PHYSIOLOGICALLY BASED MODELING OF THE MAXIMAL EFFECT OF METABOLIC INTERACTIONS ON THE KINETICS OF COMPONENTS OF COMPLEX CHEMICAL MIXTURES
作者:
Sami Haddad, Ginette Charest-Tardif, Kannan Krishnan,
期刊:
Journal of Toxicology and Environmental Health, Part A
(Taylor Available online 2000)
卷期:
Volume 61,
issue 3
页码: 209-223
ISSN:1528-7394
年代: 2000
DOI:10.1080/00984100050131350
出版商: Informa UK Ltd
数据来源: Taylor
摘要:
The objective of this study was to predict and validate the theoretically possible, maximal impact of metabolic interactions on the blood concentration profile of each component in mixtures of volatile organic chemicals (VOCs) [dichloromethane (DCM), benzene (BEN), trichloroethylene (TCE), toluene (TOL), tetrachloroethylene (PER), ethylbenzene (EBZ), styrene (STY), as well as para, ortho-, and meta- xylene ( p -XYL, o -XYL, m -XYL)] in the rat. The methodology consisted of: (1) obtaining the validated, physiologically based toxicokinetic (PBTK) model for each of the mixture components from the literature, (2) substituting the Michaelis?Menten description of metabolism with an equation based on the hepatic extraction ratio ( E ) for simulating the maximal impact of metabolic interactions (i.e., by setting E to 0 or 1 for simulating maximal inhibition or induction, respectively), and (3) validating the PBTK model simulations by comparing the predicted boundaries of venous blood concentrations with the experimental data obtained following exposure to various mixtures of VOCs. All experimental venous blood concentration data for 9 of the 10 chemicals investigated in the present study (PER excepted) fell within the boundaries of the maximal impact of metabolic inhibition and induction predicted by the PBTK model. The modeling approach validated in this study represents a potentially useful tool for screening/identifying the chemicals for which metabolic interactions are likely to be important in the context of mixed exposures and mixture risk assessment.
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