|The Prevention and Control of Iodine Deficiency Disorders - Nutrition policy discussion paper No. 3 (UNSSCN, 1988, 130 p.)|
Mahshid Lotfi and John B. Mason1
1Mahshid Lotfi is a consultant to the ACC/SCN. John B. Mason is Secretary to the ACC/SCN.
Effects of iodine deficiency - goitre and cretinism - have been observed since ancient times. Dietary treatment has been known nearly as long, making iodine deficiency perhaps the earliest nutritional disease to be recognized (quoted from Gillie, 1978). Control programmes through fortification of salt with iodine compounds have been implemented, usually following legislation, in more than 50 countries since the 1940's (DeMaeyer et al, 1979); Switzerland was the earliest, in the 1920's, to legislate salt iodization. In most cases iodine deficiency has been largely controlled, although pockets remain. But at least 40 countries have significant iodine deficiency without effective control programmes. Up to 20% of the world's population live in iodine deficient areas, the majority of these in countries where iodine distribution has not yet been undertaken.
Enlargement of the thyroid gland (whose production of hormones requires iodine) is the best-known sign of iodine deficiency, called goitre. Unless massive, goitre is not itself particularly harmful. It is the deficiency of the thyroid hormones that has very serious consequences: the worst effect is cretinism - severe mental retardation. However, there is increasing evidence that mild iodine deficiency causes lesser degrees of mental retardation, also preventable by iodine, with extensive consequences for education, productivity, and well-being.
Effects of iodine deficiency begin before birth, and have various results throughout the life cycle. Dr. Hetzel begins by documenting the range of these effects in his Table 1 on page 35. They include still-births, increased infant and child mortality, developmental abnormalities, but above all effects on brain development. Whilst iodine deficiency is most commonly assessed by goitre, this is as much an indicator as the primary disorder. Thus the term "Iodine Deficiency Disorders (IDD)" introduced by Dr. Hetzel (Hetzel, 1983) has now become accepted.
The disorders affect not only the individual but entire communities. Iodine deficiency often occurs in clusters, frequently in remote areas, so that communities may have even a majority of members with goitre, a significant proportion of cretins, and most probably lowered intellectual development among others. Whole societies, usually the poorest and most inaccessible, suffer. But because of this clustering, the beneficial effects of iodine distribution on societies can be rapid (for examples, see Section 6 of Dr. Hetzel's paper).
Surveys of the global occurrence of IDD have been compiled by WHO over the years. In 1960, WHO (Kelly and Snedden, 1960) estimated that some 200 million people had goitre taking available national statistics as a guide; by 1979, although a number of control programmes had been implemented, the number was thought to be about the same because of population growth. Moreover, with improving availability of information and assessment techniques, additional affected populations are still being identified. For example, in 1971 WHO listed only 5 African countries as having information on iodine status (DeMaeyer et al, 1979, p.51); by 1987, data had been compiled from some 30 countries from this region (WHO/UNICEF/ICCIDD, 1987).
Causes of Iodine Deficiency Disorders
Dr. Hetzel's focus is on the prevention and control of iodine deficiency disorders (IDD) through iodine supplementation. To set the context, here we give a brief introduction to the causes of IDD, and to the biological mechanisms involved.
By far the commonest cause of iodine deficiency is a low content of iodine in the local environment. This interacts with poverty and remoteness, when there is little contribution of food from outside an iodine-deficient area to the diet, as is the case with much subsistence agriculture. Poverty, with poor sanitation and general malnutrition, may worsen the effects of iodine deficiency. Goitre can improve with socio-economic development. However, there is evidence from all over the world that iodine distribution programmes have a dramatic effect as single interventions, even without a rapid improvement of other aspects of poverty. The many examples of effective programmes, cited by Dr. Hetzel (Section 6) and in the ACC/SCN's global strategy to combat IDD (ACC/SCN, 1987), virtually all succeed because they deal directly with this single primary cause, by replacing missing iodine for the individual. The two main methods are by fortification, usually of salt; and by injection (every 3-5 years) of iodized oil as an emergency measure. Administration of iodized oil by mouth may become a more widely used method in the future.
The principle factor related to the occurrence of IDD, therefore, is inadequacy of iodine intake due to environmental deficiency of this essential element. This occurs where iodine is leached out and washed away from soil by glaciers and heavy rains in hilly and mountainous areas like the Andes, the Himalayas, the Alps and the Pyrenees. However, it is now clear that IDD are significantly prevalent also in plains, flooded riverine and even coastal areas - almost wherever they are looked for in the developing countries (Stanbury, 1985). Surveys outside the known goitre areas in states of India, in other countries of Southeast Asia (Bangladesh, Burma, Nepal), and elsewhere have shown the presence of IDD in most regions irrespective of their geographical conditions.
Inadequacy of iodine intake, although the major cause, is not the only factor responsible for all cases of IDD. For instance, the degree of iodine deficiency is not always related to severity of goitre in communities with low iodine intake (Delange et al, 1968; Thilly et al, 1972; Ermans et al, 1983). Some degrees of goitre persist in regions where iodine intake is apparently adequate (Gaitan et al, 1978;Ziporyn, 1985), and not all affected people benefit to the same extent from iodine supplementation (Ingenbleek and De Visscher, 1979).
The importance of many other factors in causing iodine deficiency has been revealed by nutritional and epidemiological surveys (Gaitan, 1980; Benmiloud et al, 1983). The role of cassava which contains linamarin, converted to thiocyanate in the body, has received a lot of attention. Such compounds are known as goitrogens. Contribution of cassava to the etiology of IDD in man is confirmed, especially in North Zaire (Delange and Ahluwalia, 1983, p.17). Although a number of other staple foods contain potential goitrogens (e.g. maize, lima beans, sweet potatoes), in contrast to cassava the goitrogens are in the inedible portions of the plants and do not contribute importantly to IDD. Moreover, effects of most (but not all) goitrogens can be countered by iodine supplementation. Other naturally occurring agents with goitrogenic and/or antithyroid effects listed by Gaitan et al (1978) include sulfur-bearing organic compounds, industrial pollutants, artificial and bacterial contaminants of water.
Other forms of malnutrition, notably protein-energy malnutrition (PEM) and vitamin A deficiency, may have secondary effects on iodine nutritional status. Surveys in Lebanon (Najjar and Woodruff, 1963), Brazil (Lobo et al, 1969), Ecuador (Fierro-Benitez et al, 1969) and other parts of the world have demonstrated that endemic goitre preferentially affects rural populations and low income groups living under poor sanitary conditions. A common observation is that with improvement of socioeconomic standards even without iodine supplementation, goitres may spontaneously regress (Ingenbleek and De Visscher, 1979). Many studies show that severe PEM affects thyroid function and the metabolism of thyroid hormones (e.g. Ingenbleek and Beckers, 1975; Becker, 1983). Iodine malabsorption may be associated with PEM and thus contribute to endemic goitre (Ingenbleek and Beckers, 1973), particularly where iodine intake is limited. PEM may also interfere with iodide uptake by the thyroid (Gaitan et al, 1983), and with thyroglobulin formation (Ingenbleek and De Visscher, 1979). On the other hand, very severe PEM in some areas with extremely low iodine intakes may impair the ability to develop goitre with a resultant mild prevalence rate for this condition (Delange, 1986 p.44); this point should be remembered in any IDD prevalence survey in developing countries.
Low blood retinol levels, an indicator of vitamin A status, are correlated with higher goitre incidence (Ingenbleek and De Visscher, 1979). As cited by Ingenbleek and De Visscher (1979), dietary shortage of vitamin A as a causative factor in the development of goitre in rats was first suggested by McCarrison (1930), and similar findings were subsequently reported in man (Borjas and Scrimshaw, 1954; Horvat and Maver, 1958). Studies in Senegal have shown that concomitant vitamin A deficiency increases the severity of iodine deficiency (Ingenbleek and De Visscher, 1979; Ingenbleek et al, 1986). (The mechanism suggested for this is that decreased retinol could reduce thyroid hormone synthesis by defective glycosylation of thyroglobulin and its subsequent inefficient iodation. This is in line with vitamin A's known function in controlling production of some specific glycoproteins in other tissues (Jackson and Fell, 1963; De Luca et al, 1970; Kim and Wolf, 1974)). Out of the 34 countries with vitamin A deficiency as a significant public health problem (ACC/SCN, 1985; Vest and Sommer 1987, p.7), a great majority are reported to also have considerable iodine deficiency, although this may affect different population within the country.
Thus iodine availability for the thyroid gland can be altered by dietary or other factors especially when iodine intake is marginal, dietary patterns are less varied, and when individuals are exposed heavily and continuously to their effects.
These considerations explain something of the etiology of IDD and their continuing discovery in diverse parts of the world. But, in contrast to protein-energy malnutrition for example, there is one primary or contributory cause common to all occurrences of IDD that can almost always be corrected: a low dietary intake of iodine. Thus, although there are interactive factors, iodine supplementation can cut through these and prevent the debilitating effects of IDD.
Iodine Metabolism and Consequences of Deficiency
About half of the iodine in the diet, absorbed from the intestine as inorganic iodide, is normally taken up by the thyroid gland (the rest is excreted in urine) and there incorporated into protein (thyroglobulin) to form precursors of two related types of hormone, triiodothyronine (T-3) and thyroxine (T-4). The hormones are released into the blood, often over quite long periods, in response to various stimuli controlled by thyroid stimulating hormone (TSH). The synthesis and availability of the thyroid hormones is reduced in iodine deficiency. Hence blood levels of T-3 and T-4, as well as TSH, are used for assessment of thyroid status; in iodine-deficient areas this may be interpreted as reflecting iodine status. This much of the physiology is well-understood. Effects of deficiency of thyroid hormones are also well-described, although the mechanisms of action of the hormones, and hence the pathological effects of deficiency, remain to be fully worked out. One result of deficient hormone synthesis, in this context due to iodine deficiency, is enlargement of the thyroid gland itself - as it were in an attempt to compensate - hence the presence of an enlarged thyroid, known as goitre, is the main clinical sign of iodine deficiency.
The thyroid hormones have extensive effects throughout the body. They influence metabolic rate, protein synthesis, enzyme function, cellular transport, and other physiological processes. They have specific effects on growth in children: low levels retard growth, causing stunting and poor development. The thyroid hormones have at least two effects on brain function. Throughout life, a normal range of thyroid hormones is needed for active intellectual function; hypothyroidism is associated with apathy. This effect is probably reversible at least in the adult, in that when normal thyroid function is restored mental processes return to normal. But low thyroid activity at crucial developmental stages (including vulnerability of the foetus to maternal hypothyroidism starting soon after conception) causes irreversible brain damage, at its extreme expressed as cretinism and deaf-mutism. Lesser degrees of brain damage manifest as deafness, mental retardation, and lowered intelligence quotient.
Goitre is defined as endemic when its prevalence rate exceeds 10% in a given region; iodine intakes in such areas are generally below 50 mcg/day (ACC/SCN, 1987) compared to the recommended intake of between 150 to 300 mcg/day (Matovinovic et al, 1974). When goitre prevalences are higher than 30%, 5-10% of the population can have severe and irreversible mental retardation associated with anomalies of physical development, known as endemic cretinism. However, even higher prevalences have been reported, for example in Bhutan, parts of Indonesia (Clugston and Bagchi, 1985, p.16; 49) and Bolivia (Pretell and Dunn, 1987). Two extreme types of cretinism have been described, although mixed types also exist, namely a more common neurologic type with impaired voluntary motor activity, spasticity, deafmutism and subnormal thyroid function; and a myxoedematous endemic cretinism with clinical signs of long standing hypothyroidism, dwarfism, myxoedema, sexual underdevelopment and severely deficient thyroid function. These are described by Dr. Hetzel in section 2.
Increased foetal and prenatal mortality is frequently found in iodine deficiency (McMichael et al, 1980), lessening with iodine supplementation (Gillie, 1978; Hetzel, 1986). Iodine deficiency is reported to increase child mortality rates in many countries, e.g. in Tasmania (Potter et al, 1979), in Zaire (Thilly et al, 1980) and Papua New Guinea (Pharoah et al, 1971). Its correction is reported to increase child survival (Stanbury, 1987). Surviving infants often show low birth weight and congenital abnormalities, as well as results of intra-uterine brain damage.
Deaf-mutism has been suggested as an indicator of the severity of IDD (Goslings et al, 1975). Nearly 80% of all deafness globally occurs in developing countries, with disabling hearing impairment involving perhaps between 40 to 70 million people in the world (Wilson, 1987). The major causes are infections, but IDD accounts for hearing impairment in at least 50,000 neonates annually (Wilson, 1985). This figure may be a considerable underestimate. First, it does not include cases where hearing impairment is not recognized. Secondly, most IDD manifestations are not, even now, ascribed to iodine deficiency (Clugston and Bagchi 1985, p.2; WHO, 1986); thus much deafness in iodine-deficient areas, even when diagnosed, may not be recognized as IDD-related.
As with vitamin A deficiency (Vest and Sommer, 1987, p.3), there are reports of an association between iodine deficiency and decreased Immunity which is reversed by administration of iodine. In iodine deficient hypothyroid subjects phagocyte dysfunction has been documented, reversed on administration of triiodothyronine and correction of the hypothyroid state (Chandra, 1981). Similarly, the necessity of iodine for normal delayed immune response in school children has been reported (Marani et al, 1985).
Not only the consequences of severe iodine deficiency but also the damage done by lesser degrees of iodine inadequacy are being increasingly recognized. All the residents of a community affected by endemic goitre are potentially exposed to suboptimal levels of thyroid hormones during their development. This may become evident only after an increase in physiological needs (DeMaeyer et al, 1979). Thus there may be serious but subtle effects on the quality of the society at large. Motivation, spontaneity, creativity and intelligence may be diminished (Gillie, 1978). As quoted by Berg (1987) and by Dr. Hetzel here the apathy described among adults in northern India has been ascribed by some investigators to chronic mild deficiency of iodine. Economical and social burdens are imposed on any community by the existence of mentally retarded cretins; but a profound implication of iodine deficiency is that large sections of the population in these areas could be intellectually impaired yet appear normal. Environmental iodine deficiency is probably causing much more brain damage than is evident as overt cretinism in the millions of people living in endemic areas (Kochupillai et al, 1985).
Endemic cretinism is not an all-or-none effect, rather iodine deficiency may lead to a spectrum of subclinical deficits which place the children born to mothers on an iodine deficient diet at a developmental disadvantage (Connolly et al, 1979), which undermines children's physical and mental growth, sapping their energy and slowing the progress of both individual and community (UNICEF, 1986).
The Extent of the Problem
Areas of iodine deficiency throughout the world are shown in Fig. 1. Many of these are mountainous, but other areas exist where iodine has been leached from the soil. Important patches of the deficiency are still being identified, particularly in Africa. Estimates of the numbers of people affected in developing countries, compiled by WHO, are shown in Table 1. The estimated population at risk of 800 million refers to those living in iodine-deficient areas amounting to nearly 30% of the population of 2.8 billion in the regions assessed. Nearly a quarter of this at-risk population has goitre, some 190 million; and over 3 million are estimated to show overt cretinism.
Although trends have not been assessed directly, reports since the 1960's have consistently indicated a figure of around 200 million people worldwide with goitre, showing the persistence of the problem.
The data on goitre may underestimate the full extent of iodine deficiency disorders. A number of the surveys are local rather than national, and may select the age groups examined. For example, many were carried out on school children. These exclude both those children too severely affected to attend school, and often also the poorest in the community. Nonetheless, they are of the same order of magnitude as other estimates of IDD. For example, some 43 million people in South East Asia were estimated recently to be suffering from different degrees of mental and physical impairment due to iodine deficiency (Clugston and Bagchi, 1986).
Source: ACC/SCN, 1987
More and more new areas are being identified with iodine deficiency in Africa, Latin America and Asia (Kavishe, 1985; Martin, 1986; Pandav et al, 1986; WHO/UNICEF/ICCIDD, 1987; Ekpechi, 1987 a,b). A number of factors may account for this continuing uncovering of the problem. First, surveys have hitherto tended to be local, concentrating on known areas of deficiency. Second, diagnostic methods are improving: systematic criteria for defining goitre (given by Dr. Hetzel in Section 7 below) are more widely used, and tests such as urinary iodine ft excretion are more common. Moreover, as the damaging effects of IDD become better realized, mis-diagnosis decreases; nonetheless Clugston and Bagchi (1986) consider that much IDD remains unrecorded. Third, and of particular concern, new cases of iodine deficiency may be occurring due to environmental changes, as has been suggested with drinking water supplies in Nigeria (Van Amelsvoort, 1969, 1971).
A characteristic of iodine deficiency is that prevalences of IDD can be very high in the endemic areas. These concentrations tend to be obscured by averaged data, such as those in Table 1 below. Goitre rates of 50% or higher are commonly reported in populations where iodine intakes are less than 20 mcg/caput/day, or where there are significant contributory factors, notably goitrogens in the diet. Endemic cretinism itself, although relatively rare, has an alarming prevalence of 13% to 35% in several parts of South East Asia (Clugston and Bagchi, 1985, p.l67). Screening for neonatal hypothyroidism, which if not treated can lead to severe cretinism, has shown an incidence of 15% in parts of the state of Uttar Pradesh in India, compared with only 0.04% in non-endemic areas (Clugston and Bagchi, 1985, p.17). Some surveys have reported prevalences of IDD of 60% in parts of Bolivia (Pretell and Dunn, 1987), and a national prevalence of endemic goitre of 11% in Bangladesh, occurring in almost all regions of the country (Clugston and Bagchi, 1985). Extensive pockets of IDD are still being identified in Africa (WHO/UNICEF/ICCIDD, 1987).
IODINE DEFICIENCY DISORDERS IN DEVELOPING COUNTRIES BY WHO REGION
Total Population (millions)
Number at Risk(millions)
Number with Goitre(millions)
Number with overt cretinism (millions)
South East Asia
Asia (other countries)
Source: ACC/SCN, 1987
While Table 1 refers only to developing countries, even in developed parts of the world recent reports show that goitre remains a significant problem in some countries. The prevalence appears not to have decreased in at least 12 European countries, where IDD continues to be a major problem, occasionally involving cretinism (European Thyroid Association, 1985; Gutekunst and Scriba, 1987).
More details from surveys in many other countries are available, for example in DeMaeyer et al (1979); Dunn et al (1986); ACC/SCN (1987) and Hetzel et al (1987).
Overcoming Iodine Deficiency Disorders
Undisputed evidence shows that IDD can be successfully and inexpensively prevented and controlled (ACC/SCN, 1987).
The major methods that have been used are:
- Fortification of salt with iodine compounds;
- Periodic injection of iodized oil.
These two methods are described in detail in this paper by Dr. Hetzel. They form the basis for the United Nations Ten-Year Programme for Prevention and Control of Iodine Deficiency Disorders (ACC/SCN, 1987), which draws scientific support from the International Council for Control of Iodine Deficiency Disorders (ICCIDD). Further technical details and results of experience are given in a number of publications from the UN agencies (e.g. WHO, DeMaeyer et al (1979); PAHO/WHO, Dunn et al (1986); ICCIDD, Hetzel et al (1987) and others.
Briefly, iodization of salt has the long-term advantage of high cost effectiveness, assuring regular intakes when salt supplies come from a centralized source. Disadvantages are related precisely to some of the problems of communities affected by the deficiency. Fortified salt must penetrate isolated communities, often accustomed to (and preferring) local supplies. Expansion and sustained maintenance of salt fortification requires organization and management; problems have recently been experienced in India, for example, in this aspect. But there is little doubt that initiating and steadily improving salt iodization and distribution programmes is feasible and constitutes a major way of preventing IDD in many needy areas.
Dr. Hetzel's paper gives the essential details of ongoing salt iodization programmes in the world.
Programmes to inject iodized oil are indicated under two main circumstances. First, where IDD is severe, there will be continuing irreversible damage to infants and growing children which demands preventive action faster than can be expected from iodized salt distribution. Second, isolated communities may simply not be rapidly accessible to iodized salt. While marketing systems, infrastructure and trade develop for such communities, there may be no alternative to direct individual intervention. Iodized oil injections have been convincingly demonstrated as effective on a large-scale - for example in Papua New Guinea. These programmes are reviewed by Dr. Hetzel. In his commentary, Dr. Viteri elaborates his views on the relative merits of injection versus salt fortification, emphasizing that urgency for rapid results should not obscure the long-term need for fortification.
The balance of intervention types must be decided on a case-by-case basis. But, again to set the context and round out the subject, we first introduce the other possible measures, some of which may be considered as complements to the major policy options of salt iodization and iodized oil injection.
Other possible approaches to IDD prophylaxis include:
1. Diversification and modification of the habitual diet consumed in the endemic areas, with e.g. imported foods from outside.
2. Iodine supplementation of foods and water for human consumption.
3. Iodine medications (notably oral administration of iodized oil) to directly supplement the inhabitants at risk of IDD in endemic areas.
4. Active prophylaxis of domestic animals; use of iodine materials for plants or iodine deficient soils.
Generally, overall socioeconomic development of the community can result in diversification of dietary pattern, with imports from non-endemic areas. An interesting example is in China, where large quantities of seaweeds have been distributed in highland areas (Michanek, 1981). Here public awareness of the ways in which the new variety of foods, like seaweeds, can be prepared and the benefits in their consumption are important for their intake. Some local foods may be available with relatively higher iodine contents, but iodine deficient populations may be unaware of their presence/value or not consume them for different reasons, e.g. relatively high cost of seaweeds in Malaysia (Ma and Lu, 1987). More often, perhaps, the process of development has, as a by-product, led to increased consumption of foods with adequate iodine.
Modifying food habits is another possible means of increasing iodine intake. Conserving iodine in the process of meal preparation; eliminating goitrogens, e.g. by adequate soaking in the case of cassava (Ekpechi, 1987 a); and knowing the benefits of iodine for health are all important if the dietary iodine consumption is to be improved without iodine supplementation. However, in severely deficient areas this approach alone would not be enough to control IDD.
Apart from salt, many food items such as condiments, sauces, oil, sweets, chocolates, cereal, flours (bread), baby foods and dry skimmed milk, etc. have been used for iodization. iodization of weaning foods has been proposed in endemic areas for controlling IDD in babies. With supplementary food aid programmes an appreciable segment of vulnerable populations can be iodine-supplemented (as in the case of vitamin A fortification of dried skimmed milk powder). This issue has been emphasized recently for Africa (ICCIDD, 1987 a). In countries with major food aid programmes, the possibility of iodine fortification of donated items has been recommended for serious consideration (ACC/SCN, 1987, p.11).
Water iodization has been tried successfully in Thailand, Sicily and Malaysia, and small low cost equipment is available for this purpose (ACC/SCN, 1987, p.11). Further research is under way for using water as a vehicle for iodine (Vigneri et al, 1982; Filetti et al, 1985). Such methods are only feasible for areas with a centralized water supply. In rural areas, a few drops of Lugol's iodine solution can be added to drinking water containers for providing iodine and sterilizing water at the same time. Continuous application of such methods is required (Bailey, 1987).
Iodine medications to supplement directly the inhabitants of endemic areas have been used in various forms other than intra-muscular (IM) iodized oil injection, like oral iodized oil, drops and tablets. Administration of oral iodized oil is an effective means of controlling IDD. It should be simpler, cheaper and safer than iodized oil injection, requiring less technical training, fewer instruments and less time (Dunn, 1986). While experience with this route of iodine supplementation is not extensive, it offers an attractive alternative to injection of iodized oil and is being used increasingly for iodine supplementation in many endemic areas (Li, 1987). The duration of IDD protection offered by oral iodized oil may be half that of injection judging from urinary iodine levels after oral and intra-muscular iodized oil administrations. Since effectiveness of oral iodized oil obviously depends on the fraction of orally administered iodine absorbed from the intestine and its storage is largely limited to the thyroid and adipose tissue (Dunn, 1986), when iodine is supplied orally, its absorption and utilization in subjects with PEM must be carefully monitored. (See page 4).
Iodine prophylaxis of domestic animals has been only briefly explored. Domestic animals are likely to be iodine deficient in endemic goitre areas, adversely affecting their growth, reproduction and productivity (ACC/SCN, 1987 p.5). According to Gillie, (1978). 'goitrous sheep produce less wool, horses do less work, hens with decreased thyroid activity produce eggs with insufficient calcium in the shells leading to egg breakage and higher chick mortality. Goitre in cattle causes sterility or sickly calves and poor milk production'. (In fact, such effects are also probable in humans: as early as 1947, Robinson (1947) reported improvement in lactation and increases in breast milk output in lactating women treated with iodine). In Finland, iodized feed for cows is used extensively because it had been shown to increase their milk production (Lamberg, 1986). As a result of active iodine prophylaxis in animals, in Finland, milk and dairy products contribute more to total iodine intake than iodized salt (although this is also partly due to a gradual decrease in salt consumption). Highly effective prophylactic programmes involving iodization of animal as veil as human foods in Finland, Norway and Sweden have made these three countries goitre free in spite of having the problem in the past (European Thyroid Association, 1985; Gutekunst and Scriba, 1987). Different means of soil enrichment, e.g. use of iodine rich sea algae practiced in USSR (ACC/SCN, 1987 p.13), iodine fertilizers and iodine recycling through excreta of iodine supplemented animals (Koutras, 1986) can increase iodine in both animal and plants. Developing seaweed mariculture and utilization of the product for areas with iodine deficiency could also be emphasized (Michanek, 1981).
Global Status of Salt and Oil Iodization Programmes
Dr. Hetzel's paper reviews country-by-country the position of IDD control programmes (section 6). Here are some highlights on a regional basis, by way of introduction. According to data available from WHO (DeMaeyer et al, 1979, p.51) out of 50 countries with salt iodization programmes worldwide only 22 countries - mainly in Europe, South and North America - have large scale salt iodization programmes. Elsewhere, programmes are operating at limited level or not at all. Salt iodization in many countries in Europe and the Americas has been a major factor in significantly controlling IDD. However, even in some European countries more effective programmes are required: for example, Italy, Spain and Portugal with the highest reported goitre prevalences in Europe have control programmes functioning at voluntary/limited basis (DeMaeyer et al, 1979, p.51; European Thyroid Association, 1985).
In Latin America most countries with known severe IDD have implemented IDD control measures. Unfortunately the effective programmes in Guatemala (Sigui, 1986) and El Salvador (Molina, 1986) have recently lapsed. In Guatemala 93% of salt produced was iodized by 1969 but in 1976 this decreased to only 15% and in El Salvador from 56% in 1977 to 17% in 1981, thus there are indications of an increase in previously reduced goitre rates (Pretell and Dunn, 1987). Maldistribution of available iodized salt in Peru resulted in distribution in endemic areas of only 30% of the 86% of salt iodized for human consumption by 1976 (Pretell, 1986). On the other hand, pilot programmes using iodized oil injections have been successfully performed in some Latin American countries like Ecuador and Bolivia (Pretell and Dunn, 1987).
Of at least 32 African countries with severe IDD only 7 have instituted any significant control measures with varying degrees of success. In some countries, use of iodized salt has not been successfully maintained (Ekpechi, 1987 a).
Some of the 8 South East Asian countries with known severe IDD have already implemented control measures while others have yet to start (Clugston and Bagchi, 1985). Some pilot programmes have begun but require wider implementation, e.g. in Burma, Thailand and Bangladesh (Venkatesh Mannar, 1987). Operational problems have resulted in ineffectiveness of such programmes in parts of India (Clugston and Bagchi, 1985, p.18); in certain areas goitre prevalence rates were reported as actually higher after ten years of salt iodization (Pandav et al, 1986). China, Papua New Guinea and Pakistan have implemented continuing control measures: salt iodization has remained at a pilot stage in Pakistan, in China much progress has been made (Venkatesh Mannar, 1987).
To summarize, about half of the countries in the world with severe/moderate IDD have taken measures, including pilot studies, to control these. Comparing goitre prevalences after prophylaxis with the level of iodine in salt, for 25 countries with such data. available, generally a higher prevalence was found to correspond with lower salt iodization levels (Lamberg, 1985). On the other hand, the level of iodine is often lower than intended due to faulty iodization or loss of iodine from salt during handling and storage.
What proportion of vulnerable population is covered in those countries with some IDD control measures? Such data are not available in systematic and comprehensive manner, but are needed to evaluate progress. In India, iodized salt produced covers only 16% of the total projected needs of the known goitrous regions (Pandav et al, 1986). In Uttar Pradesh - one of the most severely IDD affected states of India-only 9 of the 16 districts have goitre control programmes (Agarwal and Agarwal, 1983). In two severely affected areas of Pakistan, the coverage of iodized salt ranges from about 10% to 80% (Mahmud, 1986). However, in China with 330 million people at risk of IDD, iodized salt now covers 87% of the iodine deficient population (Ma and Lu, 1987) compared to less than 50% in 1982 (Ma et al, 1982). Even in Germany, with reported 40% goitre prevalence in school children in some parts, iodized salt used on voluntary basis covers less than one third of the population (Gutekunst and Scriba, 1987).
Iodized oil has successfully been given in Papua New Guinea, where in a mass campaign 100,000 inhabitants were injected (McCullagh, 1963). Indonesia, with probably the most developed IDD control programme in S. E. Asia, has been able to give 4.9 million injections of iodized oil during the period 1979-1984 (Clugston et al, 1987). In Nepal 28 remote northern districts are now covered with iodized oil injections, with more than 2 million people being injected (Acharya, 1987). Similarly on the average, 85% of the vulnerable population in one district in Zaire is reported to be covered by iodized oil injection (Ermans et al, 1983).
Policy decisions: Benefits, costs and approaches
In countries with iodine deficiency, it is clear that severe and widespread disadvantages occur, in terms of human welfare and the thriving of society. These can be prevented within existing technology, at modest cost whether measured in absolute terms against alternative programmes, or by economic benefit. In global terms, there is the promise of achieving a significant betterment of the human condition through applying these results of modern science, moreover aimed at the poorest of the poor. For both national policy-makers and international agencies, decisions remain to be made to fully commit the necessary resources, organizational as much as financial. A brief review of the costs, benefits, related to the available interventions, may help to facilitate this commitment.
The benefits of preventing iodine deficiency have been introduced here, and are given in detail in Dr. Hetzel's paper: simply, they would make cretinism a matter of history; depression of communities' abilities from mild IDD - intellectual and productive - a thing of the past; and help lift societies to a better realization of their potentials. Unfortunately, these individuals and societies are usually remote, and the benefits would only slowly be perceived in national capitals and donors headquarters; but far-sighted policies should aim to achieve just this.
The costs of preventing iodine deficiency are not extensive, and methods are well known. The cost of salt iodization from experience in S.E. Asia is 5 cents/person/year. Intra-muscular oil injection was estimated to cost 10 cents/person/year, from such programmes in Zaire and Nepal (ACC/SCN, 1987, p.40). Since iodized salt covers the entire population of affected areas, whereas injection programmes are more targetted, the difference in cost of these measures might be less (Levin, 1987). Oral compared to intra-muscular iodized oil will, in most instances, cost somewhat less, but there are no good data available on this yet. Cost of iodized water is less or similar to that of iodized salt. Costs should also be separated into (a) cost of supplies and equipment and (b) costs of delivery (ACC/SCN, 1987, p.37). In Peru (Hetzel et al, 1980, p.528) and Bolivia (ICCIDD, 1987 b), of total costs of iodized oil injections, the costs of oil, syringes and needles were 83% and 68% respectively, while in Central Africa (Hetzel et al. 1980, p.529) only 41% of the total cost was needed for these.
At present using the estimate of population at risk of IDD in developing countries, cited in Table 1 on page 9, and assuming that of 800 million at risk population, 95% (760 million) are to be covered by iodized salt and 5% (40 million) by intra-muscular iodized oil injection (ACC/SCN, 1987, p.40) the annual total cost of supplies would be around US$ 42 million to supplement all estimated at risk populations in developing countries. Within individual countries, cost can be estimated from figures such as those given here. They would always work out a fairly minor proportion of, for example, the health budget- and much less of the national government expenditure. Furthermore, donor assistance should become available.
Projected regional and global costs of support programmes in affected areas (ACC/SCN, 1987, p.43-52), is about US$ 2.2 million per year. Actual costs depend on the size and severity of IDD in different regions. Supplementation and support programmes together thus have an estimated annual cost of around US$ 44 million.
Costs of iodine supplementation may be further decreased. Simultaneous fortification with both iodine and iron, already tried at field level in India (Rao, 1987) seems promising. Iodized oil cost less with mass packaging and if cheaper oil bases are used (WHO, 1987). Iodized oil for oral use can be made at lower cost than for injection because of less stringent quality controls. Use of primary health care systems can reduce the cost of delivery. Combining iodine prophylaxis and delivery of vitamin A with immunization as suggested by WHO (1986, p.10) allows cost sharing. The feasibility of linking iodine supplementation with EPI has already been shown in Nepal and Papua New Guinea (ICCIDD, 1987 c).
With the lifetime disabilities caused by IDD, the economic benefits of their correction naturally outweighs the costs incurred. One study in Federal Republic of Germany, as Dr. Hetzel has stated, showed the annual costs of diagnosis and treatment of goitre in 1979 as US$ 200 million (Pfannenstiel, 1985)- over 4 times what is required for controlling IDD. Controlling mild IDD in Ecuadorean children, showed that benefits in terms of improvements in lifetime earnings exceeded costs of intervention considerably (Correa, 1980): the overall effect of a 20% reduction in cretinism was estimated to give a 4.7% increase in per capita income (Hershman et al, 1986). This translates into about a $50 million increase in national income for a country of 1 million population and $1000 annual per capita income, if cretinism prevalence can be decreased by 20% (e.g. from 5% to 4%). Screening and treatment of congenital hypothyroidism in USA showed benefits equal to 3 times costs (Barden and Kessel, 1985). Cost-benefits have been calculated for different levels of endimicity (Dulberg et al, 1986).
IDD control has been shown to present returns on investment better than any health interventions in some endemic areas. With high goitre prevalences in rural central Java, for example, controlling IDD was found to result in a larger improvement in the health status (measured as mortality and morbidity reductions) than did equal investments in EPI or the development of medical care. Even with low IDD endimicity (goitre prevalence of 10%-20%), IDD control is cost-effective unless the total health budget is extremely limited (Clugston et al, 1987). Results also depend on general health conditions. With moderate IDD and low infant mortality, either salt iodization or intra-muscular/oral iodized oil were cost-effective. In contrast, when infant mortality and infections are high, it has been estimated that salt iodization alone is most cost-effective for controlling moderate IDD and manpower can be more effectively used in immunizing against infectious disease than for iodized oil injection (Dulberg et al, 1986).
Addressing the benefits of raising the iodine content of livestock is somewhat easier since improvement in their production is largely reflected in products with market values, such as meat, wool, etc. (Hetzel and Maberly, 1986, pp.164-173). Iodine supplementation of farm animals also merits consideration to prevent human deficiency.
The first national policy decision is to address iodine deficiency: this may require assessment of the extent and severity of the problem and the potential benefits, related to costs, of preventing it. A related decision involves methods to be used, and organization to apply them. Guidance is given in Dr. Hetzel's paper and the discussions that follow it. And assistance is available from international agencies, and from the International Council for Control of Iodine Deficiency Disorders (ICCIDD).
The UN system has proposed a ten-year international programme of support to countries (ACC/SCN, 1987). Firm commitment and close cooperation of national governments, UN agencies, government sponsored bilaterals and NGO's for technical and financial support are essential for success. National governments and consumers have in some countries already accepted part of the costs incurred. UNICEF has borne the cost of supplies and equipments in some places and WHO with UNICEF cooperation has offered technical assistance in a number of countries.
Accelerating implementation is now required. Identifying countries and areas where IDDs are prevalent with no control measures available (especially in Africa), and publicizing of such information are urgently needed. National prevention and control programmes involving a number of government sectors in countries with IDD need to be established. In such programmes the problem and potential solutions, availability of resources, national capabilities and possibilities of external assistance, technical and financial, need to be assessed to achieve complete coverage in the shortest time and at the lowest cost. External assistance may be needed to enhance national capacity for developing proposals, programme planning for funding, organization, administration, monitoring and both technical and managerial aspects of the measure taken.
The values and problems associated with the two classical methods of iodine prophylaxis i.e. iodized salt and oil, have been discussed in this State-of-the-Art Review Paper by one of the leading scientists in the field, Dr. Basil Hetzel, who is best known for his extensive work on IDD prevention and control especially in Central Java, Papua New Guinea and some province of China. The importance of the processes necessary for large scale intervention programmes, using iodized salt or intra-muscular iodized oil injection for affected populations is stressed. Practical guidance based on the scientific background provided by Dr. Hetzel and others given in this paper should be valuable to many and especially to those involved in IDD control in developing countries, The contributions made by Drs. Delange, Stanbury and Viteri in the discussion part of this volume provide some of their experiences in this same topic and are useful views of experts.
IDD prevention and control is indeed as called by ICCIDD "a major opportunity for success in the field of international nutrition and health". Undoubtedly not only the economic benefits accompanying IDD correction, but the social dimensions and values of improved quality of life for millions of people in the world, are important reasons for eradication of iodine deficiency.
ACC/SCN (1985). Prevention and Control of Vitamin A Deficiency Xeroph-thalmia and Nutritional Blindness; Proposal for Ten Year Programme of Support to Countries. Report of the 11th Session of ACC-Sub Committee on Nutritionand its Advisory Group on Nutrition. Addendum. Nairobi, Kenya, 11-15 February, Doc. No. ACC/1985/PG/5/Add.1., 8 May,. ACC/SCN, c/o FAO, Rome.
ACC/SCN (1987). A Global Strategy for the Prevention and Control of IDD: Proposal for a Ten Year Programme of Support to Countries. Report of the 13th Session of the ACC Sub Committee on Nutrition and its Advisory Group on Nutrition. Washington D.C., 2-6 March, Doc. No. SCN 87/IODA. January 1987, ACC/SCN. c/o FAO, Rome.
Acharya, S. (1987). Monitoring and Evaluation of an IDD Control Programme in Nepal. See under Hetzel et al (1987). pp.213-216.
Agarwal, D. K. and Agarwal, K. N. (1983). Current Status of the National Goitre Control Programme. In: The National Goitre Control Programme. A Blueprint for its Intensification. Nutrition Foundation of India, Scientific Report 1.
Bailey, K.V. (1987). Other Methods of Control of IDD. WHO Regional Office, Brazzaville. See under WHO/UNICEF/ICCIDD (1987). CIDD/WP/06.
Barden, H.S. and R. Kessel (1985). The Costs and Benefits of Screening for Congenital Hypothyroidism in Wisconsin. Soc. Biol. 31, 185-200.
Becker, D.J. (1983). The Endocrine Responses to Protein Calorie Malnutrition. Annual Review of Nutrition. 3, 187-212.
Benmiloud, M., H. Bachtarzi and M.L. Chaouki (1983). Public Health and Nutritional Aspects of Endemic Goitre and Cretinism in Africa. See -under Delange and R. Ahluwalia (1983). pp.49-54
Berg, A. (1987). Iodine Deficiency: Beyond Goitre. Note for World Bank staff. Jan. 1986. Additional information on IDD. Report of the 13th Session of the ACC-Sub committee on Nutrition. Washington, D.C. 2-6 March. Doc. SCN 87/IODB.
Borjas, E.A. and N.S. Scrimshaw (1954). Endemic Goitre in Honduras. Am. J. Pub. Health. 44, 1411-1415.
Chandra, R.K. (1981). Trace Elements and Immunity: A Synopsis of Current Knowledge. Fd. Nut. Bull. 3(4), 39-41.
Clugston, G.A. and K. Bagchi (1985). IDD in South East Asia. World Health Organization, Regional Office for S.E. Asia. SEARO Regional Health Papers No. 10. New Delhi, India.
Clugston, G.A. and K. Bagchi (1986). Tackling Iodine Deficiency in S.E. Asia. World Health Forum. 7, 33-38.
Clugston, G.A., E.M. Dulberg, C.S. Pandav and L. Robert (1987). IDD in South East Asia. See under Hetzel et al (1987). pp.273-308.
Connolly, K.J., O.D. Pharoah and B.S. Hetzel (1979). Fetal Iodine Deficiency and Motor Performance During Childhood. Lancet ii, 1149-1151.
Correa, H. (1980). A Cost-Benefit Study of Iodine Supplementation Programme for the Prevention of Endemic Goitre and Cretinism. See under Stanbury and Hetzel (1980). pp.567-587.
Delange, F.H., C. Thilly and A.M. Ermans (1968). Iodine Deficiency, A Permissive Condition in the Development of Endemic Goitre. J. Clin. Endocrinol and Metab. 28, 114-116.
Delange, F.H. and R. Ahluwalia (1983). (Eds.) Proceedings of a Workshop on Cassava Toxicity and Thyroid; Research and Public Health Issue. 31 May-2 June, 1982, Ottawa, Canada. IDRC 207E. International Development Research Centre.
Delange, F.H. (1986). See under Dunn et al (1986). p.44
De Luca, L., M. Schumacher and G. Wolf (1970). Biosynthesis of a Fucose Containing Glycopeptide from Rat Small Intestine in Normal and Vitamin A Deficient Conditions. J. Biol. Chem. 245, 4551-4558.
De Maeyer, E.M., F.W. Lowenstein and C.H. Thilly (1979). The Control of Endemic Goitre. World Health Organization, Geneva, p.394.
Dulberg, E., R. Tilden, R. Grosse, S. Rijadi and P. Unadi (1986). The Cost-Effectiveness of the Control of IDD in Different Level of Endimicity. Department of Population Planning and International Health. University of Michigan, Ann Arbor.
Dunn, J.T. (1986). Oral Iodized Oil for the Control of IDD. ICCIDD Newsletter. 2(1),p.2.
Dunn, J.T., E.A. Pretell, C.H. Daza and F.E. Viteri (1986). (Eds) In: Towards the Eradication of Endemic Goitre, Cretinism and Iodine Deficiency. PAHO, Pan American Sanitary Bureau. Regional Office of WHO. Scientific Publication No. 502.
Ekpechi, O.L. (1987 a). Overview of IDD in Africa; Epidemiology and Consequence of IDD. See under WHO/UNICEF/ICCIDD. Doc. No. CIDD/WP/03.
Ekpechi, O.L. (1987 b). IDD in Africa. See under Hetzel et al (1987). pp.219-236.
Ermans, A.M., P. Bourdoux, J. Kinthaert, R. Lagasse, K. Luvivila, M. Mafuta, C.H. Thilly and F. Delange (1983). Role of Cassava in the Etiology of Endemic Goitre and Cretinism. See under Delange and Ahluvalia (1983). pp.49-54.
European Thyroid Association (1985). Control of IDD in Europe. Lancet. 1, 1289-1293.
Filetti, S., S. Squatrito and R. Vigneri (1985). Iodine Supplementation Methods Other Than by Iodized Salt. In: E.R. Hall and J. Kobberling (Eds). Thyroid Disorders Associated with Iodine Deficiency and Excess. Serono Symposia Publication 22. Raven Press, N.Y. pp.95-110.
Fierro-Benitez, R., I. Ramirez, E. Estrella et al (1969). In: J.B. Stanbury (Ed). Endemic Goitre. Washington, PAHO Publication No. 193. pp.306-321.
Gaitan, E.H., G. Merino, P. Rodriguez, J.D. Medina, T.A. Meyer, Derouen and R. MacLennan (1978). Epidemiology of Endemic Goitre in Western Colombia. Bull. World Health Org. 56, 403.
Gaitan, E. (1980). Goitrogens in the Etiology of Endemic Goitre. See under Stanbury and Hetzel 1980. pp.219-236.
Gaitan, J. E., L.G. Mayoral and E. Gaitan (1983). Defective Thyroidal Iodine Concentration in PCM. J. Clin. Endocrinol. Metab. 57, 327-333.
Gillie, B.R. (1978). Endemic Goitre. In: Human Nutrition. W.H. Freeman and Co., pp.213-220.
Goslings, B.M., R., Djokomoeljanto, R. Hoedijono, H. Soepardjo and A. Querido (1975). Studies on Hearing Loss in a Community with Endemic Cretinism in Central Java. Indonesia. Acta Endocrinol. 78, 705.
Gutekunst, R. and P.C. Scriba (1987). Iodine Deficiency Disorders in Europe. See under Hetzel et al (1987). pp.249-264.
Hershman, J. M., G. A. Melnik and R. Kastner (1986). Economic Consequences of Endemic Goitre. See under Dunn et al (1986). pp.96-106.
Hetzel, B.S., C.H. Thilly, R. Fierro-Benitez, E.A. Pretell, I.H. Buttfield and J.B. Stanbury (1980). See under Stanbury and Hetzel (1980). pp.513-532.
Hetzel, B.S. (1983). IDD and Their Eradication. Lancet ii, 1126-1129.
Hetzel, B.S (1986). Iodine Deficiency Disorders (IDD): A Maternal and Child Health Issue. In: D.B. Jelliffe and E.E.P. Jelliffe (Eds.) Advances in International Maternal and Child Health. Oxford, Clarendon Press, p.79.
Hetzel, B.S., G.F. Maberly (1986). Iodine. In: Trace Elements in Human and Animal Nutrition. 2 N.Y. Academic Press, pp.139-208.
Hetzel, B.S., J.T. Dunn and J.B. Stanbury (1987). Eds. The Prevention and Control of Iodine Deficiency Disorders. Elsevier Science Publishers, Biochemical Division, Amsterdam.
Horvat, A. and H. Maver (1958). The Role of Vitamin A in the Occurrence of Goitre on the Island of Krk, Yugoslavia. J. Nutr. 66, 189-20.
ICCIDD (1987 a). Fortification of Milk with Iodine. ICCIDD Newsletter. 3(1), p.3.
ICCIDD (1987 b). IDD in the Andes. ICCIDD Newsletter. 3(1), p.9.
ICCIDD (1987c). International Council for Control of IDD. A Report to ACC/SCN Meeting in Washington D.C. 2-6 March. Doc. SCN 87/10DD. 22 February 1987.
Ingenbleek, Y. and C. Beckers (1973). Evidence for Intestinal Malabsorption of Iodine in PCM. Am. J. Clin. Nutr. 26, 1323-1330.
Ingenbleek, Y. and C. Beckers (1975). Triiodothyronine and TSH Hormones in PCM in Infants. Lancet, ii, 845-847.
Ingenbleek, Y. and M. De Visschen (1979). Hormonal and Nutritional Status: Critical Conditions for Endemic Goitre Epidemiology? Metabolism, 28(1), 9-19.
Ingenbleek, Y., D. Barclay and H. Dirren (1986). Nutritional Significance of Alterations in Serum Amino Acid Patterns in Goitrous Patients. Am. J. Clin. Nutr. 43, 310-319.
Jacson, S.F. and H.B. Fell (1963). Epidermal Fine Structure in Embryonic Chicken Skin during Atypical Differentiation Induced by Vitamin A in Culture. Dev. Biol. 7, 394-419.
Kavishe, E.P., (1985). Endemic Goitre and Endemic Cretinism in Africa. In: T.G. Taylor and N.K. Jenkins (Eds.). Proceedings of the 13th Intern. Congr. of Nutr. 13-23 August, Brighton, UK. John Libbey, London, England. Chap.10, pp.487-491.
Kelly, F.C. and W.W. Snedden (1960). Prevalence and Geographic Distribution of Endemic Goitre. In: Endemic Goitre. World Health Organization Monograph Series No. 44. WHO Geneva, pp.29-234.
Kim, Y.C. and G. Wolf (1974). Vitamin A Deficiency and the Glycoproteins of Rat Corneal Epithelium. J. Nutr. 104, 710-718.
Kochupillai, N., M.M. Godbole, C.S. Pandav, M.G. Karmarkar, Manju Mehta and M.M.S. Ahuja (1985). Iodine Deficiency and Neonatal Hypothyroidism in India. In: T.G. Taylor and N.K. Jenkins (Eds). Proc. XIII Intern. Cong. of Nutr. 18-23 August, Brighton U.K. John Libbey, London, England, Chap. X. pp.485-487.
Koutras, D.A. (1986). Iodine: Distribution, Availability and Effects of Deficiency on the Thyroid. See under Dunn et al (1986). pp.15-27.
Lamberg, B.A. (1985). Effectiveness of Iodized Salt in Various Parts of the World. In: R. Hall and J. Kobberling (Eds.). Thyroid Disorders Associated with Iodine Deficiency and Excess. Raven Press, New York. pp.81-94.
Lamberg, B.A. (1986). Endemic Goitre in Finland and Changes During 30 Years of Iodine Prophylaxis. Endocrinologia Experimentalis. 20, 35-48.
Levin, H.M. (1987). Economic Dimensions of Iodine Deficiency. See under Hetzel et al (1987). pp.195-208.
Li, J. (1987). Progress of Studies on Oral Administration of Iodized Oil. ICCIDD Newsletter. 3(2), p.11.
Lobo, G.L.C., A. Quelce-Salvado and A. Freire-Maia (1969). Endemic Goitre. Washington, PAHO Publication No. 193. pp.194-207.
Ma, T., Z. Lu, T. Tan, B.Z. Chen and X.Y. Zhu (1982). The Present Status of Endemic Goitre and Endemic Cretinism in China. Fd. Nutr. Bull. 4(4), 13-19.
Ma, T. and Z. Lu (1987). Iodine Deficiency Disorders in the Western Pacific Region. See under Hetzel et al (1987). pp.309-315.
Mahmud, S.H. (1986). Current Status of Endemic Goitre in Pakistan. IDD Newsletter. 1 (1), 13.
Marani, L., S. Venturi and R. Nasala (1985). Role of Iodine in Delayed Immune Response. Israel J. Med. Sci. 21, 864.
Martin, E.A. (1986). Endemic Goitre in Cuba. See under Dunn et al (1986). pp.288-291.
Matovlnovic, J., M.A. Child, M.Z. Nichaman and F.L. Trowbridge (1974). Iodine and Endemic Goitre. In: J.T. Dunn and G.A. Medeiros-Neto. (Eds.). Endemic Goitre and Cretinism: Continuing Threat to World Health. Washington D.C. WHO, Pan American Health Organization, Scientific Publication No. 292, pp.69-94.
McCarrison, R.C. (1930). A Goitre Survey in Albino Rats. Br. Med. J. 1, 989-992.
McCullagh, S.F. (1963). The Huon Peninsula Endemic Goitre 1. The Effectiveness of an IM Depot of Iodized Oil in the Control of Endemic Goitre. Med. J. Aust. 1, 769-777.
McMichael, A.J., B.J. Potter and B.S. Hetzel (1980). Iodine Deficiency, Thyroid Function and Reproductive Failure. See under Stanbury and Hetzel (1980). p.445.
Michanek, G. (1981). Getting Seaweed to Where It's Needed. CERES FAO Review on Agriculture and Development. 14(1), 41-44.
Molina, T. (1986). The Problem of Endemic Goitre in El Salvador. See under Dunn et al (1986). pp.296-299.
Najjar, S.S. and C.W. Woodruff. (1963). Some Observations on Goitre in Lebanon. Am. J. Clin. Nutr. 13, 46-54.
Pandav, C.S., M.M. Godbole, N. Kochupillai and M.G. Karmarkar (1986). Endemic Goitre and Endemic Cretinism in India: Current Status of Extent, Severity and Control Measures. See under Dunn et al (1986). pp. 341-356.
Pfannenstiel, P. (1985). Direct and Indirect Costs Caused by Continuous Iodine Deficiency. In: R. Hall and J. Kobberling (Eds). Thyroid Disorders Associated with Iodine Deficiency and Excess. Serono Symposia, Raven Press. 22, 447-453.
Pharoah, P.O.D., I.H. Buttfield, B.S. Hetzel (1971). Neurological Damage to Foetus Resulting from Severe Iodine Deficiency During Pregnancy. Lancet i, 308.
Potter, B.J., A.J. McMichael and B.S. Hetzel (1979). iodization and Thyroid Status in Relation to Stillbirth and Congenital Anomalies. Int. J. Epidemiol. 8, 137.
Pretell, E.A. (1986). Status of Endemic Goitre and Cretinism in Peru. See under Dunn et al (1986). pp.311-313.
Pretell, E.A. and J.T. Dunn (1987). IDD in the Americas. See under Hetzel et al (1987). pp.237-247.
Rabinson, M.(1947). Hormones and Lactation: Dried Thyroid Gland. Lancet. 2, 385.
Rao, B.S.N. (1987). Double Fortification of Salt with Iron and Iodine to Control Anaemia and Goitre. Nutrition Nevs 8(1). HIN Hyderabad, India.
Stanbury, J.B. and B.S. Hetzel (1980). (Eds). Endemic Goitre and Endemic Cretinism. John Wiley and Sons, Inc. New York.
Stanbury, J.B. (1985). Iodine Deficiency Disorders: Clinical Presentation and Continuing Problems. Food and Nutrition Bulletin 7(2), 64-72.
Stanbury, J.B. (1987). The Iodine Deficiency Disorders: Introduction and General Aspects. See under Hetzel et al (1987). pp.35-47.
Sigui, A.A. (1986). Endemic Goitre in Guatemala. See under Dunn et al,(1986). pp.300-302.
Thilly, C.H., F. Delange and A. M. Ermans (1972). Further Investigations of Iodine Deficiency in the Etiology of Endemic Goitre. Am. J. Clin. Nutr. 25, 30-40.
Thilly, C.H., R. Lagasse, G. Roger, P. Bourdoux and A.M. Ermans (1980). Impaired Fetal and Postnatal Development and High Perinatal Death-Rate in a Severe Iodine Deficient Area. In: J.R. Stockigt and S. Nagataki (Eds). Thyroid Research VIII. Proceedings of the Eighth International Thyroid Congress. Canberra, Australia Academy of Science, 20.
UNICEF (1986). Iodine: Protecting the Mind. State of the World's Children. p.86.
Van Amelsvoort, V. (1969). The Recent Appearance of Endemic Goitre. Trop. Geog. Med. 21, 397-400.
Van Amelsvoort, V. (1971). Rural Water Supply Development and the Recent Appearance of Endemic Goitre. Trop. Geog. Med. 23, 304-305.
Vigneri, R., S. Squatrito, C. Polley, P. Polesa, A.M. Ermans and S.H. Ingbar. (1982). Iodine Prophylaxis in an Endemic Area of Sicily: A New Method for Iodine Supplementation. In: D. Reinvein and E. Klein (Eds). Diminished Thyroid Hormone Formation. (Schattauer Verlag, N.Y. 1982). p.187.
Venkatesh Mannar, M.G. (1987). Control of IDD by iodination of Salt:
Strategy for Developing Countries. See under Hetzel et al (1987). pp. 111-125. West, K.P. and A. Sommer (1987). Delivery of Oral Doses of Vitamin A to Prevent Vitamin A Deficiency and Nutritional Blindness. A State-of-the-Art Review. ACC/SCN State-of-the-Art series. Nutrition Policy Discussion Paper No. 2 ACC/SCN, c/o FAO, Rome.
Wilson, J. (1985). Deafness in Developing Countries. Arch Otolaryngol iii, 2-9.
Wilson, J. (1987). Prevention of Disability. Paper Prepared by Senior Consultant, UNDP/IMPACT Programme. Global Meeting of Experts to Review the Implementation of the World Programme of Action Concerning Disabled Persons at the Mid-Point of the UN Decade of Disabled Persons. 17-22 August, Stockholm. Doc. No. SDHA/DDP/GME/CRP. 11.
WHO (1986). Integration of Immunization Activities in the Control of IDD and Vitamin A Deficiency. EPI Global Advisory Group Meeting. WHO, New Delhi 13-17 Oct. Nutrition Unit. Division of Family Health. WHO, Geneva, Switzerland. Doc EPI/GAG/86/WP11.
WHO (1987). Regional Strategy and Plan of Action for the control of IDD in the African region. Brazzaville. AFR/NUT/96. See under WHO/UNICEF-/ICCIDD (1987).
WHO/UNICEF/ICCIDD (1987). Regional Seminar on Control of Iodine Deficiency Disorders in Africa. Working Papers for the WHO/UNICEF/ICCIDD. 23-25 March 1987, Yaounde, Cameroon.
Ziporyn, T. (1985). For Many Endemic Goitre Remains a Baffling Problem. J.A.M.A., 253(13), 1846-1847.