This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 457


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

Increased Cholinergic Signaling leads to Respiratory distress/arrest

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

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

Respiratory distress as a result of increased cholinergic signalling due to AChE inhibition occurs through combined peripheral and central cholinergic effects.

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
  • The link between increased cholinergic signalling and respiratory distress/failure is based on respiratory manifestations observed in many organisms and what is well-understood about cholinergic signalling, which is mediated by both muscarinic and nicotinic receptors. 

1. Nicotinic Respiratory paralysis (Wadia 1974),

2. Muscarinic- Central respiratory depression (Costa, Peter 2014), rhinorrhea, bronchorrhea, bronchospasm (Peter 2014), increased bronchial secretions (Costa, Buels 2012), bronchoconstriction (Costa, de Candole 1953, Buels 2012), neuromuscular block at the diaphragm, potentially leading to inability to regulate movements of the diaphragm (de Candole 1953).

  • Nicotinic acetylcholine receptors (nAChRs) are expressed in brain and spinal cord regions in control of breathing, and mediate central cholinergic regulation of respiration. Activation of nAChRs in the the preBötzinger Complex (preBötC), an essential site for normal respiratory rhythm generation in mammals, modulates excitatory glutamatergic neurotransmission and depolarizes preBötC inspiratory neurons, leading to increases in respiratory frequency. nAChRs are also present in motor nuclei innervating respiratory muscles. Activation of post- and/or extra-synaptic alpha4* nAChRs on hypoglossal (XII) motor neurons depolarizes these neurons, potentiating tonic and respiratory-related rhythmic activity (Shao 2009).

  • In humans, early acute mixed central and peripheral respiratory failure. Early respiratory failure in humans involves depression of central respiratory drive from the respiratory center in the ventrolateral medulla, respiratory muscle weakness, and direct pulmonary effects such as bronchospasm and bronchorrhea. (Eddleston 2007). 

  • The first signs of OP poisoning to appear are usually muscarinic, followed by nicotinic signs. Early respiratory failure may not display clear cut symptoms (Costa). A study of neurological signs in humans exposed to OP compounds found impaired consciousness in 10%, fasciculations in 27%, convulsions in 1%, toxic delirium in 50%, and paralysis in 26%. Type 1 signs were present on admission, while type 2 signs appeared later.  Type 1 signs, such as impaired consciousness and bilateral pyramidal tract signs, respond to atropine. Of 36 cases with type 2 signs (proximal limb weakness, areflexia, and cranial nerve palsies), 15 died from respiratory paralysis after a variable period of artificial respiration (Wadia 1974).

  • A study of OP poisoning in humans found that of 376 patients, 90 (24%) required intubation: 52 (58%) within 2 h of admission while unconscious with cholinergic features. Twenty-nine (32%) were well on admission but then required intubation after 24 h while conscious and without cholinergic features. These two syndromes were not clinically distinct and had much overlap. In particular, some patients who required intubation on arrival subsequently recovered consciousness but could not be extubated, requiring ventilation for up to 6 days (Eddleston 2006).

  • In animal models, ventilation can be impaired through bronchoconstriction, neuromuscular block, and central respiratory failure, with central failure being the predominant factor (De Candole 1953, Peter 2014). Disruption of the normal firing pattern of medullary respiratory-related neurons is followed by changes in phrenic nerve activity, diaphragm EMG, diaphragm contraction and airflow (Rickett 1986).

  • In fish, reduced uptake of oxygen by the gills due to reduced respiratory surface area, as a result of direct toxicant effects on the gills. Inhibition of AChE in the gills would result in continuous stimulation of neural-muscular junctions and cause sphincters at the base of the efferent filamental arteries to constrict, reducing blood flow through the secondary lamellae (McKim 1987). 

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
  • There is abundant evidence that increased cholinergic signalling leads to respiratory failure in many organisms. There is one area of uncertainty, which relates to how the balance of nicotinic and muscarinic effects lead to respiratory failure. It is unclear which mechanism predominates and greater understanding of these mechanisms could help inform therapeutic intervention strategies.

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
  • Cats - see Rickett 1986, cited above


List of the literature that was cited for this KER description. More help
  • Buels, K.S., Fryer, A.D. 2014. Muscarinic Receptor Antagonists: Effects on Pulmonary Function. Handb Exp Pharmacol. 2012; (208): 317–341.

  • 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.

  • Eddleston M, Mohamed F, Davies JO, Eyer P, Worek F, Sheriff MH, Buckley NA. 2006. Respiratory failure in acute organophosphorus pesticide self-poisoning. QJM. 99(8):513-22. 

  • McKim, J.M., Schmieder, P.K., Niemi, G.J., Carlson, R.W., Henry, T.R. 1987. Use of respiratory‐cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish: Part 2. Malathion, carbaryl, acrolein, and benzaldehyde. Environ Toxicol Chem 6:313–328.

  • Peter, J.V., Sudarsan, T.I. and Moran, J.L. 2014. vas. Indian J Crit Care Med. 18(11): 735–745.

  • Rickett, D.L., Glenn, J.F., Beers, E.T. 1986. Central respiratory effects versus neuromuscular actions of nerve agents. Neurotoxicology. 7(1): 225-36.

  • Shao, X.M., Feldman, J.L. 2009. Central cholinergic regulation of respiration: nicotinic receptors. Acta Pharmacol Sin. 30(6):761-70. 

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

  • Dickson EW, Bird SB, Gaspari RJ, Boyer EW, Ferris CF. Diazepam inhibits organophosphate-induced central respiratory depression. Acad Emerg Med. 2003 Dec;10(12):1303-6.

  • Senanayake N, Karalliedde L. Neurotoxic effects of organophosphate insecticides: an intermediate syndrome. N Engl J Med. 1987;316:761–3.

  • de Bleecker JL. The intermediate syndrome in organophosphate poisoning: an overview of experimental and clinical observations. J Toxicol Clin Toxicol. 1995;33:683.

  • Pitcher JA, Freedman NJ, Lefkowitz RJ. G protein-coupled receptor kinases. Annu Rev Biochem. 1998;67:653–92. 

  • Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG. Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci. 2004;27:107–44.

  • 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.

  • Duangsawasdi M. 1977. Organophosphate insecticide toxicity in rainbow trout (Salmo gairdneri). Effects of temperature and investigations on the sites of action. PhD thesis. University of Manitoba, Manitoba, Canada.

  • Duangsawasdi M, Klaverkamp JF. 1979. Acephate and fenitrothion toxicity in rainbow trout: Effects of temperature stress and investigations on the sites of action. In Aquatic Toxicology, Vol 2, STP 667. ASTM International, Philadelphia, PA, USA, pp 35–51.