Upstream eventInhibition, Acetylcholinesterase (AchE)
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Acetylcholinesterase inhibition leading to acute mortality||non-adjacent||High||Moderate|
Life Stage Applicability
Key Event Relationship Description
Evidence Supporting this KER
- Acetylcholine is a critical neurotransmitter involved in a wide variety of bodily functions including regulation of heart rate, skeletal muscle contraction, vasodilation and blood pressure, salvation and lacrimation from various glands, and neuronal activity in the brain. Acetylcholinesterase catalyzes the rapid degradation of acetylcholine at the synapse, preventing sustained activation of acetylcholine receptors. Given the important roles of this AChE-mediated neurotransmission system, a linkage between AChE activity and organism survival is plausible.
Include consideration of temporal concordance here
- 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). Correlated with these symptoms was an 80-97% inhibition of AChE and mortality in 20-50% of the birds.
- AChE was inhibited from 81.5-92% in the brain of kestrels from day 1 to day 3 of a fenthion exposure, resulting in symptoms typical of AChE poisoning (e.g., paralysis, salivation, tremors, mortality), with a concurrent decrease in the amount of prey consumed (Hunt et al., 1991).
- A study reporting lethal and sublethal endpoints and AChE inhibition of 10 OP pesticides using Caenorhabditis elegans, found measurements of AChE inhibition was the most sensitive indicator of toxicity (Rajini et al., 2008).
Uncertainties and Inconsistencies
- Based on information presented herein there is strong evidence supporting the AChE AOP. The data gaps are associated with using measures of enzyme activity at the cellular/tissue level to estimate in a quantitative manner, adverse outcomes in the whole organism. Sufficient direct empirical evidence supporting impacts at the population level is also needed.
- 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). For instance, 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).
- 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).
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
- 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).
- A 20% inhibition of AChE in tissues as compared to controls has been reported as an indicator of exposure to OP pesticides (Ludke et al., 1975). The U.S. Environmental Protection Agency has identified a 10% inhibition of brain AChE as indicative of exposure to AChE inhibitors; a level that is well below any reported effect response thresholds (sublethal or lethal) based on experimental evidence in the literature (US EPA 2006).
- Measurement of AChE levels within brain and other tissues with linkages to cholinergic responses and ultimately mortality are well documented within the literature across vertebrate and invertebrate species, with 70-80% AChE inhibition associated with mortality in organisms (Grue et al. 1991; Jarvinen et al. 1983; and Ludke et al, 1975).
- Typically, inhibition of brain AChE levels below 50% of a control measurement results in changes in sublethal effects such as behavior, and physiological responses, while 70-80% inhibition is associated with mortality in organisms (Al-Zubaidy et al. 2011; Grue et al. 1991; Grue et al. 1983; Grue et al., 1997; Jarvinen et al. 1983; Ludke et al, 1975; Macek et al, 1982; Mileson et al. 1998; and Sheets et al., 1997).
- 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).