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Integration of chemical-specific exposure and pharmacokinetic considerations with the chemical-agnostic adverse outcome pathway framework
Leonard, J. Integration of chemical-specific exposure and pharmacokinetic considerations with the chemical-agnostic adverse outcome pathway framework. ORD National Postdoctoral fellow forum, NC, Durham, April 11 - 12, 2017.
Integrating exposure and pharmacokinetics along with in vitro dose-response data can be used to aid in the prioritization of data-poor chemicals for additional testing.
Traditional toxicity testing provides insight into the mechanisms underlying toxicological responses but requires a high investment in large numbers of resources. The new paradigm of testing approaches involves rapid screening of thousands of chemicals across hundreds of biological targets through use of in vitro assays. However, these approaches do not specifically connect such high-throughput (HT) toxicity testing results with apical adverse outcomes. The chemical-agnostic Adverse Outcome Pathway (AOP) concept addresses this issue by acting as a scaffold onto which pathway-based data can be arranged, in order to aid in the understanding of in vitro toxicity testing results. Application of HT toxicity testing and the AOP framework in chemical-specific risk assessment requires reconciling chemical concentrations sufficient to produce activity in vitro with those that trigger a molecular initiating event (MIE) at the relevant target site in vivo. To address this need, a tiered approach was developed that involves consideration of chemical-specific exposure and adsorption, distribution, metabolism, excretion (ADME) properties. This tiered approach was applied in a series of case studies to evaluate the potential for chemicals to reach target sites of exposure (TSEs), along with whether concentrations at these sites are sufficient for inducing an AO in vivo, to aid in chemical screening.
Record Details:Record Type: DOCUMENT (PRESENTATION/POSTER)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL EXPOSURE RESEARCH LABORATORY
COMPUTATIONAL EXPOSURE DIVISION
HUMAN EXPOSURE & DOSE MODELING BRANCH