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OCR for page 85
EFFECTS OF INGESTED
FLUORIDE ON RENAL,
GASTROINTESTESTINAL,
AND IMMUNE SYSTEMS
EFFECTS ON THE RENAL SYSTEM
The kidney is the potential site of acute fluoride toxicity because kidney
cells are exposed to relatively high fluoride concentrations. Fluoride
concentrations in the kidney show an increasing gradient of concentra-
tion, the lowest concentrations occurring in the renal cortex and the
highest in the papilla (Whitford, 1990~. Fluoride, after oral administra-
tion, is rapidly absorbed into the blood. Peak serum concentrations occur
30-90 minutes after administration and then decline rapidly (Cowell and
Taylor, 1981~. Approximately 50% of the daily intake of fluoride is
cleared by the kidneys (Whitford, 1990~. Consequently, the kidney is
thought to be a target organ for any adverse effects of fluoride because
of the bioconcentration and kinetics of fluoride metabolism and excretion
patterns.
A few experimental studies have examined the effects of fluoride
exposure on rodent kidneys. Daston et al. (1985) administered] a single
intraperitoneal dose of fluoride at 30 or 40 mg/kg of body weight to 29-
day-old rats. They observed transitory (disappearing within 120 hours)
renal effects, such as polyuria, increased urinary pH, and proximal
tubular cell necrosis. The renal effects in rodents are probably age-
dependent because suckling rats have a lower urinary pH than weanling
rats do. The lower pH likely results in more selective reabsorption of
85
OCR for page 86
86 Health Effects of Ingested Fluoride
fluoride, which results in higher tissue concentrations. Studies of wean-
ling rats consuming water with high concentrations of sodium fluoride
(NaF at 380 mg/L for 6 weeks) have demonstrated necrosis of the proxi-
mal and distal renal tubules Tim et al., 1978~. In a study of weanling
rats administered drinking water with NaF at 100 mg/L for 6 months,
Taylor et al. (1961) reported interstitial nephritis and dilation of the renal
tubules at the corticomedulIary junction. No effects were observed at 50
mg/~. Structural changes in the kidneys have also been reported by
other investigators following chronic fluoride exposure, although the
eventual effects on renal function were not examined (Hodge and Smith,
1977; Greenberg, 1986~.
In humans, the potential for health effects of fluoride exposures on
renal function is enhanced because of selective absorption by the kidney
and the kinetics of fluoride distribution ant} excretion. The healthy
kidney removes fluoride from the blooct much more efficiently than it
removes the other halogens. Furthermore, the tissue-to-plasma fluoride-
concentration ratios for soft tissues were highest in the kidneys (Whi-
tford, 19891. Studies of persons receiving the halogenated anesthesia,
methoxyflurane, observed renal insufficiency in some patients due to high
serum fluoride concentrations (Mazze, 1984~. The effect was transient,
and renal function returned to normal once the serum fluoride concentra-
tions decreased below 30 micromoles Mold/. Several epidemiological
studies have examined the possible association between fluoride exposures
and renal effects. Hanhijarvi (1975), in a study of plasma fluoride
concentrations in 2,200 hospital patients in Finland (which included 501
persons living in an area with naturally occurring fluoride concentrations
at less than 0.2 mg/L of drinking water and 1,083 persons living in an
area with fluoride added to drinking water at ~ mg/~), showed that
concentrations increased with age and were higher in individuals living
in the area with added fluoride in drinking water. Renal clearance of
fluoride increased with age in both groups but was approximately twice
as high in persons living in the area with acIded fluoride. Decreased
renal clearance of fluoride was observed in persons with renal insuf-
ficiency or with diabetes mellitus. Other studies have shown decreased
fluoride clearance in both adults and children with impaired renal func-
tion (Kong et al., 1984; Spak et al., 1985~. Several large community-
based epidemiological studies found no increased renal disease associated
with long-term exposure to drinking water with fluoride concentrations
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Effects of Fluoride on Renal, Gastrointestinal, arid Immune Systems 87
up to ~ mg/L (Leone et al., 1954; Schlesinger et al., 1956; Geever et al.
1958).
In summary, although experimental studies have shown transient and
permanent renal effects at concentrations of fluoride over 50-100 mg/L,
human epidemiological studies have not observed increased renal disease
in populations with long-term exposure to fluoride concentrations up to
X mg/L of drinking water.
EFFECTS ON THE
GASTROINTESTINAL SYSTEM
With the exception of monofluorophosphate, all fluoride-releasing
compounds form hydrogen fluoride when mixed with hydrochloric acid
in the stomach. In the acid environment of the stomach, fluoricie and
hydrogen ions form the nonionized molecule hydrogen fluoride, which
might be irritating to the stomach mucosa if the concentration is suff~-
ciently high. Hydrogen fluoride has been shown to induce structural and
functional adverse effects on the gastric mucosa of rats and dogs at
concentrations of 190 mg/L. These effects range from loss of the mu-
cous layer and scattered desquamation of mucous cells to widespread
erosions of the gastric mucosa (Whitford, 1990~.
Experimental studies in rodents given extremely high doses of NaF
(1,900 mg/L) demonstrated erosive and hemorrhagic injury to the gastric
mucosa and disruption of the structure and integrity of the gastric glancis;
healing progressed over 7 days (Easmann et al., 1984, 1985; PashIey et
al., 19844. In rats, chronic exposure to NaF at 4, 10, or 25 mg/kg in the
diet resulted in dose-dependent chronic gastritis and glandular stomach
acanthosis (Appendix D in PHS, 1991~. Gross lesions were observed in
the mucosa of the glandular stomach of male rats treated for 6 months
with NaF at 300 mg/L (NTP, 1990~. The lesions in male and female rats
included clifi~use hyperplasia of the mucosal epithelium accompanied by
cellular necrosis.
Studies of workers occupationally exposed to varying concentrations
of fluoride have reported a variety of gastrointestinal effects. These
include chronic gastritis with or without accompanying skeletal fluorosis,
duodenal ulcers, and erosion of the gastric mucosa (MecIvecleva, 1983;
Desai et al., 1986~. Neither of the studies reporteci ambient fluoride
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88 Health Effects of Ingested Fluoride
measurements, so the actual exposure concentrations are unknown but are
presumed to be high.
In summary, high concentrations of fluoride, in the form of hydrogen
fluoride, which is due to mixing in We stomach with hydrochloric acid,
Carl be irritating to We gastric mucosa, resulting in dose~ependent
adverse effects. There are limited data on humans at low exposures,
indicating that at optimal concentrations of fluoride, gastrointestinal
effects are not a problem.
HYPERSENSITnnTY AND
IMMUNOLOGICAL EFFECTS
Few animal and human data on sodium fluoride-related hyper-
sensitivity reactions are found in the literature. In animal studies, ex-
cessively high doses, inappropriate routes of administration of fluoride,
or both were used Lewis and Wilson, 1985; fain and Susheela, 1987~.
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 NaF are mostly anecdotal
(Arnold et al., 1960; Richmond, 1985; Modly and Burnett, 1987; Razak
and Latifah, 1988~. The most common reactions observed included
dermatitis, urticaria, inflammation of the oral mucosa, and gastrointestin-
al disturbances. Hypersensitivity reactions to fluoride dental preparations
were mild to moderately severe and appeared to resolve completely with
discontinuation of the product (Adair, 1989~. It was reported that those
reactions were caused by NaF or by alcohol, dyes, or flavoring agents in
the products.
Waldbott (1962) reported that ingestion of fluoride at ~ mg/L of water
produced numerous symptoms, which included gastrointestinal distress
and joint pains. Those symptoms were also reported in a few patients
who received a daily dose of 20 me or more in treatment for bone
conditions (Rich et al., 1964; Shambaugh and Sundar, 1969~. However,
those symptoms are not believed to be caused by chronic intake of
fluoride at any concentration, let alone at the low fluoride concentrations
cited by Waldbott. The findings should be disregarded for the following
reasons: (~) insufficient clinical and laboratory evidence of allergy or
intolerance to fluorides used in the fluoridation of community water, and
OCR for page 89
Effects of Fluoride or' Renal, Gastrointestinal, and Immune Systems 89
(2) no evidence of immunologically mediated reactions in a review of the
reported allergic reactions (Austen et al., 1971~.
Waidbott (1978) proposed Hat the skin lesion Chizzola maculae might
be caused by airborne fluorides. Waidbott and Cecilioni (1969) attributed
the development of these discrete skin lesions to fluoride exposure in 10
of 32 persons living near fertilizer plants in Ontario, Canada, and Iowa
and close to an iron foundry in Michigan. Evidence for Chizzola macu-
lae resulting from exposure to fluoride has been reviewed extensively by
several investigators (Hodge and Smith, 1977), who concluded that the
evidence was circumstantial and unsupported by field surveys.
The literature pertaining to immunological and immunomodulation
effects of fluoride is limited. Although direct exposure to high con-
centrations of NaF in vitro affects a variety of enzymatic activities (AIm,
1983; Mircevova et al., 1984; National Health and Medical Research
Council, 1985; Takanaka and O'Brien, 1985; O'Shea et al., 1987; Okada
and Brown, 1988; Mizuguchi et al., 19X9), the relevance of the effects
in vivo is unclear. Standardized immunotoxicity tests of NaF at relevant
concentrations and routes of administration have not been conducted.
DISCUSSION
The kidney and gastrointestinal system are exposed to varying fluoride
concentrations owing to specific characteristics of fluoride kinetics and
excretion patterns. The kidney exhibits the highest tissue-to-plasma
fluoride concentrations measured for any soft tissue with a concentration
gradient existing across the different anatomic sections of the kidney. All
the soluble fluoride-releasing compounds except monophosphate form
hydrogen fluoride when mixed with hydrochloric acid in the stomach.
Hydrogen fluoride is irritating to the stomach mucosa. For the kidney,
experimental studies have demonstrated transient renal effects at relative-
ly high fluoride concentrations (50-100 mg/L). Human epidemiological
studies have not observed increased rates of renal disease in populations
exposed to fluoride concentrations up to ~ mg/L of drinking water.
Experimental studies of the effects of fluoride on the gastrointestinal tract
in several animal species have shown dose-dependent adverse effects,
such as chronic gastritis and lesions of the stomach mucosa, at doses as
low as 190 mg/L. The limited reports on adverse gastrointestinal effects
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90 Health Effects of Ingested Fluoride
in humans are primarily studies of persons occupationally exposed to
unknown concentrations of fluoride. One problem in those studies is Hat
the workers are exposed to a variety of potentially toxic agents, so the
contribution of fluoride exposure to risk of adverse effects on Be gastro-
intestinal system is unknown.
Because of the lack of documented adverse effects on the renal and
gastrointestinal systems et fluoride concentrations below S mg/L of
drinking water, no research recommendations are made at this time. The
literature pertaining to immunological and immunomodulation effects of
fluoride is limited. The weight of evidence shows that fluoride is unlike-
ly to produce hypersensitivity and other immunological effects.
Representative terms from entire chapter:
drinking water
