Iodine: Characteristics, Sources and Health Implications : Characteristics, Sources and Health Implications [1 ed.] 9781619427105, 9781619427082

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Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved. Iodine: Characteristics, Sources and Health Implications : Characteristics, Sources and Health Implications, edited by Adelina H. Martinez, and Edelmiro

Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved. Iodine: Characteristics, Sources and Health Implications : Characteristics, Sources and Health Implications, edited by Adelina H. Martinez, and

BIOCHEMISTRY RESEARCH TRENDS

IODINE

Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved.

CHARACTERISTICS, SOURCES AND HEALTH IMPLICATIONS

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Iodine: Characteristics, Sources and Health Implications : Characteristics, Sources and Health Implications, edited by Adelina H. Martinez, and

BIOCHEMISTRY RESEARCH TRENDS

IODINE CHARACTERISTICS, SOURCES AND HEALTH IMPLICATIONS

ADELINA H. MARTINEZ AND

EDELMIRO J. PEREZ Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved.

EDITORS

Nova Biomedical Books New York

Iodine: Characteristics, Sources and Health Implications : Characteristics, Sources and Health Implications, edited by Adelina H. Martinez, and

Copyright © 2012 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com

NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS.

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Library of Congress Cataloging-in-Publication Data Iodine : characteristics, sources, and health implications / [edited by] Adelina H. Martinez and Edelmiro J. Perez. p. cm. Includes index. ISBN 978-1-61942-710-5 (eBook) 1. Iodine in the body. 2. Iodine deficiency diseases. 3. Iodine. I. Martinez, Adelina H. II. Perez, Edelmiro J. QP535.I1I53 2011 612.3'924--dc23 2011051313

Published by Nova Science Publishers, Inc. † New York

Iodine: Characteristics, Sources and Health Implications : Characteristics, Sources and Health Implications, edited by Adelina H. Martinez, and

Contents Preface Chapter I

Iodine during Pregnancy and Lactation: Supplementation Versus Exposure Inés Velasco, Cristina Santos, Maria del Carmen Millón, Lucía Zarza, and Federico Soriguer

1

Chapter II

Semiconductor-Photocatalyzed Iodine Generation C. Karunakaran and J. Jayabharathi

27

Chapter III

Iodine, Iodine Transporters and Thyroid Cancer Xiao Hong Liu, Alexander C. Vlantis, Enders K. W. Ng, Shirley Y. W. Liu, C. Andrew van Hasselt, and George G. Chen

53

Chapter IV

Thyroid Follicular Cell Carcinoma and Thyroiditis in Relation to Iodine Intake H. Rubén Harach

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vii

Chapter VI

Optical Plasma Characteristics and Kinetics of Processes in the Longitudinal Glow Dischargein Mixtures of Helium and Iodine Vapours А. K. Shuaibov, A. I. Shchedrin and А. G. Kalyuzhnaya Study on Urinary Iodine and Thiocyanate Concentrations in Bulgarian Schoolchildren and Students Aneliya V. Bivolarska, Penka D. Gatseva and Mariana D. Argirova

73

93

109

Chapter VII

Oxidation of 8-Oxoguanine with Iodineand Proposed Mechanisms Masayuki Morikawa, Katsuhito Kino, Masayo Suzuki, Takanobu Kobayashi, Rie Komori, and Hiroshi Miyazawa

121

Chapter VIII

Iodine: Characteristics, Sources, Implications Semra Cetinkaya

135

Chapter IX

Important Role of Cardiac Imaging Using Iodine Media for Implicating Arrhythmogenic Heart Disease Yasushi Akutsu, Youichi Kobayashiand Takehiko Gokan

Index

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Preface Iodine is an important trace element and an essential substrate for the synthesis of thyroid hormones. Iodine deficiency can lead to goiter, hypterthyroidism, mental retardation and impaired growth. In this new book, the authors present topical research in the study of the characteristics, sources and health implications of iodine. Discussed in this compilation is the potential mechanism of iodine and iodine transporters in thyroid cancer; iodine supplementation and exposure during pregnancy and lactation; semiconductor-photocatalyzed iodine generation; severe iodine deficiency disorders; and the role of cardiac imaging using iodine media in the detection of arrhythmogenic heart disease. Chapter I – Pregnancy is associated with a series of physiological changes in iodine metabolism that directly affect the daily needs for this micronutrient, especially during the first trimester of gestation. Chapter II – Semiconductor-photocatalyzed generation of iodine is a sustainable, ecofriendly, cost-effective method to produce iodine. Band gap-illumination of semiconductors generates charge carriers which produce iodine from iodide ion. With UV-A illumination TiO2 anatase nanocrystals in suspension show the largest photocatalytic efficiency to liberate iodine from aqueous iodide ion solution. The formation of iodine photocatalyzed by TiO2 P25 Degussa is less than that by anatase. Under UV-A light particulate V2O5 is the most active photocatalyst to generate iodine from iodide ion in aqueous ethanol. Further, iodine formation is more favorable with UV-C light than with UV-A light. On immobilizing the particulate semiconductors MoO3 displays largest photocatalytic activity to liberate iodine from aqueous iodide ion solution under UV-A illumination. While Langmuir-Hinshelwood kinetics is exhibited by the suspended particulate semiconductors clean first order kinetics is displayed by the immobilized semiconductor powders. Under natural sunlight, formation of iodine on semiconductor bed shows clean first-order kinetic behavior on iodide ion-concentration and Fe2O3 is the most efficient photocatalyst to oxidize iodide ion from aqueous solution. 1 wt. % Ag-doped nanocrystalline TiO2 photocatalyzes more effectively generation of iodine from iodide ion solution under UV light and the liberation of iodine is governed by the LangmuirHinshelwood kinetic law. Iodine formation is more in acetonitrile than in aqueous suspension. The nanodeposits of Ag on TiO2 surface act as electron-hole separation centres. Application of a cathodic bias of about 0.2 V to semiconductor bed enhances the solar-photocatalyzed iodine formation and nanoparticulate TiO2 anatase generates iodine from aqueous iodide ion solution most effectively. TiO2 rutile mixed with ZnO or SnO2 liberates more iodine and so

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also ZnO-SnO2 mixture. The solar-powered potentially induced TiO2, ZnO and SnO2catalyzed iodine generation also leads to 94 kJ mol-1 energy storage. Chapter III – Iodine is the essential element for humans. Proper intake of dietary iodine is considered crucial for the prevention of thyroid diseases. Epidemiological and animal model studies suggest that lower iodine supplements or exposure may promote the thyroid cancer transformation from differentiated to anaplastic form. Further studies disclose that iodineinduced cell cycle arrest and apoptosis may provide clues to the underlying mechanisms. Iodine transporters, sodium iodide symporter, pendrin, and apical iodide transporter, are responsible for the transport of iodine into, through and out of thyroid cancer cells. Better understanding the roles of iodine transporters has provided molecular definition to the role of iodine metabolism in thyroid carcinogenesis and therapy. A number of studies have directly demonstrated that these proteins play crucial roles in tumorigenesis and development through interfering with multiple cell signaling pathways. This chapter provides an insight into the potential mechanisms of iodine and iodine transporters which influence the formation and progression of thyroid cancer through regulating a number of cell signaling pathways controlling cell proliferation, cell survival and/or apoptosis. Chapter IV – There are many factors for assessing changes in thyroid cancer incidence. These include histological criteria for classification of thyroid tumors, pathological techniques, inclusion of papillary microcarcinomas (incidentally found in thyroidectomy specimens or detected by ultrasound guided fine needle aspiration cytology), radioactive fallout, radiation therapy, screening programs and standard of medical care particularly in sparsely populated iodine deficient areas. These factors may show significant variations with time after iodine prophylaxis. Papillary carcinoma usually forms the commonest group of thyroid malignancies, both in iodine rich and deficient areas before and after prophylaxis, where an increase in the papillary:follicular carcinoma ratio is also noted in the latter situation. In general, the increasing incidence of papillary thyroid cancer after iodine prophylaxis and the decrease of undifferentiated carcinomas are probably related to factors other than iodine itself, such as earlier detection and or better treatment of differentiated precursor tumors. Autoimmune thyroiditis is also linked to dietary iodine. Histologically diagnosed thyroiditis occurs more frequently in areas of iodine sufficiency than in areas of iodine deficiency, and increase after iodine prophylaxis. Interestingly, thyroiditis is found to be more frequently associated with papillary carcinoma than with other types of follicular cell derived thyroid malignancies regardless of iodine intake. In this chapter the authors will analyze the outcome of thyroid papillary, follicular and undifferentiated carcinoma, as well as thyroiditis, in relation to iodine intake in different regions of the world taking as a model the Province of Salta, Argentina. Chapter V – Emission characteristics of the longitudinal glow discharge in low-pressure Не-I2 mixtures used in UV glow discharge lamps are systematically investigated. The emission of plasma was studied in the spectral range 140-400 nm at an input power of 15-250 W. The pressure of the gas mixture was varied in the interval 100-1500 Ра. The emission of the I2(D’→A’) band with a maximum at λ=342 nm dominated in the region 320-360 nm, while the iodine-atom emission (183.0, 206.2 nm) prevailed in the bactericidal spectral region. The power and efficiency of UV emission of the longitudinal glow discharge are optimized with respect to the partial helium pressure, discharge current, and power introduced into plasma. A kinetic model describing plasmachemical processes in the Не-I2 glow discharge is proposed. The UV emission intensities of the 206.2-nm atomic spectral line and

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the 342-nm molecular band of iodine are investigated depending on the partial helium pressure in the mixture. The obtained theoretical dependences are in good agreement with experimental results. Chapter VI – The role of iodine deficiency as an environmental determinant in the development of endemic goiter is firmly established. However, iodine deficiency does not always result in endemic goiter, and iodine supplementation does not completely prevent goiter. Even in the presence of extreme iodine deficiency there is an unequal geographic distribution of goiter. It is clear, therefore, that there are other factors, beyond iodine deficiency, that may play a role in the etiopathogenesis of endemic goiter. Most of the substances considered to be goitrogens are chemicals found in the environment, e.g. thiocyanates, competitively inhibit the iodine uptake and its organification in the gland. The aim of this study was to evaluate the association between urinary iodine as reliable indicator of recent iodine status and urinary thiocyanate concentration supposedly related to tobacco smoke exposure of schoolchildren and university students. Subjects of study were 123 children (66 boys and 57 girls) aged 8 to 11 years and 104 medical students (51 men and 53 women) aged 19 to 25 years, all of them from the town of Plovdiv, Bulgaria. Urinary iodine was measured by the Sandell-Kolthoff reaction. The method for thiocyanate determination in urine was based on the quantitative oxidation of thiocyanate in acid permanganate solution with liberation of HCN, which reacted with picric acid. A questionnaire filled by the schoolchildren and students was used to evaluate their exposure to tobacco smoke and their smoking habits. The median urinary iodine of the inspected schoolchildren was between 100-199 µg/L, which is an indicator of optimal iodine nutrition. However, 10.6% of the children had iodine deficiency. Statistically significant association between tobacco smoke exposure and the values of urine thiocyanate concentration in the inspected children was found. The median urinary iodine of the inspected students was 141 µg/L for the men and 130 µg/L for the women, which indicates optimal iodine nutrition. Around one-third of the subjects were with iodine deficiency though mild iodine deficiency was dominated. There were statistically significant differences between urinary thiocyanate concentrations in smokers and non-smokers (P < 0.0001) with higher thiocyanate values in smokers. None of the studied subjects has a ratio urinary iodine/thiocyanate (μg/mg) below 3.5. The quantification of thiocyanate ions in urine provides a fast non-invasive method to monitor thiocyanate load from tobacco smoke. Thiocyanate levels should be carefully controlled in cases of severe iodine deficiency to avoid the competitive inhibition of iodine intake. Chapter VII – Among DNA bases, guanine is the most easily oxidized. 8-Oxoguanine (8oxoG) is a major oxidization product from guanine. Since the oxidation potential of 8oxoG is significantly lower than that of guanine, 8oxoG can be further oxidized by several oxidation reactions. Herein, the authors report that iodine can oxidize 8oxoG to several products. 8oxoG was completely oxidized by iodine, and guanidinohydantoin, dehydroguanidinohydantoin, oxaluric acid and one unknown product were produced under acidic conditions. In contrast, spirohydantoin, 2,5-diamino-4H-imidazol-4-one, diimine and two unknown products were produced under basic conditions. On the basis of these obtained results, the authors have proposed reaction pathways for these compounds.

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Adelina H. Martinez and Edelmiro J. Perez

Chapter VIII – Iodine is an important trace element and an essential substrate for the synthesis of thyroid hormones. Iodination of salt is used globally as it is not possible to ingest enough iodine through food. Iodized salt ensures an iodine intake of approximately 100-150 µg iodine per day, if a normal amount of salt is consumed. However, iodized salt is not a stable food and can be degraded if boiled or exposed to direct light. Iodine deficiency (ID) can lead to goiter, hypothyroidism, mental retardation, and impaired growth. The evidence indicates that iodine deficiency exists in some countries, leading to clinical problems of transient neonatal hypothyroidism, goitrogenesis, thyroid nodules, and thyroid disorders in pregnant women and neonates, as well as thyroid dysfunction in the elderly. Due to the importance of thyroid hormone-dependent processes, iodine deficiency has deleterious effects on individuals, especially pregnant women and growing children. The clinical and subclinical manifestations of iodine deficiency are collectively referred to as iodine deficiency disorders (IDD). Iodine deficiency disorder is a serious global public health problem, estimated to affect one billion people worldwide. Although North American populations are believed not to suffer from ID, 36% of the female population in their reproductive years have been found to suffer from this condition. Even more important is the fact that midwives and nurses and even obstetricians are not fully aware of this disorder and cannot provide preventive health services to pregnant and fertile women regarding iodine intake. However, it has been possible to develop such awareness for preventing disorders such as folic acid deficiency.Severe iodine deficiency disorders have been eradicated in many parts of the world, but milder forms still exist and may escape detection. Congenital hypothyroidism (CH) represents one of the most common preventable causes of mental retardation. If prompt treatment is delayed, irreversible mental retardation, growth failure and a variety of neurophysiological deficits develop in affected infants. In clinical practice, the authors face a large number of patients at various ages with disorders causing elevated TSH levels, i.e. transient neonatal hypothyroidism, goiter, thyroid nodules and thyroid disorders in pregnant women and neonates. WHO recommends using several indicators to assess the iodine status of a population: thyroid size by palpation and/or by ultrasonography, urinary iodine and blood constituents, TSH or thyrotropin, and thyroglobulin. The authors are able to prevent the consequences of low iodine and the fetal neurodevelopmental risk due to subtle thyroid hormone deficiency during pregnancy and the newborn period. Salt iodination is very important for preventing iodine deficiency disorders. Chapter IX – Cardiac imaging aims for the comprehensive evaluation of anatomy, physiology, prognosis, and treatment planning. Various imaging modalities have been utilized for the management of heart disease patients, and iodine (I) plays an important role as a contrast medium in angiography, computed tomography (CT), and magnetic resonance imaging and as a labeled tracer in radionuclide imaging. During the past decade, the dramatically improved spatial and temporal resolution achievable with multidetector CT has allowed technically demanding clinical applications, such as CT angiography and cardiac CT, to be practiced routinely. Conventional catheter-based diagnostic angiographic examinations have been largely replaced by CT angiography, and the use of intravenous iodine contrast medium maximizes its clinical utility. Multidetector CT allows multi-dimensional reconstruction of patient-specific cardiac anatomy. CT-rendered volumes add a third dimension to an otherwise two-dimensional ablation procedure, allowing better delineation of the complex anatomy of the left atrium with precise volume estimation and increased

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electroanatomic mapping accuracy for successful pulmonary vein catheter ablation in patients with atrial fibrillation. On the other hand, molecular cardiovascular imaging also plays an important role in imaging cardiovascular disorders at the molecular and cellular levels in vivo. This technique has the potential to assess the severity of myocardial disorders, such as heart failure, coronary artery disease, and cardiomyopathy. Various 123I-labeled compounds have been introduced for molecular imaging in most clinical centers using conventional gamma cameras without the need for a cyclotron. The longer half-life of 123I (13 hours) is suitable for long delivery distances from 123I supply centers. Japan has extensive clinical experience with 123I-meta-iodobenzylguanidine (MIBG) as a major iodinated compound. The authors and other recent investigators have focused on the important role of multidetector CT using iodine contrast media and myocardial scintigraphy using iodine-labeled radioisotope MIBG in patients with arrhythmogenic heart disease. These results confirm the significance of iodine for health in the area of arrhythmogenic heart disease.

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In: Iodine Editors: A. H. Martinez and E. J. Perez

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Chapter I

Iodine during Pregnancy and Lactation: Supplementation Versus Exposure Inés Velasco1,2, Cristina Santos3, Maria del Carmen Millón2, Lucía Zarza1, and Federico Soriguer2,4

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1

Servicio de Ginecología y Obstetricia, Hospital de Riotinto, Huelva, Spain 2 IDD Working Group of the SEEN: Sociedad Española de Endocrinología y Nutrición 3 Servicio de Análisis Clínicos. Hospital de Riotinto, Huelva. Spain 4 Servicio de Endocrinología y Nutrición, Hospital Regional Universitario Carlos Haya, Málaga, Spain

Iodine Metabolism During Pregnancy Pregnancy is associated with a series of physiological changes in iodine metabolism that directly affect the daily needs for this micronutrient, especially during the first trimester of gestation.[1] In early pregnancy, there is a significant increase in iodide clearance due to an increased glomerular filtration rate. Renal hyperfiltration and increased clearance –observed in iodine and other molecules (both smaller and larger)– begins in early pregnancy and continues until delivery, which represents a continuous renal “loss”.[2, 3] Such loss of iodine results in a depletion of circulating inorganic iodine concentrations and leads to increased thyroid iodine clearance, which reaches 60 ml/min and is associated with an increased absolute iodine input rate in the thyroid gland[4,5]. These mechanisms induce increased thyroid activity during pregnancy, as it was shown in a study where a group of pregnant women were administered an iodine radioisotope[6].

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Inés Velasco, Cristina Santos, Maria del Carmen Millón et al.

Similarly, other histological studies using thyroid follicular cell samples collected during pregnancy showed significant functional activity.[7, 8] A second mechanism of maternal iodine intake is activated at a later stage of pregnancy, when iodine from maternal circulation is partially transferred to the fetal-placental unit.[9] At mid-gestation, the fetal thyroid gland has already started to produce thyroid hormones, which are essential for proper fetal development.[10] Table 1. Epidemiological Criteria for Assessing Iodine Nutrition Based on Urinary Iodine Concentrations of Pregnant Women A,B Mean Urinary Iodine Concentations (μg/L)

Dietary Iodine Intake

500

Excessivec. This intake does not provide any additional benefit to health

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a

These criteria significantly differ from those used for assessing urinary iodine concentrations in school children, as the increase in glomerular filtration rates during pregnancy results in higher urinary iodine concentrations. b For breastfeeding women and children 500 >180

However, in 2004 Delange[25] pointed that iodine intake should range between 250 and 300 μg, which doubles the recommended intake for non pregnant adults. In fact, Utiger[26] believes that the risk of chronic excessive iodine intake has been overestimated and considers that adequate intake would be "at least" between 300 and 400 mg / day. There is no credible evidence that leads us to establish any upper limit to iodine intake. Therefore, the most reasonable recommendation is that “iodine intake in pregnant women and breastfeeding mothers should not exceed twice the daily RNI for iodine (i.e. 150 and < 500 μg/L. (Taken from “Iodine supplementation for pregnancy and lactation: United States and Canada: Recommendations of the American Thyroid Association”. Thyroid 2007; 17 (5): 483-484)[31] Figure 1. Urinary Iodine (UI) values are shown with 95% confidence intervals, and recommendations are given on sample numbers of pregnant women. National Health and Nutrition Examination Surveys (NHANES).

On the other hand, once the nutritional requirements for iodine are established, the recommendations for iodine supplementation and for adequate dosage should be adapted to each target population. Consequently, iodine-deficient areas will require iodine supplementation at a higher dose to prevent this deficiency. In this sense, further clinical research providing guidelines to adapt the recommendations to each geographic area is needed.[32] It should be noted that daily iodine intake recommendations (i.e. the need to provide iodine supplementation at a dose adapted to each geographic area) should be applicable to breastfeeding women.[32,33]

Mechanisms of Adaptation to Iodine Deficiency The metabolism of thyroid hormones has a number of mechanisms of adaptation to dietary iodine deficiency.[34] (Figure 1)

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In normal conditions, a normal adult thyroid gland suddenly exposed to severe iodine restriction is estimated to have an iodine store for more than three months, which prevents such deficiency from being a risk to health –even although the subject progressively develops goiter.[35] This is achieved by the thyroglobulin stored in the thyroid follicle, which stores iodinated compounds. Thus, in iodine-sufficient conditions thyroglobulin is synthesized, and in iodine-deficient conditions it releases iodine, thus avoiding variations in circulating thyroid hormone concentrations. The thyroid follicle is the only endocrine structure that stores hormone precursors. This store avoids dependence on iodine intake, which can daily change and varies depending on the geographic area. For healthy pregnant women with iodine sufficiency, the challenge of the maternal thyroid gland is to adjust the hormonal output in order to achieve the new equilibrium state, and thereafter maintain the equilibrium until term. In general terms, a normal thyroid easily achieves metabolic adjustment adaptation during pregnancy.[36] In contrast, the metabolic adjustment cannot easily be reached when the functional capacity of the thyroid gland is impaired (as in cases of iodine deficiency), which can result in the adaptive mechanisms failing to achieve a steady-state.[36,37] Firstly, this mechanism has a thyroid stimulating hormone –TSH– that increases hormone synthesis. Simultaneously, in deficient iodine conditions, TSH stimulates the thyroid gland, which results in an increase of the thyroid volume (goitrogenic effect). This initial mechanism triggers the release of hormones and maintains hormone levels within a normal range.[34-36] This regulating mechanism allows pregnant women to balance their thyroid function, which prevents hypothyroidism. However, such regulation critically lowers plasma free thyroxine (FT4) levels resulting in “maternal hypothyroxinemia”, which is responsible for the effects that dietary iodine deficiency has on the embryo and fetus.[38,39]    Thyroid gland stimulation                                                 Increase thyroid hormone synthesis    Thyroid gland stimulation                                                 Increase thyroid volume  Saving iodine mechanism: Preferential secretion of T3                                                                                                                           I                      I                          I      T4  T3                             I                          I                                                            I                         I   I (Iodine atom) 

Figure 2. Regulating Mechanisms in Iodine Deficiency.

If iodine deficiency persists in time, a second regulating mechanism is activated to “save” part of the iodine intake. The triiodothyronine hormone (T3) is preferentially secreted, while thyroxine levels (T4) significantly decrease.[37] T3 is the metabolically active form of the hormone at peripheral level and has several functions: •

To maintain normal metabolic conditions in the subject.

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Iodine during Pregnancy and Lactation • •

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To avoid the progressive increase of TSH. To delay the process of hyperplasia of the thyroid gland.

At experimental level, it has been demonstrated that when this regulatory mechanism is activated, thyroid hormone levels do not remain constant in the whole body, but the availability of T3 significantly varies from one tissue to another[40]. To achieve this, the body has extrathyroidal self-regulating mechanisms that are not TSH-dependent. Thus, these mechanisms maintain plasma TSH levels within normal limits, while they selectively protect some tissues (muscle, heart) against severe T3 deficiency. However, these regulating mechanisms do not prevent T3 deficiency in other tissues –such as the brain– that mostly rely on T4 to produce T3. This fact reveals that these regulatory mechanisms are clearly dependent on the availability of iodine even in mild to moderate iodine-deficient areas (such as many Western countries). This experimental model is consistent with the results obtained in some epidemiological studies that found subjects residing in iodine-deficient areas who did not have clinical hypothyroidism, as their circulating T3 levels ensure normal T3 concentrations in most tissues. Once circulating T4 normal levels have declined by 5 to 25% circulating T3 levels decrease. Even in these conditions, muscle and heart continue having normal T3 concentrations, while lung and ovary present slightly high T3 concentrations.[40]

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Maternal Repercussions of Iodine Deficiency Iodine deficiency impairs the ability of the thyroid gland to meet the metabolic challenges of pregnancy. Thus, it has significant effects on both maternal and fetal thyroid function.[14,41] According to Glinoer[36], an increase in thyroid stimulation leads to a sequence of events ranging from the physiological adaptation of the thyroid economy observed in healthy iodinesufficient women, to the pathological alterations affecting the thyroid anatomical integrity and function observed in iodine-deficient women (Figure 2). The more severe the iodine deficiency is, the more serious the fetal and maternal repercussions. [41] Globally, the changes in maternal thyroid function that occur during gestation can be viewed as a mathematical fraction, with hormone requirements in the numerator and the availability of iodine in the denominator. [27] During pregnancy, there is a higher requirement for iodine, so to sustain thyroid hormone production, the glandular machinery must draw iodine from its already depleted intrathyroidal iodine stores. This situation tends to become more severe with the progression of gestation to its final stages. During pregnancy, increased hormone requirements and iodine losses alter the preconception steady-state. In normal conditions, augmentation of iodide trapping is the fundamental mechanism by which the thyroid adapts to changes in the iodine supply, and such mechanism is the key to understanding thyroidal adaptation to iodine deficiency.[42]

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When the iodine supply is restricted (or more severely deficient), pregnancy triggers a vicious circle that leads to excessive glandular stimulation (Figure 3).[27,36]

Figure 3. From physiological adaptation to pathological alterations of the thyroidal economy during pregnancy. The scheme illustrates the sequence of events occurring for the maternal thyroid gland, emphasizing the role of iodine deficiency to stimulate the thyroidal machinery. (Taken from Glinoer. The Regulation of Thyroid Function in Pregnancy: Pathways of Endocrine Adaptation from Physiology to Pathology 1997; 18: 404-433).[36]

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Iodine during Pregnancy and Lactation

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Figure 4. Effects of Iodine Deficiency on Pregnant Women.

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The Concept of Overstimulation of the Thyroid Iodine deficiency occurring during pregnancy, even when it is considered to be only mild, results in prolonged enhanced thyroidal stimulation, and leads to goitrogenesis in both the mother and the fetus. In fact, pregnancy should be viewed as an “environmental” factor to trigger the thyroid machinery and, in turn, induce thyroid pathology in areas with a marginally reduced iodine intake.[27] However, it is long-term steady-state what determines the status of iodine intrathyroideal stores. Chronically iodine-deficient populations provide the perfect scenery to study thyroid alterations associated with pregnancy, as borderline iodine intake levels lead to increased thyroid stimulation. Lazaraus et al.[43] have convincingly proven that thyroid alterations occur even in healthy pregnant women residing in mildly iodine-deficient areas. When the iodine intake is abnormally low, adequate secretion of thyroid hormones may still be achieved by significant alterations in thyroid activity. One of the adaptive mechanisms is increased stimulation of iodine uptake by the thyroid; another mechanism includes decrease of intrathyroidal iodine and preferential T3 synthesis and secretion. These mechanisms are triggered and maintained by increased secretion of TSH.[9,44] Sustained thyrotropic stimulation results in thyroid hyperplasia. Although thyroid hyperplasia has traditionally been considered an adaptive mechanism, it is actually the first sign of failure of the regulatory mechanisms.[45] The first functional effect of iodine deficiency is an increase in NIS-mediated iodine uptake.[46] There is an inverse association between iodine intake and radioiodine uptake by the thyroid.[6] Increased radioiodine uptake may be accompanied by increased serum TSH concentrations.[42] However, the thyroid keeps sustained stimulation whatever TSH concentrations or sensitivity to TSH are. This is demonstrated by increased secretion of thyroglobulin and enhanced plasma thyroglobulin concentrations. To achieve adequate iodine supply to the thyroid, iodine uptake should meet two conditions [42]:

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Inés Velasco, Cristina Santos, Maria del Carmen Millón et al. • •

Firstly, urinary iodine levels should be reduced in order to preserve pre-existing iodine stores. Secondly, the thyroid should store above 100 μg / day of iodine for adults.

When plasma iodine concentrations decrease, an increase in thyroid iodine clearance maintains absolute iodine uptake by the thyroid constant, thus allowing to maintain thyroid plasma organic iodine within normal limits (10-20 mg). This is achieved as long as iodine intake is above 50 μg / day. Below this critical threshold, the absolute iodine uptake by the thyroid decreases, and thyroid organic iodine diminishes, which leads to goitrogenesis.[47,48] In clinical practice, some biochemical parameters have been found to be useful markers of enhanced thyroidal stimulation during an otherwise normal pregnancy, in iodine deficient conditions.[27] • • •

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•

Relative hypothyroxinemia: it is the first marker, which shows serum free T4 concentrations that tend to cluster near (or below) the lower limit of normality. Preferential T3 secretion: it is the second marker, which is shown by an elevated total T3/T4 molar ratio. Pattern of changes in serum TSH. It is the third parameter. After the initial transient lowering phase of serum TSH due to high hCG levels in the first trimester, serum TSH levels tend to remain stable in iodine-sufficient conditions, while they continue to progressively increase until term in iodine-deficient conditions. Serum TSH may reach levels that are twice (or even higher) the preconception serum TSH levels Changes in serum thyroglobulin (TG). In mild to moderate iodine deficiency conditions, serum TG increases progressively during gestation, so that at delivery, two thirds of women may have supra-normal TG concentrations.

In iodine deficiency conditions, it is very important to monitor serum TG-level variations during pregnancy, as it is a useful clinical marker. The reason is that there is a correlation between increased TG levels and gestational goitrogenesis. Therefore, serum TG level is a sensitive marker of goitrogenesis that can help prevent it by iodine supplementation.[48,49] However, there are several aspects deterring TG level from being widely accepted as a marker of iodine status. The first is that anti-Tg antibodies should be jointly measured to avoid underestimation of TG levels. The second is that the prevalence of anti-Tg antibodies is still unknown in iodine deficiency conditions; finally, it is still unknown whether they can be reduced by iodine prophylaxis.[50,51] Another limitation is the high variability and poor inter-assay reproducibility, even with the use of standardization.[52] This makes it difficult to establish normality ranges and/or thresholds to identify the severity of iodine deficiency.[53] Correctly interpreting changes in thyroid parameters as the pregnancy progresses allows to understand the underlying mechanisms that lead to the physiological (or pathological) adaptation of the thyroid to the pathophysiological processes associated with pregnancy, especially in mild to severe iodine-deficient areas.[1]

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Gestational Goitrogenesis Iodine deficiency is the primary factor causing gestational goitrogenesis, which affects both the mother and fetus. While goiter formation is not observed in pregnant women residing in iodine-sufficient areas as the United States, several European studies have found that thyroid volume significantly increases during pregnancy.[8,54,55] In iodine-sufficient regions in Europe, changes in thyroid volume are minimal (an average of 10-15%) and correspond to increased vascularization and thickening of the thyroid gland during pregnancy. But, in European regions where the iodine intake is lower, changes are more significant as the thyroid volume increases by 20-35% on average and many women double their thyroid volume during pregnancy.[56,57] For instance, before systematic iodine supplementation was established for pregnant women in Brussels, near 10% of women developed a goiter during pregnancy, which was only partially reversible after late postpartum.[58] Additionally, thyroid volume in the newborns of mothers receiving supplementation was accurately assessed and it was found to be 40% larger than that in newborns of untreated mothers. Furthermore, researchers found that thyroid glandular hyperplasia was already present in 10% of the newborns at birth (as compared with the newborns of mothers receiving iodine supplementation).[59] In Hong Kong, an almost iodine-sufficient area, researchers recently found that gestational goiter is very frequent and that the change in maternal thyroid volume was correlated positively with the change in serum thyroglobulin and negatively with urinary iodine concentration.[60] The studies conducted in Europe during the last decade in mild to moderate iodinedeficient areas have revealed that gestational goitrogenesis may be one of the environmental factors that may help understand the high prevalence of goiter among women. If this hypothesis is proven to be correct, then a correlation would be expected between parity and thyroid volume. This association has been confirmed by a retrospective study on pregnant women conducted in a moderately iodine-deficient region in Italy. A statistically significant correlation was found between increased thyroid volume and parity, which represents the first clinical demonstration of a cumulative goitrogenic effect of successive pregnancies. A later study conducted in Denmark confirmed the correlation between thyroid volume and parity. Thus, among women aged 18-65 years, the largest thyroid volume was found in multiparous or tobacco smoking women.[62] This goiter-and-nodule inducing effect of tobacco has been confirmed in subsequent studies.[63,64] Thilly et al.[65] described how the combination of these factors with iodine deficiency increase the tendency to develop thyroid alterations. The thyroid function in adults and children in areas with severe iodine deficiency is variable: some subjects present normal thyroid function while others develop varying degrees of hypothyroidism. Altogether, these results confirm the notion that several environmental factors may play a role in explaining goiter formation, tending to reinforce each other: iodine deficiency as the background, successive pregnancies as the triggering factors, and smoking habits as an additional reinforcement causal agent.[27]

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Rasmussen et al.[66] found that near 10% of women developed goiter during pregnancy (thyroid volume >22ml by ultrasound). In addition, they found that changes in thyroid volume were associated with clear biochemical evidence of increased thyroid stimulation, which strongly suggest that pregnancy induces goitrogenesis. In sum, pregnancy has a strong goitrogenic effect both on mother and fetus, even in areas with mild dietary iodine deficiency. Maternal goitrogenesis may be directly correlated with the degree of prolonged glandular stimulation occurring during pregnancy. (Figure 5) [27,52] Goiter during pregnancy is only partially reversible during late postpartum. Consequently, pregnancy becomes an environmental factor that may help understand the high prevalence of goiter and thyroid disorders among women. [58]

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Figure 5. Physiopathology of gestational goitrogenesis.

Most importantly, goiter formation also takes place in the progeny, emphasizing the exquisite sensitivity of the fetal thyroid to the consequences of maternal iodine deprivation, and also indicating that the process of goiter formation already starts during the earliest stages of the development of the fetal thyroid gland. [27] For years, the fact that some countries –such as the U.S– are iodine-sufficient has justified the absence of reports and articles revealing significant changes in thyroid metabolism associated with pregnancy.[67] This explains that even today the American Association of Obstetricians and Gynecologists (ACOG) still has reservations about the need to conduct thyroid function screening in the first trimester of pregnancy[68] and that it is thyroidologists who recommend iodine supplementation during pregnancy.[29] However, this situation has changed in the recent years, as iodine intake and urinary iodine excretion have decreased in the United States, thus resulting in an increase in IDD. [69, 70]

Maternal Hypothyroxinemia Another relevant thyroid malfunction parameter, or more exactly, another adaptation mechanism of the maternal thyroid gland to a low iodine intake is low maternal serum free T4.[71] Maternal hypothyroxinemia occurs when a steady-state is achieved in maternal thyroid metabolism, which improves metabolic control at the crucial stages of pregnancy. However, it

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indicates chronic iodine deficiency resulting in damage to the developing embryonic tissues.[72,73] The term hypothyroxinemia is based on the concept that low circulating FT4 concentrations are not necessarily accompanied by increased plasma TSH concentrations –as in clinical or subclinical hypothyroidism. Low thyroxine concentrations are accompanied by normality in other thyroid function parameters.[72] Maternal hypothyroxinemia is understood as: • • •

A “biochemical” condition (low T4 while the remaining thyroid parameters are normal). It affects healthy mothers (without any clinical manifestation or underlying thyroid pathology).[68] It reflects a state of nutritional deficiency where iodine intake is inadequate to meet the demands of pregnancy.

Hypothyroxinemia prevents the mother from supplying enough T4 to the embryo, which results in brain damage.[38,39] At present, there is solid evidence that maternal hypothyroxinemia (low T4L) at midgestation causes permanent and irreversible alterations in the neurological development of the embryo and fetus.[71-73] In addition, all degrees of iodine deficiency (mild, moderate and severe) have been found to affect maternal and neonatal thyroid function as well as mental development of the infant.[41]

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Autoimmune Thyroid Disorders and Pregnancy Traditionally, autoimmune thyroid disorders during pregnancy –even in euthyroid mothers– have been identified as risk markers of future obstetric complications.[74] In almost all the series of healthy women investigated, the prevalence of positive thyroid autoantibodies ranged from 5 to 12% of mothers. The risk of miscarriage was significantly higher in women with positive anti-TPO (13.8% versus 2.4% in women with negative TPO) and in women with elevated TSH levels. [75] Women with positive anti-thyroid antibodies have significantly higher TSH levels and lower free T4 concentrations than women with negative thyroid autoantibodies. [76] The primary deleterious effects of thyroid autoimmunity during pregnancy in areas with mild to moderate iodine deficiency are correlated with the risk of developing subclinical hypothyroidism with the progression of gestation even although anti-TPO antibodies decrease. [74, 77] Euthyroid women who express positive anti-TPO and / or anti-Tg antibodies and TSH levels above normal limits during the first trimester of pregnancy are at particular risk for developing postpartum thyroiditis and hypothyroidism. Hypothyroidism may be either triggered by pregnancy or worsened with advancing pregnancy.

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Additionally, maternal thyroid deficiency –even isolated hypothyroxinemia– may affect fetal development. Thus, undiagnosed –and untreated– hypothyroidism at mid-gestation may cause alterations in brain development in the progeny. [70, 78] Many studies have demonstrated that euthyroid women with positive thyroid autoantibodies have the same complications –although less frequently– as hypothyroid women, and their progeny obtain lower development scores. [79] Mecacci et al[80] found a significant correlation between thyroid autoantibodies (especially anti-TPO) and obstetric complications such as previous early miscarriage, fetal death or preeclampsia. The association between anti-TPO antibodies and a number of obstetric complications was recently investigated by Feki et al[81] in Tunisia. The researchers found no statistically significant association, except for non-thyroid autoimmune disease (Table 3): It should be elucidated whether this group should be treated with thyroxine from the onset of pregnancy. Negro et al [82] studied a total of 984 pregnant women of which 12% were thyroid peroxidase antibody positive. Women with positive-TPO antibodies were divided into two groups: group A was treated with thyroxine thorough gestation and group B was not treated. Striking reductions in the rates of miscarriage (75%) and premature delivery (69%) were reported among TAI-positive women who had received levothyroxine since early gestation and throughout pregnancy. The untreated positive anti-TPO group showed a 30% decrease in T4L concentrations and progressive increase in TSH concentrations.

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Table 3. Association between anti-TPO antibodies and a number of diseases / poor perinatal results in 1519 pregnant women

Diabetes Mellitus Non-thyroid Autoimmune Disease Psychiatric Illness Biochemical Abortion Late Abortion Pregnancy Loss Intrauterine Fetal Death Recurrent Miscarriage Gestational Diabetes Gestational HTA

Numbe r

TPO-Ab () (n=1420)

69 12

4.4 % 0.6 %

TPO-AB (+) (n= 99) 7.1 % 3.0 %

9 306 84 61 409 78 33 50

0.5 % 20.0% 5.3 % 3.8 % 26.4 % 5.2 % 2.2 % 3.1 %

1.9% 22.2 % 9.1 % 7.1 % 34.3 % 4.0 % 2.0 % 6.1 %

p

0.16 0.04 * 0.11 0.59 0.09 0.09 0.06 0.61 0.63 0.09

*Statistical Significance (p< 0.05).

In a later clinical assay, Glinoer et al [83] confirmed the efficiency of administering thyroxine administration to euthyroid women with positive anti-TPO antibodies. However, this author highlighted the need to confirm the beneficial effects of thyroxine by conducting a larger placebo-controlled double-blind clinical assay.

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It seems reasonable to affirm that thyroid autoantibody levels should be monitored and taken into consideration when performing screening tests during pregnancy. [84]

Epidemiology of Iodine Deficiency During Pregnancy Since the introduction of universal salt iodization programs, remarkable progress has been made in IDD control and elimination. [85] However, the iodine status of women of childbearing age is substantially different to that of schoolchildren residing in the same area. [86,87] Such situation has led researchers to perform epidemiological and clinical studies in order to assess the magnitude of iodine deficiency in pregnant women and to identify potential specific control measures. (Table 4) Table 4. Urinary iodine excretion (average ioduria) in pregnant women in different countries

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N United States (2007)[88] Thailand (2007)[89] Hong Kong (2007)[90] Hungary (2000)[54] Russia (2003)[91] Italy (2008)[13] Portugal (2008)[92] United Kingdom (2008)[93] Iran (2007)[94] China (2008)[95] Turkey (2008)[96] South Africa (2005)[97] India (2006)[98] Kuwait (2007)[99] Papua N Guinea (2006)[100] Sri Lanka (2006)[101] Tasmania (2007)[87] Brazil (2008)[102]

348 1182 ¿? 313 215 51 140 26 90 ¿? 72 924 267 212 288 147

Average Ioduria (μg/L) 141 103 100-120 92 44-87 74 75 66 207 175 77,4 280,1 144 180 185 86 224

Observations 6.9% < 50 μg/L 11.5% < 100 μg/L 53% with low T4 31.5% < 50 μg/L 24% Goiter 92% < 150 μg/L 20% are iodine-deficient 16% < 100 μg/L 15% with elevated TSH 83% < 100 μg/L Excessive iodine intake? 5% < 50 μg/L 57% < 145 μg/L 22% ID moderate to severe 1% < 50 μg/L ID Persists in women Good iodine concentrations

Despite UNICEF, ICCIDD and WHO’s recommendations, most European countries are not implementing universal iodine supplementation programs [103]. As a result IDD persist and still represent a serious Public Health problem in Europe. [12,104] There are vast regions of the world where iodine deficiency is not only chronic but also very severe, and the thyroid status of pregnant women and their offspring is seriously compromised. Iodine deficiency is extremely severe in several areas in Central Africa and Asia, where iodine intake levels are below 25 mcg / day.[12] In fact, severe iodine deficiency is associated with the presence of goitrogenic elements in the diet (i.e. cassava) and with deficiencies in other trace elements, such as selenium. [105] In regions with slightly low iodine supplementation it is particularly difficult to reach firm conclusions regarding the adequate iodine intake, mainly because there are substantial fluctuations in daily intake, both between individuals and from day to day.[77] Furthermore,

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measuring urinary iodine concentrations only reflects iodine intake in the most recent previous days. [12] The most striking example is provided by the U.S. NHANES study already mentioned.[106] But there are other important epidemiological considerations that should be taken into account in pregnant women: In Colombia, Sack et al[107] found that approximately 50% of pregnant women having a salt-restricted diet during pregnancy showed significantly elevated TSH concentrations at delivery, with a rapid normalization within a few weeks postpartum. This figure shows that in areas where iodized salt is used to correct / prevent iodine deficiency, restricted salt intake combined with gestational iodine deficiency may further aggravate the risk of developing hypothyroidism. Therefore, when prescribing a salt-restricted diet, it is highly advisable to monitor changes in TSH concentrations and provide iodine supplementation during pregnancy. Additionally, the risk of restricted-iodine intake during pregnancy should be locally assessed and closely monitored thorough gestation, as mild to moderate iodine deficiencies have been found in areas not identified as iodine-deficient.[27] Monitoring should be continuous for pregnant women even after the introduction of iodine supplementation. For example, in Belgium, where the recommended daily iodine intake during pregnancy is 100125 mg / day, a recent study on neonates in Brussels revealed that the nutritional iodine supply to Belgian neonates is still insufficient. [108] Finally, it should be noted that in regions with mild to moderate iodine deficiency there may be significant differences between different areas in the same country.

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Exposure to Iodized Agents Povidone-iodine (PVP-I) in a 10% aqueous solution is a commonly used antiseptic to disinfect the surgical field because of its antiseptic power and broad-spectrum microbicide.[109] It is used to disinfect skin in intravenous infusion and epidural catheters.[110] Vaginal cleansing with PVP-I (wipes, sponges, douches) in vaginal deliveries and before cesarean has been recommended to decrease the risk of postpartum febrile morbidity.[111.112] In some hospitals iodized antiseptics are extensively used in vaginal deliveries and before cesarean. [113] A single application of PVP-I is absorbed through the skin and the vaginal mucosa, resulting in a sudden increase in the urinary excretion of iodine with temporary inhibition of the biosynthesis and secretion of thyroid hormones. [114] The thyroid gland in people with chronic iodine deficiency or in cases of thyroid gland immaturity (premature infants and newborn infants) is particularly susceptible to acute iodine overload.[115] Therefore, when iodine-containing compounds are used in pregnant women and children, the dose administered should be considered.[116] Iodine-containing antiseptics have a very high amount of iodine exceeding the safety limits for this nutrient. Table 5 shows the iodine contained in different radiographic contrast and antiseptic agents. Additionally, Table 5 compares these amounts of iodine with the dose of iodine contained in the dietary supplements recommended for pregnancy.

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Iodine during Pregnancy and Lactation Table 5. Iodine concentrations in 1 g of iodized salt and in different widely used drugs, disinfectants and radiologic contrast agents Iodine content Iodized Salt Amiodarona Povidone-iodine Lipiodol Renografin

60 µg/ 1 g 7,500 µg/pill 10,000 µg/ml 380,000 µg/ml 370,000 µg/ml

Iodine content against 150 µg / day 0.4 x 50 x 67 x 2,500 x 2,500 x

Table 6. Studies on PVP-I effects on maternal and / or neonatal thyroid function Vorherr H, 1980[121]

Mahillón I, 1989[122]

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Robushi G, 1987[123]

Type of Study A total of 12 nonpregnant women received a two-minute vaginal disinfection with PVP-I. Total iodine concentrations in serum were measured before and 60 minutes after disinfection.

Results Overall and inorganic iodine Levels increased 5 and 15 times respectively. Risk is especially high when PVP-I is repeatedly used.

A total of 62 women with a mean duration of amenorrhea of 20 weeks underwent controlled abortion. Nineteen of them douched daily with PVP-I for 7 consecutive days before abortion and the other 43 were the control group. Mothers who used vaginal povidone-iodine (PVPI) during the last trimester of pregnancy were compared with other mothers that served as control.

In the treated group, urinary iodine increased from 6.1±0.8 µg/dl to 153± 60 µg/dl, 7 days after treatment (p< 0.001) Maternal thyroid function (TSH, T3 and T4) at delivery was similar in both groups. TSH concentration in cord blood was significantly higher in newborns of the mothers treated with PVP-I. (p He++e+e e+I2 > I2(B)+e e+I2 > I2(D)+e e+I2 > I2(D’)+e e+I2 > I2++e+e e+I2 > I-+I e+I2 > I+I+e e+I > I*+e e+I > I++e+e e+I* > I++e+e I2(B)+He > I+I+He I2(D)+He > I2(D’)+He I2(D)+I2 > I2(D’)+I2 I2(D)+I > I2(D’)+I I2(D)> I2+hv I2(D’)+He > I2 +He I2(D’)+ I2 > I2 + I2 I2(D’)+I > I2 +I I2(D’)> I2+hv (342 nm) I* > I + hv (206 nm) I+I+М > I2+М I*+I2 > I2(D)+I He*+2He > He2*+He He++2He > He2++He He*+He* > He++He+e He2*+He2* > He2++2He+e He2* > He+He He2*+e > He+He+e He2++e > He+He I++I-+М > I2+М I2++I-+М > I2+M

Rate coefficient, cm6/s, cm3/s, s-1

calculated from the Boltzmann equation

1.0e-11 1.0e-12 1.5e-11 1.5e-11 1.6e-8 1.0e-12 1.0e-11 1.0e-11 1.4e8 2.86e8 3.0e-33 1.3e-9 4.3e-34 8.0e-32 2.0e-10 5.0e-10 3.6е8 3.8е-9 1.3e-11 4.5e-26 4.1e-26

Reference 36 37 see text see text see text 34 38 34 34 34 34 39 40 40 40 34 35 35 35 34 34 35 34 41 41 41 41 41 41 41 calculated by the Flannery formulas

The electron kinetic coefficients for plasma in the mixture of helium with iodine vapours are given in [30, 32]. The plasmachemical reactions used in the kinetic model are listed in table 2. The rates of processes 1-11 were determined from the electron energy distribution function. Due to the effective dissociation of molecular iodine in the discharge, the distribution function was calculated in the He-I2-I mixture. The kinetic model used in the work takes into account three excited states of iodine molecules. For today, there exist neither experimental nor theoretical data on cross sections of electron impact excitation of iodine molecules. This fact is demonstrated in particular by the bibliographic analysis of data on electron collisions with halogen molecules published in the 20th century that was performed in 2003 by the National Institute for Fusion Science [33]. Due to this fact, calculations of the kinetics in plasma of iodine-containing mixtures are performed using some kind of approximation [34, 35].

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In this work, the cross sections of electron-impact electronic excitation of the iodine molecule were introduced as those similar to the excitation cross section of the emitting state of the iodine atom shifted by the excitation threshold for each specific level of the I2 molecule. The effect of the inaccuracy in the values of the cross sections was estimated by means of test calculations of the plasma kinetics with the use of the cross sections twice larger and lower than those accepted in the kinetic model. It was found out that the variation of the excitation cross section of the I2(D) state does not considerably influence the emission power of both atomic and molecular iodine – their change is less than 1%. The variation of the excitation cross section of the I2(D’) level results in the 8% and 35% change of the emission powers of atomic and molecular iodine, correspondingly. In the case of variation of the excitation cross section of the I2(В) level, the emission powers of atomic and molecular iodine change by 35% and 13%, correspondingly. Such a result is acceptable with regard for the fact that the error of experimental determination of the lamp emission power amounted to 30%. It is worth noting that the general behavior of the theoretical curves did not change in the case of variation of the cross sections. Molecular iodine effectively dissociates in the discharge at the expense of a number of elementary processes. Its recovery to the molecular state takes place at the walls of the discharge chamber [42]. That is why the kinetic model takes into account the diffusion of

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2

iodine atoms to the walls. The rate of diffusion losses was estimated as D / Λ [26], where D is the diffusion coefficient and Λ is the characteristic length scale. The diffusion coefficient in the mixture He-I2 = 133-133 Pа was taken equal to 100 сm2/s. In the case of variation of the quantitative composition of the active medium, the diffusion coefficient changed proportionally to the mean free path of iodine atoms in the mixture. The calculation of the kinetics in the mixture with the initial composition р(He)р(I2)=400-130 Pа has demonstrated that the emission powers of atomic and molecular iodine relate as 56%-44%, which is in good agreement with the experimental ratio W(206.2 nm)W(342 nm) ≈ 50-50 % The emission intensity of the lamp at 206 nm and 342 nm as a function of the helium pressure is shown in figure 8. One can see that the increase of the helium pressure results in the decrease of the emission intensity of molecular iodine. At the same time, the emission intensity in the 206-nm atomic line increases. Such a behavior of the considered dependences coincides with that observed experimentally. Excited iodine molecules I2(D’) are generated in the discharge due to direct electron impact excitation. The rate of this process is determined by the electron energy distribution function and grows with increasing parameter Е/N. Thus, an increase of the pressure of the mixture results in the decrease of the rate of formation of emitting I2(D’) molecules in the discharge. As was demonstrated in [43,44], another important channel of generation of I2(D’) molecules is the excitation transfer from the above-lying level I2(D) colliding with atoms and molecules of the active medium. However, at the considered pressures, the probability of radiation decay of the I2(D) state is much higher than the probability of its collision with other particles, that is why this channel makes practically no contribution to the formation of emitting I2(D’) molecules.

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Figure 8. Emission intensities of the spectral line of atomic iodine at 206 nm (а) and molecular band at 342 nm I2(D’→A’) (b) as functions of the partial helium pressure in the Не-I2 mixture (● – experiment, longitudinal glow discharge; ■ - calculation).

A considerable part of iodine molecules exists in the discharge in the dissociated state, which is confirmed by a high intensity of the 206-nm spectral line registered both in our experiment and in a number of other works. Measurements performed in [42,45] for Xe-I2 mixture at pressures close to those used in our work have demonstrated that the fraction of iodine molecules dissociating in the discharge exceeds 90%. Moreover, the minimum concentration of I2 molecules was registered at the axis of the discharge tube and the maximum one – close to the walls where iodine recovered to the molecular state. The experimental dependence of the emission power of iodine atoms on the helium pressure testifies to the fact that direct electron-impact dissociation of iodine molecules (as well as dissociative excitation) cannot serve as the dominant channels of formation of atomic iodine in the discharge. In this case, the emission power of the registered atomic line would also decrease with increasing pressure. The decay of iodine molecules into atoms is mainly provided by the predissociation of the excited I2(B) state in collisions with particles of the mixture. The rate of this predissociation considerably depends on the sort of the buffer gas: for example, predissociation in a xenon medium is much more effective than in a helium one [39]. Thus, an increase of the helium pressure in the Не-I2 glow discharge results in the competition of several processes. The rate of electron-impact dissociation of the ground state of the iodine molecule falls due to the change of the electron energy distribution function. The rate of formation of the I2(B) excited state also decreases. At the same time, the efficiency of collisional predissociation of the I2(B) level abruptly increases, which appears determinative for the resulting effect. Another important consequence of the increase of the total pressure is the deceleration of the diffusion motion of iodine atoms to the walls of the discharge chamber, which results in the less efficient recovery of molecular iodine. Thus, with increasing pressure in the working medium of the halogen lamp, the relation between the concentrations of excited iodine molecules and atoms (and consequently powers of emission from the levels I2(D’) and I*) changes in favor of the latter. With varying iodine concentration in the mixture, the emission intensities in the 206-nm atomic line and the 342-nm molecular band pass through a maximum (figure 9). At р(I2) < 200 Pа, the emission intensities grow with increasing iodine concentration, whereas at р(I2) > 200-230 Pа, they sharply fall to zero. An increase of the iodine concentration is accompanied

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by the rise of the discharge voltage and reduction of the electron concentration in the discharge. This fact is caused by the effect of iodine on the electron energy distribution function. At low iodine concentrations, the distribution function is determined by the helium buffer gas characterized by large thresholds of excitation and ionization (19.8 eV and 22.5 eV, correspondingly). The adding of iodine to the active medium results in the cut-off of the distribution function at lower energies due to the smaller thresholds of its excitation and ionization as well as the increase of the total pressure of the mixture. Moreover, the rate of dissociative attachment of electrons to I2 molecules (with a near-zero threshold) weakly depends on the iodine concentration, while the ionization rate determined by the tail of the distribution function sharply falls with increasing iodine concentration (figure 10). The discharge voltage is determined by the balance of ionization and attachment processes. That is why in order to maintain a discharge in a medium with a heightened halogen content, one should apply a larger voltage, which results in the decrease of the discharge current and, correspondingly, electron density. The decrease of the electron concentration reduces the efficiency of generation of radiating particles in the discharge resulting in the decrease of the emission intensities both in the atomic line and in the molecular band of iodine.

Figure 9. Emission intensities of the spectral line of atomic iodine at 206 nm (●) and molecular band at 342 nm I2(D’→A’) (■) (a) and total emission intensity (b) as functions of the iodine concentration in the He-I2 mixture at р(Не)= 400 Pа.

As one can see from figure 9, the emission maximum in the case of the 342-nm band is reached at higher iodine pressure ≈ 230 Pа, whereas the emission intensity of atomic iodine starts falling already at р(I2) > 200 Pa. It is explained by the fact that generation of excited iodine atoms is more sensitive to the electron density in the medium because it runs via two electron processes – electronic excitation of iodine molecules to the I2(B) levels followed by decay into atoms (or direct electron-impact dissociation of molecular iodine) and consequent excitation of iodine atoms to the radiating level.

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Figure 10. Rates of dissociative attachment (○) and ionization (●) of iodine molecules as functions of the iodine concentration in the He-I2 mixture at р(Не)= 400 Ра and electric field E = 150 V/cm.

Radiating I2(D’) molecules are formed due to direct electronic excitation of molecular iodine. If the iodine concentration in the mixture exceeds 400 Pа, then the voltage falling across the discharge gap appears insufficient for the breakdown and the emission intensities abruptly fall to zero. The maximum of the summary emission intensity is reached at the iodine pressure equal to 200 Pа. Taking into account that the emission intensities of atomic and molecular iodine reach a maximum at different iodine concentrations, it is evident that the variation of its content in the mixture will result in the change of the relation between the emission intensities at 342 and 206 nm. With increasing iodine concentration, the relative emission intensity in the molecular band grows, and in the atomic line – falls. The calculated curve is given in figure 11.

Figure 11. Relative emission intensity in the 342-nm molecular band as a function of the iodine concentration in the He-I2 mixture at р(Не)= 400 Pа. Iodine: Characteristics, Sources and Health Implications : Characteristics, Sources and Health Implications, edited by Adelina H. Martinez, and

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Conclusion Experimental investigations of the emission characteristics of the longitudinal glow discharge in mixtures of helium and iodine vapours have demonstrated that it can be used for creation of a simple UV lamp with a cheap working medium and controlled spectral characteristics. With a discharge tube made of KU quartz, such a lamp will emit approximately similarly both in the region of bactericidal ultraviolet and the more longwavelength part of UV spectrum (342 -320 nm). When using KV quartz (non-transparent at λ ≤ 250 nm), the lamp will emit only the band of molecular iodine with λmax = 342 nm. The average power of UV emission of this emitter with the working length of the discharge tube L = 0.5 m can reach 25-30 W at an efficiency of 15-20 %. The proposed model of kinetic processes in the low-pressure He-I2 mixture explains the effect of the total pressure on the emission intensities of the atomic spectral line and molecular band of iodine. The obtained theoretical dependences are in good agreement with the experimental results. The analysis of plasmachemical reactions running in the medium also allows one to determine the optimal concentration of iodine vapours.

References [1]

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[2] [3] [4] [5] [6] [7] [8]

[9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]

Lomaev M I, Skakun V S, Sosnin E A Tarasenko V F, Shitts D V and Erofeev M V 2003 Phys. Usp. 46 193. Lomaev M I and Tarasenko V F 2002 SPIE 4747 390. Shuaibov A K and Grabovaya I A 2006 Opt. Spectr. 100 200. Batalov E M and Prochukhan Yu A 2000 Vestn. Bashk. Univers. 1 56. Advanced oxidation processes for water and wasterwater treatment ed S Parsons (Cornwall: IWA Publishing, 2004) p 346. Shuaibov O K, Minya O.I., Gomoki Z T and Shimon L L Pulsed Bactericidal Lamp (Patent for invention № 34794. 26.08.2008. Bull. №16. p.1-6. Shuaibov A K, Minya O I, Gomoki Z T and Laslov G.E. 2009 Techn. Phys. 54 146. Shuaibov O K, Shevera I V, Shimon L L and Sosnin E A 2006 Modern Sources of Ultraviolet Radiation: Development and Application (Uzhgorod-Tomsk: Goverla) p 223. Golovitskii A P 1992 Sov. Tech. Phys. Lett. 18 269. Golovitskii A P and Kan S N 1993 Opt. Spectr. 75 357. Shuaibov A K and Grabovaya I A 2005 Instrum. Exp. Techn. 48 102. Shuaibov O K, Grabovaya I A and Shimon L L 2005 Techn. Phys. Lett. 31 103. Gross U, Ubelis A, Spietz P and Burrows J 2000 J. Phys. D: Appl. Phys. 33 1588. Revalde G, Silinsh J, Skudra A and Jansons J 2002 Proc. of SPIE 4747 369. Sosnin E A, Oppenlander T and Tarasenko V F 2006 J. Photochem. Photobiol. C: Photochem. Rev. 7 145. Zhang J-Y and Boyd I W 1998 J. Appl. Phys. 84 1174. Zhang J-Y and Boyd I W 2000 Appl. Phys. B. 71 177. Shuaibov O K, Shevera I V and Malinina A A 2008 Pis’ma Zh. Tekhn. Fiz. 34 874. Shuaibov A K and Malinina A A 2008 J. Appl. Spectrosc. 75 583.

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[20] Boichenko A M and Yakovlenko S I 2004 Laser Physics 1 1. [21] Boichenko A M, Lomaev M I, Tarasenko V F and Yakovlenko S I 2004 Laser Physics 8 1036. [22] Sonntag Von C 1987 Disinfection with UV radiation Process Technologies for Water Treatment (New York: Plenum Press) ed S Stucki. [23] Properties of Inorganic Compounds 1983 (Leningrad: Khimiya). [24] Shuaibov A K, Shimon L L, Dashchenko A I and Shevera I V 2001 Zh. Phys. Dosl. 5 131. [25] Shuaibov A K, Shimon L L, Dashchenko A I and Shevera I V 2002 Pribory Tekhn. Eksp. 45 95. [26] Raizer Yu P 1991 Gas Discharge Physics (Berlin: Springer) [27] Bogdanov E A and Kudryavtsev A A 2009 Techn. Phys. 54 810. [28] Tsendin L D 2010 Fiz. Usp. 53 133. [29] Datsyuk V V, Izmailov I A and Kochelap V A 1998 Fiz. Usp. 41 379. [30] Shuaibov A K, Minya A I., Gomoki Z T, Kalyuzhnaya A G and Shchedrin A I 2010 Techn. Fiz. 55 1222. [31] Shuaibov A K and Grabovaya I A 2005 J. Opt. Technol.. 72 544. [32] Shuaibov A K, Grabovaya I A, Gomoki Z T, Kalyuzhnaya A G and Shchedrin A I 2009 Techn. Phys. 54 1819. [33] Hayashi M, Bibliography of Electron and Photon Cross Sections with Atoms and Molecules Published in the 20th Century. Halogen Molecules (NIFS.DATA. 80, 2003). [34] Avdeev S M, Zvereva G N and Sosnin E A 2007 Opt. Spectr. 103 910. [35] Boichenko A M and Yakovlenko S I 2003 Laser Phys. 13 1461. [36] [37] Rejoub R, Lindsay B G and Stebbings R F 2002 Phys. Rev. A. 65, 042713. [38] Wing-Cheung Tam and Wong S F 1978 J .Chem. Phys. 68 5626. [39] Kireev S V and Shnyrev S L 1998 Laser Phys. 8 483. [40] Stoilov Yu Yu 1978 Sov. J. Quantum Electron. 8 223. [41] Baginskii V M, Vladimirov V V, Golovinskii P M and Shchedrin A I Optimization and stability of discharge in He/Xe/HCl excimer lasers Preprint of Acad. of Sci. of USSR (Kyiv 1988). [42] Barnes P N and Kushner M J 1996 J. Appl. Phys. 80 5593. [43] Sauer M C, Mulac W A, Cooper R F and Grieser F 1976 J. Chem. Phys. 64 4587. [44] Baboshin V N, Mikheev L D, Pavlov A B, Fokanov V P, Khodorkovskii M A and Shirokikh A P 1981 Sov. J. Quantum Electron. 11 683. [45] Barnes P N and Kushner M J 1998 J. Appl .Phys. 84 4727.

Iodine: Characteristics, Sources and Health Implications : Characteristics, Sources and Health Implications, edited by Adelina H. Martinez, and

In: Iodine Editors: A. H. Martinez and E. J. Perez

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Chapter VI

Study on Urinary Iodine and Thiocyanate Concentrations in Bulgarian Schoolchildren and Students Aneliya V. Bivolarska1, Penka D. Gatseva21 and Mariana D. Argirova1 1

2

Dept. of Chemistry and Biochemistry Dept. of Hygiene, Ecology and Epidemiology, Medical University of Plovdiv, Bulgaria

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Abstract The role of iodine deficiency as an environmental determinant in the development of endemic goiter is firmly established. However, iodine deficiency does not always result in endemic goiter, and iodine supplementation does not completely prevent goiter. Even in the presence of extreme iodine deficiency there is an unequal geographic distribution of goiter. It is clear, therefore, that there are other factors, beyond iodine deficiency, that may play a role in the etiopathogenesis of endemic goiter. Most of the substances considered to be goitrogens are chemicals found in the environment, e.g. thiocyanates, competitively inhibit the iodine uptake and its organification in the gland. The aim of this study was to evaluate the association between urinary iodine as reliable indicator of recent iodine status and urinary thiocyanate concentration supposedly related to tobacco smoke exposure of schoolchildren and university students. Subjects of study were 123 children (66 boys and 57 girls) aged 8 to 11 years and 104 medical students (51 men and 53 women) aged 19 to 25 years, all of them from the town of Plovdiv, Bulgaria. Urinary iodine was measured by the Sandell-Kolthoff reaction. The method for thiocyanate determination in urine was based on the quantitative oxidation of thiocyanate in acid permanganate solution with liberation of HCN, which reacted with picric acid. A questionnaire filled by the schoolchildren and students was used to evaluate their exposure to tobacco smoke and their smoking habits. 1

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A. V. Bivolarska, P. D. Gatseva and M. D. Argirova The median urinary iodine of the inspected schoolchildren was between 100-199 µg/L, which is an indicator of optimal iodine nutrition. However, 10.6% of the children had iodine deficiency. Statistically significant association between tobacco smoke exposure and the values of urine thiocyanate concentration in the inspected children was found. The median urinary iodine of the inspected students was 141 µg/L for the men and 130 µg/L for the women, which indicates optimal iodine nutrition. Around one-third of the subjects were with iodine deficiency though mild iodine deficiency was dominated. There were statistically significant differences between urinary thiocyanate concentrations in smokers and non-smokers (P < 0.0001) with higher thiocyanate values in smokers. None of the studied subjects has a ratio urinary iodine/thiocyanate (μg/mg) below 3.5. The quantification of thiocyanate ions in urine provides a fast non-invasive method to monitor thiocyanate load from tobacco smoke. Thiocyanate levels should be carefully controlled in cases of severe iodine deficiency to avoid the competitive inhibition of iodine intake.

Keywords: urinary iodine, thiocyanate, schoolchildren, students, smoking, thyroid

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Introduction Iodine deficiency (ID) causes a number of mental and physiological disorders collectively known as iodine deficiency disorders (IDD). Iodine supplementation does not always lead to complete eradication and prevention of goiter. Even in developed countries with sustained iodine prophylaxis, the goiter frequency is about 25% (Engel and Lamm, 2003). It is also clear that there are other factors, beyond iodine deficiency, that may play a role in etiopathogenesis of endemic goiter and other manifestations of IDD. Humans are nutritionally and environmentally exposed to several inorganic ions that interfere with iodide uptake, e.g. nitrates (NO3–), perchlorates (ClO4–), and thiocyanates (SCN–). Thiocyanate or thiocyanate-like compounds are known to competitively inhibit iodide uptake at the sodium-iodide symporter and suppress the iodide concentrating mechanism of the thyroid. The antithyroid and goitrogenic properties of SCN– were first discovered in 1936 when Barker (Barker, 1936) reported occurrence of goiter and/or hypothyroidism as a side effect in patients treated with thiocyanate for hypertension. The biological half life of thiocyanate was determined to be 6.4 days (Junge, 1985). Thiocyanate is not concentrated in the thyroids of most species because it is rapidly metabolized after translocation into the thyroid follicular cells (Wolf, 1964). High concentrations of thiocyanate ion inhibit the incorporation of iodide into thyroglobulin (Tg) by competing with iodide at the thyroid peroxidase (TPO) level. Thiocyanate is rapidly converted to sulfate in the thyroid gland. Administration of thyroid-stimulating hormone (TSH) increases the intrathyroidal catabolism of thiocyanate and is capable of reversing the block of iodide uptake caused by the thiocyanate ions. It has been proposed that TSH accelerates the oxidation of thiocyanate to sulfate (Engel and Lamm, 2003). Coal-conversion process is the major source of environmental thiocyanate contamination. The major source of thiocyanates in body fluids is the metabolism of cyanide ions catalyzed by Rhodanese system. Cyanides are found, although in small amounts, in certain foods (cabbage and mustard), seeds and fruit stones, e.g., those of apple, mango, peach, and bitter

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almonds. In plants, cyanides are usually bound to sugar molecules in the form of cyanogenic glycosides. Cassava, a staple food in some African regions, contains high levels of cyangenic glycosides. Hydrogen cyanide is detected in the exhaust of internal combustion engines and tobacco smoke, and also may contribute to body thiocyanate loading. The goitrogenic effect of thiocyanate is more evident in the presence of ID. Several observations suggest that thiocyanate crosses the human placenta and may cause both, goiter and neonatal hypothyroidism (Engel and Lamm, 2003). Studies on the relationship between thiocyanate levels and thyroid function have indicated that a combination of iodine deficiency and increase in thiocyanate level may co-contribute to thyroid dysfunction (Ermans et al, 1972). The role of smoking in the pathogenesis of goiter and the link between smoking and ID is still under debate (Czarnywojtek et al, 2009, 2010; Asvold et al, 2007; Erdogan, 2003; Vestergaard, 2002). The aim of this study was to evaluate the association between urinary iodine as reliable indicator of recent iodine status and urinary thiocyanate concentration supposedly related to tobacco smoke exposure of schoolchildren and university students. Since the typical Bulgarian diet is not rich in thiocyanate-containing foods, we suppose that tobacco smoke might be the major source of urinary thiocyanates.

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Materials and Methods Subjects of this study were 123 children (66 boys and 57 girls) aged 8 to 11 years, living in the town of Plovdiv and studying in the elementary school “D. Talev”; and 104 medical students (51 men and 53 women) aged 19 to 25 years studying in the Medical University of Plovdiv. The town is situated in the Trakia lowland in South Bulgaria; an area, which is known as endemic for goiter. Informed consent for participation in the survey was obtained from the children and their parents and from the students. The present study was approved by the Ethical Committee of the Medical University of Plovdiv. The participants filled appropriate questionnaires by using “yes” or “no” answers concerning their exposure to tobacco smoke, smoking habits of the students (present or previous smoking, daily or occasional smoking, amount of tobacco smoked, years of smoking), iodine intake from other sources (e.g. supplementary tablets), familial thyroid disorders, and underlying or chronic diseases. Urine samples of the participants were collected during prophylactic examinations. Iodine concentration was measured by the Sandell-Kolthoff reaction, which comprised the reduction of ceric ammonium sulfate (yellow) to cerous form (colorless) by arsenious acid. The process was catalyzed by iodine in a concentration-dependent manner. Working protocol was based on the recommendations of the International Council for the Control of Iodine Deficiency Disorders (Dunn et al. 1993; Ohashi et al. 2000; Gnat et al. 2003). Briefly: urine samples (0.25 ml) were pipetted into 13 x 100 mm glass tubes and mixed with 1 ml of ammonium persulfate (1 M in distilled water, freshly prepared). After heating for 60 minutes at 100oC and then cooling to room temperature, the digested samples were mixed with 2.5 ml arsenious acid (0.5 M in 2 M H2SO4) and let stand for at least 15 minutes. Thereafter, 0.3 ml ceric ammonium sulfate (0.02 M in 1.75 M H2SO4) was added at 30-second intervals between successive tubes. The absorbance at 420 nm of each sample was read exactly 20 minutes after

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the addition of ceric ammonium sulfate to the corresponding tube. A set of KIO3 calibrators within the range 50 – 300 µg/L iodine was ran at the beginning and end of each series of urine samples. Distilled water was used as a zero calibrator. The concentration of each standard was plotted against the optical density at 420 nm and regression analysis was applied for calculation of the iodine concentration in urine samples. Each urine sample was analyzed in duplicates. The method for thiocyanate quantification in urine samples was based on thiocyanate oxidation in acid solution of potassium permanganate at room temperature in a closed vial (Haque and Bradbury, 1999). This reaction yielded HCN that reacted with a picrate (2,4,6trinitrophenol) paper. The HCN-picrate complex was extracted with distilled water and the absorbance at 510 nm of the water extract was measured. A calibration curve was prepared using analytical grade KSCN over the range of concentrations from 0 to 100 mg/L. The thiocyanate concentration was calculated by linear least squares regression. Data were analyzed statistically using SPSS for Windows computing program (SPSS Inc, Chicago, IL). The possible association between tobacco smoke exposure and urinary iodine and thiocyanate concentrations was estimated by odd ratio (OR) in logistic regression analyses. The relative risk was expressed as OR with 95% confidence interval (CI).

Results and Discussion Figure 1 presents the relative parts (%) of the studied boys and girls with iodine deficiency (UI 300 µg/L). Around 10% of the children (10.6% of the boys and 10.5% of the girls) had iodine deficiency. Most of these children were between 8 and 9 years. With optimal iodine nutrition were 67.5% of the children (71.2 % of the boys and 63.0 % of the girls). With more than adequate iodine intake were 21.1% of the inspected children (18.2% of the boys and 24.6% of the girls). With excessive iodine intake was only one (0.8%) of the studied girls. >300 µg/L

girls boys

200-300 µg/L Urinary iodine

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Schoolchildren’s urinary iodine and thiocyanate concentrations

100-200 µg/L 50-100 µg/L 20-50 µg/L 0.05) between the mean and median urinary iodine concentrations found for the boy’s and girl’s groups. Data from the filled questionnaires showed that iodized salt had been used in all (100%) children’s families. None of the children reported for additional iodine supplementation with iodine-containing tablets. For familiar thyroid disorders and chronic diseases reported 11 children (8.94%). Exposed to cigarette smoke (passive smoking) in their living conditions were 31 (25.2%) of the children. Statistical evaluation of the relationship between tobacco smoke exposure and frequency of iodine deficiency in inspected children revealed that the association was statistically significant (OR = 6.985; 95% CI 2.856–17.084; χ2 = 20.53, P < 0.0001) with positive moderate correlation (r = 0.41). Table 1. Urinary iodine excretion (µg/L) of children’s group Indices Number of children Mean ± SD Median (50th percentile) 95% confidence interval min max Statistical parameters

Boys Girls 66 57 155.78 ± 52.56 164.42 ± 54.64 156.0 158.0 142.86 – 168.72 149.12 – 179.72 26.0 11.0 287.0 321.0 t = 0.8684; P = 0.3869

The results of thiocyanate quantification in children’s urine samples are summarized in Table 2. There was no statistical difference (P > 0.05) between the mean and median urinary thiocyanate concentrations found for the boy’s and girl’s groups.

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Table 2. Urinary thiocyanate concentration (mg/L) in the studied children Indices Number of children Mean ± SD Median (50th percentile) 95% confidence interval min max Statistical parameters

Boys Girls 66 57 1.40 ± 0.80 1.39 ± 0.90 1.31 1.22 1.17 – 1.64 1.09 – 1.71 0.02 0.05 3.94 3.58 t = 0.01783; P = 0.9858

Statistical evaluation of the relationship between tobacco smoke exposure and the values of urine thiocyanate concentration in the inspected children showed that the association was statistically significant (OR = 16.813; 95% CI 5.881–48.068, χ2=36.45, P < 0.0001) with positive significant correlation (r = 0.54). Students’ urinary iodine and thiocyanate concentrations Figure 2 presents the iodine status of the students assessed on the basis of urinary iodine (UI) excretion: The results from statistical evaluation of students’ iodine status are presented in Table 3. The mean and median urinary iodine of the inspected students (men and women) was

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between 100–199 µg/L, which is an indicator of optimal iodine nutrition. There was no statistically significant difference between both, the mean and median urinary iodine concentrations found for the men’s and women’s groups. However, analysis of the results obtained showed that more than 1/3 of the inspected students had iodine deficiency: 17 (33.3%) of the men and 19 (35.8%) of the women, although mild iodine deficiency was dominating, as depicted in Figure 3.

>300 µg/L

Women Men

Urinary iodine

200-300 µg/L

100-200 µg/L

50-100 µg/L

20-50 µg/L