alternative approach that uses nonhuman primates if long-term studies in humans are not possible.

The effects of perchlorate on sensitive populations (fetuses, infants, and pregnant women) raise a number of fundamental questions, including the role of the sodium-iodide symporter (NIS) in placental iodide transport, the sensitivity of the NIS in the lactating breast to perchlorate inhibition, the influence of iodide status on perchlorate inhibition in placenta and breast, and finally direct effects of perchlorate on fetal development. Several models and methods developed in the mechanistic studies could be used in human investigations. Epidemiologic studies that include analysis of existing data, use of monitoring data, and new studies to determine perchlorate effects in sensitive populations are also proposed. Finally, further studies of the public-health implications of iodide status of pregnant women are proposed.

CHRONIC EXPOSURE

The proposed clinical study is designed to provide information on the potential chronic effects of perchlorate exposure on thyroid function focusing on the capacity for and mechanisms of thyroid compensation. The short-term human study (Greer et al. 2002) recommended as the point of departure in Chapter 5 reported inhibition of thyroid iodide uptake at perchlorate doses that are consistent with a wide array of human, animal, and in vitro studies. Long-term studies of populations that have iodide insufficiency, post-thyroidectomy patients, and workers occupationally exposed to perchlorate have demonstrated the large capacity of the thyroid to compensate for reduced iodide intake or thyroid mass. However, a rigorously designed controlled clinical study of prolonged exposure to perchlorate would clearly provide more specific information on the compensatory response to perchlorate exposure in humans and strengthen confidence in the RfD.

The hypothesis of the proposed clinical study is that administration of perchlorate in doses of 0.04 mg/kg per day or 0.1 mg/kg per day will transiently decrease thyroid iodide uptake but will have no long-term effect on thyroid function in healthy subjects. Those doses are based on the following data. Greer et al. (2002) reported that administration of perchlorate in doses of 0.02 and 0.1 mg/kg per day for 14 days to 10 healthy subjects per group reduced 24-hr thyroid iodide uptake by 16.4% and 44.7%, respectively (see Table 2-1 in Chapter 2). Braverman et al. (2004) reported that administration of 0.04 mg/kg per day to four healthy subjects



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