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Relationship: 2007

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 Cardiovascular dysregulation

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

Cardiovascular dysregulation

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

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

Inhibition of AChE can lead to cardiovascular dysregulation when elevated acetylcholine levels overstimulate cholinergic receptors that regulate heart rate and vascular tone. In fish, acute mortality due to AChE inhibition is mediated by cardiovascular manifestations and the relationship between blood flow, gills, and respiratory physiology (Duangsawasdi and Klaverkamp 1979; Duangsawasdi 1978; McKim, Schmieder, Carlson, et al. 1987; McKim, Schmieder, Niemi, et al. 1987). In humans, cardiac effects are rarely the predominant factors leading to acute mortality caused by AChE inhibition because acute mortality is nearly always caused by respiratory failure in those cases. Nonetheless, it is still worth noting that cohort studies of patients exposed to organophosphate poisonings have documented a range of cardiovascular manifestations, including: abnormal electrocardiogram patterns, abnormal heart rate and blood pressure, and noncardiogenic pulmonary edema (Marrs 1993; Peter, Sudarsan, and Moran 2014).

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 cardiovascular system is sensitive to AChE inhibition due to vagal innervation of heart tissue and due to the presence of non-neuronal acetylcholine released by cardiomyocytes in the heart. Acetylcholine acts on muscarinic receptors in the heart and overstimulation of the main muscarinic receptor (M2) leads to bradycardia in humans and in fish (Costa, Duagsawasdi 1978, Hsieh, 2002).

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

Fish

Studies in Rainbow Trout have consistently showed decreased heart rate in response to AChE inhibitor exposure. This has been shown for malathion, carbaryl (McKim et al. 1987), acephate, and fenitrothion (Duangsawasdi and Klaverkamp 1979)
Zebrafish and Xenopus embryos exposed to AChE organophosphate inhibitors exhibited cardiovascular impairments.
- High concentrations (100 uM) of diazinon caused pericardial edema and compromised blood flow in Zebrafish embryos.
- Chlorpyrifos treatment elicited a dose-dependent decrease in heart rate in both zebrafish and Xenopus embryos (Watson, 2014).

Mammals

In a study of pigs, dichlorvos treatment inhibited AChE activity and impacted multiple measures of cardiovascular impairment. Heart rate was significantly lowered from the first time point measured until the last time point (0.5-6 hours post-dichlorvos treatment). Pulmonary vascular resistance increased and peaked at 1 hour post-dichlorvos treatment (reported as PVRI, an index calculated based on a standard formula, “PVRI = (mean pulmonary arterial pressure minus pulmonary artery wedge pressure) / CI x 80” (Cui, 2013)
Impaired cardiovascular function has been observed in laboratory studies of beagle dogs exposed to the organophosphorus nerve agent, VX (S-(2-diisopropylaminoethyl)-O- ethylmethyl phosphonothiolate). Authors concluded that VX exposure increased capillary permeability in the lungs and they propose this could lead to high-permeability edema (Lainee, 1991). In another study in beagles, VX treatment was associated with small but significant decreases in heart rate, arterial and left intraventricular pressure, and contractility index (Robineau, 1987).
According to an electronic search of PubMed records published between 1966-April 2014, two-thirds of patients with organophosphate poisoning experienced cardiac manifestations. The search terms were “organophosphorus compounds or phosphoric acid esters AND poison or poisoning AND manifestations”. As reviewed in Peter, 2014, specific cardiac manifestations observed across organophosphate poisoning cases included:
- Abnormal electrocardiogram patterns: QTc prolongation, ST-T segment changes and T wave abnormalities.
- Heart rate (HR) abnormalities: brachycardia (slow HR), tachycardia (fast HR), supraventricular and ventricular arrhythmias, and ventricular premature complexes
- Blood pressure alterations in the form of hypotension and hypertension
- Noncardiogenic pulmonary edema
Histologic evidence of myocardial damage has been reported in animal studies and in autopsies from fatal human poisonings (Reviewed by Mars, 1993).

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

While cardiovascular complications leading to death have been reported in cases of intermediate syndrome following OP poisoning in humans, the timeframe for these cases fall outside of the scope of AChE inhibition leading to acute mortality.

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

In fish, OP insecticide toxicity at cardiovascular sites of action is dependent on physicochemical properties such as lipid solubility, degree of ionization, and environmental factors such as temperature (Duagsawasdi 1978, 1979).

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

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

In fish, cardiovascular impairments are tightly connected to respiratory physiology, such that the cardio-respiratory manifestations of AChE inhibition lead to to acute mortality (McKim, 1987).
While impaired cardiovascular function is seen in humans and other mammals in cases of AChE inhibition, the subsequent contribution of cardiovascular impairment leading to death from cholinergic toxicity is minimal in humans. Even though cardiovascular effects have been observed in cases of organophosphate poisoning in humans, acute death from poisoning is usually caused by respiratory arrest mediated by the nervous system, independent of cardiovascular factors (Costa).

References

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

Duangsawasdi, M. 1978. “Organophosphate Insecticide Toxicity in Rainbow Trout (Salmo Gairdneri). Effects of Temperature and Investigations on the Sites of Action.” Manitoba, Canada.: University of Manitoba.

Duangsawasdi, M, and JF Klaverkamp. 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 667:35–51. Philadelphia, PA.

McKim, James M., Patricia K. Schmieder, Richard W. Carlson, Evelyn P. Hunt, and Gerald J. Niemi. 1987. “Use of Respiratory-Cardiovascular Responses of Rainbow Trout (Salmo Gairdneri) in Identifying Acute Toxicity Syndromes in Fish: Part 1. Pentachlorophenol, 2,4-Dinitrophenol, Tricaine Methanesulfonate and 1-Octanol.” Environmental Toxicology and Chemistry 6 (4): 295–312. https://doi.org/10.1002/etc.5620060407.

McKim, James M., Patricia K. Schmieder, Gerald J. Niemi, Richard W. Carlson, and Tala R. Henry. 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.” Environmental Toxicology and Chemistry 6 (4): 313–28. https://doi.org/10.1002/etc.5620060408.

Marrs, T. C. 1993. “Organophosphate Poisoning.” Pharmacology & Therapeutics 58 (1): 51–66. https://doi.org/10.1016/0163-7258(93)90066-m.

Peter, John Victor, Thomas Sudarsan, and John Moran. 2014. “Clinical Features of Organophosphate Poisoning: A Review of Different Classification Systems and Approaches.” Indian Journal of Critical Care Medicine 18 (11): 735–45. https://doi.org/10.4103/0972-5229.144017.

Cui, Juan, Chun-Sheng Li, Xin-Hua He, and Yu-Guo Song. 2013. “Protective Effects of Penehyclidine Hydrochloride on Acute Lung Injury Caused by Severe Dichlorvos Poisoning in Swine.” Chinese Medical Journal 126 (24): 4764–70.

Costa, LG. 2019. “Toxic Effects of Pesticides.” In Casarett and Doull’s Toxicology: The Basic Science of Poisons, 9th ed, 1055–1106. McGraw-Hill Education.

Hsieh, Dennis Jine-Yuan, and Ching-Fong Liao. 2002. “Zebrafish M2 Muscarinic Acetylcholine Receptor: Cloning, Pharmacological Characterization, Expression Patterns and Roles in Embryonic Bradycardia.” British Journal of Pharmacology 137 (6): 782–92. https://doi.org/10.1038/sj.bjp.0704930.

Lainee, P., P. Robineau, P. Guittin, H. Coq, and G. Benchetrit. 1991. “Mechanisms of Pulmonary Edema Induced by an Organophosphorus Compound in Anesthetized Dogs.” Fundamental and Applied Toxicology: Official Journal of the Society of Toxicology 17 (1): 177–85. https://doi.org/10.1016/0272-0590(91)90249-4.

Robineau, P., and P. Guittin. 1987. “Effects of an Organophosphorous Compound on Cardiac Rhythm and Haemodynamics in Anaesthetized and Conscious Beagle Dogs.” Toxicology Letters 37 (1): 95–102. https://doi.org/10.1016/0378-4274(87)90173-1.

Watson, Fiona L., Hayden Schmidt, Zackery K. Turman, Natalie Hole, Hena Garcia, Jonathan Gregg, Joseph Tilghman, and Erica A. Fradinger. 2014. “Organophosphate Pesticides Induce Morphological Abnormalities and Decrease Locomotor Activity and Heart Rate in Danio Rerio and Xenopus Laevis.” Environmental Toxicology and Chemistry 33 (6): 1337–45. https://doi.org/10.1002/etc.2559.