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Accelerating Adverse Outcome Pathway Development via Systems Approaches
Citation:
Edwards, S., N. Oki, S. Bell, M. Nelms, AND C. Tan. Accelerating Adverse Outcome Pathway Development via Systems Approaches. SETAC North America 36th Annual Meeting, Salt Lake City, UT, November 01 - 05, 2015.
Impact/Purpose:
Adverse Outcome Pathways can expand and enhance the use of ToxCast and other in vitro toxicity information by providing a mechanistic link to adverse outcomes of regulatory concern. By providing the mechanistic descriptions in a structured way via the AOP-Wiki, we should reduce the time required for risk assessors to review the information and highlights data gaps and uncertainties within the mechanistic description. We are also developing methods to accelerate the process of defining AOPs to increase our coverage of existing ToxCast assay targets and identify biological pathways that aren’t currently covered by existing screening approaches.
Description:
The Adverse Outcome Pathway has emerged as an internationally harmonized mechanism for organizing biological information in a chemical agnostic manner. This construct is valuable for interpreting the results from high-throughput toxicity (HTT) assessment by providing a mechanistic connection to adverse outcomes of regulatory interest. To facilitate the development and use of AOPs, an international knowledgebase (AOPKB; https://aopkb.org) was developed to house this information with the public release of the first module (http://aopwiki.org) in September 2014. However, the AOPs currently stored in the AOPKB include the intended targets for only a small number of HTT assays currently used for toxicity screening. To generate more AOPs within the KB, we have developed bioinformatic approaches to expedite the inclusion of computationally-predicted AOPs (cpAOPs) that include biological pathways containing ToxCast assay targets. A variety of input data sources have been used including large-scale toxicogenomics data such as the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) and public annotation databases such as the Comparative Toxicogenomics Database (CTD). They have been evaluated by comparing against previously-defined modes of action such as liver toxicity via CCl4 exposure. The cpAOPs also include integration of known mechanistic information that has not been previously documented in public annotation databases such as the role for CYP1B1 in AhR-mediated glaucoma. In all, the current cpAOP network provides annotation information for >200 EPA ToxCast assays. Through a crowd-sourcing model enabled by the AOPKB, these cpAOPs can be rapidly assessed by any scientist working in mechanistic toxicology to assemble putative AOPs. Detailed AOP development can be focused on problems where high precision is needed whereas putative AOPs may be sufficient for decisions when less quantitation and/or weight of evidence is required. If the AOPs are then combined with exposure and absorption, distribution, metabolism, excretion (ADME) predictions developed in a similar manner, we can recapitulate the mode of action for a given chemical from reusable components allowing more extensive use of AOPs in risk assessment. [This is an abstract or a proposed presentation and does not necessarily reflect EPA policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.]