Extrathyroidally Mediated Changes in Circulating Thyroid Hormone Concentrations in the Male Rat Following Administration of an Experimental Oxyacetamide (FOE 5043)

Evidence of increased hepatic metabolizing capacity coupled with reductions in serum thyroxine (T 4) levels were noted in the rat during preliminary toxicity studies with FOE 5043, an oxyacetamide with herbicidal properties. These findings were consistent with reports in the literature suggesting that declines in T 4 as a result of exposure to various classes of chemicals may be mediated extrathyroidally, such as through chemical induction of hepatic thyroid hormone metabolism. To examine this question with respect to FOE 5043, male rats were surgically thyroidectomized and provided thyroid hormone replacement therapy via implanted osmotic minipumps capable of maintaining a T 4/triiodothyronine (T 3) serum concentration for ~4 weeks at a level comparable to that of euthyroid controls. Seven days after minipump implantation, thyroidectomized + T 4/T 3 (TX + T 4/T 3) and nonthyroidectomized intact rats (NTX) were fed diets containing 0, 25, 1000, or 3000 ppm FOE 5043 for up to 3 weeks. Dose-related and equivalent declines in total and free serum T 4 levels in both TX + T 4/T 3 and NTX rats were measured at Weeks 1, 2, and 3. Alterations in thyrotropin, total, free, and reverse serum T 3 levels were also noted in both TX and NTX animals; however, a compound-related trend was difficult to discern and, when compared to the T 4 response, the changes were markedly less consistent with respect to both time and dose. Additionally, dose-related increases in absolute and relative liver weights were measured in both TX + T 4/T 3 and NTX animals. As the only source of thyroid hormone in the TX + T 4/T 3 animals was that provided by the pump, these data suggest that FOE 5043-induced alterations in serum thyroid hormone levels, most notably T 4, are being mediated indirectly, possibly as a result of increased hepatic metabolism, rather than through a direct effect on the thyroid gland.