Nerve agents, delayed neuropathy

Organophosphate Ester Hydraulic Fluids. The biomarkers of effects after exposure to organophosphate ester hydraulic fluids are well established in cases of delayed neuropathy (clinical signs of peripheral neuropathy). Further study would be helpful to determine whether certain effects (such as diarrhea after oral exposure) are due to direct action of the toxic agent on the target organ or to inhibition of acetylcholinesterase at the acetylcholine nerve receptor site on the organ. 

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... 

Willems, J.L., M. Nacaise and H.C. De Bisschop. 1984. Delayed neuropathy by the organophosphorus nerve agents soman and tabun. Arch. 

OP pesticides-induced delayed peripheral neuropathy can be caused by nerve agents only at doses many times greater than the LD50 (Davis et al, 1960)... 

OPs are known to induce time-delayed neurotoxicity. This is due to the inhibition of an esterase in nerve tissue, neuropathy target esterase (NTE), that is also found in muscle and blood cells. The NTE level in the blood is an indicator of the inhibition of the enzyme. Inhibition of NTE and aging, the process of following the OP binding to an active esterase site that prevents the reactivation of the site, is important for selection of an antidote against certain OP nerve agents. It is of primary concern for Novichok agent. There is little information available on OP-caused neurotoxicity and the cardiac toxicity. 

Small doses of nerve agents in animals can produce tolerance. They have also been demonstrated to produce neuropathies, myopathies, and delayed neurotoxicity in addition to their classical cholinergic effects. In rats, acute administration of nerve agents in subconvulsive doses produced tumors and hind-limb adduction. In animals, nerve agents can also cause behavioral as well as cardiac effects. 

Willems JL, Nicaise M, DeBisschop HC Delayed neuropathy by the organophosphorus nerve agents soman and tabun. Arch Toxicol 55 76-77, 1984 Xintaras C, Burg JR, Tanaka S, et al NIOSH Health Survey of Velsicol Pesticide Workers Occupational Exposure to Leptophos and Other Chemicals. Cincinnati, OH, U.S. Department of Health, Education, and Welfare, 1978 Zwiener RJ, Ginsburg CM Organophosphate and carbamate poisoning in infants and children. Pediatrics 81 121-126, 1988... 

Many OP pesticides produce delayed peripheral neuropathy, a phenomenon known for more than 50 years, whereas nerve agents have caused polyneuropathy in animals only at doses manifold greater than the LDjq— a phenomenon only seen in the presence of massive pretreatment and therapy with atropine and oxime. ... 

No review of subacute, subchronic, or chronic toxicity of chemical warfare nerve agents would be complete without discussion of the significant paper by Munro et al. that reviewed both animal and human studies of the nerve agents tabun (GA), sarin (GB), and VX. These studies included subacute, subchronic, and chronic toxicity studies in animals. Special attention was paid to the phenomenon of Organophosphorus-Induced Delayed Neuropathy (OPIDN). Reproductive toxicity and carcinogenicity tests were reviewed as well as in vitro studies of mutagenicity. Munro et al. s findings can be summarized as follows ... 

A continuing area of public concern regarding nerve agent exposure is the possibility of chronic neurological effects, particularly delayed neuropathy, given that neuropathic... 

Willems, J. L., Narcaise, M and EteBi.sschop, H. C, (1984). Delayed neuropathy by the organophosphorous nerve agents soman and labuo. Arch. Toxicol. 55,76-77. 

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