Kirman CR, Proctor D, Suh M, Haws L, Harris M, Thompson C, Hays S. 2017. Using physiologically based pharmacokinetic modeling to address potentially sensitive subpopulations exposed to hexavalent chromium. Poster presented at Society of Toxicology Annual Meeting, March 15, Baltimore, MD.
An updated reduction model and physiologically based pharmacokinetic model for hexavalent chromium (CrVI) was used to address potentially sensitive subpopulations. Extracellular reduction of CrVI to CrIII in the stomach lumen is considered to be protective since it reduces the amount of the toxic form of the chemical reaching the key target tissue identified in NTP’s cancer bioassay conducted in mice (i.e., small intestines). Because the reduction of hexavalent chromium is pH-dependent, subpopulations with elevated gastric pH may experience higher doses of CrVI delivered to the small intestines. Three populations with elevated gastric pH were identified: (1) neonates; (2) proton pump inhibitor (PPI) users; and (3) people with hypochlorhydria. The updated PBPK model was used to simulate exposures to all three subpopulations to determine the delivered doses of CrVI across a broad range of doses (0.0001-100 mg/kg-day). The results are compared to delivered doses experienced by an average adult across the same dose range. Nonlinear toxicokinetics due to the depletion of one or more reducing agent pools are predicted above doses of approximately 0.01 mg/kg-day, and for this reason quantitative differences between populations are dose-dependent. The results are discussed within the context of supporting the derivation of a data-derived uncertainty factor to address variation in toxicokinetic factors for CrVI human health risk assessment.