Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity

Abstract

Recent developments have prompted the transition of empirically based testing of late stage toxicity in animals for a range of different endpoints including neurotoxicity to more efficient and predictive mechanistically based approaches with greater emphasis on measurable key events early in the progression of disease. The adverse outcome pathway (AOP) has been proposed as a simplified organizational construct to contribute to this transition by linking molecular initiating events and earlier (more predictive) key events at lower levels of biological organization to disease outcomes. As such, AOPs are anticipated to facilitate the compilation of information to increase mechanistic understanding of pathophysiological pathways that are responsible for human disease. In this review, the sequence of key events resulting in adverse outcome (AO) defined as parkinsonian motor impairment and learning and memory deficit in children, triggered by exposure to environmental chemicals has been briefly described using the AOP framework. These AOPs follow convention adopted in an Organization for Economic Cooperation and Development (OECD) AOP development program, publically available, to permit tailored application of AOPs for a range of different purposes. Due to the complexity of disease pathways, including neurodegenerative disorders, a specific symptom of the disease (e.g. parkinsonian motor deficit) is considered as the AO in a developed AOP. Though the description is necessarily limited by the extent of current knowledge, additional characterization of involved pathways through description of related AOPs interlinked into networks for the same disease has potential to contribute to more holistic and mechanistic understanding of the pathophysiological pathways involved, possibly leading to the mechanism-based reclassification of diseases, thus facilitating more personalized treatment.

Keywords: Key event; Key event relationship; Mechanistic understanding; Neurotoxicity; Quantitation; Weight of evidence.

Fig. 1

An AOP consists of key events (KEs) and key events relationships (KERs) at different levels of biological organization starting from an initial interaction of a chemical with the biological system (molecular initiating event; MIE) through a sequence of KEs (cellular, tissue, organ and organism) leading to an adverse outcome (AO) of regulatory relevance that represents overt adversity at either organism or population level. At sufficient concentrations and durations of exposure, KE up will trigger KE down, overcoming cell defence mechanisms and adaptation processes.

Fig. 2

An integrated Approach to Testing and Assessment (IATA) designed for fit-for-purpose consideration of testing strategies integrates multiple sources of existing information (human data, in vivo, in vitro and non-testing data) and guides the targeted generation of new data when required. The degree to which IATA needs to be complemented by information as delineated in the associated AOP is dependent on the decision context.

Fig. 3

Graphical representation of the key events at the cellular, organ and organism level triggered by binding of an antagonist to the NMDA receptor (MIE) and resulting in the adverse outcome (AO), defined as impairment of learning and memory.

Fig. 4

Schematically represented molecular initiating event (MIE), key events identified at different biological levels and adverse outcome (AO) of the AOP entitled: Inhibition of the mitochondrial complex I of nigra-striatal neurons leads to parkinsonian motor deficits.

Fig. 5

Multiple AOPs sharing common KEs (CKE) (nodes) can be assembled into networks. AOP networks more realistically capture the complexity of biological systems where single molecular initiating events (MIE) can trigger multiple adverse outcomes and multiple MIEs can lead through a cascade of key events (KE) to the same adverse outcome (AO). Development of additional AOPs contributes to the description of such networks.