Predicting nonlinear relationships between external and internal concentrations with physiologically based pharmacokinetic modeling

• Type of Material: Article
• Authors: Daniel Hoer, U.S. Environmental Protection Agency; Hugh A. Barton, Mystic; Alicia Paini, European Commission, Joint Research Centre; Michael Bartels, ToxMetrics; Brandall Ingle, U.S. Environmental Protection Agency; Jeanne Domoradzki, Corteva Agriscience; Jeffrey Fisher, ScitoVation; Michelle Embry, Health and Environmental Sciences Institute; Philip Villanueva, U.S. Environmental Protection Agency; David Miller, U.S. Environmental Protection Agency; James Nguyen, U.S. Environmental Protection Agency; Qiang Zhang, Emory University; Stephen W. Edwards, RTI International; Yu-Mei Tan, U.S. Environmental Protection Agency
• Language: English
• Date: 2022-02-15
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1016%2Fj.taap.2022.115922
• Title of Journal or Parent Work: Toxicology and Applied Pharmacology
• Volume: 440
• Start Page: 115922
• Grant/Funding Information: This work was supported in part by the Health and Environmental Sciences Institute PBPK Committee.
• Keywords: saturation of clearance; nonlinear pharmacokinetics; saturation of absorption; animal study design; Physiologically based pharmacokinetic (PBPK); internal concentrations
• Research Categories: Health Sciences, Pharmacology

Abstract

Although external concentrations are more readily quantified and often used as the metric for regulating and mitigating exposures to environmental chemicals, the toxicological response to an environmental chemical is more directly related to its internal concentrations than the external concentration. The processes of absorption, distribution, metabolism, and excretion (ADME) determine the quantitative relationship between the external and internal concentrations. ADME processes are often susceptible to saturation at high concentration, which can lead to nonlinear changes in internal concentrations that deviate from proportionality. Using generic physiologically-based pharmacokinetic (PBPK) models, we explored how saturable absorption or clearance influence the shape of the internal to external concentration (IEC) relationship. We used the models for hypothetical chemicals to show how differences in kinetic parameters can impact the shape of an IEC relationship; and models for styrene and caffeine to explore how exposure route, frequency, and duration impact the IEC relationships in rat and human exposures. We also analyzed available plasma concentration data for 2,4-dichlorophenoxyacetic acid to demonstrate how a PBPK approach can be an alternative to common statistical methods for analyzing dose proportionality. A PBPK modeling approach is a useful tool that can be used in early stages of a chemical safety assessment program to optimize the design of longer-term animal toxicity studies or to interpret study results.