Fluoride History

Early efforts to incorporate fluoride into dental preparations as well as research towards understanding the fluoride content of teeth gave conflicting results. A phenomenon called "Brown Stain", associated with too much fluoride ingestion, was thought to be "typical caries" in a paper presented in 1904 before the German Society for Surgery.¹⁰ Mckay and Black investigated what had been termed Colorado Brown Stain as early as 1916. They found that this stain was present in other communities and associated it with the communal water supply, although they were not certain of the cause.¹⁰ These and other findings led the United States Public Health Service to do extensive epidemiological surveys to study both dental caries and dental fluorosis in the late 1930s.¹¹ When it was confirmed that fluoride intake from water was associated with the prevalence of dental fluorosis as well as a reduction in dental caries, many delivery systems and strategies were investigated to optimize the benefit of fluorides at the community level as well as the individual level.

In 1937, a dental preparation claiming to prevent decay was not favorably looked upon by the American Dental Association's (ADA) Council on Dental Therapeutics. The possibility of toxicity, conditions of usage and absorption questions led to the ADA's conclusion that "The use of fluoride in dentifrices is unscientific and irrational, and therefore should not be permitted."⁶ At that time, dental problems were considered to be a personal matter. The finding that the single greatest reason for rejecting people from the military in World War II was a result of poor oral health changed this sentiment. Very quickly, oral health became a national security issue and was recognized as a public health problem. Studies in which the water supply of cities was artificially fluoridated were done in order to determine potential effectiveness of such a measure. Initial studies were placed in Grand Rapids, MI in 1945, with Muskegon, MI acting as the control city. Other sister city studies work also begun around that same time. The overall results demonstrated a significant reduction in dental caries without cosmetically displeasing dental fluorosis, when the fluoride concentration in the local water supply was maintained at about 1 ppm.¹⁰

In 2021, researchers in Canada published a study about the effect of stopping water fluoridation on children's dental caries in the cities of Calgary, where fluoridation began in 1991 and stopped in 2011, and Edmonton, which has fluoridated its water since 1967. After testing children some 7 to 8 years after Calgary stopped fluoridating its water, researchers said the prevalence of caries was significantly higher there than in Edmonton, “[pointing] to the need for universal, publicly funded prevention activities—including, but not limited to, fluoridation.”¹²

Successfully formulating a fluoride dentifrice that was efficacious against caries was a significant oral health breakthrough because fluoride is incompatible with many ingredients or additives. In 1950, The Procter & Gamble Company formed a joint research project team headed by Dr. Joseph Muhler at Indiana University to develop and test a new dentifrice with fluoride. Results from a clinical study of this dentifrice indicated that children ages six to 16 showed an average 49% reduction in cavities, and adults showed tooth decay reduction to almost the same degree.^17,18 Interestingly, a market survey in 1958 showed the response to a therapeutic dentifrice had had little effect on market shares. It wasn't until Crest was granted the American Dental Association (ADA) Seal of Acceptance that it was able to set itself apart from all other toothpastes. A total of over 40 clinical trials had been conducted with the original stannous fluoride that have verified its efficacy. The combined importance of ADA acceptance plus no comparable therapeutic rival gave the Crest brand a chance to become a market leader. Following the success of this study, Crest^® with Fluoristan^® dentifrice launched into a number of test markets in 1955, followed by national expansion in January 1956. In 1960, and again in 1964, the American Dental Association confirmed that Crest effectively prevents tooth decay, reporting that “Crest has been shown to be an effective anticavity dentifrice that can be of significant value when used in a conscientiously applied program of oral hygiene and regular professional care” in granting its Seal of Acceptance (Figure 2).^19,20

In 1969, Colgate received endorsement for a therapeutic dentifrice. This shifted the category of toothpastes from delivering merely cosmetic benefits to those focused on more therapeutic benefits, and the entire market began to evolve. In 1976, the American Chemical Society recognized Crest^® with Fluoristan^® as one of the 100 greatest discoveries of the previous 100 years.²¹

Figure 2. Original Crest toothpaste, with the ADA Seal of Acceptance.

Figure 2. Original Crest toothpaste, with the ADA Seal of Acceptance.

One of the basic tenants of dentifrice is to contribute to cleaning efficacy. The desire to find more effective dentifrices with high compatibility between the fluoride active and different abrasive systems spurred continued research in the development of therapeutic dentifrices. After the success achieved with SnF₂ dentifrices, sodium monofluorophosphate (SMFP, Na₂FPO₃) (Figure 3) new dentifrices were eventually introduced with compatible abrasive systems, and the combinations demonstrated positive caries benefits in most clinical studies. The search for a more stable formulation capable of providing even greater anticaries effectiveness also led to the introduction of a sodium fluoride (NaF) formulation, which eventually replaced the original stannous fluoride (SnF₂) active ingredient. This new product used the advertising phrase of "Fluoristat^®" and combined NaF with a silica abrasive system that proved more effective against caries than the earlier "Fluoristan^®" formulation. This change in active agents occurred in 1981, after silica abrasive systems were developed that were compatible with most of the active agents found in dentifrices.³⁷ All of the fluoride actives have been shown to be successful, to some extent, in preventing dental caries when used in a regular program of oral hygiene. The highly competitive toothpaste market has been a factor in the research development of the chemistry to deliver a more effective product as well as improving flavor and increasing worldwide usage. This has been a great benefit to public dental health, as evidenced by the decline in the prevalence of dental caries over the past several decades in most developed countries.³⁸

Figure 3. Fluoride is the active ingredient in most dentifrices that is providing caries therapeutic benefits. The carrier fluoride molecule varies.

Figure 3. Fluoride is the active ingredient in most dentifrices that is providing caries therapeutic benefits. The carrier fluoride molecule varies.

The predominance of NaF and SMFP (Na₂FPO₃) as the active agents in most toothpastes during this time also led to the inevitable question "Are all fluoride dentifrices the same?" This question was addressed by Stookey in 1985 after a review of over 140 articles on fluoride dentifrices.³⁹ It was found that a number of dentifrices with various active ingredients (NaF, SnF₂, AmF and Na₂FPO₃) and abrasive system combinations provided significant cariostatic benefits.

The major fluoride sources approved for use in the US are stannous fluoride (SnF₂), sodium fluoride (NaF) and sodium monofluorophosphate (Na₂FPO₃). During use, NaF and SnF₂ dissociate to provide the free fluoride ion and the companion cation. The Sn cation may have some interactions on its own, although the primary effects on caries are generally associated with the fluoride component. For Na₂FPO₃, the fluoride source is in a different chemical form and requires enzymatic hydrolysis to cleave the covalent bond between the phosphate molecule and fluoride yielding slower fluoride release. Studies of SMFP have shown it is compatible with a broader range of dentifrice abrasives, but it may differ in its mode of action from the fluoride ion.

In 1999, the US Center for Disease Control (CDC) issued a statement that water fluoridation is one of the 10 most important public health measures of the 20th century.⁷ Fluoride’s presence in low concentration and high frequency is more effective at preventing caries than high levels of fluoride used in low frequency. Because water fluoridation is not available in many countries, dentifrice is considered to be one of the most important sources of fluoride globally.⁸ Common environmental sources of fluoride are depicted in (Figure 4).^4,15,16

Figure 4. Fluoride Sources. There are several common environmental sources of fluoride, including fluoridated drinking water and oral health care products.

Figure 4. Fluoride Sources. There are several common environmental sources of fluoride, including fluoridated drinking water and oral health care products.

While the popularity of non-fluoridated or fluoride alternatives toothpastes are on the rise, there are none that have demonstrated the breadth of clinical efficacy for caries prevention as Fluoride has, otherwise the FDA and other regulatory bodies would recognize them as therapeutic.

Although fluoride dentifrices and improved oral health have greatly benefited the population by reducing caries incidence, surveys showed a continued high prevalence of gingivitis and gingival recession among adults.⁴⁹ The desire to treat both caries and gingivitis, coupled with the changing patterns in oral health and the recognition of the importance of oral health in relation to systemic disease, led to extensive research by the Procter & Gamble laboratories and the "return" to stannous fluoride as an active ingredient. This required the development of a stabilized formulation that would provide sufficient stannous fluoride activity to provide the anti-gingivitis inflammatory benefit and sufficient reserves of the active fluoride to provide a caries benefit. The stabilization system developed used sodium gluconate as a chelating agent to protect SnF₂ from hydrolysis. Stannous chloride was also included as an antioxidant to protect SnF₂ from oxidation and as a stannous reservoir to reduce the SnF₂ loss onto the abrasive. The broad range of beneficial aspects of stannous fluoride, such as dentin desensitization, root surface reactivity, plaque and gingivitis benefits as well as its anticaries effectiveness strongly suggested that this unique active could be the basis for many future improvements in dentifrice formulations.^42-52 Thus, the active agents most readily available in the US market once again included SnF₂ as well as NaF and Na₂FPO₃.

Figure 5. Timeline evolution of commercially available dentifrice

Figure 5. Timeline evolution of commercially available dentifrice

Another product innovation that helped shape the market for years came from the public's desire for whiter teeth. Whitening agents were available in the dental office but not in the drugstore as an over-the-counter product. One of the first claims was the removal of extrinsic stains by existing tartar control agents. These formulas were optimized and tested for stain removal as well as tartar control. Intrinsic stains normally required the use of peroxides or carbamides which have the ability to bleach the teeth and increase "whiteness." Crest Whitestrips marked the advent of consumer applied whitening agents and allowed the individual to brighten their smile at home.⁴⁰ Dentifrice manufacturers were also aware of this public interest in a cosmetic benefit of oral health products and improved formulations for stain removal, stain prevention, tartar reduction, and whitening all became available in the marketplace. This cosmetic benefit has been a continuing focus in oral care product development since the late 1990s. The whitening effect encompasses the original cleaning function of dentifrices, such as tartar and stain removal, but may also include intrinsic stain removal agents.

As oral care products continue to evolve, we can expect to see even more interesting combinations and approaches in the future, with each iteration intended to deliver either enhanced performance or an increased number of overall oral care benefits. While some of these future products may come from unique combinations of ingredients currently in use, others may include ingredients that are completely new to oral care products. In addition, according to monograph, a product can't have 2 ingredients for the same therapeutic benefit (e.g., no fluoride combinations for caries prevention).