Aop:94
Status
This is a legacy representation of this AOP. Please see the current version here:
AOP Title
Authors
Kellie Fay
Status
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 Please follow the link to snapshots page to view and create Snapshots of this AOP.
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This AOP page was last modified on 12/11/2016.
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Abstract
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.
Background (optional)
Summary of the AOP
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Molecular Initiating Event
Molecular Initiating Event | Support for Essentiality |
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sodium channel, Inhibition | Strong |
Key Events
Event | Support for Essentiality |
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Atrioventricular block and bradycardia, Increased | |
Respiratory distress/arrest, Increased | |
hypoxia, N/A | |
Sodium conductance, Decreased | Strong |
Adverse Outcome
Adverse Outcome |
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amputations, Increased |
Relationships Among Key Events and the Adverse Outcome
Network View
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Life Stage Applicability
Life Stage | Evidence | Links |
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Foetal | Strong |
Taxonomic Applicability
Name | Scientific Name | Evidence | Links |
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Human, rat, mouse |
Sex Applicability
Sex | Evidence | Links |
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Graphical Representation
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Overall Assessment of the AOP
Domain of Applicability
Life Stage Applicability,
Taxonomic Applicability,
Sex 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).
Weight of Evidence Summary
Summary Table
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Quantitative Considerations
Summary Table
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Considerations for Potential Applications of the AOP (optional)
References
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.