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Iodine, iodide, and Lugol's solution – a noteworthy trio that is commonly subject to many misconceptions. This post aims to remedy that and provide insight into scientifically founded knowledge, proven by studies, as a basis for sound opinion formation.

Foreword

Iodine is an essential trace element that is of fundamental importance not only for thyroid function but also for numerous extrathyroidal tissues.
Lugol's iodine, an aqueous solution of elemental iodine (I₂) and potassium iodide (KI), has been used in clinical medicine for over a century.

This extended report systematically analyzes the scientific evidence on the mechanisms of action and clinical applications of iodine, iodide, and Lugol's solution, including new findings on halogen interactions, radioiodine therapy, antiviral properties, global epidemiology, and autoimmune thyroiditis.

The analysis of nearly 80 scientific publications shows that iodine acts through multiple molecular mechanisms:
Thyroid gland regulates the Wolff-Chaikoff effect hormone synthesis, while extrathyroidal tissues such as the breast, prostate, ovaries, and brain take up and utilize iodine via the sodium-iodide symporter (NIS).
Clinical studies demonstrate the efficacy of Lugol's solution in the preoperative preparation of patients with Graves' disease, achieving significant reductions in thyroid hormones and thyroid vascularization.

New findings show that halogens such as bromine can displace iodine in the thyroid gland, which can become clinically relevant with increased environmental exposure. Radioiodine therapy for differentiated thyroid carcinoma demonstrates risk-stratified efficacy, with the greatest benefit observed in high-risk patients.
Povidone-iodine demonstrates potent antiviral properties against SARS-CoV-2 in vitro.

Despite global progress through salt iodization, pregnant women in many countries remain inadequately supplied, endangering fetal brain development. At the same time, it has been shown that both iodine deficiency and excess iodine can increase the risk of autoimmune thyroiditis. Iodine is thus a double-edged sword that requires careful dosing.

Particularly noteworthy are the extrathyroidal effects: iodine exhibits antiproliferative, pro-apoptotic, and antioxidative effects in breast cancer cells, can effectively treat fibrocystic mastopathy, and possesses antimicrobial properties against multidrug-resistant pathogens.
The evidence suggests broad therapeutic potential beyond classical thyroid therapy. However, further randomized controlled trials are needed to define optimal dosages and long-term effects.

Introduction

Iodine (chemical symbol: I, atomic number: 53) is an essential trace element that is indispensable for human health. While the role of iodine in the synthesis of thyroid hormones (thyroxine, T₄, and triiodothyronine, T₃) has long been established, the extrathyroidal functions of iodine have increasingly come into focus in scientific research in recent decades.
Lugol's solution, named after the French physician Jean Lugol (1786-1851), is an aqueous solution of elemental iodine (I₂) and potassium iodide (KI) in a 1:2 ratio, which has been used in medicine since 1829.

This comprehensive scientific report analyzes the current evidence on iodine, iodide, and Lugol's solution from a systematic perspective.

The report is divided into several main sections: First, the basic mechanisms of iodine action in thyroid and extrathyroidal tissues are presented. Subsequently, clinical studies on the use of Lugol's solution in thyroid diseases, particularly Basedow's disease and preoperative preparation for thyroidectomy, are analyzed. Another focus is on the extrathyroidal effects of iodine in breast tissue, prostate, ovaries, brain, and immune system.

Six other important topic areas expand the understanding of iodine's complex role in human physiology and pathology: the interactions between different halogens (bromine, fluorine, chlorine) and iodine, the differentiated consideration of radioiodine therapy for thyroid carcinomas, the antiviral properties of iodine preparations against SARS-CoV-2 and other viruses, the global epidemiology of iodine deficiency with a particular focus on vulnerable populations, the critical importance of iodine for pregnancy and fetal development, and the complex relationship between iodine status and autoimmune thyroiditis, especially Hashimoto's thyroiditis.

The analysis is based on a comprehensive evaluation of over 80 scientific publications, including randomized controlled trials, cohort studies, systematic reviews, meta-analyses, and mechanistic investigations.
The goal of this report is to provide an evidence-based foundation for understanding the diverse effects of iodine and to critically evaluate the clinical relevance of Lugol's solution and other iodine preparations.

Mechanisms of action

Thyroid function and iodine metabolism

The thyroid gland is the organ with the highest concentration of iodine in the human body. The sodium-iodide symporter (NIS), a membrane-bound glycoprotein located on the basolateral membrane of thyrocytes, enables the active uptake of iodide from the bloodstream against a concentration gradient. This process is facilitated by the Thyroid-stimulating hormone (TSH) is regulated and energy-dependent, as it utilizes the sodium gradient maintained by the Na⁺/K⁺ ATPase.

After uptake into thyrocytes, iodide is transported to the apical membrane, where it is by the Thyroid peroxidase (TPO) is oxidized. The oxidized iodine is then bound to tyrosine residues of thyroglobulin, a large glycoprotein stored in the follicular lumen. This process, organification, leads to the formation of Monoiodotyrosine (MIT) and Diiodotyrosine (DIT). Coupling two DIT molecules results in Thyroxine (T₄), while the coupling of MIT and DIT Triiodothyronine results in (T₃).

The regulation of thyroid function occurs via the hypothalamus-pituitary-thyroid axis. Thyrotropin-Releasing Hormone (TRH) from the hypothalamus stimulates the release of TSH from the pituitary gland, which in turn promotes iodine uptake, hormone synthesis, and secretion in the thyroid gland. A negative feedback mechanism by T₃ and T₄ regulates TSH secretion and ensures homeostatic control of thyroid hormone levels.

Wolff-Chaikoff effect

The Wolff-Chaikoff effect, Described for the first time in 1948, it is an autoregulatory mechanism of the thyroid gland that temporarily inhibits hormone synthesis upon acute iodine intake. This protective mechanism prevents excessive production of thyroid hormones when there is a sudden increase in iodine supply. The effect typically occurs at plasma iodine concentrations above 10⁻⁵ M and manifests within 24-48 hours after iodine exposure.

On a molecular level, increased intracellular iodide concentration leads to decreased iodination of thyroglobulin. Several mechanisms contribute to this effect: the formation of iodinated lipids, particularly 2-iodo-hexadecanal and other iodolactones, which act as signaling molecules and inhibit TPO activity. Additionally, there is a downregulation of NIS and a decreased expression of TPO and thyroglobulin.

In healthy individuals, the Wolff-Chaikoff effect is self-limiting. After 24-48 hours, an „escape“ phenomenon occurs, where the thyroid gland resumes normal hormone synthesis despite continued high iodine intake. This escape mechanism is based on the downregulation of NIS at the basolateral membrane, which causes intracellular iodide concentration to decrease again and normalization of organification.

The clinical relevance of the Wolff-Chaikoff effect is evident in the treatment of thyrotoxic crisis and in the preoperative preparation of patients with Graves' disease. Lugol's solution utilizes this mechanism to acutely reduce thyroid hormone secretion and decrease thyroid vascularization, thereby lowering surgical risk.

Antimicrobial Effects

Iodine has long-known antimicrobial properties, which are based on its strong oxidizing power. Elemental iodine (I₂) and hypoiodite (IO⁻), which is formed in aqueous solution, are the main active species. These molecules rapidly penetrate the cell wall and cell membrane of microorganisms and oxidize essential cellular components, including nucleotides, fatty acids, and amino acids.

The antimicrobial effect of iodine is broad-spectrum, encompassing bacteria (gram-positive and gram-negative), viruses, fungi, protozoa, and spores. Unlike many antibiotics, microorganisms rarely develop resistance to iodine due to its attack on multiple cellular targets simultaneously. Studies have shown that Lugol's solution is effective against multidrug-resistant Staphylococcus aureus (MRSA), even in biofilms, which are typically difficult to eradicate. [10].

Lugol's iodine has been used as an antiseptic in various clinical settings. A study by Grønseth et al. (2022) demonstrated that Lugol's iodine in combination with gentian violet could effectively eradicate MRSA biofilms in skin wound infections. [10]. The antimicrobial activity was also demonstrated against clinical isolates of various pathogens, with low concentrations already showing bactericidal effects. [19].

Povidone-iodine (PVP-I), a complex of polyvinylpyrrolidone and iodine, is commonly used as a topical antiseptic. It releases iodine more slowly than Lugol's solution, resulting in prolonged antimicrobial activity with lower tissue toxicity. PVP-I is routinely used in preoperative skin disinfection, wound treatment, and as a mouthwash. [26].

Antiproliferative and antioxidative mechanisms

In addition to its antimicrobial properties, iodine also exhibits antiproliferative and antioxidant effects, particularly in extrathyroidal tissues. These effects are of particular interest in cancer prevention and therapy. Molecular iodine (I₂) and iodide (I⁻) demonstrate differing biological activities, with I₂ generally showing stronger antiproliferative effects.

In breast cancer cell lines, molecular iodine induces apoptosis through multiple signaling pathways. It activates the intrinsic (mitochondrial) apoptotic pathway by releasing cytochrome c and activating caspases. Additionally, iodine modulates the expression of genes involved in cell cycle control, differentiation, and apoptosis. Studies have shown that iodine upregulates the expression of p53, a tumor suppressor protein, while downregulating anti-apoptotic proteins such as Bcl-2.

The antioxidant properties of iodine are paradoxical, as iodine itself is an oxidizing agent. However, at physiological concentrations, iodine can act as an antioxidant by scavenging reactive oxygen species (ROS) and inhibiting lipid peroxidation. In the thyroid gland, iodine protects thyrocytes from oxidative stress generated by the H₂O₂-dependent iodination of thyroglobulin. This protective mechanism is essential, given that the thyroid is one of the organs with the highest H₂O₂ production.

In extrathyroidal tissues that express NIS (breast, prostate, ovaries, stomach), iodine can exert similar antioxidant functions. Iodine has been shown to increase the expression of antioxidant enzymes such as glutathione peroxidase and superoxide dismutase. These mechanisms may contribute to the protective effect of iodine against oxidative stress and DNA damage, which play a central role in carcinogenesis.

Clinical trials on the thyroid

Lugol's solution for Graves' disease

Morbus Basedow (Graves‘ disease) is an autoimmune disease caused by TSH receptor antibodies (TRAb), which stimulate the thyroid gland to overproduce thyroid hormones. The resulting hyperthyroidism can lead to serious cardiovascular, metabolic, and psychiatric complications. Lugol's solution has been used for decades as an adjuvant therapy for Morbus Basedow, particularly for preoperative preparation before thyroidectomy.

The effectiveness of Lugol's solution in Graves' disease is based on several mechanisms: The Wolff-Chaikoff effect acutely inhibits thyroid hormone secretion, while simultaneously reducing thyroid vascularization. The latter is particularly important for surgical safety, as a highly vascularized thyroid gland increases the risk of intraoperative bleeding.

A prospective study by Huang et al. (2016) investigated the effects of a two-week treatment with Lugol's solution in euthyroid patients with Graves' disease. [5]. The study included 40 patients who were pretreated with thyrostatics and additionally received Lugol's solution before planned thyroidectomy. The results showed significant reductions in free thyroid hormones (fT3 and fT4) as well as a marked decrease in thyroid blood flow, measured by Doppler sonography. The mean peak systolic velocity (PSV) in the superior thyroid artery decreased from 41.2 cm/s to 31.8 cm/s (p < 0.001), indicating reduced vascularization.

Calissendorff and Falhammar (2017) reported on a series of patients with uncontrolled Graves„ disease who received Lugol's iodine solution as “rescue" therapy. [7]. In these patients who did not respond adequately to or tolerate conventional thyrostatics, Lugol's solution led to a rapid improvement of hyperthyroidism within 7-14 days. The authors emphasized that Lugol's solution represents a valuable option for patients requiring rapid control of hyperthyroidism, for example, before urgent surgery or in cases of thyrotoxic crisis.

A pediatric study by Jeong et al. (2014) investigated the effects of potassium iodide in children and adolescents with Graves' disease. [8]. The study showed that short-term treatment with potassium iodide (average 2 weeks) led to significant reductions in fT4 and T3, while TSH increased. The treatment was well tolerated, and no serious side effects occurred. These findings support the use of iodine preparations in the pediatric population as well.

The LIGRADIS study (Lugol’s Iodine in Graves‘ Disease Study) is an ongoing multicenter randomized controlled trial systematically investigating the efficacy and safety of preoperative Lugol’s solution in euthyroid patients with Graves’ disease. [11]. This study will provide important evidence on optimal dosing and treatment duration and could contribute to the standardization of preoperative iodine therapy.

Preoperative use before thyroidectomy

The preoperative preparation with Lugol's solution before thyroidectomy for Graves' disease is an established practice aimed at increasing surgical safety. The main goals are to reduce thyroid vascularity, decrease intraoperative blood loss, and improve surgical conditions by firming thyroid tissue.

A randomized controlled trial by Schiavone et al. (2024) investigated the role of Lugol's solution in total thyroidectomy for Graves' disease. [16]. The study randomized 60 patients into two groups: one group received Lugol's solution preoperatively (5 drops three times daily for 10 days), while the control group received no iodine preparation. Both groups were pre-treated with thyrostatics and were euthyroid at the time of surgery. The results showed that the Lugol group had significantly less intraoperative blood loss (median 50 ml vs. 100 ml, p < 0.001) and a shorter operative time (median 75 min vs. 95 min, p < 0.01). Complication rates (hypoparathyroidism, recurrent laryngeal nerve palsy) did not differ significantly between the groups.

A systematic review by Hope et al. (2017) analyzed the available literature on preoperative Lugol's solution for Graves' disease. [28]. The authors identified several studies that consistently showed a reduction in thyroid vascularity and intraoperative blood loss. The optimal dosage and treatment duration varied between studies, typically using 5-10 drops of Lugol's solution three times daily for 7-14 days. The authors emphasized that despite its long-standing use, high-quality randomized studies are lacking and further research is needed.

Makay and Erbil (2019) discussed preoperative treatment with Lugol's solution in their review and emphasized the importance of patient selection. [21]. They argued that Lugol's solution is particularly beneficial in patients with highly vascularized thyroid glands and in cases of insufficient control of hyperthyroidism with antithyroid drugs alone. However, the authors warned against prolonged use (> 2 weeks) as this can lead to iodine-induced hyperthyroidism when the escape mechanism occurs.

Dralle (2019) emphasized in a German-language article the role of Lugol's iodine solution in the preoperative preparation for Graves' disease. [14]. He highlighted that Lugol's solution makes the thyroid gland „firmer,“ which facilitates surgical preparation and reduces the risk of tissue tearing. This mechanical improvement in tissue properties is an additional benefit alongside the vascular and hormonal effects.

Toxic multinodular goiter

Toxic nodular goiter, including toxic adenoma and toxic multinodular goiter, is another indication for iodine therapy, although the evidence for this is less extensive than for Graves' disease. In these conditions, autonomous thyroid nodules produce thyroid hormones uncontrollably, independent of TSH regulation.

The application of Lugol's solution in toxic nodular goiter is more complex than in Graves' disease. While the Wolff-Chaikoff effect can also temporarily inhibit hormone secretion here, there is an increased risk of iodine-induced hyperthyroidism (Jod-Basedow phenomenon) in autonomous nodules, especially if the nodules do not respond to TSH suppression. Therefore, Lugol's solution is typically used for toxic nodular goiter only short-term and under close monitoring, mainly for preoperative preparation.

Huang et al. (2023) investigated the application of oral inorganic iodine in the treatment of Graves' disease and also discussed its application in other forms of hyperthyroidism. [25]. The authors emphasized that iodine therapy should be used with caution in autonomous nodules and requires careful patient selection. They recommended limiting iodine therapy to patients being prepared for definitive therapy (surgery or radioiodine therapy) and restricting the treatment duration to a maximum of two weeks.

The preoperative preparation with Lugol's solution in toxic nodular goiter primarily aims to reduce thyroid vascularization in order to minimize intraoperative blood loss. Studies have shown that reduced blood flow can also be achieved in autonomous nodules, although the effect may be less pronounced than in Graves' disease. The decision for iodine therapy should be made individually, considering the degree of hyperthyroidism, the size and number of nodules, and the planned definitive therapy.

Iodine outside the thyroid

Breast Tissue – Mammacarcinoma Prevention and Fibrocystic Mastopathy

The mammary gland is one of the extra-thyroidal tissues with the highest iodine concentration, and it expresses the sodium-iodide symporter (NIS), indicating an important physiological role of iodine in this tissue. Epidemiological studies have shown an inverse correlation between iodine intake and breast cancer incidence, particularly in populations with traditionally high iodine intake, such as Japan.

Molecular studies have identified several mechanisms by which iodine exerts antiproliferative and pro-apoptotic effects in breast cancer cells. Molecular iodine (I₂) shows stronger effects than iodide (I⁻). In MCF-7 breast cancer cells, I₂ induces G1-phase cell cycle arrest by upregulating p21 and p27, cyclin-dependent kinase inhibitors. Additionally, iodine activates the intrinsic apoptosis pathway through the release of cytochrome c from mitochondria and the activation of caspase-9 and caspase-3.

Iodine also modulates the expression of estrogen receptors and can antagonize the proliferative effects of estrogen in breast tissue. Studies have shown that iodine reduces the expression of estrogen receptor-alpha (ERα) while upregulating estrogen receptor-beta (ERβ), leading to an antiproliferative phenotype. This mechanism could be particularly relevant for estrogen receptor-positive breast cancers.

Fibrocystic breast disease is a benign condition characterized by breast pain, lump formation, and cysts. Several clinical studies have shown that iodine supplementation can significantly improve the symptoms of fibrocystic breast disease. A study using molecular iodine (I₂) showed that 70% of the patients exhibited an objective improvement in breast texture, compared to only 30% in the placebo group. The treatment was well tolerated, and side effects were rare and mild.

The mechanism by which iodine improves fibrocystic breast disease is not fully understood but may be related to the reduction of oxidative stress and the modulation of growth factors. Iodine reduces lipid peroxidation in breast tissue and increases the expression of antioxidant enzymes. Additionally, iodine may modulate the production of prostaglandins, which are involved in the development of breast pain.

prostate

The prostate also expresses NIS and concentrates iodine, suggesting a physiological role for iodine in this organ. Iodine is found in prostatic fluid and may exert antimicrobial functions as well as regulate prostate function. Epidemiological data on the relationship between iodine intake and prostate cancer risk are limited and inconsistent.

In vitro studies have shown that iodine exerts antiproliferative effects in prostate cancer cell lines. In LNCaP and PC-3 cells, molecular iodine induces apoptosis and inhibits cell proliferation in a dose-dependent manner. The mechanisms are similar to those in breast cancer cells and include the activation of caspases, modulation of Bcl-2 family members, and induction of oxidative stress.

Iodine may also play a role in the prevention and treatment of benign prostatic hyperplasia (BPH). Animal studies have shown that iodine supplementation can reduce prostate growth and decrease inflammatory markers. However, the clinical relevance of these findings for humans is unclear, and controlled clinical trials are lacking.

An interesting aspect is the potential role of iodine in the prevention of prostatitis. The antimicrobial properties of iodine could contribute to controlling bacterial infections in the prostate. Some authors have speculated that chronic iodine deficiency could lead to increased susceptibility to prostatitis, but this hypothesis requires further investigation.

Ovarian

The ovaries are another extrathyroidal tissue that expresses NIS and concentrates iodine. Iodine may play a role in ovarian function, including follicle development, ovulation, and steroidogenesis. Animal studies have shown that iodine deficiency can lead to ovarian dysfunction, including impaired follicle maturation and reduced fertility.

In ovarian carcinoma cell lines, iodine shows antiproliferative and pro-apoptotic effects. Studies with OVCAR-3 and SKOV-3 cells have shown that molecular iodine inhibits cell proliferation and induces apoptosis. The mechanisms include the activation of p53, the upregulation of pro-apoptotic proteins such as Bax, and the activation of caspases.

Epidemiological data on the relationship between iodine intake and ovarian cancer risk are limited. Some studies have found an inverse association between iodine intake and ovarian cancer risk, but the evidence is not consistent. Further prospective studies are needed to clarify this relationship.

Iodine may also be relevant in the treatment of polycystic ovary syndrome (PCOS). PCOS is associated with insulin resistance, hyperandrogenism, and chronic inflammation. Some authors have suggested that iodine, with its antioxidant and anti-inflammatory properties, could contribute to improving PCOS symptoms. However, clinical studies on this hypothesis are lacking.

Brain and Neurology

Iodine is essential for normal brain development, particularly during the fetal and early postnatal periods. Thyroid hormones, which contain iodine, are critical for neurogenesis, myelination, neuronal migration, and synaptogenesis. Severe iodine deficiency during pregnancy results in cretinism, a condition characterized by severe mental retardation, deafness, and motor deficits.

Interestingly, neurons and glial cells also express NIS and can take up iodine independently of thyroid hormones. This suggests direct, non-thyroidal functions of iodine in the brain. Iodine may act as an antioxidant in the brain, protecting neurons from oxidative stress. Studies have shown that iodine reduces lipid peroxidation in brain tissue and increases the expression of antioxidant enzymes.

Iodine may also have neuroprotective effects in neurodegenerative diseases. In vitro studies have shown that iodine can protect neurons from amyloid-beta-induced toxicity, a key mechanism in Alzheimer's disease. Iodine reduces amyloid-beta-induced apoptosis and oxidative stress in neuronal cell cultures. Whether these effects are clinically relevant is unclear and requires further investigation.

Some authors have proposed that iodine might be useful in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and other neuropsychiatric conditions. These hypotheses are based primarily on anecdotal reports, and are not supported by controlled studies. Caution is advised, as excessive iodine intake can lead to thyroid dysfunction, which itself can cause neuropsychiatric symptoms.

immune system

Iodine plays an important role in the immune system, both through its direct antimicrobial properties and through immunomodulatory effects. Leukocytes, particularly neutrophils and eosinophils, produce hypoiodite (IO⁻) as part of the oxidative burst mechanism to kill pathogens. Myeloperoxidase (MPO) in neutrophils catalyzes the oxidation of iodide to hypoiodite in the presence of hydrogen peroxide.

Iodine also modulates the function of immune cells. Studies have shown that iodine can influence the proliferation and activation of T lymphocytes. In vitro, iodine leads to dose-dependent inhibition of T-cell proliferation, indicating immunosuppressive properties. This effect could be relevant for autoimmune diseases, although its clinical significance is unclear.

Iodine also affects cytokine production. Studies have shown that iodine can reduce the production of pro-inflammatory cytokines such as TNF-α and IL-1β, while increasing the production of anti-inflammatory cytokines such as IL-10. These immunomodulatory effects could contribute to the anti-inflammatory effects of iodine.

The relationship between iodine and autoimmunity is complex. While iodine deficiency is associated with certain autoimmune diseases, excessive iodine intake can trigger or exacerbate autoimmune thyroiditis. This apparent contradiction is discussed in more detail in the section on Hashimoto's thyroiditis. The optimal iodine intake for immune function is likely a narrow range, and both deficiency and excess can have negative consequences.

Lugol's Solution – Composition, Dosage, and Application

composition

Lugol's solution is an aqueous solution of elemental iodine (I₂) and potassium iodide (KI). The classic formulation, as developed by Jean Lugol in 1829, contains 51 parts by weight of elemental iodine and 101 parts by weight of potassium iodide in distilled water. Potassium iodide not only serves as a source of iodine but also significantly increases the solubility of elemental iodine. Without potassium iodide, elemental iodine is very poorly soluble in water (0.3 g/L at 20°C), whereas in potassium iodide solution it becomes highly soluble through the formation of triiodide (I₃⁻).

The chemical reaction in Lugol's iodine solution is:

I₂ + I⁻ ⇌ I₃⁻

The resulting triiodide ion is the species primarily present in the solution and contributes to the characteristic brown color. In aqueous solution, an equilibrium exists between I₂, I⁻, and I₃⁻, with the relative concentrations depending on the pH and total iodine concentration.

The standard formulation of Lugol's solution (5% I₂ + 10% KI) contains approximately 130 mg of iodine per milliliter. One drop (approx. 0.05 ml) therefore contains about 6.5 mg of iodine. There are also diluted formulations, such as 2% Lugol's solution (2% I₂ + 4% KI), which contains about 50 mg of iodine per milliliter.

Lugol's solution should be stored in dark glass bottles at room temperature, as light can accelerate the decomposition of iodine. When stored properly, the solution is stable for several years. Discoloration or crystal formation may indicate decomposition or evaporation, and such solutions should no longer be used.

Dosages in clinical trials

The dosage of Lugol's solution varies considerably depending on the indication and clinical context. In the studies analyzed regarding preoperative preparation for Graves' disease, 5–10 drops of 5%-strength Lugol's solution were typically administered three times daily for 7–14 days. This corresponds to a daily iodine intake of approximately 100–200 mg, which is 600 to 1,300 times the recommended daily allowance (RDA) of 150 µg for adults.

In the study by Huang et al. (2016), patients received 8 drops of Lugol's solution three times daily for 2 weeks. [5]. In the study by Schiavone et al. (2024), a dosage of 5 drops three times daily for 10 days was used. [16]. Calissendorff and Falhammar (2017) reported dosages of 3-5 drops three times daily for 7-14 days in rescue therapy. [7].

For the treatment of fibrocystic breast disease, clinical studies have typically used lower doses of molecular iodine, in the range of 3-6 mg per day. These doses are significantly lower than those used for thyroid diseases and are approximately 20 to 40 times the RDA.

When used as an antiseptic, Lugol's solution is typically applied topically undiluted or lightly diluted. For wound disinfection, the solution can be applied directly to the wound, whereas for mouth rinses, dilutions of 1:10 to 1:20 are often used.

It is important to emphasize that the high dosages used for thyroid conditions should only be administered under medical supervision and for limited periods (typically < 2 weeks). Long-term high-dose iodine intake can lead to thyroid dysfunction, including iodine-induced hyperthyroidism or hypothyroidism.

Areas of application

Lugol's iodine has a wide range of applications in clinical medicine:

Thyroid diseases

• Preoperative preparation before thyroidectomy for Graves' disease
• Emergency Treatment of Thyrotoxic Crisis
• Short-term control of hyperthyroidism in patients who do not tolerate thyreostatics
• Protection of the Thyroid from Radioactive Iodine in Nuclear Emergencies (Potassium Iodide Tablets Are Preferred, But Lugol's Solution Can Serve as an Alternative)

Antiseptic applications

• Skin disinfection before surgical procedures
• Wound Treatment and Prevention of Wound Infections
• Treatment of fungal infections of the skin and nails
• Mouthwashes for oral infections

Diagnostic Applications

• Vital Staining in Pathology for the Identification of Glycogen and Starch
• Schiller test for the identification of abnormal cervical epithelium (iodine stains normal squamous epithelium brown, while dysplastic tissue remains unstained)

Other applications

• Treatment of fibrocystic mastopathy (typically with molecular iodine, not Lugol's solution)
• Experimental applications in other extrathyroidal diseases (limited evidence)

The choice between Lugol's solution and other iodine preparations (e.g., potassium iodide tablets, povidone-iodine, elemental iodine) depends on the specific indication, desired dosage, and form of application. For systemic applications in thyroid diseases, Lugol's solution or potassium iodide is suitable, while for topical antiseptic applications, povidone-iodine is often preferred due to better tissue compatibility.

Halogen Displacement – Bromine, Fluorine, and Chlorine as Iodine Antagonists

The halogens fluorine, chlorine, bromine, and iodine belong to the same group in the periodic table and exhibit similar chemical properties. This structural relationship leads to competitive interactions within the human organism, with bromine in particular having been identified as a significant antagonist of iodine. The displacement of iodine by other halogens can have far-reaching physiological consequences, especially for thyroid function.

Bromine displaces iodine in the thyroid

Experimental studies in rats have clearly shown that increased bromide intake leads to a significant displacement of iodine in the thyroid gland. The groundbreaking study by Vobecký et al. (1996) investigated how increased bromide uptake affects the iodine content of the thyroid gland. [31]. Researchers administered elevated bromide doses to rats in their drinking water over a period of several weeks and subsequently analyzed the halogen concentrations in various tissues.

The results were remarkable: with increased bromide supply, bromine replaced more than one-third of the iodine normally present in the thyroid gland. Simultaneously, the formation of iodinated thyronines decreased, while the total concentration of halogens (iodine plus bromine) in the gland remained approximately constant. This suggests that bromine and iodine compete for the same binding sites on thyroglobulin, and that thyroid peroxidase (TPO) can oxidize and bind both halogens to tyrosine residues. [31].

Mechanisms of bromide interference

The detailed review article by Pavelka (2004) describes the multiple mechanisms by which bromide disrupts iodine metabolism. [32]. Bromide are taken up by the thyroid gland via the sodium-iodide symporter (NIS), where they compete with iodide for transport. Although the NIS has a higher affinity for iodide than for bromide, significant bromide uptake can occur at high plasma bromide concentrations.

Within the thyroid gland, bromide is oxidized by thyroid peroxidase and can bind to thyroglobulin, forming brominated thyronines. These brominated analogs of thyroid hormones are biologically less active than their iodinated counterparts and can interfere with normal thyroid function. [32].

Another important mechanism is the increased renal iodine excretion with increased bromide load. Pavelka (2009) describes in a comprehensive book chapter that excessive bromide intake increases the iodine clearance of the kidneys, leading to a reduction in the body's iodine pools. [33]. This effect is particularly problematic for individuals with already marginal iodine intake, as it can worsen a relative iodine deficiency.

The goitrogenic effects of bromide have been documented in several animal studies. Rats chronically exposed to high doses of bromide developed enlarged thyroid glands (goiters) and elevated TSH levels, indicating a compensatory response to reduced thyroid hormone production. [33]. The biological half-life of iodine in the thyroid gland was significantly shortened in bromide-exposed animals, reflecting accelerated iodine depletion.

Clinical relevance of bromine exposure

The clinical relevance of these findings from animal studies for humans is a subject of scientific discussion. Modern environmental exposures to bromine are diverse and include:

• Flame retardant
  Polybrominated diphenyl ethers (PBDEs) and other brominated flame retardants are widely used in furniture, electronics, and textiles and can be metabolized to bromide in the body.
• Pesticides
  Methyl bromide was long used as a fumigant in agriculture, although its use is increasingly restricted due to environmental concerns.
• Medication
  Some medications contain bromine, for example, certain sedatives and anticonvulsants (historically).
• Food additives
  Brominated vegetable oils were used in some soft drinks but are now banned in many countries.
• Drinking water
  Bromate can occur naturally in groundwater or be formed by disinfection with ozone (formation of bromate).

In populations with marginal iodine supply, increased bromine exposure could impair thyroid function and increase the risk of iodine deficiency disorders. Pavelka (2004) emphasizes that the combination of low iodine status and high bromide exposure is particularly problematic. [32]. In such situations, bromide-induced displacement of iodine from the thyroid and increased renal iodine excretion can lead to clinically manifest hypothyroidism or goiter.

Fluorine and Chlorine – Limited Evidence

Unlike bromine, the evidence for clinically relevant interactions between fluorine or chlorine and iodine in humans is significantly more limited. Theoretically, these halogens could also compete with iodine, as they are chemically related. Fluorine is the most electronegative element and could potentially exhibit strong interactions with biological systems.

Some authors have speculated that chronic fluoride exposure (e.g., through fluoridated drinking water or dental care products) could impair thyroid function, particularly in cases of simultaneous iodine deficiency. However, epidemiological studies on this topic have yielded inconsistent results, and a causal relationship has not been established.

Chlorine, the most common halogen in biological systems, plays important physiological roles as chloride ion. There is no convincing evidence that chloride at physiological concentrations significantly competes with iodine for uptake into the thyroid or impairs thyroid function.

Conclusions and research needs

The displacement of iodine by bromine in the thyroid gland is a well-documented phenomenon in animal models with clear mechanistic underpinnings. However, its clinical relevance in humans, particularly in populations with adequate iodine supply, remains unclear. Further human epidemiological studies are needed to clarify whether and under what conditions environmental exposure to bromine can lead to clinically relevant thyroid dysfunction.

For fluorine and chlorine, robust evidence for clinically significant interactions with iodine metabolism in humans is lacking. Future research should focus on vulnerable populations, especially pregnant women, children, and individuals with marginal iodine intake, where the effects of halogen interactions might be greatest.

From a preventive perspective, these findings underscore the importance of adequate iodine supply as a protective factor against potential goitrogenic effects of environmental halogens. Optimal iodine intake could make the thyroid more resilient to the displacing effects of bromine and other halogens. [32], [33].

Radioiodine therapy for differentiated thyroid carcinoma

Radioiodine therapy (RAI) with ¹³¹I has been a cornerstone in the treatment of differentiated thyroid cancer (DTC), which includes papillary and follicular thyroid carcinomas, for decades. The therapy leverages the ability of thyroid cells to uptake iodine via the sodium-iodide symporter (NIS). After total or near-total thyroidectomy, ¹³¹I is administered to ablate remnant thyroid tissue and potential microscopic tumor residues. However, in recent years, the discussion regarding the indications and dosage of radioiodine therapy has intensified, particularly in low-risk patients.

Risk-stratified efficacy of radioiodine therapy

A comprehensive analysis by Orosco et al. (2019) examined the effectiveness of radioactive iodine therapy using large national databases (National Cancer Database and SEER). [34]. The study included over 130,000 patients with differentiated thyroid carcinoma and analyzed the association between RAI treatment and overall survival as well as cancer-specific survival.

The results showed clear risk stratification: in high-risk patients (defined by large tumors, extrathyroidal extension, lymph node metastases, or distant metastases), radioiodine therapy was associated with significantly improved survival. The hazard ratio for overall mortality was 0.67 (95% CI: 0.62–0.73), corresponding to a 33% reduction in the risk of mortality [34].

In intermediate-risk patients, the benefit of radioiodine therapy was moderate and varied depending on specific risk factors. In low-risk patients (small tumors without extrathyroidal extension, no lymph node or distant metastases), the survival benefit from RAI was minimal or not statistically significant. [34]. These findings underscore the need for individualized, risk-adapted therapy decisions.

Radioiodine Therapy in Low-Risk Patients – Controversy and New Evidence

The question of whether low-risk patients benefit from radioiodine therapy is a subject of intense debate. A propensity score-matched analysis by Satapathy et al. (2023) specifically examined this patient group. [35]. The study compared 412 low-risk DTC patients who received radioactive iodine therapy after thyroidectomy with 412 matched patients without RAI.

The results showed no significant differences in the primary endpoints: the 5-year recurrence rate was 4.11% in the RAI group versus 5.31% in the non-RAI group (p = 0.43). Disease-free survival and overall survival also did not differ significantly between the groups [35]. These findings support the increasing practice of forgoing radioiodine therapy in carefully selected low-risk patients.

The current guidelines of the American Thyroid Association (ATA) reflect this evidence and recommend selective use of radioiodine therapy. For low-risk patients with small, unifocal, intrathyroidal tumors without lymph node metastases, RAI is not routinely recommended. The decision should be individualized, taking into account patient preferences, the quality of surgery, and the possibility of close follow-up.

Low-dose versus high-dose radioiodine therapy

Another important question concerns the optimal dosage for radioiodine therapy for remnant ablation. Traditionally, high activities (100–150 mCi or 3.7–5.5 GBq) were used, but more recent studies have investigated whether lower doses (30–50 mCi or 1.1–1.85 GBq) are similarly effective.

Liu et al. (2024) conducted a prospective study that randomized low-risk patients to either a low-dose (30 mCi) or high-dose (100 mCi) group. [36]. The primary endpoints were successful ablation (defined as undetectable thyroglobulin and negative imaging) at 6-12 months and long-term recurrence rates.

The results showed comparable ablation success rates: 89.31% in the low-dose group versus 92.11% in the high-dose group (p = 0.31). After a median follow-up of 5 years, the recurrence rates did not differ significantly (3.21% vs. 2.81%, p = 0.78) [36]. It is important that the low-dose group showed significantly fewer side effects, particularly less sialadenitis (salivary gland inflammation) and xerostomia (dry mouth).

These findings support the use of lower activities in appropriate low-risk patients when remnant ablation is indicated. Reducing the radiation dose minimizes acute and chronic side effects, including the theoretical risk of secondary malignancies, without compromising therapeutic efficacy.

Mechanism of radioiodine therapy

The success of radioiodine therapy relies on the expression of the sodium-iodide symporter (NIS) in differentiated thyroid carcinoma cells. After thyroidectomy and under TSH stimulation (either by thyroid hormone withdrawal or recombinant human TSH), NIS expression is upregulated in residual thyroid cells and tumor cells, allowing for ¹³¹I uptake.

¹³¹I is a β-emitter with a physical half-life of 8.02 days. The emitted β-particles have an average range of about 0.5 mm in tissue, leading to a local radiation dose that destroys tumor cells while relatively sparing surrounding tissue. In addition, ¹³¹I emits γ-radiation, which can be used for scintigraphic imaging (post-therapy scan).

A key limiting factor is the loss of NIS expression in dedifferentiated or aggressive thyroid carcinomas. These tumors do not take up ¹³¹I and therefore do not respond to radioiodine therapy. In such cases, alternative therapies such as tyrosine kinase inhibitors or external beam radiation therapy must be considered.

Clinical Implications and Future Perspectives

The current evidence for radioiodine therapy in differentiated thyroid carcinoma can be summarized as follows:

• Risk stratification is essential
  The greatest benefit of RAI is in high-risk patients with advanced disease. In low-risk patients, the benefit is minimal, and selective application is justified. [34], [35].
• Dose reduction in low-risk patients
  When RAI is indicated in low-risk patients, lower activities (30-50 mCi) are as effective as higher doses and cause fewer side effects. [36].
• Individualized decision-making
  The decision for or against RAI should be made considering multiple factors, including tumor characteristics, surgical quality, thyroglobulin levels, patient preferences, and follow-up capabilities.
• Long-term monitoring
  Even when foregoing RAI in low-risk patients, careful follow-up with thyroglobulin measurements and ultrasound is necessary to detect recurrences early.

Future research should focus on identifying molecular markers that can predict response to radioiodine therapy. Genomic and proteomic analyses could help identify patients who would benefit from RAI despite low clinical risk factors, as well as those for whom RAI will not be effective even with higher risk. The development of strategies for the re-differentiation of radioiodine-refractory tumors is another promising area of research.

Antiviral Effect - Iodine Against Viruses and SARS-CoV-2

The antimicrobial properties of iodine have long been known and include not only bactericidal and fungicidal effects but also virucidal effects. With the emergence of the COVID-19 pandemic, interest in iodine-based antiseptics, particularly povidone-iodine (PVP-I), as a potential measure to reduce SARS-CoV-2 transmission has significantly increased. Several studies have investigated the efficacy of povidone-iodine against SARS-CoV-2 in vitro and in clinical applications.

In vitro inactivation of SARS-CoV-2

One of the first studies on the virucidal efficacy of povidone-iodine against SARS-CoV-2 was conducted by Bidra et al. (2020). [37]. The researchers tested various commercial PVP-I mouthwashes with concentrations of 0.5%, 1.0%, and 1.5% against SARS-CoV-2 in cell culture. The results were impressive: All tested concentrations completely inactivated the virus within 15 seconds of contact. The viral load was reduced by more than 99.99% (> 4 log₁₀ reduction), demonstrating the potent virucidal effect of PVP-I [37].

Frank et al. (2020) investigated the efficacy of PVP-I nasal antiseptics against SARS-CoV-2. [38]. They tested various formulations, including aqueous solutions and in-situ gels, which were developed for nasal application. The results showed dose- and time-dependent viral inactivation. At a concentration of 0.5% PVP-I, a >4 log₁₀ reduction in viral load was achieved within 15 seconds. The in-situ gel formulations demonstrated a prolonged virucidal effect due to their longer retention time in the nasal cavity [38].

Pelletier et al. (2021) conducted a comprehensive in vitro study testing various PVP-I formulations for nasal and oral applications. [39]. The study confirmed the rapid and complete inactivation of SARS-CoV-2 at concentrations of 0.5% PVP-I or higher. In addition, toxicity studies were conducted on cell cultures and in vivo in animal models, which showed no significant toxicity at the concentrations tested [39].

Mechanism of antiviral action

The virucidal effect of iodine is due to its strong oxidizing power. Iodine penetrates the viral envelope and oxidizes essential viral proteins, lipids, and nucleic acids. In enveloped viruses like SARS-CoV-2, the oxidation of the lipid membrane leads to the destabilization of the viral envelope and loss of infectivity. Additionally, iodine can oxidatively damage viral surface proteins, including the spike protein of SARS-CoV-2, preventing binding to cellular receptors.

Unlike many other antiseptics, viruses do not develop resistance to iodine, as it attacks multiple targets simultaneously. This makes iodine-based antiseptics particularly valuable in infection control, especially with emerging viral pathogens.

Clinical Applications and Studies

Based on the promising in vitro data, several clinical trials were initiated to investigate the efficacy of PVP-I nasal and oral rinses in COVID-19 patients. The hypothesis was that reducing the viral load in the nose and throat could decrease transmission and potentially alleviate the course of the disease.

A randomized controlled trial investigated the effect of 0.51% PVP-I nasal and gargle solutions in outpatients with COVID-19. Patients were instructed to rinse their noses and gargle four times a day. The primary endpoints were the change in viral load (measured as the Ct value in PCR tests) and the duration of viral shedding.

The results showed a trend toward reduction of viral load in the treatment group, with Ct values increasing more rapidly (indicating lower viral load) than in the control group. However, the difference did not reach statistical significance at most time points, possibly due to the small sample size and high inter-individual variability in viral load. [39].

An important application of PVP-I is preoperative antisepsis in patients undergoing surgical or dental procedures. Several studies have shown that the preoperative use of PVP-I mouthwash reduces aerosol formation during procedures and lowers the risk of infection for medical personnel. This is particularly relevant for aerosol-generating procedures such as intubation, bronchoscopy, or dental treatments. [37], [38].

Broad antiviral spectrum

The antiviral effect of iodine is not limited to SARS-CoV-2. Studies have shown that povidone-iodine is effective against a broad spectrum of viruses, including:

• Influenza viruses
  PVP-I inactivates Influenza A and B viruses in vitro and in vivo. Clinical studies have shown that PVP-I gargle solutions can reduce the incidence of influenza infections in exposed populations.
• Herpesviruses
  Iodine is effective against Herpes simplex virus (HSV-1 and HSV-2), Varicella-zoster virus, and Cytomegalovirus. Topical iodine applications are used to treat herpes labialis and genitalis.
• HIV
  In-vitro studies have shown that PVP-I can inactivate HIV-1. This has implications for the prevention of sexual transmission and mother-to-child transmission.
• Noroviruses
  These highly contagious gastrointestinal viruses are resistant to many disinfectants, but susceptible to iodine.
• Respiratory viruses
  In addition to influenza and SARS-CoV-2, PVP-I is effective against respiratory syncytial virus (RSV), adenoviruses, and other respiratory pathogens.

Lugol's Solution vs. Povidone-Iodine

It is important to emphasize that most studies on antiviral activity against SARS-CoV-2 were conducted with povidone-iodine, not Lugol's solution. PVP-I has several advantages for topical applications:

• Improved tissue compatibility
  PVP-I releases iodine more slowly than Lugol's solution, leading to less local irritation.
• Prolonged effect
  Complex formation with polyvinylpyrrolidone leads to a depot effect with sustained iodine release.
• Stability
  PVP-I formulations are more stable and have a longer shelf life than Lugol's solution.
• Commercial availability
  PVP-I is commercially available in standardized formulations for various applications (mouthwashes, nasal sprays, skin disinfectants).

Direct comparative studies between Lugol's iodine and PVP-I for antiviral applications are lacking. Theoretically, Lugol's iodine should also possess virucidal properties due to its high free iodine content, but its higher tissue toxicity makes it less suitable for mucosal applications. For topical skin applications, Lugol's iodine could be a cost-effective alternative to PVP-I, but further studies are needed to validate this.

Safety and side effects

Topical application of PVP-I at the recommended concentrations (0.5–1.5%) is generally safe and well tolerated. Possible side effects include:

• Local irritation
  Burning or stinging upon application to mucous membranes, typically mild and temporary.
• Taste changes
  Metallic or bitter taste after oral administration.
• Allergic reactions
  Rare, but iodine allergies are possible.
• Thyroid dysfunction
  With prolonged or high-dose use, systemic iodine absorption can lead to thyroid dysfunction, especially in individuals with pre-existing thyroid conditions.

Contraindications for PVP-I include known iodine allergy, hyperthyroidism, pregnancy (with systemic absorption), and newborns. However, systemic effects are unlikely with short-term topical application.

Conclusions and Perspectives

The evidence for the potent virucidal effect of povidone-iodine against SARS-CoV-2 and other viruses is robust. PVP-I nasal and oral rinses represent a simple, cost-effective, and safe measure for reducing viral load in the upper respiratory tract. Their use is particularly sensible in high-risk situations such as preoperative settings, for healthcare personnel with high exposure rates, and possibly as an adjuvant measure in COVID-19 patients to reduce transmission. [37], [38], [39].

Further research is needed to define optimal concentrations, application frequencies, and durations, as well as to confirm clinical efficacy in larger randomized trials. The role of PVP-I in the prevention and treatment of other viral infections should also be further investigated. The widespread availability, low cost, and low risk of resistance make iodine-based antiseptics a valuable tool in the infection control arsenal.

Global Epidemiology of Iodine Deficiency

Iodine deficiency is one of the most common preventable causes of brain damage and mental retardation worldwide. Despite significant progress in recent decades through the introduction of Universal Salt Iodization (USI) programs, iodine deficiency remains a significant public health problem in many regions, particularly among vulnerable populations such as pregnant women and children.

Global Supply Situation – Progress and Persistent Deficits

A comprehensive analysis by Gizak et al. (2017) examined the global iodine status, with a particular focus on women of reproductive age. [40]. The study was based on data from the World Health Organization (WHO) and UNICEF and analyzed the median urinary iodine concentration (MUI) as an indicator of iodine supply at the population level.

The results showed that while the majority of countries (approximately 70%) have achieved adequate iodine intake at the population level (MUI 100–299 µg/L), significant regional differences exist. The situation among pregnant women is particularly concerning: In 37 countries, inadequate iodine intake among pregnant women was documented, even in some countries where the general population has adequate intake [40].

The WHO recommends a MUI of 150-249 µg/L for pregnant women, equivalent to a daily iodine intake of about 250 µg. This higher requirement reflects the increased iodine demand during pregnancy due to enhanced maternal thyroid hormone production, renal iodine clearance, and fetal iodine requirements. In many countries, pregnant women do not reach these target levels, even when the general population is adequately supplied. [40].

Regions with a particularly high prevalence of iodine deficiency include:

• Sub-Saharan Africa
  Many countries have not yet implemented widespread salt iodization.
• South Asia
  Despite USI programs, gaps in care often exist in rural areas.
• Eastern Europe
  Following the collapse of the Soviet Union, there was a decline in iodine supply in some countries.
• Western Europe
  Surprisingly, some Western European countries (e.g., Great Britain, Norway) show mild to moderate iodine deficiency, particularly in pregnant women.

Universal Salt Iodization - Success Story and Challenges

Universal Salt Iodization (USI) is the world's most important strategy for preventing iodine deficiency disorders. The concept is simple: by fortifying salt with iodine (typically 20-40 mg of iodine per kg of salt), the entire population can be supplied with sufficient iodine, as salt is a universally consumed food.

An impact evaluation by Lim (2022) examined the effectiveness of USI in Sarawak, Malaysia, over a 10-year period. [41]. The study compared data from schoolchildren before and after the introduction of USI. The results were impressive:

• The median urinary iodine concentration increased from 102.1 µg/L (mild deficiency) to 126.0 µg/L (adequate supply).
• The prevalence of goiter among schoolchildren decreased from 8.21% to 2.11%.
• The prevalence of iodine deficiency (MUI < 100 µg/L) decreased from 52.31% to 28.71% [41].

These results demonstrate the effectiveness of USI as a public health intervention. Similar successes have been documented in many other countries that have implemented USI programs.

A particularly comprehensive analysis comes from China, where Liu et al. (2021) investigated iodine nutrition after 20 years of universal salt iodization. [42]. China implemented a national Universal Salt Iodization (USI) program in 1995, after the country previously had one of the highest prevalences of iodine deficiency disorders (IDD) worldwide. The study analyzed data from over 22,000 individuals from all provinces of China.

The main findings were:

• The coverage of households with iodized salt reached 95.41%.
• The median urinary iodine concentration was 163.3 µg/L, which is in the optimal range.
• The prevalence of goiter among children decreased from 20.41 per 1,000 (1995) to 2.61 per 1,000 (2014).
• Cretinism, which was common in endemic areas before iodine supplementation, has been practically eliminated [42].

However, the study also identified new challenges:

• Regional differences persist, with some areas still showing iodine deficiency and others with excessive iodine intake.
• In coastal regions with high seafood consumption, excessive iodine intake has been observed in some populations (MUI > 300 µg/L).
• The need for continuous monitoring and adjustment of iodization levels was emphasized. [42].

Iodine-induced hyperthyroidism – The flip side of the coin

A paradoxical phenomenon observed during the implementation of salt iodization programs in previously iodine-deficient areas is iodine-induced hyperthyroidism (Jod-Basedow phenomenon). In individuals with long-term iodine deficiency, autonomous thyroid nodules can develop, producing hormones independently of TSH. When such individuals are suddenly exposed to increased amounts of iodine (e.g., through the introduction of iodized salt), uncontrolled overproduction of thyroid hormones can occur.

This phenomenon has been observed in several countries after the introduction of USI, typically as a transient increase in the incidence of hyperthyroidism in the early years after program initiation. Over time, the situation normalizes as new generations grow up without chronic iodine deficiency and do not develop autonomous nodules.

Experience from various countries has shown that a gradual introduction of salt iodization with moderate iodization levels can minimize the risk of iodine-induced hyperthyroidism. Additionally, close monitoring of thyroid function in the population, especially in the elderly, is important in the initial years following the introduction of USI.

Monitoring and Surveillance

The successful implementation and maintenance of USI programs require continuous monitoring at multiple levels:

• Household level
  Regular surveys on iodized salt coverage and iodine concentration in salt.
• Population level
  Periodic measurements of median urinary iodine concentration in representative samples, especially in schoolchildren and pregnant women.
• Clinical level
  Monitoring the prevalence of goiter, hypothyroidism, hyperthyroidism, and other thyroid diseases.
• Work level
  Quality control of salt iodization in production facilities.

The WHO, UNICEF, and the Iodine Global Network (IGN) have developed standardized protocols for monitoring iodine nutrition programs. These protocols enable data comparability between countries and over time, and help to identify problems early. [40], [41], [42].

Challenges and future directions

Despite the impressive successes of USI programs, several challenges remain:

• Vulnerable Populations
  Pregnant and breastfeeding women have an increased iodine requirement, which is often not met by iodized salt alone. Additional supplementation may be necessary.
• Salt Reduction Campaigns
  Public health initiatives to reduce salt intake for the prevention of hypertension and cardiovascular diseases may inadvertently reduce iodine intake. Strategies to increase iodine concentration in salt or alternative iodine sources must be considered.
• Changed eating habits
  The increasing consumption of processed foods, which often contain non-iodized salt, can reduce iodine intake.
• Political and economic instability
  Maintaining USI programs is challenging in conflict regions and economically unstable countries.
• Climate change
  Changes in agricultural practices and soil erosion can affect the iodine content in food.

The global community must continue to invest in iodine nutrition programs and develop innovative strategies to close the remaining gaps and sustain the successes achieved.

Iodine in Pregnancy and Fetal Development

Pregnancy is a critical phase in which adequate iodine supply is of fundamental importance for the health of mother and child. Iodine is essential for the synthesis of thyroid hormones, which in turn play a central role in fetal brain development. Iodine deficiency during pregnancy can lead to severe and irreversible neurological damage in the child.

Increased iodine requirement during pregnancy

The iodine requirement increases significantly during pregnancy for several reasons:

• Increased maternal thyroid hormone production
  As early as the first trimester, T₄ production increases by about 50% to meet the increased metabolic demands and to support the fetus, whose own thyroid gland does not become functional until the 10th to 12th week of pregnancy.
• Increased renal iodine clearance
  The glomerular filtration rate increases by 30–50% during pregnancy, leading to increased renal iodine excretion.
• Transplacental iodine transfer
  Iodine is actively transported across the placenta to the fetus to supply its thyroid gland.
• Increased Volume of Distribution
  The mother's blood volume increases by about 50% during pregnancy, which leads to a dilution of the iodine concentration.

Due to these factors, the WHO and other international organizations recommend a daily iodine intake of 250 µg for pregnant women, compared to 150 µg for non-pregnant adults. In many countries, pregnant women do not reach these target levels, even if the general population is adequately supplied. [40].

Fetal Brain Development – Critical Windows of Vulnerability

Fetal brain development is a highly complex process that occurs in several critical phases. Thyroid hormones are essential in all phases, from early neurogenesis to late myelination. Puig-Domingo and Vila (2013) describe the specific roles of thyroid hormones in fetal brain development in their review. [43].

First trimester

In this phase, the fetus is completely dependent on maternal thyroid hormones, as its own thyroid gland is not yet functional. T₄ crosses the placenta and is converted to T₃ in the fetal brain. Thyroid hormones regulate the expression of genes essential for neurogenesis, neuronal migration, and the formation of cortical layers. Severe iodine deficiency during this phase can lead to irreversible structural brain abnormalities. [43].

Second and third trimesters

From the 10th to 12th week of pregnancy, the fetal thyroid gland begins to produce its own hormones, but remains dependent on maternal iodine intake. During this phase, thyroid hormones are critical for myelination, synaptogenesis, and the development of specific brain regions such as the hippocampus and cerebellum. Iodine deficiency during this phase can lead to delayed myelination and impaired cognitive development. [43].

Cretinism – The most severe form of iodine deficiency disease

Severe iodine deficiency during pregnancy leads to cretinism, a syndrome characterized by severe mental retardation, deafness, spasticity, and growth disorders. Two forms are distinguished:

• Neurologic cretinism
  Dominated by mental retardation, deafness, and motor deficits, caused by irreversible brain damage during fetal development.
• Myxedematous cretinism
  Characterized by severe hypothyroidism, growth retardation, and delayed puberty, in addition to neurological deficits.

Cretinism has been virtually eliminated in regions with adequate iodine supply but persists in some endemic iodine-deficiency areas. Prevention through iodine supplementation before or during early pregnancy is highly effective. [43].

Mild to moderate maternal iodine deficiency – Subtle but significant effects

While severe iodine deficiency leads to overt clinical manifestations, the effects of mild to moderate iodine insufficiency are more subtle but still significant. Several studies have shown that even mild maternal hypothyroxinemia (low T₄ levels with normal TSH) is associated with impaired cognitive development in the child.

Melse-Boonstra et al. (2012) conducted a systematic review on the effects of iodine supplementation in pregnancy on child cognition. [45]. The analysis included several randomized controlled trials from different countries with varying baseline iodine status.

The main findings were:

• In regions with severe iodine deficiency, iodine supplementation led to significant improvements in cognitive development, as measured by IQ tests and developmental scales.
• In regions with mild to moderate iodine deficiency, the effects were less pronounced, but still detectable, particularly in specific cognitive domains such as language and fine motor skills.
• The timing of supplementation was critical: interventions that began before conception or in the first trimester showed greater effects than those that started later in pregnancy. [45].

These findings underscore the importance of preconception and early prenatal iodine supplementation, particularly in populations with suboptimal iodine intake.

Endocrine Disruptors and Iodine Deficiency – Synergistic Risks

A recent review by Grossklaus et al. (2023) highlights the complex interactions between iodine deficiency, maternal hypothyroxinemia, and exposure to endocrine disruptors. [44]. Endocrine disruptors are environmental chemicals that can interfere with thyroid function, including perchlorate, thiocyanate, polychlorinated biphenyls (PCBs), and certain pesticides.

The authors argue that the combination of mild iodine deficiency and exposure to endocrine disruptors can have synergistic negative effects on fetal brain development. Endocrine disruptors can:

• Inhibit thyroid hormone production
• To disrupt the peripheral conversion of T₄ to T₃
• The binding of thyroid hormones to transport proteins influence
• Modulating the expression of thyroid hormone receptors in the fetal brain

With adequate iodine supply, the thyroid may be able to compensate for these disruptions, but with simultaneous iodine deficiency, the compensatory capacity is limited, which can lead to clinically relevant effects. [44].

These findings have important public health implications: in populations exposed to endocrine disruptors (which is practically ubiquitous in industrialized countries), the threshold for „adequate“ iodine supply might be higher than traditionally assumed. Additional iodine supplementation could be particularly important in such contexts.

Iodine Supplementation During Pregnancy – Recommendations and Practice

Based on the evidence, most international organizations recommend iodine supplementation for pregnant women in regions with suboptimal iodine intake. The specific recommendations vary:

• WHO/UNICEF
  250 µg iodine per day for pregnant and breastfeeding women, preferably through iodized salt, supplemented as needed.
• American Thyroid Association
  150 µg iodine per day as a supplement for pregnant and breastfeeding women in North America, in addition to iodine intake from diet.
• European Thyroid Association
  Similar recommendations, with an emphasis on preconception supplementation.

In practice, compliance with supplementation recommendations is often suboptimal. Many prenatal multivitamins do not contain iodine or contain insufficient amounts. Educating healthcare professionals and pregnant women about the importance of iodine is essential.

Lugol's Solution in Pregnancy – Caution Advised

While iodine supplementation at physiological doses (150-250 µg/day) is safe and recommended during pregnancy, Lugol's solution at the high doses used for thyroid conditions should be avoided during pregnancy. High iodine doses can lead to hypothyroidism and goiter in the fetus, as the fetal escape mechanism from the Wolff-Chaikoff effect is not yet fully developed.

If treatment with Lugol's solution is medically necessary in a pregnant woman (e.g., in the case of a thyrotoxic crisis), it should only be carried out under close medical supervision and for the shortest possible duration. Fetal thyroid function should be monitored using ultrasound (goiter screening). [43].

Breastfeeding – Continuation of Iodine Supplementation

The increased iodine requirement persists during breastfeeding because iodine is secreted into breast milk and is the sole source of iodine for the breastfed infant. The WHO recommends 250 µg of iodine per day for breastfeeding women. Studies have shown that the iodine concentration in breast milk is directly dependent on maternal iodine intake.

With insufficient maternal iodine intake, breast milk cannot provide enough iodine to meet the infant's needs, which can lead to hypothyroidism and developmental delays. Therefore, continuing iodine supplementation throughout the entire breastfeeding period is important. [45].

Hashimoto's thyroiditis and iodine-induced autoimmunity

The relationship between iodine and autoimmune thyroiditis, particularly Hashimoto's thyroiditis (HT), is complex and paradoxical. While iodine deficiency is associated with various thyroid diseases, excessive iodine intake can also trigger or worsen autoimmune thyroiditis. This phenomenon makes iodine a „double-edged sword“ in thyroid health and underscores the importance of a balanced iodine supply.

Mechanisms of Iodine-Induced Autoimmunity

Several molecular and cellular mechanisms have been identified through which excess iodine can promote autoimmune thyroiditis. A recent study by Pazinjuk and Tang (2023) investigated the role of HIF-1α (Hypoxia-Inducible Factor 1-alpha) in iodine-induced apoptosis of thyroid follicular cells. [46].

Researchers exposed thyroid follicular cells in vitro to high iodine concentrations and analyzed the resulting cellular changes. The main findings were:

• Excessive iodine activated the HIF-1α signaling pathway, despite normoxic conditions (a phenomenon termed „pseudohypoxic“ activation).
• HIF-1α activation led to increased expression of pro-apoptotic proteins and activation of caspases.
• The resulting apoptosis of follicular cells led to the release of intracellular antigens, including thyroglobulin and thyroid peroxidase (TPO).
• These released antigens can be recognized by the immune system as „foreign,“ especially when they are in an oxidized or modified form, which initiates an autoimmune response. [46].

Another important mechanism is the iodine-induced increase in the immunogenicity of thyroglobulin. Highly iodinated thyroglobulin is more immunogenic than normally iodinated thyroglobulin. With excessive iodine intake, the degree of iodination of thyroglobulin increases, which increases the likelihood of it being recognized as an autoantigen.

Additionally, excessive iodine can increase the production of reactive oxygen species (ROS) in thyrocytes. While moderate ROS production is necessary for normal thyroid function (iodination of thyroglobulin), excessive oxidative stress can lead to cell damage, DNA damage, and inflammation, which in turn can promote autoimmune processes.

Epidemiological Evidence – Iodine Intake and Autoimmune Thyroiditis

Several population-based studies have investigated the association between iodine intake and the prevalence of autoimmune thyroiditis. A landmark study by Teng et al. (2011) compared three regions in China with different iodine statuses. [47]:

• Iodine-deficient region MUI < 100 µg/L
• Region with adequate iodine supply MUI 100-199 µg/L
• Region with more than adequate iodine intake: MUI 200-299 µg/L

The study included over 3,000 participants and analyzed thyroid function, autoantibodies (anti-TPO and anti-thyroglobulin), and ultrasound findings. The main results were:

• The prevalence of subclinical hypothyroidism was significantly higher in the region with more than adequate iodine intake (6.51% TP3T) than in the region with adequate intake (3.21% TP3T) or iodine deficiency (2.21% TP3T).
• The prevalence of positive anti-TPO antibodies was also highest in the region with high iodine intake (18.61% vs. 13.11% vs. 10.21%).
• Similar patterns were observed for anti-thyroglobulin antibodies [47].

These findings suggest a U-shaped relationship between iodine intake and thyroid health: both too little and too much iodine are associated with increased rates of thyroid disease, while moderate, adequate iodine intake is optimal.

Another study by Li et al. (2021) specifically investigated patients with diagnosed Hashimoto's thyroiditis, analyzing the correlation between urinary iodine concentration and autoantibody titers as well as thyroid function. [48]. The study included 286 HT patients, who were divided into three groups based on their urinary iodine concentration:

• Low iodine intake UIC < 100 µg/L
• Adequate iodine intake: UIC 100-199 mcg/L
• High iodine intake: UIC ≥ 200 µg/L

The main findings were:

• Patients with high iodine intake had significantly higher anti-TPO antibody titers than patients with adequate or low iodine intake.
• The prevalence of overt hypothyroidism was higher in the group with high iodine intake.
• TSH levels correlated positively with urinary iodine concentration in HT patients [48].

These findings suggest that in patients with pre-existing Hashimoto's thyroiditis, a high iodine intake can enhance autoimmune activity and worsen thyroid function.

Iodine-induced autoimmune thyroiditis after salt iodization

An interesting natural experiment on the relationship between iodine and autoimmunity arises from the introduction of Universal Salt Iodization (USI) in previously iodine-deficient regions. Several studies have observed a temporary increase in the prevalence of autoimmune thyroiditis in the years following USI implementation.

This increase is typically interpreted as the unveiling of previously subclinical autoimmune processes: In iodine-deficient areas, autoimmune thyroiditis may be present but does not manifest as hypothyroidism because the thyroid is already hypoactive due to iodine deficiency. Following the introduction of iodine supplementation, the autoimmune destruction of the thyroid becomes clinically apparent.

However, long-term studies have shown that the prevalence of autoimmune thyroiditis stabilizes or even slightly decreases after an initial increase when iodine intake is kept within the optimal range. This highlights the importance of a balanced, non-excessive iodine supply.

Genetic susceptibility and environmental factors

It is important to emphasize that not all individuals exposed to high iodine levels develop autoimmune thyroiditis. Genetic factors play a significant role in susceptibility. Certain HLA haplotypes (particularly HLA-DR3 and HLA-DR5) are associated with an increased risk of autoimmune thyroiditis.

The development of autoimmune thyroiditis is likely the result of an interaction between genetic predisposition and environmental factors, among which excessive iodine intake is one. Other environmental factors associated with autoimmune thyroiditis include:

• Viral Infections (Molecular Mimicry)
• Smoking (paradoxically protective for Graves' disease, but a risk factor for Hashimoto's)
• Selenium deficiency
• Vitamin D deficiency
• stress
• Certain medications (e.g., interferon-α, amiodarone)

Clinical Implications for Patients with Hashimoto's Thyroiditis

For patients with diagnosed Hashimoto's thyroiditis, the evidence suggests several clinical implications:

• Avoid excessive iodine intake
  Patients should be advised to avoid high-dose iodine supplements. The use of iodized salt in normal amounts is generally safe, but additional iodine supplements (> 500 µg/day) should be avoided unless medically indicated.
• Caution with iodine-containing medications
  Amiodarone, an antiarrhythmic drug with a high iodine content, can trigger or worsen autoimmune thyroiditis. Close monitoring of thyroid function is necessary in patients with HT who require amiodarone.
• Caution with iodine-containing contrast agents
  Radiological examinations with iodine-containing contrast agents can lead to acute exacerbation of autoimmune thyroiditis. If possible, alternative contrast agents should be used, or thyroid function should be monitored after the examination.
• Individual Iodine Status Evaluation
  In patients with newly diagnosed or worsening Hashimoto's thyroiditis, measuring urinary iodine concentration can be helpful in determining if excessive iodine intake is a contributing factor. [48].
• No general iodine restriction
  It is important to emphasize that patients with Hashimoto's should not generally avoid iodine. Adequate iodine intake (150 µg/day for adults) is also necessary for normal thyroid function in HT patients. Only excessive amounts should be avoided.

Lugol's solution for Hashimoto's thyroiditis - contraindication

The use of Lugol's solution in the high doses used for Graves' disease is contraindicated in patients with Hashimoto's thyroiditis. The high doses of iodine could intensify autoimmune activity and lead to an acute worsening of thyroid function.

In rare cases where short-term iodine therapy is medically necessary for a Hashimoto's thyroiditis patient (e.g., pre-operatively in the presence of hyperthyroidism), this should only be done under close monitoring and for the shortest possible duration.

Preventive Strategies and Public Health

From a public health perspective, these findings underscore the importance of an optimal, non-excessive iodine supply. Salt iodization programs should aim to keep the population within the optimal range (UIM 100-199 µg/L for the general population, 150-249 µg/L for pregnant women) without entering the excessive intake range (UIM > 300 µg/L).

Continuous monitoring of iodine supply and the prevalence of thyroid diseases, including autoimmune thyroiditis, is essential. If an increase in autoimmune thyroiditis prevalence is observed, the iodine concentration in salt may need to be adjusted. [47].

Educating the public about the risks of both iodine deficiency and iodine excess is important. The message „more is better“ does not apply to iodine; a balanced, adequate intake is the goal.

discussion

Therapeutic Potential and Evidence

The studies analyzed in this report demonstrate a broad therapeutic potential of iodine, iodide, and Lugol's solution, extending far beyond the classic application for thyroid diseases. The evidence can be categorized by quality and clinical relevance into several categories:

Established applications with strong evidence

• Preoperative preparation for Graves' disease
  Lugol's solution is effective in reducing thyroid vascularity and intraoperative blood loss. Several prospective studies and an ongoing randomized controlled trial (LIGRADIS) support this application. [5], [16], [28].
• Antimicrobial effect
  The broad antimicrobial activity of iodine against bacteria, viruses, fungi, and protozoa is well-documented. Its efficacy against multidrug-resistant pathogens like MRSA and its potent virucidal effect against SARS-CoV-2 are clinically relevant. [10], [37], [38], [39].
• Radioiodine therapy for high-risk thyroid carcinoma
  The efficacy of ¹³¹I in advanced differentiated thyroid carcinoma is supported by large database analyses [34].
• Prevention of iodine deficiency disorders
  Universal Salt Iodization is one of the most successful public health interventions worldwide, with documented efficacy in preventing cretinism, goiter, and cognitive deficits. [41], [42].

Promising applications with moderate evidence

• Fibrocystic breast changes
  Several clinical studies show improvements in symptoms with iodine supplementation, but the studies are often small and methodologically limited.
• Antiviral prophylaxis
  PVP-I nasal and oral rinses show promising results in reducing SARS-CoV-2 viral load, but larger clinical studies with hard endpoints (transmission, disease progression) are lacking. [37], [38], [39].
• Iodine Supplementation in Pregnancy
  The evidence for improvements in child cognition from iodine supplementation is strong in regions with severe iodine deficiency, but less consistent in regions with mild deficiency. [45].

Experimental applications with limited clinical evidence

• Cancer Prevention and Therapy
  The antiproliferative and pro-apoptotic effects of iodine in cancer cell lines are well-documented, but clinical studies in humans are largely lacking.
• Neuroprotective effects
  The evidence for direct, non-thyroidal neuroprotective effects of iodine is primarily based on in vitro and animal studies.
• Immunomodulation
  The immunomodulatory effects of iodine are mechanistically plausible, but clinical relevance is unclear.

Safety and side effects

The safety of iodine preparations depends heavily on dosage, duration of use, and individual factors:

Acute side effects at high doses

• Gastrointestinal symptoms (nausea, vomiting, diarrhea)
• Metallic taste
• Swollen and painful salivary glands
• Skin rashes (iododerma)
• Rare: Anaphylactic reactions in iodine allergy

Thyroid-related side effects

• Wolff-Chaikoff effect with transient hypothyroidism (usually self-limiting)
• Iodine-induced hyperthyroidism (Jod-Basedow phenomenon) in patients with autonomous nodules
• Exacerbation of autoimmune thyroiditis in predisposed individuals [46], [47], [48]
• Fetal/neonatal hypothyroidism and goiter at high doses in pregnancy

Long-term risks for chronically high intake

• Chronic hypothyroidism or hyperthyroidism
• Increased risk of autoimmune thyroiditis [47]
• Theoretical risk of thyroid cancer (inconsistent evidence)

Contraindications

• Known iodine allergy
• Dermatitis herpetiformis
• Hypocomplementemic vasculitis
• Relative contraindications: Autonomous thyroid nodules, Hashimoto's thyroiditis (for high-dose applications)

Interactions with halogens

• Brom can displace iodine from the thyroid gland and increase renal iodine excretion, which can be problematic with marginal iodine supply. [31], [32], [33].

Lugol's solution in the high doses used for thyroid disorders (100-200 mg of iodine per day) should only be used under medical supervision and for limited periods (typically < 2 weeks). Long-term use requires regular monitoring of thyroid function.

Limitations of current research

Despite the extensive literature on iodine, several important knowledge gaps remain:

• Lack of randomized controlled trials
  Many applications of Lugol's solution are based on observational studies or historical practice. High-quality RCTs are lacking for many indications.
• Optimal dosages unclear
  The dosages of Lugol's solution vary considerably between studies, and systematic dose-response studies are lacking.
• Long-term effects are insufficiently studied
  Most studies on Lugol's solution for thyroid diseases have short follow-up periods. Long-term effects on thyroid function and autoimmunity are inadequately characterized.
• Extrathyroidal applications
  The clinical evidence for extrathyroidal applications (breast, prostate, brain) is mainly based on preclinical studies. Translation into clinical applications is lacking.
• Mechanistic gaps
  While many effects of iodine have been described, the underlying molecular mechanisms are often poorly understood.
• Individual variability
  Factors influencing individual responses to iodine supplementation (genetic polymorphisms, the microbiome, and diet) are poorly understood.
• Halogen Interactions in Humans
  Most data on bromine-iodine interactions comes from animal studies. Clinical relevance studies in humans regarding halogen displacement are lacking. [31], [32], [33].
• Optimal iodine status
  The definition of the „optimal“ iodine status, which avoids deficiency diseases without promoting autoimmunity, is not precisely defined and may vary individually. [47], [48].

Conclusion

Iodine is an essential trace element with diverse physiological functions that extend far beyond the thyroid gland. Lugol's solution, an iodine formulation used for nearly two centuries, continues to hold a firm place in modern medicine, particularly in the preoperative preparation of patients with Graves' disease and as an antiseptic.

The studies analyzed in this extended report show that iodine is a „double-edged sword“: both deficiency and excess can lead to thyroid diseases. Optimal iodine supply lies within a relatively narrow range, and both public health programs and individual supplementation should aim to achieve and maintain this optimal range.

New findings on halogen interactions show that environmental exposure to bromine can affect iodine supply, which could become clinically relevant in cases of marginal iodine supply. [31], [32], [33]. Risk-stratified application of radioiodine therapy for thyroid carcinoma enables individualized treatment that optimally balances benefits and risks. [34], [35], [36]. The potent antiviral effect of povidone-iodine against SARS-CoV-2 and other viruses underscores the continued relevance of iodine in infection control. [37], [38], [39].

Despite global progress through universal salt iodization, vulnerable populations, particularly pregnant women, remain inadequately supplied in many countries. [40], [41], [42]. The critical importance of iodine for fetal brain development makes optimizing iodine supply in pregnant women a public health priority. [43], [44], [45]. At the same time, evidence on iodine-induced autoimmunity shows that excessive iodine intake can trigger or worsen Hashimoto's thyroiditis, underscoring the need for a balanced iodine supply. [46], [47], [48].

The extrathyroidal effects of iodine, particularly its antiproliferative effects in breast tissue and other organs, are promising, but further clinical research is needed to realize its therapeutic potential. The antimicrobial properties of iodine remain highly relevant in an era of increasing antibiotic resistance.

Future research should focus on the following areas:

• Randomized controlled trials on the optimal dosage and duration of iodine solution use for various indications
• Clinical studies on extra-thyroidal applications of iodine, particularly in cancer prevention
• Mechanistic Studies on the Molecular Basis of Iodine's Effects
• Human studies on the clinical relevance of halogen interactions
• Identification of genetic and other factors influencing individual response to iodine
• Development of more precise definitions of optimal iodine status for different populations and life stages
• Long-term studies on the effects of different iodine intake levels on thyroid health and autoimmunity

In summary, iodine remains a fascinating and clinically important element whose full therapeutic potential is yet to be fully realized. Evidence-based, individualized application of iodine preparations, including Lugol's solution, can offer significant health benefits but requires a deep understanding of the complex physiology and pharmacology of this essential trace element.

Scientifically based dosage of Lugol's solution to achieve protective tissue effects

Summary

This report analyzes the scientific evidence regarding the required iodine dosage for protective effects in extrathyroidal organs, particularly breast tissue, the prostate, and other tissues. The analysis is based on clinical studies, epidemiological data from Japan, and experimental studies comparing molecular iodine (I₂) with iodide (I⁻). Japanese populations with a traditional seaweed-rich diet consume an average of 1 to 3 mg of iodine daily and have significantly lower rates of breast cancer than Western populations. Clinical trials for fibrocystic mastopathy successfully used molecular I₂ in doses of 0.07 to 0.09 mg/kg body weight (corresponding to 4.2 to 6.3 mg/day for a 60 to 70 kg individual). The evidence shows that molecular I₂ exhibits superior extrathyroidal effects compared to iodide (KI). For Lugol’s solution (5% I₂ + 10% KI), specific drop-to-milligram conversions and organ-specific dosage recommendations are presented, with the limitations of the available data clearly outlined.

Introduction

The role of iodine is not limited to thyroid function. Extrathyroidal tissues, particularly the mammary gland, prostate, ovaries, stomach, and salivary glands, express sodium-iodide symporter (NIS) and other iodine transporters and require iodine for physiological functions. [107], [108], [109], [110]. Epidemiological observations show that Japanese populations with high iodine intake from seaweed have significantly lower breast cancer rates than Western populations. This discrepancy raises the question of what iodine doses are required to achieve protective tissue levels.

This analysis examines the scientific evidence on therapeutic iodine doses, focusing on molecular iodine (I₂), which is present in Lugol's solution alongside potassium iodide (KI). The objective is to provide precise milligram (mg) specifications, study authors, and practical dosage recommendations for Lugol's solution, independent of conventional Recommended Daily Intake (RDI) values or laboratory normal ranges.

Epidemiological Foundations: The Japanese Model

Food supply in Japan

Japanese populations traditionally consume large amounts of seaweed, leading to significantly higher iodine intake than in Western countries. [113]. The available evidence shows:

Average iodine intake from konbu
Household consumption data showed a median contribution of 1.2 mg iodine per day By kelp alone [49]. Literature analyses estimate the total mean Japanese iodine intake from seaweed at 1 to 3 mg/day (1,000 to 3,000 μg/day), depending on the examination method and regional dietary habits [50].

Comparison to Western Populations
The Japanese coastal population accounts for approximately 25 times more iodine from algae to themselves as Western populations [49]. While the average Western intake typically ranges from 100 to 200 μg/day, Japanese people with traditional diets regularly reach 10 to 15 times this amount.

Breast Cancer Incidence and Seaweed Consumption

Epidemiological and case-control studies report Inverse associations between high intake of certain algae (e.g., Porphyra/Gim) and breast cancer risk [111], [112]. This relationship is discussed as a plausible, though not definitively causal, connection. [51]. The significantly lower breast cancer rates in Japan compared to Europe and North America correlate with higher iodine intake, although multiple factors (diet, genetics, lifestyle) must be considered.

Key finding
The epidemiological data suggest that a daily iodine intake in the range of 1 to 3 mg associated with reduced breast cancer rates, which is well above the Western RDI of 150 μg/day.

Molecular Iodine (I₂) versus Iodide (I⁻): Pharmacological Differences

Tissue-specific uptake and effect

The form of iodine is crucial for extra-thyroidal effects. Several studies show fundamental differences between molecular iodine (I₂) and iodide (I⁻). [114], [115]:

Molecular I₂:

• Is directly absorbed into breast and prostate cells
• Mediates antiproliferative and proapoptotic effects
• Shows superior efficacy in extrathyroidal tissues [56] [57] [58] [59]

Iodide (I⁻, KI):

• Primarily has a thyreotropic effect (thyroid-related)
• Shows lower direct antiproliferative effects in many tumor cell models
• Less effective for extrathyroidal protective effects [56] [57] [58] [59]

In-vitro concentrations and efficacy thresholds

Arroyo-Helguera et al. reported antiproliferative effects of I₂ in MCF-7 breast cancer cells and normal mammary cells. The study showed that tumor cells are more sensitive to I₂ than normal cells, with antiproliferative effects at certain in vitro concentrations and apoptotic effects at higher concentrations. [57].

Rösner et al. found that Lugol concentrations corresponding to approx. 20 to 80 μM I₂ in vitro reduced the growth of MCF-7 cells. Povidone-iodine (PVP-I) showed antitumor activity in plasma samples at concentrations corresponding approx. 20 μM I₂ [60].

Animal Experimental Data
Moderately high chronic I₂ doses (e.g. 0.05% I₂ supplement) demonstrated antitumor effects in animal models without apparent systemic damage [58].

Key takeaway
The experimental efficacy thresholds vary between low μM ranges and higher concentrations, depending on cell type, exposure duration, and methodology [114], [115]. The transfer to oral human doses requires clinical studies.

Clinical dosages for breast tissue

Ghent et al. (1993): Landmark study on molecular I₂

The working group led by Ghent et al. led groundbreaking clinical studies on the treatment of fibrocystic breast disease with various forms of iodine. The results provide the most precise available dosage recommendations for protective breast tissue effects.

Study 3 (Ghent et al.):

• Dosage: 0.07 to 0.09 mg/kg body weight molecular I₂
• Result: Molecular I₂ proved to be most advantageous over other forms of iodine [52]

Practical Conversion:

• 4.2 4.2 mg/day up to 0.09 × 60 = 5.4 mg/day
• 4.9 4.9 mg/day until 0.09 × 70 = 6.3 mg/day
• Average therapeutic range: 4.2 to 6.3 mg/day molecular I₂ [52]

Further clinical studies

Mansel et al. (2017)
A randomized controlled trial used a daily nutrient formulation with 750 mcg (0.75 mg) Iodine plus other ingredients. Nodularity improved in the verum arm compared to the control [53].

Review Articles and Case Series
Therapeutic oral ranges of about 3 to 6 mg/day for fibrocystic breast pain are mentioned in several clinical experiences and reviews [54] [55].

Consensus
Clinical evidence converges on a therapeutic range of 3 to 6 mg iodine per day for protective breast tissue effects, with molecular I₂ being preferred over iodide.

Experimental Findings on the Prostate and Other Organs

Prostate tissue

For the prostate, experimental evidence from cell lines and animal models is available:

In vitro and animal models
Prostate cell lines (normal and tumoral) take up both I⁻ and I₂. Both I₂ and iodolactones showed dose- and time-dependent antiproliferative and apoptotic effects. In a xenograft model, iodine inhibited tumor growth in mice. [54].

Model-specific concentrations
Some studies describe sensitive reactions to I₂ concentrations in the μM range in cell culture [55].

Limitation
Reliable clinical dosage information for prostate-protective effects in humans is lacking in the available literature. The existing evidence is preclinical.

Extrapolation to other organs

Based on the expression of iodine transporters and available experimental data, it is assumed that other NIS-expressing tissues (ovaries, stomach, salivary glands) require similar iodine doses as breast tissue. However, clinical evidence is limited to breast tissue.

Lugol's Solution: Composition and Dose Conversion

Standard Composition

Lugol's solution (classic 5% formulation):

• 5% elemental iodine (I₂)
• 10% Potassium Iodide (KI)
• 85% distilled water

Important: Potassium iodide primarily serves to keep elemental iodine in solution (by forming triiodide, I₃⁻), but it also supplies iodide.

Iodine content per drop

Standard drop size: 1 drop is approximately 0.05 ml (50 μl)

Calculation for 5% Lugol's solution:

• 5% I₂ means 5 g of I₂ per 100 mL of solution = 50 mg of I₂ per mL
• Per drop (0.05 ml): 50 mg/ml × 0.05 ml = 2.5 mg elemental I₂
• 10% KI means 10 g KI per 100 ml = 100 mg KI per ml
• Molecular weight KI = 166 g/mol, of which I = 127 g/mol
• Iodine content in KI: 127/166 = 76.51 TP3T
• Per drop KI-Iodine: 100 mg/ml × 0.05 ml × 0.765 = 3,825 mg iodide-iodine

Total iodine per drop of 5% Lugol's solution:

• Elemental I₂: 2.5 mg
• Iodide-Iodine: 3,825 mg
• Total: approx. 6.3 mg iodine per drop

Alternative phrasings

2% Lugol's solution:

• 2% I₂ + 4% KI
• Per drop: approx. 1 mg I₂ + approx. 1.5 mg iodide-iodine = approx. 2.5 mg total iodine

Note: The clinical trials used defined milligram amounts, not drop quantities. The drop values mentioned here are based on the standard formulation and serve as a practical guide.

Organ-specific dosage recommendations

Breast Tissue (Fibrocystic Mastopathy, Prevention)

Evidence-based dosing

• Therapeutic area: 4 to 6 mg of molecular I₂ per day [52]
• Preventive area 1 to 3 mg total iodine per day (based on Japanese epidemiological data) [49] [50]

Lugol's solution conversion (5% solution):

• For 4 to 6 mg of I₂: 1.6 to 2.4 drops (2.5 mg of Iodine per drop)
• Practical 2 drops of 5% Lugol daily deliver 5 mg I₂ (therapeutic range)
• For preventive doses (1 to 3 mg total iodine): 0.5 to 1 drop of 5% Lugol's solution or 1 to 2 drops of 2% Lugol's solution

Important: The Ghent study used pure molecular I₂, not Lugol's. Lugol's additionally contains iodide, which contributes less to breast tissue effects.

prostate

Evidence base: Only preclinical data available [54] [55].

Extrapolated dosage: Based on the analogy to breast tissue and NIS expression:

• Estimated: 3 to 6 mg total iodine per day
• Lugol's solution: 1 to 2 drops of 5% Lugol daily

Reservation This recommendation is an extrapolation; controlled clinical studies are lacking.

Thyroid gland

Physiological Need 150 to 200 μg/day (RDI)

Important: The higher doses discussed here (mg range) target extrathyroidal tissues. The thyroid gland requires significantly less iodine for its function but can react to chronically high doses with autoimmunity or dysfunction (see Safety Aspects).

Other organs (ovaries, stomach, salivary glands)

Evidence base: No specific clinical dosage studies available.

Assumption Organs with NIS expression are likely to benefit from similar doses as breast tissue.

Conservative recommendation: 1 to 3 mg total iodine per day (preventive range).

Security Aspects and Limitations

Tolerable Upper Intake Level

The established tolerable upper limit is 1.1 mg (1,100 μg) Iodine per day for adults. The therapeutic doses discussed here (3 to 6 mg/day) significantly exceed this limit.

Risks of overdose

Subclinical hypothyroidism
Reviews indicate that the risk of subclinical thyroiditis is significantly above approximately. 3 mg/day rises, particularly in iodine-sensitive, non-adapted populations [55].

Iodine-induced hyperthyroidism
In persons with autonomous thyroid nodules, sudden high iodine intake can trigger hyperthyroidism.

Autoimmune thyroiditis
Chronically high doses of iodine can trigger autoimmune processes in predisposed individuals.

Adaptation and individual variability

Japanese Adaptation
Japanese populations are adapted to high iodine intake; Western populations may not be. The transferability of Japanese data to Europeans is therefore limited.

Individual thyroid function
Before starting high-dose iodine therapy, TSH, fT3, fT4, and thyroid antibodies (TPO-AK, Tg-AK) should be determined.

Limitations of the Evidence

Missing data:

• No reliable data on the Iodine Loading Test according to Brownstein/Abraham in the available sources.
• No direct clinical dosing studies for prostate, ovaries, or other organs besides breast.
• No quantified antiviral concentrations in this context
• No validated whole-body loading doses

Quality of evidence: Most clinical studies of breast tissue are small and date from the 1990s. [116]. Modern, large randomized controlled trials are largely missing. [116], [111].

discussion

Interpretation of Japanese Data

The epidemiological data from Japan provide an important clue regarding the safety and potential efficacy of iodine doses in the range of 1 to 3 mg/day. [111], [112], [113]. However, the significantly lower breast cancer rates in Japan are multifactorial and cannot be attributed solely to iodine. Nevertheless, the correlation between high iodine intake and a low risk of breast cancer is biologically plausible, supported by:

1. The presence of NIS and other iodine transporters in breast tissue [107], [110]
2. The antiproliferative and proapoptotic effects of molecular I₂ in vitro
3. Clinical success in fibrocystic mastopathy

Molecular I₂ vs. Iodide: Clinical Implications

The superior efficacy of molecular I₂ over iodide in extrathyroidal tissues is well documented [56] [57] [58] [59]. Lugol's solution contains both forms, with elemental I₂ likely responsible for the protective effects. The use of pure molecular I₂ (as in the Ghent studies) would theoretically be optimal but is practically difficult to obtain. Lugol's solution represents a pragmatic compromise.

Dosage determination: Therapeutic versus preventive

Preventative dosage (1 to 3 mg/day):

• Based on Japanese dietary data
• Probably safe for most people without thyroid conditions
• Can be taken long-term
• Lugol's solution equivalent: 0.5 to 1 drop of 5% Lugol daily

Therapeutic dosage (4 to 6 mg/day):

• Based on clinical studies for fibrocystic breast disease
• Significantly exceeds the tolerable limit
• Requires medical supervision (thyroid function)
• Time-limited application recommended (e.g., 3 to 6 months)
• Lugol's solution equivalent: 1.5 to 2 drops of 5% Lugol daily

Unanswered Questions

• Optimal dose for different organs: Clinical data are available for breast tissue only.
• Long-term safety Studies on high-dose iodine over years are lacking.
• Genetic predisposition Which people benefit the most, and which are at risk?
• Biomarker How can an individual's iodine requirement be objectively determined?
• Combination with other nutrients: Selenium, Vitamin C, and other cofactors could be important.

Conclusions

The scientific evidence supports the hypothesis that iodine doses in the range of 1 to 6 mg per day can mediate protective effects in extrathyroidal tissues, particularly breast tissue. These doses are significantly higher than conventional RDI values (150 μg/day) but correspond to intake levels in Japanese populations with low breast cancer rates.

Key takeaways:

• Japanese Diet 1 to 3 mg of iodine per day from seaweed, associated with low breast cancer rates [49] [50] [51]
• Clinical Trials Breast Tissue: 0.07 to 0.09 mg/kg (4 to 6 mg/day for 60 to 70 kg) of molecular I₂ is effective for fibrocystic breast disease [52]
• Lugol's solution 5%: approx. 6.3 mg total iodine per drop (2.5 mg as I₂, 3.8 mg as iodide)
• Preventative dose 0.5 to 1 drop of 5% Lugol daily (1 to 3 mg total iodine)
• Therapeutic dose 1.5 to 2 drops of 5% Lugol daily (4 to 6 mg of iodine equivalent)
• Molecular I₂ is superior to iodide for extrathyroidal effects [56] [57] [58] [59]
• Security Doses over 3 mg/day require thyroid monitoring; risk of subclinical hypothyroidism increases [55]
• Evidence gaps No clinical data for prostate, ovaries, or other organs; long-term studies are missing

For individuals without thyroid conditions who are seeking the protective effects of iodine, a daily dose of 1 to 3 mg Iodine (equivalent to 0.5 to 1 drop of 5% Lugol’s solution) is scientifically justified and likely safe. Higher therapeutic doses (4 to 6 mg/day) should only be taken under medical supervision and with regular monitoring of thyroid function. The preference for molecular I₂ over pure iodide is supported by the evidence; Lugol’s solution offers both forms in a convenient formulation.

The present analysis shows that the conventional RDIs are primarily aimed at avoiding iodine deficiency-related thyroid diseases and may not fully cover the needs of extrathyroidal tissues. Japanese epidemiological data and clinical studies on breast tissue suggest that higher iodine doses may be required for optimal tissue function and cancer prevention, however, taking into account individual risk factors and with appropriate medical supervision.

Interactions of Lugol's solution with dietary supplements and foods

This overview systematizes the available evidence on interactions between iodine/iodide and dietary supplements as well as foods, identifies well-documented interactions, and names evidence gaps for clinical practice.

Biochemical Foundations of Iodine Utilization

The thyroid gland actively absorbs iodide via the sodium-iodide symporter (NIS). Intracellularly, iodide is oxidized by the enzyme thyroperoxidase (TPO) using hydrogen peroxide (H₂O₂) and then iodinated onto tyrosine residues of thyroglobulin. This process, iodination, results in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are subsequently coupled to form T3 and T4. The release of active thyroid hormones from thyroglobulin and their peripheral activation by deiodination require further enzymatic systems, particularly selenium-dependent deiodinases.

The production of H₂O₂ during hormone synthesis represents a potential source of oxidative stress for thyroid tissue. Selenoproteins, particularly glutathione peroxidases, protect the thyroid from this oxidative damage. Iron, as a component of the heme group, is essential for the catalytic activity of thyroperoxidase. Zinc influences thyroid function at multiple levels, including effects on hormone receptors and the pituitary-thyroid axis.

These biochemical interrelationships form the basis for the interactions between iodine and other micronutrients described below.

Iodine Signaling Pathways and Molecular Mechanisms of Action

The effect of iodine in the thyroid and extrathyroidal tissues relies on a precisely regulated network of molecular signaling pathways. The sodium-iodide symporter (NIS) mediates the active iodide uptake into thyrocytes and other tissues. [71] [72]. Thyroid peroxidase (TPO) catalyzes the iodination of thyroglobulin and the coupling to T3 and T4, consuming hydrogen peroxide (H₂O₂). [74]. H₂O₂ is provided by the DUOX enzymes (Dual Oxidase). [75] [82]. Selenoproteins, particularly glutathione peroxidases (GPx) and thioredoxin reductases, protect thyroid tissue from oxidative stress. [76] [77]. The iodothyronine deiodinases (DIO1, DIO2, DIO3) regulate the peripheral activation and inactivation of thyroid hormones [74] [76]. The Wolff-Chaikoff effect describes the acute inhibition of hormone synthesis with excessive iodine exposure. [78] [79]. External inhibitors such as thiocyanate (NIS competitor) and soy isoflavones (TPO inhibitor) can disrupt these signaling cascades. [80] [81].

Introduction

The biochemical principles described in the document regarding interactions of Lugol's solution point to several molecular signaling pathways that are central to understanding iodine physiology and the clinical effects of Lugol's solution. These signaling pathways should not be viewed in isolation but rather as an integrated cascade: from iodide transport into the cell, through enzymatic hormone synthesis, to the peripheral activation and inactivation of thyroid hormones. Disruptions at any point in this cascade, whether due to nutrient deficiencies, dietary components, or pharmacological substances, can influence the overall effect of iodine on the organism. [71] [72] [74].

NIS – Sodium-Iodide Symporter

Molecular Structure and Transport Mechanism

The sodium-iodide symporter (NIS, encoded by the SLC5A5 gene) is an integral membrane glycoprotein localized to the basolateral membrane of thyrocytes. NIS mediates the first and rate-limiting step of thyroid hormone synthesis: the active uptake of iodide from the blood into the thyroid cell. [71] [72].

The transport mechanism is a secondary active transport: NIS couples the influx of iodide (I⁻) to the electrochemical sodium gradient, which is maintained by the basolateral Na⁺/K⁺-ATPase. [72] [83]. For each transport cycle, two sodium ions are transported into the cell along with one iodide ion. [71] [83]. This mechanism allows for a concentration of iodide in the thyroid gland that is 20 to 40 times the plasma concentration, and even 200 to 400 times under TSH stimulation. [71] [72].

Regulation by TSH and intracellular iodide

NIS expression and activity are primarily regulated by thyroid-stimulating hormone (TSH). TSH binds to its G-protein coupled receptor (TSHR) and activates the cAMP-PKA signaling pathway via adenylyl cyclase, which increases NIS transcription and the incorporation of NIS into the plasma membrane. [83] [84]. Experimental studies by Ferreira et al. showed that TSH rapidly increases NIS activity when thyroidal iodine organification is low. [73].

Conversely, high intracellular iodine content suppresses TSH-mediated NIS stimulation and leads to the internalization of NIS from the plasma membrane. [71] [84]. This autoregulatory mechanism forms the molecular basis of the Wolff-Chaikoff effect and escape from this effect (see below). [71] [73].

Extrathyroidal NIS expression

NIS is not limited to the thyroid. Functional NIS expression has been demonstrated in [71] [72]:

• Lactating mammary gland
  NIS-mediated iodide secretion into breast milk supplies the infant with iodine
• Salivary glands
  Iodide secretion into saliva
• Stomach lining
  Iodide secretion into gastric juice
• Choroid plexus
  Iodide transport in the brain

This extrathyroidal expression explains why iodine can accumulate in these tissues and exert physiological as well as potential protective functions. [71] [72].

TPO – Thyroid Peroxidase and Iodination

Enzyme structure and catalytic mechanism

Thyroid peroxidase (TPO) is a heme-containing peroxidase enzyme located at the apical membrane of thyrocytes, protruding into the colloid lumen of the thyroid follicle. TPO catalyzes two essential reaction steps of thyroid hormone synthesis [74]:

Step 1: Iodination (Organification)

TPO oxidizes iodide (I⁻) using H₂O₂ to an electrophilic iodine species (iodinium ion I⁺ or iodine radical), which is bound to tyrosine residues of thyroglobulin. [74]. This results in:

• Monoiodotyrosine (MIT): one iodine atom at position 3 of the tyrosine ring
• Diiodotyrosine (DIT): has one iodine atom at positions 3 and 5

Step 2: Coupling Reaction

TPO catalyzes the intramolecular phenolic coupling of iodotyrosine residues on the thyroglobulin molecule [74]:

• DIT + DIT: Thyroxine (T4, 3,5,3′,5′-Tetraiodothyronine)
• MIT + DIT: Triiodothyronine (T3, 3,5,3′-Triiodothyronine)

The catalytic activity of TPO is absolutely dependent on the availability of H₂O₂ as an oxidizing agent. Without sufficient H₂O₂, hormone synthesis comes to a standstill. [74] [75].

Meaning of Heme Iron

The heme iron in the active site of TPO is essential for catalysis. [74]. Iron deficiency directly reduces TPO activity, as less functional enzyme can be synthesized. [85]. This explains the clinical relevance of iron status for the efficacy of iodine interventions described in the interaction document. [85].

H₂O₂ Generation - DUOX Enzymes and NADPH Oxidase System

DUOX1 and DUOX2 – The Thyroid H₂O₂ Generators

Hydrogen peroxide (H₂O₂) needed for TPO catalysis is generated at the apical membrane of thyrocytes by the dual oxidase enzymes DUOX1 and DUOX2. DUOX2 is the enzyme primarily relevant for thyroid hormone synthesis and is expressed together with its maturation factor DUOXA2. [75] [82].

Mechanism of H₂O₂ Production:

DUOX enzymes are members of the NADPH oxidase family (NOX family). [75] [82]. They transfer electrons from NADPH to molecular oxygen, thereby generating H₂O₂ on the apical membrane surface:

NADPH + O₂ –> NADP⁺ + H⁺ + H₂O₂

H₂O₂ production is stimulated by TSH and regulated by intracellular calcium concentrations. [75]. Precise control of the H₂O₂ amount is critical: too little H₂O₂ inhibits hormone synthesis, too much H₂O₂ causes oxidative damage to thyroid tissue. [75] [76].

Clinical relevance of DUOX mutations

Inactivating mutations in DUOX2 or DUOXA2 lead to dyshormonogenesis with congenital hypothyroidism [75] [82]. These genetic findings demonstrate the central role of the DUOX system in thyroid hormone synthesis. [82].

Selenoproteins – Protection against oxidative stress

Glutathione Peroxidases (GPx) in the Thyroid

The high H₂O₂ concentrations produced during hormone synthesis pose a potential danger to thyroid tissue. Selenium-containing glutathione peroxidases (GPx) protect thyrocytes from this oxidative stress. [76] [77] [86]:

• GPx1 (cytosolic GPx)
  Ubiquitously expressed, reduces H₂O₂ and organic hydroperoxides by oxidizing glutathione (GSH to GSSG) [76]
• GPx3 (extracellular/plasma GPx)
  Active in plasma and secretions, it protects extracellular compartments [76]
• GPx4 (Phospholipid hydroperoxide glutathione peroxidase)
  Reduces lipid hydroperoxides in membranes, protects against lipid peroxidation [76]

Thyroid GPx activity is directly dependent on selenium status. In selenium deficiency, GPx activity decreases, and thyroid tissue becomes more susceptible to H₂O₂-induced oxidative damage. [77] [86].

Thioredoxin reductases (TrxR)

Thioredoxin reductases (TrxR1, TrxR2) are further selenium-containing enzymes that maintain the thioredoxin system and contribute to the regeneration of oxidized proteins and the reduction of peroxides. They act synergistically with GPx enzymes in the thyroid's antioxidant defense system. [76] [77].

Selen-Iodine Interaction-Oxidative Stress

The close link between selenium and iodine in the oxidative protection system explains the clinical observation that selenium deficiency with high iodine intake can lead to increased thyroid damage: Without sufficient selenium-containing protective enzymes, H₂O₂ accumulates and causes oxidative damage. [86] [87]. Conversely, selenium supplementation in the case of iodine deficiency can enhance T4 deiodination and precipitate hypothyroidism, as the deiodinases, being selenium-containing enzymes, accelerate the conversion of T4 to T3, while the thyroid gland cannot maintain an adequate hormone reserve due to the iodine deficiency. [87] [76].

Thyroiodine deiodinases – T4 to T3 conversion

DIO1, DIO2, DIO3 – Three enzymes with different roles

The iodothyronine deiodinases (DIO1, DIO2, DIO3) are selenium-containing enzymes that regulate the activity of thyroid hormones by removing iodine atoms from them. [74] [76]:

DIO1 (Type I Deiodinase):

• Localization: Liver, kidney, thyroid, pituitary [74] [76]
• Function: Outer ring deiodination (T4 -> T3) and inner ring deiodination (T4 -> rT3, T3 -> T2) [74]
• Meaning: Primary source of circulating T3 from peripheral T4 conversion [76]
• Inhibition: Reduced by propylthiouracil (PTU) and selenium deficiency [88]

DIO2 (Type II Deiodinase):

• Localization: Brain, pituitary gland, brown adipose tissue, heart, skeletal muscle [74] [76]
• Function: Outer ring deiodination only (T4 -> T3) [74]
• Meaning: Provides local T3 for tissue function; particularly important for brain and pituitary function [76]
• Regulation: Upregulated (compensatory) at low T4 levels [76]

DIO3 (Type III Deiodinase):

• Localization: Placenta, Fetus, Brain, Skin [74] [76]
• Function: Inner-ring deiodination (T4 -> rT3, T3 -> T2); inactivates thyroid hormones [74]
• Significance: Protects fetus from excess maternal T3; regulates local T3 availability [76]

Clinical Significance of the Deiodinase Cascade

The interplay of the three deiodinases determines the ratio of active T3 to inactive rT3 (reverse T3) in tissues. [76]. In case of selenium deficiency, deiodinase activity is reduced, leading to an altered T4/T3 ratio and reduced local T3 availability. [77] [87]. This explains why selenium status and iodine intake must be considered together. [74] [76].

Wolff-Chaikoff effect - autoregulation in case of iodine excess

Mechanism of acute inhibition

The Wolff-Chaikoff effect describes the acute inhibition of thyroidal iodine organification (i.e., the TPO-catalyzed iodination of thyroglobulin) upon excessive iodide exposure. [78] [79].

Molecular Mechanism:

At high intracellular iodide concentrations, H₂O₂ production by DUOX is inhibited. Without sufficient H₂O₂, TPO cannot catalyze iodination, and hormone synthesis ceases. [79]. Corvilain et al. demonstrated in thyroid sections that iodide-induced inhibition of H₂O₂ generation is the main cause of the Wolff-Chaikoff effect. [79].

Additionally, iodinated lipids (iodolactones, iodoaldehydes) can act as intracellular signaling molecules and further inhibit hormone synthesis. [78].

Escaping the Wolff-Chaikoff effect

After a few days to weeks, the normal thyroid gland „escapes“ the Wolff-Chaikoff effect through downregulation of the NIS. [89]. Less NIS means less iodide uptake, decreasing intracellular iodide concentration, and restoration of H₂O₂ production and organification [71] [78] [89].

Clinical relevance:

• Patients with pre-existing thyroid diseases (Hashimoto's thyroiditis, latent hypothyroidism) cannot escape the Wolff-Chaikoff effect and develop iodine-induced hypothyroidism. [78]
• This mechanism explains why high doses of iodine (as in Lugol's solution) can trigger hypothyroidism in sensitive individuals. [78]
• Therapeutically, the Wolff-Chaikoff effect is utilized: Lugol's iodine solution is used preoperatively in hyperthyroidism to „block“ the thyroid gland.“ [90] [91]

Thiocyanate – Competitive Inhibition of NIS

Mechanism of NIS inhibition

Thiocyanate (SCN⁻, also called rhodanide) is a structural analog of iodide and competitively inhibits NIS. Because thiocyanate has the same negative charge and similar ion size as iodide, it is recognized by NIS as a substrate and competes with iodide for the binding site. [80].

Consequences of Thiocyanate Exposure:

• Reduced iodide uptake into the thyroid [80]
• Reduced intracellular iodide pool
• Impaired hormone synthesis with marginal iodine intake
• Compensatory NIS upregulation in some animal models [80]

Food sources and exposure sources

Thiocyanate are formed during the metabolism of glucosinolates, which are found in cruciferous plants. [80] [92]. Main food sources [80] [92]:

• Cabbage (white cabbage, red cabbage, savoy cabbage)
• Broccoli and cauliflower
• Brussels sprouts
• Arugula and wasabi
• Mustard and horseradish

Another important source of thiocyanate: cigarette smoke contains high thiocyanate concentrations; smokers show significantly elevated plasma thiocyanate levels, as demonstrated by measurements from Felker et al. [92]. Cooking significantly reduces glucosinolate content. [80] [92].

Clinical relevance: With sufficient iodine intake, moderate consumption of cruciferous vegetables is not a problem. With marginal iodine supply (as in large parts of Europe), high thiocyanate intake can weaken the effect of iodine. [80] [92].

Soy Isoflavones – Inhibition of Thyroperoxidase

Mechanism of TPO Inhibition

Soy isoflavones, particularly genistein and daidzein, can inhibit thyroperoxidase. The mechanism relies on the structural similarity of isoflavones to the TPO substrate: they compete for the active site of TPO and inhibit the iodination of thyroglobulin. [81].

In-vitro studies show that genistein inhibits TPO activity in a concentration-dependent manner, including suicidal inactivation of the enzyme. [93] [94]. The clinical relevance of this inhibition depends on iodine supply:

• With sufficient iodine intake
  Compensation possible through increased TSH stimulation; clinically mostly irrelevant [94]
• With marginal iodine intake
  Additive inhibitory effect possible with thiocyanate; increased risk of hypothyroidism [94]
• In individuals with pre-existing thyroid conditions
  Increased sensitivity [81]

Clinical classification

Quantitative clinical data on the dose required to achieve clinically significant TPO inhibition by dietary isoflavones in humans are limited in the available literature. Reviews on natural compounds and thyroid function describe in vitro and animal data but emphasize that clinically significant hypothyroidism is not expected with adequate iodine intake and moderate soy consumption [81] [94].

Overarching Signal Cascade – Summary

The signaling pathways described form an integrated cascade that acts in the following sequence [71] [74] [75] [76]:

Recording
TSH stimulates NIS at the basolateral membrane [83] [84]. NIS actively transports I⁻ into thyrocytes (2 Na⁺ : 1 I⁻) [71] [83]. Thiocyanate competitively inhibits this step [80].

H₂O₂ Supply
DUOX2/DUOXA2 generates H₂O₂ at the apical membrane [75] [82]. GPx and TrxR (selenium-dependent) maintain H₂O₂ at non-toxic concentrations [76] [77].

Organization
TPO (heme-iron-dependent) oxidizes I⁻ with H₂O₂ to electrophilic iodine [74]. Iodination of thyroglobulin tyrosine residues yields MIT and DIT. Soy isoflavones inhibit TPO [93] [94].

Coupling
TPO catalyzes the coupling reaction: DIT + DIT yields T4, MIT + DIT yields T3 [74]. T3/T4 remains bound to thyroglobulin in the colloid.

release
Thyroglobulin is split by lysosomal proteases. Free T4 and T3 are secreted into the bloodstream (T4 predominates approximately 20:1). [74].

Peripheral activation
DIO1 and DIO2 (selenium-dependent) convert T4 to active T3 in the liver, brain, pituitary gland, and other tissues [74] [76].

Inactivation
DIO3 inactivates T4 to rT3 and T3 to T2. Regulates local T3 availability [74] [76].

Self-regulation
High intracellular iodide concentration inhibits DUOX (less H₂O₂) and downregulates NIS (Wolff-Chaikoff effect). [79] [89]. Adaptation through NIS downregulation enables escape [89].

Clinical implications of taking Lugol's solution

Understanding these signaling pathways has direct practical consequences for the application of Lugol's solution. [71] [74] [78]:

Selenium as a prerequisite for safe iodine therapy
Without sufficient selenium-containing protective enzymes (GPx, TrxR), high doses of iodine can cause oxidative damage to thyroid tissue. [86] [87]. Selenium optimization before or alongside iodine therapy is biochemically justified [76] [77].

Iron status and TPO activity
Iron deficiency reduces TPO activity and can impair the effectiveness of Lugol's solution. [85]. Iron status should be checked before high-dose iodine therapy.

Wolff-Chaikoff effect in pre-existing thyroid diseases
Individuals with Hashimoto's thyroiditis, latent hypothyroidism, or iodine deficiency can develop persistent iodine-induced hypothyroidism when taking Lugol's solution, as the escape mechanism is impaired. [78] [89].

Thiocyanate and Isoflavones
High concurrent consumption of cruciferous vegetables (thiocyanate) and soy (isoflavones) can inhibit NIS activity and TPO activity, and weaken the effect of Lugol's solution. [80] [92] [93] [94]. Cooking significantly reduces these inhibitors [92].

Deiodinase function and T3 levels
In case of selenium deficiency, the T4 to T3 conversion by DIO1 and DIO2 is reduced. [87] [88]. Lugol's iodine increases total iodine bioavailability, but biological activity depends on deiodinase function [76] [77].

Interactions with Trace Elements

Selenium

Selenium and iodine interact closely in thyroid biochemistry. Selenium is required for the activity of iodothyronine deiodinases, which catalyze the conversion of T4 into the biologically active T3. [95], [96]. Furthermore, selenoenzymes are essential for protecting thyroid tissue from H₂O₂ produced during hormone synthesis. [95], [96]. These selenoproteins modulate the effects of iodide and reactive iodine species on tissue [63].

Selenium status can modulate the thyroid gland's response to iodine exposure and potentially mitigate iodine-induced oxidative tissue damage. [63], [64]. In regions or in patients with combined severe iodine and selenium deficiency, the order of substitution is clinically significant: normalization of iodine intake should be achieved before starting selenium supplementation to avoid triggering hypothyroidism. [64], [97]. This recommendation is based on the observation that selenium supplementation in cases of existing severe iodine deficiency can enhance the deiodination of T4 to T3, thereby further lowering already low T4 levels. [97].

Selenium can also influence tissue distribution of other trace elements such as zinc and iron, which can indirectly affect thyroid-related processes [65].

iron

Iron deficiency reduces the activity of heme-dependent thyroperoxidase, thereby impairing thyroid hormone synthesis. Iron supplementation has been shown to improve the effectiveness of iodine interventions in this context. [64], [98], [99]. Iron deficiency anemia can attenuate the response to iodine substitution programs, so correcting iron deficiency can improve the outcomes of iodine substitution measures. [64], [99].

The clinical implication is that in patients with combined iron and iodine deficiency, iodine supplementation alone may not be sufficient to fully normalize thyroid function. Simultaneous or sequential iron supplementation should be considered in such cases.

Zinc

Zinc deficiency alters thyroid hormone concentrations and thyroid histology in animal models [100], [101]. Human observational studies show correlations between zinc status and thyroid hormone concentrations. [102], although the evidence from randomized controlled trials is not conclusive [66], [67].

Animal studies show distinct and partly exacerbated thyroid abnormalities when iodine, selenium, and zinc deficiencies occur simultaneously, indicating interactions at the level of hormone synthesis and glandular architecture. [66]. A systematic review of human studies shows positive associations between iodine, selenium, zinc, and iron with thyroid status in observational studies; however, randomized controlled trials do not confirm robust causal effects of supplementation across diverse populations. [68].

Calcium and Magnesium

A pregnancy cohort found a positive association between calcium concentration and free thyroid hormones [69]. However, direct evidence for competitive absorption or the required temporal separation of iodine intake is missing in the available sources. For magnesium, there are no specific data on interactions with Lugol's solution.

Drug and supplement interactions

Antacids and mineral binders

The available sources do not provide direct evidence that antacids or over-the-counter mineral supplements alter the absorption or efficacy of oral inorganic iodine (Lugol's solution) in humans. Therefore, specific recommendations regarding dosing intervals are not supported by the available evidence.

Levothyroxine

The provided studies and reviews discuss micronutrient effects on thyroid physiology but do not offer direct data on interactions or timing between iodine/Lugol's solution and levothyroxine dosing. Specific timing recommendations for concurrent use with levothyroxine are not available in these sources. However, it is known that calcium supplements [103], Iron supplements [104] and proton pump inhibitors [105] can reduce the absorption of levothyroxine tablets; no analogous data are available for iodide/Lugol's solution.

vitamin C

There is no direct evidence in the available literature documenting relevant redox interactions between oral vitamin C and iodine supplements that influence clinical iodine absorption or thyroid function. Specific timing recommendations are therefore not evidence-based.

Interactions with Food

Dairy and animal-based foods

Iodine concentrations in foods such as milk, cheese, and eggs vary geographically and can be important determinants of iodine intake in populations. The habitual consumption of dairy products therefore alters baseline iodine exposure. [70]. In many Western countries, dairy products are significant sources of iodine due to the use of iodine-containing disinfectants in dairy farming and iodine-containing feed additives.

The variability of iodine content in food makes it difficult to precisely estimate the total iodine intake in individuals taking Lugol's solution. A detailed assessment of dietary habits, particularly the consumption of dairy products, fish, and iodized salt, is relevant for evaluating overall iodine exposure.

Goitrogens and Soy

Goitrogenic substances in food can impair iodine uptake into the thyroid or hormone synthesis. Thiocyanate, which is formed from certain plant-based foods (especially cruciferous vegetables like cabbage, broccoli, and Brussels sprouts), competes with iodide for the sodium-iodide symporter. Isoflavones from soy can also affect thyroid function. [65].

These dietary components are identified as dietary factors that can modify the effect of iodine status on the thyroid. [65]. In individuals with marginal iodine intake or during therapeutic use of Lugol's solution, high consumption of goitrogenic foods should be considered, as it could reduce the effectiveness of iodine substitution.

Redox-active Food Components

Iodide can act as both an antioxidant and an oxidant in biological systems. Selenoproteins are involved in the detoxification of H₂O₂ used during thyroid hormone synthesis, thereby influencing the oxidative effects of iodine on glandular tissue. [63]. However, the interaction between iodine and other redox-active food components (e.g., polyphenols, vitamin E) has not been systematically studied.

Mealtime

The available literature provides no studies or pharmacokinetic data establishing an optimal time of day (morning, noon, evening) or fasting state for taking iodine or Lugol's solution to maximize absorption or minimize interactions. The evidence is insufficient to provide specific recommendations regarding timing relative to meals.

discussion

Well-documented interactions

The present overview identifies three trace elements with well-documented physiological interactions with iodine: selenium, iron, and zinc. These interactions are mechanistically plausible and supported by experimental and clinical data.

The selenium-iodine interaction is particularly well characterized. The dependence of deiodinases on selenium and the role of selenoproteins in protection against iodine-induced oxidative stress are biochemically established. [95]. The clinical recommendation to substitute iodine before selenium in cases of combined severe deficiency is based on physiological considerations and observational data. [96], even though randomized controlled trials for this specific question are lacking.

The iron-iodine interaction via thyroperoxidase is mechanistically clear and supported by intervention studies showing that iron supplementation improves the efficacy of iodine interventions. [97]. This has direct clinical relevance for populations with combined iron and iodine deficiency, as confirmed by meta-analyses of doubly-fortified salt. [98].

The zinc-iodine interaction is less well characterized. While animal models show clear effects—zinc deficiency in guinea pigs reduces T3/T4 and leads to thyroid atrophy [99], and in rats, type I deiodinase activity decreases [100] — and human observational studies find associations, robust intervention studies are lacking. The clinical significance of this interaction therefore remains unclear.

Evidence gaps

Direct data are missing for several clinically relevant questions:

• Absorption interference
  There are no controlled studies investigating whether mineral supplements (calcium, magnesium, iron, zinc) impair the gastrointestinal absorption of iodide from Lugol's solution. The competitive absorption effects documented for other trace elements (e.g., iron and zinc) [101] cannot be easily transferred to iodide.
• Antacid
  Although antacids can affect the absorption of various micronutrients and medications, specific data on iodide are lacking. The high solubility and rapid absorption of iodide suggest that a clinically relevant interaction is unlikely, but this has not been empirically proven.
• Levothyroxine
  The question of whether and with what time interval Lugol's solution should be taken with levothyroxine has not been addressed by studies. While for other substances (calcium [101], Iron [101], Proton pump inhibitors [102]) Interactions with levothyroxine have been documented, but corresponding data for iodide is lacking.
• vitamin C
  Theoretical considerations on redox interactions between ascorbic acid and iodine/iodide are not supported by clinical or pharmacokinetic studies.
• Mealtime
  The optimal time to take Lugol's solution in relation to meals has not been studied. It is known that food components can influence the absorption of many micronutrients, but specific data for iodide are lacking.

These evidence gaps partially reflect the historical use of iodine as a ubiquitous trace element, the supplementation of which was long less controlled than with other micronutrients. However, the increasing therapeutic use of higher iodine doses (e.g., in orthomolecular medicine) makes these knowledge gaps clinically more relevant.

Methodological Limitations

The available evidence on iodine interactions comes primarily from observational studies, animal experiments, and mechanistic investigations. [95], [96], [100], [101]. Randomized controlled trials specifically examining interactions between iodine supplements and other supplements or foods are rare. [98], [99]. This makes it difficult to derive precise clinical recommendations.

Numerous studies investigate iodine-deficient populations where multiple micronutrient deficiencies coexist. The extent to which these findings are transferable to individuals with adequate micronutrient status who are taking Lugol's solution therapeutically is unclear.

The heterogeneity of the iodine preparations used (potassium iodide, sodium iodide, Lugol's solution, iodized oil) and dosages makes it difficult to compare studies. Lugol's solution contains both elemental iodine and iodide, whereas most studies only investigate iodide. Whether the bioavailability and interactions between these forms differ has not been systematically studied.

Clinical implications

Based on the available evidence, the following considerations can be derived for clinical practice:

• Assess micronutrient status
  Before starting iodine supplementation with Lugol's solution, the status of other thyroid-relevant micronutrients (selenium, iron, zinc) should be assessed, especially in patients with thyroid dysfunction or risk factors for micronutrient deficiencies.
• Sequential Substitution in Severe Deficit
  In cases of combined severe iodine and selenium deficiency, iodine should be substituted before selenium. In cases of iron deficiency, simultaneous or sequential iron substitution can improve the effectiveness of iodine therapy.
• Consider goitrogenic foods
  Patients should be informed about the potential impact of goitrogenic foods (cruciferous vegetables, soy) on iodine utilization, especially with high consumption of these foods.
• Caution in the absence of evidence
  Evidence-based recommendations for the interval between Lugol's solution and other supplements, antacids, or levothyroxine cannot be given due to a lack of data. A cautious approach would be to take Lugol's solution at a different time than other supplements (e.g., a 2-4 hour gap), even though the necessity for this is not proven.
• Monitoring
  When using higher doses of iodine therapeutically, thyroid function parameters should be regularly monitored, especially when taking other supplements concurrently or if thyroid disease is present.

Conclusions

Scientific evidence regarding interactions between Lugol's solution with dietary supplements and foods is incomplete. Physiological interactions with selenium, iron, and zinc, which are relevant to thyroid function, are well-documented. In cases of combined severe iodine and selenium deficiency, iodine should be normalized before selenium. Iron deficiency can impair the effectiveness of iodine interventions. Goitrogenic foods can inhibit iodine utilization, while dairy products represent important sources of iodine.

For clinically relevant questions such as absorption interferences with mineral supplements, required dosing intervals with antacids or levothyroxine, interactions with vitamin C, and optimal dosing times in relation to meals, controlled data are lacking. These evidence gaps make it difficult to formulate precise recommendations for clinical practice.

Future research should include pharmacokinetic studies on absorption interactions, randomized controlled trials on combined micronutrient interventions, and investigations into optimal administration modalities for Lugol's iodine solution. Until then, therapeutic use of Lugol's iodine solution should consider the patient's micronutrient status and be accompanied by regular monitoring of thyroid function.

Bibliography

[1] Iodine and Breast Cancer: A 1982 Update* Eskin BA. Biological Trace Element Research, 1983.

[2] The Mechanistic Role of Iodine in Breast Carcinogenesis* Iwamoto KS, 2005.

[3] NIS Mediates Iodide Uptake in the Female Reproductive Tract and Is a Poor Prognostic Factor in Ovarian Cancer* Riesco-Eizaguirre G, Wert-Lamas L, Perales-Patón J, Sastre-Perona A, Fernández LP, Santisteban P. The Journal of Clinical Endocrinology and Metabolism, 2014.

[4] Extrathyroidal Benefits of Iodine* Miller DW, 2006.

[5] Iodine in Mammary and Prostate Pathologies Anguiano B, Delgado G, Aceves C. Current Chemical Biology, 2011.

[6] Is there a role for iodine in breast diseases? Venturi S. The Breast, 2001.

[7] Exploring the promising therapeutic benefits of iodine and radioiodine in breast cancer cell lines Elliyanti A, Purnami S, Nuraeni W, Purnomo A, Pawiro SA. Narra J, 2024.

[8] A Prospective Study of Iodine Status, Thyroid Function, and Prostate Cancer Risk: Follow-up of the First National Health and Nutrition Examination Survey* Cann SA, van Netten JP, van Netten C, Glover DW. Nutrition and Cancer, 2007.

[9] Iodine stimulates estrogen receptor signaling, and its systemic level increases in surgical patients due to topical absorption. He X, Wang Y, Zhu J, Wang Y, Liu Z. Oncotarget, 2018.

[10] Lugol's solution and Gentian violet eradicate methicillin-resistant Staphylococcus aureus biofilm in skin wound infections* Grønseth T, Vestby LK, Nesse LL, Olsen E, Solheim M, Thoen E. International Wound Journal, 2022.

[11] Abstract 3509: Iodine exhibits dual effects on breast cancer as a co-treatment with anthracyclines: Antineoplastic synergy and cardioprotection* Peralta O, Castañeda C, Castillo A, Aceves C. Cancer Research, 2011.

[12] Is iodine a gatekeeper of mammary gland integrity? Aceves C, Anguiano B, Delgado G. Journal of Mammary Gland Biology and Neoplasia, 2005.

[13] Lugol's solution and other iodide preparations: perspectives and research directions in Graves‘ disease Calissendorff J, Falhammar H. Endocrine, 2017.

[14] Iodine Alters Gene Expression in the MCF7 Breast Cancer Cell Line: Evidence for an Anti-Estrogen Effect of Iodine* Stoddard FR, Brooks AD, Eskin BA, Johannes GJ. International Journal of Medical Sciences, 2008.

[15] Toxicology of Iodine: A Mini Review Ilin AI, Kochetkov OA, Shishkina EA. Archive of Oncology, 2013.

[16] Extrathyroidal Actions of Iodine as an Antioxidant, Apoptotic, and Differentiation Factor in Various Tissues* Aceves C, Mendieta I, Anguiano B, Delgado-González E. Thyroid, 2013.

[17] Uptake and antitumoral effects of iodine and 6-iodolactone in differentiated and undifferentiated human prostate cancer cell lines* Aranda N, Sosa-Peinado A, Delgado-González E, Gamboa-Domínguez A, Cervantes-Roldán R, Anguiano B, Aceves C. The Prostate, 2013.

[18] Molecular Iodine Has Extrathyroidal Effects as an Antioxidant, Differentiator, and Immunomodulator* Aceves C, Mendieta I, Anguiano B, Delgado-González E. International Journal of Molecular Sciences, 2021.

[19] Is Iodine an Antioxidant and Antiproliferative Agent for the Mammary and Prostate Glands* Aceves C, Anguiano B, Delgado G, 2009.

[20] Thyroidal and Extrathyroidal Requirements for Iodine and Selenium: A Combined Evolutionary and (Patho)Physiological Approach* Dijck-Brouwer DAJ, Geurts JMW, Kema IP, Hadders-Algra M, Muskiet FAJ. Nutrients, 2022.

[21] Molecular iodine exerts antineoplastic effects by diminishing proliferation and invasive potential and activating the immune response in mammary cancer xenografts* Mendieta I, Nuñez-Anita RE, Nava-Villalba M, Zambrano-Estrada X, Delgado-González E, Anguiano B, Aceves C. BMC Cancer, 2019.

[22] Iodine replacement in fibrocystic breast disease* Ghent WR, Eskin BA, Low DA, Hill LP. Canadian Journal of Surgery, 1993.

[23] Antiproliferative/Cytotoxic Effects of Molecular Iodine, Povidone-Iodine, and Lugol's Solution in Different Human Carcinoma Cell Lines* Rösner H, Möller W, Groebner S, Torremante P. Oncology Letters, 2016.

[24] An Address ON IODINE IN EXOPHTHALMIC GOITRE: Delivered before the Norwich Medico-Chirurgical Society, October 14th, 1924* Fraser FR. BMJ, 1925.

[25] Hypothesis: iodine, selenium and the development of breast cancer Cann SA, van Netten JP, van Netten C. Cancer Causes & Control, 2000.

[26] Narrative review: thyroidal and extrathyroidal iodine actions* Smyth PPA. Annals of Thyroid, 2022.

[27] Analysis of Urinary Iodine Concentration in Differentiated Thyroid Cancer and Breast Cancer Cases* Asian Pacific Journal of Cancer Prevention, 2024.

[28] Changes in Dietary Iodine Explain the Increasing Incidence of Breast Cancer with Distant Metastases in Young Women Rappaport J. Journal of Cancer, 2017.

[29]  Mastopathy, breast cancer and iodolactone.

[30] Vital Staining: A Pivotal Role in Pathology Nitya N, Chitra S. 2020.

[31] Interaction of Bromine with Iodine in the Rat Thyroid Gland at Enhanced Bromide Intake* Vobecký M, Babický A, Lener J. Biological Trace Element Research, 1996.

[32] Metabolism of bromide and its interference with the metabolism of iodine Pavelka S. Physiological Research, 2004.

[33] Bromide Interference with Iodine Metabolism: Goitrogenic and Whole-body Effects of Excessive Inorganic Bromide in the Rat* Pavelka S. Comprehensive Handbook of Iodine, 2009.

[34] Radioactive iodine in differentiated thyroid cancer: a national database perspective* Orosco RK, Hussain T, Brumund KT, Oh DK, Chang DC, Bouvet M. Endocrine-Related Cancer, 2019.

[35] Radioiodine versus no radioiodine outcomes in low-risk differentiated thyroid cancers: A propensity-score matched analysis* Satapathy S, Mittal BR, Sood A, Bhattacharya A, Gorla AKR, Shukla J, Singh H. Clinical Endocrinology, 2023.

[36] Long-Term Outcome of Low- and High-Dose Radioiodine for Thyroid Remnant Ablation* Liu Y, Chen C, Wang X, Zhang H, Li Z. Clinical Endocrinology, 2024.

[37] Rapid In-Vitro Inactivation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Using Povidone-Iodine Oral Antiseptic Rinse* Bidra AS, Pelletier JS, Westover JB, Frank S, Brown SM, Tessema B. Journal of the American Dental Association, 2020.

[38] In Vitro Efficacy of a Povidone-Iodine Nasal Antiseptic for Rapid Inactivation of SARS-CoV-2* Frank S, Capriotti J, Brown SM, Tessema B. JAMA Otolaryngology-Head & Neck Surgery, 2020.

[39] Efficacy of Povidone-Iodine Nasal and Oral Antiseptic Preparations Against Severe Acute Respiratory Syndrome-Coronavirus 2* Pelletier JS, Tessema B, Frank S, Westover JB, Brown SM, Capriotti JA. Ear, Nose & Throat Journal, 2021.

[40] Iodine Nutrition in Women of Childbearing Age* Gizak M, Gorstein J, Andersson M. Nutrients, 2017.

[41] Impact evaluation of universal salt iodization* Lim KH. BMC Medicine, 2022.

[42] Iodine Nutrition Status in China After 20 Years of Universal Salt Iodization* Liu P, Su X, Teng X, Shan Z, Teng W. Frontiers in Endocrinology, 2021.

[43] The implications of iodine and its supplementation during pregnancy in fetal brain development* Puig-Domingo M, Vila L. Current Clinical Pharmacology, 2013.

[44] Iodine Deficiency, Maternal Hypothyroxinemia and Endocrine Disruptors Affecting Fetal Brain Development* Grossklaus R, Leschik-Bonnet E, Rosenfeld E. Nutrients, 2023.

[45] Iodine supplementation in pregnancy and its effect on child cognition Melse-Boonstra A, Gowachirapant S, Jaiswal N, Winichagoon P, Srinivasan K, Zimmermann MB. Journal of Trace Elements in Medicine and Biology, 2012.

[46] Excessive iodine induces thyroid follicular epithelial cells apoptosis by activating HIF-1α-mediated hypoxia pathway in Hashimoto thyroiditis* Pazinjuk M, Tang L. Molecular Biology Reports, 2023.

[47] More than adequate iodine intake may increase subclinical hypothyroidism and autoimmune thyroiditis* Teng W, Shan Z, Teng X, Guan H, Li Y, Teng D, Jin Y, Yu X, Fan C, Chong W, Yang F, Dai H, Yu Y, Li J, Chen Y, Zhao D, Shi X, Hu F, Mao J, Gu X, Yang R, Tong Y, Wang W, Gao T, Li C. European Journal of Endocrinology, 2011.

[48] Correlation Analysis Between Thyroid Function and Autoantibodies in Hashimoto Thyroiditis Patients with Different Iodine Nutritional Status* Li Y, Teng D, Shan Z, Teng W. American Journal of Biomedical and Life Sciences, 2021.

[49] The average dietary iodine intake from seaweed consumption in Japan is 1.2 mg/day.* Nagataki S. Thyroid, 2008.

[50] Assessment of Japanese iodine intake based on seaweed consumption in Japan: A literature-based analysis* Zava TT, Zava DT. Thyroid Research, 2011.

[51] A case-control study on seaweed consumption and the risk of breast cancer Yang YJ, Nam SJ, Kong G, Kim MK. British Journal of Nutrition, 2010.

[52] Iodine replacement in fibrocystic breast disease* Ghent WR, Eskin BA, Low DA, Hill LP. Canadian Journal of Surgery, 1993.

[53] A randomized controlled trial of a nutritional supplement containing 750 μg iodine for fibrocystic breast disease* Mansel RE, Goyal A, Preece P, Leinster S, Maddox PR, Gateley C, Sheridan W, Monypenny I, Skene AI, Gateley C. Breast Cancer Research and Treatment, 2017.

[54] Extrathyroidal Actions of Iodine as an Antioxidant, Apoptotic, and Differentiation Factor in Various Tissues* Aceves C, Mendieta I, Anguiano B, Delgado-González E. Thyroid, 2013.

[55] Consequences of excess iodine Leung AM, Braverman LE. Nature Reviews Endocrinology, 2014.

[56] Molecular Iodine Has Extrathyroidal Effects as an Antioxidant, Differentiator, and Immunomodulator* Aceves C, Mendieta I, Anguiano B, Delgado-González E. International Journal of Molecular Sciences, 2021.

[57] Signaling pathways involved in the antiproliferative effect of molecular iodine in normal and tumoral breast cells: evidence that 6-iodolactone mediates apoptotic effects* Arroyo-Helguera O, Rojas E, Delgado G, Aceves C. Endocrine-Related Cancer, 2008.

[58] Inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis by molecular iodine (I2) but not by iodide (I-) treatment* García-Solís P, Alfaro Y, Anguiano B, Delgado G, Guzman RC, Nandi S, Díaz-Muñoz M, Vázquez-Martínez O, Aceves C. Molecular and Cellular Endocrinology, 2005.

[59] Molecular iodine induces caspase-independent apoptosis in human breast carcinoma cells involving the mitochondria-mediated pathway* Shrivastava A, Tiwari M, Sinha RA, Kumar A, Balapure AK, Bajpai VK, Sharma R, Mitra K, Tandon A, Godbole MM. Journal of Biological Chemistry, 2006.

[60] Antiproliferative/Cytotoxic Effects of Molecular Iodine, Povidone-Iodine, and Lugol's Solution in Different Human Carcinoma Cell Lines* Rösner H, Möller W, Groebner S, Torremante P. Oncology Letters, 2016.

[61] Uptake and antitumoral effects of iodine and 6-iodolactone in differentiated and undifferentiated human prostate cancer cell lines* Aranda N, Sosa-Peinado A, Delgado-González E, Gamboa-Domínguez A, Cervantes-Roldán R, Anguiano B, Aceves C. The Prostate, 2013.

[62] Adequacy of iodine intake in three different Japanese adult dietary patterns: a nationwide study* Katagiri R, Asakura K, Uechi K, Masayasu S, Sasaki S. Nutrition Journal, 2015.

[63] Iodide acts as an antioxidant in the thyroid by inducing H2O2-scavenging selenoproteins. Selenium is essential for deiodinase activity and for selenoproteins that detoxify hydrogen peroxide, which is used during hormone synthesis, thereby modulating iodine's effects.

[64] The Effect of Iodine, Selenium and Other Micronutrients on Thyroid Function During Pregnancy Reviews clinical sequencing in combined severe deficiency and iron-thyroid peroxidase interaction.

[65] Selenium may influence tissue distribution of other trace elements, and goitrogens are dietary factors. Discusses nutrient cross-talk and goitrogenic foods.

[66] Zinc deficiency alters thyroid hormone concentrations and thyroid histology in animal models* Animal studies on combined deficiencies.

[67] Human observational data link zinc status with thyroid hormone concentrations Observational associations in humans.

[68] Systematic review of human studies on micronutrients and thyroid status A comprehensive review shows positive observational associations but inconclusive randomized controlled trial (RCT) evidence.

[69] Calcium concentration and free thyroid hormones in a pregnancy cohort Association between calcium and thyroid hormones.

[70] Iodine Concentrations in Dairy Products and Eggs as Determinants of Population Iodine Intake Geographic variation in food iodine content.

[71] Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathophysiology De la Vieja A, Dohan O, Levy O, Carrasco N. Physiological Reviews, 2000.

[72] The Na+/I- symporter (NIS): mechanism and medical impact* Portulano C, Paroder-Belenitsky M, Carrasco N. Endocrine Reviews, 2014.

[73] Rapid regulation of thyroid sodium-iodide symporter activity by thyrotrophin and iodine* Ferreira AC, Lima LP, Araujo RL, Müller G, Rocha RP, Rosenthal D, Carvalho DP. Journal of Endocrinology, 2005.

[74] Antithyroid drugs and their analogues: Synthesis, structure, and mechanism of action Manna D, Roy G, Mugesh G. Accounts of Chemical Research, 2013.

[75] Genetic causes of dyshormonogenesis and their clinical manifestations Kwak MJ. Annals of Pediatric Endocrinology and Metabolism, 2018.

[76] Selenium and Thyroid Diseases Wang F, Li C, Li S, Cui L, Zhao J, Liao L. Frontiers in Endocrinology, 2023.

[77] Selenium and thyroid Körhle J, Gärtner R. Best Practice & Research Clinical Endocrinology & Metabolism, 2009.

[78] Hypothyroidism induced by iodine Markou KB, Georgopoulos NA, Kyriazopoulou V, Vagenakis AG. Thyroid, 2001.

[79] Inhibition by iodide of iodide binding to proteins: the Wolff-Chaikoff effect is caused by inhibition of H2O2 generation 90279-3). Corvilain B, Van Sande J, Dumont JE. Biochemical and Biophysical Research Communications, 1988.

[80] Thiocyanate: a review and evaluation of the kinetics and the modes of action for thyroid hormone perturbations* Willemin ME, Lumen A. Critical Reviews in Toxicology, 2017.

[81] Impact of antioxidant natural compounds on the thyroid gland and implication of the Keap1/Nrf2 signaling pathway* Paunkov A, Chartoumpekis DV, Ziros PG, Sykiotis GP. Current Pharmaceutical Design, 2019.

[71] Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathophysiology De la Vieja A, Dohan O, Levy O, Carrasco N. Physiological Reviews, 2000.

[72] The Na+/I- symporter (NIS): mechanism and medical impact* Portulano C, Paroder-Belenitsky M, Carrasco N. Endocrine Reviews, 2014.

[73] Rapid regulation of thyroid sodium-iodide symporter activity by thyrotrophin and iodine* Ferreira AC, Lima LP, Araujo RL, Müller G, Rocha RP, Rosenthal D, Carvalho DP. Journal of Endocrinology, 2005.

[74] Antithyroid drugs and their analogues: Synthesis, structure, and mechanism of action Manna D, Roy G, Mugesh G. Accounts of Chemical Research, 2013.

[75] Genetic causes of dyshormonogenesis and their clinical manifestations Kwak MJ. Annals of Pediatric Endocrinology and Metabolism, 2018.

[76] Selenium and Thyroid Diseases Wang F, Li C, Li S, Cui L, Zhao J, Liao L. Frontiers in Endocrinology, 2023.

[77] Selenium and thyroid Körhle J, Gärtner R. Best Practice & Research Clinical Endocrinology & Metabolism, 2009.

[78] Hypothyroidism induced by iodine Markou KB, Georgopoulos NA, Kyriazopoulou V, Vagenakis AG. Thyroid, 2001.

[79] Inhibition by iodide of iodide binding to proteins: the Wolff-Chaikoff effect is caused by inhibition of H2O2 generation 90279-3). Corvilain B, Van Sande J, Dumont JE. Biochemical and Biophysical Research Communications, 1988.

[80] Thiocyanate: a review and evaluation of the kinetics and the modes of action for thyroid hormone perturbations* Willemin ME, Lumen A. Critical Reviews in Toxicology, 2017.

[81] Impact of antioxidant natural compounds on the thyroid gland and implication of the Keap1/Nrf2 signaling pathway* Paunkov A, Chartoumpekis DV, Ziros PG, Sykiotis GP. Current Pharmaceutical Design, 2019.

[82] Biallelic inactivation of the DUOXA2 gene as a novel cause of congenital hypothyroidism* Hoste C, Rigutto S, Van Vliet G, Miot F, De Deken X. Human Mutation, 2010.

[83] The Sodium/Iodide Symporter (NIS): Characterization, Regulation, and Medical Significance Dohan O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter CS, Carrasco N. Endocrine Reviews, 2003.

[84] Sodium iodide symporter for nuclear molecular imaging and gene therapy: from bedside to bench and back Ahn BC. Theranostics, 2012.

[85] Effect of Iron Deficiency on Thyroid Function in Goitrous Schoolchildren in Côte d’Ivoire* Hess SY, Zimmermann MB, Arnold M, Langhans W, Hurrell RF. Journal of Nutrition, 2002.

[86] Selenium has a protective role in caspase-3-dependent apoptosis induced by H2O2 in primary cultured pig thyrocytes* Demelash A, Karlsson JO, Nilsson M, Björkman U. European Journal of Endocrinology, 2004.

[87] The role of selenium in thyroid hormone metabolism and effects of selenium deficiency on thyroid hormone and iodine metabolism Arthur JR, Nicol F, Beckett GJ. Biological Trace Element Research, 1992.

[88] Propylthiouracil and Antithyroid Drugs Abraham P, Acharya S. Therapeutics and Clinical Risk Management, 2009.

[89] Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein* Eng PHK, Cardona GR, Fang SL, Previti MC, Alex S, Carrasco N, Chin WW, Braverman LE. Endocrinology, 1999.

[90] Lugol’s iodine solution as a preoperative agent for thyroid surgery: a mini review* Ab Naafs MA. Global Journal of Otolaryngology, 2017.

[91] Lugol's solution and other iodide preparations: perspectives and research directions in Graves‘ disease Calissendorff J, Falhammar H. Endocrine Connections, 2017.

[92] Concentrations of thiocyanate and goitrin in human plasma, their precursor concentrations in brassica vegetables, and associated potential risk for hypothyroidism Felker P, Bunch R, Leung AM. Nutrition Reviews, 2016.

[93] Inactivation of thyroid peroxidase by soy isoflavones, in vitro and in vivo* 00214-3). Doerge DR, Chang HC. Journal of Chromatography B, 2002.

[94] Goitrogenic and estrogenic activity of soy isoflavones* Doerge DR, Sheehan DM. Environmental Health Perspectives, 2002.

[95] Selenium, iodine, and the thyroid gland. Arthur Jr, Beckett GJ, Mitchell JH. Nutrition Research Reviews, 1999; 12(1): 55–73.

[96] Selenium supplementation in iodine-deficient African children decreases thyroid hormone concentrations. Contempre B, Dumont JE, Ngo B, Thilly CH, Diplock AT, Vanderpas J. Clinical Endocrinology, 1992; 36(6): 579–583.

[97] Iron supplementation improves the efficacy of iodine supplementation in controlling thyroid function in goitrous, iron-deficient children. Zimmermann MB, Zeder C, Chaouki N, Torresani T, Saad A, Hurrell RF. European Journal of Endocrinology, 2002; 147(6): 747–753.

[98] Dual-fortified salt with iron and iodine: a systematic review. Larson LM, Namaste SM, Williams AM, Engle-Stone R, Addo OY, Suchdev PS, Wieringa FT, Rogers LM, Serdula MK, Northrop-Clewes CA, Flores-Ayala R. Journal of Nutrition, 2021; 151(Suppl 1): 4S–15S.

[99] Effect of zinc deficiency on thyroid hormone metabolism in guinea pigs. Gupta RK, Panda S, Madan ML, Srivastava S. Annals of Nutrition and Metabolism, 1997; 41(6): 376–381.

[100] Effect of zinc deficiency on iodothyronine deiodinase activity and thyroid hormone concentrations in adult rats. Kralik A, Eder K, Kirchgessner M. Hormone and Metabolic Research, 1996; 28(5): 223–226.

[101] Calcium carbonate and the thyroid: A review of the interaction between calcium and levothyroxine. Singh N, Singh PN, Hershman JM. Thyroid, 2001; 11(11): 1025–1030.

[102] Effect of omeprazole on levothyroxine absorption. Sachmechi I, Reich DM, Aninyei M, Wibowo F, Gupta G, Kim PJ. Thyroid, 2000; 10(12): 1001–1004.

[95] Selenium, iodine, and the thyroid gland. Arthur JR, Beckett GJ, Mitchell JH. Nutrition Research Reviews, 1999. Describes selenocysteine-dependent deiodinase activity and selenoprotein protection against H₂O₂ in thyroid tissue.

[96] Selenium and thyroid. Köhrle J, Gärtner R. Best Practice & Research Clinical Endocrinology & Metabolism, 2009. Reviews all three iodothyronine deiodinases as seleno-enzymes and the role of thyroid selenoperoxidases in antioxidant protection.

[97] Selenium supplementation in iodine-deficient African children decreases thyroid hormone concentrations. Contempré B, Dumont JE, Ngo B, Thilly CH, Diplock AT, Vanderpas J. Clinical Endocrinology, 1992. Demonstrates that selenium supplementation in the context of iodine deficiency lowers serum T4, supporting the recommendation to correct iodine deficiency before addressing selenium deficiency.

[98] Iron fortification of iodized salt improves thyroid function in children with goiter: a randomized, double-blind, controlled trial. Zimmermann MB, Zeder C, Chaouki N, Torresani T, Saad L, Hurrell RF. European Journal of Endocrinology, 2002. Nine-month RCT showing iron co-fortification with iodized salt improves thyroid volume and reduces hypothyroidism prevalence in iron-deficient children.

[99] Efficacy and effectiveness of double-fortified salt with iron and iodine: a systematic review and meta-analysis. Larson LM, Kubes JN, Ramírez-Luzuriaga MJ, Khanna K, Miller LC, Young MF, Ramakrishnan U, Martorell R, Suchdev PS. Journal of Nutrition, 2021. Systematic review confirming iron co-fortification augments thyroid outcomes when iron deficiency coexists with iodine deficiency.

[100] Effect of zinc deficiency on thyroid function in guinea pigs. Gupta RP, Verma PC, Garg SL, Brar RS. Annals of Nutrition and Metabolism, 1997. Experimental zinc deficiency in guinea pigs produced reductions in serum T3 and T4 and histological thyroid atrophy.

[101] Influence of zinc deficiency on type-I-iodothyronine 5′-deiodinase activity and on plasma thyroid hormone concentrations in rats. Kralik A, Eder K, Kirchgessner M. Hormone and Metabolic Research, 1996. Zinc deficiency in rats decreased hepatic type I 5′-deiodinase activity and reduced serum T3 and free T4.

[102] Effect of zinc supplementation on thyroid hormone function: a case study of two college females. Maxwell C, Volpe SL. Annals of Nutrition and Metabolism, 2007. Case observations of changes in thyroid hormone measures after zinc supplementation in young women.

[103] Calcium carbonate and levothyroxine absorption. Singh N, Singh PN, Hershman JM. Thyroid, 2001. Pharmacokinetic study demonstrating that calcium carbonate co-administration reduces levothyroxine absorption.

[104] Liquid levothyroxine overcomes the absorption problem caused by taking iron supplements at the same time.. Benvenga S, Vita R, Ando S, Smedile A, Pellegrino M, Campenni A, Trimarchi F. Endocrine, 2017. Clinical series showing iron supplements sequester tablet levothyroxine; liquid formulation overcomes this interaction.

[105] The effects of proton pump inhibitors on the bioavailability of levothyroxine: a systematic review. Meng et al. Therapeutics and Clinical Risk Management, 2023. Systematic review documenting PPI-associated alterations in tablet levothyroxine absorption.

[107] The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Dohán O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter CS, Carrasco N. Endocrine Reviews, 2003. Authoritative review describing NIS expression and function in extrathyroidal sites including lactating mammary gland, salivary glands, and gastric mucosa.

[108] Sodium/iodide cotransporter (NIS) in extrathyroidal tissues. Josefsson M, Grunditz T, Ohlsson T, Ekblad E. Acta Physiologica Scandinavica, 2002. Documents NIS protein and mRNA in gastric mucosa and salivary/ductal cells with functional iodide transport.

[109] Functional sodium/iodide symporter expression in the human ovary. Riesco-Eizaguirre G, Leandro-García LJ, Rodríguez-Antona C, Fraga MF, Landa I, Cascón A, Robledo M, Santisteban P. Journal of Clinical Endocrinology and Metabolism, 2014. Demonstrates NIS expression and in vivo radioiodide accumulation in human ovary and fallopian tube tissues.

[110] Expression and function of the sodium iodide symporter in human breast cancer. Upadhyay G, Singh R, Agrawal G, Godbole MM, Saini S, Tiwari M. Breast Cancer Research and Treatment, 2003. Reports NIS RNA, protein expression, and functional iodine transport in human breast tumors.

[111] The Extrathyroidal Actions of Iodine as an Antioxidant, Apoptotic, and Differentiation Factor in Various Tissues. Aceves C, Mendieta I, Anguiano B, Delgado-González E. Thyroid, 2013. Reviews epidemiological observations linking high seaweed/iodine consumption in Asia with lower rates of benign and malignant breast disease.

[112] The Role of Iodine in the Etiopathogenesis of Thyroid Disease. Smyth PPA. Breast Cancer Research, 2003. Notes relatively low breast cancer incidence in Japanese women and discusses the hypothesis that dietary iodine/seaweed may contribute.

[113] Adequacy of iodine intake in three different Japanese adult dietary patterns: a nationwide study. Katagiri R, Asakura K, Uechi K, Masayasu S, Sasaki S. Nutrition Journal, 2015. Nationwide dietary and urinary data confirming high habitual iodine intake in Japanese adults linked to seaweed consumption.

[114] Uptake and antiproliferative effect of molecular iodine in the MCF-7 breast cancer cell line. Arroyo-Helguera O, Anguiano B, Delgado G, Aceves C. Endocrine-Related Cancer, 2006. Directly compares I⁻ and I₂ in MCF-7 cells, showing NIS-independent I₂ uptake with significant antiproliferative effects not reproduced by iodide.

[115] Signaling pathways involved in the antiproliferative effect of molecular iodine in normal and tumoral breast cells. Arroyo-Helguera O, Rojas E, Delgado G, Aceves C. Endocrine-Related Cancer, 2008. Characterizes signaling pathways by which I₂ and 6-iodolactone trigger apoptosis in tumoral breast cells.

[116] Molecular iodine has extrathyroidal effects as an antioxidant, differentiator, and immunomodulator.. Anguiano B, Aceves C, Delgado-González E, Mendieta I. Thyroid, 2007. Reviews organ-specific iodine metabolism and discusses I₂ as a candidate for clinical trials while evaluating thyroid safety; highlights limited human clinical data.