5
Prevention of Iodine Deficiency

John B. Stanbury, M.D.

International Council for the Control of

Iodine Deficiency Disorders

Requirements For Iodine

The thyroid hormones, thyroxin and triiodothyronine (T4 and T3), contain four and three atoms of iodine, respectively (For a comprehensive review of this section, see Hetzel, 1989b). Triiodothyronine, formed by monodeiodination of thyroxin, is the effective hormone. Iodine must be obtained from the environment. It has no recognized role in mammalian biology other than as a component of the thyroid hormones, although there is some suspicion that iodine deficiency may be involved in fibrocystic disease of the breast. Normal development requires the thyroid hormones. They are synthesized and secreted solely by the thyroid gland and are largely circulated in the blood bound to thyroxin-binding globulin and less firmly to other circulating plasma proteins (Braverman and Utiger, 1996).

The absolute requirement for iodine is quite small (DeLange, 1994). Adult needs can be met by 100 to 150 micrograms daily, with perhaps another 50 micrograms daily in the event of pregnancy. Infants and children require less overall, but somewhat more per kilogram of body weight. The capacity of the thyroid to store iodine, the relatively long half-life of thyroid hormone in the blood, and the capacity of the thyroid system to adjust to fluctuating supplies of iodine ensure a constant supply of thyroid hormone to the organs and tissues of the body, although daily iodine intake fluctuates widely. The thyroid system is intrinsically stable.

The normal thyroid contains between 2 and 20 mg of iodine. About 70 percent is in the form of the amino acids mono- and diiodotyrosine, the precursor molecules of the thyroid hormones. They are in peptide linkage in the large storage iodoprotein, thyroglobulin (MW about 660,000). The hormones



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--> 5 Prevention of Iodine Deficiency John B. Stanbury, M.D. International Council for the Control of Iodine Deficiency Disorders Requirements For Iodine The thyroid hormones, thyroxin and triiodothyronine (T4 and T3), contain four and three atoms of iodine, respectively (For a comprehensive review of this section, see Hetzel, 1989b). Triiodothyronine, formed by monodeiodination of thyroxin, is the effective hormone. Iodine must be obtained from the environment. It has no recognized role in mammalian biology other than as a component of the thyroid hormones, although there is some suspicion that iodine deficiency may be involved in fibrocystic disease of the breast. Normal development requires the thyroid hormones. They are synthesized and secreted solely by the thyroid gland and are largely circulated in the blood bound to thyroxin-binding globulin and less firmly to other circulating plasma proteins (Braverman and Utiger, 1996). The absolute requirement for iodine is quite small (DeLange, 1994). Adult needs can be met by 100 to 150 micrograms daily, with perhaps another 50 micrograms daily in the event of pregnancy. Infants and children require less overall, but somewhat more per kilogram of body weight. The capacity of the thyroid to store iodine, the relatively long half-life of thyroid hormone in the blood, and the capacity of the thyroid system to adjust to fluctuating supplies of iodine ensure a constant supply of thyroid hormone to the organs and tissues of the body, although daily iodine intake fluctuates widely. The thyroid system is intrinsically stable. The normal thyroid contains between 2 and 20 mg of iodine. About 70 percent is in the form of the amino acids mono- and diiodotyrosine, the precursor molecules of the thyroid hormones. They are in peptide linkage in the large storage iodoprotein, thyroglobulin (MW about 660,000). The hormones

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--> are released through proteolysis under the stimulus of thyrotropin from the anterior pituitary. Iodine is absorbed with high efficiency after ingestion. Most iodine containing substances are deiodinated in the gut and the resulting iodine absorbed. It is captured by the thyroid from the blood at a rate dependent on the history of supply. Most appear in the urine in inorganic form in amounts that largely reflect recent rates of ingestion. The daily excretion is the amount absorbed and that derived from hormone degradation, but not taken up by the thyroid. Under normal circumstances, the thyroid takes about 20 percent of the available iodine. There are limits: too little iodine over too long a time leads to serious consequences, as described below. When too much is ingested, the thyroid may shut down; under certain circumstances, it becomes overactive. Consequences Of Iodine Deficiency And Its Correction Goiter The anatomical response to chronic iodine deficiency is enlargement of the thyroid gland. Initially there is hypertrophy of the thyroid epithelial cells. With fluctuating iodine supply, involuntary changes occur; the epithelial cells flatten, follicles fuse to form nodules, degenerative changes occur, cysts form, and calcifications are seen. The changes may be highly irregular from one site to another within the gland. Iodine-deficiency goiter may appear in preadolescence and nodules may form when the deficiency is severe, but there is usually a modest enlargement in the young that progresses over the years to multinodular goiter (Kopp et al., 1994; Parma et al., 1994; Taylor, 1953). It is customarily more evident in the female; regression usually occurs in the postadolescent male. When deficiency is severe, goiter rates may approach 100 percent, even in the young. Goiter is usually harmless, if unattractive. Nevertheless, nodules may cause tracheal obstruction or impair the function of the laryngeal nerves. When surgery is required or elected, the risks of surgery in the local setting must be considered, and these may not be negligible. Malignant degeneration is a much debated issue; there is probably a slightly increased risk in endemic goiter (Riccabona, 1972). Mental and Neuromotor Retardation Neuromotor and cognitive impairments are the most important consequences of iodine deficiency. The endemic cretin is the classic example.

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--> This outcome is seen when iodine deficiency is severe and of long duration; it is also likely that the mother has been severely iodine-deprived. The damage begins during the second trimester of pregnancy and is reversible if iodine is supplied, but the damage sustained after the end of the second trimester is permanent (DeLong et al., 1989). The neurological features are characteristic and distinct (DeLong, 1989). In addition to severe cognitive impairment, they may include hearing and speech deficits; a distinctive proximal neuromotor rigidity with sparing of the distal extremities; and, in some instances, cerebellar signs. Cretins are usually tractable and can often perform simple tasks; autonomic function seems undisturbed. DeLong has pointed out that head circumference is often reduced. The hearing impairment may arise both from middle-ear and central damage (Halpern, 1994). Less extreme levels of iodine deficiency are responsible for lesser degrees of impairment, but the number of individuals affected is much greater than the population subject to the effects of severe deprivation. These changes extend from modest but detectable neurological changes to impaired learning capacity and performance in school or reduced capacity to handle formal tests of psychomotor function (Stanbury, 1994). A crucial question, and one that is difficult to answer, is how these changes within the community affect socioeconomic development. The consequences of moderate degrees of iodine deficiency for cognitive and motor performance have been examined in great detail (Stanbury, 1994). One of the earliest formal observations arose from the case of a village in rural, Andean Ecuador. Many residents were without physical deformity or other signs suggestive of cretinism, but it seemed quite obvious that they were mentally retarded (Dodge et al., 1969a,b). A meta-analysis of 18 studies of cognitive and neuromotor function (Bleichrodt et al., 1989) that covered a total of 2,214 individual subjects provided mean scores that were 13.5 IQ points lower in the iodine-deficient group than among the controls. Reproductive Impairment Rates of reproduction may continue to be high in iodine-deficient populations, but there is evidence that the rates are lower than in otherwise similar communities that are not deficient (McMichael et al., 1980; Pharaoh et al., 1971; Thilly et al., 1980). There are many possible reasons for this disparity. Fetal and pre- and postnatal survival are reduced by iodine deficiency (Connolly et al., 1979), as is motor performance during childhood (Connolly et al., 1979). Correction in one group of Chinese communities resulted in a doubling of the survival rate of neonates (G. R. DeLong, Division of Pediatric Neurology, Duke University Medical Center, personal communication).

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--> Impaired Agricultural Productivity Information on this point is scanty, but the question is an important one. DeLong (1989) has reported from China that there has been a remarkable increase in sheep survival and growth following introduction of iodine into the drinking water in an iodine-deficient region. The value of introducing iodine in the sheep industry of Australia and the cattle industry of the American Northwest has been reported, and iodine supplementation of feeds has been implemented. There is little evidence that iodine has any influence on plant growth. (Pandav and Mannar, 1996). Economic Stagnation While it seems intuitively obvious that iodine deficiency causes economic stagnation, it is difficult to produce unassailable supporting evidence. Socioeconomic conditions improved dramatically in a traditionally deprived and backward village in China, Jixian, after iodization of salt, but confounding variables leave doubts about the exclusive role of the fortification (Hetzel et al., 1987). Reduced energy, lowered learning capacity, and the burden of increased fetal and postnatal mortality must surely impede socioeconomic development (Dunn, 1994a; Hershman et al., 1986). Physical Growth It has been difficult to prove a relationship between physical growth and iodine nutrition alone because of the confounding variables of the other deficiencies that are usually present in iodine-deficient regions (Greene, 1973). Nevertheless, hypothyroidism (a consequence of iodine deficiency) clearly retards growth and development, and iodine-deficient individuals frequently are shorter than their iodine-sufficient peers. Consequences Of The Correction Of Iodine Deficiency Correction of iodine deficiency pays huge dividends in improved quality of life, elimination of cretinism and other lesser degrees of neuromotor and cognitive function, improved survival, and so on, but correction programs are not without some undesirable consequences (see following section on Costs and Benefits). Whenever thyroid nodules develop in the iodine-deficient gland and iodine is introduced—especially if introduction is poorly controlled and monitored—a fraction of the population will develop thyrotoxicosis. Because autonomy of function occurs in the iodine-deficient thyroid as a consequence of

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--> mutational events, it is probable that the changes are irreversible without medical intervention. The magnitude of this problem is not known. Epidemics of thyrotoxicosis were reported when iodine was introduced into the diet in the United States, Tasmania (Stewart and Vidor, 1976), and a number of other countries, but the consequences have not been measured in their prevalence and long-term damage. The problem is age-old: how much harm can one accept in order to reap the many obvious benefits? Interaction With Other Micronutrients Interactions of other micronutrients with iodine deficiency have not been defined with sufficient clarity, and further investigation is needed. Vitamin A deficiency may impair thyroid hormonogenesis by reducing retinol-binding protein, which is involved in glycosylation of the key protein thyroglobulin (Ingenbleek, 1983). It was observed that the presence of vitamin A deficiency appeared to worsen clinical features of iodine deficiency in Senegal (Ingenbleek, 1983). Selenium is a key component of a large number of enzymes, some of which, such as thyroxin deiodinase, are involved in thyroid function. Lack of selenium, a component of glutathione peroxidase, may contribute to the accumulation of peroxide in the gland, which is destructive and may contribute to the damaged gland observed in a study of the cretins of Zaire (Contempre et al., 1995). Uptake of iodine by the thyroid is an oxidative process, and energy is required for hormone synthesis and secretion. These processes require iron-containing catalysts, but the role of iron deficiency in thyroid function is not well defined. Iron is less well absorbed in the hypothyroid state, and subjects with hypothyroidism are frequently anemic (Ansell, 1991). While not micronutrients in a restricted sense, other dietary components may contribute to the impact of iodine deficiency. One group, the thioglucosides, such as linamarin, found in cassava, yields thiocyanate on hydrolysis in the gut if improperly prepared, and the resulting thiocyanate competes with iodine for uptake of iodine by the thyroid. There are many other dietary and environmental substances that interfere with thyroid function that merit consideration (Gaitan, 1989). Extent Of Iodine Deficiency Assessment Techniques* Goiter Rates This traditional technique continues to be useful as a preliminary screen or when more precise methods of assessment are not available. It has the limitation *   Hetzel, 1989b; UNICEF, 1994.

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--> of observer variation, especially in classifying thyroids of smaller sizes by palpation. In recent years ultrasonography has permitted improved precision and definition of what is abnormal; it has also provided a graphic account of structure. The technique can be applied in field conditions with portable equipment, and subject turnover can be quite rapid and efficient. A simplified classification for practical purposes is provided below in Box 5-1, adapted from a consensus statement by ICCIDD, WHO, and UNICEF (UNICEF, 1994). Iodine deficiency may be strongly suspected if more than 5 percent of school-age children fall into grade 1 or 2. Ultrasonography is rapidly becoming widely available for estimation of thyroid size and configuration. Several recent studies (e.g., DeLange et al., in press) have established mean and median values for normal thyroid volume in relation to age, gender, height, weight, and body surface for iodine-sufficient children. Thyroids greater than 2 standard deviations (SDs) from the mean for normals are classified as goiters. This method can be applied to as many as 200 children in a day. It has the advantage that it may disclose nodules that are missed in routine examination. Urinary Iodine Advances in methodology now permit rapid and accurate measurements of the iodine in urine. When done in samplings of appropriate size, these measures provide an excellent measure of the recent iodine nutrition of a community (UNICEF, 1991). The results are customarily expressed in ug/L; values below 50 are considered unacceptably low, and those above 100 are taken to signal sufficiency. Values below 25 ug/L indicate an urgent need for preventive action. Measurement of urinary iodine (UI) in representative samples from a population is presently the most convenient and reliable method to assess iodine nutritional status (Dunn et al., 1993a,b). Many studies confirm that iodine excretion rates correlate inversely with goiter size, and that when values are very low, the prevalence of neuromotor and cognitive impairment is high. Box 5.1 Classification of Goiter Grade 0: No palpable or visible goiter Grade 1: Not visible with the neck in normal position. The mass moves upward when the subject swallows. Nodular alterations can occur even when the thyroid is not visibly enlarged. Grade 2: A swelling in the neck that is visible when the neck is in a normal position and is consistent with an enlarged thyroid by palpation.

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--> Measurements of UI (urinary iodine) serve as an excellent monitoring technique. Failure in programs of salt iodization can be detected, as well as the addition of too much iodine to the salt supply. Continuing spot monitoring of UI should be part of every prophylactic program, and occasional samples should be confirmed by an independent laboratory. Measurements of TSH The technology of TSH measurements has advanced rapidly and is becoming available for the assessment of iodine deficiency. There are easier and less expensive methods to detect iodine deficiency, but universal neonatal screening can provide a good ongoing indicator of iodine deficiency, and it can also monitor the adequacy of a continuing prophylactic program, provided the neonatal screening is universal. The samples should be collected by heel stick and spotted on paper for later analysis. This technique is not yet available in most countries experiencing a significant iodine deficiency. It is also not applicable as an initial survey method unless there are sufficient births for sampling within the time frame of the survey, which is rarely the case. At the same time, surveys with larger population groups may disclose evidence of iodine deficiency if representative samples are available. The upper limit of normal in current assay methods is 5 to 6 uU/ml, and a significant number of results above this level suggests the presence of iodine deficiency. Introduction of high-sensitivity TSH assays has made it possible to determine the prevalence of iodine-induced thyrotoxicosis after the introduction of replacement iodine. Surveys of this kind could answer questions about the persistence and incidence of thyrotoxicosis or clinically inapparent thyrotoxicosis in regions with limited medical care. Values below 0.2 uU/ml raise concern about the presence of iodine-induced thyrotoxicosis. The current disadvantage of TSH measurements as a survey instrument is cost. UI is far less expensive and more readily applicable in the field. Thyroglobulin The abnormal thyroid of iodine deficiency leaks thyroglobulin into the blood, and this can be measured routinely with commercially available kits. This may prove to be a more accurate and reliable method for the assessment of iodine deficiency than goiter surveys by palpation or TSH measurements (Benmiloud et al., 1994). The method is sensitive and can be performed on dried bloodspots (Missler et al., 1994). This measure is also nonspecific—other conditions raise serum Tg values just as they produce goiters, but such conditions are fairly uncommon in the general population. The available assays

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--> vary in their normal range, and thus the technique and normative data must be specified when results are reported. Persons with adequate intake of iodine have mean levels of serum thyroglobulin of 10 ng/ml, with an upper normal limit of 20 ng/ml. The method has the disadvantage of expense. Iodine in Food and Water Methods are available for field use to assess the presence or degree of iodine deficiency, but assays on food are difficult. Measurements of the iodine content of locally available water, while technically satisfactory, are at best a poor indicator of the level of iodine deficiency in the community because sources vary in less developed communities, there are seasonal fluctuations, and there is a poor correlation with the levels of iodine available from other sources. Extent and Distribution of Iodine Deficiency Iodine is sparsely distributed in the earth's surface. As a result, iodine deficiency disorders (IDDs) have been exceedingly common in most populations (Hetzel, 1989b; Hetzel and Pandav, 1996; Mannar, 1996). These disorders were highly prevalent in the United States prior to the introduction of iodine through iodized salt. In the past, IDDs were frequent in much of Western Europe, and a severe problem in most Latin American countries, throughout most of Africa, in the Middle East, in the Himalayan region and southward on the subcontinent, in China, and in Southeast Asia. Iodine deficiency is a current problem among the countries of the former Soviet Union. Fortunately, the efforts of the past decade have made signal advances in elimination of IDDs through universal salt iodization (USI). WHO has estimated that over 1.5 billion persons worldwide reside in regions of environmental iodine deficiency (ID) and are at risk of IDDs. This may be a soft figure, but it suggests the importance of the problem for public health. Of those at risk, possibly half have clinically detectable thyroid abnormalities; of this group, probably one-fifth have health-significant impairments, and an unknown number have reduced intellectual function. Recognition of the baleful effects of iodine deficiency on the development of the nervous system has led to the recognition of ID (iodine deficiency) as the most common cause of preventable mental retardation in the world. Economic Costs of Iodine Deficiency Any attempt to assess the costs of iodine deficiency would be subject to tenuous assumptions and large-scale errors. Costs would be region-dependent:

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--> for example, the costs of a case of cretinism in the rural highland Andes or Central Africa are not comparable to the costs in an industrial region. The costs of lost productivity, premature death, fetal losses, and reduced energy would require—at best—guesswork. The costs of surgical procedures for goiter in Germany have been calculated, and they have been huge (Gutekunst, 1993). It has been said that only a few years ago, half the surgical procedures done in the major hospital in western Austria were performed to address goiter. Thyroidectomies were the mainstay of some of the busiest and most important clinics in the United States before the iodization of salt. Calculating costs without comparing benefits would be a relatively pointless enterprise. When efforts have been made to do so, the ratio of benefits to costs has been enormous (Correa, 1980; Dunn, 1994a; Hershman et al., 1986). Prevention is thus a highly advantageous undertaking. Indicators Of Iodine Deficiency And Impact Of Prevention Identifying Target Populations One may begin with the assumption that ID exists virtually everywhere, except where satisfactory prevention programs have been introduced or in the few regions of the world with ample iodine in the environment. What is a target population for an intervention program? Is it one with a borderline or moderately low mean daily intake of iodine, but no clinically evident IDDs, or only populations with positively identified IDDs? The former condition and grades of the latter will dictate the urgency of a program of fortification or supplementation. Identification of a target group is partially dependent on formally designed surveys that employ one or more of the tools described above. The structure of surveys depends on local or regional conditions, geography, transport, and resources. Highly stylized epidemiological surveys run the risk of missing important pockets of IDDs; some exploration may be required to follow up dubious information or intuition. Monitoring Intervention Programs and Their Impact The key to success in prevention of IDD is longitudinal monitoring of both the supply of iodine and the impact of the prevention program on the targeted population. Too many programs have lapsed because of failed monitoring, with the subsequent reappearance of IDDs. Monitoring should be institutionalized on a continuing and stable basis. The iodine content of salt should be measured

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--> from the factory or import portal, to the retailer, and on to the household. Swings in concentration should be investigated and corrected. Quite simple and reliable methods are now generally available to measure the iodine content of salt to assure that it is within satisfactory limits (Sullivan et al., 1994). Results should be confirmed by external control laboratories. The impact of programs should be monitored by periodic assessment of the status of IDDs. Success is signaled by a decline in IDDs as indicated by one or more of the assessment techniques described above. Care is needed in interpreting the information gained through monitoring, For example, if the surveyed population is comprised of older subjects with long-standing goiter and the technique of assessment is goiter rate, little change may be observed. The time frame for monitoring depends on what is being monitored. The iodine content of salt should be monitored on a daily basis at the factory or at the point of import and it should be frequently checked again at the store or point of sale, whereas little would be gained by measuring thyroid size more frequently than once each year. A national neonatal TSH screening program—if universally employed—would provide continuous monitoring of the frequency of IDDs. The ideal framework for monitoring would include most or all of the following components. Monitoring must include appropriate and effective responses if deficiencies are detected: After an initial goiter survey by ultrasonography, zones of suspicion would be monitored annually. A neonatal TSH screening program that is universally applied is needed. The iodine content of salt is monitored daily at the site of production or point of import. Spot monitoring of table salt is done at the retailer and at the consumer's table. Measurements are taken of UI. Initial measurements are made in statistically valid samples; measurements are done occasionally after the program of iodine distribution has begun. Measurements are made of plasma thyroglobulin in statistically valid samples of serum. Prevention And Correction Fortification Salt* Fortification of salt has a unique advantage among the micronutrient supplements—it requires no change in dietary habits, because everyone uses salt *   Fernandez, 1990; Mannar, 1996.

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--> (Mannar, 1996). The one disadvantage it shares with any other program of micronutrient fortification is that the improved product costs slightly more than the original. This must be countered, either through subsidy by donor organizations or by intensive social marketing that makes the iodized salt more desirable and worth the additional cost. The experience is that cost has rarely been a major stumbling block. Importation of noniodized salt across borders has occasionally been a problem, especially when the product has been labeled as iodized but actually contains no iodine. Small traders or local producers of salt near salt deposits have been a problem in rural Bolivia, Ecuador, and Argentina, for example. Demand for the iodized product has been created by professional social marketing techniques, as in Ecuador. Mass media campaigns that employed posters, press, pamphlet distribution, and radio were used in all regions. The goal in the prevention of IDDs is universal salt iodization (USI). Programs must take into account possible losses between point of manufacture or import and the consumer's table. Losses may vary among the forms of iodine used (iodide vs. iodate), heat, purity, humidity, packaging, shelf time, and losses in cooking. Programs should also be designed around salt consumption patterns in order to make the maximum effort to ensure an intake of iodine within the desired range. A mean consumption of 15 grams or more daily has been observed in some communities; in others as little as 2 grams have been consumed. Salt may be iodized in several ways, including dry mixing, drip, or spray techniques. Generally the iodine is sprayed or drip-fed on the salt as it flows down a mixing-screw conveyer; if the salt is finely ground, the iodine may be added dry (Dunn, 1995; Holman and McCartney, 1960). The long-term costs of producing iodized salt to supply the needs of an individual amounts to only three or four cents yearly. Unfortunately, in some instances a high, unwarranted premium is added to the cost of the salt to the consumer. Iodine is available principally from Chile and Japan. Difficulties arise in implementing programs when the salt industry is widely dispersed among a large number of small producers. Ensuring distribution of iodate to all parties for local production is difficult, and compliance is a problem. In Thailand, small, electrically powered rotating drums for mixing iodate into the salt are manufactured and are being widely distributed to remote areas to address this problem. The increasing use of plastic bagging has reduced iodine losses between manufacture and consumer, as has the sale of smaller packaging to effect more rapid turnover of the product. A customary level of fortification is in the range of 25–50 mg of iodine per kg of salt. This level will require variation to accommodate local conditions. The cost—considering all factors of plant operation, cost of the iodate, and control—should add little to the cost to the consumer and is a trivial increment, considering the low cost of bulk salt. When the salt is imported it must be reprocessed

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--> mental deficiency in an agriculturally primitive society would be quite different from the costs of the same abnormality in the industrial world, and the ratio might be adjusted downward accordingly. Value of Benefits. Several attempts have been made to quantify the benefits of IDD prophylaxis. These are subject to many assumptions, but the benefits clearly outweigh the costs by a substantial value. In India, Pandav (Pandav, 1994) found a benefit—cost ratio of 3. Correa (Correa, 1980) has estimated the value of improvements in the intelligence quotient brought about by iodization and elimination of cretinism with the gain in income, and found that iodization was more valuable than a number of other interventions, such as education, infant nutrition, and physical capital. Elimination of cretinism, improvement in general intelligence and neuromotor function, and an enhanced energy level are the dividends of the elimination of iodine deficiency. Action Plans For The International Agencies Independent Evaluation Evaluation of the current status of ID, IDDs, and the structure of country programs has been made in a few countries by independent external teams. For permission, credibility, and future corrections, these evaluations must be requested by the respective governments. If no ID commission is operational, creation of such a body can be strongly recommended by the external team. External evaluation also assures objectivity. The external team must have access to suspect regions and must be permitted to obtain independent data. Its report should go to the responsible government agency. ICCIDD (International Council for the Control of Iodine Deficiency Disorders) has proposed guidelines for assessing progress toward the sustainable elimination of ID (see Appendix). Strengthening Monitoring Independent evaluation will necessarily take time. Meanwhile, monitoring is essential and urgent. This will continue to be a high priority for agencies involved in ID and IDD control, such as ICCIDD. Efforts are being made to improve methods for measuring iodine in salt and in urine. Failure to monitor the iodine content of salt could undermine the whole structure of IDD preventive programs by allowing wide variations in iodine content to continue uncorrected (Pandav, 1994).

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--> Strengthening the Role of Regional and Country Program Directors The commitment and participation of groups that have a network of regional coordinators and country members involved in micronutrient nutrition, such as ICCIDD, need to be enhanced. This requires enthusiastic and dedicated leadership in addition to fiscal resources. Enhancing Cooperative Efforts among Agencies There are instances where interagency rivalries have paralyzed progress toward elimination of IDDs. But there are also examples of agencies that have begun to work together because of their common objective of eliminating ID. There is plenty for everyone to do. Pursuing Relevant Research Needed research includes basic inquiries into the nature of IDDs, the impact of prophylactic programs on the health of differing segments of a targeted society, and applied research directed toward the improvement of programs. Research costs money, and the international agencies must recognize their obligation to support acquisition of new knowledge. (Examples appear elsewhere in these paragraphs.) Extension of a Micronutrient Database A database in iodine nutrition has been established by ICCIDD with USAID support. It can be readily accessed on ICCIDD's homepage (http:avery.med.virginia.edu/˜jtd/iccidd/home.html), and contains country-based information on ID and IDDs and information regarding current and recent publications. Hundreds of papers appear each year that cover problems related to iodine deficiency, and many appear in journals that are not immediately available to all those in the field. Also, many of the publications derive from regional meetings or appear in agency publications that do not find their way into libraries. These elusive articles can be accessed with increasing ease through an extended database. Comparable information about iron and vitamin A could be added to this base. Extending and Expanding Communications E-mail is widely available to members of the ID and IDD community and is extensively used. ICCIDD has a page on the Worldwide Web, and it is linking with other databases, including those of Micronutrient Initiatives (which already

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--> has a database on iron and vitamin A), the Salt Institute, and the Latin American Thyroid Association. Others are being developed. Extending Advocacy Advocacy must be expanded by exposing government officials, health professionals, and the general public to the IDD message through formal and informal pathways. Regional representatives should develop and exploit contacts with the appropriate persons in government and industry to promote advocacy. Closing Gaps in Knowledge of the Extent of ID and IDDs The ID map of the world needs to be completed. With the current rapid progress in the campaigns against IDDs, the IDD and the USI maps require frequent updating through information supplied by ICCIDD regional representatives and the other international agencies, such as WHO and UNICEF. Conferences and Workshops at the Country, Regional, and International Levels Conferences and workshops have proved invaluable in sustaining enthusiasm, consolidating knowledge, and identifying needs and opportunities. They require organizational effort and financial support. The former has come from ICCIDD or its regional representatives, but the financial support has come, and will continue to come, from the international agencies; private foundations, such as the Thrasher Research Foundation and Kiwanis; and industry, such as Merck Darmstadt and segments of the salt industry. Resource Development Funding for ID, IDD action plans, and the organizations involved is currently grossly inadequate for the task of sustained correction. The bilateral and multilateral international agencies and nongovernmental organizations (NGOs) must constantly be reminded of their commitment and obligations to the correction of iodine deficiency. Dedicated Team Approach A useful approach to IDD elimination is offered by a team comprised of persons of diverse professional and geographical backgrounds that is organized

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--> to work as a unit in correcting micronutrient deficiencies. The ICCIDD has been one such group since its formation in 1985. It has been a resource for the development and guidance of programs; advocacy through conferences, publications, and personal contacts; aggregating a large constituency; and research regarding the varied aspects of IDDs. Such a group can only be successful if it is comprised of professionals who are dedicated to the mission. Examples of such individuals, and their years of involvement in IDD elimination, would include Fierro-Benitez in Ecuador (35 years), Pretell in Peru (30 years), Pandav in India (20 years), Lantum in Cameroon (15 years), Kavishe in Tanzania (10 years), and others. Summary In summary, the following points are cited. The thyroid hormones are essential for normal development. Iodine, an integral component of the thyroid hormones, has no other function, although a role has been suggested, but not proven, in fibrocystic disease of the breast and stomach cancer. Iodine is scarce in most countries, and when insufficient, results in the iodine deficiency disorders (IDD). Prominent among these is retarded neuromotor and cognitive development of varying degrees of severity, depending upon the degree of the iodine deficiency. Although much progress has been made in the past decade in the control of iodine deficiency in many countries around the world, the problem of the disorders deriving from iodine deficiency continues to exist. Iodine deficiency and IDDs have largely but not entirely disappeared from North America and Western Europe, but some areas of Germany, Italy, Denmark, and Belgium continue to have suboptimal levels of iodine that require correction. ID is still present in much of the African continent, the Middle East, and large parts of Asia. It is also found in the countries of the former Soviet Union, but less is known about its extent and severity. The techniques available to assess ID and IDDs include palpation of the thyroid, ultrasonographic mapping of thyroid size and structure, measurements of iodine in the urine, and assays for thyroid hormone, TSH, and thyroglobulin. Of these methods, the one currently providing the most information for epidemiological purposes and the most practicable is measurement of urinary iodine. Universal iodization of salt is the most effective method for preventing IDDs. When the degree of IDDs demands a prophylactic program and iodized salt is not immediately available, iodinated oil may be given intramuscularly or orally as a long-term, interim preventative. The single most important activity in programs of IDD prevention after a program has been initiated is careful monitoring. This includes measurement of

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--> iodine in the salt from point of manufacture or entry to the consumer's table. Biological monitoring is also essential, and urinary iodine concentration is usually the preferred indicator. When facilities, skills, and resources are available, other biological monitoring is useful, such as measurements of TSH, T4, plasma thyroglobulin, and clinical status. Other important activities include general education regarding the role of iodine in health and continuing research on iodine deficiency and its prevention at the basic and applied levels. Many problems impede progress toward elimination of IDDs. Political or popular support may be lacking for a variety of reasons. The salt industry may also present difficulties. Complacency and fiscal constraints may impose barriers to success or the continuation of prophylaxis. By virtually any measure, the benefits to a community or country far outweigh the costs of programs. Action plans directed toward minimizing IDDs include internal monitoring of national programs, periodic monitoring by an independent commission, strengthening the role of regional and country program directors, enhancing cooperation among involved international agencies, expanding communications among those involved, and securing the resources needed to put the effort on a sound financial base. Appendix: ICCIDD Guidelines For Assessment Of Progress Toward IDD Elimination A country with universal neonatal screening, using a sufficiently sensitive TSH assay, may be declared free of iodine deficiency if fewer than 3 percent of the newborns have TSH levels of more than 5 mU/l whole blood. For countries where there is no universal newborn screening, at least two of the following three criteria should be met: All salt for human and animal consumption in the regions where IDD is known or suspected is iodized at a recommended level at the factory. This will ensure that representative samples obtained regularly from retail outlets, or preferably from homes, have an iodine content sufficient to ensure a daily intake of 150 mg of iodine per person daily. [The actual requirement for the level of iodine in salt at the household level will vary, depending on the quality of salt, the prevailing climate conditions (warm-moist, warm-dry, or cool-moist, cool-dry), pack-aging (bulk sack with polyethylene lining or retail pack), storing, and the daily consumption of salt.] More than 50 percent of urine samples obtained on a regular basis in a statistically valid mode have an iodine content of 100 mg/l or

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--> greater, and more than 80 percent of urine samples have an iodine content of 50 mg/l or greater. In regions where IDD has been known or suspected, the prevalence of total goiter in representative surveys of children of school-age (6–12 years old) is less than 5 percent as ascertained by competent observers, and preferably confirmed by ultrasonography, if available. In addition to meeting two of the above three criteria, sustainability should be established according to the following guidelines, as applicable: A national IDD program has been set up; it is responsible for continuous monitoring of the status of iodine deficiency and of iodine content of salt, according to established criteria. The responsibility also includes mandatory public reporting of IDD status at regular specified intervals (e.g., every 3 to 5 years), by designated units (e.g., the program, the Ministry of Health) that are technically competent and adequately financed. The government, the private sector, and consumers have a high awareness of iodine deficiency and are committed to its sustained elimination. The salt industry has the commitment, technical resources, and responsibility (frequently mandated by legislation) to sustain effective iodization of salt, including its production, distribution, and monitoring. The supply of iodine for salt iodization is ensured, either through private purchase by the salt manufacturers or through the government. The availability and perceived health benefits of iodized salt, despite its marginally higher cost, compel consumers to buy iodized salt rather than the noniodized product. The IDD program has ready access to local and regional facilities to measure iodine levels in salt and to a central laboratory, competent to measure iodine in urine or neonatal blood TSH, or both, at affordable rates. References There is a voluminous literature relating to iodine deficiency. The references given below can serve only as point of entry into that literature. Ansell, J. E. 1991. The blood in hypothyroidism. In The Thyroid, L. E. Braverman and R. D. Utiger, eds., p. 1022. Philadelphia: J. B. Lippincott.

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--> Asuquo, M. H. 1995. How salt companies can take the lead in iodization: an example from Nigeria. ICCIDD Newsl. 11:31. Benmiloud, M., M. L. Chaouki, R. Gutekunst, et al. 1994. Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection. J. Clin. Endocrinol. Metab. 79:20. Bleichrodt, N., R. Escobar del Rey, G. Moreale de Escobar, I. Garcia, and C. Rubio. 1989. Iodine deficiency. Implications for mental and psychomotor development in children. In Iodine and the Brain, G. R. DeLong, J. Robbins, and P. G. Condliffe, eds. New York: Plenum. Braverman, L. E., and R. D. Utiger, eds. 1996. The Thyroid, 7th ed. Philadelphia: J. B. Lippincott. Cao, X-Y, X-M Jiang, A. Kareem, et al. 1994. Iodination of irrigation water as a method of supplying iodine to a severely iodine-deficient population. Lancet 344:107. Connolly, K. J., P. O. D. Pharoah, and B. S. Hetzel. 1979. Fetal iodine deficiency and motor performance during childhood. Lancet ii:1149. Contempre, B., J. E. Dumont, J-F Denef, and M-C Many. 1995. Effects of selenium deficiency on thyroid necropsis, fibrosis and proliferation: a possible role in myxedematous cretinism. Eur. J. Endocrinol. 133:99–109. Correa, H. 1980. A cost–benefit study of iodine supplementation programs for the prevention of endemic goiter and cretinism. In Endemic Goiter and Endemic Cretinism, J. B. Stanbury, ed., pp. 566–588. New York: John Wiley & Sons. DeLange, F. 1994. The disorders induced by iodine deficiency. Thyroid 4: 107–128. DeLange, F., G. Benker, P. Caron, O. Eber, W. Ott, F. Peter, et al. In press. Thyroid volume and urinary iodine in European schoolchildren. Standardization of values for assessment of iodine deficiency. Eur. J. Endocrinol. DeLong, G. R. 1989. Observations on the Neurology of Endemic Cretinism in Iodine and the Brain, G. R. DeLong, J. Robbins, and P. G. Condliffe, eds. New York: Plenum. DeLong, G. R., J. Robbins, and P. G. Condliffe, eds. 1989. Iodine and the Brain. New York: Plenum. Dodge, P. R., I. Ramirez, and R. Fierro-Benitez. 1969a. Neurological Aspects of Endemic Cretinism. In Endemic Goiter, J. B. Stanbury, ed. Pan American Health Organization Scientific Publication No. 193, Washington, D.C. Dodge, P. R., H. Palkes, R. Fierro-Benitez, and I. Ramirez. 1969b. Effect on intelligence of iodine in oil administered to young Andean children—a preliminary report. In Endemic Goiter, J. B. Stanbury, ed. Pan American Health Organization Scientific Publication No. 193, pp. 378–380, Washington, D.C. Dunn, J. T. 1991. IDD control in Latin America: Guatemala. IDD Newsl. 7:(2)12. Dunn, J. T. 1994a. Societal implications of iodine deficiency and the value of its prevention. In The Damaged Brain of Iodine Deficiency, J. B. Stanbury, ed., pp. 309–314. New York: Cognizant Communications. Dunn, J. T. 1994b. Bhutan makes dramatic progress toward IDD elimination. IDD Newsl. 10:23. Dunn, J. T. 1995. Technical aspects of salt iodization: an update. IDD Newsl. 11:26–30. Dunn, J. T. 1996a. Bolivia conquers iodine deficiency. IDD Newsl. 12:33–34. Dunn, J. T. 1996b. Nigeria advances towards IDD elimination. IDD Newsl. 12:27–28. Dunn, J. T. 1996c. Seven deadly sins in confronting endemic iodine deficiency, and how to avoid them. J. Clin. Endocrinol. Metabl. 81:1332–1335.

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--> Dunn, J. T., and F. van der Harr. 1990. A Practical Guide to the Correction of Iodine Deficiency. Brussels: ICCIDD. Dunn, J. T., H. E. Crutchfield, R. Gutekunst, and A. D. Dunn. 1993a. Methods for Measuring Iodine in Urine. ICCIDD/UNICEF/WHO. The Netherlands. Dunn, J. T., et al. 1993b. Two simple methods for measuring iodine in urine. Thyroid 3:119–128. Fernandez, R. L. 1990. A Simple Matter of Salt. Berkeley: University of California Press. Fierro-Benitez, R., I., Ramirez, E. Estrella, et al. 1969. Iodized oil in the prevention of endemic goiter and associated defects in the Andean region of Ecuador. In Endemic Goiter, J. B. Stanbury, ed., pp. 306–340 (see also pp. 341–365). Washington, D.C.: PAHO. Fisch, A., E. Pichard, T. Prazuk, et al. 1993. A new approach to combating iodine deficiency in developing countries: the controlled release of iodine in water by a silicone elastomer. Am. J. Publ. Health 83:540–545. Gaitan, E., ed. 1989. Environmental Goitrogenesis. Boca Raton, Fla.: CRC. Greene, L. S. 1973. Physical growth and development, neurological maturation and behavioral functioning in two Andean Ecuadorian communities in which goiter is endemic. Am. J. Phys. Anthropol. 38:119–134. Gutekunst, R. 1993. Iodine deficiency costs Germany over one billion dollars per year. IDD Newsletter 9:29-31. Halpern, J. P. 1994. The motor deficit in endemic cretinism and its implications for the pathogenesis of the disorder. In The Damaged Brain of Iodine Deficiency, J. B. Stanbury, ed. New York: Cognizant Communications. Havron, M. D. 1988. Bolivia fights iodine deficiency. IDD Newsl. 4:1–3. Hershman, J. M., G. A. Melnick, and R. Fastner. 1986. Economic consequences of endemic goiter. In Towards the Eradication of Endemic Goiter, Cretinism, and Iodine Deficiency, J. T. Dunn, E. A. Pretell, C. H. Daza, and F. E. Viteri, eds. Washington, D.C.: PAHO. Hetzel, B. S. 1989a. National IDD control programs. In The Story of Iodine Deficiency, pp. 123–144. New York: Oxford Medical Publications. Hetzel, B. S., ed. 1989b. The Story of Iodine Deficiency. New York: Oxford Medical Publications. Hetzel, B.S., and C. S. Pandav. 1996. S.O.S. for a Billion, 2d ed. New York: Oxford University Press. Hetzel, B. S., C. H. Thilly, R. Fierro-Benitez, et al. 1980. Iodized oil in the prevention of endemic goiter and cretinism. In Endemic Goiter and Endemic Cretinism, J. B. Stanbury and B. S. Hetzel, eds., pp. 513–532. New York: John Wiley & Sons. Hetzel, B. S., J. T. Dunn, and J. B. Stanbury. 1987. The Prevention and Control of Iodine Deficiency Disorders. New York: Elsevier. Holman, J. C. M., and W. McCartney. 1960. Iodized salt. In Endemic Goiter, pp. 411–441. Geneva: WHO. Ingenbleek, Y. 1983. Vitamin A deficiency impairs the normal mannosylation, conformation and iodination of thyroglobulin: a new etiological approach to endemic goiter. Experientia 38(Suppl. 44):264. Kopp, P., E. T. Kimura, S. Aeschmann, et al. 1994. Polyclonal and monoclonal thyroid nodules coexist within human multinodular goiters. J. Clin. Endocrinol. Metab. 89:134.

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--> Mannar, V. G. 1996. The iodization of salt for the elimination of iodine deficiency disorders . In S.O.S. for a Billion, B. S. Hetzel and C. S. Pandav, eds., pp. 99–118. New York: Oxford University Press. Marine, D. 1923. Prevention and treatment of simple goiter. Atlantic Med. J. 26:437–443. Marine, D., and O. P. Kimball. 1921. The prevention of simple goiter in man. J. Am. Med. Assoc. 77:1068. Markel, H. 1987. ''When it rains it pours": endemic goiter, iodized salt, and David Murray Cowie, M.D. Am. J. Public Health 77:219–229. McMichael, A. J., J. D. Potter, and B. S. Hetzel. 1980. Iodine deficiency, thyroid function and reproductive failure. In Endemic Goiter and Endemic Cretinism, Iodine Nutrition in Health and Disease, J. B. Stanbury and B. S. Hetzel, eds., p. 445. New York: John Wiley & Sons. Missler U., R. Gutekunst, and W. G. Wood. 1994. Thyroglobulin is a more sensitive indicator of iodine deficiency than thyrotropin: development and evaluation of dry blood spot assays for thyrotropin and thyroglobulin in iodine-deficient geographical areas. Eur. J. Clin. Chem. Clin. Biochem. 32:137–143. Pandav, C. S. 1994. The economic benefits of the elimination of IDD. In S.O.S. for a Billion, B. S. Hetzel and C. S. Pandav, eds., pp. 128–145. New York: Oxford University Press. Pandav, C. S. and Mannar, M. G. V. 1996. IDD in livestock—ecology and economics. In S.O.S. for a Billion, B. S. Hetzel and C. S. Pandav, eds., p. 375. New York: Oxford University Press. Parma, L., J. Duprez, J. Van Sande, et al. 1994. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning adenomas. Nature 335:649. Pharoah, P. O. D., I. H. Buttfield, and B. S. Hetzel. 1971. Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet i: 308. Riccabona, G. 1972. Die Endemische Struma. Vienna: Urban & Schwarzenberg. Stanbury, J. B., ed. 1994. The Damaged Brain of Iodine Deficiency. New York: Cognizant Communications. Stewart, J. C., and G. I. Vidor. 1976. Iodine-induced thyrotoxicosis: a common unrecognized condition? Brit. Med. J. i:372. Sullivan, K.M., Houston, R., Gorstein, J. and Cervinskas, J., eds. 1994. Monitoring Universal Salt Iodization Programmes. WHO, UNICEF, PAMM, and ICIDD. Obtainable from WHO, Geneva or UNICEF, New York. Suwanik, R., R. Pleehachinda, C. Pattanachak, et al. 1989. Simple technology provides effective IDD control at the village level in Thailand. IDD Newsl. 5:1–6. Taylor, S. 1953. The evolution of nodular goiter. J. Clin. Endocrinol. 12:1232. Thilly, C., R. Lagasse, G. Roger, et al. 1980. Impaired fetal and postnatal development and high perinatal death-rate in a severe iodine deficient area. In Thyroid Research VIII, J. R. Stockigt and S. Nagataki, eds., p. 20. Canberra: Australian Academy of Sciences. Todd, C. H., T. Allain, Z. A. R. Gomo, J. A. Hasler, M. Ndiweni, and E. Oken. 1995. Increase in thyrotoxicosis associated with iodine supplementation in Zimbabwe. Lancet 346:1563–1564. UNICEF (United Nations Children's Fund). 1991. Training Course in Ultrasonography for Endemic Goiter. New York: Medizinische Universitat zu Lubeck. Also refer to

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--> Gutekunst, R., Becker, W., Hermann, W., et al. 1988. Ultraschaldiagnostik der Schildruse. Dtsch. med Wschr. 113:1109. UNICEF. 1994. Indicators for Assessing Iodine Deficiency Disorders and Their Control Through Salt Iodization. New York.

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