INHALATION TOXICOKINETICS OF SOMAN STEREOISOMERS IN THE ATROPINIZED GUINEA-PIG WITH NOSE-ONLY EXPOSURE TO SOMAN VAPOR

The toxicokinetics of the four stereoisomers of the nerve agent C(+/-) P(+/-)-soman were studied in anesthetized, atropinized guinea pigs for nose-only exposure to soman vapor. During exposure the respiratory mi nute volume (RMV) and respiratory frequency (RF) were monitored. Blood samples were taken for chiral gas chromatographic analysis of the con centrations of nerve agent stereoisomers and for measurement of the pr ogressive inhibition of acetylcholinesterase (AChE). The animals were exposed for 4-8 min to 0.4-0.8 LCt50 of C(+/-)P(+/-)soman. Concentrati ons of the P(-)-isomers increased rapidly during exposure, up to sever al nanograms per milliliter of blood. Mathematical equations describin g the concentration-time courses of the P(-)-isomers were obtained by nonlinear regression. The kinetics were mathematically described as a discontinuous process, with a monoexponential equation for the exposur e period and a two-exponential equation for the postexposure period. T he absorption phase of C(+)P(-)-soman lagged behind that of the C(-)P( -)-isomer, presumably due to preferential covalent binding at as yet u nidentified binding sites. The terminal half-life observed after nose- only exposure is longer than that observed after an equitoxic iv bolus administration, which suggests the presence of a depot in the upper r espiratory tract from which absorption continues after termination of the exposure. Two types of nonlinearity of the toxicokinetics were obs erved, i.e., with dose and with exposure time. The AChE activity was r apidly inhibited during exposure to the nerve agent vapor. There were no soman-related effects on RMV and RF. The toxicokinetics of the soma n stereoisomers observed for nose-only exposure are compared with thos e determined for iv bolus and sc administration. (C) 1998 Academic Pre ss.