title: Physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the Jersey girl study.
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.
authors.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.
authors.forename: Dwaipayan
authors.initials: D
authors.lastname: Mukherjee
authors.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.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Royce
authors.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.
authors.forename: Jocelyn A
authors.initials: JA
authors.lastname: Alexander
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Buckley
authors.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.
authors.forename: Sastry S
authors.initials: SS
authors.lastname: Isukapalli
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey, United States of America; Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey, United States of America.
authors.forename: Elisa V
authors.initials: EV
authors.lastname: Bandera
authors.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; Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey, United States of America.
authors.forename: Helmut
authors.initials: H
authors.lastname: Zarbl
authors.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; Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey, United States of America.
authors.forename: Panos G
authors.initials: PG
authors.lastname: Georgopoulos
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001835:Body Weight / Q000187:drug effects; D002648:Child; D015331:Cohort Studies; D005260:Female; D005504:Food Analysis; D006207:Half-Life; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D009010:Monte Carlo Method; D009515:New Jersey; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D066007:Toxicokinetics; D015025:Zearalenone / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D015029:Zeranol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
chemical_list: D015415:Biomarkers; C029659:zearalenol; D015025:Zearalenone; D015029:Zeranol