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Event: 613

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Occurrence, Epileptic seizure

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Occurrence, Epileptic seizure

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
seizures occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Blocking iGABA receptor ion channel leading to seizures AdverseOutcome Ping Gong (send email) Open for citation & comment TFHA/WNT Endorsed


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI
honeybee Apis mellifera High NCBI
eisenia fetida eisenia fetida High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Adult High

Sex Applicability

No help message More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Blockage of the GABA-gated chloride channel reduces neuronal inhibition and induces focal seizure. This may further lead to generalized seizure, convulsions and death (Bloomquist 2003; De Deyn et al. 1990; Werner and Covenas 2011). For instance, exposure to fipronil produces hyperexcitation at low doses and convulsion or tonic-clonic seizure and seizure-related death at high doses (Gunasekara et al. 2007; Tingle et al. 2003; Jackson et al. 2009).

As described in Bromfield et al. (2006), seizure propagation, the process by which a partial seizure spreads within the brain, occurs when there is sufficient activation to recruit surrounding neurons. This leads to a loss of surround inhibition and spread of seizure activity into contiguous areas via local cortical connections, and to more distant areas via long association pathways such as the corpus callosum. The propagation of bursting activity is normally prevented by intact hyperpolarization and a region of surrounding inhibition created by inhibitory neurons. With sufficient activation there is a recruitment of surrounding neurons via a number of mechanisms. Of equal interest, but less well understood, is the process by which seizures typically end, usually after seconds or minutes, and what underlies the failure of this spontaneous seizure termination in the life-threatening condition known as status epilepticus (Bromfield et al. 2006).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Electrophysiological measurements and physical (visual) observation (for mortality) are the methods often used to detect epileptic seizure-related effects (Ulate-Campos et al. 2016). One may also visit for more information on how medical doctors diagnose epilepsy in patients.

Recently, a new technique called micro-electrode array (MEA) recording has been developed and tested both in vitro (Novellino et al. 2011) and ex vivo (Dossi et al. 2014). MEAs, which are microfabricated devices embedding an array of spatially arranged microelectrodes, provide a unique opportunity to simultaneously stimulate and record field potentials, as well as action potentials of multiple neurons from different areas of the tissue (Dossi et al. 2014). Thus, MEAs recordings constitute an excellent tool for studying the spatio-temporal patterns of spontaneous interictal and evoked seizure-like events, the mechanisms underlying seizure onset and propagation, and electrophysiological activity of the neurons in response to chemical exposures (Novellino et al. 2011; Dossi et al. 2014).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Substance-induced epileptic seizures have been documented in a wide range of species including invertebrates and vertebrates (see Tingle et al. (2003) and Gunasekara et al. (2007) for reviews on the list of aquatic and terrestrial species affected by fipronil). For instance, fipronil can induce seizures in fruit flies (Stilwell et al. 2006) and house flies (Gao et al. 2007).

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for 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-related pathology 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, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

As a neurotoxicity endpoint, information with regard to the seizure or epilepsy is often used by regulators such as EPA, FDA and DHS for human and environmental health assessment and regulation of chemicals, drugs and other materials. For instance, the Office of Pesticide Programs (OPP) in US EPA, regulates, monitors and investigates the use of all pesticides in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) ( Many pesticides like fipronil target the iGABAR causing seizure and mortality. Another example is the regulatory actions of US FDA to ensure drug safety (see


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help

Bloomquist JR. 2003. Chloride channels as tools for developing selective insecticides. Arch. Insect Biochem. Physiol 54(4), 145-156.

Bromfield EB, Cavazos JE, Sirven JI, editors. 2006. An Introduction to Epilepsy [Internet]. West Hartford (CT): American Epilepsy Society. Chapter 1 Basic Mechanisms Underlying Seizures and Epilepsy. Available from:

De Deyn PP, Marescau B, Macdonald RL. 1990. Epilepsy and the GABA-hypothesis a brief review and some examples. Acta Neurol. Belg. 90(2), 65-81.

Dossi E, Blauwblomme T, Nabbout R, Huberfeld G, Rouach N. 2014. Multi-electrode array recordings of human epileptic postoperative cortical tissue.J Vis Exp. (92):e51870.

Gao JR, Kozaki T, Leichter CA, Rinkevich FD, Shono T, Scott JG. 2007. The A302S mutation in Rdl that confers resistance to cyclodienes and limited crossresistance to fipronil is undetectable in field populations of house flies from the USA. Pestic. Biochem. Physiol. 88, 66−70.

Gunasekara AS, Truong T, Goh KS, Spurlock F, Tjeerdema RS. 2007. Environmental fate and toxicology of fipronil. J. Pestic. Sci. 32(3), 189-199.

Jackson D, Cornell CB, Luukinen B, Buhl K, Stone D. 2009. Fipronil Technical Fact Sheet. National Pesticide Information Center, Oregon State University Extension Services,

Novellino A, Scelfo B, Palosaari T, Price A, Sobanski T, Shafer TJ, Johnstone AF, Gross GW, Gramowski A, Schroeder O, Jügelt K, Chiappalone M, Benfenati F, Martinoia S, Tedesco MT, Defranchi E, D'Angelo P, Whelan M. 2011. Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals.Front Neuroeng. 4:4.

Stilwell GE, Saraswati S, J. Troy Littleton JT, Chouinard SW. 2006. Development of a Drosophila seizure model for in vivo high-throughput drug screening. European J Neurosci. 24, 2211-2222.

Tingle CC, Rother JA, Dewhurst CF, Lauer S, King WJ. 2003. Fipronil: environmental fate, ecotoxicology, and human health concerns. Rev. Environ. Contam Toxicol. 176, 1-66.

Ulate-Campos A, Coughlin F, Gaínza-Lein M, Fernández IS, Pearl PL, Loddenkemper T. 2016. Automated seizure detection systems and their effectiveness for each type of seizure. Seizure. 40:88-101.

Werner FM, Covenas R. 2011. Classical neurotransmitters and neuropeptides involved in generalized epilepsy: a focus on antiepileptic drugs. Curr. Med. Chem. 18(32), 4933-4948.