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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Abduljalil K, Cain T, Humphries H, Rostami-Hodjegan A (2014) Deciding on success criteria for predictability of pharmacokinetic parameters from in vitro studies: an analysis based on in vivo observations. Drug Met Disp 42:1478–1484
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 1–287
Boxenbaum H (1982) Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J Pharmacokin Biopharmaceut 10:201–227
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
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 27:246–249
Chen Y, Jin JY, Mukadam S, Malhi V, Kenny JR (2012) Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy and approach during the drug discovery phase with four case studies. Biopharm Drug Disp 33:85–98
Chen L, Yu M, Wu Q, Peng Z, Wang D, Kuča K, Yao P, Yan H, Nüssler AK, Liu L, Yang W (2016) Gender and geographical variability in the exposure pattern and metabolism of deoxynivalenol in humans: a review. J Appl Toxicol 37:60–70
Chiba M, Ishii Y, Sugiyama Y (2009) Prediction of hepatic clearance in human from in vitro data for successful drug development. AAPS J 11:262–276
Dänicke S, Brezina U (2013) Kinetics and metabolism of the Fusarium toxin deoxynivalenol in farm animals: consequences for diagnosis of exposure and intoxication and carry over. Food Chem Toxicol 60:58–75
De Buck SS, Sinha VK, Fenu LA, Nijsen MJ, Mackie CE, Gilissen RA (2007) Prediction of human pharmacokinetics using physiologically based modeling: a retrospective analysis of 26 clinically tested drugs. Drug Met Disp 35:1766–1780
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 39:820–829
Devreese M, Antonissen G, Broekaert N, De Mil T, De Baere S, Vanhaecke L, De Backer P, Croubels S (2015) Toxicokinetic study and oral bioavailability of DON in turkey poults, and comparative biotransformation between broilers and turkeys. World Mycotox J 8:533–539
Guillemette C (2003) Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenom J 3:136–158
Heyndrickx E, Sioen I, Huybrechts B, Callebaut A, De Henauw S, De Saeger S (2015) Human biomonitoring of multiple mycotoxins in the Belgian population: results of the BIOMYCO study. Environ Int 84:82–89
Ito K, Houston B (2005) Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharmaceut Res 22:103–112
Ivanova L, Fæste CK, Van Pamel E, Daeseleire E, Callebaut A, Uhlig S (2014) Presence of enniatin B and its hepatic metabolites in plasma and liver samples from broilers and eggs from laying hens. World Mycotoxin J 7:167–175
Iwatsubo T, Hirota N, Ooie T, Suzuki H, Shimada N, Chiba K, Ishizaki T, Green CE, Tyson CA, Sugiyama Y (1997) Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol Ther 73:147–171
Jolivette LJ, Ward KW (2005) Extrapolation of human pharmacokinetic parameters from rat, dog, and monkey data: Molecular properties associated with extrapolative success and failure. J Pharmaceut Sci 94:1467–1483
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 15:4718
Lattanzio VM, Solfrizzo M, De Girolamo A, Chulze SN, Torres AM, Visconti A (2011) LC–MS/MS characterization of the urinary excretion profile of the mycotoxin deoxynivalenol in human and rat. J Chromatogr B 879:707–715
Lindstedt SL, Schaeffer PJ (2002) Use of allometry in predicting anatomical and physiological parameters of mammals. Lab Anim 36:1–19
Mahmood I, Balian JD (1996) Interspecies scaling: a comparative study for the prediction of clearance and volume using two or more than two species. Life Sci 59:579–585
Maul R, Warth B, Kant JS, Schebb NH, Krska R, Koch M, Sulyok M (2012) Investigation of the hepatic glucuronidation pattern of the Fusarium mycotoxin deoxynivalenol in various species. Chem Res Toxicol 25:2715–2717
Maul R, Warth B, Schebb NH, Krska R, Koch M, Sulyok M (2015) In vitro glucuronidation kinetics of deoxynivalenol by human and animal microsomes and recombinant human UGT enzymes. Arch Toxicol 89:949–960
Meky FA, Turner PC, Ashcroft AE, Miller JD, Qiao YL, Roth MJ, Wild CP (2003) Development of a urinary biomarker of human exposure to deoxynivalenol. Food Chem Toxicol 2:265–273
Nagilla R, Ward KW (2004) A comprehensive analysis of the role of correction factors in the allometric predictivity of clearance from rat, dog, and monkey to humans. J Pharm Sci 93:2522–2534
Nagl V, Schatzmayr G (2015) Deoxynivalenol and its masked forms in food and feed. Curr Opin Food Sci 5:43–49
Nagl V, Wöchtl B, Schwartz-Zimmermann HE, Hennig-Pauka I, Moll WD, Adam G, Berthiller F (2014) Metabolism of the masked mycotoxin deoxynivalenol-3-glucoside in pigs. Toxicol Lett 229:190–197
Naritomi Y, Nakamori F, Furukawa T, Tabata K (2015) Prediction of hepatic and intestinal glucuronidation using in vitro–in vivo extrapolation. Drug Met Pharmacokin 30:21–29
Obach RS, Reed-Hagen AE (2002) Measurement of Michaelis constant for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach. Drug Metab Disp 30:831–837
Obach RS, Baxter JG, Listin TE, Silber BM, Jones BC, MacIntyre F, Ranve DJ, Wastall P (1997) The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther 283:46–58
Payros D, Alassane-Kpembi I, Pierron A, Loiseau N, Pinton P, Oswald IP (2016) Toxicology of deoxynivalenol and its acetylated and modified forms. Arch Toxicol 90:2931–2957
Pestka JJ (2010) Deoxynivalenol: mechanisms of action, human exposure and toxicological relevance. Arch Toxicol 84:663–679
Pestka JJ, Clark ES, Schwartz-Zimmermann HE, Berthiller F (2017) Sex is a determinant for deoxynivalenol metabolism and elimination in the mouse. Toxins 9:240–251
Prelusky DB, Veira DM, Trenholm HL, Foster BC (1987) Metabolic fate and elimination in milk, urine and bile of deoxynivalenol following administration to lactating sheep. J Environ Sci Health B 22:125–148
Prelusky DB, Hartin KE, Trenholm HL, Miller JD (1988) Pharmacokinetic fate of 14C-labeled deoxynivalenol in swine. Fundam Appl Toxicol 10:276–286
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 91:3857–3872
Setiabudi M, Sheng HP, Huggins RA (1976) Growth of the pig: changes in red cell and plasma volumes. Growth 40:127–132
Smith R, Jones RDO, Ballard PG, Griffiths HH (2008) Determination of microsome and hepatocyte scaling factors for in vitro/in vivo extrapolation in the rat and dog. Xenobiotica 38:1386–1398
Soars MG, Burchell B, Riley RJ (2002) In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. J Pharm Exp Therap 301:382–390
Sundheim L, Lillegaard IT, Fæste CK, Brantsæter AL, Brodal G, Eriksen GS (2017) Deoxynivalenol exposure in Norway, risk assessments for different human age groups. Toxins 9:46
Tang H, Mayersohn M (2006) A global examination of allometric scaling for predicting human drug clearance and the prediction of large vertical allometry. J Pharm Sci 95:1783–1799
Turner PC, Taylor EF, White KLM, Cade JE, Wild CP (2009) A comparison of 24 h urinary deoxynivalenol with recent v. average cereal consumption for UK adults. Brit J Nutr 102:1276–1279
Uhlig S, Ivanova L, Fæste CK (2016) Correction to enzyme-assisted synthesis and structural characterization of the 3, 8-, and 15-glucuronides of deoxynivalenol. J Agri Food Chem 64:3732
Warth B, Sulyok M, Berthiller F, Schuhmacher R, Krska R (2013) New insights into the human metabolism of the Fusarium mycotoxins deoxynivalenol and zearalenone. Toxicol Lett 220:88–94
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 36:1196–1214
Wu Q, Dohnal V, Huang L, Kuča K, Yuan Z (2010) Metabolic pathways of trichothecenes. Drug Met Rev 42:250–267
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).
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.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
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
- Allometric scaling
- Deoxynivalenol (DON)
- Human exposure