Organophosphate-induced delayed organophosphates associated with

One of the main human health concerns about organophosphate esters is the potential for neurotoxicity reactions, in particular a condition known as organophosphate-induced delayed neurotoxicity (OPIDN). Tri-ort/20-cresyl phosphate (TOCP) has been identified as one of the more potent OPIDN neurotoxins in humans, and was formerly a constituent in some organophosphate ester hydraulic fluid products (Marino 1992 Marino and Placek 1994). Production processes now routinely remove virtually all the TOCP. For instance, tricresyl phosphate (TCP) products now typically are manufactured to contain over 98% meta and para isomers and virtually no TOCP (Marino and Placek 1994). Products containing these compounds associated with OPIDN have now entirely disappeared from commercial use, and the vast majority of the industrial organophosphate esters are based on triaryl phosphates with no halogenated components (Marino 1992). At waste disposal sites, however, site contaminants from older product formulations containing the ortho form may be encountered. 

Organophosphorus compounds (OPC) cause two major toxic effects. The first is the well-known acute toxicity initiated by inhibition of acetylcholinesterase (AChE) with subsequent accumulation of acetylcholine at nerve endings. The second effect is organophosphate-induced delayed polyneuropathy (OPIDP) (ataxia and paralysis appearing 2-3 weeks after exposure) associated with inhibi-... 

Acute oral exposure to several organophosphate ester hydraulic fluids produced deaths in rabbits, chickens, and cows. The deaths were associated with severe cholinergic symptoms or symptoms of organophosphorus induced delayed neuropathy (OPIDN). (See Section 22.2 A for further details on the neurological effects.)... 

The subcommittee considered other possible toxicity end points, notably neurotoxicity, associated with GD exposure. Organophosphate compounds like GD may act directly on nerve cell receptors or, by inhibiting neural AChE, interfere with neuromuscular transmission and produce delayed-onset subjunctional muscle damage. In addition, some organophosphate compounds cause a neurotoxic effect (organophosphate-induced delayed neuropathy, or OPIDN) that is not associated with ChE inhibition. Emerging research in this area might indicate alternative... 

Exposure to some organophosphate cholinesterase inhibitors results in a delayed neuropathy characterized by degeneration of axons and myelin. This effect is not associated with the inhibition of acetylcholinesterase, but rather with the inhibition of an enzyme described as neuropathy target esterase (NTE) however, the exact mechanism of toxicity is not yet fully understood (Munro et al., 1994). For some organophosphate compounds, delayed neuropathy can be induced in experimental animals at relatively low exposure levels, whereas for others the effect is only seen following exposure to supralethal doses when the animal is protected from the acute toxic effects caused by cholinesterase inhibition. 

AChEs and BuChEs are specialized carboxylic ester hydrolases that preferentially hydrolyze choline esters. They are classed among the B-esterases, enzymes that are inhibited by OPs. Another B-esterase is neuropathy target esterase (NTE), an enzyme associated with organophosphate-induced delayed neuropathy (OPIDN). Enzymes that actively hydrolyze OPs are known as A-esterases. They provide an important route of detoxification. Examples are par-aoxonase and DEPase (Table 1). The tertiary structure and amino acid sequences of several AChEs and BuChEs have been elucidated. 

Physiological substrate for CarbE is probably O-acetyl sialic acid [57], CarbE can be differentiated from other serine esterases AChE (EC 3.1.1.7) and ChE (EC 3.1.1.8) in that AChE and ChE react with positively charged esters such as acetylcholine and butyrylcholine and can be inhibited with carbamates, while CarbE do not react with positively charged esters and inhibition with carbamates occurs only at high concentrations. Inhibition of CarbE, except inhibition of neuropathy target esterase associated with organophosphate-induced delayed polyneuropathy, does not cause any known toxic effects. 

Separate from the acute effects of anticholinesterases upon the neuromuscular junction (discussed previously), two further syndromes involving the neuromuscular system have been associated with OP poisoning. These are (1) the intermediate syndrome (IMS), and (2) organophosphate-induced delayed polyneuropathy (OPIDP). 

A number of syndromes have been associated with OP exposure, and these are listed in Table 10.3. Some of these syndromes, notably the acute cholinergic syndrome, are largely caused by acetylcholine aeeumulation, whereas another, organophosphate-induced delayed polyneuropathy (OPIDP), clearly is not. 

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