Iodine: Deficiency and Therapeutic Considerations...that iodine deficiency allows for increased radioactive iodine uptake. Although the pathology tnay be differ-ent in extrathyroidal

Alternative Medicine Review Volume 13, Number 2 2008

Iodine: Deficiencyand Therapeutic Considerations

Lyn Patrick, ND

Abstract

Iodine deficiency is generaily recognized as the most commonly

preventable cause of mental retardation and the most common

cause of endochnopathy (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.

Med Rev 2008;13(2):116-127)

IntroductionThe oceans are rhe worldwide repository of

iodine; very little of the earth's iodine is actually foundin 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 iniodine than soils further inland. So-called goiter beltscan occur in areas of elevated soil iodine because iodineis bound strongly to soil and vegetable crops are pooriodine sources.'

Deficiency WorldwideIodine deficiency is considered to be the most

common endocrinopathy and most preventable cause ofmental retardation globally In 1998, one-third of theworld's population lived in iodine-deficient areas.^

Although the primary recognized manifesta-tion of iodine deficiency is endemic goiter, it is only themost visible and well-documented sign of a deficiency.There are several manifestations of iodine deficiencynow termed iodine deficiency disorders. The major-ity of these manifest in infants and children as a resultof maternal iodine deficiency.' Hearing loss, learningdeficits, brain damage, and myelination disorders canoccur due to fetal or perinatal bypothyroidism. Infantmortality rates have decreased 65 percent in commu-nities where iodine deficiencies have been eliminated."*Maternal iodine deficiency manifests as low thyroxine,elevated thyroid stimulating hormone (TSH), andsubclinical thyroid enlargement (subclinical goiter). Aspregnancy and lactation increase iodine loss, the risk forgoiter continues, and even after lactation ceases it maymanifest as multinodular goiter and hyperthyroidism.Iodine deficiency in women can lead to overt hypotby-roidism and consequent anovulation, infertility, gesta-tional hypertension, spontaneous first-trimester abor-tion, and stillbirth."*

Iodine deficiency is also associated with in-creased risk for thyroid carcinoma in animal models andhumans.'''* In the Bryansk region of Russia, an area of

Lyn Patrick, ND - Bastyr University graduate 1984; private practice, Durango,CO, specializing in environmental medicine and chronic hepatitis C; faculty ofthe Postgraduate Certification Course in Environmental Medicine, SouthwestCollege o( Naturopathic Medicine; contributing editor, Alternative MedicineReview: physician-member of the Hepatitis C Ambassadors TeamCorrespondence address: 117 CR 250 Suite A, Durango, CO 81301Email: [email protected]

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Review ArticleAlternative Medicine Review Volume 13, Number 2 2008

known radioactive 1-131 exposure following the Cher-nobyl disaster, the risk of all types of thyroid cancer wasdirectly inversely associated with urinary iodine excre-tion levels.^ Multiple studies assessing radioactive iodineuptake in iodine-deficient thyroid glands have affirmedthat iodine deficiency allows for increased radioactiveiodine uptake. Although the pathology tnay be differ-ent in extrathyroidal cancers, Stadel has postulated thatgiven the geographical associations of iodine deficiency,prevalence of goiter, and incidence of reproductive can-cers, there is a direct association with iodine deficiencyand increased risk for prostate, endometrial, ovarian,and breast cancers.'"

Table 1, Sources of Iodine

Soil

NalOi

NalO.,

Sodium iodine

Sodium periodate

Seaweed/Algal Phytoplankton

KI

Nal

I2

r

Potassium iodide

Sodium iodide

Iodine

Iodide

Seawater

r Iodide

In mild deficiencies, euthyroid (normal thyroidhormone levels) stares may occur hut at the expense ofthyroid enlargement, neck compression, and thyroidnodules with possible development of hyperthyroid-ism." Mild hypothyroidism in pregnant women sec-ondary ro iodine deficiency is associated with lower IQand cognitive deficits in their children.'"'"

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 arole of iodine sufficiency in normal delayed immunity.''*

Iodine Deficiency in DevelopedCountries

Although frank iodine deficiency is primarilyfound in the underdeveloped world (Africa, Southeastand Central Asia), countries in Europe, including Ger-many, France, Italy, and Belgium, are also considerediodine-deficient. Germany spends the equivalent of onebillion dollars annually in both healthcare expendituresand lost work time as a result of iodine deficiency andresultant thyroid disease.'^

Although North Americans are consideredan iodine-sufficient population, that assumption ischanging. The National Health and Nutrition Survey(NHANES) data monitoring urine iodine shows io-dine intake has dropped by 50 percent from the periodof 1971-1974 to 1988-1994, with median urine iodinelevels dropping from 320 mcg/L ro 145 mcg/L."' Al-though the next NHANHS 2001-2002 survey showedan increase in median urine iodine levels to 165 mcg/L,an apparent leveling off of a precipirous drop, womenof childbearing age did not fare as favorably. Accordingto a Centers for Disease Control (CDC) evaluation ofNHANES 2001-2002, approximately 36 percent ofwomen of childbearing age in the United States mayreceive insufficient dietary iodine.'' Iodine insufficiencywas defined by urine iodine levels below 100 mcg/L andassessed from single samples, the cutoff for iodine in-sufficiency defined by the World Health Organization(WHO) and diagnostic of mild iodine deficiency. IbeW H O found that in populations with mean values be-low this level the prevalence of goiter increases signifi-cantly."* Fifteen percent of the same sample of womenfrom NHANES 2001-2002 had urinary iodine levelsless tban 50 mcg/L, a level at which thyroid hormonesecretion is considered inadequate and is considered byrbe W H O to be an indication of moderate-to-severedeficiency.

Public health officials voice concern over thisdata because of its implications for maternal/childhealth.'^ The thyroid gland and the hypothalamic/

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pituitary/thyroid axis begins to function in the devel-oping fetus at 11 weeks of gestation. The main role oftetal thyroid hormone secretion (T4 levels are demon-strable at 18-20 weeks of gestation) is development ofthe nervous system. A U.S. retrospective study assess-ing maternal hypothyroidism and subsequent IQ defi-cits in children ages 7-9 years found iodine deficiencymay be causing fetal brain damage and other neurologi-cal detects, including lowered IQ, spasticity, ataxia, anddeaf-mutism. ** Evidence also indicates autoimmunethyroidiris occurring during pregnancy appears to bethe result oí iodine deficiency."' Iodine is also crucialduring lactation to provide continuing neurological de-velopment of the infant.'^ Breast-milk iodine levels ina recent study of lactating mothers in Boston revealed47 percent had levels insufficient to provide adequateiodine to meet infant requirements.''

Dietary Levels of Iodine: The JapanesePhenomenon

Japanese populations have historically con-sumed significant amounts of dietary iodine from sea-weed intake, possibly consuming a minimum of 7,000meg iodine daily from kombu alone.'' Estimates of theaverage daily Japanese iodine consumption vary from5,280 meg to 13,800 mcg;"'^^ by comparison the aver-age U.S. daily consumption is 167 meg. The Japanese,therefore, consume dietary iodine approximately 5-14times 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 theU.S. NHANES 2001-2002 data.^" These higher lev-els, however, appear ro have no suppressive effect onthyroid function as indicated by thyroid volume mea-surements, the accepted standard for assessing thyroid

Figure 1. Thyroid Hormone Synthesis

Iodide

Adapted from: De la Vieja A, et al. Physiol Rev20ÛO;80:1083-1105-

lodine. in ttie form of iodide, is absorbed in the thyroid follicle through thesodium/iodine symported protein (NIS) found in the basolateral membrane of thefollicular cell. The activity of NIS is up-regulated by the binding of TSH totheTSHreceptors on the follicular cells {TSH-R). This allows the absorption and concentrationof iodine inside the ceil to levels 20-40 times greater than that found in the blood.Iodide is then orgamfied (oxidized) to iodine by thyroid peroxidase (TPO) and incorpo-rated into the thyroglobulin molecule (Tg). Thyroid hormones (T3 andT4) are thensecreted into the bloodstream from ttie follicular cell.

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enlargemenr. A study comparing urine iodine and thy-roid volume in Japanese children showed 16 percentof those tested excreted over 1,000 mcg/L. "* Elevatedlevels of urinary iodine did not predict increased thy-roid gland volume, as might be expected from data instudies of Chinese populations associating excess levelsot iodine with autoimmune thyroiditis and hypothy-roidism. ' Japanese women who consume a traditionalhigh-seaweed diet also have a low incidence of benignand malignant breast disease. " Japanese women who

Figure 2. Antioxidant Functions of Iodine

Iodine ( I j is catalyzed by thyroid peroxidase using Hfi^. H^Oj used in this reactiondecreases the amount of H O that would otherwise be available for damagingoxidation reactions. Selenium containing GPX removes H O from the tissues, alsodecreasing oxidative damage.

TPO - ThyroperoxidaseGPX - Glutathione PeroxidaseT, -TriiodothyronineT^ - Tetraiodothyronine

Adapted from: Smyth PR Role of iodine in antioxidant defence in thyroid and breast disease.ö/ofeciore2003:t9:12M30.

consume a Western diet low in seaweed or who emi-grate to the United States lose this protective advantageand gain the same risk for fibrocystic breast disease andbreast cancer as their Western counterparts.^'^'" Japanalso h:is a low incidence of iodine-deficiency goiter andautoimmune thyroiditis.'•^ It has been hypothesized theamount of iodine in the Japanese diet has a protectiveeffect for breast and thyroid disease.^^

The Role of Iodine in the Human BodyIodine is found in nature in various forms:

inorganic sodium and potassium salts (iodides andiodates), inorganic diatomic iodine (molecular iodineor IJ , and organic monoatomic iodine (Tiible 1). Sea-weeds, such as wakame, nori ov mekabu (used in sushi,soups, salads, and in powdered form as a condiment)and widely consumed in Asian cultures, contain highquantities of iodine in several chemical forms, includingiodine in the molecular form (IJ and iodine organified

to proteins. These forms of iodine areabsorbed through the intestinal tract viatwo different mechanisms. Moleculariodine (I,) is transported by facilitateddiffusion. Iodides (I) are absorbed via atransport protein in the gastric mucosacalled the sodium-iodide symporter, amolecule found in a variety of tissuesin the body that utilize and concentrateiodine - the thyroid, mammary tissue,salivary gland, and cervix."

In order to produce concentra-ted iodine-based hormones, the thyroidtissue sodium-iodide symporter pro-tein, a critical plasma membrane proteinin the tliyroid follicular cells, sequestersiodide from the extracellular fluid. Theiodide molecule then moves across theapical membrane to the cell-colloidsurface where it is oxidized by thyroidperoxidase (TPO). In this form it isbound to tyrosine residues in the thyro-globulin molecule and these niono- anddiiodotyrosines become the precursorsto commonly known thyroid hormonesT^ and Tj (Figure 1). Iodine accountsfor 65 percent of the molecular weightof T and 59 percent of the molecular

weight of T^."

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 ofthe bodys iodine is concentrated in the thyroid tissueand thyroid hormones. The remaining nonhormonal io-dine is found in a variery of tissues, including mammarytissue, eye, gastric mucosa, cervix, and salivary glands.With the exception of mammary tissue, the function of

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Alternative Medicine Review Volunte 13, Number 2 2008

iodiiie in these tissues is largely unknown." Mammarytissue's role in sequestering and concentrating iodine isrelated to fetal and neonatal development and is largelyevolutionary, as detailed below. However, iodine's rolein mammary and other tissues has also been shown tohave an antioxidant function. Iodide can act as an elec-tron donor in the presence of hydrogen peroxide, perox-idasc, and some polyunsaturated fatty acids, decreasingdamage by tree oxygen radicals (Figure 2).'"''^ Iodine-deficient glands contain increased amounts of malondi-aldchyde, a product of lipid peroxidation that can occura.s a result of inadequate iodine stores.'*^ Concentrationsoí iodine as low .is 15 niicromolar (achievable in humanserum) have the same antioxidant activity as ascorbicacid.' This antioxidant effect of Iodine may explain thetherapeutic effects ot seaweed baths or iodine-rich so-lutions known as thalassotherapy used historically totreat ocular diseases, thyroid disease, diabetes, cardiacand respiratory disease, and arteriosclerosis.''

Animal studies have shown iodine normalizeselevated adrenal corticosteroid hormone secretion re-lated to the stress response"* and reverses the effect ofhypothyroidism on the ovaries, testicles, and thymus inchyroidectomised rats.''' Iodine may also have a role inimmune fiinction; when placed in a medium contain-ing 10 *'M iodide, human leukocytes synthesize thyrox-

Testing Iodine LevelsMore than 90 percent of dietary iodine is ex-

creted in the urine. Single random urine sampling is thestandard accepted method of measuring body storesof iodine. The World Health Organization has deter-mined 50-99 mcg/L indicates mild deficiency, 20-49nicg/L indicates moderate deficiency, and less than 20indicates severe deficiency."* Because random urinesamples have been found to be adequate for populationscreening, there is little advantage in calculating urineiodine:creatinine ratios. For individual measurements,however, multiple spot urine iodine measurements or24-hour urine iodine evaluations are more precise.'"

Medical Uses of IodineLugoVs Solution

Lugol's solution (produced by French physi-cian Jean Lugol in 1829) consists of five-percent iodineand 10-percent potassium iodide in solution. It wasoriginally used to treat "scrofula" and 40 years later totreat anthrax infections. Lugol's solution became widelyused in medicine in the early 1900s to treat a variety ofdisorders, including simple goiter and Graves disease,''^and by 1932 had become commonplace in medical prac-tice."" Even as late as 1995, pharmaceutical texts recom-mended the use of 0.1-0.3 niL Lugol's five-percent solu-tion for the treatment of simple goiter,''' the equivalentof 12.5-37.5 mg iodine. Lugol's solution fell out of favorfor the treatment of iodine-deficiency diseases as theavailability ot thyroid extracts and iodized salt becamemore widely used. Multiple pharmaceutical medicationsused currently contain iodine.

Iodine and Fibrocystic Breast DiseaseThe breast concentrates iodine to a greater

degree than the thyroid gland;'' human milk containsa concentration of iodine four times greater than thy-roid tissue.''' This evolutionary mechanism is necessaryfor neonatal thyroid function and consequent normalneural development."' Mammary tissue also producestwo separate deiodinase enzymes: deiodinase type 1and deiodinase type 2, which can convert T^ ro T^. De-iodinases control the amount of free iodine present inbreast tissue - higher levels during puberty, pregnancy,and lactation, and lower levels in nonpregnant or post-partum phases (Figure 3).'''

Biopsy-proven studies find fibrocystic breastdisease (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 significantlylarger prevalence."* Studies by Eskin et al found iodinedeficiency in a rat model resulted in breast hyperplasiathat responded to iodine repletion at a dose of 0.1 mg/kg body weight,''' equivalent to a 5-mg dose in a 50-kg(110-pound) female. This group also determined thatmolecular iodine is the active form of iodine in breasttissue in animal models and it is less thyrotoxic than io-dide because more of the molecular iodine is selectivelyconcentrated in breast tissue than thyroid tissue. A sig-nificant amount of data shows the mammary gland is

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more efficient in capturing and concentrating moleculariodine than the thyroid gland."''

Ghent and Eskin continued their iodine-repletion studies in women with diagnosed FBD.^"'''Til rough a series of three trials assessing different formsof iodine - first sodium iodide or protein-bound iodide,then molecular iodine - they examined efficacy andtoxicity of weight-based iodine dosing, extrapolatingfrom the animal model dose. Beginning with an uncon-trolled study of 233 women with FBD, they comparedsodium iodide to protein-bound iodide for a period of2-5 years. Patients (n = l,365), including those who didnot respond to either form of iodide were switched tomolecular iodine using a 0.07-0.09 mg/kg dose. Tlieyconcluded that the molecular form of iodine was moreeffective and had a significantly lower side-effect profilethan iodide forms. Both subjective and physician-eval-uated clinical improvements were noted in 65 percentof women on a weight-based dose of 3-6 mg molecular

iodine. This compared to a subjective improvement of33 percent in the placebo group (Table 2). No subjectstreated with molecular iodine had thyroid-related sideeffects, and no changes were noted in thyroid lab val-ues or on physical examination. In study #3, 56 womenwith FBD were randomized to either molecular iodineor placebo for six months. They were assessed by phy-sician examination and subjective evaluation every twomonths, and followed with thyroid blood tests andmammography at the beginning and end of the trial.^"After six months, 65 percent of the treatment group ex-perienced significant improvement. By contrast, in theplacebo group 33 percent experienced improvementwhile three percent demonstrated worsening on physi-cian examination.

Another human study evaluating iodine andFBD examined the effect of an iodine compound ofsodium iodide and iodate.^^ Based on animal stud-ies showing molecular iodine is less thyrotoxic than

Figure 3. Deiodinase Control of Iodine in Breast Tissue

Basal Membrane

Mammary gland produces either a majority of deiodinase type 1 (DU)during pregnancy/iactation or a majority of deiodinase type 2 duringnonpregnant or postpartum (postlactation) periods, iodine is absorbed viathe sodium iodine symporter (NIS) and oxidized by iactoperoxidase (LPO).

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Table 2, Iodine Repletion Studies in Women with FBD

Typeof Study

Duration

Number ofParticipants

Medication& Dosage

Evaluation

Study #1 ProspectiveUncontrolled

2 years/5 years

233 on Lugoi'sfor 2 years

588 on iodized caseinfor 5 years

31-62 mg I

(n-233)Iodine caseinate

10mâ/day{n-588)

Subjective and clinicalevaluation

Study #2 ProspectiveControi Crossover

9.9 monthspost crossover

1,365 for minimum of

8.9 months: totaltreatment time

4,813 viioman years

Molecular iodine0.07-0.09 mg/kg body

weight/day

Subjective and clinicalevaluation

Study #3 ProspectiveControl Double-blind

6 months

56

Molecular iodine 0.07-0.09 mg/kg

body weight/day

Pre & postmammography;

TSHJ3J4

iodide, this particular formulation was u.sed because itgenerates molecular iodine as ii result oí dissolution instomach acid. The randomized, double-blinded, place-bo-controlled study evaluated the safety and efficacy ofthree dosages - 1.5, 3.0, and 6.0 mg - in 111 women.Patients were assessed by physicians and reported painbased on a standardized scale. The greatest reduction inpain, evident by month 3, occurred at the 6.0-mg dose.Iiy month 6, 51.7 percent oí study participants on 6.0mg reported at least a 50-percent pain reduction, whilethe placebo group reported an 8.3 percent reduction.Tlie eiïicacy of this iodine compound appeared to bedose-related, with a 6.0-mg dosage resulting in a greaterlevel of pain reduction in a greater number of patientsthan the 3.0-iiig dose (Table 3). Due to the small num-ber of women in the study, however, the p value did notreach significance.

Iodine and Breast CancerIn 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 andthe U.K. rate is 27 per 100,000.'^' Japan also has sig-nificantly lower rates of hypothyroidism, autoimmunethyroid disease, and hyperthyroid conditions, while theaverage daily dietary iodine intake may be as high as25 times that of the United States.-' The incidence ofbreast cancer in Japanese women who emigrate to theUnited States and adopt a Western diet equals that ofnon-Japanese women living in the United States.'' Thelower incidence of both FBD and breast cancer havebeen attributed to the increased dietary intake of iodinein the traditional Japanese diet.-''

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

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Table 3. Dose-dependent Efficacy of an Iodine Compound for FBD

Placebo1.5 mgIodine

3.0 mgIodine

6.0 mgIodine

All randomized subjects with pain, tenderness, and

nodularity at baseline

All randomized subjects with moderate or severe pain,tenderness, and nodularity at baseline

0/15(0%) 0/10(0%) 7/28(25.0%) (18.5%)

0/12(0%) 0/9(0%) 5/22 5/27(27.3%) (18.5%)

0.047

0.106

Adapted from: Kessler JH. Ttie effect of supraphysiologic levels of iodine on patients with cyclic mastalgia. Breast Journal 2004:10:328-336.

show no significant association.^''^" Smyth found a sig-nificantly greater mean thyroid volume in female breastcancer patients compared to controls.^^

Tlie studies on iodine and breast cancer in bothhumans 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 fimc-tion of the mammary glands of rats, especially alveolarcells. I is distinctly more effective than I in diminishingductal hyperplasia and perilobular fibrosis in mammaryglands, using the same total iodine doses in both treat-ments.''^ A clinical study of breast cancer patients foundbreast tissue levels of iodine were significantly lower inthe breast tissue of women with diagnosed breast can-cer than in breast tissue of women with either normalbreasts or benign fibroadenoma.'"

Animal and human studies show that in io-dine-deficient states the breast parenchyma in rodentsand women show atypia, dysplasia, and even neopla-sia/ ' Eskin et al demonstrated that iodine-deficientbreast tissue in animals is more susceptible to the effectof carcinogens, and breast lesions occur in greater num-bers and earlier in the process of neoplasia. Metabolic-ally, iodine-deficient breasts show pathological changesin RNA/DNA ratios, estrogen receptor proteins, andcytosol iodine levels that lead to neoplasia.*"" Clinically,Eskin also demonstrated that women with hyperplasticbreast tissue have significantly higher radioactive iodineuptake than women with normal breast tissue. The au-thor hypothesized this was a result of inadequate breasttissue iodine levels.*''

Supplementation with iodine alone or in com-bination with progesterone has been shown to shrinkbreast tumors in animals. Lugol's solution (1 g iodineand 2 g potassium iodide in 100 niL 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)/'*^ l l ic most effectivedose of iodine was the lowest given - 0.0025 n^g dailyTlie weight-based dose equivalent of Lugol's solutionwould be 5.0 mg inorganic iodine for a 50-kg female.ITiis dose correlates with Eskin's researcli finding 0.1mg/kg body weight per day inorganic iodine promotessufficiency in the rat necessary to improve signs andsymptoms of FBD.''''

Another study of chemically-induced mamma-ry cancer in rats found molecular iodine is more effectiveat inhibiting mammary cancer than iodide or thyrox-ine/" Tlie iodine used in the study was a 0.05-percentmolecular iodine compared to 0.05-percent potassiumiodide or thyroxine (3 mcg/mL), all in drinking water.Rats receiving molecular iodine demonstrated greaterthan 50-percent reduction in incidence of mammarycancer (30%) compared to controls (72.7%). Iodine-treated rats exhibited a strong and persistent reductionin mammary cancer, and only the I, treatment was capa-ble of diminishing basal lipoperoxidation in mammaryglands - the theoretical mechanism for iodine's actionin mammary cancer reduction. Reactive oxygen species,specifically lipoperoxides, are involved in initiation andpromotion of carcinogenesis, where specific mutation.sof certain genes occur.'^ In both studies, no toxic ef-fects of iodine on thyroid fiinction or other side effects

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at effective dosages were noted. Both authors recom-mend the initiation of human breast cancer trials withiodine."'"

Thyroid Toxicants: PerchloratePerchlorate is an inorganic anion that occurs

naturally in soil and is also made synthetically. The am-monium salt of perchlorate is manufactured primarilyfor use as a rocket propellant, in explosives manufactur-ing, and as a pliarmaceutical. Perchlorate is also natur-ally occurring in fertilisers th.it contain nitrate-richmineral deposits.^

Recent studies have found significant perchlo-rate contamination in groundwater throughout thewestern United States as a result of ammonium perchlo-rate disposal. Perchlorate (at levels over 4 ppb) has beenfound to contaminate the drinking water of 11 millionpeople in the United States, and high levels of perchlo-rate have also been found in the food supply. Humanmilk has been found to contain five times the perchlo-rate levels (10.1 mcg/L) oí cow milk (2 mcg/L).''^ Per-chlorate contamination has also been documented ingrain, fruit, vegetables, dietary supplements, and foragecrops for livestock.''^ ''**

Perchlorate is a known competitive inhibitor ofthe sodium-iodide symporter in humans and can inhi-bit iodide uptake, leading to the suppression of T^ andTj. Potassium perchlorate is currently used as a phar-maceutical to treat thyrotoxicosis and hypothyroidisminduced by amiodarone.'''*

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 fiinctionin the general population. An evaluation of the recentNHANHS 2001-2002 survey examined the relation-ship of urinary perchlorate levels, urinary iodine levels,serum TSH, and serum T^ levels in adult men and wom-en,'^ resulting in three surprising findings. First, 36 per-cent of women in the NHANES subset had low urineiodine levels (<100 mcg/L), equivalent to 2.2 millionwomen nationwide, considering that the NHANESsubset is representative of the population in general.The second finding was that perchlorate contamination,as low as 5 ppb, is associated with elevations of TSHand decreased serum T in all 1,111 women regardless

of iodine status. Third, in women with low urine iodinelevels under 100 mcg/L (suggesting iodine insufficien-cy), perchlorate at levels as low as 5 ppb was associatedwith a 16-percent decrease in T levels and elevation ofTSH levels, consistent with inhibition of iodide uptake.In the group at highest risk of thyroid deficits, womenwith urine iodine levels under 100 mcg/L, exposure to5 ppb perchlorate could theoretically cause subclinicalhypothyroidism in 10 percent oí that population."

Subclinical hypothyroidism is currently definedas an elevated TSH with Tj and T^ levels within normalreference ranges.'' Tlie concern with this population ofwomen of childbearing age who have low urine iodinelevels is that undetected, subclinical hypothyroidismcan lead to fetal neurological damage.'"

Iodine ToxicityThe U.S. recommended daily intake (RDI)

for dietary iodine is 150 meg for adults, 220 meg forpregnancy, and 270 meg during lactation. ' The safe up-per limit has been set at 1,000 meg (1 mg) as a resultof studies assessing TSH levels with supplementation.Iodine supplementation over this limit has been shownto potentially contribute to an underlying thyroid pa-thology in those with Hashimoto's thyroiditis. Graves'disease, or exaeerbation of nodularities in euthyroid in-dividuals if intake exeeeds 20 mg iodine or iodide.'^'^

Population studies have shown exeessive io-dine intake may inerease the prevalence of autoimmunethyroiditis in animals and humans, increasing the riskof overt hypothyroidism.-'' Studies following indi-viduals with elevated anti-thyroid antibody titers haveshown that progression of hypothyroidism is correlatedwith increasing iodine intake. "* Some reports of iodinerepletion, causing hyperthyroidism in individuals withprior severe iodine deficiency, have shown reversion tobaseline in the continued presence of iodine repletion3-5 years later.'^ Another study of a large population inChina 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 and1.9 mlU to maintain the lowest incidence of abnormalthyroid function during iodine supplementation.'"

In addition to pre-existing thyroid pathologiesexacerbated with iodine supplementation, exeessive in-gestion of iodine in medieation (amiodarone) or water

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Review ArticleAlternative Medicine Review Volume 13, Nunnber2 2008

contamination may contribute to goiter, hypothyroid-ism, elevated TSH levels, and ocular damage/' How-ever, in studies referenced above by Eskin and Ghent, "^which excluded patients with pre-existing autoimmunethyroid pathologies and used 3-6 mg molecular iodinefor up to five years, no associated thyroid abnormalitieswere observed.^"' ^

Selenium is required for the production ofdeiodinase selenoenzymes. Clinical investigators in se-lenium- and iodine-deficient populations conclude thecoexisting deficiencies cause increased TSH levels andcontribute to goiter development.'^ One French studyfound an inverse relationship between selenium statusand thyroid volume.''' Co-existing deficiencies becomeproblematic in areas where iodine supplementation ispromoted on a population-wide basis. Selenium sup-plementation may be necessary to prevent potential thy-roid damage from iodide supplementation in selenium-deficient individuals.^"

ConclusionIodine is an essential mineral for normal thy-

roid function, mammary gland development, and fetaland infant neurological growth. Iodine deficiency is epi-demic in developing countries and parts of Europe. Re-cent evidence shows iodine deficiency is also strikinglycommon among adult women in the United States. Theresulting risk for neurological impairment in fetal andinEint brain development and potential tor mammarydysplasia warrants closer evaluation of the general fe-male population for iodine sufficiency. Also of concernis widespread contamination of food and water supplieswith the known thyroid toxicant perchlorate, whichblocks iodine uptake in the thyroid gland and mam-mary gland via competitive inhibition of the sodiumiodide symporter protein. Perchlorate may also increasethe risk tor subclinical hypothyroidism in a subgroup ofwomen with low urine iodine levels.

The safety and efficacy ot molecular iodine asa therapeutic tool in the treatment of fibrocystic breastdisease has been well documented. Animal studies us-ing iodine as a therapeutic intervention in breast cancerhave created an opportunity to investigate this therapyin human breast cancer trials. Iodine replacement insituations of diagnosed iodine deficiency must considerpre-existmg thyroid disease and the possibility of co-existing selenium deficiency.

References1. Fuge R. Iodine deficiency; an ancient problem in a

modern world. Ambio 2007; 36:70-72.2. Dunn JT. Seven deadly sins in confronting endemic

iodine deficiency, and how ro avoid them. / C7t»Emiocrinol Mctab 1996:81:1332-1335.

3. DunnJT, Delangc F. Damaged reproduction: themost important consequence of iodine deficiency. /Clin Endocrinol Metah 2001;86:2360-2363.

4. DeLong GR, Leslie PW, Wang SH, et al. Effect oninfant mortality of iodination of irrigation waterin a severely iodine-deficient area of China. Lancet1997:350:771-773.

5. Schaller RTJr, Stevenson JK. Development otcarcinoma of the thyroid in iodine-deficient mice.Gííiirer 1966;19:1063-1080.

6. Mellcmgaard A, From G, Jorgensen T, et al. Cancerrisk in individuals with benign thyroid disorders.%ro¿íí 1998:8:751-754.

7. Burgess JR, Dwyer T, McArdlc K, ct ;iL Tlie changingincidence and spectrum of thyroid carcinoma inTasmania (1978-1998) duringa transition fromiodine sufficiency to iodine deficiency. / CUnEndocrinol Metab 2OOO;85:1513-1517.

8. Franceschi S, Preston-Martin S, Dal Maso L, et al.A pooled analysis of case-control studies of thyroidcancer. IV. Benign thyroid diseases. Cancer CausesControl 1999:10:583-595.

9. Shakhtarin VV, Tsyb AF, Stepanenko VF, et al.Iodine deficiency, radiation dose, and the risk ofthyroid cancer among children and adolescentsin the Bryansk region of Russia tollowing theChernobyl power station accident. intJ Epidemiol2003:32:584-591.

10. Stadel BV. Dietary iodine and risk of breast,endometrial, and ovarian cancer. Lancet1976;l:890-891.

11. DunnJT. What s happening to our iodine? J ClinEndocrinol Metab 1998:83:3398-3400.

12. Haddow JE, Palomaki GE, Allan WC, et al. Maternalthyroid deficiency during pregnancy and subsequentneurophysiological development oí the child. N EnglJMeíí 1999:341:549-555.

13. Klein RZ, Sargent JD, Larsen PR, et al. Relationof severity of maternal hypothyroidism to cognitivedevelopment of offspring. / Med Screen 2001;8:18-20.

14. Marani L, Venturi S. Iodine and delayed immunity.Minerva Med 1986:77:805-809. [Article in Italian]

15. Gutekunst R. Iodine deficiency costs Germanyover one billion dollars per year. ¡DD Newsletter1993:9:29-31.

Page 125


16. Hollowell JG. Staehling NW, Haiinon WH, et al.Iodine nucrition in the Unites States. Trends andpublic health implications: iodine excretion datafrom Narion;il Health and Nutrition ExaminationSurveys I and III (1971-1974 and 1988-1994)J Cíí«Endomnol MctM' 1998:83:3401-3408.

17. Caldwell KL, Jones R, Hollowell JG. Urinary iodineconcentration: United States National Health andNutrition Examination Survey 2001-2002. TÏJ TOIVÎ2005; 15:692-699.

18. W H O , UNICEF, and ICCIDD. Assessment ofthe Iodine Deficiency Disorders and Monitoringtheir Elimination. W H O / N H D / 0 1 . 1 . Geneva,Switzerland: World Health Organization;2001:1-107.

19. Utiger RD. Maternal hypothyroidism and fetaldevelopment. N EnglJ Med 1999;341:601-602.

20. Haddow JE, Palomaki GE, Allan WC, et al. Maternalthyroid deficiency during pregnancy and subsequentnourophysiological development of the child. N EnglJMai 1999;341:549-555.

21. Glinoer D. Ilie regulation ot thyroid functionin pregnancy: pathways of endocrine adaptationfrom physiology to pathology. Endocr Rev1997:18:404-433.

22. lÍazraíshan HR, Mohammadian S, Ordookhani A, etal. An assessment of urinary and breast milk iodineconcentrations in lactating mothers from Gorgan,Iran, 2003. T)jyroiJ2005;15:1165-l 168.

23. Pearce EN, Leung AM, Blount BC, et al. Breast milkiodine and perchlorate concentrations in lactatingBoston-area women.J Clin Endocrinol Metab2007;92:1673-1677.

24. Fuse Y, Saito N, Tsuchiya T, ct al. Smaller thyroidgland volume with high urinary iodine excretionin Japanese schoolchildren: normative referencevalues in an iodine-sufficient area and comparisonwith the W H O / I C C I D D reference. Ihyroid2007:17:145-155.

25. Cann SA, van Netten JP, van Netten C. Hypothesis:iodine, selenium and the development of breastcancer. Ctinccr Causes Controls 2000;ll:121-127.

26. Nagataki S, Shizume K, Nakao K. Tliyroid functionin chronic excess iodide ingestion: comparison otthyroidal absolute iodine uptake and degradationof thyroxine in euthyroid Japanese subjects. / ClinEmiocrinol Metab 1967:27:638-647.

27. Konno N, Taguchi H, Miura K, et al. Serumthyrocropin concentration in apparently healthyadults, in relation to urinary iodide concentration.ClinChetn 1993:39:174-175.

28. I eng W, Shan Z, Teng X, et al. Effect of iodineintake on thyroid diseases in China. N EnglJ Med2006)354:2783-2793.

29. Pi.sani P, Parkin DM, Bray F, FerlayJ. Estimates of theworldwide mortality from 25 cancers in 1990. IntjCaiiaTl999;83:18-29.

30. LeMarchand L, Kolonel LN, Nomura AM. Breastcancer survival among Hawaii, Japanese, andCauscasian women. Ten-year rates and survival byplace of birth. AmJ Epidemiol 1985;122:571-578.

31. Minami Y, Takano A, Okuno Y, et al. Trends in theincidence of female breast and cervical cancers inMiyagi Prefecture, Japan, 1959-1987. Jp« / Cancer Res1996;87:10-17.

32. Konno N, Yuri K, Miura K, et al. Clinical evaluationof the iodidc/creatinine ratio of casual urine samplesas an index ol daily iodide excretion in a populationsmdy.EndocrJ 1993;40:163-169.

33. Spitzweg C, Harrington KJ, Pinke LA, et al . Clinicalreview 132: the sodium iodide symporter and itspotential role in cancer tlierapy.J Clin EndocrinolMcirtii 2001:86:3327-3335.

34. Venturi S. Is there a role for iodine in breast diseases?ß a w i 2001:10:379-382.

35. Cocchi M, Venturi S. Iodide, antioxidant functionand omega-6 and omega-3 fatty acids: a newhypothesis of biochemical cooperation? Prog Nutr2000;2:15-19.

36. Many MC, Papadopolos C, Martin I, et al. Iodineinduced cell damage in mouse hyperplastic thyroidis associated with llpid peroxidation. In: GordonA, Gross J, Hennemann G, eds. Progress in lljyroidResearch. New York, NY: Routledge: 1991:213-215.

37. Smyth PA. Role of iodine in antioxidantdefence in thyroid and breast disease. Biojactors2003:19:121-130.

38. Nolan LA, Windle RJ, Wood SA, et al. Chroniciodine deprivation attenuates stress-induced anddiurnal variation in corticosterone secretion in femaleWistar rats.J Neuroendocrinol 2000;12:l 149-1159.

39. llirall KD, Bull RJ. Differences in the distribution ofiodine and iodide in the Sprague-Dawley rat. I'undamApp/Tamo/1990:15:75-81.

40. Stole V. Stimulation of iodoproteins and thyroxineformation in human leukocytes by phagocytosis.Biochem Biophys Res Commun 1971:45:159-166

41. Andersen S, Pedersen KM, Pedersen IB, LautbergP. Variations in urinary iodine excretion and thyroidfunction. A 1-year study in healthy men. EurJHíuíon-imíí 2001:144:461-465.

42. lliompson WW, Brailey AG, Ihompson B, et al.Range of effective iodine dosage in exopthalmic goiterIII. Arch hit Med 1930:45:430.

43. Crohn BNH. Absorption of compound solution ofiodine from the gastrointestinal tract. Arch InternMed 1932;49:950-956.

44. Gennaro AS. Remmgton: Tije Science and Practiceof Pharmacy. 19th ed. Easton, PA: Mack Pub Co.;1995:1267.

45. Bretthauer EW. Milk transfer comparisons ofdifferent chemical forms of radioiodine. Health Phys1972:22:257-260.

46. Topper YJ, Freeman CS. Multiple hormoneinteractions in the developmental biology of themammarygland.PÍJ^-íioí Reu 1980:60:1049-1106.

Page 126


Review Article

47. Aceves C, Rodon C, Ramirez-Cl, et al. Mammary5'deiodinase (5'D) during the breeding cycle of therat: indirect evidence that 5'D type I is specific to rhealveolar epithelium. Endocrine 1995;3:95-99.

48. Goehring C, Morabia A. Epidemiology of benignbreast disease, with special attention to histologietypes. Epidemiol Rev 1997;l9-3lO-?>27.

49. Eskin BA, Grotkowski CE, Connolly CP, Ghent WR.Different tissue responses for iodine and iodide in ratthyroid and mammary glands. Biol Trace Elem Res1995:49:9-19.

50. Ghent WR, Eskin BA, Low DA, Hill LP. Iodinereplacement in fibrocystic disease of the breast. GanJSurg 1993:36:453-460.

51. Aceves C, Anguiano B, Delgado G. Is iodine agatekeeper of the integrity of the mammary glandijMammary Gland Biol Neophisia 2005;10:189-196.

52. Kessler JH. Tlie effect of supraphysiologic levelsof iodine on patients with cyclic mastalgia. Breast]2004;10:328-336.

53. Parker SL.TongT, Bolden S, Wingo PA. Cancerstatistics, 1997. CA Cancer] Clin 1997;47:5-27.

54. Ziegier RG, Hoover RN, Pike MC, et al. Migrationpatterns and breast cancer risk in Asian-Americanwomen.J Nati Cancer inst 1993;85:1819-1827.

55. Smyth PP. The thyroid and breast cancer: a significantassociation? AtJM Mecí 1997;29:189-191.

56. Goldman MB. lliyroid diseases and breast cancer.Epidemiol Rev 1990;12:16-28.

57. Türken O, Narin Y, Demlrbas S, et al. Breast cancerin association with thyroid disorders. Breast Canceriifs2003:5:R110-R113.

58. Smyth PP. Thyroid disease and breast cancer.JBuhcrinol Invest 1993;16:396-401.

59. Kilbane MT, A]jan RA, Weetman AP, et al. Tissueiodine content and serum-mediated 1251 uptake-blocking activity in breast cancer. / Clin EndocrinolMetai) 2000:85:1245-1250.

60. Eskin BA. Iodine and mammary cancer. Adv ExpMa/B/oi 1977:91:293-304.

61. Eskin BA, Parker JA, Bassett JG, George DL- Humanbreast uptake of radioactive iodine. Obstet Gynecol1974:44:398-402.

62. Funahashi H, Imai T, Tanaka Y, et al. Suppressiveefîect of iodine on DMBA-induced breast tumorgrowth in the rat.J Surg Oncol 1996;61:209'213.

63. Garcia-Solis P, Alfaro Y, Anguiano B, et al.Inhibition of N-methyl-N-nitrosourea-inducedmammary carcinogcnesis by molecular iodine (12)but not by iodide (I-) treatment. Evidence that 12prevents cancer promotion. Mol Cell Endocrinol2005:236:49-57.

64. Greer MA, Goodman G, Pleus RC, Greer SB. Healtheffects assessment for environmental perchloratecontamination: the dose response for inhibition ofthyroidal radioiodine uptake in humans. EnvironHealth Pcrspect 2002; 110:927-937.

65. Baicr-Anderson C, Blount BC, Lakind JS, etal. Estimates of exposures to perchlorate fromconsumption of human milk, dairy milk and water,and comparison to current reference dose.J ToxicolEnviron Health A 2006:69:319-330.

66. Sanchez CA, Krieger RI, Kliandaker N, et al.Accumulation and perchlorate exposure potential oflettuce produced in the Lower Colorado Rivet region./ Agrie Food Chem 2005:53:5479-5486.

67. Sanchez CA, Krieger RL Khandaker NR, et al.Potential perchlorate exposure from Citrus sp.irrigated with contaminated water. Anal Chim Acta2OO6;567:33-38.

68. Snyder SA, Pleus RC, Vanderford Bj, Holady JC.Perchlorate and chlorate in dietary supplementsand flavor enhancing ingredients. Anal Chim Acta2006:567:26-32.

69. Wolff J. Perchlorate and the thyroid gland. PharmacolJíív 1998:50:89-105.

70. Blount BC, Pirkle JL, Osterloh JD, et al. Urinaryperchlorate and thyroid hormone levels in adolescentand adult men and women living in the United States.Environ Health Perspect 2006:114:1865-1871.

71. Cooper DS. Subclinical thyroid disease: consensus orconundrum? Clin Endocrinol (Oxf) 2004:60:410-412.

72. Surks MI, Ortiz E, Daniels GH, et al. Subclinicalthyroid disease: scientific review and guidelinesfor diagnosis and management. JAMA2004:291:228-238.

73. Dunn |T, Semigran MJ, Delange F. Tlic preventionand management of iodine-induced hyperthyroidismand its cardiac features. Ihyroid 1998:8:101-106.

74. Burgi H, Schaffner T H , Seilci JP. The toxicologyof iodate: a review of the literature. Ihyroid2001:11:449-456.

75. Robison LM, Sylvester PW, Birkenf¿ld P, et al.Comparison of the effects of iodine and iodide onthyroid function in humans. / Toxicol Environ HealthA 1998:55:93-106.

76. Markou K, Georgopoulos N, Kyriazopoulou V,Vagenakis AG. Iodine-induced hypothyroidism.%roi . i 2001:11:501-510.

77. Stanbury JB, Ermans AE, Bourdoux P, et al.Iodine-induced hyperthyroidism: occurrence andepidemiology. V?yroid 1998:8:83-100.

78. Giray B, Hincal F, Tezic T, et al. Status ol seleniumand antioxidant enzymes of goitrous children islower than healthy controls and nongoitrous childrenwith high iodine deficiency. Biol Trace Flcm Res2001:82:35-52.

79. Derumeaux H, Valeix P, Castetbon K, et al.Association of selenium with thyroid volume andechostructure in 35- to 60-year-oId French adults.HwrJEMííocriHo/2003:148:309-315.

80. Zimmermann MB, Kohrle J. Tlie impact of ironand selenium deficiencies on iodine and thyroidmetabolism: biochemistry and relevance to publichealth. Ihyroid 2002:12:867-878.

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Iodine: Deficiency and Therapeutic Considerations...that iodine deficiency allows for increased radioactive iodine uptake. Although the pathology tnay be differ-ent in extrathyroidal