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Introduction
In
several parts of the world, thyroid insufficiency due to the lack of dietary
iodine leads to cretinism. Cretinism
is a severe and clinically obvious problem characterized by defective physical
and neurological development of children (Cao et al., 1994).
Iodine deficiency may also result in spastic motor disorders, deaf mutism,
severe hypothyroidism (Hollowell and Hannon. 1997) and impaired intellectual
development in apparently normal persons (Boyages et al., 1989).
Perchlorate compounds have been widely used as solid rocket
propellants and ignitable sources in munitions and fireworks.
Perchlorates are also a laboratory waste by-product of perchloric acid.
Perchlorate salts, particularly potassium perchlorate, have been used
therapeutically to treat hyperthyroidism resulting from Graves’ disease
(Connell, 1981; Crooks and Wayne 1960; Godley and Stanbury, 1954; Morgans and
Trotter, 1960; Stanbury and Wyngaarden, 1952) and amiodorone-induced
thyrotoxicosis. Perchlorate has
also been used to treat thyroid gland disorders resulting from the
over-accumulation of iodine; a common side effect/toxicity seen in some anti-hypertensive
treatments (Bartalena et al., 1996). Finally,
perchlorate has been used diagnostically in humans to determine the ability of
the thyroid gland to correctly use dietary iodine.
Perchlorate
competitively inhibits the active transport of iodine into the thyroid.
As a result, perchlorate replaces iodine in the thyroid, resulting in a
decrease of thyroid hormone production (T4 and T3) and an increase of thyroid
stimulating hormone (TSH) production (U.S. EPA, 1998).
In
light of the severe consequences of insufficient dietary iodine, perchlorate’s
known mode of action on iodine intake, and recently discovered perchlorate
contamination of water supplies, questions have been raised regarding its safe
dose for long-term exposure. Present
approaches for estimating this safe dose have focussed on the development of a
Reference Dose (RfD) using methods developed by the U.S. Environmental
Protection Agency (Barnes and Dourson, 1988; Dourson, 1994).
Current drinking water action levels in states where perchlorate has been
found are based on an RfD of 0.0005 mg/kg-day (Dollarhide, 1995). Following a
review of newly developed data on perchlorate toxicity, U.S. EPA, (1998)
recently developed an RfD of 0.009 mg/kg-day.
Recently,
additional investigations of the toxicity of perchlorate have been conducted to
aid in determining the appropriate RfD value.
These studies include a:
· 90-day bioassay in rats designed to identify the threshold for thyroid effects of perchlorate, address the potential for toxicity of other organs, and to produce results suitable for benchmark modeling (Siglin et al, 1998);
·
Neurobehavorial developmental study in rats designed to address the
potential for perchlorate to affect neurological development and learning after
fetal/neonatal exposure;
·
Segment II study in rabbits designed to evaluate the potential for
perchlorate to cause developmental effects (York 1998);
·
Two-generation reproduction study in rats designed to evaluate the
potential for perchlorate to cause reproductive effects (York 1999);
·
Immunotoxicity assay designed to address questions regarding the
potential for perchlorate to alter the immune system (Keil et al, 1999);
·
Genotoxicity assay designed to resolve questions regarding the
potential for mutagenic effects.
Study protocols and results can be found at the TERA
website.
The purpose of this research is to compare the
effects of ammonium perchlorate drinking water exposures on thyroid hormone
levels and thyroid weights in four different species (humans, mice, rats, and
rabbits) at various life stages (pregnant, newborn, young, young adult and older
adult). Occupational studies in
adult humans are provided for comparison.
© 2003 Toxicology Excellence for Risk Assessment
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Cincinnati OH 45211
Phone: 513-542-7475
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Email: TERA@TERA.org