An Evaluation of Neurotoxicity Following Fluoride Exposure from Gestational Through Adult Ages in Long-Evans Hooded Rats

Abstract

At elevated levels, fluoride (F−) exposure has been associated with adverse human health effects. In rodents, F− exposure has been reported to induce deficits in motor performance and learning and memory. In this study, we examined Long-Evans hooded male rats maintained on a standard diet (20.5 ppm F−) or a low F− diet (3.24 ppm F−) with drinking water exposure to 0, 10, or 20 ppm F− from gestational day 6 through adulthood. At postnatal day 25, brain F− levels were 0.048 or 0.081 μg/g and femur 235 or 379.8 μg/g for 10 and 20 ppm F−, respectively. Levels increase with age and in adults, levels for plasma were 0.036 or 0.025 μg/ml; for the brain 0.266 or 0.850 μg/g; and for the femur, 681.2 or 993.4 μg/g. At these exposure levels, we observed no exposure-related differences in motor, sensory, or learning and memory performance on running wheel, open-field activity, light/dark place preference, elevated plus maze, pre-pulse startle inhibition, passive avoidance, hot-plate latency, Morris water maze acquisition, probe test, reversal learning, and Y-maze. Serum triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) levels were not altered as a function of 10 or 20 ppm F− in the drinking water. No exposure-related pathology was observed in the heart, liver, kidney, testes, seminal vesicles, or epididymides. Mild inflammation in the prostate gland was observed at 20 ppm F−. No evidence of neuronal death or glial activation was observed in the hippocampus at 20 ppm F−.Electronic supplementary materialThe online version of this article (10.1007/s12640-018-9870-x) contains supplementary material, which is available to authorized users.

Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses

“…Male pups were exposed throughout adulthood and underwent neurobehavioral testing using different paradigms to assess learning and memory (NTP 2015). No exposure-related differences in motor, sensory, or learning and memory performance (running wheel, open-field activity, light/dark place preference, elevated plus maze, pre-pulse startle inhibition, passive avoidance, hot-plate latency, Morris water maze (MWM) acquisition, probe test, reversal learning, and Y-maze) were observed with either of the two exposure levels investigated (McPherson et al 2018). Therefore, a LOAEL and a doseresponse assessment could not be established.…”

“…A number of studies also reported such effects in rats at 2-50 mg/L fluoride [corresponding to 0.1-2.5 mg/kg b.w./day applying EFSA default conversion factors (EFSA 2012)]. However, many of these findings occurred in the presence of motor dysfunction or general toxicity, thus diminishing confidence in any conclusion regarding learning deficits (McPherson et al 2018;NTP 2016). Overall, the systematic review by the NTP reported a low to moderate level of evidence for adverse effects on learning and memory in exposed animals with fluoride concentrations substantially higher than 0.7 mg/L (NTP 2016).…”

“…Eight studies published since 2017 investigated the effect of fluoride on learning and memory following exposure during development (Bartos et al 2018;Chen et al 2018a;Ge et al 2018;McPherson et al 2018;Mesram et al 2017;Sun et al 2018;Wang et al 2018;Zhao et al 2019); and five additional studies examined exposure during young Sprando et al (1997Sprando et al ( , 1998 adulthood (Dong et al 2017;Li et al 2019;Pulungan et al 2018;Sharma et al 2018a;Yang et al 2018). Only one study among them was conducted according to the generally accepted guidelines considering all of the aforementioned key requirements (McPherson et al 2018). This recent study from the NTP laboratories was designed to address limitations identified in the NTP systematic review (McPherson et al 2018;NTP 2016), and used exposure levels near the recommended level for community water fluoridation in the USA.…”

“…Only one study among them was conducted according to the generally accepted guidelines considering all of the aforementioned key requirements (McPherson et al 2018). This recent study from the NTP laboratories was designed to address limitations identified in the NTP systematic review (McPherson et al 2018;NTP 2016), and used exposure levels near the recommended level for community water fluoridation in the USA. For this purpose, equivalent human daily water intake of 1.74 mg fluoride/day for an adult, or 0.63-1.23 mg/day for children 1 to 14 years of age (EPA 2010) were approximated in rodents by using drinking water concentrations of 7-9 mg/L fluoride (NTP 2016).…”

“…For this purpose, equivalent human daily water intake of 1.74 mg fluoride/day for an adult, or 0.63-1.23 mg/day for children 1 to 14 years of age (EPA 2010) were approximated in rodents by using drinking water concentrations of 7-9 mg/L fluoride (NTP 2016). The highest dose of 20 mg/L fluoride was selected based upon the US EPA's maximum contaminant level of 4 mg/L, based on the assumption that approximately fivefold higher doses are required for rats to achieve serum concentrations similar to those in humans (Dunipace et al 1995;McPherson et al 2018;NRC 2006). Pregnant Long-Evans hooded rats received a standard diet (20.5 mg/kg fluoride) or a low fluoride diet (3.24 mg/kg fluoride) with drinking water containing 0, 10, or 20 mg/L fluoride from gestational day 6 throughout lactation.…”