Thyroid hormones in serum are extensively bound to plasma proteins. The proteins that bind thyroxine (T4) and triiodothyronine (T3) vary widely among species, and their binding affinities for the thyroid hormones also differ. In humans and other primates, thyroxine-binding globulin (TBG) is the principal protein that binds T4 (Dohler et al. 1979). It has a very high affinity for T4: only about 0.03% of the T4 in serum is in the free unbound form (Hill et al. 1989). Binding sharply reduces clearance of T4 from serum.

Rats do not have TBG, and most T4 in rat serum is bound to albumin and transthyretin. The binding affinity of T4 for TBG is more than a 100 times greater than that of albumin or transthyretin (Hill et al. 1989), and the difference contributes to the higher rate of T4 clearance in rats. The increased clearance contributes to the need for a higher rate of production of T4 per unit of body weight in rats to maintain normal concentrations of T4 (Dohler et al. 1979). The higher production rate is reflected in the histologic appearance of the rat thyroid, which has small thyroid follicles that contain much less colloid than those of primates (McClain 1995). Those features give the rat thyroid a more “functionally active” histologic appearance than that of primates, including humans. The follicular epithelium in rats is cuboidal; that of monkeys appears flattened in comparison. The change in the height of the follicular cells from flattened to cuboidal to columnar represents follicular-cell hypertrophy and is characteristic of the increased functional activity.

There appear to be some differences in the metabolism of T4 by the liver between rats and humans. Some 50% of T4 is eliminated via bile in rats, but only 10-15% in humans (Hill et al. 1989). The difference does not reflect a qualitative difference in metabolism, because the major metabolite in bile (glucuronide conjugate) is the same in both species (Hard 1998).

The biochemical and physiologic differences between rats and humans related to the thyroid affect their responses to goitrogens, such as perchlorate. For example, Yu et al. (2002) evaluated inhibition of radioiodide uptake by the thyroid in rats exposed to perchlorate in drinking water at 0, 1.0, 3.0, and 10.0 mg/kg of body weight for 1, 5, and 14 days. After 1 day of perchlorate administration, inhibition of iodide uptake was about 15%, 55%, and 65% at 1.0, 3.0, and 10 mg/kg, respectively. After 5 days, inhibition of iodide uptake was 0, 10%, and 30%. After 14 days, inhibition of iodide uptake was observed only at 10 mg/kg. The data show that the initial inhibition of radioiodide uptake by perchlorate in rats is similar to that in humans. However, rats compensated for the inhibition within 5 days of perchlorate administration, most likely by increasing the expression of NIS in the thyroid. A similar response was not observed in a 14-day human study with perchlorate administration (Greer et al. 2002). The data suggest

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