Differentiation of the mechanisms of oncogenicity of 1,4-dioxane and 1,3-hexachlorobutadiene in the rat

Abstract

1,4-Dioxane (DX) and 1,3-hexachlorobutadiene (HCBD) have induced liver and kidney neoplasms, respectively, upon chronic ingestion of cytotoxic dosages to rats. DX and HCBD were compared in male Sprague-Dawley rats to the genotoxic carcinogen dimethylnitrosamine (DMN) with regard to cyctotoxicity (DNA synthesis, histopathology) and genotoxicity (DNA alkylation, in vivo DNA repair). Treatment of rats with tumorigenic dose levels of DX (1 g/kg/day) in drinking water for 11 weeks or HCBD (20 mg/kg/day, po) for 3 weeks resulted in a 1.5× increase in hepatic DNA synthesis and a 1.8× increase in renal DNA synthesis, respectively. Treatment-related histopathological changes were also observed in treated animals. Cytotoxicity was not detected in rats dosed orally with nontumorigenic levels of DX (10 mg/kg/day), HCBD (0.2 mg/kg/day), or with a tumorigenic dose level of DMN (3 mg/kg/day) for 3 weeks. Alkylation of hepatic DNA and DNA repair was not detected in rats dosed with 1 g [ 14C]DX/kg (po). Renal DNA alkylation (0.78 alkylation/10 6 nucleotides) and a 1.40× increase in DNA repair were observed in rats dosed with 20 mg [ 14C]HCBD/kg (po). Neither compound elicited a positive response in the Ames' bacterial mutagenicity or Williams' hepatocyte DNA repair in vitro assay. In contrast, rats dosed with 3 mg [ 14C]DMN/kg po resulted in alkylation of hepatic and renal DNA at levels of 167 and 28.3 alkylations/10 6 nucleotides, respectively. Large increases in hepatic (3.72×) and renal (2.87×) DNA repair were also noted in DMN-dosed rats (20 mg/kg, po). The lack of genotoxic activity by DX and its cytotoxicity at tumorigenic dose levels suggests a nongenetic mechanism of liver tumor induction in rats. Unlike DX, the data suggested that HCBD has a relatively low degree of genetic interaction. While kidney tumors, induced only at toxic HCBD doses, may be caused primarily by a nongenetic mechanism, a minor genetic contribution cannot be discounted.