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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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Model predictions for adult human subjects.Total chemicals in (a) venous blood, (b) urine, and (c) feces after ingestion of 1.23 mg/kg body weight of α-ZAL by adult healthy human subjects: results from PBTK model (red line) compared with in vivo measurements from Migdalof et al.[16].
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pone-0113632-g008: Model predictions for adult human subjects.Total chemicals in (a) venous blood, (b) urine, and (c) feces after ingestion of 1.23 mg/kg body weight of α-ZAL by adult healthy human subjects: results from PBTK model (red line) compared with in vivo measurements from Migdalof et al.[16].

Mentions: The results from the PBTK model for human subjects were compared with in vivo measurements from Migdalof et al.[16]. Accordingly, the model was run with the physiological parameters of a 61 kg human which is the mean body weight of the human subjects studied by Migdalof et al. Physiological parameters were extracted from the NHANES database [54] corresponding to body weights of subjects. Migdalof et al. presents total radioactivity amounts in venous blood, feces and urine. The amounts of individual chemicals in the PBTK model results were added to reflect the total biomarker levels in urine and feces. Fig. 8 compares model predictions with measurements from Migdalof et al.[16], showing good agreement of model estimates with observations. However, data for comparing model results for other metabolites are not available. Migdalof et al. have analysed biomarker levels for individual chemicals, but only briefly, stating the fraction of zeranol and metabolites which are free or conjugated.


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)

Model predictions for adult human subjects.Total chemicals in (a) venous blood, (b) urine, and (c) feces after ingestion of 1.23 mg/kg body weight of α-ZAL by adult healthy human subjects: results from PBTK model (red line) compared with in vivo measurements from Migdalof et al.[16].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0113632-g008: Model predictions for adult human subjects.Total chemicals in (a) venous blood, (b) urine, and (c) feces after ingestion of 1.23 mg/kg body weight of α-ZAL by adult healthy human subjects: results from PBTK model (red line) compared with in vivo measurements from Migdalof et al.[16].
Mentions: The results from the PBTK model for human subjects were compared with in vivo measurements from Migdalof et al.[16]. Accordingly, the model was run with the physiological parameters of a 61 kg human which is the mean body weight of the human subjects studied by Migdalof et al. Physiological parameters were extracted from the NHANES database [54] corresponding to body weights of subjects. Migdalof et al. presents total radioactivity amounts in venous blood, feces and urine. The amounts of individual chemicals in the PBTK model results were added to reflect the total biomarker levels in urine and feces. Fig. 8 compares model predictions with measurements from Migdalof et al.[16], showing good agreement of model estimates with observations. However, data for comparing model results for other metabolites are not available. Migdalof et al. have analysed biomarker levels for individual chemicals, but only briefly, stating the fraction of zeranol and metabolites which are free or conjugated.

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