Towards translating in vitro measures of thyroid hormone system disruption to in vivo responses in the pregnant rat via a biologically based dose response (BBDR) model

Jeffrey Fisher (a,*), Conrad Housand (b) David Mattie (c), Andy Nong (a), Marjory Moreau (a),

Mary Gilbert (d)

(a) ScitoVation, LLC, Research Triangle Park, NC 27713, USA

(b) Magnolia Sciences, Winter Springs, FL, United States of America

(d) Office of Research and Development, Center for Public Health and Environmental Assessment, US EPA, RTP, NC, United States of America

Abstract:

Despite the number of in vitro assays that have been recently developed to identify chemicals that interfere with

the hypothalamic-pituitary-thyroid axis (HPT), the translation of those in vitro results into in vivo responses (in

vitro to in vivo extrapolation, IVIVE) has received limited attention from the modeling community. To help

advance this field a steady state biologically based dose response (BBDR) model for the HPT axis was constructed

for the pregnant rat on gestation day (GD) 20. The BBDR HPT axis model predicts plasma levels of thyroid

stimulating hormone (TSH) and the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Thyroid hormones

are important for normal growth and development of the fetus. Perchlorate, a potent inhibitor of thyroidal

uptake of iodide by the sodium iodide symporter (NIS) protein, was used as a case study for the BBDR HPT axis

model. The inhibitory blocking of the NIS by perchlorate was associated with dose-dependent steady state decreases

in thyroid hormone production in the thyroid gland. The BBDR HPT axis model predictions for TSH, T3,

and T4 plasma concentrations in pregnant Sprague Dawley (SD) rats were within 2-fold of observations for

drinking water perchlorate exposures ranging from 10 to 30,000 μg/kg/d. In Long Evans (LE) pregnant rats, for

both control and perchlorate drinking water exposures, ranging from 85 to 82,000 μg/kg/d, plasma thyroid

hormone and TSH concentrations were predicted within 2 to 3.4- fold of observations. This BBDR HPT axis model

provides a successful IVIVE template for thyroid hormone disruption in pregnant rats.