Many goitrogenic
xenobiotics that increase the incidence of thyroid
tumors in rodents exert a direct effect on the thyroid gland to disrupt one of several possible steps in the biosynthesis and secretion of
thyroid hormones. This includes: (1) inhibition of the
iodine trapping mechanism (
thiocyanate or
perchlorate); (2) blockage of organic binding of
iodine and coupling of iodothyronines to form
thyroxine (T4) and
triiodothyronine (T3) (e.g.
sulfonamides,
thiourea,
methimazole, and
aminotriazole, amongst others); (3) inhibition of
thyroid hormone secretion by an effect on proteolysis of active
hormone from the
colloid (
lithium or an excess of
iodide). Another large group of goitrogenic chemicals disrupts
thyroid hormone economy by increasing the peripheral metabolism of
thyroid hormones through an induction of hepatic microsomal
enzymes. This group includes CNS-acting drugs (
phenobarbital,
benzodiazepines),
calcium channel blockers (
nicardipine,
nifedipine),
steroids (
spironolactone),
retinoids,
chlorinated hydrocarbons (
chlordane,
DDT,
TCDD), polyhalogenated biphenyls (PCB, PBB), and
enzyme inducers.
Thyroid hormone economy also can be disrupted by
xenobiotics that inhibit the 5'-monodeiodinase which converts T4 in peripheral sites (e.g. liver and kidney) to biologically active T3. Inhibition of this
enzyme by
FD&C Red No. 3,
amiodarone, and
iopanoic acid lowers circulating T3 levels which results in a compensatory increased secretion of
thyroid stimulating hormone (TSH), follicular cell
hypertrophy and
hyperplasia, and an increased incidence of follicular cell
tumors in 2-year or lifetime studies in rats. Physiologic perturbations alone, such as the feeding of an
iodine-deficient diet, partial
thyroidectomy, natural
goitrogens in certain foods, and
transplantation of TSH-secreting
pituitary tumors in rodents also can disrupt
thyroid hormone economy and, if sustained, increase the development of thyroid
tumors in rats. A consistent finding with all of these
goitrogens, be they either physiologic perturbations or
xenobiotics, is the chronic hypersecretion of TSH which places the rodent thyroid gland at greater risk to develop
tumors through a secondary mechanism of thyroid
oncogenesis.