Dear Selectman Ball:

This letter accompanies transmission of the report "Should Natick Fluoridate?" prepared jointly by the Fluoridation Study Committee of the Town of Natick. A summary version of this report is being prepared and copies will be provided as soon as it has been completed. Please advise if we can be of further service to the Board of Selectmen.

Sincerely,

Norman R. Mancuso, Ph. D.
Chairman, Natick Fluoridation Study Committee

Findings, Conclusion, and Recommendations of the Natick Fluoridation Study Committee

This statement of Findings, Conclusion and Recommendation specifically addresses the following question of the Board of Selectmen:

On the basis of the documentation provided to you by the proponents and opponents, do you believe that the potential side effects associated with fluoridating Natick's public water supply outweigh the potential benefits?

Findings

The Natick Fluoridation Study Committee conducted a thorough review of the scientific literature and made the following findings regarding the benefits and risks of water fluoridation.

• Recent studies of the incidence of cavities in children show little to no difference between fluoridated and non-fluoridated communities.
• Ten to thirty percent (10-30%) of Natick's children will have very mild to mild dental fluorosis if Natick fluoridates its water (up from probably 6% now). Approximately 1% of Natick's children will have moderate or severe dental fluorosis. Dental fluorosis can cause great concern for the affected family and may result in additional dental bills. It should not be dismissed as a "cosmetic" effect.
• Fluoride adversely effects the central nervous system, causing behavioral changes and cognitive deficits. These effects are observed at fluoride doses that some people in the US actually receive.
• There is good evidence that fluoride is a developmental neurotoxicant, meaning that fluoride effects the nervous system of the developing fetus at doses that are not toxic to the mother. The developmental neurotoxicity would be manifest as lower IQ and behavioral changes.
• Water fluoridation shows a positive correlation with increased hip fracture rates in persons 65 years of age and older, based on two recent epidemiology studies.
• Some adults are hypersensitive to even small quantities of fluoride, including that contained in fluoridated water. At least one such person is a Natick resident.
• The impact of fluoride on human reproduction at the levels received from environmental exposures is a serious concern. A recent epidemiology study shows a correlation between decreasing annual fertility rate in humans and increasing levels of fluoride in drinking water.
• Animal bioassays suggest that fluoride is a carcinogen, especially for tissues such as bone (osteosarcoma) and liver. The potential for carcinogenicity is supported by fluoride's genotoxicity and pharmacokinetic properties. Human epidemiology studies to date are inconclusive, but no appropriate major study has been conducted.
• Fluoride inhibits or otherwise alters the actions of a long list of enzymes important to metabolism, growth, and cell regulation.
• Sodium fluorosilicate and fluorosilicic acid, the two chemicals Natick intends to use to fluoridate the water supply, have been associated with increased concentrations of lead in tap water and increased blood lead levels in children, based on case reports and a new, as-yet-unpublished study.
• If Natick fluoridates its water supply at the proposed level, most children under the age of three will daily receive more fluoride than is recommended for them.

The scientific literature supporting these findings is summarized in the full report which also discusses a variety of non-health related concerns that have been raised about water fluoridation

Conclusion

The Committee reached the firm conclusion that the risks of overexposure to fluoride far outweigh any current benefit of water fluoridation.

1. The Natick Fluoridation Study Committee unanimously and emphatically recommends that the town of Natick NOT fluoridate the town water supply.

2. The Natick Fluoridation Study Committee unanimously and emphatically recommends that the Board of Selectmen take appropriate action to ensure that fluoridation of the town water supply does not take place.

In May of 1988, the Natick Board of Health ordered the upward adjustment of fluoride in the town water supply. A petition was filed by more than ten (10%) per cent of the town's registered voters to place the question on the ballot. A public referendum was held on Nov. 8, 1988 on the question:

"Shall the public water supply for domestic use in this Town be fluoridated?"

The voters approved the issue by a vote of 7453 (51.4%) yes to 7044 (48.6%) no. A subsequent referendum was held on Mar. 25, 1997 on the identical question, except that in this case, the status of the question was non-binding. In this latter case, the voters did not approve this question by a vote of 2635 (54.3 %) no to 2220 (45.7 %) yes, a reversal of opinion of almost six (6%) percent.

Subsequent Town Meeting Articles 35 and 36 sought to put aside the 1988 vote and to pass special legislation which would place the issue on the ballot at the next annual town election or biennial state election, whichever was held first. Town Meeting voted to indefinitely postpone both articles.

The Chairmen of the Board of Health and the Selectmen requested a legal opinion from the Town Counsel, John P. Flynn, Esq., which was provided on May 8, 1997. (1)

Recognizing the existence of an incredibly large database of conflicting opinion and that both proponents and opponents on the fluoridation issue were entrenched and unlikely to reach a consensus, on April 28, 1997, the Board of Selectmen voted to appoint a special committee of unbiased and qualified people to study the fluoridation issue and to report back on their findings to the Board of Selectmen within approximately ninety (90) days. Hearings at two subsequent Selectmen's meetings produced a number of qualified, scientifically trained and experienced people and from that group, the Natick Fluoridation Study Committee (hereinafter NFSC) was formed by the Board of Selectmen. (2) The present document constitutes the report requested by the Board.

Since an exhaustive literature search of the issues of fluoride and fluoridation could consume the resources of the committee for several months, the Board of Selectmen recommended that the committee obtain from the proponents and opponents of the issue suitable documentation with which to begin the pursuit of the resolution of the issue. (3)

The fluoridation proponents in Natick consist of the Natick Board of Health (hereinafter BOH) and those citizens of the town who are similarly disposed on the issue of fluoridation. A letter was sent by NFSC to the BOH on July 3, 1997 requesting that the BOH provide:

Five sets of documents, each comprised of a maximum of six study reports which in the opinion of the BOH most clearly explain why the public water supply of Natick should be fluoridated.

In addition, a maximum of six endorsements, letters and other non-data-intensive documents that support their contention that fluoridation is both beneficial and lacking in undesirable side effects.

On August 11, the BOH complied with this request by providing five copies of each of the above sets of documents (see Appendix A - Source Materials).

The opponents of the fluoridation issue in the town are represented by Ms. Shirley Brown of Megonko Road in Natick and Dr. Myron Coplan of Intellequity, Inc., also of Natick. Each of these individuals were also requested on July 3, 1997 to provide to NFSC similar packets of materials as follows.

Five sets of documents, each comprised of a maximum of three study reports which in the opinion of the opponents most clearly explain why the public water supply of Natick should not be fluoridated.

In addition, a maximum of three endorsements, letters and other non-data-intensive documents that support their contention that the undesirable side effects of fluoridation outweigh its beneficial effects.

The above materials were provided immediately by Ms. Brown and on July 9, 1997 by Dr. Myron Coplan (see Appendix A - Source Materials).

In this manner, it was anticipated that the most driving arguments for and against the issue would be immediately present, as would be the best reference list(s) of supporting original research papers. All of the above notwithstanding, the NFSC was not constrained to limit its search to the above materials and has instituted wide-ranging literature searches on the entire issue, often spending several hours per day in reading and/or pursuing further information.

1. On the basis of the documentation provided to you by the proponents and opponents, do you believe that the potential side effects associated with fluoridating Natick's public water supply outweigh the potential benefits?

2. If your answer to question 1 is "No" -- i.e. you believe Natick's water should be fluoridated -- do you believe that steps should be taken to establish the appropriate dosage before such fluoridation begins?

3. If your answer to question 2 is "Yes", do you believe that an outside organization should be engaged to examine Natick school children and determine their DMFS (decayed, missing and filled surfaces) levels as an aid to selecting an optimum fluoridation level?

4. If your answer to question 3 is "Yes", what organizations (identify at least two) are qualified to conduct such a survey, and what are preliminary estimates of the costs involved?

The format being used for this report is based upon the four charges of the Board of Selectmen with regard to the fluoridation issue. Each charge or question constitutes one section of the report. The individual issues addressed within each section result from the nature of the associated charge or question. In any publication of this nature, the issue of providing references must be addressed. On the one hand, material for public consumption is rarely well-received when numerous references are included. This is particularly so when the references take the form of foot-notes as opposed to end-notes. On the other hand, nothing makes a report such as this more suspect than when no verifiable references are included and the reader is tacitly expected to accept the discussion and conclusions on faith alone. We feel strongly enough about this issue to insist on the presence of references. The only relaxation of this requirement was an attempt to reduce the tedium that would be caused by having to constantly flip to the end of the report to find a reference or explanatory note. This was accomplished by placing all of the references for each section immediately following that particular section. This has the necessary consequence of occasionally having more than one occurrence of the same reference but improves the readability and overall usefulness to the reader.

Scientific information that has an impact on political and economic interests often generates controversy, even within the scientific community. This controversy is often magnified when the information is presented in the lay press. It is not that truly non-partisan reporting is unavailable, rather it is that the entrenched partisans of any such issue are only willing (able?) to accept those portions of the report which support their contentions. Be that as it may, there are some reviews of the fluoridation issue that are unbiased, chief among which is a review by Bette Hileman appearing in Chemical & Engineering News. (5) As background material, it is required reading for anyone interested in the issue of fluoridation. A brief portion of this review is quoted below in order to set the stage for further discussion. (Contrary to normal usage, direct quotes appearing within the text below are emboldened and not italicized in order to distinguish them from the remaining commentary.)

Throughout this report, the reader will note the recurrent use of the words "optimal", "optimum" and such phrases as "optimally fluoridated". It is important to understand that this usage is a direct contribution of the profluoridation argument and is therefore vigorously objected to by the antifluoridation contingent. In most cases, we have placed quotation marks around these words and phrases to indicate that the term is disputed and should be read as "so-called optimum".

".........The style of promotion that fluoridation's proponents have used from the very beginning probably made the issue more controversial than it need have been.

The idea of fluoridating water supplies first arose from studies of dental mottling in areas, such as communities in Texas, where the water supply is fluoridated naturally. In the 1930s, H. Trendley Dean, a dental surgeon at the U.S. Public Health Service, correlated the occurrence of mottling or dental fluorosis with the fluoride content of water supplies in 345 U.S. communities. Fluorosis was most common in cities that had the highest concentration of fluoride in their water. He and his colleagues also unexpectedly found a lower incidence of dental caries in areas of endemic dental fluorosis.

Dean concluded that the fluoride content of the drinking water causes a lower rate of dental caries. He also determined that the incidence of mottling was very minor when the fluoride content was 1 ppm or lower but rose linearly at higher concentrations. From this, PHS officials decided in 1943 that 1 ppm was an optimal level at which to artificially fluoridate water supplies in temperate climates. In areas where the fluoride content exceeded 2 ppm, they recommended fluoride be reduced to a level near 1 ppm.

In 1945, PHS initially planned to conduct 10-year studies of artificial fluoridation in two experimental projects, one in New York and one in Michigan. One city in each state would be fluoridated artificially and another would serve as a control. PHS officials intended to complete these projects before deciding whether to recommend fluoridation of drinking water as a general practice for all communities.

However, two public health officers in Wisconsin, Francis A. Bull and John Frisch, quickly became convinced of the effectiveness of fluoridation and launched a nationwide campaign to persuade PHS to endorse it. Also, results from the two projects that leaked out in 1950, after the trials had been going on for five years, revealed a sharp reduction in dental caries in the fluoridated cities. As a result of this disclosure and Bull's and Frisch's campaign, PHS officials endorsed fluoridation on June 1, 1950.

Several deficiencies in research by PHS were subsequently aired at Congressional hearings in 1952 and 1957. There had been almost no careful studies to assess the possible adverse health effects of lifelong consumption of fluoridated water. Aside from their dental health, the medical condition of residents of naturally fluoridated areas had been examined superficially, at best. In one of the fluoridation trials, research plans included a study of adverse effects of artificial fluoridation on children, but none on adults. No studies focused on malnourished children and infants, despite a warning in 1952 by Maury Massler, professor of pedodontics at the University of Illinois College of Dentistry, that "low levels of fluoride ingestion which are generally considered to be safe for the general population may not be safe for malnourished infants and children, because of disturbances in calcium metabolism."

Neither PHS nor anyone else had investigated potential carcinogenic effects, effects on pregnant women, or effects on people with chronic kidney impairment or other chronic diseases. Even in the early 1950s, enough was known of fluoride's toxicity profile to identify these as important topics to investigate.

From the beginning, the movement to fluoridate water was conducted more like a political campaign than a scientific enterprise. At a meeting of state dental directors with PHS officials in June 1951, Bull recommended tactics for promoting fluoridation. ''If it is a fact that some individuals are against fluoridation, you just have to knock their objections down. The question of toxicity is on the same order. Lay off it altogether. Just pass it over. 'We know there is absolutely no effect other than reducing tooth decay,' you say, and go on. If it becomes an issue, then you will have to take it over, but don't bring it up yourself."

"The minute doubt is created in the minds of the public, any public health program is doomed to failure," Bull later wrote in the Journal of the American Dental Association.

The political role of dentists has been emphasized throughout the history of fluoridation. In 1970, even after 25 years of fluoridation, John W. Knutson, then professor at the University of California Medical Center, advised dentists that when they discussed fluoridation with the public, they must realize that "they are propagandizing, not simply educating." This attitude, widely shared by political proponents, led early advocates to treat fluoridation campaigns as debates to be won with dogmatic assertions and attacks on the credibility of the opposition. To promoters, the debate has never been seen as a scientific search for truth.

As a result, profluoridationists prepare booklets for the public that contain highly biased information. If scientific studies are cited, only those that support their side of the argument are mentioned. Those opposed to fluoridation counter with equally biased propaganda........" (5)

According to many opponents of fluoridation, other tactics which were also widely used to denigrate any potentially negative effects include character assassination, inflammatory portrayal of the opposition, the widespread suppression of opposing results (see Appendix B) and the widespread use of sensationalism, etc. In the latter case at least, the antifluoridationists are no less culpable.

1. On the basis of the documentation provided to you by the proponents and opponents, do you believe that the potential side effects associated with fluoridating Natick's public water supply outweigh the potential benefits?

This is the main question to be addressed in this report. It also includes the reasons why the issue of fluoridation is so controversial. In spite of the other topics presented in this report, the main issue remains whether the benefits of fluoridation outweigh the risks. Moreover, it appears that the only significant benefit of fluoridation is the reduction of dental caries, this in spite of other past reports touting the applicability of fluoridation to osteoporosis as well (see the section on other positive effects of fluoridation). The "profluoridationists" have repeatedly asserted that there are no negatives associated with the process, or alternatively, that all of the negative reports are without scientific justification or merit. Because of this position, an examination of these negative reports tends to cast the examiners in the role of a "devil's advocate", the chief difficulty of which is that the examiners are then also perceived as being "antifluoridationists", when in fact they are merely seeking to extract the truth from the polemics and hysteria of the issues and to expose this information to a critical and unbiased analysis. With this in mind we report on the following material.

During the course of dental research conducted in the early part of this century on the condition then known as "Colorado Brown Stain" (a.k.a. "Texas Teeth" or dental fluorosis as it came to be medically known), it was discovered that individuals, living in areas where the water is known to contain elevated (relative to most water supplies) fluoride concentrations, exhibited a decreased rate of incidence of dental caries. (1) Several studies conducted during the decades prior to 1960 confirmed that when a small quantity (ca. 1 part per million, ppm) of fluoride was added to a community water supply, the incidence of tooth decay among the residents of those community decreased substantially. (2) The initial studies indicated a reduction in tooth decay of 50 to 60 per cent. (3) As a result of these achievements, the process of fluoridation of community water supplies has continued and resulted in more than half of the U. S. population being served by a fluoridated supply. (4) Numerous scientific papers have supported fluoridation throughout its history. (5-9) More recent studies , as interpreted by profluoridationists, indicate that reductions of between 20-40% are routinely achievable. (10-12)

The desirability of the process of fluoridation of community water supplies, as maintained by the profluoridation community, is based upon the following reasoning: (13)

• Fluoridation is the least expensive and most effective way to reduce tooth decay.
  
• Fluoridation is safe.
  
• Fluoridation benefits both children and adults.
  
• Fluoridation benefits continue for a lifetime when fluoridated water consumption continues.
  
• Fluoridation is the surest way for everyone in the community to benefit.
  
• Fluoridation benefits everyone when they drink fluoridated water and consume foods and beverages prepared with it.

The following non-exhaustive list illustrates the wide-spread support for the fluoridation programs. (13, 14)

• Mass. Dept. of Public Health
  
• American Association of Public Health Dentistry
  
• American Dental Association
  
• Centers for Disease Control & Prevention
  
• American Medical Association
  
• World Health Organization

Proponents of fluoridation have also attempted to show that fluoride can be used to alleviate the symptoms of osteoporosis, and therefore that people living in fluoridated areas may be helped by the fluoride they are accumulating in their bones. Because fluoride increases bone mass, (see the section on Osteosclerosis) numerous patients have been given and are still being given large doses of fluoride as a treatment for osteoporosis. Recent data has not produced compelling evidence of beneficial results. The FDA has not approved the use of fluoride for osteoporosis. In spite of this, the National Osteoporosis Foundation reports that an FDA advisory committee has recommended that slow-release sodium fluoride be approved for the treatment of osteoporosis. (15)

Fluoride was first investigated as an anti-caries agent because of the inverse relationship noted in many areas of the country between the prevalence of dental caries and the level of fluoride in drinking water. At first, scientists believed that the anti-caries activity of fluoride was the direct result of its incorporation into the apatite crystal of enamel, thus increasing its stability and reducing its acid solubility. The theory of pre-eruptive fluoride incorporation as the principal mechanism of caries prevention has been largely discounted. (1) Recent studies have suggested that the anti-caries action of fluoride may be related to the fluoride levels in the saliva and plaque fluids rather than the enamel surface itself, i.e., the action is topical rather than systemic. (2,3) Indeed, if one diligently searches the literature of fluoridation, it becomes clear that there are widespread differences of opinion among experts as to the actual mechanism. Moreover, it is significant that in one survey, only 66% of physicians thought that community fluoridation is very effective and only 37% think that dietary supplements are very effective. (4) This same survey reported that only a small percentage of physicians and dentists believe that topical fluorides are very effective preventive measures, so it is clear that even among "those who should know", there is a large measure of discordant opinion.

The sources of fluoride intake for the U. S. population are primarily water, food, dental products and air (see Tables I & II). Children may also receive fluoride in supplements. Although fluoride exposure is generally greater in areas with fluoridated water than in areas with non-fluoridated or low-fluoridated water, populations in both areas are exposed to fluoride from food sources, drinking water, processed beverages and dental products. In one recently published survey, Dabeka and McKenzie have reported that the average intake of fluoride from food, averaged over all ages and sexes, was 1.76 mg/day. (5) Fluoride exposure differs markedly, depending upon several factors, e.g., lifestyle, dietary practices, age, gender and health status. It is clear however that drinking water provides minimal topical fluoride.

The Agency for Toxic Substances and Disease Registry (ATSDR) sets the Minimal Risk Level (MRL) for ingestion of fluoride at 0.4 mg/kg/day. (6) In a 20 pound child this amounts to 3.6 mg/day and for a 50 pound child, the minimal risk level is about 9 mg/day. The MRL is an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse non-cancer health effects over a specified duration of exposure. However, to avoid an undesirable degree of dental fluorosis, children should consume no more than 0.10 mg of fluoride per kg of body weight per day.(7)

Studies show that tooth decay has declined in every country in the developed world. (2,3,9) The largest study in this country (the NIDR 1986-87 survey of 39,000 U.S. school children, (1)) showed no significant difference in dental caries in those living in fluoridated as opposed to those living in non-fluoridated communities. (11) See Fig. I.

1. (A) US PHS, Review of Fluoride Benefits and Risks., Report of the Ad Hoc Subcommittee on Fluoride; Un-numbered publication of the Department of Health and Human Services, September 1991
   
2. (B) US PHS, Water Fluoridation A Manual for Water Plant Operators., Center for Disease Control and Prevention, Division of Oral Health, Atlanta, April 1994.
   
3. Hilderbolt CF, et al., Caries Prevalences Among Geochemical Regions of Missouri., American Journal of Physical Anthropology 78:79-92, (1989)
   
4. Leroux BG, et al., The Estimation of Caries in Small Areas., Journal of Public Health Dentistry, 75:1947-56, (1996)
   
5. Moreno EG, et al., Fluoridated hydroxyapatite Solubility and Caries formation., Nature 247:64-65, (1974)
   
6. Pendrys DG, and Stamm JW, Relationship of Total Fluoride Intake to Beneficial Effects and Enamel Fluorosis., Journal of Dental Research 69:529-538 (1990)
   
7. Evans RW and Stamm JW, Dental Fluorosis Following Downward Adjustment of Fluoride in Drinking Water., Journal of Public Health Dentistry, 52(2):91-98, (1991)

In British Columbia, only 11% of the population lives in areas containing fluoridated water, as opposed to 40-70% in other Canadian regions. However British Columbia has the lowest rate of tooth decay in Canada. (10) According to a 1987 report by Dr. Allan Gray, then director of the Division of Dental Health services for British Columbia, DMFT (decayed, missing or filled teeth) rates (see Appendix D) were falling drastically in both fluoridated and non-fluoridated areas. (11)

Mark Diesendorf, an applied mathematician and health researcher in the Human Sciences Program at Australian National University has found, by comparing results from about 24 studies of unfluoridated districts in eight countries, that reductions in dental caries are just as great in non-fluoridated areas as in fluoridated areas. (2)

One of the most significant factors in any comparison of the incidence of dental caries is the manner in which this is expressed (see Appendix D for a discussion of the methods of describing these incidence rates). In the early days of DMFS (decayed, missing or filled surfaces) scores (in the range of 18-20), a 20% difference (fluoridated vs. non-fluoridated) would indicate several cavities per child. However, given the current average DMFS scores (in the range of 2-4) it is clear that a 20% difference represents less than one cavity per child.

It seems clear that there is a link between fluoride intake and the reduction of dental caries. Although the mechanism is not fully understood, the effect is now thought to be due primarily to topical rather than systemic fluoride. In the early days of fluoridation, there were few other sources of fluoride in the daily diet. The introduction of fluoride into the daily diet (beverages prepared in communities with fluoridated water, toothpaste, food, supplements, etc.) starting in the 1950's has had the effect of reducing dental caries worldwide, even in those countries that do not fluoridate. In fact, fluoride is so widespread today that introducing it into public water supplies seems to have a very minimal effect in reducing dental caries. Current data seems to indicate little difference between the health of teeth in communities having fluoridated water supplies compared to communities having unfluoridated water.

The next several sections deal with those issues which have been raised as being either detrimental or non-beneficial side-effects caused by the fluoridation process and/or the ubiquity of various forms of (chiefly) inorganic fluoride compounds in the environment or as used in the treatment of dental caries. Each section analyzes the scientific literature, paying particular attention to those primary research results which have appeared recently. Each section is comprised of both a discussion as well as a summary with respect to the particular issue treated.

"Fluoride is a halogen with unique properties that enable it, in toxic quantities, to alter calcium availability to tissues, to effect changes to blood clotting parameters, to cause severe cardiac dysfunction, to alter bone and tooth structure, to cause severe anxiety in those who drink fluoridated water and to lead to death where it has been misused either accidentally , in suicide or in homicide."(1,2)

The principal uses of fluoride include prophylaxis of dental caries, toothpastes, animal husbandry, timber preservation and pesticides. Both sodium fluoride and sodium fluorosilicate have been widely used as insecticides and rodenticides. (9) Ellenhorn and Barceleaux list the therapeutic dose at 0.25 to 0.50 milligrams per day (mg/d) and the oral lethal dose as 5-10 grams of sodium fluoride, (3) although less than 1 gram by mouth has caused severe poisoning. (4) Overfluoridation has resulted in mass intoxication (5) and death has resulted from ingesting 2 g of fluoride. (10)

Waldbott and others (6,7) have also remarked upon the extremely small safety margin between therapeutic doses and those causing toxic effects in humans, when compared to safety margins normally employed in medicinal products.

H. C. Hodge, a toxicologist of wide repute, notes that the minimum safety factors in the dietary regimen of any toxic material should be at least one hundred times the therapeutic dose. (8) Other workers in the field consider even this safety margin far too narrow.

On the basis of acute toxicity, it is unreasonable to take a strong position against water fluoridation. On the other hand, there are questions about the nature and significance of chronic toxicity effects which must be addressed, as in the case of proper therapeutic quantities of fluoride. Moreover, the question which must be resolved prior to taking such a position appears to be the determination of what constitutes the proper or safe and effective therapeutic dose. This question has great significance to many of the subjects treated in the following sections. Therefore, Appendix C is included to provide the responses to this question by a number of independent organizations as well as to provide guidelines relative to the total daily individual ingestion of fluoride for different age groups.

1. Throughout this document, the use of the term fluoride refers to the materials to be used in process of fluoridation. When a specific fluorine-containing compound is being referenced, the full name will be used, as, e. g., sodium fluoride, or the chemical formula, in this case NaF.
   
2. Ellenhorn, MJ and Barceloux, DG, Medical Toxicology, p. 531, Elsevier (1988)
   
3. Haynes, RC, Jr., in Gilman, AG, et al., (Eds.), The Pharmacological Basis of Therapeutics, 6th Ed., MacMillan, p. 1524, (1980)
   
4. Greenwood, DA, Fluoride intoxication., Physiol. Rev 20, 582 (1940)
   
5. Waldbott, GL, Mass intoxication from accidental overfluoridation of drinking water, Clin. Toxicol., 18, 531 (1981)
   
6. Waldbott, GL, Fluoridation: The Great Dilemma, p. 107, Coronado Press (1978)
   
7. Schour, I, and Smith, MC, in Fluorine and Dental Health, Moulton, F. R., Ed., (1942)
   
8. Hodge, HC, Research needs in the toxicology of food additives, Food Cosmet. Toxicol., 1:25, (1963)
   
9. Agency for Toxic Substances and Disease Registry, Clement International Corp. Toxicological profile for fluorides, hydrogen fluoride and fluorine (F). U.S. Dept. Health Human Services, Public Health Service, TP-91/17, (1993).
   
10. The Merck Index, (Eighth Ed.) p. 959, (1968)

Varying amounts of fluoride are found naturally in the water supplies of many communities, including Natick. Natick's water has only a small amount of fluoride, on the order of about 0.1 ppm (0.1 mg fluoride per liter water). (1) If too much fluoride is ingested by children it results in a toxic dental condition known as dental fluorosis. This condition is marked by visible mottling and/or discoloring of tooth enamel, pitting of the enamel and disturbed tooth shape. (2, 3) Teeth with moderate dental fluorosis typically "....may have yellow and brown strains...... they are pitted, brittle, and susceptible to fracture." Severe dental fluorosis "...not only produces unattractive teeth but also may increase the risk of tooth loss because it destroys parts of the protective enamel." (4) Historically, dental fluorosis was first noted in children who grew up in areas where the drinking water supplies had a relatively high content of dissolved fluoride as shown in Table I which also lists communities with little or no dissolved fluoride in their water. Children in these latter communities had very little dental fluorosis. (5) It was also noted that children with dental fluorosis had fewer cavities. (2) Thus began the start of the "fluoride tradeoffs" which resulted in 80% to 90% of "treated" children with fewer cavities and 10% to 20% of those with dental fluorosis.

When, why and how does Dental Fluorosis occur?

Dental fluorosis occurs during early childhood while deciduous and permanent teeth and tooth enamel are still being mineralized and before they erupt within the mouth. (6,7) It is believed that dental fluorosis occurs because of the toxicity of fluoride to the enamel-forming cells of the teeth. (6) The degree to which a child experiences dental fluorosis depends on the amount of fluoride (s)he ingests. (2, 3, 6, 8) Dental authorities estimate that a child should ingest daily 0.03 mg to 0.07 mgs of fluoride per kg of body weight. When this amount is exceeded, dental fluorosis results. Moreover, the greater the fluoride overdose, the more severe is the dental fluorosis. Even with supervision, it is possible for a small child to overdose on fluoride each day with only one brushing with a fluoride tooth paste by swallowing much of it during the brushing process. (7)

The current model of fluorosis development proposes that "....fluoride affects the forming enamel by making it porous. The degree and extent of the porosity depend on the concentration of fluoride in tissue fluids when the teeth are developing..." and "....the porosity and discoloration can vary in degree among different areas of the same tooth....." (2) The ultimate result is the increasing porosity of the teeth and, in extreme cases, loss of the affected teeth. (9) Dental fluorosis is an excellent biomarker of excess fluoride ingestion and fluoride intoxication. (10) It is a visible, sometimes easily seen and noticed marker of fluoride intoxication. Unfortunately it tells us of excessive fluoride intake after-the-fact, i. e. after the newly emergent teeth have already been altered.

There is now widespread recognition of the fact that the prevalence of dental fluorosis has increased substantially throughout those countries where fluoridation is practiced. (11-13) However, in spite of some reports to the contrary, (2) there does not appear to be general agreement within the dental community as to whether the severity of dental fluorosis has increased.

The nationwide increase of dental fluorosis was first recognized, documented and published by the National Institute of Dental Research (NIDR) after conducting (1986-1987) a survey that involved 32,241 U.S. school children. The total prevalence of dental fluorosis in this group of children was estimated to be 22.3 percent and included (mostly) very mild to mild dental fluorosis. (2) However some moderate to severe dental fluorosis was also found in approximately 1% to 2% of the children in "optimally" fluoridated water districts. (4) Another NIDR report published in 1988, studied four areas in Illinois with water concentration of one, two, three and four times the recommended "optimal" fluoride level. As of 1985, in the "optimally" fluoridated areas, twenty nine per cent of all tooth surfaces examined were reported to be affected by dental fluorosis. In those areas that had 2 to 4 times the optimal dose of fluoride in the water supply, dental fluorosis affected close to seventy per cent of the teeth involved. (2) An even more recent study, published in 1990 ( Table II) listed dental fluorosis in additional comparable cities in the United States and New Zealand with water systems "optimally" fluoridated and those with low fluoride. (14)

In carefully comparing the data in Table 1 and Table 2, a number of observations can be made:

(l) the incidence of dental fluorosis in the children of Kewanee IL (selected because it is included in both studies and uses "optimally" fluoridated water) has increased from 1939 to 1990;

(2) the prevalence of dental fluorosis is greater in "optimally" fluoridated communities than in communities with fluoride-deficient water and;

(3) the percentage of dental fluorosis found today in "optimally fluoridated" communities approaches those found in communities with water containing 2, 3 and 4 times the "optimal level" of fluoridation 50 years ago.

The Anticipated Occurrence of Dental Fluorosis and Needed Corrective Measures

Now, as well as in the past few years, parents are being cautioned by the dental profession against excessive fluoride intake by infants and children by carefully regulating their total intake of fluoride in order to prevent dental fluorosis in developing teeth. This becomes increasingly more difficult as the infant/child grows older because of the ubiquity of fluoride in our country. Excessive amounts of fluoride can be ingested from a number of available sources: daily dietary fluoride supplemental pills, using fluoridated toothpaste, eating fluoride containing vegetables and fruits, other foods and drinks prepared with fluoridated waters and the application of topical fluoride products to teeth. (2, 7, 15) This is especially applicable if more fluoride is added to the communal water supply. Based on previously published data from other areas with drinking water fluoridated to about 1 ppm or 1 mg/liter ("optimal") our most optimistic scenario will show a minimum of one child out of every ten showing evidence of some degree of dental fluorosis. (2,5) However, if care is not exercised in preventing excessive fluoride intake, two to three children out of ten may develop dental fluorosis. The problem is exacerbated by the permissible fluoride levels in drinking water established by the U.S. Environmental Protection Agency's Safe Drinking water Act of 1974, in which the EPA set, on April 2, 1986, drinking water regulations for fluoride as follows:

1. "Primary Maximum Contaminant Level (MCL) of 4 mg F/L to protect against crippling skeletal fluorosis," and
2. "Secondary Maximum Contaminant Level of 2 mg F/L to protect against moderate to severe dental fluorosis".

This suggests that water-based consumer products should be made with water containing 2 ppm of fluoride or less.

The most effective corrective measure is to have children with developing teeth, especially permanent teeth, avoid the intake of toxic quantities of fluoride. This may be difficult to do for several reasons. Firstly, a child can unknowingly and unintentionally get unwanted fluoride from dental products, foods and drinks as mentioned above. Secondly, the expressed symptoms of dental fluorosis are not identical for all children exposed to the same dose of fluoride. Therefore there is difficulty in predicting fluorotic effects. Thirdly, there is also difficulty in diagnosing very mild to mild dental fluorosis by dental clinicians thereby missing opportunities to aesthetically correct objectionable fluorosis. (2)

The severity of the dental fluorosis and the psycho-socio-economic status of a child afflicted with dental fluorosis will determine if corrective action will be taken. Corrective procedures, when required or desired, include vital bleaching, abrasion and bonded veneers. These corrective procedures are performed by dental clinicians. However, at the present time dental fluorosis is considered to be a cosmetic effect (2) and therefore these corrective procedures are not covered by most dental insurance companies. Moderate-to-severe fluorosis results in unattractive misshapen teeth and probably will result in psychological damage to the affected child. However little research on the psychological effects of dental fluorosis on children has been conducted. (9)

Summary and Conclusions

Excessive fluoride intake by children causes a toxic dental condition known as dental fluorosis which is marked by visible mottling/discoloring of tooth enamel, pitting of the enamel and disturbed tooth shape. Dental fluorosis occurs during early childhood while the baby and permanent teeth and tooth enamel are still being mineralized and before they erupt in the mouth. The severity of the dental fluorosis is directly proportional to fluoride ingested in excess of 0.03 mg to 0.07 mg fluoride/kg of body weight/day. The ultimate result is the increased porosity of the teeth and, in extreme cases, loss of afflicted teeth. The prevalence of dental fluorosis is increasing in communities that have water supplies that are "optimally fluoridated" and in those with fluoride deficient doing water because of the ubiquity of products containing fluoride. However the prevalence and severity of dental fluorosis is greater in "optimally fluoridated" communities than those with fluoride-deficient water. Parents are being advised to protect against excessive fluoride intake by infants and children by carefully regulating their total intake of fluoride. It is anticipated that fluoridation of the Natick water supply to 1 ppm or 1 mg/L will result in dental fluorosis to some degree in at least one child out of every ten. However if care is not exercised in preventing excessive fluoride intake, two to three children out of every ten may develop dental fluorosis. Corrective procedures, when required, can be performed by dental clinicians. However, the cost of teeth rehabilitation will be borne, most likely, by the individual/parent since dental fluorosis is considered to be a cosmetic defect and therefore is not covered by most dental insurance plans.

Skeletal Fluorosis, Osteosclerosis & Related Disorders

Two diseases of the skeletal system are osteosclerosis and osteoporosis. Osteosclerosis is a disease involving an increase in bone density (and thickening) accompanied by an increase in bone brittleness. Osteoporosis is a disease involving a decrease in bone density (due to loss of calcium) leading to decreased bone strength. (1) Osteofluorosis is an osteosclerosis caused by prolonged overdoses of fluoride.

Osteoporosis

Prolonged or increased ingestion of fluoride is known to result in increased bone mass. However, the bone formed in response to these high and/or prolonged doses of fluoride is reported to exhibit both reduced strength and increased fragility. (2, 3, 4) The abnormal bone resulting from fluoride is of poor quality and while the increased mass helps compressive strength, it generally leads to weakness of tensile strength. Thus, tests of fluoride "treatment" for osteoporosis finds a decrease in vertebral compression fractures but an increased incidence of hip and long bone fractures, compared to control patients. Other researchers have advised abandoning fluoride as a legitimate treatment for osteoporosis for that reason as well as for the well known toxicity of fluorides. In fact, in a 1987 review of fluoride therapy for osteoporosis, Louis V. Avioli, professor at the Washington University School of Medicine, concludes: "Sodium fluoride therapy is accompanied by so many medical complications and side effects that it is hardly worth exploring in depth as a therapeutic mode for postmenopausal osteoporosis, since it fails to decrease the propensity toward hip fractures and increases the incidence of stress fractures in the extremities." (5)

Skeletal (Osteo)Fluorosis

Osteofluorosis is a complicated disease with a number of stages. The first two stages are preclinical, that is, the patient feels no symptoms but changes have taken place in the body. In the first preclinical stage, biochemical changes occur in the blood and bone composition; in the second stage histological changes can be observed in bone biopsies. Some experts call these changes harmful because they are precursors of more serious conditions. Other experts say they are harmless. (6) Most admit that the effects of long term ingestion of fluoridated water on bone are poorly understood. (6)

The clinical stages of osteofluorosis includes pain in the bones and joints, muscle weakness, fatigue, calcification of ligaments and bone spurs. Most experts in skeletal fluorosis agree that ingestion of 20 mg of fluoride per day for 20 years or more can cause crippling skeletal fluorosis and doses as low as 2 to 5 mg per day over the same time period can cause the preclinical stages. (7) Moreover, the total quantity of fluoride ingested is the single most important factor in determining the clinical course of osteofluorosis. (8) The severity of the symptoms correlates directly with the level and duration of exposure. For almost 40 years, investigators in the United States have searched for evidence of osteofluorosis. The U. S. Public Health Service (8) reports that:

"....Radiographic changes in bone indicative of skeletal fluorosis, changes in bone mass, and effects on skeletal maturation were not observed at water fluoride concentrations of 1.2mg/l for 10 years and from 3.3 to 6.2 mg/l for a lifetime. In a survey of 170,000 radiographs of patients living in Texas and Oklahoma with water fluoride levels between 4 and 8 mg/l, Stevenson and Watson (1957) found 23 cases of radiographic osteosclerosis, but no evidence of skeletal fluorosis." (references deleted.)

Nevertheless, large numbers of people in Japan, China, India. the Middle East and Africa have been diagnosed with skeletal fluorosis. (9) In India, Tanzania and South Africa, crippling forms of skeletal fluorosis have been reported in pediatric age groups as well. (8)

Hip and other Fractures

In clinical practice, the occurrence of atraumatic minor compression fractures of vertebra is common in postmenopausal osteoporotic women and is frequently asymptomatic, being found only by radiographs, though the patient may have noted a slight decrease in height over time. The more morbid consequence of osteoporosis is hip fracture which has the potential for seriously disabling patients. It has been suggested that sodium fluoride could be used as a treatment for osteoporosis since it is associated with 'bone thickening'. Dr. C. Y. C. Pak and others are conducting a USPH funded and FDA approved study using slow-release sodium fluoride in the management of postmenopausal osteoporosis. (10) In this study, Dr. Pak is administering about 25 mg of fluoride per day in a slow release form to post menopausal women in order to raise their serum fluoride levels from 50 ng/ml to slightly over 100 ng/ml while avoiding fluoride's known gastric inflammatory effects such as mucosal erosions, ulcers, and bleeding which regularly accompany usual oral fluoride supplementation at this dosage. However, according to a critical review of this study appearing in the journal, "Fluoride", Dr. John Lee states that: "....(Dr. Pak's study) seems limited to demonstrating the obvious, i.e., that excessive fluoride causes osteofluorosis."(10)

The one interesting finding in Pak's interim report is the fact that fluoride supplementation did not cause any reduction in vertebral fractures in women on estrogen supplementation compared to controls. Among estrogen-treated women, the fracture-free rate of the placebo (no fluoride) group compared to that of the fluoride group was 75.0% and 76.9% respectively, an inconsequential difference

In a national study of ecological design (11), Jacobsen et al., examined the association between water fluoridation and the incidence of hip fractures. For the period 1984-1987, a total of 218,951 eligible hip fracture cases were studied. (12) Raheb characterized the results of Jacobsen's study as "...A small, statistically significant, positive association was found between fluoridation and fracture incidence rates." (13) However, a careful review of the data of Jacobsen and his co-workers show an eight (8%) percent increase in women [±2 percent] and a seventeen (17%) percent increase for men [±4 percent]. A more recent study on a smaller population (which was restricted to Mormon communities in Utah to correct for confounding factors such as smoking and/or use of alcohol) showed an increased incidence of hip fractures of 27% in women and 41% in men, albeit with a larger 95% confidence interval. (14) While four other studies indicate either no effect or a negative effect of fluoridation, these studies involved a total of only 6,874 subjects as opposed to positive correlation in the case of 781,575 subjects.

Summary

Well controlled studies have not demonstrated a beneficial effect of the use of high doses of fluoride in reducing osteoporosis and related bone fractures. However, there has been shown to be a positive relationship between water fluoridation and increased hip fractures in persons 65 years of age and older. Human crippling osteofluorosis is endemic in several countries of the world, but is extremely rare in the United States. A number of factors govern the amount of fluoride deposited in the skeleton. The important factors include:

• 1) age at exposure
  
• 2) duration of exposure
  
• 3) dose of fluoride
  
• 4) nutritional status
  
• 5) renal status
  
• 6) individual biological variation.

Whether or not fluoride causes cancer in humans has been a subject of heated debate. Based on the journal articles and other documents reviewed by this committee, the debate has not been resolved and appropriate epidemiology studies have yet to be conducted. This section of the committee report summarizes the two major animal bioassays that have tested fluoride for its carcinogenic potential. It also reviews some of the human epidemiology studies that have been published.

Animal Studies

The US National Toxicology Program (NTP) tested sodium fluoride for carcinogenicity in a 2 year bioassay using rats (F344/N) and mice (B6C3F1) (1) The most often cited result of this study is that it provided "equivocal" evidence of carcinogenicity based on a statistically significant elevation of osteosarcoma (a type of bone cancer) in male rats. No bone cancer was observed in female rats and male or female mice. However, a careful review of the data presented in the published report of this study (1) shows that one additional osteosarcoma was observed, but not counted in male rats. In addition, one male and one female mouse treated with fluoride also developed osteosarcoma, although these were not included in the summary table, only in the footnotes.

In addition to bone cancer, the NTP study showed marginal differences between control animals and dosed animals with respect to cancer of the oral mucosa, thyroid gland and uterus of rats and the hematopoietic system and liver in mice. While several liver tumor types were observed in male and female mice, two tumor types were considered highly unusual and worthy of note: hepatoblastoma and hepatocholan-giocarcinoma (1).

In general, animal bioassays test chemicals at doses much higher than received by humans, and the results are then extrapolated to lower doses. In the NTP study, sodium fluoride was administered in drinking water at 25, 100 and 175 ppm. A special low fluoride diet was formulated. A measure of cumulative dose (dose taken in over a long period) for fluoride is the ash content in the bone. Comparison of the fluoride in the bones of the animals in the high (125 ppm) dose group with humans drinking water with fluoride concentrations above 2 ppm show that older humans have more fluoride in their bones than the high dose animals (1,2). In other words, this study was conducted using fluoride doses that humans actually receive.

The NTP study has been criticized by all sides: some charge the study understates the cancer potency, others say it overstates the potency and is irrelevant to humans (2,3,4).

William Marcus, an EPA toxicologist, compared the rate of osteosarcoma in historical controls (control animals used in previous toxicology testing studies) with those obtained in the dosed animals in the fluoride study. He assumed the fluoride dose in the historical controls was due to ingestion of normal rat chow, and represented a dose between the 25 ppm and 100 ppm dose group in the fluoride drinking water study (the NTP agrees with this calculation). Marcus found that the observed "historical" control rate of osteosarcoma fit exactly where expected based on the fluoride dose (2). Marcus also reports that the original pathologist's classifications of the liver tumors in the rat, oral tumors in the rat, and adrenal pheochromocytomas were consistently downgraded by a review panel (2). This would serve to underestimate the evidence for cancer based on the animal study. Marcus recommended that EPA assemble an independent panel of pathologists to review the slides from the NTP study.

James Bawden, representing the American Associations for Dental Research (AADR) at a peer review panel of the NTP study, claimed that the types of bone tumors observed in the rat differ from osteosarcoma observed in humans, and thus the NTP study has no relevance to humans (4). However, Bawden's statement represents a fundamental misunderstanding of the purpose of the 2 year bioassay: it is not a model for a specific cancer at any particular site in the body. The purpose of the bioassay is only to show the potential for a chemical to induce cancer; correlation of cancer sites in the animal and humans is not required and indeed, is rarely observed. John Stamm, representing the American Dental Association at the peer review panel (5), expressed concern about how the NTP did its statistical analysis and suggested the data were not strong enough to call fluoride an "equivocal" carcinogen.

Proctor and Gamble (P&G) sponsored a 2 year bioassay in which rats (Sprague - Dawley) were administered sodium fluoride in food. Rats were fed 1.8, 4.5, or 11.3 mg fluoride per kg body weight each day in a low fluoride semi-synthetic diet. There were two control groups, one fed the low fluoride semi-synthetic diet and one fed normal rat chow (fluoride content not determined). The fluoride content of the drinking water was not reported. The study ended early because too many animals died in both the fluoride fed and control groups. There were multiple problems with this study, including that the semi-synthetic diet may not have provided the nutrients for normal growth and development and a virus is likely to have infected the animals (6).

The original laboratory conducting the P&G rat study reported one osteosarcoma in a low dose female and a few other tumors. The carcinogencity assessment committee of the FDA reassessed the data and found another osteosarcoma in a low dose female and one in a high dose male. Moreover, not all the animals were carefully examined for bone cancer and thus other tumors may have been missed. The FDA review concluded that "...there are flaws and uncertainties in the studies that keep them from providing strongly reassuring data" (6).

The P&G study was also conducted with mice. Osteomas (non-malignant bone tumors) were observed in all groups with a significantly higher incidence in the high fluoride dose group. However, the mouse study hasn't been deemed useful for risk assessment because the mice in both the treatment and control groups were infected with a virus (C-type retrovirus), and it is suggested that the tumors were formed via an interaction between the virus and fluoride (7).

Human epidemiology studies

Many epidemiology studies examining possible associations of fluoride and cancer have been conducted. Some studies examine bone cancer or cancers at particular sites, others examine overall cancer incidence rates or cancer mortality rates. Few of the studies are of individuals; rather they look at effects of populations who are assumed to be exposed or not exposed to fluoride or fluoridated water. Only a few will be summarized here.

Early epidemiology studies compared cancer mortality (death) rates in cities with and without water fluoridation. An analysis by Yiamouyiannis and Burk in 1977 found 4-5% lower death rates in non-fluoridated cities (comparison of 10 largest US cities with fluoridated water and 10 largest US cities without fluoridated water). At about the same time, three British scientists completed an analysis of the same 20 cities and found no effect of fluoridation on mortality rates. A review of these two studies by the US National Research Council concluded that the differences could be explained by use of different data sets and analytical methodologies; the differences showed the relative insensitivity of the data and measurements (3). Yiamouyiannis disputes this and claims that the British scientists omitted data and made mathematical errors (12).

Freni and Gaylor examined international trends in bone cancer based on incidence (not mortality) data in a study published in 1992 (8). In general, they found no relationship between water fluoridation and bone cancer with the possible exception of an increased risk for females in fluoridated areas of the United States. The study was weakened by lack of good exposure data; non-differential misclassification of exposure will lead to an underestimate of an effect. Freni and Gaylor (8) also demonstrated that mortality data is a far less reliable measure of bone cancer than incidence data.

Several small case control studies examining the relationship between fluoride and bone cancer have been conducted, with mixed results. One small study in New Jersey found that males under age 20 years who resided in communities with fluoridated water at the time of diagnosis had a higher osteosarcoma rate than those who resided in nonfluoridated communities (9). A small case control study of osteosarcoma and water fluoridation (among other factors) conducted in Wisconsin showed no association between osteosarcoma and residence in an area with fluoridated water at time of diagnosis (10). Both of these studies suffer from lack of explicit exposure data. Exposure classification is based on residence at time of diagnosis, which may or may not reflect exposure to fluoridated water for any period of time.

A larger case control study examining the association between fluoride intake (and water fluoridation) and childhood (less than 25 years old) osteosarcoma was conducted in New York State (11). This study included contacting both cases (or their parents) and controls, and asking questions related to fluoride exposure. The study found no association between total fluoride exposure and osteosarcoma for either males or females. A statistically significant risk (odds ratio) for osteosarcoma was found at the lowest level of water fluoridation for females, and for males and females combined (but not for males alone). However, the risk did not increase with increasing exposure to fluoride in the drinking water, and the risk at the higher water fluoridation exposure was not significantly elevated (11).

Yiamouyiannis examined the relationship between incidence of and mortality from bone cancer in males and water fluoridation using several US data sets (12). He reported an association between water fluoridation and bone cancer incidence and death from bone cancer among males under the age of 20. He also suggested there is a 30-60% increase in oral cancers because of fluoridation. Several problems are apparent with this paper. For example, for bone cancers, he assumed that only males would have bone cancer linked to fluoride, and then used females as an unaffected reference population. The validity of this assumption has not been proven; indeed, other data reviewed here suggest this is an incorrect assumption.

A recently published study from Okinawa, Japan reports a relationship between fluoride concentration in drinking water and mortality from uterine cancer (13). However, it does not seem that important variables, such as water chlorination, were appropriately taken into account. It is also noted that, in Okinawa, the fluoridated water ranged between 0.19 and 0.37 mg/l fluoride. These waters would generally be considered non-fluoridated in the U.S.

Summary of cancer data

The animal study conducted by the National Toxicology Program (NTP) provides evidence that fluoride causes osteosarcoma, a malignant bone tumor. Although the NTP concluded that its study gave "equivocal" results with respect to cancer, the background memos and documents suggest that the results are actually stronger than suggested by the report. Similarly, the Procter and Gamble study likely gave stronger evidence of carcinogenicity, notably bone cancer, than suggested in the summary statements.

That fluoride is associated with bone cancer is reasonable from the point of view of what is known about the effects of fluoride: fluoride causes the division of immature bone cells (proliferation of osteoblasts) and fluoride accumulates in the bone and thus can cause damage there. Fluoride has been shown to be genotoxic in numerous test systems which is another property that is associated with carcinogens (1,5). In other words, the biochemistry, pharmacokinetics, and other toxicology studies support the view that fluoride maybe a bone carcinogen.

Epidemiology studies examining cancer in general and bone cancer in particular have been inconsistent. Studies using ecologic designs (the studies are based on cancer incidence or mortality for given geographic areas, not for individuals) have given conflicting results for cancer in general, for all bone cancer, and for osteosarcoma. The larger case-control studies do not show an association of fluoride or water fluoridation with bone cancer although at least one small study has shown an association. Most of these studies are handicapped by completely inadequate measures of exposure which would mask any effects that may be there because of non-differential misclassification of exposure. Given the widespread deliberate exposure of humans to water fluoridation and the suggestive animal data regarding cancer, especially osteosarcoma, it is incomprehensible why a large case-control epidemiology study with good measures of fluoride exposure has not been initiated.

This section discusses the impact of fluoride on metabolic and enzymatic processes. Included in these areas are the direct action of the fluoride anion as well as that of other inorganic fluorine-containing materials related to the process of fluoridation. In addition, the impact of fluoride on biochemical pathways and/or enzymatically controlled processes based upon either the formation of fluoride-metal complexes or upon the interference caused by fluoride in the interruption of enzyme-substrate spatial arrangements is discussed.

Background Material

Although it is beyond the scope of this report to present a pedagogical background in biochemistry or the chemistry of fluorine-containing compounds, a few principles should be discussed in order to understand the issues involved and the degree to which these issues would have had an impact on the widespread introduction of fluoride into the human food chain.

Fluorine is contained in significantly fewer than 10 % of more than 700 minerals. Of these, only 5 or 6 minerals are truly common and almost all of these are either insoluble or have very limited solubility in water of neutral pH, although some exhibit enhanced solubility in water in the lower pH (acidic) range. (1)

In those areas of the world where there is an abundance of the common fluorine-containing minerals in contact with either ground or surface water below pH 7, dissolved fluorine-containing minerals will be present in the indigenous water supplies. As a result, those areas will have an increased presence of fluorine in the vegetable and animal food-stuffs produced there. The fluorine that does enter the human food-chain, whether naturally occurring or as a result of artificial fluoridation, corresponds primarily to the sodium salt of the fluoride anion (F^-) and either sodium fluorosilicate or fluorosilicic acid. Clearly it is the nature of these materials which most concern us in this section and, in addition, the nature of the biological materials with which these interact. (2)

Characteristics of Fluorine and Fluoride Ion

The primary action of fluoride in metabolic and enzymatic reactions is related to the formation of "complexes" in one form or another. The fluoride anion has the highest charge density of any negative ion. (3) As a result of this, it is now known that fluoride forms an exceptionally strong hydrogen bond (> 148 kJ/mol.) with substrates in amide-fluoride systems. (4) Strong hydrogen bonding is now recognized as being clearly distinguishable from normal hydrogen bonding.

Another related characteristic of fluoride ion is that it exhibits an affinity for many metal ions, especially magnesium, manganese, aluminum, and calcium and therefore it can effect the bioavailability of these ions either separately or may cause either inhibition or otherwise interact with any enzyme system which requires one of these metals as a co-factor. (5,6)

Structural Susceptibility of Biomolecules

The impact of strong hydrogen bonding is that proteins, which consist of a repetitive sequence of amide linkages, are particularly susceptible to this type of hydrogen bonding. The end results of this type of interaction are two-fold. The lesser effect is that the carbonyl-nitrogen (amide) bond in proteins may become more susceptible to cleavage even though fluoride itself is a less nucleophilic anion. The second, and probably enormously greater, effect is that the spatial arrangement or macromolecular structure of these materials depends heavily upon normal hydrogen bonding to produce the secondary stereochemical structure required for appropriate enzymatic activity to take effect. (7) This has been demonstrated by Edwards and co-workers, who studied the perturbations caused by fluoride on the structure of Cytochrome C peroxidase. (8) Further, ab initio calculations by Emsley et al. lead to the conclusion that the fluoride ion may completely disrupt the Thymine-Adenine linkage in DNA. (9) A survey of the literature reveals no shortage of supporting research results. (10) The conclusions reached in several of these studies are listed below.

• Fluoride inhibits metalloproteins (12)
• Fluoride inhibits DNA polymerase (13)
• Fluoride induces chromosome aberrations (14)
• Fluoride effects the adenyl cyclase system (15)
• Fluoride inhibits yeast enolase (16)
• Fluoride inhibits protein synthesis enzymes(17)
• Fluoride inhibits gycolytic enzymes (18)
• Fluoride inhibits cell growth enzymes (19)
• Fluoride inhibits testosterone synthesis (11)

It is of interest to note that the latter interaction may be responsible for those deleterious effects of fluoride which appear to be restricted to males (e. g. testosterone is involved in bone growth in males but not in females). (11) The above list is by no means exhaustive. Rather, it should be taken to indicate that there is sufficient evidence to warrant more extensive research into this area. However, over all, the results described in the above references "suggest that sodium fluoride is potentially dangerous to humans." (14)

Fluoride and Calcium Metabolism

The interaction of fluoride in those metabolic processes involving calcium are also of great significance. This type of interaction may have been responsible for the recent observation that even when calcium is supplemented in osteoporotic patients, a large number of those who have also been treated with fluoride still show evidence of calcium deficiency. (20) The lack of availability of calcium, either as a result of precipitation by fluoride or the formation of fluoroapatite, may result in hypocalcemia which may have other widespread and, as yet, poorly understood effects on bone formation and other regulatory mechanisms of the body.

Summary and Conclusion

The information above and the references cited illustrate that fluoride can seriously disturb the balance of enzymatically activated biochemical reactions. These effects clearly were not well-known at the commencement of fluoridation activities. However, the recent literature contains many references (e.g. 21-25) to original research results that illustrate that fluoride effects the metabolism of a number of common oral bacteria, (e.g., Streptococcus mutans) so that, equally clearly, this phenomenon of fluoride effects on enzymes should be as well known to the proponents of fluoridation as to anyone. Thus, while there can be no doubt that fluoridation has contributed to the reduction of dental caries in the past, there is likewise little doubt that the continuation of the fluoridation process in the light of recent evidence outlined above is inappropriate without first answering the serious and potentially health-effecting questions raised.

Some humans appear to be hypersensitive to fluoride, although there is some question about whether the reaction is allergic. At the very least, some components of the hypersensitivity appear to be allergic (i. e. an immune system effect); other portions may be related to the central nervous system or altered fluoride metabolism (pharmacokinetics). However, from the viewpoint of the sufferer of these effects, it is a moot question since the end result is virtually the same. With apologies to the sufferers and those physicians who use the terms "allerg-(ies,ic)" in their discussions or papers, this section refers to the manifestations of these effects as hypersensitivity.

Hypersensitivity reactions to fluoride, including fluoridated water, have been known to and reported by medical practitioners for decades (1). A search of the recent literature identified several references to occupational asthma induced by fluoride exposure in the aluminum industry (aluminum potroom asthma)(2), but no references to environmental exposures. While this absence of recent literature suggests that this is not an active area of current research, it does not invalidate the older observations.

George Waldbott, M. D., summarized both the medical literature and his own observations on the allergic reactions to fluoride in a 1964 article in the Journal of Asthma Research. He reported six cases of urticaria (hives) due to fluoridated water. The urticaria was accompanied by other fluoride associated health effects, including paresthesias, cephalgia (headaches), arthritis in the lower spine, gastrointestinal and urinary disturbances. For at least some of these patients, the association of the urticaria with fluoride was demonstrated in double blind challenge tests. These patients appeared to retain more fluoride than most individuals, putting them at higher risk of fluoride-associated health effects. In the same journal article, Waldbott also described other effects on fluoride on the skin of sensitive individuals. These included atopic dermatitis and contact dermatitis, including on the fingers of dentists after applying sodium fluoride to patients.

Summary

This paper demonstrates that there is a sub-population of adults that is hypersensitive to even low doses of fluoride such as those in water fluoridated to 1 ppm. While the size of this sub-population is unknown, there appears to be at least one Natick resident who is hypersensitive to fluoridated water.

Several papers published in the last few years report that fluoride has adverse effects on the central nervous system (CNS), including intelligence and behavioral patterns. These papers encompass biochemical, histological, animal, and human studies and give a consistent picture regarding previously untested adverse consequences of fluoride exposure. Four important features of the animal toxicology and human studies are:

• 1) the fluoride doses are in the range that some humans actually receive; the animal studies are in the range of the upper end of fluoride food and water intake in the U. S.;
• 2) for some effects, the timing of the dose is critical, prenatal and early life exposures appear to be the critical periods for IQ deficits and some behavioral changes,
  
• 3) the adverse effects due to prenatal exposures are not reversible, and
• 4) the adult onset symptoms may be reversible if fluoride exposure is eliminated.

Animal Toxicology Studies

Dr. Phyllis Mullenix and co-workers published a study on the neurotoxicity of sodium fluoride in rats in 1995. (1) The study used behavioral methodology that focused on behavioral repertoire, responses to novelty, and the temporal or sequential organization of spontaneous behavior. This methodology had been previously used to study alterations in CNS function and behavioral alterations including cognitive deficits (mental retardation) due to chemotherapy for childhood acute lymphoblastic leukemia (2), amphetamine induced hyperactivity, and triethyltin-induced hypoactivity. (1) Thus, the methodology used to test the sodium fluoride should be considered a validated one.

In all, 532 rats (Sprague-Dawley, male and female) were used in the study. Fluoride was given at different doses and three life stages: prenatal, weanling and adult. Prenatal doses were administered via subcutaneous injections of the pregnant dam on either gestational days (GD) 14-18 or GD 17-19. The dose schedules produced plasma fluoride peaks of 0.15 to 0.2 ppm. Weanling and adult rats were dosed via incorporation of 75 ppm, 100 ppm or 125 ppm sodium fluoride in drinking water for 6 - 20 weeks. While these drinking water concentrations are higher than would be used in water fluoridation, the cumulative exposures to fluoride, as measured by the concentrations of fluoride in plasma, are similar to plasma levels observed in humans with high end exposures. For example, the plasma level of fluoride in the rats ranged from 0.059 - 0.640 ppm. Plasma fluoride levels of 0.076-0.25 are found in humans ingesting 5-10 ppm fluoride in drinking water and plasma fluoride levels of 1.44 ppm have been found in children 1 hour after receiving topical applications of acidulated phosphate fluoride gel.

The prenatal exposures (also referred to as in utero exposures) during GD 17-19 altered the behavioral outcome in male (but not female) offspring in a manner correlated with hyperactivity. There was no overt toxicity to the dams or offspring based on reduced body weight, suggesting the behavioral alterations were not secondary to another toxicity. [Note that absence of overt toxicity in the dam is a key test in defining a developmental toxicant according to EPA guidelines.] (3) Plasma fluoride concentrations at 3 and 9 weeks of age were not elevated, suggesting that the damage occurred in utero and as a result of a short term exposure. It should be noted that the nervous system develops throughout gestation and during the early postnatal period, and that the higher cognitive functions develop towards the end of gestation (gestation period is 20-21 days in rats) and during the postnatal period. It is also a common feature of developmental toxicants that adverse effects are observed if a toxicant is given during one period of gestation, but not during others (other adverse effects may or may not be observed at other periods).

Weanling exposures to fluoride affected the behavior of both males and females in a dose dependent manner (based on plasma fluoride levels), although the female rats were affected at lower doses. These doses also induced slight toxicity as judged by body weight gains. The behavioral changes for both sexes and at all doses were consistent with respect to the controls, and were different from the behavioral changes observed in male rats exposed pr