Chronic Inhalation Toxicity Study of 1,2-Dichloroethane in Rats Treated with Disulfiram or Ethanol. Part 2. Disposition, Metabolism and Binding Studies

摘要

Possible mechanisms of action were sought to explain the synergistic effects of simultaneously administered 1,2-dichloroethane (107062) (EDC) and disulfiram (97778) in the production of cancer in rats. In animals receiving only EDC, blood samples revealed the presence of EDC at 15 minutes and at 2 hours following the termination of the EDC exposure. Simultaneous exposure to ethanol (64175) revealed the same concentrations of EDC in the blood. In rats simultaneously exposed to EDC and disulfiram, these EDC levels were five times higher. Expired air from rats treated with EDC contained 28 to 30 percent of the unmetabolized EDC; urine contained 47 to 55 percent of the administered dose, and fecal elimination amounted to 1 to 2 percent. In rats also treated with disulfiram, expired air contained 58 percent of the administered dose. Urinary metabolic profiles for rats treated with EDC plus disulfiram were similar to those treated with EDC alone. Binding of EDC to hepatic DNA was not changed by additional exposure to disulfiram. The authors conclude that the reduced EDC elimination as a result of the simultaneous exposure to disulfiram may have been responsible for the increased incidence of hepatic, testicular, and mammary tumors found in these rats, as opposed to changes in biotransformation and binding of the offending carcinogen.