Institute it must be added externally during

Institute of Hygiene and Epidemiology
First Faculty of Medicine
Charles University, Prague
Head: Prof. Milan Tu?ek, MD, PhD.
Tutor: Vladimir Bencko

Iodine Essentiality and Deficiency Disorders

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Prague, date                 Name:Ahmed Atef Ramadan Mostafa Ali

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Iodine is a halogen with an atomic number of 53 and a molecular number of 131. Iodine is also a solid at room temperature. Iodine can only be obtained from ones diet as the body cannot produce it. Iodine is also scarce within food thus it must be added externally during processing and usually is added to salt in the form of iodized salt. Most of the iodine in the world is found within the ocean especially in seaweed.

As iodine is an essential trace element its risk assessment must include low intake leading to deficiencies, and high intake leading to toxicity. The U.S. Environmental Protection Agency (EPA) delved and dealt mainly with the toxicity end of the spectrum, thus developing Reference Doses (RfDs) for a large number of chemicals, including some essential trace elements. The World Health Organization (WHO) has also set similar values for toxicity, termed Acceptable Daily Intakes (ADIs) and Provisional Maximum Tolerable Daily Intakes (PMTDIs).

The U.S. Food and Nutrition Board of the Institute of Medicine has dealt with nutritional deficiency side mainly as well as toxicity by setting Dietary Reference Intakes (DRIs), which includes the Recommended Dietary Allowance (RDA), the Estimated Average Requirement (EAR), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL) for essential trace elements. In the United States, these levels were published in 2000 and 2001, and took the place of the RDAs and the Estimated Safe and Adequate Daily Dietary Intakes (ESADDIs) that were set by the Food and Nutrition Board of the National Academy of Sciences in 1989. The U.S. Food and Drug Administration (FDA) has also examined the issue of nutritionally essential levels in setting Reference Daily Intakes (RDIs) for a number of essential elements.

The toxicity risk assessment as per the U.S. Environmental Protection Agency, the EPA set the Reference Doses of essential trace elements; these values represent an estimate of the range of concentrations that are well tolerated by the human body continuously over its lifetime without leading deleterious effects. Note that these values may have an uncertainty spanning an order of magnitude, and should be representative of the whole human population including the sensitive sub-population. This range must be calculated in a way where all critical effects are avoided. The RfD is calculated as follows: EPA reviews many human and/or animal studies and determines the highest dose level tested at which a critical adverse effect does not occur (NOAEL), or the lowest dose level at which a critical adverse effect does occur (LOAEL). Alternatively, EPA may determine the benchmark dose, which is the dose, associated with a specified level of risk; it is determined by using a dose-response model. Uncertainty factors and an additional modifying factor may then be applied to the NOAEL, LOAEL, or benchmark dose, according to the procedures listed below in the table. The RfD is calculated in units of milligram per kilogram body weight per day (mg/kg-day) (U.S. EPA, 2002a). 

Uncertainty factors used by EPA, adapted from Abernathy and Roberts (1994)

The toxicity risk assessment as per the World Health Organization, takes one of 2 routes. Firstly, calculating the ADI (acceptable daily intake ) , the ADI is calculated by taking a similar approach to the EPA’s RFDs, a NOAEL or LOAEL is selected from a human or animal study and an uncertainty factor is applied to correct for any skews. Secondly, the WHO also sets a PMTDI for all contaminants and trace elements that do not have accumulative effects . This PMTDI permits for all the encounters with that element in drinking water or food. For trace elements a range is expressed with the smaller number expressing the essentiality and the latter number representing the PMTDI (Dourson and Lu, 1995).

The PMTDI for iodine is 1mg/day or the equivalent to 17 micrograms per kilogram per day from all sources, this data is based primarily on data on the effects of iodide. A recent study on rats has shown that the iodine in water has a different effect than iodide intake on the thyroid hormone concentration. As iodine is the sole element required for the synthesis of thyroid hormone the required daily intake for an adult is 80-150 micrograms per day and thus any lower intake will lead to deficiency diseases and in severe cases may lead to neurological symptoms.(WHO)(http://www.who.int/water_sanitation_health/water-quality/guidelines/chemicals/gdwq4-with-add1-chap12.pdf?ua=1)

As iodine is an integral part of the thyroid hormones and thus is essential for all animals species including humans. Deficiency can lead to a multitude of diseases, ranging from thyroid enlargement to sever cretinism and mental retardation. The Pan American Health Organization considered a study relating the excretion of iodine per gram of creatinine to thyroid function, they have found that an excretion of more than 0.05 mg of iodine per gram of creatinine is adequate for normal function of the thyroid gland, excretion of between 0.025-0.05 mg/g is associated with an increased risk of hypothyroidism, and excretion of less than 0.025mg/g is inductive of a serious risk of cretinism.(Querido et al., 1974)

According to the FDA the RDA for iodine is 0.15 mg/day and this value is in direct accordance with the WHO’s values as mentioned above. The FDA’s value is also based on an EAR of 0.095mg/day these values were calculated from a study carried out by them using radio-iodine accumulation within the thyroid gland. Their coefficient of variance was 40% meaning that there is a 40% variance within the population in accordance to the mean.

Toxicity from excess iodine mainly results in goiter, hypothyroidism or hyperthyroidism in humans. Acute iodine toxicity for animals was said to be around 200-500mg/kg/day which was lethal to those animals. While      levels greater than 10mg/kg/day lead to toxicity in some people, most cases were accidental poisonings due to the intake of drugs containing iodine. Even though these number stand there were 48 cases where people developed adverse effects including goiters with iodine levels equal to or below the cut off value of 10mg/kg/day.(IPCS, 1998). Another study reported that a constant daily intake of 18mg/day for a prolonged period of time were at risk of developing goiters.(Wolff,1969). Other studies have reported an association between increased iodine intake and the risk of developing thyroid papillary cancer in humans.(Franceschi, 1998; Lind et al., 1998). Even though the EPA have not set a RfD a UL has been set at 1.1mg/day based upon thyroid dysfunction being the critical cut off point. A LOEAL of 1.7 mg/day was selected based on 2 studies that reported an elevation in the thyroid stimulating hormone (TSH) concentrations in men taking iodine supplements. An uncertainty of 1.5 was applied to the LOAEL to derive the NOAEL of 1-1.2 mg/day. A further uncertainty factor was not applied to the NOAEL as there was very little uncertainty about the ranges of iodine intake that lead to the elevation of TSH.(Institute of Medicine Washington DC, 2001) The WHO’s PMTDI was set at 1mg/day as mentioned above, this value is said to be safe for the majority of the population but may cause some adverse effects to some people like people with thyroid disorders or those who are extremely sensitive to iodine. (International Programme on Chemical Safety,1988)

Endemic goiter has been always synonymous with iodine deficiency, and thus countries have been divided into 2 groups endemic and non-endemic according to the prevalence of goiter. With the ever-growing research in public health, it has become clear that iodine deficiency goes far beyond thyroid disease.(Zimmermann, M. B., Jooste, P. L. & Pandav, C. S. 
Iodine-deficiency disorders. Lancet 372 , 1251–1262 (2008). The term iodine deficiency disorders (IDDS) was coined in the year 1983 to emphasize that iodine deficiency can affect all human beings at any age with a varying spectrum of adverse effects including but not limited to mental and physical impairment, disturbed thyroid function and goiters. A study has shown that children between the age of 2 months and 15 years born in areas in with moderate to severe iodine deficiency have had a drop of 13.5 IQ points. (Qian, M. et al. The effects of iodine on intelligence in children: a meta-analysis of studies conducted in China. Asia Pac. J. Clin. Nutr. 14 , 32–42 (2005). At a population level, iodine deficiency has a negative impact on the country’s overall health and productivity thus hindering their socio-economic progression. 
The recognition of iodine deficiency as being a major public health issue has led to the acceleration of efforts to combat this deficiency. Despite the progress of IDD elimination programs more than 2 billion people worldwide suffer from insufficient iodine intake.(Rogers, L. Iodine deficiency in 2007: global progress since 2003. Food Nutr. Bull . 29, 195–202 (2008). (Andersson, M., de Benoist, B. & Rogers, L. Epidemiology of iodine deficiency: salt iodization and iodine status. Best Pract. Res. Clin. Endocrinol. Metab. 24 , 1–11 (2010). In developing countries there are 38 million newborns per year who are not protected from the devastating effects of IDDs.(UNICEF. Sustainable Elimination of Iodine Deficiency (UNICEF, New York, 2008). This problem is not limited to the developing countries only as the distribution is 52% in European countries to 47% East Mediterranean countries. (MALNUTRITION MUDr. Eva Kudlová, CSc.) 
Dietary iodine is readily absorbed from the gastrointestinal track then reach the bloodstream where it is transported as iodide. Iodide is then cleared by the kidney and the thyroid gland. Iodine has been also found in lactating mothers where it is excreted in the breast milk. The table on the right shows the recommended iodine intake for multiple age groups. In the thyroid gland iodine is converted back to iodine and is concentrated in the follicular cells. The thyroid thus contains 70-80% of the total body iodine in a healthy adult. In iodine-sufficient humans the thyroid only takes up 10% of the iodine from the blood while in an iodine deprived person more than 80% is absorbed from the bloodstream. As iodine is a constituent part of the thyroid hormones (T4 and T3). The iodine is incorporated into tyrosine residues of the thyroglobulin molecule and is stored in the colloid. During secretion the proteolysis of the thyroglobulin molecule leads to the release of T3 and T4 into circulation this whole process is initiated and controlled by TSH. When there is a high intake of iodine it is readily excreted in the urine nearly 90% with meniscal amounts being excreted in faces and sweat.
The thyroid gland adapts to low dietary iodine intake in multiple ways, which are mediated through the increased secretion of TSH by the pituitary gland. Firstly, TSH enhances iodine absorption from the blood leading to decreased iodine clearance and excretion through the urinary system. Secondly, TSH stimulates thyroglobulin break down thus increasing the peripheral T3 and T4 concentration TSH also stimulates the conversion of T4 to the more active T3. In chronic iodine deficiency despite these changes the total thyroid iodine is depleted which results in thyroid hyperplasia and thus the development of goiters as a natural consequence. Also there is a markedly elevated serum thyroglobulin in chronic iodine deficiency. 
The are three main indicators for assessing iodine deficiency. The total goiter rate has been used for a long time, it shows the association between iodine deficiency and the prevalence of goiters within a population. However this method seems to be outdated since the iodization of salt program has taken effect as it shows a significant delay and thus may cause a skew in the total goiter rate. The main method used to prove goiters is palpation and a thyroid ultrasound. Although outdated this method this still used to evaluate the changes in the prevalence of iodine deficiency in developing countries after the introduction of iodization programs in those countries.  
The median urinary iodine concentration remains to be the best method used to assess iodine intake as 90% of the absorbed iodine is eventually excreted through the kidney and into the urine.The WHO, UNICEF and ICCIDD have recommended the median UIC in schoolchildren as the main indicator for assessing and monitoring the iodine nutritional status of a population. This method can show the intake over a preceding period of time usually around a week.The  table above shows the epidemiological criteria for assessing iodine nutrition based on UIC and IDD status on the basis of the TGR.
Finally Neonatal TSH concentration which is inversely related to the serum free T4 concentration. As iodine deficiency decreases T4 levels TSH will therefore increase. Thus this proves as a vital indicator of the level of iodine deficiency, however this value my be skewed due to the use of iodine containing antiseptics during delivery which can discredit the the data and its interpretation. 
After the introduction of the salt iodization programs in many countries the level of iodized salt coverage is used as an important indicator for assessing the progress of these programs. 
The early 1990s were the turning point in the global efforts to combat iodine deficiency. During that time multiple committees met finally leading to the WHO recommending the elimination of IDD by modeling all salt for human consumption by 1994. This caused a shift in the focus from endemic areas to more and more countries. This implementation caused a drastic change in the percentage of people consuming iodized salt from 5% were classified as iodine deficient.The global prevalence of goiter was calculated  to be at 12% and 110 countries were classified as iodine deficient.(WHO, UNICEF & International Council for the Control of Iodine Deficiency Disorders. Global Prevalence of Iodine Deficiency Disorders (WHO, Geneva, 1993). 
 
(WHO.WHA58.24: Sustaining the Elimination of Iodine Deficiency Disorders (WHO, Geneva, 2005)), (UNICEF. The State of the World’s Children 2009 (UNICEF, New York, 2009) ),(Andersson, M., de Benoist, B., Delange, F. & Zupan, J. Prevention and control of iodine deficiency in pregnant and lactating women and in children less than 2 – years – old: conclusions and recommendations of the technical consultation. Public Health Nutr. 10 , 1606–1611 (2007))
Research was carried out in Tanna in Vanuatu which showed contradicting results as even though their intake was within the limit their UCI was low. This lead to the derivation of  goitrogenic agents, such as thiocyanate and its precursors, which are found in a number of foods (including cassava and sweet potatoes) which were their staple food in the ,but the consumption of foods containing goitrogenic substances did not seem to be associated with thyroid size. The most probable cause for their goiter was probably the lack of intake of iodine even though they reported a high fish intake.
(Li, M. et al. Iodine nutritional status of children on the island of Tanna, Republic of Vanuatu.Public Health Nutr. 12 , 1512–1518 (2009). )
Due to the increased requirement of iodine during pregnancy there has been a remarkable decrease in the urinary iodine concentration within pregnant females, to a point where only 17% of women met the WHO criteria (>150 micrograms/liter) in a country-wide assessment in Portugal, where 3600 women were tested. This seems to be a developed country issue as developed countries like Australia, New Zealand, and many European countries suffer from it .
(Kong.Limbert, E. et al. Iodine intake in Portuguese pregnant women: results of a countrywide study. Eur. J. Endocrinol. 163  631–635 (2010).)(Andersson, M. et al. The Swiss iodized salt program provides adequate iodine for school children and pregnant women, but weaning infants not receiving iodine-containing complementary foods as well as their mothers are iodine deficient. J. Clin. Endocrinol. Metab. 95 , 5217–5224 (2010). )(Kibirige, M. S., Hutchison, S., Owen, C. J. & Delves, H. T. Prevalence of maternal dietary iodine insufficiency in the north east of England: implications for the fetus. Arch. Dis. Child .Fetal Neonatal Ed. 89 , F436–F439 (2004).) (Lazarus, J. H. & Smyth, P. P. Iodine deficiency in the UK and Ireland. Lancet 372 , 888 (2008).) (Luton, D. et al. Iodine deficiency in northern Paris area: impact on fetal thyroid mensuration. PLoS ONE 6 , e14707 (2011)) (González Mateo, M. C. et al. Assessment of iodine nutritional status and thyroxine levels in pregnant women from different geographic areas of the Castile and Leon Spanish. Endocrinol. Nutr. 58 , 416–421 (2011).) 
In conclusion