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AOP Title

Sodium channel inhibition leading to reduced survival
Short name: sodium channel inhibition


Kellie Fay


OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

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This AOP page was last modified on 12/11/2016.

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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.

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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
sodium channel, Inhibition Moderate

Key Events

Event Support for Essentiality
Sodium conductance, Decreased Moderate
swimming speed, Reduced Moderate

Adverse Outcome

Adverse Outcome
feeding, Reduced
predation, Increased
survival, Reduced

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
sodium channel, Inhibition Directly Leads to Sodium conductance, Decreased Strong
Sodium conductance, Decreased Indirectly Leads to swimming speed, Reduced Moderate
swimming speed, Reduced Directly Leads to feeding, Reduced
swimming speed, Reduced Directly Leads to predation, Increased
feeding, Reduced Indirectly Leads to predation, Increased
predation, Increased Directly Leads to survival, Reduced
feeding, Reduced Indirectly Leads to survival, Reduced

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Life Stage Applicability

Life Stage Evidence Links
Adult Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links
medaka Oryzias latipes Moderate NCBI
Gammarus pulex Gammarus pulex Moderate NCBI

Sex Applicability

Sex Evidence Links

Graphical Representation

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Overall Assessment of the AOP

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

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

Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

Weight of Evidence Summary

Summary Table
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.

Quantitative Considerations

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)

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).


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.