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Physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the Jersey girl study.

Mukherjee D, Royce SG, Alexander JA, Buckley B, Isukapalli SS, Bandera EV, Zarbl H, Georgopoulos PG - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey, United States of America; Department of Environmental and Occupational Medicine, Rutgers University - Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America; Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, New Jersey, United States of America.

ABSTRACT
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.

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Human exposure.Human exposure routes of zearalenone and zeranol.
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pone-0113632-g002: Human exposure.Human exposure routes of zearalenone and zeranol.

Mentions: Alpha-zearalanol (α-ZAL), commonly known as zeranol, is a fungal metabolite produced from zearalenone (ZEA), a non-steroidal estrogenic mycotoxin. Fig. 1(a) shows the various compounds of the zeranol family. The study of biotransformation of this family of compounds has been the focus of world-wide interest due to their estrogenic function. Humans are exposed to both ZEA and α-ZAL mainly through consumption of contaminated grains [11], though there have been examples of other routes of exposure such as inhalation exposure in farm workers [12], [13]. However, the most important exposure pathway for α-ZAL can be meat treated with it as a growth additive. α-ZAL is administered to livestock in the form of 12 mg pellets, and a dose of 3 pellets (36 mg) is considered to be sufficient for 90-120 days [14]. Human exposure to α-ZAL might also result from consumption of farm animals which have consumed and metabolized ZEA-contaminated fodder. Fig. 2 shows the various exposure pathways resulting to human intake of ZEA and ZAL.


Physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the Jersey girl study.

Mukherjee D, Royce SG, Alexander JA, Buckley B, Isukapalli SS, Bandera EV, Zarbl H, Georgopoulos PG - PLoS ONE (2014)

Human exposure.Human exposure routes of zearalenone and zeranol.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256163&req=5

pone-0113632-g002: Human exposure.Human exposure routes of zearalenone and zeranol.
Mentions: Alpha-zearalanol (α-ZAL), commonly known as zeranol, is a fungal metabolite produced from zearalenone (ZEA), a non-steroidal estrogenic mycotoxin. Fig. 1(a) shows the various compounds of the zeranol family. The study of biotransformation of this family of compounds has been the focus of world-wide interest due to their estrogenic function. Humans are exposed to both ZEA and α-ZAL mainly through consumption of contaminated grains [11], though there have been examples of other routes of exposure such as inhalation exposure in farm workers [12], [13]. However, the most important exposure pathway for α-ZAL can be meat treated with it as a growth additive. α-ZAL is administered to livestock in the form of 12 mg pellets, and a dose of 3 pellets (36 mg) is considered to be sufficient for 90-120 days [14]. Human exposure to α-ZAL might also result from consumption of farm animals which have consumed and metabolized ZEA-contaminated fodder. Fig. 2 shows the various exposure pathways resulting to human intake of ZEA and ZAL.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey, United States of America; Department of Environmental and Occupational Medicine, Rutgers University - Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America; Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, New Jersey, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus