Review of the PRIODAC project on thyroid protection from radioactive iodine by repeated iodide intake in individuals aged 12+

in European Thyroid Journal
Authors:
Jean-Charles Martin Centre de recherche en CardioVasculaire et Nutrition (C2VN), Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), Institut National pour la Santé Et la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Marseille, France

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Thierry Pourcher Transporter in Imaging and Radiotherapy in Oncology Laboratory (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des sciences du vivant Frederic Joliot, Commissariat à l’Energie Atomique et aux Energies alternatives (CEA), Université Côte d’Azur (UCA), School of Medicine, Nice, France

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Guillaume Phan Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-Santé, Fontenay-aux-Roses, France

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Julien Guglielmi Transporter in Imaging and Radiotherapy in Oncology Laboratory (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des sciences du vivant Frederic Joliot, Commissariat à l’Energie Atomique et aux Energies alternatives (CEA), Université Côte d’Azur (UCA), School of Medicine, Nice, France

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Caroline Crambes Pharmacie Centrale des Armées (PCA), Direction des Approvisionnements en produits de Santé des Armées, Fleury-les-Aubrais, France

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François Caire-Maurisier Pharmacie Centrale des Armées (PCA), Direction des Approvisionnements en produits de Santé des Armées, Fleury-les-Aubrais, France

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Dalila Lebsir Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-Santé, Fontenay-aux-Roses, France

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David Cohen Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-Santé, Fontenay-aux-Roses, France

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Clément Rosique Centre de recherche en CardioVasculaire et Nutrition (C2VN), Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), Institut National pour la Santé Et la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Marseille, France

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Lun Jing Transporter in Imaging and Radiotherapy in Oncology Laboratory (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des sciences du vivant Frederic Joliot, Commissariat à l’Energie Atomique et aux Energies alternatives (CEA), Université Côte d’Azur (UCA), School of Medicine, Nice, France

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Maha Hichri Transporter in Imaging and Radiotherapy in Oncology Laboratory (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des sciences du vivant Frederic Joliot, Commissariat à l’Energie Atomique et aux Energies alternatives (CEA), Université Côte d’Azur (UCA), School of Medicine, Nice, France

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Lisa Salleron Transporter in Imaging and Radiotherapy in Oncology Laboratory (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des sciences du vivant Frederic Joliot, Commissariat à l’Energie Atomique et aux Energies alternatives (CEA), Université Côte d’Azur (UCA), School of Medicine, Nice, France

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Jacques Darcourt Transporter in Imaging and Radiotherapy in Oncology Laboratory (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des sciences du vivant Frederic Joliot, Commissariat à l’Energie Atomique et aux Energies alternatives (CEA), Université Côte d’Azur (UCA), School of Medicine, Nice, France

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Maamar Souidi Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-Santé, Fontenay-aux-Roses, France

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Marc Benderitter Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-Santé, Fontenay-aux-Roses, France

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Correspondence should be addressed to M Souidi: maamar.souidi@irsn.fr
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Background

Intake of potassium iodide (KI) reduces the accumulation of radioactive iodine in the thyroid gland in the event of possible contamination by radioactive iodine released from a nuclear facility. The World Health Organization (WHO) has stated the need for research for optimal timing, appropriate dosing regimen, and safety for repetitive iodine thyroid blocking (ITB). The French PRIODAC project, addressed all these issues, involving prolonged or repeated releases of radioactive iodine. Preclinical studies established an effective dose through pharmacokinetic modeling, demonstrating the safety of repetitive KI treatment without toxicity.

Summary

Recent preclinical studies have determined an optimal effective dose for repetitive administration, associated with pharmacokinetic modeling. The results show the safety and absence of toxicity of repetitive treatment with KI. Good laboratory practice level preclinical studies corresponding to individuals >12 years have shown a safety margin established between animal doses without toxic effect. After approval from the French health authorities, the market authorization of the two tablets of KI, 65 mg/day, was defined with a new dosing scheme of a daily repetitive intake of the treatment up to 7 days unless otherwise instructed by the competent authorities for all categories of population except pregnant women and children under the age of 12 years.

Conclusion

This new marketed authorization resulting from scientific-based evidence obtained as part of the PRIODAC project may serve as an example to further harmonize the application of KI for repetitive ITB in situations of prolonged radioactive release at the European and international levels, under the umbrella of the WHO.

Abstract

Background

Intake of potassium iodide (KI) reduces the accumulation of radioactive iodine in the thyroid gland in the event of possible contamination by radioactive iodine released from a nuclear facility. The World Health Organization (WHO) has stated the need for research for optimal timing, appropriate dosing regimen, and safety for repetitive iodine thyroid blocking (ITB). The French PRIODAC project, addressed all these issues, involving prolonged or repeated releases of radioactive iodine. Preclinical studies established an effective dose through pharmacokinetic modeling, demonstrating the safety of repetitive KI treatment without toxicity.

Summary

Recent preclinical studies have determined an optimal effective dose for repetitive administration, associated with pharmacokinetic modeling. The results show the safety and absence of toxicity of repetitive treatment with KI. Good laboratory practice level preclinical studies corresponding to individuals >12 years have shown a safety margin established between animal doses without toxic effect. After approval from the French health authorities, the market authorization of the two tablets of KI, 65 mg/day, was defined with a new dosing scheme of a daily repetitive intake of the treatment up to 7 days unless otherwise instructed by the competent authorities for all categories of population except pregnant women and children under the age of 12 years.

Conclusion

This new marketed authorization resulting from scientific-based evidence obtained as part of the PRIODAC project may serve as an example to further harmonize the application of KI for repetitive ITB in situations of prolonged radioactive release at the European and international levels, under the umbrella of the WHO.

Introduction

The Repeated Stable Iodide Prophylaxis in Accidental Situations project (PRIODAC) (https://en.irsn.fr/research/priodac-project) was launched by Institute for Radiation Protection and Nuclear Safety in 2014 for a duration of 8 years (1). It aimed to define the conditions for repetitive administration of potassium iodide (KI) in order to protect the population undergoing prolonged exposure to radioactive iodine in a nuclear or radiological accidental situation. The results obtained in a series of studies conducted as part of this project are reported here as a review, with a special focus on an application to the adult population. Besides an obvious interest with regard to the previous Chernobyl and Fukushima nuclear accidents, our results dedicated to population protection against radioactive iodine spreading can also be also contextualized in the shadow of the war in Ukraine with the threat on Ukrainian nuclear power plants.

The main threat observed after radio-iodine contamination concerns papillary thyroid cancer, the most frequent histologic type of thyroid cancer that has been observed in such a situation (2). The World Health Organization (WHO) recommends the implementation of iodine thyroid blocking (ITB) in the event of radiological and nuclear emergencies (3), and it is advisable to do so in response to the prevailing geopolitical context (4). The protective effect of KI against exposure to radioactive iodines results mainly from the saturation of iodide transport, the dilution of circulating iodide, and the increased excretion of iodide. However, the regulation of thyroid function (including Wolff–Chaikoff effect) must also be taken into account (5). Indeed, iodide-induced thyroid regulation leads to the inhibition of several steps of thyrocyte function such as iodide uptake and its organification as well as thyroid hormone secretion. These effects increase the protection of the thyroid, though by inhibiting hormone secretion, radioactive iodine that has been previously incorporated could be retained. Although thyroid regulation by iodide was first described in the 1940s, little is known about the underlying molecular mechanisms which still need to be better characterized (5, 6). The recommended single dosage of KI according to age group was proposed by the WHO, i.e. 130 mg KI for adults and adolescents (over 12 years), 65 mg for children (3–12 years), 32 mg for infants (1 month–3 years), and 16 mg for neonates (birth to 1 month). The key factor for the effectiveness of this countermeasure effectiveness is a rapid and timely implementation. Indeed, the physical half-lives of radioactive iodine are quite short (8 days for iodine-131, 6.57 h for iodine-135) and thus require administration preferably in the few hours preceding the exposure or, failing that, as quickly as possible in the first hours afterward. If taken too long before exposure, this medication loses all its protective effects. If taken too late after exposure, the thyroid is no longer protected, as the radioactive iodine has already accumulated in the thyroid. When ITB is initiated in the optimal time window, thyroid protection is greater than 80% during the first 2 days of unique KI administration (7).

In 2017, the WHO Guideline Development Group identified the need for more data on the dosage, optimal timing, regimen, and safety for repetitive ITB in the case of protracted releases of radioactive iodine (8). A review of the medical and scientific literature revealed a lack of knowledge concerning the side effects of repetitive administration of KI, both in humans and in animals. However, some early clinical studies in the adult population showed transient changes in blood thyroid hormone levels following KI administration (9, 10, 11, 12). The objective of the present paper is to present new knowledge recently published covering scientific evidence based on pharmacokinetics, bio-distribution, efficacy, and toxicology of repetitive ITB in preclinical models. KI is an antidote, used in the context of an exceptional health emergency following a nuclear accident, therefore it does not fall within the register of a conventional drug for therapeutic management. As this is a special application (nuclear emergency), it is not conceivable to carry out conventional clinical studies for its use in humans. These new data were challenged against a unique ITB, leading to the development of a secure and effective prescription extending up to 7 days for individuals aged 12 years and above.

Pharmacokinetics of repetitive ITB

A correlation between KI concentrations in the plasma and a blockade of the uptake of iodine radioisotopes into the thyroid has already been suggested in early studies (9, 10), but it has never been fully characterized experimentally or by pharmacokinetic–pharmacodynamic modeling. Part of our work was to revise and complete the data on KI prophylaxis using pharmacological approaches.

First, an optimal single dose of 1 mg/kg KI has been determined from dose-response preclinical experiments in rodents and was selected based on the level of thyroid protection against iodine-125 incorporation as well as on the thyroid distribution and urinary elimination of KI (11). Then, the pharmacokinetic parameters of KI were determined after oral and intravenous administration of this specific dose of 1 mg/kg in order to assess the duration of the thyroid protective effect and to propose an optimal dose regimen for repetitive KI prophylaxis (12). In terms of thyroid protection, it has been reported in the literature that in humans the percentage of avoided dose to the thyroid is between 50% and 75% even if the exposure occurs 48 h after a single oral administration of 100 mg to 200 mg of KI (i.e. 1.8 to 3.7 mg/kg KI) (7). Such levels of thyroid protection could serve as target values of minimal efficacy and were selected for the assessment of the KI dose regimen in our study. Hence, the pharmacokinetic parameters of KI were determined in order to model a dose regimen consisting of daily administration of the dose of 1 mg/kg over 8 days. We confirmed the previously described good correlation (9, 10) between the effect of KI administration against the incorporation of iodine-125 into the thyroid and stable KI plasma concentrations, which allowed us to verify the efficacy of the proposed repetitive prophylaxis. The results showed that this dose regimen would provide over 75% thyroid protection for 14 h after the first KI administration and over 60% protection before subsequent KI dosing (12). These results showed that KI doses superior to 1 mg/kg should be considered for optimal thyroid protection in protracted prophylaxis and that the currently recommended dose in humans should be suitable, provided that no adverse effect is induced with 1.8 mg/kg/day KI for 7 days. Other experiments using SPECT (single-photon emission computed tomography) imaging were performed (13). The addition of radioactive iodine-123 to the KI dose (1 mg/kg) allowed us to determine the behavior of iodine in the thyroid and the other organs. It also confirmed the rapid elimination of the excess iodide within 12 h. SPECT imaging also allowed the determination of the kinetics of radioactive iodine and modeling of the thyroid protection at different time points in between two KI doses. Daily KI (1 mg/kg) administrations led to very effective protection (90%) against iodine-125 exposure after the last KI dose. This protection decreased to less than 60% 23 h after the last KI dose (Fig. 1). The overall protection was calculated to be about 85% for acute exposure at any time between two KI doses (13). In conclusion, these studies were useful in predicting the duration and efficacy of daily KI administration as a function of the pharmacokinetic parameters and in suggesting an operational dosing regimen for repetitive KI prophylaxis. From a fundamental point of view, these studies also provided further data on thyroid iodine metabolism and its regulation by iodide.

Figure 1
Figure 1

Correlation between thyroid protection against radioactive iodine isotope incorporation and plasma stable iodide concentrations as a function of time after repeated doses of KI (1 mg/kg/day) for 8 days in rats: the percentage of thyroid protection or avoided dose (green curve) and plasma stable iodide (blue curve) were simulated by pharmacodynamic/pharmacokinetic modeling of data obtained after oral administration of stable KI 1 h before iodine-125 intravenous injection (23).

Citation: European Thyroid Journal 13, 1; 10.1530/ETJ-23-0139

Standard, preclinical safety studies of repetitive ITB

The ability of the thyroid gland to concentrate iodide is essential for the synthesis of thyroid hormones through a complex mechanism involving several functional proteins (14, 15). The levels of circulating thyroid hormones are tightly regulated in physiological processes and have a major impact on the homeostasis of the body. Excess iodide can cause a transient downregulation of thyroid hormone levels, the so-called Wolff–Chaikoff effect (16, 17, 18, 19).

Repetitive administration of KI could be used as an option for prolonged exposure to radioiodine, but there is a real lack of knowledge on health outcomes about repetitive ITB.

Thus, as stated earlier, to experimentally mimic repetitive prophylaxis, a dose of 1 mg/kg/day for 8 days has been used in preclinical studies, as this has been shown to be an optimal dose in terms of efficacy (11). Urine iodine concentration was measured 10 days and 30 days after the end of treatment to assess iodide status, and no significant difference for any phenotypical outcomes was observed between the treatment and control groups (20). These results are in agreement with other preclinical studies where excess iodide for a relatively long period of time did not alter the overall body weight of Wistar rats (21, 22). In addition, given the importance of thyroid function on physiological homeostasis, a preclinical study showed that plasma and urinary biochemical parameters did not differ between rats given repetitive doses of iodide and controls (21). Yoshida and his colleagues also demonstrated that after administration of iodide at more than 3 mg/day to rats for 4 weeks, no change was observed in specific biochemical parameters (alanine aminotransferase, aspartate aminotransferase, total cholesterol, and triglycerides) (21), reflecting the harmlessness of this treatment on metabolism, particularly that of the liver. Finally, we showed that repetitive treatment with stable iodide for 8 days had no biological effects on the cardiovascular system (23).

To assess thyroid function 30 days after ending repetitive administration, blood levels of thyroid-stimulating hormone and free thyroid hormones were assessed as relevant biomarkers. No difference was observed between the treated and control groups, which may suggest that thyroid function was not affected by the repetitive setting (20). These findings align with the outcomes of other clinical and preclinical studies conducted in repetitive settings, which consistently report no discernible impact of iodide on pituitary–thyroid axis activity (10, 22, 24, 25, 26, 27, 28, 29, 30).

In preclinical studies, histological analysis of the thyroid showed no changes attributable to the repetitive iodide supplementation. Follicle shape and size and cell proliferation index showed no difference between treated and control rats (20). This is in contrast with previous studies in rats, where histological analysis of the thyroid showed a significant enlargement of the thyroid follicles and an increase in the amount of extracellular matrix around them in response to an acute and single dose of excessive iodide treatment (29, 31). In the thyroid, two proteins play an important role in iodide transport and thyroid hormone synthesis, namely, the sodium–iodide symporter (NIS) and thyroid peroxidase (TPO). In a study by Arriagada and colleagues (28), immunohistochemical characterization of thyroid tissue indicated that the abundance and localization of these two proteins were unaffected 30 days after discontinuation of KI and these results are in agreement with Faggiano and colleagues (32). Finally, the results of histological analysis, proliferation assessment, and immunohistochemical characterization showed no negative effect of KI 1 mg/kg/day for 8 days on cytoarchitecture and thyroid function (33).

The absence of recognized harmful effects or clinical dysfunctions consecutive to repetitive iodide administration-based thyroid blocking does not mean that no subclinical dysfunction would occur. However, conventional toxicological approaches might lack the sensitivity needed to reveal physiological modifications in the subclinical range and occurring from subtle changes in thyroid function. Omics technologies, including transcriptomics and metabolomics, would bring further complementary information. They could reveal subclinical phenotypes or a ‘silent’ sensitization phase at the molecular level prior to the occurrence of phenotypic changes (34). It is well known that the Wolff–Chaikoff effect and its escape occur during exposure of the thyroid to supraphysiological concentrations of iodide (16). Leoni and colleagues analyzed the transcriptomic profile of a rat follicular cell line under normal and excess iodide conditions and found that 84 transcripts (specifically categorized as protein metabolism) were differentially expressed in response to excess iodide (35). In an in vivo study, the transcriptome profile of the rat thyroid was analyzed under treated and untreated conditions in a repetitive administration setting. No difference in the expression profile between treated and control groups was observed (20). Furthermore, even the expression of genes involved in iodide metabolism and thyroid hormone synthesis was similar between the treated and control groups 30 days after prophylaxis. This indicates that repetitive treatment with KI at a dose of 1 mg/kg/day does not affect important molecular and cellular processes.

We further conducted a metabolome characterization of the thyroid, plasma, and urine of adult male Wistar rats (aged 3 months) 30 days after completion of the ITB regimen (1 mg/kg/7 days of KI) (36), beyond acute thyroid blocking. The metabolomics analyses revealed many differences between the rats of the study group (control and KI treated), amongst which the thyroid still remained the most sensitive to ITB. This was exemplified by the highest number of associated biological functions that significantly diverged in treated vs control rats (60% of the total biological functions, vs 38% and 22% in both plasma and urine, respectively). This indicated a limited systemic impact of ITB compared to thyroid effects. In this organ, tyrosine and catecholamine metabolisms were among the top significant functions that were changed 30 days after the cessation of the treatment. In thyroid, tyrosine metabolism was also correlated with other metabolic functions (catecholamine metabolism, antioxidant status, vitamins metabolism, etc.), together with other metabolic outcomes measured in both plasma and urine (metabolic adjustment, amino-acid metabolism, antioxidant status). We showed that thyroid tyrosine metabolism modulated by ITB was more driven by the catecholamine pathways (dopamine) than the synthesis of thyroid hormones. Conversely, macroscopic evaluation did not reveal any differences between the treated and nontreated rats one month after the end of KI repetitive intake (body, liver, kidneys, thyroid masses, thyroid hormones). It was also elsewhere observed that the analysis of metabolic profiles of individuals (metabotypes) could better reveal subclinical outcomes to identify subjects at high risk for metabolic disruptions despite shifts in classical clinical parameters not yet being detectable (37, 38). Furthermore, the changes of a persistent metabolomics response after cessation of the KI trial would locate in the range of physiological variations, called ‘allostatic regulations’ (39), since they remained clinically asymptomatic. Therefore, it is unlikely that our metabolomics observations would project into the pathological metabolic space per se. Conversely, our findings highlighting allostatic regulation would indicate a shift toward a new but still healthy stage that prepares the physiological response for another challenge (40). However, if such allostatic conditions continue or are accompanied by other odd metabolic disruptions, then the cost could be pathological outcomes (40).

In the absence of clear clinical signs of dysfunction or toxicity, we concluded that the measured metabolomics response to the new ITB strategy is unlikely to reveal a pathological condition at the time of examination.

Thus, the results obtained in these preclinical studies showed that repetitive KI administration at a dose of 1 mg/kg/day for 8 days had no harmful effect on the health status, as well as the structure and function of the thyroid.

Molecular mechanisms associated with excess iodide

The mechanisms behind the effect of high dose iodide have been studied and are well documented in the literature (16). Indeed, the major consequence is that thyroid hormone synthesis is reduced when the thyrocyte intracellular iodide concentration is elevated (41), this mechanism being known as the Wolff–Chaikoff effect (42). This transient effect is associated with modulation of NIS and the enzyme TPO (26, 43). The mechanism that leads to escaping this blockade is the decrease of Nis expression and this is associated with the reduction of the NIS protein (16). More recently, posttranscriptional regulation of Nis at the level of mRNA stability has also been demonstrated (25). These mechanisms lead to a decrease in the intracellular iodide concentration, thus inducing inhibition of thyroid hormone synthesis.

During chronic KI administration, Nis expression is also downregulated (26, 29) and it has been shown that the thyroid hormones transport (Mct8), iodide organification (Tpo), and chloride iodide transporter (Pds) genes may also be differentially expressed, although other studies have found no difference (29, 31, 33). The mechanism behind the regulation of these genes upon repetitive administration of KI is currently unknown. However, we suggested that the Wolff–Chaikoff effect during chronic KI administration consists of a two-step mechanism: first, iodide rapidly inhibits Nis and Mct8 expression upon ingestion, and the second step is a late Wolff–Chaikoff effect, which essentially involves inhibition of Nis gene expression by excess iodide (20) (Fig. 2).

Figure 2
Figure 2

Hypothetical mechanism of the Wolff–Chaikoff effect in response to repetitive administration of potassium iodide (KI) on genes involved in iodide transport (sodium/iodide symporter (Nis), pendrin (Pds), and apical iodide transporter (Ait)), iodide organification (thyroid peroxidase (Tpo), thyroglobulin (Tg), dual oxidase (Duox)), and thyroid hormone transport (monocarboxylate transporter 8 (Mct8)). 1—thyrocyte basal state; 2—sequential Wolff–Chaikoff effect after repetitive administration of KI, in blue a rapid Wolff–Chaikoff effect, and in green a delayed Wolff–Chaikoff effect; 3—escape from the Wolff–Chaikoff effect after the end of the treatment (thyrocytes return to basal state).

Citation: European Thyroid Journal 13, 1; 10.1530/ETJ-23-0139

Recently, through a systems biology approach, we proposed a new mechanism for the regulatory effect of repetitive prophylaxis of stable iodide on Nis expression (44). To understand the regulation of the Wolff–Chaikoff effect and its molecular constituents upon repetitive KI administration, a network of biochemical reactions was constructed as a ‘geographical’ map of the thyrocyte representing iodide metabolism and thyroid hormone synthesis. In this study, a putative mechanism of the Wolff–Chaikoff regulation was proposed, by which the sequential regulation of the highly organifed thyroglobulin protein affects the level of both Nis and Tpo and regulates thyroid hormone synthesis step (Duox2), Mct8, and thyroglobulinitself. Of course, the ultimate validation would be experimental to test whether this hypothesis is correct. With this study, a putative mechanism was shown to regulate NIS and TPO without causing nontoxic adverse effects on repetitive administration of KI (42, 43, 44).

Toxicological assessment: good laboratory practice safety study of repetitive ITB

Generally speaking, KI is an antidote used in a context of an exceptional health emergency following a nuclear accident. Therefore, KI does not fall within the register of a conventional drug for therapeutic management. KI is indicated to prevent the accumulation of radioactive iodine in the thyroid in the case of possible contamination by radioactive iodine emitted during an incident/accident on a nuclear installation. As this is a special application (nuclear accident), in view of the classification of the product as an antidote, it is not conceivable to conduct conventional clinical studies for its use in humans.

The toxicological investigations reported below were conducted as part of the preclinical development phase of KI. The main studies were performed in accordance with the Organization for Economic Co-operation and Development (OECD) guidelines, guidelines concerning good laboratory practice (GLP), and other applications (45). Experiments were performed in accordance with well-established procedures in regulatory experimental toxicology and were deeply reviewed by the expert committee that provided a positive advice for a new marketing authorization of repeated KI administration (46). One rodent and one nonrodent species were selected as test systems, first looking for the maximum tolerated dose for 7 days and then the no observed adverse effect level (NOAEL) for a 28-day test. These data were provided for the modification of the marketing authorization of KI (65 mg, scored pills) for repetitive ITB in adults and children aged 12+, validated by the French National Agency for the Safety of Medicines and Health Products (ANSM).

Potential mutagenic activity of KI was assessed using Ames’ test in five Salmonella typhimurium strains (TA1535, TA1537, etc.) tested both in the presence and in the absence of metabolic activation, in two independent assays according to OECD guideline 471 (47), using the maximum recommended dose, i.e. 5000 µg/plate. Under these experimental conditions, no mutagenic activity was revealed. Similarly, potential genotoxic activity of KI was assessed with the in vitro micronucleus test in human lymphocytes treated in the presence and absence of metabolic activation, both with short-term and long-term treatment, according to OECD guideline 487 and International Council for Harmonization of technical requirements for pharmaceuticals for human use (ICH) guideline S2(R1) (48). The highest concentration was chosen in accordance with the ICH recommendation. Under these experimental conditions, no genotoxic activity was observed in the presence and in the absence of metabolic activation.

In order to support an extension of the duration of treatment with KI from 1 or 2 days to 7 days in humans, two pivotal GLP toxicological studies were performed in rats and dogs for 28 days. These preclinical rodent and nonrodent models are commonly used as references in toxicology (49). Several parameters were studied, such as clinical signs, body temperature and weight, ophthalmological, hematological and biological parameters, thyroid hormones, organs macroscopic examination, histopathology, and weight. A toxicokinetics analysis was also conducted, as well as a safety pharmacology study for the cardiovascular and respiratory system (in the dog) and for the central nervous system (Irwin test in the rat (50)). From the aforementioned biological parameters examined, target organs in rats and dogs were determined as liver and kidneys, since hepatic and renal functions were modified at a higher dose of 500 mg/kg in the rat and from 40 mg/kg onward in the dog. In addition, KI administered during the 28 days at 500 mg/kg/day to rats did not induce any CNS disturbances (Irwin test). When KI was administered to dogs during the 28 days at 60 mg/kg/day, no changes were noted in respiratory or cardiovascular parameters recorded, compared with control groups (safety pharmacology studies).

Data obtained on the two species were extrapolated to humans in accordance with the ICH M3(R2) guideline (51) and the U.S. Food and Drug Administration recommendations (52). The GLP regulatory toxicology studies allowed to define a NOAEL of 100 mg/kg/day for 28 days in rats and 20 mg/kg/day for 28 days in dogs. Referring to the two abovementioned applications as well as to the article by Reagan-Shaw et al. (53), the NOAEL was calculated for extrapolation to humans, Human Equivalent Dose (HED), for each of the two species studied (toxicological data necessary to shift from the preclinical model to the clinical model). HEDs of 16.1 mg/kg and 11 mg/kg were obtained from the rat and dog models, respectively. Thus, the daily KI dosage of 130 mg (1.8 mg/kg) proposed in the application for the modification of the marketing authorization is much lower than the HED calculated. A safety factor >10 was noted for both rat and dog models. This safety factor >10 respects the recommendations put forward in the abovementioned reference documents.

Preclinical studies concluded a favorable benefit–risk balance for repetitive intake of KI up to 7 consecutive days. These data supported the extension of the new marketing authorization of KI (65 mg scored pills) for repetitive ITB (130 mg daily up to 7 days) in adults and children aged 12+. A first modification of the marketing authorization of KI for repetitive prophylaxis in adults (except pregnant or breastfeeding women) and children aged 12+ was thus obtained in France in March 2020 from the ANSM. A synopsis of the posology as a function of age is provided in Table 1.

Table 1

Synopsis of KI posology as a function of age.

Age Iodine (mg) KI (mg) Length of treatment
Adult and child above 12 100 130 Dose with possible repeat after 7 days
Pregnant/breastfeeding woman 100 130 Single dosea
Newborn (up to 1 month) 12.5 16 Single doseb
Infant/toddler (1 month to 3 years) 25 32 Single doseb
Child (3 to 12 years) 50 65 Single doseb

aMarketed authorization evolution running; bMarketed authorization evolution planned.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This results of the PRIODAC consortium summarized in the manuscript were funded by the French Government under the ‘Investments for the Future’ program (Nuclear Safety and Radioprotection Research (RSNR) action), managed by the French National Research Agency (ANR- 11-RSNR-0019).

Author contributions statement

JCM, TP, GP, CC, MS, and MB were involved in conception, writing, review, and critical review. All authors contributed to the results produced by the laboratories of the PRIODAC consortium and commented on the manuscript.

Acknowledgements

The authors thank the ANR program manager Dr Antony Lebeau for his support and confidence and Dr Stéphane Flamant for grammatical correction and proofreading of the manuscript.

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    World Health Organization. Protection of the Human E, Radiation and health Team. Iodine thyroid blocking: guidelines for use in planning and responding to radiological and nuclear emergencies. Geneva: World Health Organization 2017.

    • PubMed
    • Search Google Scholar
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    Blum M, & Eisenbud M. Reduction of thyroid irradiation from 131-I by potassium iodide. JAMA 1967 200 10361040. (https://doi.org/10.1001/jama.1967.03120250070012)

    • PubMed
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  • 10

    Sternthal E, Lipworth L, Stanley B, Abreau C, Fang SL, & Braverman LE. Suppression of thyroid radioiodine uptake by various doses of stable iodide. New England Journal of Medicine 1980 303 10831088. (https://doi.org/10.1056/NEJM198011063031903)

    • PubMed
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    Phan G, Rebière F, Suhard D, Legrand A, Carpentier F, Sontag T, Souidi M, Jourdain JR, Agarande M, & Renaud-Salis V. Optimal KI Prophylactic Dose Determination for Thyroid Radiation Protection After a Single Administration in Adult Rats. Dose-Response 2017 15 1559325817746558. (https://doi.org/10.1177/1559325817746558)

    • PubMed
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    Phan G, Chioukh R, Suhard D, Legrand A, Moulin C, Sontag T, Rebière F, Bouvier-Capely C, Agarande M, Renaud-Salis V, et al.Repeated KI prophylaxis in case of prolonged exposure to iodine radioisotopes: pharmacokinetic studies in adult rats. Pharmaceutical Research 2018 35 227. (https://doi.org/10.1007/s11095-018-2515-1)

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    Guglielmi J, D’Andréa G, Cambien B, Graslin F, Chatti K, Robart E, Schiazza A, Zwarthoed C, Humbert O, Lindenthal S, et al.New insights into iodide metabolism based on preclinical models: impact on radiotherapy efficacy and protection against radioactive iodine exposure. bioRxiv 2023. (https://doi.org/10.1101/2023.10.11.561684)

    • PubMed
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    Pesce L, & Kopp P. Iodide transport: implications for health and disease. International Journal of Pediatric Endocrinology 2014 2014 8. (https://doi.org/10.1186/1687-9856-2014-8)

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    Portulano C, Paroder-Belenitsky M, & Carrasco N. The Na+/I- symporter (NIS): mechanism and medical impact. Endocrine Reviews 2014 35 106149. (https://doi.org/10.1210/er.2012-1036)

    • PubMed
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    Eng PH, Cardona GR, Fang SL, Previti M, Alex S, Carrasco N, Chin WW, & Braverman LE. Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. Endocrinology 1999 140 34043410. (https://doi.org/10.1210/endo.140.8.6893)

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    Zaballos MA, Garcia B, & Santisteban P. Gβγ dimers released in response to thyrotropin activate phosphoinositide 3-kinase and regulate gene expression in thyroid cells. Molecular Endocrinology 2008 22 11831199. (https://doi.org/10.1210/me.2007-0093)

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    Maia AL, Goemann IM, Meyer EL, & Wajner SM. Deiodinases: the balance of thyroid hormone: type 1 iodothyronine deiodinase in human physiology and disease. Journal of Endocrinology 2011 209 283297. (https://doi.org/10.1530/JOE-10-0481)

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  • 19

    de Souza EC, Dias GR, Cardoso RC, Lima LP, Fortunato RS, Visser TJ, Vaisman M, Ferreira AC, & Carvalho DP. MCT8 is Downregulated by Short Time Iodine Overload in the Thyroid Gland of Rats. Hormone and Metabolic Research 2015 47 910915. (https://doi.org/10.1055/s-0035-1550008)

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  • 20

    Lebsir D, Manens L, Grison S, Lestaevel P, Ebrahimian T, Suhard D, Phan G, Dublineau I, Tack K, Benderitter M, et al.Effects of repeated potassium iodide administration on genes involved in synthesis and secretion of thyroid hormone in adult male rat. Molecular and Cellular Endocrinology 2018 474 119126. (https://doi.org/10.1016/j.mce.2018.02.017)

    • PubMed
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    Yoshida M, Mukama A, Hosomi R, Fukunaga K, & Nishiyama T. Serum and tissue iodine concentrations in rats fed diets supplemented with kombu powder or potassium iodide. Journal of Nutritional Science and Vitaminology 2014 60 447449. (https://doi.org/10.3177/jnsv.60.447)

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  • 22

    Calil-Silveira J, Serrano-Nascimento C, Laconca RC, Schmiedecke L, Salgueiro RB, Kondo AK, & Nunes MT. Underlying mechanisms of pituitary-thyroid axis function disruption by chronic iodine excess in rats. Thyroid 2016 26 14881498. (https://doi.org/10.1089/thy.2015.0338)

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    Lebsir D, Cantabella E, Cohen D, Sache A, Ebrahimian T, Kereselidze D, Amine Benadjaoud M, Maurisier FC, Guigon P, René Jourdain J, et al.Effect of repetitive potassium iodide on thyroid and cardiovascular functions in elderly rats. Biochemistry and Biophysics Reports 2020 24 100816. (https://doi.org/10.1016/j.bbrep.2020.100816)

    • PubMed
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    • Export Citation
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    Theodoropoulou A, Vagenakis AG, Makri M, & Markou KB. Thyroid hormone synthesis and secretion in humans after 80 milligrams of iodine for 15 days and subsequent withdrawal. Journal of Clinical Endocrinology and Metabolism 2007 92 212214. (https://doi.org/10.1210/jc.2006-1189)

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    Serrano-Nascimento C, Calil-Silveira J, & Nunes MT. Posttranscriptional regulation of sodium-iodide symporter mRNA expression in the rat thyroid gland by acute iodide administration. American Journal of Physiology 2010 298 C893C899. (https://doi.org/10.1152/ajpcell.00224.2009)

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    Solis-S JC, Villalobos P, Orozco A, Delgado G, Quintanar-Stephano A, Garcia-Solis P, Hernandez-Montiel HL, Robles-Osorio L, & Valverde-R C. Inhibition of intrathyroidal dehalogenation by iodide. Journal of Endocrinology 2011 208 8996. (https://doi.org/10.1677/JOE-10-0300)

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  • 27

    Schneider AB, & Smith JM. Potassium iodide prophylaxis: what have we learned and questions raised by the accident at the Fukushima Daiichi Nuclear Power Plant. Thyroid 2012 22 344346. (https://doi.org/10.1089/thy.2012.2204.com)

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    Arriagada AA, Albornoz E, Opazo MC, Becerra A, Vidal G, Fardella C, Michea L, Carrasco N, Simon F, Elorza AA, et al.Excess iodide induces an acute inhibition of the sodium/iodide symporter in thyroid male rat cells by increasing reactive oxygen species. Endocrinology 2015 156 15401551. (https://doi.org/10.1210/en.2014-1371)

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  • 29

    Chen XY, Lin CH, Yang LH, Li WG, Zhang JW, Zheng WW, Wang X, Qian J, Huang JL, & Lei YX. The effect on sodium/iodide symporter and pendrin in thyroid colloid retention developed by excess iodide intake. Biological Trace Element Research 2016 172 193200. (https://doi.org/10.1007/s12011-015-0580-4)

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  • Figure 1

    Correlation between thyroid protection against radioactive iodine isotope incorporation and plasma stable iodide concentrations as a function of time after repeated doses of KI (1 mg/kg/day) for 8 days in rats: the percentage of thyroid protection or avoided dose (green curve) and plasma stable iodide (blue curve) were simulated by pharmacodynamic/pharmacokinetic modeling of data obtained after oral administration of stable KI 1 h before iodine-125 intravenous injection (23).

  • Figure 2

    Hypothetical mechanism of the Wolff–Chaikoff effect in response to repetitive administration of potassium iodide (KI) on genes involved in iodide transport (sodium/iodide symporter (Nis), pendrin (Pds), and apical iodide transporter (Ait)), iodide organification (thyroid peroxidase (Tpo), thyroglobulin (Tg), dual oxidase (Duox)), and thyroid hormone transport (monocarboxylate transporter 8 (Mct8)). 1—thyrocyte basal state; 2—sequential Wolff–Chaikoff effect after repetitive administration of KI, in blue a rapid Wolff–Chaikoff effect, and in green a delayed Wolff–Chaikoff effect; 3—escape from the Wolff–Chaikoff effect after the end of the treatment (thyrocytes return to basal state).

  • 1

    Benderitter M, Pourcher T, Martin J-C, Darcourt J, Guigon P, Caire-Maurisier F, Pech A, Lebsir D, Rosique C, & Guglielmi J. Multiple administrations of stable iodide protect population chronically exposed to radioactive iodine: what is priodac research program (2014-22) teaching us? Radiation Protection Dosimetry 2018 182 6779. (https://doi.org/10.1093/rpd/ncy129)

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    World Health Organization Protection of the Human E. Guidelines for Iodine Prophylaxis Following Nuclear Accidents: Update 1999. Geneva: World Health Organization 1999.

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    Toft DJ, & Schneider AB. Protecting the thyroid in times of conflict (Ukraine 2022). Thyroid 2022 32 607610. (https://doi.org/10.1089/thy.2022.0135)

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    Dayem M, Navarro V, Marsault R, Darcourt J, Lindenthal S, & Pourcher T. From the molecular characterization of iodide transporters to the prevention of radioactive iodide exposure. Biochimie 2006 88 17931806. (https://doi.org/10.1016/j.biochi.2006.07.015)

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  • 6

    Leoni SG, Kimura ET, Santisteban P, & De la Vieja A. Regulation of thyroid oxidative state by thioredoxin reductase has a crucial role in thyroid responses to iodide excess. Molecular Endocrinology 2011 25 19241935. (https://doi.org/10.1210/me.2011-0038)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Verger P, Aurengo A, Geoffroy B, & Le Guen B. Iodine kinetics and effectiveness of stable iodine prophylaxis after intake of radioactive iodine: a review. Thyroid 2001 11 353360. (https://doi.org/10.1089/10507250152039082)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    World Health Organization. Protection of the Human E, Radiation and health Team. Iodine thyroid blocking: guidelines for use in planning and responding to radiological and nuclear emergencies. Geneva: World Health Organization 2017.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Blum M, & Eisenbud M. Reduction of thyroid irradiation from 131-I by potassium iodide. JAMA 1967 200 10361040. (https://doi.org/10.1001/jama.1967.03120250070012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Sternthal E, Lipworth L, Stanley B, Abreau C, Fang SL, & Braverman LE. Suppression of thyroid radioiodine uptake by various doses of stable iodide. New England Journal of Medicine 1980 303 10831088. (https://doi.org/10.1056/NEJM198011063031903)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Phan G, Rebière F, Suhard D, Legrand A, Carpentier F, Sontag T, Souidi M, Jourdain JR, Agarande M, & Renaud-Salis V. Optimal KI Prophylactic Dose Determination for Thyroid Radiation Protection After a Single Administration in Adult Rats. Dose-Response 2017 15 1559325817746558. (https://doi.org/10.1177/1559325817746558)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Phan G, Chioukh R, Suhard D, Legrand A, Moulin C, Sontag T, Rebière F, Bouvier-Capely C, Agarande M, Renaud-Salis V, et al.Repeated KI prophylaxis in case of prolonged exposure to iodine radioisotopes: pharmacokinetic studies in adult rats. Pharmaceutical Research 2018 35 227. (https://doi.org/10.1007/s11095-018-2515-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Guglielmi J, D’Andréa G, Cambien B, Graslin F, Chatti K, Robart E, Schiazza A, Zwarthoed C, Humbert O, Lindenthal S, et al.New insights into iodide metabolism based on preclinical models: impact on radiotherapy efficacy and protection against radioactive iodine exposure. bioRxiv 2023. (https://doi.org/10.1101/2023.10.11.561684)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Pesce L, & Kopp P. Iodide transport: implications for health and disease. International Journal of Pediatric Endocrinology 2014 2014 8. (https://doi.org/10.1186/1687-9856-2014-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Portulano C, Paroder-Belenitsky M, & Carrasco N. The Na+/I- symporter (NIS): mechanism and medical impact. Endocrine Reviews 2014 35 106149. (https://doi.org/10.1210/er.2012-1036)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Eng PH, Cardona GR, Fang SL, Previti M, Alex S, Carrasco N, Chin WW, & Braverman LE. Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. Endocrinology 1999 140 34043410. (https://doi.org/10.1210/endo.140.8.6893)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Zaballos MA, Garcia B, & Santisteban P. Gβγ dimers released in response to thyrotropin activate phosphoinositide 3-kinase and regulate gene expression in thyroid cells. Molecular Endocrinology 2008 22 11831199. (https://doi.org/10.1210/me.2007-0093)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Maia AL, Goemann IM, Meyer EL, & Wajner SM. Deiodinases: the balance of thyroid hormone: type 1 iodothyronine deiodinase in human physiology and disease. Journal of Endocrinology 2011 209 283297. (https://doi.org/10.1530/JOE-10-0481)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    de Souza EC, Dias GR, Cardoso RC, Lima LP, Fortunato RS, Visser TJ, Vaisman M, Ferreira AC, & Carvalho DP. MCT8 is Downregulated by Short Time Iodine Overload in the Thyroid Gland of Rats. Hormone and Metabolic Research 2015 47 910915. (https://doi.org/10.1055/s-0035-1550008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Lebsir D, Manens L, Grison S, Lestaevel P, Ebrahimian T, Suhard D, Phan G, Dublineau I, Tack K, Benderitter M, et al.Effects of repeated potassium iodide administration on genes involved in synthesis and secretion of thyroid hormone in adult male rat. Molecular and Cellular Endocrinology 2018 474 119126. (https://doi.org/10.1016/j.mce.2018.02.017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Yoshida M, Mukama A, Hosomi R, Fukunaga K, & Nishiyama T. Serum and tissue iodine concentrations in rats fed diets supplemented with kombu powder or potassium iodide. Journal of Nutritional Science and Vitaminology 2014 60 447449. (https://doi.org/10.3177/jnsv.60.447)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Calil-Silveira J, Serrano-Nascimento C, Laconca RC, Schmiedecke L, Salgueiro RB, Kondo AK, & Nunes MT. Underlying mechanisms of pituitary-thyroid axis function disruption by chronic iodine excess in rats. Thyroid 2016 26 14881498. (https://doi.org/10.1089/thy.2015.0338)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Lebsir D, Cantabella E, Cohen D, Sache A, Ebrahimian T, Kereselidze D, Amine Benadjaoud M, Maurisier FC, Guigon P, René Jourdain J, et al.Effect of repetitive potassium iodide on thyroid and cardiovascular functions in elderly rats. Biochemistry and Biophysics Reports 2020 24 100816. (https://doi.org/10.1016/j.bbrep.2020.100816)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Theodoropoulou A, Vagenakis AG, Makri M, & Markou KB. Thyroid hormone synthesis and secretion in humans after 80 milligrams of iodine for 15 days and subsequent withdrawal. Journal of Clinical Endocrinology and Metabolism 2007 92 212214. (https://doi.org/10.1210/jc.2006-1189)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Serrano-Nascimento C, Calil-Silveira J, & Nunes MT. Posttranscriptional regulation of sodium-iodide symporter mRNA expression in the rat thyroid gland by acute iodide administration. American Journal of Physiology 2010 298 C893C899. (https://doi.org/10.1152/ajpcell.00224.2009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Solis-S JC, Villalobos P, Orozco A, Delgado G, Quintanar-Stephano A, Garcia-Solis P, Hernandez-Montiel HL, Robles-Osorio L, & Valverde-R C. Inhibition of intrathyroidal dehalogenation by iodide. Journal of Endocrinology 2011 208 8996. (https://doi.org/10.1677/JOE-10-0300)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Schneider AB, & Smith JM. Potassium iodide prophylaxis: what have we learned and questions raised by the accident at the Fukushima Daiichi Nuclear Power Plant. Thyroid 2012 22 344346. (https://doi.org/10.1089/thy.2012.2204.com)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Arriagada AA, Albornoz E, Opazo MC, Becerra A, Vidal G, Fardella C, Michea L, Carrasco N, Simon F, Elorza AA, et al.Excess iodide induces an acute inhibition of the sodium/iodide symporter in thyroid male rat cells by increasing reactive oxygen species. Endocrinology 2015 156 15401551. (https://doi.org/10.1210/en.2014-1371)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Chen XY, Lin CH, Yang LH, Li WG, Zhang JW, Zheng WW, Wang X, Qian J, Huang JL, & Lei YX. The effect on sodium/iodide symporter and pendrin in thyroid colloid retention developed by excess iodide intake. Biological Trace Element Research 2016 172 193200. (https://doi.org/10.1007/s12011-015-0580-4)

    • PubMed
    • Search Google Scholar
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