Ethylene Dichloride: The Influence of Disulfiram or Ethanol on Oncogenicity, Metabolism, and DNA Covalent Binding in Rats

Abstract

Ethylene Dichloride: The Influence of Disulfiram or Ethanol on Oncogenicity, Metabolism, and DNA Covalent Binding in Rats. CHEEVER, K. L., CHOLAKJS, J. M., EL-HAWARI, A. M., KOVATCH, R. M., AND WEISBURGER, E. K. (1990) Fundam. Appl. Toxicol14, 243–261. Male and female Sprague-Dawley rats were exposed to 50 ppm ethylene dichloride (EDC) for 7 hr/ day, 5 days/week, for 2 years by inhalation. Additional rats were exposed to 50 ppm EDC either with 0.05% disulfiram in the diet or with 5% ethanol in the drinking water. Histopathologic lesions related to the combination of inhaled EDC and dietary disulfiram were observed in the liver, mammary, and testicular tissues of rats. This combined exposure resulted in a significant increase in the incidence of intrahepatic bile duct cholangiomas in both male and female rats. Male rats exposed to both EDC and disulfiram also had an increased incidence of subcutaneous fibromas, neoplastic nodules, and interstitial cell tumors in the testes. The female rats exposed to EDC and disulfiram also had a higher incidence of mammary adenocarcinomas. No significant increase in the number of any tumor type was observed in rats exposed to only EDC, disulfiram, or ethanol. Similarly, no significant increase in the number of tumors was observed in rats exposed to inhaled EDC and ethanol in water. At the end of the 2-year period animals from each group were evaluated for EDC metabolism and DNA binding. Blood levels of EDC at the end of a 7-hr exposure period were significantly higher for rats exposed to both EDC and disulfiram than for rats exposed to EDC alone. In addition, the elimination of a single oral dose of radiola-beled EDC was affected. The urinary excretion of I4C from control rats was 47 to 55% of the administered dose with 28 to 30% detected as unchanged EDC in the breath. In disulfiram-treated rats, only 35 to 36% of the administered I4C was eliminated in the urine with 41 to 55% as unchanged EDC in the breath. The urinary metabolite HPLC profile was qualitatively unchanged by long-term EDC, disulfiram, or ethanol treatment, either alone or in combination, and consisted primarily of thiodiglycolic acid, thiodiglycolic acid sulfoxide, and chloroacetic acid.