Mini-reviewMolecular mechanisms of fluoride toxicity
Introduction
The fluoride ion is derived from the element fluorine, a gas that never occurs in a free state in nature. Fluoride is abundant in the environment and exists only in combination with other elements as fluoride compounds, which are constituents of minerals in rocks and soil. Therefore, fluoride is commonly associated with volcanic activity.
Sources of fluoride include natural fluoride in foodstuffs and water, i.e., fluoridated water (usually at 1.0 mg/l), fluoride supplements (such as fluoride tablets), fluoride dentifrices (containing on average 1000 mg/kg), and professionally applied fluoride gel (containing on average 5000 mg/kg). The main source of fluoride for humans is the intake of groundwater contaminated by geological sources (maximum concentrations reaching 30–50 mg/l). The level of fluoride contamination is dependent on the nature of the rocks and the occurrence of fluoride-bearing minerals in groundwater. Fluoride concentrations in water are limited by fluorite solubility, so that in the absence of dissolved calcium, higher fluoride solubility should be expected in the groundwater of areas where fluoride-bearing minerals are common and vice versa [1].
Excessive fluoride intake over a long period of time may result in a serious public health problem called fluorosis, which is characterized by dental mottling and skeletal manifestations such as crippling deformities, osteoporosis, and osteosclerosis. Endemic fluorosis is now known to be global in scope, occurring on all continents and affecting many millions of people [2].
In some regions, artificial fluorides used to fluoridate community water supplies (mostly at around 1 mg/l) include silicofluoride compounds (sodium silicofluoride and hydrofluosilicic acid) and sodium fluoride (NaF). At neutral pH, silicofluoride is dissociated to silic acid, fluoride ion, and hydrogen fluoride (HF) [3]. The primary benefit associated with fluoride supplementation is linked to the potential to reduce the risk of dental caries due to the cariostatic effects of fluoride. Even in the past, fluoride was considered an essential element. In actuality, there is a lack of consensus as to the role of fluoride in human nutrition and optimal development and growth [4].
Additional risks of increased fluoride exposure are known; the most significant are effects on bone cells (both osteoblasts and osteoclasts) that can lead to the development of skeletal fluorosis. It is now recognized that fluoride also affects cells from soft tissues, i.e., renal, endothelial, gonadal, and neurological cells [5].
The minimal risk level for daily oral fluoride uptake was determined to be 0.05 mg/kg/day [6], based on a non-observable adverse effect level (NOAEL) of 0.15 mg fluoride/kg/day for an increased fracture rate. Estimations of human lethal fluoride doses showed a wide range of values, from 16 to 64 mg/kg in adults and 3 to 16 mg/kg in children [6].
Organofluoride compounds (carbon–fluoride bond) are increasingly used. These compounds have a wide range of functions and can serve as agrochemicals, pharmaceuticals, refrigerants, pesticides, surfactants, fire extinguishing agents, fibers, membranes, ozone depletors, and insulating materials [7]. An estimated 20% of pharmaceuticals and 30–40% of agrochemicals are organofluorines [8]. However, environmental and health issues are still a problem for many organofluorines. Because of the strength of the carbon–fluoride bond, many synthetic fluorocarbons and fluorocarbon-based compounds are persistent global contaminants and may be harming the health of wildlife [7]. Their effects on human health are unknown. However, the toxicity of fluorinated organic chemicals is usually related to their molecular characteristics rather than to the fluoride ions that are metabolically displaced.
The present review is focused on the molecular effects of inorganic fluoride with respect to potential physiological and toxicological implications. It addresses the current understanding of the signal transduction pathways and mechanisms underlying the sensitivity of various organs and tissues to fluoride. This review provides information on the cellular and molecular aspects of the interactions between fluoride and cells, with an emphasis on tissue-specific events in humans.
Section snippets
Uptake and accumulation
Fluoride is very electronegative, which means that it has a strong tendency to acquire a negative charge and forms fluoride ions in solution. In aqueous solutions of fluoride in acidic conditions such as those of the stomach, fluoride is converted into HF, and up to about 40% of ingested fluoride is absorbed from the stomach as HF [9].
Fluoride transport through biological membranes occurs primarily through the non-ionic diffusion of HF. Classic studies with artificial lipid bilayers and pH
Cellular effects of fluoride
Fluoride exerts diverse cellular effects in a time-, concentration-, and cell-type-dependent manner. The main toxic effect of fluoride in cells consists of its interaction with enzymes. In most cases, fluoride acts as an enzyme inhibitor, but fluoride ions can occasionally stimulate enzyme activity. The mechanisms depend on the type of enzyme that is affected [20]. Fluoride at micromolar levels is considered an effective anabolic agent because it promotes cell proliferation, whereas millimolar
Consequences of co-exposure to fluoride and other substances
Drinking water is the primary source of fluoride exposure in humans. In this route of exposure, fluoride coexists with several other xenobiotics, frequently metals. Fluoride consumption within these mixtures could modify its kinetic and toxicity properties. Here, we present some mixtures that should be mentioned given their frequency and biological relevance.
Conclusions
In this work, we focused on showing the effects of inorganic fluoride compounds on the cellular function of several biological systems. The studies described above demonstrated that fluoride can interact with a wide range of cellular processes such as gene expression, cell cycle, proliferation and migration, respiration, metabolism, ion transport, secretion, endocytosis, apoptosis/necrosis, and oxidative stress, and that these mechanism are involved in a wide variety of signaling pathways (Fig.
Conflicts of interest
None.
Acknowledgement
This review was made possible by the Mexican Council for Science and Technology supported (Conacyt, grants 56785 and 104316).
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