Detection of thyroid toxicants in a Tier I screening battery and alterations in thyroid endpoints over 28 days of exposure

Phenobarbital (PB), a thyroid hormone excretion enhancer, and propylthioura cil (PTU), a thyroid hormone-synthesis inhibitor, have been examined in a T ier I screening battery for detecting endocrine-active compounds (EACs). Th e Tier I battery incorporates two short-term in vivo tests (5-day ovariecto mized female battery and 15-day intact male battery using Sprague-Dawley ra ts) and an in vitro yeast transactivation system (YTS). In addition to the Tier I battery, thyroid endpoints (serum hormone concentrations, liver and thyroid weights, thyroid histology, and UDP-glucuronyltransferase [UDP-GT] and 5'-deiodinase activities) have been evaluated in a 15-day dietary restr iction experiment. The purpose was to assess possible confounding of result s due to treatment-related decreases in body weight. Finally, several thyro id-related endpoints (serum hormone concentrations, hepatic UDP-GT activity , thyroid weights, thyroid follicular cell proliferation, and histopatholog y of the thyroid gland) have been evaluated for their utility in detecting thyroid-modulating effects after 1, 2, or 4 weeks of treatment with PB or P TU. In the female battery, changes in thyroid endpoints following PB admini stration, were limited to decreased serum tri-iodothyronine (T-3) and thyro xine (T-4) concentrations. There were no changes in thyroid stimulating hor mone (TSH) concentrations or in thyroid gland histology. In the male batter y, PB administration increased serum TSH and decreased T-3 and T-4 concentr ations. The most sensitive indicator of PB-induced thyroid effects in the m ale battery was thyroid histology (pale staining and/or depleted colloid). In the female battery, PTU administration produced increases in TSH concent rations, decreases in T-3 and T-4 concentrations, and microscopic changes ( hypertrophy/hyperplasia, colloid depletion) in the thyroid gland. In the ma le battery, PTU administration caused thyroid gland hypertrophy/hyperplasia and colloid depletion, and the expected thyroid hormonal alterations (incr eased TSH, and decreased serum T-3 and T-4 concentrations). The dietary res triction study demonstrated that possible confounding of the data can occur with the thyroid endpoints when body weight decrements are 15% or greater. In the thyroid time course experiment, PB produced increased UDP-GT activi ty (at all time points), increased serum TSH (4-week time point), decreased serum T-3 (1-and 2-week time points) and T-4 (all time points), increased relative thyroid weight (2- and 4-week time points), and increased thyroid follicular cell proliferation (1- and 2-week time points). Histological eff ects in PB-treated rats were limited to mild colloid depletion at the 2- an d 4-week time points. At all three time points, PTU increased relative thyr oid weight, increased serum TSH, decreased serum T-3 and T-4, increased thy roid follicular cell proliferation, and produced thyroid gland hyperplasia/ hypertrophy. Thyroid gland histopathology, coupled with decreased serum T-4 concentrations, has been proposed as the most useful criteria for identify ing thyroid toxicants. These data suggest that thyroid gland weight, couple d with thyroid hormone analyses and thyroid histology, are the most reliabl e endpoints for identifying thyroid gland toxicants in a short-duration scr eening battery. The data further suggest that 2 weeks is the optimal time p oint for identifying thyroid toxicants based on the 9 endpoints examined. H ence, the 2-week male battery currently being validated as part of this rep ort should be an effective screen for detecting both potent and weak thyroi d toxicants.