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4093082 
Journal Article 
Cholinesterase And Sarin (GB) Regeneration Profile Following Low Level GB In Guinea Pigs: Usefulness For PBPK Modeling 
Lumley, LA; Whalley, C; Mcguire, J; O'Malley, M; D'Ambrozio, A; Robison, C; Mason, E; Krauthauser, C; Jakubowski, E; Mcavoy, S; Et al 
2005 
1 
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 
TOX/5000910 
84 
1-S 
English 
Physiologically based pharmacokinetic (PBPK) modeling may be a useful risk assessment tool for interspecies extrapolation and prediction of response to chemical warfare nerve agent (CWNA) exposure. The current study was performed to integrate CWNA toxicity data across different routes of exposure in guinea pigs. Animals were given a single subcutaneous (sc) dose of GB (0.1 and amp; 0.4 LD50). Arterial blood was drawn from the right carotid artery at time intervals between 1 min and 4 hr post-exposure. Blood levels of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and blood and tissue levels of regenerated sarin (rGB) were assayed. AChE and BuChE were significantly inhibited 1 min following 0.4LD50 GB, and remained inhibited at 4 hr, with the greatest level of inhibition at 40 min. Following 0.1 LD50 GB, AChE was decreased at 40 and 60 min, while BuChE was not affected. In plasma, rGB reached maximal levels 20 min after 0.1 and 0.4 LD50 GB and gradually declined over 4 hr. In red blood cells (RBC), rGB reached maximal levels 10 min after 0.4 LD50 GB exposure and remained elevated over the course of 4 hr; however, RBC rGB was not as great as plasma rGB. After 0.1 LD50 GB exposure, rGB in RBC was not significantly elevated. These findings suggest that both plasma and RBC measures of rGB and cholinesterase indicate low level exposure, but that plasma rGB and RBC AChE may be more sensitive measures of extremely low level GB exposure. In the 2-4 hr after low level GB exposure, the highest levels of rGB were in lung and kidney. A future goal is to compare the pharmacokinetics of low dose GB in guinea pigs exposed by acute inhalation with our current measures following sc exposure. PBPK modeling will then be used to extrapolate these findings to different routes of administration and to compare similar exposures in other species.