Studies on the Metabolism of Vinyl Chloride

H. Antweiler
1976 Environmental Health Perspectives  
Vinyl chloride (VCM) is not carcinogenic by itself. it is bioactivated to the highly reactive alkylating oxirane chloroethylene oxide. Further metabolism, apparently, leads via an interaction of the primary alkylating metabolites with glutathion to S-(2-carboxymethyl)-cysteine and thiodiacetic acid which are eliminated with the urine. Up to now, it has not been ascertained whether the oxirane alone is the essential carcinogenic factor or whether other metabolites are also involved in
more » ... olved in carcinogenicity. Likewise, it is still unknown whether the metabolites excreted in the urine might be used as biological criteria for exposure to VCM, because these metabolites probably can originate from a series of substances other than VCM. This problem could stimulate investigations on the possible carcinogenic activity of these substances. Studies on the pathway of the carcinogenic and mutagenic activity of vinyl chloride (VC) are not only of interest in relation to this special substance. Such studies also allow further insight into the possibly carcinogenic and mutagenic mechanism of chemically related substances which are suspected to be dangerous in occupational exposure. Furthermore, the knowledge of carcinogenic metabolites may furnish us with biochemical criteria to judge the dimension of risk in exposure to potentially carcinogenic and mutagenic substances. Moreover, research into the carcinogenic activity of VC becomes more and more interesting when we just learn that also tobacco smoke contains about 30 ppb of VC, a concentration which may not be important per se, but which could assume increased importance in connection with the other carcinogenic substances contained in the smoke (1). I want to report briefly some investigations which were performed in our country quite recently by Norpoth and co-workers in a working group in Munster in the Department of Occupational Medicine and the hypothesis derived from the results of these experiments. In 1966 Grigorescu and Toba (2) had found chloroacetic acid as a metabolite of VC. This was confirmed in 1974 by Hefner and co-work-* Universitat Dusseldorf, Dusseldorf, W. Germany. ers (3) and in 1975 by Radwan and Henschler (4). Bartsch and colleagues (5) then supposed that the presumed intermediary metabolite, chloroethylene oxide, would be really the active alkylating substance because this substance proved to be a strong mutagen as well as VC in the presence of an oxygenating system. Its mutagenic activity in certain sensitive bacteria was superior to the activity of chloroacetaldehyde and chloroacetic acid. About the same time Green and Hathway (6) as well as Norpoth and co-workers (7) identified thiodiacetic acid as a conjugated metabolite in the urine of rats which inhaled VC. This finding was in good agreement with the statement of Hefner and colleagues that free SH-groups in the liver, not bound to proteins, are strongly used by VC and its metabolites respectively. Reynolds et al. (8) , however, were not able to confirm a loss of SH groups. On the contrary, they reported an increase of SH groups. It is not yet clear if this can be explained as a rebound effect. Hefner et al. supposed S-(2-carboxymethyl) cystein to be a further metabolite. This compound has since been confirmed a metabolite of VC by Norpoth and co-workers. Since Yllner (9, 10) also found this substance and additionally also thiodiacetic acid to be the main metabolite of chloroacetic acid in experiments October 1976 217
doi:10.2307/3428629 fatcat:f27i2x5ht5cozfpdcinivrqq5q