OPIDN Delayed Neurotoxicity

The available inhalation data for Durad MP280, Fyrquel 220, Cellulube 220, Skydrol 500B-4, and cyclotriphosphazene (reviewed in the next paragraph) are inadequate to derive intermediate-duration MRLs for these individual fluids, principally because the studies were conducted in species (rats or rabbits) that are generally considered to be insensitive to the delayed neurotoxicity of acute exposure to organophosphate esters. Cats, dogs, or nonhuman primates more accurately model the human expression of OPIDN than rats and rabbits, and studies in these species would provide a better basis for MRL derivation. 

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. 

No studies were located regarding organophosphate-induced delayed neurotoxicity (OPIDN) in humans or in animals after inhalation exposure to diazinon. 

M.B. Abou-Donia, The cytoskeleton as a target for organophosphorus ester-induced delayed neurotoxicity (OPIDN). Chem. Biol. Interact. 87(l-3) 383, 1993. 

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... 

FIGURE 57.5. Subclasses of neuropathy target esterase (NTE) inhibitors. Type A inhibitors include phosphates, phosphonates, and phosphoramidates these are neuropathic and capable of aging. T pe B inhibitors include phosphinates, sulfonates, and carbamates these are nonneuropathic and not capable of aging. However, inhibition of NTE with a type B inhibitor will protect against organophosphorus compound-induced delayed neurotoxicity (OPIDN) from subsequently administered type A inhibitors. Reproduced with permission from Richardson (2005). 

Histological examination of hens exposed to TOCP revealed a wallerian dying-back degeneration of the larger diameter axons and myelin sheaths. If the neuropathic target esterase is inhibited by 70%, the typical organophophorus ester-induced delayed neurotoxicity (OPIDN) will follow after an approximate 7-14 day delay. 

The term delayed neurotoxicity may be used to describe any type of toxicity to the nervous system involving a delay between the precipitating chemical exposure and the appearance of neurological signs or symptoms. However, this designation usually refers to organophosphorus (OP) compound-induced delayed neurotoxicity (or delayed neuropathy) (OPIDN), also known as OP compound-induced delayed polyneuropathy (OPIDP). 

Randall, J.C., Yano, B.L., and Richardson, R. J., Potentiation of organophosphorus compound-induced delayed neurotoxicity (OPIDN) in the central and peripheral nervous system of the adult hen distribution of axonal lesions, J. Toxicol. Environ. Health., 51(6), 571-590,1997. 

OP compounds that produce delayed neurotoxic effects are esters of phosphtsrus-containing acid.s. More than 35 years ago, tri-o-cresyl phosphate (TOCP) was known to produce delayed neurotoxic effects in humans and chickens characterized by ataxia and weakness of the limbs, developing 10-14 day.s after exposure (John,son. 1969). This syndrome is called OP-induced delayed neuropathy (OPIDN). TOCP and certain other compounds have minimal or no anti-AChE... 

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