An evaluation of the human relevance of the thyroid follicular cell tumors observed in rats treated with the synthetic fungicide, pyridachlometyl, based on mode of action

Abstract

In a carcinogenicity study with SD rats exposed to pyridachlometyl (dietary dose levels, 0, 200, 2000, 10,000 and 20,000 ppm), an increase in thyroid follicular cell (TFC) adenoma and/or carcinoma was observed in male rats at ≥ 2000 ppm but not in female rats. We evaluated the mode of action (MOA) of pyridachlometyl-induced TFC tumor formation and its relevance to humans. Pyridachlometyl was neither genotoxic, cytotoxic nor immunosuppressive based on a series of toxicity studies. Data from general toxicity studies suggested that the MOA involve altered homeostasis of the hypothalamic-pituitary-thyroid (HPT) axis by hepatic uridine diphosphate glucuronosyltransferase (UGT) induction. Short-term in vivo MOA studies in SD rats showed that pyridachlometyl caused T₄-UGT induction in liver, an increase in serum TSH, TFC hypertrophy and/or an increase in TFC replicative DNA synthesis at the early phase of the treatment. In a perchlorate discharge test, pyridachlometyl did not inhibit iodine uptake or iodine organification, indicating that pyridachlometyl does not inhibit sodium iodide symporter nor thyroperoxidase in vivo. Since rats are more sensitive to TFC tumors due to HPT axis perturbations than humans, it is generally accepted that TFC tumors in rats caused by this MOA are not relevant to humans. Overall, these data strongly support that the MOA for pyridachlometyl-induced TFC tumors in male rats is via HPT axis perturbations by UGT induction, indicating that the TFC tumor formation by pyridachlometyl observed in male rats is not relevant to human cancer risk.