title: Evaluation of perturbations in serum thyroid hormones during human pregnancy due to dietary iodide and perchlorate exposure using a biologically based dose-response model.
abstract: A biologically based dose-response model (BBDR) for the hypothalamic pituitary thyroid (HPT) axis was developed in the near-term pregnant mother and fetus. This model was calibrated to predict serum levels of iodide, total thyroxine (T4), free thyroxine (fT4), and total triiodothyronine (T3) in the mother and fetus for a range of dietary iodide intake. The model was extended to describe perchlorate, an environmental and food contaminant, that competes with the sodium iodide symporter protein for thyroidal uptake of iodide. Using this mode-of-action framework, simulations were performed to determine the daily ingestion rates of perchlorate that would be associated with hypothyroxinemia or onset of hypothyroidism for varying iodide intake. Model simulations suggested that a maternal iodide intake of 75 to 250 µg/day and an environmentally relevant exposure of perchlorate (~0.1 µg/kg/day) did not result in hypothyroxinemia or hypothyroidism. For a daily iodide-sufficient intake of 200 µg/day, the dose of perchlorate required to reduce maternal fT4 levels to a hypothyroxinemic state was estimated at 32.2 µg/kg/day. As iodide intake was lowered to 75 µg/day, the model simulated daily perchlorate dose required to cause hypothyroxinemia was reduced by eightfold. Similarly, the perchlorate intake rates associated with the onset of subclinical hypothyroidism ranged from 54.8 to 21.5 µg/kg/day for daily iodide intake of 250-75 µg/day. This BBDR-HPT axis model for pregnancy provides an example of a novel public health assessment tool that may be expanded to address other endocrine-active chemicals found in food and the environment.
authors.affiliation: Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland 20817, USA. Annie.Lumen@fda.hhs.gov
authors.forename: Annie
authors.initials: A
authors.lastname: Lumen
authors.forename: David R
authors.initials: DR
authors.lastname: Mattie
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Fisher
mesh_terms: D000328:Adult; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects; D005506:Food Contamination; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D007454:Iodides / Q000493:pharmacokinetics / Q000633:toxicity*; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D008954:Models, Biological; D010472:Perchlorates / Q000493:pharmacokinetics / Q000633:toxicity*; D011247:Pregnancy / Q000097:blood*; D013961:Thyroid Gland / Q000187:drug effects*; D013963:Thyroid Hormones / Q000097:blood*
chemical_list: D007454:Iodides; D010472:Perchlorates; D013963:Thyroid Hormones
keywords: BBDR-HPT axis model; fetus; human pregnancy.; iodide; perchlorate; thyroid hormones