4.2 Fluoride metabolism

About 90% of fluoride is absorbed in the gastrointestinal tract after consumption (up to 25% in the stomach and around 77% in proximal part of the small intestine). The remaining 10% is excreted in feces (15). After absorption, fluoride is transported into the bloodstream and is distributed through the organism (4). The mean time of the peak concentration is 20-60 minutes after consumption (15). In the plasma, fluoride ions are bound to plasma protein (15). Concentration rarely exceeds 0.06 ppm (parts per million). It is usually about 0.01 ppm and is not homeostatically regulated in the blood. Adults retain around 36% of fluoride, whereas children retain approximately 50% of fluoride; 99% of that is contained in mineralized tissues (bone and teeth) and 1% can be found in soft tissue (15). The remaining part of the absorbed fluoride is excreted through the kidneys into the urine; excretion through saliva and sweat is negligible (4). The kidneys are therefore the only human organ that helps maintain the fluoride concentration in our bodies. There are different factors that can influence fluoride metabolism. The most important are: acid base disorders, hematocrit, altitude, physical activity, circadian rhythm, hormones, kidney function, genetic predispositions and diet (15). In pregnant women, uptake of fluorides in the placenta is dependent on the fluoride concentration in the mother`s bloodstream. When the concentration is low, fluoride is transmitted into the placenta (16). On average, the concentration in the placenta is about 60% of the concentration in the mother`s bloodstream (17). If the fluoride concentration increases over 0.4 ppm (17), the placenta works as a barrier, preventing the fluoride from passing through and thus protecting the fetus from a high fluoride concentration (16). Fluoride can also be transmitted through the plasma into the mother’s milk; however, the concentration is low (18).

4.3 Historical overview of fluoride use

The idea of using fluoride as a beneficial agent in caries prevention is not new. The pioneers in the field were Black and McKay. They started observing and describing the effects of fluoride in the late 19^th and beginning of the 20^th century (19). McKay was studying brown stains on enamel observed in the population from different parts of the USA. A condition which he termed mottled enamel. In 1931, Churchill’s chemical analysis discovered the reason behind those changes – fluoride (20, 21). After the discovery, Dean systematically conducted a series of epidemiological investigations (22). He listed enamel spots based on size and color and measured the degree of tooth impairment. He compared enamel changes to fluoride concentration in drinking water and made the connection between fluoride content and the quantity of enamel spots, which he termed dental fluorosis (23). He documented dental fluorosis prevalence in the USA until 1942 and then compared it to caries prevalence in children. He noticed a strong inverse relationship (24). After concluding his 21-city study (25, 26), he found that drinking water with 1 ppm of fluoride can prevent dental caries, increase tooth strength and does not have a negative impact on enamel. The first studies about positive effects were conducted in 1945 with systemic fluoridation of drinking water in four American cities (Grand Rapids, Evanston, Brantford and Newberg), where 1 mg of fluoride per liter was added to drinking water. The results were convincing. Caries incidence reduction was at least 50%. They came to the conclusion that fluoride in suitable concentrations significantly affects dental caries prevalence (27–30). These observations and discoveries triggered massive drinking water fluoridation, the use of fluoridated salt and milk and an increase in diet supplement production (pills, drops, chewing gum, lozenges). Consequently, caries prevalence was successfully decreased. In 1950, Bibby et al (31) conducted a study comparing the efficacy of fluoride-coated pills intended to be swallowed, with fluoride lozenges intended to be dissolved slowly in the mouth. Research showed a lower number of new caries lesions in the research group which consumed lozenges. This research triggered different studies comparing pre- and post-eruptive effects, which consequently led to a rethinking of the theory of systemic use of fluoride and its incorporation into enamel during teeth development (odontogenesis). In the last 30 years, studies have shown that the maximum anti-caries benefits of fluoride are primarily through topical use and direct contact on the tooth surface. Daily use of topical supplements with suitable fluoride concentration is beneficial (2).

Methods, which led to greater fluoride exposure and lowered caries prevalence, are considered to be one of the greatest accomplishments in the 20^th century`s public dental health (32).

4.4 The mechanism of fluoride action

The primary and most important action of fluoride is topical, when the fluoride ion is present in the saliva (33) in the appropriate concentration. Hydroxyapatite is the main mineral responsible for building the permanent tooth enamel after the development of the teeth is finished (34). During tooth growth, the enamel is constantly exposed to numerous demineralization processes, but also important remineralization processes, if the appropriate ions are present in the saliva. These processes can either weaken or strengthen the enamel. The presence of fluoride in an acidic environment reduces the dissolution of calcium hydroxyapatite. The main action is inhibition of demineralization of enamel, which is carried out through different mechanisms. There are different cariogenic bacteria in the plaque fluid the most important being S. mutans. When bacteria metabolize sugars, they produce lactic acid (33) which decreases the pH in saliva. When the pH falls below the critical level of hydroxyapatite (pH 5.5), the process of demineralization of enamel takes place and caries is formed. At the beginning, the process is reversible and it is possible to reduce the formation of new lesions with appropriate preventive measures. If fluoride is present in plaque fluid, it will reduce the demineralization, as it will adsorb into the crystal surface and protect crystals from dissolution. Because the fluoride ion coating is only partial, the uncoated parts of the crystal will undergo dissolution on certain parts of the tooth, if the pH falls below level 5.5. When the pH rises above the critical level of 5.5, the increased level of fluoride ion leads to remineralization, because it absorbs itself into the enamel and forms fluorhydroxyapatite (33). After repeated cycles of demineralization and remineralization, the outer parts of enamel may change and become more resistant to the acidic environment due to a lowered critical pH level of newly formed crystals (pH 4.5) (33). The most important effect of fluoride on caries progression is thus on demineralization and remineralization processes. It has also been proposed, that the fluoride ion can affect the physiology of microbial cells, which can indirectly affect demineralization. Fluoride ions affect bacterial cells through several mechanisms. One of them being a direct inhibition of cellular enzymes – glycolytic enzymes, H+ATPases). It affects cellular membrane permeability and also lowers cytoplasmic pH, resulting in a decrease in acid production from glycolysis (33).

4.5 Overuse and toxicity of fluoride

Dental fluorosis is a developmental disturbance of enamel which occurs during enamel forming. It is caused by systemic overexposure to fluoride during the first six years of life, when the enamel of the crowns of permanent teeth is formed. The enamel contains more protein, is porous, opaque and less transparent. Clinical manifestation vary from (quantitative) narrow, white horizontally running lines, larger patches or yellow to light brown colored areas of porous enamel, to (qualitative) loss of enamel in varying degrees (35). For the optimal effect of fluoride toothpaste, it is important to follow recommended guidelines for the use of products containing fluorides (Table 2) (7). In this way, the probability for fluorosis is decreased and the protective effect of fluoride on the development of caries is significantly important (1).

Just like any other substance we are exposed to in our everyday lives (oxygen, water, table salt), fluoride can be toxic in certain quantities. Acute toxicity can occur after ingesting one or more doses of fluoride over a short time period which then leads to poisoning. The stomach is the first organ that is affected. First signs and symptoms are nausea, abdominal pain, bloody vomiting and diarrhea. This is followed by a collapse with paleness, weakness, shallow breathing, weak heart sounds, wet, cold skin, cyanosis, dilated pupils, hypocalcaemia and hyperkalemia, and in to two to four hours even death. Other possible effects include muscle paralysis, carpopedal spasms and extremity spasms. Based on research papers and some overdose cases, the probable toxic dose (PTD) was defined at 5 mg/kg of body mass. The PTD is the minimal dose that could trigger serious and life-threatening signs and symptoms and requires immediate treatment and hospitalization (36). Example: PTD in a 20 kg child would be achieved at ingesting 100g (75 ml) of toothpaste which contains 1000-1500 ppm of fluorides or 100 pills, that contain fluorides (0,5-1 mg fluoride) (36).

Despite the widespread presence of fluoride in our life and the seriousness of the conditions associated with its toxicity, the number of cases of acute toxicity today, compared to the first half of twenty first century, is very rare. At that time, sodium fluoride was used as a pesticide and rat poison. Because of its appearance it was often mistaken for flour, powdered sugar or any other white powder product, which is used in the kitchen. The most notable example is from the Oregon State Hospital from 1942. During the preparation of scrambled eggs powdered milk was replaced by sodium fluoride which caused 467 cases of acute poisoning of which 47 were fatal. This incident is considered to be the largest mass fluoride poisoning (37).

Today, poisoning is mainly due to unsupervised ingestion of products for dental and oral hygiene and over-fluoridated water (example: Hooper Bay, Alaska, 1992) (37).

The authors acknowledge the support of Lijana Zaletel-Kragelj, MD, PhD, Professor, Chair of Public Health, Faculty of Medicine, University of Ljubljana, Slovenia for helpful comments on earlier drafts of this review.