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.


         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

         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.


         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,

         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.


    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

         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

         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

    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.,

         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

    -    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

         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.


         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

         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.


         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. WHO has recommended a dietary
    allowance of iodine of 0.10 to 0.14 mg/day per adult (WHO, 1974);
    however, the Committee noted that the nutrient requirement of
    iodine is to be re-evaluated by WHO in the near future. For
    purposes of safety, the Committee set a provisional maximum
    tolerable daily intake of 1 mg iodine/day (0.017 mg/kg bw) from
    all sources. The Committee further recommended that physicians and
    public health authorities should be aware of the need to balance
    therapeutic need with potential iodine excess in relation to the
    use of iodine-containing drugs.


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    See Also:
       Toxicological Abbreviations
       Iodine (ICSC)
       IODINE (JECFA Evaluation)
       Iodine (PIM 280)