API

Aop: 91

AOP Title

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Sodium channel inhibition leading to reduced survival

Short name:

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sodium channel inhibition 1

Authors

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Kellie Fay

Point of Contact

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Kellie Fay

Contributors

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  • Kellie Fay

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.29 Included in OECD Work Plan


This AOP was last modified on December 03, 2016 16:37

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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

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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.


Background (optional)

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This optional section should be 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.

Instructions

To add background information, click Edit in the upper right hand menu on the AOP page. Under the “Background (optional)” field, a text editable form provides ability to edit the Background.  Clicking ‘Update AOP’ will update these fields.


Summary of the AOP

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Stressors

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Describes stressors known to trigger the MIE and provides evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. The evidence supporting the stressor will typically consist of a brief description and citation of literature showing that particular stressors can trigger the MIE.

Instructions

To add a stressor associated with an AOP, under “Summary of the AOP” click ‘Add Stressor’ will bring user to the “New Aop Stressor” page. In the Name field, user can search for stressor by name. Choosing a stressor from the resulting drop down populates the field. Selection of an Evidence level from the drop down menu and add any supporting evidence in the text box. Click ‘Add stressor’ to add the stressor to the AOP page.


Molecular Initiating Event

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Title Short name
Inhibition, sodium channel Inhibition, sodium channel

Key Events

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Title Short name
Decreased, Sodium conductance 1 Decreased, Sodium conductance 1
Reduced, swimming speed Reduced, swimming speed

Adverse Outcome

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Title Short name
Reduced, feeding 1 Reduced, feeding 1
Increased, predation Increased, predation
Reduced, survival Reduced, survival

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Life Stage Applicability

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Life stage Evidence
Adult Moderate

Taxonomic Applicability

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

Sex Applicability

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Graphical Representation

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Click to download graphical representation template

Overall Assessment of the AOP

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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

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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

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The essentiality of various of the KEs is influential in considering confidence in an overall hypothesised AOP for potential regulatory application being secondary only to biological plausibility of KERs (Meek et al., 2014; 2014a). The defining question for determining essentiality (included in Annex 1) relates to whether or not downstream KEs and/or the AO is prevented if an upstream event is experimentally blocked. It is assessed, generally, then, on the basis of direct experimental evidence of the absence/reduction of downstream KEs when an upstream KE is blocked or diminished (e.g., in null animal models or reversibility studies). Weight of evidence for essentiality of KEs would be considered high if there is direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important key events [e.g., stop/reversibility studies, antagonism, knock out models, etc.) moderate if there is indirect 25 evidence that experimentally induced change of an expected modulating factor attenuates or augments a key event (e.g., augmentation of proliferative response (KEupstream) leading to increase in tumour formation (KEdownstream or AO)) and weak if there is no or contradictory experimental evidence of the essentiality of any of the KEs (Annex 1).

Instructions

To edit the “Essentiality of the Key Events” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Essentiality of the Key Events” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Essentiality of the Key Events” section on the AOP page.


Weight of Evidence Summary

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This involves evaluation of the Overall AOP based on Relative Level of Confidence in the KERs, Essentiality of the KEs and Degree of Quantitative Understanding based on Annexes 1 and 2. Annex 1 (“Guidance for assessing relative level of confidence in the Overall AOP”) guides consideration of the weight of evidence or degree of confidence in the predictive relationship between pairs of KEs based on KER descriptions and support for essentiality of KEs. It is designed to facilitate assignment of categories of high, moderate or low against specific considerations for each a series of defined element based on current experience in assessing MOAs/AOPs. In addition to increasing consistency through delineation of defining questions for the elements and the nature of evidence associated with assignment to each of the categories, importantly, the objective of completion of Annex 1 is to transparently delineate the rationales for the assignment based on the specified considerations. While it is not necessary to repeat lengthy text which appears in earlier parts of the document, the entries for the rationales should explicitly express the reasoning for assignment to the categories, based on the considerations for high, moderate or low weight of evidence included in the columns for each of the relevant elements. 24 While the elements can be addressed separately for each of the KERs, the essentiality of the KEs within the AOP is considered collectively since their interdependence is often illustrated through prevention or augmentation of an earlier or later key event. Where it is not possible to experimentally assess the essentiality of the KEs within the AOP (i.e., there is no experimental model to prevent or augment the key events in the pathway), this should be noted. Identified limitations of the database to address the biological plausibility of the KERs, the essentiality of the KEs and empirical support for the KERs are influential in assigning the categories for degree of confidence (i.e., high, moderate or low). Consideration of the confidence in the overall AOP is based, then, on the extent of available experimental data on the essentiality of KEs and the collective consideration of the qualitative weight of evidence for each of the KERs, in the context of their interdependence leading to adverse effect in the overall AOP. Assessment of the overall AOP is summarized in the Network View, which represents the degree of confidence in the weight of evidence both for the rank ordered elements of essentiality of the key events and biological plausibility and empirical support for the interrelationships between KEs. The AOP-Wiki provides such a network graphic based on the information provided in the MIE, KE, AO, and KER tables. The Key Event Essentiality calls are used to determine the size of each key event node with larger sizes representing higher confidence for essentiality. The Weight of Evidence summary in the KER table is used to determine the width of the lines connecting the key events with thicker lines representing higher confidence.

Instructions

To edit the “Weight of Evidence Summary” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Weight of Evidence Summary”  section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Weight of Evidence Summary” section on the AOP page.


Quantitative Considerations

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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)

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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

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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.