An evaluation of in vivo models for toxicokinetics of hexavalent chromium in the stomach

Abstract

Hexavalent chromium (Cr6) is a drinking water contaminant that has been detected in most of the water systems throughout the United States. In 2-year drinking water bioassays, the National Toxicology Program (NTP) found clear evidence of carcinogenic activity in male and female rats and mice. Because reduction of Cr6 to trivalent chromium (Cr3) is an important detoxifying step in the gastrointestinal (GI) tract prior to systemic absorption, models have been developed to estimate the extent of reduction in humans and animals. The objective of this work was to use a revised model of ex vivo Cr6 reduction kinetics in gastric juice to analyze the potential reduction kinetics under in vivo conditions for mice, rats and humans. A published physiologically-based pharmacokinetic (PBPK) model was adapted to incorporate the new reduction model. This paper focuses on the toxicokinetics of Cr6 in the stomach compartment, where most of the extracellular Cr6 reduction is believed to occur in humans. Within the range of doses administered by the NTP bioassays, neither the original nor revised models predict saturation of stomach reducing capacity to occur in vivo if applying default parameters. However, both models still indicate that mice exhibit the lowest extent of reduction in the stomach, meaning that a higher percentage of the Cr6 dose may escape stomach reduction in that species. Similarly, both models predict that humans exhibit the highest extent of reduction at low doses.

An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: a case study with hexavalent chromium, captan, and folpet

“…Cr(VI) reduction rate, as do feeding patterns and gastric motility (McConnell et al 2008;Kirman et al 2012Kirman et al , 2013. Physiologically based pharmacokinetic (PBPK) models integrating gastric transit and reduction collectively and consistently predict that a higher percentage of Cr(VI) may escape stomach reduction in mice relative to humans, which exhibit the highest extent of reduction at low doses compared to rats and mice (Kirman et al 2012(Kirman et al , 2013(Kirman et al , 2017Proctor et al 2012;Sasso and Schlosser 2015). For example, nonlinear kinetics are predicted to begin in humans at doses >0.01 mg/ kg-day or in mice and rats at doses >0.1 mg/kg-day, largely due to differences in reduction capacity (Kirman et al 2017).…”

Hexavalent Chromium in Drinking Water

“…Physiologically based pharmacokinetic (PBPK) models were developed to describe the internal behavior of Cr(III) and Cr(VI) in mice, rats, and humans (Kirman et al , , ; Sasso & Schlosser ). By modeling key species differences, sources of saturable toxicokinetics and sources of uncertainty and variation, the rodent and human PBPK models can provide a robust characterization of toxicokinetics in the target tissue (small intestine) for risk assessment.…”

Chemical Composition of Soil Contaminated with Tri- and Hexavalent Chromium Amended with Compost, Zeolite and Calcium Oxide

“…In each case, chromium compounds at a higher state of oxidation are absorbed more effectively than those at lower states (Mathebula et al 2017). Such a large difference in the level of absorption is connected with the ability of stomach acid to reduce Cr(VI) to Cr(III), which is characterized by poorer absorbability (Sasso and Schlosser 2015). Under physiological conditions, Cr(VI) occurs in the form of chromates, whereas Cr(III) is a cation.…”