Nerve agents OPIDN

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... 

GA, a unitary chemical munition, inhibits AChE, the enzyme responsible for the breakdown of the neurotransmitter ACh. When inhaled, its toxicity is half that of sarin. It depresses plasma and RBC-AChE activities significantly in the blood. At 20-25% of red blood cell AChE baseline, the effect of the nerve agent becomes noticeable. There is no evidence of systemic toxicity other than the cholinesterase activity (Parker et al, 1990 Munro et al, 1994). GA has not been shown to produce OPIDN except at extremely high doses. The cardiac effect of GA conforms to OP-caused arrhythmias and AV block. 

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. 

In conhast to conventional nerve agents, DN agents produce permanent neurological dysfunction in the form of OPIDN rather than cholinergic toxicity and death (Richardson, 2005). Like conventional nerve agents, DN agents are OP compounds of pentavalent phosphorus that are readily synthesized, but they are designed to inactivate... 

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 ... 

For nerve agent VX, no evidence for likely development of OPIDN was found. VX exposure sufficient to significantly depress RBC-AChE activity produced no subchronic toxicity, no evidence of carcinogenicity was found, and based on multiple studies, VX was not considered a potential mutagen or a teratogen. 

---