Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study

Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This...

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Main Authors:	Mukherjee, Dwaipayan, Royce, Steven G., Alexander, Jocelyn A., Buckley, Brian, Isukapalli, Sastry S., Bandera, Elisa V., Zarbl, Helmut, Georgopoulos, Panos G.
Format:	Online
Language:	English
Published:	Public Library of Science 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256163/

id	pubmed-4256163
recordtype	oai_dc
spelling	pubmed-42561632014-12-11 Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study Mukherjee, Dwaipayan Royce, Steven G. Alexander, Jocelyn A. Buckley, Brian Isukapalli, Sastry S. Bandera, Elisa V. Zarbl, Helmut Georgopoulos, Panos G. Research Article Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population. Public Library of Science 2014-12-04 /pmc/articles/PMC4256163/ /pubmed/25474635 http://dx.doi.org/10.1371/journal.pone.0113632 Text en © 2014 Mukherjee et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Mukherjee, Dwaipayan Royce, Steven G. Alexander, Jocelyn A. Buckley, Brian Isukapalli, Sastry S. Bandera, Elisa V. Zarbl, Helmut Georgopoulos, Panos G.
spellingShingle	Mukherjee, Dwaipayan Royce, Steven G. Alexander, Jocelyn A. Buckley, Brian Isukapalli, Sastry S. Bandera, Elisa V. Zarbl, Helmut Georgopoulos, Panos G. Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study
author_facet	Mukherjee, Dwaipayan Royce, Steven G. Alexander, Jocelyn A. Buckley, Brian Isukapalli, Sastry S. Bandera, Elisa V. Zarbl, Helmut Georgopoulos, Panos G.
author_sort	Mukherjee, Dwaipayan
title	Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study
title_short	Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study
title_full	Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study
title_fullStr	Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study
title_full_unstemmed	Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study
title_sort	physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the jersey girl study
description	Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population.
publisher	Public Library of Science
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256163/
_version_	1613164085311963136

Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study

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