Citation:

Edwards, S. Effectively connecting exposure information with the Adverse Outcome Pathway (AOP) framework to support high throughput risk assessment. International Society of Exposure Science Annual Meeting, Durham, NC, October 15 - 19, 2017.

Impact/Purpose:

High throughput toxicity testing (HTT) holds the promise of providing data for tens of thousands of chemicals that currently have no data due to the cost and time required for animal testing. Interpretation of these results require information linking the perturbations seen in vitro with adverse outcomes in vivo and requires knowledge of how estimated exposure to the chemicals compare to the in vitro concentrations that show an effect. This abstract discusses how Adverse Outcome Pathways (AOPs) can be used to link HTT with adverse outcomes of regulatory significance and how Aggregate Exposure Pathways (AEPs) can connect concentrations of environment stressors at a source with an expected target site concentration designed to provide exposure estimates that are comparable to concentrations identified in HTT.

Description:

Risk assessment processes have traditionally relied on low throughput in vivo studies involving one chemical at a time, and the power of in vitro toxicity testing arises from its ability to analyze a large number of chemicals in a high throughput (HT) manner. In order to provide the biological context necessary for interpreting these HT in vitro results, the Adverse Outcome Pathway (AOP) framework has emerged to link the activation of an observed in vitro response to a molecular initiating event (MIE), which is causally connected to an adverse outcome in biological organisms. The Adverse Outcome Pathway (AOP) framework was developed as an organizing principle for toxicological information, and an international repository has been built for this information (http://aopkb.org/). This international effort has enabled better collaboration and information exchange within the research community; it also provides a more uniform representation of mechanistic information for the risk assessment and regulatory communities. Interpretation of AOPs and high-throughput screening results, however, require consideration of exposure and pharmacokinetic properties of chemicals in order to be fully applicable to risk assessment approaches. Bringing external exposure to a target site exposure at the cellular/tissue level will better match exposure predictions with the MIE described in the AOP framework, and thus, allow for better integration of HT in vitro toxicity data. At the same time, exposure data, which currently reside in different silos, require a mechanism for better organization. Lessons learned from the AOP framework can be applicable to a similar framework for exposure science, and connecting exposure predictions at the target site of the MIE with adverse outcomes predicted by the AOP should result in more effective use of in vitro dose-response data. [This is an abstract of a proposed presentation and does not necessarily reflect U.S.EPA policy.]

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