Human relevance of follicular thyroid tumors in rodents caused by non-genotoxic substances

Abstract Chronic stimulation of the thyroid gland of rodents by TSH leads to thyroid follicular hyperplasia and subsequently to thyroid follicular adenomas and carcinomas. However, the interpretations of rodent thyroid tumors are contradictory. The U.S. Food and Drug Administration (FDA) concluded that findings with drugs that lead to increased levels of thyroid-stimulating hormone (TSH) in rats are not relevant to humans, whereas the U.S. Environmental Protection Agency (US EPA) concluded that chemicals that produce rodent thyroid tumors may pose a carcinogenic hazard for humans although the thyroid of rodents appears to be more sensitive to a carcinogenic stimulus than that of humans. Meanwhile, based on the CLP Criteria of the European Chemicals Agency (ECHA), rodent thyroid tumors caused by the induction of uridine-diphosphate-glucuronosyl transferases (UDGT) were assessed as not relevant to humans. To clarify these discrepant positions, the function and regulation of the thyroid gland are described and the types of thyroid tumors and the causes of their development in humans and animals are examined. Based on these data and the evidence that so far, except radiation, no chemical is known to increase the incidence of thyroid tumors in humans, it is concluded that rodent thyroid tumors resulting from continuous stimulation of the thyroid gland by increased TSH levels are not relevant to humans. Consequently, compounds that induce such tumors do not warrant classification as carcinogenic.