Cholinesterase inhibition carbamates

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... 

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. 

Carbamates are used as insecticides, nematocides, fungicides, and herbicides the toxicity of carbamate insecticides is similar to that of OP compounds and is based on the inhibition of ACHE. Also, carbamate metabolites may inhibit ACHE but are usually weaker inhibitors than the unchanged compound. Cholinesterase inhibition caused by carbamates is labile, of short duration, and rapidly reversible in fact, the half-life of the inhibited enzymes ranges between some minutes and 2 to 3 hours for RBC-ACHE and is on the order of some minutes for PCHE. Accumulation of cholinesterase activity on repeated exposures, as observed with OP compounds, does not occur with... 

Occupational exposure to carbamate insecticides may be monitored by measuring RBC-ACHE and/or PCHE. However, given the low cholinesterase inhibition levels and the short time duration of this effect, ACHE inhibition can generally be used as a biomarker of exposure only when exposure levels are high. Three sequential samples are recommended to establish an individual baseline before exposure. In exposed workers, blood sampling and analysis should be carried out soon after the end of exposure (WHO, 1986). 

L. Pogacnik and M. Franko, Optimisation of FIA system for detection of organophosphorus and carbamate pesticides based on cholinesterase inhibition. Talanta 54, 631-641 (2001). 

Pharmacologically, carbofuran inhibits cholinesterase, resulting in stimulation of the central, parasympathetic, and somatic motor systems. Sensitive biochemical tests have been developed to measure cholinesterase inhibition in avian and mammalian brain and plasma samples and are useful in the forensic assessment of carbamate exposure in human and wildlife pesticide incidents (Bal-lantyne and Marrs Hunt and Hooper 1993). Acute toxic clinical effects resulting from carbofuran exposure in animals and humans appear to be completely reversible and have been successfully treated with atropine sulfate. However, treatment should occur as soon as possible after exposure because acute carbofuran toxicosis can be fatal younger age groups of various species are more susceptible than adults (Finlayson et al. 1979). Carbofuran labels indicate that application is forbidden to streams, lakes, or ponds. In addition, manufacturers have stated that carbofuran is poisonous if swallowed, inhaled, or absorbed through the skin. Users are cautioned not to breathe carbofuran dust, fumes, or spray mist and treated areas should be avoided for at least 2 days (Anonymous 1971). Three points are emphasized at this juncture. First, some carbofuran degradation... 

The major action resulting from human exposure to diazinon is the inhibition of cholinesterase activity (refer to Section 2.4 for discussion). Two pools of cholinesterases are present in human blood acetylcholinesterase in erythrocytes and serum cholinesterase (sometimes referred to as pseudocholinesterase or butyrlcholinesterase) in plasma. Acetylcholinesterase, present in human erythrocytes, is identical to the enzyme present in neural tissue (the target of diazinon action) while serum cholinesterase has no known physiological function. Inhibition of both forms of cholinesterase have been associated with exposure to diazinon in humans and animals (Coye et al. 1987 Edson and Noakes 1960 Soliman et al. 1982). Inhibition of erythrocyte, serum, or whole blood cholinesterase may be used as a marker of exposure to diazinon. However, cholinesterase inhibition is a common action of anticholinesterase compounds such as organophosphates (which include diazinon) and carbamates. In addition, a wide variation in normal cholinesterase values exists in the general population, and there are no studies which report a quantitative... 

The coupling of HPLC with a cholinesterase-inhibition AutoAnalyzer for the determination of organophosphate and carbamate insecticides has much potential for the routine screening of residues of these compounds [58]. 

CHOLINESTERASE INHIBITION (RELATIVE TO CGA 18809) OF SOME ORGANOPHOSPHATES AND CARBAMATES USING BUTYRYLTHIOCHOLINE AND HUMAN PLASMA... 

In California, mixer-loaders and spray applicators who work with toxicity category I and II organophosphates or N-methyl carbamates more than 30 hours per 30-day period are required to have medical supervision. Supervision consists of an interview and a medical examination to determine if a medical condition exists which would make the worker unusually susceptible to poisoning due to cholinesterase inhibition, and to caution the individual about the use of certain drugs such as the pheno-thiazine tranquilizers vdtich potentiate the effects of cholinesterase (ChE) inhibition. Two blood samples, taken several days apart, are analyzed to determine the individual s preexposure plasma and red blood cell (RBC) ChE activity (baseline value). The physician arranges a routine ChE testing program and provides for extra ChE tests should the worker be accidently exposed to OP s. If ChE activity is depressed to 50 percent of the baseline value, the physician may ask the employer to place the worker on... 

Tests for specific classes of chemicals include the measurement of transmitter stimulated adenyl cyclase and Na/K-ATPase for chemicals that affect receptor function or cholinesterase inhibition for organophosphates or carbamates. Electrophysiological techniques may detect chemicals such as DDT or pyrethroids, which affect impulse transmission. 

Bendiocarb is absorbed through all the normal routes of exposure (oral, dermal, and inhalation), but dermal absorption is especially rapid. Carbamates generally are excreted rapidly and do not accumulate in mammalian tissue. If exposure does not continue, cholinesterase inhibition and its symptoms reverse rapidly. In nonfatal cases, the illness generally lasts less than 24 hours.7 Bendiocarb is moderately toxic to birds. The LD50 in mallard ducks is 3.1 mg/kg, and in quail is 19 mg/kg.8 Bendiocarb is moderately to highly toxic to fish. The LC50 (96 hours) for bendiocarb in rainbow trout is 1.55 mg/L.2... 

US Environmental Protection Agency (USEPA) (2000). Office of Pesticide Programs science policy on the use of data on cholinesterase inhibition for risk assessment of organophos-phorus and carbamate pesticides. Office of Pesticide Programs, US Environmental Protection Agency, Washington, DC. 

These compounds inhibit the hydrolysis of the neurotransmitter acetylcholine by the enzyme acetylcholinesterase within the mammalian nervous system (Zwiener and Ginsburg, 1988). This inhibition causes acetylcholine levels to rise, thus causing cholinergic hyperstimulation at muscarinic and nicotinic receptors. There are important differences in the way carbamates and OPs bind to acetylcholinesterase as well as their abililty to affect the CNS. Carbamates are reversible inhibitors of cholinesterase enzymes. Carbamates create a reversible bond to the cholinesterase enzyme through carbamylation which can spontaneously hydrolyze, reversing toxicity. Carbamate poisoning produces toxicity similar to that of OPs however, the toxicity is usually of a shorter duration and less severe in nature (Lifshitz et al, 1994). In contrast, OPs inhibit cholinesterase via an irreversible bond of phosphate radicals... 

Sometimes repeated exposures to a pesticide or family of pesticides will result in a delayed effect, but a larger exposure will cause an acute effect. Qr-ganophosphate and carbamate pesticides inhibit a chemical, called cholinesterase, in the nervous system of humans. A large exposure causes immediate acute illness. Smaller exposures cause no apparent problem at first. They inhibit the cholinesterase, but not enough to cause immediate illness. Small, repeated exposures to these pesticides over several days or weeks may greatly reduce cholinesterase levels in the body. At that point, even a small exposure to a pesticide with relatively low cholinesterase-inhibiting properties may trigger severe illness. 

Theory. Cholinesterase inhibition by organophosphorus insecticides has been the subject of several excellent reviews by O Brien (I, 2) and Heath (3). The basis of toxic action of organophosphates and carbamates in mammals is generally associated with their ability to inhibit cholinesterase in the central and peripheral nervous systems where it plays an important role in the transmission of nerve impulses. 

Table I. Cholinesterase-Inhibitive Effects" of Several Organophosphate and Carbamate Insecticides...

Certain specialized reagents are used to visualize compounds based on their biological activity. Cholinesterase-inhibiting pesticides (e.g., organophos-phates, carbamates) are detected sensitively by treating the layer with the enzyme and a suitable suljstrate, which react to produce a colored product over the entire layer except where colorless pesticide zones are located due to their inhibition of the enzyme-substrate reaction. 

Hetnarski, B. and O Brien, R.D. (1973). Charge Transfer in Cholinesterase Inhibition. Role of the Conjugation Between Carbamyl and Aryl Groups of Aromatic Carbamates. Biochemistry, 12, 3883-3887. 

See also Carbamate Pesticides Cholinesterase Inhibition Pesticides. 

The ability of PBO in synergize cholinesterase-inhibiting insecticides has often been ignored when the mode of action of PBO is discussed. Moore field (I95KJ presented detailed data on this subject and showed that both aromatic and heterocyclic carbamates can be potentiated with PBO. A graphical presentation of data is reproduced in Fig. 19.3 on the effect of adding PBO to iwo carbamate insecticides to control house flics. This is of particular interest in that application was only made to female flies by individual measured drops - much more precise and relevant to effective control than spray applications to Hies of both sexes. This was a classic demonstration of the powerful synergistic action of PRO... 

The organophosphates and the carbamates differ typically in speed or ease of reversibility of cholinesterase inhibition (Ol). As a rule, reversibility is much greater with the carbamates, which include such drugs as neostigmine, pyridostigmine, and the alkaloid physostigmine or such in-... 

Based on features of their interaction with ChE, anti-cholinesterase substances are clas-sified as reversible and irreversible inhibitors. Referred to the reversible anti-cholinesterase substances are quaternary ammonium compounds and aminoformic acid esters OPC are referred to the irreversible anti-cholinest-erase substances. At the same time, a great amount of anti-cholinesterase substances, carbamates in particular, though induce transitional reversible inhibition of ChE, are irreversible reagents. They are destroyed on the enzyme surface. 

The Pesticide Manual from 1977 describes 100 organophosphorus and 25 carbamates in common use, compared with a total of 543 pesticides, while the newer editions (1994) describe 72 organophosphorus insecticides out of a total of 515 pesticides (14% of all pesticides in common use are cholinesterase-inhibiting organophosphates). 

Oxamyl has a high acute toxicity displaying the typical effects of carbamate insecticides, e.g. rapid onset of cholinesterase inhibition followed by rapid recovery. Symptoms of acute intoxication in animals included tremors, salivation, lacrimation, bulging eyes, and muscular twitching. The oral LD50 for oxamyl in the rat is the range of 5 to 15 mg/kg. 

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