DOSE-DEPENDENT KINETICS AND METABOLISM OF 1,2-DICHLOROBENZENE IN RAT - EFFECT OF PRETREATMENT WITH PHENOBARBITAL

1. Toxicity of halobenzenes has been ascribed mainly to their eposides , but recent studies with bromobenzene have shown that secondary quino ne metabolites are also involved in the alkylation of hepatic proteins . However, the relative contribution of the quinones and the epoxides to the toxicity of halobenzenes is still unclear. In order to investig ate the relation between metabolism and toxicity of 1,2-dichlorobenzen e (1,2-DCB), the biotransformation, tissue distribution, blood kinetic s, and excretion at three different oral dose levels (5, 50 and 250 mg /kg) of the radiolabelled compound were ere investigated in the male W istar rat. A toxic dose level (250 mg/kg, as demonstrated by Allis et al. 1992) was included. 2. The major route of elimination (75-85%) was renal excretion. Excretion via the faeces ranged from 19% for the low dose to 7% for the high-dose level. Excretion was nearly complete wit hin 24 h for the low and mid-dose level, and within 48 h for the high- dose level. Pretreatment with phenobarbital resulted in a more rapid e xcretion for the high-dose level and an overall higher urinary excreti on. Biliary excretion was 50-60%, indicating a considerable enterohepa tic circulation. 3. Highest concentrations of radioactivity after a lo w dose were found in far, liver and kidney at 6 h after administration , and then declined rapidly. 4. The maximum concentration of radioacti vity in blood was reached at 6-8 h for the low and mid-dose level, and at 24 h for the high-dose level. The concentration of parent chemical was essentially constant during 3 and 6 h for the mid- and high-dose level respectively, and then declined. 1,2-DCB could only be detected in blood in the first 2 h after administration of the 5-mg/kg dose. 5. The major route of biotransformation was via the glutathione pathway and 60% of the urinary metabolites were mercapturic acids. In addition , the major metabolites in bile were conjugates of glutathione. Other major metabolites in urine were the sulphate conjugates of 2,3- and 3, 4-dichlorophenol (DCP). No significant differences in metabolic profil es were observed between the different doses. Induction with Dhenobarb ital resulted in the increased excretion of sulphate conjugates (30% i n the induced rat, 20% in the control rat), mainly the conjugate of 3, 4-DCP. 6. The mercapturic acids in urine and glutathione conjugates in bile were epoxide-derived, whereas no quinone- or hydroquinone-derive d metabolites were observed. Therefore the hepatotoxicity of 1,2-dichl orobenzene is assumed to be related, at least partly, to the presence of the intermediate arene oxide. A high dose of 1,2-DCB will result in depletion of GSH, followed by oxidative stress and possible binding t o macromolecules .