Reactive intermediates of xenobiotics in thyroid: formation and biological consequences.

The formation of reactive intermediates from xenobiotics in thyroid and their potential toxic effects on the organ have received only very little attention up to now. At first glance this appears surprising, as numerous chemicals have been shown to be capable of inducing thyroid tumours in experimental animals. The lack of interest in the fate of these chemicals in thyroid is largely the consequence of the current theory of thyroid follicular cell carcinogenesis which centers on perturbations of the hormonal regulatory system which are caused by many thyroid carcinogens (Hill et al. 1989, Thomas and Williams 1991). To understand the way in which administration of xenobiotics may lead to thyroid tumours through a disturbance of thyroid hormone homeostasis, it may be helpful to have a short look on the mechanisms responsible for maintaining homeostasis. The highest tier of control is exerted by the hypothalamus, which secretes thyrotropin-releasing hormone, TRH. TRH causes the release of thyroid-stimulating hormone (TSH) from the anterior pituitary. TSH stimulates several key stages in thyroid hormone synthesis which results in increased secretion of thyroid hormones into the blood. The circulating thyroid hormones, especially T4, depress TSH release by the pituitary. There is, therefore, an inverse relationship between the levels of circulating thyroid hormones and the level of TSH secretion. This system provides an extremely sensitive feedback mechanism to maintain adequate production of thyroid hormones. Application of xenobiotics which inhibit thyroid hormone synthesis, so-called "antithyroid" agents, reduces the output of thyroid hormones into the blood, which results in compensatory release of excess TSH from the pituitary. TSH is the main growth factor for the thyroid epithelium, and one effect of a long-term application of these compounds is a chronic growth stimulus to the thyroid which is thought to result in an increased frequency of mutations due to increased cell replication (Cohen and Ellwein 1990). It is assumed that some of the mutated cells aquire the ability to secrete certain growth factors, such as IGF-1