API

Aop: 213

AOP Title

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Molecular events lead to nonalcoholic hepatic steatosis (NASH)

Short name:

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Network of nonalcoholic hepatic steatosis (NASH)

Authors

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Lyle Burgoon

Point of Contact

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Lyle Burgoon

Contributors

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  • Hsin-Yen Wu
  • Edward Perkins
  • Lyle Burgoon

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development


This AOP was last modified on July 24, 2017 15:36

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Revision dates for related pages

Page Revision Date/Time
Increase, insulin April 12, 2017 14:24
Activation, insulin receptor April 12, 2017 14:25
Activation, mTORC2 April 12, 2017 14:26
Activation, AKT April 12, 2017 14:27
Activation, mTORC1 April 12, 2017 14:28
Activation, SREBP-1 April 12, 2017 14:29
Activation, L-FABP April 13, 2017 14:06
Increase, cytosolic fatty acid April 12, 2017 14:40
peroxisome proliferator activated receptor promoter demethylation September 16, 2017 10:14
Activation, SCD-1 September 16, 2017 10:14
Increased, lipogenesis April 12, 2017 14:46
Activation, NRF2 September 16, 2017 10:15
Activation, FXR April 12, 2017 14:51
Activation, SHP September 16, 2017 10:15
Activation, PPARα September 16, 2017 10:14
Activation, HSD17B4 April 12, 2017 15:16
Inhibition, LXR April 12, 2017 15:21
Inhibition, PPAR alpha September 16, 2017 10:15
Inhibition, LRH-1 April 12, 2017 15:42
Activation, FAS September 16, 2017 10:14
Activation, aPKC April 13, 2017 10:40
Activation, PI3K April 13, 2017 10:41
Inhibition, Steatosis April 13, 2017 10:43
Induction, fatty acid beta-oxidation April 13, 2017 10:46
Decrease, cytosolic fatty acid April 13, 2017 10:48
Activation, LXR September 16, 2017 10:14
Activation, LRH-1 April 13, 2017 14:03
Increase, insulin leads to Activation, insulin receptor April 12, 2017 13:48
Activation, insulin receptor leads to Activation, mTORC2 April 12, 2017 13:48
Activation, mTORC2 leads to Activation, AKT April 12, 2017 13:59
Activation, AKT leads to Activation, mTORC1 April 12, 2017 14:37
Activation, mTORC1 leads to Activation, SREBP-1 April 12, 2017 14:38
Activation, AKT leads to Activation, L-FABP April 12, 2017 14:39
Activation, L-FABP leads to Increase, cytosolic fatty acid April 12, 2017 14:40
demethylation, PPARg promoter leads to Activation, SREBP-1 April 12, 2017 14:43
Activation, SREBP-1 leads to Activation, SCD-1 April 12, 2017 14:44
Activation, SCD-1 leads to Increased, lipogenesis April 12, 2017 14:46
Increased, lipogenesis leads to Increase, cytosolic fatty acid April 12, 2017 14:47
Activation, NRF2 leads to Activation, FXR April 12, 2017 14:53
Activation, FXR leads to Activation, SHP April 12, 2017 14:54
Activation, FXR leads to Activation, PPARα April 12, 2017 14:56
Activation, SHP leads to Activation, PPARα April 12, 2017 14:57
Activation, PPARα leads to Activation, HSD17B4 April 12, 2017 15:17
Activation, SHP leads to Inhibition, LXR April 12, 2017 15:21
Activation, SHP leads to Inhibition, LRH-1 April 12, 2017 15:42
Activation, HSD17B4 leads to Induction, fatty acid beta-oxidation April 13, 2017 10:47
Induction, fatty acid beta-oxidation leads to Inhibition, Steatosis April 13, 2017 10:47
Induction, fatty acid beta-oxidation leads to Decrease, cytosolic fatty acid April 13, 2017 11:02
Activation, PI3K leads to Activation, AKT April 13, 2017 11:03
Activation, PI3K leads to Activation, L-FABP April 13, 2017 11:03
Activation, PI3K leads to Activation, aPKC April 13, 2017 11:04
Activation, aPKC leads to Activation, SREBP-1 April 13, 2017 11:04
Activation, FAS leads to Increased, lipogenesis April 13, 2017 11:21
Activation, L-FABP leads to demethylation, PPARg promoter April 13, 2017 11:22
demethylation, PPARg promoter leads to Activation, FAS April 13, 2017 11:23
Activation, LXR leads to Inhibition, PPAR alpha December 03, 2016 16:37
Activation, LXR leads to Activation, FAS December 03, 2016 16:37
Activation, LRH-1 leads to Activation, FAS April 13, 2017 14:04

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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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.

Instructions

To add a stressor associated with an AOP, under “Summary of the AOP” click ‘Add Stressor’ will bring user to the “New Aop Stressor” page. In the Name field, user can search for stressor by name. Choosing a stressor from the resulting drop down populates the field. Selection of an Evidence level from the drop down menu and add any supporting evidence in the text box. Click ‘Add stressor’ to add the stressor to the AOP page.


Molecular Initiating Event

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The MIE is the direct site of interaction with a chemical. The MIE involves a chemical interaction (e.g., a reaction, covalent binding, hydrogen bonding, electrostatic interaction, etc.) between a chemical stressor and chemically defined biomolecules within an organism. In some cases, this may be a highly specific interaction, for example between an exogenous ligand and a specific receptor. In other cases, it may be non-specific, as in the case of a reactive chemical that can covalently modify a wide array of proteins. Either can be described as an MIE, provided that the general nature of the stressor-biomolecule interaction is understood. Therefore, when a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic applicability it is useful to list known chemical initiators (or other stressors known to trigger the MIE) and provide evidence supporting that initiation.

Instructions

To add a molecular initiating event to an AOP page, under Summary of the AOP, click ‘add molecular initiating event.’ User will be brought to a new page entitled ‘Add Event to AOP.’ Entering text into the Title field will bring a drop-down list of already existing MIE’s. If the user wishes to create a new MIE that doesn’t already exist, they should type in the name of the MIE without selecting a choice from the drop down menu. User should fill Title, Short name, Biological organization, and Essentiality fields and click ‘Create Molecular Initiating event.’ This brings user back to the AOP page with updated MIE under the heading “Molecular Initiating Event.”

To edit an MIE, click the ‘Edit’ button beside an MIE will bring user to the ‘Editing Aop Event’ page on which they can edit the Essentiality of the MIE from the drop down list. Clicking ‘Update Molecular Initiating Event’ will update the AOP page.


Key Events

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Title Short name
Increase, insulin Increase, insulin
Activation, insulin receptor Activation, insulin receptor
Activation, mTORC2 Activation, mTORC2
Activation, AKT Activation, AKT
Activation, mTORC1 Activation, mTORC1
Activation, SREBP-1 Activation, SREBP-1
Activation, L-FABP Activation, L-FABP
Increase, cytosolic fatty acid Increase, cytosolic fatty acid
peroxisome proliferator activated receptor promoter demethylation demethylation, PPARg promoter
Activation, SCD-1 Activation, SCD-1
Increased, lipogenesis Increased, lipogenesis
Activation, NRF2 Activation, NRF2
Activation, FXR Activation, FXR
Activation, SHP Activation, SHP
Activation, PPARα Activation, PPARα
Activation, HSD17B4 Activation, HSD17B4
Inhibition, LXR Inhibition, LXR
Inhibition, PPAR alpha Inhibition, PPAR alpha
Inhibition, LRH-1 Inhibition, LRH-1
Activation, FAS Activation, FAS
Activation, aPKC Activation, aPKC
Activation, PI3K Activation, PI3K
Inhibition, Steatosis Inhibition, Steatosis
Induction, fatty acid beta-oxidation Induction, fatty acid beta-oxidation
Decrease, cytosolic fatty acid Decrease, cytosolic fatty acid
Activation, LXR Activation, LXR
Activation, LRH-1 Activation, LRH-1

Adverse Outcome

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A key criterion of defining the terminal end of an AOP is that it represents an outcome that is considered relevant to regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example in humans, this may constitute increased risk of disease in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic applicability, it is useful to describe the established regulatory relevance of the AO.

Instructions

To add an adverse outcome to an AOP page, under Summary of the AOP, click ‘add adverse outcome.’ User will be brought to a new page entitled ‘Add Event to AOP.’ Entering text into the Title field will bring a drop-down list of already existing KE’s. If the user wishes to create a new AO that doesn’t already exist, they should type in the name of the AO without selecting a choice from the drop down menu. User should fill Title, Short name, Biological organization fields and click ‘Create Adverse outcome.’


Relationships Between Two Key Events (Including MIEs and AOs)

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Title Directness Evidence Quantitative Understanding
Increase, insulin leads to Activation, insulin receptor Directly leads to
Activation, insulin receptor leads to Activation, mTORC2 Directly leads to
Activation, mTORC2 leads to Activation, AKT Directly leads to
Activation, AKT leads to Activation, mTORC1 Directly leads to
Activation, mTORC1 leads to Activation, SREBP-1 Directly leads to
Activation, AKT leads to Activation, L-FABP Directly leads to
Activation, L-FABP leads to Increase, cytosolic fatty acid Directly leads to
demethylation, PPARg promoter leads to Activation, SREBP-1 Directly leads to
Activation, SREBP-1 leads to Activation, SCD-1 Directly leads to
Activation, SCD-1 leads to Increased, lipogenesis Directly leads to
Increased, lipogenesis leads to Increase, cytosolic fatty acid Directly leads to
Activation, NRF2 leads to Activation, FXR Directly leads to
Activation, FXR leads to Activation, SHP Directly leads to
Activation, FXR leads to Activation, PPARα Directly leads to
Activation, SHP leads to Activation, PPARα Directly leads to
Activation, PPARα leads to Activation, HSD17B4 Directly leads to
Activation, SHP leads to Inhibition, LXR Directly leads to
Activation, SHP leads to Inhibition, LRH-1 Directly leads to
Activation, HSD17B4 leads to Induction, fatty acid beta-oxidation Directly leads to
Induction, fatty acid beta-oxidation leads to Inhibition, Steatosis Directly leads to
Induction, fatty acid beta-oxidation leads to Decrease, cytosolic fatty acid Directly leads to
Activation, PI3K leads to Activation, AKT Directly leads to
Activation, PI3K leads to Activation, L-FABP Directly leads to
Activation, PI3K leads to Activation, aPKC Directly leads to
Activation, aPKC leads to Activation, SREBP-1 Directly leads to
Activation, FAS leads to Increased, lipogenesis Directly leads to
Activation, L-FABP leads to demethylation, PPARg promoter Directly leads to
demethylation, PPARg promoter leads to Activation, FAS Directly leads to
Activation, LXR leads to Inhibition, PPAR alpha Directly leads to
Activation, LXR leads to Activation, FAS Directly leads to
Activation, LRH-1 leads to Activation, FAS Directly leads to

Network View

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Life Stage Applicability

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Is the AOP specific to certain tissues, life stages / age classes? Indicate if there are critical life stages, where exposure must occur, to results in the final adverse effect. Or specify if there are key events along the pathway which are dependent on the life stage although the AOP is known to be initiated regardless of life stage. Indicate also if the AOP is associated also with age- or sex-dependence.

Instructions

To add a life stage term to an AOP page, under “Life Stage Applicability” select ‘add life stage term.’ User will be directed to a page entitled “Add Life Stage to AOP.” This page will list the AOP name, with drop down menu options to select a Life Stage term and Evidence. Evidence can be left blank and added later.

To edit a life stage term on an AOP page, under “Life Stage Applicability” click ‘Edit.’  User will be directed to a page entitled “Editing AOP Life Stage” where they can edit the Evidence field using the drop down menu. Clicking ‘Update Aop life stage’ will update the Evidence field and redirect the user back to the AOP page.


Taxonomic Applicability

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Indicate the relevant domain of applicability in terms of taxa.

Instructions

To add a taxonomic term to an AOP page, under “Taxonomic Applicability” select ‘add taxonomic term.’ User will be directed to a page entitled “Adding Taxonomic Term to AOP.” The user can search for and select an existing term from the drop down list of existing terms to populate the “Term” field. If a relevant term does not exist, click ‘Request New Taxon Term’ to request a term from AOP-Wiki administrators. Click ‘Add taxonomic term’ to add this term to the AOP page. Evidence can be left blank and added later.

To edit a taxonomic term on an AOP page, under “Taxonomic Applicability” click ‘Edit.’  User will be directed to a page entitled “Editing AOP Taxonomic Term” where they can edit the Evidence field using the drop down menu. Clicking ‘Update taxonomic term’ will update the Evidence field and redirect the user back to the AOP page.


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).

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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The relevant domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Domain of applicability is informed by the “Description” and “Taxonomic Relevance” section of each KE description and the “Description of the KER” section of each KER description. The relevant domain of applicability of the AOP as a whole will most often be defined based on the most narrowly restricted of its KEs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the domain of applicability of the AOP as a whole would generally be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE descriptions, the rationale for defining the relevant domain of applicability of the overall AOP should be briefly summarised on the AOP page.

Instructions

To edit the “Domain of Applicability” 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 “Domain of Applicability” 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 “Domain of Applicability” section on the AOP page.


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.