This AOP is licensed under a Creative Commons Attribution 4.0 International License.

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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Graphical Representation

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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

Status

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Author status	OECD status	OECD project	SAAOP status
Under development: Not open for comment. Do not cite

This AOP was last modified on June 04, 2021 15:17

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

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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

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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)

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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

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

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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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