This study was conducted to test the hypothesis that the margin of safe fluoride exposure is narrowed in rats that are physiologically compromised by renal dysfunction. The study objective was to determine whether increases in fluoride retention and tissue fluoride levels in rats with surgically induced renal insufficiency result in toxic fluoride effects not ordinarily observed in healthy animals. Uremic and sham-operated control rats received 0 µg/ml, 5 (0.26 mmol/l), 15 (0.79), or 50 µg/ml (2.63 mmol/l) of fluoride in their drinking water for 3 or 6 months. Fluoride retention was monitored, and, following euthanasia, tissue fluoride and biochemical markers of tissue function were analyzed. Selected tissues were saved for histology, and bone marrow cells were harvested for determining the frequency of sister chromatid exchange, a marker of genetic damage. In spite of significantly higher levels of fluoride in the tissues of the animals with renal insufficiency, there were no clinically adverse, fluoride-induced, extraskeletal physiological, biochemical, or genetic effects of chronic exposure to common levels of fluoride in these rats.