OPIDN associated

A few OP compounds cause delayed neuropathy in vertebrates because they inhibit another esterase located in the nervous system, which has been termed neuropathy target esterase (NTE). This enzyme is described in Chapter 10, Section 10.2.4. OPs that cause delayed neuropathy include diisopropyl phosphofluoridate (DFP), mipafox, leptophos, methamidophos, and triorthocresol phosphate. The delay in the appearance of neurotoxic symptoms following exposure is associated with the aging process. In most cases, nerve degeneration is not seen with initial inhibition of the esterase but appears some 2-3 weeks after commencement of exposure, as the inhibited enzyme undergoes aging (see Section 16.4.1). The condition is described as OP-induced delayed neuropathy (OPIDN). 

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.)... 

Organophosphate Ester Hydraulic Fluid. The most widely examined target of organophosphate ester hydraulic fluids is the nervous system. Two types of neurological effects have been observed following exposure to certain organophosphate ester hydraulic fluids cholinergic symptoms associated with acetylcholinesterase inhibition and delayed neuropathy (OPIDN). 

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. 

Application of in vitro test methods have become advantageous in specific cases, such as structurally defined compounds and delayed neuropathy, since target cell data and biochemical processes associated in delayed neuropathy are known. Microscopic studies reveal that cases of OPIDN have degeneration of axons followed by demyelination of the nervous system.25,26 Epidemiologic studies have indicated mild impairment of the brainstem, spinal cord, and peripheral nerve functions in Gulf War veterans.27 Such studies are consistent with the spectrum of OPIDN syndrome. The main nerve agents have been shown to inhibit NTE in vitro as well as in vivo. Sarin has been shown to produce delayed neurotoxicity when administered at higher doses in protected hens.25-27... 

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... 

A few OPs have been shown to cause OPIDN, a retrograde degeneration of long and large nerve fibers in the spinal cord and peripheral nerves of humans and experimental animals. Some OPs, such as GB, chlorpyrifos, and isofenphos, require very high doses to be acutely neuropathic (WHO 1986 Lotti 1991). Inhibition of approximately 70% or more of the carboxylesterase NTE often is associated with the disorder (WHO 1986 Lotti 1991). Onset of OPIDN is usually 10 days to several weeks after exposure. It is not clear whether OPIDN can occur after long-term exposure to low concentrations of OPs. 

OPIDN is defined as a delayed onset central and peripheral distal sensorimotor polyneuropathy caused by exposure to nerve agents (Brown and Brix, 1998), typically within 1 to 2 weeks, and less than 4 weeks, after exposure (Johnson, 1980). Symptoms attributable to effects on sensory (numbness, tingling, pain) and motor (fatigue, weakness, and paralysis) targets are present and display a typical axonal length-associated pattern (e.g. predominantly lower extremities, with upper extremities affected at higher agent exposure). No treatment exists, and recovery is slow and rarely complete. 

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. 

OPIDN is subdivided into two forms, type I and type II on the basis of phosphorus atom valence state (5 or 3) and associated pathologic sequela [2,8], Pentacovalent OP compounds are more stable and more commonly used than trivalent ones, and type I OPIDN has been much more extensively studied than type II. Therefore for the remainder of this review, OP compounds will be understood to denote the pentacovalent chemical species and OPIDN will mean the type I disease. 

Clinical manifestations specifically associated with OPIDN including... 

Different research factors and regulatory actions are associated with each level of organization. Each of these, environment, body surface, metabolism, cells and molecules, and nucleic acids, present special features. Although outside the hierarchy of organization of living systems, the major problem of Identification of OFs that cause OPIDN Is also Included In the diagram. 

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