Old dog, new tricks – The increasing use and impact of the Sandell-Kolthoff-reaction in toxicological studies on endocrine disruptors of the thyroid hormone system

More than 80 years ago, in 1937, Sandell and Kolthoff described a sensitive method for the spectrophotometric determination of iodide using the iodine-catalysed redox reaction between cerium (IV) and arsenic (III). This reaction was (and still is) widely used to determine urinary iodide as a meaningful biochemical marker for the control of iodine deficiency disorders in population studies. While this classic application is increasingly being replaced by methods with higher precision but also higher technical requirements (e.g. ICP-MS), the SK reaction has gained new attention due to its increasing use as a readout in medium- to high-throughput in vitro assays. Several relevant MIEs within the thyroid hormone system, which are potential targets of endocrine disruptors, can be tested in vitro using simple assays/test systems, e.g. iodide uptake via the sodium iodide symporter (NIS), iodide release from thyroid hormones (TH) by deiodinases (DIOs) or dehalogenase (DEHAL1/IYD) or transmembranal TH transport via respective transporters, e.g. MCT8. In these in vitro assays the SK reaction can be used to determine iodide release or transport as a final readout, being an indirect indicator of the respective biological activity. Most of these protocols were miniaturised for streamlined handling in microtiter format, adapted by several labs over the globe and potential candidates for (pre-)validation initiatives. Furthermore, the SK setup also allows access to enzymatic markers from ex vivo tissues as local indicators of TH action. We will describe and discuss the setup of the Sandell-Kolthoff reaction and its successful use as a standardised readout for various in vitro and ex vivo assays.