Dental caries is a major public health problem and the most widespread chronic disease. It affected about 60% to 90% of schoolchildren and in several developing countries the prevalence rates are increasing [1]. The use of fluoride (F) has contributed in the decline in dental caries prevalence in the developed countries. On the other hand, in developing countries, the limited use of F was linked to the increase in dental caries prevalence [2]. Hence, F is the cornerstone of preventive dentistry. It plays an important role in the prevention of dental caries, as well it is a cost-effective preventive measure [1]. Nevertheless, F has harmful effects on human health [3].

This review discussed the previous literature of F, concerning the following topics; the history of discovery the action of F in preventing dental caries: occurrence of F in the environment: intake of F in Human: F metabolism: methods of F delivery: and the harmful effects of F.

In 1901 a dentist in Colorado, USA is called Frederick McKay noticed that many of his patients, who had spent all their lives in the area, had a distinctive stain on their teeth known locally as ‘Colorado stain [4]’. With the assistance of a dental researcher G.V.Black, it was found that histologically the enamel was imperfectly calcified and the affected teeth were less susceptible to dental caries than normal teeth [5]. They implicated the water supplies in the aetiology of the staining and pits, this staining is now known as dental fluorosis [6]. After that, in 1933 a local dentist in Bauxite, USA noticed that children had mottled teeth. Thus, Mr. H.V. Churchil analysed the water and found that the F ion concentration in the water supply of the Bauxite community was 13.7 ppm, which is considered abnormally high [4]. In 1938 extensive surveys of all communities affected by mottling in the USA conducted by Dr Trendly Dean. He showed that below the level of 1 ppm F ion concentration, mottling disappeared or was minimal. Further studies in the USA showed that at a F ion concentration of 1 ppm there was a reduction in dental caries, with no associated mottling of teeth [5]. In 1944, Dean and co-workers began to test the safety of artificially fluoridating the water at 1 ppm. Finally, in 1953 it was reported that after 6 years of artificially fluoridating the water in Grand Rapids, USA, dental caries are reduced by half compared to the control group [6]. F has made a great contribution in declining dental caries prevalence since the discovery of its anti-caries effect in 1938 by Dr Trendly Dean [5].

Fluorine is the most reactive nonmetal and the most electronegative element. It almost never occurs in nature in its elemental state, it combines with all elements, except oxygen and the noble gases, to form fluorides [7]. Inorganic and organic fluorides are present in air, all soils and water, and in the plants and animals consumed by humans for food [8]. In addition, F is released in the form of hydrogen fluoride during the volcanic eruption [9]. The distribution of F in the environment is uneven and largely is believed to derive from geographic causes. The major F-containing minerals are fluorite or fluorspar CaF2 that is 49% F, and many other minerals such as fluorapatite, mica and cryolite [10]. Once F is dissolved in water from mineral sources, it presents in ionic form (F⁻). The high F concentration in water usually reflects its solubility, also it is often associated with soft, alkaline, and calcium-deficient waters. The groundwater is more susceptible to F accumulation and contamination than are other environmental media, primarily because of its contact with geological substrates underneath [11]. Additionally, the anthropogenic sources of F that include coal burning, oil refining, steel production, brick-making industries, and phosphatic fertilizer plants, have occasionally been considered to be major ones [12].

A human can obtain F from air, drinking water and food. However, respirable intake of fluorides is almost negligible except under occupational exposure conditions [13]. In the main, the amount of F ingested by drinking and from food depends on the concentration of F in them, the size and age of the person, and on personal and dietary habits [12]. Additional intentional F intake may occur through the ingestion of fluoride tablets and the use of fluoride-containing therapeutic agents and topical fluoride preparations [11,14]. As well, F in water adds considerably to F levels in prepared food [15].

The metabolism of F is constituted of the following processes; absorption: secretion: distribution: and excretion. Once ingested, inorganic ionic F is normally rapidly and nearly completely absorbed from the gastrointestinal tract by simple diffusion [16]. F absorption depends on the stomach pH and solubility of the ingested F compound [17]. F is not protein-bound and occurs as a free ion in the plasma, and plasma levels of F increase at 10 minutes after its absorption. Whereas, the maximum plasma F concentration is found 30-60 minutes after ingestion of a dose of soluble F [8].

F is secreted in saliva, as with an increase in plasma levels, the salivary levels also increase by the same proportion. Although, F concentrations in human saliva are slightly less than those found in plasma, their important role in dental caries prevention cannot be underestimated [8,10].

After absorbed, F is distributed within minutes through the extra-cellular fluid of most organs and tissues [10]. The major site of F accumulation in the body is the hard tissues, because of the affinity of F for calcium. In descending order, the highest levels are found in cementum, bone, dentin, and enamel [18]. Bone deposition of F occurs to the extent of 50% in growing children, but only 10% in adults [19]. Mobilization from calcified tissues is dependent on the F content of bone which reflects previous F intake, mainly in drinking-water [11]. F is deposited in dental tissues in several ways during the tooth life, initial deposition occurs while the organic and mineral phases are being laid down, following F is deposited from the tissue fluids during the pre-eruptive maturation phase [18]. Finally, F is acquired topically by enamel during the post-eruptive maturation and aging period [10].

The principle route of elimination of soluble F is by urine, as 90-95% of ingested F is excreted in the urine [20]. With normal renal function, F is excreted in hours to days, but in the presence of end-stage renal disease the elimination phase is prolonged up to 2 years. F is also excreted in the faeces and in sweat in small amounts [21].

A distinction is made between F that is ingested systemically and that is applied topically (shown in Figure 1). Systematic F provides a low concentration of F to teeth over a long period of time [10]. An increase in enamel F level may occur when F is made available shortly before tooth eruption, but an effect on fissure morphology requires an exposure to F during an earlier stage of crown formation [4,22]. Once the tooth has erupted, it can no longer be expected to benefit systemically from fluoride, except for the transient slight elevation of its salivary level [6]. Topical F is applied locally or topically to the erupted tooth surface to prevent new carious lesions and halting the progression of established lesions [10]. At the time of tooth eruption, the enamel is not yet completely calcified and undergoes a post eruptive period of maturation for approximately two years. During this period, the enamel is porous and immature and its calcification continues [23]. Thus, the application of topical F immediately after tooth eruption leads to deposit it in the superficial layer of enamel and makes it more resistant to caries [24]. As well as, the presence of F in contact with tooth surface promotes remineralization of the early carious lesion and interferes with microorganisms [23]. For many years, it was thought that the most important mode of action of F was through its incorporation into the enamel during tooth formation. Thus, systemic F had been widely recommended until the 1970s [4]. Afterwards, when the new concept of understanding the anti-caries mechanisms of F was introduced, it was established that F prevents dental caries mainly through its topical effect [24]. Nevertheless, as seen by Murray and Naylor 1996, such distinctions are not helpful since all methods of F delivery can have both systemic and topical effects [6].

Figure 1. Methods of fluoride de-livery.

F is an essential nutrient, and its prolonged use at recommended levels does not produce harmful physiological effects in human [25]. However, like every chemical, there are safe limits for F ingestion beyond which harmful effects occur [10]. At excessive exposure levels, ingestion of F causes dental fluorosis, skeletal fluorosis, and manifestations such as gastrointestinal, neurological, and urinary problems [12]. These effects can be classified as acute toxicity and chronic toxicity (shown in Figure 2).

Figure 2. Fluoride toxicity.

1. Acute toxicity

Acute toxicity is a rapid intake of an excess dose of F over a short period of time, but the ingestion of acute fatal dose of F is very rare [26]. The single dose of F that causes acute toxic effects is 5-10 mg F/kg body weight [27]. Certainly lethal dose, which is the amount of soluble F considered lethal when taken orally, is 70-140 mg F/kg body weight [28].

The acute effects of F inhalation are extreme irritation of the respiratory tract with coughing and choking [11]. Liquid or vapour F can cause severe irritation when it contacts with skin that may result in severe burns. Moreover, it could lead to prolonged or even permanent visual defects, if it contacts with eyes [27].

Following ingestion, fluorides react with gastric acid to produce highly corrosive hydrofluoric acid, which can cause nausea, vomiting, diarrhea, excessive salivation and thirst, painful abdominal cramping and haemorrhagic gastroenteritis [10]. Then, cardiac arrhythmias, hyperactive reflexes and tetanic contractures occur due to hypocalcaemia. Subsequently, respiration is first stimulated then depressed, and death is usually caused by respiratory paralysis [28].

2. Chronic toxicity

Chronic toxicity is a long-term ingestion of F in amounts that exceed the approved therapeutic level. Chronic effects from F ingestion are dental fluorosis, skeletal fluorosis, weight loss, malaise and anaemia [27].

Dental fluorosis is a systemic disturbance of tooth formation caused by excessive intake of F during the formative period of the dentition [10]. The excessive ingestion of F during the first 6 to 8 years of life could be a risk factor, as the excess intake of F in any amount cannot produce dental fluorosis in an erupted tooth [6]. It is an irreversible condition that is endemic in areas with high level of F occurring naturally in the water, and it is the most common adverse effect of F use in prevention of dental caries [8]. Teeth with mild dental fluorosis may be more resistant to decay due to the higher levels of F existing in the enamel surface. However, heavily fluoridated teeth are more susceptible to decay, most likely due to the uneven surface or loss of the outer protective layer [29,30]. Therefore, F use for oral health has to always involve a balance between the protective benefit against dental caries and the risk of developing fluorosis [6]. The safe level for daily F intake is 0.05 to 0.07 mg F/Kg/day, and above this level the risk of developing fluorosis due to chronic F consumption will be obvious [4].

These alterations become more severe with increasing F intake and time of exposure [31]. Whereas, the severity of fluorosis is related to the concentration of F in plasma, which is in equilibrium with concentration of F in the tissue fluid surrounding the enamel organ [32]. Many factors can influence the plasma F level, which include; total fluoride intake: type of intake: renal function: rate of bone metabolism: and metabolic activity [33]. The primary pathological finding of fluorosed enamel is a subsurface porosity, along with hyper- and hypo-mineralized bands within the forming enamel [34]. In severe cases, hypo-mineralization below the surface may reach 25% or more, where the severest porosity occurs in the outer third of the enamel [10]. In addition, it may extend more deeply, where the entire enamel may be affected to some degree. As well, fluorosis can result in mineralization-related effects on dentin formation [35].

Clinically, dental fluorosis is usually limited to the permanent teeth, but the primary dentation may also be affected [6]. The reason for this may be related to a modifying effect of the placenta on F transfer to the fetus, or to a shorter period of enamel formation in the primary dentation [36]. Generally, fluorosis occurs symmetrically within the dental arches, however the premolar is usually the most affected, followed by the 2^nd molar, upper incisors, canine, 1st molars and lower incisors. In addition, it is most visible on the incisal or occlusal two-thirds of enamel [10].

In its mild form, dental fluorosis appears as white opacities on the surface of the enamel. With increased subsurface porosity, many white thin horizontal lines can be seen running across the tooth surfaces [36]. However, not all tooth opacities that may be present are due to F, as the clinical diagnosis of the mild form of dental fluorosis is often problematic due to similarities in its appearance to other non-fluorotic enamel conditions [37]. As the degree of fluorosis increases, the white lines in the enamel become more defined and thicker, and entire tooth may become chalky white and lose its transparency [36]. In its moderate to severe form, the deeper layers of the enamel are affected and the enamel becomes less mineralized and its surface can be easily damaged [30]. At this stage, teeth may erupt with pits and additional pitting can occur with enamel fracture after eruption, as the enamel can easily chip after eruption during normal mechanical use [38]. In addition, yellow to dark brown staining is observed in areas of enamel damage. In severe cases, larger areas of enamel hypoplasia appear, leading to a loss of the normal morphology of the tooth [29].

It is a chronic metabolic bone and joint disease caused by ingesting a dose of 8 ppm F or more daily [39]. Once this occurs, bone density slowly increases, the ligaments calcify, the joints stiffen and become painful, and movement becomes restricted. The advanced stage of this disease called “crippling fluorosis” as it causes obvious deformity, where extreme fixation of spine and chest in inspiration position [10].

F is an important and cost-effective caries preventive measure, as it has made a great contribution to declines in dental caries since the discovery of its anticaries effect in 1938 by Dr Trendly Dean. Inorganic and organic fluorides are present in air, all soils and water, and in the plants and animals consumed by humans for food. Thus, a human can obtain F from air, drinking-water and food. Additional intentional F intake may occur through the ingestion of F tablets and the use of F-containing therapeutic agents and topical F preparations. During the tooth life, F is deposited in dental tissues in several ways. Initial deposition occurs while the organic and mineral phases are being laid down, following F is deposited from the tissue fluids during the pre-eruptive maturation phase. Finally, F is acquired topically by enamel during the post-eruptive maturation and aging period. A distinction is made between F that is ingested systemically and that is applied topically. Nevertheless, as seen by Murray and Naylor 1996, such distinctions are not helpful since all methods of F delivery can have both systemic and topical effects. At excessive exposure levels, ingestion of F causes dental fluorosis, skeletal fluorosis, and manifestations such as gastrointestinal, neurological, and urinary problems.

No potential conflict of interest relevant to this article was reported.