Document G5Z8xXY8rd3w1gvO0p3ajReLx

J Cancer Res Clin Oncol (1981) 102: l-ll Guest Editorial* Cflnica! Oncology RECErV7"!^ Springcr-Verlag 1981 FEB 9 1982 v! T, feArtff Malignant Tumors After Chronic Exposure to Vinyl Chloride K.H. Emmerich1 and K. Norpoth2 1 Institute of Pathology (Director: Prof. E. Grundraann, MD, University of Munster, Domagkstr. 17, D-4400 MOoster, Federal Republic of Germany * Institute of Industrial Medicine and Silicosis Research Summary. Correlations between exposure to vinyl chloride and the develop ment of malignant tumors in the liver have been known since 1974 and have been confirmed by many an experimental investigation. Based on the evaluation of mortality statistics from nine different countries an increased 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 increases, however, are only found in the incidence ofmalignant liver tumors. Metabolism and toxicology of vinyl chloride are discussed in detail. Key words: Human carcinogenesis--Vinyl chloride - Toxicology - Liver tumors - Metabolism Introduction The industrial production of monomeric vinyl chloride (VCM) started some 30 years ago. Iq 1976, the USA produced 2.58, Western Europe 3.925, and Japan 1.281 million tons. About 95% of this output went into polymerization, the re maining 5% into the production of other chemicals, such as methylchloroform (IARC 1978). The "Journal of Cancer Research and Clinical Oncology" publishes in loose succession "Edi torials" and "Guest Editorials" on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author. The Editors Die Zeitschrift `Journal ofCancer Research and Clinical Oncology" bringt in zw&ngloser Folge "Edi torials" und "Guest Editorials" zu akcueJlen und/oder kontroversen Problemen der experimeateilen and klinischcn Onkologie. Diese Beitr&ge gebea ausschliefllkh die persBnllche Metnung des Aurora wieder. Die Kerausgebcr Offprint requests to: K. H. Emmerich, MD (address see above) NY 0171-5216/81/0102/0001/$2.20 AP00016969 2 K. H. Emmerich and K. Korpoth The very nature of the polymerization process allows for various ways ofVCM release into the environment. Workers were exposed to particularly high concen trations of VCM during manual autoclave cleansing. Up to the 1960s the health risk of vinyl chloride was thought to be negligible (Lefaux 1966). Concentrations of 1,000 ppm at the individual working place were not uncommon in certain plants. First recommendations for limiting the exposure to 500 ppm were issued in 1955 in the United States. The average concentration levels of that period can be esti mated approximately in retrospect: 1945-1955: 1,000 ppm 1955-1960: 400-500 ppm 1960-1970: 300-400 ppm 1973: 140 ppm 1975: 5 ppm (Bames 1976). In the Federal Republic of Germany the statutory MAK level1 was fixed at 500 ppm until 1970, then reduced to 100 ppm until 1974. Today the technical limit concentration at the work place in the FRG is below 5 ppm for older and currently working plants, under 2 ppm for new plants under construction. The management soon realized that VCM concentration could be effectively reduced to the statutory levels by technical innovation and financial investments. One Swedish firm was able to reduce mean VCM concentrations from 12.2. ppm (2nd quarter of 1974) to 0.6 ppm (4th quarter of 1975) (Englund and Holmerg 1976). Due to the physicochemical binding of VCM in PVC products, workers in PVC-processing or -manufactoring industries are equally exposed to a certain con centration ofVCM, although at much lower levels than during the process of poly merization. In a 1974 survey of PVC-manufacturing plants levels were below 1 ppm in more than 60% of all firms checked. The first reports about the potential risk of VCM had been published in 1949. Since 1957 reports had appeared here and there about a certain disease occurring in VCM industrial workers, manifested in scleroderma-like skin changes, Raynaud syndrome, and acro-osteolysis (Juehe and Lange 1972). Some years later, further symptoms of the disease were described as liver damage, splenomegaly, and throm bocytopenia (K.T. Muller et al. 1976). Detailed investigations were carried out on liver changes since the first cases of hemangiosarcoma had been found among VCM workers. These liver changes were graded histologically in five steps, correla ting the length of exposure, and the severity of recorded changes (Gedigk et al. 1975; R. Muller et al. 1975). Even in VCM-exposed workers showing no clinical symptoms of liver damage, sequential scintigraphy would reveal RHS changes in liver and spleen (Biersack et al. 1975). In addition to liver changes a considerable number of workers showed an im pairment of pulmonary functions, and roentgenologic changes up to pulmonary fi brosis (Miller et al. 1975; Miller 1975; Lilis et al. 1976). These findings equally re flected a signification correlation between the length of exposure and the severity of changes. The first reports about tumors induced by VCM were published in 1974, re cording the increased incidence of a very rare neoplasm, liver hemangiosarcoma, 1 MAK = maximale Arbeitsplatz-Konzentration (maximum concentration at work) AP00016970 Malignant Tumors After Exposure to Vinyl Chloride 3 CHjeCHCI vinylehloride aa --W ,C -- C --* H 0H ehleroethylenexide _ CHjOH 1 cyi-S-CHj S-<2- Hydroxye!hyU-cyitem t G-S-CHj-CHO S-tormylmelhytglutathione 1 T cy-S*CH2-CHO S- formyl methyleysliui* * COOH CHyC- NH-C-H 11 0 ch2.s-ch2*ch2oh chtoro- acet- -- C1CH2C00H aldehyde -----------1 T ehloroaeetote glyeallat* I t O-S-CHj-COOH 1 S-corWxymethylglutathione 1T cys-$-CHrC00H C00H I h2cnh2 S-carboxymtfiylcyftcine U.UHJ Uco2 glycine 1 C00H ,CH? > C00H ch2-cooh HoN-CH 1 HjC-OH CCOH I C00H oalat* 11 C00H l HjNCH ch2 1 CH^S-CHj N-ttcttyl-S-(2-fwdroxv-*thvU*cv*Uiri thiodiglyeollote senne methionine Fig. 1. Major metabolic pathways of vinyl chloride. The main urinary metabolites are underlined 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 the following years (Lloyd 1974, 1975; Lange ct at 1974, 1975; Byrfcn and Holmberg 1975). Based on 13 cases of liver hemangiosarcoma reported in the USA, the risk of VCM workers for this rare tumor was determined to be 400 times higher than that of the normal population (Heath et al. 1975). Histological studies of Thomas and Popper (1975) suggested the possibility of multicentric sarcoma de velopment. 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 PRC until 1978 (Reinl et al. 1979). The cases subjected to detailed investigation until then revealed a longer latency period between first exposure and diagnosis, and a higher age at first diagnosis of hemangiosarcoma. A possible cause for this pattern was seen in the higher initial doses to which workers had been exposed during the first years ofVCM production (Spinas and Kaminski 1978). Environmental stud ies conducted in the immediate neighborhood of VCM-producing plants failed to assess an increased incidence ofhemangiosarcoma in the general population ofthis area (Saric et al. 1976). VCM Metabolism and Pharmacokinetics The metabolism ofmonomeric vinyl chloride was studied by Green and Hathaway (1975), Watanabe et aL (1976), G. Muller et al. (1976), and many others. Figure 1 presents the major metabolic steps according to current concepts. In the mam malian organism monomeric vinyl chloride undergoes oxidative biotransforma- AP00016971 4 K.H. Emmerich and K. Norpoth tion involving the cytochrome P 450 system. Chlorethylenoxide, an alkylating cancerogen, is the resulting primary metabolite (Malaveille et al. 1975; Greim et al. 1975; Kappus et al. 1975) which is subsequently rearranged to chloracetic aldehy de. Via several, partly unknown metabolic steps, this substance is transformed to S-carboxymethyl-cystein and thiodiacetic acid (Yllner 1971). The latter, a rather stable terminal metabolite, may be excreted via the urine. Quantitative demonstra tion of thiodiacetic acid is done by GC.MS technique after methylation (G. Muller et al. 1979). Another metabolic pathway, coupling chlorethylenoxide to glutathi one, leads to ^-hydroxyethyl mercapturic acid (Watanabe et al. 1976). The urinary level of this equally stable end product may be demonstrated by exchange chroma tography after hydrolysis, or by the GC.MS test after derivation (G. Muller et al. 1980). It must be emphasized that ^-hydroxyethyl mercapturic acid is the main uri nary metabolite in the rat (Watanabe et al. 1976), but not in man (G. Muller et al 1980). The concept of VCM carcinogenicity being essentially mediated by its metab olite chlorethylenoxide has been substantially verified in recent years. In a muta genicity test with Salmonella typhimurium TA 1535 the effect of this strongly reacting alkylating agent was 450 times stronger than that of the metabolite chloracctaidchyde (Rannug et al. 1976). Tumor Induction in rats with chlorethylenoxide was 100% successful, whereas chloracetaldehyde failed to show any cancerogenic effect in a parallel assay (Zajdela et al. 1980). The role of intracellular chloracet aldehyde, i.e., whether or not it might contribute essentially to VCM cancerogenesis (Guengerich et al. 1979), is still unclear. VCM pharmacokinetics in rats and in man were extensively studies by Hefner et al. (1975), Whitey (1976), Bolt et al. (1976, 1977), Bolt (1978), Buchter et al. (1978), and Filser and Bolt (1979). According to them, man reacts to VCM levels around 2 ppm by establishing within a few minutes an equilibrium between en vironmental (air) and intracorporeal concentration. The constants of this equilib rium depend on the individual constitution, being approximately 0.8 in persons of normal weight. Overweight individuals will absorb a higher amount in proportion to their weight, and so the constant rises above 1.0, possibly due to the higher pro portion of fatty tissue (Buchter et al. 1978). Experimental studies with rats have shown that the speed constant of VCM uptake and clearance after stopping the ex posure (ifc=0.216 min-1) is always much higher than the constant of metabolization (ft 0.0037 min-l) and of urinary metabolite excretion (fc=0.0032 min'l). Assuming human conditions to be similar, we may deduce that physiologic varia tions of ventilation levels will have either no or only minor influence on the VCM uptake by inhalation. From data on the dose dependency ofVCM biotransformation (G. Muller et al. 1976; Gehringetal 1978,1979) we may infer that reactive cancerogenic VCM me tabolites will not increase in linear correlation with exposure, but rather follow the Michaelis-Menten function. Tumor incidence in rats (Gehring et al. 1978) and even in man (Gehring et al. 1979) is most adequately demonstrated in a probate model offrequency percentage correlated with exposure (Gehringetal. 1979). Functional correlation may be complicated if experimental exposure is under 50 ppra, by the glutathione-mediated detoxication of chlorethylenoxide, which is an effective pro tection mechanism at lower levels of exposure. Gehring et al. (1979) had even dis- AP00016972 Malignant Turnon After Exposure to Vinyl Chloride J cussed the possibility ofa veritable threshold dose ofVCM, below which the tumor latency period would be longer than the normal life expectancy of the exposed per son. VCM Genotoxicity and Embryotoxicity The mutagenicity of monomeric vinyl chloride on salmonella typhimurium strain in vitro was studied by Rannug et al. (1974), Bartscb et al. (1975). Greim et al. 71975), McCann et al. (1975), Andrews et al. (1976), and Garro et al. (1976). In a recent paper De Meesteretal. (1980), though confirming the often cited mutagenic effect, reported that its action was considerably enhanced by the addition of an oxigcnase-enriched preparation of mammalian liver tissue (S9 Mix). Hubermann et al. (1975) described the mutagenic effect of VCM on cultures mammalian cells. In studies ofDrosophila melanogatser Magnusson and Ramel (1978) recorded an in crease oflethal dominants under VCM exposure. Pretreatment with phenobarbitol for 24 h would enhance the mutagenicity of VCM, probably via the induction of mixed-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 Rdbrbom (1980) reported a time-dependent increase in sister-chromatid exchanges and structural chromosome 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 disease, and an increased proportion of chromosomal aberrations was also found by Ducatman et al. (1975) among VCM-exposed workers in the USA, and in Sweden by Funes-Cravioto et al. (1975). Szentesi et ai. (1976) recorded a rise of chromatid aberrations and instable chromosomal aberrations among VCM-ex posed 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 chromosome fractures in lymphocyte cultures from workers exposed to high levels of VCM, which would return to lower values when doses were reduced. Purchase et al. (1978) in similar studies also registered a significant rise of chromosomal anomalies in VCM-exposed workers as compared to non-exposed control collec tives. Heath et al. (1977) pointed out that cytogenetic damage might be due to other agents besides VCM. Finally, Infante et al. (1976) reported an increased rate of miscarriages among the wives of workers exposed to high VCM levels. According to them, an increasing rate of malformations was found even among the neonates of the general population of towns with VCM-processing factories. Experimental Studies of VCM Carcinogenicity The first experimental investigations of VCM-induced carcinogenesis were per formed by Viola et al. (1971) who exposed Wistar rats to high doses of VCM (30,000 ppm) for 20 h each week over a whole year. Under this extreme exposure the animals developed tumors of skin, lungs, and bone. Subsequent animal studies AP00016973 6 K, H. Emmerich and K. Korpoth Table 1. Standardized mortality rates for tumor disease among VCM workers Authors Bytin et al. 1976 Chiazze et al. 1977 Period 1958-1974 1964-1973 No. 771 65,000 DucketaL 1975 Fox and Collier 1977 Monson et al. 1974 Nicholson et aL 1975 ReioletaL 1979 Tabershaw and Gaffcy 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 1,294 SMR _ 1.19 m 1.31 f 0.96 0.75 1.50 3.90 1.03 1.10 1.49 ,, revealed chat the cancerogenic effect oflow doses (50 ppm) would depend on the duration of the exposure. Extensive serial studies recorded VCM-induced tumors in all reodent species, such as rats, mice, and hamsters. Besides angiosarcoma mice were found to develop mammary carcinomas, pulmonary adenomas, and skin tu mors. Apart from angiosarcomas rats would develop malignant neoplasms of the skin and zymbal gland, nephroblastomas, heptomas, angiomas, and neuroblas tomas. In hamsters, VCM induced liver hemangiosarcomas, trichoepithelomas, and lymphomas (Maltoni and Lefemine 1975). Suzuki (1978) induced pulmonary tumors in mice by exposing them to VCM doses of 2,500 and 6,000 ppm for 5-6 months. On the whole, these experimental results suggest that VCM exposure is likely to induce neoplastic changes also in other organs than the liver. Epidemiological Data Reports about angiosarcoma incidence among VCM workers, and also the results of experimental studies, have stimulated a survey of mortality statistics and pro portional VCM mortality among former and present workers in VCM-processing factories. These studies attempted to determine the particular risk of VCM workers to acquire certain diseases, compared with the average normal population. Risks were assessed quantitatively by comparison with the standardised mortality (SMR), but the studies are based on a wide variety of collectives and observation periods (Table 1). The only Swedish VCM factory registered an increased incidence of liver tu mors (SMR--4.5) and an accumulation ofcardiovascular diseases among 58 work ers dying between 1958 and 1974. The problem of a general increase in the overall SMR of tumors was not discussed by the authors of this report (Byren et al. 1976). An extensive study was conducted between 1965 and 1975 in some 65,000 people working in the American VCM production (Chiazze et al. 1977). Cancer mortality was generally increased (SMR in males --1.19, females--1,31). Men showed an increased incidence of gastrointestinal tumors (SMR= 1.34), liver tu mors (SMR--1.43), pulmonary tumors (SMR --1.17) tumors of theCNS (= 1.15) and of the lymphatic system (--1.30). Women showed a particular increase in the AP00016974 Malignant Tumors After Exposure to Vinyl Chloride 7 Table 2. Standardized mortality rates of malignancies among VCM workers according to different organ sites Authors Byr4a et al. 1976 Chiazze et al. 1977 Duck et al 1975 Eox and Collier 1977 Monson et al. 1974 Rdal et al 1979 Tabershaw and Gaffey 1974 Waxweiler et al 1976 Gastroint Liver M 1.34 F 1.66 0.99 0.91 - UO 0.94 >1 4.13 1.43 0.0 - 3.22 11.00 15.23 - 11.55 Lung 1.68 1.17 1.07 1.03 0.89 1.60 0.96 1.12 1.56 CNS 6.12 1.15 1.14 _ 0.54 420 1.62 - 3.29 Lymph. Others _ UO US _ 0.99 1.50 214 1.06 1.59 _ 1.09 2.42 1.89 1.55 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 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 was relatively higher than that of cardiovascular disease. The possibility of cancerogenic action on organs other than the liver was refused by these authors. Another study analyzed 161 deaths recorded among the workers of two PVCproducing factories in the USA between 1954 and 1973. SMR for tumors in general was 1.5 in this period; a striking increase was found in liver tumors ( = 11.0) and in tumors 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 255 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 mors =1.62, tumors of the lymphatic system--2,14, Tabershaw and Gaffey (1974) has 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 slightly elevated (l. 10), but organ, tumor rates were more distinct: 1.89 for tumors of the oral cavity and pharynx, 1.55 for cancer with unknown primary. There was also the case report of a 22-year-old man who, after 14 years of habitually chewing PVC-coated cables, developed a keratinizing squamous carcinoma of the buccal mucosa (Casterline et al. 1977). A survey of 1,294 VCM-exposed workers from 1941 to 1973) Waxweiler et al. 1976) recorded an increase in the SMR of tumors in general (1.49) with a distinct AP00016975 s Table 3. Increased standard mortality rates for non neoplastic disease in VCM workers Authors SMR Disease Byrn et al. 1976 Chiazze et al. 1977 Duck et aL 197S Rein! et si 1979 Waxweiler et aJ. 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. Norpoth rise in liver tumors (11.55) and CNS tumors (3.29), and lesser elevations in pulmo nary tumors (1.56), lymphatic malignancies (1.59); tumors of the gastrointestinal tract are registered with the rate "greater than one". Increasing standardized mortality rates for other diseases are not considered in the same way by all these authors. Some of than did mention rising SM rates for certain diseases, but the latter are not confirmed by other authors. Table 3 com pares the rates registered by different authors for nonneoplastic disease occurring in different organs. Conclusions Various surveys ofstandardized 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 sev eral studies conducted in Great Britain. Besides a very striking elevation in the risk of liver tumors, nearly all these studies revealed an increasing incidence of gastro intestinal, pulmonary, CNS, and lymphatic malignancies. Although the SMR for malignant neoplasms in general was only slightly higher than 1, exposed workers were found to have an increased risk of dying of these tumors. This may be due to the high VCM concentrations registered in factories during the first years of VCM production and processing to PVC, i.e., at levels that were subsequently found to be positively cancerogenic in experimental studies. Recent years brought a worldwide endeavour to reduce VCM concentrations in the factories to minimize the risk for the exposed workers. Although the levels have been effectively lowered, the potential latency period of 20 years for the induc tion of VCM tumors in man is a strong point in favor of keeping a close watch on occupational tumor development in the next decades. Ten -of fifteen years arc a pe riod of risk especially in VCM or PVC workers, because the dangerously high con centrations had been recorded in some factories until 1974. The effectivity of such closely knit surveillance systems in the early detection of VCM tumors in the ex posed group is hard to predict It is equally undecided whether CEA tests (pro posed by Anderson et al. 1978) or alkaline phosphatase tests (Lilis et al. 1975) might help to detect liver damage at an early stage. A practicable way may be found in coordinating biological monitoring of individual exposure, with the analytical monitoring of concentration limits in the occupational environment. APOOOt 6976 Malignant Tumors After Exposure to Vinyl Chloride 9 References Anderson HA, Snyder J, Lewinson T, Woo C, Lilts R, Selikoff U (1978) Levels of CEA among vinyl chloride and polyvinyl chloride workers. Cancer 42 (Suppl 31:1560--1567 Andrews AW, ZanistowskI ES, Valentine CR(1976) A comparison ofthe mutagenic properties ofvinyl chloride and methyl chloride. Mutat Ree 40:273-276 Barnes AW (1976) Vinyl chloride and the production of PVC. 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