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Physiologically based modeling of the toxicokinetic interaction between toluene and m-xylene in the rat.
Toxicol Appl Pharmacol. 1993 Jun; 120(2):266-73.TA

Abstract

The present study was undertaken to investigate the mechanism of toxicokinetic interaction between toluene (TOL) and m-xylene (XYL) in vivo in the male Sprague-Dawley rat by physiologically based toxicokinetic (PBTK) modeling. First, the metabolic constants (Vmax and Km) were determined for TOL and XYL individually by conducting a series of closed-chamber inhalation exposures of three rats to starting concentrations of 500 to 4000 ppm. The values of Km (TOL, 0.55 mg/liter; XYL, 0.20 mg/liter) and Vmax (TOL, 4.8 mg/hr/kg; XYL, 8.4 mg/hr/kg) were obtained following best visual fit of PBTK model simulations to experimental data. Then using the same experimental set-up, rats were exposed to three different mixtures of both solvents (500 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 500 ppm XYL). The data from the time course of chamber solvent concentrations were analyzed with a binary chemical mixture PBTK model that had four mechanistic hypotheses of metabolic interaction (i.e., no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition) quantitatively defined in the liver compartment. The validity of the various model descriptions was verified with open-chamber inhalation exposure data on toxicokinetics of TOL and XYL. Overall, the results of this combined experimental and modeling approach are consistent with a competitive metabolic inhibition between XYL and TOL in the rat.

Authors+Show Affiliations

Département de médecine du travail et d'hygiène du milieu, Faculté de médecine, Université de Montréal, PQ, Canada.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8511796

Citation

Tardif, R, et al. "Physiologically Based Modeling of the Toxicokinetic Interaction Between Toluene and M-xylene in the Rat." Toxicology and Applied Pharmacology, vol. 120, no. 2, 1993, pp. 266-73.
Tardif R, Laparé S, Krishnan K, et al. Physiologically based modeling of the toxicokinetic interaction between toluene and m-xylene in the rat. Toxicol Appl Pharmacol. 1993;120(2):266-73.
Tardif, R., Laparé, S., Krishnan, K., & Brodeur, J. (1993). Physiologically based modeling of the toxicokinetic interaction between toluene and m-xylene in the rat. Toxicology and Applied Pharmacology, 120(2), 266-73.
Tardif R, et al. Physiologically Based Modeling of the Toxicokinetic Interaction Between Toluene and M-xylene in the Rat. Toxicol Appl Pharmacol. 1993;120(2):266-73. PubMed PMID: 8511796.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Physiologically based modeling of the toxicokinetic interaction between toluene and m-xylene in the rat. AU - Tardif,R, AU - Laparé,S, AU - Krishnan,K, AU - Brodeur,J, PY - 1993/6/1/pubmed PY - 1993/6/1/medline PY - 1993/6/1/entrez SP - 266 EP - 73 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 120 IS - 2 N2 - The present study was undertaken to investigate the mechanism of toxicokinetic interaction between toluene (TOL) and m-xylene (XYL) in vivo in the male Sprague-Dawley rat by physiologically based toxicokinetic (PBTK) modeling. First, the metabolic constants (Vmax and Km) were determined for TOL and XYL individually by conducting a series of closed-chamber inhalation exposures of three rats to starting concentrations of 500 to 4000 ppm. The values of Km (TOL, 0.55 mg/liter; XYL, 0.20 mg/liter) and Vmax (TOL, 4.8 mg/hr/kg; XYL, 8.4 mg/hr/kg) were obtained following best visual fit of PBTK model simulations to experimental data. Then using the same experimental set-up, rats were exposed to three different mixtures of both solvents (500 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 500 ppm XYL). The data from the time course of chamber solvent concentrations were analyzed with a binary chemical mixture PBTK model that had four mechanistic hypotheses of metabolic interaction (i.e., no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition) quantitatively defined in the liver compartment. The validity of the various model descriptions was verified with open-chamber inhalation exposure data on toxicokinetics of TOL and XYL. Overall, the results of this combined experimental and modeling approach are consistent with a competitive metabolic inhibition between XYL and TOL in the rat. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/8511796/Physiologically_based_modeling_of_the_toxicokinetic_interaction_between_toluene_and_m_xylene_in_the_rat_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(83)71111-7 DB - PRIME DP - Unbound Medicine ER -