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Relationship: 11

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 ACh Synaptic Accumulation

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

ACh Synaptic Accumulation

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	Moderate	Dan Villeneuve (send email)	Under Development: Contributions and Comments Welcome	Under Development
Acetylcholinesterase Inhibition Leading to Neurodegeneration	adjacent	High	Moderate	Karen Watanabe (send email)	Under development: Not open for comment. Do not cite
Acetylcholinesterase Inhibition leading to Acute Mortality via Impaired Coordination & Movement	adjacent			Kristie Sullivan (send email)	Under development: Not open for comment. Do not cite
Organo-Phosphate Chemicals induced inhibition of AChE leading to impaired cognitive function	adjacent	High	Moderate	SAROJ AMAR (send email)	Under development: Not open for comment. Do not cite

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

Term	Scientific Term	Evidence	Link
Metapenaeus monoceros	Metapenaeus monoceros	High	NCBI
Philosamia ricini	Samia ricini	High	NCBI
Rana cyanophlyetis	Euphlyctis cyanophlyctis	Moderate	NCBI
Tilapia mossambica	Oreochromis mossambicus	High	NCBI
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	High	NCBI
zebrafish	Danio rerio	Moderate	NCBI
Japanese quail	Coturnix japonica	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages

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

AChE is an enzyme responsible for controlling the level of acetylcholine available at cholinergic synapses by degrading this neurotransmitter via hydrolysis to acetic acid and choline (Wilson 2010). Inhibition of AChE prevents degradation of acetylcholine which leads to accumulation of acetylcholine in synapses associated with muscarinic and nicotinic receptors (Soreq and Seidman, 2001; Lushington 2006).
See KEGG Reaction R01026

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

As it pertains to AOP 281, evidence was collected in multiple ways: literature searches of external databases, review of related KEs and KERS in the AOPWiki, and consultation with experts. Extensive literature searches were conducted in Scopus, Pubmed, and Google Scholar using keywords applicable to each KE, with an initial focus on zebrafish data to then focusing on rat data. Related KEs and KERs in the AOPWiki were also reviewed for relevant evidence and their sources. The “snowball method” was used to find additional articles, i.e., relevant citations within an article were obtained if they provided additional evidence. EndNote reference managing software was used to store results from the literature searches and when possible, a pdf of the manuscript was attached to each record. Papers were reviewed and categorized by whether they contained data to support one or more parts of the AOP. An Excel spreadsheet was used to record reviewed papers and any information worth noting.

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

Acetylcholine is a critical neurotransmitter localized to neuronal synapses. Biological plausibility to support the relationship between AChE inhibition and accumulation of acetylcholine is rooted in evidence demonstrating that AChE catalyzes degradation of acetylcholine into choline and acetate. Therefore, inhibition of the AChE leads to acetylcholine accumulation.

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

In a study where female ICR mice were exposed to either the fenobucarb or propoxur, authors reported a significant increase in acetylcholine in brain tissue 10 minutes after injection, with a concurrent significant increase in AChE inhibition (Kobayashi et al., 1985).
An acute (48h) sublethal exposure to methyl parathion found that AChE levels in brain tissue in fish (Oreochromis mossambicus) were significantly inhibited at all measured durations ranging from 12-48 hrs with inhibition increasing from 36-62% as compared to controls over the time span (Rao and Rao, 1984). The researchers found a significant increase in acetylcholine at all time courses measured (12-48hr) with acetylcholine levels increasing from 33-83% as compared to controls over the same time span (Rao and Rao, 1984).
A study of quail (Coturnix japonica) exposed to lethal concentrations of two OP pesticides (i.e., DDVP or fenitrothion), found significant increases in total and free acetylcholine, and significant inhibition of AChE as compared to controls (Kobayashi et al., 1983).
Measurements (in vitro) of AChE inhibition, acetylcholine and electrophysiological responses on the pedal ganglion of the gastropod Aplysia californica, were found to be dose-dependent, with increase in dose resulting in increased AChE inhibition, increased levels of acetylcholine, and a decrease in the electrophysiological response (Oyama et al., 1989).
Wister rats injected with a sublethal concentration of dichlorvos found a significant decrease in AChE activity, increased acetylcholine concentrations, and enhanced contractile responses in jejunum muscle (Kobayashi et al., 1994).
At sublethal concentrations ( 56% of the LD50), researchers found a statistically significant (18%) increase in the amount of acetylcholine in brain tissue of Charles River rats exposed to disulfoton for 3 days, with measured AChE inhibition of 68% as compared to controls (Stavinoha et al., 1969).
An acute sublethal exposure of chlorpyrifos to Sprague-Dawley rats found significant dose and time related effects including increased inhibition of AChE, increased levels of acetylcholine, and significant impacts to motor activity (nocturnal rearing response) (Karanth et al., 2006).
Tadpoles (20 d) were exposed to single sublethal concentration of the methyl parathion for 24 h. Analysis of brain tissue found a significant inhibition in AChE activity and a concurrent increase in acetylcholine levels, as compared to controls (Nayeemunnisa and Yasmeen 1986).
Study of fourth instar Ailanthus silkworm exposed to malathion for 5 days found increased mortality, decreased AChE, and increases in acetylcholine as compared to controls (Pant and Katiyar 1983).
Faria et al (2015) exposed zebrafish (Danio rerio) larvae to different concentrations of chlorpyrifos oxon (CPO). A strong inhibitory effect on AChE activity was found as early as 1h after exposure with a 50% inhibitory concentration (IC50) of 64 nm CPO. The authors showed that the zebrafish model mimicked most of the effects seen in humans, including AChE inhibition, calcium dysregulation, ad inflammatory and immune responses.

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
enzyme	butylcholinesterase	Butylcholinesterase can affect the substrate interaction and should be accounted for	Wilson (2001)

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

The general kinetic equation is:

Where AX is the substrate, either acetylcholine or an inhibitor of AChE (e.g., OP or carbamate);
AChE-AX is the enzyme-substrate complex;
AChE-A is the acylated, carbamylated or phosphorylated enzyme;
X is the leaving group (e.g., choline);
AChE is the free enzyme; and
A is acetic acid, phosphate (P(=O)(=O)(R2)or methylamine.
In a normally functioning enzyme system k1 is the rate-limiting step for hydrolysis of acetylcholine, but k3 is the rate limiting step when AChE is inhibited by carbamates or OPs (Wilson 2010).
Some rate constants for OPs and carbamates have been published for use in PBPK models (Knaak et al., 2004, 2008)

Table 1: Summary of available quantitative data describing responses of ACh to AChE inhibition. Data are grouped by species.

AChE Inhibitor	CAS RN	Inhibitor Dosage	Species / Model	Brief Summary	Reference
Donezepil	120014-06-4	0.625, 1.25, 2.5 (mg/kg)	Male Wistar rats (210-290 g \| 7 weeks)	Timecourse data on both extracellular hippocampal ACh concentration and AChE activity given varying concentrations of inhibitor. Brain concentrations of drugs over time are also provided.	Kosasa et al., 1999
Tacrine	321-64-2	1.25, 2.5, 5, 10 (mg/kg)
ENA-713 (Rivastigmine)	129101-54-8	0.625, 1.25, 2.5 (mg/kg)
Dichlorvos (DDVP)	62-73-7	5 (mg/kg)	Male Wistar rats (180-230 g)	AChE activity (μmol AthCh hydrolyzed/g tissue) and ACh content (nmol ACh/g tissue) in jejunum either 10 minutes after single injection or 1 day after 10 injections.	Kobayashi et al., 1994
Propoxur	114-26-1	10 (mg/kg)	Male Wistar rats (180-230 g)		Kobayashi et al., 1994
Paraquat (PQ)	1910-42-5	0.1, 1, 10, 20, 30 (μM)	Wistar rats (fetal days 17-18) Primary hippocampal neurons	In Vitro AChE activity (% control) and ACh concentration (pmol / mL) at 24h and 14 days post exposure	Del Pino et al., 2017
Tacrine	321-64-2	1.25, 2.5, 5 (mg/kg)	Male Wistar rats (210-290 g \| 6 weeks)	Timecourse data on both extracellular hippocampal ACh concentration and AChE activity given varying concentrations of inhibitor. Note: Several sections of text are verbatim from Kosasa et al., 1999.	Kim 2003
Parathion (PS)	56-38-2	adult: 1.8, 3.4, 6, 9, 18, 27 (mg/kg) aged: 1.8, 3.4, 6, 9 (mg/kg)	Male Sprague-Dawley rats (adult: 3 months) (aged: 18 months)	Diaphragm and striatum AChE activity (% control). Striatal dialysates of ACh (fmol/60 μL fraction) on day 3 and 7 post-exposure	Karanth et al., 2007
Chlorpyrifos (CPF)	2921-88-2	84, 156, 279 (mg/kg)	Male Sprague-Dawley rats (325-350 g \| 3 months)	Diaphragm and striatum cholinesterase activity (% control). ACh concentration (fmol/60 μL fraction) through In Vivo microdialysis at 1, 4, and 7 days post-exposure	Karanth et al., 2006
Paraoxon	311-45-5	0.03, 0.1, 1, 10 (μM)	Male Sprague-Dawley rats (275-299 g \| 2-3 months)	Timecourse data on changes in striatal AChE activity (% control) and ACh concentration (fmole/fraction (60 μL)) over 4 hours post exposure.	Ray et al., 2009
Propoxur	114-26-1	10 (mg/kg)	Female ICR mice (30-40 g \| 8-10 weeks)	AChE activity (μmol acetylthiocholine hydrolyzed /min/g wet tissue) and ACh content (nmol/g wet tissue) both measured at 0, 10, 60, 180 minutes after injection (and 360 minutes for AChE activity)	Kobayashi et al., 1988
BPMC	3766‑81‑2	10 (mg/kg)	Female ICR mice (30-40 g \| 8-10 weeks)	Timecourse data on AChE activity (μmole acetylthiocholine hydrolyzed / min / g tissue or ml blood) and ACh content (nmol/g tissue) of forebrain homogenate, taken at 0, 10 and 60 minutes.	Kobayashi et al., 1985
Propoxur	114-26-1	2 (mg/kg)	Female ICR mice (30-40 g \| 8-10 weeks)		Kobayashi et al., 1985
DE-71	32534-81-9	31.0, 68.7, 227.6 (μg/L)	Zebrafish larvae	Changes in AChE activity (nmol / min / mg protein) and ACh concentration (nmol / mg protein) measured at 120 hours post-fertilization	Chen et al., 2012
Dichlorvos (DDVP)	62-73-7	3 (mg/kg)	Male Japanese quail (100 g \| 8-14 weeks)	AChE activity (μmol ACh hydrolyzed/g) and ACh content (nmol ACh/g wet tissue) measured 10 and 60 minutes post exposure for DDVP and Fenitrothion, respectively.	Kobayashi et al., 1983
Fenitrothion	122-14-5	300 (mg/kg)	Male Japanese quail (100 g \| 8-14 weeks)		Kobayashi et al., 1983
Methyl Parathion	298-00-0	0.09 (ppm)	Tilapia mossambica	Timecourse data on AChE activity (μmol ACh hydrolysed/mg protein/h) and ACh content (μmole/g wt. tissue) in muscle, gill, liver, and brain tissue at 12, 24, 36, and 48 hr timepoints	Rao and Rao, 1984
Methyl Parathion	298-00-0	2.5 (ppm)	Rana cyanophilicitus Frog tadpole (1.5-2 g \| 20 days)	AChE activity (μmol ACh hydrolyzed /min) and ACh content (μmol/g) measured after 24 hours post exposure	Yasmeen and Yasmeen, 1986
Malathion	121-75-5	60 µg each/g insect weight/day	Philosamia Ricini larvae	AChE activity and ACh concentration changes measured daily for 5 days.	Pant and Katiyar, 1983

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Striatal AChE activity and extracellular ACh levels were measured in rats intracerebrally perfused with paraoxon (0, 0.03, 0.1, 1, 10 or 100 μM, 1.5 μl/min for 45 min). Acetylcholine was below the limit of detection at the low dose of paraoxon (0.1 uM), but was transiently elevated (0.5–1.5 hr) with 10 μM paraoxon. Concentration-dependent AchE inhibition was noted but reached a plateau of about 70% at 1 μM and higher concentrations (Ray, 2009).

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

The relationship between AChE inhibition and ACh accumulation at the synapse can be observed within 30 minutes after application of an AChE inhibitor (Ray, 2009). Other experiments have shown significant differences in ACh after AChE inhibition as soon as an hour after application of a chemical stressor (Kim et al., 2003, Faria et al., 2015).

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

Cholinergic transmissions mediated by acetylcholinesterase occur in a wide variety of species, both vertebrates and invertebrates, and cholinergic transmissions occur at all stages in life.

Taxonomic Applicability

The literature includes many studies linking increases in acetylcholine in brain tissues after exposure to an OP or carbamate pesticide with increased AChE inhibition in various taxa. Examples include studies with crustacea (Reddy et al., 1990); tadpoles (Nayeemunnisa and Yasmeen, 1986); fish (Rao and Rao 1984; Verma et al., 1981); birds (Kobayashi et al., 1983); and rodents (Kobayashi et al., 1988).

References

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

Chen, L., Huang, C., Hu, C., Yu, K., Yang, L. & Zhou, B. 2012. Acute exposure to DE-71: Effects on locomotor behavior and developmental neurotoxicity in zebrafish larvae. Environmental Toxicology and Chemistry, 31, 2338-2344. DOI: 10.1002/etc.1958.
Del Pino, J., Moyano, P., Díaz, G. G., Anadon, M. J., Diaz, M. J., García, J. M., Lobo, M., Pelayo, A., Sola, E. & Frejo, M. T. 2017. Primary hippocampal neuronal cell death induction after acute and repeated paraquat exposures mediated by AChE variants alteration and cholinergic and glutamatergic transmission disruption. Toxicology, 390, 88-99. DOI: 10.1016/j.tox.2017.09.008.
Faria, M., Garcia-Reyero, N., Padrós, F., Babin, P. J., Sebastián, D., Cachot, J., Prats, E., Arick Ii, M., Rial, E., Knoll-Gellida, A., Mathieu, G., Le Bihanic, F., Escalon, B. L., Zorzano, A., Soares, A. M. & Raldúa, D. 2015. Zebrafish Models for Human Acute Organophosphorus Poisoning. Sci Rep, 5, 15591. DOI: 10.1038/srep15591.
Karanth, S., Liu, J., Mirajkar, N. & Pope, C. 2006. Effects of acute chlorpyrifos exposure on in vivo acetylcholine accumulation in rat striatum. Toxicology and Applied Pharmacology, 216, 150-156. DOI: https://doi.org/10.1016/j.taap.2006.04.006.
Karanth, S., Liu, J., Ray, A. & Pope, C. 2007. Comparative in vivo effects of parathion on striatal acetylcholine accumulation in adult and aged rats. Toxicology, 239, 167-179. DOI: https://doi.org/10.1016/j.tox.2007.07.004.
Kim, Y. K., Koo, B. S., Gong, D. J., Lee, Y. C., Ko, J. H. & Kim, C. H. 2003. Comparative effect of Prunus persica L. BATSCH-water extract and tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) on concentration of extracellular acetylcholine in the rat hippocampus. J Ethnopharmacol, 87, 149-54. DOI: 10.1016/s0378-8741(03)00106-5.
Kobayashi, H., Sato, I., Akatsu, Y., Fujii, S., Suzuki, T., Matsusaka, N. & Yuyama, A. 1994. Effects of single or repeated administration of a carbamate, propoxur, and an organophosphate, DDVP, on jejunal cholinergic activities and contractile responses in rats. J Appl Toxicol, 14, 185-90. DOI: 10.1002/jat.2550140307.
Kobayashi, H., Yuyama, A., Kajita, T., Shimura, K., Ohkawa, T. & Satoh, K. 1985. Effects of insecticidal carbamates on brain acetylcholine content, acetylcholinesterase activity and behavior in mice. Toxicology Letters, 29, 153-159. DOI: https://doi.org/10.1016/0378-4274(85)90036-0.
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. DOI: https://doi.org/10.1016/0300-483X(83)90119-1.
Kobayashi, H., Yuyama, A., Ohkawa, T. & Kajita, T. 1988. Effect of Single or Chronic Injection with a Carbamate, Propoxur, on the Brain Cholinergic System and Behavior of Mice. The Japanese Journal of Pharmacology, 47, 21-27. DOI: 10.1254/jjp.47.21.
Kosasa, T., Kuriya, Y., Matsui, K. & Yamanishi, Y. 1999. Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats. European Journal of Pharmacology, 380, 101-107. DOI: 10.1016/S0014-2999(99)00545-2.
Lushington, G. H., Guo, J. X. & Hurley, M. M. 2006. Acetylcholinesterase: molecular modeling with the whole toolkit. Curr Top Med Chem, 6, 57-73. DOI: 10.2174/156802606775193293.
Nayeemunnisa and Yasmeen, N. 1986. On the Presence of Calmodulin in the Brain of Control and Methyl Parathion-Exposed Developing Tadpoles of Frog, Rana cyanophlictis. Curr.Sci.(Bangalore) 55[11], 546-548.
Oyama, Y., Hori, N., Evans, M. L., Allen, C. N. & Carpenter, D. O. 1989. Electrophysiological estimation of the actions of acetylcholinesterase inhibitors on acetylcholine receptor and cholinesterase in physically isolated Aplysia neurones. Br J Pharmacol, 96, 573-82. DOI: 10.1111/j.1476-5381.1989.tb11855.x.
Pant, R. & Katiyar, S. K. 1983. Effect of malathion and acetylcholine on the developing larvae ofPhilosamia ricini (Lepidoptera: Saturniidae). Journal of Biosciences, 5, 89-95. DOI: 10.1007/BF02702598.
Rao, K. S. P. & Rao, K. V. R. 1984. Impact of methyl parathion toxicity and eserine inhibition on acetylcholinesterase activity in tissues of the teleost (Tilapia mossambica) — a correlative study. Toxicology Letters, 22, 351-356. DOI: https://doi.org/10.1016/0378-4274(84)90113-9.
Ray, A., Liu, J., Karanth, S., Gao, Y., Brimijoin, S. & Pope, C. 2009. Cholinesterase inhibition and acetylcholine accumulation following intracerebral administration of paraoxon in rats. Toxicology and applied pharmacology, 236, 341-347. DOI: 10.1016/j.taap.2009.02.022.
Reddy, M. S., Jayaprada, P. & Rao, K. V. 1990. Impact of methylparathion and malathion on cholinergic and non-cholinergic enzyme systems of penaeid prawn, Metapenaeus monoceros. Biochem Int, 22, 769-79.
Soreq, H. & Seidman, S. 2001. Acetylcholinesterase--new roles for an old actor. Nat Rev Neurosci, 2, 294-302. DOI: 10.1038/35067589.
Stavinoha, W. B., Ryan, L. C. & Smith, P. W. 1969. Biochemical effects of an organophosphorus cholinesterase inhibitor on the rat brain. Ann N Y Acad Sci, 160, 378-82. DOI: 10.1111/j.1749-6632.1969.tb15859.x.
Verma, S. R., Tonk, I. P., Gupta, A. K. & Dalela, R. C. 1981. In vivo enzymatic alterations in certain tissues of Saccobranchus fossilis following exposure to four toxic substances. Environmental Pollution Series A, Ecological and Biological, 26, 121-127. DOI: https://doi.org/10.1016/0143-1471(81)90042-8.
Wilson, B. W. 2001. CHAPTER 48 - Cholinesterases. In: KRIEGER, R. I. & KRIEGER, W. C. (eds.) Handbook of Pesticide Toxicology (Second Edition). San Diego: Academic Press.
Wilson, B. W. 2010. Cholinesterases. In: KRIEGER, R. (ed.) Hayes' Handbook of Pesticide Toxicology. Third ed. Amsterdam, The Netherlands: Elsevier.
Yasmeen, N. & Yasmeen, N. 1986. ON THE PRESENCE OF CALMODULIN IN THE BRAIN OF CONTROL AND METHYL PARATHION-EXPOSED DEVELOPING TADPOLES OF FROG, RANA CYANOPHLICTIS. Current Science, 55, 546-548. http://www.jstor.org/stable/24090019