debate. Some believe that the adverse effect should be defined as inhibition of iodide uptake by the thyroid or as decreases in T3 and T4 production with corresponding increases in thyroid-stimulating hormone (TSH) production. Others contend that those effects are “preadaptive” or “adaptive” effects and that the adverse effect is one or more clinical manifestations of hypothyroidism, such as developmental deficits. Defining the adverse effect is important because it influences how the RfD is derived and ultimately the value of the drinking-water standard.

Finally, the application of various uncertainty factors has become a source of controversy. When an RfD is calculated, uncertainty factors are used to extrapolate from the study population to the larger general population. Those factors account for interspecies differences (extrapolation from animal to human populations, if applicable), intraspecies differences (possible variations or sensitivities that might be present in the general population), failure to identify a no-observed-adverse-effect level, absence of chronic toxicity data, and other database gaps. The uncertainty factors typically range from 1 to 10; 1, 3, and 10 are the values most commonly used. No absolute rules exist for application of the factors, and professional judgment is a large component of their use. Regarding derivation of EPA’s RfD for perchlorate, some have questioned the use of specific uncertainty factors, particularly the factor used to account for database uncertainties (see Chapter 5 for further discussion of uncertainty factors). Questions regarding the use of uncertainty factors and the other issues discussed above all played a role in determining the charge provided to this committee.


The members of the NRC committee were selected for their expertise in pediatrics; endocrinology; pediatric endocrinology; thyroid endocrinology, physiology, and carcinogenesis; immunology; veterinary pathology; animal toxicology; neurotoxicology; developmental toxicology; physiologically based pharmacokinetic modeling; epidemiology; biostatistics; and risk assessment. The committee was asked to accomplish the following tasks:

  • Evaluate the current state of the science regarding potential adverse effects of disruption of thyroid function in humans and laboratory animals at various stages of life. Specifically, evaluate whether science supports the model that predicts potential adverse neurodevelopmental and neoplastic effects from changes in thyroid hormone regulation that result from disrup-

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