A biologically based pharmacodynamic model for lipid peroxidation stimulated by trichloroethylene in vitro

It is often necessary for chemical risk assessment to determine a quantitative relationship between the internal dose of a chemical and its biological effect. The tool best suited for this purpose is a biologically based pharmacodynamic (BBPD) model. Such a BBPD model was developed previously (10) t...

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Bibliographic Details
Published in:Journal of biochemical and molecular toxicology 1999, Vol.13 (3-4), p.205-214
Main Authors: Byckowski, Janusz Z., Channel, Stephen R., Miller, Clay R.
Format: Article
Language:English
Subjects:
Algorithms
Animals
free radicals
lipid peroxidation
Lipid Peroxidation - drug effects
liver slices
Male
mathematical model
Mice
Models, Biological
trichloroethylene
Trichloroethylene - pharmacology
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Summary:It is often necessary for chemical risk assessment to determine a quantitative relationship between the internal dose of a chemical and its biological effect. The tool best suited for this purpose is a biologically based pharmacodynamic (BBPD) model. Such a BBPD model was developed previously (10) to simulate chemically induced lipid peroxidation, and it was experimentally calibrated in precision‐cut mouse liver slices in vitro. The BBPD model simulated formation of lipid hydroperoxides and thiobarbituric acid reactive substances (TBARS) over time and was originally calibrated with different concentrations of tert‐butyl hydroperoxide and bromotrichloromethane. The objective of the present work is to refine this BBPD model so it can describe the kinetics and the dose response of lipid peroxidation induced by a weakly pro‐oxidant chemical, trichloroethylene (TCE). The chemical‐dependent model parameters were optimized to reflect the chemistry of TCE. Two basic algorithms, linear and square root, for the description of stoichiometric free radical production from TCE were tested. Predictions with the square root algorithm fit the experimental data employing TBARS as an end point better than those by the linear algorithm. The calibrated BBPD model will be used to support our future mathematical description of TCE pharmacodynamics in vivo. © 1999 John Wiley & Sons, Inc. J Biochem Toxicol 13: 205–214, 1999
ISSN:1095-6670
1099-0461
DOI:10.1002/(SICI)1099-0461(1999)13:3/4<205::AID-JBT11>3.0.CO;2-B