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1.  Debromination of Polybrominated Diphenyl Ethers by Nanoscale Zerovalent Iron: Pathways, Kinetics, and Reactivity 
Environmental science & technology  2010;44(21):8236-8242.
The debromination of selected polybrominated diphenyl ethers (PBDEs) by nanoscale zerovalent iron particles (nZVI) was studied to investigate the degradation pathways and the reaction kinetics of the PBDEs. The primary PBDE investigated was 2,3,4-tribromo diphenyl ether (BDE 21) to assess degradation pathways. nZVI could effectively debrominate the selected PBDEs into lower brominated compounds and diphenyl ether, a completely debrominated form of PBDEs. The susceptibility of the meta-bromine by nZVI was observed from the debromination tests for PBDEs with single-flanked (2,3-diBDE and 3,4-diBDE) and unflanked (three monoBDEs) bromines. The stepwise debromination from n-bromo- to (n-1)-bromodiphenyl ether was observed as the dominant reaction process, although simultaneous multistep debromination seemed to be plausible for di-BDEs having two bromines adjacent on the same phenyl ring. The reaction rate constants were estimated by assuming the reaction between PBDEs and nZVI was a pseudo-first order reaction and the rates decreased with fewer bromine substituents. The reaction rate constants were correlated with the heat of formation and the energy of the lowest unoccupied molecular orbital of the corresponding compounds, and these appear to be useful descriptors of relative reaction rates among PBDE homologue groups.
doi:10.1021/es101601s
PMCID: PMC2969174  PMID: 20923154
2.  Innovative application of Fluoro-tagging to trace airborne particulate and gas phase PBDE exposures 
Chemical research in toxicology  2009;22(1):179-186.
Polybrominated diphenyl ethers (PBDEs) are flame retardants applied as coatings to many consumer products, including household items. PBDEs are released and produce airborne vapors and dusts. Inhalation of particle-phase and/or gas-phase PBDEs is therefore a major route of exposure. In an attempt to mimic realistic airborne exposures, actual uptake and deposition of particles and vapors, we prepared and characterized particles for future animal exposure studies. To trace the particles in environmental and biological systems, we employed fluoro-tagging. We synthesized, characterized and employed three PBDE congeners 35, 47 and 99, and five fluoro-substituted-PBDEs (F-PBDEs), 17-F5′, 25-F5′, 28-F3′, 35-F5′, 47-F3, 99-F3′ for this study. The PBDE congeners were selected because they are commonly found in house dust. For that reason we coated spherical silica particles of 3 μm and C18 endcapped silica as representative and inert support materials, with 20%, 30% and 40% PBDEs. We determined the particle size distributions by aerodynamic particle size spectrometry and the morphology by scanning electron microscopy. The suitability of the fluoro-tagged tracers to mimic their corresponding parent PBDEs was investigated by extraction studies from spiked blood serum. Our study is of fundamental importance to the development of xenobiotic tracers for monitoring routes of human exposure to PBDEs and understanding uptake of PBDEs from particles and vapors.
doi:10.1021/tx8003032
PMCID: PMC3120107  PMID: 19111055
3.  Hydroxylation Increases the Neurotoxic Potential of BDE-47 to Affect Exocytosis and Calcium Homeostasis in PC12 Cells 
Environmental Health Perspectives  2008;116(5):637-643.
Background
Oxidative metabolism, resulting in the formation of hydroxylated polybrominated diphenyl ether (PBDE) metabolites, may enhance the neurotoxic potential of brominated flame retardants.
Objective
Our objective was to investigate the effects of a hydroxylated metabolite of 2,2′,4,4′-tetra-bromodiphenyl ether (BDE-47; 6-OH-BDE-47) on changes in the intracellular Ca2+ concentration ([Ca2+]i) and vesicular catecholamine release in PC12 cells.
Methods
We measured vesicular catecholamine release and [Ca2+]i using amperometry and imaging of the fluorescent Ca2+-sensitive dye Fura-2, respectively.
Results
Acute exposure of PC12 cells to 6-OH-BDE-47 (5 μM) induced vesicular catecholamine release. Catecholamine release coincided with a transient increase in [Ca2+]i, which was observed shortly after the onset of exposure to 6-OH-BDE-47 (120 μM). An additional late increase in [Ca2+]i was often observed at ≥1 μM 6-OH-BDE-47. The initial transient increase was absent in cells exposed to the parent compound BDE-47, whereas the late increase was observed only at 20 μM. Using the mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and thapsigargin to empty intracellular Ca2+ stores, we found that the initial increase originates from emptying of the endoplasmic reticulum and consequent influx of extracellular Ca2+, whereas the late increase originates primarily from mitochondria.
Conclusion
The hydroxylated metabolite 6-OH-BDE-47 is more potent in disturbing Ca2+ homeostasis and neurotransmitter release than the parent compound BDE-47. The present findings indicate that bioactivation by oxidative metabolism adds considerably to the neurotoxic potential of PBDEs. Additionally, based on the observed mechanism of action, a cumulative neurotoxic effect of PBDEs and ortho-substituted polychlorinated biphenyls on [Ca2+]i cannot be ruled out.
doi:10.1289/ehp.11059
PMCID: PMC2367675  PMID: 18470311
bioactivation; brominated flame retardants; calcium; catecholamine; exocytosis; intra-cellular calcium stores; neurotoxicity; neurotransmitter release; persistent organic pollutants; poly-brominated diphenyl ether
4.  Flame retardant exposure: polybrominated diphenyl ethers in blood from Swedish workers. 
Environmental Health Perspectives  1999;107(8):643-648.
Polybrominated diphenyl ethers (PBDEs) are used as additives in polymers and textiles to prohibit the development of fires. Because of the production and use of PBDEs, their lipophilic characteristics, and persistence, these compounds have become ubiquitous environmental contaminants. The aim of the present study was to determine potential exposures of PBDEs to clerks working full-time at computer screens and personnel at an electronics-dismantling plant, with hospital cleaners as a control group. Five PBDE congeners--2,2',4,4'-tetraBDE; 2,2',4,4',5,5'-hexaBDE; 2,2',4,4',5, 6'-hexaBDE; 2,2',3,4,4',5',6-heptaBDE; and decaBDE--were quantified in blood serum from all three categories of workers. Subjects working at the dismantling plant showed significantly higher levels of all PBDE congeners in their serum as compared to the control group. Decabromodiphenyl ether is present in concentrations of 5 pmol/g lipid weight (lw) in the personnel dismantling electronics; these concentrations are comparable to the concentrations of 2,2',4, 4'-tetraBDE. The latter compound was the dominating PBDE congener in the clerks and cleaners. The major compound in personnel at the dismantling plant was 2,2',3,4,4',5',6-heptaBDE. Concentrations of this PBDE congener are almost twice as high as for 2,2',4, 4'-tetraBDE in these workers and seventy times the level of this heptaBDE in cleaners. The total median PBDE concentrations in the serum from workers at the electronics-dismantling plant, clerks, and cleaners were 37, 7.3, and 5.4 pmol/g lw, respectively. The results show that decabromodiphenyl ether is bioavailable and that occupational exposure to PBDEs occurs at the electronics-dismantling plant.
Images
PMCID: PMC1566483  PMID: 10417362
5.  Receptor interactions by polybrominated diphenyl ethers versus polychlorinated biphenyls: a theoretical Structure-activity assessment 
The extensive body of literature regarding the interaction of polychlorinated biphenyls (PCBs) with transcription factors (receptors) has great value to understand similarities and distinctions and in formulating hypotheses regarding the activity of polybrominated diphenyl ethers (PBDEs) toward those same receptors. Our goal is to present the most comprehensive overview of PBDE effects on AhR, CAR, PXR, ER, AR, PR, DHT, TH, T3, T4 and IGF, as well as hypothetical biological activities of PPAR, RyR, GR and GABA. Aside the influence of the conformation of the ligand, we discuss its constitution influencing the binding affinity: size and polarizability, hydrophilicity, Gibbs free energy of solvation, inductive and mesomeric effects. We evaluate the techniques to determine the biologically relevant conformation of these halogenated hydrocarbons, including computation methods, X-ray and microwave spectroscopy. A novel fluoro-tagged ligand approach holds promise as tools for illuminating the steric and electronic effects in ligand-receptor interaction. Based on our assessment, we predict that PBDEs do not exhibit AhR activity themselves, but impurities are responsible for these effects.
doi:10.1016/j.etap.2007.10.017
PMCID: PMC2746664  PMID: 19768137
polybrominated diphenyl ethers; PBDEs; polychlorinated biphenyls; PCBs; AhR; CAR; PXR; ER; AR; PR; DHT; TH; T3; T4; IGF; PPAR; RyR; GR; GABA; Conformation; Constitution; Binding affinity; Polarizability; Hydrophilicity; Gibbs free solvation energy; Inductive effects; Mesomeric effects
6.  Species-Specific Differences and Structure-Activity Relationships in the Debromination of PBDE Congeners in Three Fish Species 
Environmental science & technology  2011;45(5):1999-2005.
Previous studies have suggested that there may be species-specific differences in the metabolism of polybrominated diphenyl ethers (PBDEs) among different fish species. In this study, we investigated the in vitro hepatic metabolism of eleven individual PBDE congeners (tri- through decaBDEs) in three different fish species: rainbow trout (Oncorhynchus mykiss), common carp (Cyprinus carpio), and Chinook salmon (O. tschwatcha). In addition, we evaluated the influence of PBDE structural characteristics (i.e., bromine substitution patterns) on metabolism. Six of the eleven congeners we evaluated, BDEs 99, 153, 183, 203, 208, and 209, were metabolically debrominated to lower brominated congeners. All of the congeners that were metabolized contained at least one meta-substituted bromine. Metabolites were not detected for congeners without one meta-substituted bromine (e.g., BDEs 28, 47, and 100). Metabolite formation rates were generally 10–100 times faster in carp than in trout and salmon. BDEs 47, 49, 101, 154, and 183 were the major metabolites observed in all three species with the exception of BDE 47, which was only detected in carp. Carp demonstrated a preference towards meta-debromination, while trout and salmon debrominated meta- and para- bromine atoms to an equal extent. We compared glutathione-S-transferase (GST) and deiodinase (DI) activity among all three species as these enzyme systems have been hypothesized to play a role in PBDE debromination among teleosts. Carp exhibited a preference for meta-deiodination of the thyroid hormone thyroxine, which was consistent with the preference for meta-debromination of PBDEs observed in carp.
doi:10.1021/es103934x
PMCID: PMC3047442  PMID: 21291240
PBDEs; debromination; carp; trout; salmon; fish; structure-activity; metabolism; deiodinase
7.  DEVELOPMENT AND VALIDATION OF A CONGENER-SPECIFIC PHOTODEGRADATION MODEL FOR POLYBROMINATED DIPHENYL ETHERS 
With the phaseout of the manufacture of some polybrominated diphenyl ether (PBDE) formulations, namely penta-brominated diphenyl ether (BDE) and octa-BDE, and the continued use of the deca-BDE formulation, it is important to be able to predict the photodegradation of the more highly brominated congeners. A model was developed and validated to predict the products and their relative concentrations from the photodegradation of PBDEs. The enthalpies of formation of the 209 PBDE congeners were calculated, and the relative reaction rate constants were obtained. The predicted reaction rate constants for PBDEs show linear correlation with previous experimental results. Because of their large volume use, their presence in the environment, and/or importance in the photodegradation of the deca-BDE formulation, BDE-209, BDE-184, BDE-100, and BDE-99 were chosen for further ultraviolet photodegradation experiments in isooctane. The photodegradation model successfully predicted the products of the photochemical reactions of PBDEs in experimental studies. A gas chromatography retention time model for PBDEs was developed using a multiple linear regression analysis and, together with the photodegradation model and additional PBDE standards, provided a way to identify unknown products from PBDE photodegradation experiments. Based on the results of the photodegradation experiments, as well as the model predictions, it appears that the photodegradation of PBDEs is a first-order reaction and, further, that the rate-determining step is the stepwise loss of bromine. Our results suggest that, based on photodegradation, over time, BDE-99 will remain the most abundant penta-BDE, while BDE-49 and BDE-66 will increase greatly and will be comparable in abundance to BDE-47.
doi:10.1897/07-570.1
PMCID: PMC3056650  PMID: 18613751
Polybrominated diphenyl ether; Photodegradation; Model; Theoretical calculation
8.  Body Burdens of Polybrominated Diphenyl Ethers among Urban Anglers 
Environmental Health Perspectives  2005;113(12):1689-1692.
Polybrominated diphenyl ethers (PBDEs) have been widely used in the United States and worldwide as flame retardants. Recent PBDE production figures show that worldwide use has increased. To determine whether fish consumption is a source of PBDE exposure for humans, a cross-sectional epidemiologic study of New York and New Jersey urban anglers was conducted during the summers of 2001–2003. Frequency of local fish consumption was assessed by questionnaire, and blood samples for PBDE analysis were collected from 94 anglers fishing from piers on the lower Hudson River and Newark Bay. We analyzed PBDEs by gas chromatography–isotope dilution–high-resolution mass spectrometry. The congeners found in anglers’ serum at the highest concentrations were, by International Union of Pure and Applied Chemistry numbers, BDE-47, BDE-153, and BDE-99. Anglers reporting consumption of local fish had higher, but nonstatistically significantly different, concentrations of PBDEs than did anglers who did not eat local fish. For some congeners (BDE-100 and BDE-153), we observed moderate dose–response relationships between serum PBDE levels and frequency of reported fish intake. These findings suggest that consumption of locally caught fish is not a major route of human exposure for this study population.
doi:10.1289/ehp.8138
PMCID: PMC1314906  PMID: 16330348
fish consumption; PBDE; polybrominated diphenyl ethers
9.  Diet Contributes Significantly to the Body Burden of PBDEs in the General U.S. Population 
Environmental Health Perspectives  2009;117(10):1520-1525.
Background
Exposure of the U.S. population to polybrominated diphenyl ethers (PBDEs) is thought to be via exposure to dust and diet. However, little work has been done to empirically link body burdens of these compounds to either route of exposure.
Objectives
The primary goal of this research was to evaluate the dietary contribution to PBDE body burdens in the United States by linking serum levels to food intake.
Methods
We used two dietary instruments—a 24-hr food recall (24FR) and a 1-year food frequency questionnaire (FFQ)—to examine food intake among participants of the 2003–2004 National Health and Nutrition Examination Survey. We regressed serum concentrations of five PBDEs (BDE congeners 28, 47, 99, 100, and 153) and their sum (∑PBDE) against diet variables while adjusting for age, sex, race/ethnicity, income, and body mass index.
Results
∑PBDE serum concentrations among vegetarians were 23% (p = 0.006) and 27% (p = 0.009) lower than among omnivores for 24FR and 1-year FFQ, respectively. Serum levels of five PBDE congeners were associated with consumption of poultry fat: Low, medium, and high intake corresponded to geometric mean ∑PBDE concentrations of 40.6, 41.9, and 48.3 ng/g lipid, respectively (p = 0.0005). We observed similar trends for red meat fat, which were statistically significant for BDE-100 and BDE-153. No association was observed between serum PBDEs and consumption of dairy or fish. Results were similar for both dietary instruments but were more robust using 24FR.
Conclusions
Intake of contaminated poultry and red meat contributes significantly to PBDE body burdens in the United States.
doi:10.1289/ehp.0900817
PMCID: PMC2790504  PMID: 20019900
biomarkers; diet; exposure; NHANES; PBDEs
10.  Instrumental methods and challenges in quantifying polybrominated diphenyl ethers in environmental extracts: a review 
Increased interest in the fate, transport and toxicity of polybrominated diphenyl ethers (PBDEs) over the past few years has led to a variety of studies reporting different methods of analysis for these persistent organic pollutants. Because PBDEs encompass a range of vapor pressures, molecular weights and degrees of bromine substitution, various analytical methods can lead to discrimination of some PBDE congeners. Recent improvements in injection techniques and mass spectrometer ionization methods have led to a variety of options to determine PBDEs in environmental samples. The purpose of this paper is therefore to review the available literature describing the advantages and disadvantages in choosing an injection technique, gas chromatography column and detector. Additional discussion is given to the challenges in measuring PBDEs, including potential chromatographic interferences and the lack of commercial standards for higher brominated congeners, which provides difficulties in examining degradation and debromination of BDE congeners, particularly for BDE 209.
doi:10.1007/s00216-006-0400-y
PMCID: PMC1764596  PMID: 17165211
Polybrominated diphenyl ethers; Brominated flame retardants; Methods; Analysis; Review
11.  Polybrominated Diphenyl Ethers (PBDEs) and Hexabromocyclodecane (HBCD) in Composite U.S. Food Samples 
Environmental Health Perspectives  2009;118(3):357-362.
Objectives
This study was designed to update previous U.S. market basket surveys of levels and polybrominated diphenyl ether (PBDE) dietary intake calculations. This study also quantifies hexabromocyclododecane (HBCD) levels in U.S.-purchased foods for the first time and estimates U.S. dietary intake of HBCD. This is part of a larger market basket study reported in two companion articles, of current levels of certain persistent organic pollutants (POPs) PBDEs, HBCD, perfluorinated compounds, polychlorinated biphenyls, and pesticides in composite food samples collected in 2008–2009.
Methods
In this study, we measured concentrations of 24 PBDE congeners and total HBCD in composite samples of 31 food types (310 samples). U.S. dietary intake of PBDEs and HBCD was estimated referencing the most current U.S. Department of Agriculture loss-adjusted food availability report.
Results
Total PBDE concentrations in food varied by food type, ranging from 12 pg/g wet weight (ww) in whole milk to 1,545 pg/g ww in canned sardines and 6,211 pg/g ww in butter. Total HBCD concentrations also varied substantially within and among food groups, ranging from 23 pg/g in canned beef chili to 593 pg/g in canned sardines. HBCD was not detected in any dairy samples. Dietary intake of all PBDE congeners measured was estimated to be 50 ng/day, mostly from dairy consumption but also from meat and fish. HBCD intake was estimated at 16 ng/day, primarily from meat consumption.
Conclusion
PBDEs and HBCDs currently contaminate some food purchased in the United States, although PBDE intake estimated in this study is lower than reported in our previous market basket surveys. HBCD is in food at higher levels than expected based on previously reported levels in milk and blood compared with PBDE levels and is comparable to European levels.
doi:10.1289/ehp.0901345
PMCID: PMC2854763  PMID: 20064778
dietary intake; food; HBCD; PBDE; United States
12.  Kinetics and Pathways for the Debromination of Polybrominated Diphenyl Ethers by Bimetallic and Nanoscale Zerovalent Iron: Effects of Particle Properties and Catalyst 
Chemosphere  2012;89(4):426-432.
Polybrominated diphenyl ethers (PBDEs) are recognized as a new class of widely-distributed and persistent contaminants for which effective treatment and remediation technologies are needed. In this study, two kinds of commercially available nanoscale Fe° slurries (Nanofer N25 and N25S), a freeze-dried laboratory-synthesized Fe° nanoparticle (nZVI), and their palladized forms were used to investigate the effect of particle properties and catalyst on PBDE debromination kinetics and pathways. Nanofers and their palladized forms were found to debrominate PBDEs effectively. The laboratory-synthesized Fe° nanoparticles also debrominated PBDEs, but were slower due to deactivation by the freeze-drying and stabilization processes in the laboratory synthesis. An organic modifier, polyacrylic acid (PAA), bound on N25S slowed PBDE debromination by a factor of three to four compared to N25. The activity of palladized nZVI (nZVI/Pd) was optimized at 0.3 Pd/Fe wt% in our system. N25 could debrominate selected environmentally-abundant PBDEs, including BDE 209, 183, 153, 99, and 47, to end products di-BDEs, mono-BDEs and diphenyl ether (DE) in one week, while nZVI/Pd (0.3 Pd/Fe wt%) mainly resulted in DE as a final product. Step-wise major PBDE debromination pathways by unamended and palladized Fe° are described and compared. Surface precursor complex formation is an important limiting factor for palladized Fe° reduction as demonstrated by PBDE pathways where steric hindrance and rapid sequential debromination of adjacent bromines play an important role.
doi:10.1016/j.chemosphere.2012.05.078
PMCID: PMC3408778  PMID: 22732301
Polybrominated diphenyl ether (PBDE); Nanoscale zero-valent iron (nZVI); Palladium; Nanofer; Debromination; Pathways
13.  Polybrominated Diphenyl Ethers (PBDEs) in Breast Milk and Neuropsychological Development in Infants 
Environmental Health Perspectives  2012;120(12):1760-1765.
Background: There is increasing interest in the potential effects of polybrominated diphenyl ethers (PBDEs) on children’s neuropsychological development, but only a few small studies have evaluated such effects.
Objectives: Our goal was to examine the association between PBDE concentrations in colostrum and infant neuropsychological development and to assess the influence of other persistent organic pollutants (POPs) on such association.
Methods: We measured concentrations of PBDEs and other POPs in colostrum samples of 290 women recruited in a Spanish birth cohort. We tested children for mental and psychomotor development with the Bayley Scales of Infant Development at 12–18 months of age. We analyzed the sum of the seven most common PBDE congeners (BDEs 47, 99, 100, 153, 154, 183, 209) and each congener separately.
Results: Increasing Σ7PBDEs concentrations showed an association of borderline statistical significance with decreasing mental development scores (β per log ng/g lipid = –2.25; 95% CI: –4.75, 0.26). BDE-209, the congener present in highest concentrations, appeared to be the main congener responsible for this association (β = –2.40, 95% CI: –4.79, –0.01). There was little evidence for an association with psychomotor development. After adjustment for other POPs, the BDE-209 association with mental development score became slightly weaker (β = –2.10, 95% CI: –4.66, 0.46).
Conclusions: Our findings suggest an association between increasing PBDE concentrations in colostrum and a worse infant mental development, particularly for BDE-209, but require confirmation in larger studies. The association, if causal, may be due to unmeasured BDE-209 metabolites, including OH-PBDEs (hydroxylated PBDEs), which are more toxic, more stable, and more likely to cross the placenta and to easily reach the brain than BDE-209.
doi:10.1289/ehp.1205266
PMCID: PMC3548276  PMID: 23052368
children; environmental; neurodevelopment; persistent organic pollutants (POPs); polybrominated diphenyl ethers (PBDEs)
14.  Apparent Half-Lives of Hepta- to Decabrominated Diphenyl Ethers in Human Serum as Determined in Occupationally Exposed Workers 
Environmental Health Perspectives  2005;114(2):176-181.
The aim of the present study was to model apparent serum half-lives of polybrominated diphenyl ethers (PBDEs) with 7–10 bromine substituents. Workers with occupational exposure to PBDEs have elevated serum levels of PBDEs, but these substances are also found in the general population and are ubiquitous environmental contaminants. The calculations were based on exposure assessments of rubber workers (manufactured flame-retarded rubber compound) and electronics dismantlers who donated blood during a period with no work-related exposures to PBDEs, and referents without any known occupational exposure (clerks, cleaners, and abattoir workers). The workers had previously been found to have elevated levels of high- and medium-brominated diphenyl ethers compared with the referent populations. We performed nonlinear mixed-effects modeling of kinetics, using data from previous and present chemical analyses. The calculated apparent half-life for decabromodiphenyl ether (BDE-209) was 15 days (95% confidence interval, 11–18 days). The three nona-BDEs and four octa-BDE congeners were found to have half-lives of 18–39 and 37–91 days, respectively. BDE-209 has a short half-life in human blood. Because BDE-209 is commonly present in humans in general, the results of this study imply that humans must be more or less continuously exposed to BDE-209 to sustain the serum concentrations observed. BDE-209 is more readily transformed and/or eliminated than are lower brominated diphenyl ether congeners, and human health risk must be assessed accordingly.
doi:10.1289/ehp.8350
PMCID: PMC1367828  PMID: 16451851
BDE-209; BFR; brominated flame retardants; deca-BDE; half-life; human exposure; PBDEs; polybromodiphenyl ethers
15.  Contamination of U.S. Butter with Polybrominated Diphenyl Ethers from Wrapping Paper 
Environmental Health Perspectives  2010;119(2):151-154.
Objectives
Our aim was to report the first known incidence of U.S. butter contamination with extremely high levels of polybrominated diphenyl ethers (PBDEs).
Methods
Ten butter samples were individually analyzed for PBDEs. One of the samples and its paper wrapper contained very high levels of higher-brominated PBDEs. Dietary estimates were calculated using the 2007 U.S. Department of Agriculture Loss-Adjusted Food Availability data, excluding the elevated sample.
Results
The highly contaminated butter sample had a total upper bound PBDE level of 42,252 pg/g wet weight (ww). Levels of brominated diphenyl ether (BDE)-206, -207, and -209 were 2,000, 2,290, and 37,600 pg/g ww, respectively. Its wrapping paper contained a total upper-bound PBDE concentration of 804,751 pg/g ww, with levels of BDE-206, -207, and -209 of 51,000, 11,700, and 614,000 pg/g, respectively. Total PBDE levels in the remaining nine butter samples ranged from 180 to 1,212 pg/g, with geometric mean of 483 and median of 284 pg/g. Excluding the outlier, total PBDE daily intake from all food was 22,764 pg/day, lower than some previous U.S. dietary intake estimates.
Conclusion
Higher-brominated PBDE congeners were likely transferred from contaminated wrapping paper to butter. A larger representative survey may help determine how frequently PBDE contamination occurs. Sampling at various stages in food production may identify contamination sources and reduce risk.
doi:10.1289/ehp.1002604
PMCID: PMC3040599  PMID: 21138809
butter; dietary intake; food; PBDEs; United States
16.  Serum PBDEs and Age at Menarche in Adolescent Girls: Analysis of the National Health and Nutrition Examination Survey 2003–2004 
Environmental research  2011;111(6):831-837.
BACKGROUND
Polybrominated Diphenyl Ethers (PBDEs), widely used as flame retardants since the 1970s, have exhibited endocrine disruption in experimental studies. Tetra- to hexa-BDE congeners are estrogenic, while hepta-BDE and 6-OH-BDE-47 are antiestrogenic. Most PBDEs also have antiandrogenic activity. It is not clear, however, whether PBDEs affect human reproduction.
OBJECTIVES
The analysis was designed to investigate the potential endocrine disruption of PBDEs on the age at menarche in adolescent girls.
METHODS
We analyzed the data from a sample of 271 adolescent girls (age 12–19 years) in the National Health and Nutrition Examination Survey (NHANES), 2003–2004. We estimated the associations between individual and total serum BDEs (BDE-28, -47, -99, -100, -153, and -154, lipid adjusted) and mean age at menarche. We also calculated the risk ratios (RRs) and 95% confidence intervals (CI) for menarche prior to age 12 years in relation to PBDE exposure.
RESULTS
The median total serum BDE concentration was 44.7 ng/g lipid. Higher serum PBDE concentrations were associated with slightly earlier ages at menarche. Each natural log unit of total BDEs was related to a change of −0.10 (95% CI: −0.33, 0.13) years of age at menarche and a RR of 1.60 (95% CI: 1.12, 2.28) for experiencing menarche before 12 years of age, after adjustment for potential confounders.
CONCLUSION
These data suggest high concentrations of serum PBDEs during adolescence are associated with a younger age of menarche.
doi:10.1016/j.envres.2011.05.016
PMCID: PMC3143295  PMID: 21663902
Environmental exposure; NHANES; Menarche; Female; PBDEs; Puberty
17.  Hormone Activity of Hydroxylated Polybrominated Diphenyl Ethers on Human Thyroid Receptor-β: In Vitro and In Silico Investigations 
Environmental Health Perspectives  2009;118(5):602-606.
Background
Hydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disrupt thyroid hormone status because of their structural similarity to thyroid hormone. However, the molecular mechanisms of interactions with thyroid hormone receptors (TRs) are not fully understood.
Objectives
We investigated the interactions between HO-PBDEs and TRβ to identify critical structural features and physicochemical properties of HO-PBDEs related to their hormone activity, and to develop quantitative structure–activity relationship (QSAR) models for the thyroid hormone activity of HO-PBDEs.
Methods
We used the recombinant two-hybrid yeast assay to determine the hormone activities to TRβ and molecular docking to model the ligand–receptor interaction in the binding site. Based on the mechanism of action, molecular structural descriptors were computed, selected, and employed to characterize the interactions, and finally a QSAR model was constructed. The applicability domain (AD) of the model was assessed by Williams plot.
Results
The 18 HO-PBDEs tested exhibited significantly higher thyroid hormone activities than did PBDEs (p < 0.05). Hydrogen bonding was the characteristic interaction between HO-PBDE molecules and TRβ, and aromaticity had a negative effect on the thyroid hormone activity of HO-PBDEs. The developed QSAR model had good robustness, predictive ability, and mechanism interpretability.
Conclusions
Hydrogen bonding and electrostatic interactions between HO-PBDEs and TRβ are important factors governing thyroid hormone activities. The HO-PBDEs with higher ability to accept electrons tend to have weak hydrogen bonding with TRβ and lower thyroid hormone activities.
doi:10.1289/ehp.0901457
PMCID: PMC2866673  PMID: 20439171
application domain; density functional theory; docking; HO-PBDEs; hydroxylated polybrominated diphenyl ethers; PBDEs; quantitative structure-activity relationship; thyroid hormone receptor
18.  Polybrominated diphenyl ethers (PBDEs), hydroxylated PBDEs (OH-PBDEs), and measures of thyroid function in second trimester pregnant women in California 
Environmental science & technology  2011;45(18):7896-7905.
Prenatal exposure to polybrominated diphenyl ethers (PBDEs) may disrupt thyroid function and contribute to adverse neurodevelopmental outcomes. We conducted a pilot study to explore the relationship between serum concentrations of lower-brominated PBDEs (BDE-17 to -154), higher-brominated PBDEs (BDE-183 to -209), and hydroxylated PBDE metabolites (OH-PBDEs) with measures of thyroid function in pregnant women. Concentrations of PBDEs, OH-PBDEs, thyroid-stimulating hormone (TSH), total thyroxine (T4), and free T4 were measured in serum samples collected between 2008 and 2009 from 25 second trimester pregnant women in California. Median concentrations of lower-brominated PBDEs and OH-PBDEs were the highest reported to date in pregnant women. Median concentrations of BDE-47 and the sum of lower-brominated PBDEs (ΣPBDE5) were 43.1 ng/g lipid and 85.8 ng/g lipid; and 0.084 ng/mL for the sum of OH-PBDEs (ΣOH-PBDE4). We observed a positive association between the weighted sum of chemicals known to bind to transthyretin (ΣTTR binders) and TSH levels. We also found positive associations between TSH and ΣPBDE5, ΣOH-PBDE4, BDE-47, BDE-85, 5-OH-BDE47, and 4′-OH-BDE49; and an inverse association with BDE-207. Relationships with free and total T4 were weak and inconsistent. Our results indicate that PBDE exposures are elevated in pregnant women in California, and suggest a relationship with thyroid function. Further investigation is warranted to characterize the risks of PBDE exposures during pregnancy.
doi:10.1021/es200422b
PMCID: PMC3191110  PMID: 21830753
19.  Toxicity of the Flame-Retardant BDE-49 on Brain Mitochondria and Neuronal Progenitor Striatal Cells Enhanced by a PTEN-Deficient Background 
Toxicological Sciences  2013;132(1):196-210.
Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years. PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms. Recently, PBDEs with < 5 Br substitutions (i.e., 2,2′,4,4′-tetrabromodiphenyl ether [BDE-47] and 2,2′,4,5′-tetrabromodiphenyl ether [BDE-49]) have gained interest because of their high bioaccumulation. In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown. To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC). BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC50 = 6 nM) and Complex IV (noncompetitive inhibition; IC50 = 40 nM). These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1–3 orders of magnitude in the cells, particularly in mitochondria and microsomes. Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy. PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain.
doi:10.1093/toxsci/kfs339
PMCID: PMC3693513  PMID: 23288049
mitochondria; polybrominated diphenyl ethers; Complex IV; bioenergetics; PTEN; autism; epilepsy
20.  Hydroxylated Metabolites of Polybrominated Diphenyl Ethers in Human Blood Samples from the United States 
Background
A previous study from our laboratory showed that polybrominated diphenyl ethers (PBDEs) were metabolized to hydroxylated PBDEs (HO-PBDEs) in mice and that para-HO-PBDEs were the most abundant and, potentially, the most toxic metabolites.
Objective
The goal of this study was to determine the concentrations of HO-PBDEs in blood from pregnant women, who had not been intentionally or occupationally exposed to these flame retardants, and from their newborn babies.
Methods
Twenty human blood samples were obtained from a hospital in Indianapolis, Indiana, and analyzed for both PBDEs and HO-PBDEs using electron-capture negative-ionization gas chromatographic mass spectrometry.
Results
The metabolite pattern of HO-PBDEs in human blood was quite different from that found in mice; 5-HO-BDE-47 and 6-HO-BDE-47 were the most abundant metabolites of BDE-47, and 5′-HO-BDE-99 and 6′-HO-BDE-99 were the most abundant metabolites of BDE-99. The relative concentrations between precursor and corresponding metabolites indicated that BDE-99 was more likely to be metabolized than BDE-47 and BDE-100. In addition, three bromophenols were also detected as products of the cleavage of the diphenyl ether bond. The ratio of total hydroxylated metabolites relative to their PBDE precursors ranged from 0.10 to 2.8, indicating that hydroxylated metabolites of PBDEs were accumulated in human blood.
Conclusions
The quite different PBDE metabolite pattern observed in humans versus mice indicates that different enzymes might be involved in the metabolic process. Although the levels of HO-PBDE metabolites found in human blood were low, these metabolites seemed to be accumulating.
doi:10.1289/ehp.11660
PMCID: PMC2627872  PMID: 19165393
bromophenols; flame retardants; HO-PBDEs; human blood; metabolites; PBDEs; polybrominated diphenyl ethers
21.  Household Exposures to Polybrominated Diphenyl Ethers (PBDEs) in a Wisconsin Cohort 
Environmental Health Perspectives  2009;117(12):1890-1895.
Background
Human exposure to polybrominated diphenyl ethers (PBDEs) is virtually universal in the United States. Although the uses of these chemicals as flame retardants in fabrics, foams, and plastics are well defined, human exposure pathways are not well understood.
Objectives
This study was designed to assess current PBDE body burdens and identify residential sources of exposure among 29 men and 15 women in 38 households.
Methods
Portable X-ray fluorescence (XRF) analyzers were used to measure bromine levels in upholstered furnishings, bedding, vehicle interiors, and electronic devices. Vacuum cleaner contents, indoor air samples, and blood sera were analyzed for PBDE congeners using conventional gas chromatograph methods.
Results
Bromine levels varied widely within similar household items. The greatest range for upholstered items was found among vehicle seat cushions (7–30,600 ppm). For electronic devices, television sets ranged from 4 ppm to 128,300 ppm. Based on mixed effects modeling, adjusting for couple households, the bromine content in the participants’ sleeping pillows and primary vehicle seat cushions were the strongest predictors of log lipid-adjusted blood serum PBDE concentrations (p-values = 0.005 and 0.03, respectively). The total pentaBDE congener levels found in dust samples and in passive air samples were not significant predictors of blood sera levels.
Conclusions
This study demonstrates the usefulness of the portable XRF analyzer in identifying household items that may contribute to human exposure to PBDEs.
doi:10.1289/ehp.0900839
PMCID: PMC2799463  PMID: 20049208
bromine; passive air sample; PBDE; vacuum dust; X-ray fluorescence
22.  Birth Delivery Mode Modifies the Associations between Prenatal Polychlorinated Biphenyl (PCB) and Polybrominated Diphenyl Ether (PBDE) and Neonatal Thyroid Hormone Levels 
Environmental Health Perspectives  2008;116(10):1376-1382.
Background
Developing infants may be especially sensitive to hormone disruption from chemicals including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs).
Objective
We investigated relationships between cord serum levels of PCBs and PBDEs and thyroid hormones measured in cord blood serum and neonatal blood spots.
Methods
We measured PCBs and PBDEs, thyrotropin (TSH), thyroxine (T4) and free T4 (FT4) in cord blood serum from 297 infants who were delivered at the Johns Hopkins Hospital in 2004–2005. We abstracted results of total T4 (TT4) measured in blood spots collected in the hospital and at neonatal visits. We used delivery mode (augmented vaginal deliveries and nonelective cesarean deliveries) as a surrogate for intrapartum stress, which is known to alter cord blood thyroid hormones.
Results
In the full study population, no compounds were associated with a change in average TSH, FT4, or TT4. BDE-100 was associated with increased odds of low cord TT4, BDE-153 with increased odds of low cord TT4 and FT4, and no compounds were associated with increased odds of high TSH. For infants born by spontaneous, vaginal, unassisted deliveries, PCBs were associated with lower cord TT4 and FT4 and lower TT4 measured in neonatal blood spots. PBDEs showed consistent but mainly nonsignificant negative associations with TT4 and FT4 measurements.
Conclusions
Prenatal PCB and PBDE exposures were associated with reduced TT4 and FT4 levels among infants born by spontaneous, unassisted vaginal delivery. Intrapartum stress associated with delivery mode may mask hormonal effects of PCBs and PBDEs.
doi:10.1289/ehp.11379
PMCID: PMC2569098  PMID: 18941581
children; cord blood; endocrine disruption; environmental health; polychlorinated biphenyls; polybrominated diphenyl ethers; thyroid hormones
23.  Facing the Challenge of Data Transfer from Animal Models to Humans: the Case of Persistent Organohalogens 
Environmental Health  2008;7:58.
A well-documented fact for a group of persistent, bioaccumulating organohalogens contaminants, namely polychlorinated biphenyls (PCBs), is that appropriate regulation was delayed, on average, up to 50 years. Some of the delay may be attributed to the fact that the science of toxicology was in its infancy when PCBs were introduced in 1920's. Nevertheless, even following the development of modern toxicology this story repeats itself 45 years later with polybrominated diphenyl ethers (PBDEs) another compound of concern for public health. The question is why? One possible explanation may be the low coherence between experimental studies of toxic effects in animal models and human studies. To explore this further, we reviewed a total of 807 PubMed abstracts and full texts reporting studies of toxic effects of PCB and PBDE in animal models. Our analysis documents that human epidemiological studies of PBDE stand to gain little from animal studies due to the following: 1) the significant delay between the commercialisation of a substance and studies with animal models; 2) experimental exposure levels in animals are several orders of magnitude higher than exposures in the general human population; 3) the limited set of evidence-based endocrine endpoints; 4) the traditional testing sequence (adult animals – neonates – foetuses) postpones investigation of the critical developmental stages; 5) limited number of animal species with human-like toxicokinetics, physiology of development and pregnancy; 6) lack of suitable experimental outcomes for the purpose of epidemiological studies. Our comparison of published PCB and PBDE studies underscore an important shortcoming: history has, unfortunately, repeated itself. Broadening the crosstalk between the various branches of toxicology should therefore accelerate accumulation of data to enable timely and appropriate regulatory action.
doi:10.1186/1476-069X-7-58
PMCID: PMC2596097  PMID: 19014546
24.  Polybrominated diphenyl ethers (PBDEs) in U.S. mothers' milk. 
Environmental Health Perspectives  2003;111(14):1723-1729.
No previous reports exist on polybrominated diphenyl ether (PBDE) congeners in human milk from individual U.S. mothers. This article on PBDEs is an extension of our previous studies on concentrations of dioxins, dibenzofurans, polychlorinated biphenyls, and other chlorinated organic compounds in human milk in a number of countries. PBDE commercial products are used as flame retardants in flexible polyurethane foam (penta-BDE), in acrylonitrile-butadiene-styrene resins (octa-BDE), and in high-impact polystyrene resins (deca-BDE). Their use is permitted in the United States but is banned in some European countries because of presumed toxicity, demonstrated persistence, and bioaccumulation. Different commercial products can be found in various consumer products such as television sets, computers, computer monitors and printers, carpets, and upholstery. Analyses of human levels of these compounds suggest low but rising levels in European human milk, which may have peaked, at least in Sweden, in the late 1990s. Very few data exist on levels of PBDEs in humans in the United States, and none from milk from individual nursing mothers. To address this issue, we analyzed 47 individual milk samples from nursing mothers, 20-41 years of age, from a milk bank in Austin, Texas, and a community women's health clinic in Dallas, Texas. Up to 13 PBDE congeners were measured. The concentrations of the sum of PBDE congeners varied from 6.2 to 419 ng/g (or parts per billion) lipid, with a median of 34 ng/g and a mean of 73.9 ng/g lipid. The PBDE levels in breast milk from Texas were similar to levels found in U.S. blood and adipose tissue lipid from California and Indiana and are 10-100 times greater than human tissue levels in Europe. Their detection in breast milk raises concern for potential toxicity to nursing infants, given the persistence and bioaccumulative nature of some of the PBDE congeners. These results indicate a need for more detailed investigation of the levels of PBDE in people and food, as well as determining if animal fat in food is the major route of exposure of the general U.S. population. Other routes of intake may also be significant.
PMCID: PMC1241714  PMID: 14594622
25.  Human prenatal and postnatal exposure to polybrominated diphenyl ethers, polychlorinated biphenyls, polychlorobiphenylols, and pentachlorophenol. 
Environmental Health Perspectives  2003;111(9):1235-1241.
The aim of this study was to determine human prenatal and postnatal exposures to polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), hydroxylated metabolites of PCBs (polychlorobiphenylols; OH-PCBs), and pentachlorophenol (PCP). The median PBDE fresh-weight concentrations in maternal and cord blood plasma and in breast milk were 24, 4.3, and 75 pg/g, respectively. The PCB concentrations were approximately 60 times higher in each compartment (1,560, 277, and 4,310 pg/g, respectively). Calculated on a lipid weight basis, the levels were comparable in maternal blood plasma and breast milk. In contrast to PCBs, differences were found between PBDE congener distribution in maternal and cord blood plasma. The OH-PCBs constituted up to 26% of the PCB levels in maternal blood plasma and 53% in cord blood plasma, with levels of 120 and 88 pg/g fresh weight, respectively, and in breast milk 3 pg/g. The corresponding concentrations for PCP were 2,830, 1,960, and 20 pg/g. The ratios of PCB to OH-PCB were 13, 3, and 1,400 in maternal, cord plasma, and breast milk, respectively. It is evident that prenatal exposures occur for all the analytes. Moreover, the exposure continues after birth via breast milk. However, levels of OH-PCBs and PCP in breast milk are low compared with levels in blood plasma. Exposures to both PCBs and PBDEs, and in particular to the endocrine-active halogenated phenolic compounds, are of concern and implicate a potential risk for developmental disturbances.
PMCID: PMC1241580  PMID: 12842779

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