Point of Contact
- Kellie Fay
|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 Do not cite||Under Development||1.29||Included in OECD Work Plan|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
|Activation, Glutamate-gated chloride channel||December 03, 2016 16:37|
|Increased, Chloride conductance||September 16, 2017 10:16|
|hyperpolarisation, neuron||September 16, 2017 10:16|
|N/A, Ataxia, paralysis, or hyperactivity||September 16, 2017 10:16|
|Increased, Mortality||May 15, 2017 11:34|
|Decreased, population 1||December 03, 2016 16:37|
|Activation, Glutamate-gated chloride channel leads to Increased, Chloride conductance||December 03, 2016 16:38|
|hyperpolarisation, neuron leads to N/A, Ataxia, paralysis, or hyperactivity||December 03, 2016 16:38|
|Increased, Mortality leads to Decreased, population 1||December 03, 2016 16:38|
|N/A, Ataxia, paralysis, or hyperactivity leads to Increased, Mortality||December 03, 2016 16:38|
|Increased, Chloride conductance leads to hyperpolarisation, neuron||December 03, 2016 16:38|
Macrocylcic lactone (ML) antihelmintics, insecticides and acaricids (e.g. abamectin and ivermectin) target the alpha subunits of the glutamate-gated chloride channels (GluCl) present in nematodes, arthropods, crustaceans (daphnia), and mollusks. The binding of the ML may result in directly opening the ion channel, or may potentiate the effects of the endogenous agonist, glutamate, resulting in increased chloride entry into the cell. With the increased influx of chloride ions, the cell becomes hyperpolarized (neuron) or depolarized (myocyte), resulting in paralysis and death. Mammals do not possess glutamate-gated chloride channels, but the structure of the GluCl channel is similar to the glycine === Background (optional) ===
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
StressorsDescribes 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
|Activation, Glutamate-gated chloride channel||Activation, Glutamate-gated chloride channel|
|Increased, Chloride conductance||Increased, Chloride conductance|
|hyperpolarisation, neuron||hyperpolarisation, neuron|
|N/A, Ataxia, paralysis, or hyperactivity||N/A, Ataxia, paralysis, or hyperactivity|
|Increased, Mortality||Increased, Mortality|
|Decreased, population 1||Decreased, population 1|
Relationships Between Two Key Events (Including MIEs and AOs)
|Activation, Glutamate-gated chloride channel leads to Increased, Chloride conductance||Directly leads to|
|hyperpolarisation, neuron leads to N/A, Ataxia, paralysis, or hyperactivity||Indirectly leads to|
|Increased, Mortality leads to Decreased, population 1||Directly leads to|
|N/A, Ataxia, paralysis, or hyperactivity leads to Increased, Mortality||Indirectly leads to|
|Increased, Chloride conductance leads to hyperpolarisation, neuron||Directly leads to|
Life Stage ApplicabilityIs 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.
|Bombus impatiens||Bombus impatiens||NCBI|
|chaetanaphothrips orchidii||chaetanaphothrips orchidii||NCBI|
|Radopholus similis||Radopholus similis||NCBI|
|Daphnia magna||Daphnia magna||NCBI|
|Orius insidiosus||Orius insidiosus||NCBI|
|Helicoverpa zea||Helicoverpa zea||NCBI|
|Liriomyza trifolii||Liriomyza trifolii||NCBI|
|orius isidiosus||orius isidiosus||NCBI|
|Acyrthosiphon kondoi||Acyrthosiphon kondoi||NCBI|
Graphical RepresentationClick to download graphical representation template
Overall Assessment of the AOP
Strong evidence exists for population decline in pest species (e.g., worms, ticks and mites) resulting from targeted glutamate-gated chloride channels, as well for non-target species (bees, butterflies). However, this AOP has been developed with minimal research. Given GluCl channels exist in several cell types, specific key events likely vary among species, which are not elucidated here. The review by Wolstenholme (2012) describes specific GluCl-controlled sensory inputs in worms and flies (e.g., behavioral responses to odour, temperature and light) which suggest pathways other than paralysis may be more sensitive. As such, this AOP should be considered putative with minimally-researched support.
Domain of Applicability
Glutamate-gated chloride channels are absent in vertebrates (Slimko et al., 2002).
Life Stage Applicability,
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.
Essentiality of the Key EventsThe 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 SummaryThis 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 ConsiderationsThe 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)
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.
Slimko, E.M., McKinney, S., Anderson, D.J., Davisodn, N., and Lester, H.A. (2002) Selective electrical silencing of mammalian neurons in vitro by the use of invertebrate ligand-gated chloride channels. J. Neurosci. 22, 7373-7379.
Wolstenholm, A. (2012) Glutamate-gated chloride channels. J. Biological Chem. 287: 48, 40232-40238.