Focus on hepatotoxic modes-of-action in SEURAT-1: rationale and strategy

This chapter serves as a concise "memorandum" that outlines the rational basis for the major study focus on liver toxicity within the mode-of-action working group (MAWG) of the SEURAT-1 project cluster. An overview is provided on the strategy adopted to implement (hepato)toxicological modes-of-action into the different projects. This approach consists of 3 consecutive steps:
Step 1: identification of relevant toxicological modes-of-action and prioritization of chemicals.
Step 2: development of relevant adverse outcome pathway (AOP) constructs.
Step 3: verification of the draft AOP constructs.
As such, these steps are in line with the overall SEURAT-1 strategy, implying proof-of-concept stratified into 3 distinct levels:
Theoretical level: description of selected modes-of-action/AOPs to a sufficient extent so that they can be used as blueprints for system design.
Systems level: demonstration of integrated systems for associating a chemical with a mode-of-action/AOP category and for predicting points of departure of a pathway of toxicity.
Application level: use of the information derived from predictive systems to support safety assessment and decision-making processes.
Steps 1 and 2 of the strategy described form the basis for the theoretical proof-of-concept level, while step 3 practically elaborates on both the systems and application aspects of the SEURAT-1 vision.