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Point of Contact
Kellie Fay (email point of contact)
- Kellie Fay
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite||1.29||Under Development|
This AOP was last modified on January 27, 2018 15:34
|Inhibition, sodium channel||September 16, 2017 10:15|
|Increased, Atrioventricular block and bradycardia||September 16, 2017 10:14|
|Increased, Respiratory distress/arrest||September 16, 2017 10:14|
|N/A, hypoxia||December 03, 2016 16:37|
|Increased, amputations||December 03, 2016 16:37|
|Decreased, Sodium conductance 1||September 16, 2017 10:15|
|Increased, Atrioventricular block and bradycardia leads to Increased, Respiratory distress/arrest||December 03, 2016 16:37|
|Increased, Respiratory distress/arrest leads to N/A, hypoxia||December 03, 2016 16:37|
|N/A, hypoxia leads to Increased, amputations||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 Increased, Atrioventricular block and bradycardia||December 03, 2016 16:37|
Anti-epileptic and anti-arrhythmic drugs which block voltage-gated ion channels (e.g., voltage-gated sodium channels) are associated with major congenital malformations including amputations.
Summary of the AOP
Events: Molecular Initiating Events (MIE)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||584||Inhibition, sodium channel||Inhibition, sodium channel|
|2||KE||444||Increased, Atrioventricular block and bradycardia||Increased, Atrioventricular block and bradycardia|
|3||KE||445||Increased, Respiratory distress/arrest||Increased, Respiratory distress/arrest|
|4||KE||590||N/A, hypoxia||N/A, hypoxia|
|5||KE||585||Decreased, Sodium conductance 1||Decreased, Sodium conductance 1|
|6||AO||591||Increased, amputations||Increased, amputations|
Relationships Between Two Key Events
(Including MIEs and AOs)
|N/A, hypoxia leads to Increased, amputations||non-adjacent||Moderate|
Life Stage Applicability
|Human, rat, mouse||Human, rat, mouse||NCBI|
Overall Assessment of the AOP
Domain of Applicability
Life Stage Applicability,
Mammals exposed in utero to sodium channel blockers (or similar) have significantly higher rates of cardiovascular anomalies and amputations (shortened limbs, missing digits, etc). Hypoxic conditions generated from poor heart function during development result in hemorrhages in distal parts of the embryo/fetus (Danielsson et al., 2003; Webster et al., 1996; Webster 2007). Similar amputations may not be relevant for species which develop in an egg and receive their oxygen supply via diffusion from the surrounding environment (air or water).
Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
Rat whole embryo cultures exposed to sodium channel blockers (experimental drugs AZA and AZB)for 1 hr had severly reduced heart rates (bradycardia) but returned to normal within 1 hr of drug washout (Nilsson et al., 2013).
Considerations for Potential Applications of the AOP (optional)
Danielsson, B.R., Skold, A., and Azarbayjani, F. 2001. Class III Antiarrhythmics and Phenytoin: Teratogenicity due to embryonic cardiac dysrhythmia and reoxygenation damage. Current Pharmaceutical Design 7:787-802.
Webster, W., Brown-Woodman, P., Snow, M., and Danielsson, B. 1996. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. Teratology 53:168-175.
Webster, W.S. and Abela, D. 2007. The effect of hypoxia in development. Birth Defects Research Part C: Embryo Today: Reviews 81:215-228.