completely removed. Bulb (Mass) Polymerization. In this process VCM is polymerized in two stages without the additon of other liquids. The two reactors are operated batch-wise and in series. The first reactor (a `prepolymerizer') provides for the initial liquid phase, while the second one is used for agitating the slurry, which is transformed, through a sticky solid state, to essentially dry particles until the conversion from monomer to polymer reaches a level of about 75%--80%, The resins obtained by bulk polymerizatipn are characterized by high purity and particle uniformity, resulting in an end-product of good optical clarity. i s W.K. Lelhach and H.J. Marstcller Solution Polymerization. This type of precipitation polymerization is carried out in organic solvents such as n-butane or cyclohexane. It accounts for only a small percent age of the total amount of all PVC resins produced and it is used for the production of copolymers. Copolymers arc mixtures of comonomers (such as vinyl acetate, vinylstearate. vinylidene chloride, propylene, acrylonitrile etc.) and vinyl chloride. The co monomers tend to improve flexibility and limited solubility of the product in solvents and exert an influence on the temperatures required for compounding. 2.213 Compounding As a next step, depending on the end use, the dried polymer, a whitish powdery or granular product, is then compounded (or dry blended) under pressure at fusion tem perature with the aid of plasticizers (mainly phthalate or other organic esters) and light and heat stabilizers (heavy metal salts, organotin compounds, and other stabilizers). Lubricants or dyes can be added. Plasticizers are added for the production of flexible PVC: rigid PVC contains little or no plasticizer. These additives can also be a source of toxicity. The plasticizers may slowly diffuse out of the final product depending on its compatibility. Lead-containing stabilizers may also pollute the working atmosphere (SmotFic 1966: Tola 1975). Compounding is carried out by hot mixing at fusion tem peratures below or within the softening range (120C-160C). 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 100C to 300C. 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 foodstuff packaging (bottles, films, foils) even less. 2.2.4 Sources of Exposure to VCM in PVC Production Both polymerization of VCM and subsequent processing (centrifuging, drying, screen ing, bagging) arc usually carried out in closed buildings. Exceptions can be found in hot climates (Aryanpur 1977). Polymerization is of necessity a batch process that re quires a large number of single operations. Therefore, valves, gaskets, shaft-openings and control gear are subject to heavy wear and thus to leakage. Other sources of pollu tion of the working atmosphere are exchange of parts and repair jobs. The degree of pollution also depends to a large extent on the quality and effectivity of monitoring equipment and special exhaust systems. Opening of autoclave vats for cleaning and control purposes resulted in larger spill-over of the tank atmosphere into the work en vironment. Numerous reports of workers with prenarcotic symptoms (dizziness etc.) Vinyl ( it t' 3) P; Oo lei W) a: W w ad (0 -4 :d cn Ci X *r tion still marily. t those wi (centrifu ties of i ventilatii shipmem nomer, v are drive Table 2. 1 pp! me (Pal: I nig/lili 1 mg/nv 1 ppm 2.2.5 7 In the p nant mo covers. {Lefaux led as a opened became vlarsteller out in i peregut:-.'ct i f sinyl. Tlic qo solvents .-ry or :on temi and light itzers). 1 tlexible source of ing on its sphere ion ternmtpound- iducts. Hicts is nivssion used in iK i of liorir-yv m-tin, ' } mauled Joined foils) 30 W CO CO CD -4 ;setc.) Vinyl Chloride-Associated Disease 9 permit the conclusion that episodes of acute overexposure to VCM were not rare events in the past. There is no doubt, however, that those workers who manually cleaned the auto clave vats by scraping away or chipping off the `polymer skin' formed on the reactor walls (`polyclcaners'), and who in the past had to spend several hours inside the reac tors, had been exposed to the highest concentrations of VCM. Although the vats were degassed prior to entry, unreacted monomer remained trapped in the polymer skin, and larger amounts of VCM were released when cavities formed in the polymer crust were opened by chipping. The later introduction of automatic cleaning systems reduc ed the frequency of entry into the reactors, but some manual cleaning of shorter dura tion still had to be done after every 20th-30th run. It is, therefore, plausible that, pri marily, the most severe adverse effects of exposure to VCM were fully recognized in those workers who had been employed in this job category. But the subsequent steps (centrifuging, drying, screening) also involve the release of some of the lesser quanti ties of unreacted residual monomer from the particles to pollute the environment if ventilation, notably of the drying facilities, is inadequate. Finished polymer, ready for shipment or subsequent compounding, still contains small quantities of unreacted mo nomer, which either slowly diffuse out and pollute the bagging areas during storage or are driven out by the high temperatures necessary for compounding. Table 2. Conversion table for concentration of VCM in ambient air Mol. vvt. Ippm= ) "OOO x 24J5 ms/litre 24.45 x I 000 I nig p* er litre = -----Mr--ol-.--w--t-,-------- ppm (ratty 1958) 1 mg/litre = 1 mg/m' = 1 ppm = 2.50 mg/mJ l'f = lOOOOppm 391 ppm 0.391 ppm = 0.00256 me/litre = 25.6 mg/litre 2,2.5 The Explosion Hazard In the past only the explosion and fire hazard of VCM was thought to be the domi nant monitoring problem in handling gaseous vinyl chloride (Irish 1963). This hazard covers a concentration range of 4%--22% by volume of air (40 000-220 000 ppm) (Lefaux 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 fire. At least two instances of disastrous VCM explosions became known: In 1964, a large plant for the polymerization of VCM in the United 10 W.K. Lelbacli and H.J. Marsteller States was almost completely destroyed when VCM escaping from a leak detonated (Albright 1967a). Another explosion in one of the two Rumanian'factories operating at that time was mentioned by Suciu et al. (1975). Monitoring of VCM concentrations polluting the work environment was then directed largely towards preventing VCM from reaching the flammability limit. 2.2.6 The Odour Threshold Unfortunately, gaseous VCM has no irritating or unpleasant warning properties. Its mild odour is described as faintly pleasant, sweet or ethereal. Some of the PVC workers we interviewed reported that they had even enjoyed `sniffing the gas', which soon resulted in a feeling of light-headedness. For the early days of PVC production, when appropriately sensitive monitoring equipment was not yet available, workers' re ports about perception of the odour of VCM can be taken as circumstantial evidence for a rough estimate of the actual degree of exposure. It should be kept in mind, how ever, that in chemical production units the presence of other odoriferous chemicals and the possibility of olfactory fatigue, as well as different levels of individual sensitiv ity, may render it very' difficult to determine the factual odour threshold of a certain gaseous substance unless it possesses irritating warning properties. In 1929, Schmidt and Schaumann declared that the faintly sweet gas is practically odourless at concentrations of 5%--10% by volume. Veltman and Lange (1977a, b) assumed an odour threshold of 5 000-10 000 ppm. Volunteers exposed to VCM detected a slight odour at 4 100 ppm; a distinct odour was noted at 6 600 ppm for 30 min and this was accompanied by subjective symptoms of dizziness and sleepiness (Irish 1963). Gehring et al. (1979) recently mentioned a threshold of approximately 3500 ppm. Others have claimed that a concentration of 400-500 ppm is the lower limit for detection of VCM by its odour (Baretta et al. 1969; Cook et al. 1971 \Markowitz et al. \912\Lcfcvre 1975, cited by Hublet 1975).Baretta et al. (1969) conducted experiments with concentrations of 50, 250 and 500 ppm in an exposure chamber, in wluch 13 volunteers participated. At 500 ppm only some of them claimed that they were able to detect the odour, but this was inconstant. Table 3 shows that differences between the various estimates are at least one order of magnitude. The close proximity between the perception of the odour of VCM and incipient CNS symptoms as reported by Irish (1963), however, makes it likely that the actual odour threshold can be as sumed ator 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 (Deese and Joyner 1969). 2.2.7 VCM as an Anaesthetic Agent VCM was once even considered for use as an anaesthetic agent. In 1929, Schmidt and Schaumann speculated about using VCM as a supplementary narcotic at concentra tions of 3%-5% (v/v) (= 30 000--50 000 ppm) in combined nitrogen oxide oxygen Vinyl Chlor Table 3. Och Lower limit 5 000-10 0 50 4 I' 3 $ 51 400-5' 4' 4t anaesthesia f tic and letha oxygen ;com however, tha eluded. In ti 10% VCM to several hours commented ; mined about 3.5-5 mmol mmol (244 0 Osier et al., i cardiotoxicit. man because r hai 'risk g fora /) --* ffect CO CO lhid CO Tab! ICUti IS su adequate war exposure to h A 21-year-olc , 10 min after i which had be cardiac enlarg have been aci; which occum doubt that he found dead w il.J. Marsteller detonated ",'s operating jncei ions ling VcM -t'fics. its PVC fas', which noduction, workers're'ai evj(jencs 1 TM'nd,how- chemicaJs dua/ sensitiv es certain 5 Practically iQ77a,b) to VCM Ppm for I sleeping *''mate/y lie lower "J7l ' i)l"rkoI von^ ted hamber, in nat they differences Proximity as reported >n be as- met wam. eye and a concern and entra- 3J CO CO CO CD ^4 CO Vinyl Chloride-Associated Disease ' Table 3. Odour threshold Lowe; limit of detection 5 000-10 000 ppm 5 000 ppm 4 ]00 ppm 3 500 ppm 500 ppm 400-500 ppm 400 ppm 400 ppm Author Veltman and Lange 1977a, b Viola 1974 Irish 1963 Gehring et al 1979 Baretta et a|. 1969 Lefevre 1975 (cited by Hublet I 915) Cook et al. 1971 Markowitz et al. 1972 11 anaesthesia because of its potent narcotic action and the wide margin between narco tic and lethal concentrations. In animals it produced anaesthesia at 7%-10% in air or oxygen; concentrations above 12% proved to b.e dangerous. The authors pointed out, however, that adverse late effects of this halogenated hydrocarbon could not be ex cluded. In toxicity studies with guinea pigs Patty et al. (1930) found concentrator of 10% VCM to be lethal within 30--60 min, 5% to cause marked narcosis, and 0.5% for several hours to be the maximum tolerable exposure without serious effects. They also commented upon the potential use of VCM for surgical anaesthesia but were undeter mined about its practicability. In mice, the minimal anaesthetic range was found to be 3.5-5 mmol (85 000-122 000 ppm) for 10 min, the minimal lethal range 10-12 mmol (244 000-293 000 ppm) (Peoples and Leake 1933). It was not until 1947 that Osier et al., in contrast to Schaumann's earlier assumption (1934) of a relatively low cardiotoxicity, warned against the use of VCM as a potential general anaesthetic in man because of serious cardiac irregularities and ECG changes observed in dogs. VCM, like other halogenated hydrocarbons, sensitizes the heart to the effect of catechol amines (Irish 1963). We could not ascertain whether VCM has actually been used in the past for anaesthesia in man. 2.2.8 Effects of Acute Overexposure in Man Some individual responses of volunteers to increasing concentrations of VCM are listed in Table 4.Lester et al. concluded in 1963 that the maximum concentration without acute effects in man lies between 8 000 and 12 000 ppm for 5 min, and that symptoms such as dizziness, light-headedness and disorientation should be taken as adequate warning signs for imminent acute danger. Two fatalities after occupational exposure to high concentrations of VCM are reported in the literature (Danziger 1960). A 21-year-old autoclave cleaner at a Canadian polymerization plant was found dead 10 min after entry at the bottom of a probably insufficiently ventilated reactor tank which had been declared safe solely after an explosiometer test. Heart failure cells and cardiac enlargement found at autopsy, however, implied that the cause of death might have been acute functional disturbance in pre-existing heart disease. In the second case which occurred at the same plant, however, circumstantial evidence apparently left no doubt that heavy VCM exposure was the cause of death in a 39-year-old worker. He was found dead within 20 min, lying in a pit near the opened valve of a recycling pipeline W.K. Leibach and H.J. Marstellcr Table 4. Individual responses of volunteers to increasing concentrations of VCM Concentration 500 ppm 'X'U 000 ppm 6 600 ppm Dura Lion of Symptoms exposure- Reference 7.5 h (Inconstant odour detection) Barctra et al. mild headache, dryness of (1969) eyes and throat in 2 of 7 subjec ts) - Generally accepted odour Irish (1963) threshold 30 min (Distinct odour) dizziness, sleepiness Irish (1963) S 000 ppm \ 12 000 ppm 1 5 mina (twice on 16 000 ppm J each of 3 succes sive days) 20 000 ppm ) 2 of 6 subjects `slightly heady' 1 of 6 subjects had reeling, swimming head, `just like getting gas' 5 of 6 subjects, various degrees of intoxication All 6 subjects had more intense symptoms of acute intoxication than at 16 000 ppm Lester et al. (1963) 25 000 ppm 3 min 2 experimenters: dizziness, disorientation, burning sensation in the soles of the feet Patty et al. (1963) a Exposure to six different concentrations: 0 ppm; 4 000 ppm; S 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 (Spirtas et al. 1975). A maintenance worker experienced acute narcosis while repairing a VCM leak, and a worker cleaning a polymerization vat from outside with a water jet sudden ly collapsed across the open manhole. Subsequently he complained about tightness of the chest, nausea, abdominal pain and headache. Occasional loss of consciousness was also reported by Lilis et al. (1975) in 14 of 354 workers at Niagara Falls and by Sticiu et al. (1963) at a Rumanian plant. VCM-induced narcosis, at least on one occasion in the past, had occurred in 46 of 58 workers (79%) referred for medical surveillance from one British PVC-producing plant (Ward et al. 1976), with a 100% incidence of narcosis in 28 symptomatic workers (Raynaud's syndrome and/or acroosteolysis). Successful resuscitation after VCM-induced narcosis of several hours' duration with out evidence of permanent damage was mentioned by Rety et al. (1974). Vinyl Chlor- 7 Mom 2D 9 CO tg the t! ta on V CO rected CO ID arentl; CO O lcshc erg U. poly --u.08 n* centration ot Inspectorate or from the c mg/litre (= 1 mg/litre (= 3- In the cei air ranged frc ppm, which \ ventilation, 1 trations. som pursuit of im ment in the v ic drying faci: centrations o' continued to nutted concei In a plant the range of 0 ppni (2.93 mr ication appar. remarkable th the liver, alth. past have pro! liyrcn et a which occurrc cated peak ex between 1962 Rumanian PV about 120 mg exposures to X 300 Rumaniai Greek plant w resulted in hig (Gitsios 1971) of the reactors up to 10 000 | I.J. Marsteller : VCM ere i ct/a et al. >69).' ui (1963) sA.< 1963) iter et al. %3) itv et al. 963) p,n. 12 000 r wive tank: nly just .195) (Spirtas liring a VCM 'er jet suddcnt tightness of musness was and by Suctu occasion in rveiiiance icidence of -teolysis). ation with- 33 C/3 Vinyl Chloride-Associated Disease 13 2.2.9 Monitoring VCM Concentrations in Working Areas During the first two decades of PVC production (1930-1950) no publication contain ed data on VCM concentrations in tire working environment. The main interest then was directed towards prevention of the explosion hazard. In 1957, the observation of an apparently toxic angioneurosis in Russian PVC production workers (Smirnova \954\P!csbchitser et al., cited in Filatova and Gronsberg 1957) induced Filatova and Gronsberg to investigate environmental VCM concentrations in various parts of a Russian polymerization plant in Gor'kij. Although most readings were in the range of 0.05-0.08 mg/litre (= 20-313 ppm), e.g. below the maximum permitted VCM con centration of 1 mg/litre (approximately 400 ppm) as specified by the State Sanitary Inspectorate at that time, escapes of VCM in the reactor areas from defective fittings or from the discharge of operating autoclaves resulted in excursions up to 29.5-41,4 mg/litre (= 1 1 500--16 200 ppm) for periods of 5-10 min. One peak reading of 87.3 mg/litre (= 34 000 ppm) was recorded. In the centrifuging and drying area of tliis plant the VCM content of the ambient air ranged from 4 ppm to 3 100 ppm with most readings between 2Q ppm and 195 ppm, which was attributed to release of residua] VCM from wet PVC resin 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 modern ventilation equip ment in the vicinity of the autoclaves, substitution of hand-operated by semi-automat ic drying facilities, and avoidance of leakages succeeded in reducing the ambient con centrations of VCM to below 0.05 mg/litre (= 20 ppm), but toxic angioneurosis still continued to be diagnosed. This led the authors to recommend that the maximum per mitted concentration of VCM should be reconsidered. In a plant producing VCM, Filatova et al. (1958) found lower concentrations in the range of 0.04-1.1 mg/litre (16--430 ppm), with maximum values of about 1200 ppm (2.93 mg/litre), the latter having been'observed in close proximity to the rectif ication apparatuses and having resulted from spillage during sample collection. It is remarkable that up to now the Soviet Union has reported no cases of angiosarcoma of the liver, although production of PVC resins started early and VCM exposures in the past have probably been in the same range as those observed in Western countries. Byrcn et al. (1976) pointed out that during the 1950s episodes of unconsciousness which occurred among workers of the one Swedish plant operating at that time indi cated peak exposures of at least 10 000-15 000 ppm.Swc/w et al. (1975) noted that between 1962 and 1972 a reduction of the average VCM concentration in the two Rumanian PVC plants had been achieved from 2298 mg/m3 (= 900 ppm) in 1962 to about 120 mg/m3 (= 50 ppm) in 1965--1972, In 1969, Anghclcsctt et al. mentioned exposures to VCM concentrations of 1 12--545 mg/m3 (44--213 ppm) for a group of 300 Rumanian workers, eight of whom (2.7%) had Raynaud's phenomenon. At a Greek plant which started operation in 1967, certain stages in the production process resulted in high concentrations of VCM in the work environment for brief periods (Gitsios 1971). In air displaced from reactors during addition of water and on opening of the reactors to obtain PVC samples at the end of a reaction cycle, concentrations of up to 10 000 ppm were found. In open waste-drums into which waste polymer scraped i 14 W.K. Lelbach and H.J. Marsteller away from reactor walls during cleaning was placed, concentrations of up to 600 ppm were measured. In the report of a World Health Organization (WHO) working group on vinyl chlor ide (1ARC 1974) it was stated that in a reactor of 15 m3 (production of 4--5 tons of PVC per cycle) a crust of 4 kg PVC containing 3%-- 5% VCM can be formed on the inner surface. During the cleaning procedure 30%--50% of this VCM content is liber ated. It was calculated that the probable concentration of VCM within the reactor after a 1-h cleaning operation was about 2700 ppm, but that it could be reduced to 90 ppm by 30 renewals of air per hour. In the past a polycleaner used to spend 4-5 h/ day inside the reactor but later the introduction of (not fully sufficient) automated cleaning reduced manual cleaning procedures to shorter periods of 10-15 min follow ing every 20th.-30th reactor cycle. A Belgian company, where monitoring in the work ing area was started in 1967, claimed that measurements at various sites inside a 9000litre autoclave during the manual cleaning operations had shown VCM concentrations varying between 50 and approximately 540 ppm, with a mean of 413 ppm (Hublet et al. 1977). According to data provided by Cook et al. (1971), VCM concentrations within the reactors prior to ventilation were in the order of 3000 ppm. The reactor cleaners usually did not enter the autoclaves until an aeration period of 15--20 min had reduced the VCM concentration to what was considered satisfactory' limits. In the early days, this was tested either by `sniffing at the manhole opening' (the lower limit of detection of VCM by its odour having then been accepted as 400 ppm) or by use of a flammable vapour indicator which required a minimum of 400 ppm for positive read ings, equalling 4% of the lower explosive limit,of VCM. Later more sensitive methods such as gas chromatography were said to have shown that VCM concentrations inside the reactors tended to be below 100 ppm during cleaning operations, but VCM releas ed from the residue during scraping resulted in concentrations of 600-1000 ppm measured close to the hand. The Dow Chemical Company started monitoring the work environment in 1950 by means of grab samples; continuous monitoring was installed in 1959. While timeweighted average (TWA) concentrations ranged from 10 to 385 ppm during this period (1950-1959), excursions up to 4000 ppm occurred, agreeing with employees' reports of experiencing dizziness while loading or unloading reactors (Otr et al. 1975). In a second unit with modernized equipment excursions up to 600-1300 ppm still occur red during the period of 1953-1959. In 1959, when toxicological data indicating ad verse effects in animals exposed to 100-500 ppm VCM had become available (Torkelson et al. 1961), the Dow Chemical Company introduced a new 50 ppm guideline for the work environment. Excursions and peaks up to 500 ppm did continue. Measure ments of TWA exposures for various specified job categories in two production units of this plant between 1950 and 1966 were presented by Ott et al. (1975), In 1968 BASF (West Germany) introduced continuous monitoring by infrared absorption spectrophotometry for VCM concentrations well below 500 ppm; in 1974 more sensi tive equipment was installed and concentrations were kept below 25 ppm and later below 10 ppm, with occasional Ailing values of 70 ppm (Flcig and Tliless 1974). In several surveys individual jobs were grouped into three exposure categories ac cording to job classification to evaluate past exposure experiences (Spirtas et al. 1975; Williams et al. \916\Blendis et al. 1978). These exposure indices were: (a) light = less ' Vinv! than : pm). Ian ts 33 mpit (/> him. ore i co a rag CO CD 00 NO ble 10S[ ;mi 194519551960mid-19 19 19 Acc Eqt tions in equipn; vidual e binatio. (3) The ly spec, ment sh peak co for the Curr compri:. tion det> (`ionofh which c; conditio lag of re A ca' industrL in 1975 : 2.2.10 1 Raw PV< unreacte. 'larsteller 600 ppm myl ^ (torts of -in the :s liber.uctor :ccd to nd 4--5 h/ omated :in followi the work,1c a 9000nirations Ilublet et .itions reactor 20 min its. In the over limit by use of .it1 ini us u y </) w CO to i OO 00 i ). Ill a 11 occuru.ng ad(TorkelMine for easure>n units 1968 :ion ire sensi later 4). ries actl. 1975; it = less Vinyl Chloride-Associated Disease 15 than 50 ppm; (b) medium = 50-200 ppm; (c) high = 200 ppm and above (up to ) 500 ppm). In the past, however, estimates of exposure concentrations were based in most plants not on continuous monitoring during the entire work shift but at best on spot samples not necessarily representative of the different phases of a given operation. Estimates of past exposure levels such as those represented in Table 5 are, therefore, more or less conjectural. It can be assumed that considerable deviations from these average values have occurred all too often in the past. Table 5, Average concentrations of VCM in the working atmosphere of PVC-producing plants*3. (Estimated by Chemical Industries Association Ltd.) 1945-1955 1955-1960 1960-1970 mid-1973 1974 1975 1000 ppm ^400-500 ppm x.200-400 ppm v 150 ppm v 50 ppm and less "w 5 ppm 3 According to Fleig and Thiess \914\Barnes 1976 Equipment for optimal continuous multipoint monitoring of exposure concentra tions in the working areas should meet certain basic requirements: (1) For stationary equipment strategically placed sample probes should yield data representative of indi vidual exposure levels in the breathing zone of workers, preferably to be used in com bination with personal samplers. (2) Analysing methods should have a high selectivity. (3) The limit of detection should be at least one order of magnitude below the current ly specified standard regulating the permissible upper level of exposure. (4) Measure ment should be instantaneous (within seconds) to guarantee rapid detection of critical peak concentrations. (5) Recording and data processing techniques should be provided for the daily estimation of TWA exposure during the whole work shift. Currently available methods for the determination of ambient VCM concentration comprise such analytical tools as long-path infrared spectrophotometry, flame ioniza tion detection, gas chromatography, mass spectrometry', combustion-conductivity (`ionoflux'), and personal samplers in combination with gas chromatography, none of which can at present be considered as absolutely satisfactory for all individual plant conditions because they all differ with regard to selectivity, limit of detection and time lag of response. A catalogue of the methodologies that have proved to be of value in the control of industrial hygiene and personnel protection regarding exposure to VCM was compiled in 1975 by Rowe. 2.2.10 Exposure to VCM in PVC-Processing (-Fabricating) Plants Raw PVC powder ready for compounding and fabricating purposes contains residual unreacted vinyl chloride monomer in varying amounts. In the past, monomer content 16 W.K. Lelbach and H.J. Marstelier was reported to have been as high as 6000--7000 ppm (w/w) in some types of raw PVC, but a level of 500--1000 ppm probably was a more representative range (Schweitzer 1975; VKE 1974\Kantadi 1976). The monomer slowly escapes into the environment exponentially with time, depending on length of storage period, tempera ture, size and porosity of particles and other physical properties of the polymer and, more recently, on the effectivjty of special degassing techniques (Fiver \916\Schiitz and Wolf 1977). In 1975, the Association of the German Plastics Industry announced that in future only PVC powder with a maximum monomer content of 10 ppm would be put on the market due to the development of special degassing technologies (VK.E 1975), Analyses of the types of raw PVC, chiefly suspension polymer, which are now used in German plants showed tii3t in most products the content of unreacted mono mer was now less than 20 ppm but in some foreign products it still ranged between 150 and 250 ppm; it also turned out that there may be considerable variation between different batches of the same product (Schiitz and Wolf 1977). Cold and particularly hot mixing or compounding of PVC, a procedure which usu ally precedes fabricating processes, favours the escape of unreacted monomer and, therefore, requires special ventilation equipment. Depending on the content of residual monomer, considerable amounts of VCM could be set free during the mixing process, as was shown by Bruder and Straby (1975). Apart from hot compounding, other ther moplastic operations, such as extruding, calendering and welding of tiles, also resulted in release of unreacted monomer into the work environment. Although recently con ducted measurements of the concentration of VCM in working areas of six German PVC fabricating plants have shown that in 90% of the readings mean levels integrated over 1 -h periods now range below 0.1 ppm, numerous short bursts with excursions up to 60 ppm during a .workshift were recorded in one instance (Schiitz and Wolf 1977). Similarly low concentrations of VCM in breathing zone samples (maximum: 12 ppm) with 60% of the values ranging below 1 ppm had been found in 1974 in nine United States fabricating plants, but source samples had ranged up to 340--540 ppm (Karztadi 1976). These present results, however, do not permit any conclusions as to past levels of atmospheric VCM during the years when residual monomer content of PVC resins was high and ventilation insufficient, particularly in compounding and extruding units. Whatever the extent of the risk might have been in the past, it can be safely assumed that the ambient monomer concentrations in fabricating plants have always been con siderably lower than in PVC-producing plants. When it was.suspected that certain VCM-related symptoms might also have afflict ed PVC process workers, this problem was investigated by our group. Although no cases of acroosteolysis, pseudoscleroderma'or angiosarcoma of the liver were observed, evidence was presented wliich demonstrated that minor and inconspicuous lesions such as mild hepatic fibrosis, bromsulphalein (BSP) retention, thrombocytopenia and slight enlargement of the spleen could be found in 28 process workers who had been em ployed for years in compounding and fabricating units (Lange et al. 1975,1976a: Wcgtnait 1975\Manteller et al. 1976). In principle, these lesions were identical with those seen after heavy exposure as we will describe, but the degree of damage attribut able to occupational VCM exposure observed in these workers was not considered suf ficient to entitle them to disability compensation under German law. Although the in- Vinyl conspj spons quants observ progrr male f find a: Ai two G died re lation `health overall record 2.2.1) Indus!, of exp- tion' o `indust zentra; Ameru exceed tions s. basic aj cupati (1974) used in are sun discrep to . The 30 Co : a s- W ruld itly co lilabi CO CD w ini 00 t of 5 rious -calk- -ool foi ysis of t In ti ppm in *' " ' , ' T. ` ;' X. ' \ : ' / ' -r 1 V *? \' ; ` ,'T. > r`- : > V` .!! J. Marsteller ;-es of raw :ange^* mes. j the hod. tempera-.ilyrne; and, 76; Schiitz -y announced 10 ppm would alogies (VKE iiicli are now .'acted monod between r.tion between :-.t which usu>mer and, ent of residual xing process. ;e, other ther* also resulted ecently coni\ German !; integrated xcursions up Wolf 1977V nr 12 ppm) United 'pm . suih ast levels of . C resins was ing units. I !v assumed I -j been con- have afflictiough no ;re observed, s lesions such lia and slight been em. 1976a: uical with iage attribute nsidered suf- Vjnvl Chloride-Associated Disease conspicuous character of these lesions agrees well with the assumption of a dose-re sponse relationship of VCM-related disorders and the alterations may seem to be. quantitatively, of little importance, they should not be minimized. Nevertheless, an observation period up to the present of almost 7 years did not reveal any spontaneous progression. In a proportional mortality study for 1970-1972 among roughly 35 000 male PVC fabrication workers in England and Wales, Baxter and Fox (1976) did not find an excess of angiosarcoma or other liver diseases. A recently completed cohort study of 4007 people who had been employed by two German PVC-fabricating plants between 1934 and 1974 and of whom 360 had died revealed that overall mortality, although marginally below that of the male popu lation of the Federal Republic of Germany, was slightly elevated with respect to the `healthy worker effect'. No angiosarcomas of the liver were observed and no excess in overall cancer mortality was noted, but an excess mortality from brain tumours was recorded in one of the two plants (Rein/et al. 1978). 2.2.11 National Standards for the Control of Exposure Industrial hygienists have used several designations for acceptable or permissible limits of exposure to chemicals at the work place, such as `maximum allowable concentra tion1 or `maximum acceptable concentration' (MAC), `threshold limit value' (TLV), `industrial hygiene standard' in the United States and as `Maximale Arbeitsplatzkonzentration' (MAK) in West Germany. These empirical standards were defined by the American Standards Association as setting a limiting concentration "for exposures not exceeding 8 hours daily during a 40-hour work week with the understanding that varia tions should fluctuate below this value" (Irish 1963). An extensive discussion of the basic approach to the principles used in setting environmental quality standards for oc cupational respiratory exposure to toxic agents can be found in the paper of Ziclhuis (1974). In this paper, the conceptual differences between threshold limit values as used in the United States and maximum allowable concentrations as used in the USSR are summarized and the differences in approach and emphasis, which may explain past discrepancies between permissible limits, are elucidated. For details the reader is refer red to this paper. The standard is noi an index of relative toxicity, far less of hazard, and certainly not a sort of 'average'. A standard set as the ceiling level implies that any fluctuations should be around a median of perhaps half the standard and that it should be compe tently used in full awareness of its physiological basis and the limitations of currently available knowledge (Irish 1963). Tire standard will be subject to revision as soon as new information is available. An essential element of the annually published German list of MAK values (MAK-Werte) is its preamble, which exhaustively defines the various modalities for the interpretation of such standards (Henschlcr 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 below the standard. ' In the Federal Republic of Germany the standard for VCM (MAK) was set at 500 ppm in 1966, The German Standards Advisory Committee reduced this to 100 ppm IS W.K. Lelbach and H.J. Marsteller in 1970 in conformity with the proposal of Torkclson et al. (1961), which was based on the results of their animal experiments. In June 1974, when the carcinogenic prop erties of VCM had been well established, the MAK regulation for this chemical was re pealed and instead a preliminary technical guideline (Technische Richtkonzentration) of 50 ppm was instituted (VKE 1975). The Chemical Industries' Liability Insurance Association (Berufsgenossenschaft der Chemischen Industrie) also issued instructions for the prevention of health hazards arising from handling of VCM in July 1974, As of July 1975, a technical guideline (TRK = Technische Richtkonzentration) of 5 ppm. defined as annual mean, for PVC-producing and -fabricating plants was instituted, per mitting excursions up to 15 ppm during periods of not more than 1 h. In order to adapt operating plants, a provisional regulation was issued with reduction of the an nual mean concentration to 20 ppm as of July 1975, and to 10 ppm as of July 1976 and peak concentrations over 1 -h periods not exceeding 60 or 30 ppm, respectively {Velumn and Lange 1977a). The technical guideline (TRK value) was revised in 1977 (2 ppm annual mean/5 ppm per 1 h). In the United States the threshold limit value for VCM was originally set at 500 ppm in 1947. It was reduced to 50 ppm in April 1974 as a temporary emergency stan dard and finally reduced to 1 ppm/8 h in 1976. Haley (1975) summarized the conflict ing views on vinyl chloride regulations proposed by Government and industry in 1974, Table 6 shows threshold limit values in a number of PVC-producing countries. 2.2.12 Exposure to VCM Outside the Working Area The Environmental Protection Agency estimated that PVC-producing plants in the United States discharged about 90 million kg VCM annually into the environment (4%-8% losses), most of it as air emissions and lesser quantities dissolved in water effluent streams and entrapped in sludge and solid wastes (Schweitzer 1975). In a pioneer study, concentrations of 1 --2 ppm VCM were found in the ambient air near such a plant (1ARC 1974), 2-3 ppm in the primary water effluent and 100--200 ppm in the sludge at the plant site, but sampling and analysis methods used were later found to have been inadequate so no conclusions were drawn from these figures since they could have been in error by as much as one order of magnitude {Schweitzer 1975). For people who live within 5 miles of monomer and polymer production facil ities in the United States an average exposure of 17 ppb'during the years of uncontrol led emissions was calculated (Nicholson 1977). In the past VCM has been widely used as an aerosol propellant, either alone or mix ed with fluorocarbons, hydrocarbons and inert organic gases, in household and cosmet ic products (hair sprays, deodorants, pesticides, room disinfectants, paint sprays, furniture polish and window cleaners). In Germany, VCM was proposed as propellant for aerosols in 1958 {Ostennayer 1967), in Japan it has been used as 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 huge, particularly for women, the extent and the potential health implica tions of which are unknown. Use of aerosol products in confined spaces has been re ported to result in air concentrations of VCM of up to 400 ppm in closed rooms, even after only short bursts (30 s) {Gay et al. 1975), which could persist for several Vinyl Chi Table 6. i nV 33 </) CO CO (0 00 O) 1 Japan Netherlan Rumania Sweden Switzerl;1 United Ki USA USSR Federal Ri Germans Sources: i 73; 1ARC h and H.J. Marsteller which was based : car<ri"-s>eenic propihis deal was relichtkonzentration) liability Insurance issued instructions 1 in July 1974, As entration) of 5 ppm, ,s was instituted, peri 1 h. In order to duction of the annm as of July 1976 ppm, respectively ) was revised in 1977 tonally set at 500 >r jencvstann he conflict3 .ry in 1974. i (f) ies. CO CO CO CD ts in the onmcnt . ,n water uzer " 15) In a ic arih,.cnt air near .i and 100-200 ppm used were later m these figures since jde (Schweitzer tier production facille years of uncontrol- t. either alone or mix\ousehold and cosmetis, paint sprays, oposed as propellant J as a propellant since : 1962 (Schweitzer of exposure for the tial health implicaspaces has been re in closed rooms, i persist for several Vinyl Chloride-Associated Disease 19 Table 6. Threshold limit values (TLV) in various countries Country Year TLV (ppm) Comment Belgium Canada Finland France German Democratic Republic (DDR) Iran Italy Japan Netherlands Rumania 1975 1975 1975 1975 -- 1976 1976 1975 (future) 1970 1974 1975 1975 Sweden Switzerland United Kingdom USA USSR 1975 1976 1975 (future) 1975 October 1975 1947 April 1974 October 1974 1976 ' Federal Republic of Germany 1966 1970 June 1974 1975 1977 25/50 10/25 5/10 25 200 - 12 25/50 50 (25/50) 500 200 = 10 10 1 00 mg/m1 (40 ppm) 5/20 1/5 100 10 25/50 10/30 500 50 25 1/5 1 mg/litre (391 ppm) 30 mg/m1 (= 12 ppm) 500 100 50 5/15 2/5 TWA (8 h/1 5 min) TWA (8 h/15 min) TWA (8 h/15 min) TWA (8 h) MAC (Schortek 1969) (Konctzke et al, 1 978) TWA (8 h/1 h) TWA (8 h) (TWA 8 h/15 min) MAC MAC (25 mg/m1) TWA (8 h) MAC (Prodan et al. 1 975) TWA (8 h/1 5 min) TWA (8 h/1 5 min) MAC TWA (8 h) TWA (8 h/15 min) TWA (personal/ceiling) MAC (Amer. Conf. Governm. lndustr. Hygienists) TWA (8 h). 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 (Filatova and Gronsberg 1957) MAC (Schottek \969\Kettner 1 975) (Sanitarnyc normy) MAK MAK TRK (preliminary technical guideline). Annulment of MAK regulation. TRK (annual mean/1 h) TRK (annual mean/I h) Sources: Smyth \956\Filatova and Gronsberg \9Sl\Sehottek 1969:Henschler 1972/ 72: JARC Report \974\Haley \97S\Sakabe 1 975; Prodan el al. \97S\Aryanpur 1977;Schut: and Wolf 1977; MAK-Wcrte-Uste \911. Kettner 1975 20 W.K. Lelbach and H.J. Marstellcr hours alter repeated spraying in smaller-sized rooms (IARC 1974). Haley (1975) pre sented a list of pesticide products containing VCM as a propellant and registered for indoor use, which were banned in 1974 by tire Food and Drug Administration. In Japan, tile monomer was also banned as a propellant in 1974 (JAMA 1974,229:855). There is a case on record of a worker who died from noncirrhotic portal hypertension and angiosarcoma of the liver after 14 years' employment at a chemical plant in south ern Germany where he had been engaged in loading such pesticide cans (ReinI and Weber 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 (Meyerson and Meier 1972) is apt to make one wonder what influence the frequent indoor use of VCM-propelled spray cans (Bridbord et al. 1975) may have had in this unique case. Sputum samples collected from frequent users of pressurized spray cans who had no respiratory symptoms were found to con tain a significant excess of moderate and marked atypical metaplastic bronchial cells compared with two groups of controls (Good et al. 1975). PVC bottles, films and foils have been used for many years for packaging food and beverages (cooking oil, margarine, meat, mineral water, fruit squashes and other soft drinks, hard liquor etc.). The content of residual VCM in PVC bottles was found to have ranged formerly between 5 and 400 ppm (w/w), and in PVC foils up to 800 ppm (van Esch and van Logien 1975). The problem of migration of unreacted VCM from the PVC containers into the foodstuffs became recognized in 1973. Reports of un pleasant tastes in American brands of vodka and whisky which had been stored in PVC bottles led to the discovery that VCM had leaked into the liquors;in some samples levels up to 10-20 ppm (w/w) were found (van Esch and van Logtcn 1975-.Davies and Perry 1975). Data available in 1974 to a group of WHO experts revealed that samples of gin and wliisky had contained 0.57 and 0.62 ppm (w/w) of VCM respectively, after storage in miniature PVC bottles for periods up to 3 years; VCM concentrations in orange squash and cooking oil were found to be in the range of 0.01 -0.08 ppm and 0.01 -0.04 ppm, respectively (IARC 1974). Levels of 0-0.4 ppm found in British PVC-bottled liquids were mentioned by Davies and Perry (1975): in their own analyses of samples of PVC-bottled spirits supplied by British Airways they found concentra tions of 0--0.25 ppm (w/w). Methods were developed for the detection of VCM in liquids with a maximum sensitivity down to the 1 ppb level (van Lierop and Sick 1976; Drcssman and McFarren 1977). It was tentatively estimated that even during the years when PVC-packaged food and beverages had not been heeded as a potential source of contamination, the likely average daily human intake of VCM from this source could have been in the order of 0.1 mg/person (IARC 1974). Schlatter (1976) calculated that today it would be less than- 0.01 mg/person (equalling 250 mg during a whole life time): in comparison, he calculated that the inhalational intake of VCM in diseased workers who had been exposed to concentrations of 500--1000 ppm during a period of 10-20 years would have amounted to at least 25 kg. The Association of the German Plastics Industry expects that the use of technology available at present for the production of PVC food-packaging materials decreases the VCM content of food stuffs to below 50 ug/kg (50 ppb) even after prolonged storage (VKE 1975). Results of carcinogenicity assays in experimental animals after oral administration of VCM are discussed in Sect. 3.3. Vinyl Chloride-As'i 3 Toxicology o 3.1 Acute Toxtcitv During the first threi the assessment of tin concentrations varyii and Leake 1933;Sch malteo et al. 1960;/. anaesthesia, deep nai this range of exposut tive and haemorrhage hepatocellular injury inducing substances ( 3.2 Chronic Toxicih Torkelson et al. (1961 exposure to concentre 4.5-6 months. All spt however, caused an in- histological changes in pigs and dogs. An incr in rats exposed to 20 C (1963); no histological Gor'kij Institute were > exposure of experimci mias. bradv-ardia, chai 0.05 ) for 5 me crea: jon of ca post othalamu 350( C/) ipm (9-1 of th _L and the a comi 00 GJ iges in ci: posu CO and rabb resor 00 00 ie change: nerve n dysfum avail; nee for V VCM snouid De suspect' statutory maximal allov cratic Republic) should Of particular import Viola et al. 1971) with .. full year. It was only al 1 II.J. Marsteller c.f (1975) pre registered for Mrat^-, In f>74J... 9:855). 1 hypertension ; plant,in south(Reinl and cal Raynaud's 'lysis who never to make one cans (Bridbord d from frequent found to conronchial cells iging food and uj other soft as found to ip to 800 ppm J VCM from '.-rts of un; stored in PVC ne samples 75: Davies and that samples actively, after rations in >8 ppjn and n a 'i owtTanak. -es concentref VCM in adStek IP76: ring the years a! source of aurce could alculated j whole V in diseased ig a period f the resent for nt of food>). Results of VCM Vinyl Chloride-Associated Disease 3 Toxicology of VCM 3.1 Acute Toxicity During the first three decades of PVC production, animal experiments were limited to the assessment of the acute inhalational toxicity of VCM in short-term exposures to concentrations varying between 50 000 and 400 000 ppm (Parry et al. 1930\Pcoplcs nndLcakc \933\Schaumann 1934, 1938;Osrcr et al. \9Al\Carr et al. 1949: Mastromatico et a!. \96Q:Lesrcr et al. 1963), In mice, rats, guinea-pigs, rabbits and dogs anaesthesia, deep narcosis, cardiac arrhythmias and lethal effects were observed within this range of exposure but no relevant organ pathology was noted except for conges tive and haemorrhagic changes in lungs, liver and kidneys on fatal outcome. Acute hepatocellular injury was later found only in animals pretreated with potent enzymeinducing substances (see Sect. 3.4.2.2). 3.2 Chronic Toxicity Torkelson et al. (1961) were the first to describe results of experiments with prolonged exposure to concentrations ranging from 50 to 500 ppm, 7 h/day, 5 days/week, for 4.5--6 months. All species tolerated exposure to 50 ppm for 6 months; 100 ppm, however, caused an increase in liver weight and 200-500 ppm caused, in addition, histological changes in the liver and kidneys of rats and rabbits, but not in guineapigs and dogs. An increase in liver weight and decrease in spleen weight was also seen in rats exposed to 20 000 ppm, 8 h/day, 5 days/week, for 3 months by Lester et al. (1963): no histological lesions were found after 3 months. Soviet investigators at the Gor'kij Institute were mainly interested in neuroendocrine changes after prolonged exposure of experimental animals to various concentrations of VCM. Cardiac arrythmias, bradycardia, changes in phonocardiogram in rats exposed to 12--20 ppm (0.030.05 mg/litre) for 5 months were reported (Vazin and Plokliova 1969b) as well as in creased secretion of catecholamines in rabbits and changes in the biopotential of the posterior hypothalamus (Vazin and Plokhova 1969a). After a 5.5-month exposure to 3500-4000 ppm (9-10 mg/litre) changes in the bioelectric activity (EEG recordings) of the cortex and the anterior and posterior hypothalamic nuclei in rabbits with con comitant changes in circulatory functions were seen (Vazin and Plokhova 1968). Ex posure of rats and rabbits to 0.03-0.04 mg/litre (12-16 ppm) for 6 months produced resorptive bone changes and osteoporosis in addition to cardiovascular and central nervous system dysfunction (Basalaev et al. 1972). In 1969Schotrek 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 Viola's experiments (1970a, b; Viola et al. 1971) with exposure of rats to 30 000 ppm, 4 h/day, 5 days/week, for a full year. It was only after this length of exposure that histopalhological examination W.K. Lelbaeh and H.J. Marsteller revealed lesions similar to human acroosteolysis and also similar to the type of nontumorous liver diseases which we observed in PVC workers 3 years later (Marsteller et al. 1973). Viola described lesions of the skin, the smali arterial vessels, the connective tissue and elastic reticulum of the paws, and periosteal proliferation with chondroid nietaplasis of metatarsal bones. Fibrosis of small peripheral nerves and degenerative changes of the grey and white matter of the brain were prominent, whereas the kid neys were not markedly affected. The liver showed pronounced degenerative lesions with parenchymal necrosis, cytoplasmic and nuclear polymorphism, abnormal prolifer ation of hypertrophic Kupffer cells and intense fibrosclerotic reactions. 3.3 Oncogenic Properties The earliest documentation of the carcinogenic action of VCM was Viola's preliminary report presented at the 10th International Cancer Congress in Houston, Texas in May 1970a. Of 26 Wistar rats exposed to 30 000 ppm for 12 months 17 developed epider moid carcinoma, mostly in the paraauricular region; 6 also developed adenocarcinoma of the lungs and 5 osteochondroma of metacarpal and metatarsal regions of all 4 limbs (Viola et al. 1971; Viola 1974).Maltoni and Lefemine (1975) later interpreted these paraauricular tumours as arising from the sebaceous glands of the exterior acoustic duct, also known as Zymbal's glands, the cell matrix of which seems to be the target tis sue of a number of carcinogens. They were of the opinion that the pulmonary' malig nancies were metastases from the Zymbal gland tumours. Autoradiograms of sections of whole rats dosed orally with ['4C]-labelIed VCM revealed a discrete localization of 14C in the paraauricular region (Zymbal gland?) and in the region of salivary glands and Harder's glands (Green and Hallway 1975). In this context Neumann et al. (1979), who analysed the peroxidase activity in Zymbal glands of Wistar rats, proposed the concept that peroxidase-mediated bioactivation of carcinogens (in their study;.stilbene derivatives) might offer an explanation for these tissue-specific effects. At the end of 1970 Maltoni and his group, with the support of Italian, British, Belgian and French chemical companies, started to plan and subsequently execute a large-scale carcinogenicity bioassay designed to study the effects of chronic exposure to VCM in relation to various experimental factors such as route of administration, dose level, length of treatment, and species, strain, sex and age of animals (Maltoni 1973, 1977\Maltoni and Lefentine 1974a, b, 1975;Afa/rou/ 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 mammary carcinoma, as well as a number of single tumours of other target tissues. Different types of tumours were found to coexist in the same animal. On oral administration of VCM dissolved in olive oil (5 days/week) angiosarcoma of the liver was found after 50 weeks in two animals of the two groups of 80 Sprague-Dawley rats each of which had been treated with the .highest doses of 50 and 16.65 mg/kg body wt. (Maltoni et al. 1975). Maltoni (1977) succeeded in demonstrating that the route of administration of this clearly multipo Vinyl Chi. tential car, dy of o red in s 3J tys/wei 99 > only ^ not m d the 03 05 >tOX S arco O 'e-D; to 1 , rat be carcinor 10, 5 and 1 1979). Am the dose-re exposure h histologica1 the liver an the inducti posure to 1 al. 1974b; I endothelial perplasia ai even in the was scanty doses. In il: fibrosis war of ossifying feet was su; offspring o; mine 1975) posed to V< ed from Gr, it was seen maturity ol to 2000 pp; foci of hep; Holrnbi week, for 5 spleen chan mais exposi cutaneous a ppm group 1 See also Inrsteller non'dler'-' uectiV droid .Hive' e kid'sions ' prolifer- 30 <Z> i CO CO CO CO s- cottons >tion of r.ands .1.(1979), ihf' : stilbtme itish, v.ne a ,,..)sure ation, :l'oni 5). Con500, 500, ttion perither roaangio; well as S were J in olive animals with the f 1977) nltipo- Virnl Chloride-Associated Disease 23 tential carcinogen may significantly vary the type of neoplastic response. In a subacute study of oral VCM toxicity, lasting only 13 weeks, in which rats were given VCM dis solved in soya bean oil by gavage in daily doses of 30, 100 and 300 mg/kg body wt., 6 days/week,Feron et al. (1975) found a significant increase in liver-io-body weight ratio only at the highest dose level. This was interpreted as a merely nonspecific reac tion not necessarily indicative of a toxic response. Based on these results, Feron et al, placed the oral no-toxic-cffect level at 30 mg VCM/kg body wt./day and suggested that the no-toxic-effect level may actually be even higher. Zymbal gland carcinoma, hepatic angiosarcomas and nephroblastomas had never occurred spontaneously in the breed of Sprague-Dawley rats used at the Bologna Institute. The neoplastic response to VCM proved to have a direct dose-time relationship. Even levels of 50 ppm were carcino genic in rats and mice. Later Maltoni (1977) found exposure to 25 ppm VCM also to be carcinogenic in rats, whereas no carcinogenic effect was observed at lower levels of 10, 5 and 1 ppm in a study which, however, is still incomplete (quoted from Griciute 1979). Another American study designed to complement Maltoni's results confirmed the dose-related induction of liver angiosarcoma and mammary carcinoma in mice at exposure levels of 2500,200 and 50 ppm (A'eplinger et al. 1975). On reexamining histological slides of his past experiments, Viola later also detected angiosarcomas of the liver and other malignancies of skin', lung and intestine in his rats; he also reported the induction of skin acanthomas and pulmonary adenocarcinomas in rabbits after ex posure to 10 000 ppm VCM, 4 h/day, 5 days/week, for at least 15 months (Maltoni et al. 1974b; IARC 1974). Maltoni and Lefemine (1975) considered the effect of VCM on endothelial tissue to be a systemic one since they found dilatation of blood spaces, hy perplasia and atypia of endothelial cells also in organs and tissues other than the liver, even in the absence of angiosarcomas or benign angiomas. Evidence of hepatic fibrosis was scanty and inconstant in their.animals and was more likely to occur at the lower doses. In the spleen of treated rats and mice fibroangioblastic proliferation undergoing fibrosis was frequently observed. No acroosteolytic lesions were found, but a few cases of ossifying angiosarcoma were observed. A potential transplacental carcinogenic ef fect was suggested in 1975 by the development of subcutaneous angiosarcomas in the offspring of breeding animals exposed for 7 days during pregnancy (Maltoni and Lefe mine 1975). Later, Maltoni (1976) detected angiosarcoma in the offspring of rats ex posed to VCM during the period between the 12th and 18th day of pregnancy (quot ed from Griciute 1979). Hepatocellular carcinoma was not found in adult animals but it was seen to develop readily in newborn animals, possibly in connection with the im maturity of their bioactivation pathways (Maltoni J977). Exposure of newborn rats to 2000 ppm VCM, 8 h/day, 5 days/week, for at least 4 weeks elicited preneoplastic foci of hepatocellular ATPase deficiency, notably in female animals {Laib et al. 1979). Holmberg et al. (1976) exposed mice to 50 and 500 ppm VCM, 6'h/day, 5 days/ week, for 52 and 26 weeks respectively. They did not observe hepatic fibrosis or spleen changes, but multiple benign alveologenic adenomas developed in 18 of 24 ani mals exposed to 50 ppm and in all 24 animals exposed to 500 ppm1. In addition, sub cutaneous and/or subperitoneal haemangiosarcoma developed in 14 animals of the 50ppm group and in 8 of the 500-ppm group. Only one haemangiosarcoma of the liver 1 See also Winell et al. (1976) 24 W.K. Lelbach and H.J. Marsteller was found in an animal exposed to 500 ppm. A few mammary adenocarcinomas, one rhabdomyosarcoma and one renal haemangiosarcoma were also seen. From their ex periments Holmberg et al, concluded that a lower exposure over a longer period may intensify the cancerogenic response and that an inverted relationship between dose level and latency time seems to exist in the case of VCM. as had already been observed with other carcinogens. Recently the results of still another animal experiment with exposure of Wistar rats to 5000 ppm, 7 h/day. 5 days/week, for 52 months was pub lished by Fcron et al. (1979a, b; Fcron and Kroes 1979) in an eventually fruitless at tempt to elaborate suitable parameters for early detection of VCM-disease in man. Ear ly effects were a shortening of blood clotting time and the occurrence of swollen and malformed hepatocytic mitochondria. At a later stage progessive tubulonephrotic changes in the kidneys, foci of celular alterations in the liver with reduced gIucose-6phosphatase activity in hepatocytes, strong sinusoidal activity of alkaline phosphatase and increase of smooth endoplasmic reticulum in parenchymal liver cells were observ ed. In the final stage areas of necrosis in the liver parenchyma, focal dilatation of sinus oids and proliferation of normal and atypical sinusoidal cells, multicentric hepatic-an giosarcoma and Zymbal gland carcinoma occurred. Feron et al. (1979b) also observed hepatocellular carcinoma in three animals.-Surprisingly, the induction of very malig nant metastasizing carcinomas of the nasal cavity originating from the olfactory epi thelium and Bowman's gland was noted, which had not been reported before in con nection with VCM. Marked hepatic fibrosis was only seen within fully developed an giosarcoma or as a reaction to extensive necrosis of the hepatic parenchyma. The in vestigators svere 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. 3.4 Toxicodynamics Prior to 1974 very little information was available about the fate and the toxicody namics of VCM in the mammalian organism, but the discovery of VCM-induced angio sarcoma of the liver in humans and experimental animals provoked a large number of studies which resulted in a flood of publications on the metabolism of VCM. In 1934 Schaumann reported that in mammals unchanged VCM was excreted via the lungs after inhalational administration; the pulmonary route is the main excretory route of nonmetabolized VCM (Green and Hallway 1975). Blocking of nonprotein sulphydryl groups in the blood of vinyl chloride operatives, less pronounced after dis continuous contact, was observed as early as 1964 by Gabor et al, and indicated deple tion of the glutathione pool, which has since also been found in exposed rats {Hefner et al. 1975a). Hepatic glutathione plays a fundamental role in protecting tissues against attack by alkylating agents. The appearance of monochloroacetic acid in the. urine of workers exposed to VCM was reported in 1966 by Grigorescu and Toba, indicating that a polar excretable metabolite of VCM had been formed (Vainio 1978). Toxicodynamic studies have revealed that VCM per se is not the ultimate toxin or carcinogenic. It is the process of biotransformation (metabolic activation) of VCM, primarily by hepatic microsomal enzymes (mixed function oxidases) that yields short Vjnvl Chlon. lived but higl mutagenic an cretable prod 1975). The t. live velocities tion of its res nation of VC so that above following a z. cordance will 3.4.1 Uptak Pulmonary u; in the animal' with the pool shown by cor. Bolt et al. (19 as albumin, a. pound goes in After oral ing- has to be com is excreted via 1976c). This, able process. I body wt. adtii vestigation oi gavage in dosi found a signil- plasmic reticu but only min. rats i>n a diet . almost all the testina] tract, in this way. 'ercutanei followin' 33 apm of ' ` C/> legligible tudies of oa 00 he liver ( CD metaboli CD to t, lungs a ^s, spied versibly nreversibly bo ij H.J. Marsteiler arcinomas. one Frorr^~ -ir exger p'enbd may between dose ly been observed pertinent with nnths was pub.dly fruitless atease in man. Ear: of swollen and ulonephrotic need gIucose-6line phosphatase ells were observlilatation of sinusntric hepatic an'b) also observed u of very malig: olfactory-epi1 before in con. developed anehyma. The inceded those of ip between VCMhicidated. r the loxicodyl-induced angioirge number of i' VCM. as excreted via main excretory M nonprotein -unced after dis! indicated deple ted rats (Hefner mg tissues against in the urine of 'w, indicating 978). Itimate toxin or .on) of VCM, hat yields short Vjn\! Chloride-Associated Disease 25 lived but highly reactive alkylating intermediates which are responsible for the toxic, mutagenic and oncogenic effects. VCM is metabolized rapidly to polar nonvolatile excretable products (Hefner et al. 1975a:iwr Duurcn \975\Raclwan and Henschlcr 1975). The toxicity of VCM seems to be largely determined by the ratio of the rela tive velocities of both biotransformation of the compound and protective detoxifica tion of its reactive intermediates (Henschlcr 1977a). The capacity for metabolic elimi nation of VCM in rats is saturable at an atmospheric concentration of 200-250 ppm, so that above this concentration VCM is metabolized at a constant maximal velocity following a zero-order kinetic, whereas below 200-250 ppm it is metabolized in ac cordance with first-order rate kinetics (Hefner et al. 1975a;2?<?/r et al. 1977). 3,4.1 Uptake and Distribution Pulmonary uptake of VCM from the atmosphere depends on the rate of its metabolism in the animal's organism. The atmospheric concentration of the compound equilibrates with the pool of unmetabolized VCM distributed in the animal's tissues, as has been shown by complete inhibition of microsomal oxidative metabolism (Bolt et al. 1977a). Bolt et al. (1977a) also concluded that lipids or lipoproteins, rather than proteins such as albumin, are the velucles that transport VCM in the blood and from which the com pound goes into the adipose tissue or is taken up by the liver for metabolic conversion. After oral ingestion and absorption from the gastrointestinal tract, a `first pass effect' has to be considered, but an increasingly substantial percentage of unmetabolized VCM is excreted via the lungs in direct relation to the dose administered (Watanabe et al. 1976c). This confirms the finding that VCM metabolism is a dose-dependent and satur able process. Pulmonary elimination of over 92% within 4 h of a dose of 300 rng/kg body wt. administered orally to rats was also reported by Fcron et al. (1975) in an in vestigation of the subacute toxicity of VCM incorporated in soya bean.oil and fed by gavage in doses of 30, 100 and 300 mg/kg daily, 6 days/week, for 13 weeks. They found a significant increase in liver-to-body weight ratio and hypertrophy of the endo plasmic reticulum of hepatocytes as indications of a toxic effect at the highest dose but only minimal histological changes in the liver. In a second experiment, they fed rats on a diet containing PVC powder with a high monomer content and observed that almost all the VCM 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 al. (1975b) in male Rhesus mon keys following whole-body exposure (head excluded) to concentrations of 7000 and 800 ppm of 14C-labelled VCM for 2--2.5 h. The quantity absorbed via the intact skin was negligible (0.02%--0.03%) and most of it was expired. Studies of the distribution of [ 1,2-'4 C]-labelled VCM in the body clearly revealed that the liver (predominant site of metabolism) and the kidneys (site of excretion of polar metabolites) contain the highest concentrations of14C activity, followed by spleen, lungs and small intestine (Watanabe et al. ]976c;5o/r et al, 1976a, b). Liver, kidneys,spleen,lung 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 26 W.K. Lelbach and H.J. Marsteller Total radioactivity 48 h after a single exposure decreased considerably in these organs, in accordance with the relatively rapid metabolization of VCM and excretion of its polar metabolites. In contrast, the amount of irreversibly protein-bound radioactivity remained constant during this time. Buchter et al. (1977) also showed that unmetab olized VCM possesses a great affinity for adipose tissue, in contrast to its metabolites, which are concentrated primarily in liver and kidneys. 3.4.2 Metabolism 3.4.2.1 Relation between Chemical Structure, Reactivity and Mutagenic or Carcinogenic Effect Before discussing the metabolic pathways of VCM (monochloroethylene) and its pre sumptive toxic intermediates two features of the chemical structure of this compound should be mentioned. Vinyl chloride is a monohalogenated ethylene and its chlorine substitution is asymmetric. Chlorination of alkenes (olefinic compounds), in general, tends to stabilize the double bond by exerting an electron withdrawal effect on the carbon atom involved. Thus, the chemical reactivity of alkenes decreases with increas ing degree of chlorine substitution, as was shown in 1968 by Williamson and Cveranovic for reaction rates with ozone. Vinyl chloride, as a monohalogenated alkene, is the least stable compound with the highest reaction rate in the series of chlorinated ethvlenes and ranks next to unsubstituted ethylene. Secondly, the first step in the oxidative metabolism of all chlorinated alkenes is a transformation to epoxides (oxiranes) which are short-lived, highly reactive electro philic intermediates (Bonse et al. \915\Henschler 1977b). Such chlorinated epoxides may react, by alkylation, with essential cellular constituents, a mechanism which Rannug et al. (1974), Bartsch et al. (1975a, b) and Malaveille et al. (1975) claimed to be responsible for the carcinogenic and mutagenic effects of VCM and vinylidene chloride. Epoxides resulting from biotransformation of asymmetrically substituted ethvlenes, such as VCM, vinylidene chloride and trichloroethylene, seem to be particu larly unstable with increased electrophilicity and thus enhanced alkylating effect. Their mutagenicity and, inversely, the nonmutagenicity of oxiranes of symmetrically chlorine-substituted ethvlenes was indicated by the studies of Greim et al. (1975, 1977). 3.4.2.2 Metabolic Pathways From 1974 onwards the fate of VCM has been studied extensively in vitro with rat liver microsomes in the presence of a NADPH-generating system (Kappus et al. 1975, \976\Bartsch et al. 1975b, \97b\MalaveiIle et a], \91S\Bolt et al. 1916a;Pcssayre et al. 1979), with the aid of isolated perfused liver preparations (Radwan and Henschler 1975;Bonse et al. 1975;Radwan 1977\Henschler 1977a) and in vivo {Hefner et al. 1975a; Watanabe et al. 1976d, 1978a, b\Bolt et al. 1977a, b) in both control animals and animals pretreated with various types of enzyme-inducing and enzyme-inhibiting substances. Present biochemical knowledge strongly suggests that the first step of the predo minant metabolic pathway is the oxidation of the double-bond of VCM by the hepatic Vinyl Chlor. naJ re a 33 ll (/> mi ixi p T>] ir, w ai sy CO i 19 (0 4* \ Cl >C=C 11 Ni VCM Fig. 1. Metal metabolized acetic acid ar roethylene o: protein sulph way (1977).i (Norpoth et ; S-carboxyme acid) (Henscl identified in i J. Marstcller hese organs, m of"" dioacu.ity unmetablctabolites. J3 Qo U) >re' >und W ne CO al. CD (D e 01 eas- lOvic least ! ethylenes alkenes is a e electro* cd epoxides i which ) claimed to ylide''" bstitufed o he particu: effect, 'imctrically .(1975, . with rat ct al. 1975, : Pessayre and Hensch1Hefner et al trol animals e-inhibiting the predoy the hepatic Vinyl Chloride-Associated Disease 21 microsomal mixed-function oxidase system, forming chloroethylene oxide, a chemical ly highly reactive epoxide (Fig. 1). A negligible amount of VCM can be metabolized via the formation of peroxides, very unstable compounds decomposing rapidly to car bon monoxide, HC1 and formaldehyde which, however, do not seem to play any ap preciable tole in the toxicity of VCM (Hcmchler 1977b). It has also been shown that in vitro an artifical superoxide (OF) generating system can replace rat liver microsomal systems and transform VCM to the active intermediate (Kappus ct al. 1975;5o/( et al. 1976a). The epoxide rearranges spontaneously to chloroacetaldehyde, which is rapidly ('malem binding !o cellular macromok'culcs (alkylationi Conjugation with sulphydry I groups (glutathione. cysteine 1 l O/ Chlnti/ciln true Oxnic I \TM epoxide I Thermal rearrangement ll> ilroli sis I epoxide h) drasc l OH OH Cl--C--C-H II II H ( hloroucctaldeliy de Fig. 1. Metabolic pathways. Adapted from Henschler (1977b) metabolized to monochloroacetic acid. Both chloroacetaldehyde and monochloroacetic acid are also metabolites which are chemically reactive but less potent than chloroethylene oxide. All three intermediates can be detoxified by conjugation with nonprotein sulphydryl compounds (glutathione, cysteine) as described by Green and Hathway (1977)..Sulphur-containing excretable metabolites such asS-hydroxyethylcysteine (Norpoth et al. 1976), N-acetyl-S-(2 chloro)-ethyl-cysteine^Oee/i and Hathway 1975), S-carboxymethylcvsteine-flFa/a/iaie et al. 1976a), and thiodiglycolic acid (thiodiacetic acid) (Henschler 1977a;Muller et al. 1976, \97&;Multer and Norpoth 1975) have been identified in the urine of exposed workers and animals. A progressive depression of the :s W.K. Lelbach and H.J. Marstelier level of hepatic nonprotein sulphydryl content has been observed in rats after expo sure to VCM in concentrations from 150 to 2000 ppm for 2--7 It. No depression was seen after 10 ppm and a concentration of 50 ppm caused only an inconsistent reduc tion {Watanabc et al. 1976b). Protein-bound hepatic sulphydryl content remained unaffected. Hepatic microsomal cytochrome P450, the coenzyme of microsomal monooxieenases, also decreases linearly with time in animals exposed to VCM (Reynolds et al. 1975b). This destruction of cytochrome P,, s0 may prevent further metabolism and toxicity of VCM (Pcssayrc et al. 1979). Another mode of deactivation of the primary reactive intermediate, the epoxide, is its transformation to the inactive dihydrodiol by the inducible microsomal enzyme epoxide hydrase. The reactive metabolite of VCM, cliloroethylene oxide, is a powerful alkylating agent which covalently binds to various cellular macromolecules, notably vital proteins and nucleic acids. By binding to cellular DNA and RNA or critical proteins the metab olite may alter vital functions and the genetic information of the cell and thus exert its hepatotoxic,mutagenic and carcinogenic effect. Eventually, however, the only fraction of the formed epoxide that binds to macromolecules is the one that is not detoxified by protective scavenging mechanisms such as conjugation with cytosolic glutathione or inactivation by epoxide hydrase. Simultaneous presence of other xenobiotics which have to be detoxified will impair the effectiveness of the detoxification mechanisms. In assessing the risk of exposure to VCM, Henschler (1977a) concluded that there might be a greater risk in intermittent peak exposures over brief periods than might be ex pected from simple integration over time and that the chances for effective detoxifica tion are greater in long-term exposure to relatively low levels. It was shown by Watanabc et al. (1978a) that repeated exposures of rats to VCM do not appear to induce its biotransformation, but significantly augment the binding of the reactive metabolite with hepatic macromolecules and may thus enhance the po tential toxicity of VCM. On single exposures of rats to increasing concentrations of labelled VCM ranging from 1 ppm to 5000 ppm, the amount of radioactivity covalent ly bound to hepatic macromolecules did not increase proportionately to the increase in concentration but followed a sigmoid curve with low and high inflection points be low 50 ppm and above 250 ppm, respectively, when binding was plotted as a function of the log of the exposure concentration {Watanabe et al. 1978b). This correlates well with Maltoni's report (1975) of a linear percentage induction of hepatic angiosarcoma in rats between 50 ppm and 500 ppm when expressed as the log of the exposure con centration. Metabolites of VCM can alkylate nucleic acids, a commonly accepted mechanism for carcinogenesis. Covalent binding to the adenosine (Barbin et al. \91S\Laib and Bolt 1977), cytidine (Laib and Bolt 1978), and guanine moiety of nucleic acids (Osrcrmann-Golkar et al. 1977) has been described. But the degree of covalent binding of electrophilic metabolites of labelled VCM to hepatic nucleic acids seems to be very small (Watanabc et al. \91Zb\Laib 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 incorp.oration of label into nucleic acids after exposure to radioactive VCM. Watanabc 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 tl of cellular eluded as; above all. This ar work will 1 endoplasm tible to V( phologicaf mixed funlobular, m; found (Jac 1978). Sec endothelia At pres cesses are 1 the hepato some meta (3) Media; tissues othi rant cell re; 1Q-7b). n equ. :oplas go tud's (/) was lesidw Sion vativ Cl ibr- r the or; 11c nervou; Iming cells tion) or wi: 4 Clinic: During the; might prove presented in marked the pational liar Marsteller or expossiop'-'S :nt re.nained >mal monojynolds et holism and epoxide, is enzyme kylating rial proteins the metablius exert its aly fraction detoxified .itathione or cs which chanisms. In there might :ht be ex detoxifica- :s to VCM ie binding :.cC the pontioi ' t> covaient: increase , i>oints be; a function -elates well igiosarcoma ,-osure con- nechanism I jib and acids (Ostcrmding of i be very presented he deterler exoosure Virtvl Chloride-Associated Disease 29 exclude the possibility of other,more subtle interactions which may impair the control of cellular replication. Alkylation of nucleic acids, however, cannot at present be ex cluded as the mechanism for VCM-induced carcinogenesis after repeated exposure and, above all, in the target cells rather than the hepatocytes. This aspect carries on to an unresolved problem on which future experimental work will have to focus. Although the site of formation of the active metabolite is the endoplasmic reticulum of the hepatocyte, the liver cell itself is not particularly suscep tible to VCM-induced toxicity. Acute hepatocellular injury has not been observed mor phologically after exposure to VCM unless pretreatment with potent inducers of the mixed function oxidase system had preceded the exposure;in pretreated rats centrolobular, midzonal and panlobular hepatocellular vacuolization and even necrosis was found (Jaeger et al. 1974,1975,1977;Reynolds et al. 1975a, \916\Conolly et al. 1978). Secondly, the site of carcinogenicity in the liver is not the hepatocyte but the endothelial cell of the hepatic sinuses. At present it can only be speculated which of the following four most likely pro cesses are effective, either singly or in conjunction: (1) The active metabolite leaves the hepatocyte and is conveyed to the endothelial cell. (2) The endothelium itself has some metabolic capacity (Bolt 1978), as may tissues of organs other than the liver. (3) Mechanisms for the detoxification of the active metabolite(s) are insufficient in tissues other than the hepatocytes. (4) Repair mechanisms for the correction of aber rant cell replication are less effective than they are in the hepatocyte (Waianabe et al. 1978b). An equally puzzling problem is the role of VCM in the pathogenesis of the distal nonneoplastic vascular lesions which are responsible for the development of the triad, Raynaud's phenomenon, sclerodermoid skin indurations and acroosteolysis. This syn drome was the earliest indication of adverse effects of chronic exposure to VCM in man. Besides, its latency period was considerably shorter than either the nonmalignam liver lesions or angiosarcoma of the liver. Whereas it is now established that hepatic bioactivation of VCM plays the central part in the pathogenesis of both noncirrhotic portal fibrosis and angiosarcoma of the liver, 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, (b) the sympathe tic nervous system, (c) smooth muscle cells of the media of arterioles, (d) endothelial lining cells of small arteries (with fibroblast transformation and endothelial prolifera tion) or whether (e) the action is mediated by the formation of immune complexes. 4 Clinical Spectrum During the mid-1950s it began to emerge that chronic occupational exposure to VCM might prove to be not quite as harmless as had been claimed. The historical synopsis presented in Table 7 summarizes those clinical studies from the world literature that marked the gradual recognition of the full spectrum of damage due to this new occu pational hazard. Ll 30 \V,K. Lei bach and H.J. Marsteller Table 7. Gradual emergence of evid ence for VCM-associated pathology Year Reference Findings 1949 Tribukh et al. Hepatomegaly, more or less marked `anicteric hepatitis', 'chronic gastritis', hypotension, anaemia, skin lesions 1954 1957 1957 1960 Smirnova Filatova and Cronsberg Kubota Danziger Toxic angioneurosis Toxic angioneurosis Symptoms similar to Raynaud's phenomenon Two cases of accidental fatal poisoning by VCM, 1 nonfatal acute overexposure 1961 Smirnova Reversible osteolytic lesions of distal phalanges. Pseudoclubbing, thickening of skin on volar side of forearms, slight haemolysis and reticulocytosis 1963 Suciu et al. CKS: prenarcotic symptoms (dizziness, euphoria, somnolence), nervousness, insomnia, blunting of memory, general asthenia, headache Vascular: Raynaud's syndrome Dermatol.: pruritus, reversible sclerodermalike skin induration, chemical and allergic dermatitis Digest, symptoms: anorexia, nausea, fullness, hepatomegaly without hyperbilirubinaemia, splenomegaly Endocrine: hypothyroidism 1966 Cordier el al. Raynaud's syndrome, sclcrodermalike skin changes, acroosteolysis, pseudoclubbing, joint pain, tiredness, sleep reversal; 2 episodes of acute overexposure (loss of consciousness) 1967 Harris and Adams Acroosteolysis, skin lesions, Raynaud's phenom enon, pseudoclubbing, involvement of sacroiliac joints and patella, hepatomegaly with persistent ly raised scrum bilirubin. Skin biopsy 1967 1967 Benoit Wilson et al. Arteriography. Skin and bone biopsy `Occupational acroosteolysis' with Raynaud's symptoms, sclerodermalike skin changes, pseudoclubbing 1968 1971 A ntonvuzhenko Dinman et al. Mentions thrombocytopenia Prevalence of acroosteolysis and Raynaud's phenomenon 1971 1972 Dodson et al. Kramer and Mutschler Vascular lesions preceding the bone lesions Increased BSP retention and raised icterus index related to degree of exposure Vinyl Chlon Table 7 (con K. 33 -- Qcon M w 03 is (> ID 00 'ii. 1973 AL 1974(a) Cr 4.1 TheTri: A first indica plant produc. non (`toxic a in detail in lit personnel w! hourly sanipi drome was a! {Kubota 195 moregulation and CNS sytr (1954) also n durations on there was evil of red cells, u evidence of u acroosteolysioperators) at': junction with was found in lesions to be <. reversible cha vibration trau the full range cupational ac In 1963 S analysis of th i H.J. Marsteller ----- 7. V J 'anicteric intension, f henomenon ' ' VCM. O37o ->nges. W >lar ,`ticulo- CO CO CD jphoria, CO i n ti n c CD b nalike Irrgic dermatitis v.a. fullness, hubinaemia. iike^jkin Jubl joint CpiS0cn;S Ol 'ciousness) njud's phenoment of sacroiliac . with persistentbiopsy >psy It Raynaud's t changes, Raynaud's .me lesions ed icterus index Vinyl Chloride-Associated Disease 31 Table 7 (continued) Year Reference 1972 Mark own: et al. 1972 Julie and Lange 1973 Marsteller et al. 1974(a) Creech et al. Findings Progressive thickening of hands and forearms, arthralgia. Blanching upon exposure to cold with cyanosis of hands accompanied by severe pain. Skin biopsy 1st German report of 7 workers with sclerodermalike skin lesions, Raynaud's syndrome, and acroosteolysis. Tests showed abnormal liver in 2, occlusion of digital arteries in 1 worker Noncirrhotic portal fibrosis with portal hyper tension and splenomegaly 4 cases of angiosarcoma of the liver 4.1 The Triad: Raynaud's Phenomenon, Pseudoscleroderma and Acroosteolysis A first indication of adverse effects due to chronic VCM exposure arose in workers at a plant producing VCM who presented with symptoms similar to Raynaud's phenome non (`toxic angioneurosis'). This was reported by Smirnova in 1954 and later described in detail in her thesis (1959). The syndrome was found predominantly in laboratory personnel who had intermittently been exposed to high concentrations of VCM during hourly sampling for chemical analysis (purity of the product), in 1954 Raynaud's syn drome was also observed among several workers at a Japanese PVC producing plant (Kubota 1957). Apart from a painful vasospastic disorder of the hands, impaired ther moregulation, acrocyanosis, positive cold test, capillaroscopic alterations, paraesthesias, and CNS symptoms such as headache, blunting of memory'and sleep reversal,Smirnova (1954) also mentioned swelling of fingers and development of circumscribed skin in durations on the volar side of the forearms in those most severely affected. In addition, there was evidence of mild haemolysis (borderline anaemia, decreased osmotic fragility of red cells.urobilinuria,and reticulocytosis). In 1961 Smirnova described radiographic evidence of destructive bone lesions of terminal phalanges in the hands identical with acroosteolysis in three workers at a PVC-producing plant (one fitter, two centrifuge operators) after exposure for 3-9 years. Since these bone lesions developed in con junction with 'toxic angioneurosis' and since complete recalcification of the defects was found in two workers 3 years after removal from exposure, Smirnova believed the lesions to be characteristic of chronic VCM intoxication. She pointed out that their reversible character might serve to distinguish the lesions from similar defects seen in vibration trauma. In retrospect, Smirnova's observations are the earliest descriptions of the full range of symptoms which much later became known as `the syndrome of oc cupational acroosteolysis'. In 1963 Suciu et al, (see also 1967 and 1975) published the first comprehensive analysis of their observation of a multiform symptomatology in subactue and chronic * %. i 1 I I W.K.. Lelbach and H.J. Marsteller VCM intoxication. During a 4-year period, they examined 168 mostly young workers from two Rumanian PVC-producing plants who had not previously been employed in other industries. In their classic paper, the authors described in detail the various cen tral nervous, digestive, angioneurotic and cutaneous symptoms (listed here in their order of manifestation). Acroosteolysis, however, was nor mentioned. Episodes of acute overexposure (usually occurring at the end of a batcli run, during retrieval of unreacted monomer, or at repair jobs) rapidly resulted in a state of light-headedness and transient euphoria similar to a mild degree of inebriety and were accompanied by a feeling of heaviness in the legs and disturbed locomotor coordination. Several workers claimed to have been able to identify escaping monomer by its faint but agreeable odour. Apparently during periods of particularly high ambient concentrations, workers repeatedly noticed formication in the lower limbs and a general feeling of bodily warmth. Six subjects had experienced loss of consciousness when repairing leakages, but recovered rapidly after being carried out into the open air. After a few months of work, unusual fatigue and sleepiness set in, there were complaints about persistent somnolence, even outside the work premises, and a tendency to fall asleep at the work place, particularly during night-shifts. In addition, headache, dizziness, irritability, blunting of memory', paraesthesias, and general weakness were reported; some workers noticed insomnia or sleep reversal. A reappraisal of these nonspecific complaints (see also Vale et al. 1976) 6 years later, after improvement in industrial hygiene, revealed that the frequency of their oc currence had considerably decreased (Suciu et al. 1975). Following a prolonged period of repeated overexposure, vague nonspecific digestive symptoms also developed, such as anorexia with ensuing weight loss, nausea, fullness, upper abdominal discomfort, bloating and epigastric pains. Enlargement of the liver was found in 51 workers (30%); in 6% there was also splenomegaly. Classic Raynaud's phenomenon was found in 6%, but a tenfold higher percentage of the total work force showed evidence of vasospastic alterations on plethysmography (Rancher et al., cited by Suciu et al. 1975). Pruritus of the hands, forearms and face was an early complaint followed later by what was theought to be (allergic?) `contact dermatitis'; finally, nodular and scleroderma- or scleroedema-like cutaneous lesions developed in some workers, involving the dorsal surface of the hands, the volar side of wrists and forearms and the face, with firm thickening of subcutaneous tissue or formation of whitish papular or slightly elevated plaquelike indurations. The cutaneous manifestations largely disappeared after removal from the work place. In addition, mention was made of features of hypothyroidism in a few workers. Also, transient loss of libido in 24% was recorded, with return to nor mal after a break from work or during holidays. With the exception of acroosteolysis and the two most alarming late sequelae -- noncirrhotic portal hypertension and hepatic angiosarcoma -- Suciu's early documen tation of the prevalence of disease in PVC production workers encompassed a com paratively complete description of the various aspects of chronic VCM intoxication. Later publications supplemented the spectrum of knowledge mainly by providing ad ditional information on epidemiological, roentgenological, thermographic, angiograph ic, and histomorphological aspects of the lesions encountered in subjects chronically exposed to VCM. Vinyl Chlor The disc two Belgian classifiable c marked the syndrome w year a numb United State cases of OA( the various \ end of 1979 vascular phe> symptoms t! begin with il the fingers atips on hard to cold acco. are likewise; ance of pain' osteolytic pi with striatio: I 1 It IS 19 IV 19o9 |97| 197: 1972/1973 1973 1974 1974 1975 1975 1976 1978 1979 3 One of 2 c Marsieller ; workers D103'`"l rtousV-n i their des of eval of idcdness panied by ral workers -eeable >ns, workers odily . 'eakages, months of tsistent it the work ability, ,;e workers 3 years '! their ocsued period ped. such omfort, ts(30S); id in 6G-. .iiOSpa.Stic Prui liat was ma- or - dorsal n firm \ elevated ter removal . roidism in m to nor- l' 30 V fi i 0) c iV CO ai o o ir Vinyl Chloride-Ai'.ociaie'd Disease 33 The discovery of unusual osteolytic defects in the distal phalanges of the hands of two Belgian autoclave cleaners who had suffered from Raynaud's phenomenon and unclassifiable degenerative lesions of the dermal connective tissue (Corjicr et al. 1966) marked the recognition of this new occupational disease in the Western World. The syndrome was termed `occupational acroosteolysis' (OAOL). and during the following year a number of additional cases were reported from France. Great Britain and the United States. Later Lefcvre (1972) who together with Cordicr described the first two cases of OAOL, reported that a subsequent investigation revealed another *en cases in the various plants affiliated to the same corporation in Spain. Italy and Brazil. By the end of 1979, a total number of 126 cases had been published in detail (Table 8). The vascular phenomena preceding or accompanying OAOL comprise a broader range of symptoms than those characteristic of Raynaud's syndrome. The conditions seems to begin with ill-defined pains in fingers, wrists and also large joints (shoulders, knees); the fingers are numb and tingling, tender on palpation, handgrip and tapping finger tips on hard surfaces is painful; there is increasing sensitivity of the hands and fingers to cold accompanied by a tendency io cyanotic discolouration. In some cases, the toes are likewise affected. Later, classic Raynaud's phenomenon develops (sudden appear ance of painful, sharply demarcated blanching) and, concomitant with the onset of osteolytic processes, there is a shortening and broadening of the terminal phalange with striaiion of nails (pseudoclubbing). Table S. Publications on `Occupational Acroosteolysis' since 1966 Year 19o6 1967 1967 1967 1967 1969 1969 1971 1972 1972/1973 1973 1974 1974 1975 1975 1976 1978 1979 Country Number Authors of cases Belgium 2 France 5 France 5 United Kinedom 2 USA Rumania . 31 2 Yugoslavia S USA 4] USA 2 Fed. Republic of 6 Germany J apan 1 France 4 USA 1 USA 4 United Kingdom 1 United Kingdom 4 Brazil Israel 5 2 126 Cordier et al. Benoit; Chatelain and MotHlon Bourrichon fcited by Marin et al. 1967) Harris and Adams Wilson et al. Angltelescu et al. Kovac et al. Dinman et al. Markowitz et al. Jiihe and Veltman; Stein et al. (a, b) Takeuchi and Mabuchi 3 Moulin et al. Trapp et al. Litis et al. Stewart et al. Preston et al.; Walker; Mitchell Johnston (1978) Gama and Meira Hahn et al. 3 One of 2 clear cases, in addition. 48 suspected cases (see Sakabe 1975) 34 W.K. Lelbach and H.J. Marsteller 4.1.1 Familial and Idiopathic Acroosteolysis Acroosteolysis is a very rare disease. The aetiology and pathogenesis of this condition is still obscure. Osteolytic bone changes in late stages of so-called Raynaud's disease (accompanied by necrosis and gangrene), characteristically presenting as loss of part or of an entire distal phalanx of one or more fingers and also of toes, have been mention ed in the literature since 1921 (Assmann 1921 \Monahan 1926; Borak 1927;Kornblum 1929). Kornblum attributed the lytic bone defects to vascular abnormalities and noted that he had found identical lesions in early stages of scleroderma and in leprosy. The term acroosteolysis was first introduced by Laroche and Hochfeld (1948), who held a neuroendocrine syndrome responsible for the lesions. Independently Harnasch (1949) reported another case of symmetrical idiopathic acroosteolysis, particularly involving the terminal phalanges of the fingers with preservation of tufts, progressive clubbing and shortening, and ill-defined symptoms of disturbed peripheral circulation. By 1952 Giacci mentioned that 68 cases of the familial type of acroosteolysis and 33 cases of the nonfamilial, idiopathic form had been reported in the medical literature. He added another five cases, but his case reports pertain almost exclusively to mutilating proces ses involving only the feet, with recurrent ulceration and discharge of bone fragments (see also Harms 1954), In 1957 Lievre and Gama listed 16 observations of idiopathic acroosteolysis and commented extensively upon these lesions; the whole range of dif ferential diagnosis (various congenital, neurogenic and endocrine osteolytic diseases, leprosy, arthritis mutilans, progressive systemic sclerosis, ainhum etc.) was considered in their study and could be rejected with reasonable certainty. In a later review, Cheney (1965), who added another four cases of the familial type, stated that this variety and the nonfamilial idiopathic type may actually belong to the same disease entity and may be part of a degenerative bone process more generalized than the term implies. It was the puzzling character and the rarity of this peculiar bone lesion that captured the attention of site medical personnel and industrial hygienists when in November 1963 the condition was detected in two Belgian autoclave cleaners {Lefevrc 1972). 4.1.2 Epidemiology of Occupational Acroosteolysis Attempts at assessing the prevalence of OAOL among personnel involved in VCM . manufacture and polymerization revealed that in general this occupational type of osteolytic bone lesion was found in only 1%--3% of the work population at risk. Hublci et al. (1977) considered the fact that only 3% of all workers who had been engaged in manual cleaning of autoclaves at a Belgian plant suffered from OAOL and Raynaud's phenomenon to be indicative ofithe importance of individual factors. Wilson et al. (1967) observed 31 cases among 3000 employees of one large company. In 1971 Dinman et al. conducted a survey in 32 plants belonging to 19 corporations throughout the United States and Canada. The details of this elaborate epidemiologi cal study, comprising a total of 5011 employees, illustrates the difficulties and limita tions encountered in a retrospective study of this dimension. All of these 5011 workers had been engaged in various stages of VCM and PVC manufacturing, but 1257 of them were workers who only handled finished PVC polymer. Five of the 32 plants worked Vinvl rhioi 33 y c ea d CP c e if w CO 4* L d o o jc to 0 a[ o was aeiectct use for react entry into tl Table 9. Pri Country France USA United Kingdom Fed. Rep. Germany United Kingdom Total More coi related syny. Lange and I ologicafchci pathological were affecte cold, 15 woi morbidity u found classic numbness ar. 8.7% and in\ Allen test in. people with pseudoclubb finding that duration of t d H.J, Marsteller i` this't__idition 'laud's disease as loss of part or : been mention- 19 27; Kornblum i.dities and noted n leprosy. The 48), who held a 'larnasch (1949) ularlv involving ubbing ID By 1952 ;ases of /) rie added g proces* CO agments o o spathic CO : of di seases. isidered -r revjew, ted that this same disease J than the term no lesion that its w, , in leaners (Lcfivre cd in VCM inal type of on at risk. :o had been am OAOL and ,il factors, arge company. ' corporations cpidemiologities and limita>c 5011 workers it 1257 of them plants worked Vinyl Chloride-Associated Disease 35 exclusively with the finished PVC-derived consumer products. Dinman et al. found only 25 clear-cut cases of OAOL among the 5011 employees (mean age: 35.8 years), defined as characteristic X-ray film abnormalities combined with Raynaud's phenom enon: 18 of them had been reactor cleaners at some time;another 16 individuals (10 with experience in reactor cleaning) with early stages or minimal degrees of the syn drome were suspected of suffering from OAOL. It emerged that the two lowest-paid jobs, both reactor cleaning and bagging/packing, had a strong association with OAOL (1 case per 72, or 86 workers at risk, respectively). Manipulation of the finished polymer appeared not to be associated with a risk of contracting OAOL. Only 1 case of OAOL was detected in those plants where high-pressure water lances or solvents had been in use for reactor cleaning. Furthermore, it seemed that the extent of degassing prior to entry into the autoclaves correlated with the manifestation of the disease. Table 9. Prevalence of acral disease in VCM-exposed populations Country Number of cases Size of group at risk OAOL Classical Severe Sclero Raynaud's sensitivity dermoid phenomenon to cold skin lesions References France 130 USA 354 United 37 Kingdom Fed. Rep. 100 Germany United 104 Kingdom Total 725 5 12 4 20 15 99 1 25 20(^3%) 71{M0%) 15 5 63 23 84 33 10 1 1 19(M6%) 43K6%) Benoit 1967 Lilis et al. 1975 Walker 1976 Lange and Veltman 1977 Maricq et al. 1978 More commonly seen than OAOL were Raynaud's phenomenon (see Table 9) and related symptoms of abnormal peripheral circulation (Benoit ]961; Lilis et al. 1975; Lange and Veltman 1977).Benoit pointed out that a complete medical and roentgen ological check-up of all 528 employees at a French PVC-producing plant revealed pathological manifestations only among the group of 130 reactor cleaners of whom 32 were affected (OAOL, 5; Raynaud's phenomenon without OAOL, 12: sensitivity to cold, 15 workers). He stressed the fact that in this group of workers at risk the overall morbidity was almost 25%. Similar results were obtained by Lilis et al. (1975), who found classic Raynaud's phenomenon in 5.6% of 354 heavily exposed PVC workers, numbness and tingling in 24%, excessive sensitivity to cold in 18%, pseudoclubbing in 8.7% and involvement of the toes in 7%. Besides, in 26.6% of the total an abnormal Allen test indicated impaired peripheral arterial circulation. It was noted that in some people with past exposure Raynaud's phenomenon had gradually faded, whereas pseudoclubbing persisted or even progressed. Most important, however, was Litis' finding that the prevalence of all these abnormalities increased significantly with the duration of past exposure to VCM. l i' 36 W,K. Lelhach and H.J. Marstcller Occupational acroosteolysis is a condition predominantly observed in younger workers. The age range was 20--45 years and half of all cases reported fell in the 30-39 years age-group. Duration of VCM exposure prior to onset of Raynaud's phenomenon ranged from 1 to 23 months (Dodson ct al. 1971). For OAOL the latency period was at least 12 months (Wilson et al. 1967): in most cases, OAOL developed insidiously within 2 to 4 -6 years. There is at least one patient on record in whom OAOL was first discovered two years after termination of exposure (Benoit 1967). Longitudinal studies of the bone lesions demonstrated partial or complete but mostly defective restitution, resulting in shortened and deformed distal phalanges, within 2--3 years after removal from VCM exposure, but Raynaud's phenomenon and cutaneous lesions may persist (Williams and.1McLachlan 1976). Stein et al. (1973a, b) reported partial healing with restitution of tufts but progressive lysis of the proximal portion of terminal phalanges 3 years after termination of exposure. Although OAOL developed predominantly in PVC production workers who had at least for some time been engaged in reactor cleaning, the syndrome has also been ob served in association with other job assignments which were believed to carry a sub stantially lower risk of exposure. Trapp et al. (1974) reported a 31-year-old white male suffering from Raynaud's phenomenon, clubbing of the fingers and typical bilateral acroosteolysis.in whom specific inquiry revealed that his employment by an industrial chemical company had included daily handling of small concentrations of vinyl chlo ride (no details given). Typical OAOL was also observed in a worker after 6 years' em ployment as spray dryer/bagger, pre-mix operator, recovery and charging operator who had never cleaned autoclave vats (Stewart et al. 1975). According to routine plant monitoring of VCM levels in the past and as measured in 1973 by gas chromatography of grab samples, his average exposure had been within the threshold limit values of the day (200 ppm). Radiographs taken in 1966 at the end of his first year during an earlier survey of OAOL were normal; in 1972 he presented with Raynaud's phenom enon, pseudoclubbing, typical OAOL and dermal thickening of hands and wrists. Ar teriography demonstrated narrowing of most digital arteries, even in fingers without bone defects, and abnormal collections of small vessels in the pulps of deformed finger tips, but no vascular occlusion. Apart from the chemical insult by inhalational (rather than transdermal --Dinmatt et al. 1971 \Stewart et al. 1975) exposure to VCM, individual susceptibility or idio syncrasy appears to have played some (undefined) role in the development of the syn drome. It does not seem likely, however, that repeated physical microtrauma during cleaning operations (removal of polymer crusts by hand scraping or chiselling) was a decisive factor in the pathogenesis of the condition as had been speculated by Wilson et al. (1967). 4.1 3 Clinical and Roentgenological Features 4.1.3.1 Occupational A croosteolysis Jn the majority of cases osteolytic lesions are confined to the hands. Involvement of the feet was observed only rarely in OAOL. Wilson et al. (1967) believe that OAOL differs from familial or idiopathic acroosteolysis in several respects. Although the bone Vinyl Cli defects ii osteopon skull, des shortenin nonoccu; genologk 1) Th one or m< 2) In) tufts, or c 3) Tht tufts toge defects (s* (`bandlike 2. Oc ostee * - > car-old a 4) In t and broad fragments and increa Sodiut mineraliza multaneoi i and H.J. Marsteller ved in younger cdfe'v" -the30-39 aud's r.ienomenon latency period was L>ped insidiously iom OAOL was first Longitudinal studies efective restitution, ears after removal rsions may persist irtial healing with terminal phalanges workers who had at has also been ob:d to carry a subyear-old white male 1 typical bilateral mt by an industrial ions of vinyl chlor after 6 years' enl arging operator w'ho 0 routine plant as chromatography 1 limit values of st year during an ynaud's phenomds a: rists. Ari fingers without of deformed sdermal --Dinman ptibility or idio>pment of the synrotrauma during c 1 was a 3J Wilson t*> CO CO A o o cn . . :ment ol t OAOL gh the bone Vinyl Chloride-Associated Disease 37 defects in the distai phalanges are similar in both conditions, other features, such as osteoporotic compression fractures of the spine, basilar impression fracture of the skull, destruction of mid-phalanges or osteosclerotic changes of wrists and hand bones, shortening of metacarpals and cortical thickening of the shafts of long bones seen in the nonoccupational type have never been found in OAOL. Wilson ei al. worked out roent genological criteria for the diagnosis of OAOL: 1) The earliest changes in OAOL are marginal defects and loss of cortex in tufts of one or more of the terminal phalanges of the hands. 2) In the next stage this is followed by small `half-moon' cuts in the cortex of the tufts, or a so-called slice-effect along one or more tufts. 3) The advanced stage of destruction is characterized by either a complete loss of tufts together with a portion of the shaft or there may be transverse or oblique bone defects (see Fig. 2) cutting off the shafts from the remaining distal rim of the tufts (`bandlike acroosteolysis'). Fig. 2. Occupational acroosteolysis. Transverse or oblique bone defects ('bandlike acroosteolysis') or partial loss of terminal phalanges in all fingers of both hands. (33year-old autoclave cleaner: duration of exposure 3 1/2 years) 4) In the healing stage there may be either complete bony union with shortening and broadening of the residual parts of the end phalanx or a fibrous union of bone fragments. Fingertips remain short and plump with persistent clubbing of soft tissues and increased lateral and longitudinal curvature of fingertips. Sodium fluoride 1 F scintiscan data of affected bones suggested that active de mineralization (resorptive) and remineralization (reparative) processes may occur si multaneously even in the same hand {Dodson et al. 1971). In some cases, bones of 38 W.K. Lelbach and H.J. Marsteller other body regions were also involved. Erosive and sclerotic changes in the sacro-iliac joints and circumscribed resorptive defects (cortical erosions) in patella, clavicle, man dible, humerus, styloid process of ulna, femoral condyles, os calcis, cuneiform and metatarsal bones have repeatedly been observed (Cordier et al. 1966`.Hams and Adams \961\Dodson et al. 1971 \ Juhe et al. 1974;Lange et al. 1974a:Preston et al. 1976: Jayson et al. 1976a:Lange and Vchman 1977). 4.1.3.2 Pseudoscleroderma Concomitant with the manifestation of paraesthesias, pain, tenderness of the fingers and Raynaud's phenomenon, cutaneous lesions similar to stigmata seen in progressive scle roderma develop with thickening of the skin of fingers, hands and forearms, sometimes accompanied by swelling or puffiness and coarsening of the skin of the face (mostly on the forehead and cheeks). Raised, ivory-coloured, firm nodules or elevated, sharply de lineated plaquelike skin indurations are seen on the dorsal surface of fingers and hands and on the volar side of the wrists and lower forearms. It was this combination of Ray naud's phenomenon and cutaneous lesions which first prompted a search for other symptoms of progressive systemic sclerosis in affected workers. The syndrome of OAOL, however, can be clearly distinguished (Table 10). Notably, the diffuse immobil* Table 10. Differential diagnosis: syndrome of occupational acroosteolysis (Raynaud's phenomenon, sclerodermoid skin changes, AOL) / progressive scleroderma with (rare) osteolytic lesions Occupational AOL Progressive scleroderma Sex ratio Exclusively d=e =1:2 Hands Clubbing and shortening of finger tips; hyperhidrosis; no ulceration Atrophy and tapering off of fingertips; anhydrosis; ulcerative lesions Perioral puckering of skin Skin appendages Telangiectases Shortening of frenulum Subcutaneous deposits of calcium salts 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 (skin and bone lesions tend to heal after removal from exposure) Common Loss of skin appendages Common Early symptom Common Common (Common) Usually spontaneous progression V tride- izi go iis <; tio (p orrv. rea thi. 03 4.1/ 4.1.4. O O 03 V t Severa__ .-mg. disease (Cordiu al. \912\Langc we found only 1967;Marin et neural changes * who suffered `n Dermal chat mis with disorie broad interlacin faintly stained t Schiff (PAS). A histiocytes was The most notal of elastic fibres full thickness r sue. Skin apper Walker (1976) t not exceeding t some fibrous th Vascular U capillaries were and pericapillai thelia! cells wit! tion of lumina myocytes, was to narrowing u: Degeneratiu (Benoit 1967;,' hyalinosis of `.I: Meissner, Pacin 4.1.4.2 Bone! The most striki. worker with 0/ ening and hyali most layer. Sup d H.J. Marsteller the sacro-iliac 1, cla'"~ M, man:ieifoi.,, and irris and Adams ' et a|-. ] 976: i ?ers and p go 1 scleai Cfi uimes - f* ly on ate > demge o nds ..bin; o_4 .ayrch ft ndro diffu. ...miooil- sis (Raynaud's r.na with (rare) 'e 'deroderma an 1 .... .ring off i'p- anhydrosis; - 9 --inns kin appendages i niptom t n) -pontaneous MOn Vinyl Chloride-Associated Disease 39 izing sclerosis of the skin with tapering off of fingertips was never seen in the occupa tional syndrome. After cessation of exposure the skin lesions seem to regress more readily than the osteolytic changes. 4.1.4 Histology 4,1,4.1 Cutaneous Lesions Several investigators described the histomorphology of skin lesions in vinyl chloride disease (Cordieret al. 1966Harris and Adams 1967;Marin et al. 1967;Markowitz et al. \912\Langc et al. 1974a; Vcltman et al. 1975; Walker \916\Hahn et al. 1979), but we found only one description of bone histology in OAOLin the literature (Benoit \961\Marin et al. 1967). Skin biopsies showed various degrees of dermal, vascular and neural changes which were essentially identical in patients showing OAOL and in those who suffered `merely' from Raynaud's phenomenon. Dermal changes consisted of hyperkeratosis and pronounced thickening of the der mis with' disorientation, swelling and nonfibrillary eosinophilic homogenization of broad interlacing collagen bundles. There was some degree of interstitial oedema which faintly stained metachromaticaily with toluidine blue, alcian blue and periodic acidSciiiff (PAS). An inflammatory reaction with infiltration of lymphocytes and a few histiocytes was scanty and, if present at all, of predominantly perivascular distribution. The most notable feature was marked disorganization, fragmentation and rarefication of elastic fibres. In areas corresponding to nodular or plaquelike skin indurations, the full thickness of the dermis consisted of an acellular, partly hyalinized collagenous tis sue. Skin appendages were preserved. In 15 apparently less severely affected workers, Walker (1976) found only some destruction of elastic tissue of the dermis, probably not exceeding normal age changes; in one worker with severe Raynaud's phenomenon some fibrous thickening of the media of dermal arterial was seen. Vascular lesions affected capillaries and small dermal arteries. Numerous dilated capillaries were seen in the subepidermal papillae with swelling of endothelial cells and pericapillar oedema. Capillaries of the cutis showed cuffiike hyperplasia of peri thelia! cells with fibroblast transformation, hyalinosis of vessel walls and final oblitera tion of lumina. Marked medial thickening of dermal arterioles, due to hypertrophy of myocytes, was accompanied by parietal fibrosis and hyalinosis, which ultimately led to narrowing or even complete occlusion of the lumen. Degenerative lesions of small dermal nerves were mentioned by French investigators (Benoit 1967;Marin et al. \961\Chatclain and Motillon 1967). They found sclerosing hyalinosis of the perineurium with atrophy of ncurofibrils. Tactile corpuscles (WagnerMeissner, Pacini) were unaffected. 4.1.4.2 Bone Lesions The most striking feature in a biopsy specimen of the bone, obtained from a French worker with OAOL (case 4 of both Benoit 1961;Marin et al. 1967) was marked thick ening and hyalinization of the periosteum with chondroid metaplasia of the inner most layer. Supplying capillaries and arterioles showed occlusive changes identical with 40 W.K. Lclbach and H.J. Marsteller those observed in the dermis. The bone matrix per se was barely affected. There was minimal thinning of cortex, normal spongy bone and only mild fibrosis of the bone marrow. Experience with histomorphulogy of bone lesions in the familial and idiopathic type of acroosteolysis is limited. In the few cases where biopsy material could be ob tained, there was replacement of bone by nonspecific fibrous tissue, but inflammatory and degenerative changes or osteoid formation were not found (Dtipas et al. 1936; Elson and Burnstcin \9S4\Grccnberg and Sircc! 1957;Schwarzwcilcr 1957). In this context, it should be kept in mind that Viola succeeded in reproducing dermal, vascular, neural and skeletal lesions in the skin of the paws and in small meta tarsal bones of experimental animals which were very similar to those observed in man. Viola exposed rats to 30 000 ppm VCM, 4 h/day, 5 days/week, for 12 months and de scribed the histology of these lesions in detail (1970b). 4.1.5 Arteriography, Capillaroscopy, Infrared Thermography Arteriographic evaluation of the vascular tree of the hands revealed patency of the large arteries in all cases examined. The vascular lesions were almost invariably con fined to the small digital arteries, although the superficial and deep palmar arterial arch may occasionally show some narrowing and a paucity of side-branches (Lange et al. 1974a;Moulin et al. 1974). The most prominent arteriographic features were ir regularities and segmental stenosis of digital arteries, ranging from localized or diffuse narrowing to subtotal or even total occlusion with development of collateral vessels. Besides, a conspicuous retardation of flow of contrast medium was noted, and peculiar tortuosities of patent digital arteries were found. Circumscribed hypervascularity of the terminal tufts and in the region of the wrists was noted in some cases (Benoir 1961: Lange et a], 1974a; Velnnan et al, 1975; Preston et al. 1976; Steuvrt et al. 1975; Gama and Meira 1978). Angiographic findings in a larger group of 19 symp tomatic PVC workers with either Raynaud's phenomenon and/or acroosteolysis (5/19) were recently described in detail by Koischwit: et al. (1980). Raynaud's phenomenon had been observed to persist in these patients for prolonged periods after termination of exposure and even after roentgenological evidence of healing of resorptive bone defects in those who had formerly suffered from acroosteolysis. In addition to vary ing degrees of stenosis or occlusion of digital arteries with reopening of small collat eral vessels, acral hypervascularity and considerable retardation of perfusion in spite of premedication with tolazoline (Priscoline, United States), the most conspicuous features observed in the majority of these patients (14/19) were circumscribed elonga tions and tortuosities of digital arteries resembling cirsoid aneurysms. An example is shown in Fig. 3 of generalized tortuosity and elongation of digital arteries in a 54year-old patient who started to complain of severe sensitivity to cold 3 years after cessation of VCM exposure (about 1 year prior to death from both angiosarcoma of the liver and hepatocellular carcinoma). The pathogenesis of these peculiar vascular alterations is not clear, but the possibility presents itself that they may be due to de struction of elastic fibres in the vessel walls in analogy to similar alterations of digital arteries seen in rheumatoid arthritis {Laws et al. 1963. 1967). Vinyl i 00 ons ;rp va: Jar area those s ferent d laroscc controi ence in PVCw. of distu induce. A si a PVC-; chemic; normal was cor numbei emplov related It also t more sc Marsteller There was he K~ " itopalhic nld be obfiammatory ..1. 1936: :t). ;>Jucing small meta:rved in man, uths and de- .y of the ;Toly con- arterial s t Lange et . were ir! or diffuse ial vessels, md peculiai jrity of "ennit ') v ' '719) ion 5 on fio W / 00 oe o to nga- is rs after ueoma of vascular due to de> of digital Vinyl Chloride-Associated Disease 4! Fig, 3. Conspicuous tortuosities and elongation of digital arteries Studies of microvascular changes by wide-field capillary microscopy (direct obser vations complemented by photography) of selected skin sites -- such as nail folds, fmgerpads, dorsum of phalanges and of proximal in terphalangeal joints - demonstrat ed a variety of capillary' abnormalities, i.e. dilated or giant capillary loops, pale avascu lar areas, capillary' and subungual haemorrhages. The abnormalities were similar to those seen in scleroderma but were usually less conspicuous, less numerous and of dif ferent distribution. In a survey of a group of 152 American PVC workers, these capillaroscopic findings proved to be significantly more prevalent than in 50 nonexposed control subjects (Maricq et al. 1976). There was also a statistically significant differ ence in the prevalence of these abnormalities between symptomatic and asymptomatic PVC workers. The alterations were not only found in workers with clinical symptoms of disturbed acral circulation but also in 6 nonsymptomatic males with either VCMinduced angiosarcoma of the liver (2) or splenomegalic portal hepatic fibrosis (4). A similar survey was later undertaken in an unselected sample of 129 employees of a PVC-producing chemical plant in England with 26 employees of a non-PVC-producing cheniical plant serving as controls {Maricq et al. 1978). The prevalence of capillary ab normalities found in these British workers, which were of the same type and degree, was comparable to that in the American sample, although the latter included a larger number of more severely affected symptomatic patients with greater mean length of employment (15 years vs 3.5 years). 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 serious VCM-induced disorders. In a small subgroup of 15 clinically affected W.K. Lelbach and H.J, Marstellcr British workers who were examined 6-24 months after leaving the plant (termination of exposure), the prevalence of capillary abnormalities was not less than that among those who continued work. For an evaluation of the reversibility of this condition, however, the group was considered to be too small. The same type of capiliaroscopic 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 (Bycikowska and Langauer-Lcwowicka 1974). Infrared thermography, another non-invasive method, used by Rcty et al. (1974) for the study of acral circulation, revealed abnormalities of surface temperature rang ing from marked hypothermia of terminal phalanges (which are normally warmer than the rest of the fingers) to "complete terminal amputation" in four PVC workers suf fering from OAOL. In one of them vascular disturbances as evidenced by infrared thermography persisted in spite of complete healing of OAOL. Stewart et al. (1975) demonstrated uneven blood flow in the fingers and patchy hyperthermia in the distal part of the OAOL-affected left index and middle finger of their atypical case. Local ized acral hyperthermia seen on IR thermography corresponded to the angiographic finding of circumscribed abnormal collections of small vessels (compensatory collat erals?) in the pulps of the affected fingers. Using IR thermography in a survey involv ing 143 PVC production workers and 56 controls, Williams et al. (1977) assessed the time needed for heat return after immersion of one hand for 10 s in a water bath kept at 19C: however, no difference between VCM-exposed subjects and controls and be tween groups within the exposed population was noted. 4.1,6 Immunological Studies Early experience with the syndrome of occupational acroosteolysis suggested certain similarities between this disorder and corresponding lesions seen in progressive systemic sclerosis (diffuse scleroderma). Differential diagnosis of these two unrelated conditions is now well established (Table 10). Such similarities stimulated the search for other manifestations of a systemic collagen disease, notably immunological features, as pro posed by Marin et al. in 1967. Ward et al. (1976a, b) carried out immunological studies in 58 workers from a British polymerization plant who were referred to them'out of a total past and present work force of 320. Mean duration of exposure to VCM was 39 months (6-75 months). Of these 58 workers, 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 hyperimmunoglobulinaemia, usually, IgG, the presence of mixed cyroglobulins, and in vivo conversion of both C3 and Cj were found in 19 patients in the symptomatic group, with additional evidence of reduced T-cell population and increased B-cell proliferation. Mixed cryoglobulins, in vivo con version of complement and depressed values for C3 or Cj were taken as evidence for the presence of circulating immune complexes. Autoantibody screening demonstrated low-titre antinuclear antibodies (IgG 1/20-1/50) in eight of the nine patients with Raynaud's phenomenon. Aggregates of IgG, C4, C3, and fibrinogen/fibrin were reveal ed by direct immunofluorescence in the lumen of vessels, adherent to vascular endo thelium. Aggregates were similarly seen in the media and subintimal regions of small Vinyl Chi" and mediui lung (1 casi The aut and bone c; bolic intern plasma pro: which slimi cular occlu' as a result c ators of tiss to further a Jayson et a! suffering fr< than in non ride disease In an ea in four Poli decrease in ever, Langa after Sepht 6 together\ agglutinins were obsersponses pla' (1974a) ait deuce of an tion of rhe. termination immunofhiwere later a creases in ir taken up ag ed to sugge: hypergami'. with far ads three patio; with Rayna degrees of i S 00 CO is nj. 03 jn O-a o Id d J HJ. Marsteller ;it (termination n that---nong i.conVv on, npillaroscopic rs, 2 fitters) for 2--5 years et al. (1974) iperature rangly warmer than C workers sufSy infrared et al. (1975) <ia in the distal :d case. Localangiographic >satory collatsurvey involv' 1 assessed the vater bath kept uurols and be- .cited certai1'. Hssivp-^vsteimc \:*-`d- - Jitions ;h for other lures, as prolologica] stu lies 'hem out of a VCM was 3ri ivnaud's phutd. excessive ually IgG, the l C4 were e of reduced s, in vivo conevidence for demonstrated uients with in were reveallseular endoions of small Vinyl Chloride-Associated Disease 43 and medium-sized arterioles in biopsy specimens of the skin (10 cases), muscle and lung (1 case each). The authors proposed as explanation for the induction and pathogenesis of skin and bone changes in VCM-induced disease a theoretical model based on reactive meta bolic intermediates of VCM formed during biotransformation binding covalently to plasma proteins. These may act as antigens (as a result of a structurally abnormal protein) which stimulate B-cell proliferation and antibody response. Platelet aggregation, vas cular occlusion and ischaemia were thought to be secondary to complement activation as a result of formation of immune complexes which were implicated as possible medi ators of tissue injury. Ischaemia, in turn, by leading to collagen synthesis, was believed to further activate the complement pathway and thus to recycle the mechanism. Jayson et al. (1976b), who carried out collagen studies in a skin biopsy of one patient suffering from OAOL found the rate of collagen synthesis to be considerably higher than in normal controls. The pathogenesis of excess collagen formation in vinyl chlo ride disease has not been fully elucidated. In an earlier study no cryoglobulinaemia or presence of cold agglutinins was found in four Polish workers with severe Raynaud's phenomenon; in two of them a slight decrease in IgG was noted (Byczkowska and Langauer-Lewowicka 1974). Later, how ever. Langauer-Lewowicka et al. (1976) observed latent cryoglobulinaemia, detectable after Sephadex G-200 filtration, in 18 of 22 workers with Raynaud's phenomenon (in 6 together with acroosteolysis and sclerodermalike changes). Again, there were no cold agglutinins detectable, but in five patients marginal to slight elevations of IgG levels were observed. The authors suggested that a pathological alteration of immune re sponses plays a key role in the pathogenesis of vinyl cldoride disease. Lange et al. (1974a) and Vehman et al. (1975) concluded from their results that convincing evi dence of autoimmune disease was lacking. Immunological studies including determina tion of rheumatoid factor (latex agglutination test), quantitative immunoglobulin de termination (Manzini radial diffusion technique) and autoantibody screening (indirect immunofluorescence) were initially introduced in our first series of 50 patients but were later abandoned because of mostly negative results, except for occasional in creases in immunoglobulin levels (Marsieller et al. 1975a). These studies were later taken up again with an additional 43 patients engaged in PVC production but still fail ed to suggest more than an erratic connection (unpublished data). We did not observe hypergammaglobulinaemia (see comment in Ward et al, 1976a) except in a few patients with far advanced portal fibrosis and portal hypertension and in the-terminal phase of three patients who died from angiosarcoma of the liver. In a group of 18 PVC workers with Raynaud's phenomenon in whom arteriography of the hands disclosed various degrees of occlusion of digital arteries, autoantibodies, cryoglobulins and cold aggluti nins were found in none;a moderately increased IgG level (1.93--3.68 g/litre;normal range: x s = 0.8-1.8 g/litre) was seen in five patients who suffered from OAOL and sclerodermoid skin changes (unpublished data). Elastin antibody titres (the specificity of which is doubtful) were negative. In summary, currently available evidence does not seem sufficient to suggest an autoimmune disease as a pathogenetic mechanism. Further studies will be needed to establish the true significance of the possibly transient immunological abnormalities in VCM-induced disorders. * i 'i i% r \ It ! s 1: ! $ . \ > 1 v * 1 i 44 W.K. Lelbach and H.J. Marsteller 4.1.7 Pathogenetic Considerations Raynaud's phenomenon as a premonitory clinical symptom, histomorphology in man and experimental animals and angiological experience suggest that the common de nominator in the pathophysiology of both skin and bone lesions in chronic VCM in toxication is probably to be sought in the local impairment of blood circulation in peripheral regions, as Benoit pointed out as long ago as 1967. By reason of their vas culature, the distal phalanges are the skeletal segments which may be most susceptible to impairment of blood supply, particularly to disturbances of microcirculation (Gama and Meira 1978). Yet the answer to the next question, the pathogenesis of peripheral 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. 4.2 Noil-malignant 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 al. (1949) studied environmental conditions in a Russian plant where polyvinyl chloride resins were produced and compounded. Without going into detail, the authors pointed out that moderate nontender hepatomegaly was found in a larger porporlion of a group of 73 workers (48 males, 25 females) mostly engaged in PVC compounding; `anicteric hepatitis' was diagnosed in 21 of them (15 <J,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 from halogenated aromatic hydrocarbons (such as chlorinated naphthalenes and diphenyls) used as plasticizers responsible for the systemic toxicity. They urged, however, that strict monitoring of the health of these workers should be introduced to prevent the development of severe liver damage, and they suggested the installation of ventilation facilities of sufficient capacity. Nonicteric hepatomegaly was again recorded by Suciu et al. (1963) 14 years later in almost one-third of the total work population (51 of 168 employees) of two Rum anian PVC-producing plants, including 10 cases with additional splenomegaly. Liver 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, Pushin (1965) found the highest morbidity among employees of the PVC production unit, compared with other units engaged in the production of nonPVC plastic materials; 1 70 workers of ancillary industries served as control subjects. Viny' ~ 'e-Ai The t 23 mpt W many (/> f tl; survey crib develc 03 >nk charac -P* O im In . --k. to 'Hi had bet ;1\ time-we er environr ,,at; wise multiple linea tion and, to a lesse level of past expos; the individuals stut TWA levels of 300 in clinical laborato; ed BSP retention u ease {Marsteller et : In West Germa; dermatologists in B At first sight, the s\ derma. This provok Progressive systemi. a first group of 13 from a nearby PVC from either OAOL phageal varices due a group of 20 relati previous liver diseas Medical Departmen patient and revealeu capsularfibrosis of ly, marked portal by al, 1973). it was no' encompassed a largt Hence Jii/ic et al. (ll In retrospect, th spleen alterations in the long latency peri disease wlijch is acct hepatic parenchyma. Only 3 months 1. was surpassed by the Ih er. an exceedingly i workforce of 274en ican plant {Creech el upper gastrointestim. d H.J. Marstelier 33 n man de- I C/3 4 inin CO 1 -fc* vas- o iptible 1 w (Gama 1 literal f itter of :=>n, distributed : ihe liver, can jals, after a vandamage to perivious chapter (see lificance. cd in PVC prosis in a Russian Without going galy was found : mos^*" 'ugaged <J5^,-0 ?).AJions of VCM hey explicitly i the powdery ther volatile jhlorinaied Uemic toxicity, kers should be > suggested the I 14 years later s) of two Rummegaly. Liver e prevalence of oe Sverdlovsk nployees of the ction of nonitrol subjects. Vinyl Chloride-Associated Disease 45 The clinical symptomatology of - typically nonicteric - liver disease observed in as many as 1551 of the current work force of the PVC production unit during a 3-year survey was described as having been consistent with the diagnosis of an insidiously developing chronic hepatitis. No histological data were available, however, and the true character of nonmalignant liver disease found in these workers remained obscure. In 1973 Kramer and Mutdder examined a group of 98 healthy male workers who had been routinely exposed to VCM for periods up to 25 years and for whom career time-weighted average exposure estimates were available. In an attempt to correlate environmental data and results of a medical surveillance programme by means of step wise multiple linear regression analysis, it emerged that bromsulphthalein (BSP) reten tion and, to a lesser degree, the icterus index were significantly correlated with the level of past exposure to VCM. Although no overt clinical disease was found in any of the individuals studied, Kramer and Mutchkr concluded that exposure to VCM at TWA levels of 300 ppm or more for a working lifetime could result in certain changes in clinical laboratory 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 (Marstcllcr et al. 1975a). In West Germany the first cases of occupational OAOL were observed in 1972 by dermatologists in Bonn (Julie and Lange 1972;/r7/re et al. l973;Siein et al. 1973a, b). At first sight, the symptomatology appeared to resemble atypical progressive sclero derma. This provoked a thorough search for manifestations of visceral involvement. Progressive systemic sclerosis, however, could be excluded. On medical examination of a first group of 13 polycleaners who were referred to the Department of Dermatology from a nearby PVC-producing plant it emerged that 3 of them, who did not suffer from either OAOL or scleroderma, had a history of unheralded bleeding from oeso phageal varices due to portal hypertension (Jiihe et al. 1973). Further investigation of a group of 20 relatively young PVC production workers (mean age:40 years), in whom previous liver disease could be excluded, was carried out in collaboration with the Medical Department. Peritoneoscopy and guided liver biopsy were performed in each patient and revealed varying degrees of noncirrhotic portal, pcrisinusoidal and subcapsular fibrosis of the liver, with splenomegaly, thrombocytopenia and, less frequent ly. marked portal hypertension, but strikingly little hepatic dysfunction (Marstcllcr 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) proposed the term `vinyl chloride disease'. In retrospect, this comparatively late recognition of the true nature of liver and spleen alterations in chronic VCM intoxication can be attributed, at least in part, to the long latency period as well as the insidious onset and course of this type of liver disease which is accompanied, even far into the advanced stages, by only minimal hepatic parenchymal dysfunction. Only 3 months later, however, in February 1974 the significance of tlus discovery was surpassed by the alarming announcement that four cases of angiosarcoma of the liver, an exceedingly rare malignant tumour, had been found among a comparatively small work force of 274 employees of the PVC polymerization section of a large North Amer ican plant (Creech et al. 1974a). Two of these four patients had first presented with upper gastrointestinal bleeding due to portal hypertension between 1964 and 1970. R&S 134014 46 W.K. Lelbach and H.J. Marsteller There is no longer any doubt that chronic exposure to vinyl chloride monomer can produce two different types of liver disease in man as well as in experimental animals: 1) Noncirrhotic portal hypertension 2) Angiosarcoma of the liver. The two conditions have one feature in common: they are both rare disorders which are not easily recognized during life. Noncirrhotic portal hypertension and (often inconspicuous) portal fibrosis are not pathognomonic. Primary splenic enlargement and gastroocsophageal haemorrhage due to marked portal hypertension in the absence of, or preceding, the development of cirrhosis was first described by Band in 1894. As `Band's syndrome', this symptom complex and its aetiology and pathogenesis have continued to be a matter of debate. Under the designation `idiopathic', or `primary, portal hypertension' the syndrome has been observed notably in India and other South-East Asian regions (Ramalingaswami et al. 1962\Imanaga et al. l962;Bas<t et al. 1967a, b;Boyer et a], I967;5aw<7 et al. 1971). It has been seen only sporadically in the Western World (Roussclot 1940; Ravenna 1940; Tisdale et al. 1959'.Polish et al. 1962;hfiller and Brandt 1962\Siderys and Veliios 1964\Mikkelsen et al. 1965\Iber \9l0\Escartin Marin et al. 1974; Mendenhall et al. \914\Grannis 1975; Villeneuvc et al. 1976). Iher (1969) estimated that "centers throughout the world reviewing their experience with portal hyperten sion encounter 3 to 57c of patients who do not clearly fit into the category of cirrhosis or blockage of the portal vein." In the absence of an identifiable aetiology it has been speculated that in noncirrhotic portal fibrosis observed in India, unknown toxins contained in indigenous drugs, herbal medicines or adulterated food might have been responsible for the condition (Sama et al. 1971). Villeneuvc et al. (1976) suggested that, apart from VCM and inorganic arsenicals, other still unidentified toxins could be the cause of this syndrome. Idio pathic portal hypertension has also been observed to occur in association with known hcpatotoxic agents, their common link with VCM being, so far with the exception of vitamin A, the induction of angiosarcoma of the liver. These agents are: a) Inorganic arsenicals (Zeegen et al. 19 70; Wec/e and Azzopardi 1971 \Knolle et al. 1974;Morris et al. 1974;//iver et al. 1975; Villeneuve et al, \916\Cowlishaw et al. 1979); b) Hypcrvitaminosis A (Muenter et al. 1971 ;RusselI et al. 1973, 1974\Hntban et al. \ 914\Kistler et al. 1977); and c) Recently.copper sulphate in Portuguese vineyard workers (Pimentel andMenezes 1977). Arsenical preparations (usually prescribed as Fowler's solution - potassium arsenite) have in the past been used as a tonic in neurasthenia, as an adjunct to iron therapy for anaemia, as antiepileptic drugs 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 renowmed German pharmacology textbook of this period (Nothnagcl and Rossbach 1880) Fowler's soludon is also listed as a traditional antimalarial drug of 1 and H.J. Marsteller iloride monomer can perirr"''tal animals: ii rare disorders ,>rtal. fibrosis are not :ai haemorrhage due : development of ie', this symptom a matter of debate, m' the syndrome has > (Ramalingasicami 1961 \ Santa et al. ntssclot 1940; trandt 1962', Siderys 'i et al. 1974; t (1969) estimated ,h portal hypertencategory of cirrhosis d that in noncirrhotic icenous drugs, herbal - condition (Santa et I and inorganic syndrome. Idio, ,atic>n. with known ;h tr'--'xei lion of are: \Knolle et al. __ owetal. 30 ^ Hruhan el 03 ind.Uencccs O in ium to iron s for the treatment 898) that anaemia reparations is of d (Nothnagel and imalarial drug of Vinyl Chloride-Associated Disease 47 long standing. Chainuvati and Viranuvatti (1979) recently implicated an indigenous Thai medicine contaning arsenic as a possible aetiological factor in a case of idiopathic portal hypertension. Datta et al. (1979) found significantly elevated levels of arsenic in liver tissue specimens of four of nine Indian patients with idiopathic portal hyperten sion resulting from chronic arsenic intoxication (contaminated drinking water, use of Ayurvedic medicines). Typical!)', liver disease in these cases occurs in conjunction with other evidence of chronic arsenic intoxication, such as skin pigmentation, palmar and plantar hyperkeratosis, skin cancer and sometimes carcinoma of other sites. However, neither histological nor radiological or haemodynamic criteria permit a clear distinc tion between `idiopathic' portal hypertension and noncirrhotic portal hypertension caused by chronic arsenic toxification or chronic exposure to VCM, as was demon strated by Villeneuve et al. (1976) in a study of five patients. After prolonged treatment with excessively high doses of vitamin A (psoriasis, ichthyosis and other dermatological conditions, adjuvant cancer therapy and in health faddism) chronic intoxication has been seen to cause hepatic fibrosis and cirrhosis (Muenter et al. 1971 \Fleischmann et al. 1977;Kistler et al. 1911; Russell el si. 1973, 1974). Storage of vitamin A in hepatocytes and one type of fat storing, nonphagocytic perisinusoidal cells (Ito cells (Ito and Nemoto 1952)] could be demonstrated by fluo rescence microscopy. Stimulation and proliferation of Ito cells, which are probably fibroblast precursors (Popper and Udenfriend \91Q\Schnack et al. 1967), provokes an increase in basement-membrane-like material and collagen within the perisinusoidal space and leads to perisinusoidal fibrosis with partial obliteration of Disse's spaces and the sinusoidal lumen (Hruban et al. 1974). The recognition of idiopathic portal hypertension, hepatic fibrosis, cirrhosis and angiosarcoma of the liver coexistent with excessively abundant hepatic deposition of copper (besides evidence of`vineyard sprayer's lung') in a group of 30 vineyard workers in Portugal is, to our knowledge, the first report in which chronic copper intoxication is implicated as the aetiological agent. For periods varying from 3 to 45 years, these workers had been engaged in spraying vineyards with a mixture containing copper sulphate on 15-100 days per year. The authors noted a close morphological resem blance of the lesions to those resulting from exposure to inorganic arsenicals and to vinyl cliloride (Pimentel and Mcnezes 1977). Although extrinsic chronic copper intoxi cation is virtually unknown in man, potential hepatotoxicity of long-continued uptake of copper was discussed by Blomfield et al. in 1971 in connection with recurrent haemodialysis. Although nonmalignant liver disease seems to be a more common lesion in PVC production workers than angiosarcoma, it has received less attention than the spectac ular discovery of the rare hepatic neoplasm. In continuation of our first two surveys (Marstcllcr e1 al. 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 advanced portal hypertension (Table 11). A larger proportion of them first presented with symptoms of unheralded gastrointestinal bleeding. On follow up, we strongly suspected that angiosarcoma was developing in four of them but were unable to prove it during life. Only post-mortem examination finally confirmed the diagnosis. In a smaller series of seven patients with noncirrhotic portal fibrosis and 4S W.K. Lelbach and H.J. Marsteller Table 11.17 pvc workers with advanced portal hypertension (marked oesophageal varices, episodes of upper G1 bleeding, splenomegaly) Age at diagnosis Duration of exposure Peritoneoscopic and So. (years) (years/months) histological diagnosis i 30 31 3 32 4 35 5 3 35 6 39 7 39 8 41 9 3 41 10 a 47 1 1 50 12 5 1 13 52 14 52 15 54 16 a 58 17 a 61 5 5/9 3/6 4 9 10/6 13/6 7 18 IS 6/6 17 15/3 11 6/6 21 13 Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis 3 On follow-up patients 5,9, 10, I 6 and I 7 subsequently developed angiosarcoma of the liver and died 3-6 years after diagnosis of portal hypertension. Patients 6 and 14 are at present (19S1) under observation for suspected development of angio sarcoma of the liver, 6 and 11 years after peritoneoscopic diagnosis of portal fi brosis associated portal hypertension, Smith et al. (1976a) observed later development of angiosarcoma in one of them. If a rough estimate based on these two small series were acceptable.it would appear that approximately one of five to seven individuals suffer ing from advanced VCM-induced portal hypertension might be expected to develop angiosarcoma later, although PVC-induced hepatic fibrosis per $e is probably not a premalignant lesion. 4.2.1 Clinical Manifestations of Non-malignant Liver Disease Physical examination is usually disappointing. In the more advanced stages of VCMinduced nonmalignant liver disease, palpable splenomegaly and a slightly to moderate ly enlarged liver may be the only physical signs. On palpation, we found hepatomegaly in 31 and splenomegaly in 16 of 50 selected PVC production workers who had been heavily exposed in the past (Marsteller et al, 1975a). Lilis et al. (1975) reported hepa tomegaly in 15% and splenomegaly in 3.4% of 354 consecutively examined employees (267 currently employed, 87 former workers) of one PVC polymerization plant in New York State, USA, a number which included virtually the entire current produc tion work force. A significantly higher prevalence of hepatomegaly was found in those- Vi 1 DO exj fio i spl. _j. , me CO i ect O--i. : not 07 v ph; wo < h is (JUixl preceded ad\ only one case development 4.2.2 Labor Owing to the not the targe: value for the This makes it 1974; Creed: thrombocytu logical biochi the levels ol . quo tit (Marsh (ICC; 0.5 an. liver function workers of a (Tamburro et progressive!) of abnormal there was ove phosphatase: alkaline phos megaly and.* Except ftand Veltman the reticulocy parameters ut presenting fe. sion (Smith e be dealt with Assessmer. matic worker facture of PV coproporphyi il.J. Marsteller esophageal __r-_ SiTopie and .at diagnosis <die fibrosis ..uic fibrosis . tic fibrosis iotic fibrosis iotic fibrosis unic fibrosis totic fibrosis iotic fibrosis otic cirrhosis ;otic fibrosis >sis )S1S 3J >sis 99 (/) isis isis osts CO t* isis O ta of and ! of .alt series w e ividuals sutleri iu develop 'nbly not a pre cis of VCMv to moderate; hepatomegaly ho had been ;cported hepanad employees on plant in rent producfound in those Vinv] Chloride-Associated Disease 49 exposed for more than 5 years, whereas the difference in the prevalence of palpable splenomegaly was not significant. In contrast to cirrhosis of the liver, clinical symptoms indicating serious impair ment of hepatic function such as jaundice, vascular spiders, palmar erythema, telangi ectases; gynaecomastia, peripheral oedema and ascites or hepatic encephalopathy are not seen. Even after massive bleeding from oesophageal varices portosystemic ence phalopathy does not develop. Ascites and hepatic coma have been observed in these workers only in terminal stages of angiosarcoma of the liver. It is puzzling that acroosteolysis and sclerodermoid skin induration have only rarely preceded advanced stages of VCM-induced liver disease. To our knowledge there is only one case of angiosarcoma of the liver on record which was associated with prior development of acroosteolysis (Roclte et al. 1978). 4.2.2 Laboratory Findings Owing to the fact that hepatocytes, although being the primary site of metabolism, are not the target of toxicity, standard biochemical liver function tests are only of limited value for the detection of liver disease in populations at risk (Williams et al. 1975b). This makes it very difficult to devise adequate screening programmes (Martin et al. 1974: Creech andMakk 1975; Wyatt et al. \91S\Berk et al. 1975, 1976). Apart from thrombocytopenia, we found 45-min BSP retention to be the most consistently patho logical biochemical test; usually minimal hypeibilirubinaemia and minor elevation of the levels of serum alkaline phosphatase, SCOT and SCPT were considerably less fre quent (.Marsteller et al. 1975a), Another dye-removal test, indocyanine green clearance (ICG; 0.5 and 5.0 mg/kg), also proved to be more reliable than standard biochemical liver function tests in correctly identifying early hepatic injury in 1200 vinyl chloride workers of a chemical plant in Louisville, Kentucky, during a 4-year screening period (Tamburro et al. 1978b). The exposure rank was found to be closely correlated with progressively increasing frequency of abnormal ICG clearance, whereas the frequency of abnormal SGOT, and alkaline phosphatase only increased in late stages, often when there was overt clinical disease. In the survey conducted by Litis et al. (1975), alkaline phosphatase levels were elevated in 16.6% of the 354 workers examined. In their series, alkaline phosphatase was also closely correlated with the clinical symptom of hepato megaly and/or splenomegaly. Except for thrombocytopenia (less than 150 x 109 platelets/litre) which Lange and Veitman (1977) found to be present in 76 of 100 workers, and a slight increase in the reticulocyte count (in 35 of 79 workers,Lange and Vcltman 1977), haeniatological parameters usually do not contribute to the diagnosis. Thrombocytopenia was also the presenting feature in two of seven British workers with noncirrhotic portal hyperten sion (Smith et al. 1976a). Thrombocytopenia and abnormal platelet function tests will be dealt with separately in Sect. 4.4.1, Assessment of urinary excretion of porphyrins and porphyrin precursors in sympto matic workers who had been engaged in the production of PVC (n = 23) or the manu facture of PVC articles (n = 17) revealed varying but mostly mild degrees of secondary coproporphyrinuria in the majority of them (Lange et al. 1976b). The significance of i ! ii I I 1 i L S 50 W.K. Lelbach and H.J. Marsteller these findings as an indication of toxic liver damage is not clear and the relation to previous exposure to VCM remains to be determined. 4.2.3 Gross Inspection of the Liver and Spleen The gross appearance of the liver, as assessed by peritoneoscopy {Marsteller et al. 1975a, b'.Marstcller and Lelbach 1977; Lelbach and Marsteller 1977) or at exploratory laparotomy, is that of a normal-sized or slightly to moderately enlarged organ with often blunted and irregular anterior edge. Inspection of the liver at peritoneoscopy also permits exclusion of partial nodular transformation as described by Sherlock et al. (1966). In most cases, the surface of the liver is smooth or slightly uneven with shallow indentations, but it may be finely granular, trabeculated or have a peau d'orange-like appearance. At most, there are micronodular changes but the diffuse coarse nodularity of cirrhosis is only rarely seen. Progression to frank cirrhosis with severe derangement of hepatic lobular architecture was observed by Smith and Williams (1974), and also in two of our recent cases in combination with development of angiosarcoma. On palpation (direct or by peritoneoscopic probe), 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 1 jsi-v v >1 12?. Jf: A - .-m . T , -v * ^ '.vrA Fig. 4. Peritoneoscopic view of left hepatic lobe in noncirrhotic portal hypertension (January 1979). Blunted anterior edge, smooth to finely granular surface, conspicuous patchy capsular fibrosis. (42-year-old autoclave cleaner. VCM exposure 1963-74. 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 Table 1 1) Vinyl Citl contras: s pectedly r is a focal opacities, stellate ing (Marst tissue in C extending nective tis processes' or more dt are seen in 4.2.4 Hi; Histologic, is generall) sis, strikin' fibrosis arc (Fig. 5a-d reactions,. throughou- nsis. S: deal c- 33 ). 9 cpei,. CO if bic CO ver F* mar O -j. 'S S: 00 t IV bu et 4.2.4.1 H. In its fully of dense, p: bile ducts a with formal central and of connecti with enlarg; perisinusoid oidal walls. Mliller et al. mm 11 J. Marsteller relation to r'- \ .-/i. / et al. it Exploratory organ with oneoscopy also dock et al. n with shallow d'orange-like arse nodularity - derangement 74), and also 'coma. ' liver is normal portal hyperid the intes the abdomirtension often r\ jj 09 Sion ^ icuous W 4.4^ ( O 11 -* lageal CO Vinyl Chloride-Associated Disease 5 11 contrast sharply not only with minimal alterations of the surface but also with unex pectedly scanty histological evidence of hepatic fibrosis. The most conspicuous feature is a focal or diffuse capsular fibrosis of varying pattern (Fig. 4), presenting as whitish opacities. The degree of capsular involvement ranges from diffuse tiny commalike or stellate scars to coarsely reticular and irregularly patchy milk-white capsular thicken ing {Marsteller et al. 1975a). Histology showed that this focal increase of connective tissue in Glisson's capsule may extend into the parenchyma and connect with septa extending from enlarging fibrosed portal tracts (Popper and Thomas 1075). The con nective tissue capsule of the enlarged spleen also seems to be sensitive to VCM-induced processes that have taken place in the underlying tissue so that focal white thickening or more diffuse opacities together with circumscribed subcapsular haemorrhagic cysts are seen in cases with marked splenomegaly. 4.2.4 Histology Histological examination of biopsy specimens shows that normal lobular architecture is generally maintained, but varying patterns of portal and, in some cases, septal fibro sis, striking intralobular perisinusoidal fibrosis, and focal capsular and subcapsular fibrosis are found in combination with peculiar alterations of sinusoidal lining cells (Fig. 5a-d). Hepatocellular changes usually play a negligible role and inflammatory reactions, if present at all, are insignificant. The lesions are distributed quite irregularly throughout the liver and may vary from minor inconspicuous degrees to quite striking fibrosis. Surgical wedge biopsy of sufficient depth appears to be more suitable for his tological evaluation than needle biopsy specimens (Smith et al, \97fsts\Blendis et al. 1978). Depending on length and degree of exposure, interval between last exposure and date of biopsy, as well as individual factors, histopathology of VCM-induced nonmalignant liver disease is represented by the following features whose manifestation is sub ject to marked interindividual and topical variation: the same variability of tissue alter ations is seen in the nontumorous areas of the liver in angiosarcoma {Popper and Thomas 1975; Thomas et al. 1975)Berk et al. 1976; Gedigk et al. 1975: Weinbren 1976). but in these cases the nontumorous lesions may be even more conspicuous (Popper et al, 1978). 4.2.4, l Hepatic Fibrosis In its fully developed form, minimal to marked enlargement of portal tracts by excess of dense, pauciccllular 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 be connected by septa with enlarged infracapsular portal tracts. A more striking feature is an intralobular perisinusoidal `netlike' fibrosis with more or less prominent collagenization of sinus oidal walls, in some areas even progressing to frank capillarization (Gedigk et al. 1975; Miillcr et al. 1975). The focal intrasinusoidal fibrosis may be subtle and in some cases W.K. Lelbach and H.J. Marsteller Vin ;xv '^ < * -'L * " . - -.w y t \ T 'a . * v. ^ . '.'* 'j * ;&* ." * . . r.. -"'j * < !?' , *t . % *. t' Fig. 5a. Needle biopsy specimen of the liver shown in Fig. 4. Enlargement and fibrosis of portal tracts. Moderately large droplet steatosis. Focal dilatation of sinusoids. H &E. x 80. b Close-up of Fig. 5a. Indistinct border of enlarged and fibrosed portal tract to wards parenchyma (left!. Proliferation of capillaries (> <) with polymorphism and hyperchromasia of endothelial cells. PAS, x 400 Patn Vinv] Chloride-Associated Disease 53 f.^4 (), '> 'J: 1 * t yr *' V V-v, -> ,, ,> .'-. IW; Vi.-4*.':^ -'' f r' ' 4i-v>. ^..'*V V. 'i`y>f V :v *-v** -'i - * V** ?*u 0 ^ ~ W-'.v '* ' -. ^ ' V r/ " c ^ ^^ ** * '"`^ Sv^:r'>r^ Vjir * * ^<_ ^ "7-^ Fig. 5c. Focal portal fibrosis (left upper comer) and reticulated perisinusoidal fibrosis with activated proliferating and pleomorphic sinusoidal lining cells. Trichrome (Goldner) stain, blue filter, x 250. d Conspicuous focal dilatation of sinusoids. Activation and moderate polymorphism of proliferated hyperchromatic sinusoidal lining cells. Enlarged hepatocytes with hyperchromatic nuclei, some of them binuclear. (Potential precursor stage of angiosarcoma?) Courtesy of Professor Miiller-Wallraf. Institute of Pathology. Amberg. H &. E, X 400 54 W.K. Lelbach and H.J Marsteller may be recognized only in connective tissue stains. Trichc et al. (1975) pointed out that in one worker with severe acroosteolvsis but normal hepatic function and essen tially normal liver histology on light microscopy (except for a minimal and easily over looked increase of perisinusoidal collagen in occasional lobules), electron microscopy revealed a striking centrilobular increase in collagen between hepatocytes and in Disse^ spaces together with proliferation and hyperplasia of sinusoidal lining cells (see also Kurokawa et al. 1977). The same ultrastructural deposition of perisinusoidal collagen was observed by Schattenberg et al.(1977) in 15 PVC workers in whom we could ob tain liver tissue for electron microscopy at peritoneoscopy. Similar changes (enlarge ment of Kupffer cells, abundant deposits of collagen in the Disse's space and resulting reduction of sinusoidal diameter suggesting a possible factor in the pathophysiology of `sinusoidal - portal hypertension) were seen on electron microscopy in a number of cases of idiopathic portal hypertension of unknown aetiology (occupational histories not mentioned) (Sommerschild and Kluge 1971; Kluge et al. 1970; Tandon 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 hyperchromatic nuclei of these cells may show a bizarre shape or resemble short pegs, and are often arranged in a chainlike fashion (Gedigk et al. 1975). These perisinusoidal and sinusoidal cells include three types: (1) normal endothelial cells, (2) lipocytes (Ito cells), considered to be precursors of fibroblasts and (3) plump cells with spindle-shaped nuclei and PAS-positive cytoplasm. Formation of excess reticulin suggests fibroblastic activity of some of these cells. Focal dilatation of sinusoids, not explained by passive congestion, is another peculiar feature usually associated with particularly pronounced alterations of these mesenchymal cells. There is reason to be lieve that this combination of changes may represent a premalignant stage. 4.2.4.3 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 endoplasraatic reticulum of hepato cytes in focal areas without inflammatory reactions), can be seen to disappear gradual ly with increasing intervals between the last exposure and the date of biopsy, in con trast to the apparently irreversible damage to mesenchymal structures (Gedigk et al. 1975,1977-.Muller et al. 1975). In poorly demarcated areas there is hyperplasia and hypertrophy of hepatocytes with polyploidy and increased number of binucleated cells. Two types of focal hepatocytic proliferation associated with varying degrees of sinusoidal cell alterations were recently described and are thought to play some as yet undefined role in the precursor stage of angiosarcoma (Popper et al. 1978), 4.2.4.4 Histology of the 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 Chloride and Thomas et. to be characteri. geneous red pul- follicles with nn endothelial cells occasional fresh spicuous fibrosis In ten cases v. Heusermann and terial, together -. splenectomy. Th process. Excess a tiv iotat am ulp,: Th> go :arru me: (/) id re and of: of tl W 3rd- font biz. colla ^ s. 5 the n on: volun am matio.. mpdla found within the ' thrombocytes b\ hanced pooling o help to explain t: stages of vinyl ch and Heusermann VCM-inducedspl. of the liver or ev in the spleen in vi dicate a primarv port correlating c tients is being pre the spleen in non. able for comparis. 4.2.5 Pathophys The pathophysiof unresolved problr to splenoportogra of intrahepatic vavenous radicles (B and a normal, or c H.J Marsteller pointed out on an^ssenmd e. / over"i microscopy s and/ in Disse's :11s (see also oidal collagen we could ob liges (enlarge: and resulting mphysiology it a number of mnal histories ;Jon et al. u 30 oly- UK (/> al p: tble 19 00 e U -C* oi S) N> ells GO ilin '!ll ot vL.. ^ . . ..1 ^ rea o be- ge. i.ior degrees of i, increase of \ of hepatoippear gradualopsy, in conn'digk et al, ierplasia and mucleated ng degrees of :y some as yet 7S). eus of the 7lomas (1975) Vinyl Chloride-Associated Disease 55 and Thomas et al. (1975) found the cut surface of surgically removed enlarged spleens to be characterized by conspicuously hyperplastic Malpighian follicles in a beefy homo geneous red pulp. Histologically, they noted large germinal centres of the Malpighian follicles with merging of perifollicular zones, dilatation of red pulp sinuses lined by endothelial cells of variable, often cuboidal shape, thickening of the pulp cords with occasional fresh haemorrhages, and in one case Gandy-Gamna bodies, but only incon spicuous fibrosis of the red pulp. In ten cases we obtained needle biopsy specimens of spleen tissue at peritoneoscopy. Heusennann and Stutte (1977b) and Stutte and Heusermami (1978) studied this ma terial, together with spleen tissue specimens available from three spleens obtained at splenectomy. They found evidence for an involvement of the spleen in the fibrosis process. Excess amounts of newly formed extracellular elements of reticular connec tive tissue, notably collagen, produced by stimulation of fibroblastic cells of the red and white pulp, particularly in perifollicular and subcapsular areas, were observed. There was scarring of periarterial lymphatic sheaths, obliteration of the pulp cord meshwork and reduction of pulp cord volume, in addition to an increase in number and diameter of sinuses. The reticular connective tissue of the walls of the sinuses and of the pulp cords showed marked alterations with thickening of reticular fibres and formation of bizarre platelike amorphous structures containing irregularly distributed collagen fibrils. Narrowing of the labyrinthine cordal tissue with marked increase of the reticular connective tissue caused a reduction of microcirculatory sequestration volume with parallel decrease of the number of pulp cord macrophages and approxi mation of capillaries and sinuses. Frequently, focal accumulation of platelets was found within the narrowed pulp cordbed in addition to increased phagocytosis of thrombocytes by residual macrophages. This lends support to the hypothesis of en hanced pooling of platelets in the spleen (Heusennann and Stutte 1977a), and may help to explain the pathogenesis of thrombocytopenia often seen even in the early stages of vinyl chloride disease. By structural analysis of histometricaJ results, Stutte and Heusennann (1978) outlined certain diagnostic criteria for the differentiation of VCM-induced splenic alterations from those seen in portal hypertension due to cirrhosis of the liver or extrahepatic portal vein occlusion. They concluded that fibrotic changes in the spleen in vinyl chloride disease are not the result of portal hypertension but in dicate a primary action of VCM or its metabolites on the spleen. A comprehensive re port correlating clinical and morphological data gathered from this group of 13 pa tients is being prepared for publication at present. Results of histometricaJ studies of the spleen in noncirrhotic portal hypertension of unknown aetiology are now avail able for comparison (Seki 1965: Yamamoto 1978, 1979). 4,2.5 Pathophysiology of Portal Hypertension The pathophysiology of portal hypertension in VCM-induced liver disease is as yet an unresolved problem. Patency of the portal vein was demonstrated in all cases subjected to splenoportography. Portography usually showed no or only minimal derangement of intrahepatic vascular pattern such as tapering or `cut-off of small peripheral portal venous radicles (Blendis et al. 1978; Villeneuvc et al. 1976). High intrasplenic pressure and a normal, or only slightly raised, wedged hepatic vein pressure indicate that the mk iw wmwxiiw w mub w w g w W gtw w 11ftn w tmvx'w m w 1vtw ta*vw w ,viv /iw a raaiv.u1 t.v 1 56 W.K. Lelbach and H.J. Marsteller portal flow is obstructed at the sinusoidal or presinusoidal level. In a group of five PVC workers selected for haemodynamic studies, Blcndis et al. (1978) could not demon strate a direct relationship between the degree of hepatic fibrosis in needle biopsy spec imens and portal hypertension. But it should be kept in mind that the distribution of fibrosis in these workers is quite irregular. It has also been suggested by Popper and Thomas (1975) and Thomas et al. (1975) that the increased splenic and hepatic blood flow, as a result of decreased splenic resistance in splenomegaly cannot properly be ac comodated in the hepatic portal vein bed owing to impairment of adaptive distension of portal veins and sinusoids by the subcapsular, portal and perisinusoidal fibrosis. Blcndis et al. (1978) found no correlation between spleen or estimated liver blood ab Fig. 6a, b. Progression of noncirrhotic portal hypertension despite termination of ex posure. Oesophageal varices. (Autoclave cleaner, age at diagnosis: 35 years. VCM-exposure, 1962-1972. 1972 Raynaud's phenomenon, sklerodermoid skin indurations, thrombocytopenia, splenomegaly, and grade 1 oesophageal varices. Gradual progression of portal hypertension. Sudden death from ruptured anaplastic angiosarcoma of the liver in June 1978. Histologically only mild perisinusoidal fibrosis in nontumorous areas) Vinyl flow a veiled 4.2.6 In 197 tic fib: could tests : biopsy of brid the fib cytes f ing ceil followmassi' exposu sarcon or less terrain oped V Liv deterir (BMHI after b and lo. aid of1 the ret. increas PVC^ t et 20 CO A 21 o ro iary io! iar cen san sarcom vase u la1 one at c hood (1 the nun . Lelbach and H.J. Marsteller ' level. In a group of five PVC (19?" muld not demonitbrosi- ni needle biopsy specnnd that the distribution of suggested by Popper and ed splenic and hepatic blood egaLy cannot properly be acment of adaptive distension <d perisinusoidal fibrosis, i or estimated liver blood i despite termination of ex5 years. VCM-exskin indurations, il ^3 jradual progression I. fto osarcoma of the I CO nontumorous 03 O N) Vinyl Chloride-Associated Disease 57 flow and the porta) pressure. However, they point out that this relationsliip may be veiled by the amount of blood bypassing the liver via a collateral circulation. 4.2.6 Follow-up of Non-malignant VCM-induced Liver Disease In 1974 Manin et al. (see also Berk et al. 1975) pointed out that VCM-associated hepa tic fibrosis, once established, may progress even after cessation of exposure. They could demonstrate this progression despite normalization of all routine liver function tests in a 27-vear-old worker on a follow-up examination including peritoneoscopy and biopsy 2 1/2 years after cessation of exposure. Progression of fibrosis and appearance of bridging between portal and central veins were indicative of persisting activity of the fibroblastic process, whereas the previously observed activation of both hepatocytes (marked variation of cell size and numerous binucleated cells) and sinusoidal lin ing cells had disappeared. Since 1973 we have observed a number of workers who on follow-up showed evidence of progressing portal hypertension with development of massive oesophageal varices and subsequent bleeding episodes despite removal from exposure (Fig. 6). In five (7?) of these patients 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 (or rare progression to cirrhosis) was the parental terrain in wlrich 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 197 Hg-bromomercury-hydroxy propane (BMHP) labelled artificially damaged red cells, and sequential perfusion scintigrams after bolus injection of "mTc-pertechnetate have been found useful in the diagnosis and follow-up of nonmalignant liver disease in PVC-polymerization workers. With the aid of these nonin vasive methods, inhomogeneous uptake of labelled sulphur colloid in the reticuloendothelial system of the liver and enhanced uptake in the spleen, gradual increase in spleen size and reduction of portal venous perfusion have been observed in PVC polymerization workers developing portal fibrosis and portal hypertension (Biersack et al, 1975a, b, 1977a, b). 4.3 Angiosarcoma of the Liver 43.1 Epidemiology Primary angiosarcoma of the liver (ASL) is described under a variety of synonyms (angioblastic sarcoma,angioblastic reticulosarcoma,endothelioma,endothelioblastoma, haemangioblastoma, haemangioendothelioma, haemangioendothelial sarcoma, Kupffer cell sarcoma, malignant haemangioma, metastasizing haemangioma, reticuloendothelial sarcoma, primary sarcoma of the liver). It is an exceedingly rare malignancy, arising from vascular lining cells. It occurs spontaneously with two peaks in the age distribution: one at early infancy (infantile haemangioendothelioma) and the other in late adult hood (fourth to sixth decade). The numerous synonyms render it difficult to estimate the number of reported cases and to determine its true incidence. In a recent review 58 W.K. Lelbach and H.J. Marsteller of the liierature./J/re/jj (1975) listed 165 published cases of primary angiosarcoma of the liver in adults. In the six autopsy series collected by Alrcnga, ASL constituted only 1.87c (0.9%-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 1 2. Incidence of angiosarcoma of the liver (ASL) in autopsy series Authors Year Observation No. of No. of cases period autopsies of ASL Region Simpson et al. 1955 1914-1953 24 196 1 Mayo Clinic, Rochester, Minn., USA Edmondson 1958 1918-1954 5 2 000 MacSween et al. 1973 1900-1969 _ a 1 3 Los Angeles, County Hosp.. USA Western Infirmary Glasgow. U.K. A Ircnga 1975 1951-1973 39 700 6 Cook County Hosp. Chicago, USA Rein and Hitth 1975 1954-1974 30 079 Byrcn and Holmberg 1975 1958-1969 _ b 4 (6) c Diisseldorf. Fed.Rep. Germany 12 Sweden (adult cases) Dalderup et al. 1976 1960-1975 At least 40 000 8 Netherlands (population: 10-14 million) a Among 120 cases of primary malignant liver tumours studied post mortem during this 70-year period, h Among 8 million inhabitants. c 4 Angiosarcomas, 1 haemangioendothelioma, 1 malignant haemangiopericytoma Accordingly, the identification of 4 cases of ASL among approximately 270 em ployees of the vinyl chloride polymerization section at a B.F. Goodrich plant near Louisville, Kentucky,between September 1967 and December 1973 was duly recog nized as an alarming situation indicative of a serious new occupational hazard (Creech et al."l 974a; 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- Vjnvl f on of UO organ 9? oxide (/) n and 03 Thai 4* itrast O N> evid 03 )ne i tli. bee. and Mot A specie caused t 'thorotr from a ! ASL (R< Devc man vim tensiveh 1950-1 tion rcvt of multi- approve- occurred but nota produce- Haustrui (3%-5: Roth (1* 18.6-8.- Fowler's Chm haemans tension 1 womai; \ ride) dur had a hn manifest The p be elicits, period U history c Among i observed other ha; 391 auto 1 J. M3rste11 er giosarcoma ;onst:"'ed 'rich o. .iemthe incidence ith a mean (1975) it was * kOnujn 33 Q U) oa 4o* ro -- 'i "J eeles, Hosp.. USA ; Infirmarv v. U.K. nuntv Hosp. . V SA irf. Fed.Rep. mds non. million) tem during ricytoma y 270 emant near July recogard (Creech with the lal prepara Vinyl Chloride-Associated Disease 59 tion of thorium dioxide (thorotrast) for diagnostic purposes, and chronic exposure to inorganic arsenicals. Both substances are stored mainly in the liver: injected thorium dioxide particles are rapidly taken up by phagocytic cells of the reticuloendothelial sys tem and are permanently retained: arsenicals are only slowly released from the liver. Thorotrast came into use in 1928 and was internationally employed as an injectable contrast medium until the mid-1950s, when its use was abandoned because of mount ing evidence of the carcinogenic action of thorium dioxide deposits. MacMahon et al. reported the first case of thorium dioxide-induced ASL in 1947. Since then ASL has been the type of liver tumour which occurred most frequently among patients who had been given thorotrast injections in the past (da Silva Horta \961\da Silva Horta and Motta 1967; Wegener et al. 1971; Futh and Pitzke 1974 \Selinger and Koff 1975). A special type of progressive portal and subcapsular hepatic fibrosis was another lesion caused by thorium dioxide retained in the liver, da Silva Horta (1967) considered this 'thorotrast fibrosis' to be clearly distinguishable from true cirrhosis. Gamma radiation from a lost radium needle has also been implicated as a causative agent in one case of ASL (floss 1932). Development of ASL as a late complication of chronic arsenic intoxication in Ger man vineyard workers was first described by Liebegott (1949,1952) and has been ex tensively documented by Roth (1956, 1957a, b, 1959). During the 10-year period, 1950-1959, autopsies of 82 Moselle vintners suffering from chronic arsenic intoxica tion revealed ASL in 8 cases among a total of 61 individuals (74%), with cancer often of multiple sites (Roth 1959). In 1925, arsenic insecticide sprays and dusts had been approved for use in German vineyards but they were banned by law in 1942. Exposure occurred not only via inhalation during spray periods (approximately 30 days/year) but notably by daily consumption of quantities of cheap grape wine (`Haustrunk'), produced from a second pressing of the grape skin residue by addition of water. This Haustrunk, an allowance in kind to the vineyard workers, had a low alcohol content (3%-5% v/v) but contained high levels of residual arsenic (0.2-8.9 mg AsjOj/litre). Roth (1956) calculated the mean total ingestion of As203 to have 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 (Regclson et al. \968\Landcr et al, 1975). Citowdury et al. (1977) reported an anecdotal case of apparently benign diffuse haemangioendotheliomatosis of the liver with considerable fibrosis and portal hyper tension but normal liver function. This condition was found in a middle-aged black woman who had been exposed to various chemical fumes (including carbon tetrachlo ride) during 20 years in a dry-cleaning establishment, though it must be noted that she had a high alcohol consumption. The possibility that these symptoms could have been manifestations in later life of congenital disease cannot be ruled out. The proportion of patients with ASL in whom a pertinent history' of exposure could be elicited has varied considerably. In an earlier survey of the literature covering the period 1875-1960, von Becker and Biissciter (1961) listed 12 of 54 adult cases with a histoo' of exposure to either thorium dioxide (7) or arsenicals (5 of Roth's cases). Among more than 15 000 autopsies performed in Bonn during 1950--1959, all 8 cases observed were found exclusively in vintners exposed to arsenicals (Roth 1959). On the other hand, Fiechtner and Ryes (1976) recently observed a cluster of 4 cases among 391 autopsies during a 29-month period at a hospital in rural central Wisconsin serving 60 W,K. Lelbach and H.J. Marsteller Table 1 3. Personal data of 68 polyvinyl chloride production workers with angiosarcoma of the liver reported to NIOSH up to August 1978 (Spirtas and Kaminski 1978,1 Birth date No. Country3 (m/d/y)b Date of death (m/d/'y) Age at death Total years exp. Job classification'' i B (1) 01.12.13 06.29.76 63 17 1. 2 CND (1) 12.15.13 3 CND (2) 03.06.14 4 CND (3) 08.26.19 5 CND (4) 04.05.19- 6 CND (5) 05.07.11 7 CND (6) 12.15.19 S CND (7) 1 1.09.19 9 CND (8) 05.13,20 10 CND (9) 07.19.21 1 I CND (1 0) 05.16.15 09.02.55 12.21.57 03.22.62 01.21.68 07.05.68 04.10.71 12.24.72 06.12.73 09.04.74 04.00.77 41 43 42 48 56 51 52 53 53 61 1 1 1. 2 14 2, 3. 12.13 20 2,5 22 1, 2,5. 14 5 1, 14 23 1,12, 13. 15 25 1,9. 17 5 1, 12, 17 26 3. 12. 16 14 2, 16 12 CSR (1) 00.00.28 13 CSR (2) 00.00.26 12.00.73 00.00.66 (64?) 45 40 (37?) 16 15 (14?) 1 1 14 D(l) 15 D (2) 16 D (4) 17 D(5) IS D (7) 19 D(S) 20 D(9) 21 D OO) 22 D (1 1) 23 D (1 2) 06.04.30 07.26.31 09.04.30 01.01.32 09.29.26 10.19.17 12.13.34 07.23.29 12.29.36 06.14.38 01.25.69' 12.14.71 1 1.25.74 01.09,75 1 1.13.75 12.25.75 03.24,78 06.28.77 03.07.77 10.07.77 38 39 44 43 49 58 42 47 41 39 12 11 n 17 2 12 2.4,5 12 11.(1) 21 2 15 10 22 10 16 10 61 24 F (1) 25 F (2) 26 Fl3) 27 F (4) 28 F (5) 29 F (6) 30 F (7) 31 F (S) 32 F (9) 33 F (10) 34 CB(1) 35 GB (3) 36 1 O) 37 1 (3) 04.15.24 06.03.11 01.06.20 01.27.27 01.29.38 04.14.34 00.00.27 04.01.34 10.08.14 05.24.19 04.20.01 06.02.37 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 1 1.13.29 03.14.20 12.27.72 07.10.75 43 55 , 19 1.2 12 2 29 2 26 2, 6 1 1 1.2 13 6.7 -> 19 28 2 21 2 22 8 41 (3 1/2?) 62 21 38 JO) 39 J (2) 08.01.22 08.02.29 10.24.75 08.10.76 52 37 22 13 40 NO) 12.23.15 01.04.72 56 21 Vin\ Tablt No. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 C *7 33 fio (/) fi 03 -fa. O to 00 a B, CNi CSh D. F. GB b 00. c 1,J 2 , D' 3-P 4, p 5, U 6, `f 71 * v1 S.p, 9, ci (Tables referen R&S Marsteller .'Hjsarcoma ' "S) -!Mcati,onc 12.13 ..'.14 -1 13, is . 17 n 16 s r 03 O to Vinyl Chloride-Associated Disease 61 Table 1 3 (continued) Birth date No. Country2 (m/d/yi0 41 S (1) 42 S (3 I 43 S(4) 06.23.27 06.10.10 1 1.16.14 44 USA (1) 10.17.23 45 USA (2) 08.19.33 46 USA (3) 05.25.15 47 USA (4) 01.15.24 48 USA (5) 01.25.12 49 USA (6) 1 1.23.28 50 USA (7) 05.03.22 51 USA (8) 05.06.20 5 2 USA (9) 1 1.08.31 53 USA (10) 08.16.13 54 USA (11) 05.27.09 55 USA (12) 1 1.17.18 56 USA (13) 12.01.21 0 / USA (16) 1 1.04.27 5 S USA (17) 05,06.31 59 USA (IS) 04.22.28 60 USA (1 9) 00.00.15 61 USA (20) 08.31.17 62 USA (21) 09.02.09 63 USA (22) 10.02.23 64 USA (23) 00.00.23 65 USA (24) 05.07.17 66 USA (25) 08.07.10 67 USA (26) ?(1978) 68 Y U (1) 04.05.14 Date of death (m/d/y) 10.20.70 03.19.76 05.12.77 Ape at death 43 65 62 Total years exp. 18 21 31 Job classification1-' 03.03.73 09.27.71 12.19.73 01.07.68 04.09.64 07.24.75 03.23.68 08.28,61 03.00.75 05.10.68 03.16.70 05.02.69 07.04.74 03.27.69 1 978 alive 1 1.02.75 04.06.76 01.30.77 01.02.77 12.04.76 04.06.73 05.27.77 03.10.77 ?(1978) 49 37 58 43 52 46 45 41 43 55 61 50 52 41 43 46 60 58 67 52 50 60 67 ? (1978) 21 13 28 15 20 12 17 15 24 17 23 19 28 4 19 11 22 21 21 28 14 26 20 ? (1978) 9 9 10 10 10 10 9(1) 08.04.73 59 20 1,2.5 3 B. Belgium CND, Canada CSR, Czechoslovakia D. West Germany F. France GB, Great Britain U 00. data not a\ai!able. c 1, au toclave cleaner 2. autoclave operator, 3, pipe fitter 4, polymerizer 5, foreman 6. `filtreur' 7. `preparateur de solution' 8, process worker 9. chemical operator I, Italy J. Japan N, Norwa> S. Sweden USA, United States of America YU, Yugoslavia. 1 0, polymerization worker 11, technical assistant 1 2, maintenance worker 13, millwright 14, water cooling unit 15, reager 16, furnace operator 1 7, machine shop worker (Tables 13-15 arc compiled with the aid of information contained in the literature; references sec Table 15) 62 W.K. Lelbach and H.J. Marsteiler 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. Tire other three may have had nondocumented exposure to arsenical pesticides, which were used for many years in this region, but such conjectural deliberations must await further investigation for confirmation. Death certificates for the periods 1963--1973 in England and Wales and 1965--1973 in Scotland recorded 41 cases of ASL (1-9 cases per year; mean: 4 cases per year). An unexplained peak was observed in 1968/1969 (Baxter and Fox 1975). Six additional cases not mentioned on the death certificates were detected by a panel of specialists (Baxter et al. 1977). In reassessing 36 of these 47 patients for whom histological sec tions were available, the panel of histopathologists unanimously agreed on the diagno sis in only 14 cases (7 doubtful, 3 unclassifiable, 12 non-ASL). For 12 of these 14 cases occupational and residential histories were obtained which revealed one un doubtedly VCM-induced case, two cases with possible exposure to (low levels of?) VCM and one case attributable to thorium dioxide. After the first three cases of ASL among vinyl chloride polymerization workers in the United States had come to the attention of the National Institute for Occupational Safety and Health (NIOSH) in January 1974 (Lloyd 1974), this institution continued to collect information on additional cases reported to them from nations with an im portant PVC industry (Lloyd \91S\Spirtas and Kaminski 1977), As of August 1978, data had been presented on a total of 68 cases of ASL among polymerization workers (Spirtas and Kaminski 1978, pers. comm.); another eight cases had been observed among nonpolymerization workers exposed to VCM in various jobs. On the basis of this data collection communicated to us in 1978 -- for which we wish to thank Drs. R. Kaminski and R. Spirtas, NIOSH, Cincinnati, USA - we attempted to trace these cases and their individual symptomatology as well as other relevant information pub lished in the literature up to 1979 (see Tables 13 -- 18). The ten Canadian cases of VCM-induced ASL (cases 2--11) are dealt with summarily in the papers published by Delorme (1978a) and Delorme and Makk (1975); seven of them were described in more detail by Makk et al. (1976). Cases 19 and 23 were observed at our clinic in Bonn but details have only been published for case 19 (E.U. in Lelbach and Marsteiler 1977). In reviewing the literature we could not trace cases 37-40,43, 50, 51,53-67 and C, F and H. According to the latest annual report of the Staatlichcr Gewerbearzt, Dusseldorf (Reinl et al.1978), the number of deaths from VCM-induced ASL in the Federal Republic of Germany had increased to 16 by the end of 1978, to which we now add a 1 7th case (Figs. 8 and 9). In retrospect, it was discovered that the first case of VCM-induced ASL had already occurred in 1955 in a Canadian polymerization worker. For the 67 VCM polymeriza tion workers for whom details were available, total years of exposure ranged from 4 to 31 years (mean and median 18 and 19 years, respectively). In comparison, mean dura tion of exposure in our group of 17 individuals with advanced nonmalignant liver dis ease (see Table 11) was 10 3/4 years (range: 3 1/2--21 years). The latency period (years from first exposure to diagnosis of ASL) ranged from 9 to 38 years (mean and median: 21 years). The average age at diagnosis of ASL was 50 years (range: 37-71 years). Vinv! ID So CD -0C0s o CO o o 'eft o > 3 c Q. 0 > o ~0 I c_ c . "E3 S_I Irj 3E a < v. ./.si/, SdiVL.'i' .J',- ... ;. * . >: . .. '.i,.', and H.J. Marsteller ^t> w 12 a3 i-eom ssu fQb. O ?car PJ vO CO 3 =3 5coo.' *c5u o30)' Vinyl Chloride-Associated Disease Table 14. Clinical and morphological data on 68 polyvinyl chloride fTVC) production workers willi angiosarcoma ot the liver reported to NlOStI by August 1978 Hepato No. megaly 1+ (2900 g) 2^ Spleen Atrophic, slightly indu rated Ocsoplingcal Hepatic varices fibrosis Thrombocy topenia i+> Noncirrholic 7 perisiiiusoidal & capsular Capsular ^ Acroosteolysis (f Raynaud's phenomenon Metastases 00 3 Capsular, portal, pcrisinusoidal 4 5 6 7 eases: \ (+) - + 7 f <1860- 5200 g) \ No details ' available 8 9 Sclerosis of wall of portal vein Capsular, portal, pcrisinusoidal > Capsular, portal, pcrisinusoidal V ' Capsular, portal, peristnusoidal Portal, pcrisinusoidal No details available 1 case: multiple metastases (lung, pleura, pericardium, ileum, colon, kidneys, left adrenal) V I case: mediastinal lymph n ode / case: peritoneal spread 3 crises: local spread 10 Capsular, portal, pcrisinusoidal I1 /) Capsular, portal, pcrisinusoidal ) ) Table [4 (continued) 1 lepato- No. meguly Spleen Oesophageal Hepatic varices fibrosis Thrornb ocytopenia 12 + Moderately (+> (7300 g) enlarged 13 + (2750 g) ') + (Cirrhosis), fibrosis (Cirrhosis) 't 14. + S pie no- . megaly 7 ? 15 + Slightly 7 7 7 enlarged 16 + Spleno (2650 g) megaly (830 g) + 17 + 18 7 Spleno megaly + Perisplenitis 7 19 c+) Spleno (1450 g) megaly (400 g) 20 ? 7 21 + Spleno (1900g) megaly <+) 7 + Capsular, portal, septal + + (72 000, 65 000) 7 7+ (134 000, 68 000) Progressive + perisinusoidal,(80 000, portal and 47 000, septa! cirrhosis 30 000) 77 +7 Aeroosteolysis 0 0 0 0 0 0 0 0 7 0 Raynaud's phenomenon Mctastases +9 0 Left lung 0 4th left rib 00 0 1st thoracic vertebra 0 Brain + 3rd luriibar vertebra 09 77 00 W.K, Lelbach and H.J. Marsteller Vinyl 22 Spleno megaly 7 Capsular, portal, + 0 0 0 perisinusoidal 2eom ssu 23 + Spleno 0 (2700 g) megaly (4 55 g) Focal perisrnusoidal 7 0 0p 1 J. Marsteller 20 7 7 21 + Spleno (1900 b) megaly 7 + >\ ` ,il K. U ' ' l> >-i > .'IM U'.J t 1o + ! ? 7 9 7 ceom ssu 00 V inyl Chloride-Associated Disease 022 Spleno 7 Capsular, + ft 0 megaly portal, perisinusoid al 23 Spleno- 0 (2700 g) megaly (4 55 g) I'ocat perisinusoidal ? 9 00 24 + 7 25 + Spleno { 161 0 g) megaly (450 g) 7 + ft ? Portal, + perisinusoidal (60 000, fibrosis 80 000) 0 / 7 0 Local spread to cava! vein 0 0 926 + 7 07 7 Duodenal wall 27 + Splen o- (2230 g> megaly (400 g) 7 Reticulated ? 990 capsular fibrosis, micronodular cirrhosis 28 + Spleno megaly (650 g) + 29 + `Modifications 0 (1750 g) fibro- congestivc' Portal, peri- + sinusoidal, (80 000) capsular fibrosis Slight portal 0 fibrosis 0 + f> 7 4th and 7111 thoracic vertebra. 5th left rib. left adrenal 0 30 + ft 9 9Minimal ff Small intestine fibrosis 31 + Splenomegaly 7 7 7 9 P Paraaortal lymph nodes (3000 g) (270 g) 32 + 7 7 0+ f 90 (80 000, 40 000) 33 + 7 o Capsular, 0 0 0 0 porlal fibiosis Table 14 (conlinued) Hepato megaly Spleen Oesophageal Hepatic varices fibrosis Thrombo cytopenia + Slight 0 0 + (2625 g) splenomegaly {80 000) + (3240 g) Congested, + firm (200 g) Noncirrhotic 7 fibrosis +9 +9 9 37 38 39 40 41 + 42 7 43 44 + Splenomegaly ? ?7 Splenomegaly + 45 + Splenomegaly + 46 + Spleno- (1860 g) megaly 1 79 7? Su bcapsular and porta! fibrosis + Markedly + thickened capsule; marked fibrosis Portal fibrosis 7 Acroosteolysis 0 0 0 ? 9 0 0 0 Raynaud's phenomenon Melastascs 00 CT> cr> 00 0 Local spread to abdominal wall and colon; lymph nodes ?? ?9 00 00 '0 Spread to duodenum W.K, Lelbach and'H.J. M 3rsteller 47 + 48 f Splenomegaly 7 7 7 Portal fibrosis + (35 000) ft Spread to diaphragm and abdominal wall Sli.-' ! fll. ll 7 A 0 t HIH'r I-, ,i,l .......... tl V in \ 9eot?e u s'Sd 45 + Splenome gal y 46 + Spleno- (1860 g) mcgaly 47 Spleno megaly 48 (5 200 g) 49 ? Normal 50 51 Details not published 52 + (2810b) 53 54 55 56 57 58 59 60 Details not published 61 62 63 64 65 66 67 68 H.J. M arsteller V in y l C hloride-Associated Disease Mjrkeilk t- lliic1' -yicd eai( ); marked fibrosis I'ortal fibrosis P P Spread to duodenum I'orlai fibrosis + (35 000) P Spread to diaphragm and abdominal wall Slight focal hepatitis (`minimal hepatitis') P i Lungs, large and small bowel, pleura, perieatdium myocardium, kidneys, left adrenal Capsular and portal fibrosis ? Diaphragm, regional, retro peritoneal and mediastinal lymph nodes, lungs, adrenal glands, cerebellum Peculiar 7 portal fibrosis, moderate cirrhosis Diaphragm, gall bladder, regional lymph nodes, lungs, scalp, skull + (51 000) jf $ 94 68 W.K. Lelbach and H.J. Marstellcr Table IS, Publications on the 68 cases of angiosarcoma of the liver listed in Tables 18 and 1 4 No References Additional relevant information i Hublet et al. (1977) Hypertrophic, hyperchromatic and at> pica! endothe lial cells in the glomeruli; foci of haematopoctic cells in liver and spleen 3 4l 5 6l 7r 8 9 10 11 ) Delorme and Makk (1975) Makk et al. (1976) Delorme (1978a,b) Delorme and Theriault (1 978) 12 1 Schmidt and Batora ' (1976) 13 14 ' Lange et al. (1 974b) 15 ] Cedigk et al. (1975) 16 Coke! et al. (1976) 17 A rnann (1975) Riibsamen (1 976) 18 Reml et al. (1 976) 19 (Observed in Bonn) 20 Rein! et al. (1 976) 21 Reinl et al. (1977) 22 Reinl et al..(1 977) 23 (Observed in Bonn) 24 Ravier et al. (1 975) 25 Roche et al. (1978) 26 Rety et al. (1976) Case no. 7: ASL associated with hepatocellular carcinoma (Delorme 1978b) (All cases from one plant in Shawinigan, district Trois Rivieres, Quebec) At the same plant: 4 cases of VCM-induced cirrhosis of the liver plus 1 case of cirrhosis and generalized reticulosarcoma and 4 cases of carcinoma of the Cl tract or lungs See also Rein! and Weber (1974) See also Reinl and Weber (1 974) Foci of haematopoesis within the tumour areas 1974 portocaval anastomosis;cholecystectomy. Hypertrophic, hyperchromatic and markedly atypical endothelial cells in the glomeruli andvin the capillaries of the lungs Moderate hepatic siderosis; chronic fibrosing pancrea titis; tubular and interstitial fibrosis of the testes Focal interstitial fibrosis of the pancreas See also Berrod et al. (1 978) 1942 gastrectomy. 1974 splenectomy, fight hepatic lobectomy (640 g). See also Roche (1 977); Puech et al. (1 911).Bonneton et al. (1 975, 1 977); Berrod et al, (1 978) No autopsy (see also Berrod et al. 1978) teller 3J 0) 03 -Pv O 03 -si rhosis zed :e Gl 'illjritns-' mcrea- ~S patic ch et d et Vinyl Chloride-Associated Disease 69 Table 1S (continued) No. References Additional relevant information 27 Roche et al. (1 978) Chronic alcoholic. See also Roche (1 977): Puech et al. (1977):Berrod et al. (1978) 28 Roche et al. (1 978) First symptom: vertebral and costal metastases. Right hepatic lobectomy. See also Roche (1 977); Puech et al. (1 977); Pilichowski et al. (1 979); Couderc et al. (1976); Berrod et al. (1 978) 29 Roche et al. (1 978) 1 960sclerodermaWkt skin induration (hands), swell ing of face, upper extremities and feet. 1971 bilateral acroosteolysis. Tumour penetration of the abdominal wall (fistula). Severe interstitial fibrosis of testes; fibrosis of interstitial wall; slight mesangial fibrosis of glomeruli. Variable but generally slight fibrohyalinosis of arterial and venous vessel walls (skin, heart, lungs, intestine, testes) 30 \ 31 ( 32 ' 33 / Berrod et al. (1978) 34 Lee and Harry (1 974) 35 Smith et al. ( 1976b) Latency period (1st exposure -* death) only 8 years (see also Fox and Collier 1977) 36 Maltoni (1974) 37 - 38 39 40 - 41 Byrcn and Holm berg (11975) 42 Byren et al. (1 976) 43 - 44 Bloch (1974) (case 3) 1 965 portocava! shunt. 1 970 cholecystectomy. See also Falk-et al. (.1 974a) (case 4); Whelan et al. (1 976) (case 1) 45 Block (1974) (case 2) No autopsy. See also Creech and'Johnson (1974); Falk et al. (1 974a) (case 3); Whelan et al. (1 976) (case 2); Makk e t al. (1 976) (case 6) 46 Block (1974) (case 4) See also Falk et al. (1974a) (case 5); Makk et al. (1976) (case 10) R&S 134038 70 Table 1 5 (continued) No. References 47 Block (1974) (case 1) 48 Block (1 974) (case 5) 49 Stock (1974) (case 6) 50 51 52 Whelan et al. ( 1976) (case 3) 53-67 - 68 Zorica et al. (1 975) W.K. Lelbaeh and HJ. Marsteller Additional relevant information See also Falk et al. (1 974a) (case 2);Makk et al. (1976) (case 4) See also Falk et al. (1 974a) (case 1 ):Makk et al. (1976) (case 2) See also Falk et al. (1974a) (case 6): Whelan et al. (1976) (case 4);Makk et ai.(1976) (case 14; Chronic alcoholic. See also Makk et al. (1976) (case 13); Berk et al. (1976) (case 2) Among a work force of 180(1 20, PVC polymeriza tion; 60, production of VCM) employed at this plant, 15 died of malignant disease (2 ASL. 5 bronchogenic carcinomas, 1 case each of carcinoma of the larynx, rib, mamma, spermatic cord; glioma, melanosarcoma, leukaemia, Hodgkin's disease) First exposure to VCM for these 67 cases of ASL dated back to the period 19391966 (median: 1951). Twenty-one years later, i.e. from 1972 onwards, a gradual in crease in the number of new cases diagnosed and reported to N10SH can be observed (Fig. 7). The onset of this gradual increase coincides with the calculated mean latency period of 21 years (Spirtas and Kaminski 1977). Spirtas and Kaminski also suggested that in future cases the age at diagnosis and the length of the latency period may in crease as a result of the later reduction in levels of exposure. From the synopsis in Table 13 -- 18 it can be seen that in about two-thirds of the cases of ASL for which morphological details are available varying degrees of associat ed hepatic fibrosis in nontumorous areas of the liver were mentioned. Less often, evi dence of portal hypertension and splenomegaly were noted. Metastasis of angiosarco ma to distant sites was observed in approximately half the published cases. It is of note that acroosteolysis and cutaneous stigmata of scleroderma have been observed in only 1 of these 76 patients, a French PVC worker who had apparently not been engaged in reactor cleaning (case 29.Roche et al. 1978). Another noteworthy piece of informa tion is that strikingly atypical endothelial cells with hypertropliic 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,Hublei et al. \911\Riibsamen 1976). Hublet et al. (1977) also found such cells in the myocardium and in the adipose tissue enveloping the adrenals. All this may lend support to the idea that the effect of VCM metabolites is not restricted to the vascular endothelium of the liver and spleen. Angio- Uarsteller -i! al et al. ,-w < 33 <*> me hi> w cii -t* o CO -a (D ! 1939-- lual in r' i later.., '.crested na> in- hi the aisociati.ii. eviiosarco> of note I in only icaged l" informahromatic autopsy . 76). >Si tissue ofVCM n. Angio- Vjnyl Chloride-Associated Disease 71 Table 16. Personal data on eight cases of angiosarcoma of the liver among VCM-exposed personnel not employed in PVC pioduction (as reported to NIOSH bv August 1 978>a Birth dajte No, Country (m/d/y)b Date of death (m/d/y) Age at death Total years exp. Job classification A D (3) 07.16.30 10.10.73 43 14 Loading pesticide cans with VCM propellant B D (6) 05.09.36 12.16.74 38 3.5 Assistant factory chemist ,C GB (2) 09.08.14 12.00.70 55 11 Pouring PVC oil mix ture onto fabric bases D 1(1) 06.15.34 04.16.71 36 3 Fabrication of PVC sacks and wrappings (extrusion at tempera tures of 1 20C) E SC) 1 1.27.1 1 08.16.71 61 23 Assistant factory chem ist (production ofVCM) F USA (15) 00.00.25 02.15,73 47 n Accountant at plant producing PVC fabric G VUC) 1 1.15.31 07.12.73 42 IS Production of VCM H YU (3) 12.21.31 01.1 1.76 45 2? Production of VCM 3 Update of NIOSH register, August 1 978. prepared by Kaminski as in Table 13. b 00, data not available sarcoma arising from the kidneys or other types of malignant renal neoplasms, how ever. have not been described in VCM-exposcd individuals, although malignant nephro blastoma has been induced in experimental animals. The extremely rare coincidence of angiosarcoma and hepatocellular carcinoma was found in three instances (case 7, Dclonne 1978b; case E,Byren and Holmbcrg 1975, and a case not included in the 1978 NIOSH update Tamburro et al. 1978a). In the case reported by Tamburro et al. chronic alcoholism may have played a cofactor role in the development of liver cancer. We can now add a fourth case observed in 1978 at the Department of Medicine in Bonn (see Sect. 4.1.5 and Fig. 3). This patient (patient 9 in Table 11), a PVC-polymerization worker (total period of exposure: 18 years) was first admitted to our department in February 1975 and was found to suffer from atyp ical cirrhosis of the liver with portal hypertension, splenomegaly and Raynaud's phe nomenon. During follow-up ASL was clinically suspected but could not be confirmed during life, despite exploratory laparotomy and generous surgical biopsies. The patient *--*.. 7-YJ^-> -is / Table 17, Clinical and morphological data on eight cases of angiosarcoma of the liver among VCM-exposed personnel not employed in I'VC polymerisation * Hepato No. megaly A+ (fiooo e) B+ (3650 g) C Spleen Oesophageal Hepatic vnrives fibrosis Thrombo cytopenia S pie nomegaly + I'ortal fibrosis + Spleno- + megaly (A25 g) Focal capsular ,0 fibrosis, portal and centrolobular fibrosis Aeroosteolysis 0 0 Itaynamfs phenomenon Melaslascs 0 Diaphragm, gastric mucosa, abdominal lymph nodes 0 Diaphragm, pleura, abdominal lymph nodes D (+) I- + Not enlarged jf> ?? ? 7 7 0 0 Lungs, pericardium +00 ? f 104 000) F G+ II Splenomegaly 7 7 0i ff Dura, cranium W.K. Lelbach and H.J. M arstellcr 01?0m ssu < n 5 _ 3f. "a? 3 <2 S- -,,o =n m R&S 134041 Marsleller Vinyl Chloride-Associated Disease 73 Table 18, Publications on the eight cases of angiosarcoma of the liver listed in Tables I 6 and 1 7 No, References Additional relevant information A Ran! and h'eber (1974) 1967 idiopathic portal hypertension; portocaval shunt B Zimmcrmann and Fck 1973 right hcminephrectomy for unilateral hvdro- (1975) nephrosis associated with bilateral double kidnev. Rein! (1 975) Foci of hacmatopoctic cells in spleen and kidney. Fibrosis of the pancreas. Slight fibrosis of testes and of the small intestinal serosa c\a D Maltoni (1 974) Autopsy: angiomatous epulis. Angiosarcoma involv ing liver, lungs and pericardium. The pericardium might have been the primary site! E Bvren and Holmbcrg Probable coexistence of a hepatocellular cancer of 1 i 975J both low and high grade differentiation P G Zorica et al. (1 975) H died on 7 August 197S, after a massive haemorrhage from oesophageal varices. Autop sy revealed both multicentric metastasizing angiosarcoma and hepatocellular carcino ma of the liver as well as slight fibrosis of the pancreas (to be published in detail). It is still unexplained why hepatocytes are generally exempted from the carcino genic effect of VCM metabolites but, as predicted by Popper in 1975, three anecdotal cases of hepatocellular carcinoma, one German (Gokel et al. 1976) and two British PVC workers (Fox and Collier 1977). have now also been observed after exposure to VCM. It may be mentioned tli3t a review of the distribution of primary liver cancer in the Province of Quebec covering the period 1969-1972 showed a preponderance of adult male cases in urban areas clustered in the district of Trois-Rjviere in congru ence with the distribution of the plastics industry, a coincidence which calls for further investigation of a possible exposure to industrial carcinogens (Jacob and Theriault 1975). . Not included in the NIOSH register are several anecdotal cases of ASL, capillary and cavernous angiosarcoma of the liver and haemangiosarcomatosis of sites other than the liver, for which a relation to occupational or even possibly residential exposure to VCM has been discussed (Nona et al. 1911 \Brady et al. \911\Dor et al. 1975; Wallnofer and Zinnagl 1977). Although of undetermined relcvance.it should finally be mentioned that, in addi tion to hepatic fibrosis, varying degrees of interstitial fibrosis of the pancreas were noted at autopsy in four German workers fcases 19. 23, B and the above-mentioned 74 W.K. Lelbach and H.J. Marsteller patient witii 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/ hvalinosis in vessels of skin, heart, lungs and intestinal wall. CUMULATIVE N* OF CASES REPORTED TO NIOSH 7068 66 64 :1'1 62 cn _ 58 56 *11 t:!1 1:!! 54 52 ou 48 46 44 .= ; >1!1 ; , `f 1 1 ,1 42 I' 11 , 11 ! 11'; i'ii i'111 1::1 :; j|,j i1; ' til! " ' ' i!41 ifT rSL > 11I11i '1 ' | 't 1 ___!1 1 1 1 11;.! *;i 1 1 1 1 ' ; 11 : M : !' 1 , S- - i 5 iii' 2 1 1 * 1 ; ' 4"C^ t 1!ii 'i: ! 1 -(3S 5 .2 1 1.: 38 36 | 1 34 32 ou * 28 ' "i- l ' .1 .i , 1, 11. 9; a1 si t. TM 1 t , mvm^m, 1 ' 24 on . 16 - 12 in. 6 6 1 : 1, 1 ,E 1 --1-------- .125' 31 ! ---->--------'-----------E-----------' ----1 1 ; 1 1 , t; '***1l11 ' ' 1 1I 1 -i. ' ,, ,1 iS ; . 2 -1 1 ar ; '1': ' ~ 1955 1960 1965 1970 year of diagnosis 1975 1978 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 (data from Spinas and Kaminski 1977, 1978) ** w rt O -. ro 4.3.2 Clinical Manifestations The clinical symptomatology of usually multicentric ASL is unspecific. Gradually de clining general health and loss of weight combined with ill-defined upper abdominal discomfort and slight epigastric or right upper quadrant pain are usually the first symptoms. Recurrent bleedings from oesophageal varices may have been antecedent events in patients with portal hypertension who otherwise felt fairly well. In a number ' larsteller ' testes fibro-' ' JJ S C/> w oc* w Vinyl Chloride-Associated Disease 75 of cases, the tumour first came to attention with massive, often fatal, intraperitonea] haemorrhage. Important tender hepatomegaly (hepatosplenomegaly), slight jaundice and occasionally development of moderate ascites and oedema were observed. Except for mild to moderate hyperbilirubinaemia, some elevation of serum levels of alkaline phosphatase and gammaglutamyl transpeptidase and only slightly abnormal levels of serum transaminases, the spectrum of biochentical tests is hardly revealing. Alpha-feto protein determination has not been helpful in the diagnosis. Ultrasonography, scinti graphy,hepatic angiography and, notably, computer tomography of the upper abdomen are the diagnostic procedures of choice if ASL is suspected. A technetium-99TM -liver scan visualizes intrahepatic tumour defects (Biersack et al. 1977b) together with abnormal splenic fixation, but peripheral defects of uptake may be difficult to interpret (Whelan et al, 1976). Characteristic features of angiography are a normal-sized hepatic artery with possible displacement caused by tumour enlarge ment, a certain degree of central hypervascularity of the tumour, a peripheral tumour stain, and puddling of contrast medium persisting into the late venous phase. In addi tion. varying degrees of peliosis hepatis may be observed in some cases. However, even repeated hepatic angiography may fail to confirm the suspected diagnosis, as was evi dent in one case reported by Roche et al. (1978). The example of a 54-year-old polymerization worker who died of metastasizing angiosarcoma of the liver in February 1980 may serve to illustrate the clinical course. In 1972/73. after an exposure of 18 years' duration, we found him to suffer from Ray naud's phenomenon and noncirrhotic portal fibrosis and portal hypertension with sple nomegaly and moderate thrombocytopenia. Despite termination of exposure, there was progressive splenomegaly and development of massive oesophageal and gastric . ported rom ially deitninal irsl cedent i number Fig. 8. Computer tomography showing a large, irregular, hypodense angiosarcoma of the liver involving both lobes. Courtesy of Professor Thurn, Department of Radiology, University of Bonn 76 W.K. Lelbach and H.J. Marsieller varices during the following years with repeated episodes of bleeding which required (successful) sclerosing therapy (major surgery was declined by the patient). In August 1979 he presented again with recurrent epistaxis and slight but permanent epigastric and upper right quadrant pain, but declared that he felt otherwise fairly well. He com plained about a sharp localized epigastric pain on sneezing. There was marked spleno megaly, and an ill-defined hard mass was palpable in the epigastrium. Apart from mod erate elevation of alkaline phosphatase and borderline hyperbilirubinaemia, biochem istry was normal. Computer tomography showed a large irregular hypodense tumour mass in the liver, involving both right and left lobes (Fig. 8), which became practically isodense after intravenous injection of contrast medium. A liver scan corroborated the tumour defect. Shortly after this there was mounting evidence of brain involvement and rapid deterioration. Computer tomography now revealed multiple brain mctasiases (Fig. 9). Autopsy confirmed the tentative diagnosis of metastasizing angiosarcoma of the liver (Fig. 10). mu *& Fig. 9. Computer tomography showing multiple brain metastases of angiosarcoma of the liver. See text. Courtesy of Professor Thum. Department of Radiology, University of Bonn 433 Peritoneoscopy Little information is available in the literature concerning the peritoneoscopic aspect of VCM-induced ASL (Roche et al. 1978). It may be impossible to make a diagnosis of the initial phase of ASL in VCM-exposed workers by peritoneoscopy and needle biop sy of the liver, as documented in one of our patients who died of multicentric ASL 78 W.K. Lei bach and H.J. Marsteller 11 months after peritoneoscopic diagnosis of severe hepatic fibrosis (case 19; see also Lclbach and Marsteller 1977). In addition to the findings described in connection with hepatic fibrosis, there may be hypervascularized or cystic tumour formation visible on the surface of a nodular, quasi-cirrhotic liver, or a gross aspect resembling hepatic nictastases if the vascular malignancy involves the superficial regions of the liver. It should be stressed here that needle biopsy is absolutely contraindicated if there is any suspi cion of ASL. 4.3.4 Gross and Histological Morphology The liver is usually markedly enlarged. Liver weight in cases of ASL ranged from 1600 to 7300 g (Thomas and Popper \91S\Roche et al. 1978). The gross appearance of angio sarcoma of the liver is mostly that of large bulky, irregularly shaped cystic tumour masses; a multinodular form with numerous, sometimes umbilicated nodules, is less often encountered. Extensive haemorrhagic and necrotic areas or solid and spongy por tions of tumour tissue replace much of the liver parenchyma. Rupture of large cavern ous cysts may cause fata] intraperitonea] haemorrhage. Thomas et al. (1975) and Thomas and Popper (1975) distinguished four basic devel opmental patterns of histomorphologv of ASL, which can be found in different por tions even of the same tumour and appear to represent stages of progressive evolution: sinusoidal, papillary, cavernous and anaplastic patterns. Indistinct areas of transition and merging of patterns can be observed. Dilated sinusoidal spaces lined by hypertrophic and hyperplastic sarcoma cells with pleomorphic, elongated, hypejchromatic and often bizarre nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells of varying differen tiation envelop liver cell plates and may invade enlarged and fibrosed portal tracts, ac companied by proliferation of bile ductules (Fig. 11). In papillary angiosarcoma atro phy of liver cells results in larger and more irregular blood-filled vascular spaces, into which loose papillary strands of surviving hepatic cords on an axis of connective tissue project, lined by sarcomatous cells (Weinbren 1976). Even larger blood-filled spaces are seen in the cavernous type, where they may be surrounded by thick fibrotic walls. In a smaller percentage of cases, solid areas or nodules of anaplastic sarcoma are found, resembling solid spindle-cell sarcoma, or even suggesting an epithelial type of tumour. Gedigk et al. (1975) also observed a reticulosarcomalike pattern. The differentiation of the tumour cells varies widely.it ranges from the inconspicuous endothelial lining cell type to irregularly shaped, grossly distorted giant-cell forms. Morphologically, vinyl chloride-related ASL cannot be distinguished from ASL associated with other aetiological factors or from the cryptogenic type {Popper et al. 1978). In tumour-free portions of livers with angiosarcoma widely varying degrees of ex cess formation of fibrous connective tissue are usually observed, analogous to that seen in nontumorous livers of heavily exposed persons. Fibrosis of enlarged portal tracts with modest proliferation of bile ductules, mostly only scanty infiltration of lympho cytes and occasional formation of perilobular septa or thin connective-tissue septa ex tending into the lobular parenchyma can be found. A more or less conspicuous intra lobular, perisinusoidal fibrosis is often detected only by special staining methods for collagen or reticulin fibres. As a rule, irregular focal or nodular fibrotic thickening of I-' JO K C/5 03 O -P* 03 1 '/ Fi. Innu in- ol 1} Th O! lit! oir ph me ret cyt deg reti ere yrrv rjs w rxrrrrvr\ c a/1 ; H J. Marstelier 19: see also nnect'"n with nonle on : hepatic meliver. It should is any suspi red from 1600 to mnee of angiotic tumour lules, is less md spongy por>f large cavern. our b liffert =sive e 73 1- CD of tra; coma c .'terize 03 -P* O -P* -4 ying di Mai tra i.arco"-' atro- i spac^ int" tu.ective tissue filled spaces librotic walls. nna are found, pe of tumour. I ferentiation of dial lining cell .'ioally, vinyl other aetiol- legrees of exsus to that seen tortal tracts on of Iymphoissue septa exoicuous intra methods for ihickening of Vinyl Chloride-Associated Disease 79 Fig. 11. Angiosarcoma of the live: (upper parr of photomicrograph) invading adjacent liver parenchyma (case 14 = DI; see Table 13). Note hyperplastic and hyperchromatic nuclei of proliferating neoplastic lining cells enveloping hepatic cords. Reproduced by permission, Ann NY Acad Sci 246:278-285 (1 975). Courtesy of Professor Gedigk, institute of Pathology, University of Bonn. H it E, x 250 of Glisson's capsule is present: these fibrotic capsular areas may extend into the under lying parenchyma and may connect with adjacent enlarged subcapsular portal tracts. The cellular and nuclear size of hepatoevtes may vary widely; groups of binucleated or even multinuclear parenchymal cells with abundant cytoplasm are seen. Focal pro liferation of sinusoidal lining cells may be encountered, especially within foci of sinus oidal dilatation. In connection with conspicuous sinusoidal dilatation, two types of focal hyper plastic precursor lesions were described by Popper et al. (1978): 1) Poorly circumscribed foci of hyperplastic, often binucleated hepatocytes with increased number of various sinusoidal lining cells and only insignificant increase of reticulum framework. 2) .Almost nodular areas of conspicuously hyperplastic and hypertrophic hepato cytes with more pronounced variation of markedly increased sinusoidal cells without degeneration or necrosis of liver parenchyma, but accompanied by excess formation of reticulum framework and compression of surrounding parenchyma. The transition of sinusoidal lining cells to angiosarcoma cells is characterized by in creasing atypia and anaplasia of these proliferating endothelial cells accompanied either ce v t1 *y v ***{>wfft**.*f n; hcth w ' v*wav voowie.y ite.tyui.,1'w w *>i itiw w w w m SO W.K. Lelbacli and H,J. Marsteller by formation of excess connective tissue or by accentuation of sinusoidal dilatation leading to primary peliosis. Involvement of portal areas in the evolution of angiosarco ma results in considerable fibroplasia and formation of hyalinized collagen together with proliferation of bile ductules. In occasional cases connective tissue bridging be tween portal tracts or between portal tracts and central veins with subdivision of lobu les followed by rearrangement of hcpatocytic plates may lead to a cirrhosislike picture. 4.3.5 Therapy The multicentric development of ASL (Thomas and Popper 1975) as well as the dif fuse spread of the tumour usually encountered by the time of diagnosis precludes ef fective surgical or radiation therapy in the majority of cases. A survival period of two years after surgery (Berrod et al. 1978) or chemotherapy (Dannahcr 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 present, no generally accepted guidelines for chemotherapy are available. 43.6 Risk Assessment When in the United States 13 white male cases of ASL had been detected from 1961 to May 1974, among an estimated total population ofVCM 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), wluch expected for the total United States population ait annual incidence of this tu mour in the order of 0.014/100 000. This would have meant only about 0.03 cases per 20 000 polymerization workers within a 10-year period. Dose-response and attendant biotransfonnation data on experimental animals have since been used to elaborate sev eral different models of extrapolation to man. These were calculated witli reference to relative body surface areas, for estimating the risk of ASL in human populations ex posed to VCM and for establishing guidelines to assist the research for 'realistic safe doses' that do not affect the average lifespan of a person exposed (Schnciderman et al. 1975 -.Gehring et al. 1979, 1978: Woods 1979). Gchring et al. (1979) consider a probit percent model to be a reliable tool for risk prediction, which works without the assump tion of a threshold. They predicted a cancer risk of 1.5 cases of ASL in 100 000 000 workers on exposure to the current National Standard in the United States of 1 ppm VCM 8 h/day, 5 days/week, for a 35-year working life, an incidence which does not significantly deviate from the spontaneous incidence rate. A linear model modified by adjustments for differences in the rate of inhalation, distribution, metabolism, cell proliferation and tumour latency times between rats and humans was described by Woods (1979).This mjpdel 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 (Mattgh 1978-.Hooper et al. \919\Schneidcnnan 1979; Weigcri \919\Rcin et al. 1979). Vini R (exc! ASL Tills the l conf) had . the rpoly: was t viron ceedi lesser magi. ting. milh< vinyl modi the e grou: 4.3.7 Foi a haza. the v tudi 33 ure t he h (/) 1. 1<- iV.vi- ca 4* if Br o 976 00 'Osci t al. oicc Bern empf and c but r, 1976 Ir (197- epidc (197t facto ^teller .on -arcc' : her be- lobu-. icture. difes eff two i is a vc par> lies for 1961 xers of nion of data 11. 1U>ises j mlant i;e sev:nce to - exsafe et al. probit 'sump>000 ppm not led by el! by corkers ity of expo et al. Vinyl Chloride-Associated Disease SI Results of a recent survey by Brady ct al. (1977) indicated that for New York State (excluding New York City), a highly industrialized area, the annual incidence rate of A5L during the 6-vear period from 1970 through 1975 was 0.25 per million residents. Tills considerably exceeded the national average rate of 0.14 per million per year in the United States. In a concomitant case-control study. 26 patients with histologically confirmed ASL were found in the study area front 1958 to 1975. and 7 of these had had documented long-temt exposure to either As, ThO; or VCM. Five (all female) of the remaining 19 patients lived at a distance of 500--4500 feet from VC fabrication or polymerization facilities for long periods. No pertinent exposure or residential history was obtained from the other 14 patients. Discharge of unreacted monomer into the en vironment as result of losses in the PVC production process was estimated to have ex ceeded 200 million pounds annually, most of which escaped into the atmosphere with lesser amounts dissolved in water effluent (Schweitzer 1975). Concerning the order of magnitude of ambient exposure beyond the work place, i.e. outside the industrial set ting. an average annual exposure concentration of 17 ppb was estimated for the 4.6 million persons throughout the United States who resided within a 5-mile radius of vinyl chloride emission sources (Kuzmack and McGaughv 1975). If the risk assessment model elaborated by Woods (1979) is applied to this population of 4.6 million people, the estimated incidence of angiosarcoma per year would not be above expected back ground levels. 43.7 Mortality and Cancer Morbidity Studies For a tumour disease as rare as angiosarcoma of the liver even quite small increases in hazard over background levels should be detectable (Doll 1975). The situation with the common types of cancer is far more difficult. Since 1974 a number of mortality studies of VCM-exposed populations have suggested that in humans long-term expo sure to VCM may also be associated with cancer of sites other than the liver, notably the lungs, and the lymphatic and central nervous system (Monson et al. 1974; On et al. 1975; Tabcrshaw and Gaffey 1974;Nicholson et al. 1975; Wagoner et al. 1976; Waxwciler et al. \916\Nicholson \911\Buffler et al. 1979). Epidemiological studies of British workers failed to confirm this suggestion (Duck et al. \91S\Duck and Carter 1976\Fox and Collier 1976, 1977), as did a prospective study of a VCM/PVC-exposed cohort of 1618 employees of a West German chemical plarrt (Frentzcl-Beyme et al. 1978). Criticism of design and interpretation of some of the studies has been voiced (Falk et al. 1974b;Purchase and Williamson \914\Reger \911\Daldentp 1975; Berry and Rossitcr 1976). A follow-up of all VCM-exposed persons (750 traced) ever employed at the one Swedish factory, which started operation in 1945, for mortality and cancer morbidity patterns revealed a fourfould excess of pancreas/liver tumours but no deviation in the number of brain tumours from the expected level (Byren et al. 1976). In addition to the three extensive mortality studies of Tabcrshaw and Gaffey (1974). Waxwciler el al. (1976), and Fox and Collier (1977), a fourth comprehensive epidemiological study (Rein! and Weber 1976) was completed in 1977 by Rein! et al. (1978). wliich included three study populations from 11 VCM- and PVC-producing factories in the Federal Republic of Germany, covering the period from before 1959 S2 W.K. Lelbach and H.J. Marsteller ' through 1974: (a) 7021 workers engaged in the production of VCM and PVC;(b) 4910 chemical workers from the same plants not exposed to VCM: and (c) 4007 workers engaged in PVC manufacture. Not included were non-German workers of Mediterranean origin. This German study permits comparison not only with the mor tality ratio of the total maJe population but also with a comparable occupational group exposed to VCM. With regard to the `healthy worker effect' (McMichacl et al. 1975), overall mortality was elevated for the VCM-exposed population (group a), but not for the other chemical workers (group b). Apart from the markedly elevated stan dardized mortality ratio (SMR) for malignant liver tumours (1523), which proved to have been closely related to the duration of exposure, a significantly elevated SMR was found for tumours of the lymphatic and haematopoetic system (214). The group of chemical workers not exposed to VCM (b) also showed a significant elevation of the SMR for liver tumours (401), a result that deserves further investigation. No signifi cantly increased risk was found concerning tumours of the central nervous system or the respiratory tract. It has already been mentioned (Sect. 2.2.10) that an excess mortality from brain tumours (SMR 535) was recorded among PVC workers engaged in manufacture at one of two plants: in the second plant an elevated SMR (434) for liver tumours was found. At present, there is no explanation for the increased SMR for accidents found in the VCM-exposed population, particularly during the period 1970 through 1974, about 40% of deaths having occurred in ex-PVC workers. A recalculation of the available data would have been necessary' for the evaluation of a conceivable influence of VCM on vigilance. As an addendum it may be noted that determination of plasma carcinoembryonic antigen, titre (CEA) in 200 Canadian PVC production workers (mean duration of em ployment: 10 years) showed a more than threefold higher frequency of levels above 10 ng/ntl than in a normal healthy population (1.7% vs. 0.5%) {Page et al. 1976). Levels of CEA were also determined in 1363 workers of five different VCM polymeri zation (3) and PVC processing (extrusion) plants (2) in the United States (Anderson et al. 1978). After removal of possible confusing factors (smoking, alcohol intake, past medical history), it emerged that the distribution of CEA litres among the polymeriza tion workers was significantly different from that in the extrusion plant group and in a nonexposed reference group. Significant differences were also found for two of six job categories examined (polymerization and maintenance) compared with extrusion workers and the reference group. However, the usefulness of the CEA titre as a predic tive indicator of possible increased risk seems doubtful. 4.4 Miscellaneous Aspects 4.4,1 Thrombocytopenia and Platelet Function Tests Thrombocytopenia in chronic VCM intoxication was first mentioned - rather paren thetically and without further comment -- in a paper published by Antonyuzhenko in 1968. Later Jiihe et al. (1973) noticed that each of the first 13 autoclave cleaners re ferred to them during 1972 from a West German plant because of suspected skin and Vi bv Bi ce 01 Wl 01 33 til C/3 de pi: oo af -oE* ai CJ1 o .3 1CO Ol iii al. cs o: x\ T. u, Gi A B C D pe pr. lit: lin Fi: Tl:  teller nor- ; al. ' but : nanJ to IR was p of the tin'ii tain a' one iound. , the out 33 CO oo 0 01 id in i six i'ion vedic- ircn;ko in - reand Vinyl Chloride-Associated Disease 83 bone lesions presented with mild to marked thrombocytopenia (30-119 X 10`9/litre). Bone marrow aspirates in 6 patients permitted exclusion of disturbed platelet forma tion or osteomvelofibrosis/sclerosis, but in 12 of them splenomegaly was found. Ex cept for slight reticulocvtosis in 8 and leucopenia in 5 of the workers, other 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 might serve as an early and easily detectable symptom. The high prevalence of thrombocytopenia (as determined by phase-contrast microscopy) found later on detailed analysis of platelet function and other parameters of blood coagulation in the total cohort of PVC production (and also fabrication) workers from this plant strengthened this suggestion {Bachner e.t al. 1974a, b, 1975a, b, \9~6\Sehn-Bachner and Etzel 1977). Wegman (1975) also commented upon abnormal platelet counts in 13 of 37 PVC fabricating workers who had only handled PVC powder which, however, might have contained substantial amounts of residual monomer. In contrast,Lilts et al. (1975) detected thrombocytopenia in only 1 of 354 polymerization workers, but an electronic cell counter was used for platelet counts (personal communication). According to Sehrt-Bachner and Etzel (1977), the mean platelet count in a cohort of 132 PVC polymerization (and processing) workers was significantly lower than that in a nonexposed control group of 150 healthy men. As could be expected, Bachner et al. (1975b) also demonstrated a positive correlation between the degree of thrombo cytopenia and the prevalence of an enlargement of the spleen (palpable splenomegaly or spleen size determined by selective scintigraphy with 197-Hg-bromo-mercury-hydroxypropane-labelled red cells) in 70 PVC polymerization workers (see Table 19). It ap- Table 19, Prevalence of enlargement of the spleen3 among 70 PVC-polymerization workers in relation to increasing degrees of thrombocviopenia (Bachner et al. I 975a) Group No. of workers examined Platelets (x 1 O' */litre) Range Mean Enlargement of the spleen A 14 B 24 C 25 D7 > 130 100-130 70- 99 < 70 168 117 87 44 3 ( 2 1 %) 1 1 146%) 19(76%) 6 (86%) As determined by palpation or by selective spleen scintigraphy pears, however, that the development of thrombocytopenia is not dependent on the presence of splenomegaly since we observed mild thrombocytopenia (100-120 x 10"9/ litre) in a small number of workers in whom spleen size was definitely within normal limits on selective spleen scintigraphy (Milzflachenindex <4.5 x 10`3 according to Fischer and Wolf 1963). Thrombocytopenia was accompanied by abnormalities in platelet function tests. There was an increase in the number of large (> 10 /rm) `juvenile' platelets (increased / 'V - z*yt. \ . v ' , ``rtlsi * ^ ; < , 7 .1; v ^ ,, W.K. Lelbach and H.J. Marsteller platelet spreading), enhanced response (platelet aggregation) to addition of ADP and collagen (Bom test) and increased availability of phospholipid-containing platelet fac tor 3 (Bachncr ct al. 1975a). This pattern was thought to he compatible with the no tion of an increased turnover rate due to derangement of microcirculation (CD1C) in liver and spleen and defective reticuloendothelial system (RES) clearance of activated clotting factors (Bachncr et al. 1974b). Ward (1976) and Ward et al. (1976) suggested that thrombocytopenia could be construed as confirmatory evidence of an immune complex disorder. Hciiscnnann and Stulte (1977a) noted unusual focal aggregation of platelets in klatsch preparations of spleen tissue and increased platelet pooling (plate lets trapped within the subsinusoidal mcshwork of pulp cords) in the red pulp of the spleen on electron microscopy as well as phagocytosis of thrombocytes by sinusoidal macrophages. Schaffncr at al. (1976) found platelet thrombi in and around hepatic sinusoids in mice after exposure to VCM. A direct toxic action of VCM (or metabo lites) on the bone marrow has not been demonstrated so far. Although the pathogenesis of thrombocytopenia in VCM-induced disease is not fully understood.it seems at present most likely that it is caused by increased turnover and consumption of platelets within the abnormal vascular spaces of the liver and spleen. A similar type of consumption coagulopathy was described as complication of spon taneous haemangiosarcoma of the liver by Truell et al. (1973). A haemostatic defect more complex than mere pooling and destruction of platelets in the enlarged spleen has also been commented upon in the paper by Cenits et al. (1974) in connection with splenomegaly of various noncirrhotic origin. 4.4.2 Central and Peripheral Nervous System Miscellaneous nonspecific and somewhat indefinite symptoms have been described in connection with chronic inhalational exposure to VCM in PVC-production workers, such as dizziness, disorientation, blurring of vision and memory, headache, irritability, excessive fatigue and somnolence, sleep reversal or insomnia and other pseudoneur asthenic symptoms (Suciit et al. 1963, 1975\Schotiek 1969;Z./7/s et al. 1975 and others). This prenarcotic syndrome was interpreted as a manifestation of a potentially reversible acute toxic encephalopathy. Its danger to the individual was thought to lie mainly in resultant inadequate reactions to critical situations (Schotlck 1969). How ever, Vale et al. (1976) reported that several individuals in a group of 95 comparatively* young ex-workers, the majority of whom had no other symptoms, complained of fa tigue. headache. listlessness and depression, with onset of symptoms having been de layed as long as 2 years after cessation of employment. With reference to such `pseudoneurasthenic complaints', which may be interpreted as the mildest degree of a toxic encephalopathy, Penin et al. (1975) examined a group of 21 autoclave cleaners at varying intervals after cessation of exposure, all of whom presented with other (cutaneous, angioneurotic, hepatic) manifestations of vinyl chlo ride disease. Clinical symptoms of a more or less distinct encephalopathy (including cerebellar ataxia in 4) were found in all but one of them. EEC recordings were normal in only five of these patients; in the others, parenrhythmia, dysenrhythmia 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- lat: en aticlu vin da; sib. ThPVt ap thn dur we: def um vioi exp fou pos C. for cre.. valc waTlu sea: ah. bro; ic_. Mursteller DP and del f " the n^. DIC) in etivated uggested nnune cation of g (platen of the msoidal epatic r-etabo- > not fully iover and 1 spleen, 'fspon. defect spleen . lion with nbed in 'thei oiabilny, nvurand ntially i to lie t. Howparatively i of facm de- terpreted i a group whom inyl chloluding v normal i a soiropathy, tal circu Vjny! Chloride-Associated Disease 85 lation with resultant hypoxic damage. The pathogenesis of a possibly VCM-induced encephalopathy is not clear. It would be conceivable that clinical and bioelectric alter ations found in some patients, in whom portosystemic encephalopathy could be ex cluded, may have been due to toxic or hypoxic brain damage. However, no other con vincing evidence has so far emerged to indicate that chronic irreversible cerebrotoxic damage may have resulted from prolonged exposure to VCM, notwithstanding the pos sibility of an induction of brain tumours. 4.4.3 Pulmonary Changes The suspected development of nonmalignant pulmonary changes due to VCM and/or PVC dust exposure is still a matter of controversy. Soon after VCM was recognized as a potent carcinogen, three groups of employees (n = 290, 250,445, respectively) from three large North American PVC-producing plants (A, B, C), characterized by different duration and levels of past environmental exposure to VCM as well as to PVC dust, were studied with respect to chest x-ray film abnormalities and pulmonary function defects as assessed by spirometry and determination of maximum expiratory flow vol ume (Miller 1975,Miller et al. 1975:Ar7/s et al. 1975, 1976, 1977). All cases with pre vious exposure to asbestos, silica or coal dust had been excluded in these studies. Un expected linear, reticular and, less often, rounded opacities on chest x-ray films were found in about one-fifth of the two groups of employees from plants A (highest ex posure) and B (22.757, and 18.8%, respectively), but in only 43% 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 years), but the pre valence of a positive history of smoking, although identical in both groups A and B, was also found to be significantly higher in workers with abnormal chest x-ray plates. The overall prevalence of a positive history of chronic bronchitis (British Medical Re search Council criteria) was 20.4% in group A (highest exposure) and 16.0% in group B, although group B was significantly older. The somewhat higher prevalence of chronic bronchitis in workers with abnormal chest x-ray plates did not attain statistical signif icance. On the other hand, age did not appear to be an important factor. Pulmonary func tion tests showed a strikingly 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 effects of occupational exposure to VCM and PVC dust, A restrictive pattern was found in 9.3% of group A and in only 2.3% of group B, al though group A was significantly younger. In conclusion, this extensive study, includ ing a total of 985 workers exposed in the past to VCM as well as PVC dust, may point to a potential multiple factor effect of smoking and VCM-PVC exposure. In this con nection, it is of interest to note that according to a cohort study of mortality among VCM polymerization workers the SMRs for respiratory cancer as well as for `other respiratory disease' were found to have been in excess of expected figures (156 and 1 76, respectively) (Waxweiler et al. 1976). Bronchopulmonary7 changes thought to be due to long-continued, intense exposure to PVC dust were observed by several authors (Parmeggiani and Sassi 1955; Broussard S6 W.K. Lelbach and H.J. Marsteller 1969.Szende et ai. 1970; Vertkin and Mamontov 1970; Frongia et al. 1914 \ Darke \9l6\Arnaud ct al. 1978). Considerable exposure to VPCdust is the rule in the drying, bagging and storage areas of PVC-producing plants. Photographs contained in Kan tad t'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 Pamicggiani and Sassi. In 1969 Broussard mentioned the possibil ity of development of chronic bronchitis caused by the inhalation of PVC dust. The insoluble and inactive dust particles were thought to accumulate in the lungs blocking alveolar spaces and being taken up by alveolar cells. This could lead to elimination of these cells via lymph vessels to regional lymph nodes, with either enlargement of the hilar region or a micronodular aspect of interstitial pulmonary fibrosis without hilar lymph node enlargement but progressive respiratory insufficiency. Szende et al. (1970) reported the case of a 31-year-old worker who presented with severe dyspnoea; a chest x-ray examination revealed diffuse micronodular pulmonary lesions. He had been engaged for only 1 year in shovelling PVC powder at a processing factory. Lung biopsy revealed moderate diffuse fibrosis and small focal granulomatous lesions containing ovoid or polygonal birefringent foreign material which could be eluted by treatment with a known solvent of PVC. Microscopic examination of PVC dust particles collected at the patient's place of work showed them to be morphologic ally identical with the particles found in the patient's lungs. Another anecdotal case of pneumoconiosis after 23 years of employment in a PVC bagging area, with radiological evidence of diffuse micronodular infiltrates and granu lomatous lesions found in a lung biopsy identical with those recorded by Szende et al., was published by Arnaud et al. in 1978. Histology of open lung biopsies in 1 of 14 VCM-exposed British workers, who complained of breathlessness, revealed focal alveo lar wall thickening with macrophages in alveolar spaces and increased reticulin and col lagen on electron microscopy (Darke 1976). Although chest x-ray appearances were normal and routine respiratory function tests showed only slightly impaired C03 dif fusion in six individuals, perfusion and ventilation scans revealed strikingly abnormal pictures, including marked perfusion defects of upper lobes. Darke pointed out that some of the men worst affected had been engaged in the polymerization of `plastisol', a very fine PVC powder with particle size around 0.5 pm, Selikoff (1976) called attention to results obtained by Frongia et al. (1974). who observed significant histopathological changes in the lungs of guinea-pigs and rats ex posed for 2-7 months to inhalation of the airborne PVC dust in a PVC bagging area. Lesions began to appear at 2 months of exposure (alveolar histiocyte-macrophage re actions); they proved to be fairly marked after 4 months, with appearance of foreign body giant cells, and proceeded to development of large interstitial granulomatous foci. Vertkin and Mamontov (1970) who examined 96 workers engaged in the manu facture of articles made from PVC powder, also found a considerable proportion of them were suffering from functional and morphological alterations of the broncho pulmonary' system, which they ascribed to their exposure to PVC dust. They quoted results of earlier animal experimenta conducted in 1963 by Golovatyuk and later by Slilyakherskii. 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. I J. Marsteller '4; Darke in the"' Ting. lirtAu .adr's icnts of the reported as the possibil' dust. The nigs blocking ruination of nent of the thout hilar esented with pulmonary a processing anulomatous could be ion of PVC m ic- DD :i go 'C s; V) i- J., o- 1 Ol cn al- IlLMIVlIIlUj i nut that 1 `plastisol-, ') 74), who rd rats exgging area, ophage reof foreign mtatous the manuurtion of ironcho:y quoted 1 later by timals to ly to a sort Vinyl Chloride-Associated Disease S7 Certain types of PVC dust (one of two samples tested) were found to exhibit a strong haemolytic potential due to the presence of an undetermined but readily solu ble surface-associated agent which was not VCM (Richards et al, 1975). These authors also studied the effect of the haemolytic sample of PVC dust on lung fibroblast cul tures, but they did not obtain any significant results. Contrary to earlier indications (Lange et al. 1974a) and despite continued efforts we failed to detect any significant restrictive changes of pulmonary' function in the overwhelming majority of patients we had occasion to examine. It may be of interest to note that Maltoni et al. (1974b) reported a high prevalence of pathological changes of respiratory epithelium (squamous metaplasia, squamous dysplasia, typical and atypical adenomatous proliferation) in sputum samples from employees of Italian VCM-PVC factories. Nevertheless, contrary to the now well-established role of VCM in the production of nonmalignant lesions of bone, skin, small vessels, liver and spleen, it is still open to debate precisely what importance can be ascribed to pulmonary changes within the spectrum of VCM-induced disease. 4.4.4 Genetic Effects of VCM The discovery of the carcinogenic properties of VCM also stimulated interest in its mutagenic potential. A number of studies have been carried out that demonstrated a mutagenic response to VCM or its metabolites in microbial test systems. Point muta tions due to base-pair substitution have been produced in various strains of Salmonella typhimurium by VCM in the presence of animal and human liver microsomes as a sys tem of metabolic activation (Rannug et al. 1974, 1916;Bartsch et al. 1975a, 1976; McCann et al. 1975\Malaveille et al. \915\Garro et al. 1976). Mutagenicity of VCM metabolites was also demonstrated in yeast strains (Lopricno et al. 1976, \911\Shahin 1976) and in mammalian cells (Hubennan et al. 1975). In comparison to nonexposed controls, a significantly higher incidence of chromosomal aberrations (fragmentation, rearrangement) in lymphocytes of workers occupationally exposed to VCM was re ported by Ducatman et al. (1975), Funes-Cravioto et al. (1975),Purchase et al. (1975, 1976), and Fomenko et al. (1976). Fleig 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 absolutely exclude genetic effects on human gonads. The outcome of pregnancy among wives of VCM-polymerization workers as against wives of rubber and PVC-fabrication workers (Infante et al. 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 part of a larger survey of workers' health, interview questionnaires (Infante 1976a, b) showed that after paternal age adjustment a significantly higher incidence of fetal mortality subsequent to paternal exposure was recorded among the wives of VCM-exposed workers. This trend was found to be maintained after elimination of S8 W.K. Lelbach and H.J. Marstellcr pregnancies in women who had more than two abortions. The findings of this study raised the question of possible genetic risks of VCM to man and led to the suggestion that germ-cell damage in the father through direct VCM exposure might be a possible explanation. No clear-cut linkage of PVC production and increased occurrence of congenital malformations (primarily CNS malformations) emerged from preliminary studies in three Ohio communities with PVC production plants. But the need for further study of possible contributary factors was indicated {Infante 1976). In fact, none of the par ents of affected children in Painsville, one of the three Ohio communities, had ever worked at either of the two PVC polymerization plants in Painsville or lived within two miles of these plants {Edmonds et a], 1975). 5 Conclusion and Outlook The combined efforts of multiple disciplines have been necessary to arrive at the full recognition of the range of pathology associated with occupational exposure to vinyl chloride. It can only be hoped that the lesson from the vinyl chloride problem may help to bring about an increased awareness of the risks and hazards which are inevitably the consequence of an ever-expanding technology. The importance of this lesson lies in its exemplary nature. A single substance of rather simple chemical structure, which was long held to be a comparatively safe com pound,even by experts, turned out after ail to be a carcinogen with a very long latency period for those who were heavily exposed to it. But its carcinogenic properties would most probably still have gone unnoticed if the resulting malignancy had been any can cer other than of an exceptionally rare type. Animal experiments in the early days later proved to have been broken off before the oncogenicity of this chemical com pound could have been delected. The lesson to be learned is that in future any new chemical which is to be widely introduced into the environment should be scrutinized closely, for a sufficient length of time, and with the aid of all available methods for the detection of potential car cinogenic effects. In addition, we should keep in mind that in industrial surroundings we almost never deal with a single compound, but with a very complex occupational environment whose carcinogenic potential is still a completely unresolved problem. If currently adopted guidelines for industrial hygiene are strictly adhered to, there is reason to hope that initiation of new cases of VCM-induced angiosarcoma of the liver can be effectively prevented. Unfortunately, however, it can be expected that in view of the long latency period for tumour promotion additional cases will appear dur ing the next decade. Considering the ever-increasing complexity of environmental influences, future re search will be faced with almost insurmountable obstacles in its endeavour to establish `safe' levels for potentially hazardous chemicals. Promising areas for further studies in the field of vinyl chloride and allied compounds may be the problem of the interaction Vinyl Chlori' between pred tissue such as short exposu. will carry' the References Albright LF i Albright LF t Albright LF i Albright LF ( polyvinyl v Albright LF ( processes. 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S: Bachner U, M; 1 000 patie: Bachner U, Et und Osoph Blutungen . '.J Marsteller this study sugg"" 'on ; a pL .ulc mgenftal studies in ther study .e of the par. had eve: ed within . at the full ire to vinyl dem may ate inevitably ranee of ly safe com* l.ing latency enies would en ati'"'an* 'I; >cal com- be widely ; nt length .niial carirroundings cupational problem, ed to, there la of the ted that in 1 appear dur- s. future re* to establish r studies in c interaction Vinyl Chlonde-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 Albright LF (1 967a) Vinyl Chloride processes. Chem Eng 74:123-180 Albright LF (1967b) Manufacture of vinyl chloride. Chem Eng 74:219-224 Albright LF (1 967c) Polymerization of vinyl chloride. 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