Thompson CM, Suh M, Proctor DM, Harris MA. Ten factors for considering the mode of action of Cr(VI)-induced intestinal tumors in rodents. Society of Toxicology Annual Meeting, San Antonio, TX, March 11-15, 2018.
The determination of whether a chemical induces a specific cancer through a mutagenic or non-mutagenic mode of action (MOA) plays an important role in whether linear or nonlinear low-dose extrapolation is used to derive safety criteria. Currently, no formal framework exists for determining whether environmental chemicals act through a mutagenic or non-mutagenic MOA. As a result, most MOA determinations are made on an ad hoc basis. Eastmond [Mutat Res 751 (2012)] recently conducted a systematic investigation of MOA determinations by U.S. and international regulatory agencies and organizations, and identified 10 key factors that influence MOA determinations. These factors include: i) nature of tumors, ii) mutations in tumors, iii) chemical properties, iv) toxicokinetics, v) structural similarity to other carcinogens, vi) understanding relevant genotoxicity assays, vii) in vivo genotoxicity, viii) origins of observed genotoxicity, ix) data quality and reproducibility, and x) evidence for alternative MOAs. These 10 factors were used to assess the likelihood of a mutagenic or non-mutagenic MOA for gastrointestinal tumors induced by oral exposure to hexavalent chromium [Cr(VI)] in drinking water. Comprehensive assessments were conducted on in vivo genotoxicity, toxicokinetics, and MOA. To our knowledge, this is the first demonstration of using the 10 factors identified by Eastmond for making MOA determinations. Based on these analyses, we conclude that the MOA for Cr(VI) induced gastrointestinal tumors is non-mutagenic. Comparisons between Cr(VI) and intestinal carcinogens previously determined to have non-genotoxic MOAs revealed similar datasets, thus further supporting the MOA conclusion for Cr(VI). As such, threshold risk assessment approaches for oral Cr(VI) exposure are appropriate. The analyses also indicate that an adverse outcome pathway (AOP) for intestinal carcinogenesis mediated by chronic villus wounding and regenerative hyperplasia would benefit future risk assessment efforts of intestinal carcinogens.