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. 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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