Acetylcholinesterase activity

Exposure of two species of freshwater fish to 0.106 ppb of a commercial formulation containing 50% methyl parathion increased serum levels of T3 and reduced T4 (Bhattacharya 1993). This effect was attributed to inhibition of acetylcholinesterase activity in the fish brain, but no direct evidence was presented. Similar treatment of freshwater perch for 35 days resulted in decreased release of progesterone from the ovaries (Bhattacharya and Mondal 1997). Also, treatment of freshwater perch for up to 90 days with methyl parathion induced a decrease in the gonadosomatic index (not defined) after day 15 of... 

The only other information regarding the potential for age-related differences in susceptibility to methyl parathion came from a study by Garcia-Lopez and Monteoliva (1988). The investigators showed increasing mean erythrocyte acetylcholinesterase activity levels with increasing age range, starting at birth (in 10-year increments and >60 years of age) in both males and females. However, it is not known whether increased erythrocyte acetylcholinesterase activity indicates a decreased susceptibility to methyl parathion toxicity. 

Pope et al. (1991) found that 7-day-old Sprague-Dawley rat pups were approximately twice as sensitive as 80-100-day-old adults to single subcutaneous doses of methyl parathion the highest nonlethal dose 7.8 mg/kg for the neonates and 18.0 mg/kg for adults. Initially, both neonates and adults exhibited similarly reduced brain acetylcholinesterase activity levels (approximately 10% that of controls) ... 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

Several studies in animals suggest that age may affect susceptibility to methyl parathion toxicity, and that children may be more susceptible than adults, but the data are limited. (See Section 3.7 for more information on Children s susceptibility.) A study in humans showed that mean erythrocyte acetylcholinesterase activity levels increase with increasing age from birth through old age in both sexes (Garcia-Lopez ad Monteoliva 1988), but it is not known whether increased erythrocyte acetylcholinesterase activity indicates decreased susceptibility to methyl parathion. 

Following inhibition by methyl parathion, acetylcholinesterase activity recovers as a result of the synthesis of new enzyme, generally at a rate of approximately 1% per day. However, the symptoms of methyl parathion poisoning usually resolve much more rapidly. Therefore, even though they are symptom-free, persons poisoned by methyl parathion may be hypersusceptible to its effects and should avoid reexposure for several weeks (Aaron and Howland 1998 Proctor et al. 1988). 

In a study of 135 workers in the ehemical industry who handle methyl parathion, the methyl parathion concentration in plasma, the 4-nitrophenol concentration in urine, and the cholinesterase and acetylcholinesterase activities were determined to assess the pesticide burden in such workers (Leng and Lewalter 1999). The mean concentration of methyl parathion in the plasma of the workers was 233 pg/L no clinical symptoms were reported by the workers. In an additional group of 19 workers handling methyl parathion, who were also exposed to the pyrethroid cyfluthrin, the mean concentrations of methyl parathion in plasma were 269 and 241 pg/L (for groups without and with clinical S5miptoms, respectively), and 7 of the workers exhibited skin paraesthesia, while none of the 427 workers exposed only to the pyrethroid experienced the symptom (Leng and Lewalter 1999). 

Kumar MVS, Desiraju T. 1992. Effect of chronic consumption of methyl parathion on rat brain regional acetylcholinesterase activity and on levels of biogenic amines. Toxicology 75 13-20. 

Maitra SK, Sarkar R. 1996. Influence of methyl parathion on gametogenic and acetylcholinesterase activity in the testis of whitethroated munia Lonchura malabarica). Arch Environ Contam Toxicol 30 384-389. 

Roberts DK, Silvey NJ, Bailey EM Jr. 1988. Brain acetylcholinesterase activity recovery following acute methyl parathion intoxication in two feral rodent species comparison to laboratory rodents. Bull Environ Contam Toxicol 41 26-35. 

Other additional studies or pertinent information that lend sunnort to this MRL Methyl parathion affects the nervous system by inhibiting acetylcholinesterase activity. Cholinesterase inhibition and neurological effects have been observed in humans and animals, for all exposure routes and durations (for example. Dean et al. 1984 Desi et al. 1998 EPA 1978e Gupta et al. 1985 Nemec et al. 1968 Suba 1984). 

In cases where the mode of action is the strong or irreversible inhibition of an enzyme system, the assay may measure the extent of inhibition of this enzyme. This may be accomplished by first measuring the activity of the inhibited enzyme and then making comparison with the uninhibited enzyme. This practice is followed when studying acetylcholinesterase inhibition by organophosphates (OP). Acetylcholinesterase activity is measured in a sample of tissue of brain from an animal that has been exposed to an OP. Activity is measured in the same way in tissue samples from untreated controls of the same species, sex, age, etc. Comparison is then made between the two activity measurements, and the percentage inhibition is estimated. 

Banks, A. and Russell, R.W. (1967). Effects of chronic reductions in acetylcholinesterase activity on serial problem-solving. Journal of Comparative Physiology and Psychology 64, 262-267. 

Engenheiro, E.L., Hankard, P.K., and Sousa, J.P. et al. (2005). Influence of dimethoate on acetylcholinesterase activity and locomotor function in terrestrial isopods. Environmental Toxicology and Chemistry 24, 603-609. 

Morgan, M.J., Fancey, L.L., and Kiceniuk, J.W. (1990). Response and Recovery of Brain Acetylcholinesterase Activity in Atlantic Salmon (Sahno-Salar). Exposed to Fenitrothion. Canadian Journal of Fisheries and Aquatic Sciences 47, 1652-1654. 

Sancho, E., Ferrando, M.D., and Andreu, E. (1997). Response and recovery of brain acetylcholinesterase activity in the European eel, Anguilla anguilla, exposed to fenitrothion. Ecotoxicology and Environmental Safety 38, 205-209. 

Rizvi s I and zaid m a (2001), Insulin-like effect of (-)-epicatechin on erythroc)de membrane acetylcholinesterase activity in type 2 diabetes mellitus , Clin Exp Pharmacol Physiol, 28 (9), 776-8. 

The dual inhibition of acetylcholinesterase and butyrylcholinesterase may lead to broader efficacy. As acetylcholinesterase activity decreases with disease progression, the acetylcholinesterase-selective agents may lose their effect, while the dual inhibitors may still be effective due to the added inhibition of butyrylcholinesterase. However, this has not been demonstrated clinically. 

Consistent decreases in plasma cholinesterase may not have been observed in rats and dogs because they were treated with lower doses of diisopropyl methylphosphonate. In general, depression of plasma cholinesterase, also known as pseudocholinesterase or butyrylcholinesterase, is considered a marker of exposure rather than an adverse effect. Depression of cholinesterase activity in red blood cells (acetylcholinesterase) is a neurological effect thought to parallel the inhibition of brain acetylcholinesterase activity. It is considered an adverse effect. Acetylcholinesterase is found mainly in nervous tissue and erythrocytes. Diisopropyl methylphosphonate was not found to inhibit RBC... 

Although this study (Hart 1980) did not identify an effect level, the NOAEL is below the LOEL found in all studies examining the toxicity of diisopropyl methylphosphonate. The LOEL for diisopropyl methylphosphonate is 262 mg/kg/day for male mink and 330 mg/kg/day for female mink (Bucci et al. 1997), doses at which statistically significant decreases in plasma cholinesterase (butyrylcholinesterase) but not RBC cholinesterase (acetylcholinesterase) activity were observed (Bucci et al. 1997). In general, a decrease in plasma cholinesterase activity is considered to be a marker of exposure rather than a marker of adverse effect, while a decrease in RBC acetylcholinesterase activity is a neurological effect thought to parallel the inhibition of brain acetylcholinesterase activity and is thus considered an adverse effect. Diisopropyl methylphosphonate was not found to inhibit red blood cell cholinesterase at doses at which plasma cholinesterase was significantly inhibited. No effects were observed in males at 45 mg/kg/day (Bucci et al. 1997) or at 63 mg/kg/day (Bucci et al. 1994), and no effects were observed in females at 82 mg/kg/day (Bucci et al. 1994), or at 57 mg/kg/day (Bucci et al. 1997). 

Organophosphate Ester Hydraulic Fluids. Interpretation of the biomarkers of exposure to organophosphate ester hydraulic fluids is complicated by the diversity of composition among the hydraulic fluids in this class. Erythrocyte acetylcholinesterase activity is a good biomarker of exposure to certain organophosphates (e.g., insecticides), but results are inconsistent with organophosphate components of... 

Mallick, B. N. Thakkar, M. (1991). Short-term REM sleep deprivation increases acetylcholinesterase activity in the medulla of rats. Neurosci Lett. 130, 221-4. 

Ordendich, A., Barak, D., Kronman, C., Flashner, Y., Leitner, M., Segall, Y., Ariel, N., Cohen, S., Velan, B. and Shafferman, A. (1993) Dissection of the human acetylcholinesterase active center determinants of substrate specificity. Journal of Biological Chemistry 268, 17083—17095. 

Ulrichova, J., Walterova, D., Preininger, V., Slavik, J., Lenfeld, J., Cushman, M. and Simanek, V. (1983). Inhibition of acetylcholinesterase activity by some isoquinoline alkaloids. Planta Medica 48 111-115. 

A decrease in brain acetylcholinesterase activity in rats (Gietzen and Wooley 1984). 

Gietzen, D.W. and D.E. Woolley. 1984. Acetylcholinesterase activity in the brain of rat pups and dams after exposure to lead via the maternal water supply. Neurotoxicology 5 235-246. 

No deaths. Exposure-dependent decrease in tissue acetylcholinesterase activity and increase in acetylcholine content LC50 (48-96 h)... 

Di Marzio, W.D. and M.C. Tortorelli. 1993. Acute toxicity of paraquat and no-inhibitory chronic effect on brain acetylcholinesterase activity of freshwater fish Bryconamericus iheringii (Pisces, Characidae). Jour. Environ. Sci. Health 28B 701-709. 

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