Iodine: Deficiency and therapeutic considerations

Abstract

Iodine deficiency is generally recognized as the most commonly preventable cause of mental retardation and the most common cause of endocrinopathy (goiter and primary hypothyroidism). Iodine deficiency becomes particularly critical in pregnancy due to the consequences for neurological damage during fetal development as well as during lactation. The safety of therapeutic doses of iodine above the established safe upper limit of 1 mg is evident in the lack of toxicity in the Japanese population that consumes 25 times the median intake of iodine consumption in the United States. Japan's population suffers no demonstrable increased incidence of autoimmune thyroiditis or hypothyroidism. Studies using 3.0- to 6.0-mg doses to effectively treat fibrocystic breast disease may reveal an important role for iodine in maintaining normal breast tissue architecture and function. Iodine may also have important antioxidant functions in breast tissue and other tissues that concentrate iodine via the sodium iodide symporter.

Full text

Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 2 June 2008
Alternative Medicine Review Volume 13, Number 2 2008
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Lyn Patrick, ND – Bastyr University graduate 1984; private practice, Durango,
CO, specializing in environmental medicine and chronic hepatitis C; faculty of
the Postgraduate Certification Course in Environmental Medicine, Southwest
College of Naturopathic Medicine; contributing editor, Alternative Medicine
Review; physician-member of the Hepatitis C Ambassadors Team
Correspondence address: 117 CR 250 Suite A, Durango, CO 81301
Email: lpatrick@frontier.net
Abstract
Iodine deficiency is generally recognized as the most commonly
preventable cause of mental retardation and the most common
cause of endocrinopathy (goiter and primary hypothyroidism).
Iodine deficiency becomes particularly critical in pregnancy
due to the consequences for neurological damage during
fetal development as well as during lactation. The safety of
therapeutic doses of iodine above the established safe upper
limit of 1 mg is evident in the lack of toxicity in the Japanese
population that consumes 25 times the median intake of
iodine consumption in the United States. Japan’s population
suffers no demonstrable increased incidence of autoimmune
thyroiditis or hypothyroidism. Studies using 3.0- to 6.0-mg
doses to effectively treat fibrocystic breast disease may reveal
an important role for iodine in maintaining normal breast tissue
architecture and function. Iodine may also have important
antioxidant functions in breast tissue and other tissues
that concentrate iodine via the sodium iodide symporter.
(Altern Med Rev 2008;13(2):116-127)
Introduction
e oceans are the worldwide repository of
iodine; very little of the earth’s iodine is actually found
in soil. Iodine in the soil is deposited as a result of vola-
tilization from ocean water caused by ultraviolet radia-
tion. As a result, coastal soils are significantly higher in
iodine than soils further inland. So-called goiter belts
can occur in areas of elevated soil iodine because iodine
is bound strongly to soil and vegetable crops are poor
iodine sources.
1
Iodine: Deficiency
and erapeutic Considerations
Lyn Patrick, ND
Deficiency Worldwide
Iodine deficiency is considered to be the most
common endocrinopathy and most preventable cause of
mental retardation globally. In 1998, one-third of the
world’s population lived in iodine-deficient areas.
2
Although the primary recognized manifesta-
tion of iodine deficiency is endemic goiter, it is only the
most visible and well-documented sign of a deficiency.
ere are several manifestations of iodine deficiency
now termed iodine deficiency disorders. e major-
ity of these manifest in infants and children as a result
of maternal iodine deficiency.
3
Hearing loss, learning
deficits, brain damage, and myelination disorders can
occur due to fetal or perinatal hypothyroidism. Infant
mortality rates have decreased 65 percent in commu-
nities where iodine deficiencies have been eliminated.
4
Maternal iodine deficiency manifests as low thyroxine,
eleva ted thyroid stimulating hormone (TSH), and
subclinical thyroid enlargement (subclinical goiter). As
pregnancy and lactation increase iodine loss, the risk for
goiter continues, and even after lactation ceases it may
manifest as multinodular goiter and hyperthyroidism.
Iodine deficiency in women can lead to overt hypothy-
roidism and consequent anovulation, infertility, gesta-
tional hypertension, spontaneous first-trimester abor-
tion, and stillbirth.
4
Iodine deficiency is also associated with in-
creased risk for thyroid carcinoma in animal models and
humans.
5-8
In the Bryansk region of Russia, an area of

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Alternative Medicine Review Volume 13, Number 2 2008
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known radioactive I-131 exposure following the Cher-
nobyl disaster, the risk of all types of thyroid cancer was
directly inversely associated with urinary iodine excre-
tion levels.
9
Multiple studies assessing radioactive iodine
uptake in iodine-deficient thyroid glands have affirmed
that iodine deficiency allows for increased radioactive
iodine uptake. Although the pathology may be differ-
ent in extrathyroidal cancers, Stadel has postulated that
given the geographical associations of iodine deficiency,
prevalence of goiter, and incidence of reproductive can-
cers, there is a direct association with iodine deficiency
and increased risk for prostate, endometrial, ovarian,
and breast cancers.
10
In mild deficiencies, euthyroid (normal thyroid
hormone levels) states may occur but at the expense of
thyroid enlargement, neck compression, and thyroid
nodules with possible development of hyperthyroid-
ism.
11
Mild hypothyroidism in pregnant women sec-
ondary to iodine deficiency is associated with lower IQ
and cognitive deficits in their children.
12,13
In an area of endemic goiter, iodine administra-
tion to infants was shown to normalize delayed immu-
nity using skin testing with tetanus toxoid, suggesting a
role of iodine sufficiency in normal delayed immunity.
14
Iodine Deficiency in Developed
Countries
Although frank iodine deficiency is primarily
found in the underdeveloped world (Africa, Southeast
and Central Asia), countries in Europe, including Ger-
many, France, Italy, and Belgium, are also considered
iodine-deficient. Germany spends the equivalent of one
billion dollars annually in both healthcare expenditures
and lost work time as a result of iodine deficiency and
resultant thyroid disease.
15
Although North Americans are considered
an iodine-sufficient population, that assumption is
changing. e National Health and Nutrition Survey
(NHANES) data monitoring urine iodine shows io-
dine intake has dropped by 50 percent from the period
of 1971-1974 to 1988-1994, with median urine iodine
levels dropping from 320 mcg/L to 145 mcg/L.
16
Al-
though the next NHANES 2001-2002 survey showed
an increase in median urine iodine levels to 165 mcg/L,
an apparent leveling off of a precipitous drop, women
of childbearing age did not fare as favorably. According
to a Centers for Disease Control (CDC) evaluation of
NHANES 2001-2002, approximately 36 percent of
women of childbearing age in the United States may
receive insufficient dietary iodine.
17
Iodine insufficiency
was defined by urine iodine levels below 100 mcg/L and
assessed from single samples, the cutoff for iodine in-
sufficiency defined by the World Health Organization
(WHO) and diagnostic of mild iodine deficiency. e
WHO found that in populations with mean values be-
low this level the prevalence of goiter increases signifi-
cantly.
18
Fifteen percent of the same sample of women
from NHANES 2001-2002 had urinary iodine levels
less than 50 mcg/L, a level at which thyroid hormone
secretion is considered inadequate and is considered by
the WHO to be an indication of moderate-to-severe
deficiency.
Public health officials voice concern over this
data because of its implications for maternal/child
health.
19
e thyroid gland and the hypothalamic/
Table 1. Sources of Iodine
Soil
NaIO
3
Sodium iodine
NaIO
4
Sodium periodate
Seaweed/Algal Phytoplankton
KI Potassium iodide
NaI Sodium iodide
I
2
Iodine
I
-
Iodide
Seawater
I
-
Iodide

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Alternative Medicine Review Volume 13, Number 2 2008
Iodine
Page 118
pituitary/thyroid axis begins to function in the devel-
oping fetus at 11 weeks of gestation. e main role of
fetal thyroid hormone secretion (T4 levels are demon-
strable at 18-20 weeks of gestation) is development of
the nervous system. A U.S. retrospective study assess-
ing maternal hypothyroidism and subsequent IQ defi-
cits in children ages 7-9 years found iodine deficiency
may be causing fetal brain damage and other neurologi-
cal defects, including lowered IQ, spasticity, ataxia, and
deaf-mutism.
20
Evidence also indicates autoimmune
thyroiditis occurring during pregnancy appears to be
the result of iodine deficiency.
21
Iodine is also crucial
during lactation to provide continuing neurological de-
velopment of the infant.
22
Breast-milk iodine levels in
a recent study of lactating mothers in Boston revealed
47 percent had levels insufficient to provide adequate
iodine to meet infant requirements.
23
Dietary Levels of Iodine: e Japanese
Phenomenon
Japanese populations have historically con-
sumed significant amounts of dietary iodine from sea-
weed intake, possibly consuming a minimum of 7,000
mcg iodine daily from kombu alone.
24
Estimates of the
average daily Japanese iodine consumption vary from
5,280 mcg to 13,800 mcg;
25,26
by comparison the aver-
age U.S. daily consumption is 167 mcg. e Japanese,
therefore, consume dietary iodine approximately 5-14
times above the upper safety limit of 1 mg by U.S. stan-
dards. Mean urinary iodine levels in Japanese popula-
tions are approximately twice the levels found in the
U.S. NHANES 2001-2002 data.
27
ese higher lev-
els, however, appear to have no suppressive effect on
thyroid function as indicated by thyroid volume mea-
surements, the accepted standard for assessing thyroid
Figure 1. yroid Hormone Synthesis
Adapted from: De la Vieja A, et al. Physiol Rev 2000;80:1083-1105.
Iodine, in the form of iodide, is absorbed in the thyroid follicle through the
sodium/iodine symported protein (NIS) found in the basolateral membrane of the
follicular cell. The activity of NIS is up-regulated by the binding of TSH to the TSH
receptors on the follicular cells (TSH-R). This allows the absorption and concentration
of iodine inside the cell to levels 20-40 times greater than that found in the blood.
Iodide is then organified (oxidized) to iodine by thyroid peroxidase (TPO) and incorpo-
rated into the thyroglobulin molecule (Tg). Thyroid hormones (T
3
and T
4
) are then
secreted into the bloodstream from the follicular cell.
TPO
NIS
Tg
TSH-R
2Na
+
Na
+
Na
+
Na
+
K
+
K
+
I
–
I
–
I
–
I
–
Apical
Colloid
COOH
HO
O
HO O
NH
2
CH
2
C H
Basolateral
I I
I I
II
II
CO
NH
CH
2
C H
T
4
Iodide

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enlargement. A study comparing urine iodine and thy-
roid volume in Japanese children showed 16 percent
of those tested excreted over 1,000 mcg/L.
24
Elevated
levels of urinary iodine did not predict increased thy-
roid gland volume, as might be expected from data in
studies of Chinese populations associating excess levels
of iodine with autoimmune thyroiditis and hypothy-
roidism.
28
Japanese women who consume a traditional
high-seaweed diet also have a low incidence of benign
and malignant breast disease.
29
Japanese women who
consume a Western diet low in seaweed or who emi-
grate to the United States lose this protective advantage
and gain the same risk for fibrocystic breast disease and
breast cancer as their Western counterparts.
30,31
Japan
also has a low incidence of iodine-deficiency goiter and
autoimmune thyroiditis.
32
It has been hypothesized the
amount of iodine in the Japanese diet has a protective
effect for breast and thyroid disease.
25
e Role of Iodine in the Human Body
Iodine is found in nature in various forms:
inorganic sodium and potassium salts (iodides and
iodates), inorganic diatomic iodine (molecular iodine
or I
2
), and organic monoatomic iodine (Table 1). Sea-
weeds, such as wakame, nori or mekabu (used in sushi,
soups, salads, and in powdered form as a condiment)
and widely consumed in Asian cultures, contain high
quantities of iodine in several chemical forms, including
iodine in the molecular form (I
2
) and iodine organified
to proteins. ese forms of iodine are
absorbed through the intestinal tract via
two different mechanisms. Molecular
iodine (I
2
) is transported by facilitated
diffusion. Iodides (I
-
) are absorbed via a
transport protein in the gastric mucosa
called the sodium-iodide symporter, a
molecule found in a variety of tissues
in the body that utilize and concentrate
iodine – the thyroid, mammary tissue,
salivary gland, and cervix.
33
In order to produce concentra-
ted iodine-based hormones, the thyroid
tissue sodium-iodide symporter pro-
tein, a critical plasma membrane protein
in the thyroid follicular cells, sequesters
iodide from the extracellular fluid. e
iodide molecule then moves across the
apical membrane to the cell-colloid
surface where it is oxidized by thyroid
peroxidase (TPO). In this form it is
bound to tyrosine residues in the thyro-
globulin molecule and these mono- and
diiodotyrosines become the precursors
to commonly known thyroid hormones
T
3
and T
4
(Figure 1). Iodine accounts
for 65 percent of the molecular weight
of T
4
and 59 percent of the molecular
weight of T
3
.
11
In an adult with sufficient iodine intake, ap-
proximately 15-20 mg iodine is concentrated in the tis-
sues of the thyroid gland. However, only 30 percent of
the body’s iodine is concentrated in the thyroid tissue
and thyroid hormones. e remaining nonhormonal io-
dine is found in a variety of tissues, including mammary
tissue, eye, gastric mucosa, cervix, and salivary glands.
With the exception of mammary tissue, the function of
Figure 2. Antioxidant Functions of Iodine
Iodine (I
2
) is catalyzed by thyroid peroxidase using H
2
O
2
. H
2
O
2
used in this reaction
decreases the amount of H
2
O
2
that would otherwise be available for damaging
oxidation reactions. Selenium containing GPX removes H
2
O
2
from the tissues, also
decreasing oxidative damage.
TPO - Thyroperoxidase
GPX - Glutathione Peroxidase
T
3
- Triiodothyronine
T
4
- Tetraiodothyronine
Adapted from: Smyth PP. Role of iodine in antioxidant defence in thyroid and breast disease.
Biofactors 2003;19:121-130.
I
–
I
2
+ Tyrosine
Deiodination
Monoiodotyrosine (MIT)
Diiodotyrosine (DIT)
T
3
TPO
GPX(Se)
2H
2
O
2
H
2
O
T
4
Diiodotyrosine (DIT)

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Iodine
Page 120
iodine in these tissues is largely unknown.
11
Mammary
tissue’s role in sequestering and concentrating iodine is
related to fetal and neonatal development and is largely
evolutionary, as detailed below. However, iodine’s role
in mammary and other tissues has also been shown to
have an antioxidant function. Iodide can act as an elec-
tron donor in the presence of hydrogen peroxide, perox-
idase, and some polyunsaturated fatty acids, decreasing
damage by free oxygen radicals (Figure 2).
34,35
Iodine-
deficient glands contain increased amounts of malondi-
aldehyde, a product of lipid peroxidation that can occur
as a result of inadequate iodine stores.
36
Concentrations
of iodine as low as 15 micromolar (achievable in human
serum) have the same antioxidant activity as ascorbic
acid.
37
is antioxidant effect of iodine may explain the
therapeutic effects of seaweed baths or iodine-rich so-
lutions known as thalassotherapy used historically to
treat ocular diseases, thyroid disease, diabetes, cardiac
and respiratory disease, and arteriosclerosis.
37
Animal studies have shown iodine normalizes
elevated adrenal corticosteroid hormone secretion re-
lated to the stress response
38
and reverses the effect of
hypothyroidism on the ovaries, testicles, and thymus in
thyroidectomized rats.
39
Iodine may also have a role in
immune function; when placed in a medium contain-
ing 10
-6
M iodide, human leukocytes synthesize thyrox-
ine.
40
Testing Iodine Levels
More than 90 percent of dietary iodine is ex-
creted in the urine. Single random urine sampling is the
standard accepted method of measuring body stores
of iodine. e World Health Organization has deter-
mined 50-99 mcg/L indicates mild deficiency, 20-49
mcg/L indicates moderate deficiency, and less than 20
indicates severe deficiency.
18
Because random urine
samples have been found to be adequate for population
screening, there is little advantage in calculating urine
iodine:creatinine ratios. For individual measurements,
however, multiple spot urine iodine measurements or
24-hour urine iodine evaluations are more precise.
41
Medical Uses of Iodine
Lugol’s Solution
Lugol’s solution (produced by French physi-
cian Jean Lugol in 1829) consists of five-percent iodine
and 10-percent potassium iodide in solution. It was
originally used to treat “scrofula” and 40 years later to
treat anthrax infections. Lugol’s solution became widely
used in medicine in the early 1900s to treat a variety of
disorders, including simple goiter and Graves disease,
42
and by 1932 had become commonplace in medical prac-
tice.
43
Even as late as 1995, pharmaceutical texts recom-
mended the use of 0.1-0.3 mL Lugol’s five-percent solu-
tion for the treatment of simple goiter,
44
the equivalent
of 12.5-37.5 mg iodine. Lugol’s solution fell out of favor
for the treatment of iodine-deficiency diseases as the
availability of thyroid extracts and iodized salt became
more widely used. Multiple pharmaceutical medications
used currently contain iodine.
Iodine and Fibrocystic Breast Disease
e breast concentrates iodine to a greater
degree than the thyroid gland;
45
human milk contains
a concentration of iodine four times greater than thy-
roid tissue.
45
is evolutionary mechanism is necessary
for neonatal thyroid function and consequent normal
neural development.
46
Mammary tissue also produces
two separate deiodinase enzymes: deiodinase type 1
and deiodinase type 2, which can convert T
4
to T
3
. De-
iodinases control the amount of free iodine present in
breast tissue – higher levels during puberty, pregnancy,
and lactation, and lower levels in nonpregnant or post-
partum phases (Figure 3).
47
Biopsy-proven studies find fibrocystic breast
disease (FBD) in nine percent of women. Autopsy stud-
ies, however, reveal only 10-20 percent of FBD cases ap-
peared to have been biopsied, leading to a significantly
larger prevalence.
48
Studies by Eskin et al found iodine
deficiency in a rat model resulted in breast hyperplasia
that responded to iodine repletion at a dose of 0.1 mg/
kg body weight,
49
equivalent to a 5-mg dose in a 50-kg
(110-pound) female. is group also determined that
molecular iodine is the active form of iodine in breast
tissue in animal models and it is less thyrotoxic than io-
dide because more of the molecular iodine is selectively
concentrated in breast tissue than thyroid tissue. A sig-
nificant amount of data shows the mammary gland is

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Review Article
Page 121
more efficient in capturing and concentrating molecular
iodine than the thyroid gland.
49
Ghent and Eskin continued their iodine-
repletion studies in women with diagnosed FBD.
50,51
rough a series of three trials assessing different forms
of iodine – first sodium iodide or protein-bound iodide,
then molecular iodine – they examined efficacy and
toxicity of weight-based iodine dosing, extrapolating
from the animal model dose. Beginning with an uncon-
trolled study of 233 women with FBD, they compared
sodium iodide to protein-bound iodide for a period of
2-5 years. Patients (n=1,365), including those who did
not respond to either form of iodide were switched to
molecular iodine using a 0.07-0.09 mg/kg dose. ey
concluded that the molecular form of iodine was more
effective and had a significantly lower side-effect profile
than iodide forms. Both subjective and physician-eval-
uated clinical improvements were noted in 65 percent
of women on a weight-based dose of 3-6 mg molecular
iodine. is compared to a subjective improvement of
33 percent in the placebo group (Table 2). No subjects
treated with molecular iodine had thyroid-related side
effects, and no changes were noted in thyroid lab val-
ues or on physical examination. In study #3, 56 women
with FBD were randomized to either molecular iodine
or placebo for six months. ey were assessed by phy-
sician examination and subjective evaluation every two
months, and followed with thyroid blood tests and
mammography at the beginning and end of the trial.
50
After six months, 65 percent of the treatment group ex-
perienced significant improvement. By contrast, in the
placebo group 33 percent experienced improvement
while three percent demonstrated worsening on physi-
cian examination.
Another human study evaluating iodine and
FBD examined the effect of an iodine compound of
sodium iodide and iodate.
52
Based on animal stud-
ies showing molecular iodine is less thyrotoxic than
Figure 3. Deiodinase Control of Iodine in Breast Tissue
Mammary gland produces either a majority of deiodinase type 1 (DI1)
during pregnancy/lactation or a majority of deiodinase type 2 during
nonpregnant or postpartum (postlactation) periods. Iodine is absorbed via
the sodium iodine symporter (NIS) and oxidized by lactoperoxidase (LPO).
Basal Membrane
T
4
T
4
T
4
DI type 1
NIS LPO
NaINaI I
DI type 2
T
3
+ I
T
3
I
Milk
T
3
+ I
T
3
+ I
T
3
+ I

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Alternative Medicine Review Volume 13, Number 2 2008
Iodine
Page 122
iodide, this particular formulation was used because it
generates molecular iodine as a result of dissolution in
stomach acid. e randomized, double-blinded, place-
bo-controlled study evaluated the safety and efficacy of
three dosages – 1.5, 3.0, and 6.0 mg – in 111 women.
Patients were assessed by physicians and reported pain
based on a standardized scale. e greatest reduction in
pain, evident by month 3, occurred at the 6.0-mg dose.
By month 6, 51.7 percent of study participants on 6.0
mg reported at least a 50-percent pain reduction, while
the placebo group reported an 8.3 percent reduction.
e efficacy of this iodine compound appeared to be
dose-related, with a 6.0-mg dosage resulting in a greater
level of pain reduction in a greater number of patients
than the 3.0-mg dose (Table 3). Due to the small num-
ber of women in the study, however, the p value did not
reach significance.
Iodine and Breast Cancer
In Japan, age-adjusted breast cancer incidence
is 6.6 per 100,000. In comparison, the U.S. age-ad-
justed breast cancer incidence is 22 per 100,000 and
the U.K. rate is 27 per 100,000.
53
Japan also has sig-
nificantly lower rates of hypothyroidism, autoimmune
thyroid disease, and hyperthyroid conditions, while the
average daily dietary iodine intake may be as high as
25 times that of the United States.
27
e incidence of
breast cancer in Japanese women who emigrate to the
United States and adopt a Western diet equals that of
non-Japanese women living in the United States.
53
e
lower incidence of both FBD and breast cancer have
been attributed to the increased dietary intake of iodine
in the traditional Japanese diet.
25
Data on the link between breast cancer and thy-
roid disease is unclear, with some studies clearly show-
ing an increased incidence of hypothyroidism and auto-
immunity in breast cancer patients, while other studies
Table 2. Iodine Repletion Studies in Women with FBD
Type
of Study
Duration
Number of
Participants
Medication
& Dosage
Evaluation
Study #1 Prospective
Uncontrolled
2 years/5 years
233 on Lugol’s
for 2 years
588 on iodized casein
for 5 years
31-62 mg I
(n=233)
Iodine caseinate
10 mg/day (n=588)
Subjective and clinical
evaluation
Study #2 Prospective
Control Crossover
9.9 months
post crossover
1,365 for minimum of
8.9 months: total
treatment time
4,813 woman-years
Molecular iodine
0.07-0.09 mg/kg body
weight/day
Subjective and clinical
evaluation
Study #3 Prospective
Control Double-blind
6 months
56
Molecular iodine 0.07-
0.09 mg/kg
body weight/day
Pre & post
mammography;
TSH, T
3
, T
4

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Page 123
show no significant association.
54-57
Smyth found a sig-
nificantly greater mean thyroid volume in female breast
cancer patients compared to controls.
58
e studies on iodine and breast cancer in both
humans and animal models point to a closer associa-
tion with iodine and malignant cell growth. Iodine de-
ficiency has been shown to alter the structure and func-
tion of the mammary glands of rats, especially alveolar
cells. I
2
is distinctly more effective than I
-
in diminishing
ductal hyperplasia and perilobular fibrosis in mammary
glands, using the same total iodine doses in both treat-
ments.
49
A clinical study of breast cancer patients found
breast tissue levels of iodine were significantly lower in
the breast tissue of women with diagnosed breast can-
cer than in breast tissue of women with either normal
breasts or benign fibroadenoma.
58
Animal and human studies show that in io-
dine-deficient states the breast parenchyma in rodents
and women show atypia, dysplasia, and even neopla-
sia.
59
Eskin et al demonstrated that iodine-deficient
breast tissue in animals is more susceptible to the effect
of carcinogens, and breast lesions occur in greater num-
bers and earlier in the process of neoplasia. Metabolic-
ally, iodine-deficient breasts show pathological changes
in RNA/DNA ratios, estrogen receptor proteins, and
cytosol iodine levels that lead to neoplasia.
60
Clinically,
Eskin also demonstrated that women with hyperplastic
breast tissue have significantly higher radioactive iodine
uptake than women with normal breast tissue. e au-
thor hypothesized this was a result of inadequate breast
tissue iodine levels.
61
Supplementation with iodine alone or in com-
bination with progesterone has been shown to shrink
breast tumors in animals. Lugol’s solution (1 g iodine
and 2 g potassium iodide in 100 mL of water) and me-
droxyprogesterone acetate given to rats with chemical-
ly-induced breast tumors resulted in a significant reduc-
tion of tumor growth compared to the control group
(that received no intervention).
62
e most effective
dose of iodine was the lowest given – 0.0025 mg daily.
e weight-based dose equivalent of Lugol’s solution
would be 5.0 mg inorganic iodine for a 50-kg female.
is dose correlates with Eskin’s research finding 0.1
mg/kg body weight per day inorganic iodine promotes
sufficiency in the rat necessary to improve signs and
symptoms of FBD.
49
Another study of chemically-induced mamma-
ry cancer in rats found molecular iodine is more effective
at inhibiting mammary cancer than iodide or thyrox-
ine.
63
e iodine used in the study was a 0.05-percent
molecular iodine compared to 0.05-percent potassium
iodide or thyroxine (3 mcg/mL), all in drinking water.
Rats receiving molecular iodine demonstrated greater
than 50-percent reduction in incidence of mammary
cancer (30%) compared to controls (72.7%). Iodine-
treated rats exhibited a strong and persistent reduction
in mammary cancer, and only the I
2
treatment was capa-
ble of diminishing basal lipoperoxidation in mammary
glands – the theoretical mechanism for iodine’s action
in mammary cancer reduction. Reactive oxygen species,
specifically lipoperoxides, are involved in initiation and
promotion of carcinogenesis, where specific mutations
of certain genes occur.
37
In both studies, no toxic ef-
fects of iodine on thyroid function or other side effects
Table 3. Dose-dependent Efficacy of an Iodine Compound for FBD
All randomized subjects with pain, tenderness, and
nodularity at baseline
All randomized subjects with moderate or severe pain,
tenderness, and nodularity at baseline
Placebo
0/15 (0%)
0/12 (0%)
1.5 mg
Iodine
0/10 (0%)
0/9 (0%)
3.0 mg
Iodine
7/28
(25.0%)
5/22
(27.3%)
6.0 mg
Iodine
5/27
(18.5%)
5/27
(18.5%)
p
0.047
0.106
Adapted from: Kessler JH. The effect of supraphysiologic levels of iodine on patients with cyclic mastalgia. Breast Journal 2004;10:328-336.

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Alternative Medicine Review Volume 13, Number 2 2008
Iodine
Page 124
at effective dosages were noted. Both authors recom-
mend the initiation of human breast cancer trials with
iodine.
62,63
yroid Toxicants: Perchlorate
Perchlorate is an inorganic anion that occurs
naturally in soil and is also made synthetically. e am-
monium salt of perchlorate is manufactured primarily
for use as a rocket propellant, in explosives manufactur-
ing, and as a pharmaceutical. Perchlorate is also natur-
ally occurring in fertilizers that contain nitrate-rich
mineral deposits.
64
Recent studies have found significant perchlo-
rate contamination in groundwater throughout the
western United States as a result of ammonium perchlo-
rate disposal. Perchlorate (at levels over 4 ppb) has been
found to contaminate the drinking water of 11 million
people in the United States, and high levels of perchlo-
rate have also been found in the food supply. Human
milk has been found to contain five times the perchlo-
rate levels (10.1 mcg/L) of cow milk (2 mcg/L).
65
Per-
chlorate contamination has also been documented in
grain, fruit, vegetables, dietary supplements, and forage
crops for livestock.
65-68
Perchlorate is a known competitive inhibitor of
the sodium-iodide symporter in humans and can inhi-
bit iodide uptake, leading to the suppression of T
3
and
T
4
. Potassium perchlorate is currently used as a phar-
maceutical to treat thyrotoxicosis and hypothyroidism
induced by amiodarone.
69
Due to recent evidence that perchlorate con-
tamination of food and water is a widespread phe-
nomenon, attempts have been made to evaluate the ef-
fect of perchlorate contamination on thyroid function
in the general population. An evaluation of the recent
NHANES 2001-2002 survey examined the relation-
ship of urinary perchlorate levels, urinary iodine levels,
serum TSH, and serum T
4
levels in adult men and wom-
en,
70
resulting in three surprising findings. First, 36 per-
cent of women in the NHANES subset had low urine
iodine levels (<100 mcg/L), equivalent to 2.2 million
women nationwide, considering that the NHANES
subset is representative of the population in general.
e second finding was that perchlorate contamination,
as low as 5 ppb, is associated with elevations of TSH
and decreased serum T
4
in all 1,111 women regardless
of iodine status. ird, in women with low urine iodine
levels under 100 mcg/L (suggesting iodine insufficien-
cy), perchlorate at levels as low as 5 ppb was associated
with a 16-percent decrease in T
4
levels and elevation of
TSH levels, consistent with inhibition of iodide uptake.
In the group at highest risk of thyroid deficits, women
with urine iodine levels under 100 mcg/L, exposure to
5 ppb perchlorate could theoretically cause subclinical
hypothyroidism in 10 percent of that population.
70
Subclinical hypothyroidism is currently defined
as an elevated TSH with T
3
and T
4
levels within normal
reference ranges.
71
e concern with this population of
women of childbearing age who have low urine iodine
levels is that undetected, subclinical hypothyroidism
can lead to fetal neurological damage.
70
Iodine Toxicity
e U.S. recommended daily intake (RDI)
for dietary iodine is 150 mcg for adults, 220 mcg for
pregnancy, and 270 mcg during lactation.
72
e safe up-
per limit has been set at 1,000 mcg (1 mg) as a result
of studies assessing TSH levels with supplementation.
Iodine supplementation over this limit has been shown
to potentially contribute to an underlying thyroid pa-
thology in those with Hashimoto’s thyroiditis, Graves’
disease, or exacerbation of nodularities in euthyroid in-
dividuals if intake exceeds 20 mg iodine or iodide.
73-75
Population studies have shown excessive io-
dine intake may increase the prevalence of autoimmune
thyroiditis in animals and humans, increasing the risk
of overt hypothyroidism.
28
Studies following indi-
viduals with elevated anti-thyroid antibody titers have
shown that progression of hypothyroidism is correlated
with increasing iodine intake.
28
Some reports of iodine
repletion, causing hyperthyroidism in individuals with
prior severe iodine deficiency, have shown reversion to
baseline in the continued presence of iodine repletion
3-5 years later.
76
Another study of a large population in
China did not show a return to baseline after five years,
and those authors suggest maintaining serum TSH lev-
els in iodine-supplemented patients between 1.0 and
1.9 mIU to maintain the lowest incidence of abnormal
thyroid function during iodine supplementation.
28
In addition to pre-existing thyroid pathologies
exacerbated with iodine supplementation, excessive in-
gestion of iodine in medication (amiodarone) or water

Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 2 June 2008
Alternative Medicine Review Volume 13, Number 2 2008
Review Article
Page 125
contamination may contribute to goiter, hypothyroid-
ism, elevated TSH levels, and ocular damage.
77
How-
ever, in studies referenced above by Eskin and Ghent,
50
which excluded patients with pre-existing autoimmune
thyroid pathologies and used 3-6 mg molecular iodine
for up to five years, no associated thyroid abnormalities
were observed.
50,52
Selenium is required for the production of
deiodinase selenoenzymes. Clinical investigators in se-
lenium- and iodine-deficient populations conclude the
coexisting deficiencies cause increased TSH levels and
contribute to goiter development.
78
One French study
found an inverse relationship between selenium status
and thyroid volume.
79
Co-existing deficiencies become
problematic in areas where iodine supplementation is
promoted on a population-wide basis. Selenium sup-
plementation may be necessary to prevent potential thy-
roid damage from iodide supplementation in selenium-
deficient individuals.
80
Conclusion
Iodine is an essential mineral for normal thy-
roid function, mammary gland development, and fetal
and infant neurological growth. Iodine deficiency is epi-
demic in developing countries and parts of Europe. Re-
cent evidence shows iodine deficiency is also strikingly
common among adult women in the United States. e
resulting risk for neurological impairment in fetal and
infant brain development and potential for mammary
dysplasia warrants closer evaluation of the general fe-
male population for iodine sufficiency. Also of concern
is widespread contamination of food and water supplies
with the known thyroid toxicant perchlorate, which
blocks iodine uptake in the thyroid gland and mam-
mary gland via competitive inhibition of the sodium
iodide symporter protein. Perchlorate may also increase
the risk for subclinical hypothyroidism in a subgroup of
women with low urine iodine levels.
e safety and efficacy of molecular iodine as
a therapeutic tool in the treatment of fibrocystic breast
disease has been well documented. Animal studies us-
ing iodine as a therapeutic intervention in breast cancer
have created an opportunity to investigate this therapy
in human breast cancer trials. Iodine replacement in
situations of diagnosed iodine deficiency must consider
pre-existing thyroid disease and the possibility of co-
existing selenium deficiency.
References
Fuge R. Iodine deficiency: an ancient problem in a 1.
modern world. Ambio 2007;36:70-72.
Dunn JT. Seven deadly sins in confronting endemic 2.
iodine deficiency, and how to avoid them. J Clin
Endocrinol Metab 1996;81:1332-1335.
Dunn JT, Delange F. Damaged reproduction: the 3.
most important consequence of iodine deficiency. J
Clin Endocrinol Metab 2001;86:2360-2363.
DeLong GR, Leslie PW, Wang SH, et al. Effect on 4.
infant mortality of iodination of irrigation water
in a severely iodine-deficient area of China. Lancet
1997;350:771-773.
Schaller RT Jr, Stevenson JK. Development of 5.
carcinoma of the thyroid in iodine-deficient mice.
Cancer 1966;19:1063-1080.
Mellemgaard A, From G, Jorgensen T, et al. Cancer 6.
risk in individuals with benign thyroid disorders.
yroid 1998;8:751-754.
Burgess JR, Dwyer T, McArdle K, et al. e changing 7.
incidence and spectrum of thyroid carcinoma in
Tasmania (1978-1998) during a transition from
iodine sufficiency to iodine deficiency. J Clin
Endocrinol Metab 2000;85:1513-1517.
Franceschi S, Preston-Martin S, Dal Maso L, et al. 8.
A pooled analysis of case-control studies of thyroid
cancer. IV. Benign thyroid diseases. Cancer Causes
Control 1999;10:583-595.
Shakhtarin VV, Tsyb AF, Stepanenko VF, et al. 9.
Iodine deficiency, radiation dose, and the risk of
thyroid cancer among children and adolescents
in the Bryansk region of Russia following the
Chernobyl power station accident. Int J Epidemiol
2003;32:584-591.
Stadel BV. Dietary iodine and risk of breast, 10.
endometrial, and ovarian cancer. Lancet
1976;1:890-891.
Dunn JT. What’s happening to our iodine? 11. J Clin
Endocrinol Metab 1998;83:3398-3400.
Haddow JE, Palomaki GE, Allan WC, et al. Maternal 12.
thyroid deficiency during pregnancy and subsequent
neurophysiological development of the child. N Engl J
Med 1999;341:549-555.
Klein RZ, Sargent JD, Larsen PR, et al. Relation 13.
of severity of maternal hypothyroidism to cognitive
development of offspring. J Med Screen 2001;8:18-20.
Marani L, Venturi S. Iodine and delayed immunity. 14.
Minerva Med 1986;77:805-809. [Article in Italian]
Gutekunst R. Iodine deficiency costs Germany 15.
over one billion dollars per year. IDD Newsletter
1993;9:29-31.

Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 2 June 2008
Alternative Medicine Review Volume 13, Number 2 2008
Iodine
Page 126
Hollowell JG, Staehling NW, Hannon WH, et al. 16.
Iodine nutrition in the Unites States. Trends and
public health implications: iodine excretion data
from National Health and Nutrition Examination
Surveys I and III (1971-1974 and 1988-1994). J Clin
Endocrinol Metab 1998;83:3401-3408.
Caldwell KL, Jones R, Hollowell JG. Urinary iodine 17.
concentration: United States National Health and
Nutrition Examination Survey 2001-2002. yroid
2005;15:692-699.
WHO, UNICEF, and ICCIDD. 18. Assessment of
the Iodine Deficiency Disorders and Monitoring
their Elimination. WHO/NHD/01.1. Geneva,
Switzerland: World Health Organization;
2001:1-107.
Utiger RD. Maternal hypothyroidism and fetal 19.
development. N Engl J Med 1999;341:601-602.
Haddow JE, Palomaki GE, Allan WC, et al. Maternal 20.
thyroid deficiency during pregnancy and subsequent
neurophysiological development of the child. N Engl J
Med 1999;341:549-555.
Glinoer D. e regulation of thyroid function 21.
in pregnancy: pathways of endocrine adaptation
from physiology to pathology. Endocr Rev
1997;18:404-433.
Bazrafshan HR, Mohammadian S, Ordookhani A, et 22.
al. An assessment of urinary and breast milk iodine
concentrations in lactating mothers from Gorgan,
Iran, 2003. yroid 2005;15:1165-1168.
Pearce EN, Leung AM, Blount BC, et al. Breast milk 23.
iodine and perchlorate concentrations in lactating
Boston-area women. J Clin Endocrinol Metab
2007;92:1673-1677.
Fuse Y, Saito N, Tsuchiya T, et al. Smaller thyroid 24.
gland volume with high urinary iodine excretion
in Japanese schoolchildren: normative reference
values in an iodine-sufficient area and comparison
with the WHO/ICCIDD reference. yroid
2007;17:145-155.
Cann SA, van Netten JP, van Netten C. Hypothesis: 25.
iodine, selenium and the development of breast
cancer. Cancer Causes Controls 2000;11:121-127.
Nagataki S, Shizume K, Nakao K. yroid function 26.
in chronic excess iodide ingestion: comparison of
thyroidal absolute iodine uptake and degradation
of thyroxine in euthyroid Japanese subjects. J Clin
Endocrinol Metab 1967:27:638-647.
Konno N, Taguchi H, Miura K, et al. Serum 27.
thyrotropin concentration in apparently healthy
adults, in relation to urinary iodide concentration.
Clin Chem 1993;39:174-175.
Teng W, Shan Z, Teng X, et al. Effect of iodine 28.
intake on thyroid diseases in China. N Engl J Med
2006;354:2783-2793.
Pisani P, Parkin DM, Bray F, Ferlay J. Estimates of the 29.
worldwide mortality from 25 cancers in 1990. Int J
Cancer 1999;83:18-29.
LeMarchand L, Kolonel LN, Nomura AM. Breast 30.
cancer survival among Hawaii, Japanese, and
Causcasian women. Ten-year rates and survival by
place of birth. Am J Epidemiol 1985;122:571-578.
Minami Y, Takano A, Okuno Y, et al. Trends in the 31.
incidence of female breast and cervical cancers in
Miyagi Prefecture, Japan, 1959-1987. Jpn J Cancer Res
1996;87:10-17.
Konno N, Yuri K, Miura K, et al. Clinical evaluation 32.
of the iodide/creatinine ratio of casual urine samples
as an index of daily iodide excretion in a population
study. Endocr J 1993;40:163-169.
Spitzweg C, Harrington KJ, Pinke LA, et al . Clinical 33.
review 132: the sodium iodide symporter and its
potential role in cancer therapy. J Clin Endocrinol
Metab 2001;86:3327-3335.
Venturi S. Is there a role for iodine in breast diseases? 34.
Breast 2001;10:379-382.
Cocchi M, Venturi S. Iodide, antioxidant function 35.
and omega-6 and omega-3 fatty acids: a new
hypothesis of biochemical cooperation? Prog Nutr
2000;2:15-19.
Many MC, Papadopolos C, Martin I, et al. Iodine 36.
induced cell damage in mouse hyperplastic thyroid
is associated with lipid peroxidation. In: Gordon
A, Gross J, Hennemann G, eds. Progress in yroid
Research. New York, NY: Routledge; 1991:213-215.
Smyth PA. Role of iodine in antioxidant 37.
defence in thyroid and breast disease. Biofactors
2003;19:121-130.
Nolan LA, Windle RJ, Wood SA, et al. Chronic 38.
iodine deprivation attenuates stress-induced and
diurnal variation in corticosterone secretion in female
Wistar rats. J Neuroendocrinol 2000;12:1149-1159.
rall KD, Bull RJ. Differences in the distribution of 39.
iodine and iodide in the Sprague-Dawley rat. Fundam
Appl Toxicol 1990;15:75-81.
Stolc V. Stimulation of iodoproteins and thyroxine 40.
formation in human leukocytes by phagocytosis.
Biochem Biophys Res Commun 1971;45:159-166
Andersen S, Pedersen KM, Pedersen IB, Laurberg 41.
P. Variations in urinary iodine excretion and thyroid
function. A 1-year study in healthy men. Eur J
Endocrinol 2001;144:461-465.
ompson WW, Brailey AG, ompson B, et al. 42.
Range of effective iodine dosage in exopthalmic goiter
III. Arch Int Med 1930;45:430.
Crohn BNE. Absorption of compound solution of 43.
iodine from the gastrointestinal tract. Arch Intern
Med 1932;49:950-956.
Gennaro AS. 44. Remington: e Science and Practice
of Pharmacy. 19th ed. Easton, PA: Mack Pub Co.;
1995:1267.
Bretthauer EW. Milk transfer comparisons of 45.
different chemical forms of radioiodine. Health Phys
1972;22:257-260.
Topper YJ, Freeman CS. Multiple hormone 46.
interactions in the developmental biology of the
mammary gland. Physiol Rev 1980;60:1049-1106.

Copyright © 2008 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 13, Number 2 June 2008
Alternative Medicine Review Volume 13, Number 2 2008
Review Article
Page 127
Aceves C, Rodon C, Ramirez-CI, et al. Mammary 47.
5’deiodinase (5’D) during the breeding cycle of the
rat: indirect evidence that 5’D type I is specific to the
alveolar epithelium. Endocrine 1995;3:95-99.
Goehring C, Morabia A. Epidemiology of benign 48.
breast disease, with special attention to histologic
types. Epidemiol Rev 1997;19:310-327.
Eskin BA, Grotkowski CE, Connolly CP, Ghent WR. 49.
Different tissue responses for iodine and iodide in rat
thyroid and mammary glands. Biol Trace Elem Res
1995:49:9-19.
Ghent WR, Eskin BA, Low DA, Hill LP. Iodine 50.
replacement in fibrocystic disease of the breast. Can J
Surg 1993;36:453-460.
Aceves C, Anguiano B, Delgado G. Is iodine a 51.
gatekeeper of the integrity of the mammary gland? J
Mammary Gland Biol Neoplasia 2005;10:189-196.
Kessler JH. e effect of supraphysiologic levels 52.
of iodine on patients with cyclic mastalgia. Breast J
2004;10:328-336.
Parker SL, Tong T, Bolden S, Wingo PA. Cancer 53.
statistics, 1997. CA Cancer J Clin 1997;47:5-27.
Ziegler RG, Hoover RN, Pike MC, et al. Migration 54.
patterns and breast cancer risk in Asian-American
women. J Natl Cancer Inst 1993;85:1819-1827.
Smyth PP. e thyroid and breast cancer: a significant 55.
association? Ann Med 1997;29:189-191.
Goldman MB. yroid diseases and breast cancer. 56.
Epidemiol Rev 1990;12:16-28.
Turken O, NarIn Y, DemIrbas S, et al. Breast cancer 57.
in association with thyroid disorders. Breast Cancer
Res 2003;5:R110-R113.
Smyth PP. yroid disease and breast cancer. 58. J
Endocrinol Invest 1993;16:396-401.
Kilbane MT, Ajjan RA, Weetman AP, et al. Tissue 59.
iodine content and serum-mediated 125I uptake-
blocking activity in breast cancer. J Clin Endocrinol
Metab 2000;85:1245-1250.
Eskin BA. Iodine and mammary cancer. 60. Adv Exp
Med Biol 1977;91:293-304.
Eskin BA, Parker JA, Bassett JG, George DL. Human 61.
breast uptake of radioactive iodine. Obstet Gynecol
1974;44:398-402.
Funahashi H, Imai T, Tanaka Y, et al. Suppressive 62.
effect of iodine on DMBA-induced breast tumor
growth in the rat. J Surg Oncol 1996;61:209-213.
Garcia-Solis P, Alfaro Y, Anguiano B, et al. 63.
Inhibition of N-methyl-N-nitrosourea-induced
mammary carcinogenesis by molecular iodine (I2)
but not by iodide (I-) treatment. Evidence that I2
prevents cancer promotion. Mol Cell Endocrinol
2005;236:49-57.
Greer MA, Goodman G, Pleus RC, Greer SE. Health 64.
effects assessment for environmental perchlorate
contamination: the dose response for inhibition of
thyroidal radioiodine uptake in humans. Environ
Health Perspect 2002;110:927-937.
Baier-Anderson C, Blount BC, Lakind JS, et 65.
al. Estimates of exposures to perchlorate from
consumption of human milk, dairy milk and water,
and comparison to current reference dose. J Toxicol
Environ Health A 2006;69:319-330.
Sanchez CA, Krieger RI, Khandaker N, et al. 66.
Accumulation and perchlorate exposure potential of
lettuce produced in the Lower Colorado River region.
J Agric Food Chem 2005;53:5479-5486.
Sanchez CA, Krieger RI, Khandaker NR, et al. 67.
Potential perchlorate exposure from Citrus sp.
irrigated with contaminated water. Anal Chim Acta
2006;567:33-38.
Snyder SA, Pleus RC, Vanderford BJ, Holady JC. 68.
Perchlorate and chlorate in dietary supplements
and flavor enhancing ingredients. Anal Chim Acta
2006;567:26-32.
Wolff J. Perchlorate and the thyroid gland. 69. Pharmacol
Rev 1998;50:89-105.
Blount BC, Pirkle JL, Osterloh JD, et al. Urinary 70.
perchlorate and thyroid hormone levels in adolescent
and adult men and women living in the United States.
Environ Health Perspect 2006;114:1865-1871.
Cooper DS. Subclinical thyroid disease: consensus or 71.
conundrum? Clin Endocrinol (Oxf) 2004;60:410-412.
Surks MI, Ortiz E, Daniels GH, et al. Subclinical 72.
thyroid disease: scientific review and guidelines
for diagnosis and management. JAMA
2004;291:228-238.
Dunn JT, Semigran MJ, Delange F. e prevention 73.
and management of iodine-induced hyperthyroidism
and its cardiac features. yroid 1998;8:101-106.
Burgi H, Schaffner TH, Seiler JP. e toxicology 74.
of iodate: a review of the literature. yroid
2001;11:449-456.
Robison LM, Sylvester PW, Birkenfeld P, et al. 75.
Comparison of the effects of iodine and iodide on
thyroid function in humans. J Toxicol Environ Health
A 1998;55:93-106.
Markou K, Georgopoulos N, Kyriazopoulou V, 76.
Vagenakis AG. Iodine-induced hypothyroidism.
yroid 2001;11:501-510.
Stanbury JB, Ermans AE, Bourdoux P, et al. 77.
Iodine-induced hyperthyroidism: occurrence and
epidemiology. yroid 1998;8:83-100.
Giray B, Hincal F, Tezic T, et al. Status of selenium 78.
and antioxidant enzymes of goitrous children is
lower than healthy controls and nongoitrous children
with high iodine deficiency. Biol Trace Elem Res
2001;82:35-52.
Derumeaux H, Valeix P, Castetbon K, et al. 79.
Association of selenium with thyroid volume and
echostructure in 35- to 60-year-old French adults.
Eur J Endocrinol 2003:148:309-315.
Zimmermann MB, Kohrle J. e impact of iron 80.
and selenium deficiencies on iodine and thyroid
metabolism: biochemistry and relevance to public
health. yroid 2002:12:867-878.