The committee thinks that EPA’s mode-of-action model adequately represents the possible early sequence of events after perchlorate exposure, but it does not think that the model provides an accurate representation of events that follow changes in thyroid hormone and TSH production. Specifically, the development of thyroid tumors as an ultimate result of perchlorate exposure is an unlikely outcome in humans. As discussed in Chapter 4, the committee is not surprised that rats treated with moderate or high doses of perchlorate would develop thyroid follicular-cell tumors. Rats are sensitive to the development of thyroid tumors because their thyroid function is easily disrupted. Humans are much less susceptible than rats to disruption of thyroid function and therefore are not likely to develop thyroid tumors as a result of perchlorate exposure. The committee concludes that the most reasonable pathway of events after changes in thyroid hormone and TSH secretion would be thyroid hypertrophy or hyperplasia, possibly leading to hypothyroidism. At that point, the pathway would diverge to two potential outcomes: (1) metabolic sequelae, such as decreased metabolic rate and slowing of the function of many organ systems, occurring at any age, and (2) abnormal growth and development in fetuses and children. The committee’s suggested mode-of-action model is provided in Figure 5-1.

The committee emphasizes that inhibition of iodide uptake by the thyroid has been the only consistently documented effect of perchlorate exposure in humans. The continuum of possible effects of iodide-uptake inhibition caused by perchlorate exposure is only proposed and has not been demonstrated in humans exposed to perchlorate (with the exception that in patients with hyperthyroidism doses of 200 mg daily or higher may reduce thyroid secretion). More important, the outcomes at the end of the continuum are not inevitable consequences of perchlorate exposure. As discussed in Chapter 2, the body can compensate for decreases in T4 and T3 production unless there is a severe pre-existing thyroid disease. Specifically, the resulting increase in TSH secretion can return T4 and T3 production to normal without causing adverse effects on human health.

ADVERSE EFFECT AND KEY EVENT

EPA defines changes in serum thyroid hormone and TSH concentrations as adverse effects. The effects that would be downstream of those changes in its mode-of-action model would also be considered adverse effects. EPA states that the neurodevelopmental and neoplastic outcomes “confirm that the perturbation of the thyroid hormone economy should be



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