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.
Highlights
Growth-promoting hormones are produced naturally in the animal body and can be artificially synthesized and supplemented
Massart et al [8] reported ZEA to be associated with central precocious puberty (CPP) in young females in a study of 63 girls in Italy, important covariates were not taken into account
The Physiologically-Based Toxicokinetic (PBTK) model developed here was implemented for a set of case studies and the results are compared with in vivo results available from multiple literature sources and for multiple species
Summary
Growth-promoting hormones are produced naturally in the animal body and can be artificially synthesized and supplemented. There are about 30 growthpromoting hormonal products currently used in the United States [1], the most important being estradiol, progesterone, testosterone, zeranol, trenbolone acetate, diethylstilbestrol (DES) and melengestrol acetate [1]. They are used primarily in animal husbandry to improve meat output and increase feed-to-meat conversion. ZEA, ZAL and their metabolites have been implicated in a number of incidences involving precocious puberty among young girls in various countries, including Italy in 1979 [4], and Puerto Rico in the 1980s [5,6,7], actual levels were not measured. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) sets the Allowable Daily Intake (ADI) of ZAL for humans at 0.5 mg per kg body weight [10], which amounts to a 35 mg allowable daily intake for a 70 kg male
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