Kirman CR, Proctor D, Suh M, Thompson CM, Harris MA, Haws LC, Hays SM. 2014. Variation analysis of PBPK model parameters for describing the delivery of Cr(VI) to the small intestines of humans. Presented at the Society of Toxicology’s 53rd Annual Meeting, March 23-27, Phoenix, AZ.
Sensitivity analyses were used to identify PBPK model parameters that are important for predicting the delivered dose of Cr(VI) to the small intestines in humans. These include physiological parameters (GI lumen pH, transit rates, reduction capacities, and volumes), chemical-specific parameters (pH-dependent reduction rate, absorption rates), and exposure parameters (number of drinking events, event duration). Monte Carlo methods were used to characterize the impact of parameter variation on PBPK model predictions for Cr(VI) internal dose. Coefficients of variation for the key model parameters ranged from approximately 25% to 120%. The impact of correlations between model parameters was assessed. Monte Carlo simulations were conducted for neonates, infants/children, youths, adults, and elderly, using two exposure levels, and two measures of internal dose to the small intestines. Model parameters contributing to greater than 10% of the variance in the predictions for both dose measures include the reduction rate constant and gastric transit rate. Stomach lumen volume was an important contributor to gastric flux, and the absorption rate constant was an important contributor to SI flux. At high doses, the number of drinking water events per day and exposure event time (during fed or fasted states) also become an important variables. The results of the initial analyses were used to calculate data-derived extrapolation factors to account for inter-individual variation. The ratios of the predicted 95th percentile to predicted mean lifetime average dose of CrVI delivered to the small intestines, ranged from approximately 2 to 4. These results indicates the default value of 3 (USEPA) or 4 (IPCS) for intraspecies variation in toxicokinetic processes sufficiently characterizes variability in Cr(VI) SI tissue dose.