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 administered ad libitum in 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 (approximately 18 mg/kg/day) for rats, and 200 ppm (approximately 18/mg/kg/day rabbits. The NOAEL for developmental toxicity was > or = 300 ppm sodium fluoride (approximately 27 mg/kg/day) for rats and > or = 400 ppm (approximately 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.
The authors comments on the Embryo–fetal effects on rats:
… Although there were no significant pairwise effects from sodium fluoride administration, the percentage of litters with one or more external malformed fetuses, the percentage of externally malformed fetuses per litter and the percentage of skeletally malformed fetuses per liter, exhibited increasing trends with increasing dose of sodium fluoride (Table 2 and 3). No significant effect were noted in the prevalence of variations in the examined fetuses (Table 3).
… Examination of individual fetal findings indicated that no fetuses with external malformations were observed in the control or low-dose groups. The external malformations observed in the mid- and high-dose groups are given as follows and 0ther types of malformations in the same fetus are shown in brackets:
(1) at 150 ppm, one male fetus (1/362 fetuses examined) exhibited gastroschisis (and cleft sternum], the fetus weighed 3.0 g; (2) at 300 ppm, three fetuses (3/373 fetuses examined) exhibited multiple malformations as follows: one male fetus (3.1 g) exhibited anasarca [and displaced and small kidney, displaced testis, and bipartite thoracic centrum], one male fetus (1.7 g) displayed craniorachischisis and micropthalmia [as well as fused ribs and bipartite thoracic centrum]; and one female fetus (1.3 g) exhibited bilateral anophthalmia, cranioraschischisis, gastroschisis, and ectocardia [as well as renal agenesis, right side]. At 300 ppm, two of the three fetuses with malformations were clustered in one litter. All of the external malformations, as well as the associated visceral and skeletal malformations, occur spontaneously in this species and strain with a low incidence (Charles River, 1993), with the possible exception of ectocardia. The one rat fetus with ectocardia (externalization of the heart or thorachoschisis) in this study was also reported to show gastroschisis. Thus, fissure of the ventral wall was quite extensive, and ectocardia was not an isolated defect. Considering the low incidence of these external malformations, and the lack of a statistically significant difference among groups, there was insufficient evidence to establish a clear cause and effect relationship between the occurrence of these external malformations and sodium fluoride exposures.
In light of these considerations, as well as the absence of any effect on fetal growth or viability, there was insufficient evidence to clearly characterize the group at 300 ppm as an adverse effect level for developmental toxicity in the rat. Higher concentrations of sodium fluoride in drinking water were not evaluated in the rat study due to reported toxicity in adult rats >300 ppm in drinking water (NTP, 1990). Thus, it was not feasible to determine whether the finding of uncommon malformations in a small number of rodent fetuses at the high dose might constitute the lower tail of a dose-response curve. As noted above, administration of higher concentrations of sodium fluoride throughout gestation is not feasible due to the unpalatability of the solution.
… Fluoride crosses the placenta of humans and animals, including rats and rabbits (Ericsson and Malmnas, 1962; Zipkin and Babeaux, 1965). Thus, maternal supplementation during pregnancy results in increased fluoride concentrations not only in maternal blood, but also in cord blood and offspring tissues, especially bones and teeth (Theuer et al., 1971; Katz and Stookey, 1973; Drinkard et al., 1985; Speirs, 1986; Caldera et al., 1988; Gedalia and Shapira, 1989; Chan et al., 1989).