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 Chromium

Abstract

Mode of action (MOA) analysis provides a systematic description of key events leading to adverse health effects in animal bioassays for the purpose of informing human health risk assessment. Uncertainties and data gaps identified in the MOA analysis may also be used to guide future research to improve understanding of the MOAs underlying a specific toxic response and foster development of toxicokinetic and toxicodynamic models. An MOA analysis, consistent with approaches outlined in the MOA Framework as described in the Guidelines for Carcinogen Risk Assessment, was conducted to evaluate small intestinal tumors observed in mice chronically exposed to relatively high concentrations of hexavalent chromium (Cr(VI)) in drinking water. Based on review of the literature, key events in the MOA are hypothesized to include saturation of the reductive capacity of the upper gastrointestinal tract, absorption of Cr(VI) into the intestinal epithelium, oxidative stress and inflammation, cell proliferation, direct and/or indirect DNA modification, and mutagenesis. Although available data generally support the plausibility of these key events, several unresolved questions and data gaps were identified, highlighting the need for obtaining critical toxicokinetic and toxicodynamic data in the target tissue and in the low-dose range. Experimental assays that can address these data gaps are discussed along with strategies for comparisons between responsive and nonresponsive tissues and species. This analysis provides a practical application of MOA Framework guidance and is instructive for the design of studies to improve upon the information available for quantitative risk assessment.

Hexavalent chromium-induced erythrocyte membrane phospholipid asymmetry

“…Chromium (VI) further leads to hemolysis, an effect, however, affecting only a small percentage of erythrocytes. The concentration required for the effect on cell membrane scrambling is well in the range of concentrations observed during chromium intoxication in vivo (Thompson et al 2011). While in healthy individuals, chromium serum concentrations are less than 0.1 lM (Chernecky and Berger 1997), values as high as 42 lM have been observed in severe chromium intoxication (Schiffl et al 1982).…”

“…Chromium pollution is a major health hazard in distinct mining areas (Das and Singh 2011). Chromium (VI) may be absorbed in the intestine and triggers oxidative stress, inflammation, cell proliferation, malignant transformation, growth arrest, cytotoxicity, and apoptosis (Chiu et al 2010;Holmes et al 2008;McCarroll et al 2010;Nickens et al 2010;Stout et al 2009; Thompson et al 2011;Wise et al 2008;Yao et al 2008). Mechanisms implicated in chromium (VI) toxicity include mitochondrial damage as well as DNA damage including base modification, single-strand breaks, double-strand breaks, Cr-DNA adducts, DNA-Cr-DNA adducts, protein-Cr-DNA adducts, and mutagenesis (Asatiani et al 2010;Chiu et al 2010;Hartwig 1995;Wise et al 2008).…”

Heavy Metals and Human Health

“…respiratory, gastrointestinal, immune, liver, and kidney). More recently, a great number of laboratory and epidemiological studies were reviewed focussing on the health hazards induced by hexavalent chromium-based chemicals (Singh et al, 1999;Thompson et al, 2011). An increased incidence of lung cancer was described in those studies on workers exposed to chromate dust (Tokar et al, 2011).…”

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

“…To inform the MOA and risk assessment of oral Cr(VI) exposure, a series of studies were conducted beginning with an overall proposed MOA (Thompson, Haws, Harris, Gatto, & Proctor, 2011), and subsequent 90‐day toxicity studies (Thompson, Proctor, et al, 2011; Thompson et al, 2012), transcriptomic analyses (Kopec et al, 2012; Kopec, Thompson, Kim, Forgacs, & Zacharewski, 2012; Rager et al, 2017), genotoxicity studies (O'Brien et al, 2013; Thompson, Seiter, et al, 2015; Thompson, Wolf, et al, 2015; Thompson, Young, et al, 2015; Thompson et al, 2017), as well as ex vivo gastric reduction studies and pharmacokinetic modeling (De Flora et al, 2016; Kirman et al, 2012; Kirman et al, 2013; Kirman et al, 2016; Proctor et al, 2012). Other genotoxicity studies were conducted in response to early drafts of the NTP 2‐year cancer bioassay (De Flora et al, 2006; De Flora et al, 2008).…”