Adverse Outcome Pathway Networks: Use of 2D Chemical Structure and Bioactivity Profile to Generate Chemical Categories
Citation:
Nelms, M. AND S. Edwards. Adverse Outcome Pathway Networks: Use of 2D Chemical Structure and Bioactivity Profile to Generate Chemical Categories. SOT Annual Meeting, San Antonio, TX, March 11 - 15, 2018.
Impact/Purpose:
Adverse Outcome Pathways (AOPs) can inform risk assessment involving chemical mixtures by providing a structured description of the mechanisms underlying the chemical toxicity. A first step in this process is defining chemical groups based on specific molecular initiating events and shared structural features. In the short term, this information can provide additional confidence in decisions regarding whether a dose addition or independent action assumption should be made. In the longer term, the AOP can be used to identify intermediate key events as surrogates for the adverse outcome in cases where independent action is required. The AOP can also be used to identify key events that could be used to evaluate dose addition assumptions where the confidence in that choice is not sufficient for the decision context.
Description:
The Adverse Outcome Pathway (AOP) framework has emerged to capitalise on the vast quantity of mechanistic data generated by alternative techniques (such as in vitro and in chemico), as well as advances in systems biology, cheminformatics, and bioinformatics. AOPs provide a scaffold onto which these mechanistic data can be organised to establish a connection between a molecular initiating event (MIE) and an apical adverse outcome. The MIE is the initial interaction between the chemical and the biological system. As such, a detailed understanding of the MIE and the specific interactions between chemicals and the biological molecules underlying the MIE can help us to discern the structural and/or physico-chemical properties that may be required to perturb the MIE. This information can enable chemicals to be grouped based upon their ability to perturb an MIE using both structural and functional criteria. For example, a conserved structural fragment, in vitro activity connected to the MIE, and/or toxicological data connected to downstream key events in the AOP. Subsequently, the use of chemical groups, alongside the information relating to the associated MIE/AOP(s), can be used for a variety of applications. These include, but are not limited to: hazard/risk assessment, prioritisation of chemicals for further testing, and/or identification of the AOP network(s) most likely to be of concern if chemicals are observed to co-occur within the environment. Upon development of chemical groups data gap filling methods such as read-across can be used to provide predictions for chemicals within a chemical group that currently lack relevant toxicological data. This presentation will cover how 2D chemical structure information and bioactivity profiles can be utilised to group chemicals, and how the inclusion of bioactivity profiles may help in the refinement of these chemical groupings for chemical prioritisation and/or hazard/risk assessment. Additionally, this presentation will discuss how chemical categories can be used in conjunction with AOP networks to guide various aspects of mixtures 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.]