Toxicokinetics of soman in cerebrospinal fluid and blood of anaesthetized pigs.
The toxicokinetics of the four stereoisomers of the nerve agent C(+/-)P(+/-)-soman was analysed in cerebrospinal fluid (CSF) and blood in anaesthetized, spontaneously breathing pigs during a 90-min period after injection of soman. The pigs were challenged with different intravenous (i.v.) doses of C(+/-)P(+/-)-soman corresponding to 0.75-3.0 LD50 (4.5, 9.0 and 18 microg/kg in a bolus injection and 0.45 microg/kg per min as a slow infusion). Artificial ventilatory assistance was given if, after soman intoxication, the respiratory rate decreased below 19 breaths/min. Blood samples were taken from a femoral artery and CSF samples from an intrathecal catheter. The concentrations of the soman isomers were determined by gas chromatography coupled with high resolution mass spectrometry. All four isomers of soman were detected in both blood and CSF samples. The relatively non-toxic C(+/-)P(+) isomers disappeared from the blood stream and CSF within the first minute, whereas the levels of the highly toxic C(+/-)P(-) isomers could be followed for longer, depending on the dose. Concurrently with the soman analyses in blood and CSF, cholinesterase (ChE) activity and cardiopulmonary parameters were measured. C(+/-)P(-) isomers showed approx. 100% bioavailability in CSF when C(+/-)P(+/-)-soman was given i.v. as a bolus injection. In contrast, C(+/-)P(-) isomers displayed only 30% bioavailability in CSF after slow i.v. infusion of soman. The ChE activity in blood decreased below 20% of baseline in all groups of pigs irrespective of the soman dose. The effect of soman intoxication on the respiratory rate, however, seems to be dose-dependent and the reason for ventilatory failure and death. Artificial ventilation resulted in survival of the pigs for the time-period studied.
Defense Research Establishment, Department of Biomedicine, Umeå, Sweden.
A
A
Göransson-Nyberg
S A
SA
Fredriksson
B
B
Karlsson
M
M
Lundström
G
G
Cassel
D000758:Anesthesia; D000818:Animals; D001711:Biotransformation; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid / Q000633:toxicity*; D002802:Cholinesterases / Q000097:blood / Q000134:cerebrospinal fluid; D002946:Cisterna Magna / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006439:Hemodynamics / Q000187:drug effects; D007536:Isomerism; D007700:Kinetics; D007928:Lethal Dose 50; D008297:Male; D015656:Respiratory Mechanics / Q000187:drug effects; D012999:Soman / Q000097:blood / Q000134:cerebrospinal fluid / Q000633:toxicity*; D013552:Swine
D002800:Cholinesterase Inhibitors; D012999:Soman; D002802:Cholinesterases