The Concept of Orthoiodosupplementation and Its Clinical Implications
by Guy E. Abraham, MD
II. The Various Natural Forms of Iodine
III. Sources of Iodine in Nature
IV. Iodine Metabolism in Man
V. Thyroidal Metabolism of Iodide
VI. Extrathyroidal Metabolism of Iodide
VII. The Concept of Orthoiodosupplementation
VIII. Clinical Implications
IX. Summary of Findings
X. Misinformation in Medical Textbooks
I. Introduction Back to Table of Content
The recommended daily allowance (RDA) of elemental iodine by the Food and Nutrition Board of the United States National Academy of Sciences was not established until 1980, and it was not confirmed until 1989.1
In that year, 1989, the Executive Director of the International
Council for Control of Iodine
Deficiency Disorders (that is a very impressive title to say the
least), Basil S. Hetzel, published a
book entitled The Story of Iodine Deficiency..2 In
that book, goiter and cretinism were the only two
aspects of iodine deficiency discussed. One would assume that the
experts on human requirements
for iodine have already figured out the amounts of iodine needed for
sufficiency of the human body
(i.e., the daily amount of iodine needed for the prevention and control
of cretinism and endemic
goiter). However, the 1930 statement of Thompson, et al,3
is still valid today: "The normal daily
requirement of the body for iodine has never been determined." In the
ninth edition of the classic
textbook of nutrition, Modern Nutrition in Health and Disease,
edited by Shils, et al, and published
in 1999, the section on iodine was written by no less than Basil S.
Hetzel and coauthored with
Graeme A. Clugston.4 They reported the latest recommended
intakes of iodine established in 1996
by the World Health Organization (WHO), based on age and physiological
conditions. The highest
recommended daily intakes are for pregnant and lactating women -- 200
mcg or 0.2 mg. In a
subsection entitled "Iodine toxicity," the authors stated: "Wolff39
has suggested that human intakes
of 2,000 mcg I/day should be regarded as excessive or potentially
harmful." Please note, the unit
mcg is used instead of 2 mg in order to make the amount appear really
"excessive." For example, if
they used the unit ng, that amount would be 2,000,000 ng, a number that
would scare just about
anybody. Reference 39 in this citation was authored in 1969 by the
world famous thyroidologist, I.
Wolff,5 coauthor of the world famous Wolff-Chaikoff effect
published in 1948.6 There was a fly in
the Wolff-Chaikoff ointment, however.
In 1993, Ghent, et al,7 reported that daily intake of iodine at 0.1 mg/kg BW was effective in fibrocystic disease of the breast. The title of the article -- "Iodine replacement in fibrocystic disease of the breast" -- implies that this abnormality of the breast was due to iodine deficiency and the amount of iodine used, that is 5 mg/day for a 50 kg woman, was within the physiological ranges of iodine intake. Ghent's study did not confirm Wolff's prediction that daily iodine intake of 2,000 mcg (2 mg) was "excessive and potentially harmful" as quoted by Hetzel and Clugston.4 Based on academic credentials and reputation, the opinion of thyroidologist Wolff, from the National Institute of Health, would prevail over the findings of Canadian gynecologist Ghent. However, being interested in facts only, not in preconceived opinions of famous thyroidologists, this author initiated an extensive search of the literature on iodine in medicine.
II. The Various Natural Forms of Iodine Back to Table of ContentThe element iodine exists in nature under several forms: inorganic sodium and potassium salts of iodates (IO3-) and iodides (I-); inorganic diatomic iodine (I2); and organic monatomic iodine (C-I). The first reported, naturally occurring, halogenated organic compound was 3,5- diiodothyrosine, isolated in 1896 by Drechsel from the coral, Gorgonia cavolinii..14 Surprisingly, invertebrates and algae have the ability to synthesize the "thyroid hormone" thyroxine (T4).15 Evidence will be presented later for the synthesis of T4 by human leukocytes.
III. Sources of Iodine in Nature Back to Table of Content
The greatest reservoir of iodides is in the oceans of our planet, although present in very diluted concentrations (0.05 mcg/ml of sea water); therefore, this is not a good starting material for industrial production of iodine. However, sea algae can concentrate iodides by several orders of magnitude. For example, iodide concentrations as high as 0.5% wet weight have been reported in red algae,16 a concentration 100,000 times higher than that present in seawater. From the discovery of iodine in 1811 until 1840, France was the sole producer of iodine. Japan did not become a major iodine producer until 1888.17 Currently, the major iodine producers are the US, Japan, and Chile; caliches, oil wells, and deep well water are the major sources.The iodine cycle starts and ends in the oceans. Under the influence of sunlight, the iodides in seawater are oxidized to diatomic iodine I2. Due to sublimation at ambient temperature and atmospheric pressure, the I2 gas evaporates in the air in an estimated amount of 400,000 tons per year.2 This form of diatomic iodine can be absorbed through the lungs by breathing air, which usually contains approximately 1 mcg/m3, a very insignificant source of iodine. The high voltage currents flowing through clouds reduce the diatomic iodine to iodides dissolved in water droplets which fall on the soil in the form of rain. Rivers return the iodide to the oceans to complete the cycle.
IV. Iodine Metabolism in Man Back to Table of Content
Diatomic iodine (I2) can be absorbed through the lungs and through the skin.18, 19 However, ingested food, drinks and iodine/iodide supplementation, are the most common means of supplying iodine to the human body. Without interfering substances present in the gastrointestinal tract, inorganic iodine, iodates, and iodides are quantitatively absorbed. The elimination of peripheral inorganic iodide occurs almost exclusively through renal clearance.20 Organic and inorganic iodine are not cleared by the kidneys. When inorganic iodide is ingested in amounts ranging from 0.001 mg up to 2,000 mg, Childs, et al,20 estimated an average renal clearance of serum inorganic iodide of 50L/day over the whole range of intakes. Fisher, et al,21 and Koutras, et al,22 have measured serum inorganic iodide levels at equilibrium in subjects ingesting increasing amounts of iodide from 75-1,250 mcg/day. Their results are displayed in Table 2. When these data are plotted on an X-Y axis (Figure 1), a high degree of correlation (0.999) was obtained with a slope of 0.023. The slope is an index of renal clearance: 1/0.023 = 43.5 L/day.To compute the serum inorganic iodide levels at equilibrium in a subject ingesting a narrow range of iodine/iodide, divide the average daily intake expressed as milligrams elemental iodine by 43.5 liters to obtain the serum concentration of inorganic iodide expressed as mg/L of serum. Besides giving accurate information about the peripheral concentrations of iodide available for uptake by the cells and organs of the human body, measurement of serum inorganic iodide levels is very useful for assessing bioavailability of the iodine/iodide ingested. Alexander, et al,23 measured the serum inorganic iodide levels in normal subjects consuming an average of 70 mcg iodide per day, but no iodized salt. He observed a mean value of 1.8 mcg/L. This measured value is very close to the value computed by dividing 70 mcg/day by 43.5 liters/day = 1.6 mcg/L. This is evidence that the iodine present in the food and drink of these subjects is highly bioavailable. Pittman, et al,24 measured serum inorganic iodide levels in two groups of subjects: one group after iodization of salt, with an estimated daily intake of 750 mcg iodide, and the other group after iodization of bread, with a similar average daily intake of iodates.25 The expected mean serum level at equilibrium would be 17.2 mcg/L (750 mcg/43.5 L). The mean values observed by Pittman, et al,24 were 1.7 mcg/L for subjects after iodization of salt, and 18.7 mcg/L for subjects after iodization of bread. These data suggest that iodate in bread is very bioavailable, whereas only 10% of iodide in iodized salt were absorbed. On a molar basis, there is 30,000 times more chloride than iodide in iodized salt. Chloride competes with iodide for absorption in the intestinal tract.26 To this author's knowledge, the low bioavailability of iodide in iodized salt has never been reported.
V. Thyroidal Metabolism of Iodide Back to Table of Content
Serum inorganic iodide is in dynamic equilibrium with the exchangeable pool of inorganic iodide in the thyroid gland. This pool was estimated at 6-7 mg iodide by Koutras, et al..22 Uptake of inorganic iodide by the thyroidal Na/I symporter system increases with increased peripheral levels, but only up to a point. The maximum daily thyroidal uptake was estimated at 0.6 mg/day when 50 mg of iodide are ingested daily.11 Based on studies in farm animals by Marine, saturation of the thyroid occurs with 5 mg iodine per gm (dry wt) of thyroid.30 That would compute to 50 mg iodine per thyroid gland in an adult man, 8 times the exchangeable pool of iodide. Hyperplastic changes in the thyroid gland are observed when iodine concentrations drop below 0.1% dry weight (dry wt).31 Thyroidal concentration of 0.1% iodine corresponds to 1 mg iodine/gm thyroid (dry wt). With an estimated weight of the thyroid gland around 10 gm dry wt in the normal adult, the minimum amount of iodine/iodide in the thyroid before hyperplastic changes occur would be 10 mg (1 mg I/gm x 10 gm). F.M. Delange32 estimated, from an extensive review of the literature, that daily intake of 0.05 mg iodine and 10-20 mg iodine/thyroid were required to prevent simple goiter. Goiter development correlates better with low thyroidal iodine than with elevated TSH levels, suggesting an autoregulatory role of iodine in the thyroid gland.33
Elevated TSH induces hypertrophy, whereas intrathyroidal iodine deficiency
induced thyroid hyperplasia. In iodine-deficient goiter, iodine supplementation
abolishes not only hypertrophy, but also hyperplasia of the thyroid gland. On
the other hand, suppression of TSH with T4 abolishes hypertrophy, not hyperplasia
if there is intrathyroidal iodine deficiency.33
Therefore, administration of T4 to iodine-deficient patients does not decrease
their risk for thyroid cancer, an effect expected with iodine supplementation.34
Stubner, et al,33 concluded: "These data
indicate that iodine supplementation is the causal therapy for iodine-deficient
goiter because it abolishes not only hypertrophy, but also hyperplasia of the
glands and restores normal function and regulation." Based on the above findings,
orthoiodosupplementation is highly recommended in patients receiving thyroid
There is an inverse relationship between the iodine concentration of the thyroid gland and total DNA content, indicating an autoregulatory effect of iodine on cell proliferation (anticarcinogenic effect). Recent investigations on this autoregulatory effect of iodine on cell proliferation suggest that it is due to iodinated lipids.9 Iodination of lipids in thyrocytes requires an amount of iodine/iodide two orders of magnitude greater than the RDA, that is two orders of magnitude greater than required for iodination of thyrosine. Apparently, the thyroid gland requires higher concentrations of iodide in the thyrocyte for the iodination of lipids than for the iodination of thyrosine. For further details on the intrathyroidal metabolism of iodide and synthesis of thyroid hormones, the reader is referred to textbooks of endocrinology and thyroidology where this aspect of iodine metabolism is well described.
VI. Extrathyroidal Metabolism of Iodide back to table of content
The mammary glands can effectively compete with the thyroid gland for peripheral iodine. Eskin, et al,28 measured the 24-hour radioiodide uptake in 57 clinically normal breasts, and in eight clinically abnormal breasts. The mean ± SD percentage uptake was 6.9±0.46% in the normal breasts and 12.5±1% in abnormal breasts. These means were statistically significant at p <0.005. Considering that these measurements are representative of a single breast, and a woman has two breasts, the percentage uptake per patient is twice these amounts. This brings the 24-hour radioiodide uptake by the mammary glands of a woman in the same range as the 24-hour radioiodide uptake by the thyroid gland. The higher percentage uptake in the abnormal breasts suggests that the abnormal breasts were more deficient in elemental iodine than normal breasts.Since the radioiodide uptake study of breast tissue by Eskin, et al,28 was performed with iodide, not iodine, it is likely that the percent uptake by the breast would even be higher if radioiodine were used. There is some evidence that the udder of a lactating cow has a greater need for iodine than the thyroid gland. When the radioisotope 131I was administered to lactating cows under four different chemical forms35 -- diatomic iodine, methyliodine, iodide, and iodate -- the average maximum uptake by the thyroid gland was 3.8% of the administered dose, whereas milk from the same cows contained an average of 14% of the administered dose. A slightly higher concentration of radioactivity was observed in the milk of cows fed radioiodine than those fed radioiodide. Of interest are the findings of Eskin, et al,29 that the thyroid gland preferentially concentrates iodide whereas the mammary gland favors iodine. In I-deficient female rats, histological abnormalities of the mammary gland were corrected more completely, and in a larger number of rats treated with iodine, than iodide given orally at equivalent doses. Ghent, et al,7
reported a better response from patients with fibrocystic disease of the breast when inorganic iodine was used, compared with organic iodine and inorganic iodide.In the rats studied by Thrall and Bull,36 20% of the iodide, but not iodine, administered orally was recovered in the skin. This suggests that the skin, like the thyroid gland, has a preference for iodide. Extrathyroidal synthesis of T4 has been demonstrated in thyroidectomized rats by Evans, et al,37 following administration of iodide in amount of 25 mg/kg BW. For a 70-kg human subject, the corresponding amount would be 1.75 g, well within the range of iodides prescribed for pulmonary patients.9
Iodotherapy in these thyroidectomized rats reversed the effect of hypothyroidism on growth, on the adrenal glands, the ovaries, testicles, and thymus.Human leukocytes during phagocytosis synthesized T4 when the incubation media contained 10-6M iodide.38 Extrathyroidal hyperthyroidism with exophthalmia has been reported in patients with leukemia., 40 The administration of Lugol solution was effective in these cases.41, 42 Iodine deficiency may play an important role in leukemia. Salivary glands and stomach cells oxidized and organified iodide with the synthesis of iodolipids, mono- and diiodothyrosine, when the incubation media contained 10-6M iodide.43 The essential element iodine modulates the adrenal response to stress44 and improves immune functions.45
VII. The Concept of Orthoiodosupplementation Back to Table of Content
Orthoiodosupplementation is the daily amount of the essential element iodine required for whole body sufficiency. Whole body sufficiency for iodine is assessed by an iodine/iodide loading test.9 The iodine/iodide loading test evolved by serendipity from a project to assess the bioavailability of a tablet form of Lugol solution (Iodoral®). From the medical literature, it is stated that urinary iodide levels are the best index of iodine/iodide intake.2, 4 Studies were performed in five normal subjects (two male, three female), with the assumption that urine concentrations of iodide were a reliable index of bioavailability of the product tested.
Following oral intake of 12.5 mg Lugol in tablet form, iodide levels in the 24-hour urine collection were measured. The subjects excreted in their 24-hour urine samples only 10-30% of the amount ingested, with a mean of 20%.27 This low recovery of iodide in the urine samples could be due to either low bioavailability of the product tested or high retention in the body. In order to elucidate the cause of this low iodide excretion, we continued the administration of the supplement in those subjects for one month. Then, we repeated the 24-hour urine collection and iodide was measured again in the 24-hour urine samples. In four of the five subjects, the percentage oral dose excreted in the 24-hour urine sample increased significantly, with a mean group value of 50%.27 Contrary to medical textbooks, 80% of the iodine/iodide ingested was retained. After one month of supplementation, the body still retained 50% of the ingested amount. The iodine/iodide loading test evolved from these observations. However, instead of a one-month loading test, further studies were performed to shorten this test to a single ingestion of the preparation.Another group of six subjects, (three male and three female) were evaluated with 24-hour urinary iodide levels after ingesting one, two, and three tablets of the same preparation. The mean percentage excretions (± SD) were: 22±1.2% for one tablet, 23±2.8% for two tablets, and 25±12.3% for three tablets. In a third group of six subjects, urine iodide levels were evaluated following four tablets of the same preparation. The mean excretion rate was 39±17.2% (Figure 3). For the loading test, a single ingestion of four tablets was chosen because this dose resulted in the highest mean percent iodide excreted and in the widest interindividual variations.
The goal of orthoiodosupplementation is not the treatment of disease, but the supply of optimal amounts of an essential nutrient for whole body sufficiency and for optimal mental and physical performance. Whole body iodine deficiency, based on the concept of orthoiodosupplementation, may play an important role in several clinical conditions.
VIII. Clinical Implications Back to Table of Content
Based on the above review of the literature and this author's clinical research studies,8-12 the concept of orthoiodosupplementation can be summarized as follows:
IX. Summary of Findings Back to Table of Content
1) The nutrient iodine is essential for every cell of the human body
concentrations of inorganic iodide ranging
from 10-6M to 10-5M.
2) In non-obese subjects, these concentrations can be achieved with daily intake of 12.5-50 mg elemental iodine.
3) The thyroid gland is the most efficient organ of the human body, capable of concentrating iodide by two orders of magnitude to reach 10-6M iodide required for the synthesis of thyroid hormones when peripheral levels of inorganic iodide are in the 10-8M range.
4) Goiter and cretinism are evidence of extremely severe iodine deficiency because the smallest intake of iodine would prevent these conditions, (i.e., 0.05 mg/day) is 1,000 times less than the optimal intake of 50 mg elemental iodine.
5) The thyroid gland has a protective mechanism, limiting the uptake
of peripheral iodide to a
maximum of 0.6 mg/day when 50
mg or more elemental iodine are ingested. This amount, therefore, would serve as a preventative measure against radioactive
6) An intake of 50 mg elemental iodine/day would achieve peripheral
concentration of iodide
at 10-5M, which is the
concentration of iodide markedly enhancing the singlet triplet radiationless transition. This effect would decrease DNA damage with an anticarcinogenic effect.9, 11
7) Orthoiodosupplementation results in detoxification of the body from the toxic metals, aluminum, cadmium, lead, and mercury.
8) Orthoiodosupplementation increases urinary excretion of fluoride and bromide, decreasing the goitrogenic effects of these halides.
9) Most patients on a daily intake ranging from 12.5-50 mg elemental
iodine reported higher
energy levels and greater mental
clarity with 50 mg (four tablets Iodoral®) daily. The amount of iodine used in patients with fibrocystic disease of the breast by
Ghent, et al,7 that is 0.1 mg/kg BW/day, is 10 times below the optimal daily intake of 50 mg. In our experience, patients with
this clinical condition responded faster and more completely when ingesting 50 mg iodine/iodide/day.
10) Orthoiodosupplementation may be the safest, simplest, most
effective, and least
expensive way to solve the health-care
crisis crippling our nation.
11) For best results, orthoiodosupplementation should be part of a
program, emphasizing magnesium
instead of calcium.
12) The iodine/iodide loading test and serum inorganic iodide levels
are reliable means
of assessing whole body sufficiency for
elemental iodine and also for quantifying the bioavailability of the forms of iodine ingested.
X. Misinformation in Medical Textbooks Back to Table of Content
The concept of orthoiodosupplementation requires a major revision of commonly held beliefs expounded in medical textbooks regarding iodine metabolism and requirements.1) Ingested iodine is reduced to iodide in the intestinal tract prior to absorption. Ghent, et al,7 and Eskin, et al,29 reported that in women and in female rats, fibrocystic disease of the breast responded better to iodine than iodide. Thrall and Bull36 observed that in both fasted and fed rats, the thyroid gland and the skin contained significantly more iodine when rats were fed with iodide than with iodine; whereas the stomach walls and stomach contents had a significantly greater level of iodine in iodine-fed rats than iodide-fed animals. Peripheral levels of inorganic iodine were different with different patterns, when rats were fed with these two forms of iodine. The authors concluded: "These data lead us to question the view that iodide and iodine are essentially interchangeable."
3) Absence of goiter and cretinism are evidence of iodine
sufficiency. According to Delange,32 a daily intake of only
0.05 mg elemental iodine will prevent goiter
and cretinism, which are the manifestation of the most severe forms of
iodine deficiency. To achieve whole body sufficiency for iodine, 250 to
1,000 times that amount is required.
Day 1 = 50-20 = 30 mg
Day 90 = 50-45 = 5 mg
Daily average = 30 + 5 / 2 = 17.5 mg/day
For 90 days = 17.5 mg/day x 90 days = 1575 mgThe levels of 15-20 mg iodine mentioned in medical textbooks represent severe iodine deficiency based on the concept of orthoiodosupplementation.
Guy E. Abraham, MD, is a former Professor of obstetrics, Gynecology and Endocrinology at the UCLA School of Medicine. Some 35 years ago, he pioneered the development of assays to measure minute quantities of steroid hormones in biological fluids. He has been honored as follows: General Diagnostic Award from the Canadian Association of Clinical Chemists, 1974; the "Medaille d'Honneur" from the University of Liege, Belgium, 1976; the Senior Investigator Award of Pharmacia, Sweden, 1980. The applications of Dr. Abraham's techniques to a variety of female disorders have brought a notable improvement to the understanding and management of these disorders. Twenty-five years ago, Dr. Abraham developed nutritional programs for women with premenstrual tension syndrome and post menopausal osteoporosis. They are now the most commonly used dietary programs by American obstetricians and gynecologists. Dr. Abraham's current research interests include the development of assays for the measurement of iodide and the other halides in biological fluids and their applications to the implementation of orthoiodosupplementation in medical practice.
XI. REFERENCES Back to Table of Content1) Food and Nutrition Board, National Academy of Sciences, National Research Council. Recommended Dietary
2) Hetzel BS. The Story of Iodine Deficiency. An International
Challenge in Nutrition. Oxford
University Press, Oxford,
New York, Tokyo, 1989.
3) Thompson WO, et al. "The range of effective iodine dosage in exophthalmic goiter."Arch Int Med, 1930; 45:261-281.
4) Hetzel BS and Clugston GA. Iodine. In Modern Nutrition in Health and Disease, 9th edition. Shils ME, et al, editors. Lippincott Williams & Wilkins, 1999; 253-264.
5) Wolff J. "Iodide goiter and the pharmacologic effects of excess iodide." Am J Med, 1969; 47:101-124.
6) Wolff J and Chaikoff IL. "Plasma inorganic iodide as a homeostatic regulator of thyroid function."J Biol Chem, 1948; 174:555-564.
7) Ghent WR, et al. "Iodine replacement in fibrocystic disease of the breast."Can J Surg, 1993; 36:453-460.
8) Abraham GE. "The Wolff-Chaikoff effect of increasing iodide intake on the thyroid." Townsend Letter, 2003; 245:100-101.
9) Abraham GE. "The safe and effective implementation of orthoiodosupplementation in medical practice." The Original Internist, 2004; 11(1):17-36.
10) Abraham GE, et al. "Optimum levels of iodine for greatest mental and physical health." The Original Internist, 2002; 9(3):5-20.
11) Abraham GE, et al. "Orthoiodosupplementation: Iodine sufficiency of the whole human body." The Original Internist, 2002; 9(4):30-41.
12) Abraham GE. "Iodine supplementation markedly increases urinary excretion of fluoride and bromide." Townsend Letter, 2003; 238:108-109.
13) Brownstein D. Iodine: Why You Need It, Why You Can't Live Without It. Medical Alternative Press, West Bloomfield, MI, 2004.
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27) Abraham GE, et al. "Measurement of urinary iodide levels by ion-selective electrode: Improved sensitivity and specificity by chromatography on anion-exchange resin." Optimox Research Info #IOD-03. (Reprint available upon request).
28) Eskin BA, et al. "Human breast uptake of radioactive iodine." OB-GYN, 1974; 44:398-402.
29) Eskin B, et al. "Different tissue responses for iodine and iodide in rat thyroid and mammary glands." Biological Trace Element Research, 1995; 49:9-19.
30) Marine D and Kimball OP. "Prevention of simple goiter in man." Arch Intern Med, 1920; 25:661-672.
31) Underwood EJ. Trace Elements in Human and Animal Nutrition. Academic Press, New York, San Francisco, London, 1977.
32) Delange FM. "Iodine deficiency." In: Werner & Ingbar's The Thyroid. Braverman LE and Utiger RD, editors. Lippincott Williams & Wilkins, 2000; 295-329.
33) Stubner D, et al. "Hypertrophy and hyperplasia during goiter growth and involution in rats - separate bioeffects of TSH and iodine." Acta Endocr, 1967; 116:537-548.
34) Gaitan E, Nelson NC, and Poole GV. "Endemic goiter and endemic thyroid disorders." World J Surg, 1991; 15:205-215.
35) Bretthauer EW, et al. "Milk transfer comparisons of different chemical forms of radioiodine." Health Physics, 1972; 22:257-260.
36) Thrall K and Bull RJ. "Differences in the distribution of iodine and iodide in the Sprague-Dawley rat." Fundamental and Applied Toxicology, 1990; 15:75-81.
37) Evans ES, et al. "Biological evidence for extrathyroidal thyroxine formation."Endo, 1966; 78:983-1001.
38) Stole V. "Stimulation of iodoproteins and thyroxine formation in human leukocytes by phagocytosis." Biochem Biophys Res Commun, 1971; 45:159-168.
39) Minot GR and Means JH. "The metabolism pulse ration in exophthalmic goiter and in leukemia." J H Arch Int Med, 1924; 33:576-580.
40) Friedgood HB. "The relation of the sympathetic nervous system and generalized lymphoid hyperplasia to the pathogenesis of exophthalmic goiter and chronic lymphatic leukemia." Amer J Med Sci, 1932; 183:841-849.
41) Friedgood HB. "The effect of Lugol's solution on chronic lymphatic leukemia and its bearing upon the pathogenesis of exophthalmic goiter." Am J Med Sci, 1932; 183:515-529.
42) Friedgood HB. "The effect of Lugol's solution on the elevated basal metabolism in conditions other than exophthalmic goiter."J Clin Invest, 1931; 10:172.
43) Banerjee RK, et al. "Peroxidase-catalysed iodotyrosine formation in dispersed cells of mouse extrathyroidal tissues." J Endocr, 1985; 106:159-165.
44) Nolan LA, et al. "Chronic iodine deprivation attenuates stress-induced and diurnal variation in corticosterone secretion in female Wistar rats."J Neuroendocr, 2000; 12:1149-1159.
45) Marani L, et al. "Role of iodine in delayed immune response." Israel J of Med Sci, 1985; 21:864.
46) Kasha M. "Collisional perturbation of spin-orbital coupling and the mechanism of fluorescence quenching. A visual demonstration of the perturbation." The Journal of Chemical Physics, 1952; 20:71-74.
47) Szent-Gyorgyi A. Bioenergetics. Academic Press, NY, 1957; 113.
48) Sies H. "Damage to plasmid DNA by singlet oxygen and its protection." Mutation Research, 1993; 299:183-191.
49) Roti E and Vagenakis AG. "Effect of excess iodide: Clinical aspects."In: Werner and Ingbar's The Thyroid. Braverman LE and Utiger RD, editors. Lippincott Williams & Wilkins, 2000; 316-329.
50) Phillippou G, Koutras DA, Piperingos G, et al. "The effect of iodide on serum thyroid hormone levels in normal persons, in hyperthyroid patients, and in hypothyroid patients on thyroxine replacement." Clin Endocr, 1992; 36:573-578.
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