Pathophysiology of chemical injury of the thyroid gland

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.