Derivation of Human Toxicokinetic Parameters and Chemical-Specific Adjustment Factor of Citrinin Through a Human Intervention Trial and Hierarchical Bayesian Population Modeling
Abstract
1. Introduction
2. Results and Discussion
2.1. Sample Preparation and UHPLC-MS/MS Method
2.1.1. Method Validation
2.1.2. Matrix Effect
2.1.3. Stability
2.2. Toxicokinetic Modeling
2.2.1. TK Profiles and Deterministic Model
2.2.2. PopTK Model Fit and Posterior Predictions
3. Limitations, Strengths, and Conclusions
4. Materials and Methods
4.1. Materials
4.2. Human Intervention Trial
4.3. Sample Preparation
4.3.1. Whole Blood (VAMS Mitra® Tips)
4.3.2. Urine
4.3.3. Feces
4.4. UHPLC-MS/MS Analysis and Method Validation
4.5. PopTK Modeling
4.5.1. Hierarchical Bayesian Population Model
4.5.2. Model Fit and Predictions for Human Toxicokinetics
4.6. Adjustment Factor for Human Variability in Toxicokinetics (HKAF)
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
13C13-CIT | Isotopically labelled citrinin |
ADME | Absorption, distribution, metabolization, excretion |
AUC | Area under the blood concentration-time curve |
bw | Body weight |
Ccpt_out | Citrinin concentration in the central compartment (blood flow) |
Ccpt_met_out | Metabolites concentration in the central compartment (blood flow) |
CE | Collision energy |
CI | Confidence interval |
CIT | Citrinin |
Cltot | Clearance of citrinin |
Clmet | Clearance of citrinin’s metabolites |
Cmax | Maximum blood concentration |
CSAF | Chemical-specific adjustment factors |
CV | Coefficient of variation |
EFSA | European Food Safety Authority |
ESI | Electrospray ionization |
EU | European Union |
Fgutabs | Fraction absorbed via the gastrointestinal tract |
GI | Gastrointestinal |
GM | Geometric mean |
GSD | Geometric standard deviation |
HBM | Human biomonitoring |
HBGV | Human biomonitoring guidance values |
HO-CIT | Dihydrocitrinone |
HKAF | Human inter-individual toxicokinetic variability |
IARC | International Agency for Research on Cancer |
ICF | Informed consent form |
ICH | International Council for Harmonisation |
IS | Internal standard |
kel | Total elimination rate of citrinin |
kmet | Metabolization rate |
kgutelim | Gut elimination rate |
kgutabs | Gut absorption rate |
ku | Urinary excretion rate |
kufrac | Fraction excreted in urinec |
kumet | Urinary excretion rate of the metabolite |
LLOQ | Lower Limit of Quantification |
LOD | Limit of Detection |
MCMC | Markov chain Monte Carlo |
ME | Matrix effect |
mp | Mobile phase |
MS | Mass spectrometry/spectrometer |
MRM | Multiple reaction monitoring |
m/z | Mass-to-charge ratio |
NOAEL | No-observed-adverse-effect level |
PopTK | Population toxicokinetics |
Q | Quadrupole |
Q_fec_out | Amount of citrinin excreted via the GI tract |
Qu_met_out | Amount of citrinin’s metabolites excreted in urine |
Qu_out | Amount of citrinin excreted in urine |
Ȓ | R-hat convergence diagnostic |
RA | Apparent recovery |
RE | Extraction efficiency |
ROS | Reactive oxygen species |
RSDR | Intermediate precision |
RSDr | Repeatability |
Rt | Retention time |
SALLE | Salting-out assisted liquid–liquid Extraction |
SSE | Signal suppression enhancement |
t1/2 | Half-life |
TK | Toxicokinetic |
tmax | Time to reach Cmax |
ULOQ | Upper Limit of Quantification |
UHPLC | Ultra-high performance liquid chromatography |
VAMS | Volumetric absorptive microsampling |
Vdist | Volume of distribution of citrinin |
Vdistmet | Volume of distribution of citrinin’s metabolites |
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Matrix | R2 | LOD | Calibration Range | SSE | RA | Re | Intra-Day Bias | Inter-Day Bias | RSDr | RSDR | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
ng/mL * | LLOQ-ULOQ | % | Without IS | With IS | % | LLOQ | ULOQ | LLOQ | ULOQ | LLOQ | ULOQ | LLOQ | ULOQ | ||
ng/mL * | % | % | % | % | % | % | % | % | % | % | |||||
Urine | 0.9951 | 0.005 | 0.01–10 | 175.4 | 129.4 | 101.3 | 57.8 | 7.5 | 1.8 | 9.1 | 1.7 | 11.3 | 4.1 | 15.4 | 4.5 |
Blood | 0.9926 | 0.027 | 0.05–2.5 | 113.1 | 122.7 | 94.7 | 108.5 | −9.4 | −0.1 | −9.3 | 0.22 | 14.6 | 9.1 | 15.1 | 16.9 |
Feces | 0.9989 | 0.002 | 0.01–5 | 47.7 | 36.5 | 93.0 | 76.6 | −0.1 | 0.3 | 1.1 | 0.3 | 5.7 | 2.5 | 5.9 | 2.4 |
Mean Difference Urine (%) | Mean Difference Capillary Blood (%) | ||||||
---|---|---|---|---|---|---|---|
0.01 ng/mL | 10 ng/mL | 0.01 ng/mL | 10 ng/mL | 0.1 ng/mL | 2.5 ng/mL | 0.1 ng/mL | 2.5 ng/mL |
−20 °C 21 Days | −20 °C 21 Days | 4 °C 5 Days | 4 °C 5 Days | 4 °C 21 Days | 4 °C 21 Days | 20 °C 5 Days | 20 °C 5 Days |
15.00 | 0.10 | −1.73 | 0.03 | 6.87 | 14.12 | 4.84 | −8.55 |
Parameter | Unit | Preliminary TK Parameters (Degen et al., 2018) [16] | Population Posterior Distributions Median [90% CI] | |
---|---|---|---|---|
GM | GSD | |||
t1/2 | h | 7.5–13.8 | 9.33 [6.43–13.53] | 1.29 [1.20–1.52] |
kel | h−1 | n.a. | 0.074 [0.051–0.108] | 1.29 [1.20–1.52] |
Tmax * | h | n.a. | 0.63 [0.35–1.15] | 1.92 [1.60–2.93] |
Cmax * | ng/mL | n.a. | 0.28 [0.15–0.52] | 1.99 [1.64–3.09] |
AUC ** | ng/(L·kg bw) | n.a. | 3654.2 [2290.8–5829.1] | 1.49 [1.34–1.94] |
Cltot | L/(h·kg bw) | 0.005–0.007 | 0.025 [0.020–0.030] | 1.51 [1.32–1.71] |
Clmet | L/(h·kg bw) | n.a. | 0.033 [0.005–0.239] | 1.19 [0.98–1.45] |
Vdist | L/kg bw | 0.052–0.123 | 0.330 [0.254–0.428] | 1.18 [0.95–1.47] |
Vdistmet | L/kg bw | n.a. | 0.836 [0.136–5.079] | 1.72 [1.53–1.95] |
Fgutabs | - | n.a. | 0.246 [0.093–0.651] | 1.17 [0.97–1.41] |
kgutelim | h−1 | n.a. | 4.141 [2.565–6.686] | 1.96 [1.61–2.40] |
kufrac | - | 0.076–0.456 | 0.351 [0.273–0.451] | 1.69 [1.49–1.92] |
Analyte | Rt | Cone | [M+CH3OH-H]− m/z | CE | Product Ion m/z |
---|---|---|---|---|---|
(min) | (V) | (eV) | |||
CIT | 7.30 | 30 | 281.30 | 25 | 249.20 (Q) |
15 | 205.15 * | ||||
13C13-CIT | 7.30 | 30 | 294.30 | 25 | 262.20 (Q) |
15 | 217.20 |
Parameter | Description (Unit) | Central Value | Prior Distribution for Population Geometric Mean (Natural Logarithm) |
---|---|---|---|
Cltot | Total clearance of CIT (L/Kg·h) | 0.04 | LogNormal (−3.33, 1.15) |
Clmet | Clearance of HO-CIT (L/Kg·h) | 0.04 | LogNormal (−3.33, 1.15) |
Vdist | Volume of distribution of CIT (L/kg) | 0.90 | LogNormal (−0.10, 1.15) |
Vdistmet | Volume of distribution of HO-CIT (L/kg) | 0.90 | LogNormal (−0.10, 1.15) |
kufrac | Fraction of CIT eliminated in urine | 0.50 | TruncLogNormal (−0.7, 1.15, −4.61, −0.01) |
kumet | Elimination rate of HO-CIT in urine (h−1) | 0.50 | LogNormal (−0.7, 1.15) |
ktot | Total elimination rate of CIT (h−1) | 0.02 | LogNormal (−3.96, 1.15) |
kgutelim | Gut elimination rate (h−1) | 0.50 | LogNormal (−0.7, 1.15) |
Fgutabs | Fraction absorbed | 0.17 | TruncLogNormal (−1.76, 1.15, −2.3, 0) |
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Visintin, L.; Martino, C.; De Saeger, S.; Alladio, E.; De Boevre, M.; Chiu, W.A. Derivation of Human Toxicokinetic Parameters and Chemical-Specific Adjustment Factor of Citrinin Through a Human Intervention Trial and Hierarchical Bayesian Population Modeling. Toxins 2025, 17, 382. https://doi.org/10.3390/toxins17080382
Visintin L, Martino C, De Saeger S, Alladio E, De Boevre M, Chiu WA. Derivation of Human Toxicokinetic Parameters and Chemical-Specific Adjustment Factor of Citrinin Through a Human Intervention Trial and Hierarchical Bayesian Population Modeling. Toxins. 2025; 17(8):382. https://doi.org/10.3390/toxins17080382
Chicago/Turabian StyleVisintin, Lia, Camilla Martino, Sarah De Saeger, Eugenio Alladio, Marthe De Boevre, and Weihsueh A. Chiu. 2025. "Derivation of Human Toxicokinetic Parameters and Chemical-Specific Adjustment Factor of Citrinin Through a Human Intervention Trial and Hierarchical Bayesian Population Modeling" Toxins 17, no. 8: 382. https://doi.org/10.3390/toxins17080382
APA StyleVisintin, L., Martino, C., De Saeger, S., Alladio, E., De Boevre, M., & Chiu, W. A. (2025). Derivation of Human Toxicokinetic Parameters and Chemical-Specific Adjustment Factor of Citrinin Through a Human Intervention Trial and Hierarchical Bayesian Population Modeling. Toxins, 17(8), 382. https://doi.org/10.3390/toxins17080382