Adverse outcome pathways: opportunities, limitations and open questions

Abstract

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.

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

“…Consequently, most AOPs pages should define a single, non-branching, sequence of KEs linked by KERs. However, it is recognised that in some cases there may be exceptions for which representation of a simple AOP network on an AOP page is a more pragmatic unit of development and evaluation (see Leist et al 2017 for examples and further explanation). Under certain circumstances, representation of a branched structure on an AOP page is acceptable, so long as the principles of modularity of the KEs and KERs and overall coherence to the framework is maintained.…”

Adverse outcome pathways

“…Recently, Leist et al (2017) have contributed a comprehensive article about adverse outcome pathways (AOP) to our journal. In recent years, the AOP concept has attracted some attention in the field of toxicology (Vinken et al 2017;Ankley et al 2010).…”

“…In recent years, the AOP concept has attracted some attention in the field of toxicology (Vinken et al 2017;Ankley et al 2010). An AOP is defined as a sequence of events that begins with a molecular initiating event, progressed through a series of key events to finally lead to an adverse outcome (Leist et al 2017). Given this definition one may be surprised why some regulators consider the AOP concept a new toxicological construct, because toxicologists have known since decades that it is important to identify initial molecular events and mechanisms that finally cause an adverse effect.…”

“…Currently, AOPs have to be presented as a unidirectional chain of events (Leist et al 2017). However, a mechanism of toxicity may include positive feedback loops.…”

Stem cells in toxicological research

“…This field of research is of high interest, since it offers the perspective of an unlimited supply of all relevant human cell types that can be applied for in vitro toxicity tests (Leist et al 2017). Research efforts have focused particularly on stem cell-derived cardiomyocyte and hepatocyte like cells and on developmental toxicity as well as developmental neurotoxicity (Waldmann et al 2017;Shinde et al 2015Shinde et al , 2016Meganathan et al 2015).…”