Applying New Approach Methods for Toxicokinetics for Chemical Risk Assessment.

Abstract

Toxicokinetic (TK) modeling provides critical information linking chemical exposures to tissue concentrations, predicting persistence in the body and determining the route(s) of elimination. Unfortunately, TK data are not available for most chemicals in commerce and the environment. To better understand and address these important information gaps, researchers and regulatory scientists from the international consortium of Accelerating the Pace of Chemical Risk Assessment herein present a flexible framework for characterizing the suitability of TK new approach methods (NAMs) to address chemical risk questions. High throughput toxicokinetics (HTTK) combines chemical-specific in vitro measures of TK with reproducible transparent and open-source TK models. HTTK supports the interpretation of data from in vitro bioactivity NAMs in a public health risk context and enhances the interpretation of biomonitoring data. 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 HTTK is described with respect to measurement and modeling applications, 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 are discussed when they are appropriate. A series of examples applying the decision trees in specific public health scenarios are provided to 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 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 or risk decision making and when further expert guidance is needed.