De Ontwikkeling van een PBPK Model voor VX; Stand van Zaken V013-813 en 207C (The Development of a PBPK Model for VX: Status Report)

As a follow-up on the development of the PBPK model for soman in the guinea pig and man a new model is being developed for VX. This report describes in short the work and results which has led to this model. Based on the Physiology (Physiologically-Based) of the investigated species the 'fate&#...

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Bibliographic Details
Main Author: Trap, H C
Format: Report
Language:English
Subjects:
AQ F07-11-11540
BLOOD
Chemical, Biological and Radiological Warfare
COMPUTERIZED SIMULATION
DERMAL EXPOSURE
DUTCH LANGUAGE
EXPOSURE(PHYSIOLOGY)
FOREIGN REPORTS
GUINEA PIGS
INTOXICATION
NETHERLANDS
PBPK(PHYSIOLOGICALLY BASED PHARMACOKINETIC)
PHARMACOKINETICS
SKIN(ANATOMY)
TOXICOKINETICS
Toxicology
VX AGENT
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Summary:As a follow-up on the development of the PBPK model for soman in the guinea pig and man a new model is being developed for VX. This report describes in short the work and results which has led to this model. Based on the Physiology (Physiologically-Based) of the investigated species the 'fate' or kinetics (Pharmaco Kinetics) of a compound can be predicted after an intoxication in several organs or compartments by using a computer simulation model. The toxicokinetics of the nerve agent VX are fundamentally different from those of the nerve agents sarin or soman. Especially the persistent character of VX in blood at equitoxic doses is apparent. Animal experiments have shown the presence of toxicologically relevant concentrations of VX in blood a long time after intoxication. A number of input parameters need to be obtained either through literature searches or by research. The 6-compartment model for soman was adapted and expanded with an additional compartment, the skin. Also the reactions with the enzymes, AChE, BuChE and CaE were described individually. With the implementation of a skin compartment it becomes possible to simulate dermal exposure scenarios. Using this model and the available set of input parameters it is not yet possible to simulate the intravenous kinetics of VX in the normal' guinea pig. After adapting the numbers of slow binding sites (CaE) the toxicokinetics in the hairless guinea pig are simulated very well. Some preliminary simulations of percutaneuos exposure also show a reasonable fit of the VX toxicokinetics in the blood of the hairless guinea pig. Text in Dutch. Abstracts in Dutch and English. The original document contains color images.