Derivation of human toxicokinetic parameters and internal threshold of toxicological concern for tenuazonic acid through a human intervention trial and hierarchical Bayesian population modeling.
Lia Visintin, En-Hsuan Lu, Hsing-Chieh Lin, Yasmine Bader, Truong Nhat Nguyen, Thanos Mouchtaris Michailidis, Sarah De Saeger, Weihsueh A Chiu, Marthe De Boevre
Author Information
Lia Visintin: Centre of Excellence in Mycotoxicology and Public Health, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium. lia.visintin@ugent.be. ORCID
En-Hsuan Lu: Department of Veterinary Physiology and Pharmacology, Interdisciplinary Faculty of Toxicology, Texas A&M University, College Station, TX, USA.
Hsing-Chieh Lin: Department of Veterinary Physiology and Pharmacology, Interdisciplinary Faculty of Toxicology, Texas A&M University, College Station, TX, USA.
Yasmine Bader: Centre of Excellence in Mycotoxicology and Public Health, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Truong Nhat Nguyen: Centre of Excellence in Mycotoxicology and Public Health, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Thanos Mouchtaris Michailidis: Centre of Excellence in Mycotoxicology and Public Health, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Sarah De Saeger: Centre of Excellence in Mycotoxicology and Public Health, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Weihsueh A Chiu: Department of Veterinary Physiology and Pharmacology, Interdisciplinary Faculty of Toxicology, Texas A&M University, College Station, TX, USA.
Marthe De Boevre: Centre of Excellence in Mycotoxicology and Public Health, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
BACKGROUND: Tenuazonic acid (TeA), a mycotoxin produced by Alternaria alternata, contaminates various food commodities and is known to cause acute and chronic health effects. However, the lack of human toxicokinetic (TK) data and the reliance on external exposure estimates have stalled a comprehensive risk assessment for TeA. OBJECTIVE: To bridge this gap, a human TK trial and population-based TK (PopTK) modeling were applied to determine human TK parameters of TeA, and the results were applied for risk screening using population biomonitoring data and threshold of toxicological concern (TTC)-based approaches. METHODS: Ten healthy volunteers participated in the TK trial during which the volunteers ingested a bolus dose of TeA at the (external) TTC (1500���ng/kg bw). Blood, urine, and fecal samples were collected over 48���h and analyzed using UPLC-MS/MS. Concentration-time profiles were fit with a multi-compartmental PopTK model using a hierarchical Bayesian population structure. Utilizing a probabilistic framework, fitted TK parameters were used to derive internal TTC (iTTC) values for comparison to blood and urine biomonitoring data. Risk screening with data from five diverse biomonitoring cohorts was performed using Hazard Quotient (HQ) and probabilistic individual margin of exposure (IMOE) approaches. RESULTS: TeA was estimated to have a population median half-life of 1.9 [90% CI: 1.4-2.7] hours and volume of distribution of 4.4 [3.1-6.1] L/kg, with inter-individual variability geometric standard deviations of 2.4- and 1.7-fold, respectively. Probabilistic lower confidence bound iTTCs were derived of 0.5���nmol/L in blood and 2.53���nmol/kg-d urinary excretion. Risk screening HQs were mostly >1 for the three blood biomonitoring cohorts and < 1 for the two urinary biomonitoring cohorts; results from probabilistic IMOE calculations were qualitatively consistent. SIGNIFICANCE: A comprehensive human TK study was performed for TeA for the first time, demonstrating the importance of integrating TK and population variability for a more comprehensive risk evaluation, particularly for interpreting biomonitoring data. The results for TeA point to the critical need for toxicity data to move beyond TTC-based risk screening. IMPACT: A critical gap in food safety research was addressed studying the toxicokinetics of tenuazonic acid (TeA) in humans and using these data to derive an internal threshold of toxicological concern (iTTC) for comparison to human biomonitoring data. The innovative approach-combining a human intervention trial with population-based toxicokinetic modeling-accounts for inter-individual variability and provides a more comprehensive understanding of population exposure to TeA. The resulting probabilistic iTTC and risk screening methodologies offer improved tools for interpretation of biomonitoring data. These findings have significant implications for food safety regulations and public health protection, potentially influencing future mycotoxin risk assessment strategies.
