A chronic oral reference dose for hexavalent chromium‐induced intestinal cancer
Open Access
- 14 August 2013
- journal article
- research article
- Published by Wiley in Journal of Applied Toxicology
- Vol. 34 (5), 525-536
- https://doi.org/10.1002/jat.2907
Abstract
High concentrations of hexavalent chromium [Cr(VI)] in drinking water induce villous cytotoxicity and compensatory crypt hyperplasia in the small intestines of mice (but not rats). Lifetime exposure to such cytotoxic concentrations increases intestinal neoplasms in mice, suggesting that the mode of action for Cr(VI)-induced intestinal tumors involves chronic wounding and compensatory cell proliferation of the intestine. Therefore, we developed a chronic oral reference dose (RfD) designed to be protective of intestinal damage and thus intestinal cancer. A physiologically based pharmacokinetic model for chromium in mice was used to estimate the amount of Cr(VI) entering each intestinal tissue section (duodenum, jejunum and ileum) from the lumen per day (normalized to intestinal tissue weight). These internal dose metrics, together with corresponding incidences for diffuse hyperplasia, were used to derive points of departure using benchmark dose modeling and constrained nonlinear regression. Both modeling techniques resulted in similar points of departure, which were subsequently converted to human equivalent doses using a human physiologically based pharmacokinetic model. Applying appropriate uncertainty factors, an RfD of 0.006 mg kg–1 day–1 was derived for diffuse hyperplasia—an effect that precedes tumor formation. This RfD is protective of both noncancer and cancer effects in the small intestine and corresponds to a safe drinking water equivalent level of 210 µg l–1. This concentration is higher than the current federal maximum contaminant level for total Cr (100 µg l–1) and well above levels of Cr(VI) in US drinking water supplies (typically ≤ 5 µg l–1). © 2013 The Authors. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.Keywords
This publication has 38 references indexed in Scilit:
- Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humansCritical Reviews in Toxicology, 2013
- Assessment of Cr(VI)-Induced Cytotoxicity and Genotoxicity Using High Content AnalysisPLOS ONE, 2012
- Psychoactive Pharmaceuticals Induce Fish Gene Expression Profiles Associated with Human Idiopathic AutismPLOS ONE, 2012
- Comparison of the Effects of Hexavalent Chromium in the Alimentary Canal of F344 Rats and B6C3F1 Mice Following Exposure in Drinking Water: Implications for Carcinogenic Modes of ActionToxicological Sciences, 2011
- Investigation of the Mode of Action Underlying the Tumorigenic Response Induced in B6C3F1 Mice Exposed Orally to Hexavalent ChromiumToxicological Sciences, 2011
- Application of the U.S. EPA Mode of Action Framework for Purposes of Guiding Future Research: A Case Study Involving the Oral Carcinogenicity of Hexavalent ChromiumToxicological Sciences, 2010
- Application of Key Events Analysis to Chemical Carcinogens and NoncarcinogensCritical Reviews in Food Science and Nutrition, 2009
- Hexavalent Chromium Is Carcinogenic to F344/N Rats and B6C3F1 Mice after Chronic Oral ExposureEnvironmental Health Perspectives, 2009
- Genomic and Epigenetic Instability in Colorectal Cancer PathogenesisGastroenterology, 2008
- Within-day drinking water consumption patterns: Results from a drinking water consumption surveyJournal of Exposure Science & Environmental Epidemiology, 2008