Unraveling the toxicokinetics of the mycotoxins T-2 and HT-2 toxin in humans for developing a physiologically-based kinetic model.

T-2 toxin (T-2) and HT-2 toxin (HT-2) are trichothecene mycotoxins frequently detected in cereals. While exposure has primarily been evaluated using dietary assessment methods, human biomonitoring provides an alternative approach to assess internal exposure. This follow-up research aimed to further characterise the toxicokinetics of the mycotoxins T-2 and HT-2 and to subsequently develop a physiologically based kinetic (PBK) model, enabling prediction of urinary biomarker concentrations based on external exposure and vice versa. To this end, urine samples from 40 Norwegian adults were analysed for T-2 and its metabolites using targeted and suspect screening analytical approaches. Dietary exposure of these participants was estimated using 24-h weighed food records combined with Norwegian occurrence data. In parallel, toxicokinetic information on the mycotoxins was generated using in vitro liver microsome experiments and a literature review. Total HT-2 (HT-2 and its glucuronides) was detected in 97% of the 24-h urine voids, whereas total T-2 and T-2 triol were not detected. Suspect screening tentatively identified eight mono- and di-hydroxylated metabolites of T-2 and HT-2. In vitro, 98% of T-2 was metabolised within 2 h, with HT-2 accounting for 97% of the metabolites. Following a 2 h incubation with HT-2, 73% of the added HT-2 remained unchanged, and a large fraction was unidentified compounds (26%). Parametrisation of the PBK model was supported by data from public literature. This study advances the understanding of the human toxicokinetics of T-2 and HT-2, and demonstrates the utility of PBK modelling to link external and internal exposure. The identification of multiple hydroxylated urinary metabolites suggests that HT-2 alone does not fully represent internal exposure. This research provides direction for future metabolism studies which are needed to support further development of a robust PBK model for T-2 and HT-2.