Developmental Toxicity Evaluation of Sodium Fluoride Administered to Rats and Rabbits in Drinking Water

Abstract

Sodium fluoride (NaF; Cas No. 7681-49-4) is used in fluoridating municipal water supplies, resulting in chronic exposure of millions of people worldwide. Because of a lack of pertinent developmental toxicity studies in the literature, sodium fluoride was administeredad libitumin deionized/filtered drinking water (to mimic human exposure) to Sprague–Dawley-derived rats (26/group) on Gestation Days (GD) 6 through 15 at levels of 0, 50, 150, or 300 ppm and New Zealand White rabbits (26/group) on GD 6 through 19 at levels of 0, 100, 200, or 400 ppm. Higher concentrations via drinking water were not practicable due to the poor palatability of sodium fluoride. Drinking water (vehicle) contained less than 0.6 ppm sodium fluoride (limit of detection) and sodium fluoride content of the feed was 12.4 ppm fluoride (rats) and 15.6 ppm fluoride (rabbits). Maternal food, water, body weights, and clinical signs were recorded at regular intervals throughout these studies. Animals were killed on GD 20 (rats) or 30 (rabbits) and examined for implant status, fetal weight, sex, and morphological development. In the high-dose group of both studies there was an initial decreased maternal body weight gain which recovered over time and a decreased water consumption—attributed to decreased palatability. No clear clinical signs of toxicity were observed. Maternal exposure to sodium fluoride during organogenesis did not significantly affect the frequency of postimplantation loss, mean fetal body weight/litter, or external, visceral or skeletal malformations in either the rat or the rabbit. The NOAEL for maternal toxicity was 150 ppm sodium fluoride in drinking water (∼18 mg/kg/day) for rats, and 200 ppm (∼18 mg/kg/day) for rabbits. The NOAEL for developmental toxicity was ≥300 ppm sodium fluoride (∼27 mg/kg/day) for rats and ≥400 ppm (∼29 mg/kg/day) for rabbits administered during organogenesis in drinking water. The total exposure to fluoride (mg F/kg body weight/day from food and drinking water combined) in the mid- and high-dose groups for both species was >100-fold higher than the range at 0.014–0.08 mg F/kg/day estimated for a 70-kg person from food and fluoridated (1 ppm) drinking water.