Quantifying uncertainty in interspecies and intraspecies extrapolation for equipotent doses using a PBPK model

In traditional human health chemical risk assessments, one applies a series of uncertainty factors (UFs) to a point of departure (POD) external dose or concentration to obtain a reference dose (RfD) or concentration (RfC) that is assumed to be without appreciable lifetime risk for humans. All of the aforementioned quantities (PODs, UFs, RfDs, and RfCs) are scalars in the traditional paradigm, but the World Health Organization (WHO) International Programme on Chemical Safety (IPCS) has proposed a new risk assessment paradigm designed to determine a probabilistic RfD or RfC for any given chemical. In the IPCS approach, assessment factors (AFs) described by probability distributions rather than scalar UFs are applied to a distributional estimate of POD such as one might obtain through dose response modeling. Just as some of the traditional UFs account for interspecies (e.g., rat-to-human) and intraspecies (e.g., average-to-sensitive-human) differences in pharmacokinetics (PK) and pharmacodynamics (PD), the IPCS method incorporates corresponding AFs for interspecies and intraspecies differences. IPCS has proposed default AFs described by lognormal distributions, so we sought to determine whether the lognormality assumption is appropriate for PK AFs by using PBPK models together with information about uncertainty and variability in various anatomical and physiological quantities to perform interspecies and intraspecies extrapolations. As an illustrative example, we constructed probability distributions for PK AFs for dichloromethane (DCM), a chemical found in products such as paint thinners and solvents that has been associated with hepatic and neurological toxic effects in rodents. To account for PK variability in humans (resulting from differences in metabolic rates, body masses, etc.), we used Monte Carlo methods to randomly draw values for the parameters in a DCM PBPK model from their respective distributions, used reverse dosimetry to calculate human equivalent doses and concentrations based on animal PODs, calculated the corresponding AFs, and then compared the distributions of these AFs to various common probability distributions (e.g., normal and lognormal distributions). We determined which distributional forms are most appropriate for PK AFs for various types of exposure scenarios and internal dose metrics for DCM. In the future we plan to expand upon these results by considering PBPK models for other chemicals to determine whether our results for DCM AFs can be generalized.

Impact/Purpose

We sought to determine the distributional forms of pharmacokinetic assessment factors (the distributional analogs of uncertainty factors) by using PBPK models together with information about uncertainty and variability in various anatomical and physiological quantities to perform interspecies and intraspecies extrapolations.

Citation

Meade, A., C. Schacht, D. Kapraun, P. Schlosser, A. Bernstein, AND H. Tran. Quantifying uncertainty in interspecies and intraspecies extrapolation for equipotent doses using a PBPK model. Society of Toxicology Annual Meeting (Virtually), NA, March 12 - 26, 2021.

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