Cholinesterases carbamate toxicity

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. 

Loewenstein, Y., Dcnarie, M., Zakut, H., and Soreq, H. (1993). Molecular dissection of cholinesterase domains responsible for carbamate toxicity. Chem.-Biol. Interact. 87, 209-216. 

A highly toxic substance by ingestion, and possibly by most other routes of exposure moderately toxic by inhalation and skin contact cholinesterase inhibitor toxic effects are similar to those of other carbamate pesticides and include excessive salivation, lacrimation, slow heart rate, blurred vision, twitching of muscle and lack of coordination, nausea, weakness, diarrhea and abdominal pain oral intake of probably 1.5-3 g could be fatal to adult humans a teratogenic substance, producing adverse reproductive effects in experimental animals. 

Oxime carbamates are generally applied either directly to the tilled soil or sprayed on crops. One of the advantages of oxime carbamates is their short persistence on plants. They are readily degraded into their metabolites shortly after application. However, some of these metabolites have insecticidal properties even more potent than those of the parent compound. For example, the oxidative product of aldicarb is aldicarb sulfoxide, which is observed to be 10-20 times more active as a cholinesterase inhibitor than aldicarb. Other oxime carbamates (e.g., methomyl) have degradates which show no insecticidal activity, have low to negligible ecotoxicity and mammalian toxicity relative to the parent, and are normally nondetectable in crops. Therefore, the residue definition may include the parent oxime carbamate (e.g., methomyl) or parent and metabolites (e.g., aldicarb and its sulfoxide and sulfone metabolites). The tolerance or maximum residue limit (MRL) of pesticides on any food commodity is based on the highest residue concentration detected on mature crops at harvest or the LOQ of the method submitted for enforcement purposes if no detectable residues are found. For example, the tolerances of methomyl in US food commodities range from 0.1 to 6 mg kg for food items and up to 40 mg kg for feed items. ... 

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... 

Although bicyclophosphates do not inhibit acetylcholinesterase, they exhibit a synergistic toxic effect with materials that do. Individuals who have had previous exposure to cholinesterase inhibitors such as nerve agents and commercial organophosphate or carbamate pesticides may be at a greater risk from exposure to bicyclophosphates. 

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... 

Absorption of the quaternary carbamates from the conjunctiva, skin, and lungs is predictably poor, since their permanent charge renders them relatively insoluble in lipids. Thus, much larger doses are required for oral administration than for parenteral injection. Distribution into the central nervous system is negligible. Physostigmine, in contrast, is well absorbed from all sites and can be used topically in the eye (Table 7-4). It is distributed into the central nervous system and is more toxic than the more polar quaternary carbamates. The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well as by cholinesterase. However, the duration of their effect is determined chiefly by the stability of the inhibitor-enzyme complex (see Mechanism of Action, below), not by metabolism or excretion. 

Enzymatic techniques have also been employed in the analysis of these compounds. The toxicity of carbamate insecticides is due to the inhibition of the enzyme acetylcholine esterase, so the determination of these compounds can be achieved by enzyme inhibition (2,83,119), bioassay (118,167), or enzyme-linked immunosorbent assay (ELISA) (168-171). In the detection of carbamates by fluorimetric enzyme inhibition, the effluent from a reversed-phase chromatographic column was incubated with cholinesterase, which was introduced via a postcolumn reagent delivery pump. Then, the resulting partially inhibited cholinesterase was reacted with N-methyl indoyl acetate to produce a fluorophore and a reduction in the baseline fluorescence (172). 

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... 

The acute toxic effects of the cholinesterase inhibitors, like those of the direct-acting agents, are direct extensions of their pharmacologic actions. The major source of such intoxications is pesticide use in agriculture and in the home. Approximately 100 organophosphate and 20 carbamate cholinesterase inhibitors are available in pesticides and veterinary vermifuges used in the USA. 

While the depression of plasma and/or RBC cholinesterase may be detected after exposure to very large amounts of carbamates, enzyme activity usually recovers rapidly--within minutes to hours. Hence these tests can be misleading unless one of the rapid methods for testing cholinesterase activity has been employed. A more sensitive and specific absorption test for several of the carbamate pesticides is the measurement of their metabolites in the urine within 48 hours of exposure. Carbamate pesticides are sufficiently acutely toxic that those attending the victim must avoid contact with contaminated apparel or vomitus, and should wear rubber gloves during decontamination of hair and skin of the victim. 

Toxicity Bendiocarb is moderately toxic if it is ingested or absorbed through the skin. Skin absorption is the most likely route of exposure. It is a mild irritant to the skin and eyes.4 Like other carbamate insecticides, bendiocarb is a reversible inhibitor of cholinesterase, an essential nervous system enzyme. Symptoms of bendiocarb poisoning include weakness, blurred vision, headache, nausea, abdominal cramps, chest discomfort, constriction of pupils, sweating, muscle tremors, and decreased pulse. 

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... 

Fonnum, F., Sterri, S.H. (2006). Tolerance development to toxicity of cholinesterase inhibitors. In Toxicology of Organ-ophosphate and Carbamate Compounds (R.C. Gupta, ed.), pp. lSl-61. Elsevier Academic Press, San Diego, CA. 

Exposure to a toxic dose of OP results in inhibition of acetylcholinesterase and butyrylcholinesterase activities. The most common method to measure OP exposure is to assay acetylcholinesterase and butyrylcholinesterase activities in blood using a spectrophotometric method (EUman et al, 1961 Wilson et al, 2005 Worek et al, 1999). The drawbacks of activity assays are that they do not identily the OP. They show that the poison is a cholinesterase inhibitor but do not distinguish between nerve agents, OP pesticides, carbamate pesticides, and tightly bound, noncovalent inhibitors like tacrine and other anti-Alzheimer drugs. In addition, low-dose exposure, which inhibits less than 20% of the cholinesterase, carmot be determined by measuring acetylcholinesterase and butyrylcholinesterase activity because individual variability in activity levels is higher than the percent inhibition. 

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... 

Benomyl is a synthetic, organic fungistat having little or no acute toxic effect in mammals. No systemic poisonings have been reported in humans. Although the molecule contains a carbamate grouping, benomyl is not a cholinesterase inhibitor. It is poorly absorbed across skin that which is absorbed is promptly metabolized and excreted. 

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