Over the last 100-120 years, due to the ever-increasing importance of fluorine-containing compounds in modern technology and daily life, the explosive development of the fluorochemical industry led to an enormous increase of emission of fluoride ions into the biosphere. This made it more and more important to understand the biological activities, metabolism, degradation, and possible environmental hazards of such substances. This comprehensive and critical review focuses on the effects of fluoride ions and organofluorine compounds (mainly pharmaceuticals and agrochemicals) on human health and the environment. To give a better overview, various connected topics are also discussed: reasons and trends of the advance of fluorine-containing pharmaceuticals and agrochemicals, metabolism of fluorinated drugs, withdrawn fluorinated drugs, natural sources of organic and inorganic fluorine compounds in the environment (including the biosphere), sources of fluoride intake, and finally biomarkers of fluoride exposure.

Chemical Aspects of Human and Environmental Overload with Fluorine

Fluorides occur naturally in the environment, the daily exposure of human organism to fluorine mainly depends on the intake of this element with drinking water and it is connected with the geographical region In some countries, we can observe the endemic fluorosis—the damage of hard and soft tissues caused by the excessive intake of fluorine Recent studies showed that fluorine is toxic to the central nervous system (CNS) There are several known mechanisms which lead to structural brain damage caused by the excessive intake of fluorine This element is able to cross the blood-brain barrier, and it accumulates in neurons affecting cytological changes, cell activity and ion transport (eg chlorine transport) Additionally, fluorine changes the concentration of non-enzymatic advanced glycation end products (AGEs), the metabolism of neurotransmitters (influencing mainly glutamatergic neurotransmission) and the energy metabolism of neurons by the impaired glucose transporter—GLUT1 It can also change activity and lead to dysfunction of important proteins which are part of the respiratory chain Fluorine also affects oxidative stress, glial activation and inflammation in the CNS which leads to neurodegeneration All of those changes lead to abnormal cell differentiation and the activation of apoptosis through the changes in the expression of neural cell adhesion molecules (NCAM), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and MAP kinases Excessive exposure to this element can cause harmful effects such as permanent damage of all brain structures, impaired learning ability, memory dysfunction and behavioural problems This paper provides an overview of the fluoride neurotoxicity in juveniles and adults

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The Influence of Fluorine on the Disturbances of Homeostasis in the Central Nervous System

Recently, epidemiological studies have suggested that fluoride is a human developmental neurotoxicant that reduces measures of intelligence in children, placing it into the same category as toxic metals (lead, methylmercury, arsenic) and polychlorinated biphenyls. If true, this assessment would be highly relevant considering the widespread fluoridation of drinking water and the worldwide use of fluoride in oral hygiene products such as toothpaste. To gain a deeper understanding of these assertions, we reviewed the levels of human exposure, as well as results from animal experiments, particularly focusing on developmental toxicity, and the molecular mechanisms by which fluoride can cause adverse effects. Moreover, in vitro studies investigating fluoride in neuronal cells and precursor/stem cells were analyzed, and 23 epidemiological studies published since 2012 were considered. The results show that the margin of exposure (MoE) between no observed adverse effect levels (NOAELs) in animal studies and the current adequate intake (AI) of fluoride (50 µg/kg b.w./day) in humans ranges between 50 and 210, depending on the specific animal experiment used as reference. Even for unusually high fluoride exposure levels, an MoE of at least ten was obtained. Furthermore, concentrations of fluoride in human plasma are much lower than fluoride concentrations, causing effects in cell cultures. In contrast, 21 of 23 recent epidemiological studies report an association between high fluoride exposure and reduced intelligence. The discrepancy between experimental and epidemiological evidence may be reconciled with deficiencies inherent in most of these epidemiological studies on a putative association between fluoride and intelligence, especially with respect to adequate consideration of potential confounding factors, e.g., socioeconomic status, residence, breast feeding, low birth weight, maternal intelligence, and exposure to other neurotoxic chemicals. In conclusion, based on the totality of currently available scientific evidence, the present review does not support the presumption that fluoride should be assessed as a human developmental neurotoxicant at the current exposure levels in Europe.

/pdf/toxicity-of-fluoride-critical-evaluation-of-evidence-for-3rlr61gtwi.pdf

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

Fluorine is one of the trace elements necessary for health. It has many physiological functions, and participates in normal metabolism. However, fluorine has paradoxical effects on the body. Many studies have shown that tissues and organs of humans and animals appear to suffer different degrees of damage after long-term direct or indirect exposure to more fluoride than required to meet the physiological demand. Although the aetiology of endemic fluorosis is clear, its specific pathogenesis is inconclusive. In the past 5 years, many researchers have conducted in-depth studies into the pathogenesis of endemic fluorosis. Research in the areas of fluoride-induced stress pathways, signalling pathways and apoptosis has provided further extensive knowledge at the molecular and genetic level. In this article, we summarize the main results.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.14185

The pathogenesis of endemic fluorosis: Research progress in the last 5 years.

Fluoride (F−) originating from many natural geologic sources and anthropogenic activities has imposed a substantial environmental health risk. More than 200 million people from more than 35 nations...

Fluoride and human health: Systematic appraisal of sources, exposures, metabolism, and toxicity

Fluoride decreased the sperm ATP of mice through inhabiting mitochondrial respiration.

Effects of perinatal fluoride exposure on the expressions of miR-124 and miR-132 in hippocampus of mouse pups.

Both fluoride and lead can cross the blood-brain barrier and produce toxic effects on the central neural system, resulting in low learning and memory abilities, especially in children. In order to identify the proteomic pattern in the cortex of young animals, from the beginning of fertilization to the age of postnatal day 56, pregnant female mice and pups were administrated with 150 mg sodium fluoride/L and/or 300 mg lead acetate/L in their drinking water. Two-dimensional electrophoresis (2-DE) combined with mass spectrometry (MS) was applied to identify differently expressed protein spots. Results showed that there were eight proteins in the cortex that significantly changed, whose biological functions were involved in (1) energy metabolism (Ndufs1, Atp5h, Atp6v1b2), (2) cytoskeleton (Spna2, Tuba1a, Tubb2a), (3) glycation repair (Hdhd2), and (4) cell stress response (Hspa8). Based on the previous and current studies, ATPase, Spna2, and Hspa8 were shared by fluoride and lead both as common target molecules.

Proteome alterations in cortex of mice exposed to fluoride and lead.

Effect of sodium fluoride on the sperm mitochondrial DNA in mice.

Excessive fluoride intake for a long time has been demonstrated to provoke hepatic oxidative stress in adults. However, the response to fluoride toxicity of liver in newborns exposed to fluoride during embryonic and suckling stages remains unclear. In this study, female Kunming mice were administrated with 25, 50, and 100 mg/L sodium fluoride (NaF) from prenatal day 0 to day 21 after delivery, and the antioxidative status in the liver of their pups at postnatal day 21 was evaluated. The results showed that compared with the control group, NaF significantly increased malondialdehyde (MDA) level and reduced catalase (CAT) activity, while no statistical difference was observed in activities and mRNA expressions of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR). Notably, with comparison to the controls, the protein level of CAT was significantly reduced in medium- and high-fluoride groups, while its relative mRNA abundance was enhanced which could result from the encouragement of the lowered CAT protein expression. These findings suggested that CAT was more susceptible to low-fluoride exposure in early life.

Yuliang Zhang

Papers

Fluoride decreased the sperm ATP of mice through inhabiting mitochondrial respiration.

Effects of perinatal fluoride exposure on the expressions of miR-124 and miR-132 in hippocampus of mouse pups.

Proteome alterations in cortex of mice exposed to fluoride and lead.

Effect of sodium fluoride on the sperm mitochondrial DNA in mice.

Changes in Liver Antioxidant Status of Offspring Mice Induced by Maternal Fluoride Exposure During Gestation and Lactation