Methyl parathion activation

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the nation. These sites make up the National Priorities List (NPL) and are the sites targeted for long-term federal cleanup activities. Methyl parathion has been found in at least 16 of the 1,585 current or former NPL sites. However, the total number of NPL sites evaluated for this substance is not known. As more sites are evaluated, the sites at which methyl parathion is found may increase. This information is important because exposure to this substance may harm you and because these sites may be sources of exposure. 

Children are expected to be exposed to methyl parathion by the same routes that affect adults. Small children are more likely to come into contact with methyl parathion residues that may be present in soil and dust both outside and inside the home, due to increased hand-to-mouth activity and playing habits. Methyl parathion has been detected in a few samples of breast milk, indicating potential for exposure of nursing infants. However, available data are not adequate for determination of the importance of this route of child exposure. 

The LD50 values for methyl parathion were compared to those for methyl paraoxon, the active metabolite of methyl parathion, in rats, guinea pigs, and mice by Miyamoto et al. (1963b). Methyl paraoxon was 5.4 times more potent than methyl parathion in male rats, 5 times more potent in male guinea pigs, and 1.6 times more potent in mice. 

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. 

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... 

Routine gross and histopathological examinations revealed no treatment-related effects on the nervous system of dogs exposed to 0.03, 0.1, or 0.3 mg/kg/day methyl parathion in the diet for 1 year (Suba 1981). In addition, there were no treatment-related effects on cholinesterase activity in plasma, red blood cells, or brains in dogs under these exposure conditions. These data are in agreement with the NOAEL established above for dogs exposed to these levels for 13 weeks. 

Mean plasma, erythroc54e, and brain cholinesterase activities were significantly reduced by 67-88%, 9-20%, and 76-79%, respectively, in rats of both sexes following 2-year exposures to 2.5 mg/kg/day methyl parathion (Suba 1984). This effect did not occur in rats exposed to either 0.025 or 0.25 mg/kg/day methyl parathion. 

Results of methyl parathion assays involving effects on chromosomes have also been contradictory. For sister chromatid exchange, Waters et al. (1982) reported a positive response in Chinese hamster ovary cells only in the presence of metabolic activation system, while methyl parathion tested positive without a metabolic activation system in Chinese hamster V79 cells (Chen et al. 1981), cultured normal human lymphoid cells (Chen et al. 1981 Gomez-Arroyo et al. 1987 Sobti et al. 1982), and Burkitt s l5miphoma cells (Chen et al. 1981). Chen et al. (1981) found a significant dose-related increase in sister chromatid exchange in both hamster and human cultured cells, but dose-related cell cycle delays were less pronounced in human cell lines than in V79 cells. Negative results were obtained for chromosomal aberrations in human lymphocytes without a metabolic activation system (Kumar et al. 1993). 

Urinary excretion of metabolites of methyl parathion is rapid and efiicient in animals (Braeckman et al. 1983 Hollingworth et al. 1967). In mice, 70-80% of the activity was excreted in the urine within... 

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). 

Cimetidine, an H2 antagonist used therapeutically in patients with ulcers, inhibits activity of hepatic microsomal enzymes. When rats or mice were pretreated with cimetidine, dose-related lethality of methyl parathion was reduced, and cholinergic signs of toxicity were delayed. Simultaneous administration with methyl parathion did not reduce toxicity (Joshi and Thornburg 1986). 

Acetaminophen, which depletes hepatic glutathione, does not potentiate the toxicity of methyl parathion in mice. A possible mechanism of action may be competition between acetaminophen and methyl parathion for mixed function oxidases and subsequent prevention of activation of methyl parathion to methyl paraoxon (Costa and Murphy 1984). Diethyl maleate, an agent that depletes cytosolic glutathione and is not an enzyme inducer, potentiates toxicity of methyl parathion in mice (Mirer et al. 1977). 

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. 

Individuals with hereditary low plasma cholinesterase levels (Kalow 1956 Lehman and Ryan 1956) and those with paroxysmal nocturnal hemoglobinuria, which is related to abnormally low levels of erythrocyte acetylcholinesterase (Auditore and Hartmann 1959), would have increased susceptibility to the effects of anticholinesterase agents such as methyl parathion. Repeated measurements of plasma cholinesterase activity (in the absence of organophosphate exposure) can be used to identify individuals with genetically determined low plasma cholinesterase. 

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). 

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