Sarin delayed neuropathy

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... 

Bucci, T.J., R.M. Parker, and P.A. Gosnell. 1992. Toxicity Studies on Agents GB and GD (Phase II) Delayed Neuropathy Study of Sarin, Type II, in SPF White Leghorn Chickens. Technical Report. NCTR-TR-478,479. DTICAD-A257357. Prepared by the National Center for Toxicological Research, Jefferson, Ark., for U.S. Army Biomedical Research and Development Laboratory, Fort Detrick, Frederick, Md. 

Davies, D.R. and Holland, P., 1972. Effect of oximes and atropine upon the development of delayed neuropathy in chickens following poisoning by DFP and sarin, Biochem. Pharmacol., 21(3), pp. 145-51. 

Parker RM, Crowell JA, Bucci TJ et al. (1988). Negative delayed neuropathy study in chickens after treatment with isopropyl methylphosphonofluori-date (sarin, type 1). Toxicologist, 8, 248. 

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 ... 

Bucci TJ, Parker RM, Cosnell PA. Toxicity Studies on Agents GB and GD (Phase II) Delayed Neuropathy Study of Sarin, Type I, in SPF White Leghorn Chickens. Jefferson, Ark National Center for Toxicological Research 1992. 

Delayed peripheral neurotoxicity has been reported in animal studies. Soman produced severe delayed neuropathy in the atropinized hen assay at 1.5 mg/kg (Willems et al., 1984). Sarin, tabim, and VX cause postimplantation mortality and fetotoxicity (HSDB, 2008 RTECS, 2008). 

The structure-activity requirements for inhibition of acetylcholinesterase and NTE are different this is demonstrated by the fact that many OPs with powerful anticholinesterase properties do not have the capability to produce OPIDP. Thus, the OP chemical warfare nerve agents that are very potent anticholinesterases, have little propensity to cause OPIDP, ° although, at supralethal doses, sarin can cause delayed neuropathy in antidote-protected chickens while tri-o-cresyl phosphate, which has little anticholinesterase activity, is powerfully neuropathic. ... 

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