Thompson CM, Chappell GA, Mittal L, Gorman B, Proctor DM, Haws LC, Harris MA. Use of targeted mode-of-action research to inform human health risk assessment of hexavalent chromium. Poster presented at Society of Toxicology Annual Meeting, San Diego, CA, March 2022.
Hexavalent chromium [Cr(VI)] is widely perceived as a genotoxic carcinogen; however, lifetime exposure to high concentrations of Cr(VI) in drinking water induces a limited array of tumor responses in rodents: adenomas and carcinomas in the proximal small intestine of mice and squamous cell carcinomas in the oral cavity of rats. In addition to intestinal tumors, Cr(VI) also causes cytotoxicity-induced regenerative cell proliferation in the intestine. Lesions of the small intestine have served as the basis of several toxicity values for Cr(VI) including oral cancer slope factors based on tumor incidence and threshold reference values based on cytotoxicity-induced regenerative cell proliferation. This presentation will review evidence supporting nonlinear risk assessment approaches for Cr(VI) including nonlinearities in Cr(VI) kinetics based on PBPK models, limited dosimetry to target cell populations by fluorescence microscopy, nonlinearities in transcriptomic responses at individual gene level and compartment microdissection, evidence for villus cytotoxicity and crypt hyperplasia, and evidence against genotoxicity in target tissues (including use of transgenic rodent models). In addition, environmental monitoring data from Wisconsin was analyzed to estimate the percentage of population that would be served by water sources exceeding water standards based on either linear or nonlinear toxicity criteria. This presentation demonstrates that mode of action analysis of intestinal tumors supports development of safety criteria for Cr(VI) using nonlinear approaches.