Thompson CM. 2016. Non-mutagenic MOA for Cr(VI) involving intestinal cytotoxicity and regenerative hyperplasia. Platform presentation in the “The Cancer Risk Assessment for Ingested Hexavalent Chromium: Challenges and Controversies” Session. Presented at the Society of Toxicology’s 55th Annual Meeting, March 13-17, New Orleans, LA.
Some quantitative risk assessments for Cr(VI) have been based on tumor incidence in the small intestine of mice. However, mice in the NTP study also exhibited non-neoplastic intestinal lesions, including villous blunting and crypt hyperplasia—effects that were characterized as secondary to mucosal injury. Several studies designed to address the MOA for intestinal tumors in mice have been conducted since the NTP bioassay was completed. Collectively, these studies support that ingested Cr(VI) that is not reduced to inert Cr(III) by gastric fluid is passed into the intestinal lumen, where it can be absorbed by villous enterocytes (key event 1). At high Cr(VI) drinking-water concentrations, Cr(VI) causes cytotoxicity in villous enterocytes (key event 2). To compensate for villus damage, the proliferative crypt compartment becomes hyperplastic (key event 3). Under chronic high Cr(VI) exposure, sustained hyperplasia leads to increased spontaneous mutations in crypt stem cells (key event 4), which can ultimately result in tumorigenesis. Multiple in vivo genotoxicity assays in the small intestine (and other tissues) are negative, and indicate an absence of direct genotoxicity in the crypt compartment. Together, pharmacokinetic, histopathologic, and genotoxicity data support a non-mutagenic, non-linear, threshold-based MOA for Cr(VI)-induced tumors in the small intestine of mice. A similar MOA has been proposed for captan and folpet, which suggests that these three chemicals may converge on an adverse outcome pathway (AOP) that is predictive of small intestinal tumors. In addition to the MOA discussion, a dose-response analysis is described that characterizes cancer risk from oral exposures to Cr(VI) that is based on non-neoplastic precursor lesions observed in the NTP cancer bioassay.