Iodine in biology

Iodine  is an essential trace element for life, the heaviest element commonly needed by living organisms, and the second-heaviest known to be used by any form of life (only tungsten, a component of a few bacterial enzymes, has a higher atomic number and atomic weight).

Thyroid
Iodine's main role in animal biology is as constituents of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). These are made from addition condensation products of the amino acid tyrosine, and are stored prior to release in an iodine-containing protein called thyroglobulin. T4 and T3 contain four and three atoms of iodine per molecule, respectively. The thyroid gland actively absorbs iodine from the blood to make and release these hormones into the blood, actions which are regulated by a second hormone TSH from the pituitary. Thyroid hormones are phylogenetically very old molecules which are synthesized by most multicellular organisms, and which even have some effect on unicellular organisms.

Thyroid hormones play a basic role in biology, acting on gene transcription to regulate the basal metabolic rate. The total deficiency of thyroid hormones can reduce basal metabolic rate up to 50%, while in excessive production of thyroid hormones the basal metabolic rate can be increased by 100%. T4 acts largely as a precursor to T3, which is (with minor exceptions) the biologically active hormone.

Iodine has a nutritional relationship with selenium. A family of selenium-dependent enzymes called deiodinases converts T4 to T3 (the active hormone) by removing an iodine atom from the outer tyrosine ring. These enzymes also convert T4 to reverse T3 (rT3) by removing an inner ring iodine atom; and convert T3 to 3,3'-Diiodothyronine (T2) also by removing an inner ring atom. Both of the latter are inactivated hormones which are ready for disposal and have essentially no biological effects. A family of non-selenium dependent enzymes then further deiodinates the products of these reactions.

Selenium also plays a very important role in the production of Glutathione, the body's most powerful antioxidant. During the production of thyroid hormones, hydrogen peroxide is produced, high Iodine in the absence of selenium destroys the thyroid gland (often felt as a sore throat feeling), the peroxides are neutralized through the production of glutathione from selenium. In turn an excess of selenium increases demand for iodine, and deficiency will result when a diet is high in selenium and low in iodine.

Extrathyroidal iodine
Iodine accounts for 65% of the molecular weight of T4 and 59% of the T3. 15–20 mg of iodine is concentrated in thyroid tissue and hormones, but 70% of the body's iodine is distributed in other tissues, including mammary glands, eyes, gastric mucosa, the cervix, and salivary glands. In the cells of these tissues iodide enters directly by sodium-iodide symporter (NIS). Different tissue responses for iodine and iodide occur in the mammary glands and the thyroid gland of rats. The role of iodine in mammary tissue is related to fetal and neonatal development, but its role in the other tissues is unknown. It has been shown to act as an antioxidant and antiproliferant in various tissues that can uptake iodine. Molecular iodine (I2) has a suppressive effect on benign and cancerous neoplasias.

The US Food and Nutrition Board and Institute of Medicine recommended daily allowance of iodine ranges from 150 micrograms/day for adult humans to 290 micrograms/day for lactating mothers. However, the thyroid gland needs no more than 70 micrograms/day to synthesize the requisite daily amounts of T4 and T3. These higher recommended daily allowance levels of iodine seem necessary for optimal function of a number of body systems, including lactating breast, gastric mucosa, salivary glands, oral mucosa, arterial walls, thymus, epidermis, choroid plexus and cerebrospinal fluid, etc. In amphibian metamorphosis iodine and thyroid hormones also exert a well-studied experimental model of apoptosis on the cells of gills, tail, and fins of tadpoles. Moreover, iodine can add to double bonds of docosahexaenoic acid and arachidonic acid of cellular membranes, making them less reactive to free oxygen radicals.

Dietary reference intake and recommended daily allowance
The daily Dietary Reference Intake recommended by the United States Institute of Medicine is between 110 and 130 µg for infants up to 12 months, 90 µg for children up to eight years, 130 µg for children up to 13 years, and 150 µg for adults. Pregnant women have a DRI of 220 µg and lactating mothers require 290 µg.

The United States Recommended Daily Allowance (RDA) is 150 micrograms per day (μg/day) for both men and women, with a Tolerable Upper Intake Level (UL) for adults is 1,100 μg/day (1.1 mg/day). The tolerable upper limit was assessed by analyzing the effect of supplementation on thyroid-stimulating hormone.

Range of observed intakes
Natural sources of iodine include sea life, such as kelp and certain seafood, as well as plants grown on iodine-rich soil. Iodized salt is fortified with iodine.

As of 2000, the median intake of iodine from food in the United States was 240 to 300 μg/day for men and 190 to 210 μg/day for women. In Japan, consumption is much higher due to the frequent consumption of seaweed or kombu kelp, Hokkaido residents eat a quantity of seaweed sufficient to provide a daily iodine intake of 200 mg (200 000 mcg) a day.

After iodine fortification programs (e.g. iodized salt) have been implemented, some cases of iodine-induced hyperthyroidism have been observed (so called Jod-Basedow phenomenon). The condition mainly seems to occur in people over forty, and the risk appears higher when iodine deficiency is severe and the initial rise in iodine intake is high.

Deficiency
Worldwide, iodine deficiency affects two billion people and is the leading preventable cause of mental retardation. Mental disability is a result which occurs primarily when babies or small children are rendered hypothyroidic by a lack of the element (new hypothyroidism in adults may cause temporary mental slowing, but not permanent damage).

In areas where there is little iodine in the diet, typically remote inland areas and semi-arid equatorial climates where no marine foods are eaten, iodine deficiency also gives rise to hypothyroidism, symptoms of which are extreme fatigue, epidemic goitre (swelling in the thyroid gland), mental slowing, depression, weight gain, and low basal body temperatures.

The addition of iodine to table salt has largely eliminated this problem in the wealthier nations, but as of March 2006, iodine deficiency remained a serious public health problem in the developing world. Iodine deficiency is also a problem in certain areas of Europe. In Germany it has been estimated to cause a billion dollars in health care costs per year.

Iodine may also help prevent diseases of the oral and salivary glands.

===Iodine and cancer risk===
 * Breast cancer. The breast strongly and actively concentrates iodine into breast-milk for the benefit of the developing infant, and may develop a goiter-like hyperplasia, sometimes manifesting as fibrocystic breast disease, when iodine level is low. Studies indicate that iodine deficiency, either dietary or pharmacologic, can lead to breast atypia and increased incidence of malignancy in animal models, while iodine treatment can reverse dysplasia, with elemental iodine (I2) having been found to be more effective in reducing ductal hyperplasias and perilobular fibrosis in iodine-deficient rats than iodide (I&minus;). A protective effect of iodine against breast cancer has been suggested on the basis of the observation that Japanese women who consume iodine-rich seaweed have a relatively low rate of breast cancer.  Iodine is known to induce apoptosis in breast cancer cells. Laboratory evidence has demonstrated an effect of iodine on breast cancer that is in part independent of thyroid function, with iodine inhibiting cancer promotion through modulation of the estrogen pathway. Gene array profiling of estrogen responsive breast cancer cell line shows that the combination of iodine and iodide alters gene expression and inhibits the estrogen response through up-regulating proteins involved in estrogen metabolism. Whether iodine/iodide will be useful as an adjuvant therapy in the pharmacologic manipulation of the estrogen pathway in women with breast cancer has not been determined clinically.


 * Iodine and stomach cancer. Some researchers have found an epidemiologic correlation between iodine deficiency, iodine-deficient goitre and gastric cancer;  a decrease of the incidence of death rate from stomach cancer after implementation of the effective iodine-prophylaxis has been reported also. The proposed mechanism of action is that iodide ion can function in gastric mucosa as an antioxidant reducing species that can detoxify poisonous reactive oxygen species, such as hydrogen peroxide.

Precautions and toxicity of elemental iodine
Elemental iodine is an oxidizing irritant and direct contact with skin can cause lesions, so iodine crystals should be handled with care. Solutions with high elemental iodine concentration such as tincture of iodine and are capable of causing tissue damage if use for cleaning and antisepsis is prolonged. Although elemental iodine is used in the formulation of Lugols Solution, it becomes tri-iodide upon reacting with potassium iodide used in the solution and is non-toxic. Only a small amount of elemental iodine will dissolve in water, adding potassium iodide allows a much higher amount of elemental iodine to dissolve through the reaction of I2-I3. This allows Lugols to come in strengths varying from 2%-15% iodine.

Elemental iodine (I2) is poisonous if taken orally in larger amounts; 2–3 grams of it is a lethal dose for an adult human. Potassium Iodide on the other hand has an LD50 that is high in several other animals; in rabbits it is 10 g/kg, in rats it is 14 g/kg, and in mouse it is 22 g/kg. The tolerable upper intake level for iodine, established by the Food and Nutrition Board, is 1,100 µg/day for adults. The safe upper limit of consumption set by the Ministry of Health, Labor and Welfare in Japan is 3 mg/day (3000 µg/day).

The biological half-life of iodine is different in the various organs of the body, from 100 days in the thyroid, to 14 days in the kidneys and spleen, to 7 days in the reproductive organs. Typically the daily urinary elimination rate ranges from 100 to 200 µg/L in humans. However, the Japanese diet, high in kelp, contains 1,000 to 3,000 µg of iodine per day, and research indicates the body is able to readily eliminate excess iodine that isn't needed for thyroid hormone production. Literature reports as much as 30,000 µg/L (30 mg/L) of iodine being safely excreted in the urine in a single day, with levels returning to the standard range in a couple of days, depending on seaweed intake. One study concluded the range of total body iodine content in males was 12.1 mg to 25.3 mg, with a mean of 14.6 mg. It is presumed that once thyroid-stimulating hormone is suppressed the body simply eliminates excess iodine, and as a result, long term supplementation with high doses of iodine has no additional effect once the body is replete with enough iodine. It is unknown if the thyroid is the rate limiting factor in generating thyroid hormone from iodine and tyrosine, but assuming it isn’t, a short term loading dose of one or two weeks at the tolerable upper intake level could quickly restore thyroid function in iodine deficient patients.

Iodine vapor is very irritating to the eye, to mucous membranes, and in the respiratory tract. Concentration of iodine in the air should not exceed 1 mg/m³ (eight-hour time-weighted average).

When mixed with ammonia and water, elemental iodine forms nitrogen triiodide which is extremely shock sensitive and can explode unexpectedly.

Toxicity of iodide ion
Excess iodine has symptoms similar to those of iodine deficiency. Commonly encountered symptoms are abnormal growth of the thyroid gland and disorders in functioning and growth of the organism as a whole. Iodides are similar in toxicity to bromides.

Excess iodine can be more cytotoxic in the presence of selenium deficiency. Iodine supplementation in selenium-deficient populations is theoretically problematic, partly for this reason.

Iodine sensitivity
Some people develop a sensitivity to iodine. Application of tincture of iodine can cause a rash. Some cases of reaction to Povidone-iodine (Betadine) have been documented to be a chemical burn. Eating iodine-containing foods can cause hives. Medical use of iodine (i.e. as a contrast agent, see above) can cause anaphylactic shock in highly iodine sensitive patients. Some cases of sensitivity to iodine can be formally classified as iodine allergies. Iodine sensitivity is rare but has a considerable effect given the extremely widespread use of iodine-based contrast media.