Chemical & Engineering News, Bette Hileman, Aug.1, 1988

The controversy over fluoridation of water supplies has raged ever since fluoride was first introduced into the drinking water of Grand Rapids, Mich., in 1945. Proponents of fluoridation say it prevents tooth decay and presents absolutely no health risks. Detractors say it causes, or may cause, serious damage to the health of some people. Many also question its effectiveness. For 43 years, there seems to have been no middle ground between the two points of view. "Neither side has given the other one rational moment," explains Jacqueline M. Warren, senior staff attorney with the Natural Resources Defense Council.

U.S. policy makers have had to make other scientific decisions, such as choices about pesticide regulation, that involve the careful balancing of risks and benefits and about which information probably is even more complex. But none has aroused acrimony quite like the fluoridation question. There is hardly any individual interested in the issue who can be classified as neutral, hardly an expert in the field who seems not to be adamantly pro- or antifluoridation. Neither side seems willing to listen to the other. Neither seems able to engage the other in constructive debate.

On the surface this seems surprising. The goal of fluoridation is unarguably worthy. Since U.S. communities began fluoridation in 1945, the prevalence of dental caries has decreased dramatically. The average number of decayed, missing, and filled permanent teeth in U.S. school age children has declined from an estimated seven to about three, according to a national survey released by the National Institute of Dental Research (NIDR) in June.

Why, then, is this issue so polarized?

According to Edward Groth III, an associate technical director of Consumers Union who wrote his Ph.D. thesis in biology on the fluoridation controversy in 1973, pro- and antifluoridationists approach the issue from completely different perspectives. "Proponents see it as a simple public health measure, effective and safe, which they need to ‘sell’ to the public, almost like a box of soap. Opponents tend to be much more concerned with risks than with benefits, and view fluoridation the same way society views many other ‘environmental hazards’—granting that the risks may be small and uncertain, they believe society’s attitude should be ‘better safe than sorry. Since any risks fluoridation may present are imposed involuntarily when a water supply is fluoridated, those risks-even if they are tiny or unsubstantiated—tend to provoke a disproportionate amount of outrage."

Indeed, anyone looking closely at the fluoridation debate can discern several separate subdebates, most with more than two distinct positions. Regarding fluoridation’s benefits, proponents, such as the American Dental Association (ADA), claim it reduces the incidence of tooth decay 40 to 65% wherever it is used.

Many proponents also insist dogmatically that there is absolutely no evidence that fluoridation has had, or ever could have, harmful effects of any kind on anyone. Some argue that because most natural drinking water contains 0.1 to 0.2 ppm fluoride and nearly all food has traces of fluoride, human beings are adapted to it. For many years, they have also claimed that fluoridation may reduce the incidence and severity of osteoporosis-decreased bone density in old age. Other proponents admit there are a number of recognized potential risks, but they believe there has been enough research of good enough quality to show that these risks are very remote and that the large benefits justify society’s taking those risks.

For many opponents of fluoridation, the overriding issue is a moral one of personal rights. These critics oppose fluoridation for ethical reasons. They view it as a form of medication, imposed on the public in violation of individual choice. Given that there are several other ways for people who want fluoride to consume it (for instance, in pills, mouthwashes, toothpaste, fluoridated bottled water), those who place a high value on freedom of choice argue that the state has no right to force them to consume fluoride.

Other opponents of fluoridation claim that fluoridation causes cancer, birth defects, and a large number of other ills. Such claims are frequently made by unscientific activists, who cannot support them with scientific references. But here, too, there are other less extreme opponents who argue that research has not adequately answered most of the critical questions about potential risks. Such critics, many of whom are scientists, cite hundreds of papers published in reputable journals, a collectively large body of evidence of potential hazards that, at a minimum, demands objective assessment. From the start, they also have questioned the benefits of fluoridation, claiming that its effects on tooth decay are nonexistent or greatly exaggerated.

Yet another niche in the debate has lately been filled by environmentalists, who resist being called "antifluoridation" but whose arguments tend to support the opponents. In 1986, the Natural Resources Defense Council (NRDC), one of the U.S.’s pre-eminent environmental advocacy organizations, filed a lawsuit against the Environmental Protection Agency (EPA), seeking to block the agency’s proposed relaxation of drinking water standards for fluoride in natural waters. NRDC argued that EPA had inadequately considered the likely effects of fluoride on susceptible subsets of the overall population, had over looked a great deal of scientific literature that suggested possible harm, and had not adequately evaluated a full range of possible hazards on which the evidence is incomplete or unconvincing. At best, NRDC asserted, EPA had no scientific basis for its action and more research is needed.

In general, environmental advocates believe fluoride should be investigated in the same manner many other environmental pollutants have been studied in recent years. The range of total human intake from air, water, and food must be assessed, they say’. The effects on the most susceptible individuals and the levels at which these effects begin to occur should be determined. Extensive epidemiological studies should be done to see if fluoride is causing cancer or any other more subtle health effects in the general population.

Very little of the research advocated by the environmentalists has ever been done in this country and not much of it has been done anywhere else either. Since the early 1960s, most studies on the long-term effects of chronic exposure to fluoride on human biological systems other than teeth have been carried out in foreign countries.

Current status of fluoridation

Fluoridation of water supplies is largely confined to the English-speaking countries, the Soviet Union, and some Latin American nations. Of the estimated 250 million people in the world who drink artificially fluoridated water (usually fluoridated at 1 ppm), 120 million live in the U.S. (50% of the U.S. population), about 50 million in Brazil (33% of its population), and 40 million in the Soviet Union (15% of its population). Nine percent of the U.K.’s population drinks fluoridated water, two thirds of Australia’s and New Zealand’s, and 50% of Canada’s. However, less than 1% of the population of continental Western Europe has artificially fluoridated water. For 10 years, the Netherlands tried fluoridation and gave it up in 1976 for legal reasons. (Many citizens claimed that the government had no right to add fluoride, which they considered a medicine, to the water supply, and a number of doctors observed strong hypersensitivity reactions to fluoridated water in some people.) It also was tried and then abandoned in a few towns in West Germany for legal and health reasons.

In the U.S., fluoridation is endorsed almost universally by medical and dental associations and by many scientific bodies. The American Medical Association, ADA, the U.S. Public Health Service (PHS), and every Surgeon General since the early 1950s have agreed that water fluoridated at levels of about 1 ppm is a cheap, effective, and perfectly safe way to reduce cavities.

Outside the U.S., a number of scientific groups and individuals have decided fluoridation is not safe. In France, the Chief Council of Public Health rejected fluoridation in 1980 because of doubts about whether it harms human health. The minister for the environment in Denmark recommended in 1977 that fluoridation not be allowed primarily because no adequate studies had been carried out on its long-term effects on human organ systems other than teeth and because not enough studies had been done on the effects of fluoride discharges on freshwater ecosystems. In 1978, the West German Association of Gas & Water Experts rejected fluoridation for legal reasons and because "the so-called optimal fluoride concentration of 1 mg per L is close to the dose at which long-term damage [to the human body] is to be expected."

The battle lines between pro- and antifluoridationists in the U.S. used to be very clear, with the medical and dental establishment and a great many public health officials and scientists on one side and a number of other scientists, private citizens, and members of extreme right wing groups (such as the John Birch Society and the Ku Klux Klan, who claimed fluoridation was a communist plot) on the other. Most of those who spoke out against fluoridation were, according to profluoridationists, either members of one of these radical groups or irrational, fanatic, unscientific, and fraudulent, even if they had legitimate scientific credentials.

Now, however, the lines are not so clearly drawn. Zev Remba, the Washington Bureau editor of AGD Impact, the publication of the Academy of General Dentistry (a group of 28,000 dentists dedicated to promoting the continuing education of general practitioners), described the situation in an editorial last year: "Today ... the antifluoridation movement has found supporters on the left as well as the right, particularly among groups dedicated to safeguarding the environment. And as the base of support broadens, community fluoridation appears to be losing ground. In about 60% of 2000 referenda held in the U.S. since 1950, fluoridation has been voted down. A 1985 poll by the American Dental Association found that 36% of the 255 [planned or existing] fluoridation programs surveyed had been cancelled," primarily because they were rejected in referenda.

Last year, the Commissioner for the Department of Health in New York State, David Axelrod, decided to turn the department’s emphasis away from fluoridation of water supplies and toward the use of topical sealants and fluoride rinses for school children. The department is still in favor of fluoridating water supplies, but is no longer funding it.

Even now fluoridation remains an issue in many cities across the U.S. Since 1983, referenda have been held on the question in well over 60 communities. In more than half of these, the majority of the people voted against fluoridation. Some referenda are held in cities without fluoridation in order to decide whether to initiate it. Others are called by opponents of fluoridation in cities where it already exists in order to terminate it. ADA and NIDR carry on a continuous campaign to persuade state legislatures to pass laws making fluoridation mandatory in all communities. So far only eight states have passed such laws, but dozens of proposed similar laws have been defeated.

Fluoridation is becoming more of an issue in developing nations as their tooth decay rates rise with the increasing use of sugar and processed food. Countries such as Brazil are now deciding whether to expand fluoridation or initiate it. In May, an international conference was held in Porto Alegre, Brazil, to assess the benefits and risks of fluoridation and help the authorities evaluate the question.

If more diverse interest groups are increasingly skeptical of fluoridation, what are the reasons? Is fluoridation just as effective as it appeared to be in the past? Have scientists uncovered new evidence of real health risks?

Benefits: a changing assessment

Originally, it was thought that the fluoride ion prevented tooth decay solely by being incorporated in tooth enamel as the teeth formed in childhood. Fluoride ingested in water or food is absorbed into the bloodstream. Part of it is excreted and the remainder is deposited in the bones and teeth. The proportion of fluoroapatite in the hydroxyapatite of developing tooth enamel is then increased:

Ca10(PO4)6(OH)2 + 2F- ‡ Ca10(PO4)6F2 + 2OH-

Fluoroapatite is less easily dissolved by mouth acids than hydroxyapatite and therefore more resistant to decay.

But today dental researchers believe two other mechanisms are just as important or more so. A number of factors, including fluoride ion, influence a constant exchange of ions across tooth surfaces. Bacteria in the mouth convert sugar to acids, which cause demineralization of tooth surfaces. Demineralization and remineralization take place constantly on the surface. When the pH of the surface drops, calcium and phosphate ions pass from the enamel into the plaque, but if the pH becomes neutral, these ions may redeposit themselves into the enamel. Fluoride ions in the plaque inhibit the bacterial conversion of sugar to acids and thereby help maintain higher pH levels, allowing remineralization to occur. Therefore, the fluoride ions in saliva and plaque may be just as important in preventing tooth decay as the ions in blood-and perhaps just as easily provided by toothpaste as water.

A third mechanism by which fluoride may prevent decay involves incorporation of fluoride into the remineralizing enamel surface, making it more resistant to decay.

For many years, most dentists believed that fluoridation of water supplies reduced tooth decay about 50 to 65%. These figures were based primarily on four studies during the early years of fluoridation: in Grand Rapids, Mich.; Newburgh. N.Y.; Evanston, Ill.; and Brantford, Ont. But a great deal of evidence indicates that water fluoridation reduces dental caries much less. In fact, some research suggests little or no reduction at all.

Alan S. Gray, former director of the Division of Dental Health Services for the British Columbia Ministry of Health, finds, for example, that the average number of decayed, missing, and filled permanent teeth in British Columbia, where only 11% of the population uses fluoridated water, is lower than in parts of Canada where 40 to 70% of the people drink fluoridated water. School districts in the province with the highest percentage of children with no tooth decay are totally unfluoridated. These differences could, of course, be caused by factors other than fluoridation.

Tooth decay is a complicated process, influenced by many factors, including diet, oral hygiene, dental care, genetic predisposition, geochemical factors, and possibly other trace elements, such as strontium, as well as fluoride in the water supply. Additional factors that may affect decay rates are the use of fluoridated toothpastes or topical rinses and the presence of fluorides in foods. Most people whose diet includes little sugar and few processed foods have very low rates of tooth decay. In those few developing countries in which only small amounts of sucrose and refined foods are eaten, decay rates are often lower than in the developed nations. And if other factors are equal, districts in the developed world where the socioeconomic status is higher generally have less decay.

Therefore, comparisons between fluoridated and unfluoridated districts that don’t adequately take such factors into account can be readily confounded. None of the early epidemiological studies controlled very well for most nonfluoride variables, so many scientists today have come to regard them as only part of the evidence one must consider to assess the size of fluoridation’s benefits.

One recent development that bears on the question is the widespread observation that tooth decay rates in the U.S., Canada, New Zealand, Australia, and in all countries of Western Europe have declined greatly during the past 40 years. Mark Diesendorf, an applied mathematician and health researcher in the Human Sciences Program at Australian National University and an expert in research design, has found, by comparing results from about 24 studies of unfluoridated districts in eight countries, that reductions in dental caries are just as great in nonfluoridated as in fluoridated areas. In Queensland, which is primarily unfluoridated, the rate of tooth decay is as low’ as it is in the fluoridated districts of Australia.

Diesendorf concludes from such data that fluoridation of water supplies may not be nearly so important in preventing tooth decay as many authorities believe. Some of the decline in dental caries in unfluoridated areas might be explained by the introduction of fluoride toothpaste. tablets, and mouthrinses, he says, but decay rates began to fall in many of the nonfluoridated regions long before these were available. He believes that changes in nutrition, oral hygiene, and possibly the immune status of the population may explain part of the decline.

A number of researchers in the U.S. have reported similar findings. Stanley B. Heifetz and coworkers at NIDR note in the April issue of the Journal of the American Dental Association that "the current reported decline in caries in the U.S. and other Western industrialized countries has been observed in both fluoridated and nonfluoridated communities, with percentage reductions in each community apparently about the same."

Robert L. Glass of Forsyth Dental Center, Boston, noted that in 1965, after more than 20 years of fluoridation, counts of decayed, missing, and filled permanent teeth for Grand Rapids, Mich., and Newburgh, N.Y., were only minimally different from the average for the entire U.S., which then was about 33%.. fluoridated. Because he had expected nonfluoridated areas to have higher decay rates than fluoridated ones, and to therefore raise the average for the entire U.S., he concluded that the U.S. average had not been determined correctly. It is also plausible, however, that the effects of fluoridation had been overstated, or perhaps that Grand Rapids and Newburgh had exceptionally high levels of decay before fluoridation began.

Other recent reports indicate that fluoridated areas have lower decay rates than unfluoridated areas, but by much less than the alleged 50 to 60% difference. A 1983 study of tooth decay in 10 cities by the Robert Wood Johnson Foundation and Rand Corp. found that fluoridated cities have roughly one third less decay, which means that average 12-year-olds in fluoridated cities have about 0.6 fewer cavities than those in nonfluoridated cities. Gray points out that decay reductions of even 33%. taking place today, when average base decay rates are at such a historically low level, do not mean as much as they did in the past.

Research conducted in the 1930s and 1940s in the U.S. showed that the incidence of dental caries was reduced most effectively where the natural fluoride level of the water supply was 1 ppm or above. But five studies in India, Sweden, Japan, the U.S., and New Zealand do not support this trend. In the Japanese study, for example, children in an area with 0.3 to 0.4 ppm fluoride in the water have the lowest decay rates; above and below this range, caries prevalence increases rapidly. These results contradict a central tenet of the fluoridation theory-that the ideal fluoride level, producing low decay rates with minimal damage to the teeth, is about 1 ppm.

At NIDR, officials are reassessing the decay reductions that can be attributed to fluoridated water. Herschel S. Horowitz, formerly chief of the clinical trials section of the caries prevention and research program, says that recent studies suggest that reductions are not so large as the 50 to 60% indicated by early studies. NIDR scientists are trying to determine what they call a "new baseline." Whatever the ultimate result, a consensus seems to have emerged that the promise of "two thirds less tooth decay" with fluoridation is no longer realistic, if indeed it ever was.

In a similar vein, the economic benefits of fluoridation appear to have been exaggerated. NIDR states that every dollar spent on fluoridation, which costs only 20 to 50 cents per person per year, reduces dental costs $50. NIDR assumes that fluoridation reduces cavities some fixed percent, such as 40%, and then multiplies the total number of cavities theoretically prevented by the average cost of filling one cavity. But when the actual costs of dental care delivered in similar cities are compared, residents of fluoridated cities seem to reap no economic benefit from fluoridation. In one study, reported in a February 1972 article in the Journal of the American Dental Association, the cost of dental care in five unfluoridated cities in Illinois was compared with costs in five similar cities with naturally fluoridated water. Even though dentists’ fees and the nature of treatments in the two groups of cities did not differ significantly, the cost per patient and the average number of visits to the dentist per year were greater in the fluoridated communities.

Proponents also are trying to show that fluoride can be used to alleviate the symptoms of osteoporosis, and therefore that people living in fluoridated areas may be helped by the excess fluoride they are accumulating in their bones. Because excess fluoride produces osteosclerosis (denser bones), patients in numerous clinical trials have been given and are still being given large doses of fluoride (60 to 80 mg per day) as treatment for osteoporosis. So far this method has produced no definitive beneficial results. In a 1987 review of fluoride therapy for osteoporosis, Louis V. Avioli, professor at the Washington University School of Medicine, concludes: "Sodium fluoride therapy is accompanied by so many medical complications and side effects that it is hardly worth exploring in depth as a therapeutic mode for postmenopausal osteoporosis, since it fails to decrease the propensity toward hip fractures and increases the incidence of stress fractures in the extremities." FDA has not approved the use of fluoride for osteoporosis.

Health risks: more questions than answers

The physiological effects of fluoride on the human body range from those about which there is a great deal of scientific information to those that are less certain, but about which there is some credible evidence, to those that are almost purely speculative. Even the effects for which there is good information are controversial. Some scientists define them as health effects, but others consider them as merely cosmetic or conditions without negative implications for health.

More than any other area of fluoride research, scientific debate over potential health hazards has been polarized by the political controversy over fluoridation. Does a study show adverse effects? Is certain evidence relevant to an assessment of the safety of fluoridation at 1 ppm? The answers experts give differ, depending on whether the experts favor or oppose fluoridation. The political schism over the measure has dominated scientific discourse on the topic, almost totally blocking consensus over what the evidence of adverse effects means-or in some cases, even over whether such evidence exists.

The effects of fluoridation that have been studied the most are dental fluorosis (mottling of teeth), skeletal fluorosis, kidney disease, hypersensitivity reactions, enzyme effects, genetic mutations, birth defects, and cancer. The information about dental fluorosis is clearest and least controversial. Knowledge of skeletal fluorosis is extensive, but not at all complete. The information about fluoride and kidneys is partly established and, in part, almost purely speculative owing to a lack of research. Hypersensitivity reactions have been studied thoroughly by only a few investigators and many important issues remain unresolved. Birth defects and cancer have been much discussed, but evidence in these areas is the most uncertain.

Though profluoridation statements almost always claim that all risks have been fully investigated and found to be groundless, in fact a number of important unanswered questions remain about each of these health risk areas. The 1977 National Academy of Sciences report "Drinking Water and Health" recommends research in 11 different areas. Even though more than a decade has passed, research in only three health effects areas, dental fluorosis, cancer, and birth defects, has been funded by the federal agencies responsible for research on fluoride (PHS and EPA).

The fluoride ion is unusual among trace elements in water or food because the same range of human exposure to fluoride ion that can produce beneficial physiological effects can also produce harmful effects. For most trace elements, such as chromium, manganese, and zinc, beneficial and harmful ranges of exposure differ greatly.

In 1962, PHS set fluoride levels of 0.7 to 1.2 ppm in drinking water as the ideal range to prevent dental caries with minimal dental fluorosis. The tower level was suggested for hot climates and progressively higher levels were prescribed for cooler regions, because average water consumption varies with temperature. Natural fluoride levels exceeding twice the ideal for the climate, PHS said, constituted grounds for rejection of the water supply, but it had no power to force communities to remove excess fluoride.

In 1975, EPA took over PHS’s responsibility for regulating contaminants in drinking water and, in 1986, relaxed the maximum contaminant level to 4 ppm for all climates. Communities that add fluoride to drinking water still do so according to the old PHS formula. But communities with naturally fluoridated water are not required to remove fluoride unless the level exceeds 4 ppm. Some of the potential adverse health effects, however, may occur at levels of about 1 ppm and above and are both more pronounced and more widespread at levels near 4 ppm.

In humans, 98%. of the fluoride ingested in water is absorbed into the blood from the gastrointestinal tract. The fluoride diffuses to the body’s cellular tissues and most of it is deposited in the bones and teeth or excreted by the kidneys. The aorta is the only other tissue that normally accumulates significant amounts of fluoride, mainly in calcified deposits. The amount stored in bones and teeth varies depending on the age of the subject. According to NIDR’s Heifetz and Horowitz, in children more than 50% of an ingested dose of fluoride may be deposited in bone, but in adults only about 10% is stored there. As with teeth, fluoride is deposited in bone by simple ionic exchange with the hydroxyl groups of hydroxyapatite. It also is removed from bone, though at a slower rate than it is deposited. If the intake remains constant, the level of fluoride in the bones increases linearly with age.

The most obvious and common effect of fluoride on humans is dental fluorosis. This occurs only if children drink fluoridated water, receive fluoride supplements, or ingest significant fluoride from other sources (like toothpaste) during the years of tooth formation. In excessive amounts, fluoride interferes with the normal function of the enamel-producing cells in the jaw, called ameloblasts, in laying down amelogen matrix and in the mineralization of this enamel matrix. (Amelogen is a collagenlike material that forms the structural foundation and framework upon which calcium and phosphate are deposited, giving rise to tooth enamel.)

The late H. Trendley Dean, a dental surgeon at PHS, defined five degrees of dental fluorosis: questionable, very mild, mild, moderate, and severe. In the questionable form, evidence of fluorosis is uncertain; in the very mild form, teeth have small white specks; in the mild form, teeth have chalky white areas; in the moderate form, they may have yellowand brown stains; in the severe form, depending on the amount of fluoride ingested, they are pitted, brittle, and susceptible to fracture. Severe fluorosis not only produces unattractive teeth but also may increase the risk of tooth loss because it destroys parts of the protective enamel.

According to a recent study conducted by NIDR in areas with different concentrations of naturally occurring fluoride in their water supplies, 2% of the children developed moderate or severe fluorosis and about 12% developed very mild and mild fluorosis at 1 ppm-the level of fluoride that NIDR considers ideal. But at 4 ppm, the maximum fluoride level EPA now allows in the U.S., 7%, had moderate and 23% severe dental fluorosis (approximately the same total fraction of objectionable fluorosis Dean noted in the 1930s in 4-ppm areas). Since this study was very limited, the percents of fluorosis may not be representative of the country as a whole.

But if the fraction of children subject to moderate and severe dental fluorosis is anywhere near 1 or 2% in most areas with 1 ppm fluoride, a great many children are at risk of developing disfiguring degrees of fluorosis, And, of course, a large fraction of children in the 4-ppm areas would develop noticeable fluorosis. To avoid dental fluorosis, "children under five years of age should drink water diluted with a fluoride-free source in communities with 4 ppm fluoride," NIDR’s Horowitz says.

There seems to be little controversy over what levels of fluoride in water cause moderate and severe dental fluorosis. Scientists disagree, however, about whether moderate to severe dental fluorosis is a health effect. This may seem like an academic issue, but under the Safe Drinking Water Act, EPA is required to set recommended maximum contaminant levels (RMCLs) that will prevent known or anticipated adverse health effects with an adequate margin of safety and to set the maximum contaminant levels as close to the RMCLs as is feasible. (The RMCLs are unenforceable goals; the maximum contaminant levels are enforceable standards.) A special committee convened by the Surgeon General in 1983 to guide EPA in setting its fluoride standard wrote in the first draft of its report that moderate to severe dental fluorosis per se is a health effect. The second draft, presented to the Surgeon General in September 1983, said that moderate to severe dental fluorosis is only a cosmetic effect-the position long held by political advocates of fluoridation. This rationale allowed EPA to ignore dental fluorosis in setting the RMCL for fluoride.

Skeletal fluorosis

One solidly established concept in environmental health is that the effects of toxic agents fall on a continuum of biological change, ranging from undetectable effects at the lowest levels of exposure to severe health damage at very high doses. As exposure to an agent increases, the first detectable effect may be a subtle biochemical change, such as a decrease in the activity of an enzyme. At somewhat higher doses, measurable changes in some physiological functions may occur, but these often are not linked to clear symptoms or adverse effects, and may not be harmful. But as dosage increases, adverse effects begin to appear-at first mild ones, then moderate ones, and finally severe ones.

Most environmental health experts believe that the subtlest detectable effects-those with no outward symptoms, which are not clearly harmful-should be considered "precursors" of more serious effects. By this logic, people who show such subtle changes should be considered at risk for more serious effects if exposure continues.

Skeletal fluorosis, a complicated illness caused by the accumulation of too much fluoride in the bones, has a number of stages. The first two stages are preclinical-that is, the patient feels no symptoms but changes have taken place in the body. In the first preclinical stage, biochemical abnormalities occur in the blood and in bone composition; in the second, histological changes can be observed in the bone in biopsies. Some experts call these changes harmful because they are precursors of more serious conditions. Others say they are harmless.

In the early clinical stage of skeletal fluorosis, symptoms include pains in the bones and joints; sensations of burning, pricking, and tingling in the limbs; muscle weakness; chronic fatigue; and gastrointestinal disorders and reduced appetite. During this phase, changes in the pelvis and spinal column can be detected on x-rays. The bone has both a more prominent and more blurred structure.

In the second clinical stage, pains in the bones become constant and some of the ligaments begin to calcify. Osteoporosis may occur in the long bones, and early symptoms of osteosclerosis (a condition in which the bones become more dense and have abnormal crystalline structure) are present. Bony spurs may also appear on the limb bones, especially around the knee, the elbow, and on the surface of tibia and ulna.

In advanced skeletal fluorosis, called crippling skeletal fluorosis, the extremities become weak and moving the joints is difficult. The vertebrae partially fuse together, crippling the patient.

Most experts in skeletal fluorosis agree that ingestion of 20 mg of fluoride a day for 20 years or more can cause crippling skeletal fluorosis. Doses as low as 2 to 5 mg per day can cause the preclinical and earlier clinical stages.

The situation is complicated because the risk of skeletal fluorosis depends on more than the level of fluoride in the water. It also depends on nutritional status, intake of vitamin D and protein, absolute amount of calcium and ratio of calcium to magnesium in drinking water, and other factors.

In parts of India, China, Africa, Japan, and the Middle Fast, large numbers of people have skeletal fluorosis from drinking naturally fluoridated water. In India about a million people have this disease. Most of the victims live in areas where the water fluoride level is 2 ppm or above, but some cases are found in communities with natural fluoride levels below 1 ppm.

In the U.S., more than a dozen cases of skeletal fluorosis have been reported. Some have occurred at high fluoride levels, others at levels lower than 4 ppm when aggravating conditions were present, such as diabetes or impaired kidney function.

In setting the recommended maximum contaminant level for fluoride in drinking water in 1986, EPA considered only crippling skeletal fluorosis as a health effect and established little or no margin of safety, even for this disease. (A margin of safety is a difference between the maximum contaminant level and the level at which health effects first occur in the most susceptible individuals.) According to a Department of Agriculture survey, about 3% of the U.S. population drinks 4 L or more or water per day. Therefore, about 3/4 of the people who live in areas where the water contains the natural fluoride level of 4 ppm allowed by EPA -- such as certain communities in Texas or South Carolina -- are ingesting at least 16 mg of fluoride a day, not including the fluoride they derive from other sources, such as toothpaste, food, or air.

Also, because a more or less constant percent of intake is accumulated in bone, persons who consume 8 mg a day for 50 years accumulate about the same amount of fluoride in their bones as those who consume 20 mg a day for 20 years. Therefore, for people who drink 2 L or more per day of water with 4 ppm fluoride throughout their lives, there appears to be no margin of safety even for crippling fluorosis. In its regulations for most other drinking water contaminants, EPA has included safety factors of 10 to 100 and has calculated intakes in terms of a lifetime—that is, 70 years instead of 20.

Joseph A. Cotruvo, director of the criteria and standards division of EPA’s Office of Drinking Water, says the fact that so few people in the U.S. have actually developed crippling skeletal fluorosis indicates that fluoride levels found in U.S. water are safe and that there is therefore an observed margin of safety. But critics of EPA’s standard speculate that there probably have been many more cases of fluorosis-even crippling fluorosis-than the few reported in the literature because most doctors in the U.S. have not studied the disease and do not know how to diagnose it.

Those who ingest much less than 20 mg of fluoride per day may still be at risk of developing less severe stages of skeletal fluorosis, such as preclinical forms or the subcrippling clinical stages. In its final report, the Surgeon General’s panel said that radiologic changes have been found in bone when fluoride exposure has been about 5 mg per day. Nearly all of those drinking water containing 4 ppm of fluoride and about 3% of the more than 124 million people whose water contains only 1 ppm would have intakes as high as this. It is not known, however, what fraction of those with low-level radiologic changes would suffer joint pains or other clinically obvious adverse health effects. In his landmark study of skeletal fluorosis in cryolite workers in the 1930s, the Danish scientist Kaj Roholm found that some of those with stage I of clinical skeletal fluorosis suffered joint pains and stiffness.

Although skeletal fluorosis has been studied intensely in other countries for more than 40 years, virtually no research has been done in the U.S. to determine how many people are afflicted with the earlier stages of the disease, particularly the preclinical stages. Because some of the clinical symptoms mimic arthritis, the first two clinical phases of skeletal fluorosis could be easily misdiagnosed. Skeletal fluorosis is not even discussed in most medical texts under the effects of fluoride; indeed, a number of texts say the condition is almost nonexistent in the U.S. Even if a doctor is aware of the disease, the early stages are difficult to diagnose.

The possibility that fluoride might cause skeletal abnormalities in children’s bones is of particular concern. In its April 1983 draft report, the Surgeon General’s committee wrote that moderate and severe dental fluorosis in children may be accompanied by skeletal changes. Although this statement was omitted from the final report in September 1983, the committee did urge more research into the skeletal effects of fluoride, particularly in children. It wrote: "The effects of various levels of fluoride intake on rapidly developing bone in young children are not well understood. Also, the modifying effects of total intake, length of exposure, other nutritional factors, and debilitating illness are not well understood." Since the committee’s report was written, PHS and EPA have undertaken no research in this area.

PHS has conducted several studies that it claims show that fluoride levels found in U.S. water supplies have had no clearly adverse effects on bones. But the majority of these studies either included a study population too small to detect rare effects or excluded people who would be most likely to suffer from skeletal fluorosis, such as those with kidney disease.

EPA’s approach to subtle, preclinical effects of fluoride on the skeleton differs from its usual approach to other environmental agents. For instance, when EPA assessed the health hazards of lead, it made an extraordinary effort to connect the observable effects of low-level exposure (inhibition of certain blood enzymes) with the known adverse effects of slightly higher exposure (decreased synthesis of hemoglobin, anemia, and possible neurotoxic effects). When it set its standard for lead in air, EPA argued that to prevent more serious effects, it needed to limit the more subtle biochemical changes that lead was provoking in millions of children.

By contrast, EPA’s assessment of fluoride in water took an almost opposite tack. By defining the most severe known hazard, crippling skeletal fluorosis, as the only effect it was concerned with preventing, EPA dismissed all degrees of fluoride-induced changes in bones less drastic than crippling fluorosis as not being health concerns.

Because fluoride causes denser bones (osteosclerosis), a number of researchers have compared fluoridated and nonfluoridated areas to see if the incidence and severity of osteoporosis is lower in fluoridated areas. A small number of studies in the past 25 years have reported a lower incidence of hip fractures in areas with fluoridated water, compared with nearby areas with low-fluoride water. For example. a recent report, comparing two towns in Finland, prompted widespread media stories that fluoridation is beneficial to the bones of the elderly, as well as to teeth. But a larger number of well-designed studies have found no evidence of a beneficial effect on osteoporosis. However, some of the profluoridation literature states as a fact that fluoridation will help prevent osteoporosis.

Kidney disease

Two areas are of concern in regard to fluoride and kidneys. First, a fairly substantial body of research indicates that people with kidney dysfunction are at increased risk of developing some degree of skeletal fluorosis. Second, a small and inconclusive amount of research suggests that fluoride may actually cause or aggravate kidney disease.

D. Raja Reddy of the Gandhi Medical College in India claims, for example, that "patients suffering from chronic kidney diseases and those with transplanted kidneys do excrete fluoride, though in small quantities, but they are more vulnerable to osteofluorosis and even neurological complications than others." In its final report, the Surgeon General’s 1983 committee notes, "As renal function declines, due either to diseases or with aging, plasma and bone fluoride content both increase."

The National Kidney Foundation in its "Position Paper on Fluoridation-1980" also expresses concern about fluoride retention in kidney patients. It cautions doctors "to monitor the fluoride intake of patients with chronic renal impairment, but stops short of recommending the use of fluoride-free drinking water for all patients with kidney disease. It does recommend, however, that dialysis patients use fluoride-free water for their treatments.

Studies show that children with moderately impaired renal function (such as those who have diabetes insipidus), are at some risk of skeletal changes from consumption of fluoridated water, even if the fluoride level is no higher than 1 ppm. A number of researchers have found high concentrations of fluoride in the bones of patients who suffer from kidney disease and have found symptoms of skeletal fluorosis in some of these patients. However, there has been no systematic survey of people with impaired kidney function to determine how many actually suffer a degree of skeletal fluorosis that is clearly detrimental to their health.

Several animal studies suggest that fluoride may have direct adverse effects on the kidneys. For instance, cytological and enzyme changes have been found in the kidneys of squirrel monkeys drinking water with 5 ppm fluoride. It is not known how the changes affect kidney function in monkeys, nor is it known whether humans would suffer similar changes from relatively low levels of fluoride in drinking water. Impaired renal function, however, has been reported to be more common in areas of endemic skeletal fluorosis.

Hypersensitivity

Just as a few people react idiosyncratically to almost anything, some people may have adverse reactions to fluoride whether contained in pills or water. Some individuals seem to be hypersensitive to fluoride pills or drops containing 1 mg or less as well as to fluoride toothpaste. The 1983 edition of the "Physicians Desk Reference" states: "In hypersensitive individuals, fluorides occasionally cause skin eruptions, such as atopic dermatitis, eczema, or urticaria. Gastric distress, headache, and weakness have also been reported. These hypersensitivity reactions usually disappear promptly after discontinuation of the fluoride." (This information was omitted from later editions of the reference.)

Many of those who agree that some people are hypersensitive to fluoride pills, drops, or mouth rinses deny that anyone could be hypersensitive to fluoridated water, even though just as much or more fluoride is contained in an average person’s daily intake of such water (the average water intake of 1 to 2 L has 1 to 2 mg of fluoride) as is contained in the standard pills (0.5 to 1 mg).

Some doctors call such hypersensitive reactions allergies. The American Academy of Allergy. however, defines allergies very narrowly-"quantitatively abnormal responses mediated by specific immunologic mechanisms, and therefore by specific antibodies or by certain sensitized cells (lymphocytes)." According to this definition, the academy says. allergies to fluorides do not exist.

Hans Moolenburgh, a Dutch physician who has studied hypersensitive reactions to fluoride, believes the reactions can be explained as effects of a toxic agent rather than as allergies. In large doses, everyone reacts to fluoride. A small fraction of the population, he says, reacts to much lower levels of fluoride.

The late George L. Waldbott, founder and chief of allergy clinics in four Detroit hospitals and noted antifluoridation activist and author, reported treating at least 500 patients who he concluded reacted negatively to fluoridated water. The symptoms included muscular weakness, chronic fatigue, excessive thirst, headaches, skin rashes, joint pains, digestive upsets, tingling in the extremities, and loss of mental acuity. Waldbott used double-blind tests to determine whether fluoride was the cause of symptoms in many of his cases. In each of these patients, the symptoms disappeared when the fluoride was taken away without the patient’s knowledge and reappeared when it was given again, but not with the administration of other possible agents.

Other investigators have reported similar cases. Reuben Feltman and George Kosel. then researchers at Passaic General Hospital in New Jersey, found that 1% of their subjects. who were children and pregnant women, reacted adversely to daily pills containing 1.0 to 1.2 mg of fluoride. The reactions, which affected the skin and gastrointestinal and nervous systems, disappeared when the fluoride was discontinued without the patients’ knowledge.

Moolenburgh, G. W. Grimbergen, and a number of other Dutch doctors performed double-blind experiments on patients who became ill after fluoridation began in the Netherlands. By using coded bottles of drinking water, some fluoridated and some not, the physicians showed that the symptoms were caused by fluoride, rather than some other factor.

Moreover, a report by the British Royal College of Physicians states that some patients receiving 9 mg of fluoride per day for osteoporosis suffered adverse side effects. This is about the same intake some would have in areas where the water fluoride level is 2 ppm.

Because the number of studies has been small, it is not known with certainty what fraction of the population may be hypersensitive to fluoride. Since all of the reported symptoms can be caused by other factors, reactions to fluoride could go undiagnosed unless a physician was looking specifically for fluoride sensitivity.

Enzyme and mutagenic effects

Sodium fluoride is used in many in-vitro studies to block the action of enzymes. in part because it can interfere with so many different enzymes.

One way the fluoride ion serves as an enzyme inhibitor in the lab is by acting on the GTP-binding proteins (or G-proteins). Fluoride ion also may disrupt enzymes by forming strong hydrogen bonds with amides. Fluoride switches off an enzyme by attacking its weakest links-the delicately balanced network of hydrogen bonds surrounding the active site. In some enzymes, the fluoride ion attaches itself to the atom at the heart of the enzyme and then disrupts the active site by attracting groups that can form strong hydrogen bonds to itself. Eventually, this inactivates the enzyme by changing its molecular conformation.

Because enzymes mediate most of the biochemical processes essential to life, any environmental agent that can affect a wide range of enzymes could, at least In theory, have a wide variety of effects on an organism’s health. For that reason alone, potential effects of fluoride on enzymes are of great interest. In addition, as has been discussed earlier, effects on enzymes are often the first detectable biological changes produced In an organism exposed to a toxic agent, just as enzyme changes in the heme biosynthetic pathway precede the onset of lead-induced anemia, Detailed knowledge of fluoride’s effects on a number of human enzymes could lead to an array of sensitive tests for the earliest signs of possible harm from excessive intake of this element and more precise identification of individuals who are at risk.

Studies on enzyme preparations in test tubes. however, don’t necessarily predict what will happen in living humans. In at least 11 in-vivo animal studies, fluoride has been shown to influence enzyme activity. In some tests, enzyme activity was depressed; in others, it was stimulated, In addition, one study indicates a transient decrease in human serum enzyme activity associated with the advent of water fluoridation. But there have been few other studies to measure the effects of typical levels of fluoride intake on enzyme activity in people.

Some scientists believe that interference with enzyme activity is the major mechanism by which fluoride exerts physiological effects. Certain changes in enzyme activity can be minor, easily repaired by the body. But others could be the first signs of more serious alterations that would take place with continued exposure to fluoride.

Just as the fluoride ion may disrupt enzymes with its ability to form strong hydrogen bonds, it may also disrupt DNA by interfering with its hydrogen bonding. The evidence for this mechanism consists of theoretical calculations, however, and some scientists, such as George R. Martin, chief of the laboratory of developmental biology and anomalies at NIDR, do not find it at all convincing.

A great many lab tests have been performed to measure the possible mutagenicity of the fluoride ion. The results are contradictory and often very confusing. Some of the positive mutagenicity tests involve very high concentrations of fluoride ion, so high that they would not be found anywhere in the human body. Others involve levels comparable to those in drinking water. However, the important consideration is not fluoride levels found in drinking water, but levels found in the human body. Geoffrey E. Smith, dental surgeon from Melbourne, Australia, says that when bones lose fluoride, localized high concentrations may result.

For example, in 1982, Aly H. Mohamed and Mary E. Chandler of the University of Missouri in Kansas City reported that 1 to 200 ppm fluoride in drinking water induced changes in a dose-dependent manner in bone marrow cell chromosomes and spermatocytes of living mice. In 1978, Danuta Jachimczak of the Pomeranian Medical Academy in Szezecin, Poland, showed that fluoride levels as low as 1 ppm caused changes in the chromosomes of human leukocytes in vitro.

Even if all the mutagenicity tests were positive, this would not prove fluoride is a mutagen in humans. But scientists consider a chemical a more likely mutagen if several types of lab tests are positive

John R. Bucher of the National Institute of Environmental Health Sciences says that tests in his lab show sodium fluoride mutagenic for cultured lymphoma cells derived from mice. He notes that a number of similar studies have been published by other investigators. Because most carcinogens are also mutagens, evidence of mutagenicity also bears on the issue of fluoride’s potential for carcinogenicity. Bucher’s results do not prove sodium fluoride is a carcinogen, but do "point out the need to test the chemical in the two-year rodent bioassay, which we are doing," he explains.

Because he believes that epidemiological studies show that fluoride has no effect on birth defects and cancer, Martin says he is not concerned about the positive mutagenicity studies. John S. Small, information specialist at NIDR who has a similar view of the epidemiology studies, calls the mutagenicity question a "used-up issue."

Very little work has been done on fluoride’s potential mutagenicity in humans, In one study involving only six patients receiving fluoride treatment for osteoporosis, inhibition of DNA repair was observed in one patient. But no firm conclusions can be drawn from such limited research, and more intensive research simply has not been pursued.

Birth defects

If the fluoride ion is a mutagen, it may be capable of causing birth defects in humans. Few studies have been done in this area. During the 1950s, Ionel Rapaport, a researcher at the Psychiatric Institute of the University of Wisconsin who specialized in the epidemiology of mental disorders, found that babies born in areas of North Dakota, South Dakota, Illinois, and Wisconsin with natural fluoride in drinking water had twice the incidence of Down’s syndrome as those born in fluoride-free areas. However, a few more recent surveys have shown a smaller or no relation between water fluoridation and Down’s syndrome.

In 1976, J. David Erickson, an epidemiologist at the Centers for Disease Control, looked at the rates of overall birth defects in the fluoridated and unfluoridated counties around Atlanta and also at national birth defect data supplied by the National Cleft Lip & Palate Intelligence Service (NCLPIS). Like Rapaport, he recorded a higher rate of Down’s syndrome births among younger mothers in the fluoridated areas around Atlanta, but he found no substantial overall differences in the birth defect rates that form a consistent pattern for the metropolitan Atlanta anti the NCLPIS data. However, many’ of the mothers in the Atlanta area counties had been exposed to fluoridation for only a few years and the NCLPIS data indicated substantial underreporting of birth defects. Clearly, there is need for more work in this area.

Cancer

Two types of research have been done to determine if fluoride causes cancer-lab studies of animals and human epidemiology studies. Neither kind of research has shown clearly that fluoride is a carcinogen in animals or humans, But the studies have not been extensive enough to show’ that it clearly is not a carcinogen.

A few animal bioassays on fluoride in the 1950s produced contradictory and inconclusive evidence on the ion’s potential to cause or accelerate cancer. In 1977, Congress requested that the National Institutes of Health conduct large-scale animal tests of fluoride for carcinogenicity. In the first chronic test, certain rats in both the control and dosed groups became ill and died at an early age, probably because their feed, highly purified to remove fluoride, ‘was deficient in certain essential trace elements. The study on 360 mice and rats was done over again ‘with a different feed. Results are scheduled to be available in 1990. Because of its well-established effects on many enzymes in vitro, Groth suggests that fluoride also should probably be tested for cocarcinogenicity (ability to act as a promoter of cancer) in animals. But no such research is now under way.

Groth: science cannot say how much uncertainty we should tolerate

Cancer epidemiology studies are probably the most controversial issue in the fluoride debate. In the 1950s, PHS did some general mortality studies of crude overall death rates from all causes. It found no excess mortality from cancer or other causes in naturally fluoridated areas, compared with areas without fluoride in water.

In 1977, biochemist John Yiamouyiannis, president of the Safe Water Foundation (a citizens group opposed to fluoridation), and Dean Burk, retired after working for 35 years as a biochemist at the National Cancer Institute, published a study comparing cancer mortality rates from the 10 largest U.S. cities with fluoridated water with mortality rates from 10 of the largest cities with nonfluoridated water. Before 1952, when fluoridation had not yet begun in most of these cities, the cancer death rates rose together. After 1952, the death rates for people over 45 in the cities with nonfluoridated water were 4 to 5% lower than those for the cities with fluoridated water. In England, Sir Richard Doll and Leo Kinlen of Oxford University and Peter D. Oldham and D. John Newell of the Royal Statistical Society at about the same time completed studies that show no excess of cancer mortality in those same cities in the U.S. with fluoridated water.

The National Research Council (NRC) reviewed this discrepancy in 1977 and concluded that the conflicting results could be explained in large part by the different data sets and different analytical approaches used by the investigators. According to the NRC analysis, the margin of possible error in the most sensitive cancer study is about three cancer deaths per 100,000 people or 4000 possible excess or fewer cancer deaths per year among the 130 million individuals drinking fluoridated water in the U.S.

A June article in the Proceedings of the Pennsylvania Academy of Science by attorney John R. Graham, Burk, and Pierre J. Morin, former scientific adviser for the minister of environment in Quebec, also reviews this controversy. It concludes that, compared with the unfluoridated cities, there is an excess of 20 to 30 cancer deaths per 100,000 people who live in the major fluoridated cities of the U.S. for at least 15 to 20 years.

Several investigators have looked for a more specific relationship between stomach cancer and fluoridation. The hypothesis is that fluoride would be more likely to cause stomach cancer than any other type because fluoride in the stomach forms hydrofluoric acid, a powerful irritant that is mutagenic in several in-vitro lab tests. In 1978. CDC’s Erickson, after correcting for age, race, and sex, found the death rate from cancer of the digestive system was 9% higher in cities with fluoridated water. However, when he subtracted all subjects with Asian and Hispanic surnames and corrected for education and population density, the excess disappeared.

The Knox report, a comprehensive review of most fluoride cancer studies that was completed in 1985 by the Royal College of Physicians in England. concludes that there is no convincing evidence that cancer death rates are higher in areas with fluoridated water. Thus, as with most environmental agents that have been studied for their effects on cancer, the results for fluoride are still inconclusive.

Values influence the choice

Even if all evidence from fluoride research indicated that the risks are slight, not everyone would agree that it is proper to fluoridate water supplies. Obviously, there is never enough time or money to investigate all the scientific questions, and some research results will always be equivocal. And, at least in environmental health, it is, of course, impossible for science to establish anything with absolute certainty.

The decision to fluoridate a community’s water or not boils down to a matter of values Scientific evidence can make the choice more clearcut, more rational, but the choice can’t be made purely on the basis of scientific evidence. So long as there is uncertainty about risk from fluoridation, some people will not want to accept that risk, And others who favor fluoridation will demand proof of harm beyond a reasonable doubt before they reject it According to Groth, "A scientific assessment cannot say what degree of adverse effects is acceptable in return for the expected benefits. . . . It cannot say how much uncertainty we should tolerate in estimates of hazards when more than 100 million people are exposed to lifelong ingestion of fluoridated water. Those decisions are value judgments, and scientists’ values are no better than everyone else's.

If the risks could be shown to be minuscule beyond a reasonable doubt, it still might make no sense to fluoridate water supplies if the benefits are also small. Perhaps the best approach is, as Groth suggests, not to make the issue whether to fluoridate public water supplies or not. Such an approach allows for no compromise: A water supply is either fluoridated or it is not. Perhaps a better question for policy makers, scientists, and citizens to address is: "What is the best way to promote dental health?" he says. Fluoridation might well be part of the answer, Groth suggests. But communities should simultaneously examine the pros and cons of a variety of other approaches, too. That way, the characteristic all-or-nothing, fight-to-the-finish political battle over fluoridation might someday truly become a historical curiosity.