Prediction of deoxynivalenol toxicokinetics in humans by in vitro-to-in vivo extrapolation and allometric scaling of in vivo animal data
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.
KeywordsAllometric scaling Deoxynivalenol (DON) Human exposure IVIVE Pig Toxicokinetics
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.
This project was funded by the Research Council of Norway (Grant Number 225332).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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.
- Bernhoft A, Eriksen GS, Sundheim L, Berntssen M, Brantsæter AL, Brodal G, Fæste CK, Hofgaard IS, Rafoss T, Sivertsen T, Tronsmo AM (2013) Risk assessment of mycotoxins in cereal grain in Norway, vol 21. Norwegian Scientific Committee for Food Safety, Oslo, pp 1–287Google Scholar
- Brera C, de Santis B, Debegnach F, Miano B, Moretti G, Lanzone A, Del Sordo G, Buonsenso D, Chiaretti A, Hardie L, White K, Brantsæter AL, Knutsen H, Eriksen Sundstøl G, Sandvik M, Wells L, Allen S, Sathyapalan T (2015) Experimental study of deoxynivalenol biomarkers in urine. EFSA Supp Pub. https://doi.org/10.2903/sp.efsa.2015.EN-818 CrossRefGoogle Scholar
- Busby WF, Ackermann JM, Crespi CL (1999) Effect of methanol, ethanol, dimethyl sulfoxide, and acetonitrile on in vitro activities of cDNA-expressed human cytochromes P-450. Drug Met Disp 27:246–249Google Scholar
- Deguchi T, Watanabe N, Kurihara A, Igeta K, Ikenaga H, Fusegawa K, Suzuki N, Murata S, Hirouchi M, Furuta Y, Iwasaki M, Okazaki O, Izumi T (2011) Human pharmacokinetic prediction of UDP-glucuronosyltransferase substrates with an animal scale-up approach. Drug Met Disp 39:820–829CrossRefGoogle Scholar
- Knutsen HK, Alexander J, Barregård L, Bignami M, Brüschweiler B, Ceccatelli S, Cottrill B, Dinovi M, Grasl-Kraupp B, Hogstrand C, Hoogenboom L, Nebbia CS, Oswald IP, Petersen A, Rose M, Roudot A-C, Schwerdtle T, Vleminckx C, Vollmer G, Wallace H, De Saeger S, Eriksen GS, Farmer P, Fremy J-M, Gong YY, Meyer K, Naegeli H, Parent-Massin D, Rietjens I, Van Egmond H, Altieri A, Eskola M, Gergelova P, Bordajandi LR, Benkova B, Dörr B, Gkrillas A, Gustavsson N, Van Manen M, Edler L (2017) Risks to human and animal health related to the presence of deoxynivalenol and its acetylated and modified forms in food and feed. EFSA J 15:4718Google Scholar
- Schwartz-Zimmermann HE, Hametner C, Nagl V, Fiby I, Macheiner L, Winkler J, Dänicke S, Clark W, Pestka JL, Berthiller F (2017) Glucuronidation of deoxynivalenol (DON) by different animal species: Identification of iso-DON glucuronides and iso-deepoxy-don glucuronides as novel don metabolites in pigs, rats, mice, and cows. Arch Toxicol 91:3857–3872CrossRefPubMedPubMedCentralGoogle Scholar
- Waseem A, Ahmad Shah S, Sajjad A, Rauf Siddiqi A, Nafees M (2014) Human exposure to mycotoxins: a retrospective review of leading toxins and metabolites in human biological matrices. J Chem Soc Pak 36:1196–1214Google Scholar