Kirman CR, Thompson CM, Proctor DM, Suh M, Haws LC, Harris MA, Hays SM. 2013. Using PBPK modeling to address diurnal variation and age differences in hexavalent chromium toxicokinetics in humans. Presented at the Society of Toxicology’s 52nd Annual Meeting, March 10-14, San Antonio, TX.
A physiologically based pharmacokinetic (PBPK) model has been developed to describe the toxicokinetics of hexavalent chromium [Cr(VI)] in mice, rats, and humans. The PBPK model was used to support a human health risk assessment (HHRA) based upon mouse small intestinal (SI) tumors. Key factors contributing to the delivery of Cr(VI) to the SI were identified by sensitivity analyses, and include gastric pH, gastric transit time, and gastric reducing equivalents. These factors affect the rate of Cr(VI) reduction in gastric contents, with a higher delivery of Cr(VI) resulting from higher pH values (which causes slower rates of Cr(VI) reduction), shorter stomach transit times, and lower reducing equivalent concentrations. The PBPK model was used to address 4 important sources of variation. First, the model was used to account for normal diurnal variation in gastric lumen factors (e.g., in normal individuals, baseline gastric pH is typically between 1-3 between meals, but rises rapidly to levels of 5-7 at the start of a meal, then returning to baseline levels within a 2-3 hours). Second, the model was used to simulate exposures to different age groups, including infants, children, youths, adults, and elderly, since some age groups (e.g., infants) normally exhibit higher pH values than adults. Agespecific differences in the key factors were incorporated in the modeling to estimate human equivalent lifetime average daily dose corresponding to point of departures determined for mouse SI lesions. Third, the model was used to assess risk to specific populations (proton-pump inhibitor users) that may be sensitive to Cr(VI) due to alterations in gastric pH. Lastly, the model was used to assess the impact of the timing of Cr(VI) exposure events on delivery of Cr(VI) to the SI with respect to their occurrence during or between meals. The implications to HHRA are quantified and discussed.