Cholinesterases inhibition

The esters of monofluorophosphoric acid are of great interest because of their cholinesterase inhibiting activity which causes them to be highly toxic nerve gases and also gives them medical activity (see Enzyme inhibitors). The most studied is the bis(l-methylethyl)ester of phosphorofluoridic acid also known as diisopropyl phosphorofluoridate [155-91 DFP (5), and as the ophthalmic ointment or solution Isoflurophate USP. It is used as a... 

Several cholinergic strategies, other than cholinesterase inhibition, have been employed with the intention of ameliora ting the symptoms of AD. These include precursor loading acetylcholine release enhancement, and direct activation of both muscarinic and nicotinic receptors. 

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... 

EPA has derived an RfD of. 00025 mg/kg/day, based on a NOAEL of 0.025 for reduced hematocrit, erythrocyte counts, and hemoglobin (cholinesterase inhibition was also listed as a critical effect but the reason for this was not explained). This NOAEL appears to be from the same study as for the ATSDR chronic-duration oral MRL, although the study is referenced differently (IRIS 2001). 

Fish SA. 1966. Organophosphorus cholinesterase inhibition and fetal development. Am J Obstet Gynecol 96 1148-1154. 

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. 

Pope CN, Chakraborti TK, Chapman ML, et al. 1991. Comparison of in vivo cholinesterase inhibition in neonatal and adult rats by three organophosphorothioate insecticides. Toxicology 68 51-61. 

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). 

Case Studies in Environmental Medicine Taking an Exposure History—The importance of taking an exposure history and how to conduct one are described, and an example of a thorough exposure history is provided. Other case studies of interest include Reproductive and Developmental Hazards Skin Lesions and Environmental Exposures Cholinesterase-Inhibiting Pesticide Toxicity and numerous chemical-specific case studies. 

The inhibition of brain cholinesterase is a biomarker assay for organophosphorous (OP) and carbamate insecticides (Chapter 10, Section 10.2.4). OPs inhibit the enzyme by forming covalent bonds with a serine residue at the active center. Inhibition is, at best, slowly reversible. The degree of toxic effect depends upon the extent of cholinesterase inhibition caused by one or more OP and/or carbamate insecticides. In the case of OPs administered to vertebrates, a typical scenario is as follows sublethal symptoms begin to appear at 40-50% inhibition of cholinesterase, lethal toxicity above 70% inhibition. 

In one study with common marmosets, the animals were dosed with diazinon (10, 90, or 130 mg/kg i.m.) and measnrements of erythrocyte cholinesterase inhibition... 

Grue, C.E., Hart, A.D.M., andMineau, P. (1991). Biological consequences of depressed brain cholinesterase activity in wildlife. In Mineau, P. (Ed.) Cholinesterase Inhibiting Insecticides— Their Impact on Wildlife and the Environment, 151-210. Amsterdam Elsevier. 

Before discussing the structure of the neurotoxins, it is necessary to define the types of neurotoxins. Three types of neurotoxins have been found so far in snake venoms. The first one is a postsynaptic neurotoxin, the second is a presynaptic neurotoxin, and the last is a cholinesterase inhibiting neurotoxin. Most sea snake venoms seem to contain only the postsynaptic neurotoxin. Only in Enhydrina... 

The initial enthusiasm for tacrine and velnacrine, which are the anticholinesterases most studied clinically, has been tempered by the fact that not all patients respond. Most show the peripheral parasympathomimetic effects of cholinesterase inhibition, e.g. dyspepsia and diarrhoea, as well as nausea and vomiting, and about half of the patients develop hepatotoxicity with elevated levels of plasma alanine transaminase. While some peripheral effects can be attenuated with antimuscarinics that do not enter the brain, these add further side-effects and the drop-out rate from such trials is high (<75%) in most long-term studies. Donepezil appears to show less hepatotoxicity but its long-term value remains to be determined. 

Diarrhea was observed in rabbits administered an unspecified amount of Cellulube 220 for an intermediate duration (Carpenter et al. 1959). Soft feces were also observed in Pasture lla-mfected rabbits receiving 5,750 mg/kg/day of Fyrquel 220, but not 2,875 mg/kg for an intermediate duration (MacEwen and Vemot 1983). The diarrhea may have been the result of cholinesterase inhibition or of the underlying infection or a combination of the two. No gross or histological alterations were observed in rabbits receiving a dermal dose of 1,000 mg/kg/day of cyclotriphosphazene for an intermediate duration (Kinkead et al. 1989c, 1990). 

No NOAELs or LOAELs were identified for toxic effects in humans after inhalation exposure to organophosphate ester hydraulic fluids. Reliable NOAELs and LOAELs for acute inhalation exposure are restricted to 4-hour NOAELs for systemic effects in rats exposed to Fyrquel 220 or Durad MP280 and 4-hour LOAELs for mild lethargy in rats exposed to Durad MP280 and Fyrquel 220 (Gaworski et al. 1986). The study identifying these NOAEL and LOAEL values did not measure cholinesterase inhibition, did not allow sufficient follow-up time for the development of delayed neurotoxic effects, and used a... 

ATSDR. 1993c. Case studies in environmental medicine - cholinesterase inhibiting pesticide toxicity. Agency for Toxic Substances and Disease Registry, Division of Toxicology, Atlanta, GA. 

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