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A series of previously published physiologically based pharmacokinetic (PBPK) models describe the effect of perchlorate on iodide uptake by the thyroid, with the mechanism being competitive inhibition of iodide transport by the sodium-iodide symporter (NIS). Hence a key parameter of these models is the affinity of perchlorate for the NIS, characterized as the Michaelis-Menten kinetic constant, K-m. However, when model predictions were compared to published results of a human study measuring radio-iodide uptake (RAIU) inhibition after controlled perchlorate exposures, it was found to only fit the lowest exposure level and underpredicted RAIU inhibition at higher levels. Published in vitro data, in which perchlorate-induced inhibition of iodide uptake via the NIS was measured, were re-analyzed. K-m for binding of perchlorate to the NIS originally derived from these data, 1.5m, had been obtained using Lineweaver-Burk plots, which allow for linear regression but invert the signal-noise of the data. Re-fitting these data by non-linear regression of the non-inverted data yielded a 60% lower value for the K-m, 0.59m. Substituting this value into the PBPK model for an average adult human significantly improved model agreement with the human RAIU data for exposures <100gkg(-1)day(-1). Thus, this lower K-m value both fits the in vitro NIS kinetics and provides better predictions of human in vivo RAIU data. This change in K-m increases the predicted sensitivity of humans to perchlorate over twofold for low-level exposures. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Short abstract Published physiologically based pharmacokinetic models describe inhibition of thyroidal iodide uptake by perchlorate, via competitive inhibition of the sodium-iodide symporter (NIS). A key parameter is the affinity (1/K-m) of perchlorate for the NIS. However, the models underpredicted human radio-iodide uptake inhibition data at 20gkg(-1)day(-1) perchlorate. Re-analysis of published in vitro data for perchlorate-induced NIS inhibition yielded a 60% lower K-m (higher affinity). The revised K-m significantly improved the physiologically based pharmacokinetic model agreement with human radio-iodide uptake inhibition data.