Abstract
Toxicological responses to stressors are more complex than the simple one-biological-perturbation to one-adverse-outcome model portrayed by individual adverse outcome pathways (AOPs). Consequently, the AOP framework was designed to facilitate de facto development of AOP networks that can aid in the understanding and prediction of pleiotropic and interactive effects more common to environmentally realistic, complex exposure scenarios. The present study introduces nascent concepts related to the qualitative analysis of AOP networks. First, graph theory-based approaches for identifying important topological features are illustrated using 2 example AOP networks derived from existing AOP descriptions. Second, considerations for identifying the most significant path(s) through an AOP network from either a biological or risk assessment perspective are described. Finally, approaches for identifying interactions among AOPs that may result in additive, synergistic, or antagonistic responses (or previously undefined emergent patterns of response) are introduced. Along with a companion article (part I), these concepts set the stage for the development of tools and case studies that will facilitate more rigorous analysis of AOP networks, and the utility of AOP network-based predictions, for use in research and regulatory decision-making. The present study addresses one of the major themes identified through a Society of Environmental Toxicology and Chemistry Horizon Scanning effort focused on advancing the AOP framework. Environ Toxicol Chem 2018;37:1734-1748. © 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
Highlights
The adverse outcome pathway (AOP) framework uses a modular structure to organize information concerning the linkage between a molecular-level perturbation of a biological system and the adverse outcome(s) that perturbation may cause
As part of a Society of Environmental Toxicology and Chemistry (SETAC)-sponsored Pellston Workshop that focused on advancing the AOP framework, the development and application of AOP networks was identified as one of the major themes that emerged from a review of more than 300 questions submitted by the scientific, risk assessment, and regulatory communities (LaLone et al 2017)
The need to consider concurrent effects on multiple AOPs and their potential interactions was identified as a major theme through the SETAC Horizon Scanning exercise on “Advancing the utility of the AOP framework in research and regulation” (Lalone et al 2017)
Summary
The adverse outcome pathway (AOP) framework uses a modular structure to organize information concerning the linkage between a molecular-level perturbation of a biological system and the adverse outcome(s) that perturbation may cause. In the companion article (part I), Knapen et al (2018) highlight the distinction between network-guided AOP development on the one hand (which follows the principles outlined for development of individual AOP descriptions), and deriving AOP networks from available information in the AOP knowledgebase on the other hand (Society for the Advancement of Adverse Outcome Pathways 2017). Filters and information layers derived from structured fields in the AOP knowledgebase were proposed as useful techniques for customizing the global AOP network. Filtering and layering concepts were applied in a number of case studies to demonstrate how AOP networks can be built to provide answers to different types of questions (Knapen et al 2018)
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