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Physiologically based modeling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures.
J Toxicol Environ Health A. 2000 Oct 13; 61(3):209-23.JT

Abstract

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.

Authors+Show Affiliations

Groupe de recherche en toxicologie humaine (TOXHUM), Faculté de médecine, Université de Montréal, Québec, Canada.No affiliation info availableNo affiliation info available

Pub Type(s)

Research Support, Non-U.S. Gov't
Validation Study

Language

eng

PubMed ID

11036509

Citation

Haddad, S, et al. "Physiologically Based Modeling of the Maximal Effect of Metabolic Interactions On the Kinetics of Components of Complex Chemical Mixtures." Journal of Toxicology and Environmental Health. Part A, vol. 61, no. 3, 2000, pp. 209-23.
Haddad S, Charest-Tardif G, Krishnan K. Physiologically based modeling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures. J Toxicol Environ Health A. 2000;61(3):209-23.
Haddad, S., Charest-Tardif, G., & Krishnan, K. (2000). Physiologically based modeling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures. Journal of Toxicology and Environmental Health. Part A, 61(3), 209-23.
Haddad S, Charest-Tardif G, Krishnan K. Physiologically Based Modeling of the Maximal Effect of Metabolic Interactions On the Kinetics of Components of Complex Chemical Mixtures. J Toxicol Environ Health A. 2000 Oct 13;61(3):209-23. PubMed PMID: 11036509.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Physiologically based modeling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures. AU - Haddad,S, AU - Charest-Tardif,G, AU - Krishnan,K, PY - 2000/10/19/pubmed PY - 2001/2/28/medline PY - 2000/10/19/entrez SP - 209 EP - 23 JF - Journal of toxicology and environmental health. Part A JO - J Toxicol Environ Health A VL - 61 IS - 3 N2 - 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. SN - 1528-7394 UR - https://www.unboundmedicine.com/medline/citation/11036509/Physiologically_based_modeling_of_the_maximal_effect_of_metabolic_interactions_on_the_kinetics_of_components_of_complex_chemical_mixtures_ L2 - https://www.tandfonline.com/doi/full/10.1080/00984100050131350 DB - PRIME DP - Unbound Medicine ER -