Physiologically Based Pharmacodynamic Modeling of Chemically Induced Oxidative Stress.
Abstract
Health risk from chemicals depends on both the extent of exposure and a dose-response relationship, which is reflecting, in turn, the mode of action of chemicals. For quantitative modeling of the mode of action it is necessary to determine the exact chain of events of the chemical interaction with the biological system. To provide a tool potentially useful for risk characterization of pro-oxidant chemicals, a quantitative mathematical model (physiologically based pharmacodynamic or PBPD model) describing biological effects within the target organ was constructed In a way compatible with traditional pharmacokinetic (PBPK) models which describe the internal, local dose of a chemical. Based on the available literature and our own experimental data, the three basic modes of action of pro-oxidant chemicals were modeled and simulated in silico: i. lipid peroxidation (expressed by the formation of thiobarbituric acid reactive substance (TBARS) and the exhalation of ethane); ii. specific interaction of free radicals with homogenous cellular targets; and iii. random interaction of free radicals with multiple cellular targets. Based on the dose-response characteristic verified in vitro, a PBPD model of chemically initiated oxidative stress was developed and calibrated in B6C3Fl mice. The model consisted of three major modules. At first, a biologically based module for chemically induced lipid peroxidation was developed and calibrated in vitro using precision cut mouse liver slices. Next, the parameters describing the mechanism of action of pro-oxidant chemicals were applied to the physiologically based pharmacodynamic module describing chemically induced lipid peroxidation in mice in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1997
- Accession Number
- ADA362299
Entities
People
- C. D. Flemming
- C. R. Miller
- J. Z. Byczkowski
- M. A. Curran
- W. J. Schmidt