ToxSci Advance Access originally published online on February 15, 2006
Toxicological Sciences 2006 91(1):49-58; doi:10.1093/toxsci/kfj132
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Toxicokinetics of Tetrabromobisphenol A in Humans and Rats after Oral Administration
Department of Toxicology, University of Würzburg, 97078 Würzburg, Germany
1 To whom correspondence should be addressed at Department of Toxicology, University of Würzburg, Versbacherstrasse 9, 97078 Würzburg, Germany. Fax: +49(0)931 201 48865. E-mail: dekant{at}toxi.uni-wuerzburg.de.
Received December 22, 2005; accepted February 7, 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Tetrabromobisphenol A (TBBPA) is widely used as a flame retardant and is suspected to be stable in the environment with possible widespread human exposures. This study reports the characterization of the toxicokinetics of TBBPA in human subjects and in rats. A single oral dose of 0.1 mg/kg TBBPA was administered to five human subjects. Rats were administered a single oral dose of 300 mg TBBPA/kg body weight. Urine and blood concentrations of TBBPA and its metabolites were determined by LC/MS-MS. TBBPA-glucuronide and TBBPA-sulfate were identified as metabolites of TBBPA in blood and urine of the human subjects and rats. In blood, TBBPA-glucuronide was detected in all human subjects, whereas TBBPA-sulfate was only present in blood from two individuals. Maximum plasma concentrations of TBBPA-glucuronide (16 nmol/l) were obtained within 4 h after administration. In two individuals where TBBPA-sulfate was present in blood, maximum concentrations were obtained at the 4-h sampling point; the concentrations rapidly declined to reach the limit of detection (LOD) after 8 h. Parent TBBPA was not present in detectable concentrations in any of the human plasma samples. TBBPA-glucuronide was slowly eliminated in urine to reach the LOD 124 h after administration. In rats, TBBPA-glucuronide and TBBPA-sulfate were also the major metabolites of TBBPA present in blood; in addition, a diglucuronide of TBBPA, a mixed glucuronide-sulfate conjugate of TBBPA, tribromobisphenol A, and the glucuronide of tribromobisphenol A were also present in low concentrations. TBBPA plasma concentrations peaked at 103 µmol/l 3 h after administration and thereafter declined with a half-life of 13 h; maximal concentrations of TBBPA-glucuronide (25 µmol/l) were also observed 3 h after administration. Peak plasma concentrations of TBBPA-sulfate (694 µmol/l) were reached within 6 h after administration. The obtained results suggest absorption of TBBPA from the gastrointestinal tract and rapid metabolism of the absorbed TBBPA by conjugation resulting in a low systemic bioavailability of TBBPA.
Key Words: TBBPA; toxicokinetics; humans; rats; flame retardants.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Tetrabromobisphenol A (TBBPA) is used in the manufacture of flame-retarded epoxy and polycarbonate resins. When used as flame retardant in epoxy resins, TBBPA is chemically bound to constituents of the resin and will not be released as such. It is also used as an additive flame retardant in mixtures with antimony oxide and may be released from these applications to the environment. The approximate annual production of TBBPA worldwide is 120,000 tons per year. In general, human exposure to TBBPA from all sources except when considering specific occupational exposure scenarios, such as production of flame-retarded resins, is estimated to be low. However, exposures may be increasing due to release of TBBPA during recycling.
In rats, the toxicology of TBBPA has been studied after oral administration for 90 days and toxic effects were not observed in doses up to 1000 mg/kg body weight (bw) (EU-Report, 2005
). Moreover, TBBPA did not induce effects on fertility or reproductive performance at doses up to 1000 mg/kg bw in a two-generation reproductive toxicity study and had no convincing effects on neurodevelopmental end points. TBBPA was not genotoxic in a variety of standard assays (EU-Report, 2005). However, several in vitro studies have suggested a possible interference of TBBPA with thyroid hormone function and a potential of TBBPA as "endocrine disruptor" has been discussed (Birnbaum and Staskal, 2004; Kitamura et al., 2002, 2005; Meerts et al., 2000).
A toxicokinetic study in rats suggested absorption of TBBPA from the gastrointestinal tract after oral administration. TBBPA or its metabolites were detected in bile, to be excreted predominantly in feces. The metabolites identified in bile of rats given TBBPA were TBBPA-glucuronide, a diglucuronide, and a mixed glucuronide-sulfate. However, blood levels of TBBPA and its metabolites were not determined and excretion kinetics was not analyzed in detail (Hakk et al., 2000). Since systemic bioavailability of TBBPA in rats after oral administration is unknown and the disposition of TBBPA in humans has not been reported, this study addresses the toxicokinetics of TBBPA after a single high oral dose in rats and after administration of a low oral dose of TBBPA in humans.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Chemicals.
Purified TBBPA was supplied by the Bromine Science and Environmental Forum (Brussels, Belgium), purity of the material was > 99% as checked by high-performance liquid chromatography (HPLC)-UV. All other reagents and solvents were reagent grade or better and were obtained from several commercial suppliers. TBBPA-glucuronide and TBBPA-sulfate used as calibration standards were isolated from feces of TBBPA-treated rats by Soxhlet extraction and preparative HPLC. Both compounds were characterized by mass spectrometry (Fig. 1).
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Exposure of human subjects to TBBPA.
TBBPA was administered in a gel capsule to three healthy male (A, B, C; Table 1) and two healthy female subjects (D, E; Table 1). All subjects in the study had to refrain from alcoholic beverages and medicinal drugs 2 days before and throughout the experiment. Subjects did not abuse alcohol and were nonsmokers. Subjects were healthy as judged by detailed verbal medical history taken a few days before the start of the study. The study was carried out according to the Declaration of Helsinki, after approval by the Regional Ethical Committee of the University of Wuerzburg, Germany, and after written informed consent was given by the volunteers. Urine samples from the subjects were collected in predetermined intervals (0, 3, 6, 9, 12, 15, 23, 27, 32, 36, 39, 47, 53, 58, 63, 71, 77, 82, 87, 95, 101, 124, and 178 h). After urine volume was determined, two aliquots (50 ml each) were stored at –20°C. Blood samples (2 x 9 ml) were also taken in defined intervals (0, 1, 2, 4, 6, 8, 12, 24, 32, 36, 48, 60, 72, 84, 96, 124, and 178 h) by the supervising physician with heparinized syringes and immediately centrifuged for 15 min at 1560 x g to separate erythrocytes and plasma. Plasma samples were rapidly frozen and stored at –20°C until further sample preparation.
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Animals and treatment.
Six male Sprague-Dawley rats (10 weeks, weight range 265–276 g) were purchased from Harlan-Winkelmann, Borchen, Germany. The animals had free access to water and a standard diet (Altromin) and were kept under standard conditions (12-h day/night cycle, temperature 21–23°C, humidity 45–55%). All animal experimentation was performed under permit from the appropriate authorities in an approved animal care facility of the department. Animals were transferred into metabolic cages (one rat per cage) to collect control urine and control feces for 4 days before treatment. Animals were then administered, by gavage, a single oral dose of TBBPA (300 mg/kg bw), dissolved in corn oil, at 9:00 A.M. A dosing volume of 3.2 ml/kg bw of corn oil was used. Immediately after dosing, animals were transferred back to the metabolic cages, and blood, urine, and feces samples were collected for 100 h after dosing. Collecting vessels for urine were cooled with mixtures of ice and sodium chloride. Urine samples were collected in 6–12-h intervals, and urine volume was recorded, samples were divided into six aliquots, and then stored at –20°C. Feces were collected in 12-h intervals, weighed, and also stored at –20°C. Blood samples (up to 400 µl each) were taken from the tail vein at predetermined time points (3–12-h intervals), and plasma was immediately prepared by centrifugation (2 min at 6500 x g). Plasma samples were also stored at –20°C.
Gas chromatography/mass spectrometry.
GC/MS analysis was performed on an Agilent 6890 series GC-system coupled to an Agilent 5973 mass selective detector (Agilent, Waldbronn, Germany). For chromatographic separations, a DB-1 (No. JW4495511, J & W Scientific Product GmbH, Köln, Germany) fused silica capillary column (40 m, 0.18 mm internal diameter [ID], 0.40 µm film thickness) and helium (average linear velocity: 32 cm/s) as carrier gas were used. Samples were injected in the split mode (split ratio 5:1), and a temperature gradient starting at an oven temperature of 50–220°C with a heating rate of 15°C/min was used for separation. The final temperature was held for 1 min, and the transfer line was kept at 250°C. Injector temperature was 250°C, the electron source of the mass spectrometer was adjusted to 230°C, and solvent delay was 1 min. Full scan mass spectra were recorded from m/z 30 to m/z 400. For analyses, dried feces were weighed, extracted with methanol after lyophilization, and extracts were methylated with diazomethane. The obtained reaction mixture was concentrated under a stream of nitrogen, and the residue was taken up in a small volume of chloroform (100 µl); 1 µl of this solution was injected into the GC.
Sample preparation for LC/MS-MS.
Urine samples of the human subjects (200 µl) were fortified with the internal standards d16-bisphenol A and d14-bisphenol A–glucuronide (Völkel et al., 2005), and 200 µl of methanol was added. Precipitated proteins were removed by centrifugation. From the supernatant, 10 µl was injected into the LC/MS-MS system. Urine samples (100 µl) from rats given TBBPA were also fortified with the internal standards d16-bisphenol A and d14-bisphenol A–glucuronide, and 100 µl of methanol was added to precipitate proteins. From the obtained supernatants, 10 µl was injected into the LC/MS-MS. Quantitation of TBBPA-glucuronide and TBBPA-sulfate in human blood was performed in plasma samples (200 µl) after fortification with the internal standards d16-bisphenol A and d14-bisphenol A–glucuronide and addition of 200 µl of methanol. Samples were vortexed and centrifuged (15,000 x g), and the supernatants were stored on ice. After 30 min, acetonitrile (200 µl) was added and the samples were subjected to a second centrifugation step (15,000 x g). Finally, 10 µl of the supernatants were injected into the LC/MS-MS system. Quantitation of TBBPA, TBBPA-glucuronide, and TBBPA-sulfate in rat plasma was performed in plasma samples (25 µl) after fortification with the internal standards.
Liquid chromatography/mass spectrometry.
TBBPA and its metabolites were quantified by LC/MS-MS using electrospray ionization. Samples were separated on a ReproSil Pur ODS3 HPLC column (4.6 x 150 mm; 5 µm; Maisch, Ammerbuch, Germany) using an Agilent 1100 autosampler and an Agilent 1100 HPLC pump. Separation was performed by gradient elution with water (solvent A) and acetonitrile (solvent B) using the following conditions: 90% A, 10% B, linear increase to 100% B within 15 min, isocratic for 3 min at a flow rate of 500 µl/min. The HPLC system was directly coupled to a triple-stage quadrupole mass spectrometer (API 3000, Applied Biosystems, Darmstadt, Germany). Analytes were detected in the negative-ion mode at a vaporizer temperature of 400°C and a TurboIon Spray voltage of –4.0 kV. Spectral data were recorded with nitrogen as collision gas (collision activated disotiation, CAD = 4) in the product ion scan mode or by multiple reaction monitoring (MRM) mode.
High-performance liquid chromatography–UV.
TBBPA-sulfate and TBBPA-glucuronide were isolated from the methanol extracts of feces from rats after administration of 300 mg/kg bw TBBPA using preparative HPLC. The separation of the feces extracts was performed using a ReproSil Pur ODS III 5 µm column with 250 x 8 mm ID (Maisch) using an HPLC-UV System with an Agilent Series 1050 pump and an Agilent 1040M Series II diode array detector. For separation, a linear gradient from 100% H2O (with 0.1% trifluoroacetic acid) to 100% acetonitrile (with 0.1% trifluoroacetic acid) over 45 min, held for 5 min, with a flow rate of 1 ml/min was applied. The separation was monitored at 233 and 285 nm, and peaks of TBBPA-sulfate and TBBPA-glucuronide were collected and concentrated. Concentrations of TBBPA-sulfate and TBBPA-glucuronide in the samples were determined by HPLC with UV detection using the absorption coefficient for TBBPA.
Quantitation of TBBPA and TBBPA metabolites.
All quantitations are based on the responses of the internal standards and on calibration curves obtained by fortifying blood and urine samples from unexposed individuals with TBBPA, TBBPA-glucuronide, and TBBPA-sulfate. Calibration curves for TBBPA-sulfate (0–3.2 µmol/l) for analysis of human blood samples were recorded in methanolic solutions due to insufficient amount of standard available. The concentration ranges used for calibration curves were from 0 to 9.2 µmol/l (TBBPA), 0 to 20.8 µmol/l (TBBPA-sulfate), and 0 to 0.6 µmol/l (TBBPA-glucuronide) for rat plasma samples. Calibration curves for urine samples of rats were generated by adding 0–29.3 µmol/l TBBPA-sulfate or 0–0.8 µmol/l TBBPA-glucuronide to urine samples obtained from control rats. Calibration curves for human plasma samples were generated by addition of 0–111 nmol/l TBBPA-glucuronide to plasma samples from the human subjects collected before exposure. Calibration curves for human urine samples were generated by addition of 0–0.15 µmol/l TBBPA-glucuronide. Calibration curves were calculated from five to eight data points using Analyst, 1.4.1 (Applied Biosystems). The limit of detection (LOD) for TBBPA, TBBPA-glucuronide, and TBBPA-sulfate in plasma and urine in rats and humans was between 0.3 nmol/l and 4 µmol/l; limits of quantitation were between 1 nmol/l and 16 µmol/l. Details of the MS-acquisition conditions to quantify TBBPA, TBBPA-glucuronide, and TBBPA-sulfate are given in Table 2. Standard deviations (mean ± SD) and elimination half-lives were calculated using Microsoft Excel spreadsheets.
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RESULTS |
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Metabolite Identification
To characterize major metabolites of TBBPA, compounds with UV spectra similar to those of TBBPA in feces of TBBPA-treated rats (300 mg/kg bw) were isolated by preparative HPLC and characterized by mass spectrometry. Two compounds with UV spectra identical to those of TBBPA were present, and the isolated compounds showed electrospray mass spectra with m/z 619 (79Br) and with m/z 715 (79Br). Both compounds also showed the characteristic isotope patterns indicative for four bromine atoms in the molecules (Fig. 1). Collision-induced fragmentation showed a typical loss of 80 atomic mass units (amu) for one metabolite and 176 amu for the other metabolite, which are characteristic for sulfate and glucuronide conjugates, respectively (Völkel et al., 2002
, 2005; Ye et al., 2005). Thus, the two metabolites were identified as TBBPA-sulfate (MW 619, 79Br) and as TBBPA-glucuronide (MW 715, 79Br). To search for further minor metabolites of TBBPA, feces were extracted with methanol after lyophilization, and extracts were methylated with diazomethane. Samples were analyzed by GC/MS searching for peaks exhibiting the characteristic bromine isotope patterns in the mass spectra. Besides an intensive signal for the dimethyl ether of TBBPA, a second bromine-containing compound was present in low concentrations. The mass spectra of this compound (Fig. 2) showed two major fragments at m/z 476 (79Br) and m/z 461 (79Br) with the typical isotope patterns indicative of three bromine atoms in the molecule. The fragmentation suggests that the metabolite represents tribromobisphenol A (expected molecular ion of the derived monomethyl ether is MW 476, calculated for 79Br), and the major fragment at m/z 461 (79Br) is formed by loss of a methyl group, a typical fragment of phenyl ethers. To detect further minor metabolites of TBBPA in plasma, urine, and feces, samples were also analyzed by LC/MS-MS using acquisition conditions integrating calculated molecular ions and expected fragmentations for conceivable conjugates (diglucuronides, disulfates, mixed conjugates) of TBBPA and tribromobisphenol A and its glucuronide (Table 3). Using these conditions, the presence of several conjugates in blood samples of rats given 300 mg/kg bw of TBBPA was indicated. The concentrations of these metabolites were too low to permit a more detailed characterization due to the much lower sensitivity of the product ion scan mode in comparison to MRM acquisition (Table 3). At early time points after TBBPA administration, low concentrations of TBBPA-diglucuronide, a TBBPA-glucuronide-sulfate, tribromobisphenol A, and tribromobisphenol A–glucuronide were present. In samples from the human study using a much lower TBBPA dose, none of these metabolites of TBBPA were present in concentrations above the LOD. Since reference compounds for the minor metabolites were not available and the concentrations of these metabolites were suggested to be very low in blood and urine of rats administered a dose of 300 mg/kg of TBBPA, these compounds were not quantified.
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Toxicokinetics of TBBPA in Rats
After administration of a single oral dose of 300 mg/kg to rats, peak concentration of 103 µmol/l of TBBPA was achieved in plasma within 3 h after oral administration of TBBPA. TBBPA concentrations then declined following first-order kinetics with an elimination half-life of 13 h (Fig. 3A). Only traces of TBBPA in concentrations close to the LOD were present in the collected urine samples. Fecal excretion of unchanged TBBPA was the major excretory pathway for TBBPA in rats and > 80% of the given dose was excreted in feces with a peak excretion at 24 h after TBBPA administration (data not shown). Feces also contained TBBPA-glucuronide, which was not quantified since the extraction procedure resulted in some decomposition of TBBPA-glucuronide to TBBPA. In addition, small signals indicative for the presence of TBBPA-sulfate, tribromobisphenol A, and, at some time points, the glucuronide of tribromobisphenol A, were also observed in feces samples from TBBPA-exposed rats. TBBPA-sulfate was the major metabolite detected in plasma and reached peak concentrations of approximately 700 µmol/l at the 6-h time point after oral administration (Fig. 3B). TBBPA-glucuronide was also present in rat blood in quantifiable concentrations and reached peak concentrations of approximately 25 µmol/l at the 3-h sampling point (Fig. 3C). TBBPA-sulfate was also the major metabolite of TBBPA excreted in rat urine (Table 4), and approximately 800 nmol was excreted in the urine samples collected between 12 and 24 h after oral exposure of rats to TBBPA (Fig. 4A). TBBPA-glucuronide was also present in urine samples in low, but quantifiable, concentrations. Excretion peaked at 1 nmol between 6 and 12 h after oral administration of TBBPA (Fig. 4B).
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Toxicokinetics of TBBPA in Human Subjects after Oral Administration
Human subjects received a single oral dose of 0.1 mg TBBPA/kg bw at 8:00 A.M. After administration, blood and urine samples were collected at predetermined time points for analysis of TBBPA, TBBPA-glucuronide, and TBBPA-sulfate. The concentrations of unchanged TBBPA were below the LOD in all blood and urine samples collected. TBBPA-glucuronide was present in detectable concentrations in all blood samples taken up to 72 h after administration of TBBPA. Peak concentrations of 16 nmol/l were reached between 2 and 6 h after TBBPA administration (Fig. 5). TBBPA-glucuronide concentrations then slowly decreased over time. TBBPA-sulfate was only detected in blood samples from two of the male subjects at one or two of the early blood sampling time points. In these individuals, concentrations of approximately 20 µmol/l of TBBPA-sulfate were present 4–6 h after oral administration of TBBPA (data not shown). In all urine samples collected from the human subjects administered this low dose of TBBPA, TBBPA-glucuronide was present in quantifiable concentrations and total excretion over the given time frame peaked at approximately 4 nmol at 63 h. Only a minor part (< 0.1% of dose) of the administered dose of TBBPA was recovered in urine as TBBPA-glucuronide. No specific pattern of excretion kinetics of TBBPA-glucuronide was evident (Fig. 6), and excretion occurred with multiple peaks. TBBPA-sulfate was below the LOD in all urine samples collected during the course of the study from the human subjects.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Despite generally low concentrations of TBBPA in the average diet in Europe, the major pathway of exposure to TBBPA in the general population is expected to be through diet (EU-Report, 2005
). The results of this study show that oral exposure of both humans and rodents to TBBPA results in low blood levels of TBBPA and its metabolites, and only a minor part of the given dose of TBBPA is excreted in urine due to the high molecular weight of TBBPA metabolites. In rats, at the high dose used, a significant part (> 80%) of the applied dose is recovered as TBBPA in feces. In addition to TBBPA metabolites attributed to conjugation reactions of TBBPA with glucuronic acid and with sulfate, tribromobisphenol A is formed most likely by a reduction of TBBPA by the intestinal microflora. Some brominated diphenyl ethers are also efficiently reduced by bacteria both in rodents and in the environment (EU-Report, 2002a,b, 2003, 2005). Tribromobisphenol A thus formed may undergo conjugation with glucuronic acid. The minor metabolites of TBBPA observed in rats may also be formed in humans, however, due to the much lower doses applied, and compared to the small contribution of these compounds to the metabolism of TBBPA observed in rats, the concentrations of these minor metabolites, as expected, were below the LODs. In rats, the major metabolite of TBBPA in blood and urine was TBBPA-sulfate. Most likely, this polar and water-soluble metabolite is eliminated from liver to blood and then translocated to the kidney. In humans, TBBPA-sulfate was produced in sufficient amounts to be detected in plasma of two of the five individuals, suggesting a possible role of a polymorphic sulfotransferase catalyzing this reaction. A number of sulfotransferases are polymorphic in humans (Gamage et al., 2006; Glatt and Meinl, 2004). To establish the role of polymorphic sulfotransferases in the metabolism of TBBPA in humans, further experiments will be required. TBBPA-sulfate formed in the blood of two individuals was not detected in the urine, suggesting further metabolism of the TBBPA-sulfate or excretion in feces. The detection of TBBPA metabolites excreted in feces and the recovery of TBBPA-glucuronide and TBBPA-sulfate in bile of rats (approximately 50% of a dose of 2 mg/kg bw recovered in bile within 24 h after administration) (Hakk et al., 2000) suggests that TBBPA is absorbed to a considerable extent from the gastrointestinal tract. In the liver, TBBPA, like other bisphenols, is efficiently metabolized by glucuronyl- and sulfotransferases (Pritchett et al., 2002; Völkel et al., 2002; Ye et al., 2005). Both in humans and in rodents, the molecular weights of the formed TBBPA conjugates are above the thresholds for biliary elimination in rats (MW > 300) and in humans (MW > 450) and are thus preferentially translocated into bile. Most likely, the majority of both conjugates is excreted in bile, and TBBPA conjugates undergo enterohepatic recirculation. A major role of enterohepatic circulation is indicated by the slow elimination of TBBPA-glucuronide in urine in both humans and rats. Only a very small part of the TBBPA-glucuronide and the TBBPA-sulfate formed may be transferred to the systemic circulation and may finally reach the kidney to be excreted.
The effective elimination of TBBPA conjugates in bile and enterohepatic circulation results in a low systemic bioavailability of TBBPA in humans. When compared to a similar oral dose (0.64 mg/kg bw) of bisphenol A, maximal blood levels of bisphenol A–glucuronide of 800 nmol/l were reached within 80 min and the applied dose was completely recovered in urine as bisphenol A–glucuronide (Völkel et al., 2002). The molecular weight of bisphenol A–glucuronide is below the threshold for biliary elimination in humans, and thus bisphenol A–glucuronide presumably formed in the liver is quantitatively released into blood and then to the kidney. In contrast, maximum concentrations of TBBPA-glucuronide reached only 16 nmol/l in blood. Enterohepatic circulation, and, presumably, fecal excretion efficiently reduced elimination of TBBPA conjugates in urine.
The low systemic bioavailability of TBBPA resulting in low blood levels of TBBPA and its metabolites, even after administration of a high dose to rats, explains the very low potential of TBBPA for toxic effects in rodents. In most repeat-dose studies on toxic effects of TBBPA, no observed effect levels were very high (> 1000 mg/kg bw) and the adversity of the effects seen is questionable (EU-Report, 2005). For example, no effects of TBBPA administration on the thyroid were observed despite a high potential of TBBPA to interfere with thyroid hormone function as observed in in vitro studies (Kitamura et al., 2005). In summary, the obtained data suggest a very low systemic bioavailability of TBBPA after oral administration due to efficient hepatic metabolism and biliary excretion of conjugates formed.
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NOTES |
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The authors certify that all research involving human subjects was done under full compliance with all government policies and the Helsinki Declaration.
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ACKNOWLEDGMENTS |
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This work was supported by the Fifth RTD Framework Programme of the European Union in context of the FIRE-project, Project No. QLK4-CT-2002-00596. We thank U. Tatsch, H. Keim-Heusler, and N. Bittner for excellent technical assistance. Mass spectrometry instrumentation was purchased with support from the Deutsche Forschungsgemeinschaft.
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