Prediction of deoxynivalenol toxicokinetics in humans by in vitro-to-in vivo extrapolation and allometric scaling of in vivo animal data

Abstract

Deoxynivalenol (DON) is the most prevalent mycotoxin in cereals worldwide. It can cause adverse health effects in humans and animals, and maximum levels in food and feed have been implemented by food authorities based on risk assessments derived from estimated intake levels. The lack of human toxicokinetic data such as absorption, distribution, and elimination characteristics hinders the direct calculation of DON plasma levels and exposure. In the present study, we have, therefore, used in vitro-to-in vivo extrapolation of depletion constants in hepatic microsomes from different species and allometric scaling of reported in vivo animal parameters to predict the plasma clearance [0.24 L/(h × kg)] and volume of distribution (1.24 L/kg) for DON in humans. In addition, we have performed a toxicokinetic study with oral and intravenous administration of DON in pigs to establish benchmark parameters for the in vitro extrapolation approach. The determined human toxicokinetic parameters were then used to calculate the bioavailability (50–90%), maximum concentration, and total exposure in plasma, and urinary concentrations under consideration of typical DON levels in grain-based food products. The results were compared to data from biomonitoring studies in human populations.

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Acknowledgements

The authors would like to thank Tore Engen, Haakon Aaen, and Veronika Stabell of the Faculty of Veterinary Medicine at the Norwegian University of Life Sciences (NMBU), Oslo, Norway, for their expert help to recover piglet livers for microsome preparation. We also express our sincere thanks to Prof. Tore Framstad at NMBU’s department of Production Animal Clinical Sciences for his help in planning and organising the in vivo piglet study. Furthermore, we are very thankful to Dr. Hege Divon at the Norwegian Veterinary Institute for funding the in vitro studies through FUNtox, a strategic institute program on Fungi and Mycotoxins in a “One Health” perspective.

Funding

This project was funded by the Research Council of Norway (Grant Number 225332).

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Correspondence to Christiane Kruse Fæste.

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This article does not contain clinical studies or patient data. This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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Fæste, C.K., Ivanova, L., Sayyari, A. et al. Prediction of deoxynivalenol toxicokinetics in humans by in vitro-to-in vivo extrapolation and allometric scaling of in vivo animal data. Arch Toxicol 92, 2195–2216 (2018). https://doi.org/10.1007/s00204-018-2220-1

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Keywords

  • Allometric scaling
  • Deoxynivalenol (DON)
  • Human exposure
  • IVIVE
  • Pig
  • Toxicokinetics