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 minute volume (RMV) and respiratory frequency (RF) were monitored. Blood samples were taken for chiral gas chromatographic analysis of the concentrations of nerve agent stereoisomers and for measurement of the progressive inhibition of acetylcholinesterase (AChE). The animals were exposed for 4-8 min to 0.4-0.8 LCt50 of C(+/-)P(+/-)-soman. Concentrations of the P(-)-isomers increased rapidly during exposure, up to several nanograms per milliliter of blood. Mathematical equations describing 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 exposure period and a two-exponential equation for the postexposure period. The absorption phase of C(+)P(-)-soman lagged behind that of the C(-)P(-)-isomer, presumably due to preferential covalent binding at as yet unidentified 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 respiratory tract from which absorption continues after termination of the exposure. Two types of nonlinearity of the toxicokinetics were observed, i.e., with dose and with exposure time. The AChE activity was rapidly inhibited during exposure to the nerve agent vapor. There were no soman-related effects on RMV and RF. The toxicokinetics of the soman stereoisomers observed for nose-only exposure are compared with those determined for iv bolus and sc administration.
TNO Prins Maurits Laboratory, Rijswijk, 2280 AA, The Netherlands. langenberg@pml.tno.nl
J P
JP
Langenberg
H E
HE
Spruit
H J
HJ
van der Wiel
H C
HC
Trap
R B
RB
Helmich
W W
WW
Bergers
H P
HP
van Helden
H P
HP
Benschop
D000042:Absorption; D000110:Acetylcholinesterase / Q000097:blood; D000280:Administration, Inhalation; D000281:Administration, Intranasal; D000818:Animals; D001273:Atmosphere Exposure Chambers; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006207:Half-Life; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007928:Lethal Dose 50; D008297:Male; D008433:Mathematics; D012044:Regression Analysis; D012119:Respiration / Q000187:drug effects*; D012999:Soman / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D013237:Stereoisomerism
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D012999:Soman; D000110:Acetylcholinesterase