Incorporating toxicokinetic data and tools to support public health decision making
Citation:
Tan, C. Incorporating toxicokinetic data and tools to support public health decision making. Eurotox 2018, Brussels, BELGIUM, September 02 - 05, 2018.
Impact/Purpose:
Agency decision-making processes concerned with ecological and human health risk have traditionally relied on low throughput in vivo studies involving one chemical at a time. Under current chemicals management legislation, more efficient approaches are required to make a variety of decisions on larger sets of chemicals. : A critical component of any strategy to reduce reliance on resource intensive animal toxicity testing is incorporation of pathway-based biological data. The Adverse Outcome Pathway (AOP) framework arose as a means for interpreting results of high-throughput assays in a biological context of adverse endpoints relevant to regulation of human and ecosystem health. The AOP itself is not chemical specific. Use of AOPs and high-throughput screening results, however, requires consideration of exposure and pharmacokinetic properties or behaviors of chemicals in order to apply these data for risk assessment approaches. The lecture will cover the framework and tools generated to support the consideration of exposure and pharmacokinetics for providing Agency decision makers with a refined approach to prioritizing chemicals based on high throughput toxicity testing, high throughput exposure predictions, and the AOP framework.
Description:
In order to reduce reliance on resource-intensive animal toxicity testing that supports human and ecological health risk assessment, public health agencies are relying more on alternative test methods and strategies to assess risks of injury to health that arise from exposures to chemical substances. Application of these non-animal-based risk assessments require reconciling chemical concentrations sufficient to produce bioactivity, either measured in an in vitro system or predicted using an in silico approach, with those at the relevant in vivo target site as a result of exposure to that chemical in the environment. To address such need, toxicokinetic (TK) consideration can be incorporated in a tiered manner, depending on the availability of TK data, to evaluate the potential for a chemical to reach an in vivo target site given its likely exposure concentrations. In this lecture, a tiered approach is presented to demonstrate a variety of computational approaches that can be used to integrate TK considerations with in vitro dose-response data to support chemical risk assessment. These approaches include (1) characterizing the potential of a chemical to reach a target site based on its structure- and/or physicochemical property-based features; (2) predicting in vivo bioactivity from likely exposure concentrations using classical TK or physiologically based TK models that are linked to toxicodynamics models; and (3) identifying chemicals with potentially active metabolites using in vitro and in silico tools. This lecture will also include discussions on how uncertainties regarding TK properties influence the applications of these tools to support public health decision making. Disclaimer: The views expressed in this abstract are those of the authors and do not represent Agency policy or endorsement.
