Parathion cholinesterase inhibition

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. 

Based on the rapid appearance of clinical signs and cholinesterase inhibition, methyl parathion appears to be readily absorbed by humans and animals following inhalation, oral, and dermal exposure. Following oral administration of methyl parathion to animals, the extent of absorption was at least 77-80% (Braeckman et al. 1983 Hollingworth et al. 1967). No studies were located regarding the extent of absorption following inhalation and dermal exposure, or the mechanism of absorption. 

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... 

Nanda Kumar NV, Visweswaraiah K, Majumder SK. 1976. Thin layer chromatography of parathion as paraoxon with cholinesterase inhibition detection. J Assoc Off Anal Chem 59 641-643. 

Udaya Bhaskar S, Nanda Kumar NV. 1981. Thin layer chromatographic determination of methyl parathion as paraoxon by cholinesterase inhibition. J AOAC 64 1312-1314. 

Other additional studies or pertinent information that lend sunnort to this MRL Methyl parathion affects the nervous system by inhibiting acetylcholinesterase activity. Cholinesterase inhibition and neurological effects have been observed in humans and animals, for all exposure routes and durations (for example. Dean et al. 1984 Desi et al. 1998 EPA 1978e Gupta et al. 1985 Nemec et al. 1968 Suba 1984). 

The understandable correlation among careless technique, absenteeism, cholinesterase inhibition, and elevated average urinary PNP levels suggested that the latter was a highly reliable biological index of chronic parathion exposure and one that could ultimately predict chronic parathion toxicity. 

SAFETY PROFILE A deadly human poison by skin contact and inhalation. (A small drop on the skin can kill a man.) A deadly experimental poison by ingestion, inhalation, skin contact, subcutaneous, intravenous, intramuscular, and intraperitoneal routes. Human systemic effects muscle weakness, bronchiolar constriction, nausea or vomiting, flaccid paralysis without anesthesia, miosis (pupOlar constriction), cholinesterase inhibition. A nerve gas used as a chemical warfare agent. To fight fire, use foam, CO2, drj chemical. When heated to decomposition or reacted with steam, it emits very toxic fumes of F and PO.. See also PARATHION. 

SAFETY PROFILE Moderately toxic by ingestion, intraperitoneal, and intravenous routes. Experimental reproductive effects. Mutation data reported. Causes cholinesterase inhibition, but to a lesser extent than parathion. May be expected to cause nerve injury similar to that of other phosphate esters. Combustible when exposed to heat or flame. Can react vigorously with oxidizing materials. To fight fire, use CO2, dry chemical, alcohol foam. When heated to decomposition it emits toxic fumes of PO. See also PARATHION. 

With repeated exposures, acetylcholinesterase inhibition can persist without indications of toxicity. In most cases, cholinesterase inhibition is without overt effects. Methyl parathion cannot cause delayed neurotoxicity. 

Use Antidote for cholinesterase-inhibiting pesticides of the parathion type because of its property of reactivating the cholinesterase by removal of phos-phoryl groups. Also antidote for nerve gases. 

Transplacental transfer and pharmacokinetics of parathion methyl after dermal application were studied in pregnant rats (Abu-Qare et at., 2000). Both the parent drug and the oxon metabolite were transferred to the fetus, although concentrations were somewhat lower than in maternal tissues. It is clear that the fetus is exposed to a relatively high concentration of parathion methyl even after dermal exposure, and (his exposure leads to a significani degree of cholinesterase inhibition (Abu-Qare and Abou-Donia. 2001) also in placenta tissue (Benjaminov et al., 1992). 

A review of the literature of the distribution, function and structure of acetylcholinesterase is too voluminous for the scope of this article, and the reader is referred elsewhere [1]. Cholinesterase enzyme is a protein, and a dietary deficiency of protein can result in lower cholinesterase activity in liver microsomes and serum of rats. Cholinesterase inhibition by parathion and by Banol (6-chloro-3,4-xylyl methylcarbamate) (Upjohn) is more at lower dietary levels of casein than at higher levels, thus confirming that the toxicity of these enzyme inhibitors is greater at lower dietary protein levels [13]. This observation indicates that a causal relationship exists between amino-acid intake and cholinesterase activity. 

Dermal dose-ChE response and percutaneous absorption studies were conducted with parathion, carbaryl, and thiodicarb in the rat. Parathion and thiodicarb inhibited 50% of the red cell cholinesterase activity at dose levels of 3.2 and 33 mg/kg of bw. Carbaryl at the highest dose level tested (417 mg/kg of bw) produced no detectable red cell cholinesterase Inhibition. 

Inhibition profiles were determined for phosphorothioate OP insecticides such as parathion, malathion, and diazinon (Figure 3). Because these compounds were only weakly inhibitory, the measured concentration range extended from 0.1 nM to 100 pM. The relative order of potency was malathion > diazinon > parathion. The commercially available oxidative transformation products of parathion and malathion (i.e., paraoxon and malaoxon) as well as dichlorvos, were also measured using this assay (Figure 4). The oxidative transformation products were significantly more potent AChE inhibitors than the parent compounds and showed inhibitory profiles comparable to dichlorvos. The cholinesterase inhibition assay yielded similar IC50 values for each of these compounds. Indeed, these compounds are typically reported to have inhibition constants within an order of magnitude of each other (16, 17). 

Male rats exposed to 264 mg/m of methyl parathion by inhalation had 59% (range 53-61%) inhibition of blood (a combination of erythrocyte and plasma) cholinesterase 1 hour after exposure (EPA 1978e). These animals had typical cholinergic signs of toxicity salivation, exophthalmos, laerimation, spontaneous defecation and urination, and muscle fasciculation. Values for controls were not provided. Death was not correlated to the degree of eholinesterase inhibition in whole blood. 

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. 

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. 

---