Thompson CM, Wolf JC, Suh M, Proctor DM, Haws LC, Harris MA. Toxicity and recovery in the duodenum of B6C3F1 mice following treatment with intestinal carcinogens; captan, folpet, and hexavalent chromium: Evidence for an adverse outcome pathway. Society of Toxicology Annual Meeting, San Antonio, TX, March 11-15, 2018
High concentrations of hexavalent chromium [Cr(VI)], captan, and folpet induce duodenal tumors in mice. Many regulators have concluded that captan and folpet induce duodenal tumors by non-genotoxic threshold mechanisms, despite some evidence for genotoxicity in vitro. Recent studies on the effects of Cr(VI) in the small intestine support that the mode of action (MOA) for Cr(VI)-induced tumors involves non-genotoxic threshold mechanisms. Evidence is mounting that there may be a generic adverse outcome pathway (AOP) for intestinal tumors mediated by chronic villus wounding and regenerative crypt hyperplasia. Using standardized tissue collection procedures and diagnostic criteria, we compared the duodenal histopathology in B6C3F1 mice following exposure to captan, folpet, and Cr(VI) to determine whether they share similar histopathological characteristics. B6C3F1 mice (n=20 per group) were exposed to 180 ppm Cr(VI) in drinking water, 12000 ppm captan in feed, or 16000 ppm folpet in feed for 28 days. After 28 days of exposure, examination of H&E stained transverse sections revealed villus enterocyte hypertrophy and mild crypt epithelial hyperplasia in all exposed mice. In a subset of mice allowed to recover for 28 days, duodenal samples were generally indistinguishable from those of unexposed mice. The changes in the villi and lack of observable damage to the crypt compartment suggests that toxicity was mediated in the villi, which is consistent with earlier studies on all three agents. In addition to H&E staining, immunohistochemical (IHC) staining for Ki67, a wellknown marker of cell proliferation, was similar among treated animals. These findings indicate that structurally diverse agents can induce similar (and reversible) phenotypic changes in the duodenum. These intestinal carcinogens likely converge on common pathways involving irritation and wounding of the villi leading to crypt regenerative hyperplasia that, under protracted high-dose exposure scenarios, increase the risk of spontaneous mutation and tumorigenesis. These findings set the stage for the development of an AOP for intestinal cancer.