Applying New Approach Methods for Toxicokinetics for Chemical Risk Assessment

Toxicokinetic (TK) modeling provides critical information linking chemical exposures to tissue concentrations, predicting persistence in the body, and determining route(s) of elimination. Unfortunately, toxicokinetic data for use in modeling dosimetry are not available for most chemicals in commerce and the environment. Therefore, researchers and regulatory scientists from the international consortium of the Accelerating the Pace of Chemical Risk Assessment (APCRA) initiative have developed a flexible framework for characterizing the suitability of toxicokinetic new approach methods (NAMs) to address toxicology questions. Here we describe this framework for decision makers to apply the tools and data of high throughput toxicokinetics (HTTK). HTTK combines chemical-specific in vitro measures of TK with reproducible transparent and open-source TK models. HTTK supports interpretation of data from in vitro bioactivity NAMs in a public health risk context and enhances interpretation of biomonitoring data. HTTK is constrained by the limited chemical-specific in vitro TK data available to calibrate the models. Further there is need to justify the model assumptions that allow for HTTK predictions. A tiered framework has been developed focusing on two key aspects: 1) the regulatory decision context and 2) chemical properties and data. Differing levels of certainty are needed for relative risk prioritization, prospective risk assessment, and for protecting susceptible populations. Here we have described HTTK with respect to what can be measured and modeled with HTTK, the relevant decision contexts, applicable chemistry, value of information, and certainty of predictions. In some cases, quantitative structure-property relationship (QSPR) models exist as alternatives to measurement, and we discuss when they are appropriate. We provide a series of examples applying the decision trees in specific public health scenarios. The examples illustrate that writing short responses, prompted by the decision trees and supported by the discussion and references collected here, may provide defensible written justification for or against the use of HTTK. The framework presented is intended to serve as a guide to chemical regulators and risk assessors who are interested to know when and where HTTK might be used for public health safety decision making and when expert guidance is needed.

WAMBAUGH John;  PAUL FRIEDMAN Katie;  BEAL Marc A;  MOFFAT Ivy;  HUGHES Michael F.;  NONG Andy;  DORNE Jean-Lou C. M.;  ASHRAF Muhammad Waqar;  BARTON-MACLAREN Tara;  DEVITO Michael;  FERGUSON Stephen;  JUDSON Richard;  LONG Alexandra;  PAINI Alicia;  SAMPANI Stavroula;  THOMAS Russell;  WETMORE Barbara; 

2025-08-29

AMER CHEMICAL SOC

JRC140364

1520-5010 (online),   

https://pubs.acs.org/doi/10.1021/acs.chemrestox.5c00161,    https://doi.org/10.1021/acs.chemrestox.5c00161,    https://publications.jrc.ec.europa.eu/repository/handle/JRC140364,   

10.1021/acs.chemrestox.5c00161 (online),