1. Introduction. The reviewer's background.

1.1 I obtained my first degree from Cambridge University in Natural Sciences and my Ph.D. in Chemistry at Dartmouth College in the US. My full curriculum vita is attached. I have been concerned about the impact of pollutants on health since the late `70s. My specific research interests have included lead, chromium, dioxins and related compounds and more recently fluoride. My particular focus has been attempting to understand the mechanism of action of these pollutants at the biochemical level, in the hope that understanding such mechanisms would give clues as to their toxic effect on living systems.

1.2 Because of my work with lead and dioxins I have also been very interested in the interplay of science and public policy and the difficulty of getting objective analysis in the face of entrenched political and economic interests. More than any other pollutant I have studied fluoride exemplifies these difficulties. Thus I welcome any attempt to put this debate on a solid scientific platform.

2. The Limitations of the York Review Strategy.

2.1 The York Review is a response to a request from the British government to "carry out an up to date expert scientific review of fluoride and health". In my view, this review is extremely limited in scope and it would be unfortunate if the British government treats this as the "last word" on the "science of efficacy and safety" of fluoridation. However, even with its limited parameters, and with its shortcomings (which I will be addressing specifically, below) there should be enough in this review to shake the British government's current enthusiasm for putting this highly toxic material into the public drinking water. But to appreciate this it is necessary to take a step back and look at both the smaller and the larger picture that the York team failed to address.

2.2 The York review is analogous to a doll in a set of Russian dolls. Its focus on human epidemiology puts it somewhere in the middle of the set. Inside it is the smaller doll, which deals with the chemistry and biochemistry underlying fluoride's mechanism of action for its toxic effects and potential health effects. Outside it is the larger doll, which puts epidemiological studies into the larger context of all the science and all the ethical considerations needed to inform wise public policy. This larger set of information is needed to address the Precautionary Principle.

2. 3 The larger picture. The larger picture is that the British government is proposing to put a known highly toxic substance —albeit, at a supposedly low concentration of 1 part per million (ppm) -into the drinking water of the whole population. Since human activities and traits usually follow normal distributions (the bell shaped curve), this immediately poses concerns about two tails on two of these curves. The first distribution curve is the dose that people will get once this substance is in the water. Most people will get an average dose, but some — a small percentage (the upper tail of the curve) will get a much higher dose. The second distribution is "the sensitivity of response" to this toxic substance. Most people will have an average response, but some — a small percentage- will be super vulnerable. Inevitably, there will be some people in the population who will be at the wrong end of both these curves, they will get very high doses and they will be very vulnerable to fluoride's toxic effects. On the global level, we have examples of millions of people in India, China and parts of Africa who find themselves at the wrong end of one or both of these two curves and the consequences are devastating.

2.4 Fortunately, in the UK, we are not likely to see the kind of doses which lead to overt crippling skeletal fluorosis, as in India and China, but UK officials should be concerned about the more subtle consequences of lifelong exposure to this substance once it gets into the drinking water. Moreover, concern about exposure to fluoride in the drinking water needs to be coupled with a concern about all the other sources of fluoride we are all exposed to today, including dental products, pesticide residues and other sources of fluoride in the diet. A special concern is bottle fed babies where the water is made with fluoridated water. Based upon the fluoride urine analysis conducted by Dr. Peter Mansfield (1998), the levels of fluoride being consumed by people in Britain is already of concern. The British are known to be big tea drinkers. It is possible that to date they have been partially protected from the fluoride in this tea by the fact that they usually drink tea with milk in it and there is a suggestion that the calcium in the milk partially limits the uptake of the fluoride ion. However, another factor, which could become extremely problematic, as far as daily doses of fluoride are concerned, is the consumption of beer. Many Briton's drink copious quantities of beer. Currently, with only 10% of the British public drinking fluoridated water, we have yet to see the full impact of the multiplier effect on food processing and beverages. However, if 100% of the water is fluoridated then this fluoridated water will be used in the manufacture of beer. Some adults in Britain could then receive very high doses of fluoride. A worse case scenario would be someone who drinks a lot of tea, a lot of beer and consumes a lot of fish. For a quite a large number of people in Britain, Fish and chips is the equivalent to hamburger and French fries for Americans.

2.5 The problem with subtle health consequences is that they are notoriously difficult to discover in a human population, let alone prove cause and effect with a single pollutant or pollutants in combination. This is particularly true, if a) we are dealing with a subset of the population which is vulnerable, because the number of people examined or followed has to be very large to encompass that subset, or if, b) the effect takes many years to manifest itself. We have seen this problem with several toxic substances like lead and dioxin. By their very nature, epidemiological studies are after the fact: by the time enough evidence has accumulated to convince the most skeptical observer, or overwhelm the most entrenched special interest, many millions of people will have been exposed and possibly damaged.

2.6 Thus striving for certainty, before one acts, is a dangerous approach to public policy in these matters. This is why in Europe the "Precautionary Principle" has been espoused both by governments and non-governmental organizations. With this approach one doesn't have to be certain that a substance introduced into the environment will make people sick, or that you wait until it has made people sick, before acting. Rather, one considers at least four things: a) the weight of evidence of all the science that one can bring to bear on the matter; b) the magnitude of the calamity if one adds the chemical and it does cause long term health damage to a part or all of the population, c) the significance of the benefit being pursued and d) the alternative actions to the goal being pursued.

2.7 As far as addressing these parameters of the Precautionary Principle is concerned the York team must be given a failing grade. They have failed to achieve a), because of their exclusion of animal and other toxicological studies which provide supporting evidence to indicate that fluoride can cause great harm. I elaborate on this below. Their review of b) is limited and in certain places (e.g. hip fractures) marred by major errors and in other places with omissions (e.g. osteosarcoma — Cohn,1992). Their review of c) and d) are also limited by several things. i) They failed to acknowledge that a large number of leading dental researchers are now admitting that fluoride does not have to be swallowed to achieve its benefits. Putting this together with the fact that it is well recognized that swallowing excess fluoride leads to dental fluorosis, (a subject they covered well) would suggest that by applying fluoride topically (e.g. via toothpaste) achieves the supposed benefits while minimizing the proven problem of dental fluorosis. ii) They failed to explore, in any meaningful way, the larger experience of the vast majority of other European countries, which have either never fluoridated their water, or since rejected it, without any calamitous consequence to childrens' teeth. iii) They did not examine the major cross sectional studies which have found little difference in tooth decay between fluoridated communities and countries and non-fluoridated communities and countries. It is quite a shock to find that a review looking at fluoridation has omitted the largest studies ever conducted on tooth decay: e.g.Teotia and Teotia, 1994 (400,300 children); Colquhoun , 1994 (over 47,000 children) and Yiamouyiannis, 1990, (from NIDR data for over 39,000 children).

2.8 I will now examine the York team's rationale for excluding animal and toxicological studies in their review. In my view, the York team has made a huge mistake when they say, "In general, when human data are available, animal or laboratory data do not bear significant weight on decisions about interventions, and such data will not be considered in this review" (1.0 Background, page 1). To give one example to illustrate the dangers inherent in this approach, consider the finding that exposure to fluoride in water and in toothpaste leads to dental fluorosis. Left as a matter of a "human health effect" it is too easy for officials to miss the point and describe the effect as a "cosmetic" or "aesthetic". Pursued at the biochemical level, however, it raises a different level of concern. From animal studies it has been demonstrated that dental fluorosis is caused by fluoride inhibiting enzymes in the growing tooth cell responsible for laying down the enamel (DenBesten, 1999). The last stage in this process involves enzymes called proteases, which chew up the protein remaining between the mineral prisms, which form the enamel. If this protein is not completely removed, it leads to small opaque patches on the enamel. It is well known from biochemical studies that fluoride inhibits enzymes in test tubes, which is the reason why a number of Nobel Prize winners (e.g Dr. James Sumner, the world's leading enzyme chemist in his time) are among those who have expressed their reservations about fluoridating water. Dental fluorosis is thus an indication that fluoride even at 1 ppm in water can inhibit enzymes in the body. In a way, it is extremely lucky that fluoride inhibits these particular enzymes because the effect is visible. Thus we have a visible warning signal that something is happening. The key question then becomes (or should become): What other enzymes is fluoride inhibiting in the body that we can't see? Such questions have been probed with animal studies and to ignore them is reckless in my view. Of particular concern are the enzymes involved in bone growth and turnover, and enzymes present in other calcifying tissues like the pineal gland. The fact that the human pineal gland has been shown to accumulate fluoride to very high levels is highly significant in my view. Especially when coupled with the fact that Luke (1998) has shown that when animals are treated with fluoride, it significantly decreases their melatonin production, which is made in the pineal gland. These results suggest that one of the enzymes involved in melatonin synthesis has been inhibited by fluoride.

2.9 The inhibition of enzymes may prove to be just the tip of the biochemical iceberg. From biochemical studies it appears that fluoride, either alone or in conjunction with aluminum, interacts with G-proteins, which is a key part of the signaling mechanism for water-soluble hormones and some neurotransmitters. Interference here could pose many subtle problems for people that are most sensitive to fluoride or those who receive higher than average doses or both. Nor is the interaction between fluoride and G-proteins a matter of conjecture. Many research biochemists, who are studying cellular regulation, use fluoride and aluminum fluoride as routine tools to switch on G-proteins. A simple search of PubMed ( ) on June 29 yielded 821 papers when searching for G protein AND fluoride, and 345 papers when searching for G protein AND fluoride AND aluminum.

2.10 What goes on in the test tube, in tissue culture, in animal studies gives us very valuable clues as to what may be going on in humans. Thus when the York team states that, "Many Pharmaceutical companies can confirm that there are numerous new interventions that were promising in animal and laboratory studies that turned out to be ineffective or harmful when tested on humans" (1.0 Background, page 1) they sadly miss the point. A vast number of chemicals have been rejected by these same companies when they found that tests done in test tubes or animals suggested that the chemical would be dangerous to humans.

2.11 One of the extraordinary things about the history of fluoride is that it was imposed on large human populations in the United States before it had been comprehensively tested on animals. If one compares the standard of testing required by the US Food and Drug Adminsistration (FDA) for new drugs today, the testing done on fluoride prior to human testing was woefully inadequate. This is not only true of the chemical sodium fluoride, but is even more true today of the substances most frequently used to fluoridate the drinking water: hexafluorosilicic acid or its sodium salt. To this day very little toxicological testing has been done on these substances even though 90% of the water fluoridated in the US these use these materials to fluoridate (see 2.17 below).

2.12 Moreover, the human experimentation has been conducted very unscientifically as the York Review makes clear. After over 50 years of research, none of the human studies discussed gets an "A" rating from the York review team. There have been very few, if any, double blind randomized trials. A huge impediment for drawing any meaningful conclusion has been the usual lack of dose information. Very few studies have even attempted to relate the affect being studied to dose by using some biomarker of exposure. Most studfies have simply used the level of fluoride in the water as an indicator of dose. With such wide variation in fluoride exposure for individuals (from many sources) in both fluoridated and non-fluoridated areas, without a biomarker of exposure (like levels of fluoride in the bone) meaningful conclusions from epidemiologiocal studies are very limited.

2.13 For me, the worst example of poor science in this whole sorry human experiment is the failure of governments in the fluoridating countries to systematically and comprehensively monitor the level of fluoride in their citizens' bones. By now we could have had a wealth of data of fluoride levels as a function of diet, geography, hard or soft water, fluoridated or non-fluoridated water, age, sex, race and more. This has not been done despite the fact that it has been known for many years that about 50% of the fluoride ingested each day is deposited in the bones. Just how close are our citizens getting to the levels at which sub-clinical affects of skeletal fluorosis will occur? We have little idea. This is an extraordinary and elementary scientific omission, which does not speak well of the competence or intelligence of those paid to safeguard our health. Gordon and Corbin (1992) summarizing the findings of a special workshop of "Drinking Water Influrence on Hip Fracture on Bone Health" at the National Institutes of Health, 10 April 1991, Washington, DC, stated that, "For humans, exposure to 1 ppm fluoride in drinking water corresponds to an average 1230 ppm in bone... In comparison, exposure to 4 ppm in drinking water yields an average 6400 ppm fluoride in bone". If these figures are correct we have a serious problem. 6000 ppm is where, according to the US Department of Health and Human Services (1991, Table 23, p. 46) one would expect to see Clinical Phase I symptoms of skeletal fluorosis (symptoms: sporadic pain; stiffness of joints; osteosclerosis of pelvis and vertical column). The difference between 1 and 4 ppm is not very great. There is not much of a safety margin here.

2.14 Under the circumstances of inferior epidemiological studies, ignoring animal studies, in which one can control many factors more precisely than one can control in human populations, is a serious mistake. Moreover, the other advantage of animal studies is that they can be conducted BEFORE human exposure.

2.15 The larger picture requires recognizing that the scientific input into public policy in a matter like this should not be restricted to what can be "proved in court", whether that court be academic or legal. By restricting itself to certain human epidemiological studies, the York Review, may have put the data in a form where it can be handled in mathematical and graphical ways, but by excluding vital scientific information which can be derived from other studies it misses the critical red flags and clues that can more fully inform wise public policy.

2.16 The smaller picture. Turning to the smaller picture of the fluoride ion. In my view, all toxicological analyses should begin with an examination of the chemical species involved. Once done, this analysis should then inform the kind of biochemical studies which should be pursued and these in turn should inform the kind of studies we need to examine in the human population. By ignoring this key step by step process, the York team has neglected some vital human studies which have been performed and has failed to prepare and warn Government about vital human studies which still have not been performed.

2.17 Beginning with the chemical species used to fluoridate the water supply, there are three substances involved. These are the fluoride ion, usually administered as sodium fluoride; hexafluorosilicic acid, prepared by diluting down a 25% (approx.) solution of this acid obtained from the air pollution scrubbing devices of the superphosphate fertilizer industry and sodium hexafluorosilicate, also obtained from the superphosphate fertilizer industry. The first shock is to discover that there has been little toxicological work carried out on these latter two substances (either in their pure form or in the mix obtained from industry). Practically all the studies done to date that have pursued fluoride's toxic effects have focussed on the bare fluoride ion, in the form of sodium fluoride solutions. The assumption being made, with little supporting scientific work, is that once diluted the hexafluorosilicic acid or its sodium salt will be completely hydrolyzed to fluoride by the time it has reached the tap. The work of Masters and Coplan, which I will discuss in more detail later, is highly suggestive that this is an overly optimistic assumption.

2.18 Turning to the bare fluoride ion, there are three chemical actions which help to explain its toxic effects. 1) Its parent acid, hydrofluoric acid (HF) is a relatively weak acid, which means in acid environments in the body (like the stomach) it will be present as the hydrogen fluoride molecule. This species can cross membranes about one million times more readily than the free fluoride ion. 2) The fluoride ion can form a strong hydrogen bond with the amide function. Hydrogen bonds between the amide function and itself and with other functional groups are fundamental to the structure and function of both proteins and nucleic acids. Thus fluoride has the potential to strike at the very heart of biochemical functioning. The only argument is about whether fluoride is likely to reach concentrations in human tissues where this will actually occur. 3) Fluoride can form complexes with many metal ions, either alone or in conjunction with the phosphate ion. In fact, it complexes with nearly all of them except metals in group IA of the periodic table (i.e., the alkali metals: lithium, sodium, potassium etc). This could explain many things. It could explain why high levels of calcium are protective against some of fluoride's toxic effects in animals. It could explain why malnourished human beings are more vulnerable to fluoride's toxic effects. It could explain why many of the enzymes that are inhibited by fluoride in vivo have magnesium as a cofactor. It could explain why fluoride acts synergistically with a number of toxic metals, since metal-fluoride complexes may carry these toxic metals to places they could otherwise not go. In this latter respect, it may explain why aluminum and fluoride in combination have a different toxic effect than either species alone.

2.19 All of these properties of the fluoride ion should make a toxicologist pause before exposing the whole population to it, even at the supposedly low concentration of 1 part per million (ppm). Alien chemical species can have effects at much lower levels than this. Today, in the US, the safe drinking water standard for lead is set at 15 parts per billion (ppb). In the US we allow fluoride to be added artificially up to 2000 ppb and for naturally fluoridated water, we allow 4,000 ppb.

2.20 Based upon the small picture of the chemistry of the fluoride ion the key word should be caution. Based upon the larger picture of wise public policy, the key words should be the Precautionary Principle. As already indicated the York Review addresses neither this small nor large picture.

2.21 That having been said, it is still possible to use some of the findings of the York Review to infom public policy on this matter. But it is critically important for decision makers to recognize that this York analysis is only a part of much larger scientific perspective needed. The rest of that scientific picture needs to be brought into play before a fully informed decision can be made. In turn, as the York team itself acknowledges, the science is also only part of a larger public policy decision which should include such ethical issues as informed consent, freedom of choice, as well as the politics of allowing the superphosphate industry to get rid of its toxic waste by diluting it with the public water supply.

3.0 Weaknesses in the York Review product.

3.1 I will now examine the York Review on its own limited terms. We find there are some serious omissions which weaken some of their findings. I will discuss these under five headings. 1) The benefits to teeth 2) Dental fluorosis 3) Hip fractures 4) Cancer and 5) Other Health Effects.

3.2 The Benefits to Teeth.

3.2.1 Since I embarked on this review I have received a copy of Dr. Ziegelbecker’s critique of the York report. I feel that it is imperative that this substantial critique be carefully reviewed by independent statisticians qualified to repeat his analysis to see if his mathematical analysis is valid. If Ziegelbechers’s critique cannot be refuted by independent experts then it is clear that the case for fluoridation’s benefits to teeth has not been proved.

3.2.2 I am extremely surprised that the York team included the early studies from Newburg vs Kingston Ast (1951); Grand Rapids vs. Muskegon, Arnold (1956); Evanston vs. Oak Park, Blayney (1960) and Brantford vs Sarnia, Brown (1965) because these studies have been heavily criticized in well documented monographs by the late Dr. Philip Sutton (1960, 1980, 1996) as well as Ziegelbecher above. The onus was on the York team to deal with these criticisms before using this data.

3.2.3 However, if it is deemed appropriate to use the Ast (1951) data, then it is important to note that analysis of the teeth of the children in Newburg (still fluoridated) and Kingston (still unfluoridated) was repeated in 1986 (Kumar and Green, 1989) and 1995 (Kumar et al, 1998). In 1985 there was little difference in the DMFT values among the children in the two communities and in 1995 the average DMFTs in Kingston (unfluoridated) were slightly better than Newburg. Moreover, not only were the DMFTs slightly better for the children in Kingston but they also had about half the level of dental fluorosis compared to fluoridated Newburg. Thus if it is valid to use the Newburg vs Kingston study, then the only conclusion that can be drawn in 1995, is that the children of Kingston are better off having not had to drink fluoridated water. I enclose an attachment which contains graphs derived from those printed in a paper by Kumar and Green (1998). These graphs compares the DMFT values across the age range 7-14 years for the two communities in 1945, 1955, 1986, 1995.

3.2.4 I was surprised that Mark Diesendorf’s seminal paper printed in Nature in 1986 was not in the list of papers included in the analysis, although it was considered. I appreciate that this paper would be characterized as a review paper but within this paper the author cited a large number of studies which indicated that there were large reductions in dental caries occurring in numerous non-fluoridated communities in Australia, Denmark, Holland, New Zealand, Norway, Sweden, UK and the US. Thus he drew upon a large and important data base and yet only 7 of the 63 references cited by Diesendorf were considered, and only 2 of these made it into the final analysis. Even though meta-analysis of the type performed by the York team exclude review papers, because of the dangers of including and counting the same data twice, authors of meta-analysis are required to comb through review papers to see if there are studies referenced which should be included. Thus, I find the non-inclusion of most of the studies on which Diesendorf derived his important work, a serious omission. More so, since Diesendorf showed that in several cities in Australia the DMFT values continued to fall after the maximum benefit would have accrued from water fluoridation.

3.2.5 Nor does the York team include the work of Betty De Liefde (1998) which finds the same continuation of improvement in DMFTs in New Zealand, after the maximum benefits from fluoridation would have occurred. Nor did the dental carries studies by John Colquhoun (1987, 1994, 1997) make it into the analysis. Colquhoun not only identified the same phenomenon as Diesendorf and De liede, but he also showed that DMFTs were coming down in New Zealand before fluoridation was even begun.

3.2.6 The York team’s omission of the New Zealand data on dental caries was particularly unfortunate, because New Zealand offers one of the largest data bases on this matter anywhere in the world. Every child in New Zealand has his or her teeth inspected between the ages of 12 and 13. Thus we are not dealing with a statistical subset but nearly the whole population. It is regrettable therefore that Colquhoun’s studies (1987 and 1994) showing little difference in the DMFTs in the fluoridated and non-fluoridated cities in New Zealand were excluded from the York team’s analysis. Over 47,000 children were studied in the 1994 survey. One has to wonder about a selection process which excludes such recent high quality data while including highly questionable studies dating back to 1955.

3.2.7 The same argument applies to the very large study conducted by the National Institute of Dental Research (NIDR). This study cost the US taxpayers some $3.6 million. The NIDR looked at 39,000 children (approx.) Dr. John Yiamouyiannis had to dig out the data from the NIDR using the Freedom of Information Act. He found little difference in the DMFT’s in the permanent teeth children in the fluoridated and non-fluoridated communities (Yiamouyiannis,1990). Brunnelle and Carlos (1990) examined a sub-set of this data and found a 19% difference in decayed tooth surfaces between the two communities. This is less than half a tooth. Neither the Yiamouyiannis nor the Brunelle and Carlos studies make it into the studies included by the York Team.

3.2.8 Other large studies have been ignored: eg Teotia and Teotia in India looked at the teeth of over 400,000 children in India and examined them as a function of fluoride and calcium levels in the water. They found that tooth decay increased as fluoride concentration increased and decreased as calcium concentration increased. Pro-fluoridationists have argued that the Indian experience with both dental and skeletal fluorosis is not relevant because the impact of fluoride is more acute when children are suffering from malnutrition. However, it should be recognized that the children in the western industrialized world most likely to be suffering from malnutrition are the children from poor families and these are precisely the children who are being targeted by those who promote fluoridation in the name of "equity".

3.2.9 Another ignored study relating to fluoridation, poverty and tooth decay, was performed by Steelink in Tucson, Arizona. After a dental screening of 26,000 elementary children, his committee plotted the incidence of tooth decay versus fluoride content in the child’s neighborhood drinking water, and found that as the fluoride concentration went up (range 0.3 ppm to 0.8 ppm) tooth decay went up. They also found that the level of decay rose sharply as the family income of the children went down. The important thing about this study was that it was performed by people who had no axe to grind. Professor Steelink in a letter to Chemical Engineering News (July 27, 1992) claimed that he was abused by people from both the pro-fluoridation and anti-fluoridation camp.

3.2.10 Returning to the more formal scientific arena, I found one of the studies used by the York team to be most illustrative and that was the paper by Kunsel (1997). He found that contrary to earlier experience in the two towns he was comparing in former Eastern Germany – Chemnitz (fluooridated until reunification) and Plauen (never fluoridated) that after fluoridation ceased in Chemnitz the dental caries rate continued to decline. Kunzel writes: "…it is obvious that the relation between varying F concentrations of the drinking water and the caries level, being valid between 1959 and the mid-eighties, is no longer true". Such a conclusion again underlines the dangers of using studies from the ‘50s to inform governmental policies in the year 2000. In my view, a meta-analysis is only as good as the quality of the individual studies it contains. If bad or irrelevant studies are included it will only serve to nullify the good or relevant ones. In this case truth is not revealed but blurred.

3.2.11 Unfortunately, the selection criteria chosen by the York team appears to have excluded the largest studies of populations as a whole. In my view, this was a poor decision in view of the fact that it is intended to help inform the British government’s determination on whether to expose a whole population to fluoride via the water supply or whether to pursue other caries prevention strategies.

3.2.12 The huge missed opportunity. With respect to the comment above (3.2.11) the huge missed opportunity and strategic mistake made by the York team, was when they turned to Objective 2: If water fluoridation is shown to have beneficial effects, what is the effect over and above that offered by the use of alternative interventions and strategies?

This is where they should have switched gears and moved from small longitudinal studies to very large cross-sectional studies of Teotia and Teotia (1994); Colquhoun (1994, 1997); Yiamouyiannis (1990) and Brunelle and Carlos (1990). This is also where the references contained in the Diesendorf (1986) paper would have been invaluable. In particular, those studies should have been examined where the quality of children’s teeth has continued to improve in many communities and countries even after the maximum exposure to fluoridated water has taken place (Diesendorf, 1986, LeFiede, 1998, and Colquhoun, 1997).

This is also where the whole experience in Europe could have been reviewed and analyzed country by country. When considering dosing a population with a known toxic, which is more helpful: carefully controlled slices of theory or the practical experience of whole countries?

This in turn leads to the huge crucial question about whether fluoride’s benefits are accrued from swallowing (is it needed systemically?) or from topical application. In particular, the arguments and analysis provided by those leading dental researchers like Levine (1976), Fejerskov, Thylstrup and Joost (1981), Carlos (1983), Featherstone (1987), Margolis and Moreno (1990), Burt (1994), Shellis and Duckworth (1994) and Limeback (1998) who agree that fluoride’s benefits are largely topical, should be examined very carefully. If they are correct it goes a long way to explain why it is that the teeth in non-fluoridated European countries are just as good, if not better, than the teeth in fluoridated countries. And if they are right, you don’t have to put fluoride in the water, but simply supply the fluoride in the form of fluoridated toothpaste. (If Colquhoun, Disendorf, and Yiamouyiannis are right you don’t need fluoride at all.) This becomes even more crucial when one recognizes, as the York team does, that when fluoride is swallowed it leads to an increase in dental fluorosis and possibly other harmful effects.

To overlook this huge question is to make nonsense of much of the York team’s painstaking effort put into the analysis of much smaller studies.

3.3 Dental Fluorosis.

3.3.1 In my view, this section is the strongest section in the York report. It presents overwhelming evidence that when you fluoridate the water you see an increase in dental fluorosis – damage to the tooth enamel. It is also clear that this damage is on the increase as children are exposed to more and more sources of fluoride in the environment.

3.3.2 As I explained in the introductory section it is misleading to describe dental fluorosis as a "cosmetic" or "aesthetic" effect. These are not scientific terms but public relations terms. The simple scientific truth of the matter is that when dental fluorosis has occurred it means that fluoride has impacted the body systemically. The fluoride has moved from the water through the stomach membranes into the plasma, circulated the body and arrived inside the tooth. In the growing tooth cells it has reached a concentration such that it has inhibited the enzymes involved in laying down the enamel. Pam DenBeston’s (1999) work indicates that the enzymes involved are the ones which remove the last bit of protein from between the mineral prisms. Thus, instead of laying down a nice smooth enamel, the enamel has little patches in it.

3.3.4 Now that it is recognized that dental fluorosis is occurring with increasing frequency and severity, we have to ask what other enzymes are being inhibited in the body. What enzymes are affected in the bones, in the other calcifying tissues and in the other soft tissues?

3.3.5 One surprising piece of research in this area involves the pineal gland. I briefly discussed this in section 2.8. I will give further details of Luke’s work (1998) in section 3.6.3. Suffice it to say here, that the end result of her work would suggest that a) fluoride concentrates in the human pineal gland and b) that in animals studies fluoride appears to inhibit one of the enzymes involved in melatonin production. She also found an earlier onset in puberty with the higher dosed animals, which is what you would expect if melatonin levels are lowered. It is too early to say what ramifications this has for human health but it should give us pause. When scientists over 50 years ago (and still do today) were proclaiming with a great deal of confidence, that fluoride at 1 ppm would have no health effects, did they think of this little gland concentrating fluoride? Did they even know about melatonin or all the complicated body chemistry it regulates?

3.3.6 Knowing that dental fluorosis is caused by swallowing fluoride before the tooth has erupted draws attention to an intriguing piece of scientific information which receives far too little attention in the fluoride debate. The level of fluoride in mother’s milk is very low. At approximately 0.01 ppm it is about 100 times less than the so-called "optimal" levels of fluoride added to water. Nature seldom messes up on these matters and one has to wonder why, if fluoride is so important for teeth, that nature didn’t contrive to include it in the key source of nutrients for the growing infant. It seems far more likely that fluoride does not occur in mothers’ milk to any appreciable concentration because a) it is not needed for healthy teeth and b) because if a baby is exposed before its teeth have erupted then its teeth will be damaged by dental fluorosis. Thus, one of the difficult problems the British government will face if universal fluoridation of the water supply is introduced into the UK is how local governments and water authorities will warn mothers that if they bottle feed their babies they should not use tap water to make up the formula. Using tap water will certainly result in exceeding the fluoride doses being recommended for new born babies by the Food and Nutrition Board of the Institute of Medicine in the US ( Institute of Medicine, 1997) and other health and dental agencies.

3.3.7 Dental fluorosis is not a "cosmetic" effect, it is a red flag that something else may be happening elsewhere in the body. It is a systemic effect. For the effect to be manifested the whole system has to be exposed. This point becomes extremely important when one discovers that more and more leading dental researchers are recognizing that the benefits of fluoride (if they exist at all) are exercised topically (see section.3.2.12 above). Thus we have an interesting dichotomy: the benefits are achieved topically and the risks are experienced systemically. Simple logic would suggest that, if you believe that fluoride has some role to play in preventing caries, and you want to minimize side effects, you shouldn’t put fluoride into the water. Or as Dr. Hardy Limeback says, "If you put it in the water, rinse and spit it out!" However, the notion of using the public water supply as a mouthwash has somewhat limited appeal. Using a fluoridated toothpaste makes more sense, if you make sure that non-fluoridated brands are available for those who want no exposure to fluoride at all (which unlike the US is the case in the UK). The key point is that applying fluoride topically maximizes the benefits and minimizes the risks of dental fluorosis and other health problems. We will examine some of those other health problems in the next section.

3.3.8. Another important paper which should be considered in relation to dental fluorosis is one published by Chlebna-Sokol and Czerwinski (1993). These authors found significant bone (examined radiographicaly with computerized imaging) changes in children exposed to drinking water greater than 2.7 ppm, and who had dental fluorosis, compared to children exposed to less than 0.1 ppm.

3.4 Hip Fractures.

3.4.1 The fact that dental fluorosis indicates that fluoride has reached levels where it has interfered with enzymes in the tooth cells laying down tooth enamel, raises questions about what it is doing to enzymes in other calcifying tissues where it concentrates. Two tissues are of major concern: the bones and the pineal gland. As far as bones are concerned, there are two health effects on which I will concentrate my remarks: hip fractures in the elderly and osteosarcoma (bone cancer) in young males.

3.4.2 As far as hip fractures are concerned I will be focusing my comments on section 8.1, Figure 8.1 and Table 8.1 plus the supporting data extraction tables in appendix D.7.

3.4.3 First an important general comment. Many of the authors of the studies reviewed indicate how serious a problem hip fracture is in the United States and in other countries. For example for the US, according to Jacobsen (1992) "Hip fractures constitute a major cause of morbidity and mortality in persons aged 65 and older. An estimated 200,000 hip fractures occur in the United States each year, with an associated cost of over $7 billion. According to Phipps (1995), " As a result of osteoporosis-related hip fractures, as many as 50,000 people will die and as many as 20 per cent will be admitted for long term care in a nursing home".

3.4.3 Corrections.

a) Jacobson (1992). This is one of the largest studies of hip fracture carried out todate. Jacobsen and co-workers examined the possible association of hip fracture with water fluoridation in the US for white women and men over 65. After exclusions they examined 218,951 patients. When I asked the York review team why it was that the Jacobson et al (1992) study appeared in Table 8.1 but was not included in the Forest plot presented in Figure 8.1, I was told "There is no standard error data for the Jacobsen paper and so it can not be included in the meta-analysis" (email –June 21, 2000). However, checking the Jacobson (1992) paper I find that they report a Relative Risk (RR) for hip fracture for women of 1.08 (95% Confidence Interval 1.06 to 1.10) and for men an RR of 1.17 (CI 1.13 -1.22). Thus, there was no need to exclude it from the Forest plot or meta-analysis.

b) Cooper (1990). In Table 8.1 the study by Cooper et al is reported as "overall results not presented". However, in a letter to JAMA , Cooper et al (1991) state that they had reanalyzed their data from the 1990 study and found a significant association between fluoridation and hip fracture. Even though the reference is included in the York Review bibliography this is not acknowledged in tables D7, nor in Table 8.1, nor used in the Forrest plot. I asked Dr. Tom Webster, an epidemiologist working at the School of Public Health at Boston University, to comment on Cooper’s work and if it was possible to compute the relative risk ratio and confidence interval from the data presented in Cooper’s letter to JAMA. This is what he wrote:

"Use of population weighted least squares is more appropriate than ordinary least squares in this case. It is more appropriate to use regression coefficients than correlation coefficients. The slope is an estimate of the rate difference. The rate ratio could be estimated if we also knew the intercept but these values are not reported by Cooper. Cooper et al do not report the population weights, preventing recalculation of the regression results. The figure does show a regression line for hip fracture in men and women combined, but suggesting a RR of 2/1.4=1.4. Using the line, we can also calculate the RD=2-1.4=.6, but this does not seem to agree with the reported numerical value of 0.46. Although we cannot calculate a confidence interval for the RR with the data provided in the paper, we can calculate a confidence interval for the RD. For women, this is .65±t*SE, yielding .65 (.14,1.2)" (Webster, 2000).

c) Cooper (1990). In Table 8.1, Cooper (1990) is incorrectly linked to a study of men over 65 years of age. I believe that this is data which was generated by the Jacobsen (1992) study referred to in a) above and thus incorrectly located.

d) Sowers (1991). In Table 8.1 no RR value is listed, instead we are told that there were "No cases in low fluoride groups (1ppm)". As a result, this data, too, does not get included in the Forest plot in Figure 8.1 or the meta-analysis. However, when checking with the original paper, we find that they had five cases of hip fracture (5 out of 163) in the community with 4 ppm compared with none (0 out of 121) in the community with 1 ppm. While it is true that a relative risk from these figures would be infinity (since anything divided by zero is infinity), clearly there was a significant effect taking place here, and to exclude it because there were no cases in the control is not reasonable. I asked Dr. Tom Webster what would be done in this kind of situation and he replied:

" The York review does not provide an RR for women age 55-80 because there were "no cases" in the low fluoride group. If computed with the zero cell in Table 5 of Sowers et al., the RR would be infinity. But an estimate of the RR can still be derived using standard methods. We used dEPID (1987 version) which adds 0.5 to cells in this situation. The resulting RR and 95% confidence intervals (using two different methods) are:

RR=8.2 (1.5, 45.5) test-based, (.45, 148) Woolf/Tayor series.

Even a small amount of effort on the part of the reviewers could have derived such a result" (Webster, 2000).

e) Li (1999). In both Table 8.1 and Figure 8.1 the York team report this study as showing no significant association between hip fracture and water fluoridation level. When I went to get this paper I found that it was unpublished. I was able to locate the author and was sent a copy of the paper. The authors had looked at the rate of hip fractures and other fractures in six Chinese villages of varying water fluoride concentrations, ranging from 0.25 to 7.37 ppm. They examined a total of 8,266 male and female subjects of 50+ years. They found that:

" The prevalence of hip fractures was highest in the group with the highest water fluoride (4.32-7.97 ppm). The value is significantly higher than the population with 1.00 -1.06 ppm water fluoride, which had the lowest prevalence rate."

For subjects exposed to the various fluoride concentrations they reported an odds ratio of rate of hip fracture compared to the rate for the water concentration of 1.00 - 1.06 ppm. These odds ratios were: 3.26 for 4.32 - 7.97 ppm; 1.75 for 2.62 - 3.56 ppm; 2.13 for 1.45 – 2.19 ppm; 1.12 for 0.58 – 0.73 ppm, and 0.99 for 0.25 – 0.34 ppm.

Apparently, the York team managed to extract a no association result of (RR = 0.99) by using one data point: the hip fracture rate at 0.25 – 0.34 ppm. This is extremely misleading. Nowhere can I find a statement from the York team which says that they will strictly confine themselves to consideration of water at 1 ppm. In an answer to a question 2, of the section entitled Fluoridation of Drinking Water-Frequently Asked Questions, the York team stated that "studies must look at a positive and/or negative effects, as manifested by clinical outcomes, where a population receiving water which has either been artificially fluoridated or is naturally fluoridated is compared to a population receiving water containing a lower level of fluoride". There is no mention here of restricting such examinations to water at 1 ppm.

f) Kurttio (1999). This report has been incorrectly or misleadingly summarized in Table 8.1. and Figure 8.1 In table 8.1 the York team lists the RR for women as 1.08 (95% CI 0.3-3.2) and for men as 0.67 (95% CI 0.5 – 0.8). However, this is what Kurttio et al actually say about their findings, "No association was observed between hip fractures and estimated fluoride concentration in the well water in either men or women when all age groups were analyzed together. However, the association was modified by age and sex so that among younger women, those aged 50-64 years, higher fluoride levels increased the risk of hip fractures…The adjusted rate ratio was 2.09 (95% confidence interval 1.16, 3.76) for younger women who were most exposed (> 1.5 mg/liter) when compared with those who were least exposed (< 0.1 mg/liter).
I am very disturbed by the way this report was handled by the York team: i.e. how a finding so clearly articulated by the authors as one in which the relative risk doubles, becomes one with no significant association.

g) If adjustments are made to the Forest plot (Figure 8.1) in the light of the corrections to the Jacobsen(1992), Cooper (1991), Sowers (1991), Li (1999) and Kurttio (1999) reports, the association between fluoridation (natural and artificial) and increased hip fractures will become much clearer and much stronger.

h) A recent abstract from the 33rd Annual meeting of the Society for Epidemiological Society, for a paper by Hegmann et al (2000) further adds to the studies finding an association between hip fracture and consuming fluoridated drinking water. For women 75-84 years they found a statistically significant association with an RR of 1.43 (95% CI 1.02 - 1.84) and for women 85+ the rate approached statistical significance with an RR = 1.42 (CI 0.98 - 1.87).

i) Two other unpublished studies, which were presented and discussed at the NIH workshop in 1991, (Gordon and Corbin, 1992) also showed an increased rate of hip fracture with fluoridation (May and Wilson, 1991) and Keller (1991). These were considered by the York team but excluded from their final analysis.

3.4.4 Criticism of some of the papers included in the meta-analysis.

3.4.4.1 According to several papers published in the journal Fluoride by Dr. John Lee (1993, 2000), a bone specialist from California, the quality of bones in the elderly largely reflect the way they are built when we are young. Thus, when considering the impact of fluoride on bones it is important to look at communities exposed to fluoride for most of their lifetime. In particular, when looking at women we should particularly look at those exposed to fluoride before and during menopause, a period of extensive bone remodeling. This concern was particularly underlined in the study of Danielsen et al (1992). The authors state, "We also found an increased rate of hip fracture, which was less pronounced in those older than 80 years of old, in post menopausal women living in the community with fluoridated water. A possible explanation for this is that women younger than 80 years would have been exposed to fluoride in the water system as they passed through menopause, a period of increased bone remodelling. Women older than 80 years would have already gone through menopause at the beginning of fluoridation and would have had less bone remodeling and less incorporation of fluoride into the bone. This would not affect men." Unfortunately, several of the authors of the papers included in the meta-analysis were either unaware of this possibility, or chose to ignore it.

3.4.4.2 Cauley et al (1995). In this study, the authors looked at 828 women of 65 years or older exposed to fluoridated water. Of these, 53% were exposed for less than 10 years, 77% were exposed less than 20 years, and only 23% at most could have been exposed during menopause. Very few if any were exposed prior to menopause and of course, none were exposed in their youth or for a whole lifetime.

3.4.4.3 Phipps et al (2000)

(My comments - submitted to the York team - are not being made public on this paper until it is published in the British Medical Journal)

3.4.4.4 However, it is important to note that Kurttio’s (1999) findings do not support the association with exposure prior to menopause described by Danielsen, because it is only the younger women 50-64 for which a significant association with hip fracture and fluoride exposure is found. It is not found for the women aged 65-80 or all ages combined, even though these women too would have been exposed prior to menopause. Kurttio et al discuss this on pages 822-823 of their report. Clearly, this issue warrants further discussion and investigation.

3.4.5 The limitations and misuse of meta-analysis in section 8.1.

3.4.5.1 Meta-analysis of epidemiological studies, even at its best, has come under some criticism (Shapiro, 1994). However, as it stands, Table 8.1 is a classic example of the misuse of this technique.

3.4.5.2 The York team claimed to have applied a mathematical technique to test the heterogeneity of the studies included in Table 8.1, and found that they were "homogenous" and thus the studies could be pooled in a meta-analysis. This conclusion defies both simple scientific analysis as well as common sense. By pooling the results of all these studies the York team has bundled together different fracture sites even though there are clear differences in fraction rates for different bones in many of the studies. Moreover, there are scientific reasons why one would expect different fracture rates for different bones. (The York team did do a separate meta-analysis for the hip fractures alone). They have added together the results for men and women though it is clear that many studies found sex related differences. Again there are very plausible scientific reasons why one would expect sex related differences because of the extensive bone remodeling which occurs with women passing through menopause. Moreover, they have mixed up studies where women have been exposed pre-menopause and those that haven’t. They have mixed together good studies and bad studies. Clearly, this is not a homogenous set of studies. This meta-analysis simply blurs distinctions instead of clarifying them.

3.4.5.3 Again I asked Dr. Tom Webster to comment on the York team’s use of meta-analysis for bone fractures. He wrote:

"The York review performs a meta-analysis combining data from studies of quite different designs, both sexes, different ages and fractures at various sites (Figure 8.1). The computed Q-statistic, a measure of heterogeneity, was small. The reviewers concluded there is a lack of heterogeneity, justifying combining all of the data. This procedure is seriously flawed. There is support in earlier literature for differences in outcome depending on sex, age (at disease or exposure) and site. There is even evidence for protective effects at some sites and deleterious at others. To combine such data is absurd. A better approach is to try to describe and understand the heterogeneity, not brush over it (Poole and Greenland 1999). The statistical test gives little confidence in the assumption of homogeneity. As Greenland (1998, p.662) points out:

"To summarize, one should regard any homogeneity assumption as extremely unlikely to be satisfied, given the difference in covariates, bias and exposure variables among the studies. The question at issue in employing the assumption is whether the existing heterogeneity is small enough relative to other sources of variation to be ignored. A statistical test of homogeneity can serve as a warning light with high specificity but low sensitivity: Small P values indicate that the heterogeneity should not be ignored, but large P values do not indicate that it can be safely ignored."

The use of a random effects model does not properly deal with heterogeneity either. As Poole and Greenland (1999, p.474) point out:

"Unfortunately, random-effects summarization seem to have become one of the statistical methods, like significance testing, that tend to be applied to epidemiological data ritualistically and without much thought for important features of the data they might conceal. This unfortunate situation is no doubt due to the false hope that…it somehow accounts for that heterogeneity, explains it, or makes it go away." (Webster, 2000)

3.4.5.4 In addition to the meta-analysis the York team also provided verbal summations of their tabulated data. For example beneath Table 8.1 they write, "A total of 18 studies investigated the association of hip fracture with fluoride level, making 23 comparisons (sic, I make it 30) (e.g. men only, women only, both). Of thirteen comparisons that suggested a positive effect of water fluoridation (decreased hip fracture with increased fluoride level), 6 were statistically significant…etc." This is what Greenland has to say about such an approach in a standard epidemiological text (Rothman, 1998), under the heading:

SOME METHODS TO AVOID.

Qualitative Tally (Vote Counting)

"In many traditional, qualitative reviews, one can find the explicit or implicit use of a qualitative tally or vote count. Consider a hypothetical literature summary stating, "Of 17 studies to date, five have found a positive association, 11 have found no association, and one has found a negative association; thus the preponderance of evidence favors no association". Such a tally can be extremely misleading, even if every single study is methodologically flawless, every study is included, and all the studies are comparable in every relevant aspect…

…a qualitative tally should never serve as anything more than a provocative introduction to a more detailed analysis". (Greenland, 1998)

3.4.6 What can you do if you get mixed results from epidemiological studies? A number of European governments and non-governmental organizations are supporting a new approach to resolving questions like this. This approach is called the Precautionary Principle.

3.4.7 The Precautionary Principle. The precautionary principle asks several basic questions about the kind of situation where you have mixed results from epidemiological and other studies.

1) What is the weight of evidence from all the studies( e.g. biochemical, animal, tissue culture and epidemiological) on the debated outcome of concern?
2) How serious is the outcome of concern if you proceed with the course of action?
3) How large is the benefit being pursued?
3) Are there satisfactory alternatives to the course of action proposed which would avoid the outcome of concern?

3.4.8 The weight of evidence.

3.4.8.1 Fluoride and the biochemistry of bone. The author of a textbook on Human Biology states: " Perhaps because of their strength and durability, it is a popular misconception that bones are static, unchanging structures Nothing could be further from the truth. Bone is a living tissue and an extremely active one at that" (DeWitt, 1989). Fluoride has the ability to interfere with many of the enzymes in the numerous bone cells which provide different functions in burn growth and turnover. The possibilities are enormous and complicated. A brief glimpse of the complexity of this matter can be gleamed from a paper by Krook and Minor (1998). Commenting on the use of fluoride to treat osteoporosis patients, in the context of their findings in animal studies at the College of Veterinary Medicine, Cornell University, they state: "Fluoride is a potent enzyme poison. The concept that fluoride is a specific stimulus for bone formation is preposterous…Furthermore, because fluoride injures all the cells involved in bone formation and degradation, it is not surprising that a poor quality of bone accumulates in patients treated with fluoride (Vogorita and Suda, 1983)…It is unfortunate that many physicians who treat osteoporosis with fluoride do not realize that they are prescribing a drug that is toxic for all active bone cells".

3.4.8.2 Bone mineral density and bone quality. While it is true that treatment with fluoride (either short term with doses of 40 – 75 mg of fluoride, or long term with fluoridation of the water supply) can lead to an increase in bone mineral density. This turns out to be a crude index of bone health, and bone performance. Bely (1998, 2000) has performed elegant studies using a variety of microscopic and electron microscopic techniques to show the damage that fluoride does to the bone cells producing collagen and the eventual collagen formed. He concludes that while fluoride might lead to increasing the quantity of the bone, it damages its quality.

3.4.8.3 Animal studies. Studies have shown that when rats are treated with fluoride their bones become more brittle (Wolinsky et al, 1972, Bohatyrewicz, 1999).

3.4.8.4 Human trials. In human trials with patients with osteoporosis, it has been shown that high doses of fluoride lead to more brittle bones ( Hedlund, 1989, Riggs et , 1990).

3.4.8.5 Taking all of the above into account, as well as the mixed results from the epidemiological studies, the weight of evidence would suggest that it is highly plausible that exposure to water at 1 ppm (and the concurrent exposure to other sources of fluoride in modern life) over a whole lifetime will damage human bones and ligaments. It is also probable that this damage will at least lead to the sub-clinical symptoms of skeletal fluorosis, possibly arthritis as well as to hip fractures. This may not be true of everyone but it will probably true for a significant minority, especially those who have a poor diet, who drink excessive quantities of water and other beverages made with fluoridated water, and those who have poor renal clearance.

3.4.9 Is the outcome of concern serious?

The outcome of increased hip fracture in the elderly is very serious. Each year some 200,000 elderly people in the US have hip fracture. The annual costs of treatment are estimated as high as 10 billion dollars. Treatment is highly traumatic for the elderly. One in five of the elderly who suffer a hip fracture are dead within one year of their operation.

3.4.10 How large is the benefit being pursued?

Not very great compared to the alternatives discussed below. As discussed in section 3.2 the largest surveys in the US, Canada and New Zealand are indicating very little difference in dental decay in children from fluoridated and non-fluoridated communities. Most countries in Europe do not fluoridate their water and their children’s teeth are as good if not better than those of children in fluoridated countries.

3.4.11 Are there Alternatives?

Yes there are. Some would argue that fluoride is neither necessary nor essential for healthy teeth. That a combination of a good diet, minimizing sugar consumption, and regular brushing with any kind of toothpaste or toothpaste substitute (salt, baking soda, even soap) is just as effective. Others would argue that fluoride is beneficial to achieving good teeth, especially where it is difficult to get children to limit their input of sugar and sugary foods, but that applying the fluoride in the form of fluordated toothpaste is just as effective, or more effective, than swallowing the fluoride in drinking water. That these alternatives exist, and work, is supported by the fact that the majority of European countries do not fluoridate their drinking water and yet their childrens’ teeth are just as good, if not better, than those of fluoridated countries. Some European countries also use fluoridated salt, milk and other topical treatments as part of their strategy in fighting tooth decay

3. 4.11 Thus on all three counts, an application of the precautionary principle would require a government to reject water fluoridation on this one health effect alone.

3.4. 12 Building a bridge between scientific analysis and ethical judgement. An important aspect of the Precautionary Principle is that it builds a bridge between scientific analysis and ethical judgement. Even, if only a small minority of people have their bones affected as a consequence of water fluoridation, it would raise several ethical questions. How big does this minority have to be before the ethical arguments kick in? How can one justify the protection of the teeth of one section of the community, while damaging the bones of another? Are people being given the opportunity for "informed consent" to this trade off? How can one justify even the possibility of this damage when there are known alternative ways of protecting teeth and there are also known ways of delivering fluoride which do not involve cumulative systemic exposure?

3.5 Cancer.

3.5.1 Before addressing the York team’s review of cancer epidemiological studies, it is worth looking at both the scientific and intriguing historical background to this debate.

3.5.2 At the biochemical level it is highly plausible that fluoride would be both a cancer initiator and a promoter. By forming a strong hydrogen bond with the amide function (Emsley, 1981) it could well interfere with base pair recognition so critical to DNA repair, replication, transcription and translation (protein synthesis). Furthermore fluoride is known to inhibit a number of enzymes which have magnesium as a co-factor (Waldbot, 1978). A number of enzymes involved in nucleic acid biochemistry have magnesium as a co-factor. The magnesium by forming a complex with the phosphate group helps to steer nucleotides into the exact location for assembly and disassembly. It is highly plausible that fluoride would dislocate this mechanism so critical for nucleic acid activity. It is known that fluoride inhibits the enzymes involved in DNA repair in test tubes.

3.5.3 There is an excellent summary of what is known about fluoride’s genotoxicity from microbial, animal, and human tissue culture studies in appendix H of the 1991 Review of Fluoride by the Department of Health and Human Services in the US. From this it can be ascertained that there is nothing unscientific about entertaining the notion that the simple fluoride ion could initiate or promote cancer. It is highly plausible from a scientific point of view. It is clearly an extremely important debate to resolve before putting fluoride into the drinking water of every man, woman and child in your country. Indeed, from an historical point of view it is interesting to note that the US Congressman who took most note of the fluoridation debate was none other than Congressman Delaney (NY) who was responsible for the famous "Delaney Clause", which required that no additive be added to food which had been shown to cause cancer in animals.

3.5.4 Osteosarcoma. I will be focusing my concern on a form of bone cancer called osteosarcoma. This is a rare cancer, but is one of the most prevalent cancers in young males 9-20. It appears to strike young men in the period of rapid bone growth during puberty. Presumably, during rapid turnover mutagens have a greater access to the DNA molecule.

3.5.5 Historical concern about Osteosarcoma in young males. In light of the concern today about the possibility that fluoride might increase the risk of osteosarcoma in young males, an intriguing piece of history occurred in 1956 when Dr. Caffey examined the health data collected in the 1945-55 Newburg vs Kingston fluoridation trial (Schlesinger, 1956). He noticed a greater percentage of cortical bone defects in the bones of the children in fluoridated Newberg compared to unfluoridated Kingston. The comment he made at the time was picked up by the authors of a National Academy of Sciences report in 1977, and further amplified:

"There was an observation in the Kingston-Newburgh (Ast et al, 1956) study that was considered spurious and has never been followed up. There was a 13.5% incidence of cortical defects in bone in the fluoridated community but only 7.5% in the non-fluoridated community… Caffey (1955) noted that the age, sex, and anatomical distribution of these bone defects are ‘strikingly’ similar to that of osteogenic sarcoma. While progression of cortical defects to malignancies has not been observed clinically, it would be important to have direct evidence that osteogenic sarcoma rates in males under 30 have not increased with fluoridation" (my emphasis). (NAS, 1977).

3.5.6 If we now turn the clock forward to the 1990’s when the National Toxicology Program (NTP) finally produced their long term animal cancer studies for fluoride (they had been told to do these studies by the US Congress in the late ‘70s, as a result of the furor generated by the Yiamouyiannis and Burk (1977) study which reported higher cancer rates in 10 largest fluoridated cities compared with 10 largest unfluoridated cities in the US). They found a dose-related increase in osteosarcoma in male rats. They also found other cancers but these were eliminated by a peer review process which so angered Dr. William Marcus, who was then head of toxicology of the water division of the US EPA, that he exchanged several memos with his superiors. Rather than taking his criticism seriously he was fired. The thing that particularly amazed Marcus about these findings is that he had been trying to give osteosarcoma to animals and the only chemical that appeared to do it was radium. The notion that the lowly fluoride ion could pull off this feat was staggering.

3.5.7 US authorities have done their very best to downgrade these osteosarcoma findings. They dropped one of the sarcomas, which allowed them to call the results "equivocal". They further stress that the fluoride used in the experiments was a "high dose", however, as Marcus has pointed out the fluoride levels in the rats’ bones was within the range you expect in the human population. The Department of Health and Human Services (1991) point out that a study commissioned by Procter and Gamble failed to reproduce the same result in their rat studies. While, still others were dismissing the findings as just "animal studies" with little relevence to human beings, another bombshell fell. Under the SEER (Surveillence, Epidemiology and End Results Program Cancer Resistry) 16 years of cancer incidence data was examined for the years between 1973 and 1987. These registries cover about 10% of the US population. This examination turned up higher rates of osteosarcoma in young males in fluoridated areas compared with non-fluoridated areas. However, this is how the US Department of Health and Human Services (1991) described these findings:

"Osteosarcoma is a rare form of bone cancer, the cause of which is under study. Approximately 750 newly diagnosed cases occur each year in the United States, representing about 0.1 percent of all reported cancers. Between two time periods, 1973-1980 and 1981-1987, there was an unexplained increase in the annual incidence rates of osteosarcoma in young males under age 20 from 3.6 cases per 1,000,000 people (88 registry cases) to 5.5 cases per 1,000,000 people (100 registry cases). This compares to a decrease in young females of the same age group from 3.8 cases per 1,000,000 people (87 registry cases) to 3.7 cases per 1,000,000 people (63 registry cases). The amount of increase in observed in young males was greater in fluoridated than in non-fluoridated areas. Although the reason for the increase in young males remains to be clarified, an extensive analysis reveals that it is unrelated to the introduction and duration of fluoridation"

This extensive analysis appeared in appendix H of the DHSS report. However, the dismissal of this serious finding on osteosarcoma hinges on one piece of analysis and that is when the osteosarcoma rates are compared with length of exposure to fluoridation it is found that the highest rate occurs for five years of exposure. There is no linear increase for 10, 15 or 20 years of exposure. While this is a strange result I am told by epidemiologists at Boston University that this is not unusual in epidemiological studies of rare cancers and it not enough sufficinent grounds to dismiss the finding.

Unfortunately, because the US Public Health Service has staked its reputation on the efficacy and safety of fluoridation, for over 50 years, it is extremely difficult to separate out objective scientific analysis from their "gung ho" promotion of this measure.

3.5.7 But the history doesn’t end there. In 1992, the NJ Department of Health (Cohn, 1992) issued a report entitled: "An Epidemiologic Report on Drinking Water and Fluoridation". In this report the author Cohn, indicated that in three counties of NJ there was approximately 7 times the osteosarcoma rate in young males in the fluoridated communities compared to the non-fluoridated communities. For the years (1979-87) in the fluoridated communities (in Mercer, Middlesex and Monmouth Counties) there were 22 cases per million and in the non-fluoridated communities there were 3.2 cases per million. For young females there was little difference: 6.8 versus 5.1 cases per million (Fluoridated versus Non-Fluoridated). Other epidemeological studies in the US have not found these differences in osteosarcoma rates (e.g. Mahoney, 1991; Gelberg, 1995).

3.5.8 Turning to the York Review, I am disturbed that the Cohn (1992) study (see above, 3.5.7) was not included in their meta-analysis even though it was listed as one of the papers they had reviewed. There is nothing I can see in the York team’s exclusion criteria to explain this serious omission.

3.5.9 The York team, summarizes the studies on osteosarcoma in table 9.3. Having excluded the Cohn study, we are left with one study suggesting an increase in osteosarcoma and five which did not. However, this issue should not be left at that. We have to remember the rarity of this disease and the special difficulty this poses for epidemiological studies. Once again, this is precisely the point where the Precautionary Principle should come into play. We have two human epidemiological studies and one rat study waving red flags. We have a very serious health consequence if we proceed and we are wrong. How many teeth saved would be necessary to compensate for one child’s death from osteosarcoma? Why take these risks with water fluoridation when there are proven alternative strategies that are working in other countries. Again, this matter requires the upmost caution.

3.5.10 There are two other pieces of information, which may relate fluoride to osteosarcoma. Firstly, in animal studies it has been shown that fluoride lowers testosterone levels. Testosterone levels are definitely related to rapid bone growth in young males. Secondly, a known factor for osteosarcoma is exposure to radium. It is known that radium levels are higher in naturally high fluoride areas. Is fluoride simply a marker for radium? Or is it possible that fluoride acts synergistically with radium –e.g. does it form a complex with radium, which facilitates its uptake in the bone?

3.6 Other Health Effects.

3.6.1 Section 10 of the York review, which examines other possible health effects, is the least satisfactory of all the sections in their review. It is perhaps understandable at the end of a long review process, which I believe has been unduly rushed, that they weren’t anxious to open up too many new doors. However, putting fluoride into the drinking water of a whole population is like building a dam upstream of a village. You should be certain that you have examined the design and the fabric of the whole dam to the minutest degree before your proceed, because if you make an error the whole village could be flooded and many lives lost. All the evidence must be examined with a fine tooth comb. If you are not absolutely certain that your dam will never fail you shouldn’t build it or build it elsewhere.

3.6.2 In the case of fluoridation your whole population is in the firing line: the old, the young, the unborn, the infirm and those who maybe especially vulnerable or sensitive to fluoride’s effects. According to the Agency for Toxics and Disease Registry’s (ATSDR) Toxicological Profile on fluoride (ATSDR, 1993) there are particular subsets of the population which are, "unusually susceptible to the toxic effects of fluoride and its compounds" and these populations include:
"the elderly, people with deficiencies of calcium, magnesium and/or vitamin C, and people with cardiovascular and kidney problems… Impaired renal clearance of fluoride has also been found in people with diabetes mellitus and cardiac insufficiency. People over the age of 50 often have decreased renal fluoride clearance… Poor nutrition increases the incidence of dental fluorosis and skeletal fluorosis…" (ATSDR, 1993, page 113).

3.6.3 I, too, am running out of time and running out of steam, so I cannot begin to comment on most of the studies referenced in this section. However, I would like to make a few comments on areas which were either treated too lightly, like the effects on the central nervous system, or ignored entirely, like the effects on the thyroid gland and those individuals who appear to be super sensitive to fluoride exposure. Hopefully, my comments will serve as pointers as to what should be done in the future, either in a revised York Review or by a team of independent experts drawn from many different fields of study, including biochemistry, physiology, toxicology and public heath. Without such an expanded and more thorough treatment any government would be badly served by the information presented as is on the other health risk section. I will discuss these issues under the following headings:

i) Health effects in high endemic areas.
ii) Fluoride and the central nervous system.
iii) Fluoride and the pineal gland.
iv) Fluoride and the thyroid gland.
v) Fluoride as an endocrine disrupter.
vi) Fluoride and G proteins.
vii) Fluoride and the supersensitive.

3.6.4 Health effects in high endemic areas.

Literally millions of people worldwide have had their health impacted by exposure to high levels of fluoride from areas where the levels of naturally occurring fluoride in the drinking water are very high. To ignore the vast number of studies which have examined both the health of these citizens and their treatment is unforgivable. The excuse that these people are not relevant because exposure to fluoride is coupled with poor nutrition is lame and inappropriate. This is especially so since, if malnutrition is a compounding factor in the health impacts of fluoride, which I believe it is, it is precisely the kind of information you need when those specifically targeted for fluoridation are children from lower income families. These are the most likely children to be malnourished in an otherwise affluent society like the UK. Such a review should begin with very extensive work of Dr. Sushela and Dr Chinoy in India as well as the many studies from China. It is not at all unusual to make toxicological extrapolations from high dose animal studies to lower doses in humans. In this case one has the opportunity to extrapolate from high dose exposure in humans to possible long term low dose effects in humans. This could be particularly important for predicting the effects on bone as whole populations in English speaking countries are exposed to higher and higher doses of fluoride for longer and longer periods of time. This assumes, of course, that at some time governments get around to comprehensively monitoring the levels of fluoride in people’s bones in fluoridated countries.

Incredibly, after citing only one paper on skeletal fluorosis (Jolly, 1971) out of dozens published, they handle this disease which afflicts millions of human beings worldwide, in one sentence (along with IQ): "Skeletal fluorosis and IQ were both negative in association with water fluoride, but again no measure of the statistical significance of this association was presented". This has to be one of the most nonchalant statements in the whole of the York Review. Are they seriously implying, that there is no significant relationship between fluoride exposure and skeletal fluorosis? This does not say much about the authors understanding of this issue.

3.6.2 Fluoride and the central nervous system.

This is an area that is poorly served if the study is confined to human epidemiological studies, because few have been conducted in this area. Once again a weight of evidence approach which combines both human and animal studies would be more appropriate.

There have been several studies which indicate that fluoride can impact mental behavior. In the 1940s, US scientists working on the Manhattan Project (the making of the Atomic bomb) were concerned that exposure to fluoride could threaten the behavior and concentration of the workers in nuclear plants which were using huge quantities of fluoride in the separation of uranium isotopes. A request was made by Harold Hodge, the chief toxicologist of the project, to do a study on the impact of fluoride on rat behavior. His request was first accepted and later canceled (Giffiths and Bryson, 1997)

In 1995, Dr. Phyllis Mullenix resisted an enormous amount of political pressure to publish her investigation of the impact of fluoride on rat behavior (Mullenix, 1995). In her work she found that fluoride concentrated in the brain and that when the animals were exposed to fluoride before birth they exhibited behavior characterized as hyperactive, and when they were dosed after birth they became hypoactive ("couch potatoes"). In a non peer-reviewed critique by Gary Whitford, circulated by the Centers for Disease Control, Division of Oral Health, but not submitted to Mullenix for rebuttal (her work was attacked because of the high levels of fluoride she had used).

When Mullenix finally received a copy of Whitford’s critique from a third party she was quickly able to respond. She pointed out, "These criticisms are without merit because our doses in rats produce a level of fluoride in the plasma equivalent to that found in humans drinking 5-10 ppm fluoride in water, or humans receiving some treatments for osteoporosis. This plasma level is exceeded ten times over one hour after children receive topical applications of some dental fluoride gels. Thus, humans are being exposed to levels of fluoride that we know alter behavior in rats"(Mullenix, 1998). Mullenix also pointed out that it is standard toxicological practice to treat animals with large doses over short periods of time, in order to tease out an effect with the small number of the animals being tested. However, before she could administer small doses over a longer period of time, she was dismissed from the Forsyth Dental Center. She was told her work had little relevance to dentistry!

However, Isaacson and his co-workers have conducted low-dose, long-term fluoride studies in rats. (Varner, 1998). They found that fluoride administered daily at 1 ppm, either as aluminum fluoride or sodium fluoride in doubly distilled de-ionized water, for a period of one year, produced morphological changes to kidney and brain cells and an increased uptake of aluminum into the brain. This striking finding has been largely ignored by US authorities, as have been the studies by Guan (1998) on the impact of fluoride on membrane lipids in rat brain, and the studies from China which indicate a lowering of IQ of children as a function of their exposure to fluoride (Li, 1995) and Zhao, 1996). While it is possible that these Chinese studies may have not accounted for some potentially confounding variables, they again wave another very serious red flag?

Only one of these Chinese studies (Zhao, 1996) was reviewed by the York team. However, this important work was dealt with in the same sentence by the York Review as they dismissed skeletal fluorosis (see comment above in 3.6.4) for lack of reporting of statistical significance. However if they had read the paper, on page 190 they state:

"In Sima, where the children were exposed to higher water-borne fluoride in embryo, the average IQ was 97.69, and in the lower fluoride village of Xinghua it was 105.2. This difference is statistically significant (p < 0.01) but there was no significant difference between male and female IQ in the two areas".

Moreover, this study did control for the educational level of the parents of the children studied.

Are we going to risk damaging our childrens’ brains for the sake of, at most, half a tooth? What would the Precautionary Principle have to say about that?

The work by Isaacson et al (Varner, 1998) raises a very large issue: the possibility that because fluoride forms complex ions with very many metal ions, including toxic metals like radium, uranium, beryllium, aluminum and lead, it may facilitate the uptake of these elements into places they would not normally be able to enter. This may be particularly relevant if fluoride facilitates their crossing of the blood brain barrier or the placental membrane. Unfortunately, very few studies have pursued the synergistic effects of fluoride and other substances like toxic metal ions. In one of those rare studies that did, it was shown that a combination of lead and fluoride (the salts were dissolved in the drinking water of rats) proved to be "much more severely toxic than either compound alone" and that the fluoride produced significantly higher lead concentrations in the blood and femur (Mahaffey, 1976).

Another more recent study which may have inadvertently probed the synergistic relation between fluoride and lead is the extraordinary work of Dr Roger Masters (Professor of Government at Dartmouth) and Myron Coplan, an environmental engineer from Massachusetts (Masters and Coplan, 1999). They have found a correlation between the uptake of lead into children’s blood and the use of hexafluorosilicic acid or its sodium salt to fluoridate municipal water supplies in Massachusetts, but not with the use of sodium fluoride. They also found a correlation between the use of these same agents and the incidence of violent crime. This work has recently been criticized by Urbansky and Schock (2000). These authors claim that both hexafluorosilicic acid and the hexafluorosilicate ion will be completely dissociated when the concentrated solutions (or solid sodium hexafluorosilicate) is diluted at the public water works. The studies supporting this claim need to be scrutinized carefully. Masters and Coplan (2000) argue that the studies cited by Urbansky and Schock do not support their position and don’t reflect the real life situation of adding very concentrated solutions of these substances into the water at the public waterworks. They argue that during this process there is plenty of opportunity for partially hydrolyzed silicon fluoride complexes to be captured by other ions like aluminum.

3.6.3 Fluoride and the pineal gland.

I have already briefly described the work of Jennifer Luke and the pineal gland in sections 2.8 and 3.3.5. Here, I will add a few more details.

The pineal gland is almost at the geometrical center of the brain, between the two hemispheres. However, it is outside the blood brain barrier. It also has a very high supply of blood (a perfusion rate second only to the kidney) and it is a calcifying tissue, laying down crystals of calcium hydroxyapatite like the teeth and the bone. Because of these observations Luke argued that one would expect the pineal gland to concentrate fluoride. When she had the pineal gland from 11 human corpses analyzed she indeed found this to be the case. The levels of fluoride in the apatite crystals averaged about 9,000 ppm (and went as high as 21,000 ppm). The average level is as high as you would expect in the bones of someone afflicted with skeletal fluorosis. The average projected by Luke for the whole tissue was 300 ppm, well over the 1 ppm found to inhibit many enzymes.

Luke next examined the effect of dosing Mongolian gerbils (the animal of choice for studying the pineal gland) with fluoride. She found that animals fed higher doses of fluoride had a significant decrease in their excretion of melatonin metabolite in their urine compared to animals fed lower doses. She also found that the high dose fluoride animals took a shorter time to reach puberty. This is exactly what you would expect if melatonin production was lowered.

Luke postulates a mechanism which doesn’t involve the functioning of the hormone, but its production. In the production of melatonin in this gland there are four chemical changes between the amino acid tryptophan (a nutrient) and melatonin. All four steps are catalyzed by enzymes. The first two steps yield serotonin, a neurotransmitter, and the next two convert serotonin into melatonin. Luke argues that one or more of these enzymes which catalyze these four steps are inhibited by fluoride. Interfering with either the production of serotonin or melatonin is of extreme significance. A huge amount of research is ongoing in the attempt to elucidate all the subtle influences that melatonin has on regulatory mechanisms throughout the body, including the timing of puberty.

Of particular interest, is the knowledge that in the US there is an earlier onset of puberty, especially in girls, and no one knows what is causing this (Herman-Giddens, 1997). There are many possible candidates, but based upon Luke’s work on the pineal gland, fluoride should be added to the list.

Also of interest is the fact that when children were examined in the Newburgh-Kingston study in 1955 (ten years after fluoridation was begun) it was found that the girls in fluoridated Newburgh reached menstruation five months earlier, on average, than the girls in non-fluoridated Kingston (Schlessinger, 1956). At the time this was not considered significant, but in the light of Luke’s animal studies, the issue should be re-examined.

3.6.4 Fluoride and the thyroid gland.

In my view it is extremely regrettable that the York Review team did not take advantage of the enormous body of work that Andreas Schuld has put together on the impacts of fluoride on the thyroid gland. Perhaps they were just too rushed or exhausted covering other issues to give this matter the time it deserved. Be that as it may, it is a huge area of health concern, which needs to be carefully examined by an independent and qualified group of experts.

Here is what I have gleaned from Schuld’s review.

Andreas Schuld and his group (Parents of Fluoride Poisoned Children) has been able to show that areas of endemic fluorosis are also areas designated as being endemic with iodine deficiency disorders (IDD).

They have also found studies and documentation from the European medical literature, spanning over 30 years, testifying to fluoride’s pharmacological effectiveness in the treatment of hyperthyroidism (the term used to describe an over-functioning thyroid gland). Thyroid hormones are absolutely essential for normal growth and development. Hyperthyroidism means that the thyroid gland is producing too much of the thyroid hormones, T3 and T4.

Schuld’s group has also shown that there is a remarkable similarity between the symptoms listed for hypothyroidism (underactive thyroid gland) and those reported for fluoride poisoning. Putting these two conditions together, it appears that fluoride decreases the production of thyroid hormones. If you are suffering from hyperthyroidism, fluoride might be of some benefit. But for a normal person – or perhaps someone who is super-sensitive to fluoride - if you are exposed to too much fluoride it could result in reducing thyroid hormone production below normal and necessary levels (i.e., hypothyroidism).

It is not clear just how fluoride reduces thyroid hormone production. It may be that fluoride competes with iodine uptake into this gland. Alternatively, fluoride might inhibit the enzymes inside the gland which assemble the hormones from their precursors.

Schuld also points to research that fluoride can also stimulate the thyroid glands, which seems contradictory to the discussion above. However, stimulation may not lead to production of the hormones if iodide is in short supply. Such a situation (overstimulation coupled with iodide shortage) might explain the condition known as goiter. Here the gland grows and grows producing a swelling in the neck. The gland grows because it is being stimulated, but because there are no thyroid hormones produced, there is nothing to switch off the stimulating signal (thyrotropin or thyroid stimulating hormone) which is produced by the pituitary gland as a response to low thyroid hormone levels.

3.6.5 Fluoride as an endocrine disrupter.

Both the work of Jennifer Luke on the pineal gland, and the studies collected by Andreas Schuld, suggest that fluoride is an endocrine disrupter. In studies conducted in India, there is also evidence that fluoride lowers the levels of testosterone, the male sex hormone. Endocrine disruption by exogenous chemicals is an area of intense discussion today (Colborn, 1996). Those concerned about endocrine disruption should include fluoride in their reviews. Any government considering putting fluoride in the drinking water should also have this literature reviewed very, very carefully.

3.6.6 Fluoride and G proteins.

Isaacson et al’s work (Varner, 1998) cited above (see section 3.6.3) throws up the possibility that even at 1 ppm fluoride can act synergistically with aluminum, resulting in both brain and kidney damage. This may simply reflect the fact that fluoride might facilitate the passage of aluminum through key membranes like the blood brain barrier, or it may be part of a large phenomenon already appreciated by many research biochemists. This is the fact that a complex of aluminum and fluoride can switch on G proteins. This is highly significant because the switching on of G proteins is the key step in taking the message of a water soluble hormone from outside of the cell, it is regulating, to the inside. Aluminum fluoride complexes can switch on this signal without the hormone being present. This is so well established that research biochemists use this as a standard technique when investigating either these signaling mechanisms or the resulting cellular activities switched on by hormones (see section 2.9).

For an excellent analysis of the concern that this phenomenon could pose for human health I recommend a review by Struneka and Patoka, 1999.

3.6.7 Fluoride and the supersensitive.

For many years numerous medical practitioners and governmental officials treated citizens complaining of symptoms, which are now referred to as "multiple chemical sensitivity", like mental cases. I can’t imagine how awful it must have been for someone who was suffering from debilitating pain to be told that it was all in their head. At least today, their ailment is recognized as a real disease.

Sadly, those who complain of suffering a rag-bag of symptoms when exposed to fluoride or fluoridated water, and whose symptoms disappear when they remove the source of fluoride, are still not taken seriously. This despite the fac