FLUORIDE 31(1)
 1998 pp 33-42		International Society for Fluoride ResearchTable of Contents

FLUORIDE INTAKE, DISTRIBUTION, AND BONE CONTENT IN DIABETIC RATS
CONSUMING FLUORIDATED DRINKING WATER

I Boros, P Keszler, G Csikós and H Kalász*
Budapest, Hungary


SUMMARY: The aim of this study was to determine how metabolic and functional changes in diabetes affect the fluoride intake, distribution, and concentration in bone tissue; and whether alterations in fluoride metabolism in diabetes may influence the severity of the disorder. Two groups of rats received 0 (C) or 10 ppm (F10) fluoride via drinking water for three weeks, ad libitum. Two other groups were treated with a single dose of streptozotocin to induce diabetes, and also received 0 (D) or 10 ppm fluoride (DF10). The quantity of fluoride consumed via water by the DF10 animals was calculated daily and an equal amount was added to the drinking water of another group of non-diabetic animals (FF).

In the diabetic group (DF10) the intake of fluoride gradually increased, hyperglycemia was more severe, and renal hypertrophy was expressed less than in the diabetic group (D) which consumed deionized water. The femoral fluoride concentration increased in proportion to fluoride intake. The high fluoride intake of FF animals resulted, when compared to DF10 ones, in a further increase in the bone tissue and in relatively less elevation in plasma fluoride concentrations. It is concluded that (i) fluoride supply via drinking water may enhance the severity of diabetes in rats, and (ii) due to diabetic metabolic and functional imbalance, the fluoride metabolism may also change.

Key words: Bones, Diabetes, Distribution, Fluoride intake, Renal hypertrophy

Department of Oral Biology, Faculty of Dentistry, and *Institute of Pharmacology, Semmelweis University Medical School, Budapest, Hungary.
Presented at the XXIst Conference of the International Society for Fluoride Research, Budapest, Hungary, August 25-28, 1996.

INTRODUCTION

Animal models of diabetes induced by alloxan or streptozotocin exhibit both renal hypertrophy and hyperplasia.1,2 Presumably, the increased glomerular filtration rate and elevation in glomerular pressure may contribute to diabetic nephropathy,3 which progresses to renal disease. Classic symptoms, e.g. increased thirst, elevations in food consumption and in fluid intake are present both in humans and animals. In addition, uncontrolled diabetes can lead to significant acid-base disturbances (ketoacidosis) as well.4 Diabetic patients and animals may also be at higher risk of dental disorders.5,6 Retardation in salivary flow (xerostomia) is another common symptom of the disorder.7,8

It has often been considered that fluoride at a concentration of 1 ppm in drinking water is beneficial in reducing dental caries in humans under normal conditions and does not cause adverse effects.9 However, more definitive experiments are required to substantiate these claims. It is suggested that diabetes may influence the food and fluid intakes, and may also affect the body fluid and bone tissue fluoride concentrations, as well as the fluoride excretion. Only limited and contradictory data exist to show that fluoride retention and excretion is altered in diabetes.10-14 It was also reported that fluoride metabolism greatly depends on acid-base status, and the clearance of fluoride is directly related to the urinary pH.15,16 Reduction in renal clearance induced by acidosis may be responsible for increased enamel and plasma fluoride concentrations, elevated soft and bone tissue fluoride levels, and also for disturbances in enamel mineralization which are similar in appearance to true fluorosis.16-18

Based on these observations, the objectives of this study were to monitor the daily intake of fluoride, the plasma fluoride levels, and the fluoride concentrations in the femora of rats supplied with fluoride in drinking water for three weeks after a single IV administration of streptozotocin. Parameters were compared to non-diabetic, intact groups with or without fluoride treatment.

MATERIALS AND METHODS

Five groups of female young rats (Charles-River, Wistar, N=8/group) initially weighing 195±14 g were housed in stainless steel individual cages. In two groups, after a 16 h fasting period diabetes was induced by a single iv dose of streptozotocin (Zanosar, Upjohn Co USA, 5 mg/100 g bw). The remaining groups were given citrate buffer (pH 4.5). Rats were provided a pelleted diet with 13 ppm of fluoride (Charles-River Wiga GmbH, Germany) and deionized water (groups C and D) or fluoridated water with 10 ppm fluoride as sodium fluoride (groups F10 and DF10) ad libitum throughout the three-week treatment period. One group of the non-diabetic rats (group FF) was given the same amount of fluoride via drinking water as DF10 animals, but water consumption was not limited. The 24 h intakes of food and water by each of the groups were determined twice a week and daily, respectively. Glucosuria was checked with conventional test strips at 72 h, midterm and on the last day before sacrifice. Euthanasia was performed between 9.00-11.00 am, and animals from the different groups were sacrificed in random order by bleeding through the femoral vein and bilateral pneumothorax under pentobarbital anesthesia preceded by 14 h fasting. Blood, kidneys, and femora were used for analysis. Citrated blood was centrifuged immediately after collection, and plasma was collected for fluoride analysis. For determination of blood glucose levels deproteinized (0.3 M perchloric acid) and centrifuged samples were assayed within 2 h. The femora were removed, cleaned of soft tissues and weighed. After drying at 100°C they were ashed at 500°C for 24 h. Aliquots of pulverized ashed samples were analyzed for fluoride. Plasma samples were analyzed for fluoride by using an ion-specific electrode (Radelkis, Hungary). Plasma fluoride concentration was recorded with the known addition technique19 with some modification for better recovery and accuracy.20 Hard tissue fluoride concentrations were determined according to McCann.21 Blood glucose was detected by the glucose-oxidase method using Boehringer-kit (Test-Combination Glucose, Mannheim GmbH. Diagnostica, Germany). Results were expressed as mean values ± SD. Differences between two means were analyzed for statistical significance using Student's t-test.

RESULTS
Table 1 shows the body weights of different groups at the termination of the experiment. As shown, the fluoride intake via drinking fluid did not influence the body weight of intact, non-diabetic groups F10 and FF. In contrast, the body weight in group D was reduced and a significant weight loss in group DF10 was recorded. It is also illustrated here that the daily water consumption of diabetic groups was progressively elevated.


TABLE 1. Final body weight (g), water consumption (mL/day/rat)
and the control of glucosuria (Gu) at different time intervals
Group  Body wt  Water
cons.
1- 4 days		  Gu  Water
cons.
5-7 day		 Water
cons.
8-14 day		 Water
cons.
5-21 day		 Water
cons.
5-21 day		  Gu 
Non-diabetic
C (non-F water)		 257 ± 14 38 ± 8.0 Ø 36 ± 7.0 34 ± 6.0 Ø 36 ± 9.0 Ø
F10
(F water)		 247 ± 19 30 ± 7.0 Ø 25 ± 6.0 30 ± 6.0 Ø 31 ± 7.0 Ø
Diabetic: D
(non-F water)		 229 ± 12 111 ± 37 + 161 ± 60 172 ± 77 + 188 ± 88 +
DF10
(F water)		 170 ± 18 132 ± 25 + 217 ± 40 228 ± 23 + 256 ± 39 +
Non-diabetic:
FF (= F to DF10)		 248 ± 12 32 ± 4.0 Ø 24 ± 3.0 25 ± 3.0 Ø 24 ± 4.0 Ø
  Mean ± SD. Values between groups are significantly different; (C - DF10: p < 0.001)


The fluoride intake per day per rat at different time intervals is presented in Table 2. During the experimental period the fluoride intake from pellet of the controls showed only small variations. The total daily fluoride intake of group F10 was about twice of that of control. In group D the daily consumption of fluoride was in the same range as in group F10, as a consequence of polyphagia. Diabetic polydipsia occurred in group DF10 and resulted in an excessive fluoride intake with a mean of 3.16±0.43mg fluoride/day/rat at the last week of treatment. In this period the main source of fluoride seemed to be the fluoridated water, i.e., nearly 80% of total daily intake derived from the drinking water. In group FF compared to DF10 a nearly equal quantity of fluoride intake from water could be observed.

TABLE 2. The amount of ingested fluoride (mg F–/day/rat) at different time intervals
Group Ingested F 1-4 days 5-7 days 8-14 days 15-21 days
C (Control) W (from water) Ø Ø Ø Ø
  P (from pellets) 0.30 ± 0.03 0.26 ± 0.07 0.24 ± 0.03 0.25 ± 0.05
  T (Total, W+P) 0.03 ± 0.03 0.26 ± 0.07 0.24 ± 0.03 0.25 ± 0.05
F10 (F water) W 0.30 ± 0.07 0.25 ± 0.06 0.30 ± 0.06 0.31 ± 0.07
  P 0.26 ± 0.03 0.24 ± 0.02 0.23 ± 0.03 0.21 ± 0.05
  T 0.56 ± 0.09 0.49 ± 0.05 0.53 ± 0.05 0.52 ± 0.11
D (non-F water) W Ø Ø Ø Ø
  P 0.42 ± 0.10 0.46 ± 0.10 0.55 ± 0.13 0.57 ± 0.14
  T 0.42 ± 0.10 0.46 ± 0.10 0.55 ± 0.13 0.57 ± 0.14
DF10 (F water) W 1.32 ± 0.23 2.17 ± 0.40 2.28 ± 0.23 2.56 ± 0.39
  P 0.32 ± 0.04 0.56 ± 0.05 0.56 ± 0.12 0.61 ± 0.05
  T 1.64 ± 0.28 2.73 ± 0.45 2.84 ± 0.21 3.16 ± 0.43
FF (= F to DF10) W 1.35 ± 0.13 2.13 ± 0.23 2.53 ± 0.18 2.63 ± 0.23
  P 0.27 ± 0.04 0.28 ± 0.02 0.23 ± 0.02 0.29 ± 0.03
  T 1.62 ± 0.12 2.41 ± 0.17 2.76 ± 0.18 2.92 ± 0.22

The blood glucose fasting concentrations significantly increased in diabetic groups (Figure 1). Hyperglycemia was manifested more in DF10 than in D animals, but fluoride treatment of non-diabetic animals (groups F10 and FF) failed to cause any significant alteration.

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FIGURE 1 The terminal fasting blood glucose concentration (mmol/L)
C
Control		 F10
Non-diabetic
(F water)		 D
Diabetic
(Non-F water)		 DF10
Diabetic
(F water)		 FF
Non-diabetic
(same F as DF10)
Mean ± SD. Values between groups are significantly different;
(C-D: p < 0.001, C-DF10: p < 0.001, D-DF10: p < 0.01)

Significant elevation of kidney wet weight in group D was also recorded (Figure 2). When data of kidney weights of the group DF10 were compared to controls, no significant alteration was detected, despite the fact that hyperglycemia was more remarkable.

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FIGURE 2 Kidney wet weight (mg)
C
Control		 F10
Non-diabetic
(F water)		 D
Diabetic
(Non-F water)		 DF10
Diabetic
(F water)		 FF
Non-diabetic
(same F as DF10)
Mean ± SD. Values between groups are significantly different;
(C-D: p < 0.001, D-DF10: p < 0.001)

Plasma fluoride concentrations (Figure 3) reflected the daily intake of fluoride within groups F10 and D, which increased in accordance with the elevation of daily intake. Comparing the data of the group DF10 to group FF (both of which consumed the highest and nearly equal quantity of fluoride per day), significant differences were found, showing the most prominent elevation in plasma fluoride concentration of the group DF10.

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FIGURE 3 Plasma fluoride concentration (micromol / L)
C
Control		 F10
Non-diabetic
(F water)		 D
Diabetic
(Non-F water)		 DF10
Diabetic
(F water))		 FF
Non-diabetic
(same F as DF10)
Mean ± SD. Values between groups are significantly different;
(C-F10: p < 0.001, C-D: p < 0.001, D-DF10: p < 0.001, DF10-FF: p < 0.001)


The femoral fluoride concentration was significantly increased in group F10 (Figure 4). This value was much higher in groups DF10 and FF with excessive fluoride intakes. When data of the group DF10 were compared to that of FF, considerable difference could be seen; intact non-diabetic animals were capable of storing more fluoride in bone at relatively lower plasma fluoride levels than the corresponding diabetic ones. Because of the weight reductions of ashed samples in the diabetic groups (C: 336 ± 17, F10: 331 ± 23, D: 287 ± 23, DF10: 298 ± 15, FF: 340 ± 23 mg ash), the femoral fluoride was also expressed as total fluoride/sample (Figure 5). The total fluoride in bone tissue was significantly elevated within groups F10, DF10, and FF in accordance with the consumption of fluoridated water. Fluoride content of group D was significantly reduced and it was also evident that total femoral fluoride content of group FF significantly exceeded that calculated for the group DF10.

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FIGURE 4 Femoral fluoride concentration (microgram /g)
C
Control		 F10
Non-diabetic
(F water)		 D
Diabetic
(Non-F water)		 DF10
Diabetic
(F water))		 FF
Non-diabetic
(same F as DF10)
Mean ± SD. Values between groups are significantly different (p < 0.001):
C-F10, C-DF10, C-FF, F10-DF10, F10-FF, D-DF10, D-FF, DF10-FF.

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FIGURE 5 Femoral fluoride content (microgram)
C
Control		 F10
Non-diabetic
(F water)		 D
Diabetic
(Non-F water)		 DF10
Diabetic
(F water)		 FF
Non-diabetic
(same F as DF10)
Mean ± SD. Values between groups are significantly different (p < 0.001) in all relations


DISCUSSION
It is generally agreed that the use of fluoride via drinking water as a cariostatic agent must be well controlled, and all the conditions have to be investigated where adverse effects may be manifested. More studies are needed in diabetes which is one of the most chronic disorders, a condition where the metabolism of fluoride may be altered either by impaired metabolic and/or functional changes. The aim of this study was to observe the effects of fluoride supplied via drinking fluid in a caries preventive dose for rats22 on the kidney weight, the blood glucose level, the plasma and bone fluoride concentrations in young female diabetic rats and to compare their parameters to the intact non-diabetic animals either with different fluoride supplementation or without fluoride in the drinking water.

The dose of streptozotocin applied in this experiment is usually accepted as a dose that induces manifest but not severe diabetes.23,24 Glucosuria reflecting the manifestation of diabetic state appeared in groups D and DF10 after three days of streptozotocin injection and persisted throughout the treatment period. However, it is noteworthy that hyperglycemia was more evident, an increase kidney weight25 failed to be detected, and initial body weight loss was present in DF10 animals. Earlier publications have reported that the more severe the diabetes is, the less is the increment in kidney size. It is concluded that the absence of elevation in kidney mass in group DF10 can probably be considered as a sign of a severe diabetic state.26,27 The data of Table 2 clearly show that DF10 animals supplied with fluoride via drinking water in a cariostatic dose have ingested greater quantities of fluoride from this source than did the F10 ones and they seemed to be at higher risk of severe diabetic hyperglycemia. The mechanism reflecting the high daily intake of fluoride that increased the magnitude of hyperglycemia has not yet been reported. Little is known as to the in vivo effects of large doses of fluoride in diabetes and to its effect on the metabolic processes.28 However, the quantity of fluoride ingested per day by DF10 animals corresponds to the single acute toxic dose published for rats.29 Based on data of acute fluoride poisoning changes in the liver 30 and kidney31 metabolism, stimulation of epinephrine secretion from the adrenal medulla32 or in vitro inhibitiosn of insulin biosynthesis by fluoride33 may be involved.

The plasma fluoride concentrations were elevated in all of the experimental groups in accordance with the increased fluoride intake. It was also evident that despite the nearly equal high quantity of daily fluoride intake, the plasma fluoride level detected in group DF10 significantly exceeded that of group FF. The plasma fluoride concentration within the group DF10 was comparable with the data of rats with incisor fluorosis.34 Dental fluorosis as an adverse effect of fluoride can be related to either a transitory or a continuous elevation in plasma fluoride concentration achieved basically by high intake, but it can also be determined by other factors, e.g. impaired clearance of fluoride from plasma by bones, elimination via urine and by acidotic states.16-18,35-40 In this experiment the femoral fluoride concentration in group F10 was significantly elevated and consumption of fluoridated water and an average of about 0.5 mg daily fluoride intake of these young animals resulted in a 575 ± 38 µg F–/g ashed sample, which is comparable with earlier data.41 Non-diabetic animals that consumed higher amounts of fluoride (group FF) deposited more fluoride in their bones. In contrast, the femoral fluoride concentration as well as the fluoride content of ashed bone tissue of the group DF10 were significantly below that of the group FF. Thus, the bone fluoride uptake in fluoride-treated diabetic rats seems to be greatly reduced at the same high fluoride intake and it cannot only be related to the change in body and femoral weights. At this time there is no clear explanation for the great difference between the plasma and femoral fluoride concentrations of the DF10 and FF animals. The control of fluoride metabolism in diabetes seems to be rather complex and probably different from the non-diabetic condition.

Based on the data presented in this study, it is concluded that the untreated diabetic state may enhance the manifestations of adverse effects of long-term ingestion of fluoride via drinking water in different ways. Studies have detected high concentrations of fluoride in kidney and in urine during exposure,42 and due to elevated body fluid fluoride concentrations a urinary concentrating defect and prolonged decrease in glomerular filtration rate would occur in rats.43,44 In addition, it is also important to note that the urinary pH is a determinant of renal tubular excretion of fluoride.45 At lower urinary pH values the excreted fluoride is only a low percentage of the total filtered amount.16 It is also supposed that water diuresis may influence the fluoride clearance.16,46 Thus, it is reasonable to assume that such mechanisms may be partly responsible for the elevation of plasma fluoride concentration in diabetic-fluoride treated animals and for the changes in bone tissue fluoride concentrations. However, the amount of fluoride present in bone depends on many other factors, e.g. the amount of fluoride ingested, duration of exposure, the continuity of fluoride intake, the bone type, and age.37,38,41,47-50 It is possible that in the diabetic state the changes in
1) the rate and extent of fluoride absorption from the gastrointestinal tract,16,51
2) blood pH and hematocrit,16-18
3) direction of fluoride movement between hydration shells of bones and the extracellular fluid,16 and
4) increments or reduction in release and/or plasma levels of hormones participating in bone metabolism52-56
may interact in this condition. Involvement of impaired hormonal control of bone metabolism in diabetes has further been demonstrated in diabetic rats by an increased serum alkaline phosphatase activity.57

Data presented here call attention to the fact that more studies should be carried out to improve our understanding in this field. In order to learn about a possible hazard of fluoridation in juvenile diabetic individuals, there is a need for more detailed experimental and clinical investigations.

ACKNOWLEDGEMENT
Professor Hársing's contribution and personal inspiration to compile this manuscript before his unexpected death are gratefully acknowledged. This work was supported by grants from the University Research Council of the Semmelweis University Medical School, Hungarian Ministry of Welfare, and Zsigmond Diabetes Foundation, Budapest, Hungary.


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FLUORIDE 31(1)
 1998 pp 33 - 42		International Society for Fluoride Research
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