Hays SM, Kirman C, Aylward L, Suh M, Proctor D. 2012. Gastric reduction of Cr(VI) in mice, rats and humans. Presented at the Society of Toxicology’s 51st Annual Meeting, March 11-15, San Francisco, CA.
The gastric reduction of Cr(VI) is a critical step in the proposed mode of action for the small intestinal tumors in mice. To investigate the kinetic mechanisms of gastric reduction of Cr(VI), stomach fluid was obtained from fed mice and rats and from fasted and fed human volunteers, including patients on proton pump inhibitors (PPIs). Studies were conducted to ascertain the kinetics (rates and capacity) of the various gastric fluids to reduce Cr(VI). The pH dependence of the various kinetic factors was also investigated. The reduction of Cr(VI) in fed mouse and rat gastric fluid followed second-order kinetics, with dependence upon both the Cr(VI) concentration and the concentration of reducing agents. Approximately 16 mg equivalents of reducing agent per liter of fed stomach fluid (which contains gastric secretions, water and food) was found for both the mouse and rat. The second-order rate constant (k) was 0.005 and 0.003 min-1 for rat and mouse, respectively. Species differences in gastric fluid production rates and water intakes indicated a higher Cr(VI) load per L stomach fluid in mice compared to rats for a given Cr(VI) drinking water concentration. The amount of Cr(VI) emptying from the stomach into the duodenum was modeled in the stomach by accounting for competing rates of Cr(VI) loading via drinking water, emptying, reduction, and absorption. At doses that induce small intestinal tumors in mice, significant Cr(VI) emptying into the small intestine is predicted. Rate of reduction is faster in human gastric fluid at lower pH. The second-order rate constant for Cr(VI) reduction is higher in humans (0.4 – 0.1 min-1 at pH 1-4, respectively) than rodents. Reduction capacity and rate are lower in humans taking PPIs compared to those not on PPIs. These data can be used in a PBPK model to support a risk assessment for humans exposed to Cr(VI).