Comparative evaluation of rat and human in vitro assays for evaluation of thyroid toxicity

The effects of ten test chemicals on thyroid sodium-iodide symporter (NIS), thyroid peroxidase (TPO), and deiodinases (DIOs) type I, II, and III were evaluated and compared in in vitro rat and human systems. Test chemicals known to directly affect TH levels in vivo were confirmed to effectively inhibit at least one of the tested in vitro endpoints, without significant disparities between species, and the test compounds known to not affect thyroid function were found ineffective. Interestingly, iodide transport blocker 5, a potent non-competitive iodine uptake inhibitor, exhibited effects beyond direct NIS inhibition, impacting NIS function through ATP depletion, and also inhibited TPO and DIO1/ 2 enzymes, although to a lesser extent. Finally, of the four hepatic inducers known to affect thyroid function indirectly in rats through increased TH metabolism in the liver, dexamethasone, phenobarbital, and pregnenolone 16α-carbonitrile were found ineffective in the herein described inhibition tests, while rifampicin decreased rat and human TPO activities, suggesting a direct effect on thyroid function. This study demonstrates the usefulness of comparative data generated by rat and human in vitro NIS, TPO and DIOs test systems to support risk-based decisions.