The authors have designated this AOP as all rights reserved. Re-use in any form requires advanced permission from the authors.

AOP: 490


A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Co-activation of IP3R and RyR leads to socio-economic burden through reduced IQ and non-cholinergic mechanisms

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Co-activation of IP3R and RyR to socio-economic burden through lower IQ
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.5

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Thibaut Coustillet1, Xavier Coumoul1, Anne-Sophie Villégier2,3, Michèle Bisson4, Florence Zeman2,3, Karine Audouze1

1Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France.

2Unité Toxicologie Expérimentale et Modélisation, Institut National de l’Environnement Industriel et des Risques, 60550 Verneuil-en-Halatte, France.

3PériTox, UMR_I 01, CURS, Université de Picardie Jules Verne, Chemin du Thil, 80025 Amiens, France.

4Unité d’Expertise en Toxicologie/Ecotoxicologie des Substances, Institut National de l’Environnement Industriel et des Risques, 60550 Verneuil-en-Halatte, France.

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Karine Audouze   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Thibaut Coustillet
  • Karine Audouze
  • Xavier COUMOUL


This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on February 05, 2024 11:59

Revision dates for related pages

Page Revision Date/Time
Increased, glutamate October 11, 2021 14:58
Activation, Microglia April 07, 2022 09:25
Neuroinflammation July 15, 2022 09:54
Hippocampal Physiology, Altered August 11, 2018 09:41
Impairment, Learning and memory June 26, 2023 12:44
decreased, Bcl-2 expression September 07, 2023 03:23
increased, Bax expression September 07, 2023 03:23
decreased, Intellectual Quotient April 04, 2023 10:27
increased, socio-economic burden February 05, 2024 11:58
Cell injury/death July 15, 2022 09:46
Ryanodine receptor activation September 08, 2023 03:09
Inositol triphosphate receptor activation July 25, 2022 03:11
Activation, IP3R leads to Increased, glutamate September 08, 2023 09:12
Activation, RyR leads to Increased, glutamate September 08, 2023 09:12
Increased, glutamate leads to decreased, Bcl-2 April 04, 2023 10:36
Increased, glutamate leads to increased, Bax April 04, 2023 10:36
Increased, glutamate leads to Microglia activation April 03, 2023 06:05
Microglia activation leads to Neuroinflammation April 03, 2023 06:06
decreased, Bcl-2 leads to Cell injury/death April 04, 2023 10:37
increased, Bax leads to Cell injury/death April 04, 2023 10:38
Neuroinflammation leads to Cell injury/death November 07, 2019 10:27
Cell injury/death leads to Hippocampal Physiology, Altered April 05, 2023 03:48
Hippocampal Physiology, Altered leads to Impairment, Learning and memory April 03, 2023 06:07
Impairment, Learning and memory leads to decreased, IQ April 04, 2023 10:39
decreased, IQ leads to increased, Economic Burden April 04, 2023 10:35
Chlorpyrifos July 27, 2022 04:02
Chlorpyrifos oxon April 03, 2023 03:45
Organophosphates November 29, 2016 21:20


A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Prenatal and neonatal periods are windows of vulnerability to environmental chemical contaminants. A growing number of epidemiological and toxicological studies suggest that exposure to pesticides during these periods may impact the health of children at birth as well as their development, with potential delayed adverse effects. An AOP initiated after exposure to organophosphate pesticides such as chlorpyrifos (CPF) leading to a decrease of Intellectual Quotient (IQ) passing through non-cholinergic mechanisms was built using expert knowledges and artificial intelligence tool (the third-party tool AOP-helpFinder).

Indeed, despite the well-known mode of action of organophosphates as acetylcholinesterase (AchE) inhibitors, some studies have shown adverse effects on neurodevelopment at doses insufficient for AchE inhibition, thus suggesting the involvement of so-called non-cholinergic mechanisms. Moreover, we have introduced a new concept that allows to link the AO to a cost outcome (CO) by linking the KE ‘decrease of IQ’ to the KE ‘economic burden’, as an increasing number of studies and models showed the long-term economic impacts of stress exposure. Following, the ‘population’ level of organization of the AOP (i.e. adverse effects occur on several individuals in the same community), we propose to show that this AOP can have effects at a country scale. 

AOP Development Strategy


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. More help


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 2186 Ryanodine receptor activation Activation, RyR
MIE 2037 Inositol triphosphate receptor activation Activation, IP3R
KE 1350 Increased, glutamate Increased, glutamate
KE 2123 decreased, Bcl-2 expression decreased, Bcl-2
KE 2124 increased, Bax expression increased, Bax
KE 1998 Activation, Microglia Microglia activation
KE 188 Neuroinflammation Neuroinflammation
KE 55 Cell injury/death Cell injury/death
KE 758 Hippocampal Physiology, Altered Hippocampal Physiology, Altered
AO 341 Impairment, Learning and memory Impairment, Learning and memory
AO 2121 decreased, Intellectual Quotient decreased, IQ
AO 2122 increased, socio-economic burden increased, Economic Burden

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.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. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess 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. More help


List of the literature that was cited for this AOP. More help