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OECD Series on Adverse Outcome Pathways

An Adverse Outcome Pathway (AOP) describes a logical sequence of causally linked events at different levels of biological organisation, which follows exposure to a chemical and leads to an adverse health effect in humans or wildlife. AOPs are the central element of a toxicological knowledge framework, promoted by member countries through OECD, built to support chemical risk assessment based on mechanistic reasoning. These AOPs are available in the AOP Wiki, an interactive and virtual encyclopaedia for AOP development. Following their development and review, the endorsed AOPs are published the OECD Series on Adverse Outcome Pathways. As scientific knowledge progresses, the publication of an AOP in this series does not preclude the regular update or new contributions to a given AOP in the AOP Wiki. While the AOP Wiki is a dynamic tool, only impactful changes to the AOP will be reflected in subsequent updates of the published AOP. The number 1 in the OECD Series on Adverse Outcome Pathways is the Users’ Handbook, which is a supplement to the Guidance Document for developing and assessing AOPs. This handbook contains an updated template for AOP development and provides focused and practical instructions for both AOP developers and reviewers.

English

Adverse Outcome Pathway on Inhibition of the mitochondrial complex I of nigro-striatal neurons leading to parkinsonian motor deficits

This AOP describes the linkage between inhibition of complex I (CI) of the mitochondrial respiratory chain and motor deficit as in parkinsonian disorders. Binding of an inhibitor to CI has been defined as the molecular initiating event (MIE) that triggers mitochondrial dysfunction, impaired proteostasis, which then cause degeneration of dopaminergic (DA) neurons. Neuroinflammation is triggered early in the neurodegenerative process and exacerbates it significantly. These causatively linked cellular key events result in motor deficit symptoms, typical for parkinsonian disorders, including Parkinson's disease (PD), described as the Adverse Outcome (AO). The weight-of-evidence supporting the relationship between the described key events is based mainly on effects observed after an exposure to the chemicals rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This AOP could apply for chemicals having structural similarities to the stressors, chemicals binding to CI and supports the mechanistic biological plausibility in the process of evaluation and integration of the epidemiological studies into the risk assessment.

English

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