Characterization of the modes of action and dose-response relationship for thiocyanate on the thyroid hormone levels in rats using a computational approach.

Toxicol Appl Pharmacol

Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address:

Published: February 2019

AI Article Synopsis

  • Current risk evaluation practices for thyroid-active chemical mixtures emphasize iodide uptake inhibition via NIS, but this may not fully account for the effects of thiocyanate.
  • Research tested whether solely relying on NIS inhibition could explain the dose-response relationship of thiocyanate and its impact on serum thyroxine levels.
  • Findings indicate that considering only NIS inhibition is insufficient for chronic exposure scenarios, highlighting the need for more comprehensive mechanistic data to accurately assess the risks posed by thiocyanate.

Article Abstract

Current practices for evaluating the cumulative risk of thyroid-active chemical mixtures (perchlorate, thiocyanate, nitrate) focus on the inhibition of thyroidal iodide uptake via the sodium iodide symporter (NIS) as the mode of action for potency equivalence calculations. However, unlike perchlorate, thiocyanate presents additional modes of action within the thyroid that could contribute to the overall thyroid perturbation. We tested the hypothesis of whether assuming a single mode of action of thyroidal iodide uptake inhibition is sufficient for describing the observed dose-response relationship for thiocyanate and its effects on serum thyroxine levels. An interaction model was developed by linking a biologically based dose-response model for iodide and thyroid hormones to a thiocyanate physiologically based pharmacokinetic model. Each model, adapted from the literature, was restructured and recalibrated in a Bayesian framework for the current mode of actions study. For a chronic exposure scenario, NIS inhibition alone was found not to be sufficient to describe the dose-response relationship for thiocyanate. Inclusion of additional modes of action involving iodide flux across the thyroid membrane and inhibition of iodide organification via thyroid peroxidase showed only moderate improvements in capturing the dose-response at environmental thiocyanate doses of exposure and failed to capture trends at very high doses. Our findings emphasize the need for more mechanistic data for chronic exposure scenarios to characterize better the overall dose-response relationship for thiocyanate. Risk assessment approaches for thyroid-active chemical mixtures that rely on NIS inhibition as the single mode of action may over-predict the contribution of thiocyanate to thyroid disruption.

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Source
http://dx.doi.org/10.1016/j.taap.2019.01.007DOI Listing

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