Document KDMayzqbQXroxao5bLEkrDDN

APPENDIX 1 II III IV V VI VII VIII IX X XI XII XIII INDEX TITLE EXTRACTS FROM USFDA REGULATIONS PARTS 175-177 EXTRACTION OF BPA FROM PVC COMPOUNDS BY FOOD SIMULATING SOLVENTS LETTER RE EXTRACTION STUDIES ON BPA LETTER FROM UNION CARBIDE ANSWERING QUESTIONS ON THE NHMRC QUESTIONNAIRE EXTRACTS FROM DOCUMENTS OTHER THAN USFDA WHERE BPA IS APPROVED FOR FOOD CONTACT USE UNION CARBIDE LITERATURE ON BISPHENOL A (F40900B) DATA SHEET ON METAL CONTENT OF UNION CARBIDE PRODUCTS COPY OF THE LETTER FROM UNION CARBIDE (AUSTRALIA) RE PURITY OF BPA UNION CARBIDE LITERATURE "UCAR(R) BISPHENOL A APPLICATIONS" DEVELOPMENT OF A METHOD TO DETERMINE RESIDUAL BPA IN PVC RESIN COMPUTER PRINT OUT SUPPLIED BY BFGOODRICH CHEMICAL, USA SHOWING BPA SYNONYMS, USES, TOXICITY TOXICOLOGICAL DATA EXTRACTS FROM LITERATURE RELATING TO THE MANUFACTURE OF BPA Part 1 - from Manufacture of Plastics, Volume 1 W Mayo Smith Published by Relnhold Publishing Corporation N. York 1964 Part 2 - from Organic Polymer Chemistry K. J. Saunders Published by Chapman & Hall, London 1973 w w* & 2 21102001 P Frick G.-A.von Harnack K.Kochsiek G.A. Martini A. Prader Mit 24 Abbildungen und 23Tcbellen 1 Vinyl Chloride-Associated Disease W.K. LELBACH and HJ. MARSTELLER ' 1 Introduction.......................................... 2 2 Technoiopcai Details.............................................................................................. 2.1 Vinyl'Chioride Monomer (VCM).................................................................. 2.1.1 History................................................................................................ 2.1.2 Production of VCM..................................................................... . . 2.2 Production of Polyvinyl Clilonde (PVC)...................................................... 2.2.1 Technology of Polymerization........................................................... 2.2.2 Methods of Polymentation................................................................ 2.2.3 Compounding .................................................................................... 2.2.4 Sources of Exposure to VCM in PVC Production .......................... 2.2.5 The Explosion Hazard....................................................................... 2.2.6 The Odour Threshold ....................................................................... 2.2.7 VCM as an Anaesthetic Agent........................................................... 2.2.8 Effects of Acute Overexposure in Man ........................................... 2.2.9 Monitoring VCM Concentrations in Working Areas....................... 2.2.10 Exposure to VCM in PVC-Processing (-Fabricating) Plants.......... 2.2.11 National Standards for the Control of Exposure.................... 2.2.12 Exposure to VCM Ouside the Working Area................................. 4 4 4 5 6 6 7 8 8 9 10 10 11 13 15 17 18 3 Toxicology of VCM................................................................................................ 21 3.1 Acute Toxicity................................................................................................ 21 3.2 Chronic Toxicity.............................................................................................. 21 3.3 Oncogenic Properties...................................................................................... % 22 3.4 Toxicodynasucs......................... 24 3.4.1 Uptake and Distribution.................................... 25 3.4.2 Metabolism.......... .............................................................................. 26 3.4.2.1 Relation between Chemical Structure. Reactivity and Mutagenic or Carcinogenic Effect............................... 26 3.4 2.2 Metabolic Pathways............................................................. 26 4 Clinical Spectrum................................................................................................... 4.1 The Triad: Raynaud's Phenomenon. Pseudoscleroderma and Acroosteolysis................................................................................................ 4.1.1 Familial and Idiopathic Acroosteolysis........................................... 4.1.2 Epidemiology of Occupational Acroosteolysis............................... 4.1J Clinical and Roentgenological Features........................................... 4.1.3.1 Occupational Acroosteolysis.............................................. 4.1J.2 Pseudoscleroderma.............................................................. 4.1.4 Histology.............................................................................................. 4.1.4.1 Cutaneous Lesions................................................................ 4.1.4.2 Bone Lesions....................................................................... 4.1.5 Arteriography. Capillaroscopy. Infrared Thermography............... 4.1.6 Immunological Studies....................................................................... 29 31 34 34 36 36 38 39 39 39 40 42 1 Department of Medicine. Director Prof. Dr. HJ. Dcngier. University of Bonn. FRG s D r 1. Li W K Lelbach and H.J. Marsteller 4.1.7 Pathogenetic Considerations.......................................................... 4.2 Non-malignant Liver Disease in Vinyl ClUoride/Polyvmyl Chloride Production Workers...................................................................................... 4.2.1 Clinical Manifestations oi Son-malignant Liver Disease ............. 4.2.2 Laboratory Findings....................................................................... 4.2.3 Gross Inspection of the Liver and Spleen 4.2.4 Histology..................................................... 4.2.4.1 HepaticFibrosis................................................................. 4.2.4.2 Sinusoidal Lining Cells..................................................... 4.2.43 Hepatocytes........................................................................ 4.2.4.4 Histology of the Spleen................................................... 4.2.5 Pathophysiology of Portal Hypertension...................................... 4.2.6 Follow-up of Non-malignant VCM-induced Liver Disease.......... 43 Angiosarcomaof the Liver........................................................................... 43.1 Epidemiology.................................................................................... 43.2 Clinical Manifestations..................................................................... 433 Peritoneoscopy................................................................................... 43.4 Gross and Histological Morphology................................................. 433 Therapy............................................................................................... 43.6 Risk Assessment............................................................................... 43.7 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 4S 49 50 51 51 54 54 54 55 57 57 57 74 76 78 80 80 81 82 82 84 85 87 88 89 Key words: Acroosteolysis - Angiosarcoma of the Liver - Portal Fibrous 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 potentially hazard ous chemicals introduced each year into the workplace and the environment, this ac count should again alert us to the necessity of pretesting chemicals adequately for their potential health effects, even at the risk that technological progress will develop at a more modest rate. Large-scale production of the synthetic resin polyvinyl chloride (PVC), a thermo plastic material suitable for the most widely diversified industrial use, was begun around 1930 in the United States and in Germany. The monomer, vinyl chloride (VCM), a rather simple aliphatic compound, was believed until the early 1960s to be K C C3 U Vinyl Chlonde-Asso, one of the least harm I' later turned out, had r evaluation of acute eff to reveal its carcinoge:. might have continued ' place, considering that vapour phase under an: reactive double-bond. Today vinyl chlond formation and data on cisely a quarter of a cei uibutable to this new c with the shocking disci, tion workers heavily ex ing that the monomer i pound did not alert the in workers engaged in : lished in 1949 {Tribitki- Ultimately, it was tl cuned in workers expo a causa] relationship: (1 pseudoslerodenna; (2) liver. Particularly, the d. nancy among a compar:: alarming experience w'n a connection between \ lungs or the gastrointe. the prolonged latency p sarcoma of the liver, r-v these tw6 fatal consequ the conclusion that Vi,, cancer meeting in Hous. to VCM was a very sen. It should be stresses precise, an intermediate mainly in the mammal, merization products (PN cated from the polymer, they contain unreacted PVC (thermal decompotoxicity of pyrolysis pro mainly due to the telexA bar 1969\Dyer and E'~ and only very small or n {QHlara et al. 1971 cite Mantf He: 4.3 49 50 51 5i 5-1 55 j" 5" 57 74 76 78 80 80 81 e: s: s- 85 3' ss 89 / Portal taxis is a -"uldheip to wring rather TiaOy hazardnt. this ac* ulv for .ill develop i. a thermobegun Monde 'HiQ* to be Vinvl fhloriue-Astocuted Disease one of die lea: harmful chlorinated hycrocarrors. Early animal experiments, a it later turned out. had indeed been earned out ->tn dosages sufficiently high for the evaluation of acute effects, but chrome exposure nad not been of sufficient duration to reveal its carcinogenic properties. On purets 'neorencal grounds, however, one might have continued to feel uneasy wnn this compound as a pollutant of the work place, considering that it is (l) a halogenaiea r->crocarbon which (!) exists in its vapour phase under ambient conditions (inirtamt exposure) and i3) contains a highly reactive doubie-bond. Today vinyl chlonde-assodated pathology anil documented. A large body of in formation and data on this topic has been accu.-r.ula:ed. notably since 1974. but pre cisely a quarter of a century had to pass before the full range of symptomatology at tributable to this new occupational health hazard became recognized in January 1974 with the shocking discovery that haemanposarcoma of the liver occurred in produc tion workers heavily exposed to PVC. Early and no: easily accessible reports suggest ing that the monomer might be an environmental nsk for workers handling this com pound did not alert the experts sufficiently. The earliest indication of adverse effects in workers engaged in the production and processing of PVC. a Russian study pub lished in 1949 (Tribukh et al. 1949), received little attention. Ultimately, it was the exceptional character of the three major lesions which oc curred in workers exposed to VCM that contributed most to the final appreciation of a causal relationship: (l) the syndrome of acroosteolysis, Raynaud's phenomenon and pscudosleroderma;(2) non<irrhodc portal hypertension; and (3) angiosarcoma of the liver. Particularly, the discovery of a cluster of four cases of this extremely rare malig nancy' among a comparatively small group of workers (Creech et ai. 1974a) was an alarming experience which called for immediate action. It can easily be imagined that a connection between VCM and the more common malignancies, such as cancer of the lungs or the gastrointestinal tract, might still have gone unnoticed. On the other hand, the prolonged latency periods of both non<irrhodc portal hypertension and angio sarcoma of the liver, roughly 10 and 30 yean respeedveiy, delayed the recognition of these two fatal consequences of chronic exposure to VCM. But one can hardly escape the conclusion that Viola's discovery of cancer in experimental animals, presented at a cancer meeting in Houston in 1970, was sufficient evidence to Indicate that exposure to VCM was a very serious occupational hazard {Peters 1976). It should be stressed that the noxious agent is solely the monomer, or to be more precise, an intermediate of the monomer's metabolic bioactiviation, which takes place mainly in the mammalian liver and yields certain highly reactive epoxides. The poly merization products (PVC),Len the solid plastic and the plastic consumer goods fabri cated from the polymer, an chemically inert articles which cany no health risk unless they contain tmroacted residual monomer. Even the combustion of articles made from PVC (thermal decomposition in fires) does not yield free vinyl chloride monomer; the toxicity of pyrolysis products of polyvinyl chloride polymers and formulations is mainly due to the release of hydrochloric add and carbon monoxide (Cornish ud Abar 1969: Dyer and scA \916:Sonnson 1976\Moser 1976: Colardyn et aL 1976) and only very small or no quantities of phosgene derived from residual monomer {O'Man et ai. 1971 died by Colardyn et al. 1976). wss; KS*' cs 4 2 Technological Details 2.1 Vinyl Chloride Monomer t VCM) XV.K. Ltrlhau'h and H.J MjrstcUcr A: standard (ambient) conditions of temperature and pressure, vinyl cidoride lCH; = CHC1: chJoroethylene. cliioroethene) is a non-irritating, colourless cas with a faintly sweet odour, inflammable at concentratjonsabove 3.8% by volume in air. which is only slichtly soluble in water, soluble in ethyl alcohol and easily soluble in ether and carbon tetrachloride. VCM is mainly used as an intermediate in the manufacture of plastics, as a refrigerant and in organic synthesis. It was formerly also employed as a propellant for aerosoles. It is easily liquefied under pressure and is usually handled and shipped as a liquid. Gaseous VCM condenses at --13.8C and 760 Torr ( 101J kPa) to a colourless liquid of low viscosity (Lefaux 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 2.1 S times heavier than ait), its low solubility in water and the half-life in air. ranging from 3 to 20 h. Table 1. Pin-deal properties of VCM Mol. wt.: B. p.: F.p.: Flash point: Limits of flammability: Autoienition temperature: 62.503 -13.8'C 1-13.7 to -13.9) -153.7"C -18.5*C (Cleveland open cup) 3.8%--29.3% by volume in air above -98.5'C ( 38 000-293 000 ppm) 4?2`C Vapour pressure: mm Hs 10 100 692 2300 #C -87.5 -55.8 -15.8 20 2bo0 * 25 Vapour density: 2.15 g/litre (calculated at 25C and 760 mmllg (air - 1) Sp. gr. of liquid VCM: 0.9121 at -20*C'4*C 0.99 at --25*C/4#C Sources: Fairhatt 1957;Irish 1963;Zapp 1964;J.efau.x I9c>6:Osttrmaytr !9o7. Roubal 1972. 2.1.1 History The French chemist. Reyrtau/r (1835) was apparently the first to study systematically the synthesis and analysis of vinyl chloride. Liebig, who had done some earlier prelim inary experiments, encouraged Regneult to investigate this compound when Regnault spent several months in Liebig's laboratories. All compounds containing the vinyl group (CHjCH-) polymerize readily (FairhaU 1957). Spontaneous polymerization of vinyl chloride to a white opaque solid mass under the influence of sunlight was first described by Baumann in 1872;he.al*o quotes a paper by Saytsev and Glinsky (who l\5 h* C3 Vinyl Chi. succeeded izing subsr 2.1.2 Pro. Large-seal by employ 1) Convers CH=CH 2) Convers chloroe: CH;=C1' CHjCl-. VCM w Thus, any h tiorts in the in the ranc (1ARC 1V when VCM mayer 196' in commer 1966; Oita In the conjecture., retrieved Vi yses camesum of all it genates) u reacted mor in prepolvr the conctr.that even in methyl chi.; isobutane. fetence in p 21108006 auajAipa tuoy pot aua|Xiaot uiojj j^a uaaauaq punoj aq ppioa Xjpnd in aauaiaj -jtp lUcoymStx ou `saptsag -alina qdd atp ui aq uaqi pjdoa (*3ia aimnq-i/ `aaTjnqost `aua[Adoid) Maundun latpo nv j'O ^F jo nt ui uoncnuaauoa apuopp jXqiaui c-ncui K3A uudd 00SJl *<*eaui ppiojo |<qa m- apuopp [Xqiatu iudd 000t uaaa ltqi puiui in idaq aq pptoqs jt mg -(uidd OOOC pa* O00t uaaAuaq paSuu oontuuaouoa atp Xjuo aaunsut auo at) i^a paAatnai at iudd O0S~00I put K3A uontzuauiXiodaid ut uidd 00--Of JO taoaeaaaauos in punoj izm apuopp iXqiaui XfUQ Mauiouotu papeai -un paAsutaj joj <*f0 put ioa uoptzuavuXfodaid joj aumpa Aq -^lO'O * (saituaS ojtq jiaqi put suoqmojpAq paitmiesun jo paiuturs sc ipns) xsnundun nt jo urns aqi tctp pa*oqs -uaamoq `OAd jo siaituatjnutui ucuuao jsaj^ vis Aq jno pauita sA -Tcuy '(f161 put astin) (s)iuaat aAtitsnca aqi uaaq aasq jqSrai pqa paaauiaj ut to uonuauiA|odajd ut paurciuoo sanundtin jo rpunodmor latpo itqi paimaatuca i:a jt astasip pairpoist-apuciqa ]Aiha jo amto sip jnoqc uotnrustp Apca aqi uj (1961 JZ-fauBisO"9961 xrrji-j) imaid uoncruauiAjod aqi pmai sanunduq *pqa paanpwd Xntutaunuoa ut Xiund jo aaiSap qStq t st ssaaoid uotirzuauiAfod aqi joj aismbauid v '(196! u.udi ttisO) aStJftaj jauttiuoa ot anp ire ouaqdsoont qjin pciuoo oiut saaioa a'OA uaq.w pj/ussqo X|pairadai uaaq osp scq jijStj ut uoptzuauiXfod snoautiuods -(^61 j^vi) wdd of ot dn paSutt uonejjusauoa aqi Aiiunxoid asop u] -uidd z~\ asutr aqi ut aq ot pimoj um nuxjd SuuTuatjnutm way aautiitp awos jt aiaqdsount aqi ut suou -enuatuoo jqa J?t luaiquit aqi ut painpp Appeal sc scS aqi jo aScsrai Xut `stun saurfor; joopino ut patois put sutajsXs pasop ut ptairuocjnutm Xncran scm (P16I uumy'Svppas puuayj :stsX[OJXd) JS <rT5tn s3?uin|a DH-* DK0:HD ` 5^n=3^g; `olH + D;H3-o:HO - :o:/i + dh:-^'-h>:hd :(e/96! juiuQjy) lOA 01 (Sunptto jtuuaqi) ttsXiotXd luanbasqns put auttpaoiopp -tp-;- [ oi uotituuoppXxo astqd-ptnbt] jo assqd-modcA Xq auajXqia jo uoisaaauoo (; (M6I uusay) (poannp uo :Xftna) DH>:HD -DH + HD*HD tuoptuuoppcupXq Xq |\3a 01 aua|Xjaot jo uotsiaAUo^ (| :isjij atf) paoridjj Xiatrti wou 8ut.\ci| puosas sq: -spoil;am J|dtsuud Oa\i SuiXorduia ,<q iaic| qaruu ajutssod apcuisca\ opiX qatq c t(it.M t\'J_\ jo stsaiqu.is (etajaiuiuo.-iapoi-aStcq KOAJOuotmpoij ;-f: pi.ir snoio|t|POdXtj st qms saoutjsens Sunt ptxo io pit aqi qitM apXt|appojopi?ouoiu oi apuojqt |Xuu Sutsoduiooap m papaaoons psirt.>oSY-.-'P'iPi'!3 |au|a oq) .qputfO poriuij stM iqSrpms tjo uontzuauiXjodtm- jXouaqi Sunnci;;nnuJay uaq pane unpjd tapta auios : XircotmuauAs Xpnu i96I iHtuui( ?r or * 099: ooet -r ^ 3.s's:- aqi put lair* tr -AtiS oytaads qStq >i: psisr; art ssotadot- (cn noi )"i put pajputq Xntnsti t st paXojduia os, ip smiatittuttu. pur jatpa ui ?ior.i s; U3tq. 'itt u: i;iuitj t uit st. *:HD>sP^N3l ::;aivtr|\ f H Pu' 6 W.K. Lelbach and H.J. Marsteil 2.2 Production of Polyvinyl Chloride (PVC) 2.2.1 Technology of Polymerization The following description is meant to serve merely as a rough sketch of the procedures and technological details involved in the production of polyvinyl chloride. Vinyl chloride monomer is polymerized in large autoclaves (reactors) at tempera tures between40*C and 80C and pressures of 6-16 (8-12) atmospheres. 7Vre 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 (Bamcs 1976), is initiated with the aid of compounds soluble in VCM that form free radicals at relatively low temperatures. Initiators are such compounds as lauroyl peroxide, isopro pyl percarbonate, azo-bis-isobutyronitride, and others. The free radicals react with the double-bond of the monomer, transforming it in turn into a free radical and thus prop agating the growth of a chain of molecules with a terminal free radical. Chain growth is interrupted by saturation of the terminal free radical which often involves a reaction between two growing chains (Malten zn&Zielhuis 196-i;Lefaux 196S-.Albnght 1967 s-cDomininghaus ]972,Slater 1972). The random character of such termination steps accounts for the production of chains of different length and hence different de grees of polymerization, with molecular weights of the finished PVC being statistically distributed around a mean value. Commercial PVC polymen have average molecular weights that vary from about 50 000 to 150000 daltons (Albright 1967b). Degree and velocity of polymerization, which are influenced by temperature and the concentration of initiaton. determine the specific type of PVC produced (Frey 1973). During polymerization considerable amounts of the monomer are at first dissolved in the polymer, but most of tills is later also transformed to PVC as polymerization progresses. The polymer which is not sol uble in the liquid monomer precipitates out. The proees of polymerization slows down towards the end of the reaction.lt is terminated, depending on the method used, when approximately 8096--90% of VCM is polymerized. The tuning 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 ofheat; it has, therefore, to be cleaned away after termination of the batch process (Barnes 1976). After completion of the polymerization process, the slurry is released from the re actor into a dump tank. Residual unreacted vinyl chloride monomer is partly solvated in the polymer (about 10%); the remainder is dispersed in the water phase or is present O OD <1 Vinyl Chlor.de-' in the vapour ph. VC monomer is r is then purified h the finished pol> and must diffuse Raw PVC resin. t` (VKE 1975). Bar proximately 500 The sluny fre large enough to h are then pumped wet polymer, a gr drying methods, t merization, yield; fine solid particle drying temperatu. polymer. A cydo The solid polymer storage bins or sildried powder con 2.2.2 Methods o Four different in, PVC (Frev 1973 > Suspension Polyi which monomer (such as polyvin\1 conduction with b this method wh;. Emulsion Polynt. was added in the except that large. are added. Emulf emulsifiers cannui Bulk fMass) Poly. the additon of oti The first reactor * second one is use. solid state, to ess<reaches a level of characterized by 1 good optical dart 1 HJ. Marstelier >f the procedures ride. irs) ai tempera,eres. There are activity of the of the vinyl Ic-bood of VCM iso the source of etaboiized in the action (Bamej rrn free radicals at ' peroxide, isoproais react with the cal and thus prop11. Chain growth is olves a reaction c':Albnfit: 196" h termination cnee different defceing statistically an front about polymerizaron. :>{'. determine on considerable hi' his is later whic,. is not solnzation slows the method used, of this terminins produced. The \t be removed to .ition aids in transhe reactor. During -ere to the walls of 1 his polymer crust led with unreacted cleaned away after .ined front the re- is pertly solvated phase or is present Vinyl Oilonde-Associatfd Disease 7 in the vapour phase above the slurry. While a batch is in the dump tank, this unreacted VC monomer is retrieved by pumping it off into a VCM storage tank. Retrieved VCM is then purified by subsequent distillation for recycling purposes. Monomer solvated in the finished polymer cannot easily be extracted since it has a strong affinity for PVC and must diffuse through the particles: tltis diffusion depends on time and temperature. Raw PVC resin, therefore, still contains certain quantities of unreacted monomer (V'KE 19*51. Barnes (1976) reported that the polymer in the slurry still contains ap proximately 500 ppm of vinyl chlonde. The slurry from the dump tank is pumped into a norage tank (blend tank) which is large enough to hold several batches of the product. The contents of the blend tank are then pumped into a centrifuge which separates the wet solids from the water. The wet polymer, a granular mass, is dned either in roaring tubular dryers or by spraydrying methods, the latter being used mainly for products formed by emulsion poly merization. yielding a polymer which is similar to a very fine white flour. These very fine solid particles are fed directly into a spray-drying column without dewatering. The drying temperature should not exceed 60*C to prevent thermal decomposition of the polymer. A cyclon separator at the exit end of the dryers removes coarse: particles. The solid polymer particles are then sized by multiple-layer screens, air-conveyed to storage bins or silos and finally packaged for shipment (Albright 1967d). The resultant dried powder contains about 50 ppm of monomer (Barnes 1976). 2.2.2 Methods of Polymerization Four different methods of polymerization are used for the commercial production of PVC (Frey 1973), the firs: two now being the most widely used: Suspension Polymerization. Polymerization is carried out in an aqueous system in which monomer droplets are maintained in suspension by means of protective colloids (such as polyvinyl alcohol, gelatin, substituted celluloses) under heat and pressure in conjucrion with brisk agitation. Relatively large polymer particles can be obtained by this method which `dry blend* well. Emulsion Polymerization is the oldest technique, to which suspension polymerization was added in the 1950s. The process is similar to that in suspension polymerization, except that large amounts of emulsifying agents (such as soaps or other surfactants) arc added. Emulsion polymerization yields resins of a very small particle size. The emulsifiers cannot be completely removed. Bulk (Mass) Polymerization. In this proces VCM is polymerized in two stages without the additon of other liquids. The two reactors are operated batch-wise and in series. The first reactor (a "prepolymerixer*) provides for the initial liquid phase, while the second one is used for agittring the sluny, which is transformed, through a sticky solid sate, to essentially dry particles until the conversion from monomer to polymer reaches a level of about 75&-805. The resins obtained by bulk polymerization are characterized by high purity and parade uniformity, resulting in an end-product of good optical darity. ! k :i i i .i .t :r *I :. ;t ll (h i\ !* s W'.K. Lclbjch and H.J. Mar-uHer Vinyl i i Solution Polymerization. This type o: pr;:-?uauon polymerization is carried out in permit ri organic solvents such as n-butanc or c> clu;>exine. It accounts for only a small percent in the p: age of the total amount of all PVC resins produced and it is used for the production of The i copolymers. Copolymers arc mixtures of cumonomcrs (such as vinyl acetate, vinvl- clave va: stearate. vinylidenechloride, propylene, acrylonitrile etc.) and vinyl chloride. The co walls (`p monomers tend to improve flexibility and bruited solubility of the product in solvents tors, had and exert an intluencc on the temperatures required for compounding. degassed and larz. 2.2J Compounding were opc ed the ft. As a next step, depending on the end use. the dned 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 final product depending on its compatibility. Lead-containing stabilizers may also pollute the working atmosphere (SmolCic 1966: Tola 1975). Compounding is earned out by hot mixing at fusion tem tion still manly, tl those wi(centrifu ties of ventilatu shipmer.' nomer. are drive- peratures below or within the softening range (1 20C-160eC). Diversified compound ing and processing technologies were developed about 1950. The compounded polymers art used for the production of diverse epd-products. Table The final conversion of the thermoplastic PVC resins into consumer end-products is accomplished by such procedures as extruding, calendering, injection or compression 1 ppr moulding, blow moulding, dipping (coating) and hot spraying. Temperatures used in these processes range from 1008C to 300C. End-products include a vast number of articles used in almost every sphere of daily life. The temperatures during the fabrica 1 mg. tion operations (compounding and conversion of compound polymer into consumer articles) drive off part of the small concentrations of residual monomer still contained (Pat; in the polymer. Barnes (1976) calculated that the final fabricated articles contained approximately 5 ppm VCM and those for foodstuff packaging (bottles, films, foils) even less. ) mg/li ii 1 mg, nt5 ;& 2.2.4 Sources of Exposure to VCM in PVC Production I ppm irr Both polymerization of VCM and subsequent processing (centrifuging, dry ing, screen ing, bagging) are usually carried out in closed buildings. Exceptions can be found in hot climates (Aryanpur 1977). Polymerization is of necessity a batch process that re quires a large number of single operations. Therefore, valves, gaskets, shaft-openings and control gear are subject to heavy wear and thus to leakage. Other sources of pollu tion of the working atmosphere are exchange of parts and repair jobs. The degree of pollution also depends to a large extent on the quality and effectivity of monitoring equipment and special exhaust systems. Opening of autoclave vats for cleaning and control purposes resulted in larger spill-over of the tank atmosphere into the work en vironment. Numerous reports of workers with prenarcotic symptoms (dizziness etc.) 22S T In the p.> nant mem covers (Lefaux 1 lect as : . opened . became k '..irs teller out m I percent: iet: of -*u TIic coolvents ry or ton temi and light beers), tlexibie source of iig on its sphere >n temnpound- acts ;s o*. vv-on -.vd in *r of _ no turner -n-jmed . screenami in that reenings f polluiree of 'ttonng 3 and work eni etc.) Vinyl Chlondc-AvwviJied Diseav; 9 permit the conclusion that episodes of acute overexposure to VCM were not rare events in the past. There is no doubt, however, that those workers who manually cleaned the auto clave vats by scraping away or chipping off the 'polymer skin' formed on the teactor walls ('poiy cleaners'). and who m the past had to spend several hours inside the reac tors. had been exposed to the highest concemiations of VCM. Although the vats were degassed pr.or to entry, unreacted monomer remained trapped in the polymer skin, ar.d large: amounts of VCM were released when cavities formed in the polymer crust were opened by chipping. The iater introduction of automatic cleaning systems reduc ed the frequency of entry into the reactors, but some manual cleaning of shorter dura tion still had to be done after every 20th-30th run. It is. therefore, plausible that, pri marily. the most severe adverse effects of exposure to VCM were fully recognized in those workers who had been employed in this job category. But the subsequent steps (centrifuging, drying, screening) also involve the release of some of the terser quanti ties of unreacted residual monomer from the particles to pollute the environment if venoiauon. notabiv of the drying facilities, is inadequate. Finished polymer, ready for shipment or subsequent compounding, still contains small quantities of unreacted mo> nomer. which either' slowly diffuse out and pollute the bagging areas during storage or are driven out by the high temperatures necessary for compounding. Table 2. Conversion table for concentration of VCM in ambient air r 1 ppm mg/litre P {.Patry MAS x I 000 Mol. wi. ppm I mg/litre 1 mg/m' * 1 ppm 2Jh mg/m* !'' *10 000 ppm 391 ppm 0.391 ppm 0.00256 mg/litre 25.6 mg/litre II! Li r States was almost completely destroyed when VCM escaping from a leak, detonated (Albright 1967a). Another explosion in one of the two Rumanian factories operating at that time was mentioned by Suciu et al. (197S). Monitoring of VCM concentrations polluting the work environment was then directed largely towards preventing VCM from reaching the flammability limit. 22.6 The Odour Threshold Unfortunately, gaseous VCM has no irritating or unpleasant warning properties. Its mild odour is described as faintly pleasant, sweet or ethereal. Some of the PVC workers we interviewed reported that they had even enjoyed `sniffing the gas', which soon resulted in a feeling of light-headedness. For the early days of PVC production, when appropriately sensitive monitoring equipment was not yet available, workers' re ports about perception of the odour of VCM can be taken as circumstantial evidence for a rough estimate Of the actual degree of exposure. It should be kept in mind, how ever. that in chemical production units the presence of other odoriferous chemicals and the possibility of olfactory fatigue, as well as different levels of individual sensitiv ity. may render it very difficult to determine the factual odour threshold of a certain gaseous substance unless it possesses irritating warning properties. In 1929.Schmidt andSchaumann declared that the faintly sweet gas is practically odourless at concentrations of 5%--\0Po by volume. Veltmart and Lange (1977a. b) assumed an odour threshold of 5 000-10 000 ppm. Volunteers exposed to VCM detected a slight odour at 4 100 ppm; a distinct odour was noted at 6 600 ppm for 30 min and this was accompanied by subjective symptoms of dizziness and sleepiness (Irish 1963). Gehring et al. (1979) recently mentioned a threshold of approximately 3500 ppm. Others have claimed that a concentration of400--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\Lefcvre 1975,cited by Hubiet 1975). Baretta et al. (1969) conducted experiments with concentrations of 50,250 and 500 ppm in an exposure chamber, in which 13 volunteers participated. At 500 ppm only some of them claimed that they were able to detect the odour, but this was inconstant. Table 3 shows that differences between the various estimates are at least one order of magnitude. Tire close proximity between the perception of the odour of VCM and incipient CNS symptoms as reported by Irish (1963), however, makes it likely that the actual odour threshold can be as sumed at or above 4000 ppm. In contrast to VCM, the comonomer vinyl acetate, for instance, has distinct warn ing properties and can be detected by its odour at a level as low as 0.4 ppm; eye and throat irritation begin upward of 5 ppm and are noted by all test subjects at a concen tration of 21.6 ppm (Deese and Joyner 1969). 2.2.7 VCM as an Anaesthetic Agent VCM was once even considered for use as an anaesthetic agent. In 1929. Schmidt and Scfutumann speculated about using VCM as a supplementary narcotic at concentra tions of 3%--$% (v/v) ( 30 000--50 000 ppm) in combined nitrogen oxide oxygen H- Table 3. Od-. Lower limn , 5 000-10 0<5 O'4U 3 St S| . 400--50 40 40' anaesthesia be tic and lethal oxygen; concc however, that eluded. In.to' 10% VCM to : several hours i commented umined about >. 3.5-5 mmol ( mmol (244 00 Osteret al., in cardiotoxicity man because c like other hale mines (Irish the past for ar:. 22A Effects Some individu: listed in Table without acute. symptoms sue! adequate warm exposure to hipA 21-year-old 10 min after en which had bee cardiac enlarge: have been acut. which occurreJ doubt that he;found dead wii. J. Manteiler ettmated ! operating >cr ons ng V_.l tties. Its PVC as*, which oduction. vorkers' rel evidence mind, howliemicais ual sensitivf a certain practically 177a. b) :o VCM 3pm for sleepiness M'mately ie lower 71 -.Msrko> conducted ItaiK *.in i:4 /' lifTeitncci .-proximity a* reported n be as- met wani. eye and t a concm- Vinvi Chlonde-Assoctaied Disease Table 3- Odour threshold Lower limit ot detection : 000-10 00G ppm 5 000 ppm 4 100 ppm 3 500 ppm 500 ppm 400-500 ppm 400 ppm 400 ppm Author Velrman and Lan%t !977a. b Viola 19'4 Irish 1 963 Gfhnnt 11 al 1979 Barerra et j. 1969 Lefrvrr 19~5 ic:::d by Huble: Cook it al. 197] Markowitz et al 1973 11 anaesthesia because of its potent narcotic action and the wide margin between narco tic and lethal concentrations. In animals it produced anaesthesia at 77J-105J In air or oxygen: concentrations above 125i proved to be dangerous. The authors pointed out. however, that adversedate effects of this halogenated hydrocarbon could not be ex cluded. in toxicity studies with guinea pigs Party et al. (1930) found concentratons of 105 VCM to be lethal within 30--60 min. 5s* to cause marked narcosis, and 0 for several hours to be the maximum tolerable exposure without senous effects. They also commented upon the potential use of VCM for surgical anaesthesia but were undeter mined about its practicability. In mice, die minimal anaesthetic range was found to be 3.5-5 mmol (85 000--122 000 ppm) for 10 min. the minimal lethal range 10--12 mmol (244 000--293 000 ppm) (Peopler and Leake 1933). It was not until 1947 that Osrer et al.. in contrast to Schaumann's earlier assumption (1934) of a relatively low cardiotoxicity, wanted against the use of VCM as a potential general anaesthetic in man because of serious cardiac irregularities and ECG changes observed in dogs. VCM, like other halogenated hydrocarbons, sensitizes the heart to the effect of catechol amines {Irish 1963). We could not ascertain whether VCM has actually been used in the past for anaesthesia in man. 2.2.8 Effects of Acute Overexposure in Man Some individual responses of volunteers to increasing concentrations of VCM are listed in Table 4.Lester et al. concluded in 1963 that the maximum concentration without acute effects in man lies between 8 000 and 12 000 ppm for 5 min, and that symptoms such as dizziness, light-headedness and disorientation should be taken as adequate warning signs for imminent acute danger. Two fatalities after occupational exposure to high concentrations of VCM are reported in the literature (Denzigcr 1960). A 2 3-year-old autodare deaner at a Canadian polymerization plant was found dead 10 min after entry at the bottom of a probably insufficiently ventilated reactor tank which had been declared safe solely after an explosion*ter test. Heart failure cells and cardiac enlargement found at autopsy, however, implied that the cause of death might hare been acute functional disturbance in pre-existing heart disease. In the second case which occurred at the same plant, however, circumstantial evidence apparently left no doubt that heavy VCM exposure was the cause of death in a 39-year-old worker. He was found dead within 20 min, lying in a pit near the opened vaire of a recycling pipeline i: Vt'.K. Lelbach and HJ. Mj.-steller Table 4. Individual responses of volunteers to increasing concentrations of VCM Concentration Duration of Symptoms exposure Rclerence 500 ppm 7.5 h (Inconstant odour detection' Barcrra et al. mild headache, dryness of 119&9> eyes and throat in 2 of 7 subjects!i "V4 000 ppm - Generally accepted odour threshold tns>- 119e 3 t 6 600 ppm 30 min (Distinct odour) dizziness, sleepiness Irish (1 9b3) 8 000 ppm \ 12 000 ppm 1 / 5 min* (twice on 16 000 ppm 1 each of 3 succes sive days) 20 000 ppm / 2 of 6 subjects `slightly heady' 1 of 6 subjects had reeling, swimming head, `just like getting gas* 5 of 6 subjects, various degrees of intoxication All 6 subjects had more intense symptoms of acute intoxication than at 16 000 ppm Lester et al. (1965) 25 000 ppm 3 min 2 expenmenters: dizziness, disorientation, burning sensation in the soles of the feet Pam er al. (1963) 3 Exposure to six different concentrations: 0 ppm: 4 000 ppm; 8 000 ppm: 12 000 ppm: 16 000 ppm: 20 000 ppm through which non-polymerized residual VCM was pumped back into a reserve tank: another man coming to his rescue was himself overcome by the gas and only just escaped. Two non-fatal cases of VCM gassing were reported in Great Britain in 1951 (Spirtas et al. 1975). A maintenance worker experienced acute narcosis while repairing a VCM leak, and a worker cleaning a polymerization vat from outside with a water jet sudden ly collapsed across the open manhole. Subsequently he complained about tightness of the chest, nausea, abdominal pain and headache. Occasional loss of consciousness was also reported by Lilis et al. (1975) in 14 of354 workers ar 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 5 8 workers (79%) referred for medical surveillance from one British PVC-producing plant (Wani et al. 1976), with a 100% incidence of narcosis in 28 symptomatic workers (Raynaud's syndrome and/or acroosteolysis). Successful resuscitation after VCM-induced narcosis of several hours' duration with- ^ out evidence of permanent damage was mentioned by Rerv et al. (1974). o nss Viny! Chlor- 2.2.9 Mom: During the f; ed data on V< was directed an apparentl; 19 54 \ Pieshe Gronsberg to Russian poly: 0.05-0.08 nt centration of Inspectorate.. or from the d mg/litre ( 11 mg/litre <= 34 In the cei: air ranged fro; ppm, which w ventilation. T1 trations, sonic pursuit of imp ment in the vi. ic drying facili centrations of ' continued to h mitted concert: Jn a plant, the range of 0/ ppm (2.93 mg' ication apparji remarkable the the liver, althi past have prob. Byrin et al. which occurred cated peak exp between 1962. Rumanian PVT about 120 mg-r exposures to V; 300 Rumanian Greek plant wh resulted in high (Gitsios 1971). of the reactors t up to 10 000 p, J. Mjrste:!*: VCM sr .-.-re s: al. i>9) j 196-' * /i.(1963> ;sr al. rrv <: al. '"53) ; J nm tank: ,-isx . 1951 (Sprr-js Tuning a VCM cr jet suddent tightness of vousness was and by Sucat occasion in nveiilauce ncidence of 'tcolysts). ranoa with* V-.r.y! CliionJe-Assoc-.aievJ Disei--c 13 1.2.9 Monitoring VCM Concentrations :r. .i.'xing Areas During the first two decades of PVC praC-antion (1930-1950) no publication contain ed data on VCM concentrations m ihe 0-^:1 g environment. Tlic aum interest then was directed towards prevention of the ;\cios;on iiazard. In I957. the observation o; an apparently toxic angioneurosis In Russian P'.'C production workers tSmirnova 195-s:Ptcshchirscr et al., cited in Fihro-a Jronsdcrr 1957) induced F'hvirj and G>on?*;r? to investigate environmental VT' 1 cc.nrentrano.ns in various carts of a Russian polymerisation plant in Gor'kij Aii .o jgr. most readings were m the range of 0.05-0.08 mg/litre ( 20--313 ppm). e.g. seiow tne maximum permitted VCM con centration of 1 mg/litre (approximately *00 prmi as specified by the State Sanitary Inspectorate at that time, escapes of VCM m the reactor areas from defective fittings or from the discharge of operating autoclaves resulted in excursions up to 29.5-41.4 mg/litre ( 11 500-16 200 ppm) for periods of 5-10 min. One peak reading of 873 mg/litre (* 34 000 ppm) was recorded. In the centrifuging and drying area of thn plant the VCM content of the ambient air ranged from 4 ppm to 3 100 ppm wuh most readings between 20 ppm and 195 ppm. which was attributed to release of residual VCM from wet PVC resin and poor ventilation. The screening and bagging area was characterized by high dust concen trations. sometimes exceeding the official upper limits set for non-toxic dusts. In the pursuit of improving industrial hygiene, the installation of modem ventilation equip ment in the vicinity of the autoclaves, substitution of hand-operated by semi-automat ic drying facilities, and avoidance of leakages succeeded in reducing the ambient con centrations of VCM to below 0.05 mg/litre ( 20 ppm), but toxic angioneurosis still continued to be diagnosed. This led the authors to recommend tliat the maximum per mitted concentration of VCM should be reconsidered. In a plant producing VCM, F/Iaroro et al. (1958) found lower concentrations in the range of 0.04--1.1 mg/litre (16--430 ppm), with maximum values of about 1200 ppm (2.93 mg/litre). the latter having been observed in dose proximity to the rectif ication apparatuses and having resulted from spillage during sample collection. It is remarkable that up to now the Soviet Union has reported no cases of angiosarcoma of the liver, although production of PVC resms started early and VCM exposures in the past have probably been in the same range as those observed in Western countries. Byritt et al. (1976) pointed out that during the 1950s episodes of unconsciousness which occurred among workers of the one Swedish plant operating at that time indi cated peak exposures 0 f at least 10 000-15 000 ppm. Sucht et al. (1975) noted that between 1962 and 1972 a reduction of the average VCM concentration in the two Rumanian PVC plana had been achieved from 2298 mg/m3 ( 900 ppm) in 1962 to about 120 mg/m3 ( 50 ppm) in 1965--1972. In 1969,Angf:eletcti et al. mentioned exposures to VCM concentrations of 112-545 mg/m5 (44--213 ppm) for a group of 300 Rumanian workers, eight of whom (2.7%) had Raynaud's phenomenon. At a Creek plant which started operation in 1967. certain stages in the production process resulted in high concentrations of VCM in the work environment for brief periods (Gitsios 1971). In air displaced from reactors during addition of water and on opening of the reactors to obtain PVC samples at tire end of a reaction cyde, concentrations of up to 10 000 ppm were found. In open waste-drums into which waste polymer scraped 18 W.K. Lelbach and H.J. Marsteller in 1970 in conformity with the proposal of Torkeison et al. (1961). which was based on the results of their animal experiments. In June 1974, when the carcinogenic prop erties of VCM had been well established, the MaK regulation for this chemical was re pealed and instead a preliminary technical guideline (Technische Richtkonzentntion) of SO ppm was instituted (VKE 1975) The Chemical Industries- Liability Insurance Association (Benifsgenossenschaft der Giermschen Industrie! also issued instructions for the prevention of health hazards arising from handling of VCM in July 1974. As of July 1975, a technical guideline (TRK * Technische Richtkonzentration) of 5 ppm. defined as annual mean, for PVC-producing and -fabricating plants was instituted, per mitting excursions up to 15 ppm during periods of not more than 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 (Vehtmn and Lange 1977a). The technical guideline (TRX value) was revised in 1977 (2 ppm annual mean/5 ppm per 1 h). In the United States the threshold limit value for VCM was originally set at 500 ppm in 1947. It was reduced to 50 ppm in Apnl 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 m 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 (4G--87r 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 (1AR.C 1974), 2--3 ppm in the primary water effluent ami 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 (Schweirzcr 1975). For people who live within 5 miles of monomer and polymer production facil ities in the United States an average exposure of 17 ppb during the yean of uncontrol led emissions was calculated (Nicholson 1977). In the past VCM has been widely used as an aerosol propellant, either alone or mix ed with fluorocarbons,hydrocarbons and inert organic gases,in household and cosmet ic products (hair sprays, deodorants, pesticides, room disinfectants, paint sprays, furniture polish and window cleaners). In Germany, VCM was proposed as propellant for aerosols in 1958 (Ostermayer 1967), in Japan it has been used as a propellant since 1958, in the United States this use was probably introduced after 1962 (Schweitzer 1975). As an aerosol propellant. VCM has been a possible source of exposure for the public ai taicc. particularly lot women, the extent and the potential health implica tions of which are unknown. Use of aerosol products in confined spaces has been re ported to result in air concentrations of VCM of up to 400 ppm in closed rooms, even after only short bums (30 s) (Gay et al. 1975). which could persist for several Vmyl Chi Table 6. 1 Country Belgium Canada Finland France German Di Republic Iran Italy Japan Netherlanc Rumania Sweden Switzerljr United Km USA USSR Federal Rv Germany H* O GO Sources: 5 73:1ARC O 191" .Sell: h*  md H.J.Marsttilir >. which was based : car-'''genic prop:* teal was reichtkonzentnnon) ability Insurance issued instructions t in Juiv 1974. As .titration) of 5 ppm. -> was instituted, pet1 h. In order to Auction of the anm as of July !976 ppm. respectively was revised in 1977 -lcmaliy set at 500 -rary emergency stan-imarized the conflict ed industry in 19"-. ig countries. mg plants tn ihe the environment -- idved in water veer 19751 In a : ambient air near -< 100-200 ppm . u. were later -t these figures since mie {Schwenzcr metproduction faciihe years of uncontrol- *. either atone or mixhousehold and cosmet-tn. paint sprays, -opened u propellant -0 as a propellant since t 1962 (Schweitzer * of exposure for the mat health implicaJ spaces has been re< m dosed rooms. >J persist for several 'in si Cltionde-Associated Disease 19 Table 6. Threshold limit values iTLVl m various coumr.es Country Year TLV 'ppm Comment Belgium Canada F inijr.d Frsncj German Democratic Republic (DDR) Iran Italy Japan Netherlands Rumania !?'I 1975 1975 1975 - 1976 1976 1975 (future) 1970 1974 1975 1975 - 5'veden Switzerland Cmred Kingdom USA 1975 19 / 6 1975 (future) 1975 October I97J 1947 USSR April 1974 October 1974 *6 Federal Republic of Germany 1966 1970 June 1974 1975 1977 25/50 10/25 S-10 25 200 * t: 25/50 SO f 25/50) 500 200 *10 10 100 mg'm* (40 ppm) 5/20 1/5 100 10 25/50 10/30 500 50 25 1/5 1 mf/litn (391 ppm) 30 mt/iti` (* 12 ppm) J00 too 50 5/15 :/5 TiV.A l S n/IS min I TiVA (S h/15 min) TWa >5 ti 15 T.ir.i TWa i 3 h> MAC (Schottek 1969 \ IXonerzke et al. 197S) TVa (8 h/1 h) TWA (8 h) ITWa 9 h/15 min) MAC MAC (25 mg/m*) TWA(g h) MAC (Proden et al. 1975) TWA (8 h/15 min) TWA (8 h'JS min) MAC TWA (8 h) TWA (S h/15 min) TWA Ipersonal/ceilinp) MAC lAmer. Conf. Govemm. Industr. Hypenisu) TWA (8 hi. temporary emergen cy standard (OSHA) TWa (8 h). temporarily permit ted exposure TWa (8 h/15 min) MAC. provisional ceiling concern nation: Stare Sanitary Inspec torate. 1957 (Filatova and Groruherf 1957) SMC (Schonek 1969; X*truer 1975) (Sanirarsye normy) MAK MAX TRK (preliminary technical guideline). Annulment of MAK regulation. TRK (annual mean/1 h> TRK (annual mean/1 h) Sources: Smyth 19S6:ftiaro*a and Gronsbert 1957;5cAorre* 1969-.Htntchler t9721 73:IARC Report 197d.Haley 1975;Sekabe l975:Prodan et at. l97S;Aryenpitr 1977;JCAfirr and Wolf 1977: MAK-Werte-Ciste l977:Xettner 1975 ft i. r t i 21108020 r :o W K. Lclbjoh and H.J. MjmcIIci Vinyl Clilondc-Ai'. hours alter repealed spraying in snialler-sized rooms (I ARC 1974). Haley (1975) pre 3 Toxicology ol sented a list of pesticide products containing VCM as a propellant and registered for indoor use, which were banned in 1974 by the Food and Drug Administration. In 3.1 Acute Toxicity Japan, the monomer was also banned as a propellant in 1974 (JAMA 1974. 229-S55). There is a case on record of a worker who died from noncirrhotic portal hypertension and angiosarcoma of the liver after 14 years' employment at a chemical piant in south During the first three ern Germany where he had been engaged in loading such pesticide cans (Reml and the assessment of the hVhcr 1974). Tlte report of a female office worker suffering from typical Raynaud's concentrations vaxyii' phenomenon, pseudoscleroderma, acroosteolysis and mandibular osteolysis who never and Leake 1933:Sc/i. had occupational contact with VCM {Meyerson and Meier 1972) is apt to make one matteo et al. 1960:L` wonder what influence the frequent indoor use of VCM-propelled spray cans (BriJborJ anaesthesu. deep nai. et al. 1975) may have had in this unique case. Sputum samples collected from frequent this range of exposure users of pressurized spray cans who had no respiratory symptoms were found to con tive and haemorrhagic tain a significant excess of moderate and marked atypical metaplastic bronchial cells hepatocellular injury compared with two groups ofcontrols (Good et al. 1975). inducing substances (se PVC bottles, films and foils have been used for many years for packaging food and beverages (cooking oil. margarine, meat, mineral water, fruit squashes and other soft drinks, hard liquor etc.). The content of residual VCM in PVC bottles was found to 3.2 Chronic Toxicitv have ranged formerly between 5 and 400 ppm (w/w), and in PVC foils up to 800 ppm {van Esch and van Logten 1975). The problem of migration of unreacted VCM from Torkelson et al. (196 U the PVC containers into the foodstuffs became recognized in 1973. Reports of un exposure to concentrat pleasant tastes in American brands of vodka and whisky which had been stored in PVC 4j -6 months. All spc. bottles led to the discovery that VCM had leaked into the liquors .in some samples however, eaused an inn tt levels up to 10-20 ppm (w/w) were found {van Esch and van Logten 197 S: Davies and Perry 1975). Data available in 1974 to a group of WHO expens revealed that samples histological changes in r pigs and dogs. An incre: of gin and wltisky had contained 0.57 and 0.62 ppm (w/w) of VCM respectively, after in rats exposed to 20 01 storage in miniature PVC bottles for periods up to 3 years: VCM concentrations in r \ orange squash and cooking oil were found to be in the range of 0.01-0.08 ppm and (l965);no histological' Gor'kij Institute were rr Li 0.01 -0.04 ppm. respectively (1ARC 1974). Levels of 0-0.4 ppm found in British PVC-bottled liquids were mentioned by Davies and Perry (1975): in their own analyses exposure of experiment mias. bradycardia, chan. of samples of PVC-bottled spirits supplied by British Airways they found concentra tions of 0--0.25 ppm (w/w). Methods were developed for the detection of VCM in 0.05 mg/litre) for 5 mof liquids with a maximum sensitivity down to the 1 ppb level {van Lierop and Stek 1976: creased secretion of cat-, Dressman and McFarren 1977). It was tentatively estimated that even during the years posterior hypothalamus when PVC-packaged food and beverages had not been heeded as a potential source of 3500-4000 ppm (9- !C contamination, the likely average daily human intake of VCM from this source could of the cortex and the am have been in the order of 0.1 mg/person (IARC 1974). Schlatter (1976) calculated comitant changes in circ that today it would be less than OjO 1 mg/person (equalling 2S0 mg during a whole posure of rats and rabbit life time); in comparison, he calculated that the inhalationai intake of VCM in diseased resorptive bone changes . L workers who had been exposed to concentrations of 500-1000 ppm during a period nervous system dysfunui of 10--20 years would have amounted to at least 25 kg. Hie .Association of the available evidence fot VC German Plastics Industry expects that the use of technology available at present for VCM should be suspecteu the production ofPVC food-packaging materials decreases the VCM content of food stuffs to below 50 ug/kg (50 ppb) even after prolonged storage (VKE 1975). Results of carcinogenicity assays in experimental animals after oral administration of VCM are discussed in Sect. 3-3. N H* H* O QC statutory maximal allows cratic Republic) should h Of particular imports! Viola et al. 1971) with c> full year. It was only alto. O 0 J U .J. Mameller (.1975) prercgistered lor * ;on. In 219:355V > hypertension ' plant in south\Rcil and -;al Raynaud's lysis who never to make one . cans (Bridbord i trcm frequent found to conrunchial ceils ging Tood and ...1 other soft -as found to up to 800 ppm J VCM from - ms of un uored in PVC ;tc samples 'r:.Davies and '"that samp`:s v-ttiveiv. after irations :n iK ppm and ::i Sriush - <wn anal} es icentra*CM in -udSrefc rnnj the years res! source ut source could calculated -c i whole ~M in diseased rwf a period of the present for tent of food-75 ). ResulU m of VCM Vinyl ChtunUc^Axoc^uJ 3 Toxicology of VCM 3.1 Acute Toxicity Z\ During the first three decades of PVC production, animal experiments were limned to the assessment of the acute mhalational toxicity of VCM in short-term exposures io concentrations vary mg between 50 000 and -00 000 ppm (Pjtr. et al. 1930 .Pcopki and Leake 1933 .Sc/icununn 1934.1938: Oner et al. 1947. C:r* et al. 1949;Miuro- inairco et al. \960.Ltitcr et al. 1963). In mice. rats.guinea-pigs, rabbits and does anaesthesia, deep narcosis, cardiac arrhythmias and lethal effects were observed within this range of exposure but no relevant organ pathology was noted except for conges tive and haemorrhagic changes in lungs, liver and kidneys on fatal outcome. Acute hepatocellular injury wras later found only in animals pretreated with potent enzymeindueng substances (see Sect. 3.4.2.3). 3-2 Chronic Toxicity Torkeison et al. (1961) were the first to describe results of expenments with prolonged exposure to concentrations ranging from 50 to 500 ppm, T h/day. 5 days/week,for 4_5 -6 months. All species tolerated exposure to 50 ppm for 6 months: 100 ppm, however, caused an increase in liver weight and 200--500 ppm caused, in addition, histological changes in the liver and kidneys of rats and rabbits. but not in guineapigs and dogs. An increase in liver weight and decrease in spleen weight was also seen ir. rats exposed to 20 000 ppm, 8 h/day. 5 days/week, for 3 months by Later et al. (1963): no histological lesions were found after 3 months. Soviet investigators at the Gotti] Institute were mainly interested in neuroendocrine changes after prolonged exposure of experimental animals to various concentrations of VCM. Cardiac anythmas. bradycardia, changes in phonocardiogram in rats exposed to 12-20 ppm (03)30.05 mg/litre) for 5 months were reported (Vasin and Plokhova 1969b) as well as increased secretion of catecholamines in rabbits and changes in the biopotential of the posterior hypothalamus (Vezbt tndPloklwva 1969a). After a Si-month exposure to 3500--4000 ppm (9-10 mg/litre) changes in the bioelectric activity (EEC recordings) of the cortex and the anterior and posterior hypothalamic nuclei in rabbits with con comitant changes in circulatory functions were seen (Vasin and Pbkltora 1968). Ex posure of rats and rabbis to 03)3-03)4 reg/litre (12-16 ppm) for 6 months produced resorpave bone changes and osteoporosis in addition to cardiovascular and cenual nervous system dysfunction (Baviaer et ai. 1972). (a 1969 Schortek summarized available evidence for VCM toxicity and warned urgently that chronic exposure to VCM should be suspected of causing toxic liver damage. He moved that the currently statutory maximal allowable concentration of 200 ppm (MAC value, German Demo cratic Republic) should be lowered. Of particular importance as pioneer woric were Ilola't experiments (1970a, b: IToia et al. 1971) with exposure of rata to 30 000 ppm. 4 h/day, S davs/week, for a full year. It was only after this length of exposure that histopatholugical examination W.K. Lelb.iv.!) jnJ H.J. Marstelle: revealed lesions similar lo human acroosteolysis and also similar to the ty pe of nontumorous liver diseases which we observed in PVC workers 3 years later (ManteHer 11 ai. 1973). Viola described lesions of the skin, the small arterial vessels, the connective tissue and elastic reticulum of the paivs, and periosteal proliferation with chondroiu metaplasis of metatarsal bones. Fibrosis of small peripheral nerves and degenerative changes of the grey and white matter of the brain were prominent, wlicreas 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 fibrosclerouc reactions. 33 Oocogeok Properties The earliest documentation of the carcinogenic action of VCM was Viola't preliminary report presented at the 10th International Cancer Congress in Houston, Texas in May 1970a. Of 26 Wistar rats exposed to 30 000 ppm for 12 months 17 developed epider moid carcinoma, mostly in the paraauricular region; 6 also developed adenocarcinoma of the lunp and 5 osteochondroma of metacarpal and metatarsal regions of all 4 limbs (Viola et al. 1971; Viola 1974). Maltom and Ltfemine (1975) later interpreted these paraauricular tumours as arising from the sebaceous glands of the exterior acoustic duct, also latown as Zymbal's glands, the cell matrix of which seems to be the target tis sue of a number of carcinogens. They were of the opinion that the pulmonary malig nancies were metastases from the Zymbal gland tumours. Autoradiograms of sections of whole rats dosed orally with [` *C]4abelied 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 Narlnvay 1975). In this context iVeuma/i/r et al. (1979). who analysed the peroxidase activity m Zymbal glands of Wistar rats, proposed the concept that peroxidase-mediated bioactivation of carcinogens (in their study: stilbene derivatives) might ofTer an explanation for these tissue-specific effects. At the end of 1970.Ua/roni and his group, with the support of Italian, British. Belgian and French chemical companies, started to plan and subsequently execute a large-scale carcinogenicity bioassay designed to study the effects of chronic exposure to VCM in relation to various experimental factors such as route of administration, dose level, length of treatment, and species, strain, sex and age of animals (Malroni 1973, l977:MaltoniandLefamine 1974a,b, 1975;3fir/romet al. 1974a, 1975).Con centrations used in the inhalation experiments were 30 000,10 000,6000,2500,500, 250 and 50 ppm, with length of exposure ranging up to 52 weeks and observation peri ods up to 143 weeks. Apart from the induction of Zymbal gland carcinoma other ma lignancies developed, notably angiosarcoma of the liver but also extrahepatic angio sarcomas. nephroblastomas, pulmonary tumours and mammary carcinoma, as well as a number of single tumours of other target tissues. Different types of tumours were found to coexist in the same animal. On oral administration of VCM dissolved in olive oil (5 days/week) angiosarcoma of the liver was found after 50 weeks in two animals of the two groups of 80 Sprague-Dawley rats each of which had been treated with the highest doses of 50 and 16.65 mg/kgbody wt. (Malroni et al. 1975).Malroni (1977) succeeded in demonstrating that the route of administration of this dearly muitipo- Vinyl Clile tential carc study of or. solved in so 6 iays/weei ratio only ; tion not ne. placed the i the no-toxi. angiosarcor. Sprague-Da- proved to h. genic in rati be carrinoge 10.5 and 1 : 1979). Ano> the dose-re i.-. exposure lev histological -. the liver and the inductior posure to 10 al. 1974b; lA endothelial : perplasia and even in the a was scanty a- doses. In the fibrosis was t of ossifying : feet was sugg offspring of r mine 1975). I posed to VC." ed from Grid it was seen a maturity of r. to 2000 ppm foci of hepa;. Holmbcn- week, for 52 spleen chant mals exposed N cutaneous an H* K ppm group ai O GC i See also It livelier *on'Icr et x-cri irciv ;irve kiirions oroiiier- limmary in May epiderronocna ' 4 limbs i these .-tia targe; tis- *"'3 .wtior.s tion of '.antis :.M9T9). .ne . stilbene .JSUrt anon. 'rltotti "5). Con* >no. 500. tion pen-thermaangio; well as swere J in olive animals ` with the P77) altipo* V'irv! Chlomle-AssocuteJ Discaw tenuai carcinogen may stgniticantiy vary vie r. a: aeaplastic response. In 3 subacute study of oral VCM toxicity, lasting only :3 - .;uch rats were given VCM dis solved in soya bean oil by gavage in dmly aases of IC 100 and 300 mg.;kg body *1.. 6 days,week.Fcron et al.(l~5) founc a sign.i'.ca.-.: ..-.crease in liver-io-boiiy weight ratio only at the highest dose level. This was .nterrre:; J as a merely nonspecific reac tion not necessarily indicative of a toxic response Esses on these results. Feron et ai. placed the oral no-toxic-effect level at 30 mg VCM rodv wt./day and suggested that the no-toxic-effect level may actually be even b.:n;r Z. ratal gland carcinoma, hepatic angiosarcomas and nephroblastomas had neve' occurred spontaneously m the breed of Sprague-Dawley rats used a: the Bologna Inst:rote Tie neoplasuc response to VCM proved to have a direct dose-time relationship E(* tvru of 50 ppm were carcino genic in rats and mice. iMtxMaltoni (19771 found txoosure to 25 ppm VCM also to be carcinogenic in rats, whereas no carcinogenic e:::: waa observed at lower levels of 10.5 and 1 ppm in a study which, however, a st:'.l incomplete (quoted from Griciutc 1979). Another American study designed to corr.p.tment Maltom's results confirmed the <iose-feiated induenon of liver angiosarcoma and mammary carcinoma in mice at exposure levels of 2500. 200 and 50 ppm (k'epimtcr -i j[. 1975). On reexamining histological slides of his past experiments. Vok Utec-also detected angiosarcomas of thr liver and other malignancies of skin, iung and unitsuntan his rats: he also reported the induction of skin acanthomas and pulmonary adenocarcinomas in rabbits after ex posure to 10 000 ppm VCM. 4 h/day. 5 days/wee'k.Tof at least 15 months (Meltoni et al. 197-tb; (ARC 19741. Maltorj and Ltfemint 11975) considered the effect of VO! on endothelial tissue to be a systemic one since they found dilatation of blood spaces, hy perplasia and atypia of endothelial ceils also m organs and tissues other than the liver, even in the absence of angiosarcomas or berugn angiomas. Evidence of hepatic fibrosis was scanty arc inconstant in their animals and was more likely to occur at the lower doses. In the spicer. of treated rats and mice fibroancobiastic proliferation undergoing fibrosis was frequently observed. No acroosteoly tic lesions were found, but a few cases of ossifying angiosarcoma were observed. A potential transplacental carcinogenic ef fect was suggested in 1975 by the development of subcutaneous angiosarcomas in the offspring of bleeding animals exposed for 7 days during pregnancy (Maltoni and Left- mint J975). Later, Msltoni( 1976) detected angiosarcoma in the offspring of rats ex posed to VCM during the period between me 12th and lEth day of pregnancy (quot ed from Gridutt 1979). Hepatocellular carcinoma was r.ot found in adult animals but it was seen to develop readily in newborn animals, possibly in connection with the im maturity of their bioactivation pathways (Maltoni 1977). Exposure of newborn rats to 2000 ppm VCM. 8 h/day, 5 days/week, for at least 4 weeks elicited preneopiasric foci of hepatocellular ATPase deficiency, notably in female animals (Laib et al. 1979). Hobnbcrg et al. (1976) exposed mice to 50 and 500 npm VCM, 5 h/day. 5 days/ week, for 52 and 26 weeks respectively. They did not observe hepatic fibrosis or spleen changes, but multiple benign alveologenic adenomas developed in IS of 24 ani mals exposed to SO ppm and in ail 24 animals exposed to 500 ppm:. In addition.sub cutaneous and/or subperitoneal haemangiosarcoma developed in 14 animals of the 50- ppm group and in 8 of the 503-ppm group. Only one haemangiosarcoma of the liver I See also WintU et al. (19761 Z-t W.K. Lclbach unJ H.J Marstelle: was found in an animal exposed to 500 ppm. A few mammary adenocarcinomas, one rhabdomyosarcomaand one renal haemangiosarcoma were also seen. From their ex periments Holmbcrg et al. concluded that a lower exposure over a longer period niay intensify the cancerogenic response and that an inserted relationship between dose level and latency time seems to exist in the case of VCM. as had already been observed with other carcinogens. Recently the results of 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. (1970a. b; Feron and Kraus 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 ceiular alterations in the liver with reduced glucose-6phosphatase activity in hepatocytes. strong sinusoidal activity of alkaline phosphatase and increase of smooth endoplasmic reticulum in parenchymal liver cells were observ ed. In the final stage areas of necrosis in the liver parenchyma, focal dilatation of sinus oids and proliferation of normal and atypical sinusoidal cells, multicentric hepatic an giosarcoma and Zymbal gland carcinoma occurred. Feron et al. (1979b) also observed hepatocellular carcinoma in three animals. Surprisingly, the induction of very malig- j nant metastasizing carcinomas of the nasal cavity originating from the olfactory epi- I thelium and Bowman's gland was noted, which had not been reported before in con-___J 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- Vinyl CMoru lived but high mutagenic an cretable prod. 1975). The t. tive velocities tion of its rets nation of VC` so that above following a zt cordance with 3.4.1 Uptake Pulmonary' up in the animal'with the poo! > shown by com Bolt et al. (19' as albumin, at? pound goes in i After oral ingc- has to he eon?: ii 21108030 -pJtJXq fCUOTltd -ruoo mju siqi 01 anp aStuitp jo umnaads ipy aqi jo uopraSosai impuS aqi paijrau itui airutiaiii ppo/f. aq; uioij satprns itoturp asoqi sazntununs i aiqtj, ui paiuasaid sisdauXs jtauoisiq am 'paunvp uaaq ptq r stajuijrq n ajmb mo aq oi awaid iqSoo IOA oi umodia fcuoncdmoo siuojqs arqi aSjatoa oi orSaq ii sosfil-pnu *P iuunfl uitujaads [cauto f -Mxa|daio3 aunurnn jo uontuuoy sip Xq painpauj st uopst aqi (a) jaqiaq* jo (uou -cjaj.qoid irqaqiopua pur uoiirmjojtutJi isciqoiqtj qiM) sauaut ncun jo sjjas Suiuq Itqaqiopua (pj 'ujouaut jo ctpaui aqi jo spas apsmu qioous (3) -uiaisXs snoAiau ?n aqitdtuXs aq: (q) 'saiiuas joioiuosca .Cirpnpaui (t) no uoqat 3txoi wajtput jo isairp t uava Xcui qstq,* saiqoqnau: a*not oi jo j]asii joa oi anp si suotsa; |ust aqi jo iuaa do;a.\ap aqi jaqiaqM Jtap qt it iou si if "jaAq aqi jo tuioamotSut pot tisoiqtj jruod onoqupuou qioq jo nsauaSoqicd aqi ut utd juiuas aqi sXqd JOA J uontAtiocoiq snrdaq leqi paqsqqtisa .t%ou si ii trvaq^ -j3a<; aqi jo auicajcsodut jo suots?) j3aij iutu?rfrtuuoi; aqi jaqna urqi jauoqs Xiqtiaptsuoa r. pouad Xsuaitj sirsapisag -ucu: ui jqa o: amsodx; rtuojqs jo nsajia acaApc jo uoursipu: isaqira aq; si v. aiuoip -uXj siqj. sisXioaisoojar put suoaunpui upjs picuuapojaps-uouauiouaqd spncuXty pcui aqi jo luauidqa-vap aqi joi ajqtsuodsaj air qsiq.n suosa; jrpisstA oiiscfdoaitunu pistp aqi jo sisauaSoqitd aqi ui JOA J 8|oj aqi si uiaiqoid gutjOTd Xfltnba uy (q816l jt ia icnusicft) aiXooicdaq aqi ut ajt Xaqi utqi a.\nsajja ssa; ajt uoncoqdaj fi;j iutj -laqc jo uouraucr aqi joj suistucqsaui ireday (f) saiXsoicdaq aqi ucqi jaqio sanssn ui manijjnsu! ajt (sjaiqoqnaui a.vpot aqi jo uoiitoywoiap aqi joj suiurqj?|\ (?) laAq aqi utqi jaqio sutiio jo sanrni Xrui r `(gi61 ijog) .<iptdr3 aqoqtiaui auios srq j|asii uinqatpopua aq_i_ (j) -qa? jrqaqiopua aqi oi paXaAUoa ii put ai.iooicdaq aqi Ata] aiqoqciaut aAtue aqj_ ([) ruonounfuos ui jo XjSuis jaqiia 'aiAuaajja ajr sassao -aid X[3)(!| isoul jnoj iuu\onoj aqi jo qsiq.in paitjnsads aq Xfuo uu ii luasaid iy -sasnuis sqtdaq aqi jo pa? {tqaqiopua aqi inq ai.Cooirdaq atp iou si JaAi] aqi ui XnaiuaSouraJts jo aits aqi `Xfpuoaas -(8i6I It la Xhoiicj :9qbl tj^^i 'ir la sjgmu}/:u6l 'Sl6l 'ri61 *!* jaiar/J punoj stm sisojoau ua.\a pur uoticTnonstA jtpinaooicdaq jcpiqoiotd pot ituojptui -1010001 -ojiuao nti paitanajd oi lajnsodxa aqi papasaid ptq uiauXs asrptvo uotisunj pavitu aqi jo siasr.pui maiod qn.-.\ luauncar.aid ssapin ioa 01 aitisodxa Jayc Xncstgofoud -joiu paAiasqo uaaq iou sru .unfui jqnijoooicdaq ain.oy `Xiimkoj papnpui-jo^ oi a;qn dassns Xiicinstucc iou s; j|asu naa ia.\q aqi -ai.ooicdaq aqi jo mrqnonaj 3tuistidopua aqi si aiquonaiu a.\mr aqi 10 uoucuuoi 10 aits aqi qSnoqiiv -snooi 01 a*cq qiM ifio.* iciuauusava aitunj q3tqA\ uo uiaiqoid paA|osajun uc 01 uo sauir? isadst siqj, -sai.xsoirdati ?i|i utqi jaqicj sj]33 isSjti aip ui -p saooc put amsodva paicadai layc sisauasouisics pa3npui-|OA J0J uisiutqaaui aqi sr papnp -V3 avi luasajd it louttto `laAavoq spir'i" siapnujo uoutiXmy -uoiitsndaj irpip? 10 lOJiuo.-i atp iitduii Xcut tpiq/n suounciaim apqns aiourjaqio 10 Xupqissod aqi apnpxa c- .ivtssiq p.iici.'c-.y-aput'tqj |Xtr \ iou saop v oi8oi| ajntodxaaa< jaiapan paiuasah. Xjsao> jo Stqpui -J31SQ) spot put qtr, uistucqoai- -U00 3JTBO. cuioomoPi qaM saicp. uonaun; r -aq ""'o* as 1 = -luajtAor - i 10 SBOIK -od aqi *~ juiputk, J 10A01 -toijncciap -va aq u nrjiui aJ?p u! suisiutq- qj-.q/r 1 jo aaotqin paijncoia; U0U3C1J X|l sii uaxasn -qciaui aq. suiaioid pi Suiicpl aa'.Xru n -arrcod; put uisqo ia spinu.t -ouota jtn nauir j1 st.,, uor -odxa 1 laipisjcj; i -h - r>* -U.`iaf-.'^.^Vr. -+*`Z.* *T*;, * K'.ys; `*-'--I M'-.>. -* .,1 f-- ~qj jo swXjeut <5 961 I .'-re (tuoricdno ' aSuw nnj aijj nej) uotjuqtA tct(3 ajqtsiaAaJ -> aq oj mottt] i ui punoj rm qi<Av uonsunf ye (uoiwado <KX[oaisooi3< 'P jo aouapua :n`jjjaa paJ jo nus sbm aiaqi . uo nionunp .u osje (t>S6J) ^SMOPW uontpiSaJoiu . >61 wo?ny) -[t RM SOIOjp jdares Xjjnoq .;m jauuouad .aq ui pnap ut t ancoj.) uou nnpoid 3utjd icaipul my v TML11 I t- 'O (6)ri6l 7V 161 -.?/ Zl6 1 7V Zi. 61 'd jrsA U03)i aiqx uo(ko l-^'A aunsodxa jo aaiiap oj pairjai vapu* siuajat pancu puc uoijuxaj j$g pascauuj suois| auoq aqi Soipaaaid ruoisa) jtjnattA puc j*w9/y ft 33 VOtpOQ uouauiouaqd s.pncuXcy pu* sis.{|o33soor>t ;o anuajtAai^ ctuadoaXaoqiuojqi suonuapf 'ft 39 UPWUt(J o^uiiiinKuoiuv tuiqqnpiopnasd saJucqr- unf* aiintuuapojaps `SuioidtuXs s.pncuAeu tut.* ssXioaisoowe (cuouidnaao, .Odoiq auoq pus o^s Xqduiouauy It la uotpn jwujg Xsdoiq uiqq -uiqnjqiq unuas pami X) -luajsiviad qiiM A|cdauioiedaq`enaied putnuiof aci[i0J3O jo iuauiaA|o.\ui `duiqqotoapnaai nous -tuouaqd ,pnruXty_"suoisai ui3fl?vsXiwisooj.iy srnvpy put fuuejj (ssausnamuatPjD sso[) a/nsodxajaao ajnae jo saposida-nrxiaAaj daap 'naupaiu 'urei luiof'iuiqqniaoprinKt -saXioaisooj.ir -sadurop ui^ a^ctmapojaps 'auiojpuAs sjptcuXcjj jc ja >aiptoj uisipioiXcpeJ.414. :>uu3apuj T,Kaoiouaids ctuiaeuiqpjijiipadXq moqiiM A|cJuojfdaq ssaunnj masncu `ctxajoux. -xiuoiduiXs itsitQ snntuuap aitou* pue [caiuiaqs'uonunpui rnqs a^!ttuuapa:avxa|q;iiaAai 'snjurud : ioxbuu9Q smnqjuXs spncuAey :jbjtidsu..* aipcpcaq-Tiuaqisr priauai `Ajounui jo Sununjq nrniuosui "ssausnoAiau (rouaicunuos rijoqdna `ssaur?jtp> suioidui.Xs atjo.ucuauf .^}J fc 39 wuny MVUS3 -oin.iijai puc sisXfomacti jq*!ts sancauBj jc- ais jcioa uo uiM* jo Juiua^arqi Tuitpqfijaopnas:,) ssducjrqd icisip jo suoisaj anXimtuir aiqiuaAT^ P.IOU^IIUj ajnsodnajaAO ainac icjcjuou i `KOA Xq duiuusiod (cj (eiuapiasc jo sasra oj_ uouaiuouaqd s pncuXry oi jcjiuiis suioiduiXj si>ojnauoi8ur sixo^ <isojn?uoiiur atxoj. jSlZUVQ Bjoqn% SjiqtUOjQ puc BAOIO/tJ v.\otuuu$ suoisa) ui^s Tnuscuc UOISUSlojAtJ '.SUUUCS `.suucdaq .'iiaiaiuc. pa^jrtu **>( jo aioiu iirdauiujcda}) It ia iiinquj' sduipuy Cdoioqird paieiaossc-iOA ioj anuapwa jo aauoliaiua itnpcjy ZL61 U6I 1661 8961 696! 6961 6961 9961 961 1961 096! 6S6! C>61 6r6I aiqtj. Til pu* Ml 0 tlJ ?Jars:<!!Ie? I onurrertw ursion. henoroenon uiing by VCM. -.ai phalanges. .n on volar s jjtU rtiiwulo- nos. euphoria. nia. blunting adachr .rodern alike rgic dermatitis -~i. tyunesS. rubmaemi. ttke %km lubbmg. j'-int episodes 01 rss) naud'j'phcnomrrntof sacroiliac with persistentjpjy p5V h Raynaud's - changes. Raynaud's ne iesrons -1 icterus index Vinyl Chionde-Ascoctjted Disease 31 Table 7(continued! Year Reference 17*: .Uerf ou:.-: et ui. io*: Jiihv and Lange 1973 Marsteller et ai. I9701i) Creech ei al. Findings Progressive thickening or hands and fones;n>. arthral?:.!. Blanclnnv upon exposure to cold uitn cyanosu of hanas accompanied by severe pain. Skin biopsy 1 -t Ciermar. report o: " worker* -- itis scleroderma like skin lesions. Raynaud's syndrome, ar.d acroosteoiysis. Tests showed abnormal liver id 3. occlusion of digital arteries in I worker Noncirrhouc portal fibrosis with portal hyper tension and splenomegaly 4 cases of angiosarcoma of the liver 4.1 The Triad: Raynaud's Phenomenon. Pseudoscierodenna and Acroosteoiysis A first indication of advene effects due to chronic VCM exposure arose in workers at a plant produeng VCM who presented with symptoms similar to Raynaud's phenome non (`toxic angioneurosis'). This was repotted by Smirnova in 195- and later described in detail in her thesis (1959). The syndrome was found ptedominandy in laboratory personnel who had intermittently been exposed to high concentrations of VCM duhng hourly sampling for chemical analysis (purity of the product). Ir. 1954 Raynaud's syn drome was also observed among several workers at a Japanese PVC producing plant (Kubota 19S7). Apart from a painful vasospastic disorder of the hands, impaired ther moregulation, acrocyanosis, positive cold test, eapiilaroscopic alterations, panesthesias, and CNS symptoms such as headache.blunting of memory and sleep tvfcnai.Smirnova (1954) alsc mentioned swelling o: fingers and development of circumscribed skin in durations on the volar side of the forearms in those most severely affected. In addition, there was evidence of mild haemolysis (borderline anaemia, decreased osmotic fragility of red ceils, urobilinuria, and reticuiocytosis). In 1961 Smirnova described radiographic evidence of destructive bone lesions of terminal phalanges in the hands identical with acroosteoiysis in three workers at a PVC-producing plant (one fitter, two centrifuge operators) after exposure for 3-9 years. Since these bone lesions developed in con junction with toxic angioneuroas' and since complete recalcificadon of the defects was found in two workers 5 yean after removal from exposure. Smirnova believed the lesions to be characteristic of chronic VCM intoxication. She pointed out that their reversible character might serve to distinguish the lesions from similar defects seen in vibration trauma. In retrospect, Smirnova i observations are the earliest descriptions of the full range ofsymptoms which much later became known as "the syndrome of oc cupational acroosteoiysis'. In 1963 Suoiu et al. (see also 1967 and 1975) published the first comprehensive analysis of their observation of a multiform symptomatology in subactue and chronic W H* H O GO O CO w !T VCM intoxication. During a 4-year period, they examined 168 mostly young workers from two Rumanian PVC-producing plants who had not previously been employed in other industries. In their classic paper, the authors described in detail the various cen tral nervous, digestive, angioneurotic and cutaneous symptoms (listed here in theit order of manifestation). Acroosteolysis. however, was not mentioned. Episodes of acute overexposure (usually occurring at the end of a batch run. during retrieval of unreacted monomer, or at repair jobs) rapidly resulted in a state of licht-headedncss and transient euphoria similar to a mild degree of inebriety and were accompanied by a feeling of heaviness in the legs and disturbed locomotor coordination. Several workers claimed to have been able to identify escaping monomer by its faint but agreeable odour. Apparently during periods of particularly high ambient concentrations, workers repeatedly noticed formication in the lower limbs and a general feeling of bodily warmth. Six subjects had experienced loss of consciousness when repairing leakages, but recovered rapidly after being carried out into the open air. After a few months of work, unusual fatigue and sleepiness set in, there were complaints about persistent somnolence, even outside the work premises, and a tendency to fall asleep at the work place, particularly during night-shifts. In addition, headache, dizziness, irritability, blunting of memory, paraesthesias, and general weakness were reported: some workers noticed insomnia or steep reversal. A reappraisal of these nonspecific complaints (see also Vale et al. 1976) 6 years later, after improvement in industrial hygiene, revealed that the frequency of their oc currence had considerably decreased (Suciu et al. 1975). Following a prolonged period of repeated overexposure, vague nonspecific digestive symptoms also developed, such as anorexia with ensuing weight Joss, nausea, fullness, upper abdominal discomfort, bloating and epigastric pains. Enlargement of the liver was found in 51 workers (30%); in 6~ there was also splenomegaly. Gassic Raynaud's phenomenon was found in 6%. but a tenfold higher percentage of the total work force showed evidence of vasospastic alterations on plethysmography (Raucher ex al., cited by Suciu et al. 1975). Pruritus of the hands, forearms and face was an early complaint followed later by what was theought to be (allergic?) `contact dermatitis': finally, nodular and scleroderma- or scleroedema-like cutaneous lesions developed in some workers, involving the dorsal surface of the hands, the volar side of wrists and forearms and the face, with firm thickening of subcutaneous tissue or formation of whitish papular or slightly elevated piaquelike indurations. The cutaneous manifestations largely disappeared after removal from the work place. In addition, mention was made of features of hypothyroidism in a few workers. Also, transient loss of libido in 24% was recorded, with return to nor mal after a break from work or during holidays. With the exception of acroosteolysis and the two most alarming late sequelae nonorrhotic portal hypertension and hepatic angiosarcoma - Suciu's early documen tation of the prevalence of disease in PVC production workers encompassed a com paratively complete description of the various aspects of chronic VCM intoxication. Later publications supplemented the spectrum of knowledge mainly by providing ad ditional information on epidemiological, roentgenological, thermographic, angiograph ic, and histomorphoiogical upects of the lesions encountered in subjects chronically exposed to VCM. to H- H- O OB The disci tw o Belgian . classifiable d marked the r. syndrome w: year a numb. United State; cases of 0A0 the various pi end of 1979. vascular phem symptoms t!v begin with illthe fingers arc tips on hard > to cold accorr are likewise a: ance of painii. osteolytic pro with striation Table 8. Publ.. Year 1966 1967 1967 1967 1967 1969 1969 1971 1972 1972/197? 1973 1974 1974 1975 1975 1976 1978 1979 3 One of 2 ch .1 i. 'W*-* gj -v f:-a--'vIi *--! -A 21108031 I Vs (Ci6! >q&fBS assi *9scs psi.-iadtm g*. 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(8 9iqt2> F!tJSF u? p9M5i|Qoc uijq ?ci| s?sto 9CI jo iiqwnu jtioi f6i61 io pus 9l|l .ifl 'IlZtJQ put i(r][ 'urreg u: uoucucdios 9iuw sqi oi psititurc siuqd tnour/i 9in J! S9SC0 Hi. 39I|30I1C p9(T9\9J MOP tV> '\1II lUSnbOtqn* t 1CH3 PSUOdiJ "IOVO.l0 T3TCP o v. ] jsjij sin ptqusstp Mpjcj o 3 oqvi (,C*.61 > sj.MI'J Ji:ri s;i:is rAituji sin put uiciug 1C93Q 'j.niti j u;r:: tiijudsa 9i9A\ S9SC? [tuourcpt ic asqiunu r Jtr\ Su!.uO|;oj si): zui.'np put 'f*lOVO> ' ^jitpoj.-ic fruoucdnroo. rsiirs) scan 9u:oipu.is s'LL -pjjo.v, UJJSS9.\\ sti' UI sTtJ'i' :ti p'ltGnppo jo9u sup jo uopu.'fo:?; sip psppcu: (99t>[ Ic 19 J.vpj/'J) SnSSll 3A-.-.-S.J-C- 'ClUJtA sip jo suoisai SAntaAurSsp sjqtijissti? im pur uou3iuoii9i|d s ontu.icv uic.; --.rurs pci| oij sjamsp rAtpoinc ucri;?g o.vii to spun] sip. 10 sssutfTtid prr au\|091sp jtnsnun 10.Ojaophp 9112 r.av:a ps:rr.v-..\ -opui-p;^ | iuiA aouoru! in lunpsmptAOUiaa an p31tA9]3 ' uuii t icsaop 't:. t. .. jr.. sniutu^ 'UOJUII qtns'pai' pouid pjr -90 ilSlJJ f tlt-ji SiSXJOl* AIIPM ^jom sqi t 1U9ISK io sq3W `S3St3(C.- <1?^ SJS^JO.SJ 'Si 9|qt S3 9TSJ OAl |C ic pjiur. sssup?r 30 |tA' JO S9> JlStll ' STTO .{o; SJ.'Miaan 34 W.K. Lelbach ami H.J MarsiilL-r 4.1.1 Familial and Idiopathic Acroosteolysis Acroosteolysis is a very rare disease. The aetiology and pathogenesis of this condition is still obscure. Osteolytic bone changes in late stages of so-caUeJ Raynaud's disease (accompanied by necrosis and gangrene), characteristically presenting as loss of part or of an entire distal phalanx of one or more fingers and also of toes, have been mention ed in the literature since 1921 (Assmann 1921 .Monahan 1926: Borak 1927 :KombIum 1929). Komblum attributed the lytic bone defects to vascular abnonnalities and noted that he had found identical lesions in early stages of scleroderma and in leprosy. The term acroosteolysis was first introduced by Laroche and Hochfeld (1948), who held a neuroendocrine syndrome responsible for the lesions. Independently Hamasch (1949) reported another case of symmetrical idiopathic acroosteolysis, particularly involving the terminal phalanges of the fingers with preservation of rufts, progressive clubbing and shortening,and ill-defined symptoms of disturbed peripheral circulation. By 1952 Giacci mentioned that 68 cases of the familial type of acroosteolysis and 33 cases of the nonfamiliai, 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 (set 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 sysiemic sclerosis, ainhum etc.) was considered in their study and could be rejected with reasonable certainty. In a later review. Cheney (1965), who added another four cases of the familial type, stated that this variety and the nonfamiliai idiopathic type may actually belong to the same disease entity and may be part of a degenerative bone process more generalized than the term implies. It was the puzzling character and the rarity of this peculiar bone lesion that captured the attention of site medical personnel and industrial hygienists when in November 1963 the condition was detected in two Belgian autoclave cleaners (Leftcrc 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 15&-35J of the work population at risk. Hublet et al. (1977) considered the fact that only 3% of all workers who had been engaged in manual cleaning of autoclaves at a Belgian plant suffered from OAOL and Raynaud's phenomenon to be indicative of the importance of individual factors. Wilton et 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. AU of these 5011 workers had been engaged in various stages of VCM and PVC manufacturing, but 1257 of them were workers who only handled finished PVC polymer. Five of the 32 plants worked Vinyl Chic: exclusively v only 25 clea defined as ck enon:18 of with experic drome were jobs, both re (1 case per 7 appeared noi was detected use for reactentry into th Table 9. Pre- Country a France USA ; United Kingdom Fed. Rep. 1 Germany United 1 Kingdom Total More conrelated sympLange and I\. ological checi pathological: were affected cold, 15 work morbidity wa found classic ' numbness ami 8.7% and invr Allen test ind people with p K pseudodubbit finding that tl duration of p.- 05 :H.J Manteilcr th. ,dition aud's disease % loss of pan or : been mentton\Q2~\Kornbhm .lilies and noted > leprosy. The ). who held a 'jmasch t1949) iluriy involving stive dubbing :nion. 3y 1952 nd 33 cases of ature. He added itilating procesone fragments - of idiopathic le rang; of dif`ytic diseases, .-as considered 7 review, rd that thts same disease i than the term c lesion that -ts when in icaners (Lei'hrt edinVCM *nai type of - <11 si elk. had been rm OAOL and =4 factors. 'nrge company. * rorpoadons - epidetniotogi'ties and limita< 5011 workers 1257 of them piano worked Viinl Chloride-Associated Disease exclusively with the finished PVC-derived consumer products. Duonan it al. found only 25 clcar^ut cases of OAOL among the 5011 employees (mean age: 35.S years >. defined as characteristic X-ray tlim abnormalities combined with Raynaud's phenom enon: 13 of them had been reactor cleaners at some time: another 16 individuals 110 with experience m reactor cleaning! with early stages or minimal degrees of the syn drome were suspected of suffering from OAOL. it emerged that the two lowest-paid jobs, both reactor cleaning and baswt'packjng, had a strong association with OaOL i.l case per *2, or 86 workers at risk, respectively). Manipulation of the finished polymer appeared not to be associated with a risk of contracting OAOL. Only 1 case of OaOL was detected in those plants where high-pressure water lances or solvents had been in use for reactor cleaning. Furthermore, it seemed that the extent of degassing prior to entry into the autoclaves correlated with the manifestation of the disease. Table 9. Prevalence of acral disease in VCM-e\posed populations Number of cases Country Size of group at risk OAOL Classical Severe Sclero Raynaud's sensitivity dermoid phenomenon to cold skin lesions References France 130 USA 35-i United 37 kingdom Fed.Rep. 100 C.errv.anv United 10-i kingdom Total 725 $1 a 20 l5 99 l 20 (v-3'7) 71(^10%) fi 15 63 ' 8 < 23 4 to 1 119(-vl6%/ 43<'-6>-,-i Benoit 1967 LUis et al. 1975 Walker 1976 Lange and I'iltmcn 197" ,'fjncq et ai. 1978 More commonly seen than OAOL were Raynaud's phenomenon (see Table 9) and related symptoms of abnormal peripheral circulation (Benoit 1967: Lilts et ai. 1975: Lange and Veltman 1977).Benoit pointed out that a complete medical and roentgen ological check-up of all 528 employees at a French PVC-oroducing plant revealed pathological manifestations only among the group of 130 reactor cleaners of whom 32 were affected (OAOL. 5: Raynaud's phenomenon without OAOL. 12: sensitivity to cold. 15 workers). He stressed the fact that in this group of workers at risk the overall morbidity was almost 25%. Similar results were obtained by Lilts et ai. (1975). who found dassic Raynaud's phenomenon in 5.6% of 354 heavily exposed PVC workers, numbness and tingling in 24%, excessive sensitivity to cold in 18%, pseudodubbing in 8.7% and involvement of the toes in 7%. Besides, in 26.6% of the total an abnormal Allen test indicated impaired peripheral arterial circulation. It was noted that in some people with pest exposure Raynaud's phenomenon had gradually faded, whereas pseudodubbing persisted or even progressed. Most important, however, was Lius' finding that the prevalence of all these abnormalities increased significantly with the duration of past exposure to VCM. fO H1 h* O G5 o GJ I a" .I f : i : s:* U j r * .* s & ; * il [i n* 36 W.K. Ldhach and H.J Mar^clicr Occupational acroosteoiysis is a condition predominantly observed in youncer workers. The age range was 20--45 yean and half of all cases reported fell in the 30-59 yean age-group. Duration of VCM exposure prior to onset of Raynaud's phenomenon ranged from 1 to 23 months (Dodson ct al. 1971). For OAOL the latency period was at least 12 months (Wilson et al. 1967): in most cases. OAOL developed insidiously within 2 to 4-6 years. There is at least one patient on record in whom OAOL was first discovered two yean after termination of exposure (Benoit 1967). Longitudinal studies of the bone lesions demonstrated partial or complete but mostly defective restitution, resulting in shortened and deformed distal phalanges, within 2-3 yean after removal from VCM exposure, but Raynaud's phenomenon and cutaneous lesions may penist (Williams and McLacJtlan 1976). Stein et al. (1973a, b) reported partial healing with restitution of tufts but progressive lysis of the proximal portion of terminal phalanges 3 yean after termination of exposure. Although OAOL developed predominantly in PVC production workers who had at least for some time been engaged in reactor cleaning, the syndrome has also been ob served in association with other job assignments which were believed to carry a sub stantially lower risk of exposure. Trapp et al. (1974) reported a 31-year-old white male suffering from Raynaud's phenomenon, dubbing of the fingers and typical bilateral acroosteoiysis,in whom specific inquiry revealed that his employment by an industrial chemical company had induded dally handling of small concentrations of vinyl chlo ride (no details given). Typical OAOL was also observed in a worker after 6 yean' em ployment as spray dryer/bagger, pre-mix operator, recovery and charging operator who had never deaned autodave vats{Stcwart 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 tin 1972 he presented with Raynaud's phenom enon, pseudodubbing, typical OAOL and dermal thickening of hands and wrists. Ar teriography demonstrated narrowing of most digital arteries, even in fingers without bone defeats, and abnormal collections of small vessels in the pulps of deformed finger tips, but no vascular occlusion. Apart from the chemical insult by inhalational (rather than transdermal - Dinman et al. 1971 .Stewart et al. 1975) exposure to VCM, individual susceptibility or idio syncrasy appears to have played some (undefined) role in the development of the syn drome. It does not seem likely, however, that repeated physical microtrauma during cleaning operations (removal of polymer crusts by hand scraping or chiselling) was a decisive factor in the pathogenesis of the condition as had been speculated by Wilson et al. (1967). 4.13 Clinical and Roentgenological Features 4.1.3.1 OccupationalAcroosteoiysis In the mqority of cases osteolytic lesions are confined to the hands. Involvement of the feet was observed only rarely in OAOL. Wilson et al. (1967) believe that OAOL differs from familial or idiopathic acroosteoiysis in several respects. Although the bone Vinyl Ch defects in osteopon skull, de$' shortenin. nonoccup genoiogu 1) Tlii. one or mo 2) In t: tufts, or a 3) The tufts togei defects (sec ('bandlike Fig. 2. Oec acroosteoh year-old au 4) In th and broade fragments, i and increas. Sodium mineraiizati multaneous T jnii HJ. Mar-'t-.-lltr Ml m younger J f the '0-3= aa .enomen on tency penoc was .ped insidiously am OAOL was firs: .ongttudinal studies tsctive restitution. :in liter removal sions may persist till heaiing with terminal phalanges workers who had at has also been obd to carry a sub year-old white male typical bdateraJ nf by an industrial nns of vtnyi chlor after 6 years' smatging operator who i routine piar.t us chromatography I limit values of st year during an ynaud's phenomuis and wrists. Ar- f--*n without -o ;rmed ndermal -- Dinman ptibility or idioopment of the syncrotrauma dunng chiselling) was a ciliated by Wilson ''.Involvement of Keve that OAOL . Although the bone V-nv I Clil'irdc-Associjtrd Disej>c detects m the distal phalanges are similar in both conditions, other features, such as osteoporotic compression fractures oi the spine, basilar impression fracture of the skull, destruction ofmid-phalanges or osteosclerotic changes of wrists and hand bones, shortening of tnetacazpois and cortical thickening of the shafts of long bones seen m the nonorcupationaitype have never been found m OAOL. Wilson e: ai. worked out roent genological catena for the diagnosis of OAOL: 11 Tne earliest changes m OADL are marginal defects and lots of cortex in tufts of one or more of the terminal phalanges of tire han.ic 21 In the next stage this is foQowed by email half-moon' cuts in the cortex of the tufts, or a so-catted slice-effect along one or more tufts. 3) The advanced stage of destruction is characterized by either a complete loss of tufts together with a portion of the shaft or there may be transverse or oblique bone defects (see Fig. 2) cutting off the shafts from the remaining distal rim of the tufts I 'bandlike acroosteolysis'). Fig. Z. Occupational acroosteolysis. Transverse or oblique bone defects <`bandlike aeroosteolysis'} or partial loss of terminal phalanges in .all lingers of both hands, f 33- year-old autoclave doner:duration ofexpen* J 112 yean) 4) In the healing-stage them-may be either complete bony union with shortening I and broadening ofrise residual parts of the end phalanx or a fibrous union of bone fragments, r iagertips remain short and plump with persistent dubbing of soft tissues and increased lateral and lorigrarimal curvature of fingertips. N Sodium fluoride ,4F scintiscan data of affected bones suggested that active de K mineralization (tesorptive) and remineraiizarion (reparative) processes may occur si multaneously even in the same hand (Dodson et aL 1971). In some cases, bones of T '5 w K. Lelbach and H.J Mint other body regions were also involved. Erosive s . j scicrouc changes in the sacro-iliac joints and circumscribed resorptive defects i cornea; erosions) in patella, clavicle, mandibit, humerus, styloid process of ulna, femoral condyles, os calcis, cuneiform and metatarsal bones have repeatedly been obser. rd Conhcr et al. 1 966:1farm and A Jams 1967.Dodson et al. X^lX .Juht et al. 1974 Loire- r: al 1974a:Preston et al. 1976: Jayson et al. 1976a.Lange and X'cltman 19"i 4.1.3.2 Pseudoscleroderma Concomitant with the manifestation of paraesthesras. pain, tenderness of the fingers and Raynaud's phenomenon, cutaneous lesions similar to stigmata seen in progressive scle roderma develop with thickening of the skin of fingers, hands and forearms, sometimes accompanied by swelling or pufliness and coanemng of the skin of the face (mostly on the forehead and cheeks). Raised.tvory-coioured, firm nodules or elevated, sharply de lineated piaqueiike skin indurations are seen on the dorsal surface of fingers and hands and on the volar side of the wrists and lower forearms. It was this combination of Ray naud's phenomenon and cutaneous lesions which first prompted a search for other symptoms of progressive systemic sclerosis in affected workers. The syndrome of OAOL. however, can be clearly distinguished (Table 10). Notably, the diffuse immobit- Table 10. Differential diagnosis: syndrome of occupational acroosteolvsis (Raynaud's phenomenon, sclerodermoid skin changes. AOL), progressive scleroderma with trare) osteolytic lesions Occupational AOL Progressive scleroderma Sex ratio Exclusively s <j= * 1:2 Hands Clubbing and shortening of finger tips.hyperhidrosis: no ulceration Atrophy and tapering off of fingertips: anhydrosis: ulcerative lesions Pen oral puckering of skin Skin appendages Telangiectases Shortening of frenulum Subcutaneous deposits of calcium salts Dysphagia (oesophageal involvemen tl 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 Eariy symptom Common Common 1 Common) Usually spontaneous progression Vinyl Chloride izing sclerosis o tionai syndrom, readily than thi 4.1.4 His:olor. 4.1.4.1 Cutan. Several invesne. disease (Cordicr al. X9J2.Lange we found only c 1967;A/rin et 4 neural changes v who suffered `m Dermal chan mis with disorie: broad interlacim faintly stained :: Schiff (PAS). Ai. histiocytes was ? The most notabl of elastic fibres, full thickness i,: sue. Skin appen Walker (1976) f not exceeding r. some fibrous tlv, Vascular lc . capillaries were and pericapillar theiial cells with tionoflumina. ' myocytes, was a to nanowing or Degenerative (Benoit 1967:.'/ hyalinosis of tlsMeissner. Pacini 4.1.4.2 Bonel. fr-w The most striku Q worker with OA GQ ening and hyaln co most layer. Sum ' H.J. Mjrsttiler The sacro-iliac u clavicle, manie iand :rr,_ ^,jd etal. 1976. of tlie finger? and oroertssive scleirms. somenmes face (mostly on lied, sharply de nser* and hands -.mauon of Raych for other ndrome of diffuse immooii- .ms i Raynaud's r.r.a with 1 .'are i- -cleroderma jr I [apering off p anhydrosis; ' ns kin appendages nptom -pontaneous uon V ini I Chi >nde-Assoaated Disease 99 inng sclerosis of the skin with tapenng off of fingertips svas never seen in the occupa tional sy ndrome. After cessation of exposure the skin lesions seem to recress more readily than the osteolytic charges. a 1.4 Histology i :.J.l Cutaneous Lesions Several investigators described the histomorpnology of skin lesions in vinyl chloride disease (Cordicr et al. 1966,Harris and Adams 1961.Mann et al. 196T.Markomr: et al. 19IZ'.Langc e: al. 1974a; I'elnnen et al. 1975. Walker l9~6:Hu!tn et al. 1979). out we found only one description of bone histology in OAOL in the literature (Benoit \96~r.Marin et al. 1967). Skin biopsies showed various degrees of dermal, vascular and neural changes which were essentially identical in patients showing OAOL and in those who suffered `merely' from Raynaud's phenomenon. Dermal changes consisted of hyperkeratosis and pronounced thickening of the der mis with disorientation, swelling and nonfibriilaxy eosinophilic homogenization of broad interlacing collagen bundles. There was some degree of interstitial oedema which faintly stained metachromatically with toluidine blue, alcian blue and periodic acidSciiiff (PAS). An inflammatory reaction with infiltration oflymphocyies and a few histiocytes was scanty and, if present at all. of predominantly perivascular distribution. The most notable feature was marked disorganization, fragmentation and rareficauon of elastic fibres. In areas corresponding to nodular or plaqueiike skin indurations, the full thickness of the dermis consisted of an aceilular. partly hyalinized collagenous tis sue. Skin appendages were preserved. In 15 apparently less severely affected workers, iialker (1976) found only some destruction of elastic tissue of the dermis, probably not exceeding normal age changes; in one worker with severe Raynaud's phenomenon some fibrous thickening of the media of dermal arterial was seen. Vascular lesions affected capillaries and small dermal arteries. Numerous dilated capillaries wen seen in the subepidermal papillae with swelling of endothelial cells and pericaptilar oedema. Capillaries of the cutis showed cufflike hyperplasia of penthciial cells with fibroblast transformation, hvalinosis of vessel walls and final oblitera tion oflumina. Marked medial thickening of dermal arterioles, due to hypertrophy of myocytes, was accompanied by parietal flbrosis and hyaiinosis. which ultimately led to narrowing or even complete occlusion of the lumen. Degenerative lesions of small dermal nerves were mentioned by French investigators (Be>r>it 1967-.Marin et al. 1967; Chatelain and Motilhn 1967). They found sclerosing hyalinosts of the perineurium with atrophy of neurofibrils. Tactile corpuscles (WagnerMeissner. Pacini) were unaffected. ~.I.-i.2 Bone Lesions The most striking feature in a biopsy specimen of the bone, obtained from a French worker with OAOL (case * of both Benoit 1967-.Mann et ai. 1967) was marked thick ening and hyaiinization of the periosteum with chondroid metaplasia of the inner most layer. Supplying capillaries and arterioles showed occlusive changes identical with 00 S* c * t I l .1 if i E ;8 :f ! ' r JO W.JC. Lclbach and HJ. Mjrsteller those observed in the dermis. The bone matrix per se was barely affected. There was minimal titin nine of cortex, normal spongy bone and only mild fibrosis of the bone marrow. Experience with histomorphulugy of bone lesions in the familial and idiopathic type of acroosteolysis is limited. In the few cases where biopsy material could be ob tained. there was replacement of bone by nonspecific fibrous tissue, but inflammatory and degenerative changes or osteoid formation were not found (Dnpos et al. 1 *536; Elsun and Bumsrein 1954: Greenberg and Street 1957;Schwarz'*eiler 1957). In this context.it should be kept in mind that Viola succeeded in reproducing dermal, vascular, neural and skeletal lesions in the skin of the paws and in small meta tarsal bones of experimental animals which were very' similar to those observed in man. Viola exposed rats to 30 000 ppm VCSi. 4 h/day. 5 days/week, for 12 months and de scribed the histology of these lesions in detail (1970b). 4.1.5 Arteriography, Capillaroscopv, Infrared Thermography Arteriographic evaluation of the vascular tree of the hands revealed patency of the large arteries in all cases examined. The vascular lesions were almost invariably con fined to the small digital arteries, although the superficial and deep palmar arterial arch may occasionally show some narrowing and a paucity of side-branches {Lange et al. 1974a;Moulin et al. 1974). The most prominent arteriographic features were ir regularities and segmental stenosis of digital arteries, ranging from localized or diffuse narrowing to subtotal or even total occlusion with development of collateral vessels. Besides, a conspicuous retardation of flow of contrast medium was noted, and peculiar tortuosities of patent digital arteries were found. Circumscribed hypervascularitv of the terminal tufts and in the region of the wrists was noted in some cases (Benoit \967-.Lange et al. 1974a; Veltman et al. 197S', Preston et al. 1976;Srcu-orr et al. l975;Cama and Mein 1978). Angiographic findings in a larger group of 19 symp tomatic PVC workers with either Raynaud $ phenomenon and/or acroosteolysis (5'19 > were recently described in detail by tioischwitz et al. (1980). Raynaud's phenomenon had been observed to persist in these patients for prolonged periods after termination ofexposure and even after roentgenological evidence of healing of resorptive bone defects in those who had formerly suffered from acroosteolysis. In addition to vary ing degrees of stenosis or occlusion of digital arteries with reopening of small collat eral vessels, acral hypervascularity and considerable retardation of perfusion in spite of premedication with tolazoline (Priscoline. United States), the most conspicuous features observed in the majority of these patients (14/19) were circumscribed elonga tions and tortuosities of digital arteries resembling cirsoid aneurysms. An example is shown in Fig. 3 of generalized tortuosity and elongation of digital arteries in a 54year-old patient who started to complain of severe sensitivity to cold 3 years after cessation of VCM exposure (about 1 year prior to death from both angiosarcoma of the liver and hepatocellular carcinoma). The pathogenesis of these peculiar vascular alterations is not clear, but the possibility presents itself that they may be due to de struction of elastic fibres in the vessel walls in analogy* to similar alterations of digital arteries seen in rheumatoid arthritis (Laws et al. 1963.1967). w M O QO O Vinyl < Stw' vations. fingerp ed a vat. Ur area' those iferent d laroscc control ence in t PVC w. of dtstu induces A Si: aPVC-r chemica normal: was con number employ: related i It also s more sci Tliere was rhc.bone aid be obilammatory : 1936. Jucing .-mail raeta vfd in mar.. .ms and de- y of the wily conarterial '/../>!? it ivere :r* or ;;;us I vessels. I pecuiiai my of "-`loir al. t -ymp` :s(5/l9) * tenon -irmnation -.-bone - to varyjii collaii in spite Vicuous shed elongavample is m a 54after rtcoma of vascular .lue to de< of digital Fig. 3. (. ijii'-piwuvHiv lurtuoMiics and eion^jiicn ->i iiiiiii.il jricni" Studies of microvascular changes by wide-field capillary microscopy (direct obser vations complemented by photography) of selected skin sites - such as nail folds, Sr.gerpads, dorsum of phalanges and of proximal interphalangeal joints - demonstrat ed a variety of capillary abnormalities, ie. dilated or giant capillary loops, paic avascu lar areas, capillary and subungual haemorrhages. The abnormalities were similar to those seen in scleroderma but were usually less conspicuous, less numerous and of dif ferent distribution. In a survey of a group of 152 American PVC workers, these capillaroscopic findings proved to be significantly more prevalent than in 50 nonexposed control subjects (Maricq et ai. 1976). There was aiso a statistically significant differ ence in the prevalence of these abnormalities between symptomatic and asymptomatic PVC workers. The alterations were not only found in workers with clinical symptoms of disturbed acral circulation but also in 6 nonsymptomatic males with either VCMinduced angiosarcoma of the liver (2) or splenomegaiic portal hepatic fibrosis (*). A similar survey was later undertaken in an unselected sample of 129 employees of a PV'C-producing chemical plant in England with 26 employees of a non-PVC-producing chemical plant serving as controls (Maricq et al. 1978). The prevalence of capillary ab normalities found in these British workers, which were of the same type and degree, was comparable ic that in the American sample, although the latter included a larger number of mote severely affected symptomatic patients with greater mean length of employment (15 yean vs 3.5 yean). In the authors' opinion, this suggested that VCMrelated disease may develop independently of differences in manufacturing procedures. It also suggested that this easily detectable type of microvascular lesion may precede more serious VCM-induced disorders. In a small subgroup of 15 clinically affected W.K. LelbjJ) anil ll.J. Manteller British workers who were examined 6--24 months alter leasing the plant (termination of exposure), the prevalence of capillary abnormalities was not less than that among those who continued work. For an evaluation of the reversibility of this condition, however, the group was considered to be too small. The same type of capiJIaroscopic 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 (Bycakowska and Laitpiuer-Lcwowicka 1974). Infrared thermopaphy, another non-tnvasive method, used by Ray et a). (1974) for the study of acral circulation, revealed abnormalities of surface temperature rang ing from marked hypothermia of terminal phalanges (which are normally wanner than the rest of the fingers) to "complete terminal ampurarion" in four PVC workers suf fering from OAOL. In one of them vascular disturbances as evidenced by infrared thermography persisted in spite of complete heaiing of OAOL.5rewarr et al. (1975) demonstrated uneven blood flow in the fingers and patchy hyperthermia in the distal part of the OAOL-affected left index and middle finger of their atypical case. Local ized acral hyperthermia seen on IR thermography corresponded to the angiographic finding of circumscribed abnormal collections of small vessels (compensatory collat erals?) in the pulps of the affected fingers. Using IR thermography in a survey involv ing 143 PVC production workers and 56 controls. Williams et a!. (1977) assessed the time needed for heat return after immersion of one hand for 10 s in a water bath kept at 19SC; however. no difference between VCM-exposed subjects and controls and be tween groups within the exposed population was noted. 4.1.6 Immunological Studies Early experience with the syndrome of occupational acroosteolysis suggested certain similarities between this disorder and corresponding lesions seen in progressive systemi: sclerosis (diffuse scleroderma). Differential diagnosis of these two unrelated conditions is now well established (Table 10). Such similarities stimulated the search for other manifestations of a systemic collagen disease, notably immunological features, as pro posed by Marin et al. in 1967. Ward et al. (1976a, b) carried out immunological studies in 58 workers from a British polymerization plant who were referred to them out of a total past and present work force of 320. Mean duration of exposure t VCM was 39 months (6--75 months). Of these 58 workers, 28 were symptomatic (Raynaud's phenomenon.9:sderodenna of hands or feet, 6; OAOL, 2:sensitivity to cold, excessive fatigue,limb pain, panesthesias). Slight hyperimmunoglobulinaemia, usually IgG. the presence of mixed eyroglobulins. and in vivo conversion of both Cj and Cj were found in 19 patients in the symptomatic group, with additional evidence of reduced T<ell population and increased B-celi proliferation. Mixed cryoglobulins, in vivo con version of complement and depressed values for C} or C were taken as evidence for the presence of circulating immune complexes. Autoantibody screening demonstrated low-titre antinuclear antibodies (IgG 1/20-1/50) in eight of the nine patients with Raynaud's phenomenon. Aggregates of IgG, C, 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 subintimai regions of small Vinyl Chi'' and mediur lung (1 cas. The aur and bone c: bolic intern plasma pro: which sumi cular oceiu-. as a result c ators of tiss to further a Jayson et al suffering fnthan in non-, ride disease In an ea> in four Poll / decrease in 1 ever ,Langar after Sepha, 6 together v agglutinins were obser. sponses pb(1974a) an. . dence of au' tion of rheu termination immunofluwere later a. creases in ir taken up av ed to suggev hypergamn. with far ad\ three patici with Rayna-: degrees of inins were Lrange: x c s sclerodermo N of which is. s In sumir autoimmune establish the S in VCM-imit m 48 W.K. Lelbach and H.J. Marsieiler Tabic 11. 1 7 PVC workers with varices, episodes of upper Cil hleedine. sr; 'r::cn-K>n i marked oesopl'.aeeal Age at diagnosis Durjtio: of . \^>osure 1'entoneoseopic and Vo. (years) {years mon:;.*1 histological diagnosis i 30 31 3 32 4 35 5 3 35 6 39 7 39 S 41 9 a 41 104 47 11 50 12 51 13 52 14 52 IS 54 16 4 58 17 a 61 5 5/9 3/b 4 9 10/6 13/6 7 18 18 6/6 17 15/3 11 6/6 21 13 Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhoiic fibrosis Noncirrhoiic fibrosis Noncirrhotic fibrosis Noncirrhoiic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhotic fibrosis Noncirrhoiic fibrosis Noncirrhotic fibrosis Postnecrotic cirrhosis Noncirrhoiic fibrosis On follow-up patients 5.9, 10. 16 and 1" subsequently developed angiosarcoma of the liver and died 3-6 years after diagnosis of portal hypertension. Patients 6 and 14 are at present 11981) under observation for suspected development of angio sarcoma of the liver, 6 and 11 yean after peritoneoscopic diagnosis of portal fi brosis associated portal hypertension, S/mr/i et al. (1976a) observed later development of angiosarcoma in one of them. If a tough estimate based on these two small series were acceptable,it would appear that approximately one of five to seven individuals suffer ing from advanced VCM-induced portal hypertension might be expected to develop angiosarcoma later, although PVC-induced hepatic fibrosis per se is probably not a prenulignant lesion. Clinical Manifestations of Son-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 SO selected PVC production workers who had been heavily exposed in the past (Mantetlcr et al. 197Ja). Litis et al. (1975) reported hepa tomegaly in 15% and splenomegaly in 3.4% of 354 consecutively examined employees (267 currently employed, 87 former workers) of one PVC polymerization plant in New York State, USA, a number which included virtually the entire current produc tion work force. A significantly higher prevalence of hepatomegaly was found in those Vinyl Chlon exposed for r spienomega!;. In contra.ment of hepa ectases, gyna not seen. Eve phalopathy d workers only It is puzzl: preceded adv. only one case development 4.2.2 Labor: Owing to the not the target value for the d This makes it' 1974; Creech . thrombocytop logical biocher the levels of s. quent (Manre (ICC; OS and liver function workers of a (Tamburro et progressively of abnormal S there was ovci phosphatase 1 alkaline phospmegaiy and/i- Except for and Vcltman t the reticulocy parameten uspresenting fea' sion (Smith et be dealt with r Assessment matic workers facture of PV( coproporphyria l.J Mar teller 'OphJfral , . j r. d ul dugno*.' uc tifcrosi> jc fibrosis ae iibrosti me fibrosis -trie fibrosis ...tie fibrosis 'uc firroM> ue fibrosis tic cinhosis ue fibrosis ue fibrosis . -ue fibrosis me fibrosis - .ue fibrosis >.>tic fibrosis ie eirrbosis ue fibrcsis ..ireo~3 ol merits o jnd ** .i anj:o .`i- .-.nciit oi il series w t llssutiei- 4 develop ahiy not a yre- sisoTVCMv tc moderate: nepatomegaly -ho had been '^ported hepamo.! employees 'm plant in 'real producfinmd in those is Via:.! CUlonde-Assoctated Dkc-sc exoosed for more than 5 years, whereas the difference in the prevalence ol palpable splenomegaly was not significant. In contrast to cirrhosis of the liver, clinical symptoms indicating serious impair ment of hepatic function such as jaundice, vascular spiders, palmar erythema, telangi ectases. gynaeeomastia. peripheral oedema and ascites or hepatic encephalopathy are not seen. Even after massive bleeding from oesophageal varices portosystemic ence phalopathy does nor develop. Ascites and hepatic coma have been observed in these workers only tn terminal stages of angiosarcoma of the liver. It is puzzling that acroosteolysis and sclerodermoid skin induration have only rarely preceded advanced stages of VCM-induced liver disease. To our knowledge there is only one case of angiosarcoma of the liver on record which was associated with pnor development of acroosteolysis (Roche et il. 1978). F t.2.2 Laboratory Findings Owing to the fact that hepatocytes. although being the primary' site of metabolism, are not the target of toxicity. standard biochemical liver function tests are only oflimited i t i value for the detection of liver disease in populations at risk (Williams et al. 19~~s). This makes it very difficult to devise adequate screening programmes (Martin et al. 1974.Creech iniMakk 1975; IVvarr et al. 1995: Berk et al. 1975. 1976). Apart from 'h t; thrombocytopenia, we found 45-min BSP retention to be the most consistently patho logical biochemical test: usually minimal hyperbilirubinaemia and minor elevation of the levels of serum alkaline phojphatase. SCOT and SGPT were considerably less fre ?e l quent (Mentcller et al. 1975a). Another dye-removal test, indocyanine green clearance flCG: Of and 5.0 mg/kg), also proved to be more reliable that; standard biochemical live: function tests in correctly identifying early hepatic injury in 1200 vinyl chloride workers of a chemical plant in Louisviile, Kentucky, during a 4-vear screening period ri (Tambum et al. 1978b). Die exposure rank was found to be closely correlated with progressively increasing frequency of abnormal ICC clearance, whereas the frequency ofabnormal SCOT, and aikaiine phosphatase only increased in late stages, often when there was overt clinical disease. In the survey conducted by Lilis et al. (1975), alkaline phosphatase levels were elevated in 16.6S of the 354 workers examined. In their series, alkaline phosphatase was also closely correlated with the clinical symptom of hepato megaly and/or splenomegaly. Except for thrombocytopenia (less than 150 x 10* platelets/litre) which Lange and I'clnnait (1977) found to be present in 76 of 100 workers, and a slight increase in the reticulocyte count (in 35 of 79 workers,lerrge and Veltman 1977), haematological parameters usually do not contribute to the diagnosis. Thrombocytopenia was also the presenting feature in two of seven British workers with noncirrhotic portal hyperten sion (Smith et aL 1976a). Thrombocytopenia and abnormal platelet function tests will be dealt with separately in Sect. 4.4.1. Assessment of urinary' excretionof porphyrins and porphyrin precursors in sympto matic workers who had been engaged in the production of PVC (n * 23) or the manu facture of PVC articles (n * 17) revealed varying but mostly mild degrees of secondary coproporphynnuria in the majority of them (Ltitge et al. 1976b). The significance of r: o r :: QD C/! r 50 W.K. Lelbach and H.J. Marstelier these findings as an indication of toxic liver damage is not clear and the relation to previous exposure to VCM remains to be determined. 4.2.3 Gross Inspection of the Liver and Spleen The gross appearance of the liver, as assessed by peritoneoscopy (.Marstdhr et a!. 1975a. i>:Marstellcr tnd Lelbach l9~n,Leibach and Marstellcr 1977j or at exploratory laparotomy, is that of a normal-sized or slightly to moderately enlarged organ with often blunted and irregular anterior edge. Inspection of the liver at peritoneoscopy also permits exclusion of partial nodular transformation as described by Sherlock et ai. (1966). In most cases, the surface of the liver is smooth or slightly uneven with shallow indentations, but it may be finely granular, trabeeulated or have a peau d'orange-like appearance. At most, .there are micronoduiar changes but the diffuse coarse nodularity of cirrhosis is only rarely seen. Progression to frank cirrhosis with severe derangement of hepatic lobular architecture was observed by Smith and Williams (1974), and also in two of out recent cases in combination with development of angiosarcoma. On palpation (direct or by peritoneoscopic probe), the texture of the liver is normal or only slightly firmer than usual. Indirect peritoneoscopic evidence of portal hyper tension is presented by increased vascularity of the falciform ligament and the intes tinal serosa or numerous dilated tortuous vessels in adhesions draining to the abdomi nal wall. Even in advanced stages, symptoms of pronounced portal hypertension often Vinyl Ch! contras: s'" pectedly s is a focal .. opacities.' stellate sc: ing (Marsh tissue in G extending nective ns: processes i; or more di. are seen in 4.2.4 Hi;' Histologic^ is generally sis, strikin' fibrosis are (Fig. 5a-d> reactions... throughout fibrosis. Sir tological e'. 1975). Depend date of bic; nant liver o ject to mark ations is sc. Thomas 19* 1976). but (Popper et c- 4.2.4.1 H<: In its fully J of dense. pa> bile ducts a. with format) central and : of connects with enlarge; perismusoiJ. oidal walls, -i Muller 11 al. : 'I J Marstt'.ijr elation to ..ret al. it expiorator;. ';pn with 'neoscopy also lock et al. with shallow .1'oranee-likt rsr nodulanty derangement i t. and also :oma. live; is normal Minai hyper1 me int:s:he abdomi- urns;on often y renension -. conspicuous "63-74. c-Mon of - 'N>>pttafeal V:.ny! t'`ilondtf-4i>ciattfd Disease 51 contrast sharply not only with minimal alterations of the surface but also with unex pectedly scanty histological evidence of hepatic fibrosis. The most conspicuous feature is a focal or diffuse capsular fibrosis of varying pattern (Fig. 4). presenting as whitish opacities. The degree of capsular tnvolvcnieni ranges from diffuse any commaiike or stellate scars to coarsely reticular and irregularly patchy milk-white capsular thicken ing iMjmelkr et al. 1975a). Histology showed that inis focal increase of connective tissue in Clisson's capsule may extend into the parenchyma and connect with sepia extending from enlarging fibrosed portal tracts [Pepper and Thomas 175). The con nective tissue capsule of the enlarged spleen also seems to be sensitive to VCM-mductd processes that have taken place in the underlying tissue so that focal white thickening or more diffuse opacities together with circumscribed subeapsular haemorrhagic cysts are seen in cases with marked splenomegaly. 4.2.4 Histology Histological examination of biopsy specimens shows that normal lobular architecture is generally maintained, but varying patterns of portal and. in some cases, septal fibro sis. striking intralobular pehsinusoidal fibrosis, and focal capsular and rubcapsuiar fibrosis are found in combination with peculiar alterations of sinusoidal lining cells (Fig. 5a-d). Hepatocellular changes usually play a negligible role and inflammatory reactions, if present at ail. are insignificant. Hie lesions are distributed quite irregularly throughout the liver and may vary from minor inconspicuous degrees to quite striking fibrosis. Surgical wedge biopsy of sufficient depth appears to be more suitable for his tological evaluation than needle biopsy specimens (Smith et ai. 1976a-.Blcndis et al. 1978). Depending on length and degree of exposure, interval between last exposure and date of biopsy, as well as individual factors, histopathoiogy of VCM-induced nonmalignant liver disease is represented by the following features whose manifestation is sub ject to marked interindividuai and topical variation: the same variability of tissue alter ations is seen in the nontumorous areas of the liveT in angiosarcoma (Popper and Thomas 1975: Thomas et al. 1975:3erfc et al. 1976; Cedigk et al. 1975; Weinbren 1976). but in these cases the nontumorous lesions may be even more conspicuous (Popper et al. 1978). 4_2.4.5 Hepatic Fibrosis In its fully developed form, minimal to marked enlargement of portal tracts by excess of dense. paodceUular connective tissue, which in advanced cases contains proliferated bile ducts and some periducruiar inflammation, may in rare instances be combined with formation of periportal septa linking portal tracts or. even more rarely, connect central and portal canals. Other portal areas appear almost normal. Focal accumulation of connective tissue in the thickened Glisson's capsule may be connected by septa with enlarged infneapsular portal tracts. A more striking feature is an intralobular perisinusoidal *netlike* flbrosis with more or less prominent eoOagenization of sinus oidal walls, in some areas even progressing to frank capillarization (Cedigk et al. 1975: .1fuller et al. 1975). The focal intrasinusoidal flbrosis may be subtle and in some cases 21108052 W.K. Lelbach and H.J. Mar-teller Vm- * v. 'V.-. * - / ^ ' "* - C:rv;.' ; v :* .v^***; . *..* :`Urt; * *v>" % i r v'/ i* S;.V- Fig. Si. Needle biopsy specimen of the liver shown in Fig. 4. Enlargement and fibrosis of portal tracts. Moderately large droplet steatosis. Focal dilatation of sinusoids. H &E. x SO. b Close-up of Fig. Sa. Indistinct border of enlarged and fibrosed portal tract to wards parenchyma (left). Proliferation of capillaries (> <) with polymorphism and hyperchromasia of endothelial ceils. PAS, x 400 L* e r I --.I ir-1 * '} *-'4 vS-i'a-SS w>-. fst->w 1T I \ tr. \h o GO 00r '1TH -iiaquiy `.<3oiouwj O 10 ainiusu] icjuc/tt-jsin!ii; joimjojj jo Xsaunoj (^ouiooitsodur jo aicis jcuimid tH icnuaioji ucapnuiq uiaqi jo autos napnu ancuiaiciiadXi' qiiM sai.taoicdaq palrcju^ <H -sip-'' Suiuij yepiosnuts ancuiojquadXq paiua.tnojd ;o wstqdjouiX|od aiuapotu pue uotitAiioy 'tpiosmits jo uonnenp po/ snonoidsuo^ p oC x Ma;[y arqq -uteis (sau P19) avnojqau^ *s]pa Iunin ppiosmns 3it:diouioa|d put Sunuajfloid paitAipt ipua suojqy icpiosninsuad pwcinotiaa put (jatuoa uddn :J*u sisoiqy [tuod ftaoj ay `>!J v>r tv.o ..V<Si , -v' - ?. ;A 1 i. 'Xi - - ,,. 'L JSJ* por -OJ JOCj. `3TH * S1S04t^. t' f' * W it; >) :Vv # . 1. * 0\ % - .* / A ** ^ ` ' J | O k) /* ' V *V . ' " \ -- ' , ^ _ * v* * . . ^ *.- T ^ * ' ^i ^ * \ f ** . # ^* - 4 ^ * ^ . i.- / ,, 3 ,f - ?.-*. * * > r -- - *' - .-.'< 5 * * "' J^ - rM t , k .`f ^ \ i ^ I^a # *k^ W *S** <*%A A^M0 3sT?'(3 sru.'i'o ~s;- `il1. ~* 7' \f. -. '*'* *.f 4 ' a3!;3JSJCj; n. 54 'VI. Leibaeh and H i Mjr<teiier Vinyl Chloride may be recognized only in connective tissue stains. Trichc et a!. (1975) pointed out that in one worker with severe acroosteoiysis but normal hepatic function ami essen tially normal liver histology on light microscopy (except for a minimal and easily over looked increase of perisinusoidal collagen in occasional lobules), electron microscopy revealed a striking centrilobular increase in collagen between hepatocytes and in Disse's spaces together with proliferation and hyperplasia of sinusoidal lining cells (see also Kurokawa et al. 1977). The same ultrastructural deposition of perisinusoidal collagen was observed bySchattenberg et al(1977) in 15 PVC workers in whom we could ob tain liver tissue for electron microscopy at peritoneoscopy. Similar changes (enlarge ment of Kupffer cells, abundant deposits of collagen in the Disse's space and resulting reduction of sinusoidal diameter suggesting a possible factor in the pathophysiology of "sinusoidal' portal hypertension) were seen on electron microscopy in a number of cases of idiopathic portal hypertension of unknown aetiology (occupational histories not mentioned) (Sommenchild and Kluge 1971 ;Kluge et aJ. 1970: Tandem et al. 1970). 4.2.4.2 SinusoidalLuting 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 perisinusoidal and sinusoidal cells include three types: (1) normal endothelial cells. (2) lipocytes (Ito cells), considered to be precursors of fibroblasts and (3) plump cells with spindle-shaped nuclei and PAS-positive cytoplasm. Formation of excess reticuiin suggests fibroblastic activity of some of these cells. Focal dilatation of sinusoids, not explained by passive congestion, is another peculiar feature usually associated with particularly pronounced alterations of these mesenchymal cells. There is reason to be lieve that this combination of changes may represent a premalignant stage. 42.4.3 Hepatocytes Unimpressive, nonspecific, degenerative and adaptive lesions (such as minor degrees of fatty degeneration, cloudy swelling, ballooning or vacuolar degeneration, increase of lipofusdn pigment and proliferation of smooth endoplasmatic reticulum of hepato cytes in focal areas without inflammatory reactions), can be seen to disappear gradual ly with increasing intervals between the last exposure and the date of biopsy, in con trast to the apparently irreversible damage to mesenchymal structures (Cedigk et al. 1975,1977Midler 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 hepatocytic proliferation associated with varying degrees of sinusoidal cell alterations were recently described and are thought to play some as yet undefined role in the precursor stage of angiosarcoma (.Popper et al. 1973). 42.4.4 Histology of the Spleen Unless splenectomy is carried out in vinyl chloride disease, tissue specimens of the spleen are less easily obtainable than liver biopsy material. Popper and Thomas (1975) and Thomas et. to be eharacten. gentous red pul; follicles with mi endothelial ceils occasional fresh spicuous fibrosis In ten cases w Heusermaim and terial, together v. splenectomy. Tli process. Excess a: tive tissue, notab and white puip, r There was scarnn meshwork and re and diameter of a of the pulp cords formation of biza collagen fibrils. N the reticular com. volume with pan. mation of capillar found within the thrombocytes by s hanced pooling o' help to explain in stages of vinyl chi and Hcusermann i VCM-induced spl-c of the liver or ext: in the spleen in vtt dicate a primary . port correlating ci> tients is being prep the spleen in none able for comparis< 4.2.5 Pathophysi The pathophysiole to unresolved proble: H to splenoportograp H of intrahepatic vas O venous radicles (/. GS and a normal, or ot O C/1 r HJ Marstellrr sotitled out >n tssennd v.uily ovtri microscopy s and in Disst s Ils (see also sidal collagen we couid obges(enlarge and resulting ophysioiogy i a number of oral histories ton et al. i nuclear polynesenchymal p: or resemble ^75). These b.eiial cells. 3) plump cells xctss reticulm rnusoids. not dated with - reason to ber iior degrees of it. increase of ;i of hepatoippear gradualKipiy, is con-tditk et al. nerpUsaand '(nucleated big degrees of ay some as yet 8). <ns of the -domes (1975) Vinyl Chloride-Associated Disease 55 and Ptorms et al. (1975) found the cut surface of surgically removed enlarged spleens to be characterized by conspicuously hyperplastic Malpighian follicles in a beefy homo geneous red pulp. Histologically. they noted large germinal centres of the Malpighian follicles with merging of perifollicular zones, dilatation of red pulp sinuses lined by endothelial ceils of variable, often cubotdal shape, thickening of the pulp cords with occasional fresh haemorrhages, and in one case Gandy-Gamna bodies, but only incon spicuous fibrosis of the red pulp. In ten cases we obtained needle biopsy specimens of spleen tissue nr peritoneoscopy. Heusermann and Smrtr 11977b) and Sttitte and Heusermann (1978) studied this ma terial. together with spleen tissue specimens available from three spleens obtained at splenectomy. They found evidence for an involvement of the spleen in the fibrosis process. Excess amounts of newly formed extracellular elements of reticular connec tive tissue, notably collagen, produced by stimulation of fibroblastic cells of the red and white pulp.particularly in perifollicular and subcapsular areas, were observed. There was scarring of periarterial lymphatic sheaths, obliteration of the pulp cord meshworic and reduction of pulp cord volume, in addition to an increase in number and diameter ofsinuses. The reticular connective tissue of the walls of the sinuses and of the pulp cords showed marked alterations with thickening of reticular fibres and formation of bizarre piatelike amorphous structures containing irregularly distributed collagen fibrils. Narrowing of the labyrinthine cordal tissue with marked increase of the reticular connective tissue caused a reduction of microaiculatorv sequestration volume with parallel decrease of the number of pulp cord macrophages and approxi mation of capillaries and sinuses. Frequently, focal accumulation of platelets was found within the narrowed pulp cordbed in addition to increased phagocytosis of thrombocytes by residual macrophages. This lends support to the hypothesis of en hanced pooling of platelets in the spleen (Heusermann and Srurre 1977a), and may help to explain the pathogenesis of thrombocytopenia often seen even in the early stages of vinyl chloride disease. By structural analysis of histometrical results. Srurre and Heusermann (1978) outlined certain diagnostic criteria for the differentiation of VCM-induced splenic alterations from those seen in portal hypertension due to cirrhosis of the liver orextrahepadc portal vein occlusion. They concluded that fibrotic changes in the spleen in vinyl chloride disease are not the result of portal hypertension but in dicate a primary action ofVCM or its metabolites on the spleen. A comprehensive re port correlating clinical and morphological data gathered from this group of 13 pa tients is being prepared for publication at present. Results of histometrical studies of the spleen in nontirrhotic portal hypertension of unknown aetiology are now avail able for comparison (Seki 1965; Yamamoto 1978,1979). 4.2.5 Pathophysiology of Portal Hypertension The pathophysiology of portal hypertension in VCM-induced liver disease is ts yet an unresolved problem. Patency of the portal vein was demonstrated in all cases subjected to splenoportography. Portography usually showed no or only minimal derangement of innahepatic vascular pattern such as tapering or `cut-ofT of small peripheral portal venous radicles (Blemtis et al. 1978: ViUeneme et al. 1976). High intrasplenie pressure and a normal, or only slightly raised, wedged hepatic vein pressure indicate that the i r W.K. Lclbach and HJ. Maistclicr portal flow is obstructed at the sinusoidal or prcsinusoidal level. In a group of five PVC workers selected for haemodynamic studies, Blcndis et al. (1978) could not demon strate a direct relationship between the degree of hepatic fibrosis in needle biopsy spcciniensand portal hypertension. But it should be kept in mind that the distribution oi fibrosis in these workers is quite irregular. It has also been suggested by Pepper and Thomas (1975) and Thomas et al. (1975) that the increased splenic and hepatic blood flow as a result of decreased splenic resistance in splenomegaly cannot properly be ac comodated in the hepatic portal vein bed owing to impairment of adaptive distension of portal veins and sinusoids by the subcapsutar, portal and perisinusoidal fibrosis. Blendis et al. (1978) found no correlation between spleen or estimated liver blood Fig. 6a. b. Progression of noncirrhotic portal hypertension despite termination of ex posure. Oesophageal varices. (Autoclave cleaner, age at diagnosis: 35 years. VCM-exposure.1962-1972. 1972 Raynaud's phenomenon, sklerodermoid skin indurations, thrombocytopenia, splenomegaly, and grade 1 oesophageal varices. Gradual progression of portal hypertension. Sudden death from ruptured anaplastic angiosarcoma of the liver in June 1978. Histologically only mild perisinusoidal fibrosis in nontumorous areas) Vinyl flow 2 veiled 4.2.6 In 19tic fib: could tests:: biops> of brid the fib cytes (: ing cell followmass:'-, exposu: saxcorr. or less, terrain : oped (s . Live determ: (B.MHP after band to.i aid of " the reu inertas. PVC psack et 4.3 An 4J.1 ) Primar> (angioh' haeman. cell sarc sarcomj. vasculai h* one at c: O hood (fo GO the nunv bcibacii one* H.J. Marsreksr ' level. In a group of five PVC < 1978) could not demonil- in needle biopsy spec:iu .at the distribution of suggested by Popacr and d splenic and hepatic blood 2aiy cannot properiy be sc:ient of adaptive distension d penstnusoidal fibrosis. ' or estimated liver biood v despite termination of exifnoss: 35 yean. VCM-txnlermoid skin indurations. I varices. Gradual progression lasdc angiosarcoma of the < fibrosa in nontumorous V'tr.vi C'.iljnde-A.'^oeiated Dixaw ' 57 ilmv and the portal pressure. However, they point out that this relationship may be veiled by the amount of blood bypassing the liver via a collateral circulation. 4.2.6 Follow-up of Non-maiignant VCMmdueed Live: Disease In 19^4 Martin et al. fsee also Berk et al. 197$) pointed out that VCM-assocated hepa tic fibrosis, once established, may progress even after cessation of exposure. They could demonstrate this progression despite normalization of all routine iiver function tests in a 27-year-old worker on a follow-up examination including peritoneoscopy and biopsy 2 1/2 years after cessation of exposure. Progression of fibrosis and appearance of bridging between portal and central veins were indicative of persisting acthity of the fibroblastic process, w hereas the previously observed activation of both hepatocytes (marked variation of ceil size and numerous binudeated cells) and sinusoidal lin ing cells iud disappeared. Since 19T3 we have observed a number of workers who on follow-up showed evidence of progressing porul hypertension with development of massive oesophageal varices and subsequent bleeding episodes despite removal from exposure (Fig. 6). In five (7?) of these patients with progressing portal hypertension angio sarcoma of the liver finally developed. In this context.it is of interest to note that more or less conspicuous hepaue fibrosis (or rare progression to cirrhosis) was the parental terrain in which the majority of cases of VCM-induced angiosarcoma of the liver devel oped (see Tables 13-18). Liver and spleen scans with "mtechnetiurn-l3bcllcd sulphur colloid, quantitated determination of spleen size with the aid of 1,7Hg-bromomercury-hydroxypropane (BMHP) labelled artificially damaged red cells, and sequential perfusion semograms after bolus injection of 99mTc-pertechnetate have been found useful in the diagnosis and follow-up of nomnalignant liver disease in FVC-polymerization workers. With the aid of these noninvasive methods, inhomogeneous uptake of labelled sulphur colloid in the reticuloendothelial system of the liver and enhanced uptake in the spleen, gradual increase in spleen size and reduction of portal venous perfusion have been observed in PVC polymerization workers developing portal fibrosis and portal hypertension (Biersack et ai. 1975a. b, 1977a. b). 43 Angiosarcoma of the Liver 43.1 Epidemiology Primary angiosarcoma of the liver (ASL) is described under a variety of synonyms (angiobiastic sarcoma, angioblastic rtnculosarconu.endotheUoma.endotheliobiastoma. haemangtctlastoma, hartnangioendotheiioma, haemangioendothelial sarcoma. Kupffer cell sarcoma, malignant haemangioma, metastasizing haemangioma, reticuloendothelial sarcoma, primary sarcoma of the liver). It is an exceedingly rare malignancy, arising from vascular lining ceils. It occurs spontaneously with two peaks in the age distribution: one at early infancy (infantile hiemangioendothetioma) and the other in late adult hood (fourth to sixth decade). The numerous synonyms render it difficult to estimate the number of reported cases and to determine :u true incidence. In a recent review l | Z r r i i L i l r 58 W K Laibach jnd H J. Mjrsteiier Vinyl C of the litenvutt.Alrenga (1975) listed 165 rushed cases of primary angiosarcoma tion of ! of the liver in adults. In the six autopsy >c:;-i collected by Alrcnga. ASL constituted only l .87 (0-97-2.7) of all primary nauanant tumours of the liver, which of them inorgant dioxide ; selves are rare findings in the Western World Autopsy statistics show that the incidence of ASL ranged from 2 to 20/100000 autopsies dunng different periods with a mean tern and Thor incidence of 12/100 000 autopsies (Table 1 2 i According toHcjtit 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 > ear to: the entire United States. contrast in; evid. reported been the had beer Table 12. Incidence of angiosarcoma of tb; x-r: i ASL) in autopsy series and Mot. Authors Year Observation No of No. of cases period autopsies of ASL Region A special caused b; thorotra Simpson et al. .1955 19J4-JP55 24 J 96 1 Mayo Clinic. Rochester, Minn.. USA from a !: ASL (R. Deve: Edmondson 1958 1918-195-: s: ooo MacSween et al. 1973 1900-1969 _ a 1 3 Los Angeles. County Hosp.. USA Western Infirmary Glasgow, U.K. man vine tensively 1950-- 1c" tion reve.. of multip; A Irenga 1975 1951-1973 39 700 Rein and littth 1975 1954-1974 30 079 6 4 (6) c Cook County Hosp. Chicago. USA DiAseldorf. Fed.Rep. Germany approved occurred , but notab produced Haustrun' Byrcn and Holm berg 1975 Dalderup et al. 1976 1958-1969 _ b 1960-1975 At least 40 000 12 Sweden (adult cases) 8 Netherlands (population: 10-14 million) (37c-5". ` Roth (l018.6-814 Fowler's > Otou haemangv * Among 120 cases of primary malignant liver tumours studied post mortem during this 70-year period, b Among8 million inhabitants. c 4 Angiosarcomas, 1 haemangioendothelioma, 1 malignant haemangioperievtoma tension hi. woman * ride) duri. had a high manifests The pr Q Accordingly, the identification of 4 cases of ASL among approximately 270 em ployees of the vinyl chloride polymerization section at a BP. Goodrich plant near be elicited period 18 LouisviUe,Kentucky, between September 1967 and December 1973 was duly recog history of nized as an alarming situation indicative of a serious new occupational hazard (Creech Among nv etal. 1974a; Creech and Johnson 1974). observed' Until 1974. only two carcinogenic agents were known to be associated with the other han ' development of ASL in man, i*. the administration of a radioactive colloidal prepara 391 auto: r Table M . Clinical ami morphological data on t<8 polyvinyl chloride (I' VC) production workers with angiosarcoma <>( Ihe liver reported <> NIOSII by August 1978 62 W.K. Lelbadi and H.J. Marstelltr 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 4] cases of ASL (l -9 cases per year: mean: 4 cases per year). An unexplained peak was observed in 1968/1969 (Baxter and Fox 1975 ). Six additional cases not mentioned on the death certificates were detected by a pane! of specialists (Baxter et al. 1977). In reassessing 36 of these 47 patients for whom histological sec tions were available, the panel of histopathologists unanimously agreed on the diagno sis in only 14 cases (7 doubtful, 3 unclassifiable, 12non-ASL). For 12 of these 14 cases occupational and residential histories were obtained which revealed one un doubtedly VCM-indueed case, two cases with possible exposure to (low levels of?) VCM and one case attributable to thorium dioxide. After the first three cases of ASL among vuiyt chloride polymerization workers in the United States had come to the attention of the National Institute for Occupational Safety and Health (NIOSH) in January 1974 (Lloyd 1974), this institution continued to collect information on additional cases reported to them from nations with an im portant PVC industry (Lloyd 1975:Spirtcs and Kaminski 19") As o: August 1978. data had been presented on a total of 68 cases of ASL among polymerization workers (Spinas and Kaminiki 1978, pers. comm.); another eight cases had been observed among nonpoiymerization workers exposed to VCM in various jobs. On the basis of this data collection communicated to us in 1978 - for which we wish to thank Drs. R. Kaminski and R. Spinas. NIOSH. Cincinnati, USA - we attempted to trace these cases and their individual symptomatology as well as other relevant information pub lished in the literature up to 1979 (see Tables 13-1S). Ti e ten Canadian cases of VCM-indueed ASL (cases 2--11) are dealt with summarily in the papers published by Delorme (1978a) and Delorme and Makk (1975): seven of them were described in more detail by Makk et ai.(1976). Cases 19 and 23 were observed at our clinic in Bonn but details have only been published for case 19 (E.U. in Lclbach and Marsicller 1977). In reviewing the literature we could not trace cases 37--40.43,50,51,53-67 and C, F and H. According to the latest annual report of the Staatlicher Gewerbearzt, Diisseldorf (Rein! 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 case (Figs. 8 and 9). In retrospect.it was discovered that the First case of VCM-indueed ASL had already occurred in 1955 in a Canadian polymerization worker. For the 67 VCM polymeriza tion workers for whom details were available, total yean of exposure ranged from 4 to 31 yean (mean and median 18and 19 yean, respectively). In comparison, mean dura tion of exposure in our group of 17 individuals with advanced nonmalienant liver dis ease (see Table 11) was 10 3/4 yean (range: 3 1/2-21 yean). The latency period (yean from lint exposure to diagnosis of ASL) ranged from 9 to 38 yean (mean and median: 21 yean). The avenge age at diagnosis of ASL was 50 yean (range: 37-71 yean). Viny. (I 'r .nd HJ. Marsteiler ?nal exposure to sther three may -- i for many investigation es and 1965-19" oases per year). An >). Six 3dditionai nel of specialists n lustoiogicai see ded on the diagno12 of these 14. ealed one uni low levels of?) carron workers m te for Occupational 'titunon continued ations with an imsof August ? 9"S. tcnzanon workers been observed On the basis of <li to thank Drs. vd to tract these .formation pubiJun cases rs published by described in dinic ui Bonn -n jztellcr 1977). *1,53--67 and i oewerbearzt. fuced ASL in the 478, to which we ed ASL had already ' VCM polymerizaire ranged from 4 to "araon.raean duramiairgsant liver dislateocy period `8 yean (mean and ts (range: 37--71 Vinyl Chloride-Associated Disci'? SJ "3 C _* 2a &s *< Cf 2 55 *2 3Z 5 M 9 > Z9 2 e 3 Z ^.i >. - < 5 .5 w e c: i* ^ -s => Z cs SS ^ o r r ;L h* H O >: rt *i i 05 i L *.-* - T r t Spleno- 0 (2700 g) nicgaly (455 g) l;ocal peii- sinusoidal Vinyl Chim, W.K. Lelbjwh and H.J. Marsteller  Spleno- (1 9 0 0 k I m eg-ily r Splono- ? I'o rliil + p ff Sprc.it lo <fc;i|tiruf^nt ;iml r nicgaly film is i* (35 000) ulH lum iiul wall !U. Mamsller Vinyl Chlonie-Aaocuted Disease c. s/j Q. ciioaots i * U 4 am^. c. 's T *3 VV.K. Lclhach and H.J Mar-rciivr Table 1 5. Publications on the 63 cases of angiosarcoma of the liver listed in Tables 1 3 and I- N'o. References Additional relevant information 1 Hitbiei et al. (1977) Hypertrophic, hyperchromatic jnJ atypical endothe lial cells in the glomeruli. foci ot haetnatopoetic cells in liver and spleen 5I * Delorme and Makk 5 (1975) 6 i Makk et al. (1976) 7 ' Delorme 11978a. b) 8 Delorme and 9 Theriault (1978) 10 " Schmidt and Batora \ (1976) 14 i Lange et al. (1974b) 15 1 Cedigk et al. (197S) 16 Cokel et al. (1976) 17 A mann (1975) Riibsamen (1976) 18 Rttnlttal. (1976) 19 (Observed in Bonn) :0 Rtinl et al. (1976) 21 Reinl et al. (1977) 22 Remit tat. (1977) 23 (Observed in Bonn) 2d Ravier et al. (1975) 25 Roche et *1.(1978) 26 Rety et al. (1976) Case no. 7: ASL associated with hepatocellular carcinoma (Delorme 1978b) (All cases from one plant in Shawmigan. district Trois Rivieres. Quebec) At the same plant: A cases of VCM-tndticcd cirrhosis of the liver plus 1 case of cirrhosis and generalized reticulosarcoma and 4 cases of carcinoma of the Cl tract or lungs See also Reinl and Weberi 197a) See also Reinl and Weber (1974) Foci of haematopoesis within the tumour areas 1974 portocaval anastomosis: cholecystectomy. Hype-trophic, hyperchromatic and markedly atypical end , melial cells in the glomeruli and in the capillaries of the lungs Moderate hepatic siderosis: chronic fibrosing pancrea titis: tubular and interstitial fibrosis of the testes Focal interstitial fibrosis of the pancreas See also Berrod et al. (1978) 1942 gastrectomy. 1974 splenectomy, right hepatic lobectomy (640 g). See also Roche (1977): Ruecft et al. (1977): Bonneton et al. (1975. 1977), Berrod et al. (1978) No autopsy (see also Berrod et al. 1978) Vinyl ChiTable lSu No. Re27 R- 28 Ro. 29 Ro' 3 ) a Be, 33 ) 34 Le 35 S<r. 36 Me. 37 38 39 40 41 By. 42 Bvr. 43 44 31. (cav 45 Bio (C3- 46 Bw. (ca* 211080:3 filer oiliecrlls rhosis '.cd 01 cal t>i*uines 'C5 epanc vcli et el Vinyl Chloride-Associated Disease t)9 Table IS `continued! Vo. Rei'erencts Roche et at. i 1978) Roche et a!. I I 978) 29 RocJie et li. (1978) 30 31 1 lif BerroJ et at. i 1978) Additional relevant information Chrome alcoholic. See also Roche i (977V. Putch et jl. ( 1977):Berroj e: al. (19TS> First symptom: vertebral and costal metastases Right hepatic iobectemy. See also Roclte < :)"); Pucch et ai. l 197"). Pi-ichowiki it at. 11 97?/; CouJrt et it. < i 9?o>. SerroJ it oJ. I 1973) 1960 sclerodermalike skin induration (hands), swell ing of lace, upper extremities and tcet. 1971 bilateral scrootteolytu. Tumour penetration of the abdominal wail (fistula). Severe interstitial fibrosis of ttstes: fibrosis of interstitial wall;slight mesangial fibrosis of flomtruli. Variable but generally slight fibrohyaiinosis of arterial and venous vessel walls (skin, heart, lungs, intestine, testes) 3-t Let and Harry ( 1974) 35 Smith et al. 1 1 976b) J6 Mo!tom 11 974) 37 . Latency period (1st exposure -- death) only S years (see also Fox and Cottier 1977) 38 _ 39 40 41 Bvrrn and Helmberg ( 43 Bvrin et al.( 1976) 43 - 44 Block (1974) lease 3) 1963 portocavai shunt. 1970 cholecystectomy. See tlso Fslktt aL (,1974a) (case 4); Whelan et al. (1976) (case 1) 45 Block (1974) (case 2) 46 Block (1974) (case 4) T iK-ii 70 Table 15 (continued) No. References 47 Block (1 974) (case 1) 48 Block (1974) (case 5) 49 Block (1974) (case 6) 'V K, Lelbjvh and H.J Marvttlier Additional relevant information See also.Fa/fc et al. > ! 9~4ji lease 2).Makk et al. (1976) (case 4) See also Falk et al. (1974a) (ease 1): Makk et a! (1976) (case 2) See alsoFd/Jk ei al. t I974j) iea>c 6): Whelan et al. (1976) (case 4); ,1/akk et al. (1976) (case 14> 52 Whelan et al. (1976) (cue 3) 53-67 '- 68 Zorica et al. (1975) Chronic alcoholic. See also Makk et al. (1976) lease 13); 5er/tetal.( 1976) (ease 2) Among a work force of 180 120. PVC polymenzation;60. production oi VCMi employed at this piant. 15 died of malignant disease t 2 ASL. 5 bronchogenic carcinomas. 1 case each of carcinoma of the larynx, nb, mamma, spermatic cord; glioma, melanosarcoma. leukaemia, Hodckm's disease) First exposure to VCM for these 67 cases of ASL dated back to the period 19391966 (median: 1951). Twenty-one years later, i.e. from 1972 onwards, a gradual in crease in the number of new cases diagnosed and reported to N10SH can be observed (Fig. 7). The onset of this gradual increase coincides with the calculated mean latency period of 21 years (Spinas and Kaminski 1977). Sptnas and Kaminski also suggested that in future cases the age at diagnosis and the length of the latency period may in crease as a result of the later reduction in levels of exposure. From the synopsis in Table 13--18 it can be seen that in about two-thirds of the cases of ASL for which morphological details are available varying degrees of associat ed hepatic fibrosis in nontumorous areas of the liver were mentioned. Less often, evi dence of portal hypertension and splenomegaly were noted. Metastasis of angiosarco ma to distant sites was observed in approximately half the published cases. It is of note that acroosteolysis and cutaneous stigmata of scleroderma have been observed in only 1 of these 76 patients, a French PVC worker who had apparently not been engaged in reactor cleaning (case 29\Roche et al. 1978). Another noteworthy piece of informa tion is that strikingly atypical endothelial cells with hypertropltic and hyperchromatic nuclei have also been found in organs other than the liver (kidneys, lungs) in autopsy material from two patients (cases 1 and 17,Hublet et al. 1977;Riibsamcn 1976). Uublet 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- 21108071 C1,FtVv'K T !atdler ai. . r al. > tease nerizam plant. :hogsmc .arynx. arcoma. * 1030^ **uai m- -red icy iitited tiay in* wi the ooodat* 'cn.vi* carco of note I m only npjed finfoimehroraaric autopsy 76). ir< tissue ofVCM .*3. Anglo- Vinyl Chlonde-Asiociated Disease -y Table 16. Personal data on eight cases ot anposarcoma of the liver among VCM-ex posed personnel not employed in PVC production las reported to NIOSH by August 1978W Birth iiit No. Country 1 m.'d.'y)* A D 1 3> 07.i6,,;o Date ot death 1 m/d/y> 10.10.7; Total Act at years death tsp. 4-3 14 Job classification Loading pesticide cans with VCM propellant B D16) 05.09.36 12.16.74 r GB 12) 09.03.14 12.00.70 38 55 3.5 Assistant factory chemist 11 Pouring PVC oil mix ture onto fabric bases * D III) 06.15.34 04.16.71 36 3 Fabrication of PVC sacks and wrappings (extrusion at tempera tures of 120*0 E SO 1 1.27.1 1 08.16.71 61 23 Assistant factory chem ist (production of VCM) F USA 115) 00.00.35 02.15.73 47 9 Accountant at plant producing PVC fabnc C, YUt2) 11.15.31 07.12.73 4; 18 Production of VCM H YU 13) 12.21.31 01.1 1.76 45 Production of VCM a Update of NIOSH tegmer, August 1973. prepared by Ksmintkt as in Table 13. b 00. data not available sarcoma arising from the kidneys or other types of malignant renal neoplasms, how. ever, have not been described in VCM-exposed individuals, although malignant nephro blastoma has been induced in experimental animals. The extremely tare coincidence of angiosarcoma and hepatocellular carcinoma was found in three instances (case 7,Debrme 1978b:ease E. Byrin and Hotmbtrg 1975, and a case not included in the 1978 NIOSH update Tamburro et aL 1978a). In the case reported by Tamburro et al. chronic alcoholism may have played a cofactor role in the development of liver cancer. We can now add a fourth case observed in 1978 at the Department of Medicine in Bonn (see Sea. 9.1.5 and Fig. 3). This patient (patient 9 in Table It), a PVC-poiytnetizadoa wodeer (total period of exposure: IS yean) was first admitted to our department in February 1975 and was found to suffer from atyp ical cirrhosis of the liver with portal hypertension, splenomegaly and Raynaud's phe nomenon. During follow-up ASL was clinically suspected but could not be confirmed during fife, despite exploratory laparotomy and generous surgical biopsies. The patient r `i arstcker Vinyl Chiondc-Associated Disease Table I 3. Publications on the eight cases 01 angiosarcoma of the liver listed m Tables 16 and I " No References Additional relevant information A Run! jnJ Weber t 1967 idiopathic portal hypertension: portocavai shunt 3 Zunmermann and Bek l<J7; nght hcmmephrccromy for un-date-al hydro .10751 nephrosis associated with bilateral double kidney. Rnnl 11975) Foci of hjematopoetic cells in spleen and kidney Fibrosis of the pancreas. Slight fibrosis of testes and of the small intestinal serosa r D Msltom i 197a> Autopsy- angiomatous epulis. Angiosarcoma involv ing liver, lungs and pericardium. The pericardium might have been the primary site! E Bvrin and Holmberx Probable coexistence of a hepatocellular cancer of ( t975> both low and high grade differentiation G Zones st al. f 1975) H died on 7 August 1978. after a massive haemorrhage from oesophageal varices. Autop sy revealed both multicentric metastasizing angiosarcoma and hepatocellular carcino ma of the liver as well as slight fibrosis of the pancreas (to be published in detail). It is still unexplained why hepatocytes are generally exempted from the carcino genic effect of VCM metabolites but. as predicted by Popper in 1975. three anecdotal cases of hepatocellular carcinoma, one German (Goktl et al. 1976) and two British PVC workers (Fox and Collier 1977), have now also been observed after exposure to VCM. It may be mentioned that a review of the distribution of primary liver cancer in the Province of Quebec covering the period 1969--1972 showed a preponderance of adult male cases in urban areas clustered in the district of Trots-Rlvitre in congnience with the distribution of the plastics industry, a coincidence which calls for further investigation of a possible exposure to industrial carcinogens (Jacob and Theriault 1975). . Not included in the NIOSH register are several anecdotal cares of ASL, capillary and cavernous angiosarcoma of the liver and haemangiosareomatosis of sites other than the liver, for which a relation to occupational or even possibly residential exposure to VCM has been discussed (Soria et al. 1977, Brody et aL 1977,Dor et ai. 1975; Wstfndfer and Zitmagl 1977). Although of undetermined relevance, it should finally be mentioned that, in addi tion to hepatic fibrosis, varying degrees of interstitial fibrosis of the pancreas were noted at autopsy in four German workers (cases 19,23, B and the above-mentioned VA080TTZ ri r 74 W.K. Lelbaeh and H.J Marstelier patient with both angiosarcoma and hepatocellular carcinoma). Fibrosis of the tesies was observed in three cases (19.29, B), and Roche et al. (1978) also reported fibrosis,' hyalinosis in vessels of skin, heart, lungs and intestinal wall. CUMULATIVE N* OF CASES REPORTEO TO NIOSH o. h. ar fc P; sc p* gf an lc be an me st. tio re; de: an*. In na no: wa Fig. 7. Cumulative number of cases of ASL among PVC production workers reported to NIOSH up to August 1978. arranged according to year of diagnosis (data from Spirrat and Kaminski 1977. 1978) rt 43.2 Clinical Manifestations The clinical symptomatology of usually multicentric ASL is unspecific. Gradually de clining general health and loss of weight combined with ill-defined upper abdominal discomfort and slight epigastric or right upper quadrant pain are usually the first symptoms. Recurrent bleedings from oesophageal varices may have been antecedent events in patients with portal hypertension who otherwise felt fairly well. In a number I T I nr< teller Vinyl CilonJe-Assocuied Disease 21108079 r 78 W K. Le!ba.'li and H.J. Marstcllsr 11 months after peritoneoscopic diagnosis of severe hepatic fibrosis (case 19: see also Lelbach and Marstelkr 1977). In addition to the findings described in connection with hepatic fibrosis, there may be hypervascularized or cystic tumour formation visible on the surface of a nodular, quasi-cirrhotic liver, or a gross aspect resembling hepatic 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 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 angiotarcoma of the liver is mostly that of large bulky, irregularly shaped cystic tumour masses;a multinodular form with numerous.sometimes umbilicated nodules, is less often encountered. Extensive haemorrhagic and necrotic areas or solid and spongy por tions of tumour tissue replace much of the liver parenchyma. Rupture of large cavern ous cysts may cause fatal intraperitoneal haemorrhage. Thomas et al. (1975) and Thomas and Popper (1975) distinguished four basic devel opmental patterns of histomorphology of ASL. which can be found in different por tions even of the same tumour and appear to represent stages of progressive evolution: sinusoidal, papillary, cavernous and anaplastic patterns. Indistinct areas of transition and merging of patterns can be observed. Dilated sinusoidal spaces lined by hypertrophic and hyperplastic sarcoma cells with pleomorphic, elongated, hypejchromatic and often bizarre nuclei characterize the sinusoidal pattern, which is the most frequent type. Tumour cells of varying differen tiation envelop liver cell plates and may invade enlarged and fibrosed portal tracts, ac companied by proliferation of bile ductules (Fig. 11). In papillary angiosarcoma atro phy of liver cells results in larger and more irregular blood-filled vascular spaces, into which loose papillary strands of surviving hepatic cords on an axis of connective tissue project, lined by sarcomatous cells (Weinbren 1976). Even large: blood-filled spaces are seen in the cavernous type, where they may be surrounded by thick fibrotic walls. In a smaller percentage of cases.solid areas or nodules ofanaplastic sarcoma are found, resembling solid spindle-ceil sarcoma, or even suggesting an epithelial type of tumour. Gedigk et al. (1975) also observed a reticulosarcomalike pattern. The differentiation of the tumour cells varies widely: it ranges from the inconspicuous endothelial lining cell type to irregularly shaped, grossly distorted giant-cell forms. Morphologically, vinyl chloride-related ASL cannot be distinguished from ASL associated with ocher aetiological factors or from the cryptogenic type (Popper et al. 1978). In tumour-free portions of livers with angiosarcoma widely varying degrees of ex cess formation of fibrous connective tissue are usually observed, analogous to that seen in nontumorous livers of heavily exposed persons. Fibrosis of enlarged portal tracts with modest proliferation of bile ductules, mostly only scanty infiltration of lympho cytes and occasional formation of perilobular septa or thin connective-tissue septa extending into the lobular parenchyma can be found. A more or less conspicuous intralobular, perisinusoidal fibrosis is often detected only by special staining methods for collagen or reticulin fibres. As a rule, irregular focal or nodular fibrotic thickening of f\J ^ M1 g Cd l tst l/ I* \' >*^r* %. y0- FtV li\( nu. pci In> of * ]>:; Th. or c life i oid. i plat: inct reru cyti-j deev reiki 1 creai 1 J Marsteile: 19:see also tion with rjvti visible on t hepatic meliver. It should is any suspi- ;d from 1600 :o ince of angio tic tumour lutes, is less <ud spongy por*f large cavem- nir basic devellifferem por:ive evolution: of transition tuna ceils with lerue the ving differtn*ial tracts, acaircoma atro- ncrs, int'ctive tissue filled spaces . fibrcde walls, iraa are found, pe of tumour, -uferendation of uilial lining ceil deafly, vinyl '< other aetiol- iegrits of exus to that seen rHjtud tracts on oflymphorissae septa ex-picuous intra.-methods for thickening of Vinyl Chloride-Associated Disease 79 Fig. 11. Angiosarcoma of the liver (upper part of photomicrograph) invading adjacent liver parenchyma (case l-t Dt; see Table 1 3). Note hyperplastic and hyperehromatic nuclei of proliferating neoplastic lining cells enveloping hepatic cords. Reproduced by permission. Ann NY Acad Sci 2^6:278-285 (197J). Courtesy of Professor Cedigk, Institute of Pathology. University of Bonn. H Jt E. * 2SO of Clisson's capsule is present: these fibrodc capsular areas may extend into the under lying parenchyma and may connect with adjacent enlarged subcapsuiar portal tracts. The cellular and nuclear size of hepatocytes may vary widely; groups of binudeated or even mulctnudear parenchymal cells with abundant cytoplasm are seen. Focal pro liferation of sinusoidal lining ceils may be encountered, especially within foci of sinus oidal dilatation. In connection with conspicuous sinusoidal dilatation, two types of focal hyper plastic precursor lesions were desenbed by Popper et iL (1978): 1) Poorly circumscribed fod of hyperplastic, often binudeated hepatocytes with increased number of various sinusoidal lining ceils and only insignificant increase of reticulum framework. 2) Almost nodular area of conspicuously hyperplastic and hypertrophic hepato cytes with mote pronounced variation oF markedly increased sinusoidal cells without degeneration or necrosis of liver parenchyma, but accompanied by excess formation of reticulum framework and compression of surrounding parenchyma. The transition of sinusoidal lining cells to angiosarcoma cells is characterized by in creasing atypia and anaplasia of these proliferating endothelial cells accompanied either K: * I & er V % * v. jtr ?r& -- rt \ l ! t- O f T SO W.K. Lclbach anil H.J. Mar:eiler by formation of excess connective tissue or by accentuation of sinusoidal dilatation leading to pnmary peliosts. Involvement of portal areas in the evolution of angiosarco ma results in considerable fibroplasia and formation of hyalinized collagen together with proliferation of bile ductules. In occasional cases connective tissue bridging be tween portal tracts or between portal tracts and central veins with subdivision of lobu les followed by rearrangement of hepatocytic plates may lead to a cirrhosislike picture. 433 Therapy The multicentric development of ASL(Tliorms and Popper 1975) as well as the dif fuse spread of the tumour usually encountered by the time of diagnosis precludes ef fective surgical or radiation therapy in the majority of cases. A survival period of two years after surgery (Benod et al. 1978) or chemotherapy (Damtaher et a). 1979) is a rare exception.-Resuits of systemic chemotherapy studied in a small group of five pa tients showed that, at best, quality and duration of survival may improve to a very limited extent (Dannahcr et al. 1979). At present, no generally accepted guidelines for chemotherapy art available. 43.6 Risk Assessment Vin\ R. (excl ASL This. the L comr had u the re poiyr was o viron: ceede lesser magm ting.; millioi vinyl c modei the es: grour When in the United States 13 white male cases of ASL had been detected from 1961 to May 1974. among an estimated total population of VCM polymerization workers of 43.7 ' 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 For a ' from the National Cancer Institute's Third National Cancer Survey (1969-1971). hazard wliich expected for the total United States population an annual incidence of this tu the co- mour in the order of0.014/100 000. This would have meant only about 0.03 cases per studiv- 20 000 polymerization workers within a 10-year period. Dose-response and attendant biotransformation 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 do not affect the average lifespan of a person exposed (Schnridennan et al. 1975: Gehringeitl. 1979,1978: Woods 1979). Cehrittg et al. (1979) consider a probit percent model to be a reliable tool for risk prediction, which works without the assump tion of a threshold. They predicted a cancer risk of 13 cases of ASL in 100 000 000 workers on exposure to the current National Standard in the United States of 1 ppm VCM 8 h/day. 5 days/week, for a 35-vear working life, an incidence which does not significantly deviate from the spontaneous incidence rate. A linear model modified by adjustments for differences in the rate of inhalation, distribution, metabolism, cell proliferation and tumour latency times between rats and humans was described by sure t-.thc lu al. 19" Waxw of Bn: 1976.; posed etal. 1 voicet! Berry : empUand cu' but no 1976). Woods (1979).This model arrives at an incidence of 3.9 cases per 100 000 000 workers w In . after a lifetime exposure to 1 ppm. Much controversy, however, about the validity of (1974. risk extrapolation from animal experiments to man and from high- to low-level expo sure and the problem of threshold doses has been voiced (Afong/r 1978: Hou/ter e t al. epidem (1978.. 1979;Schneidemum 1979: Weigert 1979: Reitz et al. 1979). facion- Teller arco*wr He* ' lobuijture. dif:s etr two * is a - pa- * for lc61 \ea of uton of .lata i. c ;u- jet ...uni k* sev.71ce to e\safe ?> et al. i probit 'Mumpoooo i ppm < not i ted by <7?fl ! by worfcen iity of 1 xpo- Vinyl Chior.-e-Assocuisd Disease 31 Results of i recent survey by Brady et al. f 1077) indicated that for New York State I excluding New York City), a higliiy industrialized area, the annual incidence rate of ASL during the 6-year period from 1970 through 1975 was 0.25 per million residents. Tills considerably exceeded the .national average rate of Q.l-i per million per year in rhe L'nited Stales. In a concomitant case-control study. 26 patients with historically confirmed ASL were found in the study area from 15S to 1975. and 7 of these had had documented long-term exposure to either As. TnO: or VCM. Five (all female) of the remaining 19 patients lived at a distance of 500--1500 feet from VC tabriaation cr poiymenzauon facilities for long periods. No pertinent exposure or residential history was obtained from the other 14 patients. Discharge of unreacted monomer into the en vironment as result of losses in the ?VC production process was estimated to have ex ceeded 200 million pounds annually, most of which escaped into the atmosphere with lesser amounts dissolved in water effluent (Schweitzer 1975). Concerning the order of 'magnitude of ambient exposure beyond the work place. U. outside the industrial set ting, an average annual exposure concentration of 17 ppb was estimated for the 4.6 million persons throughout the United States who resided within a 5-mile radius of vinyl chloride emission sources (Kuzmack and McGaughy 1975). If the risk assessment model elaborated by Woods (1979) is applied to this population of 4.6 million people, the estimated incidence of angiosarcoma per year would not be above expected back ground levels. 4 3.7 Mortality and Cancer Morbidity Studies For a tumour disease as rare as angiosarcoma of the liver even quite small increases in hazard over, background levels should be detectable (Doll 1975). The situation with the common types of cancer is far more difficult. Since 1974 a number of mortality studies of VCM-exposed populations have suggested that in humans long-term expo sure to VCM may also be associated with cancer of sites other than the liver, notably the lungs, and the lymphatic and central nervous system (Monson et al. 1974; On et al. 1975: Taberthaw tad Gaffey (97A\Nkltolson et aL 297J; Wagoner ex al. 1976: Waxweiler et al. \97S\Nkholson l977\Buffler et aL 1979). Epidemiological studies * of British workers failed to confirm this suggestion (Duck et tl. 1975: Duck and Carter 1976;Fox and Collier 1976,1977). as did a prospective study of a VCM/PVC-expoted cohort of 1613 employees of a West German chemical plant (Frenrzcl-Beyme et al. 1973). Criticism of design and interpretation of some of the studies hu been voiced (Falk et al. 1974b;Purchase and Williamson 1974:eg*r 1977xDaUenip 1975: Berry and Rossircr 1976). A follow-up of all VCM-exposed persons (750 traced) ever employed at the one Swedish factory, which tuned operation in 1945. for mortality and cancer morbidity patterns revealed a fourfouid excess of pancreas/liver tumours but no deviation in the number of brain turnouts from the expected level (Syren et al. 1976). In addition to the three extensive mortality studies of Tabershaw and Gaffey (1974), Waxwcilcr et al. (1976), and Fox and Collier (1977), a fourth comprehensive epidemiological study (RenU and Weber 1976) was completed in 1977 by Reinl et aL (1978). which included three study populations from 11 VCM- and PVC-preducing factories in the Federal Republic of Germany, covering the period from before 1959 S tr r x O--L- . T r 8 2 IV.K. Lelhach and H.J. Marsteiler through 1974: (a) 7021 workers engaged in the production of VCM and PVC;(b) 4910 chemical workers from the same plants not exposed to VCM; and (e) 4007 workers engaged in PVC manufacture. Not included were non-German workers of Mediterranean origin. This German study permits comparison not only with the mor tality ratio of the total male population but also with a comparable occupational group exposed to VCM. With regard to the "healthy worker effect* (McMichael et al. 1975), overall mortality was elevated for the VCM-exposed population (group a), but not for the other chemical workers (group b). Apart from the markedly elevated stan dardized mortality ratio (SMR) for malignant liver tumours (J 523). which proved to have been closely related to the duration of exposure,* significantly elevated SMR was found for tumours of the lymphatic and haematopoetic system (214). The group of j--------- .< _____________________ _________ _l.___ -i-_____________________________ _________ f .k. Y bo Bo tio ce; or we ot. des ?h. oti- 'eiler loral. but un to R was of ;he fi- one >und. the >ut data i>i ntc rm- 'lSt '.a in six >4un >redic- atentko in ' reland Virn I Chlonde-Aisociatsd Disease 83 bone lesions presented with mild to marked thrombocytopenia f30-- 1 IQ v 10~*litrsh. Bone marrow aspirates in 6 patients permitted exclusion of disturbed platelet forma tion or osteomyelofibrosis/sderosis. but in 12 of them splenomegaly was found. Ex cept for slight rericuiocytosis in 8 and leucopenia m 5 of the workers, other haematoloeical tests were negative. The reduction of the number of leucocytes and platelets as well as reticulocytosis appeared to be attributable to splenomegaly, but further studies on the nature of thrombocytopenia were thought necessary, and it was suggested by the authors that a decrease in the number of platelets might serve as an early and easily detectable symptom. The high prevalence of thrombocytopenia (as determined by phase-contrast microscopy) found later on detailed analysis of platelet function and other parameters of blood coagulation in the total cohort of PVC production (and also fabrication) workers from this plant strengthened this suggestion {Bachner et al. 1974*, b. 1975a. b. l9~6:Sehrr-Bachner and Etzel 1977). Wepnart (1975) also commented upon abnormal platelet counts in 13 of 37 PVC fabricating workers who had only handled PVC powder wiuch. however, might have contained substantial amounts of residual monomer. In contrast.Lilts et al.(1975) detected thrombocytopenia in only 1 of 354 polymerization workers, but an electronic ceil counter was used for platelet counts (personal communication). According to Sehrt-Bachner and Etzel (1977). the mean platelet count in a cohort of 132 PVC polymerization (and processing) workers was significantly lower than that in a nonexposed control group of 150 healthy men. As could be expected, Bachner et al. (1975b) also demonstrated a positive correlation between the degree of thrombo cytopenia and the prevalence of an enlargement of the spleen (palpable splenomegaly or spieen si2e determined by selective scintigraphy with 1 * T-Hg-bromo-mercury-hvdroxypropane-labelled red ceils) in 70 PVC polymerization workers (see Table 19). It ap- Table 19. Prevalence of enlargement of the spleen3 among 70 PVC-polymerization worker* in rcijtinn to increasing degrees of thrombocytopenia (Bachner et al. 1975a) * Group No. of workers examined Platelets (x 10*'/litre) Mean Enlargement f t*,e *P,een A 14 B 24 C 25 D7 > 130 100-130 70- 99 < 70 168 117 87 44 * As determined by palpation or by selective spleen scintigraphy. 3'21*) 11t46^) 19(76S) 6 (86~> pears, however, that the development of thrombocytopenia is not dependent on the presence of splenomegaly since we observed mild thrombocytopenia (100-120x 10**/ litre) in a small number of workers in whom spleen size was definitely within normal limits on selective spieen scintigraphy (MilzflSchenindex < 43 x 10*' according to Fischer ana Wolf 1963). Thrombocytopenia was accompanied by abnormalities in platelet function tests. There was an increase in the number oflarge (> 10 (an) `juvenile' platelets (increased 9944 W K. Lelbach and H.J. Marsieiler Vjnvi Dugois P. 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