Nerve agents modeling

Menger, F. M. and Rourk, M. J. 1999. Deactivation of mustard and nerve agent models via low-temperature microemulsions. Langmuir, 15, 309-313. 

W. Kolodziejczyk et al., Probing the role of P=0 stretching mode enhancement in nerve-agent sensors Simulation of the adsorption of diisopropylfluorophosphate on the model MgO and CaO surfaces. Chem. Phys. Lett. 450, 138-143 (2007)... 

Furlong, C.D., W.F. Li, L.G. Costa, R.J. Richter, D.M. Shih, and A.J. Lusis. 1998. Genetically determined susceptibility to organophosphorus insecticides and nerve agents Developing a mouse model for die human PONl polymorphism. Neurotoxicology 19 645-650. 

Other industrially important uses of P4O10 include the reactions with ethers, an example of which is the formation of triethyl phosphate via reaction with diethyl ether followed by pyrolysis. The product (which has a worldwide production of many thousands of tons per annum) finds use as ketene synthesis, a flame retardant, and a plasticizer within the plastics industry a less conventional use is as a simulant for the sarin when modeling situations involving the latter nerve agent. 

ATSDR (2008). ToxFAQs for nerve agents. Retrieved May 5, 2008 from http //www.atsdr.cdc.gov/tfactsl66.html Babin, M.C., Ricketts, K. (2000). Systemic administration of candidate antivesicants to protect against topically applied sulfur mustard in the mouse ear vesicant model (MEVM). J. Appl. Toxicol. 20, Suppl. 1 S141-4. 

Beck, J.M., Hadad, C.M. (2008). Hydrolysis of nerve agents by model nucleophiles a computational study. Chem. Biol. Interact. May 2. (Epub ahead of print)... 

In animal models, clonidine has also been reported to prevent nerve agent-induced seizures (Buccafusco et al, 1988). Prophylactic use of clonidine may be limited by the marked ataxia and sedation produced by this drug in effective concentrations. 

These selected representative examples indicate that concentration-time profiles are variable despite common underlying basic chemical reactions of hydrolysis and adduct formation. Despite improving medical treatment of nerve agent poisoning the concurrence of numerous physiological and pathophysiological parameters should be understood. Therefore, establishment of a descriptive and predictive model is of importance for the medical defense of OP compounds. 

CWAs are represented by any one of a number of chemicals exhibiting a very high toxicity by various mechanisms. The present Handbook exhibits CWAs with structures as simple as carbon monoxide (CO) and as complex as botulinum toxin or ricin proteins. While this chapter could address the development of PBPK models of CWAs in general, the focus will primarily be on the organophosphate (OP)-based nerve agents typically represented by sarin (GB - isopropyl methylfluoro-phosphonate). 

Most attempts at describing CWA PK and PD have used classical kinetic models that often fit one set of animal experimental data, at lethal doses, with extrapolation to low-dose or repeated exposure scenarios having limited confidence. This is due to the inherent nonlinearity in high-dose to low-dose extrapolations. Also, the classical approach is less adept at addressing multidose and multiroute exposure scenarios, as occurs with agents like VX, where there is pulmonary absorption of agent, as well as dermal absorption. PBPK models of chemical warfare nerve agents (CWNAs) provide an analytical approach to address many of these limitations. 

Physiologically Based Pharmacokinetic/ Pharmacodynamic Modeling of Countermeasures to Nerve Agents... 

There is little yet in the literature approaching a complete model of the kinetic and dynamic interaction of a nerve agent and its current (multi-agent) or potential countermeasures. There have been, however, a number of important steps in that direction, both on the level of model development and in the experimental generation of... 

We restrict our discussion here to countermeasures of nerve agents (NA), and will not discuss other chemical agents such as mustards and cyanide, and their antidotes. However, the modeling ideas outlined here can also apply to other agents. 

---