Document KR6yXvK87zyr2yJqLQxj2v2z2

_T, K,,.> Clin Oncol (1981) 102: 1-11 Cancer Research Clinical Oncology Springer-Verlag 1981 Quest Editorial* Malignant Tumors After Chronic Exposure ' inyl Chloride \ *i i.mmerich1 and K. Norpoth 2 .if Pathology (Director: Prof. E. Grundmann. MD, University of Miinster. .Vrr-iAstr. 17. D-4400 Munster, Federal Republic of Germany tru-.-.au- of Industrial Medicine and Silicosis Research Summary. Correlations between exposure to vinyl chloride and the develop-cm of malignant tumors in the liver have been known since 1974 and have rven confirmed by many an experimental investigation. Based on ihe evaluation of mortality statistics from nine different countries an ncrcased incidence of malignant tumors of the lung, the gastrointestinal tract, and the central nervous system (CNS), and of malignant lymphomas is docu mented in connection with exposure to vinyl chloride. Statistically significant creases, however, are only found in the incidence of malignant liver tumors. Metabolism and toxicology of vinyl chloride are discussed in detail. Ke> words: Human carcinogenesis - Vinyl chloride - Toxicology - Liver tumors Metabolism btroduclion ac industrial production of monomeric vinyl chloride (VCM) started some 30 ago. In 1976, the USA produced 2.58, Western Europe 3.925, and Japan --' million tons. About 95% of this output went into polymerization, the re5% into the production of other chemicals, such as methylchloroform 1978). f '7;turns! j?f Cancer-Research and Clinical Oncology" publishes in loose succession "Edihie?! Editorials" on current and/or controversial problems in experimental and clinical - | j.,.<0 contributions represent exclusively the personal opinion of the author. The Editors 'Journal of Cancer Research and Clinical Oncology" bringt in zwangloser Folge "Edi- f "Guest Editorials" zu aktuellen und/oder kontroversen Problemen der experimentellen ` vhen Onkologie. Diese Beitrage geben ausschlieBlich die personliche Meinung des Autors " Die Herausgeber ' ro: K. H. Emmerich. MD (address see above) 0171-5216/81/0102/0001/S2.20 2 K. H. Emmerich and K. J* The very nature of the polymerization process allows for various ways of release into the environment. Workers were exposed to particularly high coj5 trations of VCM during manual autoclave cleansing. Up to the 1960s the risk of vinyl chloride was thought to be negligible (Lefaux 1966). Concentrate of 1,000 ppm at the individual working place were not uncommon in certain pljjfe First recommendations for limiting the exposure to 500 ppm were issued inl$< in the United States. The average concentration levels of that period can beg mated approximately in retrospect: 1945-1955: 1,000ppm 1955-1960: 400-500 ppm .. 1960-1970 : 300-400 ppm 1973: 1975: + 140 ppm 5 ppm (Barnes 1976). -^sr ~ In the Federal Republic of Germany the statutory MAK level1 was fix5T* 500 ppm until 1970, then reduced to 100 ppm until 1974. Today the technical"^ concentration at the work place in the FRG is below 5 ppm for older and curfggj} working plants, under 2 ppm for new plants under construction. The management soon realized that VCM concentration could be effectively reduced to the statuggy levels by technical innovation and financial investments. One Swedish finujjpli able to reduce mean VCM concentrations from 12.2. ppm (2nd quarter of435a to 0.6 ppm (4th quarter of 1975) (Englund and Holmerg 1976). Due to the physicochemical binding of VCM in PVC products, worketS PVC-processing or -manufactoring industries are equally exposed to a certainjsfr centration of VCM, although at much lower levels than during the process ofjgp: merization. In a 1974 survey of PVC-manufacturing plants levels were b3af 1 ppm in more than 60% of all firms checked. The first reports about the potential risk of VCM had been published inT38.~ Since 1957 reports had appeared here and there about a certain disease ocolriSt in VCM industrial workers, manifested in scleroderma-like skin changes, Rayfflflj syndrome, and acro-osteolysis (Juehe and Lange 1972). Some years later, furtfig symptoms of the disease were described as liver damage, splenomegaly, and threw- bocytopenia (K.T. Muller et al. 1976). Detailed investigations were carried ouR* liver changes since the first cases of hemangiosarcoma had been found amoBj VCM workers. These liver changes were graded histologically in five steps, correS^ ting the length of exposure, and the severity of recorded changes (Gedigk et*1975; R. Muller et al. 1975). Even in VCM-exposed workers showing no clinic^ symptoms of liver damage, sequential scintigraphy would reveal RHS liver and spleen (Biersack et al. 1975). __ - -In addition to liver changes a considerable number of workers showed ahJ* i pairment ofpulmonary functions, and roentgenologic changes up to pulmonat^fe-j brosis (Miller et al. 1975; Miller 1975; Lilis et al. 1976). These findings equally** j fleeted a signification correlation between the length of exposure and the segffi j of changes. ----1 The first reports about tumors induced by VCM were published in 1974^~ j cording the increased incidence of a very rare neoplasm, liver hemangiosafijSSjL I 1 MAK = maximale Arbeitsplatz-Konzentration (maximum concentration at work) r K. H. Emmerich and K. Nc Malianant Tumors After Exposure to Vinyl Chloride )rocess allows for various ways of Vi re exposed to particularly high co: : cleansing. Up to the 1960s the heal'tf tgligible (Lefaux 1966). Concentration} :e were not uncommon in certain plants* posure to 500 ppm were issued in 19JJ ration levels of that period can be estjf c,n a ,iCHCI --I A~A H 0H ..CNOfidi ch)oroe thylenox>de I o- s-ch2-cho CHjOH S- formyl methylglutalhione 1 : S-C<- cys-S-CH2-CHO :-nyrr5y,.:-cystene S-formylmethylcysletne chloro- occt - aldehyde acH2cooH chioroaceiale 1 G-5-CH2-COOH S-corboxymethylglutathione I cys-S-CH2-C00H S-carboxyroetr>ytcysteine 1 glycollate COOH I H2CNH2 glycine COOH >1 COOH oxclcte '6). fl je statutory MAK level1 was fixed at; in until 1974. Today the technical limit' ns below 5 ppm for older and currently; under construction. The management" \ be effectively reduced to the statuton^ 3 it .ments. One Swedish firm was' from 12.2. ppm (2nd quarter of 1974)r | d Holmerg 1976). -^ I VCM in PVC products, workers if !S are equally exposed to a certain >r levels than during the process of pbljry jufacturina plants levels were belovtr ~d. " '.'2. of VCM had been published in 194?jr :ere about a certain disease occurringjroderma-like skin changes, RaynaS ange 1972). Some years lateT, furthg_ ^r damage, splenomegaly, and tbrbiiry [ed investigations were carried out do .giosarcoma had been found among; ed histologically in five steps, comitr, 1 of recorded changes (Gedigk clSfe xposed workers showing no clink jraphy would reveal RHS changes ? number of workers showed anjng= i Jnologic changes up to pulmonary^ : al. 1976). These findings cqualJlJSL j jlength of exposure and the scvegBL I COOH ; C - ve C - H : ch2-s-ch2-ch2oh 17* yCH2-CCQH xch2-cooh 00H I H2N-CH I H2C-0H CCCH I H2NCH CH2 I CH2-S-CH3 ' :::M - S -l 2-hydroxy - ethyl}-cysteine thicdiglycollote fig. 1. Major metabolic pathways of vinyl chloride. The main urinary metabolites methion>ne among workers of a PVC-producing firm in the USA (Creech and Johnson 1974). More cases of this uncommon tumor, all among VCM workers, were published in he following years (Lloyd 1974, 1975; Lange et al. 1974, 1975; Byren and Holmx-ry 19'5). Based on 13 cases of liver hemangiosarcoma reported in the USA, the nsk of VCM workers for this rare tumor was determined to be 400 times higher nan that of the normal population (Heath et al. 1975). Histological studies of Thomas and Popper (1975) suggested the possibility of multicentric sarcoma de'lopment. Until 1978 the cases of liver hemangiosarcoma among VCM workers amounted worldwide to a total of 90 (Stafford 1980). Sixteen cases of death of liver hemangiosarcoma had been recorded in the ERG w.il 1978 (Reinl et al. 1979). The cases subjected to detailed investigation until men revealed a longer latency period between first exposure and diagnosis, and a "sher age at first diagnosis of hemangiosarcoma. A possible cause for this pattern seen in the higher initial doses to which workers had been exposed during the rsi years of VCM production (Spirtas and Kaminski 1978). Environmental stud^ conducted in the immediate neighborhood of VCM-producing plants failed to -^ss an increased incidence ofhemangiosarcoma in the general population of this -`-a (Saric et al. 1976). ' ''I Metabolism and Pharmacokinetics _ .. _ ....... .................. >y VCM were published in 197^^^. j ^neoplasm, liver hemaneiosamdffjfc I .J ' /nccnlration at work) " . ` --k- 1 ne metabolism of monomeric-vinylchloride was studied by Green and Hathaway . `J *vutanabeet al. (1976), G. Muller et al. (1976), and many others. Figure I -'-w.-onr'' the major metabolic steps according to current concepts. In the mam- `"an organism monomeric vinyl chloride undergoes oxidative biotransforma- 21190003 4 K. H. Emmerich and K. Norpf tion involving the cytochrome P 450 system. Chlorethylenoxide, an alkylating cS; cerogen, is the resulting primary metabolite (Malaveille et al. 1975; Greim ellf 1975; Kappus et al. 1975) which is subsequently rearranged to chloracetic aldebg de. Via several, partly unknown metabolic steps, this substance is transformedg S-carboxymethyl-cystein and thiodiacetic acid (Yllner 1971). The latter, a rathfr stable terminal metabolite, may be excreted via the urine. Quantitative demons tion of thiodiacetic acid is done by GC.MS technique after methylation (G. MuJJj et al. 1979). Another metabolic pathway, coupling chlorethylenoxide to gluta one, leads to /?-hydroxyethyl mercapturic acid (Watanabe et al. 1976). The urinaij level of this equally stable end product may be demonstrated by exchange chrontf tography after hydrolysis, or by the GC.MS test after derivation (G. MulleretaT 1980). It must be emphasized that /J-hydroxyethyl mercapturic acid is the mainUgr nary metabolite in the rat (Watanabe et al. 1976), but not in man (G. Muller efiL' 1980). The concept of VCM carcinogenicity being essentially mediated by its metajf olite chlorethylenoxide has been substantially verified in recent years. In a mutt' genicity test with Salmonella typhimurium TA 1535 the effect of this strongfj' reacting alkylating agent was 450 times stronger than that of the metabolite chloP acetaldehyde (Rannuget al. 1976). Tumor induction in rats with chlorethylenoridf was 100% successful, whereas chloracetaldehyde failed to show any cancerogenfc effect in a parallel assay (Zajdela et al. 1980). The role of intracellular chlorajgjf aldehyde, i.e., whether or not it might contribute essentially to VCM cancerogq? esis (Guengerich et al. 1979), is still unclear. VCM pharmacokinetics in rats and in man were extensively studies by Heiof et al. (1975), Whitey (1976), Bolt et al. (1976, 1977), Bolt (1978), BuchterefjE (1978), and Filser and Bolt (1979). According to them, man reacts to VCM Jew? around 2 ppm by establishing within a few minutes an equilibrium between tag vironmental (air) and intracorporeal concentration. The constants of this equiBh rium depend on the individual constitution, being approximately 0.8 in persons^ normal weight. Overweight individuals will absorb a higher amount in proportSt to their weight, and so the constant rises above 1.0, possibly due to the higher'plE portion of fatty tissue (Buchter et al. 1978). Experimental studies with rats big. shown that the speed constant of VCM uptake and clearance after stopping thejg* posure (A-= 0.216 min~J) is always much higher than the constant of metabofe ation (A = 0.0037 min "1) and of urinary metabolite excretion (A = 0.0032 minsk Assuming human conditions to be similar, we may deduce that physiologic vari-~ tions of ventilation levels will have either no or only minor influence on the VQ1 uptake by inhalation. From data on the dose dependency ofVCM biotransformation (G. MullerS" 1976; Gehring et al.' 1978, 1979) we may infer that reactive cancerogenic VCMJ* tabolites will not increase in linear correlation with exposure, but rather follow Michaelis-Menten function. Tumor incidence in rats (Gehring et al. 1978) and^g in man (Gehring et al. 1979) is most adequately demonstrated in a probate!* of frequency percentage correlated with exposure (Gehring et al. 1979). FuncUgg^ correlation may be complicated if experimental exposure is under 50 ppm, by glutathione-mediated detoxication of chlorethylenoxide, which is an effectives --tection mechanism at lower-levels ofexposure. Gehring-et-ah (1979) had even".- K..H. Emmerich and K. Noi Mali?inan! Tumors After Exposure to Vinyl Chloride m. Chlorethylenoxide. an alkylating ca^ lite (Malaveille et al. 1975; Greim etaj| uently rearranged to chloracetic aldehw> c steps, this substance is transformed^ acid (Yllner 1971). The latter, a ratKjg d via the urine. Quantitative demonstra? 5 technique after methylation (G. Mulk|E coupling chlorethylenoxide to glutathk acid (Watanabe et al. 1976). The urinaff? y be demonstrated by exchange chrorng, /IS test after derivation (G. Muller etaL' xyethyl mercapturic acid is the main ur^ 1976), but not in man (G. Muller etak oeing essentially mediated by its meiab?: ially verified in recent years. In a mut; :m TA 1535 the effect of this strongjf: longer than that of the metabolite chlortr induction in rats with chlorethylenoxide? dehvde failed to show any cancerogenjT ,80'' ""he role of intracellular chloracflC itri - essentially to VCM cancerogcnT L.an were extensively studies by Hefner1 1976, 1977), Bolt (1978), Buchter et *Liing to them, man reacts to VCM leveSw minutes an equilibrium between.CJfc. miration. The constants of this equiliSr* I being approximately 0.8 in persons of II absorb a higher amount in proportion^ ,ove 1.0, possibly due to the higher pro~ J). Experimental studies with rats have take and clearance after stopping theezZIligher than the constant of metabolize nabolite excretion (k = 0.0032 minj~fc , we may deduce that physiologic vaSifc: >p or only minor influence on the VCH; CM biotransformation (G. Mulleretak f fer that reactive cancerogenic VCM niCp! bn with exposure, but rather follow the::! be in rats (Gehring et al. 1978) andffis? j lately demonstrated in a probate mb^U ; "'psure (Gehring et al. 1-979). Functions^" jntal exposure is under 50 ppm, bfiSr | i4thylenoxide, which is an effective * iure.tjetmnfet al: (1979)had evert <fev~ I ..jS>cd the possibility of a veritable threshold dose of VCM, below which the tumor money period would be longer than the normal life expectancy of the exposed pervn. VCM Genotoxicity and Embryotoxicity Tho itiutagenicity of monomeric vinyl chloride on salmonella typhimurium strain n vitro was studied by Rannug et al. (1974), Bartsch et al. (1975). Greim et al. ; !>)".'). McCann et al. (1975), Andrews et al. (1976), and Garro et al. (1976). In a r.vont paper De Meester et al. (1980), though confirming the often cited mutagenic rtTooi. reported that its action was considerably enhanced by the addition of an oxiri-nase-enriched preparation of mammalian liver tissue (S9 Mix). Hubermann et a. 11975) described the mutagenic effect of VCM on cultures mammalian cells. In audios of Drosophila melanogatser Magnusson and Ramel (1978) recorded an in crease of lethal dominants under VCM exposure. Pretreatment with phenobarbitol for 24 h would enhance the mutagenicity of VCM, probably via the induction of r.ixod-function oxidases which enhance the biotransformation of VCM to chlorethylenoxide. In contrast to in vitro evidence of VCM mutagenicity, Short et al. (1977) and Peter and Ungvary (1980) were unable to register increased lethal dominants after VCM exposure in rats or mice. On the other hand, Basler and Rohrbom (1980) sported a time-dependent increase in sister-chromatid exchanges and structural enromosome aberrations in the bone marrow of Chinese hamsters after forced as piration of high doese VCM. Fleig and Thies (1978) had already registered an in creasing number of chromosomal aberrations in humans and animals with VCM Jixeasc. and an increased proportion of chromosomal aberrations was also found Ducatman et al. (1975) among VCM-exposed workers in the USA, and in -stte-Jen by Funes-Cravioto et al. (1975). Szentesi et al. (1976) recorded a rise of :hromaiid aberrations and instable chromosomal aberrations among VCM-exrosed workers as compared to non-exposed controls. In his cytogenetic studies re peated at 30-month intervals, Hansteen et al. (1978) found a high proportion of hromosome fractures in lymphocyte cultures from workers exposed to high levels -'i VCM. which would return to lower values when doses were reduced. Purchase al. (1978) in similar studies also registered a significant rise of chromosomal anomalies in VCM-exposed workers as compared to non-exposed control collec ts. Heath et al. (1977) pointed out that cytogenetic damage might be due to other igems besides VCM. Finally, Infante et al. (1976) reported an increased rate of rruisies among the wives of workers exposed to high VCM levels. According :n ^em. an increasing rate of malformations was found even among the neonates -I the general population of towns with VCM-processing factories. ^'Pcrimental Studies of VCM Carcinogenicity fie first experimental investigations of VCM-induced carcinogenesis were per iled hv Viola et al. (1971) who exposed Wistar rats to high doses of VCM ft.Ono ppm) for 20 h each week Over a" whole year. Under this extreme exposure "* animals developed tumors of skTnf lungsTand bone. Subsequent animal studies CO r K.H. Emmerich and K. Norppjgr Table 1. Standardized mortality rates for tumor disease among VCM workers Aulhors Period No. Byren et al. 1976 Chiazze et al. 1977 195S-1974 1964-1973 771 65.000 Duck et aL 1975 Fox and Collier 1977 Monson et al. 1974 Nicholson et al. 1975 Reinl et aL 1979 Tabershaw and Gaffey 1974 Waxweiler et al. 1976 1955-1975 1940-1974 1947-1973 1946-1974 1946-1974 1946-1972 1941-1973 2,120 7.717 (161 deaths) 255 7,021 S.384 12194 SMR 1.19 i.3iii 0.75^ 1.501s: 3.90 TS: 1.03-- 1.10 = 1.492^ \l.: fjhli revealed that the cancerogenic effect of low doses (50 ppm) would depend on the duration of the exposure. Extensive serial studies recorded VCM-induced turnon in all reodent species, such as rats, mice, and hamsters. Besides angiosarcoma tmcr were found to develop mammary carcinomas, pulmonary adenomas, and skinBP: mors. Apart from angiosarcomas rats would develop malignant neoplasms of tEf skin and zymbal gland, nephroblastomas, heptomas, angiomas, and neurobST tomas. In hamsters, VCM induced liver hemangiosarcomas, trichoepithelonut and lymphomas (Maltoni and Lefemine 1975). Suzuki (1978) induced pulmonan' tumors in mice by exposing them to VCM doses of 2,500 and 6,000 ppm foSST months. _ On the whole, these experimental results suggest that VCM exposure is lifcfe to induce neoplastic changes also in other organs than the liver. _ _L .V.i' Epidemiological Data Reports about angiosarcoma incidence among VCM workers, and also the resnfa. of experimental studies, have stimulated a survey of mortality statistics and pip' portional VCM mortality among former and present workers in VCM-procesmf factories. These studies attempted to determine the particular risk ofVCM worhn. to acquire certain diseases, compared with the average normal population.'Riff? were assessed quantitatively by comparison with the standardized mortigL (SMR), but the studies are based on a wide variety of collectives and observaft*" periods (Table 1). The only Swedish VCM factory registered an increased incidence of lhtff**mors (SMR=4.5) and an accumulation of cardiovascular diseases among 58 woffc? ers dying between 1958 and 1974. The problem of a general increase in the Owjjs-' SMR of tumors was not discussed by the authors of this report (Byren et al- An extensive study was conducted between 1965 and 1975 in some^sfe people working in the American VCM production (Chiazze et al. 1977).T5ljS mortality was generally increased (SMR in males=1.19, females =1.31Ise showed an increased incidence of gastrointestinal tumors (SMR= 1.34), lij^^ 1 mors (SMR = 1.43), pulmonarytumors (SMR = 1.17) tumors of the CNS --and-ofthe' lymphatic_system (= 1.30)7 Women showed a particular.increas pun|; 2X130006 K. H. Emmerich and K. Notjj^ Tumors After Exposure to Vinyl Chloride 7 se among VCM workers No. 771 65.000 2.120 7,717 (161 deaths) 255 7.021 8.3S4 134 SMg iSb. 1.19jg 1.3LSL 0.96S 0.75 -- l-MlE 3.90 ^ 1.03= 1.10== 1.49^ jjblc - Standardized mortality rates of malignancies among VCM workers according to different >ltCS Vjthors Gastroint. Liver Lung CNS Lymph. Others +.r,n el al. 1976 ,-j.o.ve et al. 1977 'j,!. -. ai. 1975 .ir.J Collier 1977 U.'iwn el al. 1974 Jfini el al. 1979 'ahershaw and Gaffey 1974 Aaxweiler et al. 1976 M 1.34 F 1.66 0.99 0.91 - 1.30 0.94 >1 . 4.13 1.43 0.0 - 3.22 11.00 15.23 - 11.55 1.68 1.17 1.07 1.03 0.89 1.60 0.96 1.12 1.56 6.12 1.15 1.14 0.54 4.20 1.62 - 33 1.30 1.18 0.99 1.50 2.14 1.06 1.59 1.09 242 1.89 1.55 doses (50 ppm) would depend on . Udies recorded VCM-induced tumorr hamsters. Besides angiosarcoma mSi is, pulmonary adenomas, and skin ^ develop malignant neoplasms of tg jep' mas, angiomas, and neurobias-; "m osarcomas, trichoepitheloinai- Suzuki (1978) induced pulmonary. i of 2,500 and 6,000 ppm for 5-6 - lugi'MC* suggest that VCM exposure is likely; rgans than the liver. - '? VCM workers, and also the resulttrvey of mortality statistics and pro-. . present workers in VCM-processog; te the particular risk of VCM workers- - average normal population. Risks J with the standardized mortality^ 'ariety of collectives and observatiqjL an increased incidence of liver uiovascular diseases among 58 work-- j m of a general increase in the overifc j rs of this report (Byren et al. 1976^1 :n 1965 and 1975 in some 65,QjSr j uction (Chiazze et al. 1977). Canccrj j 7iales= 1.19, females = OD-'MsC { pal tumors (SMR = 1.34), liver$-1 '=1*17) tumors of the CNS (.= j i showed a particular increase itCljf; incidence of urogenital tumors (SMR=2.42); tumors of the gastrointestinal tract had a SMR of 1.66, that of pulmonary tumors was only slightly elevated (=1.07) and so were the SMR of CNS (=1.14) and lymphatic tumors (=1.18). An age-standardized survey of 2,100 workers of a VCM-processing factory in England failed to reveal an increased SMR for tumors, with the exception of cere brovascular disease (SMR = 1.41) (Duck et al. 1975). Fox and Collier (1977) had been unable to delect an increasing SMR for tumors in general among 7,717 work ers of PVC-producing industries in Great Britain, except for malignant liver dis ease with a distinctly elevated SMR of 3.22. Nevertheless, the general tumor SMR vas relatively higher than that of cardiovascular disease. The possibility of can- eitogcnic action on organs other than the liver was refused by these authors. Another study analyzed 161 deaths recorded among the workers of two PVC- producing factories in the USA between 1954 and 1973. SMR for tumors in general *as 1.5 in this period: a striking increase was found in liver tumors ( = 11.0) and :n rumors of the CNS (= 4.2). A minor rise was seen in pulmonary tumors (=1.6) and malignant lymphatic disease (= 1.5) (Monson et al. 1974). A smaller study of -55 VCM-exposed workers (Nicholson et al. 1975) recorded a generally increased mortality risk (= 1.27) and a markes increase in tumor SMR ( = 3.9). A recent epidemiologic survey of 7,021 VCM-exposed workers in the Federal Republic of Germany (Reinl et al. 1979) revealed no significant overall increase in malignant tumors (SMR= 1.03), but the rates for individual organ tumors were markedly elevated: gastrointestinal tumor = 1.30, liver tumors = 15.23(1), CNS tu- mor-;= 1.62. tumors of the lymphatic system = 2.14. Tabershaw and Gaffey (1974) nj% assessed standardized mortality rates in 8,384 VCM-exposed workers em- ,"loved in 33 different factories in the USA. The rate for tumors in general was only v'lghtly elevated (1.10), but organ tumor rates were more distinct: 1.89 for tumors vfihe oral cavity and pharynx, 1.55 for cancer with unknown primary. There was pso the case report of a 22-year-old man who, after 14 years of habitually chewing C-coated cables, developed a keratinizing squamous carcinoma of the buccal ^cosa (Casterline et al. 1977)........... . .......... "- _ _A survey-of 1,294 VCM-exposed-workerS"from 194110 1973) Waxweiler et al. * j "'corded an increaseJn the SMR of tumors in general (1.49) with a distinct 21130007 8 Table 3. Increased standard mortality rates for non neoplastic disease in VCM workers Authors SMR Disease Byren ct al. 1976 Chiazze et al. 1977 Duck et at 1975 Reinl et al. 1979 Waxweiler et al. 1976 1.52 1.05 1.41 1.27 1.04 1.76 Cardiovascular Cardiovascular (males) Cerebrovascular Cardiovascular Cardiovascular Pulmonary K.H. Emmerich and K. Noi rise in liver tumors (11.55) and CNS tumors (3.29), and lesser elevations in pulnjoT nary tumors (1.56), lymphatic malignancies (1-59); tumors of the gastrointestinal tract are registered with the rate "greater than one". vrgtr Increasing standardized mortality rates for other diseases are not considered]^ the same way by all these authors. Some of them did mention rising SM rates fof certain diseases, but the latter are not confirmed by other authors. Table 3 cocf: pares the rates registered by different authors for nonneoplastic disease occurring in different organs. Conclusions Various surveys of standardized mortality rates in workers under chronic exposure to VCM have assessed the risk of developing fatal tumor disease to be distincth. higher in these workers than in the normal population, with the exception ofsef- eral studies conducted in Great Britain. Besides a very striking elevation in the rat. of liver tumors, nearly all these studies revealed an increasing incidence of gastrfe intestinal, pulmonary, CNS, and lymphatic malignancies. Although the SMRfw- malignant neoplasms in general was only slightly higher than 1, exposed wbriea were found to have an increased risk of dying of these tumors. This may hep*, to the high VCM concentrations registered in factories during the first yeaiS-X VCM production and processing to PVC, i.e., at levels that were subsequent^ found to be positively cancerogenic in experimental studies. -. v;Sss Recent years brought a worldwide endeavour to reduce VCM cohceniratfflSt. in the factories to minimize the risk for the exposed workers. Although the je?jj* have been effectively lowered, the potential latency period of 20 years fortheinqfe- tion of VCM tumors in man is a strong point in favor of keeping a close watcho occupational tumor development in the next decades. Ten of fifteen years areftFgs: riod of risk especially in VCM or PVC workers, because the dangerously high^.^ centrations had been recorded in some factories until 1974. The effect!vityofilSclosely knit surveillance systems in the early detection of VCM tumors in thgjj^ posed group is hard to predict. It is equally undecided whether CEA test^^^tj posed by Anderson et al. 1978) or alkaline phosphatase tests (Lilis et al.^|gj: | might help to detect liver damage at an early stage. A practicable way may bSWBfe-1 in coordinating_biQlogical .monitorine-of-mdividual exposure,- with themonitoring of concentration limits in the occupational environments fSOOOS-TTZ K.H. Emmerich and K. Norpqj^ Malicnant Tumors After Exposure to Vinyl Chloride 9 >n- References :s) (3.29), and lesser elevations in pulniSj? ; (1.59); tumors of the gastrointestinal han one". or other diseases are not considered if* them did mention rising SM rates for^ ;rmed by other authors. Table 3 cod5t rs for nonneoplastic disease occurrinp; tics in workers under chronic exposure^ hg fatal tumor disease to be distinctljj population, with the exception of sei*?- 'des a very striking elevation in the ri&~ Bled an increasing incidence of gastri^T malignancies. Although the SMR foo ightly higher than 1, exposed woriefl_ ing of these tumors. This may be'doTT i in factories during the first yearsTofy J.e., at levels that were subsequently; jrimental studies. avour to reduce VCM concentratjoia_ exposed workers. Although the levcb- ttency period of 20 years for the inducer ji in favor of keeping a close watch eac : decades. Ten of fifteen years are afCgl J ers, because the dangerously high cjQffiir | .ries until 1974. The effectivity ofsuc&i | detection of VCM tumors in the.tfcb- I v undecided whether CEA tests (PffBE | j phosphatase tests (Lilis et al.TSffir ) }tage. A practicable way may be foup~r J dividual exposure, with the analytSjfc. J |cupational environment. \nJcrson HA, Snyder J, Lewinson T, Woo C, Lilis R, Selikoff IJ (1978) Levels of CEA among vinyl chloride and polyvinyl chloride workers. Cancer 42 [Suppl 3]: 1560-1567 \r.urc s AW, Zanistowski ES, Valentine CR (1976) A comparison of the mutagenic properties of vinyl chloride and methyl chloride. Mutat Res 40:273-276 3jm.es AW (1976) Vinyl chloride and the production of PVC. Proc R Soc Med 69:277-281 3jn>ch H. Malaveille C, Montesano R (1975) Human, rat and mouse liver-mediated mutagenicity of \in>l chloride in S. typhimurium strains. Int J Cancer 15:429-437 jislcr A. Rohrbom G (1980) Die Induktion von strukturellen Chromosomenaberrationen und Schwe- vicr-Chromatid-Austauschen (SCE) im Knochenmark des Chinesischen Hamsters nach Begasung mil Vinylchlorid. Statusseminar der Gesellschaft fur Strahlen- und Umweltforschung mbH, Munchen-Neuherberg, 8.-9. 11. 1979, Munchen 3:crsack HJ, Lange CE, Ebinger H, Marstellcr HJ, Lelbach WK, Veltman G. Winkler C (1975) Sequcnzszintigraphische Untersuchungen von Leber und Milz bei Patienten mit Vinylchloridkrankheit. Dtsch Med Wochenschr 100:615-617 Dolt HM (1978) Pharmacokinetics of vinyl chloride. Gen Pharmacol 9:91-95 Soil HM. Kappus H. Buchter A, Bolt W (1976) Disposition of (1.2-*'*C)-vinyl chloride in the rat. Arch Toxicol 35:153-162 Bolt H M. Laib RJ, Kappus H, Buchter A (1977): Pharmacokinetics ofvinyl chloride in the rat. Toxicolo;y ': 179-188 Buchter A. Bolt HM, Filser J, Georgens HW, Laib RJ, Bolt W (1978): Pharmakokinetik und Karzir.ogenese von Vinylchlorid. Verh Dtsch Ges Arbeitsmed 18:11-124 Byrcn D. Holmberg B (1975) Two possible cases of angiosarcoma of the liver in a group of Swedish vinyl chloride-polyvinyl chloride workers. Ann N Y Acad Sci 246:249-250 3>ren D. Engholm G. Englund A, Westerholm P (1976) Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ Health Perstect 17:167-170 Caslcrline CL, Casterline PF, Javques DA (1977) Squamous cell carcinoma of the buccal mucosa as sociated with chronic oral polyvinyl chloride exposure: Report of a case. Cancer 39:1686-1688 Chia/yc L jr, Nichols WE, Wong O (1977) Mortality among employees of PVC fabricators. J Occupa tion Med 19:623-628 - rcech JLIR. Johnson MN (1974) Angiosarcoma of the liver in the manufacture of polyvinyl chloride. J tJccup Med 16:150-151 De Mo-ester C, Duverger-van Bogaert M, Lambotte-van de Paer M, Roberfroid M, Poncelet F, Merrier M119S0) Mutagenicity of vinyl chloride in the Ames test. Possible artifacts related to experimental conditions. Mutat Res 77:175--179 --caiman A. Hirschkom K, Selikoff IJ (1975) Vinyl chloride exposure and human chromosome aber rations. Mutat Res 31:163-168 Duck B\V, Carter JT. Coombes EJ (1975) Mortality studies of workers in a polyvinyl production plant. Lancet 11:1197-1199 englund A. Holmberg B (1976) Recent achievements and research initiated in the Swedish plastics and rubber industries. Environ Health Perspect 17:237-239 ftlser JG. Bolt HM (1979) Pharmacokinetics ofhalogenated ethylenes in rats. Arch Toxicol 42:123-136 "rig I. Thies AM (1978) External chromosome studies on persons and animals with VC illness; (Ab-trac!). Mutat Res 53:187 rx AJ. Collier PF (1977) Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl.chloride in Great Britain. Br J Ind Med 34:1-10 unes-Cravioto F, Lambert B, Lindstein J, Ehrenberg L. Nalarjan AT. Osterman-Golkar S (1975) Chromosome aberrations in workers exposed to vinyl chloride. Lancet 1:459 `arro aj. Guttenplan JB, Milvy P (1976) Vinyl chloride-dependent mutagenesis: effects of liver ex tracts and free radicals. Mutat Res 38:81-88 <jdigk p. Muller R. Bechtelsheimer H (1975) Morphology of liver damage among polyvinyl chloride workers. A report on 51 cases. Ann N Y Acad Sci 246:278-785 ljehring PJ. Watanabe PG, Park CN (1978) Resolution of dose-response toxicity data for chemicals r requiring metabolic activation: Example; Vinyl chloride..Toxicol Appl Pharmacol.44:581-591 . -"brine PJ. Watanabe PG, Park CN (1979).Risk ofangmsarcomain.workers.exposed In vinyl chloride------- -- predicted from studies in rats. Toxicol Appl Pharmacol 49:15-21 21130009 i i w 10 K. H. Emmerich and K. n" Green T, Hathaway DE( 1975) The biological fate in rats ofvinyl chloride in relation toitsoncoj Chem Biol Interact 11:545-562 Greim H, Bonse G, Radwan Z. Reichert D, Henschler D (1975) Mutagenicity in vitro and poi carcinogenicity of chlorinated ethylenes as a function of metabolic oxirane formation. Bit Pharmacol 24:2013-2017 Guengerich FP, Crawford WM, Watanabe PG (1979) Activation of vinyl chloride to covalently metabolites: Role of2-chloroethylene oxide and 2-chloroacetaldehyde. Biochemistry 18:5177^ Hansteen JL, Hillestad L, Thiis-Evensen E, Heldaas SS (1978) Effects of vinyl chloride in man. Aftfc genetic follow-up study. Mutat Res 51:271-278 ss Heath CW, Falk H, Creech JL (1975) Characteristics ofcases of angiosarcoma of the liver amongjjjf chloride workers in the US. Ann N Y Acad Sci 246:231-236 u -wZ Heath CW, Dumont CR, Gamble J, Waxweiler RJ (1977) Chromosomal damage in men occupatioJj3T exposed to vinyl chloride monomer and other chemicals. Environ Res 14:58-72 Hefner RE. Watanabe PG, Gehring PJ (1975) Preliminary studies of the fate of inhaled vinyl cufft monomer in rats. Ann N Y Acad Sci 246:135-148 - Hubermann E, Bartsch H, Sachs L (1975) Mutation induction in Chinese hamster V 79 cells bylj vinyl chloride metabolites, chlorethylene oxide and 2-chloroacetaldehyde. Int J Cancer 16:639-(4) L4RC (1978) 1ARC working group on the evaluation of the carcinogenic risk of chemicals to humS IARC. Vol 19. Lyon ve-sr Infante PF, Wagoner JK. McMichael AJ, Waxweiler RJ. Falk H (1976) Genetic risks of vinyl chlnri/gr Lancet 1:734-735 Juehe S, Lange CE (1972) Sklerodermieartige Hautveranderungen. Raynaud-Syndrom und AcrooaS. lysen bei Arbeiten der PVC-herstellenden Industrie. Dtsch Med Wochenschr 97:1922-1923TwS- Kappus H. Bolt HM, Buchter A, Bolt W (1975) Rat liver microsomes catalyse covalent binding nfffi- vinyl chloride to macromolecules. Nature 257:134-135 .-- Lange CE, Juehe S, Stein G, Veltman G (1975) Further results in polyvinyl chloride production Wo37 ers. Ann N Y Acad Sci 246:18-21 Lange CE. Juehe S, Veltman G (1974) Ober das Auftreten von Angiosarkomen der Leber bei beitem der PVC-herstellenden Industrie. Dtsch Med W'ochenschr 99:1598-1599 Lefaux R (1966) Chemie und Toxikologie der Kunststoffe. Krausskopf-Verlag Main Lilis R, Anderson H, Nicholson WJ. Daum S. Fischbein AS. SelikofT IJ (1975) Prevalence of diseger among vinyl chloride and polyvinyl chloride workers. Ann N Y Acad Sci 246:22-41 --.. --= Lilis R, Anderson H, Miller A, SelikofT IJ (1976) Pulmonary chances amone chloride polymerizstKg; workers. Chest 68 [Suppl 2J:299-303 "" --ssS Lloyd JW (1974) Angiosarcoma of the liver in vinyl chloride/polwinyl chloride workers. J Occup~)i 16:809 \ --W Lloyd JW (1975) Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. J OccupVK- 17:333-334 ` 3 Magnusson J. Ramel C (1978) Mutagenic effect of vinyl chloride on Drosophila melanogaster with a without pretreatment with sodium phenobarbiturate. Mutat Res 57:307-312 Malaveille C. Bartsch H. Camus AM, Montesano R (1975) Mutagenicity of vinyl chloride, chlortfSj? lene oxide, chloracetaldehyde, and chloroethanol. Biochem Biophys Res Commun 63:363-370^ Maltoni C. Lefemine G (1975) Carcinogenicity bioassavs of vinvl chloride: Current results. AnnTCC Acad Sci 246:195-219 "' -2K McCann J. Simmon V, Streitwieser D, Ames BN (1975) Mutagenicity ofchloroacetaldehyde, a possibfc" product of 1,2-dichlorethane (ethylene dichloride), vinyl chloride, and cyclophosphamide. Prnr. Natl Acad Sci USA 72:3190-3193 " Miller A (1975) Pulmonary function defects in non-smoking vinvl chloride workers. Environ He*BL Perspect 11:247-250 Miller A, Teirstein AS, Chuang M, SelikofT IJ, Warshaw R (1975) Changes in pulmonary functionja; workers exposed to vinyl chloride and polyvinyl chloride. Ann N Y Acad Sci 246:42-53 Monson RR, Peters JM, Johnson MN (1974) Proportional mortality among vinyl chloride woifct&I Lancet 11:397-398 ' Muller G, Norpoth K. Eckard R (1976) Identification of two urine metabolites of vinyl chloride bvu5- . MS investigations. Int Arch Occup Environ Health 38:69-75 Muller G, Norpoth K. Wickramasinghe RH (1979) An analytical method using GC-MS for thequji&. titative determination of urinary thiodiglycolic acid. Int Arch Occup Environ Health 44:185-t8? r K.H. Emmerich and K. No SUlicr.aru Tumors After Exposure to Vinyl Chloride f vinyl chloride in relation to its oncoj > (1975) Mutagenicity in vitro and n of metabolic oxirane formation- Bii ivation ofvinyl chloride to covalently >roacetaldehyde. Biochemistry 18:5177-; ?78) EITects of vinyl chloride in man. A ses of angiosarcoma of the liver among 231-236 Thromosomal damage in men occupatio :als. Environ Res 14:58-72 studies of the fate of inhaled vinyl chlorides ction in Chinese hamster V 79 cells by tvwr hloroacetaldehyde. Int J Cancer 16:639-644 ie carcinogenic risk of chemicals to h'TMTM^ alk H (1976) Genetic risks of vinyl chiloride? rungen, Raynaud-Syndrom und Acroosteoe>tsch Med Wochenschr 97:1922-1923 icrosomes catalyse covalent binding of "C- iilts jlyvinyl chloride production wort? i-1--^ j tngiosarkomen der Leber bei zwei'A^~ > ochenschr 99:1598-1599 i. Krausskopf-Verlag Main S. Selikoff IJ (1975) Prevalence of di .Ann N Y Acad Sci 246:22-41 ;>' changes among chloride polymerizatioafi: e/polyvinyl chloride workers. J Occup 'polyvinyl chloride workers. J Occup M<3~ jride on Diosophila melanoeaster with an^r Mutat Res 57:307-312 ' ]Mutagenicity of vinyl chloride, chlorethyr7 hem Biophys Res Commun 63:363-37Q__ i vinyl chloride: Current results. Ann tgenicity ofchloroacetaldehyde. a yl chloride, and cyclophosphamide. ig vinyl chloride workers. Environ He, (1975) Changes m pulmonary functiotnjz"! Je. Ann N Y Acad Sci 246:42-53 ! mortality among vinyl chloride w< Muller G. Heger M.Norpoth K (1980) BestimmungderHydroxyathyl-Mercaptursaure im Harn Vinylchlorid-Exponierter. Methodische Erfahrungen und analytische Ergebnisse. Verh Dtsch Ges Ar- beitsmed 20:533-536 Muller KT. Buchter A, Gross R, Bolt W (1976) Ergebnisse einer Studie an 17 Fallen von Langzeitex- position gegenuber Vinylchlorid. Med Weil 27:21-24 Muller R. Bechtclsheimer H, Gedick P, Marsteller HJ, Lelbach WTC (1975) Das morphologische Bild der Lcberschadigung nach chronischer Vinykhlorid-Exposilion. Leber Magen Darm 5:204-208 siehoison WJ, Hammond EC. Seidman H. Selikoff IJ (1975) Mortality experience ofa cohort of vinyl .blonde-polyvinyl chloride workers. Ann N Y Acad Sci 246:225-230 Peter S. L'ngvary G (1980) Lack ofmutagenic effect of vinyl chloride monomer in the mammalian spot test. Mutat Res 77:193-196 Pm-'nase IFH. Richardson CR, Anderson D. Paddle GM. Adams GF (1978) Chromosomal analyses in vinyl chloride-exposed workers. Mutat Res 57:325-334 Rur.nuc U, Johannson A. Ramel C. Wachtmeister CA (1974) The mutagenicity ofvinyl chloride after metabolic activation. Ambio:194-197 Runnue U. Gothe R. Wachtmeister CA (1976) The mutagenicity of chlorelhylene oxide, chloracetalde- hyde. 2-chloroethanol, and chloracetic acid, conceivable metabolites of the vinyl chloride. Chem Biol Interact 12:251-263 Rend W. Weber H, Greiser E (1979) ErkrankungeD durch Vinylchlorid. Jahresbericht der Gewerbeauf- ceh: des Landes Nordrhein-Westfalen fur das Jahr 1978, S 347-377 Sarie V. Kulcar Z. Zorica M. Gelic 1 (1976) Malignant tumors of the liver and the lung in an area with a FVC industry. Environ Health Perspect 17:189-192 Sher. RD. Minor JL, Winston JM, Lee CC (1977) A dominant lethal study in male rats after repeated exposures to vinyl chloride or vinylidine chloride. J Toxicol Environ Health 3:965-968 Spinas R. Kaminski R (1978) Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. 1977 update of the NIOSH register. J Occup Med 20:427-429 Stafford J (1980) Liver angiosarcoma cases (Review data. 8lh Jan. 1980). Imperial Chemistries Indus tries Ltd Plastics Division Suzuki Y (1978) Pulmonary tumors induced in mice by vinyl chloride monomer. Environ Res 16:285- 301 Szer.:es; 1. Homyak E. Ungvarv G. Czeizel A. Bognar Z. Timar M (1976) High rate of chromosomal aberration in PVC workers. Mutat Res 37:313-316 Tahe-'haw JR. Gaffey WR (1974) Mortality studies of workers in the manufacture of vinyl chloride .;::J ns polymers. J Occup Med 18:509-518 rhonsas LB. Popper H (1975) Pathology of angiosarcoma of the liver among vinyl chloride-polyvinyl chloride workers. Ann N Y Acad Sci 246:268--277 'ioia PL. Bigotti A, Caputo A (1971) Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31:516-522 SSatanabe PG. McGowan GR, Gehring PJ (1976) Fate of (MC)-vinyl chloride after single oral admin istration in rats. Toxicol Appl Pharmacol 36:339-352 '''axuciler RJ. Stringer W, Wagoner JK. Jones J. Falk H. Carter C (1976) Neoplastic risk among work ers exposed to vinyl chloride. Ann N Y Acad Sci 271:40-48 W'iihcy JR (1976) Pharmacodynamics and uptake of vinyl chloride monomer administered by various routes to rats. J Toxicol Environ Health 1:381-394 kilr.er 3 (1971) Metabolism of chloracetate-l-I,*C in the mouse. Acta pharmacol 30:69-80 ^U!de::i F. Croisy A, Barbin A, Malaveille C, Tomatis L, Bartsch H (1980) Carcinogenicity of chlorethylene oxide, an ultimate reactive metabolite of vinyl chloride, and bis-chloromelhyl ether alter subcutaneous administration, and in initiation-promotion experiments in mice. Cancer Res ->0:352-356 Received April 15, 1981/Accepted July 17, 1981 nine metabolites ofvinyl chloride by j9-75 . ............................... yti.tal methodJtsingGOMSfor ^ t Arch Occup Environ Health 44:185-15JgL ttOOSTTZ