Pesticides carbamates/cholinesterase inhibitors

Organophosphate and carbamate cholinesterase inhibitors (see Chapter 7) are widely used to kill insects and other pests. Most cases of serious organophosphate or carbamate poisoning result from intentional ingestion by a suicidal person, but poisoning has also occurred at work (pesticide application or packaging) or, rarely, as a result of food contamination or terrorist attack (eg, release of the chemical warfare nerve agent sarin in the Tokyo subway system in 1995). 

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. 

Cholinesterase inhibitor (anti-cholinesterase, ChEI) is a chemical that prevents cholinesterases (ChEs) from breaking down. ACh, which consequently increases the level and duration of action of this neurotransmitter. ChEIs such as organophosphates (esters of phosphoric acid) and carbamates (esters of carbamic acid) - serve as insecticides, pesticides, warfare agents and drugs. 

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. ... 

Organophosphate and carbamate pesticides are potent inhibitors of the enzyme cholinesterase. The inhibition of cholinesterase activity by the pesticide leads to the formation of stable covalent intermediates such as phosphoryl-enzyme complexes, which makes the hydrolysis of the substrate very slow. Both organophosphorus and carbamate pesticides can react with AChE in the same manner because the acetylation of the serine residue at the catalytic center is analogous to phosphorylation and carbamylation. Carbamated enzyme can restore its catalytic activity more rapidly than phosphorylated enzyme [17,42], Kok and Hasirci [43] reported that the total anti-cholinesterase activity of binary pesticide mixtures was lower than the sum of the individual inhibition values. 

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. 

The UK Pesticide Safety Directorate (PSD) has decided to use the TEF approach for assessment of combined risk from exposure to mixtures of acetyl cholinesterase inhibitors (organophosphate (OP) compounds and carbamates) (PSD 1999). Despite clear differences in the action of carbamates and OP compounds, the index compounds selected for all acetyl cholinesterase inhibitors were either aldicarb (carbamate) or chlorpyrifos (OP). The POD for determining relative potency was predetermined as the dose level that produced 20% inhibition of red blood cell cholinesterase in a 90-day dietary study in rats. 

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. 

Use of NLO likely improves response and reduces systemic adverse effects and should be performed by all patients administering cholinesterase inhibitors. These agents should be used with caution in patients with asthma, retinal detachments, narrow angles, bradycardia, hypotension, heart failure, Down s syndrome, epilepsy, parkinsonism, peptic ulcer, and ocular inflammation, as well as in those receiving cholinesterase inhibitor therapy for myasthenia gravis or exposure to carbamate or organophosphate insecticides and pesticides. ... 

The term pesticide includes chemicals used to eradicate rodents (rodenticides), fungi (fungicides), weeds (herbicides) and insects (insecticides). These agrochemicals may be used directly on the medicinal plant crop itself, they may be used on crops growing adjacent to the herbs or they may occur as general environmental pollutants in soil, air or water. The presence of insecticide residues is of particular concern because those of the organochlorine type (DDT etc.) have been shown to cause cancers in animals and those of the organophosphate and carbamate types are potent cholinesterase inhibitors. 

The extreme difference in toxicity toward mammals for equally potent pesticidal carbamates is striking. The difference is at least partly due to the difference in cholinesterase sensitivity, but in some cases, metabolism is important. Carbosulfan must be transformed to carbofuran in order to become an active cholinesterase inhibitor — a conversion that does not occur in vertebrates. Aldicarb is extremely poisonous and stable. It can be activated... 

One must appreciate that all cholinesterase inhibitors cannot be described easily under a single umbrella since it would include the widely used carbamates found in most household pesticides along with the deadly chemical warfare agents, which are some of the most potent chemicals ever developed by man. Although generalizations are sometimes useful, in the field of risk assessment they can be misleading and sometimes blatantly wrong. 

Highly toxic by ingestion and moderately toxic by inhalation and skin absorption cholinesterase inhibitor exhibits acute, delayed, and chronic toxicity toxic effects are those of organophosphorus pesticides and carbamate esters the symptoms include excessive salivation, lacrimation, blurred vision, headache, labored breathing, twitches of muscle, loss of reflexes, headache, weakness, sweating, nausea, giddiness, vomiting, cramps, diarrhea, convulsions, and coma U.S. EPA-listed extremely hazardous substance. 

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. 

Organophosphorus compounds and carbamates, also known more generally as cholinesterase inhibitors, are widely used pesticides that may cause poisonings after accidentai or suicidal exposure. Poisonings are particularly common in rural areas and third-world countries where more potent agents are widely available. Several chemical warfare agents (eg, GA [Tabun], GB [Sarin], GD [Soman], GF, and VX) are extremely potent cholinesterase inhibitors (see p 372 and Table 11-57). Household insect sprays often contain low-potency cholinesterase inhibitors. (Many commercial products also contain solvents such as toluene or xylene that can themselves produce toxic effects in an overdose see p 357). 

The cholinesterase surfaces described here, as in the case of OPH, are broad spectrum. The TAC and TBC surfaces indicate only the presence of a competitive inhibitor of the enzyme and not its identity, so a positive result would be observed upon exposure to an organophosphate or carbamate pesticide, nerve agent, or drug with anti-cholinesterase activity. When the two enzymes are combined on a single surface, classes of compounds can be distinguished, that is, the surface discriminates between competitive inhibitors of AChE only, competitive inhibitors of BChE only, and competitive inhibitors of AChE and BChE. Inhibitor identification can be made by comparison of the change in absorbance at the AChE peak as compared to that for the BChE peak on the combined surface. 

The mechanism by which pesticides exert their toxic effects on mammals has been characterized for only a few groups of compounds [17,18]. For example, the mechanism for organophosphorus and carbamate insecticides involves inhibition of cholinesterase also, nitrophenols and higher chlorinated phenols are inhibitors for oxidative phosphorylation [10]. Fat-soluble substances (e.g., organochlorines such as DDT, HCH, and other persistent substances) accumulate in the body and, when stored in fatty tissues, cannot be... 

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