Exposure to fluoride and risk of primary bone cancer: A systematic review.

Primary bone cancers are a group of aggressive malignant tumours arising in bone or cartilage, derived from primitive mesenchymal cells [1]. The most common malignant bone cancer subtypes include osteosarcoma (OS) accounting for 20–40% of all bone cancers, Ewing’s sarcoma (ES)<20% of all bone cancers, and Chondrosarcoma (CS) which varies ranging from <10% to >45% of all bone cancers, with <10% observed in India and Saudi Arabia, and >45% observed in Finland and Netherlands [2,3].

Few risk factors have been established but a predilection towards males has been identified on OS and ES [4]. Although some molecular characteristics have been studied, their mechanisms remain unclear [5], however, an increased risk in their development has been linked to certain heritable syndromes, such as Paget’s disease, Li-Fraumeni syndrome, and heritable retinoblastoma [6]. In addition, ionizing radiation exposure from prior cancer treatment, and exposure to environmental chemicals such as phenoxyacetic acid and chlorophenols found in herbicides and wood treatments, have been identified as potential risk factors [7]. Whether fluoride exposure is associated with an increased risk of developing bone cancers remains inconclusive [8].

To date, two systematic reviews have been conducted, investigating the safety and efficacy of fluoridation, both of which included evaluations on the effect of fluoridation on osteosarcoma and bone cancer, reporting no clear evidence of potential adverse effects from fluoridation [9,10]. Neither review was able to formally aggregate the results of their analysis on the association of cancers and fluoridation due to the varying outcome measures used by the included studies, limiting the statistical power of the systematic reviews, with both studies concluding no clear association was apparent between water fluoridation and osteosarcoma incidence and mortality. Both studies evaluated the effects of fluoride on dental caries, dental fluorosis, bone fracture, cancer, and other negative effects. However, the McDonagh review only considered water fluoridation as an exposure, while the study by Yeung and team included fluoride from multiple sources such as milk, salt, and topical supplementation [9,10]. This systematic review will include studies that have investigated any source of fluoride where the participants were investigated for primary bone cancer.

Since the establishment of water fluoridation programs in 1964, various Community Water Fluoridation (CWF) strategies have become a cost-effective public health success in the prevention of dental caries, and are now widely employed as a method to regulate fluoride levels in public water supplies (PWS) [11]. The role of CWF strategies is to prevent the development of caries in children and adults, regardless of socioeconomic status [12]. This public health strategy has led to CWF being labelled as one of the 10 greatest health achievements of the 20th century [13]. A review of the economic evaluations of water fluoridation was carried out by Mariño and Zaror [14], confirming the success of CWF was a cost-effective strategy and an appropriate use of community resources. Due to the detrimental effect of excessive fluoride exposure, such as dental and skeletal fluorosis [15,16], water fluoridation levels within PWS should not exceed 1.5 mg/L, as recommended by the World Health Organization (WHO) [17].

Within the UK, many areas’ PWS naturally contain 1 mg/L of fluoride, and the government endorses artificial fluoridation programs for those that fall below this level [18], however, a study conducted by Blakey et al. [19] suggests that up to a third of areas within the UK are currently supplied with artificially fluoridated water are below 0.7 mg/L, which is considered the lower limit of the optimal range for dental health benefits. In 1990 the public interest in the effects of fluoridation were renewed by a sodium fluoride water dosing study carried out by the National Toxicology Program NTP [20]. The study found that of the 130 male rats given 100 mg/L and 175 mg/L of fluoride, 4 developed OS, suggesting an equivocal link between fluoride ingestion and OS development. However, prior to the report by NTP being finalised [20], a two-year carcinogenicity study of sodium fluoride in male rats was conducted by Maurer et al. [21] to determine if long-term exposure induced cancer. The study, which assessed male rats on low fluoride diets, supplements with either 4/10/25 mg/kg per day sodium fluoride found that although fluoride toxicity was evident in the teeth and bones, the incidence of cancer did not increase. The authors concluded that sodium fluoride does not have a carcinogenic effect, even when administered at doses much higher than those typically found in humans.

In 2006, the USA’s National Academies released a National Research Council (NRC) report at the request of the Environmental Protection Agency (EPA) to evaluate their maximum contaminant level goal (MCLG) and secondary maximum contaminant goal (SMCL) for fluoride in drinking water [22]. The report reviewed the pharmacokinetics, adverse organ effects, genotoxicity, and carcinogenicity of fluoride exposure. The committee concluded that the current MCLG of 4 mg/L should be lowered, citing that excessive fluoride causes dental fluorosis in children and may not protect against fractures. Furthermore, the committee found that existing literature could not definitively classify fluoride as carcinogenic or non-carcinogenic in humans, noting that recommendations for individual-based cancer studies from the NRC’s 1993 report have only been partially fulfilled. While the use of cancer registries to ascertain cases was considered a strength of the included studies, the committee identified ecological studies as a weakness due to potential biases and poor adjustment for covariates.

While the body of evidence identifying the negative effects that excessive fluoride exposure has on dental health and skeletal fluorosis is well-recognised [15,16], the link between fluoridation and bone cancer development remains inconclusive [10]. The most recent systematic review addressing this association was published over a decade ago, and, with new studies published investigating the link between fluoride and bone cancer, there is a need for an up-to-date systematic review of this specific topic. Therefore, the focus of this systematic review was to analyse the literature reporting the relationship between fluoride exposure, emanating from topical or systemic origins, and the potential risk for the development of primary bone cancers.