* Division of Nephrology and Hypertension and
Division of Epidemiology, Department of Medicine, University of California, Irvine, California 92697;
Colorado State University, Fort Collins, Colorado 80532;
§ U.S. Borax, Inc., Valencia, California 91355; and
¶ Murray & Associates, San Jose, California 95138
Received October 20, 2000; accepted January 5, 2001
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ABSTRACT |
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Key Words: boric acid; boron; pregnancy; rats; clearance; half-life..
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INTRODUCTION |
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Boric acid has been shown to cause developmental toxicity in laboratory animals, and the pregnant rat is the most sensitive organism (Becking and Chen, 1998; Dourson et al., 1998
; ECETOC, 1995
; IEHR, 1995
; IPCS, 1998
; Murray, 1995
, 1996
; Price et al., 1996
; WHO, 1998
). In order to extrapolate these results to humans, it is important to consider pharmacokinetic and pharmacodynamic differences between pregnant rats and pregnant women (Dourson et al., 1998
; Murray, 1996
).
The pharmacokinetics of boric acid is similar in rats and humans with respect to absorption, distribution, and metabolism (Dourson et al., 1998; Murray, 1998
). Boric acid is readily absorbed orally in both rats and humans (Jansen et al., 1984a
; Job, 1973
; Ku et al., 1991
; Schou et al., 1984
). At least 92% of a single oral dose of boric acid was recovered in the urine of human volunteers (Jansen et al., 1984a
; Schou et al., 1984
). The substance distributes throughout body water in rats and humans, and there is no evidence of accumulation (Alexander et al, 1951
; Culver et al., 1994
; Forbes et al., 1954
; Forbes and Mitchell, 1957
; Jansen et al, 1984b
; Ku et al., 1991
, 1993
; Treinen and Chapin, 1991
; Ward, 1987
). Boric acid does not appear to be metabolized in either animals or humans most likely due to the excessive energy required to break the boron-oxygen bond (Emsley, 1989
; IPCS, 1998
; Woods, 1994
).
Renal clearance is expected to be the primary determinant of interspecies variation in the pharmacokinetics of boric acid, since more than 94% of a dose of boric acid is excreted unchanged in the urine (Jansen et al., 1984a,b
). Because glomerular filtration rates, as a function of body mass, are generally higher in rats than humans, interspecies differences in the renal clearance of boric acid might be expected. Renal clearance of sodium tetraborate, a chemical which rapidly converts to boric acid in dilute aqueous solutions at physiological pH, was recently reported in a study of male rats (Usuda et al., 1998
), but no studies of the renal clearance of boron compounds in female rats were found in the scientific literature. Since developmental toxicity in rats was the most sensitive endpoint of toxicity in a large series of toxicology studies of boric acid (reviewed in IPCS, 1998; WHO, 1998), it was particularly important to evaluate renal clearance in pregnant rats.
The purpose of the present study was (1) to determine the renal clearance of boron in female rats (nonpregnant and pregnant) given a single dose of 0.3, 3, or 30 mg/kg of boric acid by gavage, and (2) to determine the plasma half-life of boron in pregnant and nonpregnant rats given 30 mg/kg of boric acid by gavage.
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MATERIALS AND METHODS |
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The animals were maintained in a temperature-controlled room at 22 ± 2°C and 5060% relative humidity, with a light cycle of 12-h/day from 8:00 A.M. to 8:00 P.M. Animals were maintained in stainless steel cages, and potential sources of boron (B) contamination (e.g., glassware) were minimized. No glass or ceramics (e.g., bottles, syringes, diet containers) were used during the study in order to eliminate these potentially significant sources of boron.2
Drinking water.
Ultrapure water was supplied to the animals ad libitum, throughout the study, to minimize drinking water as a source of boron. The water was treated in a recirculating system at the University of California, Irvine (UCI). Water treatment included deionization (mixed bed, 8 meg OHM, U.S. Filter), reverse osmosis (UCI-built system), activated charcoal filtering, water softening (Culligan), and uv-light treatment. Boron was not detected in the drinking water (limit of detection was 1 µg/l).
Diets.
In order to conduct this study, it was necessary to maintain all rats on a special low-boron diet, since commercial rat chows contain boron in concentrations sufficiently high (equivalent to a dose of 57 mg BA/kg/day) to interfere with the measurement of boric acid renal clearance following gavage administration. All nonpregnant and pregnant female rats were maintained on a boron-supplemented casein-based rat diet supplied by DYETS, Inc. in Bethlehem, PA. A "low-boron," casein-based diet was developed by DYETS for use in boron nutritional essentiality studies. The low-boron diet (1.4 mg BA/kg of diet, or 0.25 mg B/kg of diet) was supplemented with boric acid (3.5 mg BA/kg of diet, or 0.64 mg B/kg diet), and the rats were given the supplemented diet starting 7 days prior to gavage administration of boric acid. The purpose of the 7-day initial dietary period was to achieve steady state conditions for rats given a diet comparable to that ingested by humans in terms of boron intake. The supplemented diet, containing about 1525 times less boron than Purina rat chow, was designed to deliver a dose of approximately 0.3 mg/kg/day of boric acid (equivalent to 0.05 mg B/kg/day).3
On the afternoon of the day before gavage administration of boric acid, all pregnant and nonpregnant rats were switched to the "low-boron," casein-based diet (no boric acid supplementation), containing 1.4 mg BA/kg diet (equivalent to 0.25 mg B/kg of diet). The purpose of the low-boron diet was to minimize any cross-contamination of the urine with boron in the diet and to minimize the dietary contribution of boron on the day of gavage administration of boric acid.
Dosing.
High-purity (>99%) boric acid (Special Quality Granular) was supplied by U.S. Borax, Valencia, CA. After a week on the casein-based diets, to reduce background levels of boron in the rats, groups of pregnant (GD 16) and nonpregnant rats were given a single oral dose of 0.3, 3.0, or 30 mg BA/kg body weight by gavage. When expressed in terms of boron, the dose levels were 0.052, 0.52, and 5.2 mg B/kg, respectively. The vehicle was ultrapure water, and the volume was 10 ml/kg of body weight. The lowest dose (i.e., 0.3-mg BA/kg/day) was comparable to the high end of the normal range of human dietary intake of boron (Meacham and Hunt, 1998; Rainey and Nyquist, 1998
). The mean dietary intake among women over 19 years of age in the U.S. was estimated to be 0.89 ± 0.57 mg B/day, equivalent to 5.1 ± 3.2 mg BA/day or 0.08 ± 0.05 mg BA/kg/day for a 60-kg woman (Rainey and Nyquist, 1998
). The highest dose (i.e., 30-mg BA/kg/day) was approximately half the no-observed-adverse-effect-level (NOAEL) of 55-mg BA/kg/day in the rat developmental toxicity study of Price et al. (1996).
Observations.
Body weights of all rats were determined daily for 7 days prior to and on the day of gavage administration, in both the clearance and half-life studies. Food and water consumption were measured throughout the study.
Plasma samples in the clearance study.
Two blood samples were drawn from each rat in the clearance study, the first by periorbital puncture at 3 h after gavage administration, a time intentionally chosen to miss the peak blood level of boron. This was based on the results of a pharmacokinetic study in male rats of sodium tetraborate, a chemical that rapidly converts to boric acid at physiological pH (Usuda et al., 1998). The second blood sample was collected 12 h after the initial one (15 h after gavage administration) by cardiac puncture, and the animals were sacrificed after the second sample was drawn.
Urine collections in the clearance study.
A 12-h urine sample was collected from each rat in the clearance study. Rats were placed in plastic metabolic cages immediately after the first blood sample was taken, after being coerced to urinate by handling and gently applying pressure to the abdomen over the bladder, to void before the start of the 12-h collection period. Urine was collected during the 12-h period between the first and second blood samples. The urine sample was collected in a plastic container kept on ice, and at the end of the 12-h collection period, the voided urine sample and the urine remaining in the bladder (removed by a plastic syringe) were pooled in a plastic container and frozen at 20°C. The method for calculating clearance is described by Perrier and Gibaldi (1974). Body surface area was calculated using the method described by Calder (1984).
Plasma half-life.
A separate experiment was performed to estimate the plasma half-life of boron and to confirm that the shape of the blood curve is linear during the renal clearance portion of this study. For this experiment, 6 nonpregnant and 6 pregnant rats were treated exactly as the rats in the renal clearance portion of this study. After a week on the casein-based diets, as described earlier, all rats received a single gavage dose of 30-mg BA/kg (on GD 16 for pregnant rats). This dose was the same as the high-dose level in the renal clearance portion of the study, and it was selected for the plasma half-life portion because, if any dose level were to exhibit a nonlinear plasma curve, it would most likely be the high dose. If the curve for the high dose was linear, one could assume that the curve obtained with the lower doses would also be linear. Six blood samples were drawn from each animal during a 12-h period starting 3 h after gavage administration. The blood samples were taken by periorbital puncture after light anesthesia at 3, 5, 7, 9, 12, and 15 h post-dosing. The potential effect of light anesthesia on enzyme activity was not a concern, since boric acid is not metabolized. The volume of each blood sample was approximately 0.25 ml.
Analytical procedures.
All plasma and urine samples were analyzed for boron using inductively coupled plasma mass spectroscopy (ICPMS). The boron analyses were performed by West Coast Analytical Services (WCAS), as described by Pahl et al., 2001. All urine samples and all final plasma samples were analyzed for creatinine and urea, using a quantitative, colorimetric method (Sigma Diagnostics, St. Louis, MO). Creatinine clearance was used as a measure of glomerular filtration rate (GFR) while urea clearance was used as a partially reabsorbable solute.
Statistical analyses.
Renal clearance was expressed as mean ± SD. Two-way analysis of variance (ANOVA) and multiple-range test (Student-Newman-Keuls method) were used, as appropriate. For all statistical analyses, p values less than 0.05 were considered statistically significant.
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RESULTS |
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Body weight and food and water consumption were not significantly affected by boric acid administration or by the diets given during the week prior to boric acid administration. As expected, pregnant rats gained more weight than nonpregnant rats, and therefore, pregnant rats weighed more than the nonpregnant rats on the day that boric acid was given by gavage. The mean body weights of the nonpregnant rats at the low, mid, and high doses were 249 ± 25 (standard deviation), 251 ± 19, and 251 ± 14 g, respectively; the respective values among pregnant rats were 301 ± 28, 298 ± 26, and 309 ± 23 g.
Table 1 summarizes the plasma concentrations of boron at 3 and 15 h after gavage administration of boric acid, as well as the area-under-the-curve (AUC). The plasma levels and the AUC were determined for each individual animal. The plasma boron concentrations in the clearance study were similar to those observed in the plasma half-life study. Mean plasma levels of boron and AUC were slightly higher in pregnant rats when compared to nonpregnant rats given the same dose levels of boric acid. This difference was statistically significant at the high dose only.
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DISCUSSION |
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To our knowledge, ours is the first study of boric acid clearance in nonpregnant and pregnant female rats. Most clearance studies are performed in male animals. In the case of boric acid, it was considered important to study clearance in pregnant rats, since developmental toxicity in the offspring of pregnant rats is the most sensitive endpoint of toxicity. It is presumed that the developmental toxicity observed in rats is a function of blood levels of boric acid that are delivered via the placenta to the developing embryo and fetus. Because blood serves as the vehicle for delivery, this study characterized the blood levels and rate of elimination from blood in pregnant rats, which could potentially differ from that observed in male and nonpregnant female rats.
In this study, pregnancy did not significantly alter the renal clearance of boron in rats given boric acid; however, there was a consistent trend for clearance to be higher in pregnant than nonpregnant rats. Creatinine was used as the classical standard for estimating glomerular filtration rate (GFR). In comparison, urea was selected as an example of a substance that undergoes tubular reabsorption, and as expected, the clearance rate of urea was less than that of creatinine in this study. Similarly, boron clearance was less than creatinine clearance, suggesting tubular reabsorption.
Boron is an essential element for plants, and boron has recently been shown to be essential for reproduction and early development in lower vertebrates (Fort et al., 1998; Rowe et al., 1998
). There is a growing body of evidence that boron may be essential in mammals, as well (Hunt, 1994
; Hunt et al., 1994
; Hunt and Stoecker, 1996
; Lanoue et al., 1998
; Mertz, 1993
; Nielsen, 1991
, 1992
, 1994
). Tubular reabsorption of boric acid may reflect a mechanism to conserve boron, and these results may be evidence for homeostatic control, which is common for essential elements (Sutherland et al., 1997).
Interestingly, an apparent difference in the fractional excretion of boron (boron clearance/creatinine clearance) was observed between nonpregnant and pregnant rats at all dose levels. The fractional excretion of boron was approximately 65% and 80% in nonpregnant and pregnant rats, respectively. Similarly, fractional excretion of urea was lower in nonpregnant than pregnant rats, and tubular reabsorption of urea is known to be diminished during pregnancy. The reason for this difference is not readily apparent, but it may be due to the extracellular volume expansion and renal vasodilation, which are known features of normal pregnancy. These physiological changes can inhibit tubular reabsorption of solutes by raising peritubular capillary and interstitial hydrostatic pressures and by lowering the peritubular capillary colloid oncotic pressure (dilutional hypoalbuminemia) collectively referred to as the Third Factor or physical factors. It should be noted that the above factors can modify tubular transport of potentially reabsorbable (e.g., boron, urea, etc) but not unabsorbable (e.g., creatinine, inulin) solutes. Thus pregnancy-induced enhancement of physical factors preferentially raises boron clearance relative to creatinine clearance leading to elevated fractional boron clearance.
Mean plasma boron expressed as area-under-the-curve and mean total urinary excretion of boron during the 12-h collection period were significantly greater in pregnant than nonpregnant rats at the high-dose level. In fact, the data showed trends to higher values, though they were not statistically significant, for both quantities in pregnant, compared to nonpregnant rats for most of the doses. A possible explanation for this behavior, consistent with change in body composition during pregnancy, is that the relative volume of distribution of hydrophilic compounds, including boric acid, decrease slightly in pregnancy as the hydrophilic compound is poorly sequestered in growing fat compartments. A compartmental PK study to assess the volume of distribution following an intravenous dose of boric acid in pregnant and nonpregnant rats would resolve this question. It is interesting to note that the volume of distribution of another hydrophilic substance, ethylenediamine (EDA), declined with age in male and female rats (Yang et al., 1984). On the basis of liters per kilogram, the volume of distribution of older rats was approximately one-fourth to one-half of that of younger rats. The authors attributed the alterations in volume of distribution to the changing fat composition of the rats and the low affinity of EDA for fat. A similar, though less dramatic, difference would be expected during pregnancy.
It is noteworthy that there was less variance in the measurements of boron clearance compared to the variance in measurements of creatinine and urea clearance. This difference may be explained by differences in the methodology for estimating clearance. In the case of creatinine and urea, a single blood sample was analyzed, and, as is the norm, it was assumed that plasma creatinine and urea concentrations are relatively constant. In comparison, 2 plasma samples were measured for boron, and the clearance rate was calculated on the basis of the AUC, using the actual half-life data for boron from this study.
The boron clearance values from our study compare favorably to clearance values reported in male rats given sodium tetraborate, which rapidly converts in the bloodstream to boric acid. Usuda et al. (1998) reported sodium tetraborate clearance in male rats of 40.4±3.2 ml/min/1.73m2. When the results of our study are expressed in terms of body surface area, the boron clearance rate in nonpregnant and pregnant rats ranged from 29.0±5.7 to 31.0±4.5 and from 32.2 ± 5.1 to 35.6 ± 5.7 ml/min/1.73m2, respectively. In an older study in male mice, Farr and Konikowski (1963) reported a boric acid clearance rate of 40 ml/min/1.73m2.
In order to conduct this study, it was necessary to identify a "low-boron" diet, because typical rat chow provides a daily dose of boron equivalent to the mid-dose in the current study. Even the low-boron diet used for this study contributed to the overall dose of boron, and these amounts were not included in the nominal dose levels. The nominal dose levels of boric acid administered by gavage in this study were 0.3, 3.0, and 30 mg BA/kg. However, when the dietary contribution from the low-boron diet was included in the dose (as boric acid equivalents), the actual dose levels were approximately 0.4, 3.1, and 30.1 mg BA/kg/day. At the low dose, the diet contributed another 27% and 33% to the overall dose given to nonpregnant and pregnant rats, respectively. At the mid- and high-dose levels, the dietary contribution of boric acid to the overall dose was about 3% and 0.3%, respectively.
Because several international organizations have attempted to employ data-derived uncertainty factors to this compound, we developed quantitative measures of boron's clearance in pregnant and nonpregnant humans and rats. The results of our companion study of boron renal clearance in women are published separately in this journal (Pahl et al., 2001). When clearance was expressed on the basis of body weight (ml/min/kg), pregnant rats cleared boron at a rate 3.1-fold greater than pregnant women. In comparison, when clearance was expressed on the basis of body-surface area (ml/min/1.73m2), the clearance rate of boron in pregnant rats was only 0.56 that observed in pregnant women. Dietary boron, calculated as boric acid equivalents per kg body weight per day, ingested by pregnant women was 3 times less than the low-dose level of boric acid given to pregnant rats.
A comparison of the rate of renal clearance of creatinine was also made between pregnant rats and pregnant women, based on the results of the recent boron clearance studies at our facility. The interspecies difference in creatinine clearance between pregnant rats and women was similar to that observed with boron clearance. When creatinine clearance was expressed on the basis of body weight (ml/min/kg), pregnant rats cleared creatinine at a rate 2.6-fold greater than pregnant women. In comparison, when clearance was expressed on the basis of body-surface area (ml/min/1.73m2), the clearance rate of creatinine in pregnant rats was only 0.37 the rate observed in pregnant women. The reason for apparent divergence in comparative clearances given per body weights versus surface areas between the 2 species is related to the high surface-to-mass ratio in the rats as compared to the humans.
In conclusion, the plasma half-life of boron was approximately 3 h in both nonpregnant and pregnant rats given a single dose of 30-mg BA/kg by gavage. The rate of boron clearance was 67% higher (not statistically significant) in pregnant compared to nonpregnant rats. Within the range of boric acid doses tested, boron clearance was independent of dose in nonpregnant and pregnant rats. The rate of boron clearance was less than that of creatinine, suggesting tubular reabsorption of boric acid.
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ACKNOWLEDGMENTS |
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NOTES |
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2 In this report, the term "boron" is used in a generic sense and only refers to the boron content of boric acid and inorganic borates, since elemental boron does not exist in a free state in nature. For purposes of comparison, the amount of boric acid (BA) may be converted to boron (B) equivalents based on the fraction of boron on a molecular weight basis as follows: amount of boric acid x 0.175 = equivalent amount of boron. To convert from boron (B) to boric acid (BA) multiply by 5.72.
3 An unpublished study by Dr. Carl Keen, U.C., Davis, has shown boron concentrations in blood and soft tissues are effectively reduced in rats after only a few days on a reduced boron diet; additional days on a reduced boron diet have little additional effect on blood boron concentrations.
4 Sodium tetraborate rapidly converts to boric acid in dilute aqueous solutions at physiological pH.
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