Document e135qZKXaEmE9JGxxa5R1EYp9

Clin Oncol (1981) 102: 1-11 Cancer Research Clinical Oncology Springer-Verlag 1981 Guest Editorial* Malignant Tumors After Chronic Exposure jo vinyl Chloride l .. i-nimerich1 and K. Norpoth2 Pathology (Director: Prof. E. Grundmann. MD, University of Miinsler. uckstr. 17. D-4400 Munster, Federal Republic of Germany of Industrial Medicine and Silicosis Research Summary. Correlations between exposure to vinyl chloride and the developT.cnt of malignant tumors in the liver have been known since 1974 and have rven confirmed by many an experimental investigation. Sa'di! on the evaluation of mortality statistics from nine different countries an ncrcased incidence of malignant tumors of the lung, the gastrointestinal tract, s-j the central nervous system (CNS), and of malignant lymphomas is docu mented in connection with exposure to vinyl chloride. Statistically significant increases, however, are only found in the incidence of malignant liver tumors, `diabolism and toxicology of vinyl chloride are discussed in detail. Ke> Hords: Human carcinogenesis - Vinyl chloride - Toxicology - Liver tumors Metabolism Production 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 rea;.-.;r,e 5% into the production of other chemicals, such as methylchloroform *-^1 !97S). ~ c 7-iurn;i! of Cancer Research and Clinical Oncology" publishes in loose succession "Edi- mu hiest Editorials" on current and/or controversial problems in experimental and clinical y;<> I h.-v contributions represent exclusively the personal opinion of the author. The Editors '`txhra: 'Journal of Cancer Research and Clinical Oncology" bring! in zwangloser Folge "Ediy--* un.i "Guest Editorials" zu aktuellen und/oder kontroversen Problemen der experimentellen ^ ` ":vhen Onkologie. Diese Beitrage geben ausschlieBlich die personliche Meinung des Autors -rrr^ i ..new, to -R. H. Emmerich. MD (address see above) Die Herausgeber 0171-5216/81/0102/0001/S2.20 I: r . V i i. r: X--T ' Si-1 K. H. Emmerich and K. ] The very nature of the polymerization process allows for various ways ofw release into the environment. Workers were exposed to particularly high trations of VCM during manual autoclave cleansing. Up to the 1960s the i^p risk of vinyl chloride was thought to be negligible (Lefaux 1966). Concentra of 1,000 ppm at the individual working place were not uncommon in certain p] First recommendations for limiting the exposure to 500 ppm were issued in' in the United States. The average concentration levels of that period can b mated approximately in retrospect: 1945-1955: 1,000 ppm 1955-1960 : 400-500 ppm .. ^ 1960-1970 : 300-400 ppm -3f| 1973: 140 ppm 1975: 5 ppm (Barnes 1976). In the Federal Republic of Germany the statutory MAK level1 was fixSTg 500 ppm until 1970, then reduced to 100 ppm until 1974. Today the technicsfiS concentration at the work place in the FRG is below 5 ppm for older and curing, working plants, under 2 ppm for new plants under construction. The managnjy* soon realized that VCM concentration could be effectively reduced to the statugj levels by technical innovation and financial investments. One Swedish firnnai able to reduce mean VCM concentrations from 12.2. ppm (2nd quarter ofj|g to 0.6 ppm (4th quarter of 1975) (Englund and Holmerg 1976). -- Due to the physicochemical binding of VCM in PVC products, worker** PVC-processing or -manufactoring industries are equally exposed to a certainOfr centration of VCM, although at much lower levels than during the process oifpBt merization. In a 1974 survey of PVC-manufacturing plants levels were bgif 1 ppm in more than 60% of all firms checked. -^Wk The first reports about the potential risk of VCM had been published in l94JL` Since 1957 reports had appeared here and there about a certain disease occurred in VCM industrial workers, manifested in scleroderma-like skin changes, Raynai syndrome, and acro-osteolysis (Juehe and Lange 1972). Some years later, furtfia symptoms of the disease were described as liver damage, splenomegaly, and thrt* bocytopenia (K. T. Muller et al. 1976). Detailed investigations were carried out?* liver changes since the first cases of hemangiosarcoma had been found ameet VCM workers. These liver changes were graded histologically in five steps, corn& ting the length of exposure, and the severity of recorded changes (Gedigk eTZ 1975; R. Muller et al. 1975). Even in VCM-exposed workers showing no clinist symptoms of liver damage, sequential scintigraphy would reveal RHS change** liver and spleen (Biersack et al. 1975). _;5|pE ~ -In addition to liver changes a considerable number of workers showed an * j pairment of pulmonary functions, and roentgenologic changes up to pulmonaijg-. 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 scyggf J of changes. j The first reports about tumors induced by VCM were published in I974d&~ j cording the increased incidence of a very rare neoplasm, liver hemangosareggi.} 1 MAK=maximale Arbeitsplatz-Konzentration (maximum concentration at work) I Z000STT2. K. H. Emmerich and K. Norp^f Ujiananl Tumors After Exposure to Vinyl Chloride 3 process allows for various ways of VQvf re exposed to particularly high conceal 'e cleansing. Up to the 1960s the heal egligible (Lefaux 1966). Concentration :e were not uncommon in certain plantjp .posure to 500 ppm were issued in 195$^ tration levels of that period can be est*S :CHCI -- Cl Cl s/ A.-A --* HO H Chloroocet aldehyde Sonde chloroethylenoxide I g-s-ch2-cho ch2oh S- formyl methylglutathione | ; S-CH^ :-yr-crs*y- cys-S-CH2-CHO S*formyl methylcysteine a ch2cooh ehlorodcetatc | glycollate G-S-CHj-COOH S-cor6oxymethylglotathiort 1 cys-S-CH2-COOH S-corboxymtnytcystem* COOH COOH 1 -- - 1 H2CNH2 COOH glyone oxetete 76). -M he statutory MAK level1 was fixed^ n until 1974. Today the technical limit' ms below 5 ppm for older and currently; s under construction. The management" 1 be effectively reduced to the statutory^ 5 investments. One Swedish firm wajfrom 12.2. ppm (2nd quarter of 197^ ' Holmerg 1976). | . CM in PVC products, workers es are equally exposed to a certain coif : levels than during the process of poljrT jufacturina plants levels were belotr !ed. : of VCM had been published in 1949A ' .ere about a certain disease occurring -; i-Todcrma-like skin changes, RayniSP -ange 1972). Some years later, furtheL^r damage, splenomegaly, and thrdtiFf (ed investigations were carried out M -giosarcoma had been found amonjl ied histologically in five steps, corner "j of recorded changes (Gedigk edifexposed workers showing no ctinicaL- j graphy would reveal RHS changes^ f number of workers showed anjgfe j-nologic changes up to pulmonaryjjii: | :t al. 1976). These findings equally^ i COOH :: l : ch2-s-ch2-ch2oh {-nm, Lcoj ch2-ccoh s' ch2-cooh I C00H h^N-CH 1 h2c-ch CCCH l h2nch ch2 l CHj-S-CHj S-(2-hydroxy- cthyll-cystemc thiedt glycollate serine melhionne Hg. t. Major metabolic pathways of vinyl chloride. The main urinary metabolites are underlined imong 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 Holmoere 1975). Based on 13 cases of liver hemangiosarcoma reported in the USA, the -Tsk of VCM workers for this rare tumor was determined to be 400 times higher 'han that of the normal population (Heath et al. 1975). Histological studies of Thomas and Popper (1975) suggested the possibility of multicentric sarcoma dedopmem. Until 1978 the cases of liver hemangiosarcoma among VCM workers amounted worldwide to a total of 90 (Stafford 1980). Sixteen cases ofdeath ofliver hemangiosarcoma had been recorded in the FRG anti] 1978 (Reinl et al. 1979). The cases subjected to detailed investigation until 'on revealed a longer latency period betweeri first exposure and diagnosis, and a iiehcr ^es at first diagnosis of hemangiosarcoma. A possible cause for this pattern -IS seen in the higher initial doses to which workers had been exposed during the ""s: years of VCM production (Spirtas and Kaminski 1978). Environmental stud^ conducted in the immediate neighborhood of VCM-producing plants failed to assess an increased incidence of hemangiosarcoma in the general population of this Jrca (Saric et al. 1976). jlength of exposure and the seventy. ' *- M Metabolism and Pharmacokinetics_____ . _ ...... .............. byVCM were published in 1974,1. 1 metabolism of monomeric-vinyl-ehJoride was studied-by Green and Hathaway |"|ne6pTasm, liver hemangiosarcotSEE '!r- '' atanabeet al. {1976), G. Muller et al. (1976), and many others. Figure 1 -"'-wenr^ major metabolic steps according to current concepts. In the mam- m concentration at work) ' ''an organism monomeric vinyl chloride undergoes oxidative biotransforma- 21190003 J BFG10688 4 K.H. Emmerich and K.. Norpgf tion involving the cytochrome P 450 system. Chlorethylenoxide, an alleviating^^ cerogen, is the resulting primary metabolite (Malaveille et al. 1975; Grant etlf 1975; Kappus et al. 1975) which is subsequently rearranged to chloracetic aldcfcg de. Via several, partly unknown metabolic steps, this substance is transformed^ S-carboxymethyl-cystein and thiodiacetic acid (Yllner 1971). The latter, a rathq- stable terminal metabolite, may be excreted via the urine. Quantitative demonstra tion of thiodiacetic acid is done by GC.MS technique after methylation (G. Mug et al. 1979). Another metabolic pathway, coupling chlorethylenoxide to glutathf one, leads to /I-hydroxyethyl mercapturic acid (Watanabe et al. 1976). The urinajj level of this equally stable end product may be demonstrated by exchange chromt tography after hydrolysis, or by the GC.MS test after derivation (G. Muller etaT 1980). It must be emphasized that /f-hydroxyethyl mercapturic acid is the main ttjjT nary metabolite in the rat (Watanabe et al, 1976), but not in man (G. Muller etHT 1980). ;== The concept of VCM carcinogenicity being essentially mediated by its metafrr olite chlorethylenoxide has been substantially verified in recent years. In a mutf' genicity test with Salmonella typhimurium TA 1535 the effect of this stronglj reacting alkylating agent was 450 times stronger than that of the metabolite chloP acetaldehyde (Rannuget al. 1976). Tumor induction in rats with chlorethylenoridt was 100% successful, whereas chloracetaldehyde failed to show any cancerogeafc effect in a parallel assay (Zajdela et al. 1980). The role of intracellular chlorac#- aldehyde, i.e., whether or not it might contribute essentially to VCM cancerogg| esis (Guengerich et al. 1979), is still unclear. iCSS VCM pharmacokinetics in rats and in man were extensively studies by Hciog et al. (1975), Whitey (1976), Bolt et al. (1976, 1977), Bolt (1978), BuchterefSf (1978), and Filser and Bolt (1979). According to them, man reacts to VCMJgST around 2 ppm by establishing within a few minutes an equilibrium between Or vironmental (air) and intracorporeal concentration. The constants of this equIBb rium depend on the individual constitution, being approximately 0.8 in persons^ normal weight. Overweight individuals will absorb a higher amount in proports* to their weight, and so the constant rises above 1.0, possibly due to the higherPIE portion of fatty tissue (Buchter et al. 1978). Experimental studies with rats ha>? shown that the speed constant ofVCM uptake and clearance after stopping thetfr posure (k = 0.216 min-1) is always much higher than the constant of metaRffiF ation (k = 0.0037 min - *) and of urinary metabolite excretion (k -- 0.0032 minjsf Assuming human conditions to be similar, we may deduce that physiologic van* tions of ventilation levels will have either no or only minor influence on the VQ| uptake by inhalation. From data on the dose dependency ofVCM biotransformation (G. MuliereQt 1976; Gehring et a!.` 1978,1979) we may infer that reactive cancerogenic VCMjp. tabolites will not increase in linear correlation with exposure, but rather follows Michaelis-Menten function. Tumor incidence in rats (Gehringet al. 1978) andffgin man (Gehring et al. 1979) is most adequately demonstrated in a probatelngj* of frequency percentage correlated with exposure (Gehring et al. 1979). Funct^tt. correlation may be complicated if experimental exposure is under 50 ppm. fo-- glutathione-mediated detoxication of chlorethylenoxide. which is an effectively --tectien mechanism at lower-levels ofexposure.-Gehring-et-al. (1979) had cvcpJl- t'OO&ETtg BFG10689 K. H. Emmerich and K. Norp**^ Tumors After Exposure to Vinyl Chloride 5 .m. Chlorethylenoxide. an alkylating case jlite (Malaveille et al. 1975; Greim etlj? uently rearranged to chloracetic aldchvTc steps, this substance is transformed'^ = acid (Yllner 1971). The latter, a rathg; "d via the urine. Quantitative demonstn? 5 technique after methylation (G. Mulfcf; coupling chlorethylenoxide to glutath)r acid (Watanabe et al. 1976). The urina^ y be demonstrated by exchange chromai /IS test after derivation (G. Muller etaL' xxyethyl mercapturic acid is the main uiiH !. 1976), but not in man (G. Muller et ak oeing essentially mediated by its metal? dally verified in recent years. In a mutl ;m TA 1535 the effect of this strong^ longer than that of the metabolite chlopr ' induction in rats with chlorethylenoxpe? ldehyde failed to show any cancerogenjf -80). The role of intracellular chlorates! ntribute essentially to VCM cancerogetfT n were extensively studies by HefheF i976, 1977), Bolt (1978), Buchter et aLding to them, man reacts to VCM Ievtfc w minutes an equilibrium betwecn_$jfet ; ntration. The constants of this equiliS?1 ri, being approximately 0.8 in persons of~ 11 absorb a higher amount in proportion^ ove 1.0, possibly due to the higher prqr -) Experimental studies with rats have take and clearance after stopping the efc higher than the constant of metaboiil-r itabolite excretion (k = 0.0032 min~D-, we may deduce that physiologic van3E= no or only minor.influence on the VCfrC > CM biotransformation (G. Muller etajg ifer that reactive cancerogenic VCM UJpp-' pn with exposure, but rather folloWtbeT: :e in rats (Gehring et al. 1978) andeglpi uately demonstrated in a probate mod^L: npsure (Gehring et al. 1979). Functiq#^ jntal exposure is under 50 ppm, bv'tfe"' lethvleno.xide, which is an effective 1 snre.-Getnliiget al. (1979)hadeveirdfe; the possibility of a veritable threshold dose of VCM, below which the tumor jicm-'y period would be longer than the normal life expectancy of the exposed per- \t \1 Genotoxicity and Embryotoxicity The mutagenicity 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 -vent paper De Meester et al. (1980), though confirming the often cited mutagenic rilcct. reported that its action was considerably enhanced by the addition of an oxirenase-enriched preparation of mammalian liver tissue (S9 Mix). Hubermann et ii. (1975) described the mutagenic effect of VCM on cultures mammalian cells. In studies of Drosophila melanogatser Magnusson and Ramel (1978) recorded an inrrvase of lethal dominants under VCM exposure. Pretreatment with phenobarbitol for 24 h would enhance the mutagenicity of VCM, probably via the induction of nixcd-function oxidases which enhance the biotransformation of VCM to .hlorc'hylenoxide. 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) -.ported a time-dependent increase in sister-chromatid exchanges and structural .aromosome 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::casing number of chromosomal aberrations in humans and animals with VCM disease. and an increased proportion of chromosomal aberrations was also found Ducatman et al. (1975) among VCM-exposed workers in the USA, and in v.'vtic:: by Funes-Cravioto et al. (1975). Szentesi et al. (1976) recorded a rise of :!sromaiid aberrations and instable chromosomal aberrations among VCM-exrosed workers as compared to non-exposed controls. In his cytogenetic studies re flated at 30-month intervals, Hansteen et al. (1978) found a high proportion of .hmmosome 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-ves. Heath et al. (1977) pointed out that cytogenetic damage might be due to other sgems besides VCM. Finally, Infante et al. (1976) reported an increased rate of "^carriages among the wives of workers exposed to high VCM levels. According :n them, an increasing rate of malformations was found even among the neonates i| the general population of towns with VCM-processing factories. Experimental Studies of VCM Carcinogenicity first experimental investigations of VCM-induced carcinogenesis were per"rmed by Viola et al. (1971) who exposed Wistar rats to high doses of VCM tl.Oiio ppm) for 20 h each week Over a' whole year. Under this extreme exposure ^tmtnials developed turhorsT>fskm. lungsTand bone. Subsequent animal studies BFG10690 6 K.H. Emmerich and K. NorpojF Table 1. Standardized mortality rates for tumor disease among VCM workers Authors Period No. Byren et al. 1976 Chiazze et al. 1977 1958-1974 1964-1973 771 65.000 Duck et at 1975 Fox and Collier 1977 Monson et al. 1974 Nicholson et al. 1975 Reinlet aL 1979 Tabershaw and Gafley 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 8.384 12194 SMR5 1.19 E utii U962E 0.75* 1.50 .SS 3.9075: 1.03* 1.10 = 1.492S Tahir revealed that the cancerogenic effect of low doses (50 ppm) would depend ontfce duration of the exposure. Extensive serial studies recorded VCM-induced tumor; in all reodent species, such as rats, mice, and hamsters. Besides angiosarcoma micr were found to develop mammary carcinomas, pulmonary adenomas, and skin mors. Apart from angiosarcomas rats would develop malignant neoplasms of (S' skin and zymbal gland, nephroblastomas, heptomas, angiomas, and neurobST tomas. In hamsters, VCM induced liver hemangiosarcomas, trichoepithelomaf and lymphomas (Maltoni and Lefemine 1975). Suzuki (1978) induced pulro'oran~ tumors in mice by exposing them to VCM doses of 2,500 and 6,000 ppm for-5^ months. _ On the whole, these experimental results suggest that VCM exposure is Iik&l to induce neoplastic changes also in other organs than the liver. :rar _ Epidemiological Data ' 3*' 2D- Reports about angiosarcoma incidence among VCM workers, and also the resets of experimental studies, have stimulated a survey of mortality statistics and prfc portional VCM mortality among former and present workers in VCM-processtaf factories. These studies attempted to determine the particular risk of VCM worker*, to acquire certain diseases, compared with the average normal population. Ri^ were assessed quantitatively by comparison with the standardized mordSL (SMR), but the studies are based on a wide variety of collectives and obscryatjjg periods (Table 1). The only Swedish VCM factory registered an increased incidence of livgfejjh mors (SMR = 4.5) and an accumulation of cardiovascular diseases among 58 ers dying between 1958 and 1974. The problem of a general increase in theQStS^ 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 som< people working in the American VCM production (Chiazze et al. 1977). mortality was generally increased (SMR in males =1.19, females = 1.31J showed an increased incidence of gastrointestinal tumors (SMR= 1.34), li^@^ mors (SMR = 1.43), pulmonarytumors (SMR = 1.17) tumors of the CNS(j= --and-of the lymphaticsyslem (= 1.30)7 Women showed a particular inc ncrit tu*: A rniii.c Nrcn u; c:\ ot i tjm: u rv: A. : r. tun;. m;; 155 V( * A r-. -epuh;. 21130006 BFG10691 K. H. Emmerich and K. Norpg[ vljiicnant Tumors After Exposure to Vinyl Chloride 7 ise among VCM workers No. 771 65.000 2.120 7,717 (161 deaths) 255 7,021 8.384 1.294 SM - ds 1.19^1.31.SL 0.96^ 0.75 -- 1.50'S 3.90 S 1.03== 1.10== 1.492S: Table 2. Standardized mortality rates of malignancies among VCM workers according to different wan s'lcs ,j:hors Gastroint. Liver Lung CNS Lymph. Others 3Ui.-n et al. 1976 --ia.-.-c et al. 1977 li 1975 -,>v .ir.J Collier 1977 cl al. 1974 1979 -.thershaw and Gaffey 1974 Axxweiler 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 - 3.29 - 1.30 1.18 - 0.99 1.50 Z14 1.06 1.59 - 1.09 142 1.89 1.55 doses (50 ppm) would depend on tSr udies recorded VCM-induced tumorr hamsters. Besides angiosarcoma mice' is, pulmonary adenomas, and skin'fiB develop malignant neoplasms of ig jeptomas, angiomas, and neuroblaK "nangiosarcomas, trichoepithelomas? Suzuki (1973) induced pulmohaq. s of 2,500 and 6,000 ppm for 5-6"- . suggest that VCM exposure is likdf-. >rgans than the liver. --- 'g VCM workers, and also the resuftrrvey of mortality statistics and pro-, x jpresent workers in VCM-processinjl ie the panicular risk of VCM worlcea- average normal population. Risks _) with the standardized mortality^ variety of collectives and observatiotF an increased incidence of liverjaS= uiovascular diseases among 58 work- * m of a general increase in the ovcrifc) rs of this report (Byrcn et al. 197|fe-j :n 1965 and 1975 in some 65$t| uction (Chiazze et al. 1977). CanCgj j males =1.19, females = 1.31).`Mg" I : nal tumors (SMR = 1.34), livefSfc | c = 1.17) tumors of the CNS (_=.l3?|c j n showed a particular increase inljjjj; incidence of urogenital tumors (SMR = 2.42); tumors of the gastrointestinal tract had a SM R 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 detect 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 wjs relatively higher than that of cardiovascular disease. The possibility of can- eerogcnic 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- morx= i.62. tumors of the lymphatic system = 2.14. Tabershaw and Gaffey (1974) 'ax assessed standardized mortality rates in 8,384 VCM-exposed workers em ployed in 33 different factories in the USA. The rate for tumors in general was only 'lightly elevated (1.10), but organ tumor rates were more distinct: 1.89 for tumors ''f'he oral cavity and pharynx, 1.55 for cancer with unknown primary. There was ,lso the case report of a 22-year-old man who, after 14 years of habitually chewing 1 ^ C-coated cables, developed a keratinizing squamous carcinoma of the buccal mucosa (Casterline et al. 1977). - -- ----- -- - - "~ _ A survey-of 1,294 VCM-exposcd-workers'froffi 194110 19/3) Waxweiler et al. "j recorded anincreaseJn the SMR of tumors in general (1.49) with a distinct 21,130007 8 Table 3. Increased standard mortality rates for non neoplastic disease in VCM workers Authors SMR Disease Byren et 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 puIraoT nary tumors (1.56), lymphatic malignancies (1.59); tumors of the gastrointesti^Q tract are registered with the rate "greater than one". ,f~ Increasing standardized mortality rates for other diseases are not consideredS' the same way by all these authors. Some of them did mention rising SM ratesTof certain diseases, but the latter are not confirmed by other authors. Table 3 cotE' pares the rates registered by different authors for nonneoplastic disease occunSg 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 distinctly higher in these workers than in the normal population, with the exception of sef 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 gaslift intestinal, pulmonary, CNS, and lymphatic malignancies. Although the SMR-fij- malignant neoplasms in general was only slightly higher than 1, exposed woSnT were found to have an increased risk of dying of these tumors. This may bejf* to the high VCM concentrations registered in factories during the first yeanA VCM production and processing to PVC, i.e., at levels that were subsequently found to be positively cancerogenic in experimental studies. -rpS- Recent years brought a worldwide endeavour to reduce VCM concentrattqpf in the factories to minimize the risk for the exposed workers. Although the Icjjl have been effectively lowered, the potential latency period of 20 years for the infer i tion of VCM tumors in man is a strong point in favor of keeping a close watch 0* occupational tumor development in the next decades. Ten of fifteen years areftgfe riod of risk especially in VCM or PVC workers, because the dangerously high** centrations had been recorded in some factories until 1974. The effectivityof^Kclosely knit surveillance systems in the early detection of VCM tumors in thetT posed group is hard to predict. It is equally undecided whether CEA testrig^r posed by Anderson et al. 1978) or alkaline phosphatase tests (Lilis et afcjgS: might help to detect liver damage at an early stage. A practicable way may in coordinating,bioIogicaLmonitoring-of4f(dividual exposure,- with the monitoring of concentration limits in the occupational environment^- K000ET7Z BFG10693 on References es) i (3.29), and lesser elevations in pulnio^ ; (1.59); tumors of the gastrointestiii^ than one". for other diseases are not considered ia^ them did mention rising SM rates forL `rmed by other authors. Table 3 conjE >rs for nonneoplastic disease occurring^ - in workers under chronic exposure;7 ng fatal tumor disease to be distinctly-- population, with the exception of sev*? des a very striking elevation in the risk" tied an increasing incidence of gastr^ malignancies. Although the SMR fotF 'ightly higher than 1. exposed workefl_ ing of these tumors. This may be doer d in factories during the first yeareof^ , i.e., at levels that were subsequently; Timental studies. 2". avour to reduce VCM concentrations, exposed workers. Although the levtfa- ttency period of20 years for the induCjgf ;t in favor of keeping a close watch t decades. Ten of fifteen years are a peg: ers, because the dangerously high cipjgl; ries until 1974. The effectivity ofsutfc. j detection of VCM tumors in the^SS- v undecided whether CEA tests (pgjg; . j phosphatase tests (Lilis et al.~I97.3iL~' { }tage. A practicable way may be found - j idividual exposure, with the analvtiSt i >|cupational environment. tnJerson 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 J): 1560-1567 \adrcws AW, Zanistowskj ES, Valentine CR (1976) A comparison of the mutagenic properties of vinyl chloride and methyl chloride. Mutat Res 40:273-276 Sj.tcs A\V (1976) Vinyl chloride and the production of PVC. Proc R Soc Med 69:277-281 3jrtch H. Malaveille C, Montesano R (197S) Human, rat and mouse liver-mediated mutagenicity of c my l chloride in S. typhimurium strains. Int J Cancer 15:429-437 3j>!cr A. Rohrbom G (1980) Die Induktion von strukturellen Chromosomenaberrationen und Schwe- .icr-Chromatid-Austauschen (SCE) im Knochenmark des Chinesischen Hamsters nach Begasung mil Vinylchiorid. Statusseminar der Gesellschaft furStrahlen- und Umwellforschung mbH, Munchen-Neuherberg, 8.-9. 11. 1979, Munchen 3:crsack HJ, Lange CE, Ebinger H, Marsteller HJ, Lelbacb WK. 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J Toxicol Environ Health 1:381-394 Yilr.sr c- il971) Metabolism of chloracetate-l-MC in the mouse. Acta pharmacol 30:69-80 Zatceui F, Croisy A, Barbin A, Malaveille C, Tomaiis L, Bartsch H (1980) Carcinogenicity of vhlorcihylene oxide, an ultimate reactive metabolite of vinyl chloride, and bis-chloromethyl ether after subcutaneous administration, and in initiation-promotion experiments in mice. Cancer Res 40:352-356 Received April 15, 1981/Accepted July 17, 1981 TtqOSTTz trine metabolites of vinvl chloride by ( J9-75 .. ilytical methcdaisingGOMS-for t at Arch Occup Environ Health 44:185-1'