API

Aop: 187

AOP Title

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Anticoagulant rodenticide inhibition of vitamin K epoxide reductase resulting coagulopathy and hemorrhage

Short name:

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VKOR inhibition resulting in coagulopathy

Authors

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List the name and contact information of the individual(s)/organization(s) that developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Contributors that have not met the criteria for authorship such as wiki reviewers can also be listed in this section. This section should include all individuals who participated in the AOP development effort not just those who were responsible for entering the information into the AOP-Wiki.  The text in this section is used for the author section when creating a snapshot for OECD review or any other purpose and constitutes the official author list for the AOP. If submitting the AOP for OECD review or creating a snapshot for any other official purpose, a corresponding author should be noted in this field.  This does not have to be the same as the point of contact listed below for the wiki entry and doesn't require that the individual has a wiki account.
 
 Instructions
 
 To add or edit authors, click Edit in the upper right hand menu on the AOP page, bringing the user to a page where they can edit fields of the AOP.  Under the “Authors” heading, enter authors’ names in the text box.  Upon completion, click ‘Update AOP’ in the upper right hand menu to update the list of Authors.

Point of Contact Barnett Rattner


Contributors

  • Barnett Rattner

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.31 Included in OECD Work Plan


This AOP was last modified on December 03, 2016 16:38

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Revision dates for related pages

Page Revision Date/Time
Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failure of secondary hemostasis December 03, 2016 16:37
Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) December 03, 2016 16:37
Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carboxylation of clotting factors (e.g., des-gamma-carboxy prothrombin) December 03, 2016 16:37
Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tissue, impaired carbon dioxide and waste product removal December 03, 2016 16:37
Hemostasis, Depletion from blood of fully functional carboxylated clotting factors December 03, 2016 16:37
Irreversible inhibition of hepatic VKOR by binding of AR at tyrosine 139, Failure to cycle vitamin K epoxide to vitamin K to form vitamin K hydroquinone December 03, 2016 16:37
Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction December 03, 2016 16:37
Impaired recruitment , Population trajectory December 03, 2016 16:37
Uncoupling of oxidative phosphorylation, Reduced ability to generate ATP December 03, 2016 16:37
Osteoporosis and vascular calcification, Bone deterioration December 03, 2016 16:37
Anticoagulant rodenticide interferes with carboxylation of Gla proteins in bone, Impairment of post-translational modification (carboxylation) of osteocalcin December 03, 2016 16:37
Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carbo leads to Hemostasis, Depletion from blood of fully functional carboxylated clotting factors December 03, 2016 16:38
Hemostasis, Depletion from blood of fully functional carboxylated clotting factors leads to Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failur December 03, 2016 16:38
Irreversible inhibition of hepatic VKOR by binding of AR at tyrosine 139, Failure to cycle leads to Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carbo December 03, 2016 16:38
Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failur leads to Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) December 03, 2016 16:38
Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) leads to Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tis December 03, 2016 16:38
Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tis leads to Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction December 03, 2016 16:38
Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction leads to Impaired recruitment , Population trajectory December 03, 2016 16:38
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chlorophacinone November 29, 2016 18:42
diphacinone November 29, 2016 18:42
pindone November 29, 2016 18:42
3-[3-(4'-bromo[1,1'-biphenyl]-4-yl)-3-hydroxy-1-phenylpropyl]-4-hydroxy-2-benzopyrone November 29, 2016 18:42

Abstract

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Provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: (1) the background/purpose for initiation of the AOP’s development (if there was a specific intent); (2) a brief description of the MIE, AO, and/or major KEs that define the pathway; (3) a short summation of the overall weight of evidence supporting the AOP and identification of major knowledge gaps (if any); (4) a brief statement about how the AOP may be applied. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. Instructions To add or edit the Abstract, click Edit in the upper right hand menu on the AOP page, bringing the user to a page where they can edit fields of the AOP. Under the Abstract field, a text editable form provides ability to edit the Abstract.  Clicking ‘Update AOP’ will update these fields.

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 To add background information, click Edit in the upper right hand menu on the AOP page. Under the “Background (optional)” field, a text editable form provides ability to edit the Background.  Clicking ‘Update AOP’ will update these fields.

Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
Irreversible inhibition of hepatic VKOR by binding of AR at tyrosine 139, Failure to cycle vitamin K epoxide to vitamin K to form vitamin K hydroquinone Irreversible inhibition of hepatic VKOR by binding of AR at tyrosine 139, Failure to cycle
Uncoupling of oxidative phosphorylation, Reduced ability to generate ATP Uncoupling of oxidative phosphorylation, Reduced ability to generate ATP
Anticoagulant rodenticide interferes with carboxylation of Gla proteins in bone, Impairment of post-translational modification (carboxylation) of osteocalcin Anticoagulant rodenticide interferes with carboxylation of Gla proteins in bone, Impairment

Key Events

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Title Short name
Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failure of secondary hemostasis Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failur
Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage)
Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carboxylation of clotting factors (e.g., des-gamma-carboxy prothrombin) Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carbo
Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tissue, impaired carbon dioxide and waste product removal Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tis
Hemostasis, Depletion from blood of fully functional carboxylated clotting factors Hemostasis, Depletion from blood of fully functional carboxylated clotting factors
Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction
Osteoporosis and vascular calcification, Bone deterioration Osteoporosis and vascular calcification, Bone deterioration

Adverse Outcome

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Title Short name
Impaired recruitment , Population trajectory Impaired recruitment , Population trajectory

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Directness Evidence Quantitative Understanding
Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carbo leads to Hemostasis, Depletion from blood of fully functional carboxylated clotting factors Indirectly leads to Strong Strong
Hemostasis, Depletion from blood of fully functional carboxylated clotting factors leads to Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failur Directly leads to Strong Strong
Irreversible inhibition of hepatic VKOR by binding of AR at tyrosine 139, Failure to cycle leads to Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carbo Directly leads to Strong Strong
Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failur leads to Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) Directly leads to Strong Strong
Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) leads to Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tis Directly leads to Strong Strong
Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tis leads to Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction Indirectly leads to Moderate Strong
Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction leads to Impaired recruitment , Population trajectory Indirectly leads to Weak Weak

Network View

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Life Stage Applicability

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Life stage Evidence
All life stages Strong

Taxonomic Applicability

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Term Scientific Term Evidence Link
humans Homo sapiens Strong NCBI
Rodentia spp. Rodentia sp. Strong NCBI
birds Tachycineta bicolor Moderate NCBI
mammals mammals Strong NCBI

Sex Applicability

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Sex Evidence
Male
Female

Graphical Representation

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Click to download graphical representation template

An additional form of data summation is the flow diagram of the intermediate events associated with the AOP. This graphical version of the AOP shows visually the sequence of events at the different levels of biological organisation.
 
 Instructions
 
 If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Browse…’ under the “Graphical Representation” heading, which is part of the "Summary of the AOP" section, to select the file that you have just edited. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading.
 
 If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Once the diagram is edited to its final state, upload the image file as described above.

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). Instructions To edit the “Overall Assessment of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Overall Assessment of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Overall Assessment of the AOP” section on the AOP page.

Domain of Applicability

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Life Stage Applicability, Taxonomic Applicability, Sex Applicability
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains. Female rodents are less sensitive to ARs than males Female humans are more sensitive ti ARs than males


Essentiality of the Key Events

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The essentiality of various of the KEs is influential in considering confidence in an overall hypothesised AOP for potential regulatory application being secondary only to biological plausibility of KERs (Meek et al., 2014; 2014a). The defining question for determining essentiality (included in Annex 1) relates to whether or not downstream KEs and/or the AO is prevented if an upstream event is experimentally blocked. It is assessed, generally, then, on the basis of direct experimental evidence of the absence/reduction of downstream KEs when an upstream KE is blocked or diminished (e.g., in null animal models or reversibility studies). Weight of evidence for essentiality of KEs would be considered high if there is direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important key events [e.g., stop/reversibility studies, antagonism, knock out models, etc.) moderate if there is indirect 25 evidence that experimentally induced change of an expected modulating factor attenuates or augments a key event (e.g., augmentation of proliferative response (KEupstream) leading to increase in tumour formation (KEdownstream or AO)) and weak if there is no or contradictory experimental evidence of the essentiality of any of the KEs (Annex 1). Instructions To edit the “Essentiality of the Key Events” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Essentiality of the Key Events” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Essentiality of the Key Events” section on the AOP page.

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. Instructions To edit the “Weight of Evidence Summary” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Weight of Evidence Summary”  section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Weight of Evidence Summary” section on the AOP page.

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. Instructions To edit the “Quantitative Considerations” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Quantitative Considerations” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Quantitative Considerations” section on the AOP page.

Considerations for Potential Applications of the AOP (optional)

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At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale. Detailing such considerations can aid the process of transforming narrative descriptions of AOPs into practical tools. In this context, it is necessarily beneficial to involve members of the regulatory risk assessment community on the development and assessment team. The Network view which is generated based on assessment of weight of evidence/degree of confidence in the hypothesized AOP taking into account the elements described in Section 7 provides a useful summary of relevant information as a basis to consider appropriate application in a regulatory context. Consideration of application needs then, to take into consideration the following rank ordered qualitative elements: Confidence in biological plausibility for each of the KERs Confidence in essentiality of the KEs Empirical support for each of the KERs and overall AOP The extent of weight of evidence/confidence in both these qualitative elements and that of the quantitative understanding for each of the KERs (e.g., is the MIE known, is quantitative understanding restricted to early or late key events) is also critical in determining appropriate application. For example, if the confidence and quantitative understanding of each KER in a hypothesised AOP are low and or low/moderate and the evidence for essentiality of KEs weak (Section 7), it might be considered as appropriate only for applications with less potential for impact (e.g., prioritisation, category formation for testing) versus those that have immediate implications potentially for risk management (e.g., in depth assessment). If confidence in quantitative understanding of late key events is high, this might be sufficient for an in depth assessment. The analysis supporting the Network view is also essential in identifying critical data gaps based on envisaged regulatory application. Instructions To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page.

References

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List the bibliographic references to original papers, books or other documents used to support the AOP. Instructions To edit the “References” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “References” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “References” section on the AOP page.