Lewis E. Braverman

The Effect of Short-Term Low-Dose Perchlorate on Various Aspects of Thyroid Function

Perchlorate (ClO4) salts are found in rocket fuel, fireworks, and fertilizer. Because of ground water contamination, ClO4 has recently been detected in large public water supplies in several states in the 4-18 microg/L (parts per billion [ppb]) range. The potential adverse effect of chronic low level ClO4 ingestion on thyroid function is of concern to the Environmental Protection Agency (EPA). The daily ingestion of ClO4 at these levels would be magnitudes below the therapeutic effect level of hundreds of milligrams of ClO4 used in treating hyperthyroidism. Studies were carried out in nine healthy male volunteers who had normal thyroid function and negative thyroid antibodies to determine whether the ingestion of 10 mg of ClO4 daily (approximately 300 times the estimated maximum amount of ClO4 consumed from the affected water supplies) would affect any aspect of thyroid function. They ingested 10 mg of ClO4 dissolved in a liter of spring water during waking hours for 14 days. Baseline serum thyrotropin (TSH), free thyroxine index (FTI), total triiodothyronine (TT3), 4-, 8-, and 24-hour thyroid 123I uptakes (RAIU), serum and 24-hour urine ClO4, 24-hour urine iodine, complete blood count (CBC), and chemistry profile were determined. All blood and urine tests were repeated on days 7 and 14 of ClO4 administration and thyroid RAIU on day 14 of ClO4 administration. All tests were repeated 14 days after ClO4 was discontinued. No effect of ClO4 on serum thyroid hormone or TSH concentrations, urinary iodine excretion, CBC, or blood chemistry was observed. Urine and serum ClO4 levels were appropriately elevated during the course of ClO4 ingestion in all subjects, demonstrating compliance. By day 14 of ClO4 administration, the 4-, 8-, and 24-hour thyroid RAIU values decreased in all nine subjects by a mean value of 38% from baseline and rebounded above baseline values by 25% at 14 days after ClO4 withdrawal (p < 0.01 analysis of variance (ANOVA) and Tukey). It is well known that the major effect of ClO4 on the thyroid is a decrease in the thyroid iodide trap by competitive inhibition of the sodium iodide symporter (NIS). The present study demonstrates the sensitivity of the thyroid iodide trap to ClO4 because a low dose of 10 mg daily significantly decreased the thyroid RAIU without affecting circulating thyroid hormone or TSH concentrations. It is possible, however, that the daily consumption of low levels of ClO4 in drinking water over a prolonged period of time could adversely affect thyroid function but no evidence of hypothyroidism was observed at 10 mg of ClO4 daily in this 2-week study. It is now of interest to determine a no effect level for ClO4 on the inhibition of the thyroid RAIU and to carry out a long-term ClO4 exposure study.

Thyroid health status of ammonium perchlorate workers: a cross-sectional occupational health study.

Since pharmaceutical exposures to perchlorate are known to suppress thyroid function in patients with hyperthyroidism, a study of employees at a perchlorate manufacturing plant was conducted to assess whether occupational exposure to perchlorate suppresses thyroid function. Exposure to perchlorate was assessed by measurement of ambient air concentrations of total and respirable perchlorate particles, and systemic absorption was assessed by measurement of urinary perchlorate excretion. Airborne exposures ranged from 0.004 to 167 mg total particulate perchlorate per day. Urinary perchlorate measurements demonstrated that exposure to the airborne particulate perchlorate resulted in systemic absorption. Workers were grouped into four exposure categories with mean absorbed perchlorate dosages of 1, 4, 11 and 34 mg perchlorate per day. Thyroid function was assessed by measurement of serum thyroid-stimulating hormone, free thyroxine index, thyroxine, triiodothyronine, thyroid hormone binding ratio, thyroid peroxidase antibodies, and by clinical examination. No differences in thyroid-function parameters were found between the four groups of workers across approximately three orders of magnitude of exposure and of dose. Thus human thyroid function was not affected by these levels of absorbed perchlorate. In addition, no clinical evidence of thyroid abnormalities was found in any exposure group. The blood-cell counts were normal in all groups, indicating no evidence of hematotoxicity in this exposure range. The absence of evidence of an effect on thyroid function or blood cells from occupational airborne perchlorate exposure at a mean absorption of 34 mg/day demonstrates a no-observed-adverse-effect-level (NOAEL) that can assist in the evaluation of human health risks from environmental perchlorate contamination.

Perchlorate Clinical Pharmacology and Human Health: A Review

Potassium perchlorate has been used at various times during the last 50 years to treat hyperthyroidism. Since World War II ammonium perchlorate has been used as a propellant for rockets. In 1997, the assay sensitivity for perchlorate in water was improved from 0.4 mg/L (ppm) to 4 &mgr;g/L (ppb). As a result, public water supplies in Southern California were found to contain perchlorate ions in the range of 5 to 8 ppb, and those in Southern Nevada were found to contain 5 to 24 ppb. Research programs have been developed to assess the safety or risk from these exposures and to assist state and regulatory agencies in setting a reasonable safe level for perchlorate in drinking water. This report reviews the evidence on the human health effects of perchlorate exposure. Perchlorate is a competitive inhibitor of iodine uptake. All of its pharmacologic effects at current therapeutic levels or lower are associated with inhibition of the sodium-iodide symporter (NIS) on the thyroid follicular cell membrane. A review of the medical and occupational studies has been undertaken to identify perchlorate exposure levels at which thyroid hormone levels may be reduced or thyrotropin levels increased. This exposure level may begin in the 35 to 100 mg/d range. Volunteer studies have been designed to determine the exposure levels at which perchlorate begins to affect iodine uptake in humans. Such effects may begin at levels of approximately 1 mg/d. Environmental studies have assessed the thyroidal health of newborns and adults at current environmental exposures to perchlorate and have concluded that the present levels appear to be safe. Whereas additional studies are underway both in laboratory animals and in the field, it appears that a safe level can be established for perchlorate in water and that regulatory agencies and others are now trying to determine that level.

EXPRESSION OF MULTIPLE THYROID HORMONE RECEPTOR ISOFORMS IN RAT FEMORAL AND VERTEBRAL BONE AND IN BONE MARROW OSTEOGENIC CULTURES

Thyroid hormones influence both bone formation and bone resorption. Clinical data and animal studies provide evidence of skeletal site heterogeneity (hip vs. spine) of bone responses to thyroid hormones. In vitro studies also demonstrate direct effects of thyroid hormones on cells of the osteoblast lineage. Transcriptional regulation by thyroid hormone is mediated by ligand‐dependent transcription factors called thyroid hormone receptors (TRs). Two genes, c‐ErbAα and c‐ErbAβ, generate at least four TR isoforms in the rat: TRα1, c‐erbAα2, TRβ1, and TRβ2. Although functional TRs have been identified in cells of the osteoblast lineage, it is still not known if TR isoform expression in bone differs depending upon which skeletal site is examined. We have used ribonuclease protection assay and Northern blot analysis to simultaneously examine the expression of TR isoform mRNAs in adult rat femoral and vertebral bone. TRα1, c‐erbAα2, and TRβ1 are expressed in both femur and vertebra whole bone. Bone marrow cells from both skeletal sites were also cultured under conditions whereby the osteoprogenitors differentiated into osteoblasts and formed a mineralized extracellular matrix. TRα1, c‐erbAα2, and TRβ1 mRNAs are each expressed in both femoral and vertebral osteoblast cultures. The presence of TRα1, c‐erbAα2, and β1 proteins was confirmed by Western analysis of nuclear protein extracts from femoral and vertebral cell cultures. These results indicate that the three predominant TR isoforms are highly expressed in bone and osteoblasts from femurs and vertebrae. Whether there are distinct mechanisms of thyroid hormone action mediated by TRα1, c‐erbAα2, and TRβ1 at these separate skeletal sites remain to be shown. J. Cell. Biochem. 74:684–693, 1999.

Effects of iodine repletion on thyroid morphology in iodine and/or selenium deficient rat term fetuses, pups and mothers

It has been suggested that selenium deficiency aggravates the iodine-induced thyroid inflammation and necrosis in iodine-deficient Wistar rats and possibly in man. Studies were carried out to determine whether large amounts of iodine given to iodine-deficient pregnant Sprague-Dawley rats with or without selenium deficiency would induce inflammation and necrosis in their term fetal thyroids. Iodine deficiency was induced in the dams by a low iodine diet or perchlorate in the drinking water and iodine excess was achieved by iodinated drinking water during pregnancy or daily subcutaneous injections of iodine from days 20 to 22 of pregnancy, 1 day after perchlorate was discontinued. Studies were also carried out in 30-day-old pups whose nursing mothers were iodine-deficient (perchlorate) with or without selenium deficiency from conception onward. The administration of iodine restored the morphologic changes in the thyroid induced by iodine deficiency, irrespective of selenium status, toward normal without inflammatory changes or necrosis. Possible explanations for these unexpected findings are discussed.

Recombinant interferon α (rIFN‐α) does not potentiate the effect of iodine excess on the development of thyroid abnormalities in patients with HCV chronic active hepatitis

To determine whether the administration of pharmacological quantities of iodine during interferon‐alpha (rIFN‐α) treatment of chronic viral hepatitis B and C (HCV) would exacerbate the potential adverse effects of rIFNα on thyroid function.