Kinetics of sarin (GB) following a single sublethal inhalation exposure in the guinea pig. 2007

Christopher E Whalley, and Jeffrey M McGuire, and Dennis B Miller, and Edward M Jakubowski, and Robert J Mioduszewski, and Sandra A Thomson, and Lucille A Lumley, and John H McDonough, and Tsung-Ming A Shih
U.S. Army Edgewood Chemical Biological Center, Aberdeen Proving Ground, Maryland 21010-5424, USA. christopher.whalley@us.army.mil

To improve toxicity estimates from sublethal exposures to chemical warfare nerve agents (CWNA), it is necessary to generate mathematical models of the absorption, distribution, and elimination of nerve agents. However, current models are based on representative data sets generated with different routes of exposure and in different species and are designed to interpolate between limited laboratory data sets to predict a wide range of possible human exposure scenarios. This study was performed to integrate CWNA sublethal toxicity data in male Duncan Hartley guinea pigs. Specific goal was to compare uptake and clearance kinetics of different sublethal doses of sarin (either 0.1 x or 0.4 x LC50) in blood and tissues of guinea pigs exposed to agent by acute whole-body inhalation exposure after the 60-min LC50 was determined. Arterial catheterization allowed repeated blood sampling from the same animal at various time periods. Blood and tissue levels of acetylcholinesterase, butyrylcholinesterase, and regenerated sarin (rGB) were determined at various time points during and following sarin exposure. The following pharmacokinetic parameters were calculated from the graph of plasma or RBC rGB concentration versus time: time to reach the maximal concentration; maximal concentration; mean residence time; clearance; volume of distribution at steady state; terminal elimination-phase rate constant; and area under plasma concentration time curve extrapolated to infinity using the WinNonlin analysis program 5.0. Plasma and RBC t(1/2) for rGB was also calculated. Data will be used to develop mathematical model of absorption and distribution of sublethal sarin doses into susceptible tissues.

UI MeSH Term Description Entries
D007928 Lethal Dose 50 The dose amount of poisonous or toxic substance or dose of ionizing radiation required to kill 50% of the tested population. LD50,Dose 50, Lethal
D008297 Male Males
D006168 Guinea Pigs A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001273 Atmosphere Exposure Chambers Experimental devices used in inhalation studies in which a person or animal is either partially or completely immersed in a chemically controlled atmosphere. Atmosphere Exposure Chamber,Chamber, Atmosphere Exposure,Chambers, Atmosphere Exposure,Exposure Chamber, Atmosphere,Exposure Chambers, Atmosphere
D012524 Sarin An organophosphorus ester compound that produces potent and irreversible inhibition of cholinesterase. It is toxic to the nervous system and is a chemical warfare agent. Sarin Gas,o-Isopropylmethyl Phosphonofluoridate,ortho-Isopropylmethyl Phosphonofluoridate,Gas, Sarin,Phosphonofluoridate, o-Isopropylmethyl,Phosphonofluoridate, ortho-Isopropylmethyl,o Isopropylmethyl Phosphonofluoridate,ortho Isopropylmethyl Phosphonofluoridate
D014018 Tissue Distribution Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. Distribution, Tissue,Distributions, Tissue,Tissue Distributions
D019570 Inhalation Exposure The exposure to potentially harmful chemical, physical, or biological agents by inhaling them. Exposure, Inhalation,Exposures, Inhalation,Inhalation Exposures

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