had no effect on thyroid iodide uptake, measured at baseline and at 3 and 6 months, or on serum thyroid hormone and TSH concentrations, measured monthly. The small size of the study group in the latter study makes the results somewhat problematic, but the doses used provide a reasonable basis for a more comprehensive study to determine the effects of the dose at 0.04 mg/kg per day and the effects of a larger perchlorate dose, which also would inhibit iodide uptake acutely but for which compensation would be expected in the longer term.
The detailed protocol for this study is shown in Table 6-1. Briefly, it should be a double-blind study involving 90 healthy adults (45 men and 45 women). Subjects whose urinary iodide excretion exceeded 500 µg daily, indicative of a high iodide intake, would be excluded because of the antithyroid effects of a high iodide intake, but those with a low intake would not be excluded unless their urinary iodide excretion was less than 50 µg daily. Dietary iodide intake, as measured by urinary iodide excretion, would be monitored during the study but not controlled, given the high cost of the controlling the subjects’ diet. After study selection, the participants should be randomly assigned to receive placebo or perchlorate at 0.04 or 0.1 mg/kg per day in drinking water. Thyroid function and general well-being should be monitored throughout the study. Assuming a 50% variance in mean serum TSH and a 20% variance in thyroid volume by ultrasound, a study with 30 subjects in each perchlorate treatment group and 30 subjects in the placebo group has greater than 90% power to detect a 100% increase in serum TSH and greater than 90% power to detect a 50% increase in thyroid volume by ultrasound at a 5% level of significance (Chow and Liu 1998). Given the costs of clinical testing and screening, subject payment, sample storage, and data analysis, the committee predicts that the study would cost at least $1.5 million.
If chronic studies in humans are not possible, chronic studies in nonhuman primates could provide useful information. Initial studies in monkeys could include a dose-range finding study with perchlorate and a 1-year low-dose chronic toxicity and thyroid function study. The chronic study could be designed to determine the effects of perchlorate administered in drinking water on thyroid iodide uptake and on thyroid gland function. Doses should be selected to evaluate effects of low-dose ingestion of perchlorate. Protocols for the suggested monkey studies are shown in Tables 6-2 and 6-3. Studies in pregnant monkeys could also provide useful information on the effects of perchlorate on fetal and neonatal development.
If additional studies are conducted in laboratory animals, including nonhuman primates, the committee recommends that additional research in support of physiologically based pharmacokinetic (PBPK) model develop-