Mode of Action for Hexavalent Chromium Carcinogenicity in Drinking Water Open Access
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Chronic exposure to high concentrations of hexavalent chromium [Cr(VI)] (≥ 20 mgCr(VI)/L) in drinking water leads to the development of small intestinal tumors in mice. Significant cytotoxicity and regenerative hyperplasia is observed in duodenal tissue at carcinogenic concentrations of Cr(VI) suggesting that tumors may have occurred by a non-mutagenic mode of action (MOA). However, Cr(VI) is genotoxic and mutagenic in tissue culture and yeast suggesting that Cr(VI)-induced duodenal tumors developed via a mutagenic MOA. For environmental health risk assessment, these MOAs pose a significant problem in establishing a Cr(VI) drinking water standard that is protective of human health. The objective of this study was to investigate Cr-DNA binding and K-Ras codon 12 GAT mutations in duodenal epithelial tissues from B6C3F1 mice administered a wide range of Cr(VI) concentrations (0-520 mg SDD/L) in drinking water, as sodium dichromate dihydrate (SDD), for 7 and 90 days. Cr-DNA binding increased in both a time and concentration-dependent manner reaching statistical significance at higher concentrations (i.e. 170-520 mg/L). The frequency of K-Ras codon 12 GGT to GAT mutations was analyzed using allele-specific competitive-blocker PCR (ACB-PCR). Interestingly, the K-Ras spontaneous mutation frequencies measured in mouse duodenal epithelium were observed in the 10-2 to 10-3 range, approximately 100-fold greater than observed in other tissues of mice exposed to other chemicals. However, no dose-response for GAT K-Ras codon 12 GAT mutations was observed using ACB-PCR even at concentrations that significantly increase Cr-DNA binding. The lack of dose-response concordance suggests that K-Ras codon 12 mutation is not an early key event in the MOA of Cr(VI)-induced duodenal carcinogenesis and that Cr-DNA binding is not necessarily indicative of mutagenesis. In addition, the higher than expected basal mutation frequency observed in mouse duodenal tissue is intriguing and suggests that this tissue may be particularly susceptible to neoplasia.