TY - JOUR
AU - Jourdain,, Jean-René
AB - Abstract Single dose of potassium iodide (KI) is recommended to prevent the risk of thyroid cancer during nuclear accidents. However in the case of repeated/protracted radioiodine release, a unique dose of KI may not protect efficiently the thyroid against the risk of further developing a radiation-induced cancer. The new WHO guidelines for the use in planning for and responding to radiological and nuclear emergencies identify the need of more data on this subject as one of the four research priorities. The aims of the PRIODAC project are (1) to assess the associated side effects of repeated intakes of KI, (2) to better understand the molecular mechanisms regulating the metabolism of iodine, (3) to revise the regulatory French marketing authorization of 65-mg KI tablets and (4) to develop new recommendations related to the administration of KI toward a better international harmonization. A review of the literature and the preliminary data are presented here. INTRODUCTION Five years after 1986 Chernobyl Nuclear Power Plant’s (NPP) explosion, an increase in the incidence of thyroid cancer was reported among those who were children or adolescents and resided in territories contaminated by radioactive fallout in Belarus, Ukraine and Russian Federation. The total number of cases of thyroid cancer registered in the period 1991−2015 in males and females, who were under 18 in 1986 (for the whole of Belarus and Ukraine and for the four most contaminated oblasts of the Russian Federation), approached 20 000. This number is almost three times higher than the number of thyroid cancer cases registered in the same cohort in the period 1991−2005(1). This dramatic increase, reported in a number of case-control and cohort studies, is particularly high for children under the age of 4 at the time of the accident. Consumption of milk contaminated with iodine-131 and other short-lived iodines and higher sensitivity to radiation of children’s thyroids were the main causes of cancer in this sub-population(2, 3). Furthermore, because of the interruption of national nutrition programs supporting the use of iodized salt in the former Soviet Union at the time, the local populations of the Chernobyl-affected areas suffered from iodine deficiency. This deficiency contributed to the increased thyroid uptake of radioactive iodine resulting from the accident’s fallout. The thyroid cancer risk could have been prevented, should the Soviet authorities rapidly administered stable iodine (further, KI—for potassium iodide) within the first hours following the accident for the purpose of iodine thyroid blocking (ITB). In addition to ITB, consumption of contaminated food and drinking water should be also restricted. As a result of ITB, the thyroid of exposed individuals would have been rapidly saturated by stable iodine, thus preventing the uptake and binding of radioactive iodines in children’s thyroid which is particularly sensitive to radiation. The key factor for this countermeasure effectiveness is a rapid and timely implementation. Indeed, physical half-lives of radioactive iodine are quite short (8 days for the iodine-131, 6.57 h for iodine-135) and thus require administration preferably within 5–8 h and ideally 2 h before the exposure or at the latest no later than within the 24 h following the exposure(4–6). Furthermore, the efficiency of this urgent protective action would be further strengthened by the restriction of consumption of contaminated local production and drinking water, especially dairy products, leafy vegetables, fruit, etc. In comparison to the Chernobyl accident, the Fukushima Daiichi accident in Japan differed by several radioactive releases to the environment during the last 3 weeks of March 2011. Even if the Japanese authorities managed within the first 24 h to evacuate the population living within a 20 km radius around the NPP, the population living outside this exclusion zone still would have been exposed to radioactive fallout in the days following the accident. The total releases in Fukushima were less than 10% of those of Chernobyl and thyroid doses lesser than internationally recommended for implementation of ITB. The Japanese Nuclear Safety Commission, the local authorities did not organize campaigns of preventive KI administration(7). The disaster of Fukushima highlighted the limits of ITB policy particularly in the case of repeated release of radioactive iodine in the environment. Indeed, this accident demonstrates in a non-ambiguous way that the ITB policy, which usually recommends nowadays a single intake of KI tablets (and perhaps a second one, if necessary), cannot offer an adequate protection to population groups that are repeatedly exposed to radioactive iodine. Therefore, the health authorities in Fukushima would not able to face such situation, due to the lack of protocol for repeated KI administration. Table 1. Biochemical and hormonal parameters of rat 30 days after KI discontinuation. Data are expressed as mean ± SEM (n = 13/group), ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; TW, thyroid weight; BW, body weight; TSH, thyroid-stimulating hormone; T4, thyroxine; T3, triiodothyronine; CK, creatine kinase; CK, creatine kinase myocardial band. Function Control KI 1 mg/kg General indicators Final body weight (g) 391 ± 2.08 392 ± 2.08  TW/BW ratio 0.08 ± 0.006 0.06 ± 0.005 Thyroid markers  TSH (ng/ml) 1.56 ± 0.17 1.48 ± 0.10  Free T4 (pmol/l) 24.98 ± 0.61 25.29 ± 0.68  Free T3 (pmol/l) 3.63 ± 0.12 3.80 ± 0.13 Liver markers  ALAT (U/l) 30.63 ± 1.46 30.58 ± 1.35  ASAT (U/l) 124.51 ± 12.69 112.18 ± 8.29  ASAT/ALAT 4.02 ± 0.28 3.71 ± 0.25 Kidney markers  Creatinine (μM) 44.54 ± 3.93 44.99 ± 1.99  Urea (mM) 5.46 ± 0.72 5.62 ± 0.83 Heart markers  CK (U/l) 579.46 ± 90.62 533.60 ± 57.54  CK-MB (U/l) 741.88 ± 225.22 843.36 ± 198.07 Function Control KI 1 mg/kg General indicators Final body weight (g) 391 ± 2.08 392 ± 2.08  TW/BW ratio 0.08 ± 0.006 0.06 ± 0.005 Thyroid markers  TSH (ng/ml) 1.56 ± 0.17 1.48 ± 0.10  Free T4 (pmol/l) 24.98 ± 0.61 25.29 ± 0.68  Free T3 (pmol/l) 3.63 ± 0.12 3.80 ± 0.13 Liver markers  ALAT (U/l) 30.63 ± 1.46 30.58 ± 1.35  ASAT (U/l) 124.51 ± 12.69 112.18 ± 8.29  ASAT/ALAT 4.02 ± 0.28 3.71 ± 0.25 Kidney markers  Creatinine (μM) 44.54 ± 3.93 44.99 ± 1.99  Urea (mM) 5.46 ± 0.72 5.62 ± 0.83 Heart markers  CK (U/l) 579.46 ± 90.62 533.60 ± 57.54  CK-MB (U/l) 741.88 ± 225.22 843.36 ± 198.07 Table 1. Biochemical and hormonal parameters of rat 30 days after KI discontinuation. Data are expressed as mean ± SEM (n = 13/group), ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; TW, thyroid weight; BW, body weight; TSH, thyroid-stimulating hormone; T4, thyroxine; T3, triiodothyronine; CK, creatine kinase; CK, creatine kinase myocardial band. Function Control KI 1 mg/kg General indicators Final body weight (g) 391 ± 2.08 392 ± 2.08  TW/BW ratio 0.08 ± 0.006 0.06 ± 0.005 Thyroid markers  TSH (ng/ml) 1.56 ± 0.17 1.48 ± 0.10  Free T4 (pmol/l) 24.98 ± 0.61 25.29 ± 0.68  Free T3 (pmol/l) 3.63 ± 0.12 3.80 ± 0.13 Liver markers  ALAT (U/l) 30.63 ± 1.46 30.58 ± 1.35  ASAT (U/l) 124.51 ± 12.69 112.18 ± 8.29  ASAT/ALAT 4.02 ± 0.28 3.71 ± 0.25 Kidney markers  Creatinine (μM) 44.54 ± 3.93 44.99 ± 1.99  Urea (mM) 5.46 ± 0.72 5.62 ± 0.83 Heart markers  CK (U/l) 579.46 ± 90.62 533.60 ± 57.54  CK-MB (U/l) 741.88 ± 225.22 843.36 ± 198.07 Function Control KI 1 mg/kg General indicators Final body weight (g) 391 ± 2.08 392 ± 2.08  TW/BW ratio 0.08 ± 0.006 0.06 ± 0.005 Thyroid markers  TSH (ng/ml) 1.56 ± 0.17 1.48 ± 0.10  Free T4 (pmol/l) 24.98 ± 0.61 25.29 ± 0.68  Free T3 (pmol/l) 3.63 ± 0.12 3.80 ± 0.13 Liver markers  ALAT (U/l) 30.63 ± 1.46 30.58 ± 1.35  ASAT (U/l) 124.51 ± 12.69 112.18 ± 8.29  ASAT/ALAT 4.02 ± 0.28 3.71 ± 0.25 Kidney markers  Creatinine (μM) 44.54 ± 3.93 44.99 ± 1.99  Urea (mM) 5.46 ± 0.72 5.62 ± 0.83 Heart markers  CK (U/l) 579.46 ± 90.62 533.60 ± 57.54  CK-MB (U/l) 741.88 ± 225.22 843.36 ± 198.07 The protection of thyroid function of an exposed individual by high doses of stable iodine results from the saturation of thyroid with stable iodine in which case radioactive iodine will not be uptaken, but on the other hand, the protective effect also results from the induction of a physiological regulation of the thyroid, the so-called Wolff–Chaikoff effect. The latter decreases the thyroid capacity of taking up iodine in case of iodine overload(8, 9). The thyroid cells, i.e. thyrocytes are organized in follicles delimitating a compartment, i.e. the colloid, within which iodination of the hormonal precursors is catalyzed. The iodine is actively transported into thyrocytes by the sodium/iodine symporter (NIS), which is located at the basolateral membrane of the thyrocyte(10). The iodine diffuses then through the apical membrane of the thyrocytes (via at least two membrane effectors, i.e. the pendrine (PDS) and the voltage-sensitive 5 (ClC5) channel) to penetrate into the colloid, where it oxidizes to iodide. Then, the iodide is bound to tyrosine residues (organification) as the components of thyroid hormones T4 and T3. Eng et al.(8) reported that Wolff–Chaikoff effect allows the thyroid to adapt itself to a transitory or a more constant increase in circulating iodine concentration by inhibiting iodide organification in case of high iodine plasma concentrations for 1 or 2 days. A high dose of iodine for 1 or 2 days, exceeding the daily physiological need by 20–1000 times(11, 12), inhibits the synthesis of thyroid hormones, a process known as the Wolff–Chaikoff effect. Wolff–Chaikoff effect results in transient hypothyroidism(8). The cellular mechanisms responsible for this physiological response are mediated partly by the inhibition of iodine uptake through a reduction of NIS expression(8). In the case of delayed administration of thyroid blocking (e.g. 3–5 h after the radioiodine intake), the transitory inhibition of thyroid hormones secretion will result in an accumulation of radioactive iodine already incorporated into the hormonal precursors, thus increasing the radiation dose received by the thyroid. However, the inhibition of organification by the Wolff–Chaikoff effect and the isotopic dilution of very small amounts of radioactive iodine (with respect to its mass), both resulting from administration of high doses of stable iodine, will efficiently protect the thyroid from the exposure to radioactive iodine. Ideally implemented just before radioactive iodine exposure, the administration of potassium iodide (KI) aims at the NIS receptors saturation (Wolff–Chaikoff effect) and thus blocking the thyroidal uptake and binding of radioactive iodine ingested or inhaled as a result of a nuclear accident. High doses, i.e. 20–1000 times higher than the daily nutritional supply, are necessary to achieve such effect(11, 12). The timelines of ITB implementation is of major importance, considering the short physical half-life of the released radioactive iodine potentially leading to important molecular damages within the thyroid after binding. Certainly, the main benefit of ITB is the reduction of risk of radiation-induced thyroid cancer among those exposed at early age for years and decades post-exposure(13). The major health consequence of the Chernobyl accident, where ITB was not timely implemented, was the dramatic increase of thyroid cancer incidence in persons who were 0–18 years old at the time of exposure, which was associated with the consumption of milk contaminated with radioactive iodine(1). ITB policy assumes that population groups would be exposed during a relatively short time to the release of radioactive material via inhalation from which they should be rapidly removed, thanks to the synergic action of protective measures, including population sheltering or evacuation. However, in the light of the lessons learnt from the Fukushima Daiichi 2011 NPP accident, even if population sheltering and evacuation have been decided, local population still potentially exposed because of the evacuation difficulties, during prolonged and repetitive radioactive discharges into the environment. In such a situation of prolonged and/or repeated radionuclide discharges, a single KI intake would not be sufficient to offer complete protection of the thyroid, and additional KI intake would be essential for an effective prevention of the thyroid cancer. However, very few studies are available in the literature regarding repeated KI administration, either in human beings excepted for some very specific diseases(13). A single clinical study targeting individuals with a normal thyroid function, showed a transitory modification of plasmatic thyroid hormones level; a small but significant decrease in T3 and T4 plasma concentrations with a significant increase in TSH plasma concentration, when high doses of iodide (72 and 360 mg) were administered daily for periods as long as 39 days(14). Another study carried out on elderly highlighted hyperthyroidism occurrence in one-third of the patients treated with high daily KI dosage (120 mg/day)(15). The group of Todd showed a decrease of thyroglobulin level in euthyroidic patients(16). Four other studies were published, including three on hyperthyroidic adults(17, 18). Only one concerned euthyroidic patients(19). Because of the lack of previous studies, it is therefore very challenging to assess the possible side effects to the thyroid and other organs resulting from repeated administrations of a large stable iodide amount. However, even if conditions for a first KI administration are well defined, the health authorities would not be in the position to decide on KI administration scheme if repeated administrations would be necessary. Even though ITB policies foresee a second KI administration only in the case of no possible rapid evacuation of the population, they currently do not recommend repetitive stable iodine intakes (quantity of KI to be ingested depending on the age, delay between two intakes, treatment duration and occurrence of side effects, etc.). Moreover, the French marketing authorization (MA) does not permit repetitive administrations of KI. This authorization was delivered on the basis of studies investigating KI efficacy and toxicity after a single intake. In the absence of appropriate studies, i.e. studies looking at the efficacy and toxicity of KI after several intakes, clear and precise recommendation for repetitive KI intake is not possible. Furthermore, adverse effects which could occur following repetitive intakes were not rigorously investigated. It is noteworthy that a Fukushima worker who took KI tablets for ITB over a period of more than 70 days was reported to experience transient hypothyroidism (M. Akashi, personal communication, 2014). These gaps of knowledge do not allow determining the maximal KI quantity to be administered as well as the maximal treatment duration not to be exceeded. Besides, a better understanding of the mechanisms of action, the bio-distribution and the elimination of the iodine is missing to revisit the current knowledge for those specific situations. In a recent review(20), it was pointed out the need to further raise the following/research question: ‘In vulnerable population sub-groups, i.e. infants, children, pregnant or lactating women exposed repeatedly/continuously to radioactive iodine does repeated ITB as compared to single ITB administration reduce the risk of relevant outcomes, such as thyroid cancer, hypothyroidism and benign thyroid nodules?’ Finally, a recent review of ITB policies in Europe, Japan and the USA showed significant differences between national recommendations even in neighboring countries(21). For example, while France will recommend the distribution of KI tablets to the whole population, Germany will not distribute KI tablets to individuals over 40 years, arguing the low risk for this subgroup to develop thyroid cancer and the greater risk of overt hyperhyroidism in these patients after KI administration with ‘toxic’ goiter leading consecutively to atrial fibrillation. With the view of avoiding implementation of medical countermeasures different from a country to another, it is becoming obvious that international harmonization of ITB policies is urgently needed. Moreover, preventive procedures better adapted to the protection of newborn children, young children, pregnant women, nursing mothers and elderly need to be better explored. THE PRIODAC PROJECT The PRIODAC (Prophylaxie répétée par l’iode stable en situation accidentelle) project (project page URL: https://www.irsn.fr/projet-PRIODAC) was launched by the IRSN in 2014 for the duration of 8 years. It aims to define the conditions for repetitive administration of KI in order to protect the populations potentially exposed to prolonged and/or repeated intake of radioactive iodine in a nuclear or radiological accidental situation. The results obtained within the framework of the PRIODAC project will also benefit to challenge the French national ITB policy under the auspices of the Ministry of Health and the Nuclear Safety Authority (ASN) and provide evidence base for modifying the MA of 65-mg KI tablets. Finally, the future update of the French national ITB policy, driven by PRIODAC scientific findings, may also hopefully serve to revisit international ITB policies and harmonization of protective actions across the nations in European Union. The new WHO guidelines for the use in planning for and responding to radiological and nuclear emergencies(22) identify as one of the four research priorities the need of ‘More data on the dosage, optimal timing and regimens for multiple administrations of stable iodine in case of repeated or protracted releases of radioactive iodine and the adverse health effects of stable iodine administration’. Since a randomized controlled clinical trial on the clinical effects of repeated ITB administration in nuclear emergencies will never be possible for obvious ethical reasons, the developments of robust preclinical studies, such as PRIODAC are needed. The PRIODAC research program (2014-2022) aims to: determine the posology for repeated administration of KI using pharmacokinetic and pharmacodynamics approaches, evaluate the benefit/risk ratio by investigating the therapeutic efficacy vs the potential adverse effects that may be induced by repeated administration of KI, and also on other target organs including the central nervous system and the cardiovascular system and improve knowledge of the thyroid and the extra-thyroid metabolism of iodine, particularly the molecular mechanism of the Wolff–Chaikoff effect in this specific situation of repetitive intake of KI. Special consideration is dedicated to groups of the population. Four different groups of population were modeled including the aged, adult, post-natal and in utero using rat’s models. Beyond defining the posology of iodine-repeated administration (dosage, fractionation, maximal treatment duration etc.), it is required to investigate potential adverse effects induced by repetitive KI administration and to identify the way to prevent them if necessary. It is known that thyroid dysfunction episodes induce mental retardation and neurologic disorder in children(23). Also, thyroid dysfunctions are tightly correlated to the development of cardiovascular pathologies, particularly in aged patients(24). Finally, some studies pointed out that iodine supplementation may favor autoimmune pathologies of the thyroid(25). The scientific challenges of the PRIODAC program are as follows: To determine the posology for repeated KI administration in case of protracted/chronic exposure to radioactive iodine using pharmacokinetic/pharmacodynamics approaches; To evaluate the benefit/risk ratio by investigating the prophylactic efficacy (radioactive iodine uptake in the thyroid as followed by SPECT imaging) vs the potential adverse effects that may be induced by repeated KI administration on the thyroid function but also on other target organs including the central nervous system and the cardiovascular system; To improve the knowledge of the thyroid and the extra-thyroid metabolism of iodide, particularly the molecular mechanism of the Wolff–Chaikoff effect. KI PHARMACOKINETICS AND PHARMACODYNAMICS According to the data from the literature, the current usual ITB KI dose of approximately 1.8 mg/kg (KI mass per body weight), corresponding to 130 mg KI in a standard 70 kg adult, should be sufficient to protect the thyroid against the uptake of radioactive iodine for at least 24 h(26). This dose is of the same order of magnitude than the dose range originally determined and used in the treatment of hyperthyroidism (from 150 to 300 mg of iodide per day)(27). The effectiveness of ITB(3) is highly dependent on different parameters such as the thyroid status of the individuals, the dietary iodine intake or the time of administration as function of the exposure to radioactive isotopes of iodine. For instance, the intake of 100 mg of iodide (130 mg KI) just before exposure to radioactive iodine allows avoiding 95% or more of the thyroid radiation dose in euthyroid adults. The percentage of avoided thyroid dose is then comprised between 50 and 75% if the exposure to radioisotopes of iodine occurs 48 h after the administration of 100 mg of stable iodide(26). WHO and many countries in their guidelines recommending ITB(2). Some authors consider that this dose of 130 mg KI may be excessive, particularly in adolescents and children which justifies the administration of fractions of this dose to the other groups of age of the population (65 mg in children from 3–12 years old; 32.5 mg in infants from 1 month through 3 years old and 16.25 mg in newborns)(28). Besides, it has been reported that lower KI doses corresponding to 0.2 and 0.4 mg/kg should be efficient to block the thyroid uptake of radioactive iodine, respectively, in adults with sufficient and insufficient dietary iodine(28, 29). Our aim in the PRIODAC program is to test if repeated administration of the current KI dose (<1.8 mg/kg) may lead to prolonged inhibition of the thyroid function and therefore to a sustained dysfunction of the metabolism of thyroid hormones and related extra-thyroid side effects. So the determination of an optimal KI dose in terms of thyroid protection efficiency and of the absence of side effect appears to be necessary in the case of repeated administrations in humans. Then the pharmacokinetics of the stable iodide after oral administration of KI will be thoroughly studied in rats in order to model and to propose an efficient dose regimen for protracted KI prophylaxis. Although not yet officially recommended in all the current treatment protocols, repeated administrations of KI have already been envisaged and evaluated in a limited number of studies in children or in adults and adolescents(29–31). The minimal effective dosage of iodide given repeatedly which is required to suppress the uptake of radioiodine 131I by the normal thyroid and the time required to achieve this effect were determined first in children in 1962(31). In this study, groups of children from 1 to 11 years old received iodide as sodium iodide aqueous solution at doses ranging from 0.1 to 1 mg per day for 2 weeks. The results showed that doses corresponding to 1.5–2 mg/m2 body surface were efficient to decrease the thyroid uptake of 131I given orally to approximately 5% without causing any toxic effect. Interestingly, the minimum uptake of about 5% was reached in 2–4 weeks and increasing the stable iodine dose to over 2 mg/m2 per day did not increase the suppression effect further. The authors concluded that the minimal effective daily dose of iodine would be 1–2 mg for children and 3–4 mg for adults(31). In the next studies in adults and adolescents, the choice of the first dose as well as the subsequent doses of stable iodine and the interval of time between the administrations were not systematically supported by pharmacological data or the pharmacokinetics of iodine. Nonetheless, the stable iodine was given daily in the adults and adolescents either at a dose of 2 mg/m2 body surface, corresponding to iodine doses ranging from 1.8 to 4.2 mg/day for 14 days(30) or at fractions of the maximal recommended dose of 100 mg of iodide (10, 15, 30, 50 and 100 mg)(7) for 12 days(29). The results in adults showed that daily iodine doses as low as 10 mg were sufficient to suppress the thyroid uptake of radioiodine at 24 h below 4%(30). The percentage of radioiodine 123I uptake was below 2% for daily stable iodine doses higher than 15 mg(29). The blockade of the thyroid was also associated with a significant decrease in serum concentrations of the thyroid hormones T4 and T3 and a significant increase in the thyrotropin hormone TSH observed on Day 8 in the subjects who received daily doses of iodine above 30 mg. However, this effect was transient and reversible since the hormones concentrations returned to normal values after the withdrawal of iodide on Day 12(29). It is worth mentioning that in this last study, a relationship could be drawn between the total serum concentration of stable iodine during the prophylaxis and the 24-h uptake of radioactive iodine in the thyroid, since the uptake of <2% in the thyroid has been associated with a total iodine serum concentration of at least 220 μg/l. This information emphasizes the existence of a possible correlation between the distribution of stable iodine and its pharmacologic effect and strengthens the interest to conduct further pharmacokinetic experiments in order to complete and revise the data regarding the efficacy of iodine prophylaxis in the context of a prolonged exposure to radioiodine. Dose–response studies in humans have been so far based on the use of radioactive tracers of iodine and are very limited because of the small number of volunteers(29, 32, 33). Alternatively, studies in animals, especially in rodents, usually offer the possibility to test a larger number and wider scale of doses(34–36) However, these studies are rather seldom and the effects of stable iodide on thyroid have not been analyzed from a pharmacological point of view with proper mathematical models. To our knowledge, one single study aimed to investigate repetitive administration of KI for ITB(37). To go further, the PRIODAC program aims to investigate repeated stable iodine prophylaxis in accidental situation in different animal species. Project’s findings In the frame of PRIODAC program, the first step of the research strategy was to model the effect of graded doses of stable iodine in order to determine the optimal dose associated with more than 95% of protection of the thyroid against radioactive iodine uptake. This optimal KI dose was found experimentally to be around 1 mg/kg in Wistar adult rats, when the animals were administered orally single doses of KI from 0.001 to 5 mg/kg, 1 h before contamination simulated by intravenous injection of 125I(38) Besides, the analysis of stable iodine content in the thyroids and in the urines 24 h after KI administration showed that this optimal dose of 1 mg/kg was associated with a saturation of the thyroid with iodine(38). Pharmacokinetic studies with this optimal dose are in progress in the PRIODAC program in order to correlate the distribution of administered stable iodine and its pharmacologic effect, as well as to design effective dose regimen based on the determined pharmacokinetic parameters of iodine for a prolonged prophylaxis in models with different groups of age models (adult, young and pregnant subjects). ITB EFFICACY During the period 1940–60, radioactive iodide was used in animal experiments (mostly rats) to study the tissue distribution of iodine. Minute concentrations of radioiodide could be used to trace its metabolism without interfering on it. Such experiments proved to be useful for the understanding of thyroid function and regulation. In particular, Wolff and Chaikoff found that high iodide plasma concentration inhibited several steps the thyroid function with an escape phenomenon(39). Radioiodine uptakes and organification in organs were measured ex vivo after sacrificing the animals. For several decades, radioiodine is being used for thyroid scintigraphy in humans for the diagnosis of various thyroid diseases. It has not been often used in animal experiments mainly for technical reasons: lack of sensitivity and resolution of the clinical cameras when applied to rodent imaging. These cameras have a large field of view with a high sensitivity, but with a modest spatial resolution of 5–15 mm. For mouse imaging, spatial resolution is an important issue, to distinguish, for example, the thyroid from the salivary glands located very closely and which are both capable for iodine accumulation. Some of these organs are very small; as an example, the size of a mouse thyroid lobe is approximately 1 mm x 0.3 mm. Therefore, dedicated imaging systems for small animals have been recently developed. In particular, they used multipinhole collimation systems which allow a significant increase in spatial resolution on a smaller field of view with and equivalent sensitivity. These systems, referred to as micro-SPECT (Single-Photon Emission Computed Tomography), allow small animal imaging with a spatial resolution ranging from 0.3 to 1 mm(40). They can be coupled to an X-ray computed tomography imaging system which adds anatomical information (dedicated Micro-SPECT/CT systems). Several single-photon radiopharmaceuticals are suitable for this method of molecular imaging: iodine isotopes such as 123I (123I−) as well as radioactive anions which are also substrate of the Natrium Iodide Symporter (NIS) such as 99mTc-technetium pertechnetate (99mTcO4−). The difference between iodide’s isotopes and 99mTcO4− is important to consider. As described earlier, iodide is taken up by the thyrocytes and transferred to the colloid for organification. 99mTcO4− follows the same uptake mechanism into the thyrocyte but is not further transferred for hormone synthesis. As far as the thyroid NIS-mediated uptake is concerned, both types of radiopharmaceuticals are equivalent(41). Project’s findings These radiopharmaceuticals along with the availability of high-resolution micro-SPECT/CT system makes SPECT imaging a method of choice for studying in vivo iodide metabolism in small animals in our PRIODAC program. The PRIODAC program aimed first to study the effect of the route of administration of the radiopharmaceuticals (Figure 1)(38, 42). The kinetics 99mTcO4− was studied on serial micro-SPECT acquisitions. Thyroid uptake of 99mTcO4− was higher when it was administered intraperitoneally or subcutaneously than when administered by gavage, whereas gavage administration favored 99mTcO4− accumulation in the stomach. For both thyroid and stomach, intraperitoneal, subcutaneous and intravenous administration led to similar uptake kinetics. These results suggest that administration by gavage leads to an accumulation of the radiopharmaceutical in the stomach at the expense of other NIS-expressing organs. To confirm these conclusions, animals were administered intraperitoneally or by gavage with 123I. Thyroid and salivary glands uptake were monitored over a longer time, up to 24 h. For both modes of administration, a peak of activity was reached 4 h after the administration of 123I−. The area under the curve (AUC) of 123I thyroid uptake in the intraperitoneal group was 2.35 times higher than the AUC in the gavage group. We also verified the protective effect of a single dose of nonradioactive iodine on thyroid uptake(40). Mice were administered on the one hand with 0.520 mg/kg of KI 4 days before radiopharmaceutical injection and micro-SPECT acquisition and on the other hand with 0.4 mg/kg of KI 1 day before. The 99mTcO4− thyroid uptake in the first situation was not different from the control group, whereas it was significantly reduced in the 0.4 mg/kg of KI group. This confirmed that the KI clearance is rapid and that the protective effect disappears quickly (in 48 h). Together with other kinetics experiments of KI using radioiodide as a tracer (unpublished data), these results show that small doses given within 24 h after the contamination protect efficiently the thyroid not so much through dilution effect but mainly by the Wolff and Chaikoff effect. Figure 1. View largeDownload slide Physiological pharmacokinetics of iodide in mice. A micro-SPECT/CT camera eXplore speCZT CT120 (general electric/trifoil) was used. The CZT detector technology with the multipinhole collimators allows a spatial resolution in mice of 1 mm (32). Images were acquired over the total body of the animal (A) in order to include systematically all the organs susceptible to be involved in the iodide metabolism; namely, the thyroid, salivary glands and the stomach in which NIS is known to present. Animals were studied under gas anesthesia (air and 1–2% isoflurane) in an air-warmed imaging chamber (Minerve, Esternay, France) to keep body temperature constant at 37°C. Various experiments on mice and rats were performed using 20 MBq 99mTcO4− or 10 MBq 123I− for each individual. Image analysis was performed using the AMIDE software. 3D regions of interest were drawn around the organs of interest and the measured radiopharmaceutical uptake was calculated by converting the total image counts measured in a 3D region of interest to MBq using the calibration factor. Thyroid uptake was expressed as percentage of the injected dose (%ID) after decay correction. For dynamic analysis, time activity curves were obtained on serial micro-SPECT acquisitions obtained on the same animals (B). The area under the curve (AUC) was measured to quantify the radiopharmaceutical accumulation (C). Figure 1. View largeDownload slide Physiological pharmacokinetics of iodide in mice. A micro-SPECT/CT camera eXplore speCZT CT120 (general electric/trifoil) was used. The CZT detector technology with the multipinhole collimators allows a spatial resolution in mice of 1 mm (32). Images were acquired over the total body of the animal (A) in order to include systematically all the organs susceptible to be involved in the iodide metabolism; namely, the thyroid, salivary glands and the stomach in which NIS is known to present. Animals were studied under gas anesthesia (air and 1–2% isoflurane) in an air-warmed imaging chamber (Minerve, Esternay, France) to keep body temperature constant at 37°C. Various experiments on mice and rats were performed using 20 MBq 99mTcO4− or 10 MBq 123I− for each individual. Image analysis was performed using the AMIDE software. 3D regions of interest were drawn around the organs of interest and the measured radiopharmaceutical uptake was calculated by converting the total image counts measured in a 3D region of interest to MBq using the calibration factor. Thyroid uptake was expressed as percentage of the injected dose (%ID) after decay correction. For dynamic analysis, time activity curves were obtained on serial micro-SPECT acquisitions obtained on the same animals (B). The area under the curve (AUC) was measured to quantify the radiopharmaceutical accumulation (C). The PRIODAC program tested the protective effect of repeated KI administration every 24 h on rat thyroid uptakes using 123I. The experiments were conducted according to the protocol showed in Figure 2A. Namely, the animals were given 1 mg/kg of KI every day and 123I (corresponding to the radioactive contamination) was administered at different time points after the KI administrations and with repeated acquisition to obtain the thyroid time activity curves from 0 to 36 h for each case and to measure the corresponding AUC. The results confirm an excellent protection compared to the controls at the different contamination time points: 89% just after the last KI administration (0 h), 86% 12 h after (12 h), 90% 18 h after (18 h) and 99.9% at 23 h after (Figure 2C). One should note that increased protection observed with the last time (23 h) is mostly due to the direct competitive effect of the KI administration 1 h after radiotracer injection. Figure 2. View largeDownload slide Effect of KI administration on radioiodide uptake by the thyroids of rats. Study protocols (A). Rats were fed either the normal iodide diet and KI was administrated (or not for controls) by gavage for 6 days before time zero of the kinetic measurements. At indicated times, radioiodine was administered intraperitoneally, animals were anesthetized, positioned on the scanner, and data were acquired. Kinetic of 123I− accumulation in the thyroid of control rat (B). The AUC was measured to quantify the radiopharmaceutical accumulation of control rats or treated rats after daily administrations of KI for 6 days. AUC was used to calculate absorbed doses after radioiodine administrations (C). Percentages of protection relative to control rats were calculated. Figure 2. View largeDownload slide Effect of KI administration on radioiodide uptake by the thyroids of rats. Study protocols (A). Rats were fed either the normal iodide diet and KI was administrated (or not for controls) by gavage for 6 days before time zero of the kinetic measurements. At indicated times, radioiodine was administered intraperitoneally, animals were anesthetized, positioned on the scanner, and data were acquired. Kinetic of 123I− accumulation in the thyroid of control rat (B). The AUC was measured to quantify the radiopharmaceutical accumulation of control rats or treated rats after daily administrations of KI for 6 days. AUC was used to calculate absorbed doses after radioiodine administrations (C). Percentages of protection relative to control rats were calculated. KI TOXICOLOGY Numerous preclinical and clinical studies were conducted using different drug formulation and posology of iodide. These studies aimed to assess the effect of iodide on the thyroid hormones synthesis(43, 44). Adverse reactions to stable iodine are rare and mainly include iodine-induced transient hyper or hypothyroidism and allergic reactions. Toxicological data in preclinical models showed potential acute and chronic toxicity of KI at very high dosages. Regarding acute toxicity, the oral and intraperitoneal LD50 values of KI in mice are 1177 ± 30 and 1982 ± 90 mg/kg, respectively. Signs of intoxication may include hyperactivity, lassitude, weakness, prostration and dyspnea. At higher doses excitability and convulsions frequently preceded death(45). Regarding chronic toxicity, KI given in the drinking water to rats at concentrations of 10, 100 and 1000 ppm for 2 years results in the incidence of thyroid follicular dilatation, focal acinar atrophy, ductular proliferation and squamous metaplasias in the salivary gland. Squamous cell carcinomas were observed in the submandibular gland in 4 males among 60 and 3 females among 60 of the 1000 ppm group. Lesions types with incidence quoted more than 25% were foci of cellular alteration in the liver, hyperplasia of the pituitary, C-cell hyperplasia of the thyroid, medullary hyperplasia, pheochromocytomas of the adrenals, interstitial cell tumors of the testis in males, cystic endometrial hyperplasias and endometrial stromal polyps of the uterus in females(44). Moreover, clinical observations highlight acute side effects of KI including diarrhea, nausea, vomiting and stomach pain(46). During the Chernobyl disaster, KI adverse effects were seen in 0.37% of the Polish newborns who received saturated solution potassium iodide (SSKI) on the second day of the accident (dosage was reported as follows: 15 mg for newborns, 50 mg for children 5 years or under and 70 mg for all others). Transient increase of serum TSH and decrease of serum T4 were reported in these children. Five years later (1989–90), thyroid hormones' levels of Polish children were assessed. Transient thyroid dysfunction was reported as a result of a single dose of KI administration. None-thyroidal side effects were higher than expected. It was reported that 0.2% of the population (children and adults) developed significant toxic reactions including vomiting, skin rashes, headaches, few cases of diarrhea and gastric complaints linked to SSKI intake.(47) Chronic toxicity was reported, when KI was administered for a longer period ranged from several days to several years. In these situations, patients may experience symptoms of iodism or potassium toxicity. Symptoms of iodism include burning mouth, increased watering of the mouth, metallic taste, soreness of the teeth and gums and severe headache. Signs and symptoms of potassium toxicity include confusion, arrhythmia, hand numbness or general weakness(46). KI has also been reported to cause pulmonary edema, angioedema, myalgias, eosinophilia, lymphadenopathy and urticaria(48, 49). The use of iodides can also cause acneiform eruptions and iododerma(50, 51). Finally, 22 euthyroid healthy volunteers received different doses of KI (30–100 mg) over a 12-day period; serum T4 and T3 was found to decrease slightly in these volunteers and serum TSH was found to increase slightly but not significantly on days 8 and 12. After the end of the KI administration, all parameters were normal(29). Project’s findings The PRIODAC program aimed to assess the potential toxicity of repeated KI intake by rats with an optimal dosage of 1 mg/kg(38). In our experimental conditions, no toxicity of repeated administration of KI was observed in an adult rat model(43). In this set of experiments (Figure 3), saline solution (pH 7.4) and KI solution 1 mg/kg were kindly provided by The Central Pharmacy of French Armed Forces (Orléans, France). The treated groups (repeated KI intake) were in good general status. The final body weight and thyroid weight were similar to those of the control group. The plasma markers of liver integrity (ALT and AST), kidney integrity (Creatinine and urea) and heart integrity (CK and CK-MB) were statistically similar in both groups (Table 1). Repeated KI administration resulted in non-long-term significant modification of TSH, free T4 and free T3 concentration compared to control rats. No significant difference among thyroid genes which are involved in iodide transport (NIS, AIT and PDS), iodide organification (TPO, DUOX2/A2 and Tg) and thyroid hormone transport (MCT8) between treated and control rats were reported (Figure 4). Figure 3. View largeDownload slide Protocol of repetitive KI administration in adult rats. Adult male Wistar rats (Charles River Laboratories, L’arbresle, France) were divided into KI-exposed and control groups. The treatment was carried out by gastric gavage over 8 days. Each group consisted of 13 animals. Thirty days after the treatment discontinuation, macroscopic parameters and molecular aspect were assessed. Figure 3. View largeDownload slide Protocol of repetitive KI administration in adult rats. Adult male Wistar rats (Charles River Laboratories, L’arbresle, France) were divided into KI-exposed and control groups. The treatment was carried out by gastric gavage over 8 days. Each group consisted of 13 animals. Thirty days after the treatment discontinuation, macroscopic parameters and molecular aspect were assessed. Figure 4. View largeDownload slide Selection of gene expression of molecular key actors of the Iodide metabolism and thyroid hormone (TH) synthesis in the thyroid, 30 days after the discontinuation of repetitive KI administration. Results are expressed as a ratio to GAPDH and ACTB mRNA level. The mRNA levels of control rats were arbitrarily set at 1. Data are expressed as means ± SEM (n = 13). NIS, Na+/I− symporter; PDS, pendrine; AIT, apical iodide transporter; TPO, thyroid peroxidase; DUOX2, dual oxidase 2; DUOXa2, dual oxidase maturation factor 2; Tg, thyroglobulin; MCT8, monocarboxylate transporter 8. Figure 4. View largeDownload slide Selection of gene expression of molecular key actors of the Iodide metabolism and thyroid hormone (TH) synthesis in the thyroid, 30 days after the discontinuation of repetitive KI administration. Results are expressed as a ratio to GAPDH and ACTB mRNA level. The mRNA levels of control rats were arbitrarily set at 1. Data are expressed as means ± SEM (n = 13). NIS, Na+/I− symporter; PDS, pendrine; AIT, apical iodide transporter; TPO, thyroid peroxidase; DUOX2, dual oxidase 2; DUOXa2, dual oxidase maturation factor 2; Tg, thyroglobulin; MCT8, monocarboxylate transporter 8. To get further insights, metabolomics profiles of animal belonging to the two groups were investigated. Metabolomics provides the metabolic profiles in a biological system. The complete set of metabolites forms the so-called metabolome. This metabolome represents the ultimate read out of a biological system, in response to genetic, environmental or pathological alterations leading to phenotypic changes. Since the metabolome integrates all the regulations occurring in a biological system (from genetics, gene expression, enzyme and hormone regulations, pathogens or microbiota interaction, and so on) its analysis provides a very sensitive picture of biological systems regulation. Deciphering the metabolome thus allows finding regulations determining phenotypes, as well as unexpected metabolic disruption. Since biofluids circulate across the body, their metabolomic analysis provides an interesting proxy to assess the metabolic status of individuals (Figure 5). Figure 5. View largeDownload slide Metabolomic workflow applied to the PRIODAC samples. Figure 5. View largeDownload slide Metabolomic workflow applied to the PRIODAC samples. Project’s findings With regard to the PRIODAC program, such an approach is very well suited to discover potential unexpected biological effects associated with repetitive administration of KI. Metabolomics examinations are underway, but preliminary data show that, 30 days after a sequence of repeated KI administration, the thyroid metabolome shows minor modifications of cell stress markers, inflammation markers and thyroid hormones synthesis. Whether the changes fall within the physiological ranges remains to be determined. On the top of the biofluids (urine and plasma), target organs such as kidney, thyroid and some brain tissues will be explored. We believe from our early PRIODAC results that we will be able to obtain an overview of the main metabolic disruptions attached to repetitive KI administration in various physiological situations, if occurring. This will help to address the safety issue and to edit guidelines for using repeated KI administration. KI MA IN FRANCE In France, the current national MA for the use of 65-mg KI tablets is held by Pharmacie Centrale des Armées (PCA), which is also the manufacturer of KI tablets. PCA authorizes a single administration that may be repeated only once, if the evacuation of the population is not possible. The French MA of 130-mg KI tablets was initially obtained in 1997 on the basis of the well-established medical use; from 2009, it was extended and replaced by 65-mg tablets without any supportive evidence, in order to supply adapted iodine doses to all age groups of the population, from newborn children to adults. The current French MA of KI was primarily based on bibliographic data from non-GLP studies (Good Laboratory Practices) evaluating the acute toxicity in rats, mice and rabbits (studies mainly of the 1960s). The final objective of the PRIODAC program is to collect GLP compliant data regarding iterative administration of KI in order to apply for an MA extension for repeated use of KI 65-mg tablets to the French authority (Agence Nationale de Sécurité du Médicament et des produits de Santé—ANSM). The studies coordinated by PCA in the frame of the PRIODAC project aim to assess mutagenic/genotoxic activity, safety pharmacology and repeated-dose toxicology of KI. These studies are developed in accordance with the guidelines of technical requirements for the registration of pharmaceutical for human use adopted by the International Conference on Harmonisation (ICH). The preclinical experiments performed on adult rats by the other contributors of PRIODAC project were used as inputs to initiate the repeated-dose toxicology GLP studies for KI. Two animal models, rats and dogs, were chosen to initiate GLP studies. CONCLUSIONS Operational protective actions as consequences of an accident taking place on an NPP are based on ‘in depth defense’ decision-making on population sheltering, evacuation, implementation of medical countermeasure and restriction of locally produced drinking water and food products consumption and commercialization. In those situations, provision of stable iodine to population that are at risk of being exposed to radioiodine should be implemented as an urgent protective action. The optimal period of administration of stable iodine is less 2–8 h prior, and up to 24 h after, the expected onset of the intake of radioactive isotopes of iodine. It is considered to be reasonable to administer ITB up to five, maximum 8 h after the estimated onset of the exposure. However, repeated administration of stable iodine may be necessary in the case of prolonged or repeated radioiodine incorporation. Such situations are unusual and may resulting from protracted release of radioiodine to the environment (like in Chernobyl), difficulties in the sheltering or evacuation of the population (like following the Fukushima earthquake and tsunami) or those situations in which a nuclear worker had to intervene on-site in emergency situations. Our preliminary data give scientific evidence of the efficacy and safety of a repetitive KI intake at 1 mg/kg per day over 8 days in adult male rats(38, 43). These data will be used as inputs for further GPL toxicological studies on two animal species (rodent species, rats and non-rodent species, dogs). These studies will be performed by a certified BPL laboratory (Best Practice Laboratory) under the control of the French Defense Central Pharmacy (PCA). In fact, in France, the current MA of 65-mg KI tablets manufactured by the PCA authorizes a single administration that may be repeated only once if the evacuation of the population is not possible. Extension of the MA application in France for repetitive KI intake is planned in the next years. In general, EU Member States are recommending a second administration of stable iodine on average 24 h after the first administration in the event of protracted releases(52). Some EU member states are considering a second stable iodine intake if the evacuation of population is impossible: Belgium and France. Other EU member states are considering a second stable iodine intake for some population groups: children (Finland), newborns and pregnant women (Norway), pregnant and nursing women (Italy). Other EU member states are not considering a second stable iodine intake regardless the situation. The Netherlands, Bulgaria, Romania and Turkey recommend not exceeding a total dose of 1 g of stable iodine (over a period of 10 days in Bulgaria and Romania). In 2022, at the end of the PRIODAC research program, we will be able to provide new scientific data and the further KI MA extension. 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The first meeting of the WHO guideline development group for the revision of the WHO 1999 guidelines for iodine thyroid blocking . Radiat. Prot. Dosim. 171 ( 1 ), 47 – 56 ( 2016 ). Google Scholar Crossref Search ADS © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - DO MULTIPLE ADMINISTRATIONS OF STABLE IODINE PROTECT POPULATION CHRONICALLY EXPOSED TO RADIOACTIVE IODINE: WHAT IS PRIODAC RESEARCH PROGRAM (2014–22) TEACHING US?
JF - Radiation Protection Dosimetry
DO - 10.1093/rpd/ncy129
DA - 2018-12-01
UR - https://www.deepdyve.com/lp/oxford-university-press/do-multiple-administrations-of-stable-iodine-protect-population-0vcm3sk90L
SP - 67
VL - 182
IS - 1
DP - DeepDyve
ER -