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Relationship: 456


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

ACh Synaptic Accumulation leads to Increased Cholinergic Signaling

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Acetylcholinesterase inhibition leading to acute mortality adjacent High Low Cataia Ives (send email) Under Development: Contributions and Comments Welcome Under Development
Acetylcholinesterase Inhibition leading to Acute Mortality via Impaired Coordination & Movement​ adjacent Allie Always (send email) Under development: Not open for comment. Do not cite
Organo-Phosphate Chemicals induced inhibition of AChE leading to impaired cognitive function adjacent High Low Brendan Ferreri-Hanberry (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Acetylcholine is a neurotransmitter and neuromodulator that can exert either excitatory or inhibitory effects, depending on the receptor it binds to. Acetylcholine mediates central and peripheral functions, including somatic and autonomic functions. Excessive accumulation of acetylcholine at neural synapses and at neural-muscular junctions results in increased cholinergic signalling.

  • Acetylcholine is generated in presynaptic neurons and released into the synaptic cleft where it can bind to both pre- and postsynaptic receptors. Acetylcholine availability is downregulated by the degratory effect of acetylcholinesterase and by negative feedback loops controlled by muscarinic M2 receptors on the presynaptic neuron within the synapse (Soreq and Seidman, 2001).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help
  • Biological plausibility for acetylcholine accumulation at the synapse leading to nervous system dysfunction is rooted in the well-established understanding of acetylcholine’s function as a neurotransmitter and neuromodulator. By acting upstream of a range of cellular and physiological functions, it is biologically plausible that accumulation of acetylcholine at neurological synapses will lead to systemic dysfunctions, which are often readily noticeable and measurable in clinical and research settings. 
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help
  • No known qualitative inconsistencies or uncertainties associated with this relationship.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help
  • Costa.  Toxic effects of pesticides.  In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106.

  • De Candole, C.A., Douglas, W.W., Evans, C.L., Holmes, R., Spencer, K.E., Torrance, R.W., Wilson, K.M. 1953. The failure of respiration in death by anticholinesterase poisoning. Br J Pharmacol Chemother. 8(4):466-75.

  • Picciotto MR, Higley MJ, Mineur YS., Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012 Oct 4;76(1):116-29.

  • Luchicchi A, Bloem B, Viaña JN, Mansvelder HD, Role LW., Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors. Front Synaptic Neurosci. 2014 Oct 27;6:24. doi: 10.3389/fnsyn.2014.00024. eCollection 2014.

  • Soreq H, Seidman S., Acetylcholinesterase--new roles for an old actor. Nat Rev Neurosci. 2001 Apr;2(4):294-302.

  • Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 21.4, Neurotransmitters, Synapses, and Impulse Transmission. Available from:

  • Buels, K.S., Fryer, A.D. 2014. Muscarinic Receptor Antagonists: Effects on Pulmonary Function. Handb Exp Pharmacol. 2012; (208): 317–341.

  • Coulson FR1, Fryer AD. Muscarinic acetylcholine receptors and airway diseases. Pharmacol Ther. 2003 Apr;98(1):59-69.

  • Wadia RS, Sadagopan C, Amin RB, Sardesai HV. Neurological manifestations of organophosphorous insecticide poisoning. J Neurol Neurosurg Psychiatry. 1974 Jul;37(7):841-7.

  • Stenersen J. 2004. Specific enzyme inhibitors. Chemical Pesticides: Mode of action and toxicology, CRC Press, Boca Raton, FL, USA.

  • Kobayashi, H., Yuyama, A., Kudo, M., and Matsusaka, N. 1983. Effects of Organophosphorus Compounds, O,O-Dimethyl O-(2,2-Dichlorovinyl)Phosphate (DDVP) and O,O-Dimethyl O-(3-Methyl 4-Nitrophenyl)Phosphorothioate (Fenitrothion), on Brain Acetylcholine Content and Acetylcholinesterase Activity in Japanese Quail. Toxicology 28[3], 219-227.

  • Grue CE, Shipley BK. 1984. Sensitivity of nestling and adult starling to dicrotophos, an organophosphate pesticide. Environ Res 35:454–465.

  • Verma, S.R., Tonk, I.P., Gupta, A.K., Dalela, R.C. 1981. In Vivo Enzymatic Alteration in Certain Tissues of Saccobranchus Fossilis Following Exposure to Four Toxic Substances. Environ. Pollut. (Series A). 26(2), 121-127.