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Relationship: 452

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 Mortality

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 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	non-adjacent	High	Moderate	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

Acetylcholinesterase (AChE) inhibition leads to mortality via overstimulation of neuronal cholinergic signalling pathways that control factors essential for respiration (Costa in Casarett and Doull's).

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

Development of AChE Tolerance: Under certain circumstances, tolerance to AChE inhibition can develop, instead of mortality. Rats exposed to acutely toxic, near-lethal amounts of AChE inhibitor become tolerant. Adaptation to AChE inhibitor has been described in humans in association with Myasthenia graves, asthenic syndrome, and after long exposure to some insecticides. (Stavinoha, 1969)(The reference listed here references 3 papers on rats published between ‘52-’64).
In vivo AChE Inhibition Measurement Challenges
- Correlating in vivo measures of AChE inhibition with mortality endpoints have not always been successful possibly due to interference from other esterases and partitioning issues across tissues (Wilson 2010).
- A QSAR (quantitative structure activity relationship) model developed to predict the acute LC50 for rainbow trout (Oncorhynchus mykiss) using the pI50 (concentration that inhibits AChE by 50%) found a statistically relevant linear relationship, but the model only explained 59% of the variation in toxicity observed for the series of carbamates tested (Call et al., 1989). QSAR models to estimate fish toxicity (LC50) for a series of OPs based on the reaction rate constants associated with inhibition of AChE in electric eel did result in a significant model, but the model only explained 23% of the variation in toxicity (De Bruijn and Hermens 1993).
Challenges correlating In vivo and In vitro AChE Activity Measurements: Although relationships can be made between the in vitro AChE inhibition and in vivo toxicity values observed for direct acting OPs and carbamates, these relationships typically are not significant (Wilson 2010). Factors contributing to the failure of these correlations include the tissue analyzed, method used to assay AChE or acetylcholine, organism life stage, dose compared to body size, and metabolic differences including detoxification pathways (Wilson 2010; Ludke et al., 1975; Hamadain and Chambers, 2001).

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

Mammals
- The relationship between AChE inhibition and lethality was evaluated by comparing mortality dose-response for 7 OPs in guinea pigs, and also for 1 OP (soman) in mice, rats, rabbits, and non-human primates. Regression analysis indicated that 93% of the variation in median lethal doses was explained by their in vitro rate constants for AChE inhibition (Maxwell et al 2006).
- A dose response curve between percent mortality and the AChE-inhibitor, disulfoton, in Holzman and Charles River rats was used to establish a chronic 10-day LD50 at 1.8 mg/kg. Rats were dosed with 10, 25 or 50 ppm DiSystron.
Birds
- Evaluations of incidents of bird poisonings from OPs and carbamates found that events were correlated with a >50% inhibition of brain AChE, with exposure confirmed by the detection of the pesticide within the stomach contents of the analyzed bird (Fleischli et al., 2004).
Fish
- Statistically significant effects were observed in fish mortality at 80% inhibition of brain AChE, with the maximum inhibition observed at 3-7 days after the first application of chlorpyrifos (Macek et al., 1972).
- In embryonic zebrafish exposed to 9 uM diazinon for three days, 35% mortality was observed, and some fish displayed developmental malformations (In Yen, 2011 citing Osterauer and Kohler, 2008).
- A study using zebrafish exposed to chlorpyrifos, resulted in 75-100% mortality at 3-30 uM concentrations, and 80% inhibition of AChE at 0.3 uM from 0-5 dpf. The study also demonstrated an increase in AChE activity in control fish from 0-5 dpf, with 0.3 uM chlorpyrifos significantly inhibiting AChE at 3 dpf (~50%) with inhibition increasing through to 5 dpf (80%) (Yen et al., 2011).

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

Taxonomic Applicability

Russom et al performed two parallel approaches to examine AChE sensitivity across multiple taxa: insects, crustaceans, fish, amphibians, mollusks, annelids, and plants. They generated species sensitivity curves from empirical evidence pulled from systemic searches for acute lethality toxicity data for terrestrial and aquatic species in the ECOTOX database. Daphnids were consistently found to be highly sensitive to organophosphates and carbamates. Next, they used the Daphnia pulex AChE protein sequence was used as the query sequence to make cross-species susceptibility predictions. There was strong agreement between the empirical evidence and the species sensitivity predictions based on the protein sequence similarity approach. Insects and crustaceans include the species most sensitive the AChE inhibition, followed by fish and amphibians and then by mollusks and annelids (Russom, 2014; LaLone, 2013).
Amongst fish, amphibians, mammals and birds, Wallace summarized comparative sensitivities from multiple studies. Across these groups, birds are highly sensitive to AChE inhibition, mammals are moderately sensitive and fish and amphibians are the least sensitive to AChE inhibition.

Life Stage Applicability

Studies in zebrafish have shown that mortality coincides with the onset of organogenesis for dichlorvos and diazinon and with the end of organogenesis/onset of hatching for chlorpyrifos (Watson, 2014)
In Xenopus, OP-induced mortality occurs at a time well after organogenesis and before the physiological changes associated with metamorphosis. At the peak of Xenopus mortality, the larva was swimming actively, had a well-developed mouth, and was in the process of developing hind limbs (stage 49) (Watson, 2014)