A PBPK model describing the pharmacokinetics of γ-HBCD exposure in mice.

The brominated flame retardant, hexabromocyclododecane (HBCD), is added-but not bound-to consumer products and is eventually found in the environment and human tissues. Commercial-grade HBCD mixtures contain three major stereoisomers, alpha (α), beta (ß), and gamma (γ), that are typically at a ratio of 12%:6%:82%, respectively. Although HBCD is widely used, the toxicological effects from its exposure in humans are not clearly understood. Using a physiologically based pharmacokinetic (PBPK) model could help improve our understanding of the toxicity of HBCD. The aim of this work was to develop a PBPK model, consisting of five permeability limited compartments (i.e., brain, liver, adipose tissue, blood, and rest of the body), to evaluate the pharmacokinetics of γ-HBCD in C57BL/6 mice. Physiological parameters related to body size, organ weights, and blood flow were taken from the literature. All partition coefficients were calculated based on the log Kow. The elimination in urine and feces was optimized to reflect the percent dose eliminated, as published in the literature. Compared with data from the literature for brain, liver, blood, and adipose tissue, the model simulations accurately described the mouse data set within 1.5-fold of the data points. Also, two examples showing the utility of the PBPK model supplement the information regarding the internal dose that caused the health effects observed during these studies. Although this version of the PBPK model expressly describes γ-HBCD, more efforts are needed to clarify and improve the model to discriminate between the α, ß, and γ stereoisomers.

Comparative Metabolism Studies of Hexabromocyclododecane (HBCD) Diastereomers in Male Rats Following a Single Oral Dose.

Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively accounting for 42% of dose for α-HBCD, 59% for ß-HBCD, and 53% for γ-HBCD. Urine was also an important route of HBCD excretion, accounting for 13% of dose for α-HBCD, 30% for ß-HBCD, and 21% for γ-HBCD. Total metabolism of HBCD diastereomers followed the rank order ß > γ > α, and was >65% of that administered. The metabolites formed were distinct in male rats: α-HBCD did not debrominate or stereoisomerize, but formed two hydroxylated metabolites; ß- and γ-HBCD were both extensively metabolized via pathways of stereoisomerization, oxidation, dehydrogenation, reductive debromination, and ring opening. ß-HBCD was biotransformed to two mercapturic acid pathway metabolites. The metabolites of ß- and γ-HBCD were largely distinct, and could possibly be used as markers of exposure. These isomer-specific data suggest that α-HBCD would be the most dominant HBCD diastereomer in biological tissues because it was metabolized to the lowest degree and also accumulated from the stereoisomerization of the ß- and γ- diastereomers.

Uptake Pathway, Translocation, and Isomerization of Hexabromocyclododecane Diastereoisomers by Wheat in Closed Chambers.

To study the uptake pathways of 3 main hexabromocyclododecane diastereoisomers (α-, ß-, and γ-HBCDs) in wheat, four closed chambers were designed to expose wheat to HBCDs via air and/or soil for 4 weeks. The results showed that HBCDs could be absorbed by wheat both via root from soil and via leaf from air. The Rt values (ratio of HBCDs from root-to-leaf translocation to the total accumulation in leaves) ranging from 14.4 to 29.8% suggested that acropetal translocation within wheat was limited. A negative linear relationship was found between log Rt and log Kow of the HBCD diastereoisomers (p < 0.05). The bioconcentration factors (BCFs, (µg/g wheat tissues)/(µg/g soil)) were in the order α- > ß- > γ-HBCD in wheat roots and stems, being negatively related to their Kow values. No such correlation was found in leaves, where the HBCDs came mainly from air distribution. The results of enantiomeric fractions indicated that the (-)-enantiomer of α- and γ-HBCDs and the (+)-ß-enantiomer were selectively accumulated. Furthermore, ß- and γ-HBCDs were transformed to α-HBCD in the wheat, with 0.309-4.80% and 0.920-8.40% bioisomerization efficiencies at the end of the experiment, respectively, being the highest in leaves. Additionally, no isomerization product from α-HBCD was found.

Enantioselective biotransformation of hexabromocyclododecane by in vitro rat and trout hepatic sub-cellular fractions.

α-, ß-, and γ-Hexabromocyclododecanes (HBCDs) were subjected to in vitro biotransformation experiments with rat and trout liver S9 fractions for different incubation times (10, 30, and 60 min) at 2 concentration levels (1 and 10 µM). The metabolic degradation of target HBCDs followed first order kinetics. Whereas ß-HBCD undergoes rapid biotransformation (t0.5 = 6.4 and 38.1 min in rat and trout, respectively), α-HBCD appears the most resistant to metabolic degradation (t0.5 = 17.1 and 134.9 min). The biotransformation rate in trout was slower than in rat. Investigation of HBCD degradation profiles revealed the presence of at least 3 pentabromocyclododecene (PBCD) and 2 tetrabromocyclododecadiene (TBCD) isomers indicating reductive debromination as a metabolic pathway for HBCDs. Both mono- and di- hydroxyl metabolites were identified for parent HBCDs, while only mono hydroxyl metabolites were detected for PBCDs and TBCDs. Interestingly, δ-HBCD was detected only in trout S9 fraction assays indicating metabolic interconversion of test HBCD diastereomers during biotransformation in trout. Finally, enantioselective analysis showed significant enrichment of the (-)-α-HBCD enantiomer (EF = 0.321 and 0.419 after 60 min incubation in rat and trout, respectively). The greater enrichment of (-)-α-HBCD in rat than in trout underlines the species-specific differences in HBCD metabolism and the need for caution when extending similar results from animal studies to humans.

Measurements of selected brominated flame retardants in nursing women: implications for human exposure.

We have examined several emerging brominated flame retardants (BFRs) including 2-ethyl-1-hexyl-2,3,4,5-tetrabromobenzoate (TBB), bis(2-ethylhexyl) tetrabromophthalate (TBPH), 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE), 4,5,6,7-tetrabromo-1,1,3-trimethyl-3-(2,3,4,5-tetrabromophenyl)-indane (OBIND), and decabromodiphenyl ethane (DBDPE) in paired human maternal serum (n = 102) and breast milk (n = 105) collected in 2008-2009 in the Sherbrooke region in Canada. Three legacy BFRs were also included in the study for comparison: decabromobiphenyl (BB-209), 2,2',4,4',5,5'-hexabromobiphenyl (BB-153), and 2,2',4,4',5,5'-hexabromodiphenyl ethers (BDE-153). TBB, BB-153, and BDE-153 had detection frequencies greater than 55% in both serum and milk samples. Their lipid weight (lw) adjusted median concentrations (ng g(-1) lw) in serum and milk were 1.6 and 0.41 for TBB, 0.48 and 0.31 for BB-153, and 1.5 and 4.4 for BDE-153, respectively. The detection frequencies for the other BFRs measured in serum and milk were 16.7% and 32.4% for TBPH, 3.9% and 0.0% for BTBPE, 2.0% and 0.0% for BB-209, 9.8% and 1.0% for OBIND, and 5.9% and 8.6% for DBDPE. The ratio of TBB over the sum of TBB and TBPH (fTBB) in serum (0.23) was lower than that in milk (0.46), indicating TBB has a larger tendency than TBPH to be redistributed from blood to milk. Overall, these data confirm the presence of non-PBDE BFRs in humans, and the need to better understand their sources, routes of exposure, and potential human health effects.

Species and sex-dependent toxicokinetics of 1-bromopropane: the role of hepatic cytochrome P450 oxidation and glutathione (GSH).

1. The objectives of the current studies were to evaluate the factors influencing the toxicokinetics of 1-bromopropane (1-BP) in rodents after intravenous (IV) and inhalation exposure. 2. F-344 rats were administered 1-BP via IV bolus injection at 5 and 20 mg/kg and blood concentration determined versus time. F-344 rats and B6C3F1 mice were also exposed to starting inhalation concentrations 70, 240, 800 and 2700 ppm 1-BP in a closed gas uptake system and chamber 1-BP levels were monitored for 6 h. Plasma bromide concentrations were determined to estimate total metabolized dose. Rats were pretreated with chemical inhibitors of cytochrome P450 and glutathione (GSH) synthesis, prior to exposure to 1-BP at 800 ppm within inhalation chambers. 3. Systemic clearance of 1-BP in rat was rapid and decreased with increasing dose. As inhalation chamber concentration of 1-BP increased, the terminal elimination rates decreased. Half-life of 1-BP in rats following inhibition of P450 (9.6 h) or depletion of GSH (4.1 h) increased relative to controls (2.0 h) at 800 ppm. The percentage of 1-BP metabolized decreased with increasing inhalation exposure. Hepatic levels of GSH were significantly lowered regardless of the exposure level in both rats and mice. Chamber concentration-time curves were fit to a two compartment model which was used to estimate metabolic rate constants. 4. These data suggest that in rat, 1-BP clearance is saturable and that elimination is highly dependent on both P450 and GSH-dependent metabolism. This investigation in rodents may provide an understanding of interspecies differences in toxicokinetics and eventually aid translation of animal studies to human risk assessment.

Biotransformation of Hexabromocyclododecanes (HBCDs) with LinB--an HCH-converting bacterial enzyme.

Hexabromocyclododecanes (HBCDs) and hexachlorocyclohexanes (HCHs) are polyhalogenated hydrocarbons with similar stereochemistry. Both classes of compounds are considered biologically persistent and bioaccumulating pollutants. In 2009, the major HCH stereoisomers came under regulation of the Stockholm convention. Despite their persistence, HCHs are susceptible to bacterial biotransformations. Here we show that LinB, an HCH-converting haloalkane dehalogenase from Sphingobium indicum B90A, is also able to transform HBCDs. Racemic mixtures of α-, ß-, and γ-HBCDs were exposed to LinB under various conditions. All stereoisomers were converted, but (-)α-, (+)ß-, and (+)γ-HBCDs were transformed faster by LinB than their enantiomers. The enantiomeric excess increased to 8 ± 4%, 27 ± 1%, and 20 ± 2% in 32 h comparable to values of 7.1%, 27.0%, and 22.9% as obtained from respective kinetic models. Initially formed pentabromocyclododecanols (PBCDOHs) were further transformed to tetrabromocyclododecadiols (TBCDDOHs). At least, seven mono- and five dihydroxylated products were distinguished by LC-MS so far. The widespread occurrence of HCHs has led to the evolution of bacterial degradation pathways for such compounds. It remains to be shown if LinB-catalyzed HBCD transformations in vitro can also be observed in vivo, for example, in contaminated soils or in other words if such HBCD biotransformations are important environmental processes.

Temporal trends of hexabromocyclododecane, polybrominated diphenyl ethers and polychlorinated biphenyls in ringed seals from East greenland.

Concentrations of hexabromocyclododecane (HBCD) were determined in a combination of archived and fresh blubber samples of juvenile ringed seals from East Greenland collected between 1986 and 2008. α-HBCD was the only diastereoisomer consistently above levels of quantification and showed a significant log-linear (exponential) increase from 2.0 to 8.7 ng/g lipid weight (median concentrations) with an annual rate of +6.1%. The concentrations were up to several orders of magnitude lower than those reported for marine mammals from industrialized areas. Previously presented time trends on polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) have been extended with new data for 2006 and 2008. ΣPBDE in juvenile seals was the only parameter with a slight upward trend, however, dependent on the low 1986 concentration. Removing this data point resulted in a downward trend, which also was found for adult seals with a time trend starting in 1994. ΣPCB decreased significantly in juvenile seals, again due to the 1986 value, while no trend was found for the adult animals. This indicates stagnating PCB concentrations at a relatively high level, in some cases possibly exceeding tolerable daily intake rates for seal blubber as traditional Arctic food items.

Trophic level determines levels of brominated flame-retardants in coastal herring gulls.

Liver concentrations of eight polybrominated diphenyl ethers (ΣPBDEs: sum of brominated diphenyl ethers [BDE]-28, -47, -99, -100, -153, -154, -183, and -209) ranged from 135 to 985 ngg(-1) lipid weight (lw) in coastal herring gulls (Larus argentatus) from the marine Hvaler Archipelago (The Glomma River Estuary), Norway. Hexabromocyclododecane (HBCD) concentrations ranged from 10 to 698 ngg(-1)lw. High range in δ(13)C indicates that gulls were subject to a diversity of carbon sources, likely reflecting their mixed feeding on terrestrial and marine organisms, or diversity of autochthonous and allochthonous (watershed) energy sources at the bases of their marine/estuarial food chains. Inverse relationships of HBCD, and to somewhat lesser extent of BDE-209, with δ(13)C values suggest higher abundance of these compounds in the land-derived energy-sources of the gulls. Inverse relationships of BDE-99, BDE-183 and BDE-209 with δ(15)N suggest that trophic relationships affect bioaccumulation of these compounds in the herring gulls, with greater bioaccumulation from lower trophic level prey species. This may be because these PBDE congeners are subject of debromination in higher trophic levels prey species of the gulls (e.g., teleost fish). Levels of BDE-209 (up to 95 ng/g lipid) of these herring gulls from 1998 were in the higher range reported in European birds, and not matched by other reports in North Sea seabirds. The present study suggests that the currently used brominated flame-retardants (BFRs), BDE-209 and HBCD relate to changing nutrient allocation in the herring gulls, and represent a risk to seabirds exploiting near-shore and estuary ecosystems.

Accumulation and DNA damage in fathead minnows (Pimephales promelas) exposed to 2 brominated flame-retardant mixtures, Firemaster 550 and Firemaster BZ-54.

Firemaster 550 and Firemaster BZ-54 are two brominated formulations that are in use as replacements for polybrominated diphenyl ether (PBDE) flame retardants. Two major components of these mixtures are 2,3,4,5-tetrabromo-ethylhexylbenzoate (TBB) and 2,3,4,5-tetrabromo-bis(2-ethylhexyl) phthalate (TBPH). Both have been measured in environmental matrices; however, scant toxicological information exists. The present study aimed to determine if these brominated flame-retardant formulations are bioavailable and adversely affect DNA integrity in fish. Fathead minnows (Pimephales promelas) were orally exposed to either FM 550, FM BZ54, or the nonbrominated form of TBPH, di-(2-ethylhexyl) phthalate (DEHP) for 56 d and depurated (e.g., fed clean food) for 22 d. At several time points, liver and blood cells were collected and assessed for DNA damage. Homogenized fish tissues were extracted and analyzed on day 0 and day 56 to determine the residue of TBB and TBPH and the appearance of any metabolites using gas chromatography-electron-capture negative ion mass spectrometry (GC/ECNI-MS). Significant increases (p < 0.05) in DNA strand breaks from liver cells (but not blood cells) were observed during the exposure period compared with controls, although during depuration these levels returned to control. Both parent compounds, TBB and TBPH, were detected in tissues at approximately 1% of daily dosage along with brominated metabolites. The present study provides evidence for accumulation, metabolism, and genotoxicity of these new formulation flame retardants in fish and highlights the potential adverse effects of TBB- and TBPH-formulated fire retardants to aquatic species.

A PBPK model to study the transfer of α-hexabromocyclododecane (α-HBCDD) to tissues of fast- and slow-growing broilers.

A physiologically based pharmacokinetic (PBPK) model was developed to investigate the production-specific factors involved in the transfer of α-hexabromocyclododecane (α-HBCDD) to broiler meat. The model describes growth and lipid deposition in tissues of fast- (FG) and slow- (SG) growing broilers from hatching to slaughter and simulates the exposure through the ingestion of contaminated feed or expanded polystyrene insulation material. Growth parameters were obtained from the literature while parameters relative to uptake, distribution, and elimination of α-HBCDD were adjusted using results of a previous experiment involving broilers exposed through feed throughout the rearing period or allowed to depurate before slaughter. The model was used to compare the two main edible tissues, breast and leg meat, as well as skin, and to investigate the variability within strain. Between strains and within strain, α-HBCDD assimilation efficiency (AE) is higher when the animals are slaughtered young or heavy. However, increasing slaughter age will lower α-HBCDD concentration in tissues, due to dilution. Based on fresh weight, the concentration of α-HBCDD in breast muscles and skin tends to be lower in SG than in FG broilers (-30 to +10%), while it is 10% to 80% higher in leg muscles. Compared to breast muscles, consuming leg muscles would elicit an exposure 9 and 16 times higher in FG and SG broilers, respectively. The consumption of skin together with muscles would multiply the exposure by up to 36 times compared to breast muscle alone. In case of acute exposure, the α-HBCDD concentration in tissues increased sharply, all the more since the animals are lighter in weight, and then decreased rapidly. In FG broilers, dilution through growth contributed for up to 37%, 28% and 97% to the decontamination of breast muscles, leg muscles and skin, respectively, depending on the duration of depuration before slaughter.

Persistent organochlorine and organobromine compounds in mother's milk from Sweden 1996-2006: compound-specific temporal trends.

High body burdens of persistent halogenated organic pollutants (POPs) among pregnant and nursing women are of concern because of exposure of the growing foetus and breast-feeding infant. We examined the temporal trends of polychlorinated biphenyls (PCBs), dibenzo-p-dioxin (PCDDs) and dibenzofurans (PCDFs), polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) in milk samples from Swedish women. POPs were analysed in individual mother's milk samples from randomly recruited primiparas (N=335) who lived in Uppsala County and delivered between 1996 and 2006. Results were adjusted for life-style factors that are associated with POP body burdens. PCB levels declined 3.9-8.6% per year. The levels of PCDDs decreased faster (6-9% per year) than the levels of PCDFs (3-6% per year). Temporal trends of PBDEs did not follow any consistent pattern. Concentrations of BDE-47 and BDE-99 decreased, while the concentrations of BDE-153 increased. No change in BDE-100 concentrations was observed. In most samples, concentrations of HBCD were below the quantification limit (<0.20 ng/g lipid). Generally, adjustment of the temporal trends of PCBs and PCDD/Fs for personal characteristics of the mothers (age, body mass index (BMI), weight changes during and after pregnancy) resulted in faster declining rates, with age having the greatest influence. The age of the participating mothers increased during the study period, and since the POP levels increased with increasing age, this counteracted the decreasing temporal trends in the unadjusted model. It is consequently important to include personal characteristics in the analysis of temporal trends of POPs. Compound-specific temporal trends are probably caused by differences in sources of exposure, as well as by differences in persistence between compounds.

Bioaccumulation of polybrominated diphenyl ethers and hexabromocyclododecane in the northwest Atlantic marine food web.

Seven species of teleost fishes comprising major prey of northwest Atlantic harbor seals were analyzed for polybrominated diphenyl ethers (PBDEs). PBDE concentrations in whole fish samples (n=87) were compared with those measured previously in harbor seal blubber to evaluate the transfer of PBDEs from prey to predator. Hexabromocyclododecane (HBCD) concentrations were measured in three fish species to provide an initial estimation of HBCD contamination in this ecosystem. HBCD was detected in 87% of the fish samples at concentrations ranging from 2.4 to 38.1 ng/g, lw (overall mean 17.2+/-10.2 ng/g, lw). SigmaPBDE concentrations in fish ranged from 17.9 to 94 ng/g, lw (overall mean 62+/-34 ng/g, lw). SigmaPBDE concentrations in the harbor seals were two orders of magnitude higher than levels in the fish. Biomagnification factors (BMFs) from fish to seals averaged from 17 to 76, indicating that tetra- to hexa-BDEs are highly biomagnified in this marine food web. BDE-47 was the dominant congener in all samples, suggesting exposure to the penta-BDE mixture. The presence of higher brominated congeners including BDE-209 at measurable levels in fish and seal tissue, along with the very high biomagnification of BDE-153, as well as -155, and -154, suggests recent exposure to the octa- and deca-BDE formulations in this US coastal marine food web, as well as the additional contribution of BDE-209 debromination in fish to the loading of persistent PBDEs in the seals. This is the first study to report the occurrence of BDE-209 and other higher BDEs in commercially important marine fishes from the northwest Atlantic.

Evaluating hexabromocyclododecane (HBCD) toxicokinetics in humans and rodents by physiologically based pharmacokinetic modeling.

Hexabromocyclododecane (HBCD) is a flame retardant largely found in textiles, electrical equipment and building materials. The potential exposure associated with adverse effects described in animals make HBCD a substance of interest. To better characterize the risk in humans, it is important to understand the dose-response relationship using available data concerning the exposure and toxicity of environmental contaminants such as HBCD. For this reason, a physiologically-based pharmacokinetic (PBPK) model was developed to describe the disposition of α-HBCD after a single oral administration. The results showed that the model can appropriately predict blood and tissue concentration in rodents. The model described that lipoproteins play a key role in the distribution of α-HBCD in the body even though its lipophilic nature would suggest preferential storage in adipose tissue. The model was also adapted to humans to predict plasma exposure to α-HBCD and showed reasonable estimates when compared against estimated diet levels and biomonitoring measures. As part of a larger study on integrating new toxicity data for human health risk assessment, the present PBPK model will serve as a supporting tool to help extrapolate and interpret in vitro and in vivo kinetics of flame retardants such as HBCD.

Subacute effects of hexabromocyclododecane (HBCD) on hepatic gene expression profiles in rats.

Hexabromoyclododecane (HBCD), used as flame retardant (FR) mainly in textile industry and in polystyrene foam manufacture, has been identified as a contaminant at levels comparable to other brominated FRs (BFRs). HBCD levels in biota are increasing slowly and seem to reflect the local market demand. The toxicological database of HBCD is too limited to perform at present a solid risk assessment, combining data from exposure and effect studies. In order to fill in some gaps, a 28-day HBCD repeated dose study (OECD407) was done in Wistar rats. In the present work liver tissues from these animals were used for gene expression profile analysis. Results show clear gender specificity with females having a higher number of regulated genes and therefore being more sensitive to HBCD than males. Several specific pathways were found to be affected by HBCD exposure, like PPAR-mediated regulation of lipid metabolism, triacylglycerol metabolism, cholesterol biosynthesis, and phase I and II pathways. These results were corroborated with quantitative RT-PCR analysis. Cholesterol biosynthesis and lipid metabolism were especially down-regulated in females. Genes involved in phase I and II metabolism were up-regulated predominantly in males, which could explain the observed lower HBCD hepatic disposition in male rats in this 28-day study. These sex-specific differences in gene expression profiles could also underlie sex-specific differences in toxicity (e.g. decreased thyroid hormone or increased serum cholesterol levels). To our knowledge, this is the fist study that describes the changes in rat hepatic gene profiles caused by this commonly used flame retardant.

Levels and body distribution of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecanes (HBCDs) in freshwater fishes from the Yangtze River, China.

Polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecanes (HBCDs) were determined in muscle, liver and eggs of freshwater fishes from the lower reach of the Yangtze River, China. The present study is the first to report HBCD concentrations in the environment of China. The concentrations of PBDEs and HBCDs in muscle of freshwater fishes from the Yangtze River ranged from 18 to 1100ng/g and 12 to 330ng/g lipid weight (wt.), respectively. When compared with other regions of the world, the contamination of PBDEs in biota could be regarded as moderate, whereas contamination of HBCDs in biota was relatively high. The PBDE congener profiles in fishes of the present study were markedly different from those observed in freshwater and marine fishes from other regions of the world. In the present study, BDE-15, BDE-28 and BDE-47 were the predominant congeners in the fishes. This particular congener profile in fishes from the Yangtze River revealed that a specific commercial PBDE formulation (probably made in China) might have been used in the Yangtze River Delta region.

Hexabromocyclododecane in polystyrene packaging: A downside of recycling?

While there are no regulatory fire safety obligations for polystyrene (PS) when used as packaging material, concerns exist that such packaging material may contain the flame retardant hexabromocyclododecane (HBCDD) as a result of uncontrolled recycling activities. To evaluate these concerns, we collected 50 samples of PS packaging materials from the UK and 20 from Ireland. HBCDD was detected in 63 (90%) of samples, with concentrations in 4 samples from Ireland exceeding the EU's low POP concentration limit (LPCL) of 0.1% above which articles may not be recycled. Moreover, 2 further samples contained HBCDD >0.01%. While our samples were obtained in the 12 month period prior to the March 2016 introduction of the EU's 0.01% concentration limit above which articles may not be placed on the market, our data suggest that continued monitoring is required to assess compliance with this limit value. Ratios of α vs. γ-HBCDD in our EPS packaging samples (average = 0.63) exceeded significantly (p = 0.025) those in EPS building insulation material samples (average = 0.24) reported previously for Ireland. This shift towards α-HBCDD in packaging EPS is consistent with the additional thermal processing experienced by recycled PS and suggests the source of HBCDD in PS packaging is recycled PS insulation foam. This is of concern owing to the higher bioavailability and lower metabolic clearance of α-HBCDD compared to the ß- and γ-isomers.

Bioavailability and mass balance studies of a commercial pentabromodiphenyl ether mixture in male Sprague-Dawley rats.

Polybrominated diphenyl ethers (PBDE) are common flame retardants used in polyurethane foam, high impact polystyrene, and textiles which appear to be increasing in the environment and biota. Two PBDE congeners that are particularly prominent in environmental samples are 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99). These two congeners are major components in penta-BDE formulations which constitute a minor percentage of the commercial PBDE market. In order to determine the bioavailability and bioconcentration potential of these PBDEs, we have conducted a feeding experiment in rats, dosing with low amounts of a commercial penta-BDE mixture for 21 days to mimic an environmental exposure. The carcasses, livers, and feces from control and dosed rats were quantitated for PBDEs by a high resolution GC-MS isotope dilution method. Between 25% and 50% of each of the dosed congeners was retained in the rats with the liver being a minor depot (<1% of the dose). Fecal excretion accounted for 4-12% of the dosed congeners. A large percent of the dose (40-60%) was not recovered indicating that metabolic transformations may have occurred in the rats. Hydroxylated metabolites were qualitatively identified in the feces and carcass by GC-MS. The relative congener distribution in each tissue was nearly identical to the congener distribution of the commercial mixture. Conclusions from the study suggest that the tetra- to hexa-BDEs present in commercial penta-BDE formulations are largely bioavailable, that bioavailability in the rat is not dependent on the degree of bromination, and that metabolism may occur to a large extent during a chronic exposure.

Dermal bioaccessibility of flame retardants from indoor dust and the influence of topically applied cosmetics.

Despite extensive literature on their potential adverse health effects, there is a lack of information on human dermal exposure to organic flame retardant chemicals (FRs). This study applies an in vitro physiologically based extraction test to provide new insights into the dermal bioaccessibility of various FRs from indoor dust to synthetic sweat/sebum mixture (SSSM). The bioaccessible fractions of α-, ß- and γ-hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) to 1:1 (sweat/sebum) mixture were 41%, 47%, 50% and 40%, respectively. For Tris-2-chloroethyl phosphate (TCEP), tris (1-chloro-2-propyl) phosphate (TCIPP) and tris-1,3-dichloropropyl phosphate (TDCIPP), bioaccessible fractions were 10%, 17% and 19%. Composition of the SSSM and compound-specific physicochemical properties were the major factors influencing the bioaccessibility of target FRs. Except for TBBPA, the presence of cosmetics (moisturising cream, sunscreen lotion, body spray and shower gel) had a significant effect (P<0.05) on the bioaccessibility of the studied FRs. The presence of cosmetics decreased the bioaccessibility of HBCDs from indoor dust, whereas shower gel and sunscreen lotion enhanced the bioaccessibility of target PFRs. Our bioaccessibility data were applied to estimate the internal exposure of UK adults and toddlers to the target FRs via dermal contact with dust. Our worst-case scenario exposure estimates fell far below available health-based limit values for TCEP, TCIPP and TDCIPP. However, future research may erode the margin of safety for these chemicals.

Toxicity and bioaccumulation of three hexabromocyclododecane diastereoisomers in the marine copepod Tigriopus japonicas.

The three major hexabromocyclododecane (HBCD) diastereoisomers, i.e. α-, ß- and γ-HBCD, have distinct physical and chemical properties that may potentially result in different levels of bioaccumulation and toxicity in aquatic organisms. To assess the impact of diastereomeric variation in HBCDs, the marine copepod Tigriopus japonicus was exposed to α-, ß- and γ-HBCD in isolation. Results showed that all the three diastereoisomers had a similar potency to cause growth delay in T. japonicas. Variation was observed in the overall survival rate with exposure to α- and ß-HBCD, and this resulted in significantly higher lethal toxicity in T. japonicas than that with exposure to γ-HBCD. Exposure to α-, ß- and γ-HBCD led to the generation of ROS in T. japonicas, a possibly toxic mechanism. Both α- and ß-HBCD showed a higher potential to induce oxidative stress, which may be a factor in the higher lethal toxicity observed with α- and ß-HBCD exposure. It is of note that T. japonicus was found to be more sensitive to all three diastereoisomers in the F1 generation than in the F0 generation. The bioconcentration potential of HBCD diastereoisomers can be ranked in the order α-HBCD>γ-HBCD>ß-HBCD and was found to be higher in T. japonicus than has been reported for fish species.