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Relationship: 450

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 Respiratory distress/arrest

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

Respiratory distress/arrest

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	Moderate	Low	Dan Villeneuve (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

Acetylcholinesterase (AchE) inhibition leads to respiratory distress and arrest via increased cholinergic signalling. AchE inhibition leads to accumulation of acetylcholine (Ach) within neural synaptic clefts and neuromuscular junctions. Respiratory failure follows as a consequence of a multifactor process resulting from physiological functions associated with both muscarinic and nicotinic cholinergic signalling. This process includes a direct depressant effect on the brain stem respiratory center, airway constriction, increased mucus secretion in the airways, and respiratory musculature paralysis (review in Carey, 2013).

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

Respiratory failure involves central apnea as well as pulmonary dysfunction. Multiple mechanisms, including afferent pathways, central respiratory networks, and efferent pathways are involved (Carey 2013). From Costa, “When death occurs, this is believed to be due to respiratory failure as a result of inhibition of respiratory centers in the brainstem, bronchoconstriction, and increased bronchial secretion, and flaccid paralysis of respiratory muscles (Gallo and Lawryk, 1991; Lotti, 2000, 2010).”
Central apnea- Ach is important in respiration; most aspects of respiratory control are influenced by cholinergic mechanisms. Central control of respiration occurs via a respiratory oscillator with both feedback and feed-forward afferent and efferent pathways. Cholinergic mechanisms contribute to chemosensitivity, efferent airway signaling, sub-mucosal glands, vagal afferent signaling, and rhythm generation (Carey 2013).
Pulmonary function- Effects causing impairment of respiration include bronchoconstriction, changes in pulmonary blood flow, pulmonary edema, and bronchorrhea (Carey 2013).
Acute respiratory failure is the cause of death in most cases of poisoning with AChE inhibitors; however, the overall clinical picture can be complicated by a delayed intermediate syndrome, pneumonitis/pneumonia, the specific poisoning agent, as well as interactions with other chemical exposures (Hulse et al., 2014).

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

Mammals

In a study of suicidal ingestion of organophosphorus insecticides, 14 of 52 cases with paralysis had type 2 respiratory paralysis, that appeared later and was not present on admission, indicating nicotinic rather than muscarinic effects predominating (Wadia 1974).
In a clinical study of 52 patients diagnosed with organophosphate or carbamate poisoning, 27 subjects developed Type I and 7 had Type II respiratory failure. Mechanical ventilation was required in 31 subjects (Goswamy 1994).
In a study of 80 subjects hospitalized for OP poisoning and treated with intravenous atropine and pralidoxime, the mortality rate was 18% in patients treated with pralidoxime, while patients without pralidoxime had a mortality rate of 21%. Ten patients were mechanically ventilated and the mortality rate was 50%. In patients without ventilation the mortality rate was 11.7% (Noshad 2007).
A study on dichlorvos-induced acute lung injury in swine showed that anti-cholinergic treatment reduced wet to dry weight ratio of pulmonary tissue, apoptosis index, and mitigated injury to the structure of lung. Measures of acute lung injury were cardiac index and pulmonary vascular resistance indices (Cui 2013).
- Another indicator for oxygenation problems, OI, was significantly downregulated (P <0.01) in the group exposed to dichlorvos; this may be a sign of partial anatomic shunting, ventilation/perfusion mismatch, and disturbance of gas diffusion from the “pulmonary alveolar capillary barrier” in OP poisoning (Karbing 2007 in Cui 2013).
- Acute dichlorvos toxicity caused damage to pulmonary tissue, including interstitial and alveolar edema, but treatment with atropine and PHC had protective effects.
A study of OP exposure in cats, dogs, rabbits, monkeys, sheep, goats, mice, rats, and guinea pigs found the predominant effect of anticholinesterase poisoning to be respiratory failure. It was postulated that multiple mechanisms caused respiratory failure, namely bronchoconstriction, neuromuscular block, and central respiratory failure (De Candole 1953).
- Rabbits dosed with sarin showed narrowing of the bronchi at all dosage levels.
- The height of the tetanic response of the diaphragm to stimulation of the phrenic nerve was reduced, and the diaphragm ceased to respond tetanically ten seconds after injection.
- At 40 ug/kg, impulse traffic in the phrenic nerve rapidly diminished, with no further traffic after diaphragm contractions have stopped, indicating that respiratory motor neurons have ceased firing and that diaphragm paralysis results from central action rather than peripheral (De Candole 1953).

Fish

A study of the overall respiratory-cardiovascular responses of rainbow trout to acutely lethal concentrations of malathion and carbaryl showed immediate decreases in oxygen utilization and heart rate. Ventilation volume increased, but oxygen consumption did not. A moderate to low increase in ventilation volume and oxygen consumption was followed at 50 to 60% survival time by sudden decreases in ventilation volume and oxygen consumption until death. Ventilation rate, oxygen utilization and heart rate showed a steady downward trend over the entire survival period (McKim et al., 1987b).

Birds

Within one hour of exposure of broiler chicks to dichlorvos or diazinon symptoms indicative of cholinergic poisoning were observed including respiratory difficulty (gasping), tremors and convulsions (Al-Zubaidy et al. 2011.

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

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

Symptoms of respiratory failure varied with the species studied, drugs used, and administered dose (De Candole).

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

The effects of anticholinesterase drugs on respiratory response varied by species. In rabbits, respiratory failure resulted from a combined central respiratory response with neuromuscular block at the diaphragm, while bronchoconstriction was less severe. Cats showed immediate bronchoconstriction and consequent anoxia, followed by central respiratory effects. In monkeys, respiratory failure was almost entirely caused by inhibition of central respiratory mechanism (De Candole).
Studies across multiple species show that the relative role of local pulmonary effects, central respiratory depression, and respiratory muscle paralysis may vary, but the central effects predominate in nonhuman primates (and by extension humans). Maintenance of ventilation and treatment with muscarinic blockers and reactivating agents are shown to reduce mortality in animal studies and continue to be the standard clinical treatment (Hulse et al., 2014).
In fish, the mechanism for respiratory-cardiovascular response in fish is likely explained by a decrease in respiratory surface area of the gills, or vasoconstriction. AChE inhibition in the gills would result in continuous stimulation at neuromuscular junctions, causing arterial sphincters to constrict and reduced blood flow to secondary lamellae. Oxygen utilization decreased as a result (McKim).
In birds, respiratory failure occurs after continued cholinergic stimulation exhausts the respiratory muscles. Other respiratory symptoms include muscle tremors and increased respiratory tract secretions (Blackwell's Five-Minute Veterinary Consult: Avian).

References

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

Al‐Zubaidy, M.H.I., Mousa, Y.J., Hasan, M.M., Mohammad, F.K. 2011. Acute toxicity of veterinary and agricultural formulations of organophosphates dichlorvos and diazinon in chicks. Arh Hig Rada Toksikol 62:317–323.
Carey, J.L., Dunn, C., Gaspari, R.J. 2013. Central respiratory failure during acute organophosphate poisoning. Respiratory Physiology & Neurobiology. 189(2), 403-410.
Costa. Toxic effects of pesticides. In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106.
Cui,J., C.S. Li, X.H. He, and Y.G. Song. 2013. Protective Effects of Penehyclidine Hydrochloride on Acute Lung Injury Caused by Severe Dichlorvos Poisoning in Swine. Chin. Med. J.126(24): 4764-4770.
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.
Giyanwani PR, Zubair U, Salam O, Zubair Z., Respiratory Failure Following Organophosphate Poisoning: A Literature Review. Cureus. 2017 Sep 3;9(9):e1651. doi: 10.7759/cureus.1651.
Goswamy, R., Chaudhuri, A., Mahashur, A.A. 1994. Study of respiratory failure in organophosphate and carbamate poisoning. Heart Lung. 23(6):466-72.

Graham, J.E. 2016. Blackwell's Five-Minute Veterinary Consult: Avian.
Hulse, E.J., Davies, J.O., John Simpson, A., Sciuto, A.M., Eddleston, M. 2013. Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care. American Journal of Respiratory and Critical Care Medicine. 190(12).
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.
Noshad, H., Ansarin, K., Ardalan, M.R., Ghaffari, A.R., Safa, J., Nezami, N. 2007 Respiratory failure in organophosphate insecticide poisoning. Saudi Med J. 28(3):405-7.
Rivera JA1, Rivera M., Organophosphate poisoning. Bol Asoc Med P R. 1990 Sep;82(9):419-22.
Shao, X. M., & Feldman, J. L. 2009. Central cholinergic regulation of respiration: nicotinic receptors. Acta pharmacologica Sinica, 30(6), 761–770.
Wadia, R. S., Sadagopan, C., Amin, R. B., and Sardesai, H.V. 1974. Neurological manifestations of organophosphorus insecticide poisoning. J Neurol Neurosurg Psychiatry. 37(7): 841–847.