TECHNICAL REPORT. European Food Safety Authority 2, 3. European Food Safety Authority (EFSA), Parma, Italy

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1 EFSA supporting publication 2014:EN-589 TECHNICAL REPORT Outcome of a public consultation on the Draft Scientific Opinion on the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on Dietary Reference Values for iodine 1 European Food Safety Authority 2, 3 European Food Safety Authority (EFSA), Parma, Italy ABSTRACT The European Food Safety Authority (EFSA) carried out a public consultation to receive input from the scientific community and all interested parties on the Draft Scientific Opinion on Dietary Reference Values (DRVs) for iodine, prepared by the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA Panel) and endorsed by the Panel for public consultation at its Plenary meeting on 12 December The written public consultation for this document was open from 15 January 2014 to 26 February EFSA received comments from 23 interested parties. EFSA Panels and Units were also invited to take part in the consultation; contributions were received from the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP). EFSA and its NDA Panel wish to thank all stakeholders for their contributions. The current report summarises the outcome of the public consultation, and includes a brief summary of the comments received and how the comments were addressed. The NDA Panel prepared an updated version of the Scientific Opinion on Dietary Reference Values for iodine taking into account the questions/comments received. The Opinion was discussed and adopted at the NDA Plenary meeting on 10 April 2014, and is published in the EFSA Journal. European Food Safety Authority, 2014 KEY WORDS iodine, Dietary Reference Value, Adequate Intake, public consultation 1 On request from EFSA, Question No EFSA-Q , approved on 5 May Correspondence: nda@efsa.europa.eu 3 Acknowledgement: EFSA wishes to thank the members of the Working Group on Dietary Reference Values for minerals: Peter Aggett, Carlo Agostoni, Susan Fairweather-Tait, Marianne Geleijnse, Michael Hambidge, Ambroise Martin, Androniki Naska, Hildegard Przyrembel, and Alfonso Siani for the preparatory work on this output and the members of the Panel on Dietetic Products, Nutrition and Allergies (NDA) for their contribution to this output. Suggested citation: European Food Safety Authority, 2014; Outcome of a public consultation on the Draft Scientific Opinion of the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on Dietary Reference Values for iodine. EFSA supporting publication 2014:EN pp. Available online: European Food Safety Authority, 2014

2 TABLE OF CONTENTS Abstract... 1 Table of contents... 2 Background as provided by efsa... 3 Terms of reference as provided by efsa... 3 Consideration Introduction Screening and evaluation of comments received Comments received Nature of specific comments Health consequences of deficiency and excess Iodine deficiency disorders Iodine excess Distribution to tissues Elimination Modifications of iodine metabolism during pregnancy Interactions with other nutrients Biomarkers Dietary sources and intake data Overview of Dietary Reference Values Criteria on which to base DRVs Iodine balance Iodine accumulation in the thyroid Factorial approach in adults Iodine intake and health consequences: goitre Iodine intake and health consequences: cancer Iodine intake and health consequences: Sub-clinical thyroid diseases Thyroid status, urinary excretion and clinical outcomes Supplementation studies during pregnancy Additional requirement for pregnancy owing to modifications of maternal iodine metabolism Conclusions on additional iodine requirement for pregnancy Data on which to base Dietary Reference Values Adults Infants and children Pregnancy Lactation Conclusions Recommendations for research Appendix B References Appendices Appendix A. Explanatory text for the public consultation on the draft scientific opinion on Dietary Reference Values for iodine Appendix B. Full list of comments submitted by means of the electronic form on the EFSA website Abbreviations EFSA supporting publication 2014:EN-589 2

3 BACKGROUND AS PROVIDED BY EFSA Scientific advice on nutrient intakes is important as the basis of Community action in the field of nutrition; for example, such advice has in the past been used as the basis of nutrition labelling. The Scientific Committee for Food report on nutrient and energy intakes for the European Community dates from In 2005, the European Commission asked EFSA to review and if necessary update such advice to ensure that Community action in the area of nutrition is underpinned by the latest scientific advice. To this end, EFSA has been requested to consider the existing Population Reference Intakes for nutrients and certain other dietary components. The Scientific Opinion on general principles for deriving and applying Dietary Reference Values, and the Scientific Opinions on Dietary Reference Values for water, for fats and for carbohydrates and dietary fibre were published in The Scientific Opinions on Dietary Reference Values for protein and for energy were published in 2012 and 2013, respectively. The work on Opinions on Dietary Reference Values for micronutrients is ongoing. TERMS OF REFERENCE AS PROVIDED BY EFSA In line with EFSA s policy on openness and transparency, and in order for EFSA to receive comments from the scientific community and stakeholders, EFSA shall release the Draft Scientific Opinion on Dietary Reference Values for iodine for public consultation. The comments resulting from the public consultation shall be published in a technical report. Before its adoption by the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA Panel), the Draft Scientific Opinion on Dietary Reference Values for iodine may need to be revised, taking into account the comments received during the public consultation. EFSA supporting publication 2014:EN-589 3

4 CONSIDERATION 1. Introduction Upon request from the European Commission and following previously published Scientific Opinions on Dietary Reference Values for macronutrients, energy, water, and several micronutrients, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA Panel) developed a Draft Scientific Opinion on Dietary Reference Values (DRVs) for iodine. In line with EFSA s policy on openness and transparency, and in order for EFSA to receive comments on its work from the scientific community and stakeholders, EFSA engages in public consultations on key issues. Accordingly, the Draft Scientific Opinion was published on EFSA s website for comments (15 January 2014 to 26 February 2014) (see Appendix A). The NDA Panel prepared an updated version of the Scientific Opinion, taking into account the comments received. The updated Scientific Opinion was discussed and adopted at the NDA Plenary meeting on 10 April 2014, and is published in the EFSA Journal (EFSA NDA Panel, 2014). EFSA is committed to publishing the comments received during the public consultation, as well as a short report on the outcome of the consultation. 2. Screening and evaluation of comments received 2.1. Comments received EFSA received 113 comments from 23 interested parties. Five were from universities, two were from national food safety organisations, two from national scientific advisory bodies, two from a national authority/national institute, seven from non-governmental organisations, two from industry associations, and two from individuals in their personal capacity. Joint comments were received from one university and a national control authority. Several parties submitted identical comments. EFSA Panels and Units were also invited to take part in the consultation; contributions were received from the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP). Table 1: List of organisations submitting comments Organisations Agència de Salut Pública de Catalunya. Departament de Salut. Generalitat de Catalunya American Thyroid Association EuSalt Food Supplements Europe Fundación Española de Dietistas-Nutricionistas (FEDN) Health Council of the Netherlands Histamine intolerance Switzerland International Council for the Control of Iodine Deficiency Disorders (ICCIDD) National Institute for Public Health and the Environment (RIVM) Public Health England / Scientific Advisory Committee on Nutrition Roma Tre University Schweizerische Interessengemeinschaft Histamin-Intoleranz (SIGHI) Selbsthilfeverein Jod macht krank CHE Society for the Interdisciplinary Study of Feeding and Social Habits (SEIAHS) Suisse Thyroid Association The Swedish National Food Agency (SLV) Thuringian State Institute of Agriculture Universidad de Murcia University Medical Centre Ljubljana, Department of Nuclear Medicine University of Bonn, IEL-Nutritional Epidemiology, DONALD Study / Board of Health Würzburg University of Surrey EFSA supporting publication 2014:EN-589 4

5 A summary of the comments is given below, and all written comments received are listed in Appendix B. The numerous comments related to policy or risk management aspects were considered to be outside the scope of the consultation, and are not covered in this report Nature of specific comments The main issues raised in the comments received are summarised below, together with the way in which these comments were addressed by the Panel. The NDA Panel has reviewed all comments carefully and has updated the Scientific accordingly. The updated Scientific Opinion is published in the EFSA Journal (EFSA NDA Panel, 2014). The Panel stresses that there is a huge amount of literature dealing with various aspects of iodine in human physiology and nutrition and related to public health, i.e. considering deficiency and excess. Thus, literature selection might be perceived as not comprehensive, especially for those aspects that are not central to the derivation of DRVs. The Panel has considered many more references than are cited in the Opinion. The Panel considers that it is neither the purpose of the Opinion to provide an exhaustive description of iodine nutrition, nor to elaborate on the management of iodine deficiency or excess, but rather to focus on the aspects relevant to the setting of DRVs. Therefore, suggested citations/insertions will be considered for addition on a case by case basis in the context of setting DRVs Health consequences of deficiency and excess Iodine deficiency disorders Comments received It was suggested to amend the term hyperplasia to hypertrophy/hyperplasia. It was pointed out that insufficient iodine intakes may also lead to hypothyroxinaemia (low T4 but normal TSH). It was suggested that the use of the units μg/g creatinine was confusing as WHO/UNICEF/ICCIDD (2007) cut-offs were given in μg/l. It was suggested to add various references to Section Panel consideration of comments received The pathophysiology of thyroid enlargement is indeed complex. The suggested change has been inserted. It was not the objective of this summary section to describe in detail all the clinical and biological changes induced by hypothyroidism resulting from iodine deficiency, so no further change is needed in the Opinion in relation to this comment. The more commonly used criteria for assessing iodine intake and status and for assessing the severity of iodine deficiency had already been used in the section on biomarkers of status (Section of the Opinion) and, for consistency, this section has been aligned accordingly. Some references have been inserted in the respective section in the Opinion. EFSA supporting publication 2014:EN-589 5

6 Iodine excess Comments received It was suggested that the scientific studies used to set the Tolerable Upper Intake Level (UL) for adults were not of sufficient duration to adequately assess the risk of iodine excess. It was requested that the NDA Panel should note that the current UL is based on limited data. It was noted that the UL set by the SCF (2002) does not apply to iodine-deficient populations. It was stated that Mast Cell Activation Syndrome should be mentioned in the section on iodine excess. It was suggested to include data on intake of iodised salt and algal-based supplements in the European population, as this population of consumers may be at risk of iodine excess. It was suggested to add information on chronic excessive iodine intake through seaweed consumption and risk of thyroid cancer. Panel consideration of comments received Although the Opinion on Principles for deriving and applying DRVs states that the complete set of DRVs includes the UL (EFSA NDA Panel, 2010), the mandate received from the European Commission specifically requests the revision of the Population Reference Intakes (PRIs) published by the SCF in 1993 (SCF, 1993). The revision of the UL for iodine was considered outside the scope of this mandate and may be envisaged at a later point in time. The Panel notes that the UL opinion on iodine clearly indicates that in a country with a long history of moderate/mild iodine deficiency, the UL can be lower than the value of 600 µg/day (SCF, 2002). It is not the purpose of the Opinion to consider all potential consequences of iodine excess, such as Mast Cell Activation Syndrome. In addition, it has not been established that this syndrome is linked to an iodine intake equivalent to the level of the requirement. The Panel considered that it is not the purpose of the Opinion on DRVs for iodine to characterise foods associated with excessive iodine intakes. It was considered that no change in the Scientific Opinion was needed in relation to these comments Distribution to tissues Comments received It was suggested to move the information on inhibitors to Section (Interaction with other nutrients). It was suggested to add more information on goitrogens in food and the effects of cooking. It was also suggested to point out that unless iodine deficiency is present, the goitrogens in food are not of clinical significance. Panel consideration of comments received The goitrogenic substances mentioned, though present in foods, are not considered as nutrients stricto sensu, so no change in the Opinion is needed in relation to this comment. EFSA supporting publication 2014:EN-589 6

7 The final result of any interaction between two or more compounds is the actual balance between these compounds, so that, generally, the effect of any antagonist of an essential nutrient is more easily observed in the situation of low intakes of the nutrient. This has been introduced in the respective section in the Opinion Elimination Comments received It was suggested that besides mentioning concentrations of iodine in urine, faeces, sweat and breast milk, also the ranges of iodine excretion for urine, faeces, sweat and breast milk be reported. With reference to Rasmussen et al. (1999), it was suggested that it takes one to two days for urinary iodine (UI) concentrations to reflect iodine intake. Panel consideration of comments received Concentrations of iodine in breast milk in Europe are given in the text and, providing some more information including ranges, also in Appendix A. In the Opinion, median/average concentrations are also given for sweat (though the Panel is not aware of studies reporting on values for Europe). For urine and faeces, concentrations are very variable depending on intakes, and the Panel considered that the large range was not informative as compared to the median for characterising the status of a population. It was considered that no change in the Opinion was needed in relation to this comment. On an individual basis, iodine excretion is variable from day to day in line with variable daily intake, as already reported, for example, in the balance study by Vought and London (1964), and confirmed in Denmark by Rasmussen et al. (2001). This explains why spot urinary iodine concentration cannot be used at the individual level to assess iodine intake or the status of an individual. This is not in contradiction with the fact that, at the level of a group or a population, urinary iodine excretion as a marker of usual intake (averaged on a certain duration) and status requires some time to reach a steady state following modification of the usual intake. This difference between individuals and groups has been clarified in Section in the Opinion Modifications of iodine metabolism during pregnancy Comments received It was pointed out that the statement on maternal thyroid size remaining constant during pregnancy in areas adequate for iodine is not supported by more recent data (Fister et al., 2009). It was pointed out that there is conflicting evidence in relation to urinary iodine excretion during pregnancy in areas of mild deficiency. With respect to the study by Vulsma et al. (1989) it was asked to clarify when an infant would not have a thyroid. Panel consideration of comments received The section on thyroid size has been adapted, integrating the suggested reference. The Panel notes that this paper indicates that at least a part of the increase could be linked to haemodynamic changes, and that the increase is rapidly reversed and no longer apparent four months after delivery. EFSA supporting publication 2014:EN-589 7

8 The Panel agrees with the comment on conflicting evidence in relation to urinary iodine excretion during pregnancy in areas of mild iodine deficiency; the section has been modified taking into account the information contained in the comment. With respect to the study by Vulsma et al. (1989) it has been clarified in the Opinion that the infants studied were newborns with a genetic defect of thyroid organification or thyroid agenesis Interactions with other nutrients Comments received It was suggested that this section be broadened to include nutrients and substances, and therefore to include thyroid-disrupting xenobiotic substances that directly or indirectly affect iodine status. It was asked to explain further the mechanisms of adaptation of iodine metabolism. Panel consideration of comments received As already indicated for the comments on Section 2.2.4, the exhaustive consideration of many interactions that could be relevant at the management level is outside the scope of this Opinion. The adaptations of iodine metabolism considered relevant by the NDA Panel and susceptible to influencing certain choices in the setting of DRVs have been addressed in Section 2. It was not the objective of the Opinion to describe in detail all the underlying biochemical mechanisms. It was considered that no change in the Scientific Opinion was needed in relation to these comments Biomarkers Comments received It was mentioned that there are validated Food Frequency Questionnaires (FFQs) which have been correlated with other biomarkers of iodine intake. It was asked to clarify the 24-hour urine volume used by the IOM (2001). It was noted that research has shown that 10 repeated urine samples (spot or 24-hour) are needed to assess individual iodine status. It was pointed out that no reference was provided to support the statement that serum TSH is a suitable biomarker of iodine status in neonates and possibly in pregnant and lactating women, and the suitability of TSH as a biomarker was questioned. Panel consideration of comments received The Panel does not consider that results derived from an FFQ can be used as a biomarker of intake. However, some information on these FFQs has been introduced in Section 3.1 (see also below, last paragraph of section 2.2.9). A specific urinary volume has not been used by IOM; indeed, the sentence should read Introducing the 24-hour urine volume in an equation and taking also into account absorption efficiency of dietary iodine, the iodine intake corresponding to a UI concentration can be calculated (IOM, 2001). The Opinion has been changed accordingly. EFSA supporting publication 2014:EN-589 8

9 The Panel considers that the information is already present in Section of the Opinion: At the individual level, 10 repeated collections of spot or 24-hour urinary samples are needed to assess iodine status with a 20 % precision (Andersen et al., 2008). It was considered that no change in the Scientific Opinion was needed in relation to this comment. The Opinion has been modified to take into account that TSH is a marker of thyroid function and may only be used as an indirect indicator of iodine status in specific situations Dietary sources and intake data Comments received It was suggested to give more detailed information on sources of dietary iodine, in particular on iodine in animal feed, and to refer to previous EFSA opinions on the matter. It was suggested to give more detail in relation to the iodine content of native grains consumed by humans and animals. It was mentioned that cooking reduces the iodine content of food. It was mentioned that in some countries bread and sugar were fortified with iodine. It was mentioned that iodine-containing herbicides/fungicides were also a source of iodine in food. It was suggested that more information on the influence of feeding and hygienic practices on the iodine content of milk and eggs should be added. It was also suggested that information could be included on other food sources and the agricultural, environmental and industrial influences on their iodine content. It was suggested that more information on seaweeds (algae) as a source of iodine should be given. The statement that dietary assessment methods do not accurately quantify habitual intake was questioned. It was stated that iodine intake could be accurately estimated by simulation models using data from food consumption surveys and information on the use of iodised salt. Panel consideration of comments received Considering the large amount and diversity of the available data, the Panel deliberately kept this section short. All the comments received have important implications for managing iodine deficiency at the population level or preventing risk of excess in individuals; however, recommending or warning against specific foods, as well as defining the best ways for controlling iodine content of some food categories, are clearly risk management issues and thus outside the remit of EFSA. Thus, only some references leading to further information have been added to the respective section in the Opinion. The Panel acknowledges that the uncertainties related to dietary iodine intakes could be reduced by applying more sophisticated methods; this is reflected by the insertion of the word classical (i.e. use of 24-hour/3-day/7-day dietary records) at the beginning of the sentence, Classical dietary assessment methods do not accurately quantify habitual iodine intakes (Serra-Majem et al., 2009). A sentence with the appropriate references has also been added about the use of FFQs targeted at and validated for iodine intake, which improve the correlation of intake with urinary iodine excretion (Rasmussen et al., 2001; Combet and Lean, 2014) or the use of simulation techniques, FFQs targeted and validated for iodine intake can be used (Rasmussen et al., 2001; Combet and Lean, 2014), as well EFSA supporting publication 2014:EN-589 9

10 as simulation and modelling methods (Verkaik-Kloosterman et al., 2009), which improve the correlation of intake with urinary iodine excretion Overview of Dietary Reference Values Comments received - It was repeatedly suggested to refer to the WHO Secretariat et al. (2007) recommendations on iodine intake. It was pointed out that in Spain supplementation with 200 μg iodine/day is recommended for pregnant and lactating women. Panel consideration of comments received The Panel updated the respective section of the Opinion, including information from the WHO expert consultation. In this section DRVs set by other authoritative bodies are reported; the use/application of these DRVs for managing iodine status at the country level is outside the scope of this section. It was considered that no change in the Scientific Opinion was needed in relation to this comment Criteria on which to base DRVs General considerations on the comments received Considering important divergences between expert committees, as highlighted in Section 4 of the Opinion, the importance of iodine for public health, the abundance of the literature on all these aspects, and the multiple ways for addressing the complex issue of iodine DRVs highlighted in Section 5 of the Opinion, the Panel expected a number of comments on Sections 5 and 6 of the Opinion, and is also not surprised by the diversity of the received comments covering a large spectrum of positions, supporting or disagreeing on minor/major points of the approaches and outcomes of the Opinion. Some of the comments are based on the traditional approach of DRVs where the letter R refers either to reference or recommendation. In line with its Opinion on the general principles for deriving and applying reference values (EFSA NDA Panel, 2010), the Panel makes a clear separation between reference values that try to consider only the relationship between a nutrient and health and the nutrient goals and recommendations which may take into account other considerations, such as the current status of a given population for a specific nutrient. This separation is particularly important in the case of iodine, where the iodine environment varies considerably among countries, according to geography, history of iodine deficiency management and cultural/regulatory context. As an example, the Panel considered that the increased requirement during pregnancy is rather small if iodine status is adequate before pregnancy, though not excluding that higher values could be proposed as goals and recommendations in a specific context where the prevalence of iodine deficiency before pregnancy is high Iodine balance Comment received Clarification was asked on the meaning of biological signs. Panel consideration of comment received The introductory section on balance studies is general and is similar in the different opinions on nutrients for which balance studies are addressed; these biological signs refer to unspecific or specific biological markers modified by the deficiency of the essential nutrient that may EFSA supporting publication 2014:EN

11 obviously differ according to the studied nutrients; for iodine some of these signs have been described in Sections 2 and 5. The Panel considers that no change is needed in the Opinion in relation to this comment Iodine accumulation in the thyroid Comment received It was stated that the Fisher and Oddie (1969a) equation was used inappropriately, not taking into account the iodine accumulation of the thyroid in the non-pregnant state. Panel consideration of comment received In the Opinion, the Panel noted that the average iodine accumulation by the thyroid obtained from the two studies of Fisher and Oddie (1969a, 1969b) was measured at an average UI excretion of about 410 and 280 µg/day, respectively; therefore, these results on iodine accumulation do not reflect the European situation. The Panel therefore concluded that the values of 96.5 and 91.2 µg/day for mean iodine accumulation cannot be used for deriving DRVs for the European context. Thus, the Panel deliberately decided to use the Fisher and Oddie (1969a) equation only to estimate the iodine intake corresponding to a need of women during pregnancy for an additional iodine capture by the thyroid of 25 µg/day. The Panel considers that no change is needed in the Opinion in relation to this comment Factorial approach in adults Comments received It was stated that reference ranges should support the use of qualifying terms like high and adequate. Clarification was asked on the calculation of the iodine intake required to cover the losses and provide iodine for thyroid hormone production in the factorial approach for adults. Panel consideration of comments received Throughout the Opinion, the Panel decided not to use, as far as possible, qualifications on iodine intake (e.g. low, adequate, high) used by different authors cited in the text, since these qualifications refer to different reference values. Whenever possible, as far as the actual values were reported in the papers, these were used. The Panel considers that no change is needed in the Opinion in relation to this comment. The Panel agrees that the construction of the sentence was not clear and has rephrased it, Assuming a demand of 60 µg iodine/day for thyroid hormone production, a need of 40 µg iodine/day for the sum of urinary and faecal losses, a need of 20 µg iodine/day for sweat losses, and an absorption efficiency of 92 %, an iodine intake of 130 µg/day (( )/0.92) would be required to cover the losses and provide iodine for thyroid hormone production. EFSA supporting publication 2014:EN

12 Iodine intake and health consequences: goitre Comments received Agreement was expressed that the slow modification of thyroid volume enlargement provides a valuable medium- to long-term health outcome in relation to usual iodine intakes at the population level. Clarification was asked on what daily urine volume was used to calculate the corresponding iodine intake in the section on goitre. Panel consideration of the second comment received The study by Delange et al. (1997) reports on population-based results on iodine concentration in urine which certainly come from very different urinary volumes not reported in the paper, since urinary volumes were not considered as pertinent in this context. The Panel considers that no change is needed in the Opinion in relation to this comment Iodine intake and health consequences: cancer Comments received It was suggested to add more information on the relationship between iodine intake and carcinomas. It was suggested to mention the possible relationship between seaweed consumption and risk of thyroid cancer in postmenopausal women. Panel consideration of comments received Whenever current information does not provide useful information on a quantitative relationship between intake and a given health outcome, the Panel decided to keep information related to this aspect as limited as possible. The Panel considers that this type of information rather relates to the setting of ULs, or to the management of very high iodine intakes. The Panel considers that no change is needed in the Opinion in relation to these comments Iodine intake and health consequences: Sub-clinical thyroid diseases Comment received It was stated that sub-clinical hypothyroidism is not a disease, and it was therefore suggested that the section heading sub-clinical thyroid diseases should be amended to sub-clinical thyroid dysfunction. Panel consideration of comment received The Opinion used the wording currently used in the published literature on this subject. The Panel agrees that the available evidence does not allow a definite conclusion on the fact that this is a pre-disease state that would justify specific reference values or recommendations. The heading was modified as suggested. EFSA supporting publication 2014:EN

13 Thyroid status, urinary excretion and clinical outcomes Comment received It was pointed out that the study used to support the statement that prevention of cretinism in areas of severe iodine deficiency is more efficient before conception than during pregnancy supplemented the participants using iodised oil. It was stated that iodised oil is a slow release form of iodine supplementation leading to a continuous iodine supply also during pregnancy. Panel consideration of comment received As mentioned in the Opinion, hormone production by the mother is the only source of thyroid hormone available to the embryo/fetus at the beginning of pregnancy, when the neurological system starts to develop. Therefore, it is particularly important for women of childbearing age to have an adequate iodine status. The Panel considers that no change is needed in the Opinion in relation to this comment Supplementation studies during pregnancy Comment received With reference to Rebagliato et al. (2010) it was stated that pregnant women supplemented with 200 μg/day of iodine had an increased risk of hyperthyroidism. Panel consideration of comment received The identification of appropriate public health strategies for ensuring adequate iodine status in pregnancy is a risk management issue which is outside the remit of EFSA. The Panel considers that no change is needed in the Opinion in relation to this comment Additional requirement for pregnancy owing to modifications of maternal iodine metabolism Comment received With reference to the recommendations of the American Thyroid Association and of the Endocrine Society of America, the reference to a TSH concentration of 5 mu/l during pregnancy was questioned. Panel consideration of comment received The definition of reference ranges for biological parameters is a difficult task, as evidenced by the position papers released by the International Federation of Clinical Chemistry (IFCC). The objective of the Opinion is not to determine reference values/ranges for biological parameters and therefore is limited to the presentation of some type of indicative values frequently used in the field. The Panel considers that no change is needed in the Opinion in relation to this comment Conclusions on additional iodine requirement for pregnancy Comment received With reference to the WHO Secretariat et al. (2007) recommendation on iodine intake for pregnant women, the conclusion of the NDA Panel that the increase in iodine requirement during pregnancy is only 50 μg/day was questioned. EFSA supporting publication 2014:EN

14 Panel consideration of comment received The Panel reviewed the available evidence and came to a different conclusion to that of WHO Secretariat et al. (2007) with respect to the additional iodine requirement in pregnancy, the basis of which is explained in Section 5.6 of the Opinion. The Panel considers that no change is needed in the Opinion in relation to this comment Data on which to base Dietary Reference Values General consideration on the comments received Many of the comments received for this section highlight the existence of uncertainties in the setting of DRVs for iodine that preclude the derivation of an Average Requirement and therefore of a PRI. On this basis, the Panel decided to highlight in the heading paragraph of this section that the setting of an AI is a result of these uncertainties Adults Comments received The variability in the volume of urine that an adult excretes per day was pointed out. It was stated that this variability might lead to misinterpretation of urinary iodine concentrations in populations where the average volume of urine differs from 1.5 L, and thus may cause misinterpretation of iodine status. It was suggested to provide more information on the relationship between urinary iodine concentrations and urinary volumes. Using the equation of Fisher and Oddie (1969b) and average data for daily thyroid hormone production, it was suggested to adapt the proposed AI for adults to 170 μg/day in order to meet the requirements for daily thyroid hormone synthesis. Panel consideration of comments received The volume of 1.5 L of daily urine excretion is an average rounded figure which is used for convenience and cannot correspond to all situations. It has been indicated in the Opinion (Section ) that the excretion of higher fluid volumes can lead to increased excretion of iodine that is not related to iodine intake, but this phenomenon has not been systematically addressed at the population level. Fluid volume is also generally not recorded when collecting urine samples at a population level for monitoring iodine status. For a refined analysis of iodine status in a population, other criteria should be used in addition to urinary iodine concentration (e.g. thyroid volume and thyroid hormones). The Panel notes that the equation of Fisher and Oddie (1969b), derived from a study in subjects with an average iodine intake well above the European intakes, can be interpreted in different ways. This is illustrated by the fact that IOM (2001) used this study for deriving an Estimated Average Requirement of 95 µg/day. The Panel considers that no change is needed in the Opinion in relation to these comments Infants and children Comments received With reference to IOM (2001), it was suggested that body weight may influence iodine requirement and hence the AI. EFSA supporting publication 2014:EN

15 It was suggested that for the adult AI, extrapolation from the AI for children using adult reference weights would be more appropriate. Concern was expressed about the extrapolation of the urinary iodine concentration (UIC) of 100 μg/l in school-aged children to other age groups. For infants, concern was expressed on the use of the UI concentration threshold of 100 μg/l. Instead, a UI concentration of μg/l derived from healthy term infants in positive iodine balance was recommended. It was stated that only a positive iodine balance would ensure adequate development of the growing infant. It was suggested that the proposed AI for 7-11 months-old children be increased to μg/l. Two methods were proposed in order to amend the AI, one of which was based on calculations using urinary intake and urinary volume while assuming a non-urinary iodine loss of 15 %, and the second of which proposed to use the minimal iodine intake required for positive balance (IOM, 2001; WHO/UNICEF/ICCIDD, 2007) and reference body weights. For children aged 1-3 years, it was suggested to increase the proposed AI to 98 μg/day to allow for a margin of safety and also to account for non-urinary iodine losses. For children aged 4-17 years, concern was raised that the endpoint used to set the AI should not only be the prevention of goitre but also optimisation of cognitive function. It was proposed that the AI for children aged 4-12 years should be calculated using the WHO/FAO (2004) recommendations on iodine intake related to body weight, and European reference body weights. For children aged years, extrapolation from the adult AI was suggested due to increased iodine requirements. It was stated that it is not advisable in terms of public health to accept a prevalence of thyroid enlargement in 5 % of the population, so that the AI should be higher than proposed. Panel consideration of comments received These different comments deal with the issue of extrapolation of data obtained in the age group 6-15 years to other age groups of children. The first main issue is about the threshold of urinary iodine concentration that can be used as an indicator of adequate iodine intake/status in a population of children. The application of the threshold of 100 µg/l deduced from the Thyromobile project in children aged 6-15 years is questioned on the basis of the supplementation study by Delange et al. (2001). This study shows that in young children from 6 months to 3 years of age supplemented with 90 µg iodine/day above a median basal intake of around µg/day (the reported median UIC being 101 µg/l), many weeks (i.e. around 30 weeks) are needed to obtain a steady state of UIC of µg/l, possibly corresponding to a saturation of iodine stores. However, in the absence of any measurement of other biological or clinical parameters and in the absence of long term follow-up on the results of this relatively high intake, the Panel considers that it is unclear whether such a UIC reflects a health benefit. This question is important as far as it is established that a steady state (corresponding to a null iodine balance) can be obtained with very different levels of iodine intake (see Section 5.1 of the Opinion). The second main issue is the influence of body weight on iodine requirements in children. The Panel considers that this has been covered by the proposed approach, where the extrapolation was made on the basis of age-specific urinary volume expressed by unit of body weight, using body weights representative for the European situation. The Panel considers that what could be the optimal iodine intake for maximising cognitive function in children is still a matter of debate and research, especially for the situation of mild iodine deficiency. In addition, cognitive development in children is subject to many factors (other nutritional EFSA supporting publication 2014:EN

16 factors as well as socioeconomical factors), in contrast to thyroid size which is specifically linked to iodine status. The approach whereby an iodine status of a population is considered adequate with a goitre prevalence of up to 5 % does not imply that the iodine intake of these goitreous subjects is adequate; the nongoitrous subjects towards the left of the distribution of iodine intakes have low intakes and are at increased risk of developing goitre. This group of subjects should be characterised, as well as the cause of their inadequate intake, so that the best way for addressing this public health problem can be defined. The Panel considers that no change is needed in the Opinion in relation to these comments Pregnancy Comments received - Concern was expressed about the evidence for an increment in iodine requirements during pregnancy and lactation, and it was stated that SACN (2014) considered the evidence to be very limited. It was suggested to increase the AI for pregnancy to allow for thyroid hormone synthesis. Panel consideration of comments received The basis for assessing the additional iodine requirement in pregnancy is described in Section 5.6. The Panel considers that no change is needed in the Opinion in relation to these comments Lactation Comments received It was pointed out that the daily loss of iodine estimated based on an average breast milk iodine concentration in iodine sufficiency is 120 μg/day. It was suggested that the proposed AI for lactating women be revised and calculated using the adult AI, taking into account an iodine loss of 120 μg/day. The ability of thyroid stores to provide for lactation, and the adequacy of the suggested AI to allow for sufficient provision for stores both pre- and post-conception was questioned. It was stated that the iodine requirement in lactating women from iodine-deficient populations should be considered. Panel consideration of comments received The consideration of the Panel for the iodine requirement in lactation was based on the fact that a limited number of studies show that thyroid anomalies induced during lactation can spontaneously be reversed even in the presence of moderate iodine deficiency. The theoretical consideration that a 10 mg iodine store in the thyroid could provide 100 days of iodine excretion in breast milk might also be kept in mind. The decision to compensate for only half of the iodine secreted with breast milk was based on expert judgement taking into account the presence of iodine stores in the thyroid. The Panel considers that no change is needed in the Opinion in relation to these comments. EFSA supporting publication 2014:EN

17 Conclusions Comments received It was pointed out that universal salt iodisation could be an effective way to address the mildly iodine deficient populations within Europe, which is of particular concern in pregnant women. It was noted that currently very few countries have adopted universal salt iodisation. It was suggested that the effects of excess iodine intake also be considered in the conclusions. Panel consideration of comments received The Panel reiterates that the measurement of exposure to iodine in populations and consideration on the management solutions for iodine deficiency/excess, such as universal salt iodisation, is outside the scope of this Opinion, as is the revision of the UL. The Panel considers that no change is needed in the Opinion in relation to these comments Recommendations for research Comments received It was noted that currently there is no research on thyroid disorders and excessive iodine intake in children aged 5 to 10 years. It was stated that there is a paucity of data related to exposure to iodine from disinfectants and preservatives. It was suggested that research on intake of iodised salt and algal-based supplements in the European population may be required. It was suggested to state the need for robust data in relation to excess iodine intake. It was stated that there are insufficient data on the effect of correction of iodine deficiency on development in infants and young children. It was suggested that large randomised controlled trials are needed to clarify the benefit of improved maternal iodine status on infant and child neurodevelopment. Panel consideration of comments received In the context of setting DRVs, the Panel considers that the first and the last comment dealing with how to delineate the boundary between adequacy and excess intake in infants/children on the basis of the consideration of long term consequences for health (especially neurodevelopment) is included in the existing recommendations for research. The Panel notes that research in line with the other suggestions could provide useful information for managing iodine status in a population in a given context, but are less relevant for setting DRVs. The Panel considers that no change is needed in the Opinion in relation to these comments Appendix B Comment received It was pointed out that the entry under United Kingdom was carried out in girls only. EFSA supporting publication 2014:EN

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