Comparative cytotoxicity of the aqueous chlorination products of thiobencarb, a thiocarbamate herbicide, in cultured rat hepatocytes

Abstract

Thiobencarb (S-4-chlorobenzyl N, N-diethylthiocarbamate) has been widely used in the rice fields of Japan. This herbicide is reported to decompose in aqueous chlorination to the compounds 4-chlorotoluene, 4-chlorobenzyl chloride, 4-chlorobenzyl alcohol, 4-chlorobenzaldehyde and 4-chlorobenzoic acid. We compared their cytotoxicity and the inducibility of cytochrome P-450 (P450) in cultured rat hepatocytes. Of the six compounds including thiobencarb, 4-chlorobenzyl chloride was the most hepatotoxic (EC 50: 0.17 m m), followed by thiobencarb (0.69 m m) and 4-chlorotoluene (1.2 m m). 4-Chlorobenzyl alcohol (4.6 m m) and 4-chlorobenzaldehyde (4.6 m m) were less toxic than thiobencarb, and 4-chlorobenzoic acid was the least toxic ( > 6.0 m m). From the results of the TBARS (2-thiobarbituric acid reactive substance) assay, lipid peroxidation was shown to be involved in the hepatotoxicity of 4-chlorobenzyl chloride, and less probably in that of thiobencarb and 4-chlorobenzaldehyde. 4-Chlorobenzoic acid and 4-chlorobenzaldehyde induced hepatic ethoxyresorufin O-deethylase and pentoxyresorufin O-depentylase activities, respectively. The induction of enzyme activities was accompanied by the increase in the corresponding P-450 apoprotein. Furthermore, 4-chlorotoluene, 4-chlorobenzaldehyde and 4-chlorobenzoic acid also induced CYP2B1, which was not reflected in the enzyme activity. These results provide primary information on the toxicity of the thiobencarb degradation products in cultured rat hepatocytes.