Malathion cholinesterase inhibition

The relative safety of malathion to humans has been demonstrated repeatedly. In a group of workers with an average exposure of 3.3 mg/m for 5 hours (maximum of 56mg/m ), the cholinesterase levels in the blood were not significantly lowered and no one exhibited signs of cholinesterase inhibition. In a human experiment in which four men were exposed I hour daily for 42 days to 84.8 mg/m, there was moderate irritation of the nose and the conjunctiva, but there were no cholinergic signs or symptoms. ... 

Malathion is an organophosphate cholinesterase inhibitor that is hydrolyzed by plasma carboxylesterases much faster in humans than in insects, thereby providing a therapeutic advantage in treating pediculosis (Chapter 7 Cholinoceptor-Activating Cholinesterase-Inhibiting Drugs). Malathion is available as a 0.5% lotion (Ovide) that should be applied to the hair when dry and the hair then combed to remove nits and lice after 4-6 hours. 

As with most organophosphorus insecticides, acute toxicity is predominant. However tolerance to repeated exposures can occur. The no-observed-adverse-effect level (NOAEL) established from a rabbit developmental toxicity study was 50 mg kg day based on maternal toxicity (i.e., reduced body weight gain). Developmental toxicity studies were negative in rats and rabbits. A two-generation reproductive toxicity study in rats showed no increased sensitivity in pups compared to dams. Repeated exposure to malathion does not cause delayed neurotoxicity. The NOAEL of 2.4 mg kg day was established based on plasma cholinesterase inhibition in a long-term dosing study in rats. 

AbdoUahi, M Mosiafalou., S., Pournourmohamrnadi, S.. and Shadnia, S. (2004a). Oxidative stre,ss and cholinesterase inhibition in. saliva and plasma of rats following suhchronic expo.surc to malathion. Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 137,29-34. 

A recent study of Moser eoworkers (2005) Mo,ser et uL (2005), using a do.se-additive design with mixtures of five commonly used OP pesticides (chlorpyrifos, diazinon, dimeihoate, acephaic, and malathion), showed a more-than-additive interaction on multiple end points blood and brain cholinesterase inhibition, motor activity, and gait score (tail-pinch response did not. show a more-than-additive interaction). This study is noteworthy because (i) relatively sensitive end points were used to test the toxic interaction of the OP pesticides, such as cholinesterase inhibition or depression of motor activity (ii) more than two OP compounds were used in the mixture and (iii) comprehensive statistical analyses of the data were performed. The pharmacokinetic interaction of two of the aimpounds in the mixture, chlorpyrifos and diazinon, has been studied in rats (Timchalk et a ., 2004). The authors found that one compound did not affect the pharmacokinetics of the other unless high doses were given, concluding that a more-than-additive interaction is unlikely at environmentally relevant concentrations. 

With the above discussion in mind, it may be assumed that chiral xenobi-otics are likely to be present in various foodstuffs, as human food comprises the meat of fish, birds and terrestrial animals, and of course vegetables. Many chiral pesticides are used to control insects in vegetables and cereals, and hence the presence of these pesticides in the food products is to be expected. Only a few reports are available dealing the presence of chiral pesticides in various foodstuffs. The cholinesterase inhibition activity of chiral organophosphorous pesticides, as well as that of toxic organophosphorous pesticides nerve gases, are enantioselective in nature. Scientists at the Microbiological and Chemical Exposure Assessment Research Division of NERL in Cincinnati, USA, have found the chiral insecticide permethrin, a pyrethroid insecticide, in spinach. Similarly, malathion has been observed in blackberry extract [146]. 

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). 

Irreversible cholinesterases are mostly organophosphorus compounds and combine only with esteratic site of cholinesterase and that site gets phosphorylated. The hydrolysis of phosphorylated site produces irreversible inhibition of cholinesterase. And, because, of this property, the therapeutic usefulness is very limited. Most of the compounds are used as insecticides e.g. parathion, malathion and war gases e.g. tabun, sarin, soman etc. 

The organophosphorus cholinesterase inhibitors like diisopropyl fluorophosphate, phospholine, parathion, malathion etc. are highly toxic compound and cause irreversible inhibition of both true and pseudocholinesterases. They are highly lipid soluble compound and can easily cross the blood-brain barrier. 

Excessive muscular blockade may be caused by compounds such as the cholinesterase inhibitors. Such inhibitors, exemplified by the organophosphate insecticides such as malathion (chap. 5, Fig. 12) (see also chap. 7) and nerve gases (e.g., isopropylmethylphosphonofluor-idate), cause death by blockade of respiratory muscles as a result of excess acetylcholine accumulation. This is due to inhibition of the enzymes normally responsible for the inactivation of the acetylcholine (see chap. 7). Respiratory failure may also result from the inhibition of cellular respiration by cyanide, for example, or central effects caused by drugs such as dextropropoxyphene. 

Inhibition of the cholinesterase enzymes depends on blockade of the active site of the enzyme, specifically the site that binds the ester portion of acetylcholine (Fig. 7.48). The organophosphorus compound is thus a pseudosubstrate. However, in the case of some compounds such as the phosphorothionates (parathion and malathion, for example), metabolism is necessary to produce the inhibitor. 

The amines spermidine, spermine, and putrescine, which are all hydro-philes, act synergistically with malathion, a lipophile, to inhibit cholinesterase activity in toads. 

The scale of manufacture of these organophosphonis pesticides can be guaged from data referring to the USA annual production in 1975 (tonnes) methylparathion 46000. parathion 36000 and malathion 16000. In addition, some 15 other thiooiganophosphorus insecticides are manufactured in the USA on a scale exceeding 2000 tonnes pa each. They act by inhibiting cholinesterase, thus preventing the natural hydrolysis of the neurotransmitter acetylcholine in the insect. ... 

Malathion is a pediculicide that inhibits cholinesterase activity. It is used in the treatment of head lice (Pediculus humanus capitis) and their ova of the scalp hair. 

The irreversible inhibitors, exemplified by organophosphorous compounds (diisopropyl fluorophosphate [DTP], parathion, malathion, diazinon), have long durations of action and form a covalent bond with acetylcholinesterase, which is hydrolyzed very slowly and negligibly, but the inhibition may be overcome by cholinesterase activators such as pralidoxime. 

Diazinon, malathion, parathion, chlorpyrifos, dichlorvos irreversible inhibition of red blood cell cholinesterase, acetylcholinestera.se, plasma cholinesterase Mild fatigue, headache, blurred vision, diz/.ines.s, numbness of extremities, nausea, vomiting, excessive. sweating and salivation, tightness in chest Moderate weaknc.ss, difficulty talking, muscular fasciculations, miosis Severe unconsciousness, flaccid paralysis, moist rales, respiratory difficulty, cardiac arrhythmias, cyanosis... 

Several impurities often piesenl in OPs are potent cholinesterase inhibitors and may potentiate OP toxicity. For example, of many impurities in malathion, 0,C>.5-trinicthyl phosphorothioalc (OOS-TMP) and 0,5,.S-trimcthyl phospho-rothioaic (OSS-TMP) are potent choline.sterasc inhibitors, but they inhibit immune responses at doses that produce no cholinergic symptoms (Malllpudi et at., 1979). Various cffect.s of OOS-TMP and OSS-TMP have been reviewed in detail elsewhere (Rodgers et at., 1992). 

Benslama et al. (2004) have reported two unnsnal cases of malathion poisoning with a rare-type of complication from intermediate syndrome arising 2 to 4 days after the onset of cholinergic effects. The symptoms were respiratory paresis with difficulties of weaning from assisted respiratory, deficit of proximal limbs, neck flexors and cranial nerves. The authors attributed this syndrome to prolonged inhibition of acetyl-cholinesterases and not to any mnscnlar fiber s necrosis. 

Organophosphorus insecticides such as dimethoate, diazinon, malathion, fenitrothion, and parathion are the most toxic to bees. They inhibit the enzyme cholinesterase, which mediates the transmission of nerve signals. These chemicals induce problems of regurgitation (bees are wet), distended abdomen, disorientation, lethargy, paralysis, and so on... 

Obidoxime (Lii-H6, Toxogonin, iV,)V -oxydimethylenebis-(pyridinium-4-aldoxime)dihalide) (III) appears to be more effective against inhibited cholinesterase of the red blood cell than against that of plasma following intoxication of dogs with parathion [206]. It is less effective following malathion intoxication. 

Malathion, dimpylate, and other organophosphorus insecticides inhibit the activity of plasma cholinesterase, thereby reducing the metabolism of the suxamethonium and prolonging its effects. 

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