API

Aop: 94

AOP Title

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Sodium channel inhibition leading to congenital malformations

Short name:

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sodium channel inhibition 3

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 Do not cite Under Development 1.29 Included in OECD Work Plan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
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

Abstract

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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)

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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

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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.

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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
Increased, Atrioventricular block and bradycardia Increased, Atrioventricular block and bradycardia
Increased, Respiratory distress/arrest Increased, Respiratory distress/arrest
N/A, hypoxia N/A, hypoxia
Decreased, Sodium conductance 1 Decreased, Sodium conductance 1

Adverse Outcome

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Title Short name
Increased, amputations Increased, amputations

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
Foetal Strong

Taxonomic Applicability

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Term Scientific Term Evidence Link
Human, rat, mouse Human, rat, mouse 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 section addresses the relevant domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and weight of evidence for the overall hypothesised AOP (i.e., including the MIE, KEs and AO) as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). It draws upon the evidence assembled for each KER as one of several components which contribute to relative confidence in supporting information for the entire hypothesised pathway. An important component in assessing confidence in supporting information as a basis to consider regulatory application of AOPs beyond that described in Section 6 is the essentiality of each of the key events as a component of the entire pathway. This is normally investigated in specifically-designed stop/reversibility studies or knockout models (i.e., those where a key event can be blocked or prevented). Assessment of the overall AOP also contributes to the identification of KEs for which confidence in the quantitative relationship with the AO is greatest (i.e., to facilitate determining the most sensitive predictor of the AO).

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Domain of Applicability

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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

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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

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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.

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Quantitative Considerations

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The extent of quantitative understanding of the various KERs in the overall hypothesised AOP is also critical in consideration of potential regulatory application. For some applications (e.g. doseresponse analysis in in depth risk assessment), quantitative characterisation of downstream KERs may be essential while for others, quantitative understanding of upstream KERs may be important (e.g., QSAR modelling for category formation for testing). Because evidence that contributes to quantitative understanding of the KER is generally not mutually exclusive with the empirical support for the KER, evidence that contributes to quantitative understanding should generally be considered as part of the evaluation of the weight of evidence supporting the KER (see Annex 1, footnote b). General guidance on the degree of quantitative understanding that would be characterised as weak, moderate, or strong is provided in Annex 2.

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Considerations for Potential Applications of the AOP (optional)

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References

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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.