# Mechanisms of Fluoride Toxicity: From Enzymes to Underlying Integrative Networks
## 1 Introduction  
More than 500 million people live in endemic fluorosis areas with an elevated level of fluoride in drinking water and biosphere with public health problems [1, 2]. The fluorosis symptoms span from mild effects on teeth enamel, headaches, dizziness, loss of appetite, to severe pathological disturbances. These include dental and skeletal fluorosis, hypothyroidism, sleep disorders, inflammations, IQ deficits, and suspected autism [3, 4, 5, 6].  
In 1931, [PERSON], head of the Dental Hygiene Unit at the National Institute of Health (NIH), began investigating the epidemiology of fluorosis in the USA. [PERSON] and his staff determined the fluoride levels in drinking water causing fluorosis. They discovered that fluoride levels of up to one milligram fluoride per liter of drinking water (one ppm) did not cause dental fluorosis in most people. [PERSON]'s reports formed the foundation of the concept that the ingestion of fluoride will augment the teeth enamel and make it less susceptible to dental caries [7]. [PERSON] suggested adding fluoride to water sources deficient in fluoride to bring its concentration up to the optimal value. After trials in the USA, the World Health Organization (WHO) recommended community water fluoridation (CWF), and many countries implemented this program [8, 9, 10]. The CWF recommendation has been followed for over 70 years in developed countries, such as the USA, Canada, Australia, New Zealand, Ireland, and some parts of the United Kingdom (UK) [9].  
CWF started an era of increased income from fluoride as never before in human history. Recently, 370 million people from 27 countries have a supply of fluoridated drinking water [9]. The number of fluoride sources has further expanded since fluoride is used for the improvement of food, beverages, hygiene, and medical products including fluorinated drugs.  
The fluorine atom does not exist in nature in a free and unmixed state. The mineral fluorite (CaF\({}_{2}\)) is the main source of fluorine for commercial use. Fluorine readily reacts with other elements to form fluoride compounds, within which it always adopts an oxidation state of \(-1\). Inorganic compounds are formed with hydrogen, metals, and non-metals. Therefore, fluoride refers to the negatively charged ion of the fluorine atom. In general, soil fluoride is not available to plants. There are exceptions such as tea plants that are natural accumulators of fluoride from fertilizers [1; 2; 4]. Fruits such as blueberry and grape concentrate fluoride from soil and it might appear in commercial juices. Fluorine excess had been found to be detrimental also to plants. Injury to plants is common all around industries making aluminum, fertilizers, or glass. Special plants might produce the toxic organofluorine compound fluoroacetate, which is used as a defense against grazing by herbivores.  
Conflicting views occur in debates addressing whether fluorine is an essential element for humans. The researchers of the Panel of the European Food Safety Authority (EFSA) state that fluoride has no known essential function in human physiology and development [11]. On the other hand, the WHO and the Centers for Disease Control and Prevention (CDC) consider fluoride to be an important dietary element for humans because of \"resistance to dental caries is a physiologically important function\" [12].  
Recently, concern about whether fluoride supplemented via drinking water and all other sources does not have harmful effects remains widely discussed by the scientific community. The goal of our review is to enhance understanding of the mechanisms by which fluoride impacts human health and development.