Document BRg4J3dQ97O4p4DaGZ3mE8ajJ

Ergebnisse der Inneren Medizin und Kinderheilkunde 9 B 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  W.K. Lelbach and H.J. Mantelicr i I 7 Pathogenetic Considerations........................................................... J.2 Non-malifnant Liver Disease in Vinyl Chloride/Polyvinyl Chloride Production Workers ................................................... 4 2.1 Clinical Manilesiatiuns of Non-malignant Liver Disease .............. 4.2.2 Laboratory Findings........................................................................ 4.2.3 Cross Inspection of the Liver and Spleen....................................... 4.2.4 Histology.......... 4.2.4 l Hepatic Fibrosis................................................................ 4.2.4.* Sinusoidal Lining Cells.......... ...................... 4.2.4J Hepatocytes........................................................................ 4.2.4.4 Histology of theSpleen..................................................... 4.2.5 Pathophysiology of Portal Hypertension 4.2.6 Follow-up of Non-malignant VCM-induced Liver Disease.......... 4.3 Angiosarcoma of the Liver........................................................................... 4.3.1 Epidemiology....,........................................................................... 4.3.2 Clinical Manifestations...................................................................... 4.3.3 Pentoneoseopy.................................................................................. 4.3 4 Gross and Histological Morphology.................................................. 4.3.5 Therapy. . . ........................................................................................ 4.3 6 Risk Assessment................................................................................. 4.3.7 Mortality and Cancer Morbidity Studies....................................... 4.4 Miscellaneous Aspects................................................................................... 4 4 1 Thrombocytopenia and Platelet Function Tests........................... 4 4.2 Central and Peripheral Nervous System.......................................... 4 4.3 Pulmonary Changes........................................................................... 4,4.4 Genetic Effects of VCM.................................................................... 5 Conclusion and Outlook....................................................................................... References.................................................................................................................... 44 44 43 49 50 51 Jl J4 54 S4 55 J7 37 57 74 76 78 80 80 81 82 82 84 85 87 88 89 Key words: Aeroosreotysis - Anposarcoma of the Liver - Portal Fibrosis and Portal Hypertension - Pscudoscleroderma - Raynaud's Phenomenon - Vinyl Chloride 1 Introduction The history of vinyl chloride-associated disease, its recognition and prophylaxis is a classic example of shutting the stable door after the hone has bolted. It should help to emphasize the need to shift our attention to preventing exposure from occurring rather than to reparative measures. In view of the large number of new and porenDally hazard ous chemicals introduced each year into the workplace and the environment, this ac count should again alert us to the necessity of pretesting chemicals adequately for their potential health effects, even at the risk that technological progress will develop at a more modest rate. Large-scale production of the synthetic resin polyvinyl chloride (PVC), a thermo plastic material suitable for the most widely diversified industrial use, was begun around 1930 in the United States and in Germany. The monomet, vinyl chloride (VCM). a rather simple aliphatic compound, was believed until the early 1960s to be Vmyi Chlonde-Assoi.' one of the least harmf later turned out, had 1: evaluation of acute eff to reveal its carctnogei might have continued place, considering that vapour phase under anreact,-, e double-bond. Today vinyl chlorid formation and data on cisely a quarter of a cei tributabie to this new c with the shocking disa uon workers heaviiy e> ing thar the monomer t pound did not alert thc in workers enpged in 1 hshed in 1949 (Tnbuki Ultimately, it was ti cuned in workers expo a causal relationship: (1 pseudosleroderma; (2) liver. Particularly, the nancy among a compar alarming experience wi a connection between ' lungs or the gastrointe. the prolonged latency f sarcoma of the liver. r>: these two fatal consequ the conclusion that Vh. cancer meeting in Hous to VCM was a very sen It should be stressc. precise, an intermediate mainly in the mammal, menzation products (P' cited from the polymet they contain unreacted PVC (thermal decompo toxicity of pyrolysis pr< mamiy due to the reiea: A bar 1969: Dyer and and only very small or r (O'Mara et al. 1971 cite A 2 Technological Details 2.1 Vinyl Chloride Monomer (VCM) \v K, Lelbach jnd H.J Mjpstcilcr At standard (ambient) conditions of temperature and pressure, vinyl cldoride (CH:* CHCI: chloroethylene, chloroethene) is a non-irntating, colourless gas with a faintly sweet odour, inflammable at concentrations above 3.3% by volume in air. winch is only slightly soluble in water, soluble in ethyl alcohol and easily soluble in ether and carbon tetrachloride. VCM is mainly used as an intermediate in the manufacture of plastics, as a refrigerant and in organic synthesis. It was formerly also employed as a propellant for aerosoles. It is easily liquefied under pressure and is usually handled and shipped as a liquid. Caseous VCM condenses at -13.8*C and 760 Tori (* 101J kPa) to a colourless liquid of low viscosity (Le/aux 1966). Its physical properties are listed in Table 1, the most important of which are its low boiling point, its high specific grav ity (gaseous VCM is 2.15 times heavier than air), its low solubility in water and the half-life in air. ranging from 3 to 20 h. Table 1. Ph) deal properties of VCM Mol. wt.. B.p.: F.p.: Flash point: Limits ot flammability: Autoignition temperature: 62.503 *-13.8'C(-13.7 to -13.9) -153.7`C -78.5*C (Cleveland open cup) 3.8TM -29.3?* by volume in air above -7g.J*C (-38 000-293 000 ppm) 472*C Vapour pressure: mm Hg 10 100 692 2300 *C -87.J -55.8 -15.8 20 2660 25 Vapour density: 2.15 g/litre (calculated at 25*C amt 760 mmilg (air - 1) Sp.gr. of liquid VCM: 0.9121 at -20*C/4*C 0.99 at --25*C/4*C Sources: Fairhall 1957 Jnjh 1963,Zapp 1964\lefaux \9b6 . Oirermavtr l9o"; Roubat 1972. 2.1.1 Histoty The French chemist,Regnauii (1835) was apparently the first to study sy stematically the synthesis and analysis of vinyl chloride. Liebig, who had done some earlier prelim inary experiments, encouraged Repiaulr to investigate this compound when Regnault spent several months in Liebig`s laboratories. All compounds containing the vinyl group (CHi-CH-) polymerize readdy (Fairhall 1957). Spontaneous polymerization of vinyl chloride to a white opaque solid mass under the influence of sunlight was first desenbed by Baumann in 1872; he also quotes a paper by Sayrsev and Cliniky (who Vin>l On succeeds izmg subs 2.1.2 Pro Large-seal' by employ 1) Conver CH*CF 2) Conver chloroe CHj-C CHjCl- VCMw Thus, any. tions in the in the ram: (IARC 19" when VCV ntayer 196 in commer i::6: Osre. In the e conjecture retrieved V yses-camev. sum of all i: genates), reacted mo in prepolvr the concert that even 1' methyl chl> isobutane,/ ference in ~ W K. Lelbach and H.J Marsrellsr 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 (reacton) at tempera tures between 40*C and S0*C and pressures of 6-16 (8-12) atmospheres. Tlvre 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-isobutyronitnde, and othets. 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 Zielhuis 1964;Lefaux l966:Albrtght 1967 s-cVomminghaus 1972,Slarer 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 polymen have average molecular weights that vary from about SO 000 to 150 000 daltons {Albright 1967b). Degree and velocity of polymerization, which are influenced by temperature and the concentration of initiaton. determine the specif * type of PVC produced {Frey 1973). During polymerization considerable amounts of the monomer are at first dissolved in the polymer, but most of this is later also transformed to PVC as polymerization progresses. The polymer which is not sol uble in the liquid monomer precipitates out. The process of polymerization slows down towards the end of the reaction.lt is terminated, depending on the method used, when approximately 8055-9051 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 {Barnet 1976). After completion of the polymerization process, the slurry is released from the re actor into a dump tank. Residual unreacted vinyl chionde monomer is partly solvated in the polymer (about 10%); the remainder is dispersed in the water phase or u present Vmyl Chlonde- in the vapour p VC monomer is is then purified the finished pol and must diffus Raw PVC resin. iVKE 1975). Be proximately 50' The slurry f: large enough to are then pumpc wet polymer, a drying methods menzauon, yie! fine solid partic drying tempera; polymer. A eye The solid polyr stonge bins or s dried powder cc 2.2-2 Methods Four different i PVC {Frey 1971 Suspension Pol> which monome: (such as polyvin conduction with this method wh Emulsion Polyrr was added in thi except that larg' are added. Emu! emulsifiers cann Bulk (Matt) Pol, the additon of c The first reactor second one is us solid state, to es reaches a level o characterized by good optical da. a35& S W.K. Lt-llijtli jnU H ) 'iJjrit*. It;r Sultittou Polymcnzatiun. Tins type of precipitation polymerization is carried out in organic solvents such as /i-butanc 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 copol> mers. Copolymers are mixtures of comonomers (such os vinyl acetate, vinylstearate. vinyliJcne 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 intluencc on the temperatures required for compounding. 2.2J Compounding As a next step, depending on the end use, the dried polymer, a whitish powdery or granular product, is then compounded (or dry blended) under pressure at fusion tem perature with the aid of plasticizers (mainly phthalate or other organic esters) and light and heat stabilizers (heavy metal salts, organoun 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 Anal product depending on its compatibility Lead-containing stabilizers may also pollute the working atmosphere (Smultic 1966 , Tola 1975). Compounding is earned out by hot mixing at fusion tem peratures below or within the softening range (120C-160*C). Diversified compound ing and processing technologies were developed about 1950. The compounded polymers are used for the production of diverse end-products. The final conversion of the thermoplastic PVC resins into consumer end-products is accomplished by such procedures as extruding, calendering, injection or compression moulding, blow moulding, dipping (coating) and hot spraying. Temperatures used in these processes range from I00C to 300*C. End-products include a vast number of articles used in almost every sphere of doily 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. Bamcs (1976) calculated that the final fabricated articles contained approximately 5 ppm VC.M and those for foodstuff packaging (bottles, films, foils) even less. 2.2.4 Sources of Exposure to VOl in PVC Production Both polymerization of VCM and subsequent processing (centrifuging, dry ing, screen ing, bagging) are usually earned out in closed butidinp. Exceptions can be found in hot climates (Aryanpur 1977). Polymerization ts of necessity a batch process that re quires a large number of single operations. Therefore, valves, gaskets, sharpening* and control gear are subject to heavy wear and thus to leakage. Other sources of pollu tion of the working atmosphere are exchange of ports and repair jobs. The degree of pollution also depends to a large extent on the quality and effcctivity of monitoring equipment and special exhaust systems. Opening of autoclave vats for cleaning and control purposes resulted in larger spill-over of the tank atmosphere into the work en vironment. Numerous reports of workers with prenarcotic symptoms (dizziness etc.) Vinyl ( permit t in the p Ther clave ia walls Cp tors, hadegassed and largv were opt ed the ft non sull manly, t those wi (centnfi. ties of ventilati shipmer. nomer.' are dnvc Table:. -1 ppr I mp (Pat: 1 rng/im I mp, nt1 1 ppm - 2.2.5 T In the r>.' nan i moi covets (Ltfiux lect os a opened became l 10 W.K. Lei bach and H.J. Marsteller State* was almost completely destroyed when VCM escaping from a leak detonated (Albrtglit 196'a). Another explosion tn one of the two Rumanian factones 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 riot 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%-10f& by volume. Velttnan 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 (/nth 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 '.Marko witz et al. 1972;Lcfcvrt 1975, cited by Nutlet 1975). Barerta et al.(1969) conducted expenmen is with concentrations of 50,250 and 500 ppm in an exposure chamber, in which 13 volunteers participated. At 500 ppm only some of them claimed that they were able to detect the odour, but this was inconstant. Table 3 shows that differences betwetn 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 repotted by insh (1963), however, makes it likely that the actual odour threshold can be as sumed at or above 4000 ppm. In contrast to VCM, tlie 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 S 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 consdered for use as an anaesthetic agent. In 1929. Schmidt and Sehmuwnn 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 C table 3. -- Lower li. , 0-1 400- anaesthesi tic and let oxygen; ct however, L eluded. In lOftVCM several hou commentec mined abot 3.5--5 mmc mmol (244 Otter et al., cardio toxic, man becauslike other h; amines (Inst the past for. 22S Effec: Some indivjd listed in Tabl without acute symptoms su. adequate wan exposure to hi A 21-year-old 10 min after e which had bee cardiac enlarge have been acut which occurred doubt that hea found dead wit i: U'.K. Lelbach and HJ. NU.-vteilcr Table 4 Individual responses ot volunteers to increasing concentrations ol' VCM Concentration Duration of Symptoms cxpo\urc Reference 500 ppm v.4 000 ppm 7.5 h - (inconstant odour detection' Baretta et al. mild headache, dryness of 119b9> eyes and throat in 2 of 7 subjects > Generally accepted odour threshold inn, \ |9t>5) 6 600 ppm 30 min (Distinct odour) dizziness, sleepiness iraii 119b3) 8 000 ppm \ 12 000 ppm J 5 min1 (twice on lt> 000 ppm 1 each of 3 succes sive days) 30 000 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 Ltsttr et al. (1965) 25 000 ppm 3 min 2 experimenters: dizziness, disorientation, burning sensation in the soles of the feet Pam- et at. (1963) a Exposure to six different concentrations: 0 ppm: 4 000 ppm: 8 000 ppm: 12 000 ppm: 16 000 ppm: 20 000 ppm through which non-polymerized residual VCM was pumped back into a reserve tank: another man coming to his rescue was himself overcome by the gas and only just escaped. Two non-fatal cases of VCM gassing were reported in Crest Bntain 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 Litis et al. (1975) in 14 of 354 workers at Niagara falls and by Suciu 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 38 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 Aery et al. (1974). Vinyl Chic 3.2.9 Mo- During the ed data on was directe an apparent 19 54; piesii Grvnsb&g t Russian pol 0.05-05)8 : eentration c Inspectoral: or from the mg/litre (* mg/lnre (. In the c: air ranged fr ppm, which ventilation, trations, son pursuit of in ment in the ic drying fac cen trations c continued to muted conce In a plant the range of ( ppm (2.93 m ication appar remarkable tl the liver, alth past have pro Byrin et: which occum cated peak ex between 196; Rumanian PV about 130 mg exposures to ' 300 Rumaniai Greek plant w resulted in hig (Girstos 1971) of the react is up to 10 000 p 14 W.K. Lelbach jnd HJ Mjrrdler aa> 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 (!ARC 1974) it was stated that in a reactor of 15 m1 (production of 4-5 tons of PVC per cycle) a crust of 4 kg PVC containing 3%-5'Z VCM can be formed on the inner surface. During the cleaning procedure 3075-50% of this VCM content is liber ated. It was calculated that the probable concentration of VCM wuhin the reactor after a 1 -h cleaning operation was about 2700 ppm, but that it could lc 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 pnor 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 mote sensitive methods such as gas chromatography were said to have shown that VCM concentrations inside the reactors tended to 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 (Orr et al. 1975). In a second unit with modernized equipment excursions up to 600-1300 ppm still occur red during the period of 1953-1959. In 1959, when toxicological data indicating ad vene effects in animals exposed to 100-500 ppm VCM had become available (Torkelton 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 wen 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 ceiling values of 70 ppm (Fieif and Thiess 1974). In several surveys individual jobs were grouped into three exposure categories ac cording to job classification to evaluate past exposure experiences (Spa-rat et al. 1975; Williams et al. 1976;fcrtdu et al. 1978). These exposure indicts were: (a) light * less Vin> than ppm! plant samp. Esum more averse Table atm os Chem. 194519551960mid-1c lc * Act Eq; tions ir equiprr viduai < binauo (3) The ly spec; ment sh peak co for the. Curt compris tion det< (lonofli. which c: conditio lag of re: Aca: industna in 1975 : 2.2.10 I Raw PVC unrcactei was reported to have been as high as 6000--7000 ppm (w/w) in some typos of raw PVC. but a level of 500-1000 ppm probably was a more representative range (Sehwatser 1975: VICE 1974: Aenroiir 1976). The monomer slowly escapes into the environment exponentially with time. Jepending on length of storage period, tempera ture, size and porosity of particles and other physical properties of the polymer and. more recently, on the erleetivity of special degassing techniques (Pncr 1976:5ctore and Wolj 1977). In 1975, the Association of the German Plastics Industry announced that in future only PVC powder with a maximum monomer content of 10 ppm would be put on the market due to the development of special degassing technologies (VKE 1975) . Analyses of the types of raw PVC. chiefly suspension polymer, which ate now used in German plants showed that in most products the content of upreacted 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 iSchiir; and Wolf 1977). Cold and particularly hot mixing or compounding of PVC, a procedure which usu ally precedes fabneating 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 Binder and Strabr (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 readirp mean levels integrated over 1 -h periods now range below 0.1 ppm, numerous short bums with excursions up to 60 ppm during a workshift were recorded in one instance (Schiir: 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 (KarusJt 1976) . These present results, however, do not permit any conclusions :s to past leyels of atmospheric VCM during the yean when residual monomer content of PVC resins was Inch and ventilation insufficient, particularly in compounding and extruding units. Whatever the extent of the nsk might have been in the past, it can be safely assumed that the ambient monomer concentrations in fabricating plants have always been con siderably lower than in PVC-producing plana. When it was suspected that certain VCM-related svmptoms might also have afflict ed PVC process workers, this problem was investigated by our group. Although no cases of acroosieolysis. pseudoscleroderma or angiosarcoma of the liver were observed, evidence was presented which demonstrated that minor and inconspicuous lesions such as mild hepatic fibrosis, bromsulphalein (BSP) retention, thrombocy topenia and slight enlargement of the spleen could be found in 28 process workers who had been cmployed for yean in compounding and fabricating units (Lange et al. 1975,1976a: Wcrrnn \91S\MonteUtr 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- > ! j { ; conspi spans quantt Observ progr* male F find ar Ar two G. died re' lation i health overall record 2.2.11 Indust; of expc tion* o' Tndust; zentrati Ament, exceed:tions si basic ar cupati'.(1974). used in are sun; discrep . red to t The not a s* should i tently ; availablnew mf list of M variousi SO-cadet' toot for ysis of t! In th ppm in I 18 W.K. Lelbsvh jnd H.J. Mjretcller :n 1970 in conformity with the proposal of Torkclson et al. (1961). which was baseJ 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 (Techmsche Richrkonzemration) of 50 ppm was instituted (VKE 1975). The Chemical Industries' Liability Insurance Association (Berufsgenossenschaft der Chemischen Industrie 1 also issued instructions for the prevention of health hazards arising from handling of VCM in July l74 As of July 1975, a technical guideline (TRK * Teclinische Richtkonzentrar.on) of 5 ppm. defined as annual mean, for PVC-producing and -fabricating plants was instituted, per mitting excursions up to 15 ppm during periods of not more than I h. In order to adapt operating plants, a provisional regulation was issued with reduction of the an nual mean concentration to 20 ppm as of July 1975, and to 10 ppm as of July 1976 and peak concentrations over 1-h periods not exceeding 60 or 30 ppm, respectively (Veltman and Lange 1977a). The technical guideline (TRK value) was revised in 1977 (2 ppm annual mean/5 ppm per 1 h). In the United States the tltreshold limit value for VCM was originally set at 500 ppm in 1947. It was reduced to 50 ppm m 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%--$% losses), most of it as air emissions and lesser quantities dissolved in water effluent streams and entrapped in sludge and solid wastes {Schweitzer 1975). In a pioneer study, concentrations of 1 -2 ppm VCM were found in the ambient air near such a plant (IaRC 1974), 2-3 ppm in the primary water effluent and 100-200 ppm in the sludge at the plant site, but sampling and analysis methods used were later found to have been inadequate so no conclusions were drawn from these figures since they could have been in error by as much as one order of magnitude (Schweitzer 1975). For people who live within 5 miles of monomer and polymer production facil ities in the United States an average exposure of 17 ppb during the 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 (Otremiayer 1967), in Japan it has been used as a propellant since 1958, in the United States this use was probably introduced after 1962 (Schweitzer 1 **75>. /Vs an aerosol propellant. VCM lias been a possible source of exposure for the public at large, particularly lor women, (lie extent and the potential health implica tions of which arc unknown. Use of aerosol products m confined spaces has been re ported to result in air concentrations of VCM of up to 400 ppm in closed rooms, even after only short bursts (30 s) (Cay et al. 1975), which could persist for several Vinyl Chi. Table 6. T Country Belgium Canada Finland France German D. Republic Iran Italy Japan Nethcrland Rumania Sweden Swjtzerian United Kir- USA USSR Federal Re, Germany Sources: S 73: IARC R :o W K. Lclbach and 1I J. Mjrsiclitr hows slier repeated iprayin" 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, wluclt were banned in 1974 by the FooJ and Drug Administration. In Japan, the monomer was also banned as a propcilaul in 174 (JAMA 1974. 239.S55). There is a case on record of a worker who died front noncirrhotic portjl 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 (/Jew/ and li'cber 1974). The report of a female office worker suffering from typical Raynaud's phenomenon, pseudoscleroderma, acroosteolvsis and mandibular osteolysis who never had occupational contact with VCM {Mcyenon and Meier 1972) is apt to make one wonder what influence the frequent indoor use of VCM-propelled spray cans (BrJbord et al. 1975) may have had in this unique cue. Sputum samples collected from frequent users of pressurized spray cans who had no respiratory symptom were found to con tain a significant excess of moderate and marked atypical metapiastic bronchial cells compared with two groups of controls {Good et al. 1975). PVC bottles, tllms and foils have been used for many yean for packaging food and beverages (cooking oil. margarine, meat, mineral water, fruit squashes and other soft drinks, hard liquor etc.). The content of restdual 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 Lotten 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 10-30 ppm (w/w) were found {van Esch and van Z.ojret 1975: Dunes and Perry 1975). Data available in 1974 to a group of WHO experts revealed that samples of gin and wiiisky had contained 0.57 and 0.62 ppm (w/w) of VCM respectively, after storage in miniature PVC bottles for periods up to 3 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 Pc-r-(1975): in their own analyses of simples of PVC-bottled spirits supplied by British Airways they found concentra tions of 0-0.25 ppm (w/w). Methods were developed for rise detection of VCM tn liquids with a maximum sensitivity down to the I ppb level {van Liemp and Sick 1976: Dressman ind McFarrcn 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 197$). Results of carcinogenicity assays in experimental animals after oral administration of VCM are discussed in Sect. 3 J. Vin>! Chlondc*4n. 3 Toxicology c 3.1 Acute To.xicirv During the first thre^ the assessment of ttu concentrations varyv. and Leake 1933 ;5d< imtteo et al. I960;L anaesthesia, deep nax this range of exposur ttve and haemorrhagi hepatocellular injuty inducing substances ( 3.2 Chronic Toxicin Torkelson et al.(l96i exposure to concentre 45-6 months. All spe however, caused an uu histological changes in pigs and dogs. An inen in rats exposed to 20 0 (1963); no histological Gorlcij Institute were r exposure ofexperimen mias. bradycardia, char, 0.05 mg/litre) for 5 mo creased secretion of cal posterior hypothalamus 3500-4000 ppm t.9-K of the cortex and the ar comitant changes in cir, posure of rats and rabbi resorpuve bone changes nervous system dysfum, available evidence for Vt VCM should be suspecte statutory maximal allow crane Republic) should i Of particular import: Viok et al. 1971) with c full year. It was only afu L ii UCC 088070 W.K. Lelbjvli jnJ H }. M.ir>tcl!er 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 {Maruellcr et aJ. 1973). Viola described lesions of the skin, the small arterial vessels, the connective tissue and elastic reticulum of the paws, and periosteal proliferation with chondrotd metaplasis 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. 33 Oncogenic Properties The earliest documentation of the carcinogenic action of VCM was Viola't preliminary' report presented at the lOtlt 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 Lefemme (1975) later interpreted these paraauricular tumours as arising from the sebaceous glands of the extenor 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 metasuses from the Zymbal gland tumours. Autoradiograms of sections of whole rats dosed orally with (14C]-labe0ed VCM revealed a discrete localization of 1 *C in the paraauricular region (Zymbal gland?) and in the region of salivary glands and Harder's glands (Green and Hathway 1975). In this con textjVeu/nenn 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 vanous experimental factors such as route of administration, dose level, length of treatment, and species, strain, sex and age of animals (Maltoni 1973,1977;.Va/fow and Lefamine 1974a, b, 1975;Maltoni et al. 1974a, 1975). Con centrations used in the inhalation experiments were 30 000,10 000.6000.2500,500, 250 and 50 ppm, with length of exposure ranging up to 52 weeks and observation peri ods up to 143 weeks. Apart from the induction of Zymbal gland carcinoma other ma lignancies developed, notably angiosarcoma of the liver but also extnhepatic 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 30 Sprague-Dawley rats each of which had been treated with the highest doses of 50 and 16.65 mg,leg body wt. (Maltoni et al. 1975). Maltoni (1977) succeeded in demonstrating that the route of administration of this dearly multipo- Vinyl C1-. tential ca study of c solved in 6 days/we ratio only non not n placed the the no-tox angiosarcc Sprague-D proved to genic in ra be carctnc 10. 5 and 1979). An the dose-r< exposure I histologic: the liver ar the induce posure to al. 1974b; endothelia perplasia a even in the was scanty doses. In tl fibrosis wa of ossifyin; feet was su offspring o mint 1975 posed to V ed from Gr it was seen matunty ol to 2000 pp: foci of hep: Holmbe week, for 5 spleen chan mals expose cutaneous; ppm group i Sec also was found in an aminaJ exposed to 500 ppm. A few mammary adenocarcinomas, one rhabdomyosarcoma and one renal haemangiosarcoma were also seen. Prom their experiments Holmberg et al. concluded that a lower exposure over a longer period may intensify the cancerogeme 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 Arues 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 glucose-6phosphatase activity in hepatocytes, strong sinusoidal activity of alkaline phosphatase and increase of smooth endoplasmic reticulum in parenchymal.iiver cells were observ ed. In the final stage areas of necrosis in the liver parenchyma, focal dilatation of sinusoids and proliferation of normal and atypical sinusoidal cells, multicenmc hepatic an giosarcoma and Zymbal gland careinoma occurred. Fcron et al. (1979b) also observed hepatocellular carcinoma in three animals. Surprisingly, the induction of very malig nant metastasizing carcinomas of the nasal cavity originating from the olfactory epi thelium and Bowman's gland was noted, which had not been reported before in con nection with VCM. Marked hepatic fibrosis was only seen within fully developed an giosarcoma or as a reaction to extensive necrosis of the hepatic parenchyma. The in vestigators were of the opinion that hepatic parenchymal changes preceded those of the hepatic stroma, but they stressed the fact that the true relationship between VCMinduced alterations of hepatocytes and sinusoidal cells has yet to be eiucidated. 3.4 Toxicodynamies Prior to 1974 very little ii.formation was available about the fate and the toxicodynamics of VCM in the mammalian organism, but the discovery ofVCM-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 Schaumntm 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 Hathway 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 monochJoroaceuc acid in the urine of workers exposed to VCM was reported in 1966 by Gnjorcxu and Tobe. indicating that a polar excretable metabolite of VCM had been formed (Vainio 1978). Toxicodynamic studies have revealed that VCM per sc is net the ultimate toxin or carcinogenic. It is the process of biotransformation (metabolic activation) of VCM. primarily by hepatic microsomal enzymes (mixed function oxidases) tliat yields short lived but hizlmutagenic an cretable prod. 1975). The t. uve velocities tion of its tea nation of VC so that above following a Zt cordance with 3.4.1 Uptake Pulmonary up in the animal with the pool shown by com Boltet al. (19' as albumin, art. pound goes in t After oral ingc has to be cons: is excreted via 1976c). This c able process. P body wt. adm. vestigauon ot . gavage in dosefound a signili. plasmic reticul' but only mini' rats on a diet c almost ail the * testina! tract, h in this way. Pcrcutanev keys following 800 ppm of14' was negligible i Studies of * that the liver (p polar metaboiit spleen, lunp ai, kidneys, spleen of irreversibly | irreversibly bon :6 VV.K. Lelbach and H.J Marsieller Total radioactivity 43 It after a single exposure decreased considerably in these organs, in accordance with the relatively rapid meubolization 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 ore concentrated primarily in liver and Iddneyt. 3.4.2 Metabolism 34.2.1 Relation betw een Chemical Structure. Reacth'iry and Mutagenic or Carcinogenic Effect Before discussing the metabolic pathways of VCM (monochloroethylenel and its presumpuve toxic intermediates two features of the chemical structure of this compound should be mentioned. Vinyl chlonde is a monohalogcnated ethylene and its chlonne 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 Cvetanovtc 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 ethylene* and ranks next to unsubstituted ethylene. Secondly, the first step in the oxidative metabolism of all chlorinated alkenes is a . transformation to epoxides (octanes) which are short-lived, highly reactive electro philic intermediates (Bonse et al. 1975.Henschler 1977b). Such chlorinated epoxides may react, by alkylation, with essential cellular constituents, a mechanism which Rannuget al.(1974),arrrc/t et al. (1975a, b) and Malaveilte et al. (1975) claimed to be responsible for the carcinogenic and mutagenic effects of VCM and vmylidene chloride. Epoxides resulting from biotransformation of asymmetrically substituted ethylenes, such as VCM, vinylidene chlonde 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 ethylenes was indicated by the studies of Gram et al. (1975, 1977). 3.42.2 Metabolic Pathways From 1974 onwards the fate of VCM has been studied extensively in vitro with rat liver microtomes in the presence of a NADPH-generating system (Kappus et al. 1975, I976:Bemc7i et al. 1975b, \97b.Malaveille et al. \97S\Bolt et al. \97be. Pcssayre et al. 1979), with the aid of isolated perfused liver preparations (Radwan and Hensch ler 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 know ledge strongly suggests that the first step of the predo minant metabolic pathway is the oxidation of the double-bond of VCM by the hepatic in>J ChJor. microsomal ly highly re a. via the form, bon monoxi preciable rol^ in vitro an ar systems.and : 1976a). The Cl H >(< HH rc.u Fig. 1. Metab metabolized t acetic acid are methylene ox protein sulph; way (1977). S (Norpoth et a S-carboxymet add) (Hensch identified in t :s W.K. U-lhjch jnd H.J Mar^relh-r level oi' hepatic nonprotem sulphydryl content has been observed in rats alter expo sure to VCM. in concentrations from. 150 to 2000 ppm for 2-7 h. No depression was seen after 10 ppm and a concentration of 50 ppm caused only ail inconsistent reduc tion (IVaranabe et al. 1976b). Protein-bound hepatic sulphydryl content remained unaffected. Hepatic microsomal cytochrome P4J0, the coeuzyme of microsomal monooxigenases, also decreases linearly with time in animals exposed to VCM {Reynold* et al. 1975b). This destruction of cytochrome P4,0 may prevent further metabolism and toxicity of VCM (Pessayrc 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. chluroethylene oxide, is a powerful alkylating agent which covalently binds to various cellular macromolecules, notably vital proteins and nucleic acids. By binding to cellular ONA and RNA orchtical proteins the metab olite may alter vital functions and the genetic information of the cell and thus exert its hepatotoxjc,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 greiter risk in intermittent peak exposures over brief periods than might be ex pected from simple integration over tune and that the chances for effective detoxifica tion are greater in long-term exposure to relatively low levels. It was shown by Watanabe et al. (1978a) that repeated exposures of rats to VCM do not appear to induce its biotransfotmation, but significantly augment the binding of the reactive metabolite with hepatic macromolecules and may thus enhance the po tential toxicity of VCM. On single exposures of rats to increasing concentrations of labelled VCM ranging from 1 ppm to 5000 ppm, the amount of radioactivity covalent ly bound to hepatic macromolecules did not increase proportionately to the increase in concentration but followed a sigmoid curve with low and high inflection points be low 50 ppm and above 250 ppm. respectively, when binding was plotted as a function of the log of the exposure concentration (Wannabe et al. 1978b). This correlates well with MaltonPs 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. 1975;jrb and Bolt 1977), cyudine (Latb and Bolt 1978), and guanine moiety of nucleic acids (Osiermann-Colkar et al. 1977) has been described. But the degree of covalent binding of electrophilic metabolites of labelled VCM to hepatic nucleic acids seems to be very small (Watanabe et al. 1978b;icih and Bolt 1977). Laib and Bolt (1977) presented evidence showing that the alkylating potency of VCM metabolites cannot be deter mined solely by measuring the incorporation of label into nucleic acids after exposure to radioactive VCM. Watanabe et al. (1978b) concluded that covalent binding to nucleic acids is not the preferential reaction, but they pointed out that this does not Vinyl Ch exclude t of celiuia eluded as above all. This a work will endopiasn lible ro Vi phological mixed fun lobular, m. found (Jol 1978). Sec endothelu At pre. eessesare < the hepatc some meta (3) Meehai tissues oth tint cell re 1978b). An cqu. nonneoplas Raynaud's dreme was man. Besidt liver lesion., bioactivate portal flbn mentof the a direct or i: tic nervou* lining cells c tion) or wlu 4 Clinic: During the r might prove presented in marked the c pational haz. wmm UCC 088074 30 'V.K. Lclhach and H.J Mar-teller Table 7. Gradual emergence of evidence for VCM-associated pathology Year Reference Findings 1949 Trtbukh et al. Hepatomegaly, more nr !e mjrkcJ `anictcru hepatitis', `chronic jasrnti''. hypotension, anaemia, skin lesions 1954 1957 1957 19b0 Smirnova Filatova and Cronsberg Kubota Dansiger Toxic ungioneurosis Toxic angioneurosrs Symptoms similar to Raynaud's phenomenon Two cases of accidental fatal poisoning by VCM, 1 non fatal acute overexposure 1961 Smirnova Reversible osteolytic lesions of distal phalanges Pscudodubbing, thickening of skin on volar side of forearms, slight haemolysis and reticulecytosis 1963 Suciu et al. CyS. 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 hyperbilirubinaemta. splenomegaly Endocrine: hypothyroidism 1966 Conlier et al. Raynaud's syndrome, sclerodermalike 'kin 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. pseudodubbing, 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 Antonyuzhtnko Dinman et al. Mentions thrombocytopenia Prevalence of acroosteolysis and Raynaud's phenomenon 1971 1972 Dodson et al. Kramer and Mutschler 0 Vascular lesions preceding the bone lesions Increased BSP retention and raised icterus index related to degree of exposure Vinyl Chic Table 7 (ec y7^ ; 1972 .1972 1973 197*1) C 4.1 Their A Tim indie plant produ non (toxic in detail in h personnel w hourly samp drome was a {Kubota 191 moregulatioi and CNS syn (1954) alio r durations on there was evi of ted cells a evidence of c acrooiteolys: operators) at junction with was found in lesions to be reversible ch: vibration trai the full range cupationai ac In 1963 5 analysis of th VCM intoxication. During a A-year period, they examined 168 mostly young workers from two Rumanian PVC-producmg plants who liad 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). Acroosteolysts. however, was not mentioned. Episodes of acute overexposure (usually occumng at the end of a batch run, during retrieval of unreacted monomer, or at repair jobs) rapidly resulted in a state of lieht-headedncss and transient euphoria similar to a mild degree of inebriety and were accompanied by a feelingof heaviness in the legs and disturbed locomotor coordination. Several workers claimed to have been able to identify escaping monomer by iu 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 a). 1976) 6 yean later, after improvement m industrial hygiene, revealed that the frequency of their oc currence had considerably decreased (Suciu et ah 1975). Following a prolonged period of repeated overexposure, vague nonspecific digestive symptoms also developed, such as anorexia with ensuing weight loss, nausea, fullness, upper abdominal discomfort, bloating and epigastric pains. Enlargement of the liver was found in 51 worken (3CX7); 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 worken. involving the donal surface of the hands, the volar side of wnsts and forearms and the face, with firm thickening of subcutaneous tissue or formation of whitish papular or slightly elevated 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 2415 was recorded, with return to nor mal after a break from work or during holidays. With the exception of acrooneolysis and the two most alamiing late sequelae noncirrhooe portal hypertension and hepatic angiosarcoma - Suctu'i 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 histomorpholopcal aspects of the lesions encountered in subjects chronically exposed to VCM. The dis two Beigiar classifiable marktd the syndrome v year a numt United Stat cases of OA the various ; end of 1979 vascular phe symptoms t begin with L the fingers a tips on hard to cold acco are likewise ancc of pain osteolyuc pi with stnatio Table 8. Pub Year 1966 1967 1967 1967 1967 1969 1969 1971 1972 1972/197? 1973 1974 1974 1975 1973 1976 1978 1979 a One ol 2 cl 34 4.1.1 Familial and Idiopathic Acroosteolysis W.K. Lelbadi and H.J Mariioller Acroosteolysis is a very rare disease. Tire aetiology and pathogenesis of this condition is still obscure. Osteolytic bone changes in late stages of so-called Raynaud's disease (accompanied by necrosis and gangrene), characteristically presenting as loss of pan or of an entire distal phalanx of one or more fingers and also of toes, have been mention ed in the literature since 1921 (Assmann ]92l:MonaJtan 1926.Bonk 1927:A'.cmblum 1929). Kombium 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 Hochfetd (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 ilMeflned 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, linhum 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 ranty of this peculiar bone lesion that captured the attention of site medical personnel and industrial hygienists w hen in November 1963 the condition was detected in two Belgian autoclave cleaners (Lefh-re 1972). 4.1.2 Epidemiology of Occupational Acroosteolysis Attempts at assessing the prevalence of OAOL among personnel involved in VCM manufacture and polymerization revealed that in general this occupational type of osteolytic bone lesion was found in only l%-3% of the work population at risk. Hubtei et al. (1977) considered the fact that only 3% of all workers who had been engaged m manual cleaning of autoclaves at a Belgian plant suffered from OAOL and Raynaud's phenomenon to be indicative of the importance of individual factors. Wilson et al. (1967) observed 31 cases among 3000 employees of 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 1237 of them were workers who only handled finished PVC polymer. Five of the 32 plants worked V inyl Chic exdustveK only 25 clc defined as enen; 18 o with exper drome wert jobs, both t (1 case per appeared n< was detecie use for reac entry into t Table 9. Pn Country France USA . United Kingd m Fed. Rep Germany United Kingdom Total More cor related symp Lange and l. ological chec pathological were affcctet. cold, 15 worl morbidity w; found classic numbness an; 8.7% and inv< Allen test inJ people with p pseudoclubbi finding that t' duration of p. 56 W K. Ldhst/h jnJ H.J Mar*tc!!er Occupational acroosteolysis is a condition predominantly observed in younger workers. The age range was 20--15 yean and halt'of all cases reported tell in the 30--3*5 years age-group. Duration of VCM exposure prior to onset of Raynaud's phenomenon ranged from 1 to 23 months (Dodson ct ai. 197J). For OAOL the latency period was at least 12 months (Wilton 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 detective restitution, resulting in shortened and deformed distal phalanges, within 2-3 years after removal from VCM exposure, but Raynaud's phenomenon and cutaneous lesions may persist (Wiliams and McLachlan 1976). Stein et al. (1973a, b) reported partial healing wuh 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 suffenng 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 (Sfewarr 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 inhaiational (rather than trinsdemul - Dinman 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 teem 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 Wilton et al. (1967). 4.13 Clinical and Roentgenological Features 41.3.1 OccupationalAcrootteolytis In the majority of cases osteolytic lesions are confined to the hands. Involvement of the feet was observed only rarely in OAOL. Wilton et al. (1967) believe that OAOL diffen from familial or idiopathic acroosteolysis in several respects. Although the bone Vinyl O defects I: osteopof skull, de: ihortemr nonoccu: genologu 1) Tli' one or mi 2) Intufts, or % 3) Thr tufts toge defects (s ('bindlucc Fig. 2. Oci tcreosteoi' year-old sl 4) In tl and broadr fragments and increas Sodium nrineralizai multaneoui ?S _ W.K. Lrlbach jnd HJ Marsirllcr other body region were also involved. Erosive and sclerotic changes in the sacro-iluc joinrs and circumscribed resorptive defects (cortical erosions) in patella, clavicle, man dible. humerus, sryioiJ process of ulna, femoral condyles, os calcis. cuneiform and metatarsal bones have repeatedly been observed iCordk-r et al. 1966 .Harris anJ Adams 1967. Dodson et al. 1971 .Julie et al. 1914.Lange et al. 1974a; Preston et al. 1976; Jayson et al. 1976a. Lange and I 'drman 1977). 4,1.3.2 Pseitdoxlcroderma Concomitant with the manifestation of paracsthesias, pain. tendemess of the fingers ana 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 pufiiness and coarsening of the skin of the face (mostly on the forehead and cheeks). Raised, ivory<oloured, firm nodules or elevated, sharply de lineated plaquelike skin indurations are seen on the dorsal surface of fingers and hands and on the volar side of the wrists and lower forearms. It was this combination of Ray naud's phenomenon and cutaneous lesions which first prompted a search for other symptoms of progressive systemic sclerosis in affected workers. The syndrome of OAOL. however, can be dearly distinguished (Table 10). Notably, the diffuse immobil- Table 10. Differential diagnosis; syndrome of occupational acroosteolysis i Raynaud's phenomenon, sclerodermoid skin chanps, AOL) / progressive scleroderma with (rare) osteolytic lesions Occupational AOL Progressive scleroderma Sex ratio Exclusively 1 d*e 1:2 Hands Clubbing and shortening of finger tips; hyperhidrosis; no ulceration Atrophy and tapenng off of fingertips; anhydrosis; uicereuve lesions Penoral puckering of skin Skin appendages Telangiectases Shortening of frenulum Subcutaneous deposits of calcium salts Dysphagia i 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 profession Vinyl Chloride izmg sclerosis c uonal syndrom readily than the 9.1.-I Histolo; 4.1.4.1 Cuian Several invtsug: disease {Cordicr al. 1972.Lange we found only v 1967;.l/jrwr et. neural changes' who suffered 'rr Dtmal clus> mis with disone broad intcriacin faintly stained r Schiff (PAS). A histiocytes was The most notab of elastic fibres, full thickness isue. Skin appen Walker (1976) t" not exceeding t. some fibrous th. Vascular le t capillanes were and pericapillar thelial cells with tion oflununa. ` myocytes, was. to narrowing or Degenerative (Benoit 1967..V hvalinosis of :!iMeissner, Paam 4.1.4.2 Bond The most stnku worker with OA ening and hyaln most layer. Sur 40 W.K Lelbacli and II.J. Mamciii-r 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 histomorpliulogy of bone lesions in the familial and idiopathic type of acroosteolysis is limited. In the few eases where biopsy material could be ob tained. there was replacement of bone by nonspecific fibrous tissue, but inflammatory and degenerative chances or osteoid formation were not found (Dupa* et al. 1936. Elion and Bumstcin 195-i.Cn-vnbcrr and Street 1957:Schwarzwatvr 1957). In this context, it should be kept in mind that I'tola succeeded in reproducing dermal, vascular, neural and skeletal lesions in the skin of the paws and in small meta tarsal bones of expenmental animals which were very similar to 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. Tire vascular lesions were almost invariably con fined to the small digital arteries, although the superficial and deep palmar arterial arch may occasionally show some narrowing and a paucity of side-branches (Lange et al. 197-ii.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 \9b7: Lange et al. 1974a: Veltman et al. 1975;/Vejro/i et al. 1976; Jrrwerr et al. 1975: Came and Mem 1978). Angiographic findings in a larger group of 19 symp tomatic PVC workers with either Raynaud's phenomenon and/or acroosteolysis (5 T9) were recently described in detail by A'oixhwin 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 resorptivc 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 yean after cessation of VCM exposure (about 1 year prior to death from both angiosarcoma of the liver and hepatocellular carcinoma). The pathogenesis of these peculiar vascular alterations is not dear, but the possibility presents itself that they may be due to de struction of elastic Fibres in the vessel walls in analogy to similar alterations of digital arteries seen in rheumatoid arthritis (Laws et al. 1963.19t>7). Vinyl i Stu< nations finger? ed a vat lar area' those v feient <7 Urosco. control ence in PVC w. of distu induce i A si aPVC-y chemic: normal: was cot . number empk>) related < It also i more sc 12 W.K Laibach and II J. Marctellcr Vinyl Ch British workers who were examined 6-24 months alter leaving the plant (termination and medu of exposure), the prevalence of capillary abnormalities was not less than that among lung (1 ca those w ho continued work. For an evaluation of the reversibility of this condition, The at however, the group was considered to be too small. The same type of capillaroscopic changes was also observed in three of 4 Polish workers (2 reactor cleaners, 2 fitters) who were found to suffer from Raynaud's phenomenon after exposure for 2-5 years (Byczkowska and Langauer-Lewowtcka 1974). Infrared thermography, another non*invasive method, used by Rl. v 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 Angers) 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 Angers and patchy hyperthermia in the distal part of the OAOL-aiTected left index and middle finger of their aty pical ease. Local ized acral hyperthermia seen on IR thermography corresponded to the angiographic and bone bolic inter . plasma pre which sur culai occk as a result aton of tis to further Jayson et. suffenng f than in no ride disea* In an e finding of circumscribed abnormal collections of small vessels (compensatory collat in four Pol erals?) in the pulps of the affected Angers. Using IR thermography in a survey involv decrease ir ing 143 PVC production workers and 56 controls, Williams et al.(l977) assessed the ever, Lang, time needed for heat return after immersion of one hand for 10 s in a water bath kept alter Seph. at 198C; however, no difference between VCM-exposed subjects and controls and be 6 together tween groups within the exposed population was noted. agglutinins were obser 4.1 & Immunological Studies J-.' sponses pi; (1974a)an 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 H"able 10). Such similarities stimulated the search for other manifestations of a sy-.-mic collagen disease, notably immunological features, as pro posed by Marin et al.in 1967. 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 tout past and present work force of 320. Mean duration of exposure to VCM was 39 months (6-7S 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 hyperimmunogiobulinaemia, usually IgG. the presence of mixed cyroglobulins. and in vivo conversion of both Cj and C4 were found in 19 patients in the symptomatic group, with additional evidence of reduced T-cell population and increased B-cetl proliferation. Mixed cryoglobulins, in vivo con version of complement and depressed values for Cj or C were taken as evidence for the presence of circulating immune complexes. Autoantibody screening demonstrated tow-litre antinuclear antibodies (IgG 1/20-1/50} in eight of the nine patients with Raynaud's phenomenon. Aggregates of IgG, C4. Cj, 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 subintima! regions of small dence of ai tion of rhe terminatioi immunoflu were later. creases in it taken up at ed to sugge hypergami' with far ad three patie. with Rayn; degrees of < nins were f range: TL -1 sderoderm< of which is In surm autoimmun establish th in VCM4mi SPetww UCC 088081 **1 44 W.K Lelbach and II.J. Marvicllcr Vinyl Chionde-4- 4.1.7 Pathogenetic Considerations The clinical sympt RaynauJ't phenomenon as a premonitory clinical symptom, histomorphology in man and experimental animals and angiologicaJ 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 penpheral 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 ini Metro 1978). Yet the answer to the next question, the pathogenesis of penpheral 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 vanable 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. i j many as 152- of ti: survey w describe developing chronic character of nonm: - In 1972 Kranu had been routinely time-weighted aver: environmental data wise multiple linear tion and. to a lesser level of past exposu the individuals stuc TWA levels of300 in clinical laborator ed BSP retention w: ease (Martteller et a In West German 4.2 Non-malignant Liver Disease in Vinyl Chloride/Polyvinyl Chloride Production Workers dermatologists in Bi At first sight, the s> derma. This provoke Progressive systemic 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 porportion of a group of 73 workers (48 males. 25 females) mostly engaged in PVC compounding;`anicteric hepatitis* was diagnosed in 21 of them (15 d, 6 9). Al though tiie authots knew about the narcotic action of high concentrations of VCM (75-250 mg/Utre * 30 000-98 000 ppm) from the literature, which they explicitly mention, and also knew about the release of unreacted monomerYrom 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 utged. 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 Sueiu et al. (1963) 14 years later in almost one-third of the total work population (51 of 168 employees) of two Rum anian PVC-ptodudng plants, including 10 cases with additional splenomegaly. Liver biopsy in two of these workeis revealed chronic hepatitis. Studying the prevalence of temporary disablement due to liver disease among 350 employees of the Sverdlovsk plastics industry,Bushin (1965) found the highest morbidity among employees of the PVC production unit, compared with other units engaged in the production of nonPVC plastic materials; 170 workers of ancillary industries served as control subjects. a fust group of 13 p. from a nearby PVC-from either OAOL iphageal varices due i a group of 20 relativ previous liver disease Medical Department patient and revealed capu'irfibrosis of:ly. marked portal h> al. 1973). It was now encompassed a largeHence JiUte et al. (ly In retrospect, th; spleen alterations in c the long latency perildisease which is accon hepatic parenchymal Only 3 months L* was surpassed by the. liver, an exceedingly r workforce of274emp ican plant (Creech et: upper gastrointestinal 46 W.K Lelbach and H.J Marsieller There is no longer any doubt that chronic exposure to vw>t chlonde monomer can produce two different types of liver disease tn man as well as in experimental animals: 1) Xondrrhonc portal hypertension 21 Angiosarcoma of the liver. The two conditions have one feature in common: they are both rare disorders which are not easily recognized dunng 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 Banti in 1894. As 'Band's syndrome', this symptom complex and its aetiology and pathogenesis have continued td 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 (Ramahngaswanu et al. I962:lmanaga et al. 1962,Bam et al. 1967a, b: Boyer et al. 1967;Soma et al. 1971). It has been seen only sporadically in the Western World (Roussclor 1940; Rgvenm 1940; Tisdale et al. \9S9\Polish et al. 1962:Miller and Brandt 1962;SiJetys and Vellios 1964;Mikkelsen et al. 196S;Ibcr 1970:Escartin Marin et al. 1974; Mendenhall et al. 1974; Crannis 1975; Vdleneuve et al. 1976). Jber( 1969) estimated that "centers throughout the world reviewing their experience with portal hyperten sion encounter 3 to 59i of patients who do not dearly fit into the category of cirrhosis or blockage of the portal vein." In the absence of an identifiable aetiology it has been speculated that in noncirrhotic portal fibrosis observed in India.unknown toxins contained in indigenous drugs, herbal medicines or adulterated food might have been responsible for the condition {Same et al. 1971), Villeneuve 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 hepatotoxic agents, their common link with VCM being, so far with the exception of vitamin A, the induction of angiosarcoma of the liver. These agents are: i *' a) Inorjanic ancnicals (Zeefen et al. !970:,Vee/c and Azzopanli 1971;Knolle et al. 1974;Morris et al. 1974;Huet et al. 1975; Yillcneui'e et al. 1976; Cowlishaw et al. 1979); b) Hypervitaminom A (Muenter tt al. 1971;7?usjc// et al. 1973,1974; Hruban et al. 1974;Kistlerti al. 1977); and c) Recently,copper sulphate in Portuguese vineyard workers (Pimentel tndMenezes 1977). Arsenical preparations (usually prescribed as Fowler's solution - potassium anenite) have in the past been used as a tonic in neurasthenia, as an adjunct to iron therapy fat anaemia, as antiepileptic drugs and weB into the 1950s fot the treatment of psoriasis. In this context. Band's remark in his original paper (1898) that anaemia accompanying primary splenomegaly responded best to arsenical preparations is of note. In a renowned German pharmacology textbook of this period (Sothnagcf and Rtnsbach 1880) Fowler's solution is also listed as a traditional antimalanal drag of 48 W.K. Lelbach and H.J Marsteller Table 11.17 PVC workers with advanced portal hypertension i marked oe'Ophageal vanees. cpi-odes of upper Gl bleeding, splenomegaly i Age at diagnosis Duration of exposure Perttoneoscopic and N*o. (years) (years months) histological diagnosis 1 30 *1 31 3 32 4 35 5 3 35 6 39 7 39 8 41 9a 41 104 47 11 50 i: 51 13 52 14 s: 15 54 16 * 58 17 a 61 5 5/9 31b 4 9 10/6 13/6 7 18 18 6/6 17 15/3 11 6/6 21 13 Nonwirrhm;: fibrosis Noncirrhouc fibrosis Voncirrh aiic fibrosis Xoncirrhotii. fibrosis Noncirrhouc fibrosis Xoncirrhotic fibrosis Noncirrhouc fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhouc fibrosis Noncirrhotic fibrosis Noncirrhouc fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis a On followup patients 5.9. 10. 16 and 17 subsequently developed angiosarcoma of the liver and died 3-6 years after diagnosis of portal hypertension. Patients 6 and 14 are at present (1981) 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, tf a rough estimate based on these two small senes were acceptable, it would appear that approximately one of five to seven individuals suffer ing from advanced VCM-induced portal hypertension might be expected to develop angiosarcoma later, although PVC-induced hepatic fibrosis per se is probably not a premalignam 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 (Alamellar et al. 1975a). Lilts 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 pievalenee of hepatomegaly was found in those Vin>I Chlor exposed for spltnomeea! In contra ment ofhep: ectases. gyna not seen. Eve phalopathy d workers only It is push preceded adv. only one case development 4.2- Labor: Owing to the not the target value for the, This makes it 1974;Creee/i thrombocyte: logical bioche the levels of s. quent (Mantc (ICC: 0.5 and liver function workers of a (Tamburro et progressively of abnormal S there was ove< phosphatase Ialkaline phosp megaJy and/i*; Except for and Veitman i the reticulocy panmeters uspresenting fee Sion (Smith %\ be dealt with - Assessment matic workers facturc of PVt eoproporphyn so W.K. Lelbach and H.J. Marttrller these findings as an indication of toxic liver damage is not dear and the relation to previous exposure to VCM remains to be determined. 4.2 J Cross Inspection of the Liver and Spleen The gross appearance of the liver, as assessed by peritoneoscopy {Mamdlcr et al. 1975a. bi.Marsteller and Lelbach 1977;Lelbach andMantellcr 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 exdusion of partial nodular transformation as described by Sherlock era). (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'orangedike appearance. At most, there are micronodular changes but the diffuse coarse nodulamy of cirrhosis is only rarely seen. Progression to frank cirrhosis with severe derangement of hepatic lobular architecture was observed by South and Williams (1974), and also in two of our recent cases in combination with development of angiosarcoma. On palpation (direct or by pentoneoscopic probe), the texture of the liver is normal or only slightly firmer than usual. Indirect peritoneoscopic evidence of portal hyper tension is presented by increased vascularity of the falciform ligament and the intes tinal serosa or numerous dilated tortuous vessels in adhesions draining to the abdomi nal wall. Even in advanced stages, symptoms of pronounced portal hypertension often Fig. 4. Peritoneoscopic view of left hepatic lobe in noneirThotic portal hypertension (January 1979). Blunted antenor 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 oesuphagea! varices.) See also Fig. 5 fpatient 6 in Table 11) Vinyl Ch contras: s peetedly s is a focal. opacities, stellate sc: ing {Slant tissue in C extending nective tiss processes t or more di are seen in 4.2.4 His- Histologicb generally sis, strikin'fibrosis arc (Fig. 5a-d reactions.i. through ut fibrosis. Su tological e' 1978). Depend date of bic; nant liver u jeet to mirk ations is sc. Thomas 19' 1976). but (Popper et a 4.2.4.1 tt.. In its fully 2 of dense, pc bile ducts a. with format) central and i f connects with enlarge perisinusoij. oidal walls, i Muller et al. W.K. Lclbach and H J. Mj^reller Fif. 5*. Needle biopsy specimen of the liver shown in Fip. 4. Enlargement and fibrosis of portal tracu. Moderately larie droplet steatosis. Focal dilatation of sinusoids. H&E. x 80, bClosemp of Fi|. 5a Indistinct border of enlarfed and fibrosed portal tract to* wards parenchyma fltftJ. Proliferation of capillanes (> <) with polymorphism and hypcrchromasia of endothelial cells. PAS, x 400 5* tV.K. Lelbach ami H J Mjixtciler may be recognized only in connective tissue stains. Trichc et al.l l75l pointed out that in one worker with severe acroosteofysis but normal hepatic function and essentially 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 centhlobular increase in collagen between liepatocytes and in Diases spaces together with proliferation and hyperplasia of sinusoidal lining cells (see also Kuroknva et al. 1977). The same ultrastructural deposition of perisinusoidal collagen was observed by Schsttenberg et al (1977) in 15 PVC workers in whom we could ob tain liver tissue for electron microscopy at peritoneoscopy. Similar changes (enlarge ment of 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 *sinusoidai' portal hypertension) were seen on electron microscopy in a number of cases of idiopathic portal hypertension of unknown aetiology (occupational histories not mentioned) {Sommenchild and Kluge 1971, Kluge et al. 1970: Tendon et al. 1970). 4.2.4.2 Sinusoidal Lining Cells Marked focal proliferation and hyperplasia of sinusoidal lining cells with nuclear poly morphism and hyperchromasia are the most impressive features of the mesenchymal lesion. The hyperchromatic nuclei of these cells may show a bizarre shape or resemble short pegs, and are often arranged in a chainlike fashion (Cedigk et al. 1975). These pensmusoidal and sinusoidal cells indude three types; (1) normal endothelial cells, (2) lipocytes (lto cells), considered to be precursors of fibroblasts and (3) plump cells with spindle-shaped nuclei and PA5-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 premaiignant stage. 42.4.3 Hepatoeytes Unimpressive, nonspecific, degenerative and adaptive lesions (such as minor degrees of fatty degeneration, cloudy swelling, ballooning or vacuolar degeneration, increase of lipofuscin pigment and proliferation of smooth endoplasmatic reticulum of hepatocytes in focal areas without inflammatory reactions), can be seen to disappear gradual ly with increasing intervals between the last exposure and the date of biopsy, in con trast to the apparently irreversible damage to mesenehymal structures (Cedigk 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 binudeated cells. Two types of focal hepatoeytic 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 angiosareoma (Popper et al. 1975). 42.4.4 Histology ofthe Spleen Unless splenectomy is carried out in vinyl chloride disease, tissue specimens of the spleen are less easily obtainable than liver biopsy material. Popper and T7iomas (1975) Vinyl Chloride and Thomas et to be character geneous red pu! follicles with rm endothelial cell; occasional fresh spicuous fibrosis In ten cases w Heusermonn and teriol, together v splenectomy. TV process. Excess < tive tissue, noufc and white pulp. There was scam; meshwork and rt and diameter of of the pulp cord: formation of biz. collagen Abrils, h the reticular com volume with para matron of capilla found within the thrombocytes by hanced pooling o help to explain in stages of vinyl chi and Heusermann VCM-induced spl; of the liver or ex'. in the spleen in n dicate a primary . port correlating ci tients is being prs, the spleen in nom. able for comparis< 42 J Pathophysi The pathophysioli unresolved probiei to splenoportograt of intrahepatic vjj, venous radicles (B! and a normal, or o UCC 088087 5 b W.K, Ldbach anJ H.J Mjhi.-lia portil flow is obstructed at the sinusoidal or presinusoidal level. In a group of five PVC workers selected for haemodynamic studies, Blcndu et at. f 1978) could not demon* strare a direct relationship between the decree of hepatic fibrosis in needle biopsy spec* imens and portal hypertension. But it should be kept in mind that the distribution of fibrosis in these workers is quite irregular. It has also been suggested by Pepper and Thonm (1975) and Thomas et at. 11975) 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, porta! and perisinusoidjl fibrosis. Bltmlis et al. (1975) found no correlation between spleen or estimated liver blood b Fif. 5a* b. Progression of noncirrhotic porta! hypertension despite termination of ex* posure. Oesophageal varices. (Autoclave cleaner, age at diaposit' 35 years. VCM*exposure.1962-1972.1972 Raynaud's phenomenon, skterodermoid skin indurations, thrombocytopenia.splenomegaly, and grade I oesophageal varices. Gradual progression of portal hypertension. Sudden death from ruptured anaplastic angiosarcoma of the liver in June 1975. Histologically only mild peristnusoidal fibrosis in nontumorous areas) Vin, flow veile 42.6 In 19 tic til could tests. biops Of bn the fir cytes ing ce follow massi' expos sarcor or less terrair oped ( Uv detem (BMHF after h and toi aid of > the ret. bicreas PVC p. sack et 4J A. *J.l I Primary (angiob haemari cdl sari arcoRu vasculat one ate hood (ft the num 58 . W.K. Lelbach and H.J. Marsteller of the literature..4 irengo (1975) listed 165 published cases of primary angiosarcoma of the liver in adults. In the six autopsy series collected by Alraiga. ASL constituted only 1 S% (QS'Z--2.7%) of all primary malignant turnouts 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 dunng 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 enore United States. Table 12. 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 ooo ra Edmondson 1958 1918-1954 MacSween et al. 1973 1900-1969 _ a l Los Angeies. County Hosp.. USA 3 Western Infirmary Glasgow, U.K. Alrtnga 1975 1951-1973 39 700 6 Cook County Hosp. Chicago. USA Rem and Hush 1975 1954-1974 30 079 Byrin and Holmbtrg 1975 1958-1969 _ b 4<6)c Dti*scldorf. Fed.Rep. Germany 12 Sweden (adult cases) Daldtrup ct 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 dunng this 70-year period, b Among 8 million inhabitants. c 4 Angiosarcomas. 1 haemsngioendothelioma, 1 malignant haemangiopencytoma 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 (Ovec/r ct al. 1974a;Creech ui&Jolinx>n 1974). Until 1974, only two carcinogenic agents were known to be associated with the development of ASL in man, ic. the administration of a radioactive colloidal prepara Vinyl * tion of inorgat dioxide tern an- . 7710contras in" evid reporter been th< had bee and '.to. A spent caused \ thorotr from a 1 ASL(/t Dev, man vin tensivel) 1950-1 tion rew of multi; approve, occurred but nota produce, Haustrui (3%-S' Roth (lc 18.6-t: Fowler* Giow haemangi tension h woman w ride) dun had a hie; manifesto The p: be elicitct period 18 history of Among m observed other han 391 auto; -- >t- 1* - "'r -* rtsSr** M) W K. LelbaJi and H.J, Mantellcr Table 13. Personal data ot' 68 polyvinyl chloride production workers with ann-jsareoma pi ills liu'r reported to NIOSH up in Aupust 197S |Spirits and Kaminski 19*51 Date of Birth date death No Country3 (m/J/j >b t m/d.y) A^e at death 1 Bill 01.12.13 * CNDt J) 12.15.13 3 CND 12) 03 06 14 4 CND (3) 08.26.19 5 CNDI4) 04.05.19' 6 CND (5) 05.07.11 7 CND (61 12.15,19 8 CND 17) 11.09.19 9 CND (8) 05.13.20 10 CND (9) 07.I9.2J 11 CND (10) 05.16 15 06.29.76 09,02.55 12.21.J7 03.22.62 01.21.68 07.05.68 04.10.71 J 2.24.72 06.12.73 09.04.74 04.00.77 63 41 43 42 48 56 51 52 53 53 61 Total years eep. 17 11 14 20 m 5 23 25 5 26 14 Job classification1. 1.2 1.2 2.3. U. 13 2.5 1.2,5. 14 1. 14 1. 12.15. 15 1.9. 17 1. 12.17 3.12. 16 2.16 12 fSR 11) 00.00.28 13 fSRC) 0000.26 12.00.73 00.00.66 (64?) 45 40 (37?) 16 15 (14?) 1 1 14 DU) 15 D (2) 16 D(4) 17 D (5) 18 D 17) 19 D<8) :o D (9) :9i- DUO) DUD 23 DU2) 24 F(l) 25 F(2) 26 Ft3) 27 F (4) 28 F (5) 29 F (6) 30 F (7) 31 F(8) 32 F(9, 33 F 110) 34 GBU) 35 CB (3) 36 1C) 37 1(3) 38 3(1) 39 3(2) 06.04.30 07.26.31 09.04 JO 01.01.32 09.29.26 10 19.17 12.13J4 07.23.29 12.29.36 06.14J8 04.15.24 06.03.11 01.06.20 01.27.27 01.29J8 04.I4J4 00.00.27 04.01 J4 10.08.14 05.24.19 04.20.01 06.02J7 01.25.69 12.14.71 11.25.74 01.09.75 11.13.75 12.25.75 03.24.78 06.28.77 03.07.77 10.07.77 02.19.67 01.24.75 06.26.75 01.03.76 05.13.76 09.12.76 07.02.76 01.30.77 12.25.77 01.20.78 12.03.72 12.24.74 38 39 44 43 49 58 42 47 4| 39 43 63 55 49 38 42 49 4? 62 58 71 37 11.13.29 03.14.20 08.01.22 08.02.29 12.27.72 07.10.75 10.24.75 08.10.76 43 55 52 37 12 11 * 17 12 2.4.5 12 11.(1) 21 * ^15* 10 10 ?6 10 61 19 1.2 12 * 29 * 26 2.6 11 1.2 13 6.7 *m*m *9 19 * :a 21 ** ^*9 8 4l 3 1/2?) 6 ** 21 22 13 40 Nil) 12.23.15 01.04.72 56 21 Vin> Tabic No. 68 PCS 00.1 (Tables ! referrm. UCC 088090 .vj 'iftinJ-S! 61 W.K. Lelbach and H.J. Marrteller a population of 130 000. One of the four had a history of occupational exposure to polyvinyl acetate, which has hitherto not been related to ASL. The other three may have had nondocumented exposure to arsenical pesticides, which were used for many years in this region, but such conjectural deliberations must await further investigation for confirmation. Death certificates for the periods 1963-1973 in England and Wales and 1965-1973 in Scotland recorded 41 cases of ASL (1 -9 cases per year: mean: 4 cases per year). An unexplained peak was observed in 1963/1969 (Baxter and Fox 19`'5). Six additional cases not mentioned on the death certificates were detected by a panel of specialists (Baxter et al. 1977). In reassessing 36 of these 47 patients for whom histological sec tions were available, the panel of histopathologists unanimously agreed on the diagno sis in only 14 cases (7 doubtful. 3 undassifiable, 12 non-ASL). For 12 of these 14 cases occupational and residential histones 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 thotium dioxide. After the first three cases ofASL 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 eases reported to them from nations with an im portant PVC industry (Lloyd l97S,Spirtas and Kaminski 1977). As of August 1978. data had been presented on a total of 68 cases of ASL among polymerization workers (Spirtas and Kaminski 1978, pen. comm.); another eight cases had been observed among nonpolymerization workers exposed to VCM in various jobs. On the basis of this data collection communicated to us in 1978 -- for which we wish to thank Drs. R, Kaminski andR. Spinas. NIOSH. Cincinnati, USA - we attempted to trace these cases and their individual symptomatology as weO as other relevant information pub lished in the literature up to 1979 (we Tables 13-18). The ten Canadian cases of VCM-induced ASL (caws 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). Caws 19 and 23 were obwrved at our clinic in 1 jnn but details have only been published for caw 19 (E.U. in Lelbach and MantcUer 1977). In reviewing the literature we could not traee caws 37--40.43,50,51,53--67 and C, F and H. According to the latest annual report of the Staatlicher Gewerbearzt, Diiswldorf (Retnl et al. 1978), the number of deaths from VCM-indueed ASL in the Federal Republic of Germany had increased to. 16 by the end of 1978, to which we now add a 17th caw (Figs. 8 and 9). In retrospect, it was discovered that the first caw of VCM-induced ASL had already occurred in 1955 in a Canadian polymenzation 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, respecuvely). In comparison, mean dura tion of exposure in our group of 17 individuals with advanced nonmalignant liver distaw (we Table ll>was 10 3/4 years (range: 3 1/2-21 yean). The latency period (yean from first exposure to diagnosis of ASL) ranged from 9 to 38 yean (mean and median: 21 yean). The average age at diagnosis of ASL was 50 yean (range: 37-71 yean). Vin\ Table 14. Clinical and morphological data tK polyvinyl chloride (PVC) production workers w ith angiosarcoma of tire liver reported lo NIOSH by August 1978 Tabic 14 (continued) llepaloNo. meekly Spleen Oesophageal llepalie vat ices fibrosis Throtnhocylupeuia 13 Moderately (> (7300 g) enlarged (Cirrl'itsisl, f fihrnsi) 13 (2750 g) f (Cirrhosis) * 14 Spleno ? T f megaly 15 Slightly t ? * enlarged 16 Spleno {2650(1 megaly IS I0g| Capsular, porlal, septal ' (72 000, 65 0001 17 Spleno . 1 megaly IS ? Pemplenill* * (134 000, 66 0001 19 (1 Spleno (1450(1 megaly IdlHlgl 30 21 Spleno (1900(1 megaly - (> * Progressive petismnsoidal. (SO 000, porlal and 47 000, seplal eitthods 300001 *V *f Acrnosleolysis 0 0 0 ft ft fl ft P 1 0 Haynand's phenomenon McIusIum*s t9 0 l.ell lung 0 4lh left rib 00 0 Isl Ihoraeie vertebra 0 drain 3rd lumbar vertebra 00 t \f 00 W.K. Lelbaeh and H J. M arM der Vinyl C' 22 Spleno megaly T 23 S pic no- 0 (2700() megaly (435 g) Capsular, porlal, per'sinusoidal I'ocal peri T sinusoid al ff 0 0 0 00 Table H (continued) Hepato No. megaly Spleen Octoplugcjl tlepalie varices IllttOtil Thrombo cytopenia 34 Slight * t T (2625 g) splenomegaly (80 000) 35 Congested, (3240 g) firm (2110 g) Nonelrihotic 7 ft k(o\is 36 t 7 t Acroosteolysis If i P 37 38 39 40 4) 42 * 43 44 Splenomegaly 7 77 Splenomegaly 45 Spleno megaly * 46 Spleno (I860g) megaly 7 77 t7 Suhcapsutar and portal fibrosis Markedly * thickened capsule; marked fibrosis Portal fibroids 7 7 7 t i t Kaynaod's phenomenon Mel ad ases If if fp P Local spread to abdominal wall and colon; lymph nodes 77 77 PP tp P 5tpre.nl to diiorlenutii W.K. Lelbach and H.J. Marsteiler i47 Spleno megaly T` Portal fibrosis 135 000) ff Spteail to diaphragm anil abdominal wall m hi, m 63 W.K. Lelbach and H.J Mjr-tdlcr Table IS. Publications on the 63 cates of angiosarcoma of the liter listed in Tablet 13 and 14 NO References Additional relevant information l Hublet ct al. (1977) o \ ` l | Drtome and Afakk 5 11975) 6 i, Makkttal.(1976) 7 f Delorme (1978a, b) 8 Delorme and 9 Theriault (1978) 10 11 J = Schmidt and Batora ' (1976) '3 Hypertrophic, hyperchroniatic and ji\ picol endothe lial cells in the glomeruli; foci nt liaematopoctic cells in liver and spleen Case no. 7. ASL associated with hepatocellular . carcinoma (Delorme 1978b) (All cases from one plant in Sltawinigan. district Trots Rivieres. Quebec) At the same plant: 4 cases of VCM-indiiced cirrhosis of the liver plus 1 case of cirrhosis and gmerjlired reticulosarcoma and 4 cases of carcinoma of the 01 tract or lungs 14 | Lange et at,(1974b) 15 Cedigk et al. (197$) 16 Cokel et al. (1976) 17 Amann (1975) Riibtamen (1976) Sec also Reinl and Weber (1974) See also Reinl and Weber (1974) Foci of haematopocsis within the tumour areas 1974 portocaval anastomosis :cholecvtectomy. Hypertrophic, hyperchromatic and markedly atypical endothelial cells in the glomeruli and in the capillaries of the lunge 18 Reinl et al. (1976) 19 (Observed in Bonn) Moderate hepatic siderosis: chronic fibrosing pancrea titis; tubular and interstitial fibrosis of the resres 20 Reinl et al. (1976) 21 Rtml et al. (1977) 22 Retnl et al. (1977) 23 (Observed in Bonn) 24 ReWerctal. (1975) Focal interstitial fibrosis of the pancreas See also Berrod et al. (1978) 25 Rocheet al. (1978) 1942 gastrectomy. 1974 splenectomy, right hepatic lobectomy (640 g). See also Roche (1977): Ruech et 1.(1977):Bonneton etal.(197S. 1977);Berrod et 1.(1978) 26 Rety et al. (1976) No autopsy (see also Berrod et al. 1978) Vinyl Chi' Table 15 i. No. Ret 29 Ro< 30 s 31 ! 32 33 )j>l Bet 34 U 35 Sm. 36 Me 37 - 38 39 4 - 41 By 42 Byr. 43 - 44 Bh (ca- 45 Bio (ca . 46 Bli'e (ca- 5 irr. 088094 70 Table 15 (continued) No. References 47 Block (19741 (case 1) 48 Block (1974) (case 5) 49 Block (1974) (case 6) 50 51 -- 52 Whelan et al. (1976) (case 3) 53-67 - 68 Zones et al. 11975) W.K Lelhach gnd H.J Mjrstelier Additional relevant information See also/VI; et al. 119'4j) (ease 2),Makk et al. (1976) l ease 4) See also Falk et al. (1974j)(vase \)-.Makk et al (1976) (case 2) See also Falk et al. < l974jMcae 6V. Whelan et al. (1976) (case 4):Mekk et al 11976) (case 14| Chronic alcoholic. See also Mekk et al (1976) ica>e 13y.Btrk et al. (19761 (case 2) Among a work force of 1801120. PVC polymenzatton: 60, production of VCM) employed it this plant, 1? died of malignant disease (2 ASL. 5 bronchogenic carcinomas. 1 case each ot carcinoma of the larynx, rib, mamma, spermatic cord: glioma, melanosarcoma. leukaemia. Hod akin's disease) First exposure to VCM for these 67 cases of ASL dated back to the period 1934. 1966 (median: 1951). Twenty-one years later, i.e. from 1973 onwards, a gradual in crease in the number of new cases diagnosed and reported to S10SH can be observed (Fig. 7). The onset of this gradual increase coincides with the calculated mean latency perio ' of 21 yean (Spirta: and Kaminski 1977). Spirtas and Kaminski also suggested that >n ruture 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 porta] 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 actoosieolyiis and cutaneous stigmata of scleroderma have been observed in only 1 of these 76 patients, a Freneh PVC worker who had apparently not been engaged in reactor cleaning (ease 29;Roche et al. 1978). Another noteworthy piece of informa tion is that strikingly atypical endothelial cells with hypertrophic and hyperehromatic nuclei have also been found in organs other than the liver (kidneys, lunp) in autopsy material from rego patients (cases 1 and 17.Hublet et al. \9H\kubsamcn 1976). Hubtet 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- ia<ti 'V i--1 * J* * v',- r i - *-.# : Table 17. Clinical anti iiuifpliuliigkal data m eight cases of angiosarcoma id I lie liver ami mg V(M-e sposc.t pcrsi-ncl mil cmploycil in eve HrMcriMiinn * ti Hepato No. megaly Spleen Oti\nplia|!e;il (lepatic mtvci liluiisis Ttirombncylti|H'itia A Spleno (AOOQgl megaly l*i trial lilmish t B Splcno- * (36501| me|>aly (425 |) Focal capsular 0 fibrosis, p<trial and ccnl n>!titular (ilmtsis Atmosteolysis * 0 Kjyiijuil's pltenninenon Me Iasi ases 0 Diaphragm,gastric mucosa, abdominal lymplt inhlet 0 Diaphragm. pleura, abilttuiuul lymph males C l> (> k* Not enlarged 0 tt 7 ? (104 000) 0 0 0 0 Lungs, peritardmm F Splenomegaly f * f 0 * Dura, cranium II j.' !|,' iM r|\ f pUr u ir 4|aT 3 5- 3 < c e *'te,305'<*'D,9 3 .3 o- lx o m oo "1" I O* . or 7i 'V.K. Lelbjcli and li.J Manielltr patient with toth angiosarcoma and hepatocellular carcinoma). Fibrosis of the testes was observed in three cases (19,29. B). and Roche et al. (1978) also reported fibrosis/ hyaiinosis in vessels of skin, heart, tuns and intestinal wall. CUMULATIVE N* OF CASES REPORTED TO NIOSH Fif. 7. Cumulative number o(cases of A$L among PVC production workers reported to NIOSH up to August 1978, arranged according to year of diagnosis (data from Spinas and Kaminski 1977, 1978) 0.2 Clinical Manifestations The clinical symptomatology of usually multieentric ASt is unspecific. Gradually de* dining general health and loss of weight combined with Ql-defined upper abdominal discomfort and sliest epigastric Dr right upper quadrant pain are usually the first symptoms. Recurrent bleedinp from oesophageal varices may have been antecedent vents in patients with portal hypertension who otherwise felt fairly well. In a number ~b W,K. Lelbach jnJ H.J. Mjrsrcller vances dunng the following yean with repeated episodes of bleeding which required (successful) sclerosing therapy (major surgery was declined by the patient). In August 1979 he presented again wtth recurrent epistaxis and slight but permanent epigastric and upper right quadrant pain, but declared that he lelt otherwise fairly well. He com plained about a sharp localized epigastric pain on sneezing There was marked spleno megaly. and an ill-deiined hard mass was palpable in the epigastrium. Apart from mod erate elevation of alkaline phosphatase and borderline hyperbihrubinaemia, biochem istry was normal. Computer tomography showed a large irregular hypodense tumour mass in the liver, involving both right and left lobes (Fig. 8). which became practically isodense after intravenous injection of contrast medium. A liver scan corroborated the tumour defect. Shortly after this there was mounting evidence of brain involvement and rapid deterioration. Computer tomography now revealed multiple brain metastases (Fig. 9). Autopsy confirmed the tentative diagnosis of metastasizing angiosarcoma of th* liver (Fig. 10). mm Saw*V; S -S i\ iVfV"*r.i **' r-4 'rv k_1_ m. Fig. 9. Computer tomography showing multiple brain metastases of angiosarcoma of the liver. Sec text. Courtesy of Professor Thum. Department of Radiology. University of Bonn 4JJ Peritoneoscopy Little information Is available in the literature concerning the peritoneoscopie aspect of VCM-induced ASL (Roche et al. 1978). It may be impossible to make a diagnosis of the initial phase of ASL in VCM-exposed workers by peritoneoscopy and needle biop sy of the liver, as documented in one of our patients who died of multicentric ASL Mi im W K. Lclbjkh and H.J Mjrsicller 11 months after peritoneoscopie diagnosis of severe hepatic fibrosis (case 19; see also Laibach and Marsteller 1977). In addition to the findings described in connection with hepatic fibrosis, there may be hypenascularized or cyjtic tumour formation visible on the surface of a nodular, quasi-cirrhotic liver, or a gross aspect resembling hepatic metasrases if the vascular malignancy involves the superficial regions of the liver. It should be stressed here that needle biopsy is absolutely contraindicated if there is any suspi cion of ASL. 4J.4 Cross and Histological Morphology The liver is usually markedly enlarged. Liver weight in cases of ASL ranged from 1600 to 7300 g (Thomas and Popper 1975 .Roche et al. 1978). The gross appearance of angio sarcoma of the live, is mostly that of large bulky, irregularly shaped cystic tumour masses; a multinodular form with numerous, sometimes umbilicated nodules, is less often encountered. Extensive haemorrhagic and necrotic areas or solid and spongy por tions of tumour tissue replace much of the liver parenchyma. Rupture of large cavern ous cysts may cause fatal intraperitoneal haemorrhage. Thomas et al. (1975) and Thomas ind Popper (1975) distinguished four basic devel* opmental patterns of histomorphology of ASL, which can be found in different por tions even of the same tumour and appear to represent stages of progressive evolution: sinusoidal, papillary, cavernous and anaplastic patterns. Indistinct areas of transition and merging of patterns can be observed. Dilated sinusoidal spaces lined by hypertrophic and hyperplastic sarcoma cells with pleomorphic, elongated, hypejchromatic and often bizarre nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells of varying differentiation envelop liver cell plates and may invade enlarged and fibrosed portal tracts, ac companied by proliferation of bile ductules (Fig. 11). In papittan 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 (Weinbrtn 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 eases, solid areas or nodules of anaplastic sarcoma are found, resembling solid spindle<ell sarcoma, or even suggesting an epithelial type of tumour. Cedigk et al. (1975) also observed a reticulosarcomalike pattern. The differentiation of the tumour cells varies widely: it ranges from the ineonspieuous 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 aeuol- ogical 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 liven of heavily exposed penons. Fibrosis of enlarged portal tracts with modest proliferation of bile ductules, mostly only seanty infiltration of lymphoevtes and occasional formation of perilobular septa or thin connective-tissue septa extending into die lobular parenchyma can be found. A more or less conspicuous intra lobular, perisinusoida! fibrosis is often detected only by special staining methods for collagen or reticulin fibres. As a rule, irregular focal or nodular fibrotic thickening of \ t: * ^ ' p. nu. per 1 ** `` or 1 ^1 01 " ? 1 C1 R>u cyudejc re tit I crea- !- a, jum'! vw v M m > I.f IPI. 7 W K. Lelbjeh and H.J Mjrvtclier 11 months after peiitoneoscopic diagnosis of severe hepatic fibrosis (case 19: see also Lelbach and Marsteller 1977). In addition to the findings described in connection Kith hepatic fibrosis, there may be hypervasculanzed or cystic tumour formation visible on the surface of a nodular, quasi-cirrhotic liver, or a gross aspect resembling hepatic metastases if the vascular malignancy involves the superficial regions of the liver. It should be stressed here that needle biopsy is absolutely contraindicated if there is any suspi cion of 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 1975;Roc/ie et al. 1978). The gross appearance of angio sarcoma of the live, is mostly that of large bulky, irregularly shaped cystic tumour masses:a multinodular form with numerous,sometimes umbilicated nodules, is less often encountered. Extensive haemorrhagic and necrotic areas or solid and spongy por tions of tumour tissue replace much of the liver parenchyma. Rupture oflarge cavern ous cysts may cause fatal inuaperitoneal haemorrhage. Thomas et al. (1975) and Thomas and Copper (1975) distinguished four basic devel opmental patterns of histomorphology of ASL, which can be found in different por tions even of the same tumour and appear to represent stages of progressive evolution: sinusoidal, papillary, cavernous and anaplastic patterns. Indistinct areas of transition and merging of patterns can be observed. Dilated sinusoidal spaces lined by hypertrophic and hyperplastic sarcoma cells with pleomorphic, elonpted, 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 inegular blood-filled vascular spaces, into which loose papillary strands of surviving hepatic cords on an axis of connective tissue project, lined by sarcomatous cells {Weinbmn 1978). Even larger blood-filled spaces are seen in the cavernous type, where they may be surrounded by thick flbrouc walls. In a smaller percentage'of cases,solid areas or nodules ofanaplastic sarcoma are found, resembling solid spindJe-cell sarcoma, or even suggesting an epithelial type of tumour. Gedifk et al. (1975) also observed a reticulosarcomalike pattern. The differentiation of the tumour cells varies widely; it ranges from the inconspicuous endothelial lining cell type to irregularly shaped, grossly distorted giant-cel! forms. Morphologically, vinyl chloride-related ASL cannot be distinguished from ASL associated with other aetiologieal 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 liven 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 rcticulin fibres. As a rule, irregular focal or nodular fibrotic thickening of i*: %. *. Fit liw nu. per In- f< lyu Thi ore life i Old. plat met reti. cyu degi re tii crea 80- W.K. Lclbjch jnd H.J. Mai'tdler by formation of excess connective tissue or by accentuation of sinusoidal dilatation leading to pnmary peliosis. Involvement of portal areas in the evolution of angiosarco ma results in considerable fibroplasia and formation of hyalinized collagen together with proliferation of bile ductules. In occasional cases connective tissue bodging be tween portal tracts or between portal tracts and central veins with subdivision of lobu les followed by rearrangement of hepatocytic plates may lead to a cirrhosislike picture. 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 ofcases. A survival period of two years after surgery (Berrod et al. 1978) or chemotherapy (Dannaher 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. 4J.6 Risk Assessment When in the United States 13 white male cases of ASL had been detected from 1961 to May 1974,among an estimated total population 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 Caneer Institute's Third National Cancer Survey (1969-1971), which expected for the total United States population an annual incidence or this tu mour in the onlerof0.014/100 000. This would have meant only about 0.03 cases per 20 000 polymer-ration workers within a 10-year period. Dose-response and attendant biotransformar : n data on experimental animals have since been used to elaborate sev eral different models of extrapolation to man. These were calculated with reference to relative body surface areas, for estimating the risk of ASL in human populations ex posed to VCM and for establishing guidelines to assist the research for Realistic safe doses' that dD not affect the average lifespan of a person exposed (Sehneklerman et al. l975;Ge/irif et al. 1979,1978: Woods 1979). Gehring et al. (1979) consider a probit percent model to be a reliable tool for risk prediction, which works without the assump tion of a threshold. They predicted a cancer risk ofl 5 cases of ASL in 100 000 000 workers on exposure to the cureent 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 rau and humans was described by Woods (1979).This model arrives at an incidence of 3.9 cases per 100 000 000 workers after a lifetime exposure to 1 ppm. Much controversy, however, about the validity of risk extrapolation from animal experiments to nun and from high- to low-level expo sure and the problem of threshold doses has been voiced ( Waugh 1978: Hooper et al. \919\Sehneilerman 1979: Weigert l979:Rcirz etal. 1979). Vir (ex. ASL Thu the con: had the : poly was viro; ceed lesst mag ting. milLi viny mod the e grou: 4J.7 For a hazar the ct ttudii Sure t the lu al. 19 We.vH of Bn 1976. posed t al. voiced Berry empli. and c,, but nc 1976) In (1974 epiden (1978 facto n 'n: s- ?2 W.K. Laibach and H.J. Marstciler through 1974: (a) 7021 workers encaged in the production of VCM and PVC; (b) 4910 chemical worken from the same plant* not exposed to VCM; and (cj 4007 worker* engaged in PVC manufacture. Not included were non-German worker* of Mediterranean origin. This German study permits comparison not only with the mor tality ratio of the total male population but also with a comparable occupational group exposed to VCM. With regard to the *healthy worker effect* tMcMtchoel et al. 1975), overall mortality was elevated for the VCM-exposed population (group a), but not for the other chemical worker* (group b). Apart from the markedly elevated stan dardized mortality ratio (SMR) for malignant liver tumour* (1523), which proved to have been elosely related to the duration of exposure, a significantly elevated SMR'was found for tumours of the lymphatic and haematopoeuc system (214). Die group of chemical workers not exposed to VCM (b) also showed a significant elevation of the SMR for liver tumour* (401), a result that deserves further investigation. No signifi cantly increased risk was found concerning tumour* of the central nervous system or the respiratory tract. It has already been mentioned (Sect. 22.10) that an excess mortality from brain tumours (SMR 535) was recorded among PVC worker* 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 405 of deaths having occurred in ex-PVC worker*. 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 tiire (CEA) in 200 Canadian PVC production workers (mean duration of em ployment : 10 yean) showed a more than threefold higher frequency of levels above 10 ng/ml than in a normal healthy population (1.7% vs. 0.55) (Page ct al. 1976). Levels of CEA were also determined in 1363 worken of five different VCM polymeri zation (3) and PVC processing (extrusion) plena (2) in the United States {Anderson e t al. 1978). After removal of possible contusing facton (smoking, alcohol inuke. past medical history), it emerged that the distribution of CEA titres among the polymeriza tion worken was significantly different from that in the extrusion plant group and in a nonexposed reference group. Significant differences were also found for two of six job categones examined (polymenzaoon and maintenance) compared with extrusion worken and the reference group. However, the usefulness of the CEA litre as a predic tive indicator of possible increased risk seems doubtful. 4.4 Miscellaneous Aspeca 4.4.1 Thrombocytopenia and Platelet Function Tests Thrombocytopenia in chronic VCM intoxication was flnt mentioned - rather paren thetically and without further comment - in a paper published by Antonyuzhenko in 1968, Later Juhe et al. (1973) noticed that each of the fint 13 autoclave cleanen re ferred to them during 1972 from a West German piant because of suspected skin and The  yj a H SLTd r-vty 84 'V.K. Lclbjih and HJ Marstcllrr pbtrier spreading), enhanced response (platelet aggregation) to addition of ADP and collagen (Bom test) and increased availability of phospholipid-containing piateiet fac tor 3 (fiarfutcr et al. 1975a). Thu pattern was thought to be compatible with the no tion of an increased turnover rate due to derangement of microcirculation (CDIC) in liver and spleen and defective reticuloendothelial system (RES) clearance of activated clotting factors (flac/mcr et al. 1974b). Ward (1976) and Ward et al. (1976) suggested that thrombocytopenia could be construed as confirmatory evidence of an immune complex disorder. Hcasermaim and Saute (1977a) noted unusual focal aggregation of platelets in klatsch preparations of spleen tissue and increased platelet pooling (plate lets trapped within the subsinusoidal meshwork of pulp cords) in the red pulp of the spleen on electron microscopy as well as phagocytosis of thrombocytes by sinusoidal macrophages. Schaffncr et al. (1976) found platelet thrombi in and around hepaue 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-mduced 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 Ctrrttj et al. (1974) in connection with splenomegaly of various noncirehotic origin. 4.4.2 Central and Peripheral Nervous System Miscellaneous nonspecific and somewhat indefinite symptoms have been described in connection with chronic inhalauonal 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 pseudoneursthenic symptoms (Sued/ et al. 1963, \925:Sehottek 1969: Lilis et al. 1475 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 he mainly in resultant inadequate reactions to critical situations {Schortck 1969). However. 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, listlesineis and depression, with onset of symptoms having been de layed s 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, Pcnm et al. (1975) examined a group of 21 autodave cleaners at varying intervals after cessation of exposure, ail of whom presented with other (cutaneous, angioneurotic, hepatic) manifestations of vinyl chlo ride disease. Clinical symptoms of a more or less distinct encephalopathy (including cerebellar ataxia in 4) were found in all but one of them. EEC recordinp were normal in only five of these patients; in the others, perenrhythmia, 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- Vi 4.4 trm * 86 W.K. Lelbach and H.J Mjrvieller 1969-.Szende et al. 1970:I'ertkm and Mamontov \970\Fmngia et al. l974;Z)ad.e 1976:Arnaud et al. 1978). Considerable exposure to VPCdust is the rule in the drying, bagging and storage areas of PVC-produdng plants. Photographs contained in Kantadti 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 Parmeggiani and Sassi. In 1969 Broussard mentioned the possibil ity of development of chronic bronchitis caused by the inhalation of PVC dust. Die insoluble and inactive dust panicles were thought to accumulate in the lungs blocking alveolar spaces and being taken up by alveolai 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 panicles found in the patient's lungs. Another anecdotal ease 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 Amaud 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 appearences were normal and routine respiratory function tests showed only slightly impaired CO: dif fusion in six individuals, perfusion and ventilation scans revealed strikingly abnormal pictures, including marked perfusion defects of upper lobes. Darke pointed out that some of the men wont affected had been engaged in the polymerization of `plastisof, a very fine PVC powder with particle size around OS nm. Selikoff(2 976) called attention to results obtained by Frongia et al. (1974), who observed significant histopathological changes in the lunp of guinea-pip and rats ex posed for 2-7 months to inhalation of the airborne PVC dust in a PVC bagging area. Lesions began to appear at 2 months of exposure (alveolar histiocyte-macrophage re actions): they proved to be fairly marked after 4 months, with appearance of foreign body giant cells, and proceeded to development of Urge interstitial granulomatous foci. Vertkm and Mamontov (1970) who examined 96 workers cnpged 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 FVC dust. They quoted results ofearlier animal experimenta conducted in 1963 by Golovaryuk and later by Shlyakhenkii These last authors had apparently shown that exposure of animals to PVC dust may lead to the development of ehronic pneumonia and eventually to a sort of mild fibrosis of the lunp. \. st I bi ll: tu W'' OV of er. oi de *J* Th m; mi ti> ># ter AL BK l* Civ re: po 1 an fab Jo ha. ho of an ma pb 19 of VC S3 W.K. Lelbach and H.J. Mjntellrr 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 CN5 malformations) emerged from preliminary' studies in three Ohio communities with PVC production plants. But the need for further study of possible contributaty 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 ihe two PVC polymerization plants in Painsville or lived within two miles of these plants (Edmonds et al. 1975). 5 Conclusion and Outlook The combined efforts of multiple disciplines have been necessary* to arrive at uie 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 all to be a carcinogen with a very long latency period for those who were heavily exposed to it. But its carcinogenic properties would most probably still have gone unnoticed if the resulting malignancy had been any can cer other than of an exceptionally rare type. Animal experiments in the early days later proved to have been broken off before the oneogenidty of this chemical com pound could have been detected. The lesson to be learned is that in future any new chemical which is to be widely introduced into the environment should be scrutinized closely, for a sufficient length of time, and with the aid of all available methods for the detection of potential car cinogenic effects. In addition, we should keep in mind that in industrial surroundings we almost never deal with a single compound, but with a very complex occupational environment whose carcinogenic potential is still a completely unresolved problem. If currently adopted guidelines for industrial hygiene are strictly adhered to, there is reason to hope that initiation of new cases of VCM-induced angiosarcoma of the liver can be effectively prevented. Unfortunately, however, it pan be expected that in view of the long latency period for tumour promotion additional cases will appear dur ing the next decade. Considering the 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 Chlor. between pre. tissue such a_c short exposu will cany the References Albnght LF i Albnght LF i Albnfht LF i Albright LF ( polyvinyl i Albnght LF i processes. Alrenga DP I: 198-203 Amann R (19 dcr Leber. ' Anderson H X CEA amor. 1S60-1S6 Andrews AW properties Anghelescu F VU969K employees 473-482 Annual Repo. London. Ci Antonyuzheusian text). < Antweiler H * i Perepect I" Amaud A, Por. -ride pneum Aryanpur J11 Inn. J Occi Assmann H (1 Austin GTU** 87-89 Bachner U. tv und Osoph. 2409-24H Bachner U, Ft. Befundc be Jahresbenc.' Gcntner, $: Bachner U, Mu 1000 patier Bachner U.Ei> und Osoph. Blutunccn. 90 W.K. Lelbach and H.J. Marsieller Bachner U, tzel F. Muller N, Lange CE, Egh H (1976) Praneoplastische und koilageni- sierendc Verfnderungtp der Leber und Hamosusebefunde bei PVC-Arbeuern In: GastparH(ed)Onkohamostaseolog>e. 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