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OCR for page 1
HEALTH EFFECTS OF
INGESTED FLUORIDE
EXECUTIVE SUMMARY
INTRODUCTION
Fluoridation of drinking water has been a subject of controversy for
decades. Over the past 50 years, the incidence of dental caries (cavities)
has declined considerably in the United States, an important health acI-
vance that most scientists attribute principally to increased access to
fluoridated water ant! dental products. According to the U.S. Centers for
Disease Control and Prevention, approximately 132 million Americans
now receive drinking water that contains fluoride, either naturally oc-
curring or added, at concentrations of 0.7 milligrams per liter (mg/L) or
higher. Since the 1960s, the U.S. Public Health Service (PHS) has
recommended an "optimal" fluoride concentration of 0.7-~.2 mg/L to
prevent dental caries and minimize dental fluorosis. However, there has
been an increase in the prevalence of dental fluorosis a mottling of tooth
enamel that ranges from barely discernible enamel flecks in its mildest
forms to staining and pitting in its severest forms; the severest forms are
rare in the United States. EPA considers dental fluorosis to be a cosmet-
ic effect and not an adverse health effect.
Recent fencings have renewed longstanding concerns of those who op-
pose water fluoridation, claiming that ingestion of fluoride can react to a
variety of unwanted effects. One animal study reported an equivocal
increase in osteosarcomas (malignant bone tumors) in male rats, but not
in female rats, at very high concentrations (100-175 mg/L). However,
OCR for page 2
2 Health Elects of Ingested Fluoride
that result was not substantiated in a subsequent study in rats at even
higher doses.
In the United States, a few cases of crippling skeletal fluorosis (an in-
crease in the thickness of bones, which in advanced stages, is associated
with decreased mobility of joints and pain) have been reported in humans
only when fluoride concentrations in drinking water exceeded ~ mg/L
over many years. That concentration is much higher than the PHS
recommendation of 0.7-~.2 mew. To prevent skeletal fluorosis, the
U.S. Environmental Protection Agency (EPA) set the maximum contami-
nant level (MCL) for fluoride at 4 mg/L of drinking water. In addition
to fluoride in drinking water, however, people also can ingest fluoride in
toothpaste, mouth rinse, and dietary fluoride supplements or in beverages
and foods prepared with fluoridated water. As a result, many Americans
might ingest more "incidental" fluoride than was anticipated by PHS and
EPA in recommending stanciarcis for drinking water.
EPA respondecl to the concerns by requesting that the National Re-
search Council's Board on Environmental Studies and Toxicology (BEST)
review the current toxicological and exposure data on fluoride and de-
termine whether EPA's current MCL of 4 mg/L is acceptable for protect-
ing the public from potential adverse health effects of fluoride. EPA also
asked BEST to identify gaps in the fluoride toxicity data and to make
recommendations for future research.
In response to EPA's request, BEST's Committee on Toxicology
established the Subcommittee on Health Effects of Ingested Fluoride.
The subcommittee based its evaluation on a detailed examination of
current data in the following areas:
· Intake, metabolism, and disposition of fluoride.
Dental fluorosis.
Bone strength and the risk of bone fracture.
Effects on the renal, gastrointestinal, and immune systems.
Reproductive effects in animals.
Genotoxicity.
Carcinogenicity in animals and humans.
This report deals with the possible toxic effects of ingested fluoride in
humans. It does not attempt to weigh fluoride's well-documented health
benefits against its possible adverse health effects.
OCR for page 3
Executive Summary 3
INTAKE, METABOLISM,
AND DISPOSITION OF FLUORIDE
The major sources of fluoride intake are water and other beverages,
food, and fluoride-containing dental products. Groundwater, a major
source of drinking water in many communities, can contain fluoride at
concentrations ranging from less than 0. ~ mg/L to more than 100 mg/L
in some parts of the world (e.g., Africa and China). Coffee, tea, and
soft drinks made with that water might have corresponding concentrations
of fluoride. Concentrations in food depend on the levels in the soil, but
they can increase or decrease depending on the fluoride concentrations in
the water used in food preparation. Dental products available in the
United States and meant to be used topically (and not ingested) contain
fluoride at concentrations ranging from 230 to over 12,000 parts per
million (ppm).
The average intake of dietary fluoride by young children whose water
supply contains fluoride at 0.7-~.2 mg/L is approximately 0.5 mg per
day, although substantial variation occurs. Because it is associated with
optimal fluoridation, this level of fluoride intake (0.5 mg per day, or
0.04~.07 mg per kilogram (kg) of body weight per day) generally has
also been accepted as optimal. Nursing infants receive negligible fluoride
from breast milk, but intake from formulas can range from less than 0.4
to over I.0 mg per day when reconstituting powder concentrate with
fluoridated water, a range that can exceed the optimal level. Dietary
intake by adults in areas with fluoridated water has been estimated at I.2-
2.2 mg per day, although intake by some individuals, such as outdoor
laborers in warm climates or those with urinary disorders, can be con-
siderably higher.
Accurate estimates of fluoride exposure cannot be based simply on the
concentration of fluoride in drinking water. For example, dental prod-
ucts can be an important source of ingested fluoride, especially for young
children who have poor control over the swallowing reflex. Even for
older children, intake from toothpaste and mouth rinse can still equal the
daily intake from food, water, and other beverages. Soft drinks, which
often contain fluoride at 0.3-0.5 mg per 12-ounce serving, are an impor-
tant additional source of fluoride. Studies of dental fluorosis indicate that
children's exposure to fluoride has increased since the 1970s.
Approximately 75-90% of the fluoride ingested each day is absorbed
OCR for page 4
4 Health Effects of Ingested Fluoride
from the alimentary tract. Because of its chemical affinity for calcium
compounds, about half of that fluoride becomes associated with teeth and
bones within 24 hours of ingestion. In growing children, even more of
the ingested fluoride is retained because of the large surface area provid-
ec] by numerous and loosely organized bone crystallites. The remaining
fluoride is eliminated almost exclusively by the kidneys, and the rate of
renal clearance is directly related to urinary pH. As a result, diet, drugs,
metabolism, ant} other factors can affect the extent to which fluoride is
retained in the body.
Recommendations for furler research are (~) to determine ant}
compare intake of fluoride from all sources (this recommendation
has implications for research design in several of the areas that
follow); and (2) to determine the metabolic characteristics of fluo-
ride in infants, young children, and the elderly, as well as in pa-
tients with progressive renal disease.
DENTAL FLUOROSIS
Fluoride prevents tooth decay by enhancing the remineralization of
enamel that is under attack, as well as inhibiting the prociuction of acid
by clecay-causing bacteria in dental plaque. Fluoride is also a normal
constituent of the enamel itself, incorporated into the crystalline structure
of the developing tooth and enhancing its resistance to acid dissolution.
One side effect of too much fluoride ingested in early childhood while
teeth are forming, however, is dental fluorosis; the enamel covering of
the teeth fails to crystallize properly, leading to defects that range from
barely discernible to severe brown stain, surface pitting, and brittleness.
Fluoricle intake by chilclren 2-5 years old is particularly important be-
cause the anterior (front) permanent teeth are at the early-maturation
stage, during which they are particularly susceptible to fluoride-induced
changes. Dental fluorosis also is a dose-response condition: the greater
the fluoride intake during tooth development, the more severe the dental
fluorosis. Depending upon the amount and time (relative to tooth clevel-
opment) of fluoride absorbed, severity of dental fluorosis can range from
barely discernible to severe manifestations of stained and pitted tooth
enamel. PHS's recommended fluoride concentration in drinking water,
OCR for page 5
Executive Summary 5
0.7-~.2 mg/L, was designed to maximize prevention of dental caries
while limiting the prevalence of dental fluorosis to about 10% of the
population, virtually all of it mild to very mild.
A 1991 report from PHS of the U.S. Department of Health and
Human Services compiled the results of independent investigations
conducted during the 198Os on dental fluorosis in 24 cities and compared
them with a series of PHS surveys conducted during the late 1930s and
early 1940s in 21 cities. That comparison showed that the prevalence of
dental fluorosis, most of it very mild to mild, had increased. The 198Os
data showed that the mean prevalence of dental fluorosis in four cities
with optimally fluoridatecl water supplies was around 22% (17% very
mild, 4% mild, 0.~% moderate, and 0.~% severe). In another city with
a water fluoride concentration in the range of .-2.2 mg/L, dental
fluorosis prevalence was 53 % (23 % very mild, 17 % mild, ~ % moderate,
and 5% severe). In two other cities with water fluoride concentrations
greater than 3.7 mg/L, prevalence was around 84% (25% very milct,
27 % mild, 19 % moderate, and ~ 4 % severe). The data in the PHS report
also showed that the greatest relative increase in fluorosis prevalence
since the early studies was in communities with very low water fluoride
concentrations, demonstrating the influence of sources of fluoride other
than water. Those sources make it cliff~cult to estimate fluoride exposure;
they represent a source of possible error in estimating fluoride intake in
studies of the relation between fluoride exposure and dental fluorosis.
Moreover, there is disagreement on whether dental fluorosis (even
moderate-to-severe dental fluorosis, in which substantial tooth enamel is
affected and dental treatment might be required) is a cosmetic problem
or an adverse health effect.
.
In general, the evidence supports the conclusion that fluoridation at the
recommended concentrations, in the absence of fluoride from other
sources, results in a prevalence of mild-to-very-milci (cosmetic) dental
fluorosis in about 10% of the population and almost no cases of moderate
or severe dental fluorosis. At 5 or more times the recommenciect con-
centration, the proportion of moderate-to-severe dental fluorosis is
substantially higher. The most effective approach to controlling the
prevalence and severity of dental fluorosis, without jeopardizing the
benefits of fluoride to oral health, is likely to come from more judicious
control of fluoride in foods, processed beverages, and dental products,
especially those items used by young children.
OCR for page 6
C Health Elects of Ingested Fluoride
Recommendations for further research are to identify sources of
fluoride during the critical stages of tooth development in childhood
and evaluate the contribution of each source to dental fluorosis.
Further research should be aimed at the goal of minimizing ex-
posure to fluoride concomitant with maintaining effectiveness in
preventing caries.
FLUORIDE AND BONE FRACTURES
The effect of fluoride on bone strength, hip fractures, ant! skeletal
fluorosis in humans has been addressed in two types of studies. The first
type involves clinical trials of Me effectiveness of high concentrations of
fluoride supplements in strengthening bones and preventing further
fractures in patients with osteoporosis; this treatment has been used
primarily in Europe for almost 30 years. When conducted using proper
control groups, these studies showed little or no benefit even at dosages
of 20-32 mg per day, well over 10 times the exposure from fluoridates!
drinking water. If anything, the treated groups experienced a greater
number of new fractures, including painful stress fractures in bones other
than the vertebrae.
The second type of human study involves epidemiological investiga-
tions. These studies compared the rate of bone fracture in populations
of the elderly that differed in their exposure to natural or added fluoride
in drinking water. Geographic and time-trend analyses were made; time-
trend analysis is considered the stronger methodology because there is
less opportunity for confounding by other risk factors. Of the six epide-
miological studies that used geographic comparisons (where no actual
intake data were available), four found a weak association between
fluoride in drinking water and the risk of hip fracture. Two aciditional
studies examined time trends in bone fracture before and after water
fluoridation: one found no association and the over a negative associa-
tion. Only two additional studies collected information on individual ex-
posure: one (essentially a geographic comparison) found an increased
risk of hip fracture at water fluoride concentrations of 4 mg/L, and the
other observed no difference in risk.
Studies with several species of experimental animals have yielded var-
ious outcomes. Most of the studies indicated little or no effect on bone
strength, even with very high fluoride intake and very high concentrations
OCR for page 7
Executive Summary
7
of fluoride in bone. The subcommittee identified many potential prob-
lems in the experimental design of the animal studies, including the lack
of suitable control groups with reasonably low fluoride exposures.
However, the subcommittee concluded that the weight of evidence indi-
cates 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 of drinking water or 50 mg/kg in
diet.
In view of the conflicting results and limitations of the current data
base on fluoride and the risk of hip or other fractures, the subcommittee
concludes that there is no basis at this time to recommend that EPA
lower the current standard for fluoride in drinking water for this end
point. However, the subcommittee recommends additional research to
improve the current data base.
A recommendation for further research is to conduct additional
studies of hip and other fractures in geographical areas with high
and low fluoride concentrations in drinking water and to make use
of individual information about water consumption. These studies
should also collect individual information on bone fluoride concen-
trations and intake of fluoride from all sources, as well as repro-
ductive history, past and current hormonal status, intake of dietary
and supplemental calcium and other cations, bone density, and other
factors that might influence risk of hip fracture.
EFFECTS OF FLUORIDE ON
THE: RENAL SYSTEM
Renal excretion is the major route of elimination for inorganic fluoride
from the body. As a result, kidney cells are exposed to relatively high
fluoride concentrations, making the kidney a potential site for acute
fluoride toxicity. Animal studies have shown that very high water
fluoride concentrations of 100-380 mg/L can lead to necrosis of proximal
and renal tubules, interstitial nephritis, and dilation of renal tubules.
However, human epidemiological studies have found no increase in renal
disease in populations with long-term exposure to fluoride at concentra-
tions of up to ~ mg/L of drinking water.
The subcommittee concludes that available evidence shows Hat the
OCR for page 8
8 Health Elects of Ingested Fluoride
threshold dose of fluoride in drinking water for renal toxicity in animals
is approximately 50 mg/L. The subcommittee therefore believes that
ingestion of fluoride at currently recommended concentrations is not
likely to produce kidney toxicity in humans.
EFFECTS OF FLUORIDE ON
THE GASTROINTESTINAL SYSTEM
In the acid environment of the stomach, fluoride and hydrogen ions
can combine to form hydrogen fluoride, which, at sufficiently high con-
centrations, can be irritating to the mucous membranes of the stomach
lining. Experimental studies with several animal species have shown
dose-dependent adverse effects, such as chronic gastritis and other lesions
of the stomach, at fluoride concentrations of 190 mg/L and higher.
Reports of gastrointestinal effects in humans often involve workers ex-
posecI to unknown concentrations of fluoride in the workplace, so that the
contribution of fluoride exposure to the risk of adverse health effects is
unknown. The subcommittee noted that these workers could also be
exposed to other toxic substances present in the work environment.
There have been few studies of the gastrointestinal effects of fluoride at
low concentrations.
The subcommittee concludes that the available tiara show that the
concentrations of fluoride found in drinking water in the United States
are not likely to produce adverse effects in the gastrointestinal system.
EFFECTS OF FLUORIDE ON
HYPERSENSITW~TY AND THE IMMUNE SYSTEM
Few animal and human data on sodium fluoride-related hypersen-
sitivity reactions are found in the literature. In animal studies, exces-
sively high doses, inappropriate routes of administration of fluoride, or
both were used. Thus, the predictive value of those data, in relation to
human exposures at accepted exposure levels, is questionable. Reports
of hypersensitivity reactions in humans resulting from exposure to sodium
fluoride are mostly anecdotal
OCR for page 9
Executive Summary 9
The literature pertaining to immunological effects of fluoride is limit-
ed. Although direct exposure to high concentrations of sodium fluoride
in vitro affects a variety of enzymatic activities, the relevance of the
effects in vivo is unclear. Standardized immunotoxicity tests of sodium
fluoride at relevant concentrations and routes of administration have not
been conducted. The weight of evidence shows that fluoride is unlikely
to produce hypersensitivity and other immunological effects.
EFFECTS OF FLUORIDE ON REPRODUCTION
There have been reports of adverse effects on reproductive outcomes
associated with high levels of fluoride intake in many animal species. In
most of the studies, however, the fluoride concentrations associates! with
adverse effects were far higher than those encountered in drinking water.
The apparent threshold concentration for inducing reproductive effects
was 100 mg/L in mice, rats, foxes, and cattle; 100-200 mg/L in minks,
owls, and kestrels; and over 500 mg/L in hens.
Based on these findings, the subcommittee concludes that the fluoride
concentrations associated with adverse reproductive effects in animals are
far higher than those to which human populations are exposed.
Consequently, ingestion of fluoride at current concentrations should have
no adverse effects on human reproduction.
GENOTOXICITY
Fluoride has been tested extensively for its genotoxicity. It does not
damage DNA or induce mutations in microbial systems, but it has pro-
duced mutations and chromosomal damage in several in vitro tests with
mammalian cells. Sodium fluoride, in particular, inhibits protein ant!
DNA synthesis and has been reported to cause chromosomal aberrations
in human cells. The lowest effective dose in these cell-culture studies
was a fluoride concentration of approximately 10 1lg/mL, whereas the
normal concentration in human plasma is 0.02-0.06 ~g/mL, even in areas
where drinking water is fluoridated, which means that there is a large
margin of safety.
Sodium fluoride and other fluoride salts also have been tested for
OCR for page 10
10 Health Effects of Ingested Fluoride
genotoxicity in the fruit fly Drosophila, as well as in mice and rats. The
subcommittee's review of the results of these in vivo studies was incon-
clusive, however, because of differences in protocols and insufficient de-
tai! to support a thorough analysis. There are no published studies on the
genetic or cytogenetic effects of fluoride in humans.
The subcommittee concludes Hat the genotoxicity of fluoride should
not be of concern at the concentrations found in the plasma of most
people in the United States.
CARCINOGENICITY
More than SO epidemiological studies have examined the relation be-
tween fluoride concentrations in drinking water and human cancer. Most
studies compared geographic or temporal patterns of cancer occurrences
with distributions of fluoride in drinking water. These studies provide
no credible evidence for an association between fluoride in drinking
water and the risk of cancer. The existence of such an extensive epide-
miological data base on fluoride with no consistent evidence of carcino-
genic effects suggests that, if there is any increase in cancer risk due to
exposure to fluoride, it is likely to be small. However, most of these
studies used geographic and temporal comparisons of cancer rates and
hence are of limited sensitivity. Further analytical studies with accurate
information on individual fluoride exposures and disease diagnoses are
therefore desirable.
The subcommittee also reviewed the literature on the potential car-
cinogenic effects of fluoride in animals. Although the results of earlier
animal studies were largely negative, the studies were not conducted
using current bioassay techniques and are thus of limited value. The
subcommittee placed greater weight on two recent studies. The first,
conducted by the National Toxicology Program (NTP), administered fluo-
ride at concentrations of up to 175 mg/L of drinking water. Although the
results were negative for male and female mice and female rats, there
was some evidence of a dose-related increase in the incidence of osteosar-
comas in male rats. However, these results were not confirmed by a
second study conducted by Procter & Gamble, in which fluoride was
administered in the diet at doses higher than those in the NTP study.
The Procter & Gamble study die! produce a significant dose-related in
OCR for page 11
Executive Summary ~ ~
crease in the incidence of osteomas (benign bone tumors) in male and
female mice. However, these lesions were not considered to be neoplas-
tic and, in any event, have no known counterpart in human pathology.
The subcommittee concludes that the available laboratory data are
insufficient to demonstrate a carcinogenic effect of fluoride in animals.
The subcommittee also concludes that the weight of the evidence from the
epidemiological studies completed to date does not support the hypothesis
of an association between fluoride exposure and increased cancer risk in
humans.
Nonetheless, the subcommittee recommends conducting one or
more carefully designed analytical epidemiological (case-control or
cohort) studies to more fully evaluate the relation between fluoride
exposure and cancer, especially osteosarcomas, at various sites,
including bones and joints. In conducting such studies, it is im-
portant that individual exposure to fluoride from all sources be
determined as accurately as possible.
CONCLUSIONS
Based on its review of available data on the toxicity of fluoride, the
subcommittee concludes that EPA's current MCL of 4 mg/L for fluoride
in drinking water is appropriate as an interim standard. At that level, a
small percentage of the U.S. population will exhibit moderate or even
severe dental fluorosis. However, the question of whether to consider
dental fluorosis a cosmetic effect or an adverse health effect ant! the
balancing of the health risks and health benefits of fluoride are matters
to be determined by regulatory agencies ant! are beyonc! the charge or
expertise of this subcommittee.
The subcommittee found inconsistencies in the fluoride toxicity data
base and gaps in knowledge. Accordingly, it recommends further re-
search in the areas of fluoride intake, dental fluorosis, bone strength and
fractures, and carcinogenicity. The subcommittee further recommencis
that EPA's interim standard of 4 mg/L should be reviewed when results
of new research become available and, if necessary, revised accordingly.
OCR for page 12
OCR for page 13
Health Effects of
Ingested Fluoride
OCR for page 14
Representative terms from entire chapter:
drinking water
