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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.

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Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors during brain development leading to neurodegeneration with impairment in learning and memory in aging

This AOP links chronic NMDA receptors inhibition during brain development to

neurodegeneration in hippocampus and cortex with amyloid plaque deposition and tau

hyperphosphorylation, and impairment of learning and memory, which are considered as

hallmark of Alzheimer's disease. It makes use of some KEs and KERs from AOP 13 and

introduces Neuroinflammation as KE, which is involved in several neurodegenerative

diseases. This AOP is based on the hypothesis of Landrigan and coworkers (2005)

proposing an early origin of neurodegenerative diseases in later life. The chemical initiator

used in this AOP for the empirical support is lead (Pb). In adults, cumulative lifetime Pb

exposure is also associated with decline in cognition, suggesting that long-term exposure

during development or occupational exposure increases the risk to develop

neurodegenerative disease. The long latency period between exposure and late-onset of

effects gives a very broad life-stage applicability. The gap of knowledge is mainly due to

limited quantitative evaluations.

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