MECHANISTIC CONSIDERATIONS FOR THE RELEVANCE OF ANIMAL DATA ON THYROID NEOPLASIA TO HUMAN RISK ASSESSMENT

There are two basic mechanisms whereby chemicals produce thyroid gland neoplasia in rodents. The first involves chemicals that exert a direc t carcinogenic effect in the thyroid gland and the other involves chem icals which, through a variety of mechanisms, disrupt thyroid function and produce thyroid gland neoplasia secondary to hormone imbalance. T hese secondary mechanisms predominantly involve effects on thyroid hor mone synthesis or peripheral hormone disposition, There are important species differences in thyroid gland physiology between rodents and hu mans that may account for a marked species difference in the inherent susceptibility for neoplasia to hormone imbalance. Thyroid gland neopl asia, secondary to chemically induced hormone imbalance, is mediated b y thyroid-stimulating hormone (TSH) in response to altered thyroid gla nd function. The effect of TSH on cell proliferation and other aspects of thyroid gland function is a receptor mediated process and the plas ma membrane surface of the follicular cell has receptors for TSH and o ther growth factors. Small organic molecules are not known to be direc t TSH receptor agonists or antagonists; however, various antibodies fo und in autoimmune disease such as Graves' disease can directly stimula te or inhibit the TSH receptor. Certain chemicals can modulate the TSH response for autoregulation of follicular cell function and thereby i ncrease or decrease the response of the follicular cell to TSH. It is thus important to consider mechanisms for the evaluation of potential cancer risks. There would be little if any risk for non-genotoxic chem icals that act secondary to hormone imbalance at exposure levels that do not disrupt thyroid function. Furthermore, the degree of thyroid dy sfunction produced by a chemical would present a significant toxicolog ical problem before such exposure would increase the risk for neoplasi a in humans.