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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 Âµg/day. The median intake of iodine from food in the United States is approxi- mately 240 to 300 Âµg/day for men and 190 to 210 Âµg/day for women. The Tolerable Upper Intake Level (UL) for adults is 1,100 Âµg/day (1.1 mg/day), a value based on serum thyroptropin concen- tration 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- 258
IODINE 259 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 inci- dence of gastric cancer (Venturi et al., 1993). While these other possibilities deserve further investigation, the overwhelming impor- tance of nutritional iodine is as a component of the thyroid hor- mones. 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 re- duced 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 thyro- globulin meet at the apical surface of the thyroid cell. There thyro- peroxidase and hydrogen peroxide promote the oxidation of the iodide and its simultaneous attachment to tyrosyl residues within
260 DIETARY REFERENCE INTAKES the thyroglobulin molecule to produce the hormone precursors diiodotyrosine and monoiodotyrosine. Thyroperoxidase further cata- lyzes the intramolecular coupling of two molecules of diiodotyrosine to produce tetraiodothyronine (T4). A similar coupling of one monoiodotyrosine and one diiodotyrosine molecule produces tri- iodothyronine (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. Typi- cally, 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 hor- mone, 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 thyroglobulinâs iodine is in the form of the inactive precursors, monoiodotyrosine and diiodotyrosine. This iodine is not released into the circulation, but instead is re- moved 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 bind- ing 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 meta- bolically 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 fol- lows 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 hor- mone into the circulation. An elevated serum TSH concentration indicates primary hypothyroidism, and a decreased TSH concentra- tion shows hyperthyroidism. The urine contains the fraction of the serum iodine pool that is not concentrated by the thyroid gland. Typically, urine contains
IODINE 261 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 suffi- cient iodine. Most countries in the world currently have some de- gree 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 Âµg/L, well above the lower level considered to reflect adequate intake (100 Âµg/L) (WHO Nutrition Unit, 1994), but this is a decrease from the value of 321 Âµg/L found in a similar survey in the 1970s (Hollowell et al., 1998). Estimated iodine in- takes 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 develop- ing 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. Numer- ous 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 hypo- thyroid, 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
262 DIETARY REFERENCE INTAKES hypothyroidism. It occurs in severe iodine deficiency and is charac- terized 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 fea- ture 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 hyperthyroid- ism from autonomous nodules or with thyroid follicular cancer. Goiter can be assessed approximately by palpation and more pre- cisely 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 reproduc- tive outcome, increased childhood mortality, decreased educability, and economic stagnation. Major international efforts have pro- duced 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 bodyâs needs. The affinity of the thyroid gland for iodine is estimated by the fraction of an orally administered dose of radio- active iodine (123I, 131I) that is concentrated in the thyroid gland (Wayne et al., 1964). The thyroid gland concentrates more radio- active 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
IODINE 263 to 20 percent at 24 hours. Other factors can influence the radio- active iodine uptake, including thyroidal overproduction of hor- mone (hyperthyroidism), hypothyroidism, subacute thyroiditis, and many chemical and medicinal products. Assuming iodine equilibri- um, 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 administra- tion of 131I and the calculation of thyroid iodine accumulation from measurements of thyroidal and renal radioiodine clearances, uri- nary 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 (Âµg/L), in relationship to creatinine excretion (Âµg iodine/g creatinine), or as 24-hour urine collections (Âµg/day). Most studies have used the concentration in casual samples because of the obvious ease of col- lection. 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 Childrenâs 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 (Âµg/L) was 1.16 times the urinary iodine excretion expressed as Âµg/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 con- centration 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
264 DIETARY REFERENCE INTAKES Âµg/L for men and 1.1 to 1.29 Âµg/L for women. Data are not avail- able 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 rea- sonable for population estimates. From the above information and assuming an average bioavail- ability of 92 percent, the daily iodine intake is calculated from uri- nary iodine concentration by the following formula: Urinary iodine (Âµg/L) Ã· 0.92 Ã (0.0009 L/h/kg Ã 24 h/d) Ã wt (kg) = daily iodine intake; or simplified, Urinary iodine (Âµg/L) Ã 0.0235 Ã wt (kg) = daily iodine intake. As an example, urinary iodine excretion of 100 Âµg/L in a 57-kg girl would indicate a daily iodine intake of 134 Âµg. 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 nutri- tion (days) in contrast to indicators such as thyroid size and serum thyroid stimulating hormone (TSH) and thyroglobulin concentra- tions. Thyroid Size The size of the thyroid gland increases in response to iodine defi- ciency, mediated at least in part by increased serum TSH concentra- tion. 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 pal- pation with each lobe of the normal thyroid being regarded as no larger than the terminal phalanx of the subjectâs thumb. Thyroid
IODINE 265 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) de- scribes grade 1 goiter as palpable but not visible with the neck ex- tended and grade 2 as visible with the neck in the normal position. Ultrasonography defines thyroid size much more precisely and reliably. The technologyâsafe, practical, and easily performed in the fieldâis 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 defi- ciency 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 estab- lished, and in fact negative iodine balance has been reported (Dworkin et al., 1966). Third, techniques for assessment were crude by todayâs standards and key indicators, such as serum TSH, were not avail- able. A fourth limitation is that while studies such as these try to control intake, iodine appears in many unidentified or unrecog- nized substances that are ingested; therefore control of iodine in- take in these studies would have been limited. Despite the limita- tions of balance studies, data from them were used for estimating the average requirement for iodine in children.
266 DIETARY REFERENCE INTAKES 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 func- tion in individuals. Sensitive assays have been widely available for about two decades, and serum TSH concentration is now the pre- ferred 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 hypo- thyroidism (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 in- takes, 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 re- lease 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 hor- mone 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 immuno- assays. The largest clinical use of the serum Tg concentration is in detecting metastases of differentiated thyroid cancer, but it is typi- cally 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,
IODINE 267 1993). There are insufficient dose-response data on dietary iodine intake and serum Tg concentrations to estimate iodine require- ments. Thyroxine and Triiodothyronine Concentration Assays for both thyroxine (T4) and triiodothyronine (T3) concen- trations 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 in- creased 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). How- ever, 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 assess- ing 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 per- cent (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). Ex- amples include cassava, which may contain linamarin and is metab- olized 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
268 DIETARY REFERENCE INTAKES 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 radio- contrast 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 ef- fects 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 intra- vascular 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 Chap- ter 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 con- sumed noniodized salt was 113 Âµg/L, whereas the concentration in
IODINE 269 breast milk of women who consumed low or high amounts of iodized salt was 143 or 270 Âµg/L, respectively (Gushurst et al., 1984), and within the range observed by Etling and coworkers (1986) and Johnson and coworkers (1990) (Table 8-1). The median concentra- tion of iodine in human milk for all women was 146 Âµg/L for 14 days to 3.5 years postpartum. Based on an average milk excretion of 0.78 L/day (Chapter 2) and an average concentration of 146 Âµg/L, the mean amount of iodine secreted in human milk is 114 Âµg/day. Iodine balance studies by Delange and coworkers (1984) showed that for full-term infants, aged 1 month and fed 20 Âµg/kg/day of iodine, total excretion was 12.7 Âµg/kg/day and iodine retention was 7.3 Âµg/kg/day. Thus, if the mean body weight at 6 months is 7 kg, then the infant in positive iodine balance excretes 90 Âµg/day. Based on the median intake of iodine consumed from human milk and the average urinary iodine excretion of the infant, the AI for infants ages 0 through 6 months has been set at 110 Âµg/day. Ages 7 though 12 Months. The AI for infants ages 7 through 12 months is 130 Âµg/day as determined by the method described in Chapter 2 to extrapolate from the younger infants. The AI for in- fants is greater than the Recommended Dietary Allowances (RDAs) for children and adolescents because the latter are based on extrap- olation of adult data or on balance data for a specific age group (see âChildren and Adolescents Ages 1 through 18 Yearsâ). TABLE 8-1 Iodine Concentration in Human Milk Milk Iodine Estimated Study Stage of Concentration Iodine Intakes Reference Group Lactation (Âµg/L) of Infants (Âµg/d)a Gushurst et al., 24 women, 14 dâ3.5 y 146 114 1984 21â36 y Etling et al., 23 women, 59 46 1986 < 34 y Johnson et al., 14 women < 2 mo 247 192 1990 98 76 NOTE: Maternal intakes were not reported in these studies. a Iodine intake based on reported data or concentration (Âµg/L) Ã 0.78 L/day.
270 DIETARY REFERENCE INTAKES Iodine AI Summary, Ages 0 through 12 months AI for Infants 0â6 months 110 Âµg/day of iodine 7â12 months 130 Âµg/day of iodine Special Considerations The iodine content in cow milk is dependent on the amount of iodine consumed by the animal (Swanson et al., 1990). As a result, the amount of iodine in cow milk increased by 300 to 500 percent from 1965 to 1980, partly because of the addition of organic iodine to animal feed (Hemken, 1980). There have been no studies in which the bioavailability of iodine in infant formulas and human milk have been compared. Children and Adolescents Ages 1 through 18 Years Evidence Considered in Estimating the Average Requirement Ages 1 through 3 Years. A 4-day balance study was conducted by Ingenbleek and Malvaux (1974) on children aged 1.5 to 2.5 years who were previously malnourished and then nutritionally rehabili- tated. The median iodine intake of the seven rehabilitated children was 63.5 Âµg/day, and the average iodine balance was +19 Âµg/day. The coefficient of variation (CV) was approximately 20 percent. No other studies assessing iodine requirements for this age group have been conducted. If the Estimated Average Requirement (EAR) for adults is extrapolated down on the basis of body weight (see Chap- ter 2), the EAR would be 36 Âµg/day. However, because an average intake of 63.5 Âµg/day resulted in a positive iodine balance, an EAR of 65 Âµg/day is set. Ages 4 through 8 Years. Children 8 years of age who consumed 20 to 40 Âµg/day of iodine were in negative iodine balance (â23 to â26 Âµg/day) (Malvaux et al., 1969), indicating that the average mini- mum requirement is approximately 65 Âµg/day (40 + 26). If the EAR for adults is extrapolated down on the basis of body weight (see Chapter 2), the EAR would be 47 Âµg/day. No other studies for assessing iodine requirements for this age group have been con- ducted; therefore an EAR of 65 Âµg/day is set, using the higher estimate.
IODINE 271 Ages 9 through 13 Years. The prevalence of goiter was estimated in European boys and girls aged 6 to 15 years (Delange et al., 1997). Goiter prevalence in a population increases inversely with iodine intake. Because iodine deficiency is rare in the United States, data from Europe are used to relate goiter, as determined by ultrasound, to urinary iodine excretion. As urinary iodine excretion increases, the goiter prevalence decreases and eventually changes only slightly (Figure 8-1). Although data from this figure are not available for estimating a 50 percent prevalence of goiter, the level of urinary iodine concentration at which there is only a 2 percent prevalence 40 30 Prevalence of goiter (%) 20 10 0 0 3 6 9 12 15 18 Median urinary iodine (Âµg/dl) FIGURE 8-1 Inverse relationship between median urinary iodine concentrations and the prevalence of goiter in schoolchildren. The dotted line represents the upper limit of the prevalence of goiter (WHO Nutrition Unit, 1994). Adapted from Delange et al. (1997).
272 DIETARY REFERENCE INTAKES of goiter is approximately 100 Âµg/L. This approach can be used for estimating the RDA because it estimates the requirement for ap- proximately 98 percent of the population. As described earlier, the daily iodine intake can be estimated from the urinary iodine con- centration as follows: 1. Median urine volume is 1.2 mL/hour/kg for a 10-year-old child (the median excretion rate for all children aged 7 to 15 years was 0.9 mL/hour/kg) (Mattsson and Lindstrom, 1995) and the median weight is 40 kg (Chapter 1); therefore the urine volume is about 1.15 L/day (1.2 Ã 40 Ã 24 hr). 2. Approximately 92 percent of dietary iodine is excreted in the urine (Nath et al., 1992; Vought and London, 1967). 3. Therefore, for a 10-year-old child weighing 40 kg, the urinary iodine concentration of 100 Âµg/L approximates a daily iodine in- take of 125 Âµg (1.15 Ã· 0.92 Ã 100). This value suggests an RDA of approximately 125 Âµg/day. Malvaux and coworkers (1969) conducted a balance study on 16 boys and girls (aged 9 to 13 years) in Belgium. The average iodine intake was 31 Âµg/day, and the average balance was â24 Âµg/day. This finding would suggest a minimum average requirement of approxi- mately 55 Âµg/day (31 + 24). The iodine requirement has not been determined based on energy expenditure; however, the thyroid hormones, which contain iodine, are involved with metabolic rate. Therefore, the EAR is extrapolated from adults by using metabolic body weight (kg0.75) and the method described in Chapter 2 to set an EAR at 73 Âµg/day. Ages 14 through 18 Years. Malvaux and colleagues (1969) reported that the average iodine balance of 10 children (aged 14 to 16 years) was â24 Âµg/day when they consumed an average 34 Âµg/day of iodine, which would give 58 Âµg/day as an average requirement. No other data are available for estimating an average requirement for this age group. However, extrapolating down from adult data as described in Chapter 2 and using metabolic weight gives an EAR of 95 Âµg/ day, which is used to set the RDA as it is a higher estimate. Iodine EAR and RDA Summary, Ages 1 through 18 Years EAR for Children 1â3 years 65 Âµg/day of iodine 4â8 years 65 Âµg/day of iodine
IODINE 273 EAR for Boys 9â13 years 73 Âµg/day of iodine 14â18 years 95 Âµg/day of iodine EAR for Girls 9â13 years 73 Âµg/day of iodine 14â18 years 95 Âµg/day of iodine The RDA for iodine is set by using a CV of 20 percent (see âAdults Ages 19 Years and Olderâ). The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for iodine the RDA is 140 per- cent of the EAR). The calculated values for RDAs have been rounded, and are in the range of 125 Âµg/day for a 10-year-old child as presented on the previous page. RDA for Children 1â3 years 90 Âµg/day of iodine 4â8 years 90 Âµg/day of iodine RDA for Boys 9â13 years 120 Âµg/day of iodine 14â18 years 150 Âµg/day of iodine RDA for Girls 9â13 years 120 Âµg/day of iodine 14â18 years 150 Âµg/day of iodine Adults Ages 19 Years and Older Evidence Considered in Estimating the Average Requirement Thyroid Iodine Accumulation and Turnover. Thyroidal radioiodine accumulation is used to estimate the average requirement. Turn- over studies have been conducted in euthyroid adults (Fisher and Oddie, 1969a, 1969b). In one of these studies, the average accumu- lation of radioiodine by the thyroid gland for 18 men and women aged 21 to 48 years was 96.5 Âµg/day (Fisher and Oddie, 1969a). The second study involved 274 euthyroid subjects from Arkansas. The calculated uptake and turnover was 91.2 Âµg/day (Fisher and Oddie, 1969b). The accumulation of radioidine by the thyroid gland corre- lated well with urinary radioidine excretion. DeGroot (1966) mea- sured iodine turnover in four normal subjects by three methods:
274 DIETARY REFERENCE INTAKES absolute iodine uptake (21 to 97 Âµg/day) determined by using the method of Riggs (1952), thyroid hormone secretion (69 to 171 Âµg/ day) determined by using the method of Berson and Yalow (1954), and thyroid hormone secretion (49 to 147 Âµg/day) determined by using the method of Ermans and coworkers (1963). There is no evidence to suggest that the average iodine requirement is altered with aging, or to have differences based on gender in adults. Supporting Data. Other considerations support an EAR in the gen- eral range of 95 Âµg/day for adults (Delange, 1993; Dunn et al., 1998). A study by Vought and London (1967) demonstrated that the obligatory amount of iodine excreted was 57 Âµg/day. Despite the methodologic limitations of balance studies, when 100 Âµg/day of iodine was provided to 13 subjects, an average slight positive balance (13 Âµg) was observed (Harrison, 1968). In a study of five pregnant and four nonpregnant women, balance was calculated at about 160 Âµg/day (Dworkin et al., 1966). Given this higher estimate in women, adjusting for smaller body weight in women was not justified. Iodine EAR and RDA Summary, Ages 19 Years and Older EAR for Men 19â30 years 95 Âµg/day of iodine 31â50 years 95 Âµg/day of iodine 50â70 years 95 Âµg/day of iodine > 70 years 95 Âµg/day of iodine EAR for Women 19â30 years 95 Âµg/day of iodine 31â50 years 95 Âµg/day of iodine 50â70 years 95 Âµg/day of iodine > 70 years 95 Âµg/day of iodine The CV was calculated to be 40 percent by using the data of Fisher and Oddie (1969a). Part of this variation is due to the complexity of the experimental design and calculations used to estimate turnover. Assuming that half of the variation is due to experimental design, a CV of 20 percent, rather than 10 percent based on energy (see Chapter 1), is used to set the RDA. The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for iodine the RDA is 140
IODINE 275 percent of the EAR). The calculated values for RDAs were rounded to the nearest 50 Âµg. RDA for Men 19â30 years 150 Âµg/day of iodine 31â50 years 150 Âµg/day of iodine 50â70 years 150 Âµg/day of iodine > 70 years 150 Âµg/day of iodine RDA for Women 19â30 years 150 Âµg/day of iodine 31â50 years 150 Âµg/day of iodine 50â70 years 150 Âµg/day of iodine > 70 years 150 Âµg/day of iodine Pregnancy Evidence Considered in Estimating the Average Requirement Thyroid Iodine Content of the Newborn. The daily accumulation of iodine by the newborn can be used to estimate the daily fetal iodine uptake. It is estimated that the average iodine content of the new- born thyroid gland is 50 to 100 Âµg with close to 100 percent being turned over daily (Delange, 1989; Delange and Ermans, 1991). An estimated daily thyroid iodine uptake of approximately 75 Âµg/day by the fetus and an EAR of 95 Âµg/day for nonpregnant women would yield an EAR of 170 Âµg/day during pregnancy. Iodine Balance. Iodine balance studies by Delange and coworkers (1984) showed that the average iodine retention of full-term infants was 6.7 Âµg/kg/day. With an average fetal weight of 3 kg, the mean retention of a fully developed fetus would be approximately 22 Âµg/ day. A study demonstrated that pregnant women were at balance when consuming approximately 160 Âµg/day (Dworkin et al., 1966). Based on balance studies, the EAR ranges from 117 (22 + 95) (Delange et al., 1984) to 160 Âµg/day (Dworkin et al., 1966). Iodine Supplementation During Pregnancy. In iodine deficiency, the size of the thyroid gland increases during pregnancy. Studies have measured thyroid volume by ultrasound and correlated it with uri- nary iodine excretion and the effects of iodine supplementation during pregnancy (Berghout and Wiersinga, 1998). Pregnant women in an iodine-deficient area of Italy were given iodized salt estimated
276 DIETARY REFERENCE INTAKES to add 120 to 180 Âµg/day of iodine (Romano et al., 1991). Their urinary iodine increased from 37 to 154 Âµg/day during the second trimester and was 100 Âµg/day during the third trimester. Untreated control subjects showed little change. The initial thyroid volume of 9.8 mL did not change in those treated with iodine, but increased by 16 percent in the controls. Thus, the total daily iodine intake of about 200 Âµg prevented goiter. In another study from Denmark (Pedersen et al., 1993), 54 pregnant women were given 200 Âµg/day of iodine as potassium iodide drops beginning the second trimester. Urinary iodine increased from 55 to 105 Âµg/L, their thyroid volume (initially 9.6 mL) increased by 15.5 percent, and serum thyroid stim- ulating hormone (TSH) and serum thyroglobulin (Tg) concentra- tions did not change. Untreated control subjects showed increases of 31 percent in thyroid volume, 75 percent in serum Tg concentra- tion, and 21 percent in serum TSH concentration. Thus, approxi- mately 250 to 280 Âµg/day of iodine prevented goiter during preg- nancy. In a third study (Glinoer, 1998), pregnant women with an initial urinary iodine of 36 Âµg/L were treated with an additional 100 Âµg/day. Their median urinary iodine concentration increased to 100 Âµg/L at 33 weeks, and their thyroid volume increased by 15 percent, compared with 30 percent in control subjects. Thus, a sup- plement of 100 Âµg iodine, bringing the total daily iodine intake to about 150 Âµg/day, was insufficient to prevent increased thyroid size. On the basis of the above data, the EAR is set at 160 Âµg/day. Iodine EAR and RDA Summary, Pregnancy EAR for Pregnancy 14â18 years 160 Âµg/day of iodine 19â30 years 160 Âµg/day of iodine 31â50 years 160 Âµg/day of iodine The RDA for iodine is set by using a CV of 20 percent (see âAdults Ages 19 Years and Olderâ). The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of indi- viduals in the group (therefore, for iodine the RDA is 140 percent of the EAR). The calculated values for RDAs were rounded to the nearest 10 Âµg. RDA for Pregnancy 14â18 years 220 Âµg/day of iodine 19â30 years 220 Âµg/day of iodine 31â50 years 220 Âµg/day of iodine
IODINE 277 Lactation Method Used to Estimate the Average Requirement The EAR during lactation is based on the average requirement of adolescent girls and nonpregnant women plus the average daily loss of iodine in human milk. The EAR for adolescent girls and adult women is 95 Âµg/day, and the average daily loss of iodine in human milk is approximately 114 Âµg/day (Gushurst et al., 1984). There- fore, the EAR for lactating women is 209 Âµg/day. Iodine EAR and RDA Summary, Lactation EAR for Lactation 14â18 years 209 Âµg/day of iodine 19â30 years 209 Âµg/day of iodine 31â50 years 209 Âµg/day of iodine The RDA for iodine is set by using a CV of 20 percent (see âAdults Ages 19 Years and Olderâ). The RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for iodine the RDA is 140 per- cent of the EAR). The calculated RDA value is rounded to the near- est 10 Âµg. RDA for Lactation 14â18 years 290 Âµg/day of iodine 19â30 years 290 Âµg/day of iodine 31â50 years 290 Âµg/day of iodine INTAKE OF IODINE Food Sources The iodine content in most food sources is low and can be affected by content of soil, irrigation, and fertilizers. Most foods provide 3 to 75 Âµg per serving. Foods of marine origin have higher concentra- tions of iodine because marine animals concentrate iodine from seawater. Processed foods may also contain higher levels of iodine due to the addition of iodized salt or additives such as calcium iodate, potassium iodate, potassium iodide, and cuprous iodide.
278 DIETARY REFERENCE INTAKES Dietary Intake Based on analysis of 234 core foods conducted by the Food and Drug Administration (1982â1991 (Pennington et al., 1995) and analysis of 60 additional core foods and intake data by the U.S. Department of Agriculture Continuing Survey of Food Intakes by Individuals (1994â1996), the median intake of iodine from food in the United States is approximately 240 to 300 Âµg/day for men and 190 to 210 Âµg/day for women (Appendix Table E-4). For all life stage and gender groups, less than 25 percent of individuals had intakes below the Estimated Average Requirement. Intake from Supplements Information from the Third National Health and Nutrition Exami- nation Survey (NHANES III) on the use of supplements containing iodine is given in Appendix Table C-17. The median intake of iodine from supplements was approximately 140 Âµg/day for adult men and women. In 1986, approximately 12 percent of men and 15 percent of nonpregnant women took a supplement that contained iodine (Moss et al., 1989; see Table 2-2). TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects in almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well- controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to individuals who are receiving iodine under medical supervision. Hazard Identification Most people are very tolerant of excess iodine intake from food (Pennington, 1990). Certain subpopulations, such as those with autoimmune thyroid disease and iodine deficiency, respond ad- versely to intakes considered safe for the general population. For the general population, high iodine intakes from food, water, and
IODINE 279 supplements have been associated with thyroiditis, goiter, hypo- thyroidism, 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, car- diac 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). Clin- ical hypothyroidism occurs when thyroid hormone production is inadequate. Subclinical hypothyroidism is defined as an elevation in TSH concentration while a normal serum thyroid hormone con- centration 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 hypothyroid- ism 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 random- ized, controlled clinical trial in Wales by Chow and coworkers (1991) showed significantly elevated TSH concentrations associated with total iodide intakes of 750 Âµg/day or more. The study involved supplemental intake of 500 Âµg/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 Âµg/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
280 DIETARY REFERENCE INTAKES goiter comes from studies involving pharmacological doses (Wolff, 1969) and population groups with high, chronic iodine intakes (50,000 to 80,000 Âµg/day) in Japan and China (Suzuki and Mashimo, 1973; Suzuki et al., 1965). Wolff (1969) reported that prolonged intakes greater than 18,000 Âµg/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 Âµg to 236 to 306 Âµg (Nelson and Phillips, 1985). Summary Challenged thyroid function shown by TSH concentrations ele- vated 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.
IODINE 281 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 Âµg/day of supplemental iodide for 2 weeks. Baseline urinary iodine excretion was 287 Âµg/day; there- fore baseline iodine intake from food is estimated to be approximately 300 Âµg/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 Âµg/day, for a total of 1,800 Âµg/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 Âµg/day for 14 days. Baseline urinary iodine excre- tion was 191 Âµg/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 Âµg. Those receiv- ing 1,500 Âµg/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 Âµg/ day increased TSH secretion. Both of the above studies support a LOAEL between 1,700 and 1,800 Âµg/day. Thus, the lowest LOAEL of 1,700 Âµg/day was selected. Uncertainty Assessment. There is little uncertainty regarding the range of iodine intakes that are likely to induce elevated TSH con- centration over baseline. A LOAEL of 1,700 Âµg/day and a NOAEL of 1,000 to 1,200 Âµg/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.
282 DIETARY REFERENCE INTAKES Derivation of a UL. The LOAEL of 1,700 Âµg/day was divided by a UF of 1.5 to obtain a UL of 1,133 Âµg/day of iodine, which was rounded down to 1,100 Âµg/day. UL = LOAEL = 1,700 Âµg/day â 1,100 Âµg/day UF 1.5 Iodine UL Summary, Ages 19 Years and Older UL for Adults â¥ 19 years 1,100 Âµg/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 infantâs 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 Âµg/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 non- pregnant and nonlactating females. Iodine UL Summary, Ages 0 through 18 Years, Pregnancy, Lactation UL for Infants 0â12 months Not possible to establish; source of intake should be from food and formula only UL for Children 1â3 years 200 Âµg/day of iodine 4â8 years 300 Âµg/day of iodine 9â13 years 600 Âµg/day of iodine
IODINE 283 UL for Adolescents 14â18 years 900 Âµg/day of iodine UL for Pregnancy 14â18 years 900 Âµg/day of iodine 19â50 years 1,100 Âµg/day of iodine UL for Lactation 14â18 years 900 Âµg/day of iodine 19â50 years 1,100 Âµg/day of iodine Special Considerations Autoimmune thyroid disease (AITD) is common in the U.S. popu- lation 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 supple- mented with 200 Âµg/day of iodine developed either mild transient hyperthyroidism or hypothyroidism, positive antibodies, and revers- ible 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 populationâs 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 in- take (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 cowâs 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 Âµg/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
284 DIETARY REFERENCE INTAKES 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, symp- toms 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 â¢ Correlation of community iodine intake with autoimmune thy- roid disease and papillary thyroid cancer. â¢ 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. â¢ Role of iodine in fibrocystic breast disease. â¢ Iodine nutrition and immune response. â¢ Iodine nutrition in relation to other nutrients, particularly vita- min A, iron, and selenium. â¢ Effects of iodine concentration in water purification. â¢ 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 com- pounds. J Clin Endocrinol 9:1406â1421. Ayromlooi J. 1972. Congenital goiter due to maternal ingestion of iodides. Obstet Gynecol 39:818â822. 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 79:20â24. Berghout A, Wiersinga W. 1998. Thyroid size and thyroid function during preg- nancy: An analysis. Eur J Endocrinol 138:536â542.
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