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Current guidance for fluoride intake – is it appropriate?

Marília Afonso Rabelo Buzalaf

Professor of Biochemistry and Cariology

Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Brazil
  1. Introduction

Fluorides have been extensively employed to control dental caries since the first half of the 1900s. Since the classical epidemiological studies by H. Trendley Dean, it was known that there should be an optimum level of exposure to fluoride that would be able to provide the maximum protection against caries, with minimum dental fluorosis1. Up to the 1980s, it was believed that fluoride exerted its protective effect against caries through a ‘systemic’ action, after being absorbed and taken up in the apatite crystals of the forming teeth. According to this concept, it was unavoidable to ingest fluoride in order to have protection against caries. In this sense, the occurrence of dental fluorosis was considered a necessary risk in order that the cariostatic benefits of fluoride could be achieved 2. In the 1980s and 1990s, a paradigm shift was proposed regarding the mechanisms of action of fluorides against caries3. It was observed that the amount of fluoride that could be taken up in the apatite was not enough to provide significant protection against acid dissolution4. On the other hand, the presence of low levels of fluoride in the oral fluids surrounding the enamelwas effective to inhibit demineralization and enhance remineralization. The concept that fluoride interferes in the dynamics of caries formation mainly when it is constantly present at low concentrations in the fluid phases of the oral environment became widely accepted (‘topical’ action)5-9and made it possible to obtain substantial caries protection without significant ingestion of fluorides10. Having this in mind and being aware of the increase in the prevalence of dental fluorosis in both fluoridated and in non-fluoridated areas 11-13, researchers all over the world turned their attention toward controlling the amount of fluoride intake10. It is important to point out that even the methods of fluoride delivery classically classified as ‘systemic’, such as water and salt fluoridation, can have a ‘topical’ effect against caries when fluoride is in contact with the teeth. In addition, after the ingestion of fluoride, this ion can return to the oral cavity through saliva and crevicular fluid and then exert its anticariogenic action, by interfering in de- and remineralisation processes 2. In fact, most of the anticaries effect of ‘systemic’ sources of fluoride, such as fluoridated water or salt, is nowadays attributed to the ‘topical’ contact with the teeth while these vehicles are in the oral cavity or when fluoride is redistributed to the oral environment though saliva 2. This doesnot mean that fluoride does not possess a pre-eruptive effect on caries control. The pre-eruptive effect has been described for decades based on data from epidemiological studies, such as the classical Tiel-Culemborg fluoridation study in The Netherlands 14 (for review see Murray et al. 15). More recent cohort studies have reported that the pre-eruptive effect of fluoridated drinking water is important for caries prevention especially in pit and surface surfaces of permanent molars, since these areas are of difficult access to ‘topical’ fluoride 16-18.

In the present review, we will discuss the appropriateness of the current guidance for fluoride intake, considering the windows of susceptibility to caries and fluorosis, the modern trends of fluoride intake from multiple sources, individual variations in fluoride metabolism, as well as recent epidemiological data. Based on the available evidence, further research that is required to provide additional support for future decisions on guidance in this area will be suggested.

  1. Etiology and window of susceptibility to the development of caries and fluorosis

When we try to use fluorides to obtain the best balance in the protection from caries while limiting the risk of dental fluorosis, it is necessary to have in mind the etiology of these lesions and the windows of susceptibility to both of them.

Caries is a multifactorial disease caused by the simultaneous interplay of different factors – dietary sugars, dental biofilm and the host – within the context of the oral environment 2,19. Whenever there is an unfavorable balance leading to increased periods of demineralization and reduced periods of remineralization, an initial caries lesion might form. This can take place from the crib to the grave, provided that the risk factors exceed the protective factors 9. There are some periods in life when the unfavorable balance is more likely to occur, such as in the primary dentition in the preschool years, in the mixed dentition in early school years, in the permanent dentition of adolescents at high school, young adults at college or along adulthood 20.

Dental fluorosis is caused by excessive fluoride intake during tooth formation. Considering that fluorotic changes in teeth cannot be reversed but may be easily prevented by controlling fluoride intake during the critical period of tooth formation, the identification of periods during which fluoride intake most strongly results in enamel fluorosis is of great importanceand subject of extensive investigation10.

For the whole permanent dentition (excluding the third molars), the window of susceptibility for fluorosis development has been regarded to be the first 6-8 years of life 21-23. Most of the studies concerning the window of maximum susceptibility to dental fluorosis development, however, have focused on the permanent maxillary central incisors, which are of greatest cosmetic importance. While there is general agreement that the early maturation stage of enamel development is more critical for fluorosis than the secretory stage 24-29, the evidence considering the age at which maxillary central incisors are most susceptible to dental fluorosis is not completely conclusive. Table 1 summarizes the results of studies focused on this topic 10. They can be divided into two categories: studies involving subjects whose exposure to fluoride started at different ages during tooth formation 30-37 and those involving subjects that had been exposed from birth and then had an abrupt reduction in daily fluoride intake 28,38-41. Most of them were cross-sectional, retrospective, and focused on just one or two sources of fluoride intake. Only one study(Iowa Fluoride Study), used longitudinal data on individual fluoride intake 36,37. While one study reported that the first year of life was the most critical period for developing fluorosis in the permanent central maxillary incisors 33, three studies found the first 3 years critical 37-39 and another one recognized a later period (between 35 and 42 months) 41, most of the them agreed that the first two years of life are most important 30-32,34,35. This was also reported in a meta-analysis 42, where it was reported that the duration of exposure to fluoride during amelogenesis, rather than specific risk periods, would seem to explain the development of dental fluorosis in the maxillary permanent central incisors. In other words, long periods of fluoride exposure (>2 out of the first 4 years) led to an odds ratio (OR) of 5.8 (95% CI: 2.8 – 11.9) versus shorter periods of exposure (<2 out of the first 4 years of life). This is in agreement with a more recent longitudinal study which concluded that (1) although the first 2 years of life were generally found to be more important compared with later years, fluoride intake during each individual year (until the fourth year of life) was associated with fluorosis and (2) subjects with higher levels of fluoride intake (estimated mean daily ingestion of 0.059 mg per kilogram body weight) during the whole first three years of life had the highest risk of fluorosis 36. Thus, the development of fluorosis appears to be related not only to the timing of fluoride intake relative to the periods of tooth formation, but also to the cumulative duration of fluoride exposure 36,42. From the available evidence, it seems rational to monitor fluoride intake of children during the first three years of life in order to minimize the risk of developing dental fluorosis of the permanent maxillary central incisors10,36,37,42.

In summary, the fluoride intake of importance to dental fluorosis occurs in early childhood while that of importance to dental caries occurs along the whole life course. This implies that policies aiming at reducing the fluoride intake to diminish the risk of dental fluorosis should be targeted to early childhood, while fluoride exposure should be maintained across life for the control of dental caries 43.

  1. ‘Optimal’ fluoride intake: can it be precisely determined?

The ‘optimal’ intake of fluoride (between 0.05 and 0.07 mg fluoride per kilogram body weight) 44that is still accepted worldwide was in fact empirically established. Its origin comes from the 1940s, when McClure 45 estimated that the “average daily diet” contained 1.0-1.5 mg of fluoride and this would provide about 0.05 mg fluoride per kilogram body weight for 1-12-year-old children. Farkas and Farkas 46, in the 1970s, cited various sources that suggested 0.06 mg fluoride per kilogram body weight as “generally regarded as optimum”. In the 1980s, this range of estimates started being used as a recommendation for ‘optimal’ fluoride intake 47. However, it is not clear if this level of intake is ‘optimal’ for caries prevention, for fluorosis prevention, or both10. In addition, some authors consider 0.1 mg fluoride per kilogram body weight per day to be the exposure level above which fluorosis occurs 48, while others report the occurrence of dental fluorosis with a daily fluoride intake of less than 0.03 mg fluoride per kilogram body weight per day 24.

Some prospective studies haveattempted to add evidence to the empirically established range of ‘optimal’ fluoride intake. In a small-scale study, Martins et al. 49 evaluated the relationship between fluoride intake and dental fluorosis in permanent central incisors and first molars of 49 children. When the children were aged 19-39 months, fluoride intake from diet, dentifrice and the combination of both was evaluated using the ‘duplicate-plate’ method and ‘simulated toothbrushing’50. Six years later, when the permanent central incisors and first molars of these children had erupted, they were evaluated for dental fluorosis. Dentifrice was the most contributor for the total fluoride intake, but no association was found between dental fluorosis in permanent teeth and fluoride intake from diet, dentifrice, or combined. The study had limitations such as the fact that fluoride intake was measured only once and the absence of children with severe dental fluorosis 49. The most comprehensive study on the association between fluoride intake, dental caries and dental fluorosis is the Iowa Fluoride Study (IFS), which is still ongoing. It is a longitudinal cohort study of children recruited soon after birth from 8 Iowa hospitals during March 1992 to February 1995 51-57. Initially, 1882 newborns were recruited and their mothers completed baseline questionnaires between 1992 and 1995. After this, mothers were sent questionnaires on a regular basis (3- and 4-month intervals from birth to 48 months of age and every 6 months thereafter), which included detailed information regarding children´s fluoride ingestion from different sources, such as water, beverages, food products, dietary fluoride supplements and fluoride dentifrice 51,52,54,55. Some years ago, the authors presented results relating longitudinal fluoride intake of the participants to dental caries and dental fluorosis. The main aim was to relate longitudinal fluoride intake to optimal oral health (absence of dental caries and dental fluorosis in the permanent teeth), in order to add scientific evidence to the “optimal” fluoride intake. Six-hundred and one children were included. Of these, 153 had neither fluorosis at age 9 or caries experience at age 5 or age 9; 202 had caries but no fluorosis at age 9; 96 had fluorosis but no caries; and 150 had both. Children with no caries history and no fluorosis at age 9 years had estimated mean daily fluoride at or below 0.05 mg/kg during different periods of the first 48 months of life, and this level declined thereafter. Children with caries or fluorosis had slightly lower or higher fluoride intakes, respectively.These results suggest that the accepted range of 0.05 – 0.07 mg fluoride per kilogram body weight may not be optimal in preventing fluorosis. However, given that most fluorosis was mild or very mild, and not of esthetic concern, even at high intake levels, recommendations to limit daily fluoride intake to less than 0.05 mg fluoride per kilogram body may not be justified. On the other hand, considering that most caries prevention results from topical fluoride exposure, it does not make much sense trying to establish what is the ‘optimal’ fluoride ingestion level for caries prevention.It was disappointing that after conducting this extensive and well designed cohort study the authors had to conclude that “Given the overlap among caries/fluorosis groups in mean fluoride intake and extreme variability in individual fluoride intakes, firmly recommending an “optimal” fluoride intake is problematic” 56.Moreover, the authors agree with Burt and Eklund58 that “perhaps it is time that the term optimal fluoride intake be dropped from common usage”. This study also had limitations, since it relied on parental reports of fluoride use and ingestion; it was conducted in one area of the United States with a sample that was not representative of any defined population; and there were missing data. In addition, most of fluorosis was mild or very mild, and not of esthetic concern. On the same way, most of children with caries had relatively few decayed or filled surfaces. Despite these limitations, it is the best outcome-based assessment of the ‘optimal’ fluoride intake available so far. Even so, the overlap among caries/fluorosis groups in mean fluoride intake and the high variability in individual fluoride intakes for those caries and fluorosis-free discourage a strict recommendation of an ‘optimal’ fluoride intake, especially at the individual level. This recommendation, however, seems to be desirable at the population level to guide programs of community fluoridation. For this purpose, and having in mind the windows of susceptibility to the development of dental fluorosis and dental caries, maybe it would be helpful to have different ranges of ‘optimal’ fluoride intake for small children and adults, but additional studies are required before this can be implemented.

  1. Factors that modify the metabolism or effects of fluoride

It is not surprising that the ‘optimal’ range of fluoride intake has not been precisely determined so far. In fact, this is not an easy task, as many factors modify the metabolism and effects of fluoride in the organism and alter the relationship between fluoride intake and the risk of developing dental fluorosis, especially when we consider the ‘optimal’ range of fluoride intake at the individual level59,60.

4.1.Acid-base disturbances

Many aspects of fluoride metabolism, such as absorption, distribution and renal excretion are pH-dependent, since the coefficient of permeability of lipid bilayer membranes to hydrogen fluoride (HF) is one million times higher than that of ionic fluoride 61. This implies that fluoride crosses cell membranes as HF, going from the more acidic to the more alkaline compartment 59. The kidneys are the major route of fluoride removal from the body. When the pH of the tubular fluid is lower, higher amounts of HF cross the tubular epithelium, returning to the systemic circulation 59. Thus, any condition that leads to acidic urine will increase the retention of fluoride in the organism. This includes diet composition(protein-62 and sorghum-rich diets 63,64, certain drugs (ascorbic acid, ammonium chloride, chlorothiazide diuretics, methenamine mandelate), metabolic and respiratory disorders leading to acidosis 60,65, as well as the altitude of residence 65.Significantly higher prevalence of dental fluorosis has been observed in communities at high altitude in comparison to those living at low altitude 66-71. It is believed that hypoxia in high altitude areas ultimately leads to a decrease in urinary pH, increasing fluoride retention in the body 65.

4.2.Renal impairment

Considering that the kidneys are the major route of fluoride removal from the body, it could be expected that renal impairment would increase fluoride retention in the organism, thus augmenting the risk of dental fluorosis. Intake of fluoride by nephrectomized rats increases plasma fluoride levels 72,73. In addition, children with renal disease present more severe dental fluorosis than healthy children 74.

4.3.Physical activity

Depending on the balance of several factors, exercise can be associated with either increased or decreased plasma fluoride levels. Upon prolonged physical activity, production of lactic acid might promote the diffusion of HF from the extracellular to the intracellular fluids leading to an increase in the rate of fluoride uptake by bone and other tissues, which would reduce plasma fluoride concentration. On the other hand, plasma fluoride concentration may increase during exercise because of reduced renal fluoride excretion. The factors associated with reduction in renal fluoride excretion are vasoconstriction within the kidneys due to increased sympathetic nervous system activity during exercise, which reduces the renal blood flow and glomerular filtration rate, and acidification of tubular fluid due to the production of lactic acid, increasing fluoride reabsorption in the tubules 75. Studies conducted with animals have reported reduced plasma fluoride levels 65,76 and increased bone fluoride levels in exercised (light exercise) rats compared with non-exercised ones 76. In one of these studies, the rats were submitted to acute exercise and exposure to fluoride 65 while in the other one fluoride and exercise were administered on a chronic basis (during 30 days) 76. Information available for humans is limited to a small-scale pilot study that investigated evaluated urinary fluoride excretion and plasma fluoride concentration in nine young adults undergoing acute exercise with different intensities following ingestion of 1 mg fluoride. Contrarily to what had been reported to occur in animal studies, it was observed a trend of a rise in plasma fluoride concentration and decline in rate of fluoriderenal clearance with increasing exercise intensity77. It seems that the intensity of the exercise and its nature (acute or chronic), as well as the doses of fluoride administered are important factors that influence the effect of exercise on fluoride balance in the organism. Additional human studies involving larger sample size and taking these variables into account are necessary to provide more evidence on this important matter.