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Relationship: 451

Title

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

AchE Inhibition leads to Increased Cholinergic Signaling

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

AchE Inhibition

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased Cholinergic Signaling

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	non-adjacent			Dan Villeneuve (send email)	Under Development: Contributions and Comments Welcome	Under Development
Acetylcholinesterase Inhibition leading to Acute Mortality via Impaired Coordination & Movement	non-adjacent			Kristie Sullivan (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 Do not cite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

AChE inhibition leading to increased cholinergic signaling manifests across a range of “cholinergic syndrome” symptoms appearing as organ-type-specific responses. In cases of acute cholinergic poisoning, certain signs are often measurable within just a few minutes after exposure to an AChE inhibitor.

One of the earliest and most frequent signs of cholinergic poisoning is constricted pupils (miosis) (Wadia, 1974), which is a manifestation mediated by muscarinic cholinergic receptors. Other manifestations observed in cases of cholinergic poisoning are collectively known as SLUDGE symptoms (Peter):

Salivation
Lacrimation (tears)
Urination
Defecations
Gastric Cramps
Emesis (vomiting)

Other signs of cholinergic poisoning are mediated by nicotinic cholinergic signalling. These include (Costa):

Tachycardia,
Transient hypertension
Muscle fasciculations
Twitching
Flaccid paralysis

Other signs of increased cholinergic signalling occurring in the lungs and heart include increased bronchial secretion, bronchoconstriction, bradycardia and tachycardia, hypotension and hypertension (Costa, Peter).

This KER is focussed on the signs of increased cholinergic signalling frequently described and/or measured in laboratory, field and clinical studies.

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

Extensive research provides evidence that AchE inhibition is associated with symptoms that are known to be mediated by increased cholinergic signalling. The interaction between increased acetylcholine and enhanced signalling via nicotinic and muscarinic receptors is well-established. Further, cholinergic neurons are known to innervate multiple physiological sites (reviewed in Costa, In Casarett and Doull's Toxicology, Lodish).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

A study of 200 cases of suicidal ingestion of organophosphorus insecticides in India (1971-1973) documented the incidence of numerous neurological symptoms associated with cholinergic signalling. Miosis (constricted pupils) was nearly universal amongst the patients observed. The table below lists the “Neurological Findings Associated with Organophosphorus Insecticide Poisoning” (Wadia, 1974).

Neurological signs	Patients (number)	Incidence (%)
Miosis	190	95
Impaired consciousness	20	10
Fasciculations	54	27
Convulsions	2	1
Paralytic signs	52	26

Pigs exposed to the AChE inhibitor, dichlorvos showed signs of cholinergic overstimulation, which included miosis, cyanosis, tremor, excess secretions and fasciculations. Measurement of AChE levels confirmed that dichlorvos treatment inhibited AChE activity. (Cui, 2013).
Mice exposed to AChE inhibitor, propoxur, showed overt signs of cholinergic signalling at the highest dose tested (5 mg/kg) - depression, tremor and salivation (Kobayashi, 1985)
In Japanese Quail, increased cholinergic signaling in the form of salivation and convulsions was seen in response to 2 different AchE inhibitors, dichlorvos and fenitrothion. (Kobayashi, 1983)
Sparrows exposed to lethal doses of the AChE inhibitor, fenthion, showed the following symptoms indicative of increased cholinergic signalling: body tremors, weakness, ataxia, loss of balance, partial paralysis (in the wings), full paralysis (of the legs), and salivation (Hunt, 1991)
Spontaneous movement in zebrafish embryos is regulated by cholinergic nicotinic receptors and is associated with developing primary and secondary motor neurons. These spontaneous movements were enhanced by treatment with dichlorvos, diazinon, and chlorpyrifos (Watson, 2014)

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

Exposure to high levels of AchE inhibiting insecticides (organophosphates and carbamates) is considered a factor contributing to GWS, a collection of neurological symptoms experienced by soldiers after the Persian Gulf War. Symptoms included fatigue, mood-cognitive problems, musculoskeletal symptoms. Factor analysis indicated cognitive impairment, ataxia and arthro-myo-neuropathy in some veterans and these symptoms were interpreted to reflect exposure to centrally acting anti-AChEs (Soreq & Seidman, 2001, Haley, 1997, Golomb, 2008)

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Signs of cholinergic toxicity/poisoning can show up within minutes of exposure in humans and mammals.
In humans signs of increased cholinergic signalling…
Pigs exposed to the AChE inhibitor, dichlorvos showed signs of cholinergic overstimulation within 5 minutes of treatment. AChE levels measured within 30 minutes of dichlorvos treatment showed significant inhibition, which continued to decrease over the course of the experiment (6 hours)(Cui, 2013).
Dichlorvos treatment (3-4 mg/kg) led to nervous system disruption within 7-15 minutes, whereas the response to fenitrothion treatment took longer. Quail treated with 250-350 mg/kg fenitrothion showed cholinergic signs 6-120 minutes post-treatment (Kobayashi, 1983)
A comparison of 5 organophosphate and 2 carbamate pesticides in rats showed dose-response data for a number of cholinergic signs (Moser 1995). The overall clinical picture of toxicity was similar but differences emerged in terms of specific signs, dose-response, and time-course.
Mice treated with propoxur demonstrated the following signs of increased cholinergic signalling within the timeframes noted in response to each tested dose.

AChE Inhibitor	Dose	Time (post injection)	Cholinergic symptoms
Propoxur	2 mg/kg	60 minutes	no apparent toxic signs
o-sec-butylphenyl methylcarbamate (BPMC)	10 mg/kg	60 minutes	no apparent toxic signs
o-sec-butylphenyl methylcarbamate (BPMC)	50 mg/kg	15-40 minutes	depression
Propoxur	5 mg/kg	5-30 minutes	depression, tremor and salivation

Mice treated with sublethal doses of BPMC (10 mg/kg) and propoxur (2 mg/kg) had increased acetylcholine and decreased acetylcholinesterase activity in the forebrain at 10 min post-treatment (Kobayashi, 1985).

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

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

Acetylcholine, the enzymes needed to generate it, and acetylcholine receptors have been described within metazoans in bilaterians (vertebrates, echinoderms, insects, nematodes, and annelids, etc.) and cnidarians (sea anemones, corals and hydrozoans). Acetylcholine receptors have not been described in placozoans, poriferans, and ctenophores, nor outside of metazoans. (Faltine-Gonzalez, 2018).

References

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.
Golomb, BA, Acetylcholinesterase inhibitors and Gulf War illnesses, Proc Natl Acad Sci USA. 2008 Mar 18; 105(11):4295-300.
Haley, R. W., Kurt, T. L. & Hom, J. Is there a Gulf War Syndrome? Searching for syndromes by factor analysis of symptoms. J. Am. Med. Assoc. 277, 215–222 (1997).
Cui J, Li CS, He XH, Song YG. Protective effects of penehyclidine hydrochloride on acute lung injury caused by severe dichlorvos poisoning in swine. Chin Med J (Engl). 2013; 126(24):4764-70.
Hunt KA, Bird DM, Mineau P, Shutt L. 1991. Secondary poisoning hazard of fenthion to American kestrels. Arch Environ Contam Toxicol 21:84–90.
Kobayashi H, Yuyama A, Kajita T, Shimura K, Ohkawa T, Satoh K. 1985. Effects of insecticidal carbamates on brain acetylcholine content, acetylcholinesterase activity and behavior in mice. Toxicol Lett 29:153–159.
Kobayashi H, Yuyama A, Kudo M, 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 28:219–227
Faltine-Gonzalez, DZ, Layden, MJ., The origin and evolution of acetylcholine signaling through AchRs in metazoans. bioRxiv 424804; doi: https://doi.org/10.1101/424804
Moser, VC. (1995). Comparisons of the acute effects of cholinesterase inhibitors using a neurobehavioral screening battery in rats. Neurotoxicol. Teratol. 17:617-625.