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Combining in vitro embryotoxicity data with physiologically based kinetic (PBK) modelling to define in vivo dose–response curves for developmental toxicity of phenol in rat and human

  • Toxicokinetics and Metabolism
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Abstract

In vitro assays are often used for the hazard characterisation of compounds, but their application for quantitative risk assessment purposes is limited. This is because in vitro assays cannot provide a complete in vivo dose–response curve from which a point of departure (PoD) for risk assessment can be derived, like the no observed adverse effect level (NOAEL) or the 95 % lower confidence limit of the benchmark dose (BMDL). To overcome this constraint, the present study combined in vitro data with a physiologically based kinetic (PBK) model applying reverse dosimetry. To this end, embryotoxicity of phenol was evaluated in vitro using the embryonic stem cell test (EST), revealing a concentration-dependent inhibition of differentiation into beating cardiomyocytes. In addition, a PBK model was developed on the basis of in vitro and in silico data and data available from the literature only. After evaluating the PBK model performance, effective concentrations (ECx) obtained with the EST served as an input for in vivo plasma concentrations in the PBK model. Applying PBK-based reverse dosimetry provided in vivo external effective dose levels (EDx) from which an in vivo dose–response curve and a PoD for risk assessment were derived. The predicted PoD lies within the variation of the NOAELs obtained from in vivo developmental toxicity data from the literature. In conclusion, the present study showed that it was possible to accurately predict a PoD for the risk assessment of phenol using in vitro toxicity data combined with reverse PBK modelling.

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Acknowledgments

This study was funded through the programme Alternatives to Animal Experiments III of the Netherlands Organisation for Health Research and Development (ZonMw) (Project Number 114011002).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE, Wageningen, The Netherlands

    Marije Strikwold, Bert Spenkelink, Ruud A. Woutersen, Ivonne M. C. M. Rietjens & Ans Punt

  2. Van Hall Larenstein, University of Applied Sciences, PO Box 1528, 8901 BV, Leeuwarden, The Netherlands

    Marije Strikwold

  3. TNO Innovation for Life, PO Box 360, 3700 AJ, Zeist, The Netherlands

    Ruud A. Woutersen

  4. WUR/TNO Centre for Innovative Toxicology, PO Box 8000, 6700 EA, Wageningen, The Netherlands

    Ruud A. Woutersen & Ivonne M. C. M. Rietjens

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  1. Marije Strikwold
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Correspondence to Marije Strikwold.

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Strikwold, M., Spenkelink, B., Woutersen, R.A. et al. Combining in vitro embryotoxicity data with physiologically based kinetic (PBK) modelling to define in vivo dose–response curves for developmental toxicity of phenol in rat and human. Arch Toxicol 87, 1709–1723 (2013). https://doi.org/10.1007/s00204-013-1107-4

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