Paraoxone

The rat LD qS are 13, 3.6 (oral) and 21, 6.8 (dermal) mg/kg. Parathion is resistant to aqueous hydrolysis, but is hydroly2ed by alkah to form the noninsecticidal diethjlphosphorothioic acid and -nitrophenol. The time required for 50% hydrolysis is 120 d ia a saturated aqueous solution, or 8 h ia a solution of lime water. At temperatures above 130°C, parathion slowly isomerizes to 0,%diethyl 0-(4-nitrophenyl) phosphorothioate [597-88-6] which is much less stable and less effective as an insecticide. Parathion is readily reduced, eg, by bacillus subtilis ia polluted water and ia the mammalian mmen to nontoxic 0,0-diethyl 0-(4-aminophenyl) phosphorothioate, and is oxidized with difficulty to the highly toxic paraoxon [511-45-5] diethyl 4-nitrophenyl phosphate d 1.268, soluble ia water to 2.4 mg/L), rat oral LD q 1.2 mg/kg. 

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). 

The course of the reaction has not been fully clarified. Hydrolytic and aromatization processes are probably responsible for the formation of colored or fluorescent deriva4 tives (cf. Potassium Hydroxide Reagent). For instance, sevin is converted to a-naphthalkali metal salt of the o-hydroxycinnamic acid pro- duced by hydrolytic cleavage of the pyrone ring is converted from the non-fluorescent cis- to the fluorescent trans-form by the action of long-wavelength UV light (X = 365 nm) [2]. 

Methyl parathion can enter your body if you eat food or drink water containing it if you swim, bathe, or shower in contaminated water if you touch recently sprayed plants or soil if you touch contaminated soil near hazardous waste sites or if you breathe air that contains methyl parathion, such as near factories or recently sprayed farm fields (or in recent accounts of the illegal use of methyl parathion, if you breathe air or touch contaminated surfaces inside homes where methyl parathion has been used to kill insects). By any means of exposure, methyl parathion goes into your body quickly and gets into your blood. From your bloodstream, methyl parathion goes to your liver, brain, and other organs. Your liver changes some of methyl parathion to a more harmful chemical called methyl paraoxon. Both methyl parathion and methyl paraoxon can bind to enzymes of your nerves within minutes or hours. Your liver breaks down methyl parathion and methyl paraoxon into less harmful substances. These less harmful substances leave your body in urine within hours or days. For more information, see Chapter 3. 

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. 

Methyl paraoxon may also be made unavailable by binding to noncritical tissue and plasma constituents (Benke and Murphy 1975), including cholinesterase (Parkinson 1996). In addition, the parent compound is bound to albumin, in serum, as discussed previously in Section 3.4.2.4, but this binding does not appear to limit the availability of methyl parathion to the tissues, indicating that it is reversible. Tissue binding appears to be more important than serum binding (Braeckman et al. 1980, 1983). 

The relative rates of activation and detoxification of methyl paraoxon within the liver determine whether net activation or detoxification will occur (Sultatos 1987). Sex-differences have been observed in acute... 

Data from a single study in dogs suggest that hepatic first-pass metabolism may limit systemic availability of the parent compound following oral exposure (Braeckman et al. 1983). Placental transfer of methyl parathion was demonstrated in pregnant rats 1-3 days before parturition. Thirty minutes after administration, both methyl parathion and methyl paraoxon were found in fetal brain, liver, and muscle methyl parathion, but not methyl paraoxon, was detected in placenta and maternal liver (Ackermann and Engst 1970). Methyl parathion binds reversibly to serum albumin, but is readily distributed to the tissues (Braeckman et al. 1980, 1983). 

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). 

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). 

Practically all toxicokinetic properties reported are based on the results from acute exposure studies. Generally, no information was available regarding intermediate or chronic exposure to methyl parathion. Because methyl parathion is an enzyme inhibitor, the kinetics of metabolism during chronic exposure could differ from those seen during acute exposure. Similarly, excretion kinetics may differ with time. Thus, additional studies on the distribution, metabolism, and excretion of methyl parathion and its toxic metabolite, methyl paraoxon, during intermediate and chronic exposure are needed to assess the potential for toxicity following longer-duration exposures. 

The methyl parathion released to the atmosphere can be transported back to surface water and soil by wet deposition. Methyl parathion that is released to the atmosphere can also be transformed by indirect photolysis to its oxygen analog, methyl paraoxon, by oxidation with photochemically produced oxygen radicals. However, methyl parathion is not expected to undergo significant transformation to methyl paraoxon. 

Very little information exists in the literature on the transformation and degradation of methyl parathion in air. An early study indicated that direct photolysis of methyl parathion may occur however, the products of this photolysis were not determined (Baker and Applegate 1974). A later study found a transformation product of methyl parathion, methyl paraoxon, in air samples taken from areas where methyl parathion had been applied. Formation of methyl paraoxon was attributed to the vapor phase oxidation of methyl parathion (Seiber et al. 1989). Recent monitoring studies in California have also found both methyl parathion and methyl paraoxon (Baker et al. 1996). 

In a study to determine the concentrations of pesticides in air collected during times of peak pesticide use in California, air samples were collected at applications sites and at locations adjacent to the application sites (Baker et al. 1996). Of the samples collected adjacent to the application sites, 50% had levels of methyl parathion greater than the detectable limit of 0.2 ng/m, while 21% had levels of methyl paraoxon... 

Air samples collected in the Sacramento Valley area of California near sites where methyl parathion was heavily used on rice were analyzed by Seiber et al. (1989). Methyl parathion concentrations ranged from 0.2 (minimum detectable level) to 25.67 ng/m depending on the location and time of sampling. Methyl paraoxon, the oxygen analog of methyl parathion, was also detected at a maximum of 3.07 ng/m. The highest concentrations of both compounds were found at sites near locations of heaviest use. 

Methyl parathion and methyl paraoxon concentrations were measured in the condensate from coastal fog in California. Levels ranged from 0.046 to 0.43 pg/L methyl parathion and from 0.039 to 0.49 pg/L methyl paraoxon. The authors noted that the transformation of the methyl parathion to the methyl paraoxon appeared to take place during atmospheric transport of methyl parathion away from the agricultural areas (Schomburg et al. 1991). 

In a study of the metabolism of methyl parathion in intact and subcellular fractions of isolated rat hepatocytes, a high performance liquid chromatography (HPLC) method has been developed that separates and quantitates methyl parathion and six of its hepatic biotransformation products (Anderson et al. 1992). The six biotransformation products identified are methyl paraoxon, desmethyl parathion, desmethyl paraoxon, 4-nitrophenol, />nitrophenyl glucuronide, and /wiitrophenyl sulfate. This method is not an EPA or other standardized method, and thus it has not been included in Table 7-1. 

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