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Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

  • Reproductive Toxicology
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Abstract

The use of laboratory animals for toxicity testing in chemical safety assessment meets increasing ethical, economic and legislative constraints. The development, validation and application of reliable alternatives for in vivo toxicity testing are therefore urgently needed. In order to use toxicity data obtained from in vitro assays for risk assessment, in vitro concentration–response data need to be translated into in vivo dose–response data that are needed to obtain points of departure for risk assessment, like a benchmark dose (BMD). In the present study, we translated in vitro concentration–response data of the retinoid all-trans-retinoic acid (ATRA), obtained in the differentiation assay of the embryonic stem cell test, into in vivo dose–response data using a physiologically based kinetic model for rat and human that is mainly based on kinetic model parameter values derived using in vitro techniques. The predicted in vivo dose–response data were used for BMD modeling, and the obtained BMDL10 values [lower limit of the 95 % confidence interval on the BMD at which a benchmark response equivalent to a 10 % effect size (BMR10) is reached (BMD10)] for rat were compared with BMDL10 values derived from in vivo developmental toxicity data in rats reported in the literature. The results show that the BMDL10 values from predicted dose–response data differ about sixfold from the BMDL10 values obtained from in vivo data, pointing at the feasibility of using a combined in vitro–in silico approach for defining a point of departure for toxicological risk assessment.

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Abbreviations

3Rs:

Replacement, reduction and refinement

ATRA:

All-trans-retinoic acid

AUC:

Area under the concentration–time curve

BMD:

Benchmark dose

BMDL10 :

Lower limit of the 95 % confidence interval on the BMD at which a benchmark response equivalent to a 10 % effect size (BMR10) is reached (BMD10)

C max :

Maximum concentration

CYP:

Cytochrome P450

MPPGL:

Microsomal protein per gram of liver

P app :

Apparent permeability

PBK:

Physiologically based kinetic

PDMS:

Polydimethylsiloxane

POD:

Point of departure

SPME:

Solid-phase microextraction

UGT:

Uridine 5′-diphospho-glucuronosyltransferase

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Acknowledgments

The authors would like to thank Harvey Clewell (The Hamner Institute for Health Sciences, USA) and Joost Westerhout (TNO, The Netherlands) for their contribution to discussions, Wouter Vaes and Jaap Jan Stevenhagen (TNO and TNO Triskelion, The Netherlands) for their help with the SPME studies, and Nicole Clemann (Roche, Switzerland) for providing the in vivo developmental toxicity data of Bürgin and Schmitt (2003). This work was supported by the Netherlands Organization for Health Research and Development (ZonMw; Project No. 114000088). B.J. Blaauboer received financial support from the Doerenkamp-Zbinden Foundation.

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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

    Jochem Louisse & Ivonne M. C. M. Rietjens

  2. TNO, PO Box 360, 3700 AJ, Zeist, The Netherlands

    Jochem Louisse, Sieto Bosgra & Miriam Verwei

  3. Institute for Risk Assessment Sciences (IRAS), Utrecht University, PO Box 80176, 3508 TD, Utrecht, The Netherlands

    Bas J. Blaauboer

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  1. Jochem Louisse
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  2. Sieto Bosgra
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  5. Miriam Verwei
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Correspondence to Jochem Louisse.

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Louisse, J., Bosgra, S., Blaauboer, B.J. et al. Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling. Arch Toxicol 89, 1135–1148 (2015). https://doi.org/10.1007/s00204-014-1289-4

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