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endocrine system modulation
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
Development of a screening approach to detect thyroid disrupting chemicals that inhibit the human sodium iodide symporter (NIS)
Hallinger, D.R., Murr, A.S., Buckalew, A.R., Simmons, S.O., Stoker, T.E. and Laws, S.C.
Bibliographic source:
Toxicology in Vitro 40 (2017) p. 66-78

Materials and methods

Test guideline
no guideline available
Principles of method if other than guideline:
The publication describes the development of an in vitro method to detect substances disrupting the thyroid signaling pathway. A guideline is not (yet) available. Thyroid hormone biosynthesis requires active iodide uptake mediated by the sodium/iodide symporter (NIS). Monovalent anions, such as the environmental contaminant perchlorate, are competitive inhibitors of NIS, yet limited information exists for more structurally diverse chemicals. A novel cell line expressing human NIS, hNIS-HEK293T-EPA, was used in a radioactive iodide uptake (RAIU) assay to identify inhibitors of NIS-mediated iodide uptake.

The RAIU assay was optimized and performance evaluated with 12 reference chemicals comprising known NIS inhibitors and inactive compounds. An additional 39 chemicals including environmental contaminants were evaluated, with 28 inhibiting RAIU over 20% of that observed for solvent controls. Cell viability assays were performed to assess any confounding effects of cytotoxicity. RAIU and cytotoxic responses were used to calculate selectivity scores to group chemicals based on their potential to affect NIS. RAIU IC50 values were also determined for chemicals that displayed concentration-dependent inhibition of RAIU (≥50%) without cytotoxicity. Strong assay performance and highly reproducible results support the utilization of this approach to screen large chemical libraries for inhibitors of NIS-mediated iodide uptake.

Sodium carbonate was tested as one of the 12 'inactive' reference chemicals, i.e. not acting as a NIS inhibitor. The RAIU confirmed this status.
GLP compliance:
Type of method:
in vitro
Endpoint addressed:
other: endocrine disrupting properties

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium carbonate
EC Number:
EC Name:
Sodium carbonate
Cas Number:
Molecular formula:
disodium carbonate
Specific details on test material used for the study:
Purity: 99%
Source: Aldrich

Results and discussion

Details on results:
The ability to accurately differentiate between known inhibitors of NIS-mediated iodide uptake from known inactive chemicals was demonstrated using a set of well characterized reference chemicals. Sodium carbonate is included in this set of reference chemicals.
A concentration-dependent inhibition of iodide uptake was observed for 5 reference chemicals when tested up to 100 μM using the RAIU assay.These chemicals are ranked by potency as KPF6 >KClO4 >NaClO4 >NaBF4 >NaSCN. The activity of two additional reference chemicals (NaNO3 and NaBr), which have been reported in the literature to inhibit NIS-mediated 125I uptake under other assay conditions, tested inactive in our RAIU assay as the reported IC50 values for these two chemicals exceeded the maximum concentration initially tested. However, the inhibitory activities of NaNO3 and NaBr were confirmed for our RAIU when subsequently retested at higher concentrations with observed IC50 values of 612.6 ± 0.01 μM (mean ± SD; n = 3) and 8112 ± 10 μM, respectively.

All known inactive chemicals included in the reference set (NaF, Na2CO3, Na2SCO3, Na2S2CO3, Na2HPO4) tested inactive in this study, and none of the reference chemicals elicited cytotoxicity when tested up to 100 μM. Thus, the RAIU assay results for all reference chemicals were in agreement with previously reported results in the literature for a variety of cell lines expressing functional human and rat NIS.

Applicant's summary and conclusion

Na2CO3 was found to not disrupt the thyroid signaling pathway by means of inhibition of the sodium/iodide symporter (NIS).
Executive summary:

The study describes the use of a novel cell line expressing human sodium/iodide symporter (NIS) hNIS-HEK293T-EPA in a radioactive iodide uptake assay (RAIU) to identify NIS inhibition. Sodium carbonate was used as one of the chemicals in the reference substance dataset. Based on information available in the literature, sodium carbonate was expected to be inactive towards NIS inhibition.

The RAIU test result for sodium carbonate was negative, confirming that this substance does not inhibit NIS. Therefore, sodium carbonate was found to not disrupt the thyroid signaling pathway.