Characterizing variability and uncertainty for parameter subset selection in PBPK models

Physiologically based pharmacokinetic (PBPK) models describe the absorption, distribution, metabolism, and excretion of chemicals. Probabilistic PBPK models can be used to produce distributional estimates of human equivalent doses (HEDs), which are external measures of human exposure predicted to result in a target internal dose, generated with Monte Carlo sampling and reverse dosimetry calculations. Very low HED percentiles represent individuals that are more sensitive to possible adverse effects of chemical exposures and are therefore frequently used in risk evaluation. Details of the parameter distributions used in probabilistic PBPK models impact HED distributions, but obtaining precise distributional estimates for all the parameters would be challenging. Therefore, we sought to determine methods that can identify the extent of model parameter influence on extreme HED percentiles. We first analyzed published PBPK models for dichloromethane and chloroform (for inhalation and oral exposures given 3 internal target levels each) by identifying the overall relative importance of parameters using global sensitivity analysis (GSA) methods. Then, we used a novel yet computationally expensive method to analyze the stability and sensitivity of extreme HED percentiles to input parameter distributions. Applying the traditional GSA methods allowed us to identify subsets of parameters most influential for accurately determining 1st and 99th percentiles, but the specific parameters included in those subsets varied for different models and exposure scenarios. Our results demonstrate that better characterizing PBPK model uncertainty by using precise distributional details for influential parameters informed by GSA methods may improve confidence in estimates of extreme percentiles of HEDs.