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Current guidance for fluoride intake – is it appropriate?

Ingegerd Mejàre

Professor Emerita, Malmö University, Malmö, Sweden

The purpose of this report has been to critically examine the appropriateness of current guidance for fluoride uptake in the population. More specifically, the objectives were to:

‒ critically review current guidance in light of the modern era of fluoride intake, documented in multiple sources and recent epidemiological data

‒ consider whether changes to current guidance are desirable ‒ consider whether guidance should be age-specific‒ suggest further research that will strengthen the evidence base for future decisions on

guidance/advice in this area.

BackgroundThe link between fluoride, the prevention of dental caries and dental fluorosis dates back to the 1930s. When artificial water fluoridation started in the 1940s it became important to adjust the concentration of fluoride in drinking to achieve a balance between optimal caries prevention and excessive ingestion of fluoride. At that time, the main source of fluoride was drinking water. Today, there are many other ways for fluoride to be ingested, such as from toothpastes, varnishes, gels, milk and salt.

The original studies conducted by Dean [1] found that in a community served with naturally-occurring fluoride in domestic water supplies, caries reduction peaked at a concentration of 1 ppm. Even at this level, one would expect to see 1 percent mild fluorosis, 19 percent very mild and 31 percent questionable fluorosis, which gave a cumulative total of 51 percent with some degree of fluorosis and 49 percent with no change in the appearance of the tooth enamel. In Dean’s day when drinking water was virtually the only source of fluoride and caries was relatively frequent, it was decided that, considering the reduction of caries, this level of risk (fluorosis) was acceptable.

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A brief history of sources of fluoride:

From 1945 to 1970 From around 1970

Water fluoridation Water, salt or milk fluoridation OR AND/ORpractically no Fluoride toothpastefluoride exposure Varnish, mouth rinse

Gel, tablets, drops, lozenges

Whereas from around 1945 up to around 1970 children were either exposed to fluoride from drinking water or in principle not exposed at all, in the 1970s the situation changed dramatically when fluoride toothpaste became available to the public. Since then, moreover, various topical fluoride products and fluoride supplements have been used both professionally and independently by patients/parents.

Today the main contribution to the total daily intake of fluoride comes from water and fluoridated toothpaste [2]. Fluoride toothpastes have been unequivocally demonstrated to be beneficial for preventing caries but their use by young children has been identified as a potential risk factor for fluorosis. Thus, there has been concern about the prevalence and possible increase in dental fluorosis in for example North America and Great Britain [3, 4] and, according to Browne [5], in several other countries as well. According to Burt [6], the prevalence of fluorosis has increased in the US over the last 30-50 years and the relative increase has been greatest in non-fluoridated areas.

Recommendations for fluoride intake should strive for the best balance between preventing caries and minimizing the risk of fluorosis. However, the appropriate levels of fluoride intake for optimal dental health are still uncertain, particularly for young children during the critical period of tooth development. A recent systematic map in pediatric dentistry concluded that with reference to the risk of fluorosis, the proper amount and ppm concentration of fluoride in toothpastes for preschool children remains a knowledge gap [7].

Literature Systematic reviews on dental caries and dental fluorosis were identified through an updated search based on a previous literature search [7]. Out of twenty-four identified references, six systematic reviews were singled out as dealing with both dental caries and dental fluorosis [8-

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13]. A hand search identified another two systematic reviews relevant to this report [14, 15]. Other literature comes from hand-search.

Critical age for the risk of fluorosisLike any pharmaceutical product, fluoride should be considered in relation to the individual’s bodyweight. However, the considerable time lag between fluoride exposure (ingestion) during tooth formation and the effect several years later when the permanent teeth erupt makes it difficult to arrive at a valid relationship between the ingested fluoride dose and dental fluorosis. Moreover, the bioavailability of ingested fluoride is uncertain and variable. There is also a considerable variation in fluoride intake across ages and among individuals [16].This makes the use of epidemiological studies highly relevant. Data from large American epidemiological surveys have shown that there is a significant dose-response relationship between fluoride and dental fluorosis. The relationship is clearly linear and data indicate that every increase in the dose from 0.01 mg/kg bodyweight can be expected to lead to an increase in dental fluorosis in a population. There is therefore no critical value below which the effect on dental enamel will not be manifest [17]. Nota bene, this dose-response relationship applies to the population, not to individuals.

The critical age for the development of fluorosis in anterior teeth was considered to be the second or third year of life [18]. According to Evans & Stamm [19], for upper central incisors the risk was considered to be greatest between the ages of 22 and 30 months. Refining the estimates, Evans & Darvell [20] found that the maxillary central incisor appears most at risk of fluorosis between the ages of 15 and 24 months for males and between 21 and 30 months for females. Results from a longitudinal epidemiological study indicate that the highest risk of developing fluorosis is among children who ingest higher levels of fluoride during the first two years of life [21].

This report will focus on pre-school children because it is at these ages that excessive fluoride intake may result in dental fluorosis.

Current guidance on “optimal” intake of fluorideIn the dental literature, guidance on the “optimal” intake of fluoride in children dates back to the 1940s. In his account, Burt [6] concluded that despite a “dubious genesis”, the empirical evidence suggests that 0.05–0.07 mg fluoride/kg bodyweight/day remains a useful upper limit for fluoride intake in children. Fejerskov [22] suggested a lower threshold of 0.03–0.10 mg fluoride/kg bodyweight/day as the borderline zone, at least for European children, while Forsman [23] considered fluorosis to be probable following intakes of more than 0.1 mg/kg

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bodyweight during infancy. Studies in Kenya reported that fluorosis developed with an average intake as low as 0.04 mg fluoride/kg bodyweight/day [24].

Dietary Reference Values (DRV) and recommendations for fluorideDietary reference values are given for all kinds of nutrients. Although fluoride is not an essential nutrient, various authorities have adopted DRV or adequate intake values (AI). Thus, the European Food Safety Authority (EFSA 2013) [2] considered that adequate intake values are appropriate for fluoride because of the beneficial effect on caries prevention. To establish a basis for defining an adequate mean fluoride intake (AI), the Authority used estimates of children’s mean fluoride intakes via diet and drinking water with fluoride concentrations at which the caries preventive effect approached its maximum and the risk of dental fluorosis approached its minimum. The Authority concluded that current knowledge from longitudinal studies did not warrant drawing a conclusion on a dose-response relationship between fluoride and caries risk. The AI of fluoride from all sources (including non-dietary sources) was set at 0.05 mg/kg bodyweight per day for both children and adults. It was noted that reliable and representative data on the European population’s total fluoride intake are not available.

Infants and children. The UK Department of Health (COMA) [25] arrived at a safe fluoride intake up to six years of age of 0.12 mg/kg bodyweight/day on the basis of the observation that fluoride intakes up to this level are found in areas with fluoridated water and that such intakes are not associated with cosmetically significant dental fluorosis. In addition to the European Food Safety Authority (EFSA 2013), the (D-A-CH) for German speaking countries [26], and the US Institute of Medicine (IOM) [27] give dietary reference values (DRV) for various nutrients including fluoride. All of them set their value for fluoride at 0.05 mg/kg bodyweight/day. The World Health Organization (WHO/FAO 2004) [28], the Nordic countries (NNR 2004) [29] the Netherlands Food and Nutrition Council [30] do not derive DRVs for infants and children.

Adults. The US Institute of Medicine (IOM) concluded that an Adequate Intake (AI) could be derived from estimated intakes that have been shown to maximally reduce the occurrence of caries in the population without causing adverse effects, including moderate dental fluorosis. An AI of 0.05 mg F/kg bodyweight/day was chosen for all ages above six months. Reference weights from body mass index and median heights of young adults were used to assess AI. The D-A-C-H also accepted the 0.05 mg F/kg bodyweight/day for caries protection. The UK Department of Health considered the same value to be safe because this exposure was considered to be below the dose associated with skeletal fluorosis and not associated with other adverse effects. The World Health Organization (WHO)/FAO 2004), the Nordic countries (NNR 2004) and the Netherlands Food and Nutrition Council do not derive DRVs for adults.

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All these recommendations are intended for populations, not individuals. This report also deals with populations of subgroups of populations. The main reason is that no data are available that can define a dose-response relationship on an individual basis.

Biomarkers of fluoride exposure. Urine has been found to be the most useful biomarker of contemporary fluoride exposure; assessment of renal fluoride excretion can therefore be used for effective surveillance of fluoride exposure when community prevention programs are using fluoride [31]. In these assessments, fluoride intakes between 0.05 and 0.07 mg fluoride/kg bodyweight/day are accepted as optimal, whereas intakes above 0.1 mg fluoride/kg bodyweight/day increase the risk of enamel fluorosis. However, this method suffers from several uncertainties: within subject variation, lack of correlation between urinary fluoride excretion and fluoride intake, and uncertainty about levels needed to provide protection. Even so, the method can serve as a simple and reliable means to ensure that total fluoride intake from all sources does not exceed certain limits, which is especially important in young children when permanent anterior teeth are forming. The method is suitable for groups of people but not for individuals [32]. Urinary fluoride excretion by preschool children in six European countries was measured by Ketley [33], who found a significant difference between fluoridated and non-fluoridated areas, although the data showed that urinary fluoride excretion and estimated fluoride intake appeared to be within acceptable limits.

There are just a few epidemiological studies that have used standardized methods to assess how much fluoride children ingest from toothpaste. This knowledge gap was addressed in the FLINT project [34], which collected data from seven European countries. The mean ingested amount of fluoride varied widely between the countries, ranging from 0.01 to 0.04 mg F/kg bodyweight/day [35]. The data indicated that 1.5 to 2.5-year-old children ingested an average of 64 to 84 percent of the dispensed toothpaste, depending on the country. There were considerable differences between the mean fluoride concentrations in “children’s toothpaste”, ranging from 420 to 950 ppm F.

To find out the amount of fluoride that can be ingested without resulting in disturbing dental fluorosis, most epidemiological studies have compared different concentrations of fluoride in toothpastes as a proxy for ingested fluoride (mg F/kg bodyweight/day). Both methods (using ppm fluoride in toothpaste or mg F/kg bodyweight) face the same challenge – the long time lag between the most critical age of exposure to fluoride (up to about 30 months of age) and the appearance of dental fluorosis in the permanent teeth.

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Estimating risk Exposure to fluoride can be measured or estimated as mg F/kg bodyweight/day and the outcome – fluorosis – assessed according to various indices. Exposure to fluoride from toothpastes can be used as an indirect estimate of exposure. The estimated risk can be presented as relative risk, odds ratio or attributable risk. The principal differences between these metrics are briefly explained in Box 1.

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Box 1. What does relative risk mean and what is the difference between relative risk and odd ratio?The data used come from the study by Holt [36]. This randomized controlled trial compared the effects of using one of two fluoride toothpastes in young children (550 ppm versus 1050 ppm) on the development of caries and fluorosis. The Thylstrup-Fejerskov Index (TF) was used to score fluorosis at the age of about 10. The cut-off between Fluorosis and No fluorosis is set at a TF score of 2 or more. Altogether, 9.3 percent of the children developed fluorosis with a TF score of 2 or more.

Fluorosis(case)

No fluorosis(control)

Total The incidence of exposed is a/(a+b)The incidence of unexposed is c/(c+d)The relative risk (RR) is:Incidence of exposed/incidence of unexposed:a/(a+b)c/(c+d)For these data RR= 0.113/0.073=1.55 (95 % CI=1.03;2.30)

Exposed 1050 ppmFluoride toothpaste

53

a

416

b

469

Unexposed 550 ppm Fluoride toothpaste

c

36

d

454 490

Total 89 870 959

Relative risk can be calculated for cohort data, that is, data from prospective longitudinal studies. Odds ratio can be calculated for case-control or cross-sectional data. Case-control data are obtained by selecting cases (fluorosis) and controls (no fluorosis) at a certain point in time. Cross-sectional data are obtained by determining the prevalence of fluorosis/no fluorosis in representative subjects at a certain point in time. Both methods estimate exposure/no exposure retrospectively. The odds ratio (OR) for these data is the odds that a case is exposed divided by the odds that the control is exposed:

[a/(a+c)÷c/(a+c)] [b/(b+d)÷d/(b+d)]

In this example: OR= 1.61 (95 % CI= 1.03;2.50)Note that the odds ratio (OR) is higher than the corresponding relative risk. This is a well-known observation; when the outcome becomes more frequent (fluorosis is relatively common in the example), the odds ratio tends to overestimate the relative risk [37].

The term “attributable risk” is sometimes used. It corresponds to the incidence in exposed minus the incidence in unexposed. In this example: 53/469 – 36/490= 0.04.

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Results from epidemiological studies are often presented as RR or OR (with confidence intervals) but without including the numerical data underlying the calculations. This can make it difficult to appraise the clinical relevance of a certain result. In the example above, the difference between the two interventions was statistically significant. The question is how relevant this difference is in practice. It is easy to be carried away by statistical calculations, particularly when numerical data are not presented.

Another matter of concern is the necessity to dichotomize exposure and outcome. For instance, changing the cut-off between “no fluorosis” versus “fluorosis” to “no or mild fluorosis” versus “moderate to severe fluorosis” may produce very different results. In this way, two reviews arrived at two different conclusions on the effect on fluorosis of using high versus low ppm fluoride toothpaste in young children, see page 10. Using different cut-offs based on the same original data led to either a significant or no significant difference in relative risk.

Benefits and risks of using fluoride - evidence from systematic reviewsCurrent knowledge on the benefits and risks of using fluoride has been summarized in systematic reviews [8-14, 38].

Water fluoridationQuestion: What are the effects of fluoride in water on the prevention of tooth decay and dental fluorosis? According to the systematic review by McDonagh [13], the prevalence of fluorosis at a water fluoride level of 1.0 ppm was estimated to be 48 percent and for fluorosis of aesthetic concern it was 12.5 percent. A later systematic review [8] included 20 studies on the effect of fluoridated water on tooth decay and 135 studies on dental fluorosis. The mean caries reduction was 1.81 in dmft and 1.16 in DMFT due to water fluoridation. The authors concluded that where the fluoride level in water is 0.7 ppm, there is a chance of about 12 percent of the population having dental fluorosis of aesthetic concern. Considering any level of fluorosis, the prevalence increased to 40 percent. For 1 ppm water fluoride level the figures were the same as those obtained by McDonagh. It should be noted that a majority of these studies were conducted before 1975 and the widespread introduction and use of fluoride toothpaste. Furthermore, most studies were considered to be at a high risk of bias and there was a substantial study variation. The authors concluded that they had limited confidence in the results and that there is very little contemporary evidence on the effectiveness of water fluoridation.

Comment on the review. The review does not discuss any relation to current guidance (mg fluoride/kg bodyweight/day).

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Topical fluorides/fluoride toothpasteQuestion: What is the relationship between the use of topical fluorides in young children and the risk of developing dental fluorosis?The primary objective of the review by Wong [11] was to describe the relationship between the use of topical fluorides in young children and the risk of developing dental fluorosis. The review was intended to include different topical fluoride therapies in the form of toothpastes, mouth rinses, gels, foams, paint-on solutions and varnishes. However, evidence generally focused on fluoride toothpastes. Importantly, this review is therefore about the use of toothpaste and its relationship to fluorosis. It is a Cochrane Review and as such quite unusual in that it includes not only RCTs (common in Cochrane reviews) but also case-control studies, cross-sectional- and cohort studies. This approach puts special requirements on the quality assessment of the studies. The review covered 25 studies, of which a were conducted in Europe, a third in the USA, 12 percent in Canada, 8 percent in Australia and the rest in Brazil, Mexico and India. About half were conducted in non-fluoridated areas. The prevalence of fluorosis was measured with the Thylstrup-Fejerskov Index in 14 studies, the Fluorosis Risk Index in five, the Tooth Surface Index of Fluorosis in three and the Deans Index in another three.

The following parameters were used for comparisons according to topical fluoride exposure:

1. Age at earliest use of fluoride toothpaste/toothbrushing: two RCTs, two case-control studies, nine cross-sectional surveys

2. Frequency of toothbrushing: four cross-sectional surveys3. Amount of fluoride toothpaste used: three cross-sectional surveys4. Fluoride level (ppm F) in toothpaste used: two RCTs, three cross-sectional surveys.

Results:1. Pooled estimates from four cross-sectional studies showed that starting to use fluoride

toothpaste before the age of 12 months was associated with risk of fluorosis. Pooled estimates from two case-control studies and five cross-sectional studies gave conflicting results regarding the effect of starting brushing with fluoride toothpaste before versus after 24 months of age.

2. Pooled estimates from the four cross-sectional studies showed no statistically significant association between toothbrushing frequency and fluorosis.

3. No statistically significant difference in effect was found between small/pea-sized versus medium to large/greater than pea-sized amounts of toothpaste.

4. Pooled estimates from two RCTs showed that a higher level of fluoride in the toothpaste was statistically significantly associated with an increase in fluorosis. The meta-analysis from pooling data from the three cross-sectional studies did not support the association between fluoride concentration of toothpaste used and fluorosis. The authors conclude that more evidence is needed to clarify this inconsistency.

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The prevalence of fluorosis ranged from 10 to 72 percent. The available evidence focused on mild fluorosis. Overall, the authors conclude that “there is weak, unreliable evidence that starting the use of fluoride toothpaste in children under the age of 12 months may be associated with an increased risk of fluorosis. The evidence for its use between the age of 12 and 24 months is equivocal.” The authors state that “if the risk of fluorosis is of concern, the fluoride level of toothpaste for young children (under 6 years of age) is recommended to be lower than 1000 ppm.” They also conclude that there should be a balanced consideration between the benefits of topical fluorides in caries prevention and the risk of the development of fluorosis.

Comments on the review. The choice of the study design as the basis for pooling studies in meta-analyses may seem reasonable. However, it also implies that studies with different interventions and therefore not always comparable were pooled in the same analysis. Thus, for example, two case-control studies [39, 40] were pooled and an odds ratio calculated although one of the studies was performed in a fluoridated area and the other was not. Furthermore, supplements were used from an early age in one study but not in the other.

One study used a longitudinal cohort design [41]. That study was not included in the data analyses but it does have a great advantage compared with the cross-sectional and case-control studies. It is a longitudinal cohort study where data on the use of topical fluorides were obtained from questionnaires when the children started to use fluoride toothpaste and other topical fluorides. These data are therefore not subject to the same risk of recall bias as the other studies. Albeit not without other limitations (i.e. the concentration of fluoride in the toothpaste is not reported), the results of this study should also be considered: the authors concluded that the risk of fluorosis was greatest for children who had used fluoride toothpaste at 24 months of age.

Another important comment on the review is that the exposures tested were age at starting to use fluoride toothpaste, fluoride concentration, amount of toothpaste used, and frequency of brushing. Notably, none of the identified and included studies had used children’s exposure to fluoride, measured as ingested mg F/kg bodyweight/day, as the risk factor for fluorosis. Thus, the appropriateness of the guidance that 0.05-0.07 mg F/kg bodyweight/day is “optimal” remained untested in these epidemiological studies. Ironically, what is perhaps the only prospective longitudinal study, the Iowa Fluoride Study [21], was not included in the review, the reason given being that “fluorosis in relation total fluoride was investigated, no data on topical fluoride exposure could be separated for analysis”.

The systematic review by Wright [12] did not add anything substantial to the knowledge obtained from Wong’s systematic review. One cross-sectional study published after Wong’s

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review concluded that early use of a pea-sized amount of 1000 ppm fluoride toothpaste once a day was not a significant fluorosis risk factor [42].

Fluoride supplementsQuestion: Does the use of fluoride supplements in children aged zero to 16 years prevent dental caries and increase the risk of dental fluorosis during the period of tooth development?Tablets, mouth-rinses, drops, lozenges are used both professionally and by parents/children. The systematic review by Ismail [9] included 20 studies. The authors concluded that the use of fluoride supplements during the first six years of life, and especially during the first three years, is associated with a significant increase in the risk of mild to moderate fluorosis.

Low versus standard ppm fluoride toothpasteWhat are the effects of low and standard fluoride toothpastes on the prevention of caries in primary teeth in preschool children in relation to moderate to severe fluorosis in permanent teeth?The effects on caries and fluorosis of low (<600) and standard (1000-1500) ppm fluoride toothpastes in pre-school children were investigated by Santos [10]. Based on three studies, low ppm fluoride toothpastes increased caries risk (RR=1.13 (95 % CI: 1.07-1.20). Based on two different studies, low fluoride toothpastes did not significantly reduce the risk of moderate to severe fluorosis in the upper anterior permanent teeth (RR= 0.32 (95 % CI: 0.03;2.97). The latter two studies are the same as those described in Wong’s systematic review [11, 36, 43]. Santos concluded that there is no evidence to support the use of low fluoride toothpastes in preschool children, regarding caries and fluorosis prevention.

Comments on the review. The results on the association between levels of fluoride in toothpastes and the occurrence of fluorosis differ from the results reported in Wong’s systematic review. Indeed, the latter review found the opposite: a higher level of fluoride in the toothpaste was significantly associated with fluorosis. This discrepancy arose because the reviews used different cut-offs for fluorosis. In Santos’ review, the cut-off was set at no or mild fluorosis versus moderate to severe fluorosis, whereas in Wong’s review it was set at no fluorosis versus any fluorosis.

Infant formula Question: What is the risk of developing dental fluorosis in children who are fed with formula compared with those fed with breast milk?The association between infant formula consumption and the risk of fluorosis was investigated by Hujoel [14]. On the basis of 17 studies (all but one was retrospective with possible recall bias), infant formula consumption was associated with a higher prevalence of fluorosis in the permanent dentition compared with breast milk (OR=1.8 (95 % CI=1.4-2.3). None of the studies reported information on the fluoride level in the infant formula measured at the time of

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consumption. Considering the significant heterogeneity between the studies, the authors concluded that summary odds ratio should be interpreted with caution.

Estimates of fluoride intake Total fluoride intake and its relation to fluorosisProspective longitudinal data from the Iowa Fluoride study (not included in the review by Wong) show that the mean fluoride intake from birth to 4 years of age ranged from 0.040 to 0.057 mg/kg bodyweight/day, with a higher intake in earlier times [21]. Twenty-four percent of the children had fluorosis (mild in almost all) at the age of nine. The first two years were the most important for the development of fluorosis in permanent maxillary central incisors although other individual years also played a part.

Fluoride in diet (water). The primary source of dietary fluoride is water; most foods and beverages without added water provide minimal fluoride [16]. Estimated fluoride intake from diet among 2-year-olds according to Pendrys & Stamm [44] is shown in Table 1.

Table 1. Estimated fluoride intake from diet (including water and beverages) among 2-year-olds.

Fluoride intake (mg) from diet/day

Assuming 1 ppm F in drinking water

Assuming 0 ppm F in drinking water

Mean (range) mg

0.6 (0.5-0.6) 0.3 (0.2-0.3)

Mean (range) in mg/kg bodyweight/day (13 kg)

0.046 (0.038-0.046) 0.023 (0.015-0.023)

Fluoride in tablets. The amount of ingested fluoride from tablets was calculated as a part of the FLINT project [45]. The data for 2–3-year-olds are given in Table 2.

Table 2. Amount of fluoride ingested from use of fluoride tablets recommended to 2–3-year-old children in seven European countries [45].

Fluoride intake from Tablets

Amount given to2–3-year-olds

Amount ingested(mg F/kg bodyweight/day)

0.25 - 0.75 mg/day 0.02-0.06(weight=13 kg)

Fluoride in toothpasteWhat fluoride concentration in toothpaste is safe and effective in children less than 6 years old?’

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Age when brushing commences, frequency of brushing, fluoride concentration and amount of toothpaste applied to the toothbrush and subsequently swallowed have all been implicated as potential fluorosis risk factors.

Toothpaste ingested. When used by young children, fluoride toothpaste is a potential risk factor for dental fluorosis although the research evidence to confirm this relationship is not strong. According to Ripa [46], young children brushing twice a day swallow on average 0.27 mg (0.25-0.50) mg fluoride using a standard strength toothpaste (1000 ppm F). The author concludes that “although use of a fluoride dentifrice can add to the total daily amount of ingested fluoride in preschool children, there is little evidence to suggest that dentifrice ingestion is a principal factor causing the fluorosis increase”. Because of the potential to contribute to fluorosis, toothpastes containing less than 1000 ppm F has been introduced and tested. According to a systematic review by Walsh [38] there is, however, considerable uncertainty as to the caries preventive effect of 440/500/550 ppm fluoride toothpastes. According to this review “the results support the international standard level of 1000 ppm fluoride for younger children”.

The pea-sized amount of toothpaste was introduced in the late 1980s and is now commonly recommended for preschool children. Using pea-sized reduces the amount of toothpaste being swallowed. The rationale behind the pea-sized amount is that it is the concentration of fluoride, not the amount of toothpaste that is critical for preventing caries [47, 48].

Governments can regulate the concentration of fluoride in a dentifrice but not the amount individuals dispense in everyday use. For young children, a “pea-sized amount” is generally recommended but there appears to be little guidance regarding what this means in practice, although it has been indicated to be 0.25 g. Understanding how much dentifrice is dispensed to young children by their parents or caretaker is therefore critical to understanding the child´s exposure to fluoride, for both positive and negative effects. So, what is a pea sized amount? More specifically, do parents or caretakers in practice interpret a pea-sized amount as being close to the 0.25 g anticipated in regulatory authority guidance?

In a study by Creeth [49], the majority of parents in Germany, UK and USA dosed substantially more than 0.25 g for their 3- to 6-year-old children. The mean values were 0.4 g for UK and USA parents and 0.6 g for German parents, Table 3.

Table 3. Young children’s exposure to fluoride from toothpaste, based on data from Creeth [49]. It is assumed that a 2-year-old weighs 13 kg and a 3-year-old 15 kg.

Amount of Percent Amount of 2-year-old: 3-year-old:

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toothpaste used (per brushing)

toothpaste swallowed*

toothpaste ingested in brushing twice/day**

mg F ingested using a 1000 ppm F toothpaste

mg F ingested using a1000 ppm F toothpaste

Child´s toothbrush,“normal” dispensing**

0.5 -1 g (mean 0.6 g)

50 %

0.5 -1 g (mean 0.6 g)

0.5 -1 mg/13 kg= 0.04-0.08 mg/kg bodyweight

0.5-1 mg/15 kg= 0.03-0.07 mg/kg bodyweight

Child´s toothbrush, pea-sized dispensing***

0.4 -0.6 g (mean values)

0.4-0.6 g 0.4-0.6 mg/13 kg= 0.03-0.05 mg/kg bodyweight

0.4-0.6 mg/15 kg= 0.03-0.04 mg/kg bodyweight

*assuming the child swallows half the amount of the toothpaste.** Parents´ use before explanation of the recommendation of the pea-sized amount.*** Parent´s use according to their perception of a pea-size

The children involved in this study were 3-6 years old. It is assumed that the parents would have used the same amount of toothpaste for a 2-yr-old child. It can be seen from the table that if a 1000 ppm fluoride toothpaste was used for children aged two years and assuming that the child swallowed half of it, the amounts being ingested are within the limits of the proposed guidelines (0.05-0.07 mg/kg bodyweight/day). Overdosing to 1 g of toothpaste resulted, however, in 0.08 mg/kg bodyweight/day, which is above the recommended limit.

Toothpaste swallowed. A recent study involving children from seven European countries showed that 1.5- to 2.5-year-old children swallowed an estimated average of 64 percent to 84 percent of the toothpaste dispensed [35]. This corresponded to a mean amount ingested of 0.01-0.03 mg/kg bodyweight/day.

Toothpaste retained. Another matter of concern is the amount of toothpaste left on the brush after toothbrushing. According to van Loveren [50], on average 22 percent of the fluoride dispersed on the toothbrush was retained on the brush after brushing. Furthermore, rinsing and/or spitting during toothbrushing significantly reduced the amount ingested; the total amount of fluoride recovered (on the toothbrush and in rinse/spit) amounted to 36.5 % ±16.2 % of the fluoride originally placed on the brush.

Bioavailability. Another factor that is difficult to control for is the bioavailability of fluoride, depending on the gastric content at the time of ingestion. It has been calculated that ingesting fluoride on an empty stomach doubles the amount of bioavailable fluoride, which means that fluoride bioavailability from a 1100 ppm toothpaste ingested after eating can be very similar to that of a 550 ppm toothpaste ingested on fasting [17].

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Published data on total fluoride intake for children are sparse. Pendrys & Stamm [44] produced estimates of total fluoride intake by using previously published data related to US children. They noted a considerable variation in fluoride intake among 2-year-old children. These estimates, related to fluoride content in drinking water, are given in Table 4.

Table 4. Estimates of fluoride intake from diet, fluoride supplements, fluoride toothpastes and total intake among 2-year-old children. Adapted from data by Pendrys & Stamm [44] . It is assumed that a 2-year-old weighs 13 kg.

Fluoride intake Assuming 1 ppm F in drinking water

Assuming 0 ppm F in drinking water

Mean (mg F/kg bodyweight/day),(range)

Diet (including water and beverages)

0.046(0.038-0.046)

0.023(0.015-0.023)

Dietary fluoride supplements

0.038(0.038)

Fluoride toothpaste1000 ppm

0.023(0-0.154)

0.023(0-0.154)

Total intake 0.069(0.038-0.20)

0.084(0.054-0.215)

Another example comes from a more recent study by de Almeida [51], who measured fluoride intake among 1–3- year- old children in a fluoridated area in Brazil where children’s toothpaste is relatively expensive, so that children used the family toothpaste (1500 ppm F). The data are shown in Table 5.

Table 5. Measured fluoride intake from diet and fluoride toothpaste among 1–3-year-old Brazilian children. Data from de Almeida [51].

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Fluoride intake

0.6 – 0.8 ppm F in drinking water

Mean (mg F/kg bodyweight/day) (range)

Diet (including water and beverages)

0.025(0.003-0.070)

Fluoride toothpaste1500 ppm

0.106(0.004 - 0.401)

Total intake 0.130(0.027 - 0.413)

The data from de Almeida show relatively high amounts of total fluoride intake. Interestingly, the prevalence of fluorosis from another group of children in the same area showed that while 36 percent had fluorosis, only 8 percent had a score of 2–4 according to the Fejerskov & Thylstrup index [52].

Although the data from the above examples may not apply to other populations, they illustrate the potentially wide variations in exposure and the considerable variation in the amount of ingested fluoride. The number of factors that may influence ingestion and bioavailability of fluoride further illustrates the complexity of fluoride intake. Wide variations in exposure were also observed in the Iowa Fluoride Study [21]. This emphasizes the necessity of further well designed prospective epidemiological studies with representative and sufficiently large samples from both fluoridated and non-fluoridated areas. It also points to the crucial importance of opinions in general about what level of fluorosis is acceptable to the public.

Perceptions on fluorosis among children and parentsA reasonable balance has to be established between adequate fluoride use for caries prevention and limiting its use to avoid the risk of aesthetically disturbing dental fluorosis. That balance may differ between populations and countries. A matter of concern is the opinion of parents and children about mild fluorosis. Chankanka [15] reviewed the literature on the perceptions of aesthetic appearance and dental fluorosis among children and parents. None of the 35 included studies reported negative effects of very mild to mild fluorosis, whereas severe fluorosis had a negative effect on oral-health-related quality of life. The authors conclude that efforts should focus primarily on the appropriate use of fluorides for caries prevention and preventing moderate/severe fluorosis.

Are changes to lower or upper limits of current guidance desirable? Recent epidemiological data from two Nordic countries

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In the Nordic countries, public dental awareness is high, fluoride toothpaste is widely available and widely used. To my knowledge, mild dental fluorosis is not an important issue (for either the public or the profession), at least not on a national level and not at present. A cross-sectional survey on the prevalence of fluorosis was made in a non-fluoridated city in Sweden in 2005 [53]. The Thylstrup &Fejerskov criteria were used to assess to presence and severity of dental fluorosis. While there were low levels of dental fluorosis of esthetic concern (4 %), about half of the children had some degree of dental fluorosis. Most children had their teeth brushed twice a day with a 1000 ppm toothpaste from the time of the first deciduous tooth eruption. Parents reported having used a pea-sized or smear amount of toothpaste. Some use (mostly sporadic) of fluoride tablets was reported. While there is some risk of recall bias, the use of a 1000 ppm fluoride toothpaste is probably correct since there has been a longstanding recommendation in Sweden to use a pea-sized amount of such toothpaste from the time of eruption of the first tooth. Although we know nothing about these children’s exposure in terms of mg/kg bodyweight/day, it seems likely that some overdosing occurred in early infancy. The results are probably quite representative of child populations in Sweden and perhaps in the other Nordic countries. The results indicate that early use of 1000 ppm F toothpaste increases the risk of developing fluorosis, albeit mostly mild.

Another cross-sectional survey from a non-fluoridated city in Norway used the Fluorosis Risk Index (FRI) to measure fluorosis [42]. The history of fluoride exposure showed that most parents had started to use fluoride toothpaste (1000 ppm F) during the first 24 months and about two thirds stated that they had used a pea-sized amount. Twenty percent of the children had received fluoride supplements on a regular basis from birth to 72 months of age. The results showed that the risk of developing mild to moderate fluorosis was low. No children who had exclusively used a pea-sized amount of toothpaste had fluorosis of aesthetic concern (mild to moderate fluorosis according to the FRI index). Regular use of fluoride supplements and early use of more than a pea-sized amount of toothpaste increased the risk of developing fluorosis.

Both studies are retrospective and neither of them estimated fluoride exposure in terms of mg/kg bodyweight/day. They are therefore not very useful for considering any change in current guidance. They do indicate, however, that early use of a 1000 ppm fluoride toothpaste (supposedly pea-sized amount) rarely results in fluorosis of aesthetic concern in non-fluoridated areas. These data may also indicate that the upper limit of the present guidance (0.07 mg/kg bodyweight/ day) may be too strict.

The Iowa Fluoride Study

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The suggestion that the proposed guidance represented the “optimal” fluoride intake level was never based on any direct assessment of how such intake was related to the occurrence or severity of dental caries and/or dental fluorosis and the term “optimal” seems problematic [15]. Thus, data from the Iowa Fluoride Study show that children with neither caries nor fluorosis at the age of nine had been exposed to fluoride levels less than 0.05 mg F/kg bodyweight at virtually all time points from 12 to 72 months of age. Furthermore, many children without caries or fluorosis exceeded the 0.05-0.07 mg/kg bodyweight optimal range at each time point from 0 to 72 months of age. There was also a considerable individual variation in fluoride intake. It should be noted that these children were not representative of “any defined population” since those who remained in the study until the age of nine tended to be from higher income families than those dropped out. There were also missing data, so reported means were based on variable numbers for each time point. Furthermore, concentrations and amounts of fluoride ingestion from mouth-rinses and gels or professional fluoride applications were not assessed. Nevertheless, these results illustrate the complexity of fluoride exposure and ingestion, and that we have to accept considerable individual variations. Even with more data from further epidemiological studies, we will face a challenge when trying to find a better guidance with other than the present lower and/or upper limits.

What would be needed to consider changes in current guidance?– More knowledge on the relationship between fluoride exposure and the prevalence of

mild versus moderate/severe fluorosis, from representative populations of children in communities with and without water fluoridation and from populations where salt or milk fluoridation is used.

– Professional agreement on acceptable levels of mild and moderate/severe fluorosis.– More comprehensive knowledge on the appreciation of mild fluorosis among the public

(children and parents).

Should guidance be age-specific? The rationale for an age-specific guidance (mg/kg bodyweight/day) would be to lower the risk of subsequent fluorosis during the first 2–3 years of life by restricting the use of fluorides from all sources (e.g. toothpaste, supplements, water). Based on current knowledge and the wide variations observed in estimated fluoride intake among young children, it is not feasible to suggest changes in current guidance.

Gaps in knowledge - recommendations for research Prospective cohort studies with representative and sufficiently large samples are necessary to further clarify the relationship between exposure to fluoride at an early age and the development of fluorosis. The STROBE guidelines [54] for observational studies should be

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followed. Agreement on how to present data from such studies would facilitate comparisons of results from different studies. The following is important:

Measure/estimate total fluoride intake in children from birth to 3-4 years of age and growing up with fluoridated or non-fluoridated water. Measures/estimates should be made at regular intervals and be related to:

– The effect of using low-fluoride toothpaste (≤500 ppm) versus 1000 -1100 ppm fluoride toothpaste in children before the age of 24-30 months on the risk of developing fluorosis and caries. Comparisons should be made in relation to fluoride in water supply.

– The effect of starting to use 1000 -1100 ppm fluoride toothpaste before versus after 24-30 months of age on the risk of developing fluorosis and caries. Comparisons should be made in relation to fluoride in water supply.

The public´s opinion about mild to moderate fluorosis in relation to the gain in dental health or, in other words, the society´s tolerance level and perceptions of mild to moderate fluorosis.

Urinary fluoride levels measured regularly in randomly selected subsamples to a) control that ingested fluoride is kept within proper limits, b) relate the outcome (occurrence of fluorosis) to measured urinary fluoride levels, and c) explore a possible relationship between urinary fluoride levels and severity of dental fluorosis.

Develop more timely methods for measuring total fluoride exposure. Methods such as fingernail analysis are being tested [51]. Research in these areas could result in the development of simpler, valid and reliable techniques to monitor total fluoride exposure in children.

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ConclusionsPresent knowledge is not sufficient to decide whether or not current guidance regarding exposure to fluoride (0.05-0.07 mg F/kg bodyweight/day) is appropriate. For that, prospective epidemiological studies with sufficiently large and representative samples of children are required.

Available evidence from epidemiological studies indicates that guidance on the use of fluorides (for balancing the benefits and risks) should be age-specific. Whether the limits for total fluoride intake (mg/kg bodyweight/day) should be changed in this respect has still to be evaluated.

Any change in current guidance has to take into account aesthetic issues, that is, children’s/parents´ perception of mild fluorosis. Furthermore, the occurrence of moderate/severe fluorosis cannot be completely ruled out whatever guidance is chosen. Therefore, the profession and the public must decide on a reasonable balance between the benefit of preventing caries and the risk of fluorosis. Such a balance may differ between populations.

Overall, current guidance (0.05-0.07 mg/kg bodyweight/day) may be debatable. It is, however, an established guidance and available knowledge cannot justify a change.

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