Cholinesterase activity inhibition

The maximum level of HMMA in the urine occurred 72 hours after exposure, which coincides with the time period for maximum urine catecholamine levels. There was a direct relationship between blood cholinesterase inhibition and catecholamine (adrenaline and noradrenaline) levels in the urine and blood (Brzezinski and Ludwicki 1973). Maximum inhibition of cholinesterase activity and maximum plasma catecholamine occurred during the first I-2 hours after exposure. However, catecholamine levels returned to normal more rapidly than cholinesterase activity. It was proposed that high levels of acetylcholine, which are normally associated with cholinesterase activity inhibition, caused a release of catecholamines from the stores in the adrenals. 

EPA science policy guidelines regarding use and application of cholinesterase activity inhibition data generally consider blood ChE activity inhibition to be an imperfect measure, and there appears to be no fixed percentage of blood ChE activity change that can distinguish adverse from nonadverse effects (USEPA, 2000 Storm et al,... 

Rubin et al. (1957) evaluated the effects of agent GB on the visual threshold of three adult volunteers. The test individuals were exposed to 2 mg GB/m for 2 min with the eyes exposed or protected. With the eyes unprotected, the exposure resulted in moderate miosis with no other obvious signs of cholinesterase activity inhibition, but with a significant elevation of the absolute visual threshold in the dark-adapted eye. 

The inhibition of erythrocytic AChE can differ significantly from the inhibition of neural tissue AChE with exposure to the same dose of substance. Effects on ChE of plasma and internal organs (liver, kidneys, spleen, heart, muscles) also depend upon dose. However, a disproportion, sometimes significant, exists between degrees of cholinesterase activity inhibition in different biosubstrates. For certain substances, plasma ChE is more susceptible to inhibition than erythrocytic AChE however, inverse dependence is observed more frequently. A degree of the plasma ChE activity inhibition not always corresponds to severity of intoxication. The typical cholinergic intoxication only occurs with significant inhibition of neural tissue AChE. 

One subject received neat VX on one occasion and VX mixed with -octylamine on another [3 1, amine/VX (Vocci etal, 1959)]. Absorption of agent was increased by the amine (maximal erythrocyte cholinesterase activity inhibition of 9% with agent alone, and 41 % with the mixture). 

In rats orally administered an aqueous extract (boiled for 3 hours) of peach kernel, inhibition of cholinesterase activity in the brain and plasma was observed. The inhibitory dose (ID50) for brain cholinesterase activity was 2.7 g/kg for plasma cholinesterase activity inhibition, the ID50 was 18.6 g/kg (Suh et al. 2006). 

After 4h, the higher proportion of radioactivity in all the tissues was in the form of bound [ H]DIP. Bound [ H]DIP levels did not follow a biphasic clearance curve and declined at a slower rate than [ H]DFP and free [ H]D1P tissue levels. By 5min, the greatest accumulation of boxmd [ H]DIP occurred in the liver (nearly 20% of the total body burden), with a noticeably small amount in the brain (0.1%). Total cholinesterase activity in the brain and red blood cells was inhibited by approximately 90%, with plasma pseudo cholinesterase activity and true cholinesterase activity inhibited by 99% and 97%, respectively. 

Basanta R, Nunez A, Lopez E, Fmiandez M, Diaz-Fierros F (1995) Measurement of cholinesterase activity inhibition for the detection of organophosphorus and carbamate pesticides in water. Int J Envirrai Stu 48 211—219... 

ACETYLCHOLINESTERASE INHIBITING PESTICIDES Cholinesterase activity in red Discretionary 70% of individuals Ns... 

When methyl parathion was given orally to rats at doses of 1.5 mg/kg and to guinea pigs at 50 mg/kg, plasma, erythrocyte, and brain cholinesterase activity was maximally inhibited within 30 minutes after administration. In rodents of both species that died after acute intoxication, brain cholinesterase levels decreased to 20% of control values and often to 5-7% (Miyamoto et al. 1963b). The species difference in susceptibility to orally administered methyl parathion is noted in Section 3.2.2.1. 

Permethrin, a pyrethrin pesticide, decreased the inhibition of brain cholinesterase activity by methyl parathion, but methyl parathion decreased the LD50 of permethrin when the two pesticides were simultaneously administered to rats (Ortiz et al. 1995). The potentiation of permethrin lethality may be due to the inhibition by methyl parathion of carboxylesterase, which metabolizes permethrin. 

Organophosphates, such as methyl parathion, are known to inhibit cholinesterase activity. A method has been developed to measure the extent of this inhibition and relate it to organophosphate exposure (EPA 1980d Nabb and Whitfield 1967). In this EPA-recommended method, blood is separated into plasma and red blood cell fractions. The fractions are treated with saline solution, brought to pH 8 with sodium hydroxide, and dosed with acetylcholine perchlorate. The ensuing acetic acid releasing enzyme reaction... 

Izmirova H, Shalash S, Kaloianova F. 1984. [Dynamics of inhibition of cholinesterase activity in methyl parathion intoxication]. Probl Khig 9 42-49. (Russian)... 

Grue, C.E., Hart, A.D.M., andMineau, P. (1991). Biological consequences of depressed brain cholinesterase activity in wildlife. In Mineau, P. (Ed.) Cholinesterase Inhibiting Insecticides— Their Impact on Wildlife and the Environment, 151-210. Amsterdam Elsevier. 

DF and its precursor, methylphosphonic dichloride (DC), are organophos-phonic acids. They will react with alcohols to form crude lethal nerve agents, such as crude GB. High overexposure may cause inhibition of cholinesterase activity. Although much less toxic than GB, DF and DC are toxic and corrosive materials. 

DF and its precursor, DC are organophosphonic acids. They will react with alcohols to form crude lethal nerve agents, such as crude GB. High overexposure may cause inhibition of cholinesterase activity. Although much less toxic than GB, DF and DC are toxic and corrosive materials. Because DF and DC are relatively volatile compounds, the primary route of exposure is expected to be the respiratory system. However, ingestion also results from inhalation exposures in animals and could occur in humans. DF and DC vapors have a pungent odor and may cause severe and painful irritation of the eyes, nose, throat, and lungs. Data provided is for DF only, DC has similar properties. 

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). 

Hydraulic fluids themselves cannot be measured in blood, urine, or feces, but certain chemicals in them can be measured. Aliphatic hydrocarbons, which are major components of mineral oil hydraulic fluids and polyalphaolefin hydraulic fluids, can be detected in the feces. Certain components of organophosphate ester hydraulic fluids leave the body in urine. Some of these fluids inhibit the enzyme cholinesterase. Cholinesterase activity in blood can be measured. Because many other chemicals also inhibit cholinesterase activity in blood, this test is not specific for organophosphate ester hydraulic fluids. This test is not available at most doctor s offices, but can be arranged at any hospital laboratory. See Chapters 2 and 6 for more information. 

The inhibition of two cholinesterase activities in blood can also be used to confirm exposure to certain organophosphate ester compounds. Red blood cell acetylcholinesterase is the same cholinesterase found in the gray matter of the central nervous system and motor endplates of sympathetic ganglia. Synonyms for this enzyme include specific cholinesterase, true cholinesterase, and E-type cholinesterase. Plasma cholinesterase is a distinct enzyme found in intestinal mucosa, liver, plasma, and white matter of the central nervous system. Synonyms for this enzyme include nonspecific cholinesterase, pseudocholinesterase, butyrylcholinesterase, and S-type cholinesterase (Evans 1986). Nonspecific cholinesterase is thought to be a very poor indicator of neurotoxic effects. 

Because of the physiological variations of RBC-ACHE and PCHE levels, the sensitivity of these tests to detect low-level inhibitions can be increased by comparison with individual pre-exposure values, adopted as a reference. The World Health Organization (WHO, 1982) recommends calculating individual pre-exposure values as the average of three samples cholinesterase activities after exposure should be expressed as percentage change with... 

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