Support: Final Report, Investigation of the Possible Mechanisms of Action of Ethylidenenorbornene (ENB) on the Thyroid of Rats (Phase 2), with Cover Letter dated 5/22/1998

摘要

The influence of 5-Ethylene-2-norbornene (CAS No. 16219-75-3) on the thyroid was evaluated in parallel study with male CD rats (10/group) administered gavage doses of 0 (vehicle control, corn oil), 50, 200, and 300 mg/kg bw/day or 0, 50, 200, and 350 mg/kg bw/day for 14 days. In both tests, doses at and above 200 mg/kg were associated with a dose-dependent decrease in food consumption and bodyweight that was significant at the high doses, and brownish discoloration of the thyroid. At high doses, the relative liver weight was also significantly increased, but not that of the thyroid. No level of treatment elicited significant change in thyroid hormone levels (T3, T4, TSH) relative to controls. Furthermore, there was evidence of increased enzymes of xenobiotic metabolism, while enzymes involved in the intracellular metabolism of thyroxine or thyroxine receptor were unchanged. Slight decreases in G-6-Pase at 350 mg/kg bw implied mild hepatotoxicity. Electron microscopic examination revealed dose-related increases in thyroid activity at doses of 200 mg/kg and above, as suggested by follicular hyperplasia with increased small follicles and tall columnar cells. Ultrasonically identified hypertrophy of the Golgi, dilatation of the RER, and elevated lysosomes, mitochondria, and colloid droplets (presumed thyroglobulin) also confirmed a mildly increased thyroid function at doses of 200, 300, and 350 mg/kg. A clear cellular change in all liver lobules was attributed to normal glycogen storage. The authors offered that these results suggest a mechanism of thyroid hyperactivity associated with oral ethylidenenorbornene that may reside at the liver/thyroid axis. This profile is more similar to that of hypolipidaemic and microsomal inducing agents than propylthiouracil, the positive control and a powerful goitrogen. Propylthiouracil in corn oil (3 mg/kg bw/day) induced no change in body and liver weights, enlarged and darkened thyroid, significantly depressed thyroid hormones with elevated TSH, and more pronounced thyroid hyperplasia.