Parathion activation

Ludke, J.L., J.R. Bibson and C.I. Lusk. Mixed function oxidase activity in freshwater fishes aldrin epoxidation and parathion activation. Toxicol. Appl. Pharmacol. 21 89-97, 1972. 

Stephen, W.P. and Schricker, B. (1970). The effect of sublethal doses of parathion. II. Site of parathion activity, and signal integration. J. Apic. Res. 9, 155-164. 

The reactivity of the individual O—P insecticides is determined by the magnitude of the electrophilic character of the phosphoms atom, the strength of the bond P—X, and the steric effects of the substituents. The electrophilic nature of the central P atom is determined by the relative positions of the shared electron pairs, between atoms bonded to phosphoms, and is a function of the relative electronegativities of the two atoms in each bond (P, 2.1 O, 3.5 S, 2.5 N, 3.0 and C, 2.5). Therefore, it is clear that in phosphate esters (P=0) the phosphoms is much more electrophilic and these are more reactive than phosphorothioate esters (P=S). The latter generally are so stable as to be relatively unreactive with AChE. They owe their biological activity to m vivo oxidation by a microsomal oxidase, a reaction that takes place in insect gut and fat body tissues and in the mammalian Hver. A typical example is the oxidation of parathion (61) to paraoxon [311-45-5] (110). 

Encapsulated fonofos, a soil insecticide, was developed to coat seeds before they were planted (72). Encapsulation reduces oral toxicity 100-fold and dermal toxicity 10-fold while extending activity of the fonofos. Other encapsulated pesticides available include permethrin and parathion (69). Significantly, all commercial encapsulated pesticides are prepared by interfacial polymeri2ation. 

S-oxidation of sulfur-containing pesticides such as aldicarb, parathion, and malathion can be of importance in the absence of microbial activity (29). The products of chemical vs biological oxidation are generally identical (eq. 8). 

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). 

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