Comparative evaluation of rat and human in vitro assays for evaluation of thyroid toxicity
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Abstract
The effects of ten test chemicals towards thyroid sodium-iodide symporter (NIS), thyroid peroxidase (TPO), and deiodinases (DIOs) type I, II, and III were evaluated in in vitro rat and human systems and compared. 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 tested 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, by impacting NIS function through ATP depletion, and also inhibited TPO and DIO1/2 enzymes, although to a lesser extent. Finally, while 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, rifampicin decreased rat and human TPO activities, highlighting a potential direct effect on thyroid function. This study demonstrates the usefulness of data generated by the rat and human in vitro NIS, TPO and DIOs test systems described here to support risk-based decisions.
Plain language summary
This study evaluates three non-animal experimental approaches to study thyroid hormones. This is important because chemicals can affect thyroid hormones levels in the body if they promote excretion or inhibit synthesis. Ten chemicals were studied and include chemicals that are known to affect, known not to affect, and chemicals where it is not known if they affect thyroid hormones in the body. Regulation of thyroid hormones is highly conserved across species, but differences do exist between rats (commonly used to study chemical toxicity) and humans. These experiments show that for the specific mechanisms examined, there is no difference between rat and human systems. These techniques will facilitate screening of chemicals for potential effects on thyroid hormones long before they are studied in animals, thereby supporting the principles of replacement, reduction, and refinement (3Rs) in animal testing, enhancing our understanding and contribute to protecting human health.
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