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

• Published in: Toxicology and applied pharmacology Vol. 287; no. 3; pp. 293 - 298
• Main Authors: Sasso, A.F., Schlosser, P.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.09.2015
• Subjects: 60 APPLIED LIFE SCIENCES; Administration, Oral; Animals; BIOASSAY; CARCINOGENS; CHROMIUM; Chromium - pharmacokinetics; Chromium - toxicity; Computer Simulation; Dose response; Dose-Response Relationship, Drug; DOSES; DRINKING WATER; EVALUATION; EXTRAPOLATION; FEMALES; Gastric Absorption; Gastric Juice - metabolism; Gastrointestinal tract; Hexavalent chromium; HUMAN POPULATIONS; Humans; Hydrogen-Ion Concentration; IN VIVO; LINEAR ABSORPTION MODELS; MALES; MICE; Models, Biological; Oxidation-Reduction; RATS; Risk Assessment; SATURATION; Species Specificity; STOMACH; Stomach - metabolism; Toxicokinetics; Water Pollutants, Chemical - pharmacokinetics; Water Pollutants, Chemical - toxicity; Toxicokinetics; Hexavalent chromium; Gastrointestinal tract; Dose response
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.06.016

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. •We outline a new in vivo model for hexavalent chromium reduction in the stomach.•We examine in vivo reduction for mice, rats, and humans under varying conditions.•Species differences in toxicokinetics may explain susceptibility.•We show that a simplified stomach reduction model is adequate for extrapolation.•Internal dose uncertainties still exist.