A high dietary iodine intake accelerates the development of lymphocytic thyroiditis (LT) in the BB/W rat. Our previous studies have defined the temporal sequence of the immunolgical events triggered by excess iodide intake in these animals. It was still not clear, however, whether these observed immunological changes were a direct effect on immune effector cells, or whether they represented a secondary response to a toxic effect of iodine on thyroid tissue. In the present study, the effect of excessive iodine intake on the subcellular structure of the BB/W rat thyroid gland, particulary, whether iodide had a toxic effect independent of its immune response has been examined. BB/W rats were exosed, prenatahy through maternal drinking water, to excessive iodide at two doses (Moderate 3×10-6M iodide/1; High 3×10-3M iodide/l); a third group of BB/W rats was given tap water; till 12 weeks postnatal age. Two groups of Wistar rats received high dose iodide water or tap water for the same period of time and served as controls. Thyroid gland ultrastructure was determined by electron microscopic (EM) examination. Thyroid125I uptake and perchlorate discharge tests were also performed in separate experiments.We found that thyroid glands of non-iodine supplemented Wistar rats were morphlogically normal under EM. There were no overt changes in the iodide treated Wistar rats. By contrast, iodide treated BB/W rats exhibited marked accumulation of secondary lysosomes and lipid droplets; markedly swollen and disrupted mitochondria and extreme dilatation of rough endoplasmic reticulum (RER). These cytoplasmic changes were accompanied by nuclear changes indicative of cell necrosis, particularly in more severely affected areas. The observed changes induced by iodide were dose dependent. Only minor subcellular changes, comprising slight dilatation of the RER and mitochondrial swelling were observed in non-iodine treated BB/W rats. The morphologic changes in the iodine treated BB/W rats were associated with defects in iodine uptake and organification.These data indicate that iodide appears to have a direct toxic effect on the thyroid epithelial cell of the LT-prone BB/W rat. The pattern of tissue damage implicates involvement of oxidative stress. We speculate that iodine accelerates LT by damaging subcellular structures of thyrocytes, resulting in the formation and release of yet unknown factors which in turn attract antigen presenting cells to accelerate the immunological process.