Steven H. Lamm

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.

Arsenic in drinking water and bladder cancer mortality in the United States: an analysis based on 133 u.s.counties and 30 years of observation.

This study analyzes the relationship between arsenic exposure through drinking water and bladder cancer mortality. The county-specific white male bladder cancer mortality data (1950–1979) and county-specific groundwater arsenic concentration data were obtained for 133 U.S. counties known to be exclusively dependent on groundwater for their public drinking water supply. No arsenic-related increase in bladder cancer mortality was found over the exposure range of 3 to 60 &mgr;g/L using stratified analysis and regression analyses (both unweighted and weighted by county population and using both mean and median arsenic concentrations). These results, which provide a direct estimate of arsenic-related cancer risk for U.S. residents, exclude the National Research Council’s 2001 risk estimate that was based on Southwest Taiwan data and required adjusting for differences between the body mass and water consumption rates of U.S. and Taiwanese residents.

Neonatal thyroxine level and perchlorate in drinking water

Environmental contamination of drinking water has been observed for perchlorate, a chemical able to affect thyroid function. This study examines whether that exposure affected the thyroid function of newborns. Neonatal blood thyroxine (T4) levels for days 1 to 4 of life were compared for newborns from the city of Las Vegas, Nevada, which has perchlorate in its drinking water, and those from the city of Reno, Nevada, which does not (detection limit, 4 micrograms/L [ppb]). This study is based on blood T4 analyses from more than 23,000 newborns in these two cities during the period April 1998 through June 1999. No difference was found in the mean blood T4 levels of the newborns from these two cities. Drinking water perchlorate levels measured monthly for Las Vegas ranged during this study period from non-detectable for 8 months to levels of 9 to 15 ppb for 7 months. Temporal differences in mean T4 level were noted in both cities but were unrelated to the perchlorate exposure. This study was sufficiently sensitive to detect the effects of gender, birth weight, and the day of life on which the blood sample was taken on the neonatal T4 level, but it detected no effect from environmental exposures to perchlorate that ranged up to 15 micrograms/L (ppb).

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.

Carcinogenic risks of inorganic arsenic in perspective.

Induction of cancer by inorganic arsenic occurs inconsistently between species and between routes of exposure, and it exhibits different dose-response relationships between different target organs. Inhaled or ingested arsenic causes cancer in humans but not in other species. Inhaled arsenic primarily induces lung cancer, whereas ingested arsenic induces cancer at multiple sites, including the skin and various other organs. Cancer potency appears to vary by route of exposure (ingestion or inhalation) and by organ site, and increases markedly at higher exposures in some instances. To understand what might explain these inconsistencies, we reviewed several hypotheses about the mechanism of cancer induction by arsenic. Arsenic disposition does not provide satisfactory explanations. Induction of cell proliferation by arsenic is a mechanism of carcinogenesis that is biologically plausible and compatible with differential effects for species or differential dose rates for organ sites. The presence of other carcinogens, or risk modifiers, at levels that correlate with arsenic in drinking water supplies, may be a factor in all three inconsistencies: interspecies specificity, organ sensitivity to route of administration, and organ sensitivity to dose rate.

Neonatal thyroid‐stimulating hormone level and perchlorate in drinking water

BACKGROUND The effect of perchlorate in drinking water on neonatal blood thyroid-stimulating hormone (thyrotropin; TSH) levels was examined for Las Vegas and Reno, Nevada. METHODS The neonatal blood TSH levels in Las Vegas (with up to 15 microg/L (ppb) perchlorate in drinking water) and in Reno (with no perchlorate detected in the drinking water) from December 1998 to October 1999 were analyzed and compared. The study samples were from newborns in their first month of life (excluding the first day of life) with birth weights of 2, 500-4,500 g. A multivariate analysis of logarithmically transformed TSH levels was used to compare the mean TSH levels between Las Vegas and Reno newborns, with age and sex being controlled as potential confounders. RESULTS This study of neonatal TSH levels in the first month of life found no effect from living in the areas with environmental perchlorate exposures of </=15 microg/L (P = 0.97). CONCLUSIONS This study, which was sensitive enough to detect the effects of age and gender on neonatal blood TSH levels, detected no effect from environmental exposures to perchlorate.

Has perchlorate in drinking water increased the rate of congenital hypothyroidism

Perchlorate, known to inhibit the human thyroid at doses above 200 mg/day, was detected in the drinking-water supplies of seven counties in California and Nevada at levels of 4 to 16 micrograms/L in 1997. The data from the neonatal screening programs of the state health departments in these two states were analyzed for any increased incidence of congenital hypothyroidism in those counties. County-specific, ethnicity-specific data for Nevada and California were obtained for 1996 and 1997. Within these seven counties, nearly 700,000 newborns had been screened. In all, 249 cases were identified, where 243 were expected, for an overall risk ratio of 1.0 (95% confidence interval, 0.9 to 1.2). The risk ratios for the individual counties ranged between 0.6 and 1.1. These data in this ecological analysis do not indicate an increase in the incidence of congenital hypothyroidism with the reported perchlorate levels.

Prevalence of thyroid diseases in Nevada counties with respect to perchlorate in drinking water

Perchlorate is well-known to inhibit the uptake of iodine by the thyroid and has been shown to do so at doses in the milligrams-per-day range and higher. Perchlorate has been found in the water supply of Clark County (Las Vegas), Nevada, at 4 to 24 &mgr;g/L (parts per billion) and may provide exposure dosages in the tens of micrograms per day. An analysis of the Medicaid database from Nevada was undertaken to determine whether an increase in the prevalence of any thyroid disease was associated with that level of perchlorate content. The prevalence of persons being seen for thyroid disease or for specific thyroid diseases (goiter, nodule, thyrotoxicosis, congenital hypothyroidism, acquired hypothyroidism, thyroiditis, and other thyroid disorders) and for thyroid cancer among the Medicaid-eligible population of each county was calculated for the 2-year period 1997 to 1998. The prevalences in Clark County were compared with those in Washoe County (ie, Reno), the second most populous county in the state, and with those for the rest of the state. There was no evidence of an increased rate of thyroid disease (or of any specific thyroid disease) associated with perchlorate exposure. Generally, the prevalences in the metropolitan parts of the state were lower than for the rest of the state, particularly for acquired hypothyroidism. This analysis found no evidence that perchlorate-containing drinking water at the given level increased the prevalence of acquired hypothyroidism or of any other thyroid condition

Bladder/lung cancer mortality in Blackfoot-disease (BFD)-endemic area villages with low (<150 μg/L) well water arsenic levels--an exploration of the dose-response Poisson analysis.

OBJECTIVE To examine the analytic role of arsenic exposure on cancer mortality among the low-dose (well water arsenic level <150 μg/L) villages in the Blackfoot-disease (BFD) endemic area of southwest Taiwan and with respect to the southwest regional data. METHOD Poisson analyses of the bladder and lung cancer deaths with respect to arsenic exposure (μg/kg/day) for the low-dose (<150 μg/L) villages with exposure defined by the village median, mean, or maximum and with or without regional data. RESULTS Use of the village median well water arsenic level as the exposure metric introduced misclassification bias by including villages with levels >500 μg/L, but use of the village mean or the maximum did not. Poisson analyses using mean or maximum arsenic levels showed significant negative cancer slope factors for models of bladder cancers and of bladder and lung cancers combined. Inclusion of the southwest Taiwan regional data did not change the findings when the model contained an explanatory variable for non-arsenic differences. A positive slope could only be generated by including the comparison population as a separate data point with the assumption of zero arsenic exposure from drinking water and eliminating the variable for non-arsenic risk factors. CONCLUSION The cancer rates are higher among the low-dose (<150 μg/L) villages in the BFD area than in the southwest Taiwan region. However, among the low-dose villages in the BFD area, cancer risks suggest a negative association with well water arsenic levels. Positive differences from regional data seem attributable to non-arsenic ecological factors.