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Relationship: 433

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

Respiratory distress/arrest leads to Increased Mortality

Upstream event

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

Respiratory distress/arrest

Downstream event

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

Increased Mortality

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

In cases of lethal cholinergic poisoning, mortality results from asphyxiation due to respiratory failure.

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

A functioning respiratory system is essential for delivering oxygen to organ tissues throughout an organism. Thus, mortality results following respiratory failure.

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 15 out of 36 people died from respiratory paralysis, in spite of receiving ventilation support in the form of artificial respiration. (Wadia 1974)
In Sri Lanken cohort study, 376 patients with confirmed organophosphate poisoning were observed during the duration of their admission at 3 hospitals. 24% of patients in the study required intubation and half of the intubated patients died (Eddleston 2007).
A study in a rodent model of dichlorvos poisoning, found that poisoning caused a rapid lethal central apnea, followed by delayed impairment of pulmonary gas exchange with prominent airway secretions (Gaspari 2007 in Peter 2014).
A study of OP exposure in cats, dogs, rabbits, monkeys, sheep, goats, mice, rats, and guinea pigs found asphyxiation to be the cause of death (Candole 1953).
A study of cats exposed to the nerve agents, soman, sarin, tabun, and VX, concluded that central respiratory drive was the dominant cause of respiratory failure. Nerve agents were infused up until respiratory arrest, when the phrenic nerve was stimulated to test diaphragmatic contraction. Immediately following cessation of spontaneous respiration, stimulation at 100 Hz produced a tetanic contraction of the diaphragm (Rickett 1986).

Fish

Reduced oxygen utilization leads to mortality in trout (McKim, 1987)
An acute (24-h) exposure of fingerling rainbow trout to acephate found a dose-dependent relationship between inhibition of AChE, respiratory activity, and mortality. The LC50 values ranged from 1880-3160 mg/L, with 76-89% inhibition of AChE in dead fish (at a concentration of 950-4000 mg/L), and significant increase in respiration rates at a concentration of 2,000 mg/L (Duangsawasdi 1977, 1979).
In an acute exposure of Labeo rohita to malathion the fish were observed to be gulping air at the surface and a significant respiration rate/oxygen consumption rate, resulting in fish sinking to the bottom of the test vessels having little to no opercular movements followed by death (Patil 2008).

Birds

Birds die from respiratory distress after continued cholinergic stimulation exhausts the respiratory muscles. (Blackwell's Five-Minute Veterinary Consult: Avian)
Male quail (8-14 weeks old) exposed to a single dose of either dichlorvos or fenitrothion via subcutaneous injection at four treatment levels resulted in an 80% reduction of brain AChE, and a concurrent significant increase in acetylcholine as compared to controls, with mortality preceded by respiratory distress (Kobayashi 1983).

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

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

We are unaware of any correlative relationships of significant predictive value with regard to this KER.

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

References

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

Carey JL, Dunn C, Gaspari RJ., Central respiratory failure during acute organophosphate poisoning. Respir Physiol Neurobiol. 2013 Nov 1;189(2):403-10.
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.
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.
Gaspari, R.J., Paydarfar, D. 2007. Pathophysiology of respiratory failure following acute dichlorvos poisoning in a rodent model. Neurotoxicology. 28(3): 664-71.
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.
Peter, J.V., Sudarsan, T.I. and Moran, J.L. 2014. Clinical features of organophosphate poisoning: A review of different classification systems and approaches. 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.
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.
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.