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A Multicompartment Liver-based Pharmacokinetic Model for Benzene and its Metabolites in Mice

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Abstract

Benzene is a highly flammable, colorless liquid. Ubiquitous exposures result from its presence in gasoline vapors, cigarette smoke, and industrial processes. After uptake into the body, benzene undergoes a series of metabolic transformations to multiple metabolites that exert toxic effects on the bone marrow. We developed a physiologically based pharmacokinetic model for the uptake and elimination of benzene in mice to relate the concentration of inhaled and orally administered benzene to the tissue doses of benzene and its key metabolites. This model takes into account the zonal distribution of enzymes and metabolism in the liver rather than treating the liver as one homogeneous compartment, and considers metabolism in tissues other than the liver. Analysis was done to examine the existence and uniqueness of solutions of the system. We then formulated an inverse problem to obtain estimates for the unknown parameters; data from multiple laboratories and experiments were used. Despite the sources of variability, the model simulations matched the data reasonably well in most cases. Our study shows that the multicompartment metabolism model does improve predictions over the previous model (Cole et al. in J. Toxicol. Environ. Health, 439–465, 2001) and that in vitro metabolic constants can be successfully extrapolated to predict in vivo data for benzene metabolism and dosimetry.

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Authors and Affiliations

  1. Department of Mathematics and Computer Science, Meredith College, Raleigh, NC, USA

    Cammey C. Manning

  2. CIIT Centers for Health Research, Research Triangle Park, NC, USA

    Paul M. Schlosser

  3. Department of Mathematics, North Carolina State University, Raleigh, NC, USA

    Hien T. Tran

  4. Center for Research in Scientific Computation, North Carolina State University, Raleigh, NC, USA

    Cammey C. Manning & Hien T. Tran

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  1. Cammey C. Manning
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  2. Paul M. Schlosser
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  3. Hien T. Tran
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Correspondence to Cammey C. Manning.

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Supported via a fellowship from CIIT Centers for Health Research while she was a graduate student in the Center for Research in Scientific Computation at North Carolina State University.

Current address: U.S. EPA, NCEA, M.D. B243-01, Research Triangle Park, NC, 27711.

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Manning, C.C., Schlosser, P.M. & Tran, H.T. A Multicompartment Liver-based Pharmacokinetic Model for Benzene and its Metabolites in Mice. Bull. Math. Biol. 72, 507–540 (2010). https://doi.org/10.1007/s11538-009-9459-x

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