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Aop: 91

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

Sodium channel inhibition leading to reduced survival

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

sodium channel inhibition 1

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

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

Kellie Fay

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

Allie Always (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Kellie Fay
Allie Always

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help

Author status	OECD status	OECD project	SAAOP status
Under Development: Contributions and Comments Welcome		1.29	Under Development

This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page	Revision Date/Time
Inhibition, sodium channel	September 16, 2017 10:15
Decreased, Sodium conductance 1	September 16, 2017 10:15
Reduced, swimming speed	November 29, 2016 19:16
Reduced, feeding 1	November 29, 2016 19:16
Increased, predation	December 03, 2016 16:37
Reduced, survival	December 03, 2016 16:37
Inhibition, sodium channel leads to Decreased, Sodium conductance 1	December 03, 2016 16:37
Decreased, Sodium conductance 1 leads to Reduced, swimming speed	December 03, 2016 16:37
Reduced, swimming speed leads to Reduced, feeding 1	December 03, 2016 16:37
Reduced, swimming speed leads to Increased, predation	December 03, 2016 16:37
Reduced, feeding 1 leads to Increased, predation	December 03, 2016 16:37
Increased, predation leads to Reduced, survival	December 03, 2016 16:37
Reduced, feeding 1 leads to Reduced, survival	December 03, 2016 16:37

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

Pharmaceuticals designed as anti-arrhythmics, anti-epileptics and some anti-depressants inhibit voltage-gated sodium channels (NaV1) to prevent or diminish action potentials. Natural toxins, such as tetrodotoxin, act in the same manner as a defensive or predatory venom. In neuro-muscular junctions, acetyl choline is released from the neuron, enters the synaptic cleft, and binds nicotinic acetylcholine receptors on the post-synaptic muscle fiber, causing a slight local depolarization. Sodium channels open in response to this depolarization, allowing sodium ions to enter the cell, causing rapid depolarization and the initiation of an action potential. Depolarization of the muscle fiber triggers calcium channels to release calcium ions from internal stores. The flood of calcium ions causes the muscle fiber to contract. Inhibition of sodium channels has a direct effect on muscle contraction. In fish and other aquatic organisms, exposure to sodium channel inhibitors results in slower swimming speeds and reduced feeding.

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)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

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

584

Inhibition, sodium channel

KE	585	Decreased, Sodium conductance 1	Decreased, Sodium conductance 1
KE	586	Reduced, swimming speed	Reduced, swimming speed

AO	587	Reduced, feeding 1	Reduced, feeding 1
AO	588	Increased, predation	Increased, predation
AO	592	Reduced, survival	Reduced, survival

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

Inhibition, sodium channel leads to Decreased, Sodium conductance 1	adjacent	High
Reduced, swimming speed leads to Reduced, feeding 1	adjacent
Reduced, swimming speed leads to Increased, predation	adjacent
Increased, predation leads to Reduced, survival	adjacent

Decreased, Sodium conductance 1 leads to Reduced, swimming speed	non-adjacent	Moderate
Reduced, feeding 1 leads to Increased, predation	non-adjacent
Reduced, feeding 1 leads to Reduced, survival	non-adjacent

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

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

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

Life stage	Evidence
Adult	Moderate

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Term	Scientific Term	Evidence	Link
medaka	Oryzias latipes	Moderate	NCBI
Gammarus pulex	Gammarus pulex	Moderate	NCBI
hydra	hydra		NCBI

Sex Applicability

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

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

This putative AOP is based on a few studies in aquatic species and biological plausability. It should be considered speculative and untested.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Life Stage Applicability, Taxonomic Applicability, Sex Applicability This AOP applies to organisms which rely on muscle contraction for feeding and/or predator avoidance. Embryonic stages may not be applicable.

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

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

Summary Table Carbamazepine is an anti-epileptic drug which targets the alpha subunit of NaV1 channels, inhibiting the influx of sodium ions. Medaka exposed to 6.15 mg/L carbamazepine for 9 days showed slower swimming speed and increased time to feeding compared to controls (Nassef et al., 2010). This concentration was 10% of the 96 h LC50 determined in a previous study (Nassef et al., 2009). The amphipod gammarus pulex exposed to 10 ng/L carbamazepine for 1.5 h also had reduced swimming activity compared to controls (DeLange, 2006). Hydra attenuata exposed for 96 h to 50 mg/L carbamazepine had reduced feeding (Quinn et al., 2008).

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

Behavioral responses, such as reduced foraging, may be more appropriate risk assessment endpoints than lethality because they occur, generally, at lower concentrations of toxicant than what is required for lethality (Scott and Sloman, 2004).

References

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

De Lange, H. J., et al. (2006). "Behavioural responses of Gammarus pulex (Crustacea, Amphipoda) to low concentrations of pharmaceuticals." Aquat Toxicol 78(3): 209-216.

Nassef, M., et al. (2010). "In ovo nanoinjection of triclosan, diclofenac and carbamazepine affects embryonic development of medaka fish (Oryzias latipes)." Chemosphere 79(9): 966-973.

Quinn, B., et al. (2008). "An investigation into the acute and chronic toxicity of eleven pharmaceuticals (and their solvents) found in wastewater effluent on the cnidarian, Hydra attenuata." Science of The Total Environment 389(2–3): 306-314.

Scott, GR and KA Sloman. 2004. The effect of environmental pollutants on complex fish behavior: integrating behavioural and physiological indicators of toxicity. Aquatic Toxicology 68: 369-392.