2
The Thyroid and Disruption of Thyroid Function in Humans

THYROID hormones are critical determinants of growth and development in infants and of metabolic activity in infants and adults. They affect the functions of virtually every organ system, and they must be constantly available to carry out these functions. A steady supply of thyroid hormones is provided by large reservoirs in the circulation and the thyroid gland. Thyroid hormone biosynthesis and secretion are normally maintained within narrow limits by regulatory mechanisms that are sensitive to small changes in the circulating hormone concentrations. The regulatory mechanisms protect against both hypothyroidism (deficient thyroid hormone production) and hyperthyroidism (excess thyroid hormone production).

There are two thyroid hormones, thyroxine (T4) and triiodothyronine (T3).1 All the circulating T4 and about 20% of the T3 are produced in the thyroid gland; the remaining 80% of the T3 is produced from T4 in most tissues of the body. Through a process known as deiodination, enzymes called deiodinases remove a single iodine atom from the T4 molecule to produce the more active hormone T3. Most of the effects of thyroid hormones in individual cells of the body are exerted by T3, acting to regulate thyroid hormone-responsive expression of genes that code for many cellular proteins that regulate development, growth, and metabolism.

Topics discussed in this chapter include the production of T4 and T3, the

1  

A third hormone of thyroid origin, calcitonin, is produced by different cells within the thyroid gland. It affects calcium metabolism but has no effects on iodide metabolism or T4 or T3 production or action and is not discussed further in this report.



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Health Implications of Perchlorate Ingestion 2 The Thyroid and Disruption of Thyroid Function in Humans THYROID hormones are critical determinants of growth and development in infants and of metabolic activity in infants and adults. They affect the functions of virtually every organ system, and they must be constantly available to carry out these functions. A steady supply of thyroid hormones is provided by large reservoirs in the circulation and the thyroid gland. Thyroid hormone biosynthesis and secretion are normally maintained within narrow limits by regulatory mechanisms that are sensitive to small changes in the circulating hormone concentrations. The regulatory mechanisms protect against both hypothyroidism (deficient thyroid hormone production) and hyperthyroidism (excess thyroid hormone production). There are two thyroid hormones, thyroxine (T4) and triiodothyronine (T3).1 All the circulating T4 and about 20% of the T3 are produced in the thyroid gland; the remaining 80% of the T3 is produced from T4 in most tissues of the body. Through a process known as deiodination, enzymes called deiodinases remove a single iodine atom from the T4 molecule to produce the more active hormone T3. Most of the effects of thyroid hormones in individual cells of the body are exerted by T3, acting to regulate thyroid hormone-responsive expression of genes that code for many cellular proteins that regulate development, growth, and metabolism. Topics discussed in this chapter include the production of T4 and T3, the 1   A third hormone of thyroid origin, calcitonin, is produced by different cells within the thyroid gland. It affects calcium metabolism but has no effects on iodide metabolism or T4 or T3 production or action and is not discussed further in this report.

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Health Implications of Perchlorate Ingestion regulation of thyroid hormone production, the actions of the thyroid hormones, the development of thyroid function during fetal life, and the effects of perchlorate when given deliberately to humans. The effects of environmental exposure to perchlorate are summarized in Chapter 3. ANATOMY The thyroid is a butterfly-shaped gland in the front of the neck. It weighs about 1-1.5 g at birth and 10-20 g in healthy adults in the United States. It contains millions of spherical follicles, each composed of a single layer of cells known as thyroid follicular cells surrounding a space, or lumen, filled with fluid known as colloid (Figure 2-1). Thyroid follicles are the functional units of the thyroid gland. The colloid consists mostly of thyroglobulin, a thyroid protein that serves as the framework for production of T4 and T3 and as the storage form of the two hormones. THYROID HORMONE PRODUCTION, TRANSPORT, AND ACTION T4 and T3 are the only biologically active substances that contain iodine. They are similar in that each has two six-member rings—an inner and an outer ring (Figure 2-2)—connected by an ether linkage. Their inner rings have two iodine atoms; T4 has two iodine atoms in its outer ring, whereas T3 has only one. The compound formed if an iodine atom is removed from the inner ring of T4 is 3,3',5'-triiodothyronine (reverse T3), which has no biologic activity. Production of Thyroxine and Triiodothyronine in the Thyroid Gland Transport of Iodide into Thyroid Cells Iodine is an intrinsic component of T4 and T3. Transfer of iodide from the circulation into the thyroid gland is therefore an essential step in the synthesis of the two hormones.2 Iodide is transported from the bloodstream 2   Iodide is the negatively charged ion of iodine and is the form of iodine that is found in foods and in the circulation in humans.

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Health Implications of Perchlorate Ingestion FIGURE 2-1 Diagram of thyroid cells and a thyroid follicle, showing key steps in thyroxine (T4) and triiodothyronine (T3) synthesis and secretion. A follicle consists of a single layer of thyroid follicular cells surrounding a lumen, which is filled with thyroglobulin (Tg). Iodide (I−) and sodium (Na+) ions are transported into cells via the sodium (Na+)/iodide (I−) symporter (NIS) in the basolateral membrane of the cells. Iodide diffuses to the luminal side of the cell and is transported into the lumen of the follicle, where it is oxidized and then used to form T4 and T3 (within Tg). Tg is taken up by cells and broken down, freeing its constituent T4 and T3 molecules, which then diffuse out of the cell and into the bloodstream. into thyroid cells against a chemical and electric gradient. It diffuses rapidly across the cells and is transported into the lumen of thyroid follicles, where T4 and T3 are produced (Figure 2-1). Iodide transport into the cells is mediated by a specific protein molecule, the sodium (Na+)/iodide (I−) symporter (NIS) (Dohan et al. 2003). The symporter is also present in substantial quantities in the salivary glands, stomach, and mammary glands; the iodide that is transported into these tissues is not further metabolized, as it is in the thyroid gland, but instead is secreted unchanged into saliva, gastric juice, or milk. Very small amounts of the symporter have been found in other tissues (see the last section of this chapter and Chapter 4).

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Health Implications of Perchlorate Ingestion FIGURE 2-2 Structures of thyroxine (T4), triiodothyronine (T3), and reverse triiodothyronine (reverse T3). Note that T3 is missing an iodine atom on its outer ring and reverse T3 is missing an iodine atom on its inner ring. T3 is most potent thyroid hormone. T4 is active only after conversion to T3, and reverse T3 has no biologic activity. The NIS is a glycoprotein composed of 643 amino acids and a small amount of carbohydrate. It is in the outer (plasma) membrane at the basolateral surface of the thyroid follicular cells (Figure 2-1). It is not present in the membrane at the apical surface of the cell, the part of the cell that is adjacent to the lumen of the thyroid follicle. The symporter uses the inward movement of sodium ions to transport iodide into the cells; two sodium ions are transported for each iodide ion. NIS has a very high affinity for iodide, which allows transport of iodide into the cells against a high concentration gradient. It also transports other ions with a similar shape and electric charge, such as perchlorate and thiocyanate. The affinity of NIS for those substances is higher than its affinity for iodide, so they can block iodide transport into thyroid cells, which can result in a decrease in the iodide concentration in the cells and therefore in a decrease in the availability of iodide for synthesis of T4 and T3. Among those substances, perchlorate is the best studied. It is a true competitive inhibitor of iodide transport: it blocks iodide transport through the symporter in a dose-dependent manner. Conversely, iodide blocks

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Health Implications of Perchlorate Ingestion perchlorate transport in a similar manner. Whether perchlorate itself is transported into the thyroid gland is debated (Dohan et al. 2003; Van Sande et al. 2003). Thyrotropin (thyroid-stimulating hormone, TSH) is produced by the anterior pituitary gland that stimulates all aspects of thyroid function, including the production of symporter molecules and therefore iodide transport. T4, T3, and cytokines (molecules that mediate inflammatory reactions) inhibit TSH secretion, thereby decreasing the production of symporter molecules. Iodide deficiency results in an increase in production of symporter molecules independently of TSH. A few patients have had mutations in the gene for the NIS. Because their thyroid follicular cells cannot transport iodide, they are unable to synthesize T4 or T3, and consequently they have hypothyroidism. Synthesis and Secretion of Thyroxine and Triiodothyronine in the Thyroid Gland After passage through the symporter into thyroid follicular cells, iodide rapidly diffuses to the apical surface of the cells (Figure 2-1). There, it is transported across the apical membrane into the lumen of the follicles by pendrin, a membrane iodide-chloride transporter. It is then rapidly oxidized and covalently bound (“organified”) to specific tyrosine residues of thyroglobulin; some tyrosine residues gain one iodine atom (forming monoiodotyrosine), and others gain two iodine atoms (forming diiodotyrosine). These oxidation and binding reactions are catalyzed by the enzyme thyroid peroxidase in a reaction that requires hydrogen peroxide (Taurog 2000). Thyroglobulin is a large protein that serves as the site of thyroid hormone synthesis. It is synthesized by the thyroid follicular cells and then carried to the follicular lumen. Within the thyroglobulin molecule, T4 is formed by the coupling of two diiodotyrosine residues, and T3 is formed by the coupling of one monoiodotyrosine residue to one diiodotyrosine residue. Those reactions also are catalyzed by thyroid peroxidase. The coupling process is not random; T4 and T3 are formed in regions of the thyroglobulin molecule that have unique amino acid sequences (Dunn and Dunn 2000). A normal thyroglobulin molecule contains about six molecules of monoiodotyrosine, four of diiodotyrosine, and two of T4 or T3. To liberate T4 and T3, thyroglobulin is taken up from the lumen of the thyroid follicles into the thyroid follicular cells (Figure 2-1). It is then broken down into T4, T3, and its constituent amino acids. The hormones are then released into the circulation.

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Health Implications of Perchlorate Ingestion Extrathyroid Production of Thyroid Hormones About 80% of the T3 produced each day is formed by removal of one iodine atom from the outer ring of T4 (outer-ring deiodination) in tissues outside the thyroid gland, such as the liver, kidneys, muscle, and nervous system. The deiodination reaction is stimulated (catalyzed) by enzymes called deiodinases. Two deiodinases—type 1 and type 2—catalyze the conversion of T4 to T3. Type 3 deiodinase catalyzes the conversion of T4 to reverse T3 and of T3 to 3,3’-diiodothyronine (inner-ring deiodination); neither reverse T3 nor 3,3’-diiodothyronine has biologic activity (Bianco et al. 2002). The three deiodinases differ in tissue distribution and regulation. Type 1 deiodinase is the predominant deiodinating enzyme in the liver, kidneys, and thyroid. Type 2 is the predominant deiodinating enzyme in the brain, pituitary gland, heart, and muscle. Type 3 is prominent in the skin, brain, uterus, and placenta. Thyroid Hormone Production Rate There are major quantitative and qualitative differences between T4 and T3 in production and metabolism. In healthy adults, the production rate of T4 is 80-100 µg per day, all of which is produced in the thyroid gland. T4 is degraded at about 10% per day, mostly by deiodination to form T3 or inactive reverse T3. The production rate of T3 is 30-40 µg per day, of which about 20% is produced in the thyroid gland and 80% by the extrathyroid deiodination of T4. T3 is degraded about 75% per day, mostly by deiodination. Most or all of the biologic activity of thyroid hormones is exerted by T3, whether produced in the thyroid or from T4 in other tissues. T4 is largely a prohormone, with little, if any, intrinsic biologic activity, and its conversion to T3 in effect produces the active thyroid hormone. The conversion process in extrathyroidal tissues is regulated, so production of T3 may change independently of changes in the function of the thyroid gland itself. Transport of Thyroid Hormones in Serum The thyroid hormones circulate in the bloodstream in two forms: some as the free (unbound) hormone and most bound to protein. Some 99.97% of the T4 and 99.7% of the T3 are protein-bound. The serum proteins that

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Health Implications of Perchlorate Ingestion bind the hormones are thyroxine-binding globulin (TBG), transthyretin, albumin, and lipoproteins. TBG is the most important: it carries 75-85% of the T4 and T3 in serum. As a result of the binding of T4 and T3 to those proteins, clearance of the hormones from the circulation is slow; the serum half-life of T4 is 5-7 days, and that of T3 is about 20 hours (hr). Thus, even when release of T4 and T3 from the thyroid gland abruptly ceases—for example, when the thyroid gland is surgically removed—the serum concentrations of the two hormones fall slowly. The fall is considerably smaller and slower when T4 and T3 production is only partially reduced. The binding of T4 and T3 to the serum proteins is not a determinant of the actions of the hormones in tissues. People with no TBG (a rare disorder caused by a mutation of the gene for TBG) or with twice the normal amount (caused by pregnancy, treatment with estrogen, or a duplication of the gene for TBG) have normal thyroid function. They have, respectively, low or high serum total T4 and total T3 concentrations but normal serum free (unbound) T4 and T3 concentrations. Those findings establish that it is the serum free T4 and T3 concentrations that determine the hormones’ biologic activity and ultimately the clinical status of people. The binding proteins maintain the serum free T4 and T3 concentrations within narrow limits and ensure not only that the hormones are continuously available to tissues but also that more free hormone can be made available almost instantly from the large amounts bound to the proteins in the serum if a sudden need arises. Because T4 and T3 bind to the proteins so well, tissues are protected from surges in T4 or T3 in the circulation. The proteins thus have both storage and buffering functions. Cellular Uptake and Actions of Thyroid Hormones in Tissues Free T4 and free T3 in serum are available for uptake into cells at any time. They are carried into cells primarily by transporter molecules in the cell membranes (Hennemann et al. 2001). There are several transporters, with different affinity for T4 and T3, and some hormone may enter cells by passive diffusion. T3 is also available to cells because it is produced from T4 in them (Figure 2-3). Some of the T3 produced in the cells returns to the circulation, and some remains in the cells. Indeed, locally produced T3 provides most of the T3 found in the nuclei of the cells in many tissues. Thus, there are two sources of T3 in cells: some enters the cells from the circulation, and

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Health Implications of Perchlorate Ingestion FIGURE 2-3 Diagram of a cell showing pathways of thyroxine (T4) and triiodothyronine (T3) metabolism. T4 and T3 are transported into cells, after which T4 is converted to T3 by action of deiodinases, thereby increasing the pool of T3 in the cell. Some T3 enters the nucleus of the cell, where it binds to specific T3 receptors (R). Hormone-receptor complexes then bind to DNA and alter gene transcription and therefore synthesis of many proteins, including tissue proteins, proteins that are secreted for action elsewhere, and enzymes that regulate metabolic activity. Some T3 also leaves the cell and enters the bloodstream. Source: American Heritage 2003. DNA illustration by Carlyn Iverson. Reprinted by permission of American Heritage Children's Science Dictionary, copyright 2003. some is produced in the cells by deiodination of T4. The relative contributions of the two sources to the T3 that is bound to its receptors in the nuclei of cells vary substantially from tissue to tissue (Bianco et al. 2002). In cells, T3 diffuses into the nuclei, where it binds to specific nuclear receptors (Figure 2-3). The T3-receptor complexes then bind to the regulatory regions of many different DNA molecules (genes). The interaction of the genes with the receptor-hormone complexes alters the rate at which the genes synthesize molecules of messenger RNA, and thus leads to changes in the rate of synthesis of thyroid hormone-dependent proteins (Mariash et

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Health Implications of Perchlorate Ingestion al. 2000). T3 may also have some actions at other sites of cells, such as the cell membrane, but the biologic importance of these actions is not known. Some biologic responses to T3 are stimulatory, and others inhibitory. By stimulating the production of several proteins in the heart, T3 increases heart rate and contractility. In the liver, it stimulates the synthesis of many different proteins required for growth, metabolism, and energy production. It also stimulates the production of proteins in the brain, most obviously during development. In contrast, in the pituitary gland, T3 inhibits the production of TSH, a process termed negative feedback, which ultimately leads to a decrease in hormone synthesis by the thyroid gland. REGULATION OF THYROID HORMONE PRODUCTION Thyroid hormone production is regulated in two ways: Regulation of thyroid gland synthesis and secretion of T4 and T3 by TSH. Pituitary secretion of TSH is inhibited by T4 and T3 and stimulated by a decrease in T4 and T3. TSH secretion is also stimulated by thyrotropin-releasing hormone, produced in the hypothalamus. Regulation of extrathyroid conversion of T4 to T3 by several hormones, including T4 and T3 themselves, and by nutritional and illness-related factors. The effect of those factors differs in different tissues; for example, starvation results in a decrease in conversion in the liver, but not in the brain. The first mechanism provides a sensitive defense against increases and especially decreases in thyroid hormone production. The second mechanism provides for rapid changes in the availability of T3 in different tissues, especially in response to illness or starvation. Thyrotropin-Releasing Hormone Thyrotropin-releasing hormone is distributed throughout the nervous system and elsewhere, where it is thought to modulate transmission of nerve impulses. Its content is highest in the hypothalamus, and the thyrotropin-releasing hormone produced in this region is an important regulator of TSH secretion and therefore of T4 and T3 production by the thyroid gland (Figure 2-4). The production and secretion of thyrotropin-releasing hormone in the

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Health Implications of Perchlorate Ingestion FIGURE 2-4 Diagram of the hypothalamic-pituitary-thyroid system. All thyroxine (T4) and some triiodothyronine (T3) are produced by the thyroid gland, and their production there is stimulated by thyroid-stimulating hormone (TSH, thyrotropin), a product of the anterior pituitary gland. Some T4 is converted to T3 in other tissues, including the pituitary gland and the hypothalamus. T3 inhibits pituitary secretion of TSH, and hypothalamic secretion of thyrotropin-releasing hormone (TRH), which stimulates TSH secretion. The interplay between T3 and TSH maintains thyroid hormone production within a narrow range. (+), stimulation; (−), inhibition. Sources: Liver illustration reprinted by permission of Media Lab, University of Wisconsin-Madison (2004), copyright 2003; thyroid illustration in Yale New Haven Health (2004) reprinted by permission of Nucleus Medical Art, copyright 2005. All rights reserved. www.nucleusinc.com.

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Health Implications of Perchlorate Ingestion hypothalamus are inhibited by T4 and T3 and stimulated in their absence. People with thyrotropin-releasing hormone deficiency have hypothyroidism because they have TSH deficiency. Thyrotropin TSH (thyrotropin) is synthesized and secreted by specific cells (thyrotroph cells) of the anterior pituitary gland (Figure 2-4). It stimulates virtually every step of T4 and T3 synthesis and secretion by the thyroid gland, including NIS activity, synthesis of thyroglobulin, formation of T4 and T3 in thyroglobulin, and breakdown of thyroglobulin and release of T4 and T3 into the bloodstream. It also stimulates the blood supply and growth of the thyroid gland. The secretion of TSH is inhibited by small increases in serum T4 and T3 concentrations, and it increases in response to small decreases in serum T4 and T3 concentrations. This tight control of TSH secretion results in maintenance of T4 and T3 production and secretion by the thyroid gland within very narrow limits. Thyroid gland function decreases in people with TSH deficiency, as a result of a pituitary gland disorder, just as it does in people with thyroid disease. Regulation of Extrathyroid Production of Triiodothyronine The tissue distribution and regulation of the deiodinases that catalyze the conversion of T4 to T3, the conversion of T4 to reverse T3, and the conversion of T3 to 3,3’-diiodothyronine differ (Bianco et al. 2002). The activity of type 1 deiodinase, the predominant deiodinating enzyme in the liver and kidney, is decreased by thyroid hormone deficiency (hypothyroidism) and increased by thyroid hormone excess (hyperthyroidism). The activity of type 2 deiodinase—the predominant deiodinating enzyme in the brain, pituitary, and muscle—is increased by thyroid hormone deficiency and decreased by thyroid hormone excess. The activity of those deiodinases is also altered by nonthyroid illness, caloric deprivation, other hormones, and drugs, and it differs between fetuses and adults. IODIDE NUTRITION AND METABOLISM Iodide is essential for the production of T4 and T3 by the thyroid gland. It can be obtained only by ingestion of foods that naturally contain it or of

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Health Implications of Perchlorate Ingestion TABLE 2-1 24-Hour Thyroid Radioiodide Uptake in Healthy Subjects before, during, and after Oral Administration of Potassium Perchlorate for 14 Days 24-Hr Thyroid   No. of Subjects Uptake (% of Dose) (Mean ± SE) Uptake as % of Baseline (Mean ± SE) P, Compared with Baseline 0.007 mg/kg-day Baseline 7 18.1 ± 3.1     Day 14 7 16.5 ± 1.6 98.2 ± 8.3   Day 15 post-exposure 7 17.3 ± 2.5 100.3 ± 8.4   0.02 mg/kg-day Baseline 10 18.4 ± 1.2     Day 2 8 15.7 ± 1.4 82.8 ± 5.6 <0.05 Day 14 10 15.2 ± 1.1 83.6 ± 4.1 <0.005 Day 15 post-exposure 10 19.1 ± 1.3 105.3 ± 5.5   0.1 mg/kg-day Baseline 10 19.9 ± 2.1     Day 2 8 11.8 ± 1.7 59.2 ± 3.5 <0.005 Day 14 10 11.0 ± 1.6 55.3 ± 3.9 <0.005 Day 15 post-exposure 10 20.8 ± 2.2 106.6 ± 9.1   0.5 mg/kg-day Baseline 10 21.6 ± 2.0     Day 2 8 6.5 ± 0.6 30.6 ± 2.6 <0.005 Day 14 10 6.9 ± 0.9 32.9 ± 3.8 <0.005 Day 15 post-exposure 10 21.7 ± 2.0 104.6 ± 9.4     Source: Greer et al. 2002. uptake in vitro, they estimated that a daily intake of 150 µg of iodide would protect against the effects of a daily intake of 4 mg of perchlorate (0.06 mg/kg for a 70-kg person). Serum perchlorate concentrations ranged from 0.10 to 0.17 µg/mL during administration of 0.1 mg/kg per day and from 0.45 to 0.85 µg/mL during administration of 0.5 mg/kg per day. The serum perchlorate half-life after cessation of this dose averaged 8.1 hr (range, 6.0-9.3); the half-life in the other groups could not be measured, because the values were or became undetectable very soon after perchlorate administration was stopped.

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Health Implications of Perchlorate Ingestion There were no changes in serum T4, T3, and TSH concentrations, which were measured repeatedly during the study in 24 subjects, except for a very small decrease in serum TSH concentrations in the subjects given 0.5 mg/kg per day (not an increase, as would be expected if thyroid secretion decreased, and probably explicable on the basis of multiple measurements of TSH concentration, which varies over the course of a day). One woman had a slightly high serum TSH concentration at baseline (18 mU/L), and it was slightly lower (15 mU/L) on day 14 of perchlorate (0.007 mg/kg per day) administration. In the fifth study, the chronic effects of two doses of potassium perchlorate were evaluated in a small study of 13 healthy subjects (Braverman et al. 2004). Four subjects were given placebo, five were given 0.5 mg of perchlorate daily, and four were given 3 mg of perchlorate daily for 6 months (these doses correspond to 0.007 and 0.04 mg/kg, respectively, for a 70-kg subject). Serum TSH, free T4 index, and T3 were measured at baseline, monthly during perchlorate administration, and 1 month after exposure. Thyroid radioiodide uptake was measured at baseline, at 3 and 6 months during perchlorate administration, and 1 month after exposure. There were no changes in any of the serum measurements or in thyroid radioiodide uptake, compared with baseline, at any time in either perchlorate group or in the placebo group. The results of the studies, in which thyroid function was assessed in several ways, are remarkably consistent. The study subjects were healthy men and women 18-57 years old; none was taking medications that might influence thyroid radioiodide independently of perchlorate. They were free-living, eating a self-selected diet. In the studies in which thyroid radioiodide uptake was measured, the baseline values varied somewhat among the subjects, but no more than expected in healthy people eating their usual diet. The normal range for 24-hr thyroid uptake of radioiodide in many places in the United States is 10-30%, also reflecting variation in dietary iodide intake. Although individual study groups were small, from four to 10 subjects in the studies of thyroid radioiodide uptake, the results were highly consistent within each treatment group in that the variance of the change, or lack of change, in thyroid radioiodide uptake during potassium perchlorate administration was similar to or less than the variance at baseline (Table 2-1). The effects of similar doses of potassium perchlorate on thyroid radioiodide uptake were very similar; a daily perchlorate dose of 0.007 mg/kg had no effect in two studies (Greer et al. 2002; Braverman et al. 2004), a daily dose of 0.02 mg/kg had a small effect (about 15% inhibition of thyroid iodide uptake) in Greer et al. (2002), and daily doses of 0.03 and 0.04 mg/kg had no effect in two other studies (Lawrence et al. 2000;

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Health Implications of Perchlorate Ingestion Braverman et al. 2004). Those results have been analyzed in multiple ways, but the experimental results are clear: in healthy subjects, a dose of perchlorate of 0.007 mg/kg per day has no effect on thyroid radioiodide uptake or any other measure of thyroid function, and doses of 0.02-0.04 mg/kg per day have minimal or no effect on those measures. Summary of Potential Perchlorate-Induced Perturbations of Thyroid Function in Healthy Humans The duration of the studies of potassium perchlorate administration in healthy subjects varied from 2 weeks to 6 months. In all those studies, there were no changes in serum T4, T3, and TSH concentrations to suggest that there had been any decrease in thyroid hormone secretion. Some doses of perchlorate given for 2 weeks did inhibit thyroid uptake of radioiodide. A high dose given for 4 weeks lowered thyroid iodide content by 25%, indicating some decrease in iodide uptake (Brabant et al. 1992), and resulted in a very small fall in serum free T4 concentrations, but serum TSH concentrations were also lower—not higher, as would occur if serum free T4 concentrations decreased to an important extent. If inhibition of iodide uptake were prolonged, the result should be iodide deficiency in the thyroid, similar to that which occurs in dietary iodide deficiency and with the same consequences and compensation. Lack of iodide in the thyroid gland should cause a decrease in T4 and T3 synthesis and secretion and therefore a fall in serum T4 and T3 concentrations. TSH secretion would then increase, and, assuming an adequate iodide intake, iodide uptake and T4 and T3 synthesis and secretion would return toward normal. Thus, there should be complete compensation if the maximal effect of the dose of perchlorate was only partial inhibition of iodide uptake by the thyroid gland. Even if the block were more complete, substantial or complete compensation would be expected although the thyroid gland might enlarge. There is therefore little likelihood that the decreases in thyroid iodide uptake found in the short-term studies of perchlorate administration, even at the higher doses, would be sustained, and it is highly likely that iodide uptake would return to normal. Possible exceptions might occur if the dose of perchlorate were very high comparable to those given to patients with hyperthyroidism, or if the person had severe iodide deficiency. Given the compensation that is known to occur in people with iodide deficiency, as discussed earlier, it is highly likely that in people with a normal iodide intake the dose of perchlorate would have to reduce thyroid iodide uptake

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Health Implications of Perchlorate Ingestion by at least 75% for a sustained period (several months or longer) for iodide uptake and thyroid hormone production to decline enough to cause adverse health effects (equivalent to reducing dietary iodide intake by 75%). In adults, that is likely to require sustained exposure to more than 30 mg of perchlorate per day (0.4 mg/kg per day for a 70-kg person), on the basis of the clinical studies in healthy subjects and the studies of long-term treatment of hyperthyroidism, both described in this chapter, and the studies of environmental exposure, described in Chapter 3 (Gibbs et al. 1998; Lamm et al. 1999; Crump et al. 2000). In pregnant women, infants and children, and people who have a low iodide intake or pre-existing thyroid dysfunction, the dose required to cause a decrease in thyroid hormone production may be lower. However, a dose that does not inhibit thyroid iodide uptake will not affect thyroid function, even in subjects with an abnormal thyroid gland or a very low iodide intake. NONTHYROID EFFECTS OF PERCHLORATE The NIS is present in the salivary glands; mammary glands, especially during lactation; stomach; choroid plexus of the brain; and ciliary body of the eye (Dohan et al. 2003). However, the iodide that is transported into those tissues is not further metabolized, as it is in the thyroid gland, but is rapidly returned to the circulation or secreted into the saliva or breast milk. Furthermore, iodide transport into these tissues is not known to be required for their normal function, with the possible exception of mammary tissue. TSH increases the content of the NIS only in thyroid tissue. Perchlorate acutely inhibits iodide transport in salivary and mammary tissue, but it does not appear to reduce the iodide content of breast milk (see Chapter 3). As noted above, very small amounts of the NIS have been detected in other tissues, including the heart, kidneys, lungs, and placenta. Perchlorate is not known to cause congenital malformations, but the relationship has not been well studied. The adverse effects of perchlorate given to hyperthyroid patients are described in the preceding section. Note that the effects occurred only in patients with hyperthyroidism given very high doses (many years ago) and that the effects have not been described in any of the more recent studies in which perchlorate was given to patients with hyperthyroidism in lower doses but for periods as long as 2 years. The possibility that perchlorate will adversely affect the immune system was raised by suggestions that some of the side effects of high doses of perchlorate—rashes, aplastic anemia, or agranulocytosis—might have been immunologic responses. Whether those effects were caused by a direct

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Health Implications of Perchlorate Ingestion toxic effect of perchlorate itself or a contaminant of it or by an immunologic reaction to the drug or a contaminant is not known. The fact that the effects were dose-dependent argues for direct toxicity rather than an immunologic reaction. An immunologic effect of perchlorate might also be suggested by the finding that serum concentrations of the antibodies that stimulate thyroid secretion in patients who have hyperthyroidism caused by Graves disease decline during treatment with antithyroid drugs, including perchlorate (Wenzel and Lente 1984). However, the decline in serum concentrations of those antibodies follows, rather than precedes, the drug-induced decrease in thyroid hormone secretion, and declines also occur in patients treated with other drugs, radioiodide, or thyroidectomy. Regarding a possible immunologic effect of perchlorate, a letter to the editor in 1984 reported that incubation of perchlorate at 0.12 or 1.2 mg/mL with lymphocytes of healthy people for 10 days inhibited immunoglobulin production and lymphocyte transformation (Weetman et al. 1984). However, it is not possible to assess potential clinical effects from experiments in which high doses of perchlorate were added directly to immune cells in vitro. In summary, there is no evidence that regular ingestion of perchlorate in any dose causes immunologic abnormalities in humans. REFERENCES Abalovich, M., S. Gutierrez, G. Alcaraz, G. Maccallini, A. Garcia, and O. Levalle. 2002. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 12(1):63-68. al-Adsani, H., L.J. Hoffer, and J.E. Silva. 1997. Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J. Clin. Endcrinol. Metab. 82(4):1118-1125. Allan, W.C., J.E. Haddow, G.E. Palomaki, J.R. Williams, M.L. Mitchell, R.J. Hermos, J.D. Faix, and R.Z. Klein. 2000. Maternal thyroid deficiency and pregnant complications: Implications for population screening. J. Med. Screen. 7(3):127-130. American Heritage. 2003. Children’s Science Dictionary. Houghton-Mifflin Company. Andersen, S., K.M. Pedersen, I.B. Pedersen, and P. Laurberg. 2001. Variations in urinary iodine excretion and thyroid function. A 1-year study in healthy men. Eur. J. Endocrinol. 144(5):461-465. Bartalena, L., S. Brogioni, L. Grasso, F. Bogazzi, A. Burelli, and E. Martino. 1996. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: Results of a prospective study. J. Clin. Endocrinol. Metab. 81(8):2930-2933.

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