Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans - Articles
Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal [sup.123]I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 [micro]g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 [micro]g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect on serum hormones: a slight downward trend in thyrotropin levels in morning blood draws during perchlorate exposure, with recovery by P15. Key words: clinical, human, iodine, perchlorate, risk assessment, sodium-iodide symporter,The ammonium salt of the perchlorate ion is manufactured primarily for use by the Department of Defense, the National Aeronautics and Space Administration, and the aerospace industry as a source of oxygen in solid propellant systems for rockets and missiles. Ammonium perchlorate is also manufactured for use as an oxidizer in fireworks and matches and for pharmaceutical use. In addition, perchlorate can occur naturally in nitrate-rich mineral deposits used as fertilizers. Analysis of nine commercial fertilizers revealed perchlorate in all samples tested at levels ranging from 0.15% to 0.84% by weight (1).
Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater, particularly in Utah, California, Nevada, and Arizona. Perchlorate contamination is also found in surface waters, including Nevada's Lake Mead. Recent testing by the Los Angeles Metropolitan Water District revealed 8 [micro]g/L at its Lake Mead intake, and the Southern Nevada Water authority found 11 [micro]g/L in tap water (2). Sampling by the California Department of Health Services revealed 5-9 [micro]g/L in the Colorado River. Of 2,459 drinking-water sources tested in California, 48 (2.0%) contained concentrations of perchlorate higher than the state's action level of 18 ppb (3). Assuming a default consumption rate of 2 L/day, perchlorate at 18 ppb (18 [micro]g/L) in drinking water results in ingestion of 36 [micro]g/day (0.51 [micro]g/kg-day for a 70-kg person).
Perchlorate is a competitive inhibitor of the process by which iodide, circulating in the blood, is actively transported into thyroid follicular cells (4,5). The site of this inhibition is the sodium-iodide symporter, a membrane protein located on the basolateral side of the follicular cell, adjacent to the capillaries supplying blood to the thyroid (6). The thyroid follicle is the functional unit of the thyroid; a single layer of follicular cells at the surface surrounds a colloidal protein matrix. At the colloid interface, organification of iodide occurs. Organification is a complex, enzyme-dependent process whereby iodide is oxidized and bound to tyrosyl residues within thyroglobulin, ultimately forming the thyroid hormones triiodothyronine ([T.sub.3]) and thyroxine ([T.sub.4]). If sufficient inhibition of iodide uptake occurs, formation of thyroid hormones is depressed. Depression of thyroid hormone formation secondary to inhibition of thyroidal iodide uptake is the precursor of any potentially adverse effect of perchlorate and is also the basis for its major current and former pharmaceutical usages.
Treatment of thyrotoxicosis (including Graves' disease) with 600-2,000 mg potassium perchlorate (430-1,400 mg perchlorate) daily for periods of several months or longer was once common practice, particularly in Europe (7,8). According to Wolff (9), although 400 mg of potassium perchlorate divided into four or five daily doses was used initially and found effective, higher doses were introduced when 400 mg/day was discovered not to control thyrotoxicosis in all subjects. Also according to Wolff, seven case reports of fatal aplastic anemia between 1961 and 1966 curtailed the therapeutic use of perchlorate at that time (9). However, two decades later, physicians reported treating thyrotoxicosis successfully with lower maintenance doses of potassium perchlorate (40-200 mg/day) for 2 years or longer, in the absence of adverse effects (10,11). More recently, perchlorate has been used (alone or in combination with other antithyroid drugs) to treat amiodarone-induced thyrotoxicosis or hypothyroidism, conditions in which underlying thyroid abnormalities are unmasked when the iodine-containing drug amiodarone is given to control cardiac arrhythmia (9). Treatment regimens include 500 mg potassium perchlorate twice per day for 18-40 days (12) and, for mild cases, 250 mg/day for 4-6 weeks (13). When we began the present study, we hoped our results would allow us to estimate, for the temporal dosing pattern tested, a maximum effect level for perchlorate inhibition of iodide uptake. With this information in hand, physicians might be prompted to evaluate the efficacy of perchlorate doses lower than those frequently employed.
Thyroid hormones are essential to the regulation of oxygen consumption and metabolism throughout the body. Thyroidal iodine metabolism and thyroid hormone levels in serum and tissues are regulated by a number of homeostatic mechanisms (14). Thyrotropin (TSH), a hormone synthesized and secreted by the anterior pituitary gland (hypophysis), is the primary regulator of thyroidal iodide uptake and other aspects of thyroid function (15).
When hypothyroidism occurs in a woman early in pregnancy, the fetus is at risk for impaired physical and mental development, the severity of the impairment depending upon the degree of hypothyroidism. In the human fetus, the thyroid and the hypophysial TSH system begin to function at around 11 weeks of gestation, and [T.sub.4] secretion begins at around 18-20 weeks of gestation (14). Hypothyroidism during infancy is also a major risk factor for mental retardation and other manifestations of impaired neurodevelopment (14). To ensure that perchlorate in drinking water is well below levels that would produce even mild hypothyroidism, particularly in pregnant women and infant children, it is important to determine the dose response for perchlorate inhibition of iodide uptake and the relationship between iodide uptake inhibition and depression of thyroid hormone levels.
Before we began our study, the potential health effects in humans of long-term exposure to perchlorate at doses below the therapeutic range were examined in two cross-sectional occupational studies of perchlorate plant workers. In both studies, serum tests of thyroid function revealed no evidence for any adverse effect of perchlorate. In one study, the worker population consisted of 35 males and 2 females, 40% of whom had been employed for more than 5 years; the mean perchlorate doses absorbed during a single work shift, based on urinary excretion, were estimated as 4.0, 11, and 34 mg (0.057, 0.16, and 0.48 mg/kg), with values ranging from 0.4 to 69 mg (0.006-0.99 mg/kg) overall (16). In the other study, the worker population consisted of 39 males and 9 females with employment durations of 1-27 years (mean, 8.3 years); the mean work-shift perchlorate exposure