The Science of the Total Environment 220 1998.

81]85

Serum and urine fluoride concentration: Relationships to

age, sex and renal function in a non-fluoridated population

M. TorraU , M. Rodamilans, J. Corbella

and Pro incial, Uni ersity of Barcelona, Villarroel 170, 08036 Barcelona, Spain
Toxicology Unit, Hospital Clnic

Received 13 May 1998; accepted 23 June 1998

Abstract

Serum and urine fluoride levels were determined in 250 healthy subjects 15]90 years, 122 men and 128 women.
residing in Catalonia, Spain, and in 150 patients 20]81 years, 84 men and 66 women. with chronic renal failure
undergoing regular dialysis treatment, living in the same geographical area, to determine normal range and to
investigate its relationships to age, sex and renal function. Serum and urine fluoride were determined by a fluoride
ion specific electrode system. Mean "S.D.. serum fluoride concentration was 17.5" 9.5 m grl, ranging from 1 to 47
m grl, in the control group and 58 " 31 m grl, ranging from 28 to 185 m grl, in renal patients. Urine fluoride
concentration in the healthy group was 671 " 373 m gr24 h, ranging from 156 to 1900 m gr24 h. Fluoride status in the
patient group was significantly greater than the control group. There was significant correlation between serum
fluoride and age. No sex related difference was found. Q 1998 Elsevier Science B.V. All rights reserved.

Keywords: Fluoride; Renal patients; Ion specific electrode system; Age

1. Introduction treatment for osteoporosis Jones and Berg, 1992..

Fluoride is an essential trace element, widely
distributed in the environment at a variety of
concentrations. It is found in water, soil, food,
dental products and as a therapeutic drug for
postmenopausal osteoporosis treatment.
Considerable interest has recently been fo-
cused on fluoride pharmacokinetics due to its
world-wide use for dental caries prevention, em-
phasised in view of the clinical use of fluoride as a
U
Corresponding author.
It is accepted that fluoride, at low doses, is a
highly effective anticaries agent, and for this rea-
son in some countries a programme of controlled
addition of fluoride in the public water supply was
established. Furthermore, the prevalence of
enamel fluorosis, during the time of tooth devel-
opment, has increased in optimally fluoridated
areas in recent years Aasenden and Peebles,
1978; Kalsbeek et al., 1992; Jackson et al., 1992;
Pendrys, 1995..
Fluoride is incorporated into calcified tissues,
and under most conditions, is rapidly absorbed
from the gastrointestinal tract and accumulates

0048-9697r98r$ - see front matter Q 1998 Elsevier Science B.V. All rights reserved.
PII S0048-969798.00248-4
82 M. Torra et al. r The Science of the Total En ironment 220 (1998) 81]85
mostly in teeth and bone. Peak levels in the
serum are reached in 30 min and it is removed
from the plasma by calcified tissue uptake and
renal excretion. The main pathway of fluoride
elimination is via the kidney since more than 50%
appears in urine within 24 h after ingestion
Spencer et al., 1970..
It is known that the first determinant of the
amount of fluoride excreted in urine is the
glomerular filtration rate. Taking into considera-
tion that patients with renal insufficiency have a
lower glomerular filtration rate, they have a de-
creased ability to excrete fluoride which could
lead to increased retention of this anion in bone;
faecal fluoride excretion does not compensate for
the impairment of the urinary fluoride elimina-
tion Spencer et al., 1980; Whitford, 1994..
Recently, there has been a growing interest in
using serum ionic fluoride measurements in clini-
cal investigations because it correlates with intake
and fluoride stores Waterhouse et al., 1980..
Furthermore, fluoride treatment is used to in-
crease bone formation and cancellous bone mass
in patients suffering from postmenopausal osteo-
porosis with vertebral fractures. In these patients,
serum fluoride concentration may be a useful
index to detect abnormally high levels or to detect
levels below those considered to be therapeutic,
i.e. 95]190 m grl 5]10 m M. Pak et al., 1995..
Literature references to normal serum and
urine fluoride concentrations, differ widely
between geographical areas. In Spain, no con-
trolled studies have been reported on fluoride
status in relation to age, sex, and renal function.
As a result, we initiated a study to determine the
normal range for serum and urine fluoride con-
centrations of the inhabitants of a Spanish com-
munity with a naturally low fluoride concentra-
tion in their water supply.
To assess fluoride status in relation to renal
function, the results obtained in the control group
were compared with patients with chronic renal
failure in the same community.
2. Experimental
Venous blood samples and 24-h urine collec-
tions were obtained from 250 healthy adult inhab-
itants of Catalonia Spain., to assess the normal
range of fluoride in this population. To obtain
serum fluoride ionic concentration of patients
with renal insufficiency we analysed 150 blood
samples from individuals with chronic renal fail-
ure undergoing regular hemodialysis. From a large
set of volunteers with available occupational,
medical, nutritional, and residential histories, a
group which covered a uniformly wide age range
was selected. Whole blood samples were collected
in capped 10-ml polystyrene tubes Eurotubo W
300903. and kept at 58C until analysis. All volun-
teers were informed of the purpose of the study
and gave consent for the blood extraction.
Fluoride ionic concentration of drinking water
and of dialysis fluids were analysed periodically,
to monitor the water supply in the community
and to evaluate the contribution of dialysis fluids
to fluoride status in patients with renal failure.
Serum, urine, and water ionic fluoride concentra-
tions were determined with a fluoride ion selec-
tive electrode system ORION Research Incor-
porated, Boston, MA. consisting of a model Orion
920 A digital millimeter, a fluoride electrode
9409BN, and a reference electrode 900100. Stan-
dard fluoride solution was supplied by Orion Re-
search Inc. The concentrated stock standard flu-
oride solution was 100 " 0.5 ppm. The fluoride
content was determined by direct calibration. We
had prepared diluted standards freshly each day.
Concentration of resulting working standards
were 25, 100, and 200 m grl. The mean slope
obtained was y59.4" 1 mV. The theoretical slope
range between y58.2 and y60.1 at temperatures
from 20 to 308C. To provide constant background
ionic strength, decomplex the fluoride and adjust
the solution pH, a total ionic strength adjuster
buffer TISAB III 940911., supplied by Orion
Research Inc. was added to each sample of serum
and urine or standard.
Within-day precision, between-day precision,
and the accuracy of the method was confirmed by
the analysis of standard reference material
LYPHOCHECKW 1 supplied by BIO-RAD ECS
Dir., Anahelm, CA Fluoride certified value s
1900 m grl., and by the analysis of two pools of
serum with a mean fluoride concentration of
between 15 m grl and 51 m grl. The coefficient of
 M. Torra et al. r The Science of the Total En ironment 220 (1998) 81]85 83

variation for fluoride between series was 8.1%
and within series 5.3%.
Statistical analyses were performed using re-
gression analysis and Students t-test.
3. Results
the younger population. Fluoride excretion in
urine was higher in the younger subjects than in
the old-age subjects P- 0.05; Table 2..
No age-related differences were observed
among renal patients P) 0.5.. The fluoride ionic
concentration in drinking water and in the dialy-
sis fluids are summarised in Table 3.

The mean "S.D.. and ranges of concentration 4. Discussion

of serum fluoride obtained in patients with chronic
renal failure and in a healthy group, and the
urine fluoride concentration of the normal popu- The references found in the literature in order
lation are summarised in Table 1. to get a range of values for serum and urine
Serum ionic fluoride concentration was higher fluoride concentration vary substantially accord-
in renal patients than in the control group P-
ing to the biological availability of fluoride
0.005.. Parkins et al., 1974; Husdan et al., 1976; Ab-
No sex-related differences were observed in the
denebi et al., 1995; Shiminovitz et al., 1995.. The
control group and renal patient groups P) 0.5..
individuals evaluated in this study are from a
The serum fluoride concentration in the old-age
community with a low fluoride content in the
healthy population was higher Ps 0.05. than in
water system supply - 0.2 ppm. according to the
results shown in Table 3.
Table 1 The concentration observed in our population
Serum and urine ionic fluoride concentration in the normal was similar to published values for other geo-
population and in patients with renal chronic insufficiency graphical areas without a programme of drinking
Serum fluoride Urine fluoride
water fluoridation Husdan et al., 1976.. Although
concentration concentration the limited number of studies published about
m grl. mean " m gr24 h. reference values of serum and urine fluoride con-
S.D. range. range centration render it difficult to compare our re-
Normal population 17.5" 9.7 671 " 373 sults with those obtained in other geographical
1]47. 156]1900. areas.
Renal patients 58 " 31 No data According to the results obtained in this study,
28]185. we suggest a range of reference for serum and

Table 2
Serum and urine fluoride concentration } age-related effects

N Age range Serum flouride Urine flouride

number of subjects Xmin -Xmax . concentration concentration
evaluated. years m grl. m gr24 h.
mean " S.D. range. range

25 10]19 11.3 521

28 20]29 12.8 660
45 30]39 14.7 830
41 40]49 17.6 862
41 50]59 19.6 685
40 60]69 19.7 640
30 70]90 21.3 550
84 M. Torra et al. r The Science of the Total En ironment 220 (1998) 81]85
Table 3
Water fluoride ionic concentration
Fluoride concentration in public Flouride concentration
drinking water m grl. range dialysis fluids m grl.
121.2" 53.6 -5
90]200.
urine ionic fluoride concentration in adult healthy
subjects and in patients with chronic renal insuf-
ficiency undergoing hemodialysis residents in Cat-
alonia. Generally it can be expected that serum
ionic fluoride concentrations in a healthy adult
population without a programme of water fluori-
dation, ranges between 1 and 47 m grl. These
values are clearly lower than values obtained in
patients treated with fluoride as a therapeutic
drug. The normal concentration for urine fluoride
in the healthy group ranges between 156 and
1900 m gr24 h.
The highest serum fluoride value observed in
this population 47 m grl. was in a subject that ate
fluoridated salt and drank carbonated water with
a fluoride content of 7.5 mgrl. This indicates that
even consuming fluoridated substances did not
exceed the threshold of 200 m grl. Current views
suggest that a serum fluoride concentration ) 200
m grl may correlate with an increased risk of
fluoride toxicity.
According to Husdan et al. 1976., our results
showed a statistically significant difference with
age. Lowest values are seen in young adults and
levels progressively increase with age to reach
values of 20 m grl in the seventh to the eight
decades of life. It is accepted that the concentra-
tion of fluoride in serum is regulated by two
mechanisms; skeletal uptake and urinary excre-
tion. Since, in this study, the urine fluoride excre-
tion diminished with age, our data indicate that
decreased kidney function may be responsible for
the increase in serum fluoride after the older
population. Thus, as renal function declines, flu-
oride renal clearance decrease and as a result
serum fluoride levels rise.
Serum fluoride concentrations in patients with
chronic renal failure are higher than in the con-
trols. The results show that uremic patients have
an increased retention of this element, as a con-
sequence of an impairment of renal function.
Considerable discussion has ranged on the is-
sue of whether the addition of fluoride to water
supplies could account for some of the toxic fea-
tures of chronic renal failure. In spite of the
results obtained in this work it is suggested that
there is not a risk of fluorosis in the individuals
evaluated, neither in the healthy subjects nor in
the renal patients } we have found one subject
with a serum fluoride concentration of 183 m grl
near the threshold of toxicity. Since the fluoride
content in the fluid of dialysis show that its con-
tribution to the fluoride status of these patients is
unlikely, it has been recommended that it is im-
portant to control the intake of this element and
the prolonged use of fluoridated dental products
in the subjects with chronic renal insufficiency, to
avoid a risk of fluorosis.
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