ToxSci Advance Access originally published online on January 11, 2006
Toxicological Sciences 2006 90(2):309-316; doi:10.1093/toxsci/kfj098
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Disposition of BDE 47 in Developing Mice
* UNC Curriculum in Toxicology; U.S. Environmental Protection Agency, Office of Research and Development, NHEERL, ETD, 109 TW Alexander Dr., Research Triangle Park, North Carolina 27711
1 To whom correspondence should be addressed at 3420 Executive Center Drive, Suite 114, Austin, TX 78731. Fax: 512-338-9011. E-mail: dstaskal{at}chemrisk.com.
Received October 30, 2005; accepted January 9, 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX AREFERENCES |
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Despite its minor contribution to global polybrominated diphenyl ether (PBDE) production and usage, 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) is the dominant congener found in most biotic samples in North America. The majority of public health concern has focused on potential hazardous effects resulting from exposure of infants and young children to BDE 47 because of previous studies reporting adverse developmental effects in rodent studies, in combination with human exposure estimates suggesting that nursing infants and young children have the highest exposure to BDE 47. This study was designed with two objectives: (1) to investigate the disposition of BDE 47 in infantile mice reported to be susceptible to BDE 47 and (2) to investigate the disposition and excretion of BDE 47 at various developmental stages in an attempt to further identify the mechanism responsible for rapid urinary excretion. The disposition of 14C-BDE 47 was monitored in C57BL/6 mice following a single oral dose of BDE 47 (1 mg/kg) at different stages of development. The results show that the toxicokinetics of BDE 47 are different in developing mice than in adult mice; whereas disposition patterns are similar, concentrations of BDE 47 are higher in pups because they have a reduced capacity to excrete BDE 47. These differences lead to higher concentrations of BDE 47 at target tissues during critical windows of development.
Key Words: BFR; PBDE; BDE 47; toxicokinetics.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX AREFERENCES |
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Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants (BFRs) used in a wide variety of highly flammable consumer applications which range from electronics and plastics to textiles and foam padding. Each of the commercial PBDE products is a mixture of brominated diphenyl ether congeners, their usage dependent on the final consumer application (BSEF, 2004
). Reports of PBDEs in the environment, in human tissue and milk samples, and in wildlife have increased concern for this class of chemicals in the past decade. Public health concern has focused primarily on potential hazardous effects resulting from exposure of infants and young children. These concerns are founded on two lines of evidence from rodent studies: first, PBDEs are developmental reproductive toxins and neurotoxicants, as well as endocrine disruptors (Birnbaum and Staskal, 2004; Eriksson et al., 2001; Stoker et al., 2004), and second, exposure estimates suggest that nursing infants and young children have the highest exposure to these chemicals (Jones-Otazo et al., 2005; Schecter et al., 2003; Stapleton et al., 2004).
Of the 209 potential PBDE congeners, varying in number and positioning of bromines, 2,2',4,4'-tetrabromodiphenyl ether (BDE 47; Fig. 1) is the dominant congener found in most environmental and human samples (Hites, 2004). BDE 47 has previously demonstrated developmental neurotoxicity (DNT) in mice following a single exposure (Eriksson et al., 2001). In the present study, mice exposed on postnatal day 10 (PND 10) to BDE 47 (0.7 or 10.5 mg/kg) exhibited permanent aberrations in spontaneous behavior and habituation capacity, behaviors that continued to worsen over time. Several other BDE congeners have also been shown to cause DNT in a variety of exposure scenarios (Branchi et al., 2003; Kuriyama et al., 2005; Viberg et al., 2003).
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A number of studies suggest that BDE 47 also has the potential to disrupt endocrine homeostasis and reproductive function during development. Specifically, BDE 47 exhibits anti-androgenic characteristics by inhibiting the binding of androgens to the androgen receptor in vitro (Stoker et al., 2005
). BDE 47 can affect thyroid hormones in vivo by decreasing circulating levels of free and total thyroxine following a 14-day (18 mg/kg/day) exposure in mice (Hallgren et al., 2001). Because of the mounting evidence for toxicity in combination with persistent exposure, it is important to understand the toxicokinetics of BDE 47 in potentially susceptible populations (i.e., young, developing animals) in addition to behavior in adults.
Three studies are available that characterize the toxicokinetic parameters of acute exposure to BDE 47 in adults (Darnerud and Risberg, 2005; Orn and Klasson-Wehler, 1998; Staskal et al., 2005); however, no toxicokinetic studies of BDE 47 during development are available. Previous toxicokinetic studies in adult rodents demonstrate that mice have a different pattern of excretion than rats (Orn and Klasson-Wehler, 1998). Following a single exposure, mice undergo a biphasic excretion of BDE 47 in which a large percentage of the chemical is excreted within the first days, primarily in the urine (Staskal et al., 2005). In contrast, rats excreted less than 1% of the administered dose over 5 days following a single exposure (Orn and Klasson-Wehler, 1998). Because BDE 47 is not highly metabolized in either species, we hypothesize that active transport may be responsible for the high renal clearance of this compound (Staskal et al., 2005).
The present study was designed with two objectives: (1) to investigate the disposition of BDE 47 in 10-day-old mice reported to be susceptible to BDE 47 and (2) to investigate the disposition and excretion of BDE 47 at various developmental stages in an attempt to further identify the mechanism responsible for its rapid urinary excretion. In the first part of the study, C57BL/6 mice were exposed to a single oral dose of BDE 47 (1 mg/kg) on postnatal day (PND) 10. Tissue disposition was monitored at multiple time points over a period of 10 days post-exposure, and tissue concentrations were compared to previously reported adult tissue concentrations according to the same exposure scenario (Staskal et al., 2005). Excretion was estimated using whole-body analyses of residual radioactivity. The second part of the study focused on 24-h disposition and excretion patterns in animals of increasing age (PND 22, 28, and 40). These ages were chosen based on information available regarding the ontogeny of renal transporters in mice (Cheng et al., 2005; Maher et al., 2005). Tissue and urine concentrations of BDE 47 at 24 h post-exposure were also compared to previously reported toxicokinetic data in mice following a parallel exposure paradigm.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX AREFERENCES |
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Chemicals.
Uniformly labeled [14C]2,2',4,4'-tetrabromodiphenyl ether (BDE 47) (26.7 mCi/mmol) was a generous gift from Great Lakes Chemical Corporation. It had a radio-purity of >97% as determined by reverse-phase high-pressure liquid chromatography (HPLC) (System Gold, Beckman Instruments, Inc., Fullerton, CA) using an Ultrasphere ODS column (5 µm, 25 x 4.6 cm, Beckman Instruments, Inc., Fullerton, CA) and a gradient elution of 50:50 methanol:water over 30 min to 100% methanol at a flow rate of 1.5 ml/min. A radioactive flow detector (Beckman Model 171, Beckman Instruments, Fullerton, CA), used with 1 ml/min Flo Scint III (Packard Instrument Co., Meriden, CT) was used to monitor radioactivity. All other chemicals used were of the highest grade commercially available.
Animals.
Time-pregnant C57BL/6 mice were obtained from Charles River Breeding Laboratories (Raleigh, NC). C57BL/6 mice were chosen for consistency with previous studies (Staskal et al., 2005). Animals were maintained on a 12-h light/dark cycle (AAALAC accredited facility) at ambient temperature (22°C) and relative humidity (55 ± 5%), and were provided with Purina 5008 Rodent Chow (Ralston Purina Co., St. Louis, MO) and tap water ad libitum. Dams were housed individually. Litters were weaned to six pups/litter at birth. Both male and female mice were used because previous studies have shown no effect of sex on the toxicokinetics of BDE 47 (Orn and Klasson-Wehler, 1998; Staskal et al., 2005). The study was broken into two sections (PND 10-Time Course and One-Day Disposition Study), each section was performed independently.
PND 10-Time Course Study.
All pups (6 litters, 6 pups/litter) were dosed on the same day (PND 10) and marked for identification. One pup from each litter received a control dose of corn oil for health surveillance records and the remaining five received a dose containing BDE 47. Pups remained with the litter until one BDE 47-dosed animal was selected randomly at each time point (3 h, 8 h, 1, 5, or 10 days, n = 5/time point, each from separate litters). Blood, brain, adipose, liver, kidney, skin, muscle, stomach, and lung were collected at sacrifice. Because of the animal housing requirements and the young age of the pups, we were not able to use metabolism cages; therefore, urine and feces samples were not collected from 10-day-old mice.
One-Day Disposition Study.
Pups were weaned on PND 21 and housed with littermates (eight litters used in study) of the same sex (maximum of 5/cage). Five female and five male mice were selected randomly from different litters for each time point (PND 22, 28, and 40, n = 10/time point) and administered a single oral dose of BDE 47. Each mouse was housed individually following dosing. Tissues (blood, brain, adipose, liver, kidney, skin, muscle, and lung) were collected 24 h after BDE 47 administration. At time of sacrifice, available urine was collected on a sterile parafilm surface and pooled by weight (up to approximately 0.1 g/sample). Next, 20 ml of scintillation fluid was directly added to the urine and analyzed for radioactivity by liquid scintillation spectrometry. Final urinary analyses were based on n = 2, 2, and 4 (pooled samples) corresponding to PND 22, 28, and 40, respectively, and were compared to urine collected from adult animals from previous studies (Staskal et al., 2005).
Dosing.
A stock solution of 14C-BDE 47 was made by sonicating 63.6 mg of 14C-BDE 47 (55 µCi/mg) in toluene (1 ml) until dissolved. Aliquots from this stock were used to prepare a 1 mg/kg (
5 µCi/ml) solution by direct addition of the toluene to corn oil, followed by toluene evaporation using a speed vacuum. 14C-BDE 47 dosing solutions were prepared fresh prior to dosing. A single dose (0.0 or 1.0 mg/kg, 0.0 or 0.5 µCi, respectively, at a volume of 10 ml/kg) was administered directly by oral gavage into the stomach of each mouse using a disposable feeding needle on the respective dosing day (PND 10, 22, 28, or 40).
Sample analysis.
Radioactivity in the tissues was determined by combustion (Packard 306B Biological Oxidizer, Downers Grove, IL) of triplicate samples when available (100 mg/sample) followed by liquid scintillation spectrometry (LSS; Beckman Scintillation Counter, Beckman Instruments, Fullerton, CA). Determination of residual radioactivity in the carcass was performed by freezing in liquid nitrogen and subsequent pulverization and combustion of composite samples.
Data analysis.
All tissue concentrations are presented as nanograms of BDE 47/g tissue wet weight and percent administered dose per gram of tissue. Because body composition is continuously changing during development and accurate measurements of body fat and other tissues are not available, percent dose/tissue is not presented in this study. Comparisons between pup and adult tissue concentrations focus on percent administered dose/gram tissue to normalize for changes in body weight over time. An analysis of variance (ANOVA) was used to compare exposure groups followed by Bonferroni post tests. Nonlinear regression with biphasic elimination was used to compare trends of BDE 47 remaining in the body over time. Differences between treatment groups were considered significant when p < 0.05. All data are presented as mean ± standard deviation.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX AREFERENCES |
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PND 10 Time Course
PND 10 has been previously identified as a critical window of sensitivity for neurotoxic effects (Eriksson et al., 2001
). Therefore, the distribution of BDE 47 was monitored in 10-day-old pups for 10 days following a single oral dose and compared to patterns observed in adult animals (Staskal et al., 2005). Administration of corn oil or BDE 47 dosing solution did not impact pup development (as monitored by body weight). No overt toxicity was observed in response to BDE 47. One pup/litter (three of each sex) was randomly selected 3, 8, 24 h, 5 or 10 days following exposure.
BDE 47 tissue concentrations (% dose/g tissue and ng BDE 47/g tissue wet weight) are provided in Table 1. Overall disposition trends very closely paralleled those observed in adults (data from Staskal et al. [2005] and Appendix A) in that BDE 47 distributed to lipophilic tissues. Peak concentrations in lipophilic or slower-perfused limited tissues, such as adipose tissue and skin, were observed at the 24-h time point in this study; however, time points between 1 and 5 days were not included in this study and likely peak concentrations would be observed in this period as previously demonstrated in adults (Staskal et al., 2005). Highly perfused tissues, such as kidney and brain, had peak concentrations within 3 to 8 h of administration.
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While infantile disposition trends paralleled adult trends, actual tissue concentrations of BDE 47 were generally higher in the pups than adults (Table 1; Fig. 2). The majority of comparisons in this section are based on percent administered dose per gram of tissue, which normalizes for differences in body composition during development and allows for a more direct comparison across age groups. When using this dose-metric, adipose, blood, brain, kidney, muscle, and skin were higher in pups at respective time points whereas lung and liver concentrations were not.
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Representative graphs in Figure 2 demonstrate this trend; concentrations of BDE 47 in adipose tissue are much higher in pups than adults at all time points. The trends observed in brain tissue were of particular interest; tissue concentrations were lower than adult concentrations at early time point, suggesting partitioning into the brain was slower in pups. However, at the last time point (10 days post-exposure), brain concentrations in the pups were not only significantly higher than the adults, but also higher than the day 5 measurements.
In contrast to other tissues measured, tissue concentrations of BDE 47 were similar between adults and pups at all time points in the liver and lung. Comparison of liver concentrations on a ng/g wet weight basis reveals that lower absolute concentrations in the pup were observed at the earlier time points, which could be a reflection of differential flow rates and/or lipid content of the tissue in a young animal.
Excreta were not collected from these infantile animals due to housing complexities and the inability to use metabolism cages; however, carcasses were analyzed for remaining radioactivity as an indirect measure of excretion. Figure 3 demonstrates the amount of BDE 47 remaining in the body over time, directly comparing residual radioactivity in the carcasses and tissues of pups and adults. Within 24 h, only 41% of the dose remained in the body of the adult mice versus 69% in the pups. By the tenth day following exposure, a mere 6% was in the adults, yet 34% of the BDE 47 was still in the pups.
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Indicates overall significance from adult (p < 0.05).One-Day Disposition Study
BDE 47 (1 mg/kg) was administered to developing mice pups at postnatal days 22, 28, and 40. Urine samples and tissues were collected 24 h following administration. Tissue concentrations (% dose/g tissue) were highest in adipose, skin, liver, lung, and muscle one day after a single oral dose (Table 2). When comparing individual tissue concentrations by age, concentrations of BDE 47 were highest in all tissues measured, with liver as the only exception, in animals dosed on PND 22, followed by PND 28 and 40.
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These 24-h tissue concentrations were also compared to adult tissues (
70 days of age) subjected to the same dosing paradigm which were previously reported in Staskal et al. (2005) as well as urine and tissue concentrations from the PND 10 time course study presented above. Age at time of dosing clearly had an effect on the disposition of BDE 47 in all tissues collected with the exception of liver. In general, 24-h tissue concentrations were highest in the animals given a single dose on PND 10, followed by PNDs 22, 28, 40, and 70 per adult, respectively. Representative graphs depicting the effect of age are shown in Figure 4. Blood levels in weanlings and young adults (PND 10, 22, 28, and 40) were all higher than in fully developed adults, and levels decreased with age. Similarly, 24-h adipose concentrations of BDE 47 were highest in mice dosed on PND 10 and 22. As the mice matured, 24-h adipose concentrations more closely mimicked adult tissue concentrations.
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Residual radioactivity in the carcasses was used as indirect measure of excretion as utilization of metabolism cages was not possible with the age of animals used in this study. Analyses of the carcasses revealed that 59%, 41%, and 34% of the dose remained in the mice dosed on PND 22-, 28-, and 40-day old mice, respectively, 24 h following the single exposure (Fig. 5). The percent of dose remaining in the carcass was also compared to percentages remaining in adult and PND-10 mice. A similar trend was observed with residual radioactivity in the body as was observed with tissue concentrations; highest concentrations of BDE 47 were remaining 24 h following exposure in the mice dosed on PND 10, followed by animals dosed on PND 22. 24-h residual radioactivity dropped to levels observed in adults by PND 28.
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In addition to residual radioactivity, concentrations of BDE 47 in urine were used as a direct measure of excretion; however, cumulative 24-h urine samples were not obtainable without the use of metabolism cages in this study so point urine samples were taken at the time of sacrifice. Urine from two to four animals (up to 0.1 g urine collected/pooled sample) were pooled for each sample and analyzed for BDE 47 concentrations. These concentrations were compared to a 48-h composite concentration from adult animals (Fig. 6). A 48-h composite concentration was used because urine was collected cumulatively in 24-h increments using metabolism cages for the adult animals; in order to compare to point concentrations, the 48-hr average was used. The concentrations of BDE 47 in PND 22 and 28 urine were significantly lower than what was found in adult animals, whereas the PND 40 concentrations fell between the two groups and is more closely matched with the adult profile. These data suggest a reduced urinary excretion capacity in young mice.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX AREFERENCES |
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The objectives of this study were twofold: to investigate the disposition of BDE 47 in infantile mice previously found to be susceptible to the toxic effects of the compound, and to investigate the disposition and excretion of BDE 47 throughout development in an attempt to help elucidate the mechanism behind the species differences in rapid urinary excretion. Overall disposition trends were similar to those found in adults as BDE 47 preferentially distributes to lipophilic tissues; however, tissue concentrations of BDE 47 were generally highest in animals dosed at the earliest ages. As the dosing age of the mice matured, BDE 47 tissue concentrations more closely mimicked adult tissue concentrations. Furthermore, some tissues demonstrated altered uptake of BDE 47 in the young animals, which may be attributed to differences in blood flow, differential lipophilic contents of the tissues during development, and/or altered excretion capacities.
BDE 47 disposition trends in pup brains were of particular interest in light of previous developmental neurotoxicity studies. The congener took slightly longer to get into the brain of mice dosed on PND 10; by days 5 and 10, concentrations were not only higher than what was observed in adults but also appeared to be increasing. Higher concentrations in the blood may have led to increased partitioning into the brain; however, these concentrations could also be explained by active transport of BDE into or out of the brain. It is well documented that many active transport proteins along the blood brain barrier are responsible for controlling xenobiotic access to the tissue and that these transporters may not be fully developed at early ages. Time points beyond 10 days post-exposure would offer further insight for alterations in developmental disposition of BDE 47 in the brain.
We hypothesize that the higher concentrations of BDE 47 in most tissues of the developing mice pups can be attributed to a reduced capacity to excrete BDE 47 during development. Comparisons of the amount of administered BDE 47 remaining in the body in both the PND 10 and post-weanling animals versus adult animals showed that more BDE 47 is associated with the pup carcasses than adult carcasses. If it is assumed that all BDE 47 not remaining in the body was excreted, these data would suggest that approximately 31%, 41%, 59%, and 66% of BDE 47 was excreted in the first 24 h following administration to pups 10, 22, 28, and 40 days old, respectively. Prior studies in our lab have demonstrated that approximately 50% of the administered BDE 47 (1 mg/kg, oral) was excreted within the first 24 h in adult animals. Curve fitting to the PND 10 time course data using biphasic exponential decay, or excretion, clearly exhibits slower excretion in the developing animals. Adult mice have demonstrated a biphasic excretion of BDE 47 with a terminal half life of 22 days (Staskal et al., 2005); although the data set from this study is limited, the terminal half life is estimated to double (50 days) in developing animals.
Decreased excretion in pups may be due to decreased urinary elimination; a route previously shown to be responsible for a large proportion of BDE 47 excretion in mice (Orn and Wehler, 1998; Staskal et al., 2005). Adult excretion patterns have been well documented; however, due to excreta collection restriction in young animals, we were only able to collect point samples of urine at the time of sacrifice in the young animals (PND 22, 28, and 40). The 24-h urine concentrations of BDE 47 in the PND 22, 28, and 40 animals demonstrated decreased urinary concentrations in the young animals (Fig. 6). While these point measurements only provide a snapshot, the urinary concentrations of BDE 47 in developing pups support the hypothesis that urinary excretion is decreased.
Previous studies have also shown that the urinary excretion of BDE 47 is species dependent (Orn and Wehler, 1998), and is a saturable and dose-dependent process (Staskal et al., 2005). The developmental excretion data in this study supports the hypothesis that active transport plays a role in BDE 47 toxicokinetics and therefore may also play a role in its toxicity. Preliminary data from our laboratory have shown that the multi-drug–resistant transporter (mdr) may play a minor role in the renal excretion of BDE 47 (Staskal et al., 2004). These studies in mdr-deficient mice demonstrated that renal excretion was decreased when mdr was not present; however, it did not fully explain the presence of this large lipophilic chemical in the urine.
Active transport proteins are known to develop at different rates and are present in different tissues during different times of development. Specifically, many transporters have defined expression profiles during ontogeny in murine renal tissue (Cheng et al., 2005; Maher et al., 2005). Comparing urinary concentrations of BDE 47 with profiles of transporter ontogeny may provide insight for identification of the specific transporter, or transporters, responsible. Although the ontogeny profiles are based on mRNA expression and do not include activity, only a few transporter expression profiles mimic the BDE 47 urinary excretion trend observed in our in vivo studies. Potential transporters may include OATs1-3, OCT1/2 (kidney), and MRP2/3.
The hypothesized transporters may also potentially play a role in BDE 47 developmental toxicity via direct access of BDE 47 to target tissues due to incomplete development of transporter systems, or through indirect interaction with target tissues due to the lack of active excretion pathways and consequently higher circulating BDE 47 blood levels. Some of the transporters we hypothesize to be involved include members of the three main families of transporters responsible for uptake of T4 and T3 into the brain (Bernal, 2005a, 2005b). Thyroid hormone transporters in the brain can be inhibited by amino acids and other chemicals; however the in vivo significance is not yet clear (Hennemann et al., 2001). Potential structural similarities between BDE 47 and thyroid hormones may render them substrates for the same transporter, and therefore BDE 47 could be competing with thyroid hormones for access to the developing brain and other target tissues. This connection is of particular interest because of previous suggestions of disruption of thyroid hormones as a mechanism of PBDE toxicity (Birnbaum and Staskal, 2004).
Additional studies regarding the toxicity and toxicokinetics of BDE 47 in developing animals are needed. Darnerud and Risberg (2005) evaluated maternal transfer of BDE 85 and 99 (both pentaBDE) during pregnancy and through lactation. Whole-body autoradiography analyses following a single i.v. exposure revealed that fetal uptake was low. However, these authors estimated that 20% and 24% (BDE 85 or 99, respectively) of a single i.v. dose is transferred to the litter within 4 days of administration to lactating dams 11 days postpartum. While this study did not investigate BDE 47, the transfer would likely be similar to that of the pentaBDE congeners. Furthermore, Guvenius et al. (2002) has showed that lower brominated congeners, such as BDE 47 and 99, readily cross the placenta.
Recent exposure studies suggest that postnatal exposure to PBDEs will be much greater than in utero. Jones-Otazo et al. (2005) predict that inadvertent ingestion of house dust is the largest contributor to exposure for humans at all life stages except for infancy; during which lactational transfer from breast milk is the primary route of exposure to PBDE. Webster et al. (2005) estimate that infants ingest 66 ng BDE 47/kg per day through breast milk, and an additional 1.3 ng/kg per day through inadvertent ingestion of dust. In adults, the estimated intake from diet, ingestion of dust, and inhalation is only 0.8 ng/kg per day. Other studies of PBDEs in dust approximate a daily intake of 120–6000 ng 
PBDE/day in young children (Stapleton et al., 2005).
The results of this study demonstrate that the toxicokinetics of BDE 47 are different in developing mice than in adult mice. These differences may lead to higher concentrations of BDE 47 at target tissues during critical windows of development. Because BDE 47, and other PBDE, have demonstrated toxicity during development, it is essential to understand the kinetic parameters in order to accurately describe the dose available to target tissues after exposure, which may more accurately assess risk to human health.
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APPENDIX A |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX AREFERENCES |
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Adult Tissue Concentrations (% dose/g, mean ± standard deviation; n = 4/time point)
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Dose metric not provided in original manuscript (Staskal et al., 2005)
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ACKNOWLEDGMENTS |
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Frances McQuaid, David Ross, Vicki Richardson, Henrik Viberg, and Steve Godin deserve special recognition for their assistance in these studies. We thank Michael Hughes and Prasada Kodavanti for their helpful reviews of the manuscript. Partial funding was provided by the NHEERL-DESE Training in Environmental Sciences Research, EPA CT 826513. The information in this document has been subjected to review by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The research presented in this document was funded in part by the U.S. Environmental Protection Agency.
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REFERENCES |
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