Mode of action analysis for rat thyroid gland follicular cell tumor formation by MGK-264 and human relevance

MGK-264 (N-(2-ethylhexyl)-5-norborene-2.3-dicarboximide or N-octyl bicycloheptene dicarboximide), an insecticidal synergist, produced thyroid gland follicular cell (TFC) tumors in male Sprague-Dawley (SD) rats in a carcinogenicity study. The purpose of this study was to evaluate the possible mode of action (MoA) for TFC tumor induction by MGK-264 and its relevance to humans. In short-term in vivo studies, the treatment of male SD rats with MGK-264 resulted in induction of hepatic UDPglucuronosyltransferase (UGT) activity towards thyroxine (T₄) as substrate (UGT activity), a decrease in serum T₄ levels, an increase in serum thyroid stimulating hormone levels, and TFC hypertrophy at MGK-264 dose levels where TFC tumors were noted in the carcinogenicity study. Other possible MoAs such as genotoxicity, thyroperoxidase inhibition, and sodium/iodide symporter inhibition were excluded. Therefore, it is reasonable to conclude that MGK-264 has mitogenic activity on TFCs via induction of hepatic UGT activity followed by perturbation of the hypothalamus-pituitary-thyroid axis, similar to other hepatic xenobiotic enzyme inducers like phenobarbital. Literature data demonstrates that there are marked species differences between rats and humans in the effects of hepatic xenobiotic enzyme inducers on thyroid hormones and the thyroid gland. Overall, the proposed MoA for MGK-264-induced rat TFC tumor formation is considered quantitatively not plausible for humans.