Toxicological Sciences, Vol 51, 54-70, Copyright © 1999 by Society of Toxicology
JC O'Connor, SR Frame, LG Davis and JC Cook
Phenobarbital (PB), a thyroid hormone excretion enhancer, and
propylthiouracil (PTU), a thyroid hormone-synthesis inhibitor, have been
examined in a Tier I screening battery for detecting endocrine- active
compounds (EACs). The Tier I battery incorporates two short-term in vivo
tests (5-day ovariectomized female battery and 15-day intact male battery
using Sprague-Dawley rats) 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 restriction experiment. The purpose was to
assess possible confounding of results due to treatment-related decreases
in body weight. Finally, several thyroid-related endpoints (serum hormone
concentrations, hepatic UDP-GT activity, thyroid weights, thyroid
follicular cell proliferation, and histopathology 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 PTU. In the female
battery, changes in thyroid endpoints following PB administration, were
limited to decreased serum tri-iodothyronine (T3) and thyroxine (T4)
concentrations. There were no changes in thyroid stimulating hormone (TSH)
concentrations or in thyroid gland histology. In the male battery, PB
administration increased serum TSH and decreased T3 and T4 concentrations.
The most sensitive indicator of PB-induced thyroid effects in the male
battery was thyroid histology (pale staining and/or depleted colloid). In
the female battery, PTU administration produced increases in TSH
concentrations, decreases in T3 and T4 concentrations, and microscopic
changes (hypertrophy/hyperplasia, colloid depletion) in the thyroid gland.
In the male battery, PTU administration caused thyroid gland
hypertrophy/hyperplasia and colloid depletion, and the expected thyroid
hormonal alterations (increased TSH, and decreased serum T3 and T4
concentrations). The dietary restriction 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 activity (at all time points),
increased serum TSH (4-week time point), decreased serum T3 (1-and 2-week
time points) and T4 (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 effects in
PB-treated rats were limited to mild colloid depletion at the 2- and 4-week
time points. At all three time points, PTU increased relative thyroid
weight, increased serum TSH, decreased serum T3 and T4, increased thyroid
follicular cell proliferation, and produced thyroid gland
hyperplasia/hypertrophy. Thyroid gland histopathology, coupled with
decreased serum T4 concentrations, has been proposed as the most useful
criteria for identifying thyroid toxicants. These data suggest that thyroid
gland weight, coupled with thyroid hormone analyses and thyroid histology,
are the most reliable endpoints for identifying thyroid gland toxicants in
a short-duration screening battery. The data further suggest that 2 weeks
is the optimal time point for identifying thyroid toxicants based on the 9
endpoints examined. Hence, the 2-week male battery currently being
validated as part of this report should be an effective screen for
detecting both potent and weak thyroid toxicants.
ARTICLES
Detection of thyroid toxicants in a tier I screening battery and alterations in thyroid endpoints over 28 days of exposure
Dupont Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware 19714, USA. john.c.oconnor@usa.dupont.com
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