Adverse Outcome Pathway Development II: Best Practices

Abstract

Organization of existing and emerging toxicological knowledge into adverse outcome pathway (AOP) descriptions can facilitate greater application of mechanistic data, including those derived through high-throughput in vitro, high content omics and imaging, and biomarker approaches, in risk-based decision making. The previously ad hoc process of AOP development is being formalized through development of internationally harmonized guidance and principles. The goal of this article was to outline the information content desired for formal AOP description and some rules of thumb and best practices intended to facilitate reuse and connectivity of elements of an AOP description in a knowledgebase and network context. For example, key events (KEs) are measurements of change in biological state that are indicative of progression of a perturbation toward a specified adverse outcome. Best practices for KE description suggest that each KE should be defined as an independent measurement made at a particular level of biological organization. The concept of "functional equivalence" can help guide both decisions about how many KEs to include in an AOP and the specificity with which they are defined. Likewise, in describing both KEs and evidence that supports a causal linkage or statistical association between them (ie, a key event relationship; KER), best practice is to build from and contribute to existing KE or KER descriptions in the AOP knowledgebase rather than creating redundant descriptions. The best practices proposed address many of the challenges and uncertainties related to AOP development and help promote a consistent and reliable, yet flexible approach.

The potential of AOP networks for reproductive and developmental toxicity assay development

“…It also provides biological context for mechanistic information from existing assays, which can help increase confidence in, and utility of their results for risk assessment and regulatory decision-making. In summary, an AOP is a detailed description of a chain of events following a molecular initiating event (MIE, a direct interaction of a chemical with a molecular target) leading to an adverse outcome (AO) at the individual or population level through a series of intermediate key events (KE) spanning different levels of biological organization [4]. Within an AOP context, KEs help define relevant needs for assay improvement or development.…”

Adverse Outcome Pathways--Organizing Toxicological Information to Improve Decision Making

“…2A) (Ankley et al, 2010). When describing a KE, emphasis is placed on describing the underlying biologic changes, as well as the methods available for measuring changes in the biologic state (Villeneuve et al, 2014b). The second basic component of an AOP is the KER (Table 1).…”

“…the AOP (Villeneuve et al, 2014b). Where appropriate information is available, the KER also contains the quantitative description of the relationship between KEs (i.e., the change in the downstream KE that would be expected given a measured/ predicted change in the upstream KE) and factors known to modulate that relationship.…”

“…The final consideration when defining and evaluating AOPs is the applicability (or relevance) of that AOP across various species, life stages, or sexes (Villeneuve et al, 2014b;Groh et al, 2015). In defining the AOP, this is typically restricted to those species for which empirical evidence exists.…”

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.…”