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Orthoiodosupplementation: iodine sufficiency of the whole human body.

Introduction

Iodine (I) is the only trace element required in the synthesis of hormones. These I-containing hormones are involved in embryogenesis, differentiation, cognitive development, growth, metabolism, and maintenance of body temperature. I is highly concentrated in one organ, the thyroid gland, which becomes visibly enlarged when there is a deficiency of that element. It is the most commonly deficient trace element in the world with an acknowledged third of mankind functioning below optimal level due to its deficiency.(1) Low intake of I is the world's leading cause of intellectual deficiency.(2) Yet, as unbelievable as it may sound, this essential element has suffered from total neglect regarding the amount of it required by the human body for optimal health. In 1930, Thompson et al wrote,(3) "The normal daily requirement of the body for iodine has never been determined." Unfortunately, this statement is still true today, more than 70 years later.

At the Children's Summit held in 1990, the United Nations and heads of state assembled for that occasion pledged to eliminate I deficiency by the year 2000. Commenting on this meeting, John T. Dunn stated in 1993, (4) "The goal is technically feasible, but many obstacles must be overcome before it is realized." In the list of obstacles, no mention was made of the greatest obstacle of them all -- our total ignorance regarding sufficiency of the whole human body for I. It is obvious that I deficiency has been equated with the simple goiter, cretinism, and I-deficiency disorders related to its role in thyroidal physiology. Supplementation was considered adequate if it prevented cretinism, simple goiter, and symptoms of hypothyroidism.(1, 2, 4) The assumption that the only role of I is that of an essential element in the synthesis of [T.sub.3] and [T.sub.4] became dogma. With the advent of sensitive assays, thyroid stimulating hormones (TSH) was promoted to queen of tests for thyroid functions,(5) and I was forgo tten altogether, to the point where now most endocrinologists and other medical practitioners do not request a single test for urine I concentration during their whole medical careers.

Iodophobia and misinformation about I

The fear of using or recommending I (iodophobia) is ubiquitous, and misinformation about I is found in books and articles written by laypersons, by physicians for laypersons, and by physicians for physicians. We will use two recently published books as examples -- one written by a famous endocrinologist for laypersons and the other, a textbook of endocrinology, written by physicians for physicians.

First, we will quote excerpts from The Thyroid Solution: A Revolutionary Mind-Body Program That Will Help You (1999), written by R. Arem, MD, for consumers. As editor of an educational periodical on thyroid disorders, which is read by 25,000 physicians nationwide, Dr. Arem's views influence a large segment of practicing endocrinologists. Anyone awake will realize that Eastern mysticism and New Age occultism have penetrated deeply, although insidiously, into the practice of medicine. On pages 309-310 of his book, Dr. Arem recommends guided imagery, meditation, yoga, and tai chi, without a single reference to validate the effectiveness and lack of adverse effects of those practices: "I encourage men and women to perform tai chi, yoga..." In a section titled "Iodine: A Double Edge Sword," the author states on page 305, "Research has clearly established that the high dietary iodine content in some areas of the world has resulted in a rise in the prevalence of thyroiditis and thyroid cancer." One reference is give n,(7) and when that reference is reviewed, there is no high dietary I intake involved. Essentially, that study evaluated the incidence of thyroiditis and thyroid cancer in areas of Argentina with severe I deficiency, before and after iodization of salt was made available. Urine I was 9.3 [+ or -] 1.7 [micro]g/gm creatinine before iodization and 110 [+ or -] 82 [micro]g/gm creatinine after iodization. Keep in mind that the RDA for I is 150 [micro]g/day. The incidence of the more invasive form of thyroid cancer did not change, but the incidence of papillary carcinoma was 0.78/100,000/year before and 0.84/100,000/year after iodization of salt. Obviously, the data available in this publication do not agree with Dr. Arem's conclusion about the association between high dietary I intake and thyroid cancer. In fact, the available information on this subject, to be discussed later, points to chronic I deficiency as a predisposing factor for thyroid cancer.

The iodophobic misinformation continues with anecdotal stories from Dr. Arem's archives: a female patient ingested 2-3 gm of kelp daily and developed Grave's disease, which necessitated "destruction of the thyroid gland." How strange! The mainland Japanese consume a daily average of 4.6 gm of seaweed, and they are one of the healthiest peoples on earth. (10, 11, 12, 22, 23) Another iodophobic story follows: NASA consulted Dr. Arem because their ground personnel became "low grade" hypothyroid, whatever that means. Sherlock Arem discovered the cause. The ground personnel were drinking water with 4 gm iodine per liter. That is interesting because the maximum amount of iodine that can be dissolved in water at room temperature is 3 gm per liter. Dr. Arem saved the day at NASA, "alarmed by my warnings about the potential consequences..." What is the expert's advice? "I advise not consuming more than 500 to 600 micrograms a day." With such iodophobia and misinformation coming from the top, no wonder there is a trend of decreasing I consumption nationwide in the US.

As we will now demonstrate, this kind of misinformation may have serious consequences. On page 232, Dr. Arem wrote regarding the evaluation of simple goiter, "To determine the cause of your goiter, your physician may order one or several of the following tests." In that list, no mention was made of urine I levels, when in fact, the most common cause of simple goiter worldwide is I deficiency. However, he may have given the reason for not considering urine I levels in the evaluation of simple goiter toward the end of the book on page 305, "To function normally, the thyroid requires 150 micrograms a day ... In the United States, iodine consumption ranges between 300 and 700 micrograms a day." This statement has no reference and is inaccurate. The last comprehensive nutritional survey (2) revealed that the median urine I concentration was 145 [micro]g/L, and 15% of the US adult female population suffered from I deficiency (urine I less than 50 [micro]g/L). That is one out of every seven female patients walking i nto a doctor's office. Interestingly, about same risk ratio for breast cancer in our population (1:8). (63) With this high prevalence of I deficiency, including urine I levels in the initial screening of simple goiter is justified. Without the information on urine I levels, the physician will most likely prescribe thyroid hormones to the I-deficient patient.

Hintze et al (8) compared the response of patients with simple goiter to administration of I at 400 [micro]g/day or [T.sub.4] at 150 [micro]g/day for a period of eight months, and then for four months after cessation of therapy. The results definitely favored I over [T.sub.4]. There was a similar suppression of the size of the thyroid gland with I and with [T.sub.4]. This suppression persisted four months after discontinuation of I, whereas the mean thyroid volume in the group receiving [T.sub.4] returned to pre-[T.sub.4] level four months after stopping [T.sub.4] administration. The authors concluded, "Our data clearly shows that iodine alone ... is at least equally as effective for goiter reduction as levothyroxine alone and offers the further benefit of a sustained effect after cessation of therapy."

Of greater concern, however, is the possibility that Ideficient women are more prone to breast cancer, and depriving them of I is not in their best interest. Based on an extensive review of breast cancer epidemiological studies, R.A. Wiseman (9) came to the following conclusions: 1) 92-96% of breast cancer cases are sporadic; 2) there is a single cause for the majority of cases; 3) the causative agent is deficiency of a micronutrient that is depleted by a high fat diet; and 4) if such an agent is detected, intervention studies with supplementation should lead to a decline in the incidence of breast cancer. It is the opinion of several investigators that this protective micronutrient is the essential element I. (14,16,19,20,54) Demographic surveys of Japan and Iceland revealed that both countries have a relatively high intake of I, and low incidences of simple endemic goiter and breast cancer, whereas in Mexico and Thailand, just the reverse is observed -- a high incidence of both endemic goiter and breast can cer. (10) Thomas et al (11,12) has demonstrated a significant and inverse correlation between I intake and the incidence of breast, endometrial, and ovarian cancer in various geographical areas. Thyroid volume measured by ultrasonometry and expressed as ml is significantly larger in Irish women with breast cancer than controls with mean values of 12.9 [+ or -] 1.2 in controls and 20.4 [+ or -] 1.0 in women with breast cancer. (3) Intervention studies in female rats by Eskin (14-16) are very suggestive of a facilitating role of I deficiency on the carcinogenic effect of estrogens, and a protective role of I by maintaining normality of breast tissues.

The administration of thyroid hormones to I-deficient women may further increase their risk for breast cancer. In a group of women undergoing mammography for screening purposes, (17) the incidence of breast cancer was twice as high in women receiving thyroid medications for hypothyroidism (most likely induced by I deficiency) as in women not on thyroid supplements. The mean incidences were 6.2% in controls and 12.1% in women on thyroid hormones. The incidence of breast cancer was twice as high in women on thyroid hormones for more than 15 years (19.5%) compared to those on thyroid hormones for five years (10%).

Backwinkel and Jackson (18) have presented as evidence against the association between I deficiency and breast cancer, the fact that in the state of Michigan, between 1924 and 1951, the prevalence of goiter decreased markedly from 3 8.6% to 1.4%, but no detectable change was observed in the prevalence of breast cancer during that same interval of time. These authors are making the assumption that the amount of I required to control goiter is the same as that required for protection against breast cancer. Ghent et al (19) and Eskin (20) have estimated, based on their studies, that in both women and female rats, the amount of I required for protection against breast cancer and fibrocystic disease of the breast (FDB) is at least 20 to 40 times the amount required for control of goiter.

Medical textbooks written for physicians contain the same iodophobia and misinformation about I. When I is incorporated into a drug, that drug gets all the credit for the good effects, and I is blamed for the side effects. Although there are several I-containing drugs used by physicians for various medical condition, (21) we will just cover one of these drugs, using information supplied by Roti and Vagenakis in the latest review on I (21) Amiodarone is a benzofuranic derivative containing 75 mg I per 200 mg tablet. It is widely used for the long term treatment of cardiac arrhythmia. It is long-acting, with a 100-day half-life, and releases 9 mg I daily in patients ingesting the recommended amount. In the US, amiodarone induces hypothyroidism in 20% of patients ingesting it. The authors of that review blamed I for the hypothyroidism, although no study has been performed with daily administration of 9 mg of inorganic I in a similar group of patients. It would not be surprising if inorganic I alone in equivalent amount resulted in the same beneficial effects without the side effects, including destructive thyroiditis, which requires large doses of glucocorticoids, and in some cases, thyroidectomy. Actually, there is a large population consuming close to 100 times the RDA almost daily -- the Japanese living in Japan. According to the Japanese Ministry of Health, the average daily consumption of seaweed by mainland Japanese is 4.6 gm. (22) At an average of 0.3% I in seaweed (range 0.08-0.45%), (22) that would compute to an average daily intake of 13.8 mg I. Overall, the Japanese living in Japan are among the healthiest people in the world based on cancer statistics. (23) They also have one of the lowest incidence of I-deficiency goiter and hypothyroidism. (10)

In the same review on I excess, (21) published in a textbook read by most endocrinologists and therefore influencing the national trend in the management of thyroid disorders, there is a subsection with the title, "Iodine as a Pathogen." This is an essential trace element that is being called a pathogen. Commenting on the latest nutritional survey (NHANES III), the authors stated that this trend of decreasing I intake has resulted in a lower percentage of the US population consuming excess I, defining excess I intake as urine I levels above 500 [micro]g/L (0.5 mg/L). "This trend in iodine consumption has also resulted in a decline in the percentage of the population with excessive iodine intake (>500 [micro]g/L from 27.8% in the 1971 to 1974 survey to 5.3% in the 1988 to 1994 survey." With this iodophobic mentality, a cutoff point of 0.5 mg I/L of urine has been arbitrarily chosen for excess I intake. What is considered excess I by these authors represents 3% of the average daily I intake by mainland Japanese , a population with a very low incidence of cancer of the female reproduction organs. (11,12) This attitude toward I may play an important role in the high incidence of cancer of the female reproductive organs in our population. It would be of interest to compare the prevalence of breast cancer with urine I levels from data available in the last two National Nutritional Surveys.

Currently, the average daily intake of I by the US population is 100 times less than the amount consumed by the mainland Japanese. In the 1960s, I-containing dough conditioners increased the average daily I intake to more than four times the RDA. (24) One slice of bread contained the full RDA of 150 [micro]g. The risk for breast cancer in our population was then 1:20. (63) Over the last two decades, food processors started using bromine, a goitrogen, (25) instead of I in the bread-making process. The risk for breast cancer now is 1:8, and it is increasing at 1% per year. (63) The rationale for replacing I with a goitrogen in a population already I deficient is not clear, but is definitely not logical. In rats on a diet with the rat RDA for I (3 [micro]g), adding thiocyanate, a goitrogen, at 25 mg/day caused hypothyroidism. (26) Increasing I intake to 80 times rat RDA prevented this effect. In humans, that would be the equivalent of 12 mg I/day. It is likely that a large percentage of patients receiving [T.sub .4] for hypothyroidism are I deficient. This I deficiency is worsened by the goitrogens they are exposed to. Prescribing [T.sub.4] to them further increases their risk for breast cancer. (17) What these patients really need is a supply of I large enough for I sufficiency and for neutralization of the effect of most of these goitrogens. Based on the studies of Lakshmy et al (26) in rats, that amount of I would correspond to the level of I consumed by mainland Japanese.

For those who trust the food processors to meet their nutritional needs, the last significant source of I is table salt, which contains 74 [micro]g I per gm of NaCl. An editorial in the February 2002 issue of the Journal of Clinical Endocrinology and Metabolism (27) exhorted the US and Canada to decrease the amount of I in table salt by one half. "Most other countries use 20-40 PPM as iodine, and the United States and Canada should consider lowering the level of fortification to this range." This recommended low level of I fortification between 20-40 PPM had no significant effect on urine I levels and size of goiters in published studies from Germany and Hungary. (28,29) Essentially, this amount of I was designed to give a false sense of I sufficiency but really to be ineffective. It is ironic that the title of this editorial is "Guarding our Nation's Thyroid Health."

Considering that low I intake is associated with intellectual deficiency, if we continue to lower the supply of I from our food sources, disseminate misinformation about I, and promote iodophobia, we will end up with a nation of zombies.

Requirement of the thyroid gland for I

After reviewing the available information in published studies designed to assess the effect of various amounts of I on thyroid physiology, it was possible to arrive at a tentative range of intake that would result in sufficiency of the thyroid gland for that element.

With the availability of radioactive isotopes of I and improved understanding of I metabolism, it became obvious that the thyroid gland concentrates this trace element more than two orders of magnitude, compared to most other organs and tissues. The percent of radioiodide uptake by the thyroid gland correlated inversely with the amount of I ingested. (30) In areas of severe endemic goiter, it was above 80%. (31) The percent uptake decreases progressively with increased intake of I, and at RDA levels (150 [micro]g), the percent uptake was maintained at 20-30%. (24) In the 1960s I added to bread increased the average daily intake to 4-5 times RDA levels, with a concomitant decrease in percent uptake below 20%. (24,32) During the Cold War years, the threat of nuclear attack and radioactive fallout became a topic of national interest. (33) Attempts were made to estimate the amount of I required to suppress maximally radiodide uptake by the thyroid. (34,37) It is of interest to note that these studies were not per formed to assess requirement of the human body for I but for crisis management in case of fallout of radioisotopes of I during a nuclear attack or accident. However, we will use these data to assist us in pinpointing the optimal requirement of the human body for I.

The ranges of percent radioiodide uptake by the thyroid gland from some selected publications are displayed in Table 1. The goal of this selection was to cover a wide range of I intake, from severe goiter to intake of excess I. From the publications by Karmarker et al (31) three areas were selected, representing severe, (<25 [micro]g I/day) moderate (25-50 [micro]g/day) and mild (51-100 [micro]g/day) I deficiency. Moving up into the RDA range, the two studies of Pittman et al, examined two groups of normal subjects before and after I was added to bread at a level of 150 [micro]g I/slice of bread. (24) The mean I intake in the two groups were two-thirds and 4-5 times RDA levels. Going up in the scale of I intake, Saxena et al (34) were the first to attempt a systematic study of the effect of increasing I intake on the percent uptake of radioiodide by the thyroid gland in order to find the minimum oral dose of I for maximum suppression of radioactive I uptake by the thyroid gland. These researchers used 63 euth yroid children as subjects, and they express the amount of I ingested as mg I/[m.sup.2]/day. The range of I intake covered was from 0.1 to 2.5 mg/[m.sup.2]/day, which would correspond to a range of 0.2 to 5 mg I in an adult. At 0.1 mg, the percent uptake varied from 20 to 30%. On a semilogarithmic graph, there was a linear relationship between the log of I intake and percent thyroid uptake of radioiodide. This linearity persisted up to 1.5 mg/[m.sup.2]/day where the percent uptake seems to reach a plateau at 5% uptake with oral doses of I up to 2.5 mg/[m.sup.2]/day. Because of the apparent leveling off at 5% thyroidal uptake at 1.5 mg/[m.sup.2]/day (equivalent to 3 mg I in adults), Saxena et al concluded that this percentage represented maximum suppression of radioiodide uptake by the thyroid gland. Six years later, Cuddihy (35) observed a 4% radioiodide uptake when 10 mg I was ingested. In 1940, Hamilton and Soley (36) were able to achieve a mean percent uptake of 3.5% when 14 mg I was mixed with the radioac tive tracer. In 1980, Sternthal et al (37) used amounts of I from 10-100 mg/day. At 10 mg, they confirm the 4% uptake observed by Cuddihy, and they were able to achieve near maximum suppression (0.6% radioiodide uptake by the thyroid gland) with a daily I intake of 100 mg.

If these data are plotted on a semilogarithmic graph, with percent radioiodide uptake on the y-axis and the logarithm of the amount of I ingested on the x-axis, four slopes and ranges are observed (Figure 1). By extending the first two slopes A and B to the point where their extensions cross the x-axis at 0% uptake, we can estimate the amount of I required for sufficiency of these two "pools" of I. Slope A crosses the x-axis at 0.27 mg and slope B, at 6 mg I. The range of intake covering slope A could be called the RDA range, or the goiter control range, since no more uptake of radioactive I was required at .27 mg, which is the upper limit (0.3 mg) of the RDA for control of goiter under all physiological conditions. (1)

Slope A is very steep, and therefore represents a range of I intake where the I-trapping mechanism of the thyroid gland is very inefficient. Within the linear portion of that range, that is, with intake of I less than 100 [micro]g/day, extrathyroidal tissues would be able to compete effectively with the thyroid for available I. We will discuss later the fact that the mammary glands possess an I-trapping system similar to that of the thyroid and have certain requirements for I to maintain normality. The larger breasts of women would retain more I than men, and there would be less I available for the I-trapping of the thyroid gland. This would result in a greater incidence and prevalence of thyroid dysfunction in women than in men, mainly in areas of marginal I intake. Indeed, the prevalence of goiter in endemic areas is six times higher in pubertal girls than pubertal boys. (38) Subclinical and overt hypo- and hyperthyroidism are more common in women than in men. (39,40) The physiological approach in these cas es would be to treat them with I supplementation in optimal amounts, not thyroid hormones and antithyroid drugs.

In the July 2002 issue of Bottom Line Health, there is an article by R. L. Shames, MD, entitled, "Thyroid disease could be the cause of your symptoms." This article is saturated with misinformation: "The thyroid needs iodine to function, but deficiencies of this mineral are largely a thing of the past because of our high consumption of iodized salt. Especially if you live near a coast, you may be getting too much iodine, which is harmful to the thyroid." Misinformation #1: I deficiency is a thing of the past. Fact #1: The last National Nutritional Survey revealed that 15% of the US adult female population suffered from I deficiency, defined as urine I level below 50 [micro]g/L, (2) which is a very low level by any standard. Misinformation #2: High consumption of iodized salt prevents I deficiency. Fact #2: Iodized salt contains 74 [micro]g I/gm salt. The purpose of iodization of salt was to prevent goiter and cretinism, not to provide optimal level of I required by the human body. For example, to ingest the a mount of I needed to control FDB, that is 5 mg I/day, (19) you need to consume 68 gm of salt. To reach levels of I ingested by mainland Japanese, a population with a very low prevalence of cancer of the female reproductive organs, you would need 168 gm of salt. Misinformation #3: You may be getting too much I if you live near a coast. Fact #3: Kung et al (63) after investigating I deficiency in Hong Kong, concluded, "Our experience in Hong Kong has shown that it is not safe to assume that iodine insufficiency does not exist in coastal regions." Misinformation #4: Too much I from coastal areas is harmful to the thyroid. Fact #4: From the study just mentioned, coastal areas do not even supply enough I to prevent I deficiency. The article by Dr. Shames even has a subsection teaching his readers how to reduce I intake! Considering that 15% of his female readers are already I deficient, even by the low RDA standard, what a shame!

Returning now to figure 1, slope B corresponds to I sufficiency of the thyroid gland, and represents a range where the efficiency of the I-trapping mechanism by the thyroid is markedly improved over slope A which is steeper. Slope B starts at 0.1 mg, the upper limit for mild deficiency and extends to 6 mg, theoretically, the optimal I intake for sufficiency of the thyroid gland. Slope C is almost horizontal, representing a range of I between 3 mg and 14 mg. The thyroid gland possesses maximal efficiency of the I-trapping mechanism over the range of I intake in slope C. Slope D from 15 mg to 100 mg of iodide could be called the saturation range. In order to refine further the optimal range of I intake, figure 2 displays the range of I intake from 0.1 to 100 mg.

The amount of I retained by the thyroid gland was also plotted for each intake level. The amount retained was computed by multiplying the amount of I ingested by the percent uptake of radioiodine by the thyroid gland. The 6 mg point is of interest because it is not only the crossing point of slope B at zero radioiodide uptake on the x-axis, but it also represents the 50% saturation point of the I trapping system of the thyroid gland. A system in a state of dynamic equilibrium would be the most stable at the midpoint between the two extremes -- that is, at 50% saturation. The RDA for I corresponds to 5% saturation of the I-trapping mechanism of the thyroid gland, a very unstable position, predisposing to both hypo- and hyperthyroidism. The intake of 14 mg was the maximum amount that did not trigger the autoregulatory mechanism of the thyroid gland. This amount may represent the upper limit of I required for sufficiency of the whole human body. At 15 mg intake, the thyroid gland down regulates the efficiency of the I trapping in an attempt to bring down the amount of I retained to 50% saturation (Fig. 2). Above 15 mg intake, the efficiency of the trapping mechanism increases markedly with greater intake of I to reach saturation at 50 mg intake and 0.6 mg/24 hr of trapped I by the thyroid gland (Fig. 2).

Searching the literature, we found evidence supporting the amount observed in our calculation regarding the saturation of the I trapping by the normal thyroid, that is 0.6 mg/day. For example, Wagner et at (41) observed, in an euthyroid subject who received increasing amount of iodide, that the maximum trapping of I by the thyroid was 50 [micro]g/2 hrs. This value multiplied by 12 = 600 [micro]g/24 hr. Fisher et al (42) observed, in 20 normal subjects receiving different amounts of I, that the computed I accumulation per day by the thyroid gland was highest in two subjects with values of 608 and 613 [micro]g/24 hr.

Regarding the optimal I intake of 6 mg/day for sufficiency of the thyroid gland, there are some very interesting observations reported by various investigators, with 6 mg mentioned in connection with various physiological parameters of thyroid function. With optimal intake of I, thyroid function would be the most stable under adverse conditions, maintaining homeostasis when pathological conditions tend to destabilize homeostasis in either direction, toward hypo- or hyperactivity of the thyroid gland. Therefore, the optimal intake of I for thyroid sufficiency should have the greatest effect in restoring normal functions under both conditions. The amount 6 mg/day happens to be the daily intake of I that gave the maximum reduction in basal metabolism toward the normal range in most cases of Grave's disease (hyperthyroidism). (3)

First, let us describe the form of I used in these studies. The Lugol solution contains 5% iodine and 10% potassium iodide. (43) It has been available since 1829 when it was introduced by French physician Jean Lugol, and was used extensively in medical practice during the early part of the 20th century. The recommended intake for I supplementation at that time was 2 drops/day, corresponding to 12.5 mg I. This recommendation was still mentioned in the 19th edition of Remington's Science and Practice of Pharmacy, published in 1995. (43) As quoted by Ghent et al (19) in 1928, an autopsy series reported a 3% incidence of FDB, whereas in a 1973 autopsy report, the incidence of FDB increased markedly to 89%. Is it possible that the very low 3% incidence of FDB reported in the pre-RDA early 1900s was due to the widespread use of the Lugol solution (available then from local apothecaries), and the recently reported 89% incidence of FDB is due to a trend of decreasing I consumption (2) (still within RDA limits for I, therefore giving a false sense of

I sufficiency)?

In 1923, American physician H.S. Plummer was the first to use Lugol solution pre- and post-operatively in his management of Grave's disease. He postulated that the hyperthyroidism of Grave's disease was due to I deficiency and that the high mortality rate associated with the post-operative recovery period could be controlled with I administration pre- and post-operatively. By administering 20-30 drops of Lugol pre-operatively and 10 drops post-operatively, he reported zero mortality rate. His procedure became widely used both in the US and abroad. In 1930, a systematic study was performed by Thompson et al (3) in patients with Grave's disease, using a wide range of I intake from Lugol solution, that is, from 1/5 drop to 30 drops/day. In 17 hospitalized patients and in 23 outpatients, one drop of Lugol gave the maximum reduction in basal metabolism toward the normal range in the majority of the patients, following a period of bed rest. One drop of Lugol contains a total of 6.25 mg, with 40% iodine and 60% iodi de as the potassium salt.

Koutras et al (45) administered increasing amounts of iodide from 0.1 to 0.8 mg to normal subjects over a period of 12 weeks and measured the quantity of I retained by the thyroid gland before an equilibrium with the new plasma inorganic I was reached. With all the doses administered, a total of 6-7 mg I was accumulated by the thyroid gland over a period of weeks before equilibrium was reached. Again, around 6 mg was the amount observed under those physiological manipulations. These authors stated, "From our evidence it appears that, with all the doses we used, the thyroid took up about 6 to 7 mg of iodine before an equilibrium with the new P11 (Plasma Inorganic I) was reached. It is of some interest that this is approximately the amount of the intrathyroidal exchangeable iodine." Based on the above observations and the data displayed in figure 2, we would like to propose that the optimal daily intake for I sufficiency of the thyroid gland is 6 mg, with a minimum of 3 mg, Saxena's minimal daily amount. (34)

Requirement of the extrathyroidal tissues for I

In 1954, Berson and Yalow (46) postulated that following initial clearance of an administered dose of radioiodine, the major portion of the radioiodine in the body is distributed between two compartments, the thyroidal and extrathyroidal organic I pools, which are in dynamic equilibrium. The results obtained from an elegant experimental design revealed that the total exchangeable organic I pool ranged from 7 to 13 mg. The total organic pool of I observed in Berson and Yalow's study may correspond to the range of I intake required daily for I sufficiency of the whole human body. The upper limit of 13 mg I is amazingly close to the upper limit of 14 mg observed in slope C of figure 2, the maximum intake of I that will not trigger down-regulation of the I-trapping mechanism of the thyroid gland.

The amount of I required by the human body for optimal health would not be expected to trigger down regulation of the I trapping system of the thyroid gland. We are proposing that the upper limit of the requirement of the whole human body for I would be 14 mg. If 6 mg I is the optimal amount needed for the thyroid gland, the extrathyroidal tissues need the difference, that is 14 mg - 6 mg = 8 mg. Although several extrathyroidal organs and tissues have the capability to concentrate and organify I, (47-79) the most compelling evidence for an extrathyroidal function of I is its effects on the mammary gland. Eskin et al have published the results of their extensive and excellent studies on the rat model of FDB and breast cancer and the importance of iodine as an essential element for breast normality and for protection against FDB and breast an (14-16,19,20) The amount of I required for breast normality in the female rats was equivalent, based on body weight, to the amounts required clinically to improve signs an d symptoms of FDB. That amount of I was 0.1 mg I/kg body weight/day. For a 50 kg woman, that daily amount would compute to 5 mg I.

Of interest is the findings of Eskin et a1 (20) that the thyroid gland preferentially concentrates iodide whereas the mammary gland favors iodine. In the 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. This would suggest that iodine is not reduced to iodide during intestinal absorption. Recent textbooks of endocrinology continue the tradition of the past, reaffirming that iodine is reduced to iodide prior to absorption in the intestinal tract, referring to a study by Cohn (50) published in 1932, using segments of the gastrointestinal tract of dogs, washed clean of all food particles prior to the application of I in the lumen. However, Thrall and Bull (51) observed that in both fasted and fed rats, the thyroid gland and the skin contained significantly more I when rats were fed with iodide than with iodine; whereas the stomach walls and stomach contents had a significantly greater level of I in iodine-fed rats than iodide-fed animals. Peripheral levels of inorganic I were different with different patterns, when rats were fed with these two forms of I. The authors concluded, "These data lead us to question the view that iodide and iodine are essentially interchangeable." Based on the above findings, I supplementation should contain both iodine for the mammary tissue and iodide for the thyroid gland.

The mammary glands can effectively compete with the thyroid gland for peripheral I. Eskin et al (52) measured the 24-hour radioiodide uptake in 57 clinically normal breasts, and in eight clinically abnormal breasts. The mean [+ or -] SD percent uptake was 6.9[+ or -]0.46% in the normal breasts and 12.5[+ or -]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 percent 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 percent uptake in the abnormal breasts suggests that the abnormal breasts were more I deficient than normal breasts. As previously discussed, endemic goiter is six times more common in pubertal girls than pubertal boys. (38) This suggests that in areas of marginal I supply, the larger breast of pubertal girls, wit h greater I requirement, would leave less I available for thyroid uptake than in pubertal boys, and the expected outcome would be a greater prevalence of goiter in pubertal girls than boys. The presence of simple goiter in a female patient is an indication of I deficiency of both the thyroid and mammary glands. Treating such patients with [T.sub.4] instead of I supplementation is non-physiological and increases their risk of breast cancer. (17)

Beside the greater risk for breast cancer in I-deficient women, there is convincing evidence that I deficiency increases also the risk of thyroid cancer. It is common knowledge that simple goiter due to I-deficiency, if left without I supplementation, will progress to nodular goiter with some of these nodules becoming cancerous. (30) Since simple goiter is more common in women than in men (because of their greater need for I) it is a common sense conclusion that I-deficiency will eventually result in a greater prevalence of thyroid nodules in women, and subsequently a greater incidence and prevalence of thyroid cancer. Therefore, it is not surprising that with the decreasing trend of I consumption by the US population, (1,2) there is a marked increase in thyroid nodules, resulting in 19,500 new cases of thyroid cancer in 2001, with 14,900 cases in women. An editorial in the May 2002 issue of the Journal of Clinical Endocrinology and Metabolism (53) called this increased incidence of thyroid nodules "an epidem ic." It is amazing that the author of the editorial made no mention of I deficiency as a possible cause for this "epidemic," although the connection is very obvious. It is a national tragedy that such preventable diseases continue to rise in our population as I deficiency becomes more prevalent and self-appointed experts continue to spread iodophobic misinformation. The guardians of our nation's thyroids should be more concerned about supplying the optimal requirement of the human body for I to the US population and less zealous in their crusade to eliminate I from our food supply.

Requirement of the human body for I

So far, the optimal daily requirement for I has been estimated at 6 mg of iodide for the thyroid gland and 5 mg of iodine for the mammary glands. The adrenal glands may also require adequate levels of I for normal function. A recent study of female rats exposed to noise stress revealed a decreased adaptability to stress when these rats were placed on an I-deficient diet. There was an attenuation of the pituitary adrenal axis to stress that persisted after functional recovery of the pituitary thyroid axis. Therefore, this effect of I on the adrenal response to stress is totally independent of thyroid hormones.

Certain roles of I in well-being and protection against infections, degenerative diseases, and cancer may not involve its action on specific organs and tissues. Instead, such properties of I, affecting every cell in the human body, may depend on its concentration in biological fluids. Derry (54) has reviewed some beneficial properties of I: the antimicrobial effect of I in organs capable of concentrating it to reach effective I levels; the apoptotic property of I in the body's surveillance mechanism against abnormal cells; and the ability of I to trigger differentiation, moving the cell cycle away from the undifferentiated characteristic of breast cancer (or for that matter, of all cancer). Besides, as a halogen, and because of its large size, I has the ability to markedly enhance the excited singlet to triplet radiationless transition. (55) Reactive oxygen species causing damage to DNA and other macromolecules are usually excited singlets with a high energy content released rapidly, and characterized by fluo rescence, whereas the corresponding triplet state contains lower energy levels which are released slowly, expressed as phosphorescence. Such an effect of I would depend on its concentration in biological fluids. Using a rudimentary phosphoroscope, Szent-Gyorgy was able, 50 years ago, to demonstrate this effect of I on the singlet-triplet radiationless transition, at a concentration of [10.sup.-5] M (56). It is likely that this effect would persist at [10.sup.-6] M, which would correspond to a serum I level of 12.7 [micro]g/100 ml. Such a level is easily achieved with I intake in the range consumed by mainland Japanese. This effect of I would markedly decrease the oxidative burden of the body, having a beneficial impact upon degenerative diseases and cancer. Protection of the thyroid from radioiodine fallout in cases of nuclear attack and accident would benefit from the recommended daily intake of I, discussed above. The equivalent of two drops of Lugol solution (12.5 mg I) daily would maintain a low radioiodi ne uptake by the thyroid gland (3-4%). Since the greatest damage to the thyroid occurs during the first few hours of radiation exposure, (57) this recommended level of I would serve as a prevention in cases of unexpected exposure.

Collective experience may have played a role in the choice of two drops of Lugol daily for I supplementation. (43) Amazingly, 0.1 ml (two drops) of Lugol contains 5 mg iodine and 7.5 mg iodide as the potassium salt, the near perfect total amount of I and ratio of iodine to iodide, for sufficiency of the thyroid and mammary glands. This amount of Lugol solution represents an ideal form of orthoiodosupplementation. Based on the above criteria for I sufficiency of the whole human body, the mainland Japanese represent the only population in the world consuming adequate amounts of I. Thyroid function is higher in normal Japanese woman, a low risk population for breast cancer, than in normal British women who are at high risk for breast cancer. (11) When five different ethnic groups living in Hawaii were compared with British women and mainland Japanese women, the last group showed the highest serum levels of free T. (4) There was a significant and inverse correlation (p<0.001) 1) between serum free T and the incid ence of breast cancer in these seven groups, with mainland Japanese women showing the lowest incidence. (11,12) Since [T.sup.4] therapy in I-deficient women increased their risk for breast cancer, (17) the significant correlation between serum free [T.sub.4] and breast cancer is not necessarily indicative of a protective role of [T.sub.4]. Instead, this correlation may point to the higher I levels in Japanese women, expressed as increased thyroid function. Prasad et al (58) reported significantly lower serum [T.sub.4] and higher serum [T.sub.3] levels in 40 women with histologically confirmed breast cancer, compared to 10 normal controls. Although these authors did not measure urine I levels in those cases, the pattern they reported in women with breast cancer is typical of I deficiency: increased [T.sub.3] levels and lower [T.sub.4] levels to compensate for the limited availability of I. (30)

Physician-supervised orthoiodosupplementation

Based on the information previously discussed, the optimal daily I intake for I sufficiency of the whole human body would be equivalent to two drops of Lugol solution. In the US, the initial implementation of I supplementation at this level would require medical supervision. Administration of I in liquid solution is not very accurate, may stain clothing, has an unpleasant taste, and causes gastric irritation. We decided to use a precisely quantified tablet form containing 5 mg iodine and 7.5 mg iodide as the potassium salt. To prevent gastric irritation, the iodine/iodide preparation was absorbed into a colloidal silica excipient, and to eliminate the unpleasant taste of iodine, the tablets were coated with a thin film of pharmaceutical glaze.

Our preliminary experience with I supplementation at 12.5 mg/day, confirmed the findings of Ghent et al, (19) regarding subjective and objective improvements of FDB following I supplementation. Our findings in three patients with polycystic ovarian syndrome (PCOS) confirmed the positive response observed following supplementation with 10-20 mg of potassium iodide by Russian investigators 40 years ago. (62) Prior to I supplementation, those PCOS patients were oligomenorrheic, menstruating once or twice a year. Following I supplementation for three months, they resumed normal monthly cycles. In two patients with subclinical hypothyroidism and elevated TSH levels, I supplementation suppressed TSH levels markedly. In one patient, serum TSH was 7.8 mIU/L pre-supplementation and 1.7 mIU/L three months post I supplementation. In the other patient, TSH was 21.5 mIU/L before and 11.9 mIU/L after three months of I supplementation.

Surprisingly, this program improved the symptoms of tremor and restless legs, two symptoms usually present in neurologic cretinism. (59) There was some evidence of improved [T.sub.3] receptor responsiveness, reflected by a decreased need for [T.sub.3] in some patients previously receiving this hormone. One female patient with normal size and echo pattern of the thyroid gland required 45 [micro]g [T.sub.3] to maintain clinical euthyroidism. Following I supplementation at 12.5 mg/day, she was able to titrate her daily dose of [T.sub.3] down to 7.5 [micro] during the first month of I supplementation. Previously, missing one or two days o [T.sub.3] elicited symptoms. Currently, she noticed that she can remain asymptomatic without [T.sub.3] for one week. TSH levels in this patient were below detection limits prior to I supplementation. Over the last 12 months on I supplementation, TSH levels are maintained between I and 2.5 mIU/L. The calculated [T.sub.3] secretion rate by the normal thyroid gland varies between 4 .6 and 8.3 [micro]g/day. (64) Therefore, with adequate supply of endogenous or exogenous [T.sub.4], the daily need for exogenous [T.sub.3] should not exceed 8.3 [micro]g to maintain clinical euthyroidism. Is it possible that the large number of patients currently on supraphysiologic levels of [T.sub.3] to maintain clinical euthyroidism are in reality I deficient by our definition of I sufficiency of the whole human body? Could it be that all they need is orthoiodosupplementation?

Eskin and Ghent have observed a modulating role of I at levels of 0.1 mg/kg body weight/day in the response of mammary tissue to estrogens. (14-16,19) We have some evidence of improved [T.sub.3] receptor function in female patients receiving 12.5 mg I/day. [T.sub.3] and steroid hormones share the same superfamily of receptors for hydrophobic small molecules. (60) Clur (61) has postulated that iodination of tyrosine residues in the hydrophobic portion of these receptors normalized their response to the corresponding hormones. Optimal intake of I in amounts two orders of magnitude greater than I levels needed for goiter control may be required for iodination of these receptors. Our observation has important clinical implications. If optimal intake of I reduces the need for exogenous [T.sub.3], one would expect the same effect of I supplementation on endogenous [T.sub.3]. I intake below optimal levels would result in clinical hypothyroidism in the presence of normal levels of thyroid hormones because of decrease d [T.sub.3] receptor function. If this common condition is due to I deficiency, the proper treatment would then be orthoiodosupplementation.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]
Table 1

Percent uptake of radioiodide by the thyroid gland and amount of iodide
retained by the thryoid gland in response to increasing intake of stable
iodide (all values below are means

           Thyroidal      Amount of
 Intake   Radioiodide  iodide retained          Reference
mg I/day    Uptake     by the thyroid
           (percent)   gland (ug/day)

  0.02       84.7                            Karmarkar et al
                                               Am. J. Clin.
                                           Nut 27:96-103, 1974
  0.03       68.7                                   "
  0.76       42.4                                   "

  0.11       28.6           31.8              Pittman et al
                                             N. Engl. J. Med
                                           280:1431-1434, 1969
  0.68       15.4            105                    "

  3.0         5.0            150               Saxena et al
                                             Science 138:430-
                                                431, 1962

  10.0        4.0            400             Sternthal et al
                                           N. Engl. J. Med 303:
                                             1083-1088, 1980
   15         1.9            285                    "
   30         1.6            480                    "
   50         1.2            600                    "
  100         0.6            600                    "

   14         3.5            490              Hamilton, J.G.
                                          and Soley, M.H. Am J.
                                        Physical 131:135-143, 1940


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