ABSTRACT
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 II. Nerve Agent Stereoisomers: Chiral Analysis, Isolation,
and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 III. Trace Analysis of Nerve Agents in Biological Samples . . . . . . . . . . . . . . . . 30 IV. Intravenous Toxicokinetics of Soman and Sarin in Various Species. . . . . . . 33 V. Subcutaneous Toxicokinetics of Soman . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
VI. Inhalation Toxicokinetics of Soman and Sarin . . . . . . . . . . . . . . . . . . . . . . . 45 VII. Inhalation Toxicokinetics of Soman upon Low-Level Exposure . . . . . . . . . 52
VIII. Elimination Pathways of Phosphofluoridates . . . . . . . . . . . . . . . . . . . . . . . . 57 A. Elimination by Hydrolytic Degradation . . . . . . . . . . . . . . . . . . . . . . . . . 58 B. Elimination by Covalent Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 C. Renal Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 D. Elimination Products as Tools for Retrospective
Detection of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 IX. Physiologically-Based Modeling of the Toxicokinetics
of Soman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 X. The Influence of Prophylaxis and Therapy upon the
Toxicokinetics of Soman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 XI. Toxicokinetics of V Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
XII. Future Directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Toxicokinetic studies of nerve agents deal with the in vivo absorption, distribution, and elimination of these agents as a function of animal species, route of administration, dose, and time after administration. Such studies are essential to provide a quantitative basis for the toxicology of nerve agents and, in combination with toxicodynamic studies, are the starting point for development of causal treatment of intoxications with these agents. Toxicodynamic studies of nerve agents have been
the subject of a long and rich tradition of investigations since their introduction as potential agents of chemical warfare during World War II. These studies have led to (e.g., the development of prophylaxis of intoxication based on partial inhibition of cholinesterase activity with carbamates and therapy of intoxication through administration of the muscarinic cholinergic antagonist atropine) reactivation of phosphylated cholinesterases with oximes, often in combination with the administration of a central nervous depressant in order to suppress convulsions and other central effects.
