Differences in Metabolism of Vinylidene Chloride Between Mice and Rats

Abstract

Summary.-The present finding that mice metabolize a greater proportion of an oral dose (50 mg/kg) of vinylidene chloride. (1,1 -dichloroethylene, DCE) than rats implies (a) that the efficiency of DCE metabolism follows the known activity of cytochrome P -450 in the organs of these animals, and (b) that, in accordance with the LD50 values, the real exposure (expressed as the amount of DCE metabolized) is relatively higher for orally dosed mice than rats, and (c) that DCE carcinogenicity would appear to be more likely in mice than rats.Mice metabolize DCE similarly to rats (Jones and Hathway, 1977) but there are some differences. Thus, qualitatively, treated mice (but not rats) excrete a small amount of N-acetyl-S-(2-carboxymethyl)cysteine. Quantitatively, (i) the relative proportions of the N-acetyl-S-cysteinyl acetyl derivative that are formed in mice and rats parallel the activity of liver glutathione-S-epoxide transferase in these rodents, and (ii) there are marked differences in the proportions of DCE metabolites belonging to the chloroacetic acid branch of the metabolic pathway. Furthermore, the previously assumed ,B-thionase hydrolysis of thiodiglycollic acid (Jones and Hathway, 1977) is now established in vivo, and the possible biogenesis of the N-acetyl-S-cysteinyl acetyl derivative is verified by another tracer study. The conclusion is drawn that the DCE metabolites, 1,1 -dichloroethylene oxide and chloroacetyl chloride, may be important to murine DCE carcinogenicity.WIDESPREAD use of the polymer of vinylidene chloride* (1,1 -dichloroethylene, DCE) for packaging film and for coating other packaging materials, and the recent discovery of DCE tumorigenicity in the kidneys of mice (Maltoni et al., 1977) but not in rats, warrants a systematic search for possible species differences in DCE metabolism which might account for the species susceptibility observed.Previous work (Jones and Hathway, 1977;Walker and Hathway, 1977) on the metabolism of DCE (Fig. 1(a)) in rats showed that: (i) thiodiglycollic acid (g) and an N-acetyl-S-cysteinyl acetyl derivative (e) (where R is considered to be OH and R' is unknown) where the major urinary metabolites associated with substantial amounts of chloroacetic acid (b) dithioglycollic acid (j) and thioglycollic acid (h),(ii) chloroacetic acid (b) a key metabolite of DOE (a) biotransformation, afforded in vivo several metabolites in common with DCE, and (iii) transformation of DCE (a) into chloroacetic acid (b) involved migration of one C1 atom and the loss of the other one.The experimental evidence implied that the N-acetyl-S-cysteinyl acetyl derivative (e) arises through the reaction of 1,1-dichloroethylene oxide with glutathione, a reaction catalysed by glutathione Sepoxide transferase.The present paper describes the results of an investigation of DCE metabolism in mice vis-a-vis the previous one in rats * Known commercially as VDC.

Cardiac Damage in Rodents after Exposure to Bis(2-chloroethoxy)methane

“…The heart toxicity observed may be related to the metabolism of CEM to thiodiglycolic acid, a metabolite that has been found in the urine of rats and mice treated with CEM (Mathews and Jeffcoat, 2002). Other studies have found that with other compounds (e.g., vinylidene chloride) more thiodiglycolic acid is formed in rats than in mice (Jones and Hathway, 1978). The CEM metabolism study also suggested that more thiodiglycolic acid was formed in rats than in mice, although this difference was not quantified.…”

Conjugation of glutathione with the reactive metabolites of 1,1-dichloroethylene in murine lung and liver

“…Previous studies have identified the primary metabolites formed from DCE as DCE-epoxide, 2-chloroacetyl chloride and 2,2-dichloroacetaldehyde Ivanetich, 1982, 1984;Jones and Hathway, 1978b;Liebler et al, 1985Liebler et al, , 1988Liebler and Guengerich, 1983). Three major GSH conjugates identified as S-(2,2-dichloro-1-hydroxy)ethylglutathione [A], 2-(S-glutathionyl)acetyl glutathione [B], and 2-S-glutathionyl acetate [C] were formed in rat liver microsomal incubations; minor amounts of S-(2-chloroacetyl)glutathione [D] were observed.…”

“…Species differences in susceptibility to DCE-induced toxicities have been identified in rats and mice (Maltoni et al, 1984). The LD 50 for an oral dose of DCE is estimated to be 7-fold lower in mice compared to rats (Jones and Hathway, 1978b), suggesting a species difference in the metabolic disposition of DCE.…”

Toxicokinetics of chloroethanol in the rat after single oral administration

“…In fact, thiodiacetic acid has been found in mice after administration of chloroacetic acid and S-carboxymethylcysteine (Yllner 1971b) and in rats treated with chloroacetaldehyde, chloroacetic acid and S-carboxymethylcysteine (Green and Hathway 1977). Furthermore, it has been detected as a metabolite of compounds which can be converted metabolically to chloroacetaldehyde and chloroacetic acid, such as vinyl chloride Hathway 1975, andWatanabe et al 1976), vinylidene chloride Hathway 1978a, and1978b;McKenna et al 1978;Reichert et al ICI-CH2-CH2-OHI ~ C|-CH2-CHO . CI-CH2-COOH ,,.…”