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AOP: 279

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Microtubule interacting drugs lead to peripheral neuropathy

Short name

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The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.0

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Anna Katharina Holzer, Stefan Schildknecht

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Marvin Martens (email point of contact)

Contributors

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Marvin Martens

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page	Revision Date/Time
Binding of microtubule stabilizing agents (MSA) to microtubules	January 29, 2019 10:01
Disturbance in microtubule dynamic instability	January 29, 2019 10:06
Impaired axonial transport	January 29, 2019 10:07
Sensory axonal peripheral neuropathy	January 29, 2019 10:08
Binding of MSAs to microtubules leads to Disturbance in microtubule dynamic instability	January 29, 2019 10:10
Disturbance in microtubule dynamic instability leads to Impaired axonial transport	January 29, 2019 10:11
Impaired axonial transport leads to Sensory axonal peripheral neuropathy	January 29, 2019 10:12

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Peripheral neuropathy is regularly observed as a side-effect in microtubule-targeted chemotherapies. The length of their axons, together with the absence of protection by a blood brain barrier, renders peripheral neurons particularly vulnerable to disturbances in microtubule dynamics.

The present AOP was developed to summarize mechanistic data that support the link between the interaction of “microtubule stabilizing agents” with microtubules (MIE) and sensory axonal peripheral neuropathy (AO), via disturbances in microtubule dynamic instability (KE1) and an impaired axonal transport (KE2).

The present AOP allowed the identification of the following knowledge gaps in the literature: (i) experimental support for the mechanistic link of microtubule interacting drugs with the onset of sensory axonal peripheral neuropathy is generally limited by laborious and circumstantial access to peripheral neurons in vivo and by limited availability of human in vitro models of peripheral neurons; (ii) it is necessary to distinguish the biological consequences of microtubule-stabilizing drugs on the one side, and microtubule-destabilizing compounds on the other; (iii) the link of clinical symptoms to the action of microtubule stabilizers is complicated by incomplete toxicokinetic data, by the time offset between drug treatment and clinical symptoms, and by partial reversibility of the AO following washout of the microtubule-interacting drugs.

The present AOP was developed to contribute to cross systems testing as well as to experimental studies covering the testing of National Toxicology Program compounds.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

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Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1580

Binding of microtubule stabilizing agents (MSA) to microtubules

Binding of MSAs to microtubules

KE	1581	Disturbance in microtubule dynamic instability	Disturbance in microtubule dynamic instability
KE	1582	Impaired axonial transport	Impaired axonial transport

1583

Sensory axonal peripheral neuropathy

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Title	Adjacency	Evidence	Quantitative Understanding

Binding of MSAs to microtubules leads to Disturbance in microtubule dynamic instability	adjacent	Not Specified	Not Specified
Disturbance in microtubule dynamic instability leads to Impaired axonial transport	adjacent	Not Specified	Not Specified
Impaired axonial transport leads to Sensory axonal peripheral neuropathy	adjacent	Not Specified	Not Specified

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

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Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

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Known Modulating Factors

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help