Derivation of oral cancer slope factors for hexavalent chromium informed by pharmacokinetic models and in vivo genotoxicity data.

Hexavalent chromium [Cr(VI)] is present in drinking water from natural and anthropogenic sources at approximately 1 ppb. Several regulatory bodies have recently developed threshold-based safety criteria for Cr(VI) of 30-100 ppb based on evidence that small intestine tumors in mice following exposure to ≥20,000 ppb are the result of a non-mutagenic mode of action (MOA). In contrast, U.S. EPA has recently concluded that Cr(VI) acts through a mutagenic MOA based, in part, on scoring numerous in vivo genotoxicity studies as having low confidence; and therefore derived a cancer slope factor (CSF) of 0.5 (mg/kg-day), equivalent to ∼0.07 ppb. Herein, we demonstrate how physiologically based pharmacokinetic (PBPK) models and intestinal segment-specific tumor incidence data can form a robust dataset supporting derivation of alternative CSF values that equate to Cr(VI) concentrations ranging from below background to concentrations similar to those derived using threshold approaches-depending on benchmark response level and risk tolerance. Additionally, we highlight weaknesses in the rationale EPA used to discount critical in vivo genotoxicity studies. While the data support a non-genotoxic MOA, these alternative toxicity criteria require only PBPK models, robust tumor data, and fair interpretation of published in vivo genotoxicity data for Cr(VI).