This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Sodium channel inhibition leading to reduced survival
Point of Contact
- Kellie Fay
- Allie Always
|Author status||OECD status||OECD project||SAAOP status|
|Under Development: Contributions and Comments Welcome||1.29||Under Development|
This AOP was last modified on April 05, 2021 18:16
|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|
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.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||584||Inhibition, sodium channel||Inhibition, sodium channel|
|2||KE||585||Decreased, Sodium conductance 1||Decreased, Sodium conductance 1|
|3||KE||586||Reduced, swimming speed||Reduced, swimming speed|
Relationships Between Two Key Events (Including MIEs and AOs)
|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|
Life Stage Applicability
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
Essentiality of the Key Events
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.