FLUORIDE 31(4), 1998, pp 235-244	International Society for Fluoride Research	Table of Contents

Publication of John Colquhoun’s article on why he changed his mind about fluoridation¹ along with a critique by Howard Pollick² and Colquhoun’s reply³ provides an opportunity to re-examine the issues raised by this debate on fluoridation. The problem is to determine what evidence is sound and what is not. This analysis concerns the sixteen points raised by Pollick.

1. Printing error. In the interchange of views it was clarified that this first point was a non-issue and arose from a printing error.

2. Conspiracy to withhold information. There does not appear to be any matter of scientific evidence in dispute in this point.

3. Bias in the use of titles. Again no matter of scientific evidence appears to be under dispute on this point, but the published record speaks for itself.

4. Water fluoride levels. This point is the first involving the examination of scientific data. The point raised by Pollick was that "the work of Teotia⁴ in India" concerned areas with a very high fluoride beyond the recommended concentrations for water fluoridation. Colquhoun countered that the work had included both low and high fluoride areas.

Reference to the original article indicates clearly that the studies by Teotia and Teotia⁴ involving 400,300 children were done in areas including both endemic fluorosis with fluoride levels greater than 1 ppm and non-endemic fluorosis areas with fluoride levels less than or equal to 1 ppm. The total population of children surveyed was 800,750 of whom 400,300 volunteered for complete examination and inclusion in the study. In the nonendemic area the mean water fluoride level was 0.5 ± 0.24 ppm and contained 200,000 children while the endemic area had 200,300 children and a fluoride level of 4.19 ± 2.03 ppm. A subgroup of 23,270 children were studied involving 12,150 who lived in a low-fluoride area with a mean water fluoride level of 0.70 ± 0.25 ppm and 11,120 who lived in a high fluoride area with a mean water fluoride of 2.85 ± 0.75 ppm.

Since 1962, the "optimal" concentration of fluoride in drinking water for the United States has been set at 0.7-1.2 ppm depending on the mean temperature of the locality.⁵ Assessing the evidence suggests that it is incorrect to dismiss the work of Teotia and Teotia⁴ on the grounds that only areas with very high fluoride levels were involved.

5. Effects of nutrition on tooth decay. There does not appear to be any scientific data in dispute in this point with both Pollick and Colquhoun agreeing that nutrition may have a role in tooth decay. Pollick points to the place of sugar while Colquhoun says he does "not know the answer for sure" and wonders about fresh fruit, vegetables and cheese. However, the observation that influenced Colquhoun towards changing his mind, involving the decline in tooth decay commencing before the availability of fluoride and continuing even when fluoridation was fully implemented, is the central part of Colquhoun’s argument at this stage. This point is not addressed by Pollick.

6. Benefits of fluoridation. Pollick states that Colquhoun asserts that in all of the studies published there is bias in population selection and examiner diagnosis and that "most of the examiners were keen fluoridationists". Colquhoun has replied that a study has not been produced which counters the statement that "It is just not possible to find a blind fluoridation study in which the fluoridated and nonfluoridated populations were similar and chosen randomly". In his paper Colquhoun indicates that he considered most, rather than all, pro-fluoridation studies were not blind and that the examiners knew which children received fluoride.

The Hardwick et al study,⁶ mentioned by Pollick, does not contradict Colquhoun’s position that although the examiners were blind as to where the children came from, no evidence is given to show that, of the two areas which were compared, the choice as to which one would be fluoridated was made randomly. Whether this study is the best one to illustrate a beneficial effect for fluoridation is open to debate. It is not mentioned in the review by Newbrun⁷ in 1989 on the effectiveness of water fluoridation but is referred to in reviews by Beltran and Burt,⁸ 1988, and Ripa,⁹ 1993, as evidence of the benefit fluoride may give to teeth already erupted. Hardwick et al⁶ indicate that the primary aim was to test the null hypothesis that there would be no post-eruptive effect of artificial water fluoridation on the caries increments of 12-year old children over the following three years. A difficulty in the study was that of the 305 children in the fluoride group at the baseline examination only 47% or 144 were able to attend the fourth annual re-inspection. Another difficulty for the study, in demonstrating a beneficial effect for fluoride in reducing dental decay, was that although the control and fluoride groups of children showed "close agreement" in "mean initial DMFS and DMFT rates", at the end of the study the figures given, in Table 1, show that the fluoride group did not have lower rates for either the DMFS or the DMFT (Mean ± SD; Control group DMFS 6.60 ± 4.80; Fluoride group DMFS 7.33 ± 6.47; Control group DMFT 4.27 ± 2.82; Fluoride group DMFT 4.58 ± 3.49). It is not clear that the Hardwick et al⁶ study shows that fluoridation of water supplies exerts a benefit systemically as well as topically. The authors saw "substantial topical effects on teeth already erupted at the start of fluoridation", during the study period "fluoride dentifrices were used extensively", and at the end of the four years the DMFS and DMFT rates were no better in the fluoride group than in the control group.

As has been shown elsewhere¹⁰ there is negligible benefit to be gained from fluoride ingestion and also evidence that fluoride acts topically. The mean level of fluoride in the saliva, after ingesting fluoridated water at a concentration of 1.2 ppm, is only 0.87 ± 0.047 µ mol/L or 0.017 ± 0.001 ppm.¹¹ Burt¹² has noted that the evidence for a primarily topical cariostatic effect of fluoride has grown. He notes that "fluoride most effectively controls caries when a low concentration can be maintained consistently in the oral environment".

Thus there is, in fact, wider acceptance of Colquhoun’s position that "there is negligible benefit from swallowing fluoride". The study by Hardwick et al ⁶ referred to by Pollick does not provide evidence to contradict this view.

7. Dental fluorosis. On this point Pollick gives the view that there is a "general consensus" that the increase in dental fluorosis is due to fluoride toothpaste and tablets and that it is "generally accepted" that water fluoridation is not harmful in this way. No references are given whereas there are 22 references in the review article cited by Colquhoun.¹³ Colquhoun includes a case history of a patient developing dental fluorosis with access to fluoridated water who did not use fluoridated toothpaste or tablets. In the absence of data, Pollick has not established a case to refute the evidence linking, in 11 communities, higher dental fluorosis rates in the range of 16-51% with water fluoride levels of 0.4 -1.4 ppm, in contrast to, in 9 communities, dental fluorosis rates of 2-15% with water fluoride levels of 0.0-0.4 ppm.¹³

8. Effects of fluoride on bone. Pollick indicates that studies, such as those reviewed by the National Research Council,¹⁴ have found an association between bone fractures and fluoride. Colquhoun, in his paper,¹ notes that he expressed concern that this might arise back in 1984 at a time when his colleagues dismissed his need to worry. He related how his views on fluoridation were affected by the report¹⁵ of hip fractures being associated with higher fluoride levels six years later. There appears to be a basic agreement that the effect of water fluoridation on hip fracture rates needs to be considered.

Whether one can accept the conclusion of the National Research Council "that there is no basis at this time to recommend EPA (the Environmental Protection Agency) lower the current standard for fluoride in drinking water" ¹⁴ (a maximum contaminant level of 4 ppm) would require a more detailed analysis of the evidence than is possible to provide here. Pollick suggests five of the ten studies looked at by the National Research Council¹⁴ showed a positive association between fluoride and hip fracture. In reviewing the report Lee¹⁶ found that seven of the ten showed a positive correlation and that there were reasons why the other three studies were not of value, such as lack of exposure to fluoride prior to the menopause and an insufficient number of subjects.

Pollick appears to be in agreement with Colquhoun that when fluoride is used in high doses to treat osteoporosis it has led to an increase in hip fractures. Thus on this point there appears to be a basic agreement between Pollick and Colquhoun that in some circumstances fluoride can contribute to hip fractures.

Pollick observes that the Subcommittee on Health Effects of Ingested Fluoride¹⁷ "concluded that the weight of evidence indicates that bone strength is not adversely affected in animals that are fed a nutritionally adequate diet unless there is long-term ingestion of fluoride at concentrations of at least 50 mg/L in the drinking water or 50 mg/kg in the diet". However the exact quotation¹⁷ qualifies the conclusion by referring to the "evidence currently available" and notes that recent reports from epidemiological studies of human populations have provided conflicting evidence on this subject and indicate the need for additional research. Some reservations were held about the appropriateness of the methods used to cause bone fractures. Of the 15 animal studies reviewed, reduced bone strength was found in some of the experimental conditions in seven studies.¹⁷ Higher bone fluoride levels occurred when the diet was low in calcium. The bone-ash fluoride levels reported, associated with reduced bone strength, were 640 ppm, 7,398 ppm, 12,600 ppm, 7,393 ppm, 5000 ppm, and 11,000 ppm. The presence of adequate amounts of calcium in the diet may reduce the rate of absorption of fluoride, but if the calcium intake is inadequate or the intake of fluoride is continued for a longer period, the potential for fluoride to accumulate in bone and be associated with reduced bone strength has not been excluded by the animal studies. Arnala et al¹⁸ found mean ashed trabecular bone fluoride level of 3.72 ± 2.39 mg/g (3720 ± 2390 ppm) in 25 patients with hip fracture from a high fluoride area with a fluoride level in the water greater than 1.5 ppm.

Pollick notes that Colquhoun omitted mention in his 1997 paper¹ of the successful results described in 1994 by Pak et al¹⁹ with low-dose, slow-release sodium fluoride in the treatment of osteoporosis. This first report of the study gave the results of the use of intermittent slow-release sodium fluoride plus continuous calcium citrate administered for about 2.5 years. Colquhoun notes that the opinion that this is helpful is not shared by many other clinicians. Lee²⁰ expresses such a viewpoint: that the fluoride treatment recommended by Pak et al should be regarded as controlled osteofluorosis and that the 3.5 year trial described in the final report²¹ was insufficient to evaluate the potential increased risk of hip fracture.

A recent review²² noted that while the study by Pak et al²¹ found a significant reduction in the rate of vertebral fracture, in three other studies^23-25 the effect was small. In a randomized, placebo-controlled, two-year trial of sodium fluoride (50 mg a day) and monofluorophosphate (two doses) in 354 women with osteoporosis, fluoride therapy, as compared to placebo, had a large effect on bone mineral density in the lumbar spine (increase, 10.8% vs. 2.4%), but no effect on the rate of vertebral fractures.²⁶ Thus, even at relatively low doses, fluoride had little beneficial effect on fracture rates. It was noted that sodium fluoride causes stress fractures.^23,26 In discussing the therapeutic choices for women most at risk for fractures no mention is made of a role for fluoride.²² The hope offered by fluoride in 1994 for the treatment of osteoporosis appears to have passed.

9. Omission of paper with negative evidence on hip fractures. Pollick argues that while Colquhoun referred to two papers by the Finnish researchers Alhava et al²⁷ and Arnala et al²⁸ which noted fluoride accumulation in bones with fluoridation he omitted reference to a later paper by Arnala et al¹⁸ in which no difference was found in the incidence of hip fractures between low-fluoride, fluoridated and high-fluoride areas.

No question involving the interpretation of scientific data appears to be at issue in this point. Colquhoun was recounting the factors which led him to change his mind about fluoridation, and it is understandable that studies not showing a relationship between fluoride and adverse effects would be less likely to have an influence.

He notes that, at the time, the later paper by Arnala et al¹⁸ had to be seen alongside a Finnish paper by Simonen and Laitinen²⁹ suggesting fluoridation was associated with fewer hip fractures. His point that later studies on hip fractures with larger numbers of subjects were more relevant is reasonable. The 1986 paper by Arnala et al¹⁸ had 461 subjects with hip fracture. This is fewer than the 651 patients with hip fracture in the 1993 study by Jacobsen et al³⁰ which Lee¹⁶ found to have an insufficient sample size to be able to detect important medical effects. In contrast the studies finding significant effects involved 541985 patients with hip fracture (Jacobsen et al 1990¹⁵) and 20393 patients with hip fracture (Cooper et al 1991³¹). Colquhoun has previously referred³² to the 1986 paper by Arnala et al¹⁸. Later studies with a much greater data base made it less important to cite it in his new paper under discussion. Hence there is no significance to the fact that it was omitted.

10. Fluoride and hip fractures. There does not appear to be any new point being made different from those raised in point 8.

11. Effects of fluoride on bone. Again no new issues are raised.

12. Association of fluoride and osteosarcoma. Pollick and Colquhoun agree that the appropriate reference for the study in which osteosarcomas were found in rats given fluoride was one referring to the National Toxicology Program study,³³ rather than to the Procter and Gamble study³⁴ in which the osteosarcomas found were not at a statistically significant level.

There does not appear to be any dispute about the term "equivocal evidence" of carcinogenicity. The Peer Review Panel³⁵ indicated that equivocal evidence is a category for uncertain findings demonstrated by studies that are interpreted as showing a marginal increase of neoplasms that may be chemically related.

Although Colquhoun indicates that he was influenced by the finding of 3-7 fold increases in osteosarcoma rates in young males in fluoridated areas of New Jersey compared to non-fluoridated areas,³⁶ there does not appear to be any basic difference in the interpretation of the findings. Pollick notes that Cohn³⁷ stated there was insufficient basis to draw conclusions about whether osteosarcoma incidence and fluoridation were causally linked and, in the reference cited by Colquhoun, Cohn³⁶ notes that "Because of the limitations of the study design and the small numbers of cases that occurred, this analysis does not imply a causal connection between fluoridation and osteosarcoma". Colquhoun includes a question mark after the sub-title of Bone Cancer for this section of his paper indicating questions about the nature of the link still exist.

Questions about the sample studied by Gelberg et al³⁸ are raised by Lee³⁹ because 67% of the patients were female whereas the majority of patients with osteosarcoma are usually male. Colquhoun notes that there is disagreement about whether it is safe to continue with water fluoridation while the nature of the associations between fluoridation and osteosarcoma are considered.

13. Effect of fluoride on testosterone synthesis. Pollick states that only high levels of fluoride have been associated with reductions in testosterone levels in contrast to Colquhoun’s assertion that very low levels can interfere with the male hormone testosterone. In the reference given of Kanwar et al⁴⁰ it is noted that from 1 ppm to 200 ppm of fluoride, the degree of inhibition in testosterone synthesis seems to be dependent on fluoride concentration. In an in vitro assay there was a noticeable, though marginal, inhibition even at 10 ppm, a significant marked fall at 100 ppm and maximal inhibition at 200 ppm. The highest reported levels of fluoride in soft tissues⁴¹ have been given as: brain 6.1 ppm, heart 8.1 ppm, pancreas 8.2 ppm, lung 17 ppm, thyroid 23.5 ppm, liver 61 ppm, lens 77.3 ppm, prostate 86 ppm, fat 145 ppm, hair 171 ppm, kidney 181 ppm, bladder 185 ppm, nails 186 ppm, skin 290 ppm and aorta 8400 ppm. The evidence suggests that inhibition of testosterone synthesis begins at 1 ppm of fluoride and a noticeable effect occurs with a level of 10 ppm.⁴⁰ Although a reference to fluoride levels in the testes has not been found, the levels which may occur in other soft tissues suggest that levels affecting testosterone production might occur. It thus appears to be fair comment that very low as well as high levels of fluoride might affect testosterone levels.

14. Effect of fluoride on intelligence. On this point Pollick states that Colquhoun misstates the facts of the research from China^42,43 linking dental fluorosis in children with lower intelligence and that to suggest that children with dental fluorosis have on average lower intelligence scores is a gross misstatement of the facts.

Colquhoun in his paper said "Even more chilling is the evidence from China that children with dental fluorosis have on average lower intelligence scores". In the first reference given by Colquhoun, the paper by Li, Zhi and Gao⁴² a significantly lower Intelligence Quotient was found in children from areas with medium or severe degrees of dental fluorosis compared to children from areas without dental fluorosis or only slight dental fluorosis. In the other reference by Zhao, Liang, Zhang and Wu⁴³ children in an area with a high rate of dental fluorosis, 86%, had significantly lower intelligence than those in an area with a low rate of dental fluorosis, 9%. The source of the fluoride in the study by Li et al,⁴² in the medium and severe fluorosis areas, was the coal used for cooking, heating and drying grain. In the study by Zhao et al⁴³ the area with a high dental fluorosis rate had a water supply with a high fluoride level, 4.12 ppm.

The basic concern of intelligence being affected in some children with dental fluorosis accurately reflects the concerns raised in the studies and it is difficult to see it involving misstatement, or gross misstatement, of the facts of the research. Finding it chilling that fluoride might affect brain development is understandable given that fluoridation was initially promoted as being completely safe. The query about the relevance of the effect of excess fluoride on brain development, because in one of the studies it came from coal smoke rather than water, does not appear to be relevant. The concern is that if fluoride, from whatever source, affects other organs detrimentally as well as causing dental fluorosis, then water fluoridation, which is associated with significant dental fluorosis for many, may be unsafe.

15. Relevance of animal studies of the effect of fluoride on the brain. The point is made by Pollick that the study by Mullenix et al⁴⁴ is irrelevant to water fluoridation because the pregnant rats studied were injected with fluoride, which would not occur with humans, and the weanling and adult rats then drank water with different concentrations of fluoride including, for adult rats, a period of six weeks with water at a concentration at least 100 times that recommended for water fluoridation.

Colquhoun indicates his concern that, because of accumulation within the body, lower doses taken for longer periods of time might have a similar effect to higher doses taken for a short period. He saw a model having been established with other toxins such as lead. In their paper Mullenix et al⁴⁴ note that it was the fluoride levels in plasma, not fluoride levels of exposure, which best predicted effects on behaviour. Similar plasma fluoride levels of 0.076-0.25 ppm have been found in humans ingesting 5-10 ppm fluoride in drinking water and plasma levels as high as 0.28 to 0.43 ppm have been measured in children drinking water containing 16 ppm fluoride. Fasting serum fluoride levels of 0.2 to 0.3 ppm are used in the treatment of osteoporosis, and plasma fluoride levels as high as 1.44 ppm are found in children 1 hour after receiving topical applications of an acidulated phosphate fluoride (1.23%) gel.

Mullenix et al⁴⁴ considered that because humans occasionally are exposed to high amounts of fluoride and plasma levels as high as those found in this rat study, neurotoxic risks deserve further evaluation. The closeness of the lower limit of 5 ppm, in the range of 5-10 ppm fluoride in drinking water which produced similar plasma levels to those found in the rats, to the maximum contaminant level for fluoride acceptable for drinking water of 4 ppm¹⁰ is a cause for concern. The evidence thus suggests that the adverse effects on brain function, possibly on that of the hippocampus in particular, are related to the plasma levels found rather than the method of administration.

Thus although the study by Mullenix et al⁴⁴ may not have been intended, as noted by Pollick, to determine the effects of water fluoridation, its results could be seen as being particularly relevant to assessing whether the fluoridation of water was safe. The findings of Mullenix et al⁴⁴ are consistent with clinical reports of chronic exposure to fluoride being associated with cerebral impairment, affecting particularly concentration and memory.⁴⁵

This position has been underlined by subsequent events and the publication of two papers^46,47 by Isaacson, Varner, Jensen and Horvath on the effect, in rats, of the chronic administration of aluminium fluoride and sodium fluoride on neuronal and cerebrovascular integrity. In these studies, the chronic administration of aluminium fluoride or sodium fluoride in drinking water in rats resulted in distinct morphological alterations in the brain including effects on neurones and cerebrovasculature. The concentrations of aluminium fluoride, 0.5 ppm (as 0.5ppm Al), and sodium fluoride, 2.1 ppm (as 2.1ppm NaF), used gave fluoride ion concentrations of about 1 ppm, the level often used in water fluoridation.

Thus, with the benefit of hindsight, it is clear that Colquhoun was correct to be alarmed about the studies implicating fluoride as adversely affecting brain development, even though the source of the fluoride was not always in the drinking water but included injections⁴⁴ (for pregnant rats) and coal smoke (in the study by Li et al⁴²).

16. Omission of details of dose and concentration in discussion on toxicology. Pollick argues that Colquhoun consistently alleges harm from fluoride without stating the dose or concentration of fluoride. Colquhoun indicates that low intakes for long periods might be as deleterious as high intakes for short periods. In his paper¹, when referring to harm from fluoride, he gives references which provide details of the fluoride exposure involved. For example, in the study by Zhao et al⁴³, on intelligence in children, the water fluoride concentrations in the two groups is given as 4.12 ppm and 0.91 ppm.

Colquhoun appears to be explaining what influenced him to change his mind from being an ardent advocate of water fluoridation, who fiercely poured scorn on a lay person who had heard and accepted the case against fluoridation¹, to one who was opposed to it. Given that there are space restrictions, which limit how much detail can be included from any paper referred to, it is appropriate to omit details about dose and concentration of fluoride where such information is readily available in the publications that are cited. In some instances, reference is made¹ to "fluoridated Auckland" and "fluoridated areas of America" and the meaning is conveyed that the level of fluoride in the water would be in the region of 1 ppm.

The reader, after considering the two sides of the debate, will be in a position to decide what their own view is. Colquhoun required some courage to change his mind. Somerset Maugham⁴⁸ would not have had him in mind when he wrote, in Of Human Bondage, "Like all weak men, he laid an exaggerated stress on not changing one’s mind".

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FLUORIDE 31(4), 1998, pp 235-244	International Society for Fluoride Research
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