Excerpts from National Academy of Science and CDC reports on Fluoride

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Reference Material:

From the following website (I’ve reordered the sections to put the most concerning items first, but maintained the order within each section)

CDC  Community Water Fluoridation

Safety

National Academy of Science

The 2006 NRC Report on Fluoride in Drinking Water: A Scientific Review of EPA’s Standards*

Introduction

Under the Safe Drinking Water Act, the U.S. Environmental Protection Agency (EPA) is required to establish the concentrations of contaminants that are permitted in public drinking-water systems. …Section 1412 of the act, as amended in 1986, requires EPA to publish maximum-contaminant-level goals…for contaminants in drinking water that might cause any adverse effect on human health and that are known or expected to occur in public water systems…

Fluoride is one of the natural contaminants found in public drinking water supplies regulated by EPA… In this report, the National Research Council’s (NRC’s) Committee on Fluoride in Drinking Water reviews the nature of the human health risks from fluoride, estimates exposures to the general public from drinking water and other sources, and provides an assessment of the adequacy of the MCLG for protecting public health from adverse health effects from fluoride and of the SMCL for protecting against cosmetic effects. Assessing the efficacy of fluoride in preventing dental caries is not covered in this report.

Neurotoxicity and Neurobehavioral Effects

FINDINGS

In assessing the potential health effects of fluoride at 2-4 mg/L, the committee found three studies of human populations exposed at those concentrations in drinking water that were useful for informing its assessment of potential neurologic effects. These studies were conducted in different areas of China, where fluoride concentrations ranged from 2.5 to 4 mg/L. Comparisons were made between the IQs of children from those populations with children exposed to lower concentration of fluoride ranging from 0.4 to 1 mg/L. The studies reported that while modal IQ scores were unchanged, the average IQ scores were lower in the more highly exposed children. This was due to fewer children in the high IQ range. While the studies lacked sufficient detail for the committee to fully assess their quality and their relevance to U.S. populations, the consistency of the collective results warrant additional research on the effects of fluoride on intelligence. Investigation of other mental and physiological alterations reported in the case study literature, including mental confusion and lethargy, should also be investigated.

It appears that many of fluoride’s effects, and those of the aluminofluoride complexes are mediated by activation of Gp, a protein of the G family. G proteins mediate the release of many of the best known transmitters of the central nervous system. Not only do fluorides affect transmitter concentrations and functions but also are involved in the regulation of glucagons, prostaglandins, and a number of central nervous system peptides, including vasopressin, endogenous opioids, and other hypothalamic peptides. The AlF_x binds to GDP and ADP altering their ability to form the triphosphate molecule essential for providing energies to cells in the brain. Thus, AlF_x not only provides false messages throughout the nervous system but, at the same time, diminishes the energy essential to brain function.

Fluorides also increase the production of free radicals in the brain through several different biological pathways. These changes have a bearing on the possibility that fluorides act to increase the risk of developing Alzheimer’s disease. Today, the disruption of aerobic metabolism in the brain, a reduction of effectiveness of acetylcholine as a transmitter, and an increase in free radicals are thought to be causative factors for this disease. More research is needed to clarify fluoride’s biochemical effects on the brain.

On the basis of information largely derived from histological, chemical, and molecular studies, it is apparent that fluorides have the ability to interfere with the functions of the brain and the body by direct and indirect means. To determine the possible adverse effects of fluoride, additional data from both the experimental and the clinical sciences are needed.

• The possibility has been raised by the studies conducted in China that fluoride can lower intellectual abilities. Thus, studies of populations exposed to different concentrations of fluoride in drinking water should include measurements of reasoning ability, problem solving, IQ, and short-and long-term memory. Care should be taken to ensure that proper testing methods are used, that all sources of exposure to fluoride are assessed, and that comparison populations have similar cultures and socioeconomic status.
• Studies of populations exposed to different concentrations of fluoride should be undertaken to evaluate neurochemical changes that may be associated with dementia. Consideration should be given to assessing effects from chronic exposure, effects that might be delayed or occur late-in-life, and individual susceptibility (see Chapters 2 and 3 for discussion of subpopulations that might be more susceptible to the effects of fluoride from exposure and physiologic standpoints, respectively).
• Additional animal studies designed to evaluate reasoning are needed. These studies must be carefully designed to measure cognitive skills beyond rote learning or the acquisition of simple associations, and test environmentally relevant doses of fluoride.
• At the present time, questions about the effects of the many histological, biochemical, and molecular changes caused by fluorides cannot be related to specific alterations in behavior or to known diseases. Additional studies of the relationship of the changes in the brain as they affect the hormonal and neuropeptide status of the body are needed. Such relationships should be studied in greater detail and under different environmental conditions.
• Most of the studies dealing with neural and behavioral responses have tested NaF. It is important to determine whether other forms of fluoride (e.g., silicofluorides) produce the same effects in animal models.

Effects on the Endocrine System

The conclusion from the available studies is that sufficient fluoride exposure appears to bring about increases in blood glucose or impaired glucose tolerance in some individuals and to increase the severity of some types of diabetes. In general, impaired glucose metabolism appears to be associated with serum or plasma fluoride concentrations of about 0.1 mg/L or greater in both animals and humans (Rigalli et al. 1990, 1995; Trivedi et al. 1993; de al Sota et al. 1997). In addition, diabetic individuals will often have higher than normal water intake, and consequently, will have higher than normal fluoride intake for a given concentration of fluoride in drinking water. An estimated 16-20 million people in the United States have diabetes mellitus (Brownlee et al. 2002; Buse et al. 2002; American Diabetes Association 2004; Chapter 2); therefore, any role of fluoride exposure in the development of impaired glucose metabolism or diabetes is potentially significant.

“The major endocrine effects of fluoride exposures reported in humans include elevated TSH with altered concentrations of T3 and T4, increased calcitonin activity, increased PTH activity, secondary hyperparathyroidism, impaired glucose tolerance, and possible effects on timing of sexual maturity; similar effects have been reported in experimental animals. These effects are summarized in Tables 8-1 and 8-2, together with the approximate intakes or physiological fluoride concentrations that have been typically associated with them thus far. Table 8-2 shows that several of the effects are associated with average or typical fluoride intakes of 0.05-0.1 mg/kg/day (0.03 with iodine deficiency), others with intakes of 0.15 mg/kg/day or higher. A comparison with Chapter 2 (Tables 2-13, 2-14, and 2-15) will show that the 0.03-0.1 mg/kg/day range will be reached by persons with average exposures at fluoride concentrations of 1-4 mg/L in drinking water, especially the children. The highest intakes (>0.1 mg/kg/d) will be reached by some individuals with high water intakes at 1 mg/L and by many or most individuals with high water intakes at 4 mg/L, as well as by young children with average exposures at 2 or 4 mg/L.”

“Estimates of exposure listed in these tables and in Appendix E are, in most cases, estimates of average values for groups based on assumptions about body weight and water intake. Thus, individual responses could occur at lower or higher exposures than those listed.”

“A comparison with Chapter 2 (Tables 2-13, 2-14, and 2-15) will show that the 0.03-0.1 mg/kg/day range will be reached by persons with average exposures at fluoride concentrations of 1-4 mg/L in drinking water, especially the children.”

Increased serum glucose and increased severity of existing diabetes have been reported in animal studies at fluoride intakes of 7-10.5 mg/kg/day (Table 8-1). Impaired glucose tolerance in humans has been reported in separate studies at fluoride intakes of 0.07-0.4 mg/kg/day, corresponding to serum fluoride concentrations above about 0.1 mg/L. The primary mechanism appears to involve inhibition of insulin production.

“For all the endocrine effects reported to occur from fluoride exposure, the variability in exposure and response among populations (or strains of an experimental animal) or within a human population requires further attention. For example, correlations between the fluoride intake or the presence or degree of fluorosis and the presence (or prevalence) or severity of other effects generally have not been examined on an individual basis, which could permit identification of individual differences in susceptibility or response.”

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Variability in response to fluoride exposures could be due to differences in genetic background, age, sex, nutrient intake (e.g., calcium, iodine, selenium), general dietary status, or other factors. Intake of nutrients such as calcium and iodine often is not reported in studies of fluoride effects. The effects of fluoride on thyroid function, for instance, might depend on whether iodine intake is low, adequate, or high, or whether dietary selenium is adequate. Dietary calcium affects the absorption of fluoride (Chapter 3); in addition, fluoride causes an increase in the dietary requirements for calcium, and insufficient calcium intake increases fluoride toxicity. Available information now indicates a role for aluminum in the interaction of fluoride on the second messenger system; thus, differences in aluminum exposure might explain some of the differences in response to fluoride exposures among individuals and populations.

The clinical significance of fluoride-related endocrine effects requires further attention. For example, most studies have not mentioned the clinical significance for individuals of hormone values out of the normal range, and some studies have been limited to consideration of “healthy” individuals.”

• Further effort is necessary to characterize the direct and indirect mechanisms of fluoride’s action on the endocrine system and the factors that determine the response, if any, in a given individual. Such studies would address the following:
  • the in vivo effects of fluoride on second messenger function
  • the in vivo effects of fluoride on various enzymes
  • the integration of the endocrine system (both internally and with other systems such as the neurological system)
  • identification of those factors, endogenous (e.g., age, sex, genetic factors, or preexisting disease) or exogenous (e.g., dietary calcium or iodine concentrations, malnutrition), associated with increased likelihood of effects of fluoride exposures in individuals
  • consideration of the impact of multiple contaminants (e.g., fluoride and perchlorate) that affect the same endocrine system or mechanism
  • examination of effects at several time points in the same individuals to identify any transient, reversible, or adaptive responses to fluoride exposure.

Better characterization of exposure to fluoride is needed in epidemiology studies investigating potential endocrine effects of fluoride. Important exposure aspects of such studies would include the following:

• collecting data on general dietary status and dietary factors that could influence the response, such as calcium, iodine, selenium, and aluminum intakes
• characterizing and grouping individuals by estimated (total) exposure, rather than by source of exposure, location of residence, fluoride concentration in drinking water, or other surrogates
• reporting intakes or exposures with and without normalization for body weight (e.g., mg/day and mg/kg/day), to reduce some of the uncertainty associated with comparisons of separate studies
• addressing uncertainties associated with exposure and response, including uncertainties in measurements of fluoride concentrations in bodily fluids and tissues and uncertainties in responses (e.g., hormone concentrations)
• reporting data in terms of individual correlations between intake and effect, differences in subgroups, and differences in percentages of individuals showing an effect and not just differences in group or population means.
• examining a range of exposures, with normal or control groups having very low fluoride exposures (below those associated with 1 mg/L in drinking water for humans).

• The effects of fluoride on various aspects of endocrine function should be examined further, particularly with respect to a possible role in the development of several diseases or mental states in the United States. Major areas for investigation include the following:
  • thyroid disease (especially in light of decreasing iodine intake by the U.S. population);
  • nutritional (calcium deficiency) rickets;
  • calcium metabolism (including measurements of both calcitonin and PTH);
  • pineal function (including, but not limited to, melatonin production); and
  • development of glucose intolerance and diabetes

Effects on the Gastrointestinal, Renal, Hepatic, and Immune Systems

Several investigators have shown that patients with impaired renal function, or on hemodialysis, tend to accumulate fluoride much more quickly than normal. Patients with renal osteodystrophy can have higher fluoride concentrations in their serum (see Table 9-3). Whether some bone changes in renal osteodystrophy can be attributed to excess bone fluoride accumulation alone, or in combination with other elements such as magnesium and aluminum, has not been clearly established (Erben et al. 1984; Huraib et al. 1993; Ng et al. 2004). Extreme caution should be used in patients on hemodialysis because failures of the dialysis equipment have occurred in the past, resulting in fluoride intoxication (Arnow et al. 1994).

There is no question that fluoride can affect the cells involved in providing immune responses. The question is what proportion, if any, of the population consuming drinking water containing fluoride at 4.0 mg/L on a regular basis will have their immune systems compromised? Not a single epidemiologic study has investigated whether fluoride in the drinking water at 4 mg/L is associated with changes in immune function. Nor has any study examined whether a person with an immunodeficiency disease can tolerate fluoride ingestion from drinking water.

“…There are a few case reports of GI upset in subjects exposed to drinking water fluoridated at 1 mg/L. Those effects were observed in only a small number of cases, which suggest hypersensitivity.”

As noted earlier in Chapters 2 and 3, several subpopulations are likely to be susceptible to the effects of fluoride from exposure and pharmacokinetic standpoints. With regard to the end points covered in this chapter, it is important to consider subpopulations that accumulate large concentrations of fluoride in their bones (e.g., renal patients). When bone turnover occurs, the potential exists for immune system cells and stem cells to be exposed to concentrations of fluoride in the interstitial fluids of bone that are higher than would be found in serum. From an immunologic standpoint, individuals who are immunocompromised (e.g., AIDS, transplant, and bone-marrow-replacement patients) could be at greater risk of the immunologic effects of fluoride.

• Studies are needed to evaluate gastric responses to fluoride from natural sources at concentrations up to 4 mg/L and from artificial sources. Data on both types of exposures would help to distinguish between the effects of water fluoridation chemicals and natural fluoride. Consideration should be given to identifying groups that might be more susceptible to the gastric effects of fluoride.
• The influence of fluoride and other minerals, such as calcium and magnesium, present in water sources containing natural concentrations of fluoride up to 4 mg/L on gastric responses should be carefully measured.

• • Rigorous epidemiologic studies should be carried out in North America to determine whether fluoride in drinking water at 4 mg/L is associated with an increased incidence of kidney stones. There is a particular need to study patients with renal impairments.
  • Additional studies should be carried out to determine the incidence, prevalence, and severity of renal osteodystrophy in patients with renal impairments in areas where there is fluoride at up to 4 mg/L in the drinking water.
  • The effect of low doses of fluoride on kidney and liver enzyme functions in humans needs to be carefully documented in communities exposed to different concentrations of fluoride in drinking water.
  Immune Response
  • Epidemiologic studies should be carried out to determine whether there is a higher prevalence of hypersensitivity reactions in areas where there is elevated fluoride in the drinking water. If evidence is found, hypersensitive subjects could then be selected to test, by means of double-blinded randomized clinical trials, which fluoride chemicals can cause hypersensitivity. In addition, studies could be conducted to determine what percentage of immunocompromised subjects have adverse reactions when exposed to fluoride in the range of 1-4 mg/L in drinking water.
  • More research is needed on the immunotoxic effects of fluoride in animals and humans to determine if fluoride accumulation can influence immune function.
  • It is paramount that careful biochemical studies be conducted to determine what fluoride concentrations occur in the bone and surrounding interstitial fluids from exposure to fluoride in drinking water at up to 4 mg/L, because bone marrow is the source of the progenitors that produce the immune system cells.

Genotoxicity and Carcinogenicity

Genotoxicity tests indicate the potential for fluoride to cause mutations, affect the structure of chromosomes and other genomic material; affect DNA replication, repair, and the cell cycle; and/or transform cultured cell lines to enable them to cause tumors when implanted into host animals.

The combined literature described above does not clearly indicate that fluoride either is or is not carcinogenic in humans. The typical challenges of environmental epidemiology are magnified for the evaluation of whether fluoride is a risk factor for osteosarcoma. These challenges include: detection of relatively low risks, accurate exposure classification assessment of pertinent dose to target tissues, multiple causes for the effect of interest, and multiple effects of the exposure of interest. Assessing whether fluoride constitutes a risk factor for osteosarcoma is complicated by (1) how uncommon the disease is, so that cohort or semi-ecologic studies are not based on large numbers of outcomes, and (2) the difficulty of characterizing biologic dose of interest for fluoride because of the ubiquity of population exposure to fluoride and the difficulty of acquiring bone samples in nonaffected individuals.

In summary, there has been partial but incomplete fulfillment of NRC’s recommendations on individual-based cancer studies in the intervening years since 1993; one analytic study of osteosarcoma has been published, but bone samples were not included. The alternative (hospital-based) design, including bone assays, from the Harvard group might be more useful in addressing this issue.

“Fluoride appears to have the potential to initiate or promote cancers, particularly of the bone, but the evidence to date is tentative and mixed (Tables 10-4 and 10-5). As noted above, osteosarcoma is of particular concern as a potential effect of fluoride because of (1) fluoride deposition in bone, (2) the mitogenic effect of fluoride on bone cells, (3) animal results described above, and (4) pre-1993 publication of some positive, as well as negative, epidemiologic reports on associations of fluoride exposure with osteosarcoma risk.

Several studies indicating at least some positive associations of fluoride with one or more types of cancer have been published since the 1993 NRC report. Several in vivo human studies of genotoxicity, although limited, suggest fluoride’s potential to damage chromosomes. The human epidemiology study literature as a whole is still mixed and equivocal. As pointed out by Hrudey et al. (1990), rare diseases such as osteosarcoma are difficult to detect with good statistical power.

In animal studies, the overall incidence of osteosarcoma in male rats showed a positive trend. ”

• The results of the Douglass et al. multicenter osteosarcoma study (expected in the summer of 2006) could add important data to the current body of literature on fluoride risks for osteosarcoma because the study includes bone fluoride concentrations for cases and controls. When this study is published, it should be considered in context with the existing body of evidence to help determine what follow-up studies are needed.
• Further research on a possible effect of fluoride on bladder cancer risk should be conducted. Since bladder cancer is relatively common (compared with osteosarcoma), both cohort and case-control designs would be feasible to address this question. For example, valuable data might be yielded by analyses of cancer outcomes among the cohorts followed for other health outcomes, such as fractures (see Chapter 5).

• The positive in vivo genotoxicity studies described in the chapter were conducted in India and China, where fluoride concentrations in drinking water are often higher than those in the United States. Further, each had a dearth of information on the selection of subjects and was based on small numbers of participants. Therefore, in vivo human genotoxicity studies in U.S. populations or other populations with nutritional and sociodemographic variables similar to those in the United States should be conducted. Documentation of subject enrollment with different fluoride concentrations would be useful for addressing the potential genotoxic hazards of fluoridated water in this country.

Pharmacokinetics of Fluoride

FINDINGS

• Bone fluoride concentrations increase with both magnitude and length of exposure. Empirical data suggest substantial variations in bone fluoride concentrations at any given water concentration….
• Groups likely to have increased bone fluoride concentrations include the elderly and people with severe renal insufficiency.
• Pharmacokinetics should be taken into account when comparing effects of fluoride in different species. Limited evidence suggests that rats require higher chronic exposures than humans to achieve the same plasma and bone concentrations.

RESEARCH RECOMMENDATIONS

• Additional research is needed on fluoride concentrations in human bone as a function of magnitude and duration of exposure, age, gender, and health status. Such studies would be greatly aided by noninvasive means of measuring bone fluoride. As discussed in other chapters of this report, some soft tissue effects may be associated with fluoride exposure. Most measurements of fluoride in soft tissues are based on short-term exposures and some atypically high values have been reported. Thus, more studies are needed on fluoride concentrations in soft tissues (e.g., brain, thyroid, kidney) following chronic exposure.

• Research is needed on fluoride plasma and bone concentrations in people with small to moderate changes in renal function as well as patients with serious renal deficiency. Other potentially sensitive populations should be evaluated, including the elderly, postmenopausal women, and people with altered acid-base balance.
• Improved and readily available pharmacokinetic models should be developed.
• Additional studies comparing pharmacokinetics across species are needed.
• More work is needed on the potential for release of fluoride by the metabolism of organofluorines.

One of the functions of tooth enamel is to protect the dentin and, ultimately, the pulp from decay and infection. Severe enamel fluorosis compromises this health-protective function by causing structural damage to the tooth. The damage to teeth caused by severe enamel fluorosis is a toxic effect that the majority of the committee judged to be consistent with prevailing risk assessment definitions of adverse health effects. This view is consistent with the clinical practice of filling enamel pits in patients with severe enamel fluorosis and restoring the affected teeth.

In previous reports, all forms of enamel fluorosis, including the severest form, have been judged to be aesthetically displeasing but not adverse to health (EPA 1986; PHS 1991; IOM 1997; ADA 2005). This view has been based largely on the absence of direct evidence that severe enamel fluorosis results in tooth loss, loss of tooth function, or psychological, behavioral, or social problems. The majority of the present committee finds the rationale for considering severe enamel fluorosis only a cosmetic effect much weaker for discrete and confluent pitting, which constitutes enamel loss, than it is for the dark yellow to brown staining that is the other criterion symptom of severe fluorosis.

• Additional studies, including longitudinal studies, of the prevalence and severity of enamel fluorosis should be done in U.S. communities with fluoride concentrations higher than 1 mg/L. These studies should focus on moderate and severe enamel fluorosis in relation to caries and in relation to psychological, behavioral, and social effects among affected children, their parents, and affected children after they become adults.
• Methods should be developed and validated to objectively assess enamel fluorosis. Consideration should be given to distinguishing between staining or mottling of the anterior teeth and of the posterior teeth so that aesthetic consequences can be more easily assessed.
• More research is needed on the relation between fluoride exposure and dentin fluorosis and delayed tooth eruption patterns.

Musculoskeletal Effects

FINDINGS

Fluoride is a biologically active ion with demonstrable effects on bone cells, both osteoblasts and osteoclasts. Its most profound effect is on osteoblast precursor cells where it stimulates proliferation both in vitro and in vivo. In some cases, this is manifested by increases in bone mass in vivo.

The signaling pathways by which this agent works are slowly becoming elucidated.

Life-long exposure to fluoride at the MCLG of 4 mg/L may have the potential to induce stage II or stage III skeletal fluorosis and may increase the risk of fracture. These adverse effects are discussed separately below.

The current MCLG was designed to protect against stage III skeletal fluorosis. As discussed above, the committee judges that stage II is also an adverse health effect, as it is associated with chronic joint pain, arthritic symptoms, slight calcification of ligaments, and osteosclerosis of cancellous bones. The committee found that bone fluoride concentrations estimated to be achieved from lifetime exposure to fluoride at 2 mg/L (4,000 to 5,000 mg/kg ash) or 4 mg/L (10,000 to 12,000 mg/kg ash) fall within or exceed the ranges historically associated with stage II and stage III skeletal fluorosis (4,300 to 9,200 mg/kg ash and 4,200 to 12,700 mg/kg ash, respectively). This suggests that fluoride at 2 or 4 mg/L might not protect all individuals from the adverse stages of the condition. However, this comparison alone is not sufficient evidence to conclude that individuals exposed to fluoride at those concentrations are at risk of stage II skeletal fluorosis. There is little information in the epidemiologic literature on the occurrence of stage II skeletal fluorosis in U.S. residents, and stage III skeletal fluorosis appears to be a rare condition in the United States. Therefore, more research is needed to clarify the relationship between fluoride ingestion, fluoride concentrations in bone, and stage of skeletal fluorosis before any firm conclusions can be drawn.”

“On the basis of this information, all members of the committee agreed that there is scientific evidence that under certain conditions fluoride can weaken bone and increase the risk of fractures. The majority of the committee concluded that lifetime exposure to fluoride at drinking-water concentrations of 4 mg/L or higher is likely to increase fracture rates in the population, compared with exposure at 1 mg/L, particularly in some susceptible demographic groups that are more prone to accumulate fluoride in their bones.”

• A more complete analysis of communities consuming water with fluoride at 2 and 4 mg/L is necessary to assess the potential for fracture risk at those concentrations. These studies should use a quantitative measure of fracture such as radiological assessment of vertebral body collapse rather than self-reported fractures or hospital records. Moreover, if possible, bone fluoride concentrations should be measured in long-term residents.
• The effects of fluoride exposure in bone cells in vivo depend on the local concentrations surrounding the cells. More data are needed on concentration gradients during active remodeling. A series of experiments aimed at quantifying the graded exposure of bone and marrow cells to fluoride released by osteoclastic activity would go a long way in estimating the skeletal effects of this agent.
• A systematic study of stage II and stage III skeletal fluorosis should be conducted to clarify the relationship of fluoride ingestion, fluoride concentration in bone, and clinical symptoms. Such a study might be particularly valuable in populations in which predicted bone concentrations are high enough to suggest a risk of stage II skeletal fluorosis (e.g., areas with water concentrations of fluoride above 2 mg/L).
• More research is needed on bone concentrations of fluoride in people with altered renal function, as well as other potentially sensitive populations (e.g., the elderly, postmenopausal women, people with altered acid-balance), to better understand the risks of musculoskeletal effects in these populations.

Reproductive and Developmental Effects of Fluoride

A large number of reproductive and developmental studies in animals have been conducted and published since 1990, and the overall quality of the database has improved significantly. High-quality studies in laboratory animals over a range of fluoride concentrations (0-250 mg/L in drinking water) indicate that adverse reproductive and developmental outcomes occur only at very high concentrations. A few studies of human populations have suggested that fluoride might be associated with alterations in reproductive hormones, fertility, and Down’s syndrome, but their design limitations make them of little value for risk evaluation.

• Studies in occupational settings are often useful in identifying target organs that might be susceptible to disruption and in need of further evaluation at the lower concentrations of exposure experienced by the general population. Therefore, carefully controlled studies of occupational exposure to fluoride and reproductive parameters are needed to further evaluate the possible association between fluoride and alterations in reproductive hormones reported by Ortiz-Perez et al. (2003).
• Freni (1994) found an association between high fluoride concentrations (3 mg/L or more) in drinking water and decreased total fertility rate. The overall study approach used by Freni has merit and could yield valuable new information if more attention is given to controlling for reproductive variables at the individual and group levels. Because that study had design limitations, additional research is needed to substantiate whether an association exists.
• A reanalysis of data on Down’s syndrome and fluoride by Takahashi (1998) suggested a possible association in children born to young mothers. A case-control study of the incidence of Down’s syndrome in young women and fluoride exposure would be useful for addressing that issue. However, it may be particularly difficult to study the incidence of Down’s syndrome today given increased fetal genetic testing and concerns with confidentiality.

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Data from the CDC website about the effectiveness of community water fluoridation:

Recommendations for Using Fluoride to Prevent and Control Dental Caries in the United States, CDC Working Group (published on CDC Webpage)

“Studies on the effectiveness of adjusting fluoride in community water to the optimal concentration cannot be designed as randomized clinical trials. Random allocation of study subjects is not possible when a community begins to fluoridate the water because all residents in a community have access to and are exposed to this source of fluoride.  ….Despite the strengths of early studies of the efficacy of naturally occurring fluoride in community drinking water, the limitations of these studies make summarizing the quality of evidence on community water fluoridation as Grade I inappropriate.

“Initial studies of community water fluoridation demonstrated that reductions in childhood dental caries attributable to fluoridation were approximately 50%–60% (94–97). More recent estimates are lower — 18%–40% (98,99). This decrease in attributable benefit is likely caused by the increasing use of fluoride from other sources, with the widespread use of fluoride toothpaste probably the most important.”

“Fluoride ingested during tooth development can also result in a range of visually detectable changes in enamel opacity (i.e., light refraction at or below the surface) because of hypomineralization. These changes have been broadly termed enamel fluorosis, certain extremes of which are cosmetically objectionable.”