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8
Iodine

SUMMARY

Iodine is an essential component of the thyroid hormones that are involved in the regulation of various enzymes and metabolic processes. Thyroid iodine accumulation and turnover were used to set the Estimated Average Requirement. The Recommended Dietary Allowance (RDA) for adult men and women is 150 μg/day. The median intake of iodine from food in the United States is approximately 240 to 300 μg/day for men and 190 to 210 μg/day for women. The Tolerable Upper Intake Level (UL) for adults is 1,100 μg/day (1.1 mg/day), a value based on serum thyroptropin concentration in response to varying levels of ingested iodine.

BACKGROUND INFORMATION

Function

Iodine is an essential component of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3), comprising 65 and 59 percent of their respective weights. Thyroid hormones, and therefore iodine, are essential for mammalian life. They regulate many key biochemical reactions, especially protein synthesis and enzymatic activity. Major target organs are the developing brain, muscle, heart, pituitary, and kidney.

Observations in several areas have suggested possible additional roles for iodine. Iodine may have beneficial roles in mammary dys-



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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 8 Iodine SUMMARY Iodine is an essential component of the thyroid hormones that are involved in the regulation of various enzymes and metabolic processes. Thyroid iodine accumulation and turnover were used to set the Estimated Average Requirement. The Recommended Dietary Allowance (RDA) for adult men and women is 150 μg/day. The median intake of iodine from food in the United States is approximately 240 to 300 μg/day for men and 190 to 210 μg/day for women. The Tolerable Upper Intake Level (UL) for adults is 1,100 μg/day (1.1 mg/day), a value based on serum thyroptropin concentration in response to varying levels of ingested iodine. BACKGROUND INFORMATION Function Iodine is an essential component of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3), comprising 65 and 59 percent of their respective weights. Thyroid hormones, and therefore iodine, are essential for mammalian life. They regulate many key biochemical reactions, especially protein synthesis and enzymatic activity. Major target organs are the developing brain, muscle, heart, pituitary, and kidney. Observations in several areas have suggested possible additional roles for iodine. Iodine may have beneficial roles in mammary dys-

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc plasia and fibrocystic breast disease (Eskin, 1977; Ghent et al., 1993). In vitro studies show that iodine can work with myeloperoxidase from white cells to inactivate bacteria (Klebanoff, 1967). Other brief reports have suggested that inadequate iodine nutrition impairs immune response and may be associated with an increased incidence of gastric cancer (Venturi et al., 1993). While these other possibilities deserve further investigation, the overwhelming importance of nutritional iodine is as a component of the thyroid hormones. Physiology of Absorption, Metabolism, and Excretion Iodine is ingested in a variety of chemical forms. Most ingested iodine is reduced in the gut and absorbed almost completely (Nath et al., 1992). Some iodine-containing compounds (e.g., thyroid hormones and amiodarone) are absorbed intact. The metabolic pathway of iodinated radiocontrast media, such as Lipiodol, is not entirely clear. The oral administration of Lipiodol increases the iodine stores of the organism and has been successfully used in the correction of iodine deficiency (Benmiloud et al., 1994). Iodate, widely used in many countries as an additive to salt, is rapidly reduced to iodide and completely absorbed. Once in the circulation, iodide is removed principally by the thyroid gland and the kidney. The thyroid selectively concentrates iodide in amounts required for adequate thyroid hormone synthesis, and most of the remaining iodine is excreted in urine. Several other tissues can also concentrate iodine, including salivary glands, breast, choroid plexus, and gastric mucosa. Other than the lactating breast, these are minor pathways of uncertain significance. A sodium/iodide transporter in the thyroidal basal membrane is responsible for iodine concentration. It transfers iodide from the circulation into the thyroid gland at a concentration gradient of about 20 to 50 times that of the plasma to ensure that the thyroid gland obtains adequate amounts of iodine for hormone synthesis. During iodine deficiency, the thyroid gland concentrates a majority of the iodine available from the plasma (Wayne et al., 1964). Iodide in the thyroid gland participates in a complex series of reactions to produce thyroid hormones. Thyroglobulin, a large glycoprotein of molecular weight 660,000, is synthesized within the thyroid cell and serves as a vehicle for iodination. Iodide and thyroglobulin meet at the apical surface of the thyroid cell. There thyroperoxidase and hydrogen peroxide promote the oxidation of the iodide and its simultaneous attachment to tyrosyl residues within

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc the thyroglobulin molecule to produce the hormone precursors diiodotyrosine and monoiodotyrosine. Thyroperoxidase further catalyzes the intramolecular coupling of two molecules of diiodotyrosine to produce tetraiodothyronine (T4). A similar coupling of one monoiodotyrosine and one diiodotyrosine molecule produces triiodothyronine (T3). Mature iodinated thyroglobulin is stored extra-cellularly in the lumen of thyroid follicles, each consisting of a central space rimmed by the apical membranes of thyrocytes. Typically, thyroglobulin contains from 0.1 to 1.0 percent of its weight as iodine. About one-third of its iodine is in the form of thyroid hormone, the rest as the precursors. An average adult thyroid in an iodine-sufficient geographic region contains about 15 mg iodine (Fisher and Oddie, 1969b). Thyroglobulin, which contains the thyroid hormones, is stored in the follicular lumen until needed. Then endosomal and lysosomal proteases digest thyroglobulin and release the hormones into the circulation. About two-thirds of thyroglobulin’s iodine is in the form of the inactive precursors, monoiodotyrosine and diiodotyrosine. This iodine is not released into the circulation, but instead is removed from the tyrosine moiety by a specific deiodinase and then recycled within the thyroid gland. This process is an important mechanism for iodine conservation, and individuals with impaired or genetically absent deiodinase activity risk iodine deficiency. Once in the circulation, T4 and T3 rapidly attach to several binding proteins synthesized in the liver, including thyroxine-binding globulin, transthyretin, and albumin. The bound hormone then migrates to target tissues where T4 is deiodinated to T3, the metabolically active form. The responsible deiodinase contains selenium, and selenium deficiency may impair T4 conversion and hormone action. The iodine of T4 returns to the serum iodine pool and follows again the cycle of iodine or is excreted in the urine. Thyrotropin (TSH) is the major regulator of thyroid function. The pituitary secretes this protein hormone (molecular weight about 28,000) in response to circulating concentrations of thyroid hormone, with TSH secretion increasing when circulating thyroid hormone decreases. TSH affects several sites within the thyrocyte, the principal actions being to increase thyroidal uptake of iodine and to break down thyroglobulin in order to release thyroid hormone into the circulation. An elevated serum TSH concentration indicates primary hypothyroidism, and a decreased TSH concentration shows hyperthyroidism. The urine contains the fraction of the serum iodine pool that is not concentrated by the thyroid gland. Typically, urine contains

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc more than 90 percent of all ingested iodine (Nath et al., 1992). Most of the remainder is excreted in feces. A small amount may be in sweat. Clinical Effects of Inadequate Intake The so-called iodine deficiency disorders (IDD) include mental retardation, hypothyroidism, goiter, cretinism, and varying degrees of other growth and developmental abnormalities. These result from inadequate thyroid hormone production from lack of sufficient iodine. Most countries in the world currently have some degree of iodine deficiency, including some industrialized countries in Western Europe (Stanbury et al., 1998). Iodine deficiency was a significant problem in the United States and Canada, particularly in the interior, the Great Lakes region, and the Pacific Northwest, during the early part of the 20th century (Trowbridge et al., 1975). The Third National Nutrition and Health Examination Survey study of samples collected from 1988 to 1994 showed a median urinary iodine excretion of 145 μg/L, well above the lower level considered to reflect adequate intake (100 μg/L) (WHO Nutrition Unit, 1994), but this is a decrease from the value of 321 μg/L found in a similar survey in the 1970s (Hollowell et al., 1998). Estimated iodine intakes for Canadians are in excess of 1 mg/day (Fischer and Giroux, 1987). Both countries iodize salt with potassium iodide at 100 ppm (76 mg iodine/kg salt). Iodized salt is mandatory in Canada and used optionally by about 50 percent of the U.S. population. The most damaging effect of iodine deficiency is on the developing brain. Thyroid hormone is particularly important for myelination of the central nervous system, which is most active in the perinatal period and during fetal and early postnatal development. Numerous population studies have correlated an iodine-deficient diet with increased incidence of mental retardation. A meta-analysis of 18 studies concluded that iodine deficiency alone lowered mean IQ scores by 13.5 points (Bleichrodt and Born, 1994). The effects of iodine deficiency on brain development are similar to those of hypothyroidism from any other cause. The United States, Canada, and most developed countries have routine screening of all neonates by blood spot for TSH or T4 to detect among iodine-sufficient children the approximately one in 4,000 who will be hypothyroid, usually from thyroid aplasia. Iodine treatment can reverse cretinism especially when the treatment is begun early (Klein et al., 1972). Cretinism is an extreme form of neurological damage from fetal

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc hypothyroidism. It occurs in severe iodine deficiency and is characterized by gross mental retardation along with varying degrees of short stature, deaf mutism, and spasticity. As many as one in ten of some populations with very severe iodine deficiency may be cretins. Correction of iodine deficiency in Switzerland completely eliminated the appearance of new cases of cretinism, and a similar experience has occurred in other countries (Stanbury et al., 1998). Thyroid enlargement (goiter) is usually the earliest clinical feature of iodine deficiency. It reflects an attempt to adapt the thyroid to the increased need, brought on by iodine deficiency, to produce thyroid hormones. Initially, goiters are diffuse but become nodular over time. In later stages they may be associated with hyperthyroidism from autonomous nodules or with thyroid follicular cancer. Goiter can be assessed approximately by palpation and more precisely by field ultrasonography. The International Council for the Control of Iodine Deficiency Disorders (WHO/UNICEF/ICCIDD, 1993) and the World Health Organization (WHO Nutrition Unit, 1994) have recommended surveying schoolchildren for thyroid size as one of the most practical indicators of iodine deficiency, and many reports on iodine nutrition are based primarily on such goiter surveys. Other consequences of iodine deficiency are impaired reproductive outcome, increased childhood mortality, decreased educability, and economic stagnation. Major international efforts have produced dramatic improvements in the correction of iodine deficiency in the 1990s, mainly through use of iodized salt in iodine-deficient countries. SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR IODINE Iodine Accumulation and Turnover The normal thyroid gland takes up the amount of circulating iodine necessary to make the proper amount of thyroid hormone for the body’s needs. The affinity of the thyroid gland for iodine is estimated by the fraction of an orally administered dose of radioactive iodine (123I, 131I) that is concentrated in the thyroid gland (Wayne et al., 1964). The thyroid gland concentrates more radioactive iodine in iodine deficiency and less in iodine excess. Thus, values for euthyroid individuals in Western Europe, where some iodine deficiency exists, are higher than in the iodine-sufficient United States and Canada, where typical values are in the range of 5

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc to 20 percent at 24 hours. Other factors can influence the radioactive iodine uptake, including thyroidal overproduction of hormone (hyperthyroidism), hypothyroidism, subacute thyroiditis, and many chemical and medicinal products. Assuming iodine equilibrium, the mean daily thyroid iodine accumulation and release are similar. Thus, the average daily uptake and release (turnover) of iodine in the body can be used to estimate the average requirement of iodine, provided that the subjects tested have adequate iodine status and are euthyroid. Such turnover studies have been conducted in euthyroid adults in the United States (Fisher and Oddie, 1969a, 1969b; Oddie et al., 1964). Turnover studies are based on the intravenous administration of 131I and the calculation of thyroid iodine accumulation from measurements of thyroidal and renal radioiodine clearances, urinary iodine excretion, and fractional thyroidal release rate. Urinary Iodine Over 90 percent of dietary iodine eventually appears in the urine (Nath et al., 1992; Vought and London, 1967). Data on urinary iodine excretion are variously expressed as a concentration (μg/L), in relationship to creatinine excretion (μg iodine/g creatinine), or as 24-hour urine collections (μg/day). Most studies have used the concentration in casual samples because of the obvious ease of collection. In populations with adequate general nutrition, urinary iodine concentration correlates well with the urine iodine/creatinine ratio. Urinary iodine excretion is recommended by the World Health Organization, the International Council for the Control of Iodine Deficiency Disorders, and the United Nations Children’s Fund (WHO Nutrition Unit, 1994) for assessing iodine nutrition worldwide. In the Third National Health and Nutrition Examination Survey (NHANES III), the urinary iodine concentration (μg/L) was 1.16 times the urinary iodine excretion expressed as μg/g creatinine (Hollowell et al., 1998). In NHANES I, this ratio was 1.09. Some population groups, particularly those with compromised general nutrition, have low creatinine excretion; therefore the urinary iodine to creatinine ratio is misleading (Bourdoux, 1998). The concentration of iodine in 24-hour urine samples correlates well with that in casual samples (Bourdoux, 1998). Information from NHANES III on urinary iodine excretion is provided in Appendix Table G-6. The median urinary iodine excretion was 1.38 to 1.55

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc μg/L for men and 1.1 to 1.29 μg/L for women. Data are not available on 24-hour urinary excretion of iodine. Daily iodine intake can be extrapolated from urinary concentration as follows. The median 24-hour urine volume for ages 7 through 15 years is approximately 0.9 mL/hr/kg (or 0.0009 L/hr/kg) (Mattsson and Lindstrom, 1995). The 24-hour urine volume for adults is approximately 1.5 L (Larsson and Victor, 1988), a value in general agreement with an extrapolation of the calculation for children and adolescents. Urine volume among individuals and over time can vary considerably, but these numbers for daily volume appear reasonable for population estimates. From the above information and assuming an average bioavailability of 92 percent, the daily iodine intake is calculated from urinary iodine concentration by the following formula: Urinary iodine (μg/L) ÷ 0.92 × (0.0009 L/h/kg × 24 h/d) × wt (kg) = daily iodine intake; or simplified, Urinary iodine (μg/L) × 0.0235 × wt (kg) = daily iodine intake. As an example, urinary iodine excretion of 100 μg/L in a 57-kg girl would indicate a daily iodine intake of 134 μg. Simple methods for measuring urinary iodine exist (Dunn et al., 1993). Casual samples are easy to collect and have been the main-stay for biological monitoring in global studies of iodine nutrition. The urinary iodine concentration reflects very recent iodine nutrition (days) in contrast to indicators such as thyroid size and serum thyroid stimulating hormone (TSH) and thyroglobulin concentrations. Thyroid Size The size of the thyroid gland increases in response to iodine deficiency, mediated at least in part by increased serum TSH concentration. This earliest clinical response to impaired iodine nutrition reflects an adaptation to the threat of hypothyroidism. Excess iodine can also produce goiter because large amounts inhibit intrathyroidal hormone production, again leading to increased TSH stimulation and thyroid growth. Traditionally, goiter was assessed by neck palpation with each lobe of the normal thyroid being regarded as no larger than the terminal phalanx of the subject’s thumb. Thyroid

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc size is recommended by WHO/UNICEF/ICCIDD (WHO Nutrition Unit, 1994) for assessing iodine nutrition worldwide. The WHO/ UNICEF/ICCIDD classification (WHO Nutrition Unit, 1994) describes grade 1 goiter as palpable but not visible with the neck extended and grade 2 as visible with the neck in the normal position. Ultrasonography defines thyroid size much more precisely and reliably. The technology—safe, practical, and easily performed in the field—is replacing palpation in most studies. Reference values related to body surface area and to age exist for iodine-sufficient children in the United States (Xu et al., 1999), in Europe (Delange et al., 1993), and in some other countries. Most data come from surveys in school-age children, who are easily available and whose thyroids reflect recent iodine nutrition. Individuals may continue to have thyroid enlargement permanently, even after iodine deficiency has been corrected (Delange and Burgi, 1989; Jooste et al., 2000). Iodine Balance Several attempts at iodine balance studies were published in the 1960s (Dworkin et al., 1966; Harrison, 1968; Harrison et al., 1965; Malamos et al., 1967; Vought and London, 1967). Because most iodine in the body is concentrated in the thyroid gland, the ability to determine balance within a short time is more realistic than for most other trace elements. But, as for many trace elements, there are serious limitations for deriving a daily iodine requirement based on balance studies. One limitation is that the baseline iodine intake at the study site and the long-range iodine intake of the subjects before the studies were likely different from current conditions in the United States. This applies particularly to the study of Harrison and coworkers (1965). Second, iodine balance is complicated by the need to consider the thyroidal compartment in addition to iodine intake and excretion (Dworkin et al., 1966). Thus, even in prolonged studies of several months, equilibrium is not clearly established, and in fact negative iodine balance has been reported (Dworkin et al., 1966). Third, techniques for assessment were crude by today’s standards and key indicators, such as serum TSH, were not available. A fourth limitation is that while studies such as these try to control intake, iodine appears in many unidentified or unrecognized substances that are ingested; therefore control of iodine intake in these studies would have been limited. Despite the limitations of balance studies, data from them were used for estimating the average requirement for iodine in children.

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Serum Thyroid Stimulating Hormone Concentration Because serum TSH concentration responds to circulating levels of thyroid hormone, which in turn reflect adequate production of thyroid hormone, it is an excellent indicator of altered thyroid function in individuals. Sensitive assays have been widely available for about two decades, and serum TSH concentration is now the preferred test for assessing thyroid function in individuals. It is also used on blood spots by filter paper methodology in most countries for the routine screening of neonates to detect congenital hypothyroidism (WHO Nutrition Unit, 1994). The normal serum TSH concentration range in most assays is approximately 0.5 to 6.0 mU/ L, although each individual assay system needs to be standardized for euthyroid subjects. Studies of groups with differing iodine intakes, as reflected in urinary iodine concentrations, show different mean serum TSH concentrations, although they may remain within the normal range. The sensitivity of TSH can be enhanced by previous stimulation with TSH-releasing hormone (TRH) (Jackson, 1982). The latter is a hypothalamic tripeptide that stimulates release of TSH and prolactin. It is used clinically for individuals with borderline or confusing static TSH measurements; an exaggerated response to TRH suggests the threat of inadequate thyroid hormone availability and hypothyroidism. Several studies have shown that the mean serum TSH concentration and its response to TRH are increased in iodine deficiency, although absolute values may remain within the normal range (Benmiloud et al., 1994; Buchinger et al., 1997; Emrich et al., 1982; Moulopoulos et al., 1988). Serum Thyroglobulin Concentration Although principally an intrathyroidal and follicular resident, some thyroglobulin (Tg) is normally secreted into the circulation and is detectable by standardized commercially available immunoassays. The largest clinical use of the serum Tg concentration is in detecting metastases of differentiated thyroid cancer, but it is typically elevated in thyroidal hyperplasia from any cause, including the endemic goiter of iodine deficiency. Many studies have shown a correlation between serum Tg concentration and degree of iodine deficiency as shown by urinary iodine excretion or other parameters (Benmiloud et al., 1994; Gutekunst et al., 1986). It is applicable to blood spot filter paper technology (Missler et al., 1994). Individuals with adequate iodine intake have a median serum Tg concentration of 10 ng/mL (WHO Nutrition Unit, 1994; WHO/UNICEF/ICCIDD,

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 1993). There are insufficient dose-response data on dietary iodine intake and serum Tg concentrations to estimate iodine requirements. Thyroxine and Triiodothyronine Concentration Assays for both thyroxine (T4) and triiodothyronine (T3) concentrations are standard clinical tools for measuring thyroid function, although they are not as sensitive as TSH. In iodine deficiency, serum T4 concentration is decreased and serum T3 concentration is normal or increased, relative to iodine-sufficient controls. This increased T3 concentration is an adaptive response of the thyroid to iodine deficiency. Fasting and malnutrition are associated with low T3 concentrations (Croxson et al., 1977; Gardner et al., 1979). However, most changes take place within the normal range, and the overlap with the iodine-sufficient normal population is large enough to make this a relatively insensitive and unreliable means for assessing iodine nutrition. FACTORS AFFECTING THE IODINE REQUIREMENT Bioavailability Under normal conditions, the absorption of dietary iodine is greater than 90 percent (Albert and Keating, 1949; Nath et al., 1992; Vought and London, 1967). The fate of organic compounds of iodine in the intestine is different from that of iodine. When thyroxine is orally administered, the bioavailability is approximately 75 percent (Hays, 1991). Soya flour has been shown to inhibit iodine absorption (Pinchera et al., 1965), and goiter and hypothyroidism were reported in several infants consuming infant formula containing soya flour (Shepard et al., 1960). If iodine was added to this formula, goiter did not appear. Goitrogens Some foods contain goitrogens, that is, substances that interfere with thyroid hormone production or utilization (Gaitan, 1989). Examples include cassava, which may contain linamarin and is metabolized to thiocyanate which in turn can block thyroidal uptake of iodine; millet, some species of which contain goitrogenic substances; water, particularly from shallow or polluted streams and wells, which

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc may contain humic substances that block thyroidal iodination; and crucifera vegetables (e.g., cabbage). Most of these substances are not of major clinical importance unless there is coexisting iodine deficiency. Deficiencies of vitamin A, selenium, or iron can each exacerbate the effects of iodine deficiency. Other Factors Many ingested substances contain large amounts of iodine that can interfere with proper thyroid function. These include radiocontrast media, food coloring, certain medicines (e.g., amiodarone), water purification tablets, and skin and dental disinfectants. Erythrosine is a coloring agent widely used in foods, cosmetics, and pharmaceutical products, and contains high amounts of iodine. Data suggest that the increased thyroid stimulating hormone levels found following erythrosine ingestion is related to antithyroid effects of increased serum iodide concentrations, rather than a direct effect of erythrosine on thyroid hormones (Gardner et al., 1987). Similar to erythrosine, amiodarone, a highly effective antiarrhythmic drug that contains high levels of iodine, may alter thyroid gland function (Loh, 2000). Radiographic contrast media, following intravascular administration, results in the formation of iodinated serum proteins, which alter thyroid metabolism (Nilsson et al., 1987). FINDINGS BY LIFE STAGE AND GENDER GROUP Infants Ages 0 through 12 Months Method Used to Set the Adequate Intake No functional criteria of iodine status have been demonstrated that reflect response to dietary intake in infants. Thus, recommended intakes of iodine are based on an Adequate Intake (AI) that reflects the observed mean iodine intake of infants exclusively fed human milk. Ages 0 through 6 Months. An AI is used as the recommended intake level for infants as determined by the method described in Chapter 2. The AI reflects the observed mean iodine intake of infants fed human milk. Iodine concentrations in human milk are influenced by maternal iodine intake (Gushurst et al., 1984). The median iodine concentration in human milk of American women who consumed noniodized salt was 113 μg/L, whereas the concentration in

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc supplements have been associated with thyroiditis, goiter, hypothyroidism, hyperthyroidism, sensitivity reactions, thyroid papillary cancer, and acute responses in some individuals. There may be other unrecognized sources of iodine that increase the risk of adverse effects. Because of significant species differences in basal metabolic rates and iodine metabolism (Hetzel and Maberly, 1986), animal data were of limited use in setting a UL. Adverse Effects Acute Responses. Among human cases of acute iodine poisoning, there are reports of burning of the mouth, throat, and stomach, abdominal pain, fever, nausea, vomiting, diarrhea, weak pulse, cardiac irritability, coma, cyanosis, and other symptoms (Finkelstein and Jacobi, 1937; Tresch et al., 1974; Wexler et al., 1998). These are quite rare and are usually associated with doses of many grams. Hypothyroidism and Elevated Thyroid Stimulating Hormone (TSH). Clinical hypothyroidism occurs when thyroid hormone production is inadequate. Subclinical hypothyroidism is defined as an elevation in TSH concentration while a normal serum thyroid hormone concentration is maintained. An elevation or increase over baseline (prior to iodine intake) in serum TSH concentration is considered an initial marker for hypothyroidism, although clinical hypothyroidism has not occurred. Laurberg and coworkers (1998) showed that in populations with high iodine intake, impaired thyroid function (i.e., elevated TSH concentration) is increased. Intervention studies looking for the earliest effects in iodine-sufficient populations show an increase in serum TSH concentration, or in TSH response to TSH-releasing hormone (TRH), without the TSH increasing to the abnormal range (Gardner et al., 1988; Paul et al., 1988). A randomized, controlled clinical trial in Wales by Chow and coworkers (1991) showed significantly elevated TSH concentrations associated with total iodide intakes of 750 μg/day or more. The study involved supplemental intake of 500 μg/day of iodide or placebo by 225 adult women (aged 25 to 54 years) for 28 days in addition to the estimated dietary intake of 250 μg/day. The baseline urinary iodide concentrations, however, suggest that many subjects probably had borderline iodine deficiency. Thus their conclusions may not apply to an iodine-sufficient population, such as that of the United States. Goiter. Excess iodine may produce thyroid enlargement (goiter), mostly from increased TSH stimulation. Evidence of iodine-induced

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc goiter comes from studies involving pharmacological doses (Wolff, 1969) and population groups with high, chronic iodine intakes (50,000 to 80,000 μg/day) in Japan and China (Suzuki and Mashimo, 1973; Suzuki et al., 1965). Wolff (1969) reported that prolonged intakes greater than 18,000 μg/day increased the risk of goiter. Thyroid Papillary Cancer. Chronic stimulation of the thyroid gland by TSH is known to produce thyroid neoplasms (Money and Rawson, 1950). High iodine intake has also been associated with increased risk of thyroid papillary cancer in humans (Franceschi, 1998; Lind et al., 1998). Such evidence is lacking in experimental animals (Delange and Lecomte, 2000). Thyroid Effects in Newborn Infants. Iodine goiter and hypothyroidism have been observed in newborns after prenatal exposure to excess iodine (Ayromlooi, 1972; Carswell et al., 1970; LaFranchi et al., 1977; Senior and Chernoff, 1971; Wolff, 1969). Rectal irrigation with povidone-iodine, a topical antiseptic, has been shown to be toxic to infants (Kurt et al., 1996; Means et al., 1990). Other Adverse Effects. Other adverse effects of excess iodine intake include iodermia, a rare dermatological reaction to iodine intake. These dermatoses may consist of acneiform eruptions, pruritic red rashes, and urticaria (Parsad and Saini, 1998). In its most severe form, iodermia has resulted in death (Sulzberger and Witten, 1952). Iodine-induced hyperthyroidism occurs most frequently with iodine administration to patients with underlying thyroid disease and with iodine supplementation in areas of deficiency (Delange et al., 1999; Stanbury et al., 1998). Seasonal variations in thyrotoxicosis have been related to variations in daily iodine intake from 126 to 195 μg to 236 to 306 μg (Nelson and Phillips, 1985). Summary Challenged thyroid function shown by TSH concentrations elevated over baseline is the first effect observed in iodine excess. While an elevated TSH concentration may not be a clinically significant adverse effect, it is an indicator for increased risk of developing clinical hypothyroidism. Therefore, an elevated TSH concentration above baseline was selected as the critical adverse effect on which to base a UL.

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Dose-Response Assessment Adults Data Selection. The appropriate data for derivation of a UL for adults are those relating intake to thyroid dysfunction shown by elevated TSH concentrations. Studies conducted in countries with a history of inadequate iodine intake were not included in this review because of the altered response of TSH to iodine intake. Identification of No-Observed-Adverse-Effect Level (NOAEL) and Lowest-Observed-Adverse-Effect Level (LOAEL). Gardner and coworkers (1988) evaluated TSH concentrations in 30 adult men aged 22 to 40 years who received 500, 1,500, or 4,500 μg/day of supplemental iodide for 2 weeks. Baseline urinary iodine excretion was 287 μg/day; therefore baseline iodine intake from food is estimated to be approximately 300 μg/day. The mean basal serum TSH concentration increased significantly in those receiving the two higher doses, although it remained within the normal range. This study shows a LOAEL of 1,500 plus 300 μg/day, for a total of 1,800 μg/day. In a similar study (Paul et al., 1988), nine men aged 26 to 56 years and 23 women aged 23 to 44 years received iodine supplements of 250, 500, or 1,500 μg/day for 14 days. Baseline urinary iodine excretion was 191 μg/day. Because greater than 90 percent of dietary iodine is excreted in urine (Nath et al., 1992), it was estimated that the baseline iodine intake was approximately 200 μg. Those receiving 1,500 μg/day of iodide showed a significant increase in baseline and TRH-stimulated serum TSH, effects not seen in the two lower doses. No subjects in this study had detectable antithyroid antibodies. The conclusion would be that an iodine intake of about 1,700 μg/ day increased TSH secretion. Both of the above studies support a LOAEL between 1,700 and 1,800 μg/day. Thus, the lowest LOAEL of 1,700 μg/day was selected. Uncertainty Assessment. There is little uncertainty regarding the range of iodine intakes that are likely to induce elevated TSH concentration over baseline. A LOAEL of 1,700 μg/day and a NOAEL of 1,000 to 1,200 μg/day are estimated for adult humans. This results in an uncertainty factor (UF) of 1.5 to derive a NOAEL from a LOAEL. A higher uncertainty factor was not considered because of the mild, reversible nature of elevated TSH over baseline.

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Derivation of a UL. The LOAEL of 1,700 μg/day was divided by a UF of 1.5 to obtain a UL of 1,133 μg/day of iodine, which was rounded down to 1,100 μg/day. Iodine UL Summary, Ages 19 Years and Older UL for Adults   ≥ 19 years 1,100 μg/day of iodine Other Life Stage Groups Infants. For infants, the UL was judged not determinable because of insufficient data on adverse effects in this age group and concern about the infant’s ability to handle excess amounts. To prevent high intake, the only source of intake for infants should be from food and formula. Children and Adolescents. Given the dearth of information, the UL values for children and adolescents are extrapolated from those established for adults. Thus, the adult UL of 1,100 μg/day of iodine was adjusted for children and adolescents on the basis of body weight as described in Chapter 2 and using reference weights from Chapter 1 (Table 1-1). Values have been rounded down. Pregnancy and Lactation. No altered susceptibility of pregnant or lactating women to excess iodine has been noted. Therefore, the UL for pregnant and lactating females is the same as that for nonpregnant and nonlactating females. Iodine UL Summary, Ages 0 through 18 Years, Pregnancy, Lactation UL for Infants   0–12 months Not possible to establish; source of intake should be from food and formula only UL for Children   1–3 years 200 μg/day of iodine 4–8 years 300 μg/day of iodine 9–13 years 600 μg/day of iodine

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc UL for Adolescents   14–18 years 900 μg/day of iodine UL for Pregnancy   14–18 years 900 μg/day of iodine 19–50 years 1,100 μg/day of iodine UL for Lactation   14–18 years 900 μg/day of iodine 19–50 years 1,100 μg/day of iodine Special Considerations Autoimmune thyroid disease (AITD) is common in the U.S. population and particularly in older adult women. Individuals with AITD who are treated for iodine deficiency or nodular goiter (Carnell and Valente, 1998; Foley, 1992; Massoudi et al., 1995) may have increased sensitivity to adverse effects of iodine intake. Some young adults with simple goiter and iodine deficiency who were supplemented with 200 μg/day of iodine developed either mild transient hyperthyroidism or hypothyroidism, positive antibodies, and reversible histological changes of lymphocytic thyroiditis (Kahaly et al., 1997). The sensitivities of these distinct subgroups do not fall within the range of sensitivities expected for the healthy population. Studies have correlated an increase in the incidence of AITD with a population’s higher intake of iodine (Foley, 1992). Additional data provide some correlation between the incidence of circulating antithyroid antibodies (a marker for AITD) and dietary iodine intake (Schuppert et al., 2000). At this time there is not sufficient data to determine a UL for this subpopulation. Therefore, a UL could not be set for individuals with AITD. Intake Assessment Iodine is secreted in human and cow’s milk and is present in dairy products, marine fish, and a variety of foods grown in iodide-rich soils. It is especially high in some foods, such as certain seaweed. Normal diets are unlikely to supply more than 1 mg/day. Also, a variety of environmental and therapeutic exposures are adventitious sources of iodine (Farwell and Braverman, 1996). Intake of 10 g of 0.001 percent iodized salt results in an intake of 770 μg/day. Based on the Food and Drug Administration Total Diet Study (Appendix Table E-4), the highest intake of dietary iodine for any life stage or

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Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc gender group at the ninety-fifth percentile was approximately 1.14 mg/day, which is equivalent to the UL for adults. The iodine intake from the diet (Appendix Table E-4) and supplements (Appendix Table C-17) at the ninety-fifth percentile is approximately 1.15 mg/ day. Risk Characterization For most people, iodine intake from usual foods and supplements is unlikely to exceed the UL. In North America, where much of the iodine consumed is from salt iodized with potassium iodide, symptoms of iodine deficiency are rare. In certain regions of the world where goiter is present, therapeutic doses may exceed the UL. The UL is not meant to apply to individuals who are being treated with iodine under close medical supervision. RESEARCH RECOMMENDATIONS FOR IODINE Correlation of community iodine intake with autoimmune thyroid disease and papillary thyroid cancer. Continual monitoring of U.S. urinary iodine by the National Health and Nutrition Examination Survey and inclusion of data on thyroid size in children, determined by ultrasound. Role of iodine in fibrocystic breast disease. Iodine nutrition and immune response. Iodine nutrition in relation to other nutrients, particularly vitamin A, iron, and selenium. Effects of iodine concentration in water purification. Further standardization of thyroid volume by ultrasound and urinary iodine excretion in areas with different iodine intake. REFERENCES Albert A, Keating FR Jr. 1949. Metabolic studies with I131 labeled thyroid compounds. J Clin Endocrinol 9:1406–1421. Ayromlooi J. 1972. Congenital goiter due to maternal ingestion of iodides. Obstet Gynecol 39:818–822. Benmiloud M, Chaouki ML, Gutekunst R, Teichert HM, Wood WG, Dunn JT. 1994. Oral iodized oil for correcting iodine deficiency: Optimal dosing and outcome indicator selection. J Clin Endocrinol Metab 79:20–24. Berghout A, Wiersinga W. 1998. Thyroid size and thyroid function during pregnancy: An analysis. Eur J Endocrinol 138:536–542.

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