Cholinesterases erythrocyte

Plasma and Erythrocyte Cholinesterase Eevels in Children Intoxicated by Methyl Parathion 3-3. Eevels of Significant Exposure to Methyl Parathion - Oral 3-4. Eevels of Significant Exposure to Methyl Parathion - Dermal 3-5. Genotoxicity of Methyl Parathion In Vivo... 

Neurological effects related to cholinesterase depression occurred in seven children acutely exposed to methyl parathion by inhalation as well as orally and dermally (Dean et al. 1984). The children were admitted to a local hospital with signs and symptoms of lethargy, increased salivation, increased respiratory secretions, and miosis. Two of the children were in respiratory arrest. Two children died within several days of each other. All of the children had depressed plasma and erythrocyte cholinesterase levels (Table 3-2). These effects are similar to those occurring in methyl parathion intoxication by other routes (see Sections 3.2.2.4 and 3.2.3.4). Three adults exposed in the same incident had normal plasma (apart from one female) and red blood cell cholinesterase, and urinary levels of 4-nitrophenol (0.46-12.7 ppm) as high as some of the ill children. 

Table 3-2. Plasma and Erythrocyte Cholinesterase Levels in Children Intoxicated by Methyl Parathion ...

Age/sex Plasma cholinesterase (mU per mL per minute) Erythrocyte cholinesterase (ApH/hour)"... 

Neurologic signs did not occur over a 30-day period in male prisoner volunteers in California who ingested daily doses of methyl parathion ranging from 1.0 to 19 mg. There were no uniform changes in plasma or erythrocyte cholinesterase levels at any of these doses (Rider et al. 1969). By increasing concentrations of methyl parathion administered to the same experimental population and using the same protocol, a dose that inhibited cholinesterase values was established. These additional studies were published nearly 20 years ago in abstract form only therefore, they are not discussed in this section. 

A dose-response relationship was noted in dogs exposed to 0.03, 0.3, or 3.0 mg/kg/day methyl parathion in the diet for 13 weeks (Daly 1989). Significant reductions in erythrocyte cholinesterase activity (20-23%) and cholinesterase activity in the pons and cerebellum of the brain (43-54%) occurred in dogs... 

Erythrocyte cholinesterase levels were monitored in two men exposed dermally to methyl parathion after entering a cotton field that had been sprayed with this pesticide (Nemec et al. 1968). The field was entered on two separate occasions twice within 2 hours after an ultra-low-volume spraying and a third time within 24 hours after spraying. Dermal methyl parathion residues 2 hours after spraying were 2-10 mg on the arms dermal residues 24 hours after spraying were 0.16-0.35 mg on the arms. The exposed individuals did not have signs of cholinergic toxicity, but erythrocyte cholinesterase levels after the third exposure were 60-65% of preexposure levels. 

Mice that were exposed dermally to residues of methyl parathion in emulsifiable concentrate on foliage, and were muzzled to prevent oral intake, developed inhibition of plasma cholinesterase and erythrocyte cholinesterase after two 10-hour exposures (Skinner and Kilgore 1982b). For the organophosphate pesticides tested in this study, cholinergic signs generally were seen in mice with cholinesterase inhibition >50% results for this end point were not broken down by pesticide. 

Diagnosis of organophosphate poisoning (including methyl parathion) can be confirmed by evaluation of serum (plasma) cholinesterase and erythrocyte cholinesterase. However, cholinesterase inhibition is not specific for organophosphates. For example, carbamate insecticides also result in cholinesterase inhibition, which is usually transitory. Erythrocyte cholinesterase measurement is a specific test for... 

Following exposure of humans to organophosphates, but not specifically methyl parathion, restoration of plasma cholinesterase occurs more rapidly than does restoration of erythrocyte cholinesterase (Grob et al. 1950 Midtling et al. 1985). These findings are supported by studies of methyl parathion in animals. Erythrocyte cholinesterase levels are representative of acetylcholinesterase levels in the nervous system, and, therefore, may be a more accurate biomarker of the neurological effects of chronic low level exposure of humans to methyl parathion (Midtling et al. 1985 NIOSH 1976). 

Garcia-Lopez JA, Monteoliva M. 1988. Physiological changes in human erythrocyte cholinesterase as measured with the "pH-stat". Clin Chem 34 2133-2135. 

Other additional studies or pertinent information that lend support to this MRL An intermediate-duration gavage study in rats found decreased hematocrit and erythrocyte counts relative to before-treatment values (Galal et al. 1977), but this study had some limitations, including lack of a control group and disparities between text and tables. Another intermediate duration gavage study in male rats demonstrated dose-related significant decreases in mean corpuscular volume (Undeger et al. 2000). An effect on the erythrocyte is plausible because erythrocyte cholinesterase has a function in the control of erythrocyte permeability (Wills 1972). 

In one study with common marmosets, the animals were dosed with diazinon (10, 90, or 130 mg/kg i.m.) and measnrements of erythrocyte cholinesterase inhibition... 

All doses inhibited erythrocyte cholinesterase levels by 45-95%. All groups tolerated 16.6 mg/kg BW. Severe toxicosis in the two high-dose groups (9 of 20) in bulls but not in heifers and steers 7 of the 9 bulls died or had to be euthanized necropsy showed severe pulmonary edema... 

Erythrocyte cholinesterase depression after 24 h was 43% in bulls and 33-34% in steers and heifers After 5 h, 1 of 13 bulls was anorexic and salivating After 48 h, erythrocyte cholinesterase depression was 56% in bulls, 55% in steers, and 51% in heifers 2 of 3 famphur-treated calves died... 

Using erythrocyte cholinesterase, Aldridge1 has studied the kinetics of its reaction with inhibitors. With one compound in excess, he has shown that the reaction is bimolecular, and the energy of activation is 10-11 kcal./mol. Such a value is not in agreement with a simple absorptive process, and it is assumed that a chemical change has taken place, e.g. phosphorylation of the enzyme. 

Inhibition of the two principal human cholinesterases, acetylcholinesterase and pseudocholinesterase, may not always result in visible neurological effects (Sundlof et al. 1984). Acetylcholinesterase, also referred to as true cholinesterase, red blood cell cholinesterase, or erythrocyte cholinesterase is found in erythrocytes, lymphocytes, and at nerve synapses (Goldfrank et al. 1990). Inhibition of erythrocyte or lymphocyte acetylcholinesterase is theoretically a reflection of the degree of synaptic cholinesterase inhibition in nervous tissue, and therefore a more accurate indicator than pseudocholinesterase activity of inhibited nervous tissue acetylcholinesterase (Fitzgerald and Costa 1993 Sundlof et al. 1984). Pseudocholinesterase (also referred to as cholinesterase, butyrylcholinesterase, serum cholinesterase, or plasma cholinesterase) is found in the plasma, serum, pancreas, brain, and liver and is an indicator of exposure to a cholinesterase inhibitor. 

Nervous system effects may occur in humans after occupational exposure to disulfoton (Wolfe et al. 1978). In this study, mean disulfoton concentrations of 0.460.633 mg/m caused a 22.8% depression in erythrocyte cholinesterase activity in workers at a pesticide-fertilizer mixing operation. The workers were exposed to disulfoton for 9 weeks, and there were no reports of adverse clinical signs due to disulfoton exposure. The study was limited in that baseline blood cholinesterase activities were obtained 2 weeks after the initial exposure and were compared with cholinesterase activities at 9 weeks. Therefore, the actual depression in cholinesterase activity over a 9-week period was probably >22.8%. In addition, these workers were also dermally exposed to disulfoton (see Section 2.2.3.4) therefore, the 22.8% depression in cholinesterase activity was probably due to both inhalation and dermal exposure. Despite these limitations, the study concluded that because this depression in cholinesterase activity was only associated with dry mixing operations, the wet mixing operations are less hazardous to workers. 

The MRL is based on a NOAEL of 0.5 mg/m3 for decreased acetylcholinesterase activity in rats exposed to disulfoton 4 hours/day for 5 days in a study by Thyssen (1978). The NOAEL was adjusted for intermittent exposure, converted to a human equivalent concentration, and divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability). Inhibition of erythrocyte cholinesterase activity and unspecified behavioral disorders were observed at 1.8 mg/m, and unspecified signs of cholinergic toxicity were observed at 9.8 mg/m. Similar effects were observed in rats or mice exposed to higher concentrations for shorter duMtions (Doull 1957 Thyssen 1978). The NOAEL value of 0.5 mg/m is supported by another study, in which no significant decrease in the activity of brain, serum, or submaxillary gland cholinesterase was found in rats exposed to 0.14-0.7 mg/m for 1 hour/day for 5-10 days (DuBois and Kinoshita 1971). Mild depression of erythrocyte cholinesterase activity was reported in workers exposed by the inhalation and dermal routes (Wolfe et al. 1978). 

Developmental Toxicity. No studies were located regarding developmental effects in humans after inhalation, oral, or dermal exposure to disulfoton or in animals after inhalation or dermal exposure. Developmental effects have been found in animals after acute- and intermediate-duration oral exposure to disulfoton. Plasma and erythrocyte cholinesterase depression and increased incidences of incomplete ossified parietal bones and sternebrae were observed in fetuses from rats fed... 

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