Battelle Pacific Northwest National Laboratory, Sequim, Washington 98352
2 To whom correspondence should be addressed at Battelle MSL, 1529 West Sequim Bay Road, Sequim, WA 98382. Fax: (360) 681-3681. E-mail: ir_schultz{at}pnl.gov.
Received August 24, 2004; accepted December 22, 2004
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ABSTRACT |
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Key Words: drinking water disinfection byproducts; halogenated acetic acids; bromo; chloro; bromochloro; chlorobromo acetic acids; oral bioavailability; toxicokinetics; pharmacokinetics; human risk assessment.
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INTRODUCTION |
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Trichloro- and dichloroacetic acid (TCAA, DCAA) have been the two most extensively studied HAAs due to their carcinogenic activity (Bull, 1992). Studies on the brominated and mixed bromochloro HAAs are limited. A preliminary study has found dibromo (DBAA), bromochloro (BCAA) and bromodichloroacetic acid (BDCAA) to be hepatocarcinogic in mice (Stauber et al., 1995
), which is consistent with findings that bromine substitution increases mutagenicity and reproductive and developmental toxicity of HAAs (Austin et al., 1996
; Giller et al., 1997
; Hunter et al., 1996
; Linder et al., 1994
, 1997
; Parrish et al., 1996
). Carcinogenic effects of HAAs are typically observed at high concentrations (e.g. 0.55 g/l) producing blood and tissue levels exceeding 750 nmol/ml (Schultz et al., 2002
). The high exposure levels in experimental animals compared to that identified in municipal drinking water supplies has made it difficult to estimate the health risk of individual HAAs. When results of animal studies are extrapolated downward to human exposure levels, the risk estimates can be several orders of magnitude below those calculated from epidemiology studies (Bull and Kopfler, 1991
; Morris et al., 1992
; Murphy, 1993
). Drinking water contains a mixture of HAAs whose constituents may vary due to many factors, the most important of which is the type of disinfection method used (Symanski et al., 2004
; Weinberg et al., 2002
). The chemical nature of HAAs present in finished water is significantly different between municipal sites; therefore toxicological studies of individual HAAs cannot entirely answer questions regarding the health risks of various disinfection by-products.
To increase the relevance of toxicokinetic studies of HAAs to future risk assessments, it will be important to assess the effects of HAA mixtures at lower doses than used in past studies. Determination of individual components from a mixture of HAAs can be technically challenging due to the potential for metabolism or degradation into other HAAs (Schultz et al., 1999). It is now well established that GSTzeta (GSTZ1-1) is the primary enzyme in the di-HAAs metabolism pathway (Anderson et al., 1999
) and may be involved in the metabolism of brominated tri-HAAs (Austin and Bull, 1997
; Saghir and Schultz, 2001
). An important aspect of the GSTzeta pathway in both human and rodents is its susceptibility to inactivation by exposure to DCAA and other chloro-bromo di-HAAs (Tzeng et al., 2000
). Our previous studies have shown that reduction in GSTzeta activity due to prior DCAA exposure profoundly reduces the clearance of chloro- and bromochloro di-HAAs (Saghir and Schultz, 2002
; Schultz and Sylvestor, 2001
). In rodents, the reduction in clearance is caused by depletion of hepatic immunoreactive GSTzeta protein levels (Anderson et al., 1999
; Schultz et al., 2002
) as opposed to altered gene expression (Ammini et al., 2004
). Depletion of hepatic GSTzeta protein levels can exceed 90%, making DCAA pretreatment a convenient method for modulating di-HAA metabolism and studying the impact of GSTzeta depletion on the toxicokinetics of HAA mixtures.
This study was designed to characterize the toxicokinetics and disposition of two HAAs mixtures after intravenous (iv) and oral dosing to male Fischer 344 rats with and without GSTzeta depletion. Mixture-1 contained molar equivalent concentrations of monobromo-, dichloro-, chlorodibromo-, and tribromo- acetic acids (MBAA, DCAA, CDBAA, and TBAA) and Mixture-2 consisted of bromochloro-, dibromo-, trichloro-, and bromodichloro- acetic acids (BCAA, DBAA, TCAA, and BDCAA). The selection of mixture components was based on the desire to include both di-HAAs and tri-HAAs, which are found together in drinking water, and to avoid combining tri-HAAs with di-HAAs that may be metabolites or degradation products. For example, DCAA, BCAA, and DBAA are potential metabolites of BDCAA, CDBAA, and TBAA, respectively (Austin and Bull, 1997; Saghir and Schultz, 2001
) and thus were not included in the same mixture to avoid confounding the results.
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MATERIALS AND METHODS |
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Animal care.
Animal care and treatment was conducted in accordance with established Institutional Animal Care and Use Committee guidelines of the Pacific Northwest National Laboratory. Twenty male Fischer-344 rats, 810 weeks old (236 ± 41 g) fitted with a jugular vein cannula were obtained from Taconic Laboratories (Germantown, NY) and housed individually in polycarbonate cages with wood-chip bedding and stainless steel wire tops under standard conditions (22°C, 4060% relative humidity, 12-h ligh/dark cycle) and acclimated for a minimum of 48 h prior to use in experiments. Initially, rats were provided with deionized water and Purina rat chow ad libitum. Deionized water was used throughout the experiments to avoid unwanted exposure to HAAs, which can be present in drinking water sources that may cause some inactivation of GSTzeta. Animals were fasted overnight prior to dosing.
Time-course plasma levels of HAAs.
Naïve animals (46 per dose group) were dosed (iv or gavage) with Mixture-1 or Mixture-2. The dose of each HAA to the animals was 25 µmol/kg, and the volume administered was 1 ml/kg. Selection of the dose was based on the results of an earlier study (Saghir and Schultz, 2002) showing the toxicokinetics of DCAA becomes linear at doses between 10 and 40 µmol/kg, which we assumed is true for other HAAs. After the initial dosing experiment, the rats were provided with 0.2 g/l DCAA in drinking water for 7 days to deplete/inactivate GSTzeta activity to
10% of the naïve rats (Saghir and Schultz, 2002
; Schultz and Sylvester, 2001
). The GSTzeta-depleted rats were then switched to non-DCAA fortified water overnight (16 h) to allow for the washout of residual DCAA from the animal. This short period allows only minimal resynthesis of GSTzeta (Saghir and Schultz, 2002
). GSTzeta-depleted rats (46 per dose group) were then dosed (iv or gavage) with Mixture-1 or Mixture-2 as described above.
Serial blood samples (0.0750.125 ml) were collected, and plasma was obtained, mixed with 0.2 ml of ice-cold 0.1 M sodium acetate buffer (pH 5.2), and frozen at 20°C until analyses as described earlier (Saghir and Schultz, 2002). Actual plasma volumes were determined gravimetrically using tared vials and assuming plasma density of 1.0. A typical blood sampling schedule after iv dosing was 0, 3, 6, 10, 15, 20, 30, 45 min, and variously thereafter up to 36 h depending on the mixture and pretreatment. For orally dosed animals, an additional 1-min sample was obtained. Urine was collected for 24 h on dry-ice cooled traps only from naïve rats dosed iv with Mixture-1 or Mixture-2; weighed aliquots were mixed with sodium acetate buffer and stored at 80°C until analyses.
Tissue distribution.
Twenty-seven noncannulated male F344 rats (190 ± 21 g) were purchased from Charles River Laboratories (Raleigh, NC) and pretreated with DCAA as described previously to deplete GSTzeta activity. After overnight washout, rats were dosed with Mixture-1 or Mixture-2 (25 µmol/kg each HAA) via gavage and euthanized at 0.25, 0.5, 1, 2 h (both mixtures), and 4 h (Mixture-1 only) after dosing. After euthanasia, the GI tract was removed, and the contents extruded, and the stomach, small intestine (equally separated into upper and lower sections), large intestine, lung, liver, kidney, and testis procured and stored at 80°C until analysis.
Extraction of HAAs from tissues.
Weighed (200 mg) aliquots of tissues in duplicate were placed in 7-ml glass vials and an internal standard (1 µg monochloro- or fluorochloro- acetic acid) was added followed by addition of 1 ml of sodium acetate buffer. Tissues were homogenized using Omni-mixer® (Sorvall, Norwalk, CT) until completely ground. Tissue homogenates were acidified with 0.1 ml of 50% H2SO4 and extracted in MTBE by rigorous vortexing followed by centrifugation at 2000 rpm for 30 min. Aliquots of MTBE were analyzed for HAAs as described below.
Chemical analysis.
Acetate buffer fortified samples (blood, plasma, and urine) were added with 0.2 mg internal standard (monochloro- or fluorochloro- acetic acid), acidified by adding 0.025 ml of 50% sulfuric acid, and extracted in various volumes (0.21.0 ml) of MTBE depending on the sampling time. The extracted free acids from blood, plasma, urine, and tissues were converted to the methyl ester by adding 0.010.02 ml of ethereal diazomethane as described by Schultz et al. (1999). Samples were then analyzed by GC-ECD (Hewlett-Packard 5890-Series II, Avondale, PA).
Kinetic analysis.
The toxicokinetic analysis was similar to previous studies (Saghir and Schultz, 2002; Schultz and Sylvestor, 2001
; Schultz et al., 1999
) and is briefly summarized. Individual plasma concentration-time profiles for each HAA were analyzed by noncompartmental methods to obtain estimates of area under the plasma concentration curve (AUC0
), total body clearance (Clb), apparent volume of distribution at steady-state (Vss), and the mean residence time (MRT) using WinNonlin (Pharsight Corp., Cary, NC). The plasma elimination half-life (t
) was calculated as ß/0.693, with ß being the slope of the terminal phase of the profiles determined by linear regression. The oral absorption rate (Ka), was estimated by fitting the plasma profiles to a one-compartment clearance-volume toxicokinetic model as described previously (Schultz et al., 1999
). The oral bioavailability was calculated from the ratios of the average values for AUC0
for the oral and iv doses.
Statistical analysis.
Significant differences between toxicokinetic parameter estimates of the naïve and GSTzeta-depleted groups for HAAs of each mixture were assessed by using Student's t-test. A p value 0.05 was considered statistically significant.
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RESULTS |
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Time-Course Distribution of HAAs in Mixture-1 to GI Tract of GSTzeta-Depleted Rats
Figure 2 shows the concentration-time profiles of DCAA, CDBAA, and TBAA in stomach, upper and lower small intestine and colon (GI-1, GI-2, GI-3) tissues at selected times after oral dosing. Levels of all HAAs in Mixture-1 were similar in the stomach during the course of the study (within 4 h after dosing). However, levels of DCAA in GI-1 and GI-2 tissues were much higher than CDBAA and TBAA. Higher levels of DCAA in the upper portion of the GI tissues appears to coincide with the occurrence of secondary plasma peaks.
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Oral administration.
All HAAs in Mixture-2 were rapidly absorbed after oral dosing and were detected in plasma within 1 min after dosing (Figs. 3C and 3D). The decline in the plasma concentration of the tri-HAAs was similar to the pattern observed after iv dosing. Also consistent with the iv dosing results was the significantly higher rate that orally absorbed TCAA was eliminated by the GSTzeta-depleted rats (see t values, Table 2). Elimination of ()BCAA was much faster than (+)BCAA, similar to what was seen after iv administration. Elimination of all three di-HAAs ([]BCAA, [+]BCAA, and DBAA) was rapid, both in the naïve and GSTzeta-depleted rats, although GSTzeta depletion resulted in a statistically significant increase in the AUC and decrease in the Clb of all di-HAAs (Figs. 3C and 3D, Table 2). Most other kinetic parameters remained unaffected due to GSTzeta depletion.
The elimination profiles of Mixture-2 tri-HAAs (TCAA and BDCAA) appeared monoexponential in both naïve and GSTzeta-depleted rats, consistent with the results of Mixture-1. The di-HAAs in Mixture-2 did not consistently exhibit the complex plasma concentration-time profile as was seen for DCAA, although the terminal portion of the profiles remained unusually high when compared to results from iv studies (see Fig. 3 inserts). The oral bioavailability of TCAA was 82%, both in naïve and GSTzeta-depleted rats, BDCAA bioavailability was 94% in naïve and 79% in GSTzeta-depleted rats (Table 2). With regard to the di-HAAs, estimation of oral bioavailability was problematic due to the greater AUC observed after oral dosing (Table 2).
Time-Course Tissue Distribution of HAAs in Mixture-1 and Mixture-2 in GSTzeta-Depleted Rats
Concentration of HAAs in most tissues was close to plasma levels, suggesting a rapid equilibration of HAAs between plasma and tissues (Fig. 4). There was no apparent difference between the time-course concentration pattern of CDBAA and TBAA of Mixture-1 in any of the tissues examined, with the exception that CDBAA was slightly higher in lung between 1 and 2 h when compared to TBAA. The peak concentration of Mixture-1 tri-HAAs occurred between 1 and 2 h post-dosing in all tissues, coinciding with peak plasma levels. In contrast, DCAA levels were much higher than TBAA and CDBAA in the liver and testis (Fig. 4). Tissue levels of DCAA remained high and nearly constant during the later sampling times (14 h), which is also consistent with the complex plasma profile after oral dosing and high residual levels in the GI tract (Figs. 1C, 1D, 2, and 4). All Mixture-2 di-HAA tissue levels peaked within 1 h (Fig. 4). Tissue levels of TCAA and BDCAA were similar to the levels observed for CDBAA and TBAA and were consistent with their plasma profiles (Figs. 3D and 4).
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DISCUSSION |
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To assess whether the clearance of HAAs was altered when administered as a mixture, a comparison of values obtained from past studies of individual HAAs with those obtained in the present study is presented in Table 3. At an individual dose of 500 µmol/kg, the Vss of chlorinated and brominated di- and tri- HAAs ranged from 380 to 782 ml/kg (Schultz et al., 1999; Schultz and Sylvester, 2001
). These values are consistent with those observed in the present study and from other studies of lower doses of selected HAAs, which are summarized in Table 3. In contrast, the Clb of all tri-HAAs was reduced when administered as a mixture compared to values obtained from individual doses ranging from 25 to 500 µmol/kg (Table 3). A similar trend appears to occur for di-HAAs, although comparisons for (, +)BCAA and DBAA are limited to 500 µmol/kg doses, which are likely to saturate the GSTzeta metabolism pathway and lower clearance (Saghir and Schultz, 2002
). The latter phenomenon was particularly pronounced for DBAA. The mixture-associated reduction in clearance for the tri-HAAs was surprising, as Clb would be expected to be higher at a dose of 25 µmol/kg (or the tri-HAA mixture cumulative dose of 50 µmol/kg). However, when administered as a mixture of 25 µmol/kg, the clearance of all tri-HAAs was up to 5-fold lower than when they were administered individually at doses of 25, 100, or 500 µmol/kg (Table 3), causing a corresponding increase in elimination t
. These results are indicative of competitive elimination pathway(s) for both tri- and di-HAAs causing lower than expected dose proportionality in Clb of HAAs when exposed as a mixture.
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In contrast to tri-HAA metabolism, recent studies in rats have established that chloro- and bromo- di-HAAs are primarily metabolized by GSTzeta with little or no cytochrome P450dependent metabolism (Saghir and Schultz, 2001; Tong et al., 1998
). Thus, competitive elimination interactions among di-HAAs would be expected to occur through the GSTzeta and are likely to be additive. Our results indicate some saturation of this pathway occurred at the mixture dose of 25 µmol/kg (100 µmol/kg total HAA dose). This would be consistent with previous findings that DCAA elimination is linear up to 40 µmol/kg doses in naïve rats (Saghir and Schultz, 2002
). Also consistent with earlier reports is the lack of significant urinary elimination of di-HAAs. In the present study, urinary elimination of all di-HAAs remained <0.1% of the dose in both of the mixtures and had no apparent affect of the presence of other di- and tri-HAAs in the mixtures.
The data presented in this study suggest that there is an interaction for the elimination of tri-HAAs when given in a mixture, and is likely due to competitive effects on metabolism. From the DCAA data, it appears that tri-HAAs can compete with di-HAAs for GSTzeta at the equimolar doses used in this study. It was unclear however, whether tri-HAAs compete with the other di-HAAs ([, +]BCAA and DBAA) for GSTzeta, due to the lack of data for these individual di-HAAs at the equimolar doses used in this study.
With regard to oral absorption, the primary effect of the mixture appears to be enhancement of the unusual absorption pattern of HAAs, especially di-HAAs. This was most evident from the complex absorption phenomena of DCAA and the persistently high plasma levels if other di-HAAs for extended time periods (Figs. 1 and 3). This phenomenon has been reported previously, however at much higher doses (Saghir and Schultz, 2002; Schultz et al., 1999
). The mechanism for this phenomenon is unclear, but does not involve biliary secretion (Schultz et al., 1999
). Our results suggest DCAA and perhaps other di-HAAs are retained in the upper portions of the small intestine to a greater extent than tri-HAAs (Fig. 2). This may be a significant finding, as increased risk of intestinal cancer has been associated with drinking water disinfection byproducts (Doyle et al., 1997
; Flaten, 1992
). Thus, future studies of HAAs should also focus on intestinal absorption to better understand the physiological processes that regulate HAA uptake.
In conclusion, the systemic exposure of HAAs from consumption of drinking water is dynamic and affected by a number of underlying conditions including the contents of HAA mixtures and their interactions during the process of absorption from the GI tract and elimination. Results of this study when compared with previous toxicokinetic studies (Saghir and Schultz, 2002; Schultz et al., 1999
; Schultz and Sylvester, 2001
) of individual HAAs suggest the toxicokinetics can be substantially altered when administered as a mixture. The metabolism of tri-HAAs appears to be likely affected due to competition for the enzymes responsible for their metabolism. For di-HAAs, the total dose is also important, as clearance is dose dependent, presumably due to competitive inhibition of GSTzeta. Thus, when considering HAAs dosimetry, importance should be placed on the components of the mixture (concentration of tri- and di-HAAs), total dose, and prior exposure history to di-HAAs.
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Supplementary Data |
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NOTES |
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ACKNOWLEDGMENTS |
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This work was presented in part at the 41st annual meeting of the Society of Toxicology at Nashville, TN.
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