Standardization of the perchlorate discharge assay for thyroid toxicity testing in rats

The perchlorate discharge assay (PDA) is potentially of high diagnostic value to distinguish between direct and indirect thyroid toxicity mechanisms, provided that standard treatment times are established and positive controls yield reproducible results. Therefore the PDA was evaluated after 2 and/or 4 weeks of treatment with positive control compounds in rats. Phenobarbital, Aroclor 1254 and β-naphthoflavone (indirect toxic mechanism) enhanced thyroidal radioiodide accumulation, and the administration of potassium perchlorate had no effect on thyroid: blood 125I ratio. Phenobarbital caused follicular cell hypertrophy and hyperplasia in the thyroid and centrilobular hypertrophy in the liver, without effects on serum triiodotyronine (T3), thyroxine (T4) levels. Thyroid-stimulating hormone (TSH) levels were moderately increased. Propylthiouracil (direct toxic mechanism) caused severe thyroid follicular cell hypertrophy and hyperplasia, reduced serum T3 and T4 levels and increased serum TSH levels, and reduced thyroidal radioiodide accumulation; perchlorate administration significantly reduced thyroid: blood 125I ratio, demonstrating an iodide organification block. Potassium iodide (direct toxic mechanism) virtually blocked thyroidal radioiodide accumulation, without significant effects on serum T3, T4, and TSH levels and a microscopic correlate for higher thyroid weights. Thus, positive controls yielded reproducible results and we conclude that both the 2- and 4-week PDA is suitable to distinguish between direct and indirect thyroid toxicity mechanisms.