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Marginal Iodide Deficiency and Thyroid Function: Dose-response analysis for quantitative pharmacokinetic modeling
GILBERT, M. E., E. MCLANAHAN, J. M. HEDGE, K. M. CROFTON, J. W. Fisher, L. Valentin-Blasini, AND B. C. Blount. Marginal Iodide Deficiency and Thyroid Function: Dose-response analysis for quantitative pharmacokinetic modeling. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 283(1):41-8, (2011).
Iodine is a micronutrient essential for the production of thyroid hormone. Adequate levels of iodine are critical for normal thyroid function, an important regulator of energy metabolism and crucial for the development of different tissues, particularly the brain. Insufficient levels of iodine during fetal and early neonatal life can have devastating effects upon the neurological function of the organism that persist throughout life. A number of thyroid-active environmental contaminants have also been identified that serve to interfere with the highly regulated hypothalamic-pituitary-thyroid axis. There is concern that the children born to women with marginal iodine insufficiency are at higher risk for developmental insult from environmental contaminants with a thyroid mode of action. The aim of the present study was to establish a model of marginal iodine deficiency in adult female rats using graded levels of iodine in the diet in preparation for an examination of the neurodevelopmental outcomes of marginal iodine deficiency during early development. The results of this study have provided a characterization of dose-response function for key parameters essential for quantitative modeling of the thyroid axis. They were compared with model estimates derived from a recently published biologically based dose-response (BBDR) model of the hypothalamic pituitary thyroid axis of the adult male rat and discrepancies between predicted and observed outcomes were prevalent. Data from this study will be applied to recalibrate, refine, and modify the adult male rat model for quantitative dose-response modeling of marginal iodine deficiency in pregnant and lactating rats. Once established, this model will be useful in predicting outcomes from exposures to xenobiotics that alter thyroid allostasis during critical periods of neurodevelopment.
Severe iodine deficiency is known to cause adverse health outcomes and remains a benchmark for understanding the effects of hypothyroidism. However, the implications of marginal iodine deficiency on function of the thyroid axis remain less well known. The current study examined the relationship between graded levels of iodine deficiency in rats and serum thyroid hormones, thyroid iodine content, and urinary iodide excretion. Long Evans rats (n=25, female, 40 days of age) were fed casein-based diets containing varying iodine concentrations for 8 weeks. Different iodine diets were created by adding 975, 200, 125,25, or 0 ug/kg to the base casein diet (~25 ug iodine/kg chow) to produce 5 nominal iodine levels ranging from excess iodine (Treatment 1: 1000 Ilg iodine/kg chow) to deficient (Treatment 5: 25 ug iodine/kg chow). On two consecutive days each week over the 8 week exposure period, animals were placed in metabolism cages to capture urine over an 8 hr period. At 8 weeks animals were sacrificed and blood and thyroid glands collected for thyroid hormones and iodine content, respectively. Neither food nor water intake, nor body weight gain differed among treatment groups. Mean daily iodine intakes were 26,4.2,2.5,0.65 and 0.21 ug/day for the 5 treatment groups. Serum total thyroxine (T4) was dose-dependently reduced relative to Treatment 1 with significant declines (19 and 48%) at the two lowest iodine groups, respectively. No significant changes in serum T3 or TSH were detected. Dose-dependent increases in thyroid weight and decreases in thyroidal and urinary iodide content were observed as a function of decreasing levels ofiodine in the diet. These data were compared with predictions from a recently published first generation biologically based dose-response (BBDR) model for iodide deficiency (McLanahan et aI., 2008). Based on model predictions, it appears that female Long Evans rats under the conditions of this study were more resilient to low iodine intake compared to predictions made from other genders and strains used to calibrate the first generation ofthe BBDR model. This document has been subjected to review by, the .National Health and Environmental Effects Research Laboratory and the Centers for Disease Control and Prevention, and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
TOXICOLOGY ASSESSMENT DIVISION