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A physiologically based toxicokinetic modelling approach to predict relevant concentrations for in vitro testing

  • Regulatory Toxicology
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Abstract

Our study was performed in the context of an in vitro primary hepatic cell culture as an alternative for the in vivo cancerogenic bioassay. The 29 substances which are to be used in the in vitro primary hepatic cell culture have been tested in 2-year bioassays and a 14-day short term study. The aim of this modelling study was to simulate the concentration–time profile of the compounds when given by the oral route at the doses tested in the previous studies taking into account the percentage of the dose absorbed. The model contained seven tissue compartments with uptake from the gastrointestinal tract into the portal vein. Because the primary hepatic cell culture is metabolically competent and the primary interest was to model the concentration in the portal vein, the hepatic vein and the systemic circulation (blood) in the beginning we did not include elimination. Partitioning between blood and tissues was calculated according to a published biologically based algorithm. The substances’ kinetic profile differed according to their blood: tissue partitioning. Maximal concentrations in portal vein, hepatic vein and the blood depended mainly on the dose and the fraction absorbed which were the most critical parameters in this respect. Our study demonstrates an application of BPTK modelling for the purpose to simulate concentrations for planning the doses for an in vitro study. BPTK modelling seems to be a better approach than using data from in vitro studies on cytotoxicity.

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Acknowledgments

The authors express their thanks to Walter Schmitt who provided help for the calculation of partition coefficients.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Federal Institute for Risk Assessment (BfR), Thielallee 88-92, 14195, Berlin, Germany

    Hans Mielke & Ursula Gundert-Remy

  2. Department of Toxicology, Berlin Medical School, Charité, Berlin, Germany

    Lennart T. Anger, Ralf Stahlmann & Ursula Gundert-Remy

  3. Leibniz Research Center for Working Environment and Human Factors (IfADo), Dortmund, Germany

    Markus Schug & Jan G. Hengstler

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  1. Hans Mielke
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  2. Lennart T. Anger
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  3. Markus Schug
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  6. Ursula Gundert-Remy
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Correspondence to Hans Mielke.

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Mielke, H., Anger, L.T., Schug, M. et al. A physiologically based toxicokinetic modelling approach to predict relevant concentrations for in vitro testing. Arch Toxicol 85, 555–563 (2011). https://doi.org/10.1007/s00204-010-0612-y

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  • DOI: https://doi.org/10.1007/s00204-010-0612-y

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