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Development Of A Network Of Adverse Outcome Pathways (AOPs) For Carcinogenicity

Cayley A; Stalford SA; Williams RV;

The prediction of carcinogenicity and related toxicity endpoints has always been a principle area of research for in silico prediction systems. In recent years predictions provided by these systems have become embedded in regulatory guidance, where they may be used to replace or augment other testing methods. Some systems also provide knowledge relating to the potential mode of action (MOA) of a carcinogen which can be used to reason with other in vitro or in vivo evidence and direct the subsequent testing of a compound in a weight of evidence (WOE) approach.

Derek Nexus (DX) is an expert rule-based prediction system with a well-developed knowledge base for carcinogenicity related endpoints. Previously, we have described how knowledge contained in this system was rearranged to capture a molecular initiating event (MIE) to adverse outcome (AO) relationships as opposed to the toxicity endpoint-centric information currently presented in the program. In this work we outline how these relationships have been expanded into full adverse outcome pathways (AOPs) and beyond this into a network of pathways that share common key events (KE) and can be interrogated at different levels.

It is hoped that this network will provide the basis for carcinogenicity predictions for individual compounds and that presenting knowledge in this way will allow the user to better target MOAs of particular interest to their use case, make hypotheses on the human relevance of a given prediction and determine the most appropriate next steps in the testing of a hypothesis.

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