Autism spectrum disorder (ASD) covers a range of heterogeneous neurodevelopmental conditions, characterized by persistent deficits in social and communication interactions and presenting with repetitive, stereotypic interests and behaviors. ASD incorporates autistic disorder, Asperger’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified [1
]. The word autism is traditionally used interchangeably with ASD. ASD begins early in childhood and tends to persist into adolescence and adulthood.
ASD is the fastest-growing developmental disability in the last two decades in all countries over the world. While in the period 1960–1989 autism was a rare disease with one to four per 10,000 in both Europe and America, the WHO estimates that 62 per 10,000 children (one in 160) in the world have ASD currently [2
]. The rise in the ASD rate has sparked fears of an ASD epidemic, mainly in the United States (US). In US children aged 3–17 years, the estimated prevalence of ASD diagnosis, based on parental reports, is one in 40 [5
Understanding of the ASD etiopathogenesis is therefore urgently warranted to find an effective prevention. A consensus suggests that the ASD etiopathogenesis is presumably multifactorial and results from very complex interactions between genetic and environmental factors [6
]. The high ASD prevalence has been reported from countries with artificial water fluoridation as well as from countries with endemic fluorosis areas [7
]. On the contrary, a lower ASD prevalence has been reported from some member states of the European Union (EU) [8
], where water fluoridation was banned in the 1970s–1990s. Therefore, in our previous papers, we suggested that fluoride (F) might be among the key environmental factors in the ASD etiopathogenesis [7
]. F is not currently recognized as a causative culprit of ASD, since its neurotoxic effects are not generally accepted. We assessed the risks of chronic F exposure in the ASD etiopathology regarding the F-induced effects on metabolism and mitochondrial dysfunction, oxidative stress and inflammation, immunoexcitotoxicity, and melatonin levels. Such effects have all been observed in people with ASD. Our review aims to provide evidence of F neurotoxicity. Moreover, F in the synergistic action with aluminum’s free cation (Al3+
) in molecules of aluminofluoride complexes can trigger various metabolic and pathological symptoms. This triggering takes place at F concentrations several times lower than F acting alone [12
Fluoridation of drinking water in addition to the extensive use of F in medicine and industry, started the era of supplementation of the living environment with these ions as never before in the history. It must be pointed out that F does not have any known essential function in human physiology and development. No signs of F deficiency have been identified [15
3. Fluoride as an Environmental Neurotoxin in the ASD Etiopathogenesis
Research into environmental risk factors for ASD has risen dramatically. According to recent evidence, up to 40%–50% of the variance in ASD liability might be determined by new ecotoxicological factors [6
]. How these toxicant exposures may contribute to ASD remains a significant knowledge gap. According to a report by UNICEF in December 1999, fluorosis is endemic in at least 25 countries, such as China and India, Indonesia, South Africa, Iran, and others [50
F has been linked to neurological and psychiatric disturbances since the 1930s [51
]. A sharp decline in mental activity, memory impairment, difficulties with concentration and thinking, and reduced ability to write were observed in aluminum smelter workers and persons living near a factory where F was in high concentrations in the atmosphere [52
]. A review of medical evidence in 500 people affected by chronic F intake from artificially fluoridated water appeared in 1977 [53
]. The authors made a list of the clinical features, such as chronic fatigue, headaches, loss of mental acuity and the ability to concentrate, depression, a diminished ability to focus, gastrointestinal symptoms and deterioration of muscular coordination. Carlson’s concerns about what increased F levels would do to the developing brain of newborn infants [54
] led to the refusal of water fluoridation in most of the European countries. A comprehensive historical review and over 50 papers regarding F neurotoxicity have been provided in the e-book Fluoride Fatigue [51
The surprising observation brought the study of behavior and brain F levels in rats after sodium fluoride (NaF) exposures during late gestation, at weaning, and in adults [55
]. Rats exposed prenatally had dispersed behaviors typical of hyperactivity, whereas rats exposed as adults displayed behavior-specific changes typical of cognitive deficits. The accumulations of F were found in all the regions of the brain, with the highest levels in the hippocampus.
Most of the evidence of F as a developmental neurotoxin in humans has been gathered in China. A study [56
] revealed adverse effects of F on the brains of 15 aborted fetuses between five and eight months of gestation from an endemic fluorosis area compared with those from a non-endemic area. This study showed poor differentiation of brain nerve cells and delayed brain development. Purkinje cells of fetuses from the endemic fluorosis area were abnormally disorganized, and a higher nucleus-cytoplasm ratio was observed in brain cones and hippocampus cones. F passing through the placenta of mothers with chronic fluorosis and its accumulation within the brain of the fetus impact the developing central nervous system. A meta-analysis of 16 studies carried out in China between 1998 and 2008 found that children living in an area with a high fluorosis occurrence have five times higher odds of developing a statistically lower IQ than those who live in a low F level area [57
Choi et al. [58
] performed a systematic review and meta-analysis of 27 studies published over 22 years. The authors investigate the effects of increased F exposure and delayed neurobehavioral development of children in China and Iran. Their results revealed the adverse effects of F exposures on children’s neurodevelopment, its potential neurotoxicity, particularly during fetal development and early childhood. These meta-analyses suggest an inverse association between high F exposure and children’s intelligence. From the geographic distribution of the studies, the authors concluded that it seems unlikely that F-attributed neurotoxicity could be attributable to other water contaminants [58
]. Based on this study, F was included among the most important developmental neurotoxicants [59
]. F differs from most of the current environmental chemicals with impacts on children’s intellectual development in that children are intentionally exposed to it because of its role in the prevention of caries.
The effect of chronic F exposure on children’s intelligence, measured as intelligence quotient (IQ), has been traditionally investigated as an indication of the neurotoxic effect of F in various geographical areas. Over 40 studies published in China, Iran, India, and Mexico found an association between lowered IQ and exposure to F [60
]. The strength of association between higher F concentrations in the water and children’s reduced intelligence was further supported by a dose-response meta-analysis [65
]. These authors evaluated 26 studies of 7258 children and suggested that exposure to F in water should be controlled in areas with high F levels in the water.
The effects of prenatal F exposure and development of children´s cognitive abilities were followed in 299 Mexican mother–children pairs of the Early Life Exposures to Environmental Toxicants birth cohort study [66
]. The children’s cognitive ability was evaluated at four years of age using the McCarthy Scales of Children’s Abilities and at 6–12 years of age. Children completed an IQ assessment and provided urine samples for biochemical investigation. Higher levels of F in mothers’ urine during pregnancy were associated with lower cognitive and IQ scores in their children. The authors estimated that each 0.5 mg F/L increase in maternal urinary concentration was associated with an average decrease of 3.15 and 2.50 points in cognitive and IQ scores, respectively.
The prospective multicenter birth cohort study included 601 mother–child pairs recruited from six major cities in Canada [67
]. Children were born between 2008 and 2012, and 41% lived in communities supplied with fluoridated municipal water. Children were between the ages of three and four years at the time of testing IQ scores. Data were analyzed between March 2017 and January 2019. A 1 mg higher daily intake of F among pregnant women was associated with a 3.66 lower IQ score (95% CI, −7.16 to −0.14) in boys and girls. This study found a significant interaction between child sex and maternal urinary F, indicating a differential association between boys and girls. A 1 mg/L increase in maternal urinary F was associated with a 4.49-point lower IQ score (95% CI, −8.38 to −0.60) in boys, but there was no statistically significant association with IQ scores in girls.
We found that 315 laboratory, clinical, epidemiological, and ecological studies over the whole world bring evidence about F neurotoxicity. This is in good agreement with the findings of other authors, who introduced that over 300 animal and human studies indicate that F is neurotoxic [68
]. Recently, F has been added to the WHO’s list of Ten chemicals of greatest public health concern.
Bellinger review brings surveys about how these chemicals adversely affect the brain [69
]. To support the case that F may induce neurotoxicity, Bellinger refers to the concern raised by basic neuroscience and ecological studies about the potential effects of excessive F exposure in developing animals and children.
4. Is There A Link between ASD Prevalence and a Chronic F Exposure?
In the past few decades, studies have demonstrated that ASDs occur globally and that the numbers of recorded cases are rising. However, determining the true prevalence figures is still a major challenge. The awareness of ASD, redefinition of diagnostic criteria, the age of investigated children, and the high costs of such surveys have a lot of impact on prevalence figures.
There has been a growing interest in possible environmental factors involved in the etiopathogenesis of ASD. An increasing number of epidemiological reports highlighted the potential link between ASD and chronic F exposure. We attempted to compare the current rates of the ASD prevalence from countries with artificial water fluoridation and the available rates from geographic regions with endemic fluorosis and evaluate the regions with low F supply. While a lot of progress had been made in the global awareness of ASD, much remains to be done to have a more accurate picture of the trend or global burden of the disorder [70
]. Our comparison is therefore affected and limited by the available reports. Despite these limitations, the available data are a warning.
The review of Elsabbagh et al. [8
] presents the comprehensive tables of available figures of the autism and other pervasive developmental disorders prevalence in various geographic regions over the world in the period of the 1960s–2010. Fifty more studies from 21 countries published during 2000–2016 were analyzed [9
], and 27 eligible studies from 18 countries on 5 continents were identified [71
]. These reviews demonstrate that the prevalence rates of autism/ASD have increased over time in all investigated regions.
4.1. The ASD Prevalence in Countries with Fluoridated Water
The US is at the top of the list of the current ASD prevalence in developed countries with an average value of 250 per 10,000 (one in 40) children aged 3–17 years [5
] (Table 1
). It is a further increase since the previous survey in 2014, when one in 59 among eight-year-old children was diagnosed with ASD in the US [72
]. CDC reports that 74.4% of the population has been supplied with fluoridated water for 70 years. A large increase in dental fluorosis prevalence was observed in the US [73
]. In the last survey (2010–2012), dental fluorosis was found in 65 % of adolescents aged 12–15 years. The prevalence rates of ASD are on the rise in Canada. While in 2003, one in 204 children had a diagnosis of autism/ASD, this rate rose to approximately one in 66 in 2018 [75
]. As of 2007, 45.1% of the Canadian population had access to fluoridated water supplies and water fluoridation remains a contentious issue. The Canadian Health Measures Survey found that 16% of children may have very mild or mild dental fluorosis. Australia, where 80% of the population had access to fluoridated water has revised its ASD prevalence rates from one in 200 in 2012 to an estimated one in 150 people in 2015 [77
]. New Zealand reports one person in 66 having ASD [78
], and 62% of the total population has fluoridated water supply [79
In countries with fluoridation of public water, it is vital to account additionally for other sources of F intake to assess the public health risk of its chronic exposure. Regarding the potential contribution of F in the ASD etiopathogenesis, one must include that infants and toddlers up to three years receive significantly more F than they should from infant formula. The recommended water F level in the US (0.7–1.2 mg/L) is several times higher than the F level found in the breast milk (0.001–0.004 mg/L) [68
]. F intake from other sources including swallowing toothpaste or the use of F tablets in children might further increase the daily F dose.
Tea plants (Camellia sinensis
) are well known for their ability to accumulate high concentrations of both F and Al3
]. A cup of black tea could contain 1.4 mg of F. Evidence suggests that the culture of tea drinking in the US, the UK, and New Zealand, contributes significantly to the total body burden of F [80
]. In developed countries a high intake of Al3+
from food and medicine products is obvious.
4.2. The ASD Prevalence in Countries with Endemic Fluorosis
Endemic fluorosis occurs widely in the world and is characterized by skeletal and dental fluorosis and a vast array of bodily pathological changes. Endemic fluorosis has been regarded as a severe public issue in China since the 1960s. There, endemic fluorosis consists of three types: drinking water type, coal-burning type, and drinking brick-tea type. The latter two types only exist extensively in China, but these types are overlapping in some of 34 Chinese provinces [81
]. Dental fluorosis occurred in 43%–63% of children aged 8–12 years in endemic areas where the total F intake was 2.7–19.75 mg/day [82
Recent data show the alarming increase in ASD in China. The last meta-analysis [83
] included 44 studies with 2,337,321 children aged 1.6–8 years, covering 30 of the 34 provinces of the country. These studies were conducted between 2000 and 2016. Based on diagnostic criteria, the pooled prevalence of ASD from 16 studies was 39.23 per 10,000, which is lower than in other countries worldwide. However, based on screening tools, the prevalence of ASD ranged from 33 to 1853 per 10,000 with a pooled figure of 429 per 10,000 (one in 23.3). For children in the age group ≤ 4 years, the ASD prevalence was 530 per 10,000 (one in 19) in China (Table 2
). Despite the many limitations for the comparison of various ASD prevalence studies that exist, the reports from the last decade revealed that autism prevalence in China is comparable to the Western prevalence [84
A high prevalence of ASD has been reported from Japan (161/10,000) [76
]. Recently, the prevalence of ASD in a total population sample of 5-year-old children was estimated at 3.22 % (2.66–3.76) [85
]. Dental fluorosis in 18 endemic areas in Japan was described in 1931 by Dean in his classical report [86
], which formed the foundation of the concept that the ingestion of F will harden the surface of teeth and make them less susceptible to dental caries. It is interesting that Japan has been practicing a school-based F mouth-rinse program (S-FMR) in nursery schools until graduating from junior high school since 1970 to prevent dental caries [87
]. The prevalence of fluorosis is reported as 1.7%–15.4 % of the population in Japan. It seems very probable that children, who use the mouth-rinse every day, swallow F from the mouth-rinse and that this adds to the other F sources from drinking tea, natural waters, and the typical Japanese diet.
The last available study reports the prevalence of ASD in South Asia ranging from 0.09% in India to 1.07% in Sri Lanka [88
]. Preliminary data on the prevalence ASD in a population sample of school children in Eastern India [89
] estimate 0.23% (0.07%–0.46%).
An alarmingly high ASD prevalence of 300 per 10,000 (one in 33) was found in Dhaka, the capital city of Bangladesh, which is known to have vast water contamination by various neurotoxicants [88
]. In a 2011 survey, South Korea also had a high rate of prevalence (220 per 10,000) [90
] (Table 2
4.3. The ASD Prevalence in the EU Member States
Most of the European states rejected water fluoridation shortly after its introduction in the 1970s–1990s. The Republic of Ireland (Ireland) is the only country in the EU with mandatory artificial fluoridation of drinking water. On the contrary, Northern Ireland, which is the part of the United Kingdom (UK), does not add F to drinking water since the local supply may contain naturally occurring F [91
]. In some parts of England, the level of F in the public water supply already reaches 1 mg F/L as a result of the geology of the area. In other areas of the UK, the F concentration has been adjusted by artificial fluoridation. Currently, around six million people in the UK live in areas with fluoridation schemes. Many schemes have been operating there for over 50 years. A high ASD prevalence has been estimated to have been present in the UK since the 1990s (16.8–116 per 10,000) [8
]. The National Autistic Society informs that there are around 700,000 people with ASD in the UK, which is more than one in 100 [92
Unfortunately, there is no central recording of ASD cases in any EU Member State. The European Commission (EC) considered ASD as a rare disease until 2005. The prevalence rates for autism in the EU could be estimated as varying from 3.3 to 16.0 per 10,000 [10
]. The first pilot project funded by the European Parliament and managed by the EC (ASDEU) provided an estimate of ASD prevalence in 14 European countries in the period 2015–2018 [93
]. The program scrutinized 631,619 children aged between seven and nine years. Overall, ASD prevalence estimates varied among European countries from 44 to 197 per 10,000 according to the ASDEU project [93
]. However, the estimations from this project are higher than the lower estimates made for the Czech Republic, Poland, Portugal, Finland, France, and Germany [9
] (Table 3
A recent survey of ASD prevalence in the Irish population was performed in 2017 and 2018 as part of an ASDEU project [91
]. This report indicates an estimated prevalence of autism of 2.9% in school-aged children in Northern Ireland, significantly higher than the 1.5% estimated in the Ireland in the same age group but several years earlier. Waugh et al. showed that the culture of habitual tea drinking in the Ireland could readily exceed the levels known to cause chronic F intoxication in the general population [94
], and this is probably relevant to the Irish population in Northern Ireland as well.
Similarly, an increasing ASD prevalence to 1% was reported from Spain, where fluoridated water has been provided for 10% of the population [9
]. There are substantial intra-regional differences in ASD prevalence in Sweden, where differences in the F content in drinking water (0.8–1.4 mg F/L) are also well documented [95
4.4. The Definition of a Safe Concentration of F for Humans
An awareness of the potential role of F in the ASD pathogenesis could contribute to the qualified reassessment of its widespread use in the health practice of water fluoridation, which is regarded as a valuable and safe method for reducing dental caries.
We cannot analyze the history of water fluoridation in the US and the discussion considering F standards. Under the Safe Drinking Water Act, the US Environmental Protection Agency (USEPA) sets the standards for drinking water quality. Currently, the enforceable F standard is set at 4.0 mg/L. The most commonly cited health concerns about F were assessed in the 2006 National Research Council (NRC) report. No evidence substantial enough to support the negative health effects of F at levels below 4.0 mg F/L other than severe dental fluorosis was found [99
]. Since 1962, the US Public Health Service (PHS) has recommended an optimal F concentration of 0.7 mg/L and considers that this provides the best balance of protection from dental caries while limiting the risk of dental fluorosis [100
provides the latest values for adequate intakes (AI) and upper tolerable intake levels (UL) for F (in mg/day) developed by the National Academies of Sciences, Engineering, and Medicine for the US, updated on 3/27/2019 [101
]. The F AI and UL for 0–8-year children were updated in 2017 by the National Health and Medical Research Council (NHMRC) for Australia and New Zealand. This update was intended to prevent dental caries without exceeding intakes that are associated with severe dental fluorosis [102
]. Dental fluorosis is caused by overexposure to F during the first eight years of life. The NHMRC did not establish an AI for infants less than six months of age. The review of evidence did not find a reduction in dental caries with F intake in the first six months of life [102
As F is not an essential nutrient, the panel of the European Food Safety Authority (EFSA) considered that no average requirement for the performance of its essential physiological functions could be defined (12/4/2017) [103
]. However, the panel considered that data on the dose–response relationship between caries incidence and the consumption of drinking water with different F concentrations are adequate to set an AI of 0.05 mg F/kg body weight per day for children. This can also be applied to adults, including pregnant and lactating women. However, the AI covers F intake from all sources, including toothpaste and other dental hygiene products. The available data on F intake of the European population is variable but generally at or below 0.05 mg/kg/day [103
]. For younger children (1–6 years of age) the UL was exceeded when consuming more than one liter of water at 0.8 mg F and F from other sources. For infants up to six months old receiving infant formula, if the water F level was higher than 0.8 mg/L, the intake of F exceeded 0.1 mg/kg/day, and this level is 100 times higher than the level found in breast milk [104
The analysis of the literature regarding the loss of IQ after F chronic exposure [68
] shows that to protect against a five-point IQ loss, the benchmark dose (BMD) is between 0.0014 and 0.05 mg/day for children. It means that the protective daily dose should be no higher than 0.05 mg/day for children.
The information now available supports a reasonable conclusion that F exposure of the developing human organism should be minimized. Prolonged exposure to F in the prenatal as well as postnatal stages of development might have neurotoxic effects on the development and metabolism of the brain. Infantile autism develops most likely during the second trimester of prenatal development and results in significant abnormalities in the development of the brain, including the cerebellum, brainstem, and cerebrum. The regressive autism appears to be the result of postnatal events. This form of autism is responsible for the rising ASD incidence in the last decades. Autism-specific brain imaging features were identified at six months of age. Age-specific brain and behavior changes were demonstrated across the first two years of life [105
]. This time is a period of intense postnatal synaptic development. The human cerebellum matures postnatally, with the greatest acceleration of growth and neural organization during the first two years after birth [11
However, the dose, at which dental caries reduction is expected, is not far away from the one that might cause chronic pathological effects. It is evident that the definition of a safe concentration of F for humans must consider the fact that in synergy with trace amounts of Al3+, every concentration of F might be dangerous for the developing brain.
4.5. Socioeconomic Status
ASD may significantly limit the capacity of some individuals to conduct daily activities. Since it is a life-long condition, it often imposes a significant socioeconomic burden on society, people with these disorders, and their families. In the US, the annual societal costs per the year 2011 for children with ASD were estimated to be between $
11.5–60.9 billion, including a variety of direct and indirect costs, from medical care to special education and lost parental productivity [3
]. Children and adolescents with ASD had average medical expenditures that exceeded expenditures of those without ASD by $
4110–6200 per year.
According to estimates, annual costs due to ASD in the US in 2015 were around $
268 billion [106
]. This figure is estimated to increase to about $
461 billion by the year 2025. If the prevalence of ASD continues to grow as it has in recent years, ASD costs will likely exceed those of diabetes and ADHD by far by 2025 [106
]. The economic impact of IQ loss among US children is the loss of tens of billions of dollars [68
The costs of autism for individuals (lifetime) and society (annual) in the UK was calculated in 2005. The average additional lifetime cost for an individual with autism and additional learning disability was estimated to be £2,940,538. For people with high-functioning autism, the additional lifetime cost is estimated to be £784,785 [92
One of the ASDEU’s key aims was to estimate the economic burden of ASD in the EU. The type of ASD, age, and comorbidities are important drivers of the costs. Estimations of direct costs ranged from €1594 in Romania to €22,378 in Denmark per individual annually. Lifetime costs of caring for a person with autism without an intellectual disability were estimated at €766,865 based on an average life expectancy of 70 years for people with ASD in Germany. The costs of productivity losses among carers range yearly from €615 per carer in Poland to €8934 per carer in Austria [93
]. ASDEU also found that the total cost of universal screening of ASD prevalence would range from €43,000 per year in Iceland to €5 million per year in France [93
These significant health and socioeconomic concerns could probably be lowered by focusing more on ASD prevention through the elimination of F from daily life.
A vast array of observations has been made at the cellular and the molecular levels of the ASD etiopathogenesis. Yet, a unifying mechanism to explain the various etiological factors and different symptoms of ASD has not been proposed. There is a consensus of several researchers that causal processes in the ASD etiopathogenesis involve the interactions of multiple genetic and environmental risk factors. We reviewed literature showing that F is an environmental neurotoxin. F induces symptoms which are observed in people with ASD, such as mitochondrial dysfunction and impairment of energy metabolism, oxidative stress and inflammation, immunoexcitotoxicity, and decreased melatonin levels. We showed that all these symptoms have also been observed in endemic fluorosis areas in China [7
], where daily intake of F exceeds the national standard 2 mg per day and might reach up to 20 mg per day [82
Based on the ASD prevalence in various countries and cities, we suggest that F might be the significant culprit in the ASD etiopathogenesis both in areas with artificial water fluoridation as well as in F endemic areas. Nevertheless, F is not yet included among environmental risk factors in the ASD pathogenesis in countries with fluoridated water and a high rate of dental fluorosis. CDC named community water fluoridation one of ten great public health achievements of the 20th century.
Three main categories of toxicants have been suggested as contributing to the ASD pathogenesis: heavy metals, persistent organic pollutants, and emerging new endocrine disruptors. For example, Modabbernia et al. conducted a review of the 80 studies, nine systematic reviews, and 23 meta-analyses of environmental risk factors for ASD [107
]. These authors pointed out that the association between environmental factors and ASD might include gene-related epigenetic effects, oxidative stress, inflammation, endocrine disruption, neurotransmitter alterations, and interference with signaling pathways. Nevertheless, an assessment of F participation in these events was not suggested [107
Ng et al. reviewed 315 articles regarding environmental factors associated with ASD in the years 2003–2013. Research has been conducted worldwide; many studies were concentrated in the US, the UK, Australia, and Japan [108
]. However, F was not involved in any of the 315 reviewed articles examining chemical factors [108
]. Concerning neurotoxicants, Schofield referred to the current medical databases for 100 molecules or elements that can be listed as developmental neurotoxicants [109
]. She reviewed knowledge of the six neurotoxicants, which could be involved in the growing epidemic of neurological illnesses, including autism, over the last 20–25 years. F was not included among the referred neurotoxicants. F did not receive any attention or suspect for participation among environmental factors in the ASD etiopathogenesis, nor in recent reviews of Almandil et al. [6
] nor Bjørklund et al. [110
In countries of the EU, where F daily intake is low, F does not probably work as the trigger in the complicated network of pathogenetic events, and ASD is often still considered a rare disease. The document of the EC also concluded that available human studies do not support the conclusion that F in drinking water impairs children’s neurodevelopment at levels permitted in the EU [104
Many other environmental neurotoxins, exogenous excitotoxic amino acids, and endocrine disruptors can disturb both prenatal as well as postnatal brain development [11
]. Moreover, F from natural waters (e.g., in Sweden and the UK), tea, and non-dietary sources, such as F tablets, toothpaste, and other dental hygiene products, might play a role in the ASD pathogenesis. The severity and the development of ASD symptoms depend on genetics, nutritional status, immune system, and the presence of recurrent infections [11
]. Nevertheless, an increase in the ASD prevalence is also observed in some states of the EU with water fluoridation, such as the RoI, the UK, and partially in Spain.
We showed that even very low F concentration in synergy with Al3+ can exacerbate alterations in neurotransmission and hormonal regulation. Under such circumstances, a “safe” F concentration might induce pathological effects in children with a genetic susceptibility. The heterogeneity of mutual dynamic interactions can explain the clinically heterogeneous symptoms of ASD and contribute to an understanding of the various responses in any given child to identical environmental neurotoxins.
] suggested in his review that the novel, “emergent” phenomena may arise in individuals with ASD from underlying and interacting genetic and environmental factors. Some of the ASD behavioral symptoms, including delayed stereotyped language, rigid preferences for routines, and repetitive motor mannerisms, among others, can be discussed as potentially being emergent. The rise of ASD in the last decades challenges us to change the research from a reductionistic approach to an understanding of underlying integrative networks. Our review shows how diverse molecules and biological processes can be affected by F.
In the Czech Republic, artificial water fluoridation was stopped in the 1990s for economic reasons, since tap water is used for many purposes. There are many discussions and analyses regarding the efficiency and costs of water fluoridation in the prevention of dental caries over the world. However, the possibility that chronic F intake could evoke chronic diseases with high health and socioeconomic impact would also be involved. The information now available supports a reasonable conclusion that economic losses associated with ASD may be quite large.
Moreover, while ASD is often considered purely behavioral, it comes with many different comorbidities, like gut imbalances, seizures, hormonal disorders, obesity, and sleep problems. Disturbed sleep potentially exacerbates ASD-related symptoms such as impaired social interactions, deficits in nonverbal intelligence and communication, repetitive behaviors, and mood disorders. Poor sleep may have adverse effects on children’s attention, memory, learning, and conduct aggression.
The ASD prevalence is consistently estimated as a ratio of approximately 4.5 male:1 female during 2006–2014 in the US [3
]. For example, the pooled ASD prevalence was one in 38 boys and one in 152 girls. However, the male-to-female prevalence ratios ranged from 2.7 in Utah to 7.2 in Alabama [72
]. The perspective that ASD could impact around 30% of young men in the next decades is very alarming and requires urgent solutions. The reduction of F and Al3+
consumption of pregnant women and developing children could be a very easy and inexpensive way to prevent ASD.
The rise in the ASD prevalence in countries with water fluoridation as well as in endemic fluorosis areas supports a view that F is an important environmental factor in the ASD etiopathogenesis. Our suggestion of the important role of F in the ASD etiopathogenesis is supported by the observation that a high ASD rate is found in countries with a high occurrence of dental fluorosis.
F neurotoxicity has been demonstrated in many laboratory studies with cells and animals, as well as in human epidemiological studies. We present evidence that F induces mitochondrial dysfunction, oxidative stress, inflammation, and immunoexcitotoxicity. There is a link between a known effect of F on melatonin synthesis in the pineal gland and the finding that melatonin synthesis is significantly reduced in ASD. Moreover, understanding F-induced pathways in the ASD etiopathology may lead to novel treatments. All these F-induced symptoms could evoke several disruptions of the brain development, alter neurotransmission and hormonal regulations, deficits in social interactions and induce repetitive, stereotypic interests, and behaviors resulting in ASD.
At present, there is a divergence between public health practice of water fluoridation, which is regarded as valuable and safe for reducing dental caries, and current scientific evidence, which indicates that F is a neurotoxin disturbing prenatal as well as postnatal brain development, eroding intelligence, and behavior. The potential neurotoxicity associated with exposure to F, which has generated controversy about community water fluoridation, remains unclear. In the recent Canadian study, maternal exposure to higher levels of F during pregnancy was associated with lower IQ scores in children aged 3 to 4 years [67
]. These findings support the possible need to reduce F intake during pregnancy. Intellectual disability is present in 65%–75% of individuals with a diagnosis of autistic disorder and in 30%–55% of all ASD [3
F is not an essential nutrient as no physiological function can be defined for which F is required. The presence of trace amounts of Al3+ strongly potentiates the neurotoxic effects of F. AlF4− can trigger the pathological symptoms of ASD at concentrations several times lower than those for F acting alone. In synergy with Al3+ every concentration of F might be dangerous for the developing brain. Our review suggests that the reduction of F exposure in daily life might be an efficient way to prevent an ASD epidemic soon. Monitoring of the ASD prevalence in children born after the removal of F from drinking water will provide relevant information for our hypothesis.