Document mX23vp1NZVE3K1zneDYYaNeg

cller l 1 t' nor- : al. bUT ' `tani to (R was p of the .inn <.un one lound. the out data i >n IIIC 'JSt -i- .i/a- i six >*von ;nedic- u*enxko in tv . and Vin\ l CUoride-Auoviated Disease 83 bone lesions presented with mild to marked thrombocytopenia (30-139 v 1 O'9 litreV Bone marrow aspirates in 6 patients permitted exclusion of disturbed platelet forma tion or osteomyeiofibrosU/scierosu. but in 12 of them splenomegaly was found. Ex cept for slight reticulocytosis in 8 and leueopenia in 5 of the workers, other Haematologicai tests were negative. The reduction of the number of leueocytes and platelets as well as teticulocytosis 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 phasevontnst microscopy) found later on detailed analysts 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 suQPStion (fiacimcr et al. 1974a, b, 1975a. b, 19~f}\Sthrt-Baci\ner and Exzel 1977). Wepnan (1975) also commented upon abnormal platelet counts in 13 of 37 PVC fabricating workers who had only handled PVC powder which, however, might have contained substantial amounts of residual monomer. In contrast.Mis et al. (1975) detected thrombocytopenia in only 1 of 354 polymerization workers, but an electronic cell counter was used for platelet counts (personal communication). According to Sehrr-Bac/intr and free/(1977). the mean platelet count in e cohort of 132 PVC polymerization (and processing) workers was significantly lower titan that in a nonexposed control group of ISO healthy men. As could be expected, Baeluicr et al. (1975b) also demonstrated a positive correlation between the degree of thrombo cytopenia and the prevalence of an enlargement of the spleen (palpable splenomegaly or spleen size determined by selective scintigraphy with l99-Hg-bromo-meretuy*hydroxypropane-labelled red cells) m 70 PVC polymerization workers (see Table 19). It tp- Table 19. Prevalence of enlargement of the spleen1 among 70 PVC-polymerization worker* in rvijlwm to increasing degases of thrombocytopenia iBtckntr et al. 1975a) A Croup No. of workers examined Platelets (x 1 O'*/litre) Range Mean Enlargement of the spleen A 14 B 24 C 25 D7 -0a 1 3 > 130 100--130 < 70 168 117 87 44 3*215) 11 K46%) 19(765) 6 (86?) * As determined by palpttion or by selective spleen scintigraphy. pears, however, that the development of thrombocytopenia is not dependent on the presence ofsplenomegaly since we observed mild thrombocytopenia (100-120 x I0*9/ litre) in e smaD number ofwotkets in whom spleen size was definitely within normal Hntia on aetectfte spleen edntigraphy (Mllzflldienindex <45 x 10** according to ftscfterajM l*W1963). Thrombocytopenia wn accompanied by abnocmaHties In platelet function tests. There eras an increase in the number oflarge (> 10 fan) `juvtnle' platelets (increased *84 W.K. Ulbjch anJ HJ- MarsteUer platelet spreading), enlianced response (platelet aggregation) to addition of ADP and collagen (Bont test) and increased availability of phospholipiU<ontaining platelet tactor 3 (fiachner et al. 1975a). This pattern was thought to be compatible with the no tion of an increased turnover rate due to derangement of microcirculation (CDIC) in liver and spleen and defective reticuloendothelial system (RES) clearance of activated clotting factors (flec/mer et al. 1974b). hfortf (1976) and Ward et il. 0 976) suggested that thrombocytopenia could be construed as confirmatory evidence of an immune complex disorder. Hcusenmnn and Stutre (1977a) noted unusual focal aggregation of platelets in klatsch preparations of spleen tissue and increased platelet pooling (pinelets trapped within the subsinusoidal meshwork of pulp cords) in the red pulp of the spleen on electron microscopy as well as phagocytosis of thrombocytes by sinusoidal macrophages. Scheffncr-ti al. (1976) found platelet thrombi in and around hepatic sinusoids in mice after exposure to VCM. A direct toxic action of VCM(or metabo lites) on the bone marrow has not been demonstrated so far. Although the pathogenesis of thrombocytopenia in VCM-induced disease is not fully understood, it seems at piesent most likely that it is caused by increased turnover and consumption of platelets within the abnormal vascular spaces of the liver and spleen. A similar type of consumption coagulopathy was described as complication of spon taneous haemangiosarcoma of the liver by Truell et al. (1973). A haemostatic defect more complex than mere pooling and destruction of platelets In the enlarged spleen has also been commented upon in the paper by Cemrs et al. 11974) in connection with splenomegaly of various nonorrhotic origin. 4.4J Central and Peri aheral Nervous System Miscellaneous nonspecific and somewhat indefinite symptoms have been described in connection with chronic inhilatiotul exposure to VCM in PVC-production workers, such as dizziness, disorientation, blurring of vision and memory, headache, irritability. excessive fatigue and somnolence, sleep reversal or insomnia and other pseudoncurasthenic symptoms (Sucit et al. 1963,197$;&torre* 1969:Lifts et al. 1975 and others). This pnnarcotic syndrome was interpreted as a manifestation of a potentially reversible scut* toxic encephalopathy. Its danger to the individual was thought to lie mainly in resultant inadequate reactions to critical situations (Schorrek 1969). However, Vde et al. (1976) reported that several individuals in a group of 95 comparatively young ex-workers, the majority of whom had no ocher symptoms, complained of fa tigue . headache. Usdcssness end deprewon, with onset of symptoms having been de layed ss long es 2 years after cessation ofemployment. With reference to such *pseudoAeurasthenic complaints*, which may be interpreted as the mildest degree of a toxic encephalopathy,farm et al. (1975) examined a group of21 autodsve cleaners et varying intervals after cessation ofexposure, all ofwhom presented with other (cutaneous, angioneurotic, hepatic) manifestations of vinyl chlo ride dlaeme. CMwfcal symptoms of a mote or lass distinct encephalopathy (including cerebellar ataxia in 4) were found in all but ooe of them. EEC recordings were normal In only five of these patients; In the others, paretuhythmia, dysenrhythmia or a socalled subvigil electroencephalogram was observed. Evidence of distal polyneuropathy, found in 19 patients, was atufbutrd in the first place to m abnormal peripheral circu- lat: en aitclu vindii. Sih. 4.4. JO ro ro co vt ^ J j -r . f , 1 .* *r . * ' '-^-r:.O- * r . k A- .* .* * *,*. o(j--.-yf `taRteller DP and ciet facthe no1'ilC) in ctivated iggested imune ^auon of eipiateof the msoidal rpatic u-tabo- ' not fully ~>wt and spleen. Mspon- defect <pleen tion with ohed in rKen, 'itbffity, -hrJIand ndally to lie ' How* aracively of fa* **n de* tcrpreted 1 a group whom tatin| *7 normal a* -'ropethy, aJ nm* V'inyJ Chlorid<.A,->jousted Disease 85 lauon with tesultani hypoxic damage. The pathogenesis of a possibly VCM-tnduced encephalopathy is not dear. It would be conceivable that clinical and biodcctne alter* ations found in some patients, in whom portosystemic encephalopathy could be ex cluded, may have been due to toxic or hypoxic brain damage. However, no other con vincing evidence has so far emerged to indicate that chronic irreversible cerebrotexic damage may have resulted from prolonged exposure to VCM, notwithstanding the pos sibility of an induction of brain tumours. 4.4J Pulmonary Changes The suspected development ofnonmalignant pulmonary changes due to VCM md/o; PVC dust exposure is still a aatur of centretutsy. Soon after VCM was recognized as a potent carcinogen, three groups of employees fa 290.250.445. respectively) from three large North Amencan PVC-preducing plans (A, B. C), characterized by different duration and keels of past environmental exposure to VCM as well as to PVC dust, were studied with uspect to chest x-ray film abnormalities and pulmonary function defects as assessed by spirometry and determination of maximum expiratory flow vol ume (MiUer ! 975 tUilfev ft ai. 1975;lt& ct al. 1975.1976. 1977). All cases with pre vious exposure to asbestos, silica or coal dust had been exduded in these studies. Unexpected linear, reticular and. less often, rounded opacities on chest x-ray films were found in about one-fifth of the two groups ofemployees from plants A (highest ex posure) and B (22.7%, and 18 respectively), but in only 4J% of thorn from plant C. with the lowest exposure level. The prevalence of cheat radiological abnormalities. for which no pathogenetic explanation was available, eras found to be significantly in creased with long :r duration of VCM^VC exposure (mote than 10 yean), but foe pievalence ofa posit ve hhftocy of smoking, although identical tat both groups A and B. eras also found to be significantly higher in workers with abnormal chat x-ray plates. The overall prevalence ofa peeitive history of chronic bronchitis (British Medical Re search Courted criteria) was 20.4% m group A (highest exposure) and 16JX6 in group B, although group B was significantly older. The somewhat higher prevalence ofchronic bronchitis in workers with abnormal chest x-ray plates did not attain statistical tigaif* fcance. On foe other band, age did not appear to be an important factor. Pulmonary func tion tests diowed a stzikia|iy high prevalence ofobstructive changes, but ance both smoking snd sge were related to changes in pulmonary function, it appeared difficult to isolate potential specific effects of occupations! exposure to VCM and PVC dust A restrictive pattern vs found in 9J% of group A and in only 2.3% ofgroup B, al* thou^i group A vs tignificandy younger. In coochaton, tide extern!e study, todndtag a total of915 workers expoied in the pen to VCM as well as PVC dust may point to e potential msttipk factor effect ofsmoking end VCM-PVC exposure. In this connection.lt is oftaterest to note that according to a cohort study ofmortality among VCM polymerization-workers the OCRs for respiratory cancer as well as foe other respiratory disease' wen found to hm been In excess of expected figures (156 end 176, raapectheiy) (Mnrwefler at at 1976). Bronchopulmonary changes thought to be due to longcontinued, intense exposure fo PVC dust ware observed by sevetsl authors (fiwmcgtof and Sestf !955;roua*rf 8 6 W.K. Lelbach and H.J. Mjmctler l969:S:ettde et al. 1970; Verrkin and Mamontov 1910\Fro/tfia et al. 1914: Darke 1976.Arnaud et al. 1978). Considerable exposure to VPCdust is the nite in the drying, bagging and ftonfeareas of PVC-produring plants. Riotographs contained in Kantadt'i paper (1976) give a general idea of the potential dust exposure. Measurements of the concentration of PVC dust at various sites of the bagging operations were reported as long ago as 1955 by Permegguni andSasri. In 1969 Bmussard mentioned the possibil ity of development of chronic bronchitis caused by the inhalation of PVC dust. The insoluble and inactive dust panicles were thought to accumulate in the lungs blocking alveolar spaces and being taken up by alveolar cells. This could lead to elimination of these ceils via lymph vessels to regional lymph nodes, with either enlargement of the hilar region or a micronodular aspect of interstitial pulmonary fibrosis without hilar lymph node enlargement but progressive respiratory insufficiency. Ssende et al. (1970) reported the case of a 31-year-old worker who presented with severe dyspooea: a chest x-ray examination revealed diffuse micronodular pulmonary lesions. He had been engaged for only 1 year in shovelling PVC powder at a processing factory. Lung biopsy revealed moderate diffuse fibrosis and snail focal granulomatous lesions containing ovoid or polygonal birefringent foreign material which could be eluted by treatment with a known solvent of PVC. Microscopic examination of PVC dust particles collected at the patient's place of work showed,them to be morphologic ally identical with the particles found in the patient's lungs. Another anecdotal case of pneumoconioBs after 33 yean of employment in a PVC bagging area, with radiological evidence of diffuse micronodular infiltrates and granu lomatous lesions found in a lung biopsy identical with those recorded by Szendc et al.. was published by Amaid et al. in 1978. Histology of open lung biopsies in 1 of 14 VCMexposed British workers, who complained of breathlessness, revealed focal alveo lar wall thickening with macrophages in alveolar spaces and increased retieulin and col lagen on electron microscopy (Darke 1976). Although chest x-ray appearances were normal and routine respiratory function tests showed only slightly impaired C03 dif fusion in six individuals, perfusion and ventilation scam revealed strikingly abnormal pictures, including marked perfusion defects ofupper lobes. Darke pointed out that tome of the men worst affected had been engaged in the polymerization of *pIastisor. a very fine PVC powder with partide size around Oi ton. StUkoff(1976) called attention to results obtained by Frortfia et al. (1974), who observed significant histopatbological changes in the lungs of guinea-pigs and rats ex posed for 2-7 months to inhalation of the airborne PVC dust in a PVC bagging area. Lesions began to appear at 2 months of exposure (alveolar histiocyte-macrophage re actions); they proved to be. fairly marked after 4 months, with appearance of foreign body giant cells, and proceeded to development oflarge Insestitial granulomatous fod. Vartkm and Mamontov (1970) who examined 96 workers engaged hi the manu facture ofarticles made from PVC powder, also found a considerable proportion of them were suffering from functional and morphological attentions of the bronchopulmonary system, which they ascribed to their exposure to PVC dust. They que ed results ofearlier animal experiment! conducted in 1963 by Gobvetyuk and later by ShfyakhetskU. These last authors had apparently diown that exposure of animals to PVC dost may lead to the development of chronic pneumonia and eventually to a sort of mfld fibrosa of the lungs. \. sti bl Sl; t'.: w O' of dv er,. ot despe 4.4 Th JD m- mu tit ter ,1ftme I4* co> re. po 1 an fab Jo ha> h-> of an ms pb 19' of VC t J. Homelier 74;Z>enfce <n the drying. I inKanladft nits of the - reported as the possibtl* dust. The ngs blocking minaoon of nent of the Tbout hilar ited with i pulmonary i a processing vmJomitous could be ion ofPVC morphologic- .cm in a PVC and granu* '.tiuic et al.. - 3 of 14 *>wal alveo'iiin and col lects were i CO* dif- abnormal *j <nat that 4 ^pbstteoT. i * 74), who >nd rats exggtag area, ropfcage re> of foreign hwnatota * the menu. iroon of broncho* hey quoted nd later by animate to -diytoa aort Mnyi Chioride*Associated Disease 87 Certain ty pes of PVC dust (one of two samples tested) were found to exhibit a strong haemolytic potential due to the presence of an undetermined but readily solu ble surface-associated agent which was not VCM (Richards et al. 1975). These authors also studied the effect of the haemolytic sample of PVC dust on lung fibroblast cul tures. but they did not obtain any significant results. Contrary to earlier indications (Lang* et aL 1974a) and despite continued efforts we failed to detect any significant restrictive changes of pulmonary* function in the overwhelming majority of patients we had occasion to examine. It may be of interest to note that Maltoni et al. (1974b) reported a high prevalence of pathological changes of respiratory epithelium (squamous metaplasia, squamous dysplasia, typical and atypical adenomatous proliferation) in sputum samples from employees of Italian VCM-PVC factories. Nevertheless, contrary to the now weU*stibIished role ofVCM in the production of nonnalignant lesions of bone, skin, small vessels. Uvar and spleen, it Is still open to debate piadaely what importance can be ascribed to pulmonary changes within the spectrum of VCM4nduced disease. 4.4.4 Genetic Effects ofVCM The discovery of the carcinogenic properties ofVCM also stimulated interest in its mutagenic potential. A number ofstudies have been carried out that demonstrated a mutagenic response to VCM or its metabolites in microbial test systems. Point muta tions due to base^air substitution have been produced in various strains ofSalmonella typhomtnum by VCM in the presence of animal and human liver rrucrosomes as a sys tem of metabolic activation (Ronmtg et al. 1974,1976;5omrfr et al. 1975a, 1976; McCann et al. 1975;.ifrin,<tffret al. l9?5:Gsm>et al. 1976). Mutagenicity' of VCM metabolites was also demonstrated in yean strains (Lopnono et al. 1976,1977;Sho/wt 1976) and in "*" calls (Hubenmn ex al. 1975). In comparison to nonexposed controls, a rignifleandy higher incidence of duomoaotnal aberrarioos (fragmentation, rearrangement) in lymphocytes ofworkers occupationally exposed to VCM was re* posted by Dueaonen et al. (1975),/,<MfOurie<e et aU (1975), Asrctae et aL (1975, 1976), and Fomenko et at (1976). Fkif and 77tiesr (1974) had failed to demonstrate mi increased rate ofchromosomal aberrations in six chenticsl engineers and four PVC fabrication workers. As to the Influence on germ cells, Furcheae et al. reported that no doomam lethal affects were seen in fetuses of female mice mated with males which had been exposed to 3000.10 000 and 30 000 ppm VCM for 5 consecutive days. This, however, does not absolutely exdude genetic effects on human gonads, The outcome of pnpuney among wives ofVCM-potymerixstion workers as against wives of rubber and PVC-fobricstion wosfcars (JnJmte et at 1976a. b) and rates of conganital malfor mation per 1000 resident five births in three Ottio communitiM with PVC production plants hem also been sorted (Jnfentt 1976). As pert ofa taigm survey ofworkers* tmlih. interview queirionndm {Infante 1976a,b) titowed that afar paternal agaadjunimntadgniflcsnriy higher inddence offind mortality subsequent to patamd exposure was recorded among the wives of VC1I ixptesd workers.This trend eras found to be maintdnsd after ettednation of r-o to CO s $X W.K. Lelba,,h and H.i. Mare'.kr pregnancies in women who had more than two abortions. The findings of this study raised the question or possible genetic risks of VCM to man and led to the suggestion that germ-cell damage in the father through direct VCM exposure might be a possible explanation. No clear-cut linkage of PVC production and increased occurrence of congenital malformations (primarily CN5 malformations) emerged from preliminary studies in three Ohio communities with PVC production plants. But the need for further study of possible conuibutary factors was indicated (Infavtc 1976). In fact, none of the par ents of affected children in Painsvflle, one of the three Ohio communities, had ever worked at either of the two PVC polymerization piano in Painsvilie or lived within two miles of these piano (Eamonds et ai. 1975). 5 Conclusion and'Outlook The combined efforts of multiple disciplines have been necessary to arrive at the full recognition of the range of pathology associated with occupational exposure to vinyl chloride. It can only be hoped that the lesson from the vinyl chloride problem may help to bring about an increased awareness of the risks and hazards which are inevitably the consequence of an ever^xpanding technology. The importance of this lesson lies in its exemplary nature. A single substance of rather simple chemical structure, which was long held to be a comparatively safe com pound, even by experts, turned out after all to be a carcinogen with a very long latency1 period for those who were heavily exposed to it. But its carcinogenic properties would most probably still have gone unnoticed if the resulting malignancy had been any can cer other than of an exceptionally rare type. Animal experiments in the early days later proved to have been broken off before the oncogenicity of this chemical com pound could have been detected. The lesson to be learned is that in future any new chemical which is to be widely introduced into the environment should be scrutinized closely, for e sufficient length of time, and with the aid of all available methods for the detection of potential car cinogenic efleets. In addition, we should keep in mind that in industrial surroundings we almost never deal with a single compound, but with a very complex occupational environment whose carcinogenic potential is still a completely unresolved problem. If currently adopted guidelines for industrial hygiene an strictly adhered to, there it reason to hope that initiation of new cases of VCM-indisced angiosarcoma of the Uver can be effectively prevented. Unfortunately, however, it pan be expected that in view of the long latency period for tumour promotion additional cases wfl] appear dur ing the next decade. Considering the ever-increasing complexity ofenvironmental influences, future re search will be faced with almost insurmountable obstacles in its endeavour to establish We* levels for potentially hazardous chemicals. Promising areas for further studies in the field of vinyl chloride and allied compounds may be the problem of the interaction Vinyl Chlon between pre*.1 tissue such a? short exposu will carry the References ^ iB ^ w Albright LF t Aibngtu LF < > Albright LF ( Albright LF < polyvinyl v Albnght LF < processes Alrenga DP i 1 198-203 Amann R (19 der Leber ' Anderson H \ CEA amoi; I560--I56* Andrews AW properties Angheiescu F V(l969jr employees 473-482 Annua] Repc London.Ci Anronyuzhensian (ext). * Antweiler H ' Penpect l ' Amaud A. Por. ride pneurr Aryanpur J t 1 Iran. J Occ<. Assmann HU Austin GT (10 87-89 Bachner U. t und ttsoph.3409-241 < Bachner U. Ft. Befunde be Jahreiberie! Centner. S: Bachner U, Mu 1000 patier Bachner U.Ei/ und Csoph: Blutungen .. 'J Mamtihrr this study suggestion . a possible mgenitaJ *nidies in -the: study e of the par. !uii ever rd within at the full :re to vinyl 'Jem may .re inevitably :ance of ly safe com ing latency :rties would -n any can* ft, days val cost- widely i ntlength ,*adai car* trroundings cupational : problem. Ted to, there na of the cted that in U appear dnr- .s.future ret to establish ^studies in lie ininaction Vmyl Chlonde*Associatcd Dtsca*e 89 between predominantly hepatocytic metabolism and oncogenic effect on mesenchymal tissue such as vascular endothelium, and also the question of whether intermittent short exposures at high concentrations or continuous exposure at a low concentration will carry the greater risk. References Albnght LF (1967a) Vinyl Chloride processes. Chem Eng 74:1:3-130 Albnght LF i1967b) Manufacture of vinyl chionde. Chem Eng 74 :19-22* Albright LF 11967c) Polymerisation of vinyl chloride. Chem Eng 74:151-158 Albnght LF f 1967d) Vinyl chloride polymerization by suspension processes yirlds polyvinyl chionde resins. Chem Ent 74:145-152 Albnght LF (1967$) Vinyl chloride polymenzaoon by emulsion, bulk and solution processes. Chem Eng 74:85-92 Alrenga OP < 1975) Primary angiosarcoma of the liver. Review article. Int Surg 60: 198-203 Amann R (1975) Bering zur Vmylchlorid-Knnkheit. - Ein Fall von Angioiaricom der Leber. Dissertation. Umversitit Freiburg Anderson HA, Snyder S. Lewinson I. W00C. Lilia R. Selikoff 1J (1978) Levels of CEA among vinyl chloride and polyvinyl chloride exposed workers. Cancer *2: 1560-156? Andrews AW, Zawistowslti ES. Valentine CR (1976) A comparison of the mutagenic properties of vinyl chloride and methyl chloride. Mutat Res 40:273-276 Anghelescu F, Otoju M. Dobrinescu E. Hsgi*Paruchiv*Oosrios L. Dobrinescu G. Cans* V < 1969) Clinico^>uhogeneuc considerations on Raynaud's phenomenon among employees of the polyvinyl chloride industry. (Rumanian text) Med Interna 21: 473-482 Annual Report of the Chief Inspector of Factories for the Year 1951 (I9S3) HMSO London. Cmd 8772 Aotosyuzhenko VA (1968) On the occupational vinyl chloride intoxication. (Rus sian text). Gig Tr Prof Zabol 12: 50-52 Antweikr H (1976) Studies on the mecaboiisa of vinyl chloride. Environ Health Penpect 17:217-219 Arnaud A. Pomnrier de Sand P. Garb* L. Payan H, Charpin 1 (1978) Polyvinyl chlo ride pneumoconiotis. Thorax 33:19--25 Aryanpur J (1977) Vinyl chloride: its impact on occupational medicine practice in Inn. J Occup Med 19:689-092 Assmean H (1921) Die Rbntgendiagnostik der inneren Erfcrakungen. Vogel, Leipzig Austin GT( 1974) Industrially significant organic chemicals, part 3. Chem Eng 81: 87-89 Bachner U, Etzel F. Lange CE. Mamciler HJ, Veitman G (1974a) Himoatasebefundc end Gsophagusvarizen bai Vinyfehlorid-Kiaafcheit Dtsch Med Wochenschr 99: 2409-2410 Bachner U. Enel F,Lange CE, Jflhe S, Veitman G (1974b) Gerinnungsphysiolofisebc Befunda bet VsnytettioridkiankhciL In: Lahacrt G. Szadkowsfci 0, Weber KJ (ads) Jahrasbericfatder 14. Jahrestagung der Dcuschen GemUscfctft (Br Arbeitsmedizin. Centner, Stuttgart, pp 275--280 Bachner V, MGBer R. Eitii H (1975a) Clinfell relevanca of piaiafet ftmetion tests in 1000 patients with bamorrhagfe diathesis. Thtomb Res 6:139-149 lirtmar t/.Ettd F, Lange CE. MarsteUerHJ. Veltnun G (t975b) Himostaacbefunda nnd Oeophagumariten bat Viayfehiorid-Krankheit. In: Marx R. Thin KA (eds) Btutungen das GaetrointesOnaitnkies- Schattanor, Stuttgart New York, pp 67-73 90 W.K. Lelbach and HJ. Mareteller Bachncr U, Etxel F. Muller N, Lange CE. Egii H < 1976) Praneopiastische und kollagenisierende Verinderutigen der Leber und Hamostasebefunde bet PVC-.Arbeuern. In: Gastpar H(ed) Onkohamostaseologie. Schatuucr. Stuttgart New York, pp 319-326 Banti G (1898) Splenomegalie mil Leberzirrhose. Beirr Pathol Anat AUg Pathol 2-*: 21-33 Barbin A. BresiJ H, Crouy A. Jacquignon P. Malaveille C. Montesano R. Bartsch H (1975) Liver-microsome mediated formation of alkylating agents from vinyl bro* mide and vinyl chloride. Biochem Biophys Res Commun 67:596--603 Baretta ED. Stewart RD. Mutchler JE f 1969) Monitoring exposures to \;nyl chloride vapor: breath analysis and continuous air sampling. Am Ind Hyg Assoc J 30.557544 Bames AW (i 976) Vinyl chloride and the production of PVC. Proc R Soc Med 69: 277-281 Bartsch H, Malaveille C. Montesano R.Tomatis L (1975a) Tissue-mediated mutager.Tcicy of vinylidene chloride and 2<hlorobutadiene in Salmonella typhimunum. Nature 255:641-643 Bartsch H, Malaveille C, Montesano R f 197Sb) Human, rat. and mouse liver mediated mutagenicity of vinyl chloride in S. typhimunum strains. Int J Cancer 15/3:429437 Bartsch H. Malaveille C. Barbin A. Bresit H.Tomatis L. Montesano R (1976) Mutagen icity and metabolism of vinyl chlonde and related compounds. Environ Health Perspect 17:192 -- 198 Basalaev AV, Vatin AN. Kosetkov AG (1972) On the pathogenesis of changes develop ing due to long-term exposure to the effects of vinyl chlonde. Gig Tr Prof Zabol 16:24-27 (Russian text) Basu AK. Boyer J. Bhattacharya R, Bani Maliik KC, Sen Gupta KP (1967a) Noncirrhotic portal fibrosis with portal hypertension: a new syndrome. 1. Clinical and function studies and results of operations. Indian J Med Res 55:336-350 Basu Maliik KC. Sen Gupta KP. Basu AK. Biswas SK. Pal NC, Boyer J (1967b) Noncirrhotic portal fibrosis with portal hypertension: a new syndrome. II. Histopalho! ogical studies. Indian J Med Res 55:351-359 Baumann E (1872) Uber einige Vinytverbindungen. Liebigs Ann Pharm 163:308 -322 Baxter PJ (1976) Epidemiological studies of PVC manufactures and fabricators, and primary angiosarcoma of the liver. Proc R Soc Med 69:297-299 Baxter PJ. Fox AJ (1975) Angiosarcoma of the liver as the certified cause of death 1963-1973. 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Paper presented at the 19th International Congress of Occupational Medicine, Dubrovnik, 2S-30 September, 1978 Berry G, Roetiter CE (1976) Vinyl chloride and mortality? Laaeet 11:416-417 BcnifsgenaaenschafUichcGnindsStze fQr arbeitsmedizinisehe Vonorgeuntersuchungen. Gefihrdung dutch Vlnylchlorid. Faming Juii 1974. Arbeitsmed Soziaimed Praeventivmed 9:226--229 Vinyl Ohio. Biercack HJ sztntigrai renagunj: 3 10. (Bn. Biersack HJ Cf 1975r ten mit \ Biersack HJ gnphy (Stuttgi J Biersack HJ schiden IVmylchio 88 Blendis LM. sion in vir. 75:206-2 Block JB ( 19' 229.53-5- Blomfield J. current he: Boll HM (1 97 HM.Bann. England, p Bolt HM. Rap 1:1425 Bolt HM. Kap of ,4C vir Bolt HM. Ki| 33 m the rat r~ Bolt HM. Lj:; 3^ in the rat Vo Bolt HM. Kar lite. In: G.. ehlond-Kr.. onneton G de nipnin rure de vin; Bonneton G. < Many F. r leurs du ch. Bone G. Urbj oxirane tor perfused ra- Bonk J (192* Neurol Psy. Border EA. oxide and . Interact 17 Boyer JL. 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Kilian DJ (1979) Mortality experience of workers in a vinyl chloride monomer production plant. J Occup Med 21:195-203 Byczkowska Z. Langauer-Lewowicka H (1974) Raynaud's syndrome in workers em ployed in production of polyvinyl chloride. (Polish text). Pol Tyg Lek 29:14611464 Byren 0. Holmberg B 11975) Two possible cases of angiosarcoma of the liver in a group of Swedish vinvl chlondc-polyvinvj chloride workers. Ann NY Acad Sci 246: 249-250 Byrtn D. Engholm G. Engiund A. Westerholm P (1976) Mortality and cancer morbid ity in a group of Swedish VCM and PVC production workers. Environ Health Per spect 17:167-170 Carr J. Burginson RM. Vitcha JF. Krantz JC (1949) Anesthesia. XXIV. Chemical con stitution of hydrocarbons and cardiac automaticity. J Pharmacol Exp Ther 97 | Chainuvati T, Viranuvatn V (1979) Idiopathic portal hypertension and chronic arsenic poisoning. Report of a case. Am J Dig Dis 24:70--73 Chateiain A. Molillon P (1967) Un syndrome d'acro-osteolyse d'origine professionnelk ei de constaution nouvelle en France. J Radiol Electrol Med Nuel 46:277-280 Cheney WD (1965) Acro-osteolysis. Am J Roentgenol 94:395-607 Chowdhury AR. Biac; M. LorberSH. Chey WY (1977) Haemangioendotheliomaiosis of the liver. A 12.x ear follow-up, Gastroenterology 72:137-160 Colardyn F. van der Straeten M. Lament H. van Peteghem T (1976) Acute inhalationintoxication by combustion of polyvinylchloride. Int Arch Occup Environ Health 38:121-127 Conolly RB. Jaeger RJi Szabo S (1978) Acute hepatotoxicity of ethylene, vinyl fluo ride, vinv! chloride sad vinyl bromide after aroclor 1254 pretreatment Exp Mol Pathol 28:25-33 Cook WA.Giever PM, Oinman BD. Magnuson Hi (1971) Occupational scroosteolysis. H. An industrial hygiene study. Arch Environ Health 22:74--82 Corbett TH (1975) inhalation anesthetics - more vinyl chloride? Environ Res 9:211214 Cordkr JM. Fievez C. Lefivre MJ.Sevrin A (1966) Acroosteolyse et lesions cutanees chez deux ouvriers affeetds au nettoyage d'autoclaves. Cah Med Tia 4:14, 3-39 Comoh HH, Abar EL (1969) Toxicity of pyrolysis products of vinyl plasties. Arch Environ Health 19:15-21 Couderc P, Panh MH. Pisquier B. Pasquier D. N'Golet A. Faure H (1976) Angiosarcome irtttvw livflateur d'une tumeur hepatique chez ua tnvaillcur expose au chlonsie de vinyle. Sem H6p Paris 52:1721-1722 Covriishaw JL. Pollard EJ.Cowen AE, Powell LW (1979) Liver disease associated with chronic arsenic ingestion. Aust NZ J Med 9:910-313 Creedi JL. Johnson MN (1974) Angiosarcoma of the liver in the manufacture of poly vinyl chloride. J Occup Med 16:150-151 Creech JL,MtkkL( 1975) Liver disease among polyvinyl chloride production workers. Ann NY Acad Sci 266:88-94 Creech JL. Johnson MN. Block A (1974a) Epidemiologic notes and reports. Angio sarcoma of the liver among polyvinyl chloride workers. Morbid Mortal Weekly Rep 23:49-50 C. 33 rO oJ Vinyl ChlonU. Creech JL. M. vinyl clilon Gastroentv Daiderup LM < 1 7:285--2? Ddlderup LM Lancet 1:24 DtmnaherC. ) coma cheni-. May 16-29 Danziger H (I 0 Med Assc. Darke CS(197< lion of PVC DattaDV.Mit;. toxication a cirrhotic po Davies JW.Per: Environ Poll Deese DE, Joyr lnd Hyg As* Delorme F {19' chlorate de Delorme F (19" ouvrier du c1 Delorme F. Me? tact prolong. Union Med ' Delorme F. T;i Quebec. J O Devignevjelle l` polyvinyhq.. Dmman BD. C tionai aero- - Dod'on VN. Du rional acroo- Doll R( 1975) . Domininghaus i: -- Anwendi Dor JF. Arlauu (1975) Anp, rare de poly Dressman RC. v miration of \ Sci 15:69 Du JT. Tambun chlonde expo Ducatman A. H>. chromosome Duck BW (1975 i Duck BW (197o > 307-309 Duck BW, Carle Duck BW. 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Ul |tuod 3rjoqu:s uouj uoisuauad.lir i^uod nruiedoipi ui joinc; rratlotonaf aiqissod c sc uoacatvot ui Masj ro aiuorqj (6i6I)KM ,4AgtiQ -'.sj Toeunqqj *^SJ1!K`AC *a is:-08r :69 V*K U 3g ) uop snpojd ai|) p apuomfl }.<u?a :saweg ^-y :) i(jeuiaj uo!n.**sifl(9i$i)SD Of 8-S:8:Z8 flossy pK uc^ sases oaI jo uodan apuofqp jXuu Xq ftnuostod frjuappfy (0961) H wStiurQ curtsmo-7 `sutajio '6i6i '61-91 'CK iuijaa|v '*r*u| `unjaasa^ la^ur^ joj unnrr.'osfy urr*uauj\ \dc;a;j;ou:si(.' cuo? icsotfuc rucdaq p.^jcnoisr apuojq? (61611 3 oiinqtuci `n ujc^ iatrruurQ OfT I sa^ur-j jjAii aqi jc cuio.-jcvoisuv (9161) Si lSJOtj^wo-ia `js^a 'DS ujj diuap^a 9s:->s:it r^J%; di^O f '9A!l 1,l* )o nuo.MCsorgueuxatq puc apuc'lV-' jXuja (Si6l > l\*T dnjapftg 981 19 (8o|oiMuaoj]Sf>i) wciiojd aaur(|ia.uns jo jcaX juij tuunp ua!jio.n uon3npojd (j(\d> aruo|q? |.f i.\ |Od Suouic Ait.`>ixojojrd>H qribl HJ OAinqturi *jf Jf nMM -1 'Tf q.-oajj i`6 wcasiQ piei^n?Y*apuo|tQ t.<u:A d**XW*A otSsy 'l- -ua^oa oms. Xjod jo atm- tfiua patco>>> ns aaodx-v. 'otfuv qajy 6C-OI saaucsna -oi. tit*** TTs.ljoaw--i rw <*H -onu (Xuiv mrH r-- UUIIPTfqU! osc-n: auauuotsaj\ i Muastc .'tuc'iu I -16 `U UO5 {totuiat; -JSJ mftaH piqjoui tarv Off S Pc;,\ * ui iaA>: -19W-6r ua uamo. * ui ur>.v. o*.*n (iv qstpa^< puc .Uisnpui - safiimpiit 80t-:ot:r ucuinq ui - or: -oip.<q pv jaioistvj^ ( i 94 W.K. Lelbach an-f H.J. Marsieller Dugoij P. Ambbrd P.de Bigmcourt B.Lecrand J (1972) Acropathic polyvinylique profesionndle. Bull Soc Fr Dermatol Syphiligr 79. 197-198 Dupas J. Badelon P, Daydf G (1956) Osteolysc esseniiellc profrevive de la main gauche d'origin* indeterminde- Mem Acad Clisr 62:148- ISS van Duuren L (1975) On the possible mechanism of carcinogenic action of viny l chlo ride. Ann NY Acad Sci 246:258-267 Dyer RF. Esch HV (1976) Polyvinyl chloride toxicity in Fires Hydrogen chloride tox icity in fire fighters. JAMA 256:393-397 Edmonds LD. 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Baltimore Falk H, Waxweiler RJ (1976) Epidemiological studies of vinyl chloride health effects in the United States. Proc R Soc Med 69:303-306 Falk H, Creech JL Jr. Heath CW Jr. Johnson MN, Key MM (1974a) Hepatic disease among workers at a vinyl chloride polymerization plant. JAMA 230:59-63 Falk H. Heath CW Jr, Carter CD, Wagoner JK. Waxweiler RJ. Stringer WT (1974b) Mortality among vinyl chloride workers. Lancet 11:784 Feron VJ, Kroes R (1979) One-year time sequence inhalation toxicity study of vinyl chloride in rats. II. Morphological changes in the respirator)' tract, ceruminous glands, brain, kidneys, heart, and spleen. Toxicology 13:131-141 Feron VJ, Spcek AJ. Willems Ml. van Battum D. dc Groot AP (1975) Observations on the oral administration and toxicity of vinyl chloride in rets. Food Cosmet Toxicol 13:633-638 Feron VJ. Kruyne A. Til HP (1979a) One-year time sequence inhalation toxicity study of vinyl chloride in rets. 1. Growth, mortality, haematology, clinical chem istry and organ weights. Toxicology 13:25--28 Feron VJ, Spit BJ, Immel HR, Kroes R (1979b) One-year time sequence inhalation toxicity study of vinyl chloride in rats. III. Morphological changes in the liver. Toxicology 13:143 --154 Fiechtner JJ, Reyes CN Jr (1976) Angiosarcoma of the liver in a rural population. Four cases diagnosed in a 29-month period. JAMA 236:1704-1706 Filatova VS. Babochkina MS (1964) Hygienic assessment of some types of equipment employed for drying and screening of polyvinyl chloride resins. Gig Tr Prof Zabol 8:9-13 (Rusrian text) Filatova VS. Gronsbcrg ES (1957) Hygienic working conditions in the production of polyvinyl chloride resins and measures for improvement GigSanit 1:38-42 (Russian text) Filatova VS, Balakhonova LI, Gronsberg ES (1958) Hygienic characteristics of vinyl chloride production. Gig Tr Prof Zabol 2:6-9 (Russian text) Fdatova VS.BIagodatin VM.Goffman FE( 1964) The efficacy of health measures in the production of polyvinyl chloride resins. Gig Tr Prof Zabol 8:3-6 (Russian text) Fischer J. Wolf R (1963) Die quantitative Abschitzung der Milzfribe mit Hiife der Scintigraphic. Dtsctf Med Wochenschr 88:1430--1437 3? ro t_n Vin\ I Fisch. (19 Fine 1 AriFJejscf . Ho, SIO1 Wc. Fome of ' poi- Fox A. Fox A.I sele. Fox A.1 mor 34 ! Frentz. Arb, Soz Frey HI hani A-b Frong:..' zion Funes-i Goll. Laru Futh L tion Gabor Apri * PGanu' 86 Garro A effci. Gay BW ride Gedigk . vinvi 278 Gedigk bei v Leb' Yorl. Gthrini for,. App Gehnr.i to vr 15 -. Gemts ' with Giaccai 29 aa*i\ ^****r^-***y5 f>5** ' -. ' f-. I't t 'it; f f T. '*>: X,*, 1v " :"-n- -^ -* ; . J HJ Mantellcr rlyvinylique J* la main o oi vinyl chio* --n chlonde tex9 i vinyl chloride. in: Edmond* i by Armed le mutagenicity i:i hydrate. i typical '`neuro- ciio A. Arenas Rev Gin Esp Tirpean assess* . Baltimore Jc health effects '-pane disease *0-59-63 hT(J9"4hi *tudy of cmminou-. < observanoi.' on i i'ohmi Toxicol ih toxicity .Unicsl ehem- ^nce inhalation in the liver <1 population. 06 res of equipment i$ Tr Prof label a production of iij ::Jg-42(Russiaa Tctsbs of vinyl jtth measures in t 61Russian text) mil Hilfe der Vinyl Chloride-Associated Diea 95 Fischer J. Mundschenk H. Wolf R < 190S) Mtlasainuenphic mit l-Bromomercun i 19*H^i-Hiydrosypfopan (BMHP). ROEFO 103.3-9-366 Ftetf I.Thicss AM 1I974f Oromo*omn-Cntenuchunfen tei Vinylchlorid-Exposiuon Arbeitsmcd Sorialmed Praevennvmed 9:230-283 Fleuchmann R. Schlote W. Schomerus H. Wolburg H. CastnUunOberndorfer WL. Hoensch H (19?") Kleinknotipe Leberzirrhose mit auspepriifter portaler Hyperten sion ais Folge einer Vitamm-A-Intoxikatton bei Psonasis-Behandlung. Dtsch Med Wochensctu 101.1637-16-0 Fome.-ke V\, Katosova LD. 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Popper H (1975) Pathology of angiosarcoma of the liver among vinyl chloride - polyvinyl chloride workers. Ann NY Acad Sci 246:268-277 Thomas LB. Popper H.Bcrk PD. Selikoff I. Falk H U975> Vmyl-chlonde-tnduced liver disease. From idiopethic portal hypertension (Banti's syndrome) to angio- sarcomas. N Engl J Med 292:17-22 Tisdale WA. ICIatskin G, Glenn WWL (1959) Portal hypertension and bleeding eso- phageal varices. Their occurrence in the absence of both intrahepatic and extrahe- patic obstruction of the ponaIvein. N Engl J Med 261:209-218 Tola S 41975) Occupational lead exposure in Finland. IV. The polyvinyl chloride plastic industry. Scand J Work Environ Health 1:173-177 Torkelson TR, Oyea F, Rowe VK (1961) The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Am Ind Hyg Assoc J 22:354-361 Trapp JT. Lummui FL, Hilbun BM (1974) Acro-osteolysis: a case report. J Miss State Med Assoc 15:246-248 Tribukh SL. Tikhomirovs NP, Levina SV. Kozlov LA (1949) Conditions of work and measures of industrial hygiene in the production of, and manufacture from, vinyl chloride plastics. Gig Sanit 10:38-44 (Russian text) Triche T, Nanba K, Ishak JC. WoOcoff A. Berk PD (197$) Hepatic ultrastnictural changes in rinyl chloride (VC) wotken. Clin Res 23:259A TrucU JE, Peck SD. Rciquam CW (1973) Hemaagiosarcoau of the liver complicated by disseminated intravascular coagulation. Gastroenterology 65:936-942 Vainio H (1978) Vinyl chloride and vinyl benxcnc (styrene)-owubolism. mutagenicity and carcinogenicity. Chem BM Interact 22:117-124 Vale FT, Kipling MD, Wafcer AE (1976) Miscellaneous symptoms occurring in worker* engaged in the manufacture of PVC. J Soc Occup Med 26:95-97 Vazin AN, Plokhova FT (1968) On the pathogenesis of disease due to chronic expo sure to vinyl chloride. Farmakoi Toksikoi 3:369-372 (Russian text) ^ P--* cn 40 Vinj Vazm to! (RVazir. exVKE bat' Velirr Be Veitn. In chi Veltm COti VeJtm 197 Verck;- in v 29VUJeru Via. Viola I Viola 1' Viola r Viola i to ' Wagon J`; Walk.-: t:,< Wa Ikr 34Walki- 2bWalln Mi Ward . Pr<Ward ' m>i Waian sir . Waian nd- Watan her an- Waia,. situ- Watjn nd. 391 Waur btr- Waxw. nsk Jf.J Miirm'Kcr j*ms in vm\ 1 the inhala- iu}.ii.'.urs ui resirmably ii.recnor. - i L.r.de: a causal I'jper pr?>( the Liver. preen clearance ;t presented to Annual Meet- vtqi Ultra.i.ension. Cut - freer angio0 iminary results u u*t and :*irvn ..Vinyl- np vinyl nduced ranpio- . .mp esouJ extra* * .letermincii M- 3M - IMi'sSUilc v.-rfc and *.vm. vtnv f vucturai implicated 942 >. mutagenicity mtg in workers Irrmuc expo* i Vinyl Chl>nd--^s*0fc'iat,sd 0i**3S< 110099 Vin AN. Ptokhova ET11969a) Change* ui adrenalin-iike rubsunces ui rabbit blood following chronic exposure to vinyl chloride vapour. Gif Tr Prof Zabol 13 46 -47 (Russian text) Vatin aN. Plokhova ET < 1969b) Changes of cardiac activity in rats following chronic exposure to vinyl chlonde vapour. Farmakoi Toksikol 32:220-222 (Russian text) VKE i 1974. 1975J VC'PVC: Bei'hrel <-iner ProblemlOjung- Herauspepeben vom Ver- band Jer kunstitofferteugendan Industrie a.V i VKE). Frankiurt) Veltman G. Large CE (l9"7-i) A;e;tjmedi2inische Asnekte -Jer Vinjlchlondscltiden. Beruisdcrmati'sen 25 6" '7 Veltmjn C. Large CE < |9*Tb> A/'cr;incdiz:nitche Aspekts der V:n> !c.`tlor Jschiden In: Gutacker HW. Leibacli WK ledsi Leberschaden durch Vinylchlond - Vinylchlond-Krankheic Witzstrock. Baden-Baden Bnissel Koln New York, pp 95-101 Veltman G. Lange CE. Jfthe S. Stein G, Bachner U f!'5) Clinical manifestations ir.d course of vinyl chloride disease. Ann NY Acad Set 246:6-17 Veltman G. Lange CE. Stein G (1973) Die Vlnylchlorid-Krankheii. Hautarzt 29: 1977-1982 Vertkin Yl. Mamontov YR M970) On the condition of the broncho-pulmonary rystem m workers employed in the manufacture of FVC articles. Gig Tr Prof Zabol 14. 29-32 (Russian text) VilJcneuve JP.Huet PM. Joly JG. Marleau D.Coce J. Legare A. Lafortune M, Lavoie P. Viailct A (1976) Idiopathic portal hypertension. Am J Med 61:459-464 Viola PL (1970a) Cancerogenie effect of vinyl chloride. Int Cancer Congr. Abttr 29 Viola PL (1970b) Pathology of vinyl chloride. Med Lav 61:174--180 Viola PLl 1974) La malaxtia da cloruro di vinile. Med Lav 65:81-99 Viola PL, Bifotti A.Caputo A U971) Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31:516-519 Wagoner IK. Infante PF. Sincci R (1976) Vinyl chloride and mortality? Lancet 11: 194--195 wnker AE (1974) a preliminary report of a vascular abnormality occurring in men engaged in the manufacture of polyvinyl chloride. Br I Dermatol 1974: 22-23 Walker AE (1975) Occupational euro-osteolysis (two cases). Proc R Soc Med 68:343346 Walker A( 1976) Clinical aspects of vinyl chloride disease: Skin. Proc R Soc Med 69: 286-289 Walln&fer H. Zinnagi N (1977) Himugiosartofnatose aach Poly*inylchloridexpositioa. Med KUn 72:410-413 Ward AM < 1976) Evidence of an immune complex disorder in vinyl chloride workers. Proc R Soc Med 69:289-290 Ward M, Udnoon S, Watkins J, Walker A. Darke CS (1976) Immunotogicsl mecha nisms in the pathogenesis of vinyl chloride disease. Br Med 11:936-938 Watanabe PG.GehringPJ(l976) Dosedependent fate of vinyl chloride and its pos- sibk rvlationriiip to oncogenicity in no. Environ Health Peispect 17:145-152 Watanabe PG. McGowan GR. Madrid EO. Gehring PJ (1976a) Fate of "C-nnykftlo- ride following inhalation exposure in rats. Toxicol Appl Pharmacol 37:49-59 Watanabe PG. Hefner RE Ir. Gehring PJ (1976b) Vinyl chloride-induced deprvsrion of hepatic non-prowin suifhydryl content and effects on brotnosulphaiein (BSP) clear ance in rats. Toxicology 6:1-8 Watanabe PG, McGowan GR, Gehring PJ (1976c) Fact of |4C vinyl chloride after ttfk oral administration in rats. Toxicol Appl Pharmacol 36:339-352 Watanabe PG. Zempel JA. Gehring PJ (1978a) Comparison of the fate of vinyl chlo ride fuluwhi riaMe and repeated exposure In rats. Toxicol Appl Pharmacol 44: 391-399 Watanabe PG, Zempel JA. Pen DG. Gehring PJ (I97|b) Hepatic macromoleeular Mailing following tapomit to vinyl chloride. Toxicol Appl Pharmacol *4:J7] -$79 WaxweaarRJ.StxbMBrW.WapDncrJK.JomaJ.FaBc H, Carter C( 1976} Neoplastic ririt --nni enrirsis exposed to vinyl chloride. Ana NY Acad 8d 271:40-48 r5 r~ g G A'- VaT *: f Tisiuaj EI7Ip9t\* I I rs rs 'C,UT1M 1M 9> IS S'f a f t* w rt f' o rr a it u-ut|< r c .c .t Cl SC a f'C a f i rc j re .:.^uv 4'saQ nsiui3 to r<\Ni S' <3Ia\;is j^a (c utnOJ>ocuSt 1foqtfqox *pey Iih qwv 'apuopp jXuia o) ajnsodxa Iujmoqoj ja.\i| aqj jo tuioupiOfSue jo SMC9 ox (SI6U 12*-^X *K ?>AOupucjfqo)| `p; ?uts 'IS eauoz 6S-IS:89C 0**V loqie^) qaiy M*qa*?A. JM quM^*puo|qt^<nA *P tuiQ)Cuy uaipsitoioipcj jnz (i61) H Jp3`H uueuuaunuiz Cl-ree paiuvjtaqjy qwY IU| ysSH pu* sn u#**wq qseojddc tnuojssimtp V ajuiie 3ix< oj ajnsodxa |cuoijedn>ao joj niuii) iqqnsiguaj {fX61) Ty *?nIP*Z tt9-OI9-U jnj uoisuauadXq icjjod aiiedaqcjiui>9t}nqjJi>uou q]i uuaytd jo uotnajduioaap irviod jbijc |C.\ujn$ paJuoioij (0661 >'HV tu^H `fty uos*eQ *jy piajsucis ^ us3a?2 e:r- i:p:sz t pov *H Pl uiy Jpuoiip |AWA (t96\i Vf ddr* 61-1 : udf toqiej ejDyA.jjj3UJOutq put Xdowajaiuj uojiaafa Suiuuc.'k Adoasojatui iqdij iuisn (SKOqup ja.\i| inoqiiM auioapu.^.pucg pa||c>os) uotcuai jadXq icjji'd .iiqicdotpi ui ua|ds aqi jo saipnji |C9tlo[A|dioK <6i6l) M oioiuruicx 506* !o8:8J udf v^qjcj ciy (fisoqup jsaii (-V'piM aiuojpu.\s s.uoeg paj|T!x>i) uoyuauadAq feud'd siqiedoipi ui uaajdt qj qjlw 9uucdiuoa sis oqjjia ja.\q 9i|eiauioua|ds ui uaajdf ?tujo sajpnjs |C90o(oqdJOK (t $| > )| oiouieuiex *,' 68~08:9ft PS PV AS uuy aptjopj? |XutA.{[0d jo ajmacjmieui aqi ui pa>\|<Mui ua^jo.-n jcaiuiaip Juotue sauojsiti s>3uj|i puc msaj SuiuaajM poH *>( Xpma 3i*o|oiiuapida uy ({^,611 HV ll^G Jf iaii[3neis ->jq [laqduie^ `Jf ,\\f UL-fi-.qAnq -ja iJistJJsqxiH i\f uaqsio^ *HV ut'.w 9681-1681 8C 50JJ p^i iutuinq ut juauttsatn ^su oj qseuiddc uc rsaipms riio|03(voi jo udisap aqj iqjtuoueiapisuos ortojoriuapidg (66.61 > Sf spo^AV 91 j-- | | z X1 )3adu3j qj|CaH uojL^uj Apmt jciuauiuad x uc :puoiq.i I^UIA JO naajja ica^opig CPigl) 1 0 8iquj|OH K |l?ui,>\ 'V 18S-US:I0C VKVfss icjouodag sw<(03jsooj3e feuonednaso <i96t )1f uimcx '3/W^*uuo^a^ '>fa uosp.^ 8t-"f 06 3e?'uiaq3 my f sauijaio pajcinfuo.i pur paicuyoiqa qiiM uozo ;o suou.'roi jo saicg (8961) fy syoueta.x^ *<JG uosutciip \\ 9" LS'-LZ PpK dnj9Q roj f ua^io.w apuoiqs [auia ui Xqdeiiouuaqi pucq jo luauusaict uy I) X5( sut.\3 3 suaqoy *fK0 tuicifOM ,1 tsi-:>*i:ee uapjosip iaAq Juuoiiuojv (9^61) HI .<r*soo *A\f2l JOM*X `|\'d qiuis *f|^G suierin.M t9; 1 uotuaSiQ uaqzo iautououi ppuojqr' |Xun ui sjXticqa ia.%q jo uonsaiap aiicuioiduiXs-aij msx61 > .8 tP"<l `Krl . ' pCVVi mo wea'-p loiXcx'fKa s>u*m>A\ jn; uaqjOM jawououi apuojq? i.(uu lurusaj.Aj <e;x6t) IVd ir,fyaj.>jt * iO|^X TKQ * f '/ ' 9: pA,v, vlnaso ?oS f '.i>A|oaiso*oJ.`'c u< sinajap ir^autr^r-l jo t-- < 11 ')&i**;?iq.'crjr>;^ - fj\a s",n,\k *- - * .iS-6CS' v>! ''''J'- |' I uiia cm \ i : PSl L| 1 i.vk (i.'-h.. . r ui-j43r . J| 1 /-:'f , > .. -r ->r `-1' " a ri\ f... *! 'VU-'J'i v~:: 5*h 1 *. u > u3iMuu.\v N:t*0: : M r- lele.I .l fd.J.J3.3I3A.V 'Ulf-'H " Vr- ' .'T-i9,r6r.P-''|\>X.?du3 S 10 |t>oi[?s I'f ^JCH nit n 1il-lr`*I'-''!WOdV*-. > I ^HG'ucuiSr.v, !"0 9r !-',S l'~JY K '" maj mn/nssiQ) 1 s_0(, ucu;3a^ ;86l -U6l 9p 'Ptu asoivfjj ' ojoqx Pun IU,,J* 'S ''lf(PMiopuao|n.,-iT.,>,j 1 l to l 1 H uuci'i. Juicaj *h .| ''A.w ^ *ce>ag psirtxiuv-pue((|3|.(U,A ;jsi,9me^ -fu puc iprqiai Oil I#*' r Environmental Health Perspectives Vol. il, pp. 10I-J06, 1981 Epidemiologic Study of Vinyl Chloride Workers: Mortality through December 31, 1972 by W. Clark Cooper* A population of 10.173 men. employed in 37 plant*, was identiAed as havint worked for at least one year in jobs involving probable exposure to vinyl chloride monomer (VCM) prior to January 1,1973. Ofthe 9677 men whose vital status was determined, 707 were known to have died. For $99, death certificates were obtained. The standardized mortality ratio (SMR) for all causes was 89, that for all malignancies was 104. The only type of malignancy found in significant excess was in the category of malignant neoplasms of the brain and other parts of the nervous system; 12 deaths occurred where 5.9 were expected, for an adjusted SMR of 203. There were slight but inconclusive upward trends in all malignancies, and for malignancies of the respiratory tract, digestive tract, and central nervous system associated with reported levels of maximum exposure to VCM. When groups in whom less than 20 years had elapsed from the first exposure were compared with those with 20 or more elapsed years, and 25 or more elapsed yean, no significantly different SMR's were detected for major primary sites of malignancy. Plans for an updated study of mortality, to include deaths in the period 1973-1979 are briefly discussed. The epidemiologic studies of vinyl chloride work ers summarized in this report were carried out `uringthe period June 15,1973 through December, i976 by Tabershaw-Cooper Associates, Inc., and Equitable Environmental Health, Inc., for the Manufacturing Chemists Association (MCA) (now die Chemical Manufacturers Association). An initial report, dealing with 8,384 workers from 34 plants, was prepared May 3, 1974 (1). A summarized version (#) was published in 1974. The study population was subsequently increased and hEow-up was improved. After an interim report in 1976 (), a final report based on 10,173 workers was prepared in January, 1978 U). In all ofthese studies the observation period ended December 31, 1972. Participating Plants In mid-1973, the MCA identified 43 plants in the United States, belonging to 19 companies, which "filer produced vinyl chloride monomer (VCM) or ed it in the production of poly(vinyl chloride) Jh H60 Shattoek Ave., Suite 401, Berkeley, California 94704. October 1981 (PVC). Of these, 34 were included in the initial study; four were excluded because they had been in operation less than 5 years, one had stopped production in 1966, and in others information on job histories or exposures was deficient. Three plants were subsequently added to the original 34, so the 1978 report included 37 plants. Of these, 11 pro duced only VCM, 18 produced only PVC, three produced both, and five plants produced homo polymers and copolymers, with or without VCM and PVC. The geographical distribution of those in- the Btudy, as shown in Table 1, indicates a dispropor tionate number of workers from the South, particu- Table I. Geographical (Retribution of 10.173 vinyl chloride worker* In 1978 report. Region U.S. males (1970), % Workers in tody, % Northern! North Central South West 23.8 27.9 80.9 17.4 25.9 16.4 64.8 0.9 101 292?nun ; ;3 I larly from the East South Central and West South Central States. The South, with 30.9% of the total U.S. male population in 1970, supplied 64.8% of the Table 2. Bases for development of VCM exposure categories. Criterion Unit f ( ia ( iS i ,u K study population. Of the plants participating, the one which had first begun operations with VCM had done so in Duration of exposed employment Interval from beginning of exposure to end of observation Months Months J :a *7 t 1935, the most recent was in 1968. Four plants had begun in 1942 or earlier, 13 in 1952 or earlier, and 27 in 1962 or earlier. Estimated maximum level to which an individual was exposed for at least 12 months. classified as high, medium, or low. Integrated or cumulative exposure, crediting High Medium Low 1 E >t. st 1 for each month at low, 2 for each 2 I The Study Population month at medium and 3 for each month 3 at high exposure to VCM ; Exposure index (El) " Cumulative score/average The objective was to include all male employees number of months } lc T c) whose work had involved exposure to vinyl chloride li P for at least one year prior to December 31, 1972. The designation ofjobs which involved exposure to VCM was made by staff members at individual analyses. As shown in Table 2, individual exposures in various papers were classified in a number of li plants or by a corporate industrial hygienist. In ways, including the maximum level at which an I approximately two thirds of the study population, individual had been exposed for at least 12 months, TCA staff copied personnel records on individuals an integrated or cumulative exposure, and an who were identified as having been in exposed jobs. exposure index based on the cumulative score I In the remaining portion of the population, detailed information on exposed individuals was provided by plant personnel. The methods used in doing this are described in the complete reports cited earlier. divided by the number of months. Follow-Up 1 C DO ) As is customary in historical prospective studies, rvj 1 Study Period The period of time in which the work-force of a all who had left employment were traced when possible. Methods included form letters sent by mail and use of retail credit follow-up. For the first rs> CD e r plant was included in the study depended upon the report, there was insufficient time to utilize Social date it began making or using VCM and also upon Security Administration records, but for subse the earliest date when personnel records were complete for all employees, if that was later than the foregoing. This was done to eliminate periods when there was differential record retention of workers terminated, deceased, or retired. The end of the study period was December 31, 1972. Estimates of Exposure In each plant, every job and location with VCM quent reports such follow-up was used. In the first, or 1974 report, 85% of the study population was located; for the final or 1978 report, the percentage had been increased to 95%. The mortality calculations were based only on those who were successfully traced, which is equiv alent to assuming that mortality among those not found was the same as among those who were found. This usually, but not always, results in some overestimation of mortality. Ti ucc< UCCi .eat scene ibrc uals expa 5.88 relat exposure was graded in toms of probable expo sure. Originally, a job history form was designed in Calculation of Standardized the l the expectation that the exposures could be quantified in parts per million. This proved impossible in practice. However, for each plant, jobs and loca Mortality Ratios Each worker in the study, i.e., everyone whose TaM* years. tions involving the highest exposures could be vital status was ultimately known, was considered classified as "high", and other jobs classified as to have been under observation from the date on "medium" or "low" relative to the "high". It is which he attained a year of exposed employment or -Vo. of recognized that this subjective classification is of from the date when his plant's records were com- Vo. fo questionable validity in categorizing the past and plete, whichever came later. Observation periods *\foui present exposure of a given worker. From the number of months spent in jobs with classifications of 3 (high), 2 (medium) and 1 (low), a number of exposure categories were developed for use in later ended December 31.1972, or on the date of death, whichever occurred first. Observed deaths were classified by cause accord ing to the 7th (1955) revision of the international i Vo. de Vo. ce Total i Death.- 102 _- Environmental Health Perspectives Octol I Classification of Diseases. The expected number of deaths by cause were calculated by using age and cause-specific mortality rates for United States males with the same birth years and age distribu te for the years 1950. 1955, 1959, 1965, 1967 and jths for which death certificates could not be oDtained were assumed to have the same cause distribution as the death certificates that were obtained. Appropriate increases were made in calculated SMR's. The statistical significance of the deviation of each SMR in the study population from an expected value of 100 was tested by a method derived from Chin Leong Chiang (5). The formula for determin ing the standard error of the SMR was V 100 X SMR SE No. expected deaths If an observed SMR differed from 100 by more than 1.96 standard errors, it was regarded as significant | at the 5% level; if it differed by more than 2.57 * standard errors, it was regarded as significant at the Yk level. SMR's based on fewer than five observed deaths were usually not tested for signi} ficance. Results f Table 3 summarizes the numbers of individuals, ss of follow-up, person-years and deaths in jssive phases of the study. The number of I aeaths per 1000 man-years of observation, which in ' general reflects the age distribution of the work force, suggests that the proportion of older individ. uals increased in the study population as it was ) expanded and follow-up improved. Even so, the 5.88 deaths per 1000 man-years indicates that a relatively young population was being observed; , the U.S. male population 20 and above has about 11 i TtMe 3. Number* of Individuab, iucku of foUow-up. penonjean, and deaths analysed in successive phases of the study. Report 1, Report 2, Report 3, 1974 1976 1978 No. of men No. found S found No.dettho No. certificates 7*UI men-yr Dnths/1000 man-yr 8,384 7,128 95% 352 328 77,84$ 4.52 9,109 8,714 96% 525 511 94,221 5.67 10.173 9,677 gr 707 669 120,203 5.88 iy October 1981 \ deaths per 1000 man-years. Some published occu pational epidemiologic studies will show 20 or more. Duration of Exposure to VCM In the first report, only 15.2% of those studied had begun exposure prior to 1950 (22 years before end of the observation period). In the third report, 33.4% had had 20 or more years for observation since exposure began. This resulted from finding more early employees by improved follow-up, and the inclusion of an older group from one plant in the augmented population. Standardized Mortality Ratios Standardized mortality ratios (SMR's) for selected causes of death are shown in Table 4, based on the 352 deaths analyzed in Report 1 and the 707 deaths analyzed in Report 3. Results in the first report led Tabershaw and Gaffey (2) to conclude that vinyl chloride may be associated with cancer of a number of sites, notably digestive cancer, respiratory can cer, cancer of other and unspecified sites (primarily those of the central nervous system) and lympho mas. This was based not on statistically significant excesses in each category, but upon apparent trends when different levels and durations of exposure were compared. With the enlarged study group, the SMR for malignancies in the entire population dropped slight ly, as did the SMR's for malignancies of the buccal cavity and pharynx, digestive tract and respiratory tract. However, tumors of the brain and central nervous system, when examined separately, still appeared to be in excess. A number of analyses were done in the third report in an attempt to sharpen the focus on work exposures. There appeared to be a slight but definite trend in the SMR's for all malignancies, malignancies of the digestive tract, the respiratory tract, and for other and unspecified sites with increasing levels of estimated maximum exposure (Table 6). HoweverT the numbers ofexpected deaths woe relatively few in some categories and the groups differed widely in age distribution as manifested by deaths per 1000 1 person-years. To reduce dilution ofthe study population by men whose exposures had begun only recently, a sepa rate analysis was carried out on those whose expo sures to VCM had begun 20 years or more prior to 1972, and on those whose exposures had begun 25 years or more prior to 1972 (Table 6). Another analysis was made of a population of men who had worked in plants producing only PVC 103 (where VCM exposures were presumably high), whose exposures had begun 20 years or more be fore the end of the study period and who had been reported as having medium or high VCM exposures for a year or more (Table 7). This group experi enced 210 deaths where 249.7 had been expected* The pattern of mortality from malignancies was not j appreciably different from that of the total study group. In summary, increasing the study population and Table I. Observed and expected deaths (O/E) and standardized mortality ratios for selected causes (SMB's adjusted for missing death certificates). * Cause (ICD Mo, 7th Rev) 1974 Report O/E SMR 1978 Report_____ O/E SMR All causes All malignancies (140-205) Buccal and pharynx (140-148) Digestive (150-159( Respiratory (160-164) Other and unspecified (190-199) Brain and CNS (193) Leukemia and aleukemia (204) Lymphomas (200-203, 205) Major cardiovasc. renal (330-334. 400-468. 592-594) Cirrhosis liver (581) No. of workers Person-vr 352/467 79/77 5/2.84 19/21.7 45/44.3 17/11.75 3/3.77 6/6.06 155/207 9/15.6 7,128 77,846 75* 110 189 94 112 1_55 85 106 80* 21 707/795 139/141 r 5/5.19 29/40.8 25/23.9 28/20.2 12/5.9 9/6.65 11/10.36 347,385 14/26.5 9,677 120,203 89* 104 102 75 107 147 203b 143 112 95 56b .4 URL 1226S Significant at 1% level. `'Significant at 5% level. Table 5. Observed and expected deaths (O/E) and standardized mortality ratios for selected causes as related to maximum level of reported exposure to vinyl chloride monomer (SMR's adjusted for missing death certificates). Cause (ICD Mo, 7th Rev) Reported maximum exposure VCM Low- Medium High O/E SMR O/E SMR O/E SMR AH malignancies (140-205) Digestive (150-159) Respiratory (16IM64) Other and unspecified (19CM99) No. of workers Person-yr Deaths/1000 person-yr 65/71 14/20.9 19/22.2 11/9.9 _ 4,925 58.741 6.16 . 98 72 92 119 66/53.5 1016.6 19/17.1 1S/7.5 3,021 39.927 6.6 109 18/16.5 67 5/4.4 116 7/5.1 180 4/2.7 1.731 21.535 3.9 112 117 141 150 Table 6. Analysis of deaths based on time from beginning of exposure to end of study period (SMR's adjusted for missing death certificates). Cause of death (ICD No. 7th revision) < 20 yr No. SMR > 20 yr No. SMR > 26 yr No. SMR All causes All malignancies (140-205) Digestive (150-159) Respiratory (160-164) Other and unspecified (190-199) Leukemia (204) Cardiovascular-renal 168 77* 549 93 393 96 31 95 108 107 73 104 8 96 21 70 16 74 8 80 87 116 22 100 6 108 22 162 13 146 3 155 6 137 4 137 68 84 279 97 211 105 Significant at 1% level. T04 A- < e j 4- C- " Environmental Health Perspectives * l l t ( ;, improving follow-up did<npg strengthen the sug'* gested associations between VCM exposure and malignancies other than those caused by hepatic angiosarcoma, as will be pointed out later, and a suggested association with tumors of the brain and ntral nervo&s system. Table 7. Deaths in plants producing only PVC, based on workers whose first exposures began before 1952, and w ho had medium or high VCM exposures (SMR's corrected for missing death certificates!. Cause of death (ICD No. 7th revision) O/E SMR All causes All malignancies (140-205) Digestive (150-159) Respiratory (160-164) Other and unspecified (190-199) Cirrhosis of liver (581) 210/249-7 4646.01 9/13.63 17/14.75 10/ 6.33 6/7.95 84* 106 70 122 167 80 Significant at level. t Angiosarcomas Nine angiosarcomas are known to have occurred in the U.S. during the study period, i.e., prior to 12/31/72. As shown in Table 8, eight of these were found in the study, but only three were coded as angiosarcoma on the death certificate. However, four others were coded as tumors of the digestive tract. Unfortunately, two were coded 230x so as to fall out of the category for malignant tumors of the GI tract, and one was coded as cirrhosis of the liver. As shown in Table 8, the angiosarcoma which was not found was in a man who had died in 1961. We have not determined how he failed to be in the study population. The years of exposure for the eight cases ranged from 4 to 23 years, while elapsed time from beginning of exposure to death ranged from 16 to 24 years. Tumors of the Central Nervous System The 12 tumors otthe brain had been diagnosed on death certificates as follows: glioblastoma multiforme, 4 (1 confirmed by autopsy); astrocytoma, 2 (2 au- Table 8. Angiosarcoma deaths and data on VCM exposures. ICI No.1 First exposed Year of death Time from first exposure to death, yr Total yr exposure Est. max. exposure Age at death USA-02 1955 1971 16 14 High 38 -04 1949 1968 19 18 High 43 -05 1944 1964 20 20 High 52 -07 1944 1968 24 14 Med 45 10 1946 1970 24 23 Low 70 -11 1951 1968 17 17 Med 60 -12 1949 1969 20 20 High 50 -16 1950 1969 19 4 High 41 LI -08 -- 1961 Not in study group Number used in registry periodically prepared by J. Stafford. Imperial Chemical Industries Ltd., Plastics Division. [] O' Case no. 1 2 3 IF 4 5 6 7 8 it 9 10 a 11 12 October 1981 Table 9. Summary of brain tumor deaths (ICD No. 205) and data on VCM exposures. First exposed Yr of death Time from 1st exposure to death, yr Total yr exposure Max. exposure 1958 1967 1957 1941 1960 1966 1947 1945 1949 1947 1935 . 1935 1972 1972 1968 1958 1970 1971 1971 1963 1971 1971 1966 1967 14 5 11 17 20 15 24 18 22 24 21 32 5 Low 5 Low 7 Med 6 Med 8 High 3 Med 23 Low 18 High 21 Low 23 High 18 Low 22 Low Age at death 67 43 54 61 43 54 57 44 58 49 59 57 105 tu \ 2 J' Im *. topsies); ependymoma of the 4th ventricle (autop sy); "malignant brain tumor" or "carcinoma of the brain," 5 (with no autospies). This group is cur rently being made the subject of more rigorous review. The information obtainable from our re cords, summarized in Table 9, is insufficient to prove or disprove a cause-and-effect relationship between occupational exposure and these tumors. Conclusions A study of 707 deaths in a population of 9677 men who had worked for one year or more in jobs involving exposure to vinyl chloride and whose vital status had been determined as of December 31, 1972, did not show a significant excess of deaths due to malignancies. There did appear, however, to be a significant excess of tumors of the brain and central nervous system, based on 12 such deaths. There also continued to be slight but inconclusive trends toward higher SMR's for deaths from digestive tract and respiratory tract tumors associated with maximum levels ofpast exposure. No striking changes in malignancy patterns were apparent when analy ses were directed toward individuals in whom 20 to 25 years had elapsed since first exposure. The results suggest that, except for a proven associa tion with hepatic angiosarcoma and a strongly sug gestive association with central nervous system tumors, vinyl chloride probably is not associated with significant excess cancers of other sites. It should be emphasized that the epidemiologic study summarized in this report was planned, the populations defined, and analysis under way before cases of hepatic angiosarcoma had been diagnosed in workers exposed to vinyl chloride (6). An update is scheduled with inclusion of additional deaths in the cohort during the years 1973 through 1979. The study can be improved by a separate analysis of data from the plants which began operations before 1960, and by separating, insofar as possible, expo sures to vinyl chloride monomer, polyvinyl chlo ride, and various copolymers. It is also hoped that criteria for defining exposure and for rating levels of exposure can be improved to permit better indi ces of integrated exposure. This study was begun June 15,1973 under a contract between the Manufacturing Chemists Association, 1825 Connecticut Av enue. N.W., Washington, D.C. (now the Chemical Manufactur ers Association) and Tabershaw/Cooper Associates. Inc. It was continued under later contracts with TCA and with Equitable Environmental Health. Inc. REFERENCES 1. Tabershaw/Cooper Associates. Inc. Epidemiological study of vinyl chloride workers, final report. Submitted to the Manufac turing Chemists Association, May 3, 1974. 2. Tabershaw, I.R., and Gaffey. W, R. Mortality study of workers in the manufacture of vinyl chloride and its poly mers. J. Occup. Med. 16: 509-518 (1974). 3. Equitable Environmental Health, Inc. Supplementary epi demiological study of vinyl chloride workers. Report pre pared for the Manufacturing Chemists Association. Septem ber 1976. 4. Equitable Environmental Health, Inc. Epidemiological study of vinyl chloride workers, final report. Prepared for the Manufacturing Chemists Association. January 1978. 5. Chiang, C. L. Standard error of the age-adjusted death rate. Vital Statistics Special Reports 47: 275-285 (1961). 6. Creech, J. L., and Johnson, M. N. Angiosarcoma of liver in the manufacture of polyvinyl chloride. J. Occup. Med. 16:150 (1974). X1 r" r> r 'j co --j 106 Environmental Health Perspective?