Acetylcholinesterase inhibitors toxicity

Extremely toxic acetylcholinesterase inhibitor toxic symptoms include nausea, vomiting, diarrhea, excessive salivation, lacrimation, constriction of the pupils, bron-choconstriction, convulsions, coma, and respiratory failure metabolizes to paraoxon oral LD50 value (rats) 2 mg/kg, LD50 value, skin (rats) 6.8 mg/kg RCRA Waste Number P089. 

No animal or human data were available for inhalation exposure. There are no data regarding effects in humans after oral exposure. Information is available in animals regarding health effects following acute, intermediate, and chronic oral ingestion of diisopropyl methylphosphonate. The animal data obtained after oral exposure indicate that diisopropyl methylphosphonate is moderately toxic after acute bolus exposure but has a lower order of toxicity after intermediate and chronic exposures in food. No data were found on the toxicity of diisopropyl methylphosphonate after exposure in drinking water. Further, diisopropyl methylphosphonate is rapidly metabolized and excreted and does not accumulate. It does not appear to have reproductive or developmental effects. At the doses tested, it does not appear to be an acetylcholinesterase inhibitor, although this issue has not been resolved yet. Limited data are available for dermal exposure in humans and animals. Diisopropyl methylphosphonate does not appear to be a... 

Diethyl chlorophosphate (97%) was obtained from Aldrich Chemical Company, Inc., and distilled before use (bp 58-60°C at 2 mm). This material is a highly toxic acetylcholinesterase inhibitor and must be handled with caution. 

Insects are very sensitive to fluorophosphonates, so that the compound parathion was synthesised and used as an insecticide soon after the Second World War. However, it entered the food chain and eventually found its way into mammals and caused death. An important breakthrough occurred with the synthesis of malathion, an insecticide which has high toxicity to insects, where it is converted to malaoxon, a potent acetylcholinesterase inhibitor. However, malathion is much less toxic to mammals, since it is readily detoxified (Appendix 3.8). 

Another example of this conversion of P=S found in pesticides to P = 0 is the oxidation of malathion in the atmosphere. Malathion itself is not a HAP and has relatively low acute mammalian toxicity because it is degraded by mammalian carboxylesterases. It is effective as a pesticide because in insects, it is activated to malaoxon, an acetylcholinesterase inhibitor. However, malathion itself typically contains impurities such as isomalathion whose mammalian toxicities are greater... 

Selective bioactivation (toxification) is illustrated in the case of the insecticide malathion (3.35). This acetylcholinesterase inhibitor is desulfurized selectively to the toxic malaoxon, but only by insect and not mammalian enzymes. Malathion is therefore relatively nontoxic to mammals (LDjg = 1500 mg/kg, rat p.o.). Higher organisms rapidly detoxify malathion by hydrolyzing one of its ester groups to the inactive acid, a process not readily available to insects. This makes the compound doubly toxic to insects since they cannot eliminate the active metabolite. 

The following structures are a few of the organophosphorus compounds and other acetylcholinesterase inhibitors that are selectively toxic to insects. 

One of the best-understood autoimmune diseases is myasthenia gravis, a condition associated with a decrease in the number of functional post-synaptic nicotinic acetylcholine receptors (Fig. 30-23) in neuromuscular junctions. e The resulting extreme muscular weakness can be fatal. Myasthenia gravis is not rare and affects about one in 10,000 peopled An interesting treatment consists of the administration of physostigmine, diisopropyl-phosphofluoridate (Chapter 12, Section C,l), or other acetylcholinesterase inhibitors (Box 12-E). These very toxic compounds, when administered in controlled amounts, permit accumulation of higher acetylcholine concentration with a resultant activation of muscular contraction. The same compounds... 

The toxicity of TEPP to humans and other mammals is very high it has a toxicity rating of 6, supertoxic. TEPP is a very potent acetylcholinesterase inhibitor. (The inhibition of acetylcholinesterase by organophosphate insecticides is discussed in Section 18.7.)... 

Anatoxin-a(s) inhibits acetylcholinesterase by acting as an irreversible active-site-directed inhibitor [61]. This prevents degradation of ACh and leads to over-stimulation of the muscle cells (Figure 6.1) [56,62]. Thus, although the mechanism of action of anatoxin-a(s) is quite different from that of anatoxin-a, the observed toxicity is similar. In addition, it was the first irreversible acetylcholinesterase inhibitor to be found in a cyanobacterium. 

Organophosphate insecticides with the P=S group are oxidatively desulfurated by cytochrome P450 monooxygenases of insects to their corresponding P=0 analogs. This reaction results in activation (increased toxicity), because the product, P=0, binds more tightly to the acetylcholinesterase than the parent compound and, thus, to more potent acetylcholinesterase inhibitors. For example, parathion is oxidatively desulfurated to paraoxon. 

Clinton, M.E., Misulis, K.E., Dettbam, W-D. (1988). Effects of phenytoin, ketamine, and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate. J. Toxicol. Environ. Health 24 439-49. 

FIFRA microcosm experimental unit. An example of a microcosm experimental unit designed to test the effects of a herbicide on an aquatic environment. This particular setup does not include fish since the predatory effects would tend to hide lower trophic level effects upon the invertebrate populations. Typically, a FIFRA microcosm experiment includes fish species, especially when acetylcholinesterase inhibitors or other toxicants particularly effective against animal species are tested. 

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