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Renal excretion of fluoride during water diuresis and induced urinary ph-changes in man
Toxicology Letters, 18 (1983) 141-146 Elsevier
141
RENAL EXCRETION OF FLUORIDE DURING WATER DIURESIS AND INDUCED URINARY pH-CHANGES IN MAN
(Ions, fluoride; kidney, function, nephrotoxicity, urine flow, urinary pH; pharmacokinetics, renal fluoride clearance; fluoride intoxication)
P-O. JARNBERG”, J. EKSTRANDbB* and M. EHRNEBO’ ‘Department of Anaesthesiology, Karolinska Hospital, Stockholm; bDepartment of Cariology, Karolinska Institute, Box 4064, S-14104 Huddinge, and ‘Galenus AB, Uppsala (Sweden) (Received January 20th, 1983) (Revision received and accepted March 24th, 1983)
SUMMARY Fluoride renal clearance (CF) was studied in young healthy subjects with standard clearance technique following administration of 3 mg F as a 30-min constant infusion. High urinary flow rates were induced and experiments were performed under both urinary alkaline and acidic conditions. The data showed that a high urinary flow resulted in maximum fluoride clearance. High water diuresis may therefore be an important part in the treatment of acute fluoride intoxication.
INTRODUCTION
Inorganic fluoride is cleared from plasma by renal excretion and by uptake into calcified tissues. Renal Cr is correlated to urinary flow [l] and urinary pH [2, 31. Due to the potential toxicity of the fluoride ion to the kidney when present in high concentrations in the plasma the renal handling of fluoride is of particular interest. High plasma levels of fluoride may result from an accidental overdose or from misuse of certain dental preparations [4] and following methoxyflurane anesthesia [5]. The aim of the present study was to investigate the importance of urinary flow rate and urinary pH on renal handling of fluoride following intake of a defined dose of fluoride, administered i.v.
* To whom reprint request and correspondence
should be addressed.
Abbreviations: AUC, area under the curve; CF, clearance of fluoride; GFR, glomerular filtration rate; PAH, para-aminohippuric acid; RPF, renal plasma flow. 0378-4274/83/0000-OOOO/$ 03.00 0 Elsevier Science Publishers
142
MATERIALS AND METHODS
Two healthy volunteers, 1 male aged 24 and 1 female aged 22 took part in the study. The Ethical Committee of Karolinska Hospital had approved the investigation, the scope of which was explained to the volunteers and their informed consent obtained.
0.5 ml/kg b.w. of a solution containing 85 mg/ml of inulin and 30 mglml of PAH in 5.5% glucose was given i.v. as a priming dose. The same solution was then infused at a constant rate of 0.5 ml/min by a motor pump through a peripheral vein. Blood samples were drawn from an i.v. catheter on the contralateral arm. Equilibration time before start of the study was 60 min. Urine was collected through an intravesical catheter. The bladder was emptied by air insufflation, aspiration and suprapubic pressure. ANALYTICAL
METHOBS AND CALCULATIONS
Fluoride concentrations in plasma and urine were measured with a fluoride ion sensitive electrode (96-09, Orion Research, MA, USA). Data concerning the method have been presented elsewhere (6). Inulin was analysed by the method of Heyrovsky [7] and PAH by Brun’s method [8]. GFR was determined by the clearance of inulin and the RPF by the clearance of PAH. All values were corrected to 1.73 m2 body surface area. Fractional excretion of fluoride was calculated by dividing the clearance rate with the corresponding GFR value. This enables direct comparison of clearance rates obtained under different GFRs. The renal CF was calculated by the following equation: cF
=
KJO-t (AUC)o-t
where (X,) is the amount of fluoride excreted in the urine during the time interval O-t and (AUC) is the corresponding area under the plasma concentration time curve. EXPERIMENTAL
PROCEDURE
Each of the two volunteers was studied on two different occasions under alkaline and acidic urinary conditions, respectively. Acidification of the urine was achieved by giving ammonium chloride tablets 1 g every 6 h the day before the examination. During the investigation day, 1 g NH4Cl was given 2 h before the start of the experiment and then repeated 8 times during the experimental period (from approx. 8 a.m.
143
to 3 p.m.). Alkalinization of the urine was achieved by giving 1 g of NaHCOJ tablets at the same time intervals as for the NH&l tablets and by i.v. injection of 500 mg acetazolamide at the beginning of the equilibration period. Blank samples of blood and urine were obtained. Water diuresis was induced by drinking water in an initial amount of 2% of the body weight and subsequently 0.5% of b.w. every 30 min for 3 h. After priming with inulin and PAH the constant infusion was started and allowed to equilibrate for 60 min. Renal function was then measured during two control periods of 20 min and 3 mg fluoride as an NaF solution infused at a constant rate for 30 min. Fluoride excretion and renal function were measured during 3 consecutive 20-min periods. Blood samples were taken at 10, 20, 30, 40 min and at 1, 1.33, 2, 3, 4, 5, 6, 9 h after the start of infusion. All urine was collected during the same period of time.
TABLE
I
URINARY PLASMA
pH AND FLOW, FLOW (ml/min)
2 x 20 min BEFORE
GLOMERULAR
FILTRATION
IN TWO SUBJECTS
(CONTROL
DURING
1 AND 2) AND 3
x
RATE
ACIDIC
(GFR,
ml/min)
AND ALKALINE
20 min (I, II, III) AFTER
AND RENAL CONDITIONS
THE 3 mg F-
INFU-
SION WAS STOPPED Flow (ml/min)
PH Acidic
Alkaline
Acidic
GFR (ml/min)
RPF (ml/min)
Alkaline
Acidic
Acidic
Alkaline
Alkaline
(Subject M.C.) Control
1
5.41
7.29
7.4
14.9
91
91
468
490
Control
2
5.13
7.13
10.4
15.2
92
89
448
484
I
6.10
7.30
11.5
16.0
85
91
481
521
II
6.12
7.31
11.1
15.5
90
94
537
563
III
6.02
7.25
8.5
14.0
77
81
477
518
87
n.s. 89
Mean f
7.3ob
5.99
S.D.
+ 0.48
+ 0.07
9.8 * 1.7
15.1a + 0.7
f
6
+5
f
482
515a
33
* 31
(Subject
A.F.)
Control
1
5.78
7.51
14.6
21.5
90
91
472
502
Control I
2
6.00 5.98
7.52 7.72
15.6
21.4
106
87
580
14.5
16.3
91
100
511
533 583
II
6.15
7.70
13.7
16.5
94
91
502
563
III
5.98
7.50
15.4
11.3
102
79
580
475
5.98 + 0.13
14.8
n.s. 17.4 4.2
98
n.s. 90
529
+ 0.11
6
7
n.s. 531 44
Mean z+ S.D. ‘P
(paired
T-test)
bP
(paired
T-test)
n.s.,
no significant
7.59”
difference
(paired
f
0.7
T-test)
*
49
144
RESULTS
AND
DISCUSSION
The major finding of the present study is that an induced high water diuresis results in rapid fluoride clearance. In the two sets of experiments urinary pH was strongly acidic or alkaline with values ranging from 5.4 to 7.7 and urinary flows ranging from 7.4 to 21.5 ml/min (Table I). The mean filtered fraction of fluoride (WGFR) was 77 f 10% (+: S.D., n = 10, Table II) and was determined at plasma fluoride levels ranging from about 12 PM down to 1 pM, the highest value recorded immediately after the infusion was stopped, There was, however, no significant difference in fractional clearance between the acidic and alkaline experiments. There seems to be only one previously reported study where fractional excretion of fluoride has been examined in healthy subjects [9]. The authors studied renal fluoride clearance at endogenous plasma fluoride levels, around 0.5 PM and found a reabsorbed fraction of filtered fluoride ranging from 10 to 70% and closely correlated to urinary flow. Hence, the results
TABLE
II
FLUORIDE TIONAL
EXCRETION FLUORIDE
RATE
(&min),
CLEARANCE
FOR 30 min 2 x 20 min BEFORE
(Cw‘GFR (CONTROL
FLUORIDE
CLEARANCE,
x 100) Vo FOLLOWING
CF (mllmin) i.v. INFUSION
AND
FRAC-
OF 3 mg F-
1 AND 2) AND 3 x 20 min (I, II, III), AFTER
INFU-
SION WAS STOPPED Fluoride
output
Acidic
(pg/min)
Alkaline
CF (ml/min)
CF/GFR
x 100 “70
Acidic
Alkaline
Acidic
Alkaline
(Subject
M.C.)
Control
1
0.7
1.1
0.6
0.9
71.4
61 57
79
2
55.3 52.4
72.0
ControI I
11.4
12.3
75.2
91.6
88
100
II
7.0
7.2
67.0
67.9
74
72
III
5.0
5.6
57.5
64.0
15
70 n.s. 80
Mean f
+ S.D.
61.5
73.4a
71
9.4
z!z 10.7
& 12
80
f
12
(Subject
A.F.)
Control
I
1.1
1.1
73.4
75.2
82
83
Controi I II
2
1.2
1.0 10.3
82.7
70.2 81.4
78
81 81
III
9.9 8.2 1.9
5.9
72.6 76.2
4.3
Mean z!z S.D. ‘P< 0.05 (paired T-test) n.s., no significant difference
58.9
75 87
65
89.1
58.5
87
74
78.8
n.s. 68.6 & 10.0
+ 7.0
(paired
T-test)
81 -t
4.5
ns. +
77 1.4
145
from the present study confirm the concept that the predominant mechanism of renal excretion of fluoride is glomerular filtration followed by net tubular reabsorption, since no evidence of tubular secretion was seen. In Fig. 1, all fluoride clearance data, determined from 0 to 7 h, are plotted vs. urinary pH and flow. Since the water intake was stopped after 3 h there was a gradual decrease in diuresis from that time onwards. As shown in the lower plot of Fig. 1 there was a significant correlation between clearance and flow (r=0.783, n=28, P= ~0.001). On the other hand, when pH was plotted vs. clearance (upper plot) the values formed two distinct subgroups. There was a significant correlation between pH and clearance at acidic pH (r = 0.685, n = 14, PO.OS). The plasma levels recorded during the experiments were far from those known to be toxic. High doses of fluoride may cause urinary concentration defect, polyuria
SUBJECT
AS.
SVWECT
M.C. ACIDIC
ACIDIC
8.0
:.
ALKALINE
: .
:+
ALKALINE
: X
x
Y
AA .
7.5
xxx
. .
. Y
x
7.0
I,
6.5
2 -3 z
6.0
+ +
5 5.5
+
+/.
8
A
5.0
$ E E
1412-
FL”OR,DE
Fig. 1. Fluoride The correlation
RENAL
CLEARANCE
ml/MIN
renal clearance plotted vs. urinary pH (upper plot) and vs. urinary for the regression line was r=0.783, n=28, P
flow (lower plot).
146
[IO]. The plasma level associated with this defect is reported to be around 50 $vI in man [ll]. In the treatment of acute fluoride intoxication the findings in the present study seem to be of particular interest since the results indicate that high urinary flow rates strongly influence the renal clearance of fluoride. From a toxicological point of view it is evident from Fig. 1 that an alkaline urine in itself is not sufficient to maintain maximum fluoride clearance. This seems to be most effectively achieved at high water diuresis. Thus, it seems logical to recommend that a very high water load should constitute an important part in the treatment in cases of acute fluoride intoxication. ACKNOWLEDGEMENTS
This investigation was supported by grants from the Tore Nilson Fund, The Swedish Patent Revenue Research Fund and The Swedish Medical Research Council, project No. 6002. REFERENCES 1 J. Ekstrand, M. Ehrnebo and L.O. Boreus, Fluoride bioavailability after intravenous and oral administration: Importance of renal clearance and urine flow, Clin. Pharmacol. Ther., 23 (1978) 329-337. 2 G.M. Whitford and D.H. Pashley, The effect of body fluoride distribution, toxicity and renal clearance: Continuing evaluation of the use of fluorides, in E. Johansen, D.R. Taves and T.O. Olsen (Eds.), A.A.A.S. Selected Symposium No. II, Vol. 8, 1979, pp. 187-221. 3 J. Ekstrand, M. Ehrnebo, G.M. Whitford and P.O. Jarnberg, Fluoride pharmacokinetics during acid-base balance changes in man, Eur. J. Clin. Pharmacol., 18 (1980) 189-194. 4 J. Ekstrand, G. Koch, LE. Lindgren and L. Petersson, Pha~acokinetics of fluoride gels in children and adults, Caries Res., 15 (1.981) 213-220. 5 M.J. Cousins and R.I. Maze, Methoxyflurane nephrotoxicity: A study of dose response in man, J. Am. Med. Assoc., 255 (1976) 1611-1615. 6 J. Ekstrand, A micromethod for the determination of fluoride in blood plasma and saliva, Calcif. Tiss. Res., 23 (1977) 225-228. 7 A. Heyrovsky, A new method for the determination of inulin in plasma and urine, Clin. Chim. Acta, 1 (1956) 470-475. 8 C. Brun, A rapid method for the determination of paraaminohippuric acid in kidney function tests, J. Lab. Clin. Med., 37 (1951) 955-961. 9 H. Scheffil and U. Binswanger, Renal handling of fluoride in heaithy man, Renal Physiol., 5 (1982) 192-l%. 10 G.M. Whitford and D.R. Taves, Fluoride-induced diuresis: Renal-tissue solute concentrations, functional, hemodynamic and histological correlates in the rat, Anesthesiology, 39 (1973) 416-427. 11 R. van Dyke, Fluoride from anesthetics and its consequences. In: Continuing evaluation of the use of fluorides, in E. Johansen, D.R. Taves and T.O. Olsen (Eds.), A.A.A.S. Selected Symposium No. II, Vol. 10, Westview Press, Boulder, CO, 1979, pp. 241-249.
141
RENAL EXCRETION OF FLUORIDE DURING WATER DIURESIS AND INDUCED URINARY pH-CHANGES IN MAN
(Ions, fluoride; kidney, function, nephrotoxicity, urine flow, urinary pH; pharmacokinetics, renal fluoride clearance; fluoride intoxication)
P-O. JARNBERG”, J. EKSTRANDbB* and M. EHRNEBO’ ‘Department of Anaesthesiology, Karolinska Hospital, Stockholm; bDepartment of Cariology, Karolinska Institute, Box 4064, S-14104 Huddinge, and ‘Galenus AB, Uppsala (Sweden) (Received January 20th, 1983) (Revision received and accepted March 24th, 1983)
SUMMARY Fluoride renal clearance (CF) was studied in young healthy subjects with standard clearance technique following administration of 3 mg F as a 30-min constant infusion. High urinary flow rates were induced and experiments were performed under both urinary alkaline and acidic conditions. The data showed that a high urinary flow resulted in maximum fluoride clearance. High water diuresis may therefore be an important part in the treatment of acute fluoride intoxication.
INTRODUCTION
Inorganic fluoride is cleared from plasma by renal excretion and by uptake into calcified tissues. Renal Cr is correlated to urinary flow [l] and urinary pH [2, 31. Due to the potential toxicity of the fluoride ion to the kidney when present in high concentrations in the plasma the renal handling of fluoride is of particular interest. High plasma levels of fluoride may result from an accidental overdose or from misuse of certain dental preparations [4] and following methoxyflurane anesthesia [5]. The aim of the present study was to investigate the importance of urinary flow rate and urinary pH on renal handling of fluoride following intake of a defined dose of fluoride, administered i.v.
* To whom reprint request and correspondence
should be addressed.
Abbreviations: AUC, area under the curve; CF, clearance of fluoride; GFR, glomerular filtration rate; PAH, para-aminohippuric acid; RPF, renal plasma flow. 0378-4274/83/0000-OOOO/$ 03.00 0 Elsevier Science Publishers
142
MATERIALS AND METHODS
Two healthy volunteers, 1 male aged 24 and 1 female aged 22 took part in the study. The Ethical Committee of Karolinska Hospital had approved the investigation, the scope of which was explained to the volunteers and their informed consent obtained.
0.5 ml/kg b.w. of a solution containing 85 mg/ml of inulin and 30 mglml of PAH in 5.5% glucose was given i.v. as a priming dose. The same solution was then infused at a constant rate of 0.5 ml/min by a motor pump through a peripheral vein. Blood samples were drawn from an i.v. catheter on the contralateral arm. Equilibration time before start of the study was 60 min. Urine was collected through an intravesical catheter. The bladder was emptied by air insufflation, aspiration and suprapubic pressure. ANALYTICAL
METHOBS AND CALCULATIONS
Fluoride concentrations in plasma and urine were measured with a fluoride ion sensitive electrode (96-09, Orion Research, MA, USA). Data concerning the method have been presented elsewhere (6). Inulin was analysed by the method of Heyrovsky [7] and PAH by Brun’s method [8]. GFR was determined by the clearance of inulin and the RPF by the clearance of PAH. All values were corrected to 1.73 m2 body surface area. Fractional excretion of fluoride was calculated by dividing the clearance rate with the corresponding GFR value. This enables direct comparison of clearance rates obtained under different GFRs. The renal CF was calculated by the following equation: cF
=
KJO-t (AUC)o-t
where (X,) is the amount of fluoride excreted in the urine during the time interval O-t and (AUC) is the corresponding area under the plasma concentration time curve. EXPERIMENTAL
PROCEDURE
Each of the two volunteers was studied on two different occasions under alkaline and acidic urinary conditions, respectively. Acidification of the urine was achieved by giving ammonium chloride tablets 1 g every 6 h the day before the examination. During the investigation day, 1 g NH4Cl was given 2 h before the start of the experiment and then repeated 8 times during the experimental period (from approx. 8 a.m.
143
to 3 p.m.). Alkalinization of the urine was achieved by giving 1 g of NaHCOJ tablets at the same time intervals as for the NH&l tablets and by i.v. injection of 500 mg acetazolamide at the beginning of the equilibration period. Blank samples of blood and urine were obtained. Water diuresis was induced by drinking water in an initial amount of 2% of the body weight and subsequently 0.5% of b.w. every 30 min for 3 h. After priming with inulin and PAH the constant infusion was started and allowed to equilibrate for 60 min. Renal function was then measured during two control periods of 20 min and 3 mg fluoride as an NaF solution infused at a constant rate for 30 min. Fluoride excretion and renal function were measured during 3 consecutive 20-min periods. Blood samples were taken at 10, 20, 30, 40 min and at 1, 1.33, 2, 3, 4, 5, 6, 9 h after the start of infusion. All urine was collected during the same period of time.
TABLE
I
URINARY PLASMA
pH AND FLOW, FLOW (ml/min)
2 x 20 min BEFORE
GLOMERULAR
FILTRATION
IN TWO SUBJECTS
(CONTROL
DURING
1 AND 2) AND 3
x
RATE
ACIDIC
(GFR,
ml/min)
AND ALKALINE
20 min (I, II, III) AFTER
AND RENAL CONDITIONS
THE 3 mg F-
INFU-
SION WAS STOPPED Flow (ml/min)
PH Acidic
Alkaline
Acidic
GFR (ml/min)
RPF (ml/min)
Alkaline
Acidic
Acidic
Alkaline
Alkaline
(Subject M.C.) Control
1
5.41
7.29
7.4
14.9
91
91
468
490
Control
2
5.13
7.13
10.4
15.2
92
89
448
484
I
6.10
7.30
11.5
16.0
85
91
481
521
II
6.12
7.31
11.1
15.5
90
94
537
563
III
6.02
7.25
8.5
14.0
77
81
477
518
87
n.s. 89
Mean f
7.3ob
5.99
S.D.
+ 0.48
+ 0.07
9.8 * 1.7
15.1a + 0.7
f
6
+5
f
482
515a
33
* 31
(Subject
A.F.)
Control
1
5.78
7.51
14.6
21.5
90
91
472
502
Control I
2
6.00 5.98
7.52 7.72
15.6
21.4
106
87
580
14.5
16.3
91
100
511
533 583
II
6.15
7.70
13.7
16.5
94
91
502
563
III
5.98
7.50
15.4
11.3
102
79
580
475
5.98 + 0.13
14.8
n.s. 17.4 4.2
98
n.s. 90
529
+ 0.11
6
7
n.s. 531 44
Mean z+ S.D. ‘P
(paired
T-test)
bP
(paired
T-test)
n.s.,
no significant
7.59”
difference
(paired
f
0.7
T-test)
*
49
144
RESULTS
AND
DISCUSSION
The major finding of the present study is that an induced high water diuresis results in rapid fluoride clearance. In the two sets of experiments urinary pH was strongly acidic or alkaline with values ranging from 5.4 to 7.7 and urinary flows ranging from 7.4 to 21.5 ml/min (Table I). The mean filtered fraction of fluoride (WGFR) was 77 f 10% (+: S.D., n = 10, Table II) and was determined at plasma fluoride levels ranging from about 12 PM down to 1 pM, the highest value recorded immediately after the infusion was stopped, There was, however, no significant difference in fractional clearance between the acidic and alkaline experiments. There seems to be only one previously reported study where fractional excretion of fluoride has been examined in healthy subjects [9]. The authors studied renal fluoride clearance at endogenous plasma fluoride levels, around 0.5 PM and found a reabsorbed fraction of filtered fluoride ranging from 10 to 70% and closely correlated to urinary flow. Hence, the results
TABLE
II
FLUORIDE TIONAL
EXCRETION FLUORIDE
RATE
(&min),
CLEARANCE
FOR 30 min 2 x 20 min BEFORE
(Cw‘GFR (CONTROL
FLUORIDE
CLEARANCE,
x 100) Vo FOLLOWING
CF (mllmin) i.v. INFUSION
AND
FRAC-
OF 3 mg F-
1 AND 2) AND 3 x 20 min (I, II, III), AFTER
INFU-
SION WAS STOPPED Fluoride
output
Acidic
(pg/min)
Alkaline
CF (ml/min)
CF/GFR
x 100 “70
Acidic
Alkaline
Acidic
Alkaline
(Subject
M.C.)
Control
1
0.7
1.1
0.6
0.9
71.4
61 57
79
2
55.3 52.4
72.0
ControI I
11.4
12.3
75.2
91.6
88
100
II
7.0
7.2
67.0
67.9
74
72
III
5.0
5.6
57.5
64.0
15
70 n.s. 80
Mean f
+ S.D.
61.5
73.4a
71
9.4
z!z 10.7
& 12
80
f
12
(Subject
A.F.)
Control
I
1.1
1.1
73.4
75.2
82
83
Controi I II
2
1.2
1.0 10.3
82.7
70.2 81.4
78
81 81
III
9.9 8.2 1.9
5.9
72.6 76.2
4.3
Mean z!z S.D. ‘P< 0.05 (paired T-test) n.s., no significant difference
58.9
75 87
65
89.1
58.5
87
74
78.8
n.s. 68.6 & 10.0
+ 7.0
(paired
T-test)
81 -t
4.5
ns. +
77 1.4
145
from the present study confirm the concept that the predominant mechanism of renal excretion of fluoride is glomerular filtration followed by net tubular reabsorption, since no evidence of tubular secretion was seen. In Fig. 1, all fluoride clearance data, determined from 0 to 7 h, are plotted vs. urinary pH and flow. Since the water intake was stopped after 3 h there was a gradual decrease in diuresis from that time onwards. As shown in the lower plot of Fig. 1 there was a significant correlation between clearance and flow (r=0.783, n=28, P= ~0.001). On the other hand, when pH was plotted vs. clearance (upper plot) the values formed two distinct subgroups. There was a significant correlation between pH and clearance at acidic pH (r = 0.685, n = 14, P
SUBJECT
AS.
SVWECT
M.C. ACIDIC
ACIDIC
8.0
:.
ALKALINE
: .
:+
ALKALINE
: X
x
Y
AA .
7.5
xxx
. .
. Y
x
7.0
I,
6.5
2 -3 z
6.0
+ +
5 5.5
+
+/.
8
A
5.0
$ E E
1412-
FL”OR,DE
Fig. 1. Fluoride The correlation
RENAL
CLEARANCE
ml/MIN
renal clearance plotted vs. urinary pH (upper plot) and vs. urinary for the regression line was r=0.783, n=28, P
flow (lower plot).
146
[IO]. The plasma level associated with this defect is reported to be around 50 $vI in man [ll]. In the treatment of acute fluoride intoxication the findings in the present study seem to be of particular interest since the results indicate that high urinary flow rates strongly influence the renal clearance of fluoride. From a toxicological point of view it is evident from Fig. 1 that an alkaline urine in itself is not sufficient to maintain maximum fluoride clearance. This seems to be most effectively achieved at high water diuresis. Thus, it seems logical to recommend that a very high water load should constitute an important part in the treatment in cases of acute fluoride intoxication. ACKNOWLEDGEMENTS
This investigation was supported by grants from the Tore Nilson Fund, The Swedish Patent Revenue Research Fund and The Swedish Medical Research Council, project No. 6002. REFERENCES 1 J. Ekstrand, M. Ehrnebo and L.O. Boreus, Fluoride bioavailability after intravenous and oral administration: Importance of renal clearance and urine flow, Clin. Pharmacol. Ther., 23 (1978) 329-337. 2 G.M. Whitford and D.H. Pashley, The effect of body fluoride distribution, toxicity and renal clearance: Continuing evaluation of the use of fluorides, in E. Johansen, D.R. Taves and T.O. Olsen (Eds.), A.A.A.S. Selected Symposium No. II, Vol. 8, 1979, pp. 187-221. 3 J. Ekstrand, M. Ehrnebo, G.M. Whitford and P.O. Jarnberg, Fluoride pharmacokinetics during acid-base balance changes in man, Eur. J. Clin. Pharmacol., 18 (1980) 189-194. 4 J. Ekstrand, G. Koch, LE. Lindgren and L. Petersson, Pha~acokinetics of fluoride gels in children and adults, Caries Res., 15 (1.981) 213-220. 5 M.J. Cousins and R.I. Maze, Methoxyflurane nephrotoxicity: A study of dose response in man, J. Am. Med. Assoc., 255 (1976) 1611-1615. 6 J. Ekstrand, A micromethod for the determination of fluoride in blood plasma and saliva, Calcif. Tiss. Res., 23 (1977) 225-228. 7 A. Heyrovsky, A new method for the determination of inulin in plasma and urine, Clin. Chim. Acta, 1 (1956) 470-475. 8 C. Brun, A rapid method for the determination of paraaminohippuric acid in kidney function tests, J. Lab. Clin. Med., 37 (1951) 955-961. 9 H. Scheffil and U. Binswanger, Renal handling of fluoride in heaithy man, Renal Physiol., 5 (1982) 192-l%. 10 G.M. Whitford and D.R. Taves, Fluoride-induced diuresis: Renal-tissue solute concentrations, functional, hemodynamic and histological correlates in the rat, Anesthesiology, 39 (1973) 416-427. 11 R. van Dyke, Fluoride from anesthetics and its consequences. In: Continuing evaluation of the use of fluorides, in E. Johansen, D.R. Taves and T.O. Olsen (Eds.), A.A.A.S. Selected Symposium No. II, Vol. 10, Westview Press, Boulder, CO, 1979, pp. 241-249.