This post is being reposted since I invited arn to post it here in a private message. It was removed by someone who has been here recently posting personal attacks and follows the iodine and "liver flush" cults. This person should not even have moderator privileges on this forum to begin with.
IODINE EXPLANATION Iodine has not previously been considered by the Joint FAO/WHO Expert Committee on Food Additives. Because of the availability of information on iodine in man and the limited amount of animal data, this monograph summarizes the human data for the purpose of establishing a maximum tolerated daily intake. INTRODUCTION Iodine is an essential dietary element which is required for synthesis of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). T4 and T3, which are iodinated molecules of the essential amino acid tyrosine, regulate cellular oxidation and hence effect calorigenesis, thermoregulation, and intermediary metabolism. These hormones are necessary for protein synthesis, and they promote nitrogen retention, glycogenolysis, intestinal absorption of glucose and galactose, lipolysis, and uptake of glucose by adipocytes. Iodine occurs in foods mainly as inorganic iodide, which is readily and completely absorbed from the gastrointestinal tract. Other forms of iodine in foods are reduced to iodide before absorption. Absorbed iodide is distributed throughout the body via the circulatory system. A portion (approximately 30%) is removed by the thyroid for hormonal synthesis. Iodine intake in excess of requirement is excreted primarily through the urine. Synthesis and secretion of T4 and T3 are under control of the thyroid-stimulating hormone (TSH) from the anterior lobe of the pituitary gland. TSH stimulates iodide transport from the blood into thyroid cells, oxidation of iodide to iodine, and iodine binding to tyrosine. Synthesis of thyroid hormones is regulated by the levels of circulating free T4 and T3 as a negative feedback mechanism. To ensure an adequate supply of thyroid hormones, the thyroid must trap about 0.060 mg of iodine per day (Underwood, 1977). The daily iodine requirement for prevention of goiter in adults is 0.050-0.075 mg, or approximately 0.001 mg/kg bw (Food and Nutrition Board, 1970). To provide a margin of safety, an allowance of 0.150 mg is recommended for adolescents and adults in the USA (National Academy of Sciences, 1990). The recommended allowances are 0.040- 0.050 mg/day for infants and 0.0700.120 mg/day for children 1-10 years old (National Academy of Sciences, 1980). Additional allowances of 0.025 and 0.050 mg/day are recommended for pregnant and lactating women, respectively (NAS, 1980). Similar recommendations for iodine intake have been made by WHO (Passmore et al., 1974), by the Department of Health and Social Security in the United Kingdom (1969), by Health and Welfare Canada (1976), and proposed in Australia (English, 1982). With a few exceptions, reported average daily intakes of iodine in the USA, Australia, New Zealand, Japan, and in European countries generally meet or exceed these recommendations. DIETARY EXPOSURE The chemistry of iodine is relatively complex since it can exist in a number of valence states, it is chemically reactive and forms various inorganic and organic compounds (Kirk-Othmer Encyclopedia of Chemical Technology, 1981; Whitehead, 1984). In the atmosphere, iodine is derived largely from seawater. Iodine concentrations have been reported to range from 3 ng/m3 to 50 ng/m3 with an average global concentration estimated to be about 10-20 ng/m3. Based on this latter estimate, the daily iodine intake from air would be less than 0.4 µg/person and air is therefore not considered a significant source of iodine (Whitehead, 1984). Concentrations of iodine in unpolluted surface waters in various parts of the world have been found to be generally less than 3 µg/l. Drinking water has been shown to contain iodine levels of less than 15 µg/l, except in a few instances where much higher levels were reported. Assuming daily consumption of 1.5 to 2.0 l water, iodine intake from this source would usually be less than 30 µg/day (Whitehead, 1984; Underwood, 1977). Iodine and its compounds are used in a variety of food-related applications including nutrient fortification (i.e. iodized salt), food additives (e.g., dough conditioning and maturing agents), agricultural chemicals (e.g. herbicides and fungicides), animal drugs (e.g. iodine supplements), and sanitizers (e.g. iodophors). In addition, certain foods, such as marine fish and marine algae, are naturally relatively rich in iodine. The iodine content of foods is generally reflective of background levels as well as processing technology and manufacturing practices. For example, the high iodine content of milk and dairy products has been attributed to the use of iodine-containing supplements in feed for dairy cattle, iodophor-based medications, teat dips and udder washes as well as iodophors used as sanitizing agents in dairy processing establishments. The elevated iodine levels found in grain and cereal products are related to endogenous iodine in ingredients but, in addition, likely reflects the use of iodine-containing food additives, such as iodate dough conditioners. Dietary iodine intakes have been estimated in various countries and indeed are highly correlated with the types (and amounts) of foods consumed. Nevertheless, average iodine intakes of the order of 1 mg/person were not uncommon and in a few instances intakes of several mg/person were reported when seaweed was consumed as part of the diet (Fischer & Giroux, 1987a; Fischer & Giroux, 1987b; Varo et al., 1982; Park et al., 1981; Pennington et al., 1986; Katamine et al., 1986 and Tajiri et al., 1986). In addition to dietary sources, various mineral supplements and medical preparations can further increase iodine intake to a significant extent (Skare & Frey, 1980; Philippe et al., 1986; Dela Cruz et al., 1987). In summary, food is the major route of human exposure to iodine for the general population and estimated dietary intakes are well in excess of the amount recommended for adequate nutrition. Mineral supplements or other iodine-containing drugs can also represent a substantial source of iodine intake for consumers of such products. BIOLOGICAL DATA Observations in man Iodine Deficiency Dietary iodine deficiency stimulates TSH secretion which results in thyroid hypertrophy. The enlargement of the thyroid gland due to iodine deficiency is called endemic goiter. Iodine intakes consistently lower than 0.050 mg/day usually result in goiter. Women and adolescent girls seem especially at risk. Most goitrous individuals are clinically euthyroid. Endemic goiter is currently more common in developing countries and typically occurs in mountainous areas such as the Andes, Himalayas, and the mountain chain extending through Southeast Asia and Oceania (Matovinovic, 1983). Large goiters may cause obstructive complications of the trachea, esophagus, and blood vessels of the neck. Goiters are also associated with an increased risk of other thyroid diseases and malignant growth (Matovinovic, 1983). The development of endemic goiter due to iodine deficiency may be exacerbated by the ingestion of substances which impair iodine uptake by the thyroid or impair incorporation of iodine into thyroxine. These substances are called goitrogens and include thiouracil, other related drugs, and thioglucosides. Thioglucosides are found in vegetables of the genus Brassica and family Crucifera (such as cabbage, cauliflower, broccoli, brussels sprouts, kale, kohlrabi, turnips, and rutabaga) as well as in nuts, cassava, maize, bamboo shoots, sweet potatoes, and lima beans. An adequate dietary iodine intake can usually overcome the goitrogenic effects of thiocyanates derived from foods, but dietary iodine cannot prevent goiter caused by thiouracil and related drugs. With severe and prolonged iodine deficiency, the effects of a deficient supply of thyroid hormones may occur. This condition, which is referred to as hypothyroidism or myxedema, is characterized by reduced metabolic rate, cold intolerance, weight gain, puffy facial features, edema, a hoarse voice, and mental sluggishness (Thompson et al., 1930). Iodine deficiency during pregnancy, infancy, or early childhood may cause endemic cretinism. The symptoms of cretinism are mental and physical retardation, deaf-mutism, and various neurological abnormalities. Hypothyroidism due to iodine deficiency may be cured with iodine administration, but the effects of cretinism are not reversible. Iodine supplementation programs have been developed in many countries to prevent endemic goiter and the further consequences of iodine deficiency. Iodine has been added to salt in the USA, Argentina, Czechoslovakia, France, England, Italy, New Zealand, Switzerland, Yugoslavia, Mexico, and Canada. Iodine has been added to bread in Tasmania and Holland. In poorly developed countries with limited access to medical care, intramuscular injection of iodine has been used as prophylaxis. These injections release iodine slowly over one to three years. Iodine Excess Sources of excess iodine causing adverse effects Adverse effects of iodine in humans have resulted from iodine that was ingested, injected, or applied topically to the skin or mucous membranes. Food sources of iodine that have caused adverse effects include naturally-occurring iodine in water supplies, seaweed, and ground beef containing thyroid tissue. Other food sources of iodine causing adverse effects include those foods to which iodine was added as part of a supplementation program (e.g., iodized water, bread, or salt) and milk which contained iodine resulting from feed supplements and iodophor disinfectants. Adverse effects of iodine have also been reported from dietary and nutritional supplements. The major sources of iodine that have caused adverse effects are iodine-containing pharmaceuticals. Information on the iodine content of various drugs, antiseptics, and contrast media are available from Globel et al. (1985), Guillausseau (1986), Rajatanavin et al. (1984), and Vought et al. (1972). Numerous case reports have been published that have identified the iodine in these products as the causative agent of the adverse effects. Iodine-containing drugs (most commonly potassium iodide solutions) have been prescribed for respiratory problems such as asthma, bronchitis, cystic fibrosis, and chronic obstructive pulmonary disease. These iodine-containing drugs are usually prescribed for their expectorant action. Potassium iodide and other iodine solutions have also been prescribed in the treatment of goiter and hyperthyroidism. The iodine-containing drug amiodarone, which is available in some countries, is prescribed for arrhythmias. Iodine- containing solutions are well-known antiseptics and are used in topical medications, vaginal solutions, and mouthwashes. In some cases wounds or burns are packed with dressings soaked in povidone- iodine (Betadine) (Bayliff et al., 1981; Fisher, 1977; Prager & Gardner, 1979; Scoggin et al., 1977). The iodine in these solutions is absorbed from dermal and mucosal surfaces. Iodinated contrast media (which may be ingested or injected into the body) are commonly used as diagnostic tools to determine structure and function of various body tissues. Cooper & Hokin (1954) reported finding a mineral dietary supplement in a New Zealand health food store containing 191.1 mg of iodine per dose according to the label (167.4 mg per dose by actual analysis). Several investigators have reported adverse effects from the iodine in seaweed powder and tablets, a blood mixture, and dietary supplements (Block & DeFrancesco, 1979; Skare & Frey, 1980; Shilo & Hirsh, 1986; Liewendahl & Gordin, 1974; Dimitriadou & Fraser, 1961; Bianco et al., 1971; LaFranchi et al., 1977). Excessive intake of iodine during pregnancy may have adverse effects on the fetus without affecting the mother's health. Also, excessive iodine intake by a lactating mother will increase the iodine content of breast milk and may affect the infant's health. The major sources of excess iodine during pregnancy in these cases were iodine solutions which have been prescribed for asthma, other respiratory problems, hyperthyroidism, and hypothyroidism. Responses to excess iodine There appears to be three types of responses to excess iodine. The first type is disturbance of thyroid activity which may alter the size of the thyroid gland and/or affect the production of thyroid hormones. There is also evidence to indicate that iodine (or the lack of it) may alter the pattern of thyroid malignancy. The second type of response is a sensitivity reaction, and the third type of response results from acute intakes of large quantities of iodine (iodine poisoning). The adverse effects are not uniquely related to the source of the iodine. 1. Disturbance of thyroid activity. The effect of excess iodine on the thyroid may result in goiter, hypothyroidism with or without goiter, or hyperthyroidism (thyrotoxicosis). How the thyroid reacts to excess iodine may be dependent on previous and current iodine status and on previous and current thyroid dysfunction. For example, older adults who have lived many years in an endemic (iodine deficient) area are more likely to have a thyroid response to iodization of the food supply than those who have lived in an iodine sufficient area, Those with underlying thyroid disease also respond more violently to increased iodine intake, and it also appears that females are more apt to respond to excess iodine than males. a. Iodine-induced goiter/hypothyroidism. Numerous reports of goiter and/or hypothyroidism resulting from excessive iodine are found in the open literature. In addition, Trowbridge et al. (1975a, 1975b) noted an association between goiter prevalence and high urinary excretion of iodine in the 1968-1970 Ten State Survey and in a 1971-72 survey of children from four areas in the USA. Goiter exams and measurements of urinary iodine excretion were performed on 16,799 persons in the Ten State Survey and on 754 children in the 1971-72 survey. Large dietary or therapeutic intakes of iodine may inhibit organic iodine formation (prevent the binding of iodine to tyrosine in the thyroid). The resulting decrease in circulating thyroid hormones causes an increase in TSH. The effect may be transient, and the subjects may escape from this inhibition after several days. Susceptible individuals who do not escape develop goiter (the Wolff-Chaikoff effect) and may become hypothyroid. This inhibitory effect of iodine on thyroid formation accounts for the beneficial use of iodine in the treatment of hyperthyroidism (Utiger, 1972). Excessive iodine intake by a pregnant woman is especially risky since the fetal thyroid is less able to escape the inhibitory effects of iodine on thyroid formation. Iodine-indiced goiters and/or hypothyroidism have occurred in newborn infants of mothers who have taken iodine during pregnancy. The infant goiters may regress spontaneously after several months, but deaths due to a compression of the trachea have occurred. b. Iodine-induced hyperthyroidism (thyrotoxicosis). Excessive intake of iodine may cause overstimulation of the thyroid gland which produces excess hormone and results in hyperthyroidism. This condition is referred to as jodbasedow. This may result from food, supplement, or drug sources of iodine. The incidence of thyrotoxicosis has been noted to increase among residents of an endemic goiter area (or area of moderate iodine deficiency) when they are exposed to an increased intake of iodine through supplementation programs or milk contamination. These reports are of particular interest because the thyrotoxicosis usually occurs at levels of iodine intake which are within the normal range. An increased incidence of thyrotoxicosis in the midwest USA was noted between 1926-28 following the iodization of table salt (Kimball, 1925; Jackson, 1925; Hartsock, 1926; Kohn, 1976). The marked rise in the number of patients with thyrotoxicosis in Tasmania was documented following the iodization of bread in 1966 (Stewart et al., 1971; Stewart, 1975; Connolly et al., 1970; Vidor et al., 1973). This epidemic reached a peak in 1967-69. It appears that milk high in iodine was also partially responsible for the increased incidence of thyrotoxicosis in Tasmania (Lewis, 1982; Barker & Phillips, 1984; Stewart & Vidor, 1976). Van Leewen (1954) reported an increased incidence of thyrotoxicosis in Holland resulting from a 4-year program of bread iodization. Barker & Phillips (1984) reported that the incidence of thyrotoxicosis in 12 towns in England and Wales, which resulted from high iodine milk, was strongly correlated with the previous prevalence of endemic goiter in the towns. Phillips et al. (1983) indicated that the distribution of mortality from thyrotoxicosis among women in England and Wales during 1968-78 correlated with the prevalence of endemic goiter. Nelson and Phillips (1985) speculated that the spring-summer peak in thyrotoxicosis incidence in England may be casually related to the high milk iodine levels in winter (from winter feed supplements). Common to these reports of increased thyrotoxicosis from increased dietary iodine are the previous iodine deficiency or moderate iodine deficiency of the area, the older age (over 30, 40, or 50 years) of the people who succumb, and the presence of nodular goiter or autonomous thyroid tissue in the subjects. Thyroid tissue may develop or increase its autonomous tissue during iodine deficiency (Kobberling et al., 1985), and autonomous thyroid function is common in euthyroid goitrous subjects (Miller & Block, 1970). In endemic areas, autonomous tissue is the most common precondition of uncontrolled hormone production, the extent of which is determined by the level and duration of iodine administration and by the mass of autonomous tissue (Joseph et al., 1980). The autonomous thyroid tissue (which is not regulated by TSH) produces thyroid hormones in direct response to dietary iodine. Thus excess iodine may precipitate or aggravate thyrotoxicosis in people with autonomous thyroid tissue. Persons with undiagnosed Graves' Disease who live in endemic areas may become hyperthyroid when more iodine becomes available through supplementations or milk supplies. Stewart (1975) noted that the small but real increase in the incidence of thyrotoxicosis in persons under 40 years of age in Tasmania after bread iodization was usually due to Graves' Disease. c. Thyroid malignancy. There appears to be an association between iodine availability and the incidence and type of thyroid cancer. Pendergast et al. (1960) reviewed the early literature and found both clinical (human) studies and experimental animal studies suggesting that goiter predisposes to cancer of the thyroid. Changes in the thyroid cells progress from hyperplasia to nodular hyperplasia to benign tumor to cancers. After reviewing 844 cases of thyroidectomy, Fierro-Benitez (1973) reported that the incidence of thyroid cancer was high (9.7%) in the goitrous Andean area of Ecuador as it was in other endemic areas. Wahner et al. (1966) reviewed 1,335 autopsy records from the goitrous area of Cali, Colombia and found a significant increase in the frequency of death rate from thyroid carcinoma compared to nongoitrous areas. They indicated that the proportion of follicular carcinoma was significantly higher in this goitrous area compared to nongoitrous areas. Williams et al. (1977) found that the incidence of papillary and follicular thyroid cancer were separately influenced by dietary iodine with papillary cancer five times higher and follicular cancer less frequent in Iceland (an area of high iodine) than in Northeast Scotland (an area of low iodine). Harach et al. (1985) reported that the period after iodization in Salta, Argentina was associated with a lower frequency of thyroid follicular carcinoma and a higher frequency of papillary carcinoma. In interviews with 183 women with thyroid cancer and 394 control women, McTeirnan et al. (1984) found that women who had ever developed a goiter had 17 times the risk of developing follicular cancer and almost seven times the risk of developing papillary cancer compared to women who had never had a goiter. The risk of thyroid cancer was not related to hyper- or hypothyroidism. Thus it appears that iodine deficiency may increase the incidence of thyroid malignancy and alter the type of cancer produced. It has been postulated that the cancer associated with endemic goiter may result from prolonged exposure of the thyroid to increased TSH activity (British Medical Journal, 1977). From experimental studies with rats, Ohshima & Ward (1986) and Ward & Ohshima (1986) have reported that iodine-deficient diets and goitrogens are potent promoters of thyroid tumors and that TSH plays a major role in thyroid carcinogenesis. They concluded that iodine indirectly prevents thyroid cancer development by inhibiting TSH hypersecretion and goiter development. In addition, Stadel (1976) has reported that geographic differences in the rates of breast, endometrial, and ovarian cancer appear to be inversely correlated with dietary iodine. A low dietary iodine may produce a state of increased effective gonadotrophin stimulation, which in turn may produce a hyperestrogenic state characterized by relatively high production of estrogen and estradiol. This altered endocrine state may increase the risk of breast, endometrial, and ovarian cancer. Thus provision of adequate dietary iodine may decrease the risk of these cancers. 2. Acute iodine intakes. The acute toxicity of iodine to animals in the form of sodium and potassium iodide and iodate has been reviewed by the Select Committee on GRAS Substances (1975). Depending on the species, amounts between 200 and 500 mg/kg bw/day produced death in experimental animals. The consumption of large single doses of iodine-containing solutions by humans may have extreme side effects and may result in death. A 56-year-old female who attempted suicide with an unknown quantity of Lugol's solution showed gastrointestinal irritation and ulceration, chemical pneumonitis, hyperthyroidism, hemolytic anemia, acute renal failure (due to tubular necrosis), and metabolic acidosis (Dyck et al., 1979). A fatal case of iodine poisoning in a 57-year-old male showed symptoms of weak pulse, urinary retention, delirium, stupor, and collapse (Clark, 1981). The amount of iodine consumed was not determined. Finkelstein & Jacobi (1937) reported a case of a 29- year-old male who ingested an unknown amount of tincture of iodine and experienced vomiting, abdominal cramps, anuria, fever, irrational behavior, coma, and cyanosis. He died on the sixth day after ingesting the iodine. Finkelstein & Jacobi (1937) reviewed six year records of the Medical Examiner's Office of New York City and found 18 instances of suicide by iodine. Death usually occurred within 48 hours after taking the solution. The amount taken was recorded in only nine cases and ranged from one to eight ounces of tincture (approximately 1,184 to 9,472 mg of iodine). Tresch et al. (1974) reported the case of a 54-year-old man who mistakenly ingested a potassium iodide solution which contained 15,000 mg of iodine. He survived the poisoning, but experienced ventricular irritability, swelling of face, neck, and mouth, periorbital edema, serous conjunctivitis, edematous nasal mucosa, and enlarged and tender salivary glands. The quantities of iodine given in iodinated contrast material are often quite large and may result in acute symptoms. Tucker & Di Bagno (1956) gave urographic iodinated contrast media containing 5,150 or 4,935 mg iodine per dose to 1,994 patients. Nine hundred ninety-one had no reaction; 1,003 had one or more reactions. The 30 patients who experienced hives, sneezing, pruritis, or facial edema may have responded to iodine. Witton et al. (1973) described the acute reactions of 568 patients to urographic iodinated contrast media. These included hives, cutaneous edema, diffuse erythematous rash, periorbital edema, nasal congestion, sneezing, rhinitis, angioneurotic edema, syncope with transient hypotension, hypotension (shock) with diffuse erythematous rash, cardiovascular collapse, bronchospasm, bronchial asthma, larygeal edema with airway obstruction, grand mal seizures and/or parotid swelling. The patient who suffered the cardiovascular collapse died of cardiac arrest. Susceptibility to excess iodine Case reports and studies provide some insight into the percent of the population and the segments of the population who respond adversely to excess iodine. Several of these reports and studies concerned the development of goiter and/or hypothyroidism. Results from the 1968-70 Ten State Survey in the USA indicated that 2.8 to 9.3% of the 1,206 participants with high iodine excretion had goiters (Trowbridge et al., 1975a). Among 4,344 inhabitants of a Chinese village who drank deep-well water with a high iodine content, Tai et al. (1982) reported a goiter incidence of 7.3% and enlarged thyroid incidence of 28.3%. The incidences of goiter and enlarged thyroid were considerably lower, 1,5% and 8.7% respectively, among 4,158 villagers drinking water with normal iodine concentrations. Freund et al. (1966) used iodine as a means of disinfecting the water supply of a prison community. At a concentration of one mg iodine per liter of water, two of 25 inmates (13%) had impaired organification of thyroidal iodide. Jaggarao et al. (1982) reported that of 100 patients treated for six weeks to eight years with amiodarone, one became thyrotoxic and ten (10%) developed hypothyroidism. Of 2,404 patients treated with potassium iodide for bronchial asthma or bronchitis, 12 (0.5%) developed myxedema, and four (0.2%) developed slight thyroid swelling (Bernecker, 1969; Herxheimer, 1977). Begg & Hall (1963) found myxedema in six of 18 patients (33%) who had taken Fesol (contains iodopyrin which is about 40% iodine) regularly for one to 22 years. Of 41 patients with cystic fibrosis given a saturated solution of potassium iodide, six (15%) developed goiter, two (5%) had hypothyroidism, and two (5%) developed goiter with hypothyroidism (Azizi et al., 1974). The incidence of hypothyroidism after iodine prophylaxis in Serbia, Tasmania, Holland, and Austria ranged from 0.01 to 0.06% of the population (Fradkin & Wolff, 1983). Globel et al. (1985) estimated that the incidence of iodine indiced thyrotoxicosis in the Federal Republic of Germany was 0.025%. The incidence of hyperthyroidism after iodine prophylaxis in limited population groups ranged from zero to eight percent (Fradkin & Wolff, 1983). Ek et al. (1963) reported that of 100 euthyroid patients given potassium iodide as part of an iodide repletion test, seven (7%) became hyperthyroid. Vagenakis et al. (1972) indicated that of eight patients with nontoxic goiter, four (50%) developed hyperthyroidism after taking a saturated solution of potassium iodide as part of an experimental study. Martino et al. (1985) reported that about 10% of patients treated with amiodarone in areas of mild iodine deficiency develop thyrotoxicosis. Of 58 goitrous patients given iodized oil as an iodine supplement, three (5%) developed hyperthyroidism (Boukis et al. 1983). Some studies provide insight into the incidence of iodine sensitivity in population groups. Curd et al. (1979) conducted metabolism studies of radiolabeled protein in 126 participants and found four (3.2%) who were sensitive to potassium iodide. These persons responded with urticaria, angioedema, polymyalgias, conjunctivitis, coryza, fever, and/or headache. Rosenbaum et al. (1976) reported that of 252 patients given amiodarone, one (0.4%) developed erythema nodosum. Barker & Wood (1940) reported that of 400 hyperthyroid patients treated with iodine, seven (1.75%) had febrile reactions. Of the 2,404 patients given potassium iodide for bronchial asthma or bronchitis, 125 (5%) developed swollen salivary glands, 62 (3%) had a watery running nose, 57 (2%) suffered headache, and 360 (15%) had gastrointestinal complaints (Bernecker, 1969). By means of a questionnaire, Witton et al. (1973) ascertained that of 9,934 patients, 39 (0.4%) were allergic to iodine. Of 32,964 patients who were given urographic iodinated contrast media, 568 (1.72%) had acute reactions (Witton et al., 1973). Tucker & Di Bagno (1956) reported that of 1,994 patients given urographic iodinated contrast media, 30 (1.5%) developed hives, sneezing, pruritis, or facial edema. These reactions may have indicated sensitivity to iodine. The relationship between dose and response To determine the maximum tolerable dietary intake of iodine it is essential to review the available data and establish a link between dose and adverse effect. The limitations of this procedure should be noted. - Studies concerning iodine intake from oral drugs were included here to provide further information on the relationship between dose and response; however, studies concerning iodine that was applied topically or to mucous membranes were not included because there was no adequate way to estimate absorption of iodine through the dermal or mucosal tissues. Likewise, studies concerning adverse effects from iodinated contrast materials were not included because these solutions bypass the normal absorptive route from the gastrointestinal tract. - The actual amount of iodine absorbed depends on bioavailability from the various iodine compounds. There is no way at present to estimate these bioavailabilities. - Iodine dose was evaluated on the basis of milligrams per day; however, the length of time of intake was highly variable among case reports. In some cases, the excess iodine was taken for many years before a response was seen. In other cases, a relatively short time was involved. - The age, sex, iodine status, thyroid status, and general health status of the subject determines the relationship between dose and response. Although many case histories of patients with adverse effects from iodine are available, there are few controlled, experimental studies. - Some of the studies are quite old and were not explicit about dosage of iodine. Many studies had to be omitted from dose-response consideration because it was not possible to estimate daily iodine intake. - The dose of iodine generally refers to that from the major source (e.g., seaweed, supplement, or drug) and not to the total daily intake which includes that from the rest of the food supply. This additional information was not available from the studies reviewed here. - Most people are unaffected by excess iodine. The dosages and responses presented here represent those individuals who do respond adversely to excessive levels. The studies providing incidence information indicate that probably less than 10% of the general population responds adversely to excess iodine. - Criteria for hyperthyroidism and hypothyroidism were not always clearly indicated in the studies. In some cases clinical symptoms were described and/or laboratory values were presented. A diagnosis of thyrotoxicosis was interpreted to mean hyperthyroidism. Levels of iodine over 10 mg/day, due to the intake of iodine- containing drugs or the result of intentional or accidental poisoning, were toxic for some individuals. Forty-eight individuals have been reported to have adverse effects from iodine intakes less than or equal to 10 mg/day. The adverse effects included hyperthyroidism in 28 cases; goiter in one cue; hypothyroidism in 16 cases; goiter with hypothyroidism in two cases; and sensitivity reactions in one case. The sources of the iodine included prescribed medications, seaweed in the diet, experimental study iodine solutions, dietary supplements, and nutritional supplements. Some of the 48 individuals had underlying thyroid disease which may have affected their response to extra iodine. Joseph et al. (1980) have reported that for patients with autonomous tissue, that iodine intakes of less than 0.100 mg/day pose no risk, but the critical amounts are probably between 0.100 and 0.200 mg/day. The iodization of bread in Tasmania resulted in thyrotoxicosis for some individuals at levels of iodine intake of about 0.200 mg/day (Stewart, 1975; Vidor et al., 1973). Iodinated bread in Holland contributed 0.100 mg iodine per day and increased the incidence of thyrotoxicosis. The spring-summer peak of thyrotoxicosis (related to winter milk) in England occurred with average iodine intakes of 0.236 mg/day for women and 0.306 mg/day for men. Sensitivity reactions Certain individuals appear to be sensitive to iodine and may react to excessive intake with fever, salivary gland enlargement, and/or ioderma. Fisherman & Cohen (1977) indicated that some of their patients experienced allergic anaphyllactoid reactions to iodine in the form of rhinitis, cough, dyspnea, wheezing, and cerebral symptoms secondary to hypotension. Sulzberger & Witton (1952) have characterized the dermatoses resulting from sensitivity to iodine. The ioderma reported in the cited studies was often described as pruritic red rashes or as generalized urticaria with angio-edema. In several cases there were bullous vesicular eruptions, purpuric hemorragic eruptions, pustular eruptions, or tuberous fungating eruptions. Death from these more severe forms of ioderma was reported in several cases (Eller & Fox, 1931; Hollander & Fetterman, 1936; Barker & Wood, 1940). Safe upper limits of iodine intake Side effects have not been reported from the current high levels of iodine (0.200-0.710 for teenagers and adults) in the USA food supply. The National Academy of Sciences (1980) has indicated that levels of iodine intake between 0.050 and one mg per day are safe, however no references are provided to substantiate this fact. The National Academy of Sciences (1980) is often cited by authors as establishing the one mg of iodine per day as the safe upper limit for this element. Wolff (1969) stated that iodine in amounts ten or more times daily requirements (which would be about 1.80 mg/day since he assumed that 0.180 mg/day was the dietary requirement) would lead to goiter and hypothyroidism. In a summary report of a workshop on exposure to iodine sponsored by the American Medical Association (1980), it was concluded that an iodine level of one mg or less per day was nonhazardous. The basis for this conclusion rested on work from two studies - one by Saxena et al. (1962) concerning iodine levels to suppress uptake of radioactive iodine by the thyroid, and the other (Thomas et al., 1978; Stockton & Thomas, 1978; Thomas et al., 1969; Freund et al., 1966) which reported few ill effects from an iodinated water supply. Saxena et al. (1962) conducted an experimental study to determine the minimal effective dose of iodine that would be necessary to suppress uptake of the normal thyroid for radioactive iodine. During the course of this study the authors administered 0.100, 0.300, 0.600, or 1.000 mg of iodine per day to 14, 15, 20, and 14 children, respectively one to 11 years of age without encountering any toxic effects. Saxena et al. (1962) extrapolated these findings to adults on the basis of body surface area and concluded that three to four mg of iodine per day for adults would be effective for suppressing radioactive iodine uptake. The study reported by Thomas et al. (1978), Stockton & Thomas (1978), Thomas et al. (1969), and Freund et al. (1966) concerned iodination of the water supply at a prison, As of the latest reports in 1978, the study had been ongoing for 15 years. During this time, 750 men and women had ingested approximately one to two mg of iodine per day for various time periods with no change in serum thyroxine and few side effects (Thomas et al., 1978). One hundred seventy-seven women who were incarcerated at this prison had given birth to 181 infants without adverse effects evident in the infants (Stockton & Thomas, 1978). It was, however, noted that four women who were hyperthyroid before entering became more symptomatic receiving the iodinated water supply, and that of 15 inmates tested, two had impaired organification of thyroidal iodine (Freund et al., 1966). This study of the iodinated water supply at a prison is probably the best to date in establishing an upper limit of safety for iodine intake. Its strong point is the large number of subjects; its weak points are the imprecise estimates of iodine intake and the variable duration of intake due to different sentence lengths. The work of Saxena et al. (1962) concerned only a small number of children, and the iodine was given for a relatively short time (approximately 3 months). Because only certain segments of the population are affected by excess iodine, studies with small subject numbers may not include susceptible individuals and may thus overestimate the maximum safe level of intake of this substance. Likewise, other studies (Koutras et al., 1964; Sternthal et al., 1980; Ramsden, 1967; Childs et al., 1950) administering varying doses of iodine to small numbers of subjects for short time periods without side effects should not be used to verify the safety of these iodine levels. CONCLUSIONS The human response to excess iodine is variable. Some people tolerate large intakes without side effects, while others may respond adversely to levels close to recommended intakes. Based on the studies reviewed here, it is concluded that an iodine intake of one mg per day or less [which has been deemed non-hazardous by the American Medical Association (1980)] is probably safe for the majority of the population, but will cause adverse effects for some individuals. Those who are most likely to respond adversely are: - those with other thyroid disorders (e.g., Hashimoto's Disease, euthyroid Graves' Disease); - those who are sensitive to iodine. The maximum tolerable level of iodine appears to be in the range from somewhat above recommended dietary allowances (i.e., 0.200 mg/day) to one mg/day. Such iodine levels are possible from diets which include milk, iodized salt, and/or products containing the red food coloring erythrosine (tetra-iodofluorescein). Pennington (in press) has summarized data from various investigators on the iodine content of cow milk. Mean values range from about 0.100 to 0.770 mg iodine per liter with some extreme values over 4,000 mg/liter. Thus, the consumption of a liter (about one quart) of milk could provide sufficient iodine to cause thyrotoxicosis in susceptible individuals. Levels of salt iodization vary among countries. Iodized salt in the USA provides 0.076 mg of iodine per gram (0.418 mg per teaspoon). When considering iodine supplementation of the food supply, some attempt should be made to estimate the daily iodine intake of various age-sex groups and to determine the consequences of the increased iodine. In addition to an increased incidence of thyroid dysfunction and iodine sensitivity reactions in susceptible individuals, an increase in dietary iodine will have several other consequences (Hall & Lazarus, 1987; Wartofsky, 1984): - greater difficulty in controlling Graves' Disease with antithyroid drugs and a decline of remission rates for those on antithyroid medication; - an increase in the dose of radioiodine required to induce euthyroidism and hypothyroidism; and - an alteration in the pattern of thyroid cancer. In some cases where iodination programs for endemic areas are being considered, it may be advantageous to direct them to the population groups who will most benefit from them (e.g., infants, young children, teenagers) rather than to the entire population. Iodine-containing drugs, mineral dietary supplements, topical medications, and contrast media should be used with caution. Physicians who prescribe such products should monitor their patients carefully for adverse response. Government agencies may want to review, regulate, and/or require warning labels on commercially available products that are high in iodine. Of various pharmaceuticals analyzed by Vought et al. (1972), eight contained between 0.251 and 0.375 mg of iodine per dose, and one contained 1.447 mg per dose. COMMENTS AND EVALUATION The Committee was informed that dietary iodine intakes have been estimated in various countries and are highly correlated with dietary habits. While individual human exposure to iodine may vary, an iodine intake of 1 mg per day or less is probably safe for the majority of the population, but may cause adverse effects for some individuals, e.g., people with thyroid disorders or people who are particularly sensitive to iodine. 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The number of deaths from Iodine would be higher if it were not for the fact that it combines with starches, proteins and fats in the digestive system and is inactivated.
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