Fluoride toxicity and cell death

Fluoride, an essential trace element that occurs naturally in many foods and water, has been indicated to play a role in several biological processes and is an important factor for human health. The fluoride ion is derived from the element fluorine, a gas that never occurs in a free state in nature and only exists in combination with other elements as fluoride compounds. Synthetic fluorocarbons and fluorocarbon-based compounds are man-made agrochemicals, pharmaceuticals, refrigerants, pesticides, surfactants, fire extinguishing agents, fibers, membranes, ozone depletors, and insulating materials. Fluoride enjoyed a “good reputation” for preventing caries as a component in dental toothpastes for years. The U.S. Centers for Disease Control and Prevention hails water fluoridation as one of the “top ten public health achievements of the twentieth century”. While controversy has sometimes surrounded community water fluoridation, over half of the U.S. population is served by drinking water that is fluoridated naturally or adjusted. The U.S. Public Health Service recommends addition of fluoride at a concentration of 0.7–1.2 ppm to drinking water, such that an average of 1 mg fluoride is consumed per day. Despite widespread public health adoption, water fluoridation has come under close scrutiny over the past few years. The majority of Western European population have stopped fluoridating their water supplies due to concerns about safety and effectiveness . Toxicity of fluoride was largely unknown until dental and skeletal fluorosis were linked to higher levels of fluoride intake. The debate about the health benefit of fluorinated water resurfaced in 1990 when reports showed an increased number of osteosarcomas in male rats given high fluoride water for two years. However, other related studies in humans and in animals did not show any association between fluoridated water and cancer. While the effects of synthetic fluorocarbons on human health remain unknown, a critical look at adverse impacts of fluoride ingestion is necessary given that fluoridation has been shown to be less effective than its past claims.

Although an appropriate range of fluoride is thought to be safe and effective for caries reduction, excessive fluoride intake could result in toxic effects in hard tissues of the teeth and skeleton. An overdose of fluoride has been shown to cause serious acute toxicity and adverse effects have been reported in kidneys, lungs and brain following long-term low dose fluoride ingestion. The biological effects of fluoride on human health are often extensive and could be either beneficial or detrimental. Fluoride at micromolar concentrations is an anabolic agent since it promotes cell proliferation, whereas at millimolar concentrations, it inhibits several enzymes including phosphatases. The effects of fluoride on cellular metabolism and physiology vary according to cell type, concentration, and time of exposure. For instance, in teeth and bone tissues, micromolar concentrations of fluoride elicit potentially beneficial effects by promoting cell proliferation and growth, whereas millimolar fluoride doses has the potential to suppress cell proliferation and induce apoptosis. Thus, an exposure to high fluoride doses has been reported to induce apoptotic cell death in ameloblasts, odontoblasts, and osteoblasts. Even though there have been several epidemiological, pathogenetic, clinical and cytogenetic studies on fluoride toxicity, the mechanism of action of fluoride on cells have not been thoroughly investigated.

Fluoride has been demonstrated to trigger the intrinsic mitochondria-mediated death pathway in many cell types both in vitro and in vivo. Exposure of the human promyelocytic HL-60 cells to 2–5 mM sodium fluoride (NaF) led to significant increase in the level of cytosolic cytochrome c and subsequent cleavage of intact Poly (ADP-ribose) polymerase leading to DNA damage. In the presence of higher amount of NaF (10−15 mM) - there was a gradual up regulation of proapoptotic Bcl-2-associated death promoter protein and down regulation of antiapoptotic Bcl-2 protein in human promyelocytic leukemia HL-60 cells. He and Chen reported that fluoride could induce DNA damage and cell cycle changes leading to apoptosis in oral mucosal cells and hepatocytes. When toothpastes or mouth rinses are applied to the tooth surface, a relatively high concentration of fluoride comes into contact with and can be absorbed by the oral mucosa. In an effort to better understand the molecular mechanisms by which NaF induces cell death, Tabuchi et. al examined the effects of fluoride in rat oral epithelial cells. They measured chromatin condensation with Nuclear-ID® Green Chromatin Condensation Kit from Enzo Life Sciences and observed increased cell death with increasing concentration of NaF from 2 to 4 mM. The induction of apoptosis by this compound was confirmed by the activation of caspase-3 with concomitant increase in expressions of Atf3, Ddit3 and Fos genes. The differentially expressed genes are likely to be involved in cell death accompanying ER stress. A recent study investigating the effects of NaF on the proliferation and gene expression showed that fluoride exposure increased human B cell viability at relatively lower levels (10-160 µM); however, when the concentration reached 320 µM, the cell proliferation was significantly inhibited (p < 0.05). These studies have provided novel insights into the mechanisms of action of fluoride-induced toxicity. Given the established and potential harms currently attributable to fluoride, the enthusiasm for water fluoridation is waning and its beneficial effect is still debatable.

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