Adverse Outcome Pathway (AOP) Development I: Strategies and Principles

Abstract

An adverse outcome pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organization of regulatory relevance. Systematic organization of information into AOP frameworks has potential to improve regulatory decision-making through greater integration and more meaningful use of mechanistic data. However, for the scientific community to collectively develop a useful AOP knowledgebase that encompasses toxicological contexts of concern to human health and ecological risk assessment, it is critical that AOPs be developed in accordance with a consistent set of core principles. Based on the experiences and scientific discourse among a group of AOP practitioners, we propose a set of five fundamental principles that guide AOP development: (1) AOPs are not chemical specific; (2) AOPs are modular and composed of reusable components-notably key events (KEs) and key event relationships (KERs); (3) an individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation; (4) networks composed of multiple AOPs that share common KEs and KERs are likely to be the functional unit of prediction for most real-world scenarios; and (5) AOPs are living documents that will evolve over time as new knowledge is generated. The goal of the present article was to introduce some strategies for AOP development and detail the rationale behind these 5 key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and is intended to foster greater consistency in AOP development.

Users' Handbook supplement to the Guidance Document for developing and assessing Adverse Outcome Pathways

“…Through their defacto construction as more AOPs are added to the AOP-KB, AOP networks can be viewed as capturing broader knowledge concerning the range of possible AOs a perturbation may cause, or the range of ways in which a particular adverse outcome may occur. AOP networks are also critical for addressing exposures to multiple stressors that lead to the same AO or to individual stressors that perturb multiple MIEs (Knapen et al, 2015;Villeneuve et al, 2014a, b) and for understanding potential interactions between co-occurring AOPs.…”

“…They do not necessarily provide a comprehensive molecular description of every aspect of the biology involved. With that in mind, the following "rules of thumb" can help guide the process of KE definition (Villeneuve et al 2014a, b):…”

“…The following are some general recommendations and "rules of thumb" concerning how specifically to define a KE (see also Villeneuve et al 2014a, b):…”

Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death

“…In accordance with previously defined guidance for AOP development, which identify KEs as measurable changes in biology, methods for assessing each KE are also identified (Table 2; Villeneuve et al, 2014). The KE descriptions in each section typically include: (a) an outline of the "normal" biology occurring at the specified level of biological organization, (b) support for biological plausibility linking one KE to another, and (c) when available, empirical evidence supporting those KERs.…”

Integrated Testing Strategies for Skin Sensitization Hazard and Potency Assessment—State of the Art and Challenges

“…Examples are omics data, cell-based assays with dose-response curves for both cell marker induction and cytotoxicity, reactivity assays of reaction kinetics or peptide depletion, and diverse in silico readouts: molecular descriptors, structural alerts, predictions of in vivo response. In an effort to organize these data in the context of evolving mechanistic knowledge to understand the adverse effects of chemicals, the Organization for Economic Co-operation and Development (OECD) coordinates the development of Adverse Outcome Pathways (AOP) [6][7][8]. The AOP for skin sensitization triggered by chemicals that bind covalently to proteins [9] includes four key events (KE) that occur after a substance (parent chemical or abiotically transformed product) penetrates through the skin and is potentially transformed into active metabolites: KE1: covalent binding to skin proteins; KE2: activation of inflammatory cytokines and induction of cyto-protective genes in the keratinocyte; KE3: activation (induction of inflammatory cytokines and surface molecules) and mobilization of dendritic cells in the skin; KE4: activation and proliferation of antigen-specific T-cells.…”