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Commercial hexabromocyclododecane (HBCD) is a high-production-volume flame-retardant applied in polystyrene foams. It contains three stereoisomers, of which gamma-HBCD always dominates. Here we report on the levels of HBCD in blubber of harbor porpoise and common dolphin from different European seas. The highest total (sigma)-HBCD levels were measured in harbor porpoises stranded on the Irish and Scottish coasts of the Irish Sea (median concentration 2.9 microg (g of lipid)(-1)) and the northwest coast of Scotland (median concentration 5.1 microg (g of lipid)(-1)). The median levels in other areas were, for the harbor porpoise south coast of Ireland, 1.2 microg (g of lipid)(-1), for the coasts of The Netherlands, Belgium, and France north of Calais (southern North Sea), 1.1 microg (g of lipid)(-1), for the east coast of Scotland (northern North Sea), 0.77 microg (g of lipid)(-1), and, for Galicia (Spain), 0.1 microg (g of lipid)(-1). The median levels for the common dolphin were, for west coast of Ireland, 0.9 microg (g of lipid)(-1), for the French coast of the English Channel between Normandy and Brest, 0.4 microg (g of lipid)(-1), and, for Galicia, 0.2 microg (g of lipid)(-1). A subset of 10 harbor porpoise and 9 common dolphin blubber samples representing all areas were analyzed by LC/MS to determine the diastereomeric composition of their HBCD residues. All samples showed exclusively the peak of alpha-HBCD. To test if biotransformation by the cytochrome P450 system could explain the observed compositional difference with technical HBCD mixtures, a number of in vitro assays with microsomal preparations of liver were carried out. We had to revert to material stored at -80 degrees C from laboratory rats and a fresh harbor seal found dead in the Dutch Wadden Sea, since such liver samples of cetaceans were not in our possession. The in vitro assays showed that beta- and gamma-HBCDs were indeed significantly metabolized when incubated in the presence of NADPH as electron donor, compared to a set of reference samples which were identical except for the addition of NADPH. In contrast, the peak of alpha-HBCD did not decrease significantly in the presence of NADPH. In separate microsomal assays with beta- and gamma-HBCDs, new peaks of brominated compounds (signal at m/z = 79 or 81) with masses of [M + 0] were formed only when NADPH was added. This confirms the process of cytochrome P450 mediated biotransformation. Although rat and harbor seal belong to different families of the mammalia than the cetaceans, we propose that biotransformation by the cytochrome P450 system is also the most likely process to explain the exclusive accumulation of alpha-HBCD in harbor porpoise and common dolphin.
The combinatorial bio/chemical investigation of sediments (six surface samples and one core sample) from Osaka Bay, Japan was conducted to clarify the horizontal and vertical distribution profiles of persistent organic pollutants in the sediments. Concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs), and polybrominated diphenylethers (PBDEs) were determined by chemical analysis and compared to bioassay results using H4IIE-luc/Dioxin Responsive-Chemical Activated LUciferase eXpression (DR-CALUX). For surface sediments, World Health Organization-toxicity equivalent (WHO-TEQ) values ranged from 1.8 to 92 pg g(-1) dry weight and the bioassay-TEQ (CALUX-TEQ) values (3.7-140 pg g(-1) dry weight) yielded significant correlation with them (r2 = 0.96). On the other hand, correlation between both TEQs (for WHO-TEQ, 5.5-47 and for CALUX-TEQ, 27-76 pg g(-1) dry weight) for core samples was not so good (r2 = 0.46). Comparing the vertical profiles of CALUX-TEQ and WHO-TEQ, they were different in that WHO-TEQ reached the maximum in the 1957 core section, while CALUX-TEQ reached in the 1984 core section. CALUX-TEQ values were 1-5-fold more than WHO-TEQ values in all the surface and core samples. CALUX-TEQ values were calculated for PBDE and PBDD/F concentrations, employing their CALUX toxicity equivalent factors (CALUX-TEFs). The estimated CALUX-TEQ values obtained for the brominated compounds could explain for 11% on average (range 4.7-31%) of the experimentally obtained CALUX-TEQ values in the investigated surface sediments.
This paper deals with the optimization of accelerated solvent extraction (ASE) for the analysis of the polychlorinated dibenzo-p-dioxins, benzo-p-furans (PCDD/Fs), mixed bromine/chlorine-dibenzo-p-dioxins, and benzo-p-furans (so-called MXDD/Fs) in solid samples. Previous theoretical studies have shown that these compounds exhibit similar electronic properties. It is reasonable to assume that there is little difference in the behavior, formation, and toxicity of PCDD/Fs and MXDD/Fs. Indeed, for most of the cases, the affinity is defined by these weak interactions. Only eight native standards are available for the MXDD/Fs; hence, the use of similar compounds (native and (13)C(12)-labeled), such as PCDD/Fs, is required to optimize and to validate experimental methods. This would allow conclusions to be applied for the MXDD/Fs without extended studies involving complex synthesis methods. Experimental design methodology was used to evaluate the influence of five parameters (temperature, pressure, static time, number of cycles, and solvent nature) on the polyhalogenated dibenzodioxin and -furan (PXDD/Fs) extractions in different materials. The extraction profiles and the optimal operating conditions were determined for each matrix from the modeling of extraction performance. The two following effects, the relative peak area and the co-extracted matrix (CEM), were screened in this study. The temperature of extraction was found to be the most important parameter. ASE offers automation and appears to be as efficient as Soxhlet or Soxtet; however, a major benefit was that a 4-fold decrease in extraction time was obtained. Results suggest that extraction efficiency was quantitative with extraction times as low as 15 min for all congeners at 130 degrees C with a mixed solvent (n-hexane/acetone (1/1)). Under these operating conditions, the CEM and the degradation of the highly brominated compounds were minimized. The analysis of some real life samples from municipal solid waste incinerators showed significant amounts of PXDD/Fs.
The 2,4-disubstituted and 2,3,4-trisubstituted brominated pyrroles were successfully prepared and demonstrated potent cytotoxicity against the growth of suspended murine and human tumors, i.e. leukemia and lymphomas, acute monocytic leukemia, and HeLa-S3 uterine carcinoma. The brominated compounds were more selective in inhibiting the growth of tumors derived from human solid tumors. Nevertheless, activity with some of the derivatives occurred in the human KB nasopharynx, SW-480 colon, and HCT ileum adenocarcinoma, and lung A549 carcinoma screens. In Tmolt4 T cell leukemia cells DNA synthesis was reduced over 60 min from 25 to 100 microM followed by RNA synthesis reduction. De novo purine synthesis was retarded with the regulatory enzyme PRPP-amido transferase being markedly inhibited with less effects on the activities of IMP dehydrogenase, dihydrofolate reductase,, and the nucleoside kinases. After 60 min incubations d[TTP] and d[GTP] pools were marginally reduced. In vitro ct-DNA studies suggest that the agents may affect the DNA molecule itself with increased DNA viscosity and the Tmolt4 studies suggest that DNA cross-linking of DNA strands may be present.
Environmental factors are believed to play an important role in cancer aetiology. Whether environmental pollutants act in isolation or in combination within mixtures remains unclear. Four human milk-fat extracts (from resident U.K. women) were screened for levels of organochlorinated and brominated compounds prior to being tested (1-50 mg-equiv) for micronucleus (MN)-forming activity in MCF-7 cells. Using the cytokinesis-block micronucleus assay, micronuclei (MNi) were scored in 1000 binucleate cells per treatment. Cell viability (% plating efficiency) and immunohistochemical detection of p53 induction were also measured. The effects of treatment with 1 mg-equiv of extract in combination with benzo[a]pyrene (BP) were also examined. BP-DNA adducts were detected and quantified by 32P-postlabeling analysis. Dose-related increases in MNi independent of pollutant concentrations were induced by milk-fat extracts. All four extracts elevated the percentage of p53 positive cells, although not always in a dose-related fashion. Some combinations resulted in profound low-dose-induced increases in MNi and significant elevations in the percentage of p53 positive cells, which occurred without further reduction in cell viability or mitotic rate. When one particular extract was combined with BP, a 100-fold increase in BP-DNA adducts was detected as compared with the levels induced by BP alone; an effect not induced by other extracts. This adduct-enhancing extract was fractionated into 14 fractions that were subsequently tested (1 mg-equiv of original extract) in combination with 0.01 microM BP. Fraction 1, into which nonpolar pollutants mostly eluted, enhanced MN-forming activity with BP. Surprisingly, the more polar and less likely to contain fat-soluble pollutants fractions 5 and 8 also enhanced MN-forming activity. No identifiable pollutants were present in these fractions. The results suggest that different environmental pollutants present in human tissue may influence the susceptibility of target cells to initiating events.
Capillary electrophoresis has been applied to monitor model reactions in solution-phase combinatorial chemistry. In particular, the simultaneous alkylation reactions of secondary amines with a series of benzyl halides has been investigated. Reactant and product concentrations were monitored using capillary electrophoresis in a non-aqueous buffer system. The simplified sample preparation was a key feature making this an attractive method of analysis. The results demonstrate that capillary electrophoresis is a useful tool for monitoring reactions to determine initial rates, rate constants, and extinction correlation coefficients for quantitative analysis in combinatorial chemistry, and is a broadly applicable technique for the analysis of a variety of organic and bioorganic transformations.
Twenty-six methoxylated polybrominated diphenyl ethers (MeO-PBDEs) were characterized by gas chromatography (GC) on four different GC columns with different lengths and polarities, as well as by mass spectrometry using three ionization techniques, electron ionization (EI), electron capture negative ionization (ECNI) and positive ion chemical ionization (PICI). MeO-PBDE congeners with similar retention times on a nonpolar GC column were separated when analyzed on a polar GC column. EI can be used to determine the position of the methoxy substituent (ortho, meta or para) relative to the diphenyl ether oxygen in the MeO-PBDEs. The PICI ionization technique is shown to be valuable to generate structural information of the MeO-PBDEs, i.e. the degree of bromination on both the methoxy-substituted ring and the entirely brominated phenyl ring can be obtained. This structure information can also be achieved for certain MeO-PBDEs with the methoxy group in ortho position to the diphenyl ether bond in ECNI mode. Like other brominated compounds ECNI is preferable when analyzing environmental samples for quantification of MeO-PBDEs because of the formation of bromide ions, which enables low detection limits.
Enantioselective determination of the atropisomers of 2,2',3,4',5',6-hexabromobiphenyl (PBB 149) in a purified sample from a bird egg was attempted in this work. By application of the classic method for PBB determination, i.e. gas chromatography coupled to electron capture negative ionization mass spectrometry (GC/ECNI-MS) using the bromide ions, the enantiomers interfered with another brominated compound. Subsequent measurements clarified that this interference did not occur in the mass chromatogram of the molecular ion of PBB 149. Therefore, a GC/ECNI tandem mass spectrometry (MS/MS) method was developed, based on the fragmentation of [M]-. A suitable precursor-product ion transition was found for m/z 627.5 --> 80 +/- 1.5, representing the most abundant ion trace of the molecular ion and the bromide ions. Optimization of the ion source temperature, the methane gas pressure, and the collision voltages resulted in a robust method that could solve the problem. Subsequent injections of a technical PBB product (Firemaster BP-6) resulted in the anticipated racemic proportion (enantiomer fraction (EF) = 0.50 +/- 0.02 (n = 8)). By contrast, the EF in the purified extract of a bird egg was found to be 0.42 +/- 0.02 (n = 10), indicative of a significant enantioenrichment of the second eluting atropisomer. Additional measurements were performed on a non-chiral column. These measurements allowed for the detection of 16 hexabromobiphenyls (hexa-BBs) in Firemaster BP-6. These comparisons verified that PBB 149 enantiomers did not interfere with an isomer that could falsify the enantiomer fraction in the sample. The novel method using GC/ECNI-MS/MS in the selected reaction monitoring (SRM) mode was eight times more sensitive than application of conventional GC/ECNI-MS selected ion monitoring (SIM) analysis of the molecular ion.
The main components of five technical mixtures of brominated flame retardants were identified by mass spectroscopy, H-NMR, IR spectroscopy, elementary analysis, and HRGC-MS, respectively. The mixtures have been identified as: phosphoric acid bromopropylates: Bromcal P 67-6 HP; C18-alkylated bromophenols: Bromcal P 40-3; dibromopropyl-2,4,6-tribromophenyl ether: Bromcal 73-5 PE; brominated diphenyl ethers (PBrDE): Bromcal 70-5 DE; decabromodiphenyl ether: Bromcal 82-0. Gas chromatographic retention data of the various constituents were measured on standard GC columns. The data prove the interference of some of the brominated compounds with PCBs and other halogenated pesticides in HRGC using the electron capture detector.
The Contaminant Exposure and Effects-Terrestrial Vertebrates (CEE-TV) database was developed to conduct simple searches for ecotoxicological information, examine exposure trends, and identify significant data gaps. The CEE-TV database contains 16,696 data records on free-ranging amphibians, reptiles, birds, and mammals residing in estuarine and coastal habitats of the Atlantic, Gulf, and Pacific coasts, Alaska, Hawaii, and the Great Lakes. Information in the database was derived from over 1800 source documents, representing 483 unique species (about 252,000 individuals), with sample collection dates spanning from 1884 to 2003. The majority of the records contain exposure data (generally contaminant concentrations) on a limited number (n = 209) of chlorinated and brominated compounds, cholinesterase-inhibiting pesticides, economic poisons, metals, and petroleum hydrocarbons, whereas only 9.3% of the records contain biomarker or bioindicator effects data. Temporal examination of exposure data provides evidence of declining concentrations of certain organochlorine pesticides in some avian species (e.g., ospreys, Pandion haliaetus), and an apparent increase in the detection and possibly the incidence of avian die-offs related to cholinesterase-inhibiting pesticides. To identify spatial data gaps, 11,360 database records with specific sampling locations were combined with the boundaries of coastal watersheds, and National Wildlife Refuge and National Park units. Terrestrial vertebrate ecotoxicological data were lacking in 41.9% of 464 coastal watersheds in the continental United States. Recent (1990-2003) terrestrial vertebrate contaminant exposure or effects data were available for only about half of the National Wildlife Refuge and National Park units in the geographic area encompassed by the database. When these data gaps were overlaid on watersheds exhibiting serious water quality problems and/or high vulnerability to pollution, 72 coastal watersheds, and 76 National Wildlife Refuge and 59 National Park units in the continental United States were found to lack recent terrestrial vertebrate ecotoxicology data. Delineation of data gaps in watersheds of concern can help prioritize monitoring in areas with impaired water quality and emphasize the need for comprehensive monitoring to gain a more complete understanding of coastal ecosystem health.
Eight tetrabrominated to hexabrominated diphenylethers were present at ppb levels in liver from cetaceans found stranded on the beaches of the Mediterranean Sea, Italy. The highest concentration was found in striped dolphin (sum polybrominated diphenyl ethers [PBDE] 8133 ng/g l.w.) and the lowest concentration in bottlenose dolphin (sum PBDE 66 ng/g lipid weight [l.w.]). The predominant congener in all samples was 2,2',4,4'-tetraBDE (PBDE # 47) followed by, in decreasing order, the pentaPBDE # 99 and 100 and the hexaPBDE # 154 and 153. In 12 of the 14 analyzed samples, 3 different methoxylated PBDEs (MeO-PBDE # 1, 2, and 3) were detected at semiquantitatively calculated concentration ranges of 2 to 14 ng/g l.w.; 5 to 167 ng/g l.w.; and 7 to 628 ng/g l.w., respectively. In addition, several unidentified bromine compounds were seen when screening the samples in negative-chemical ionization (NCI) mode monitoring m/z 79 and 81, which illustrates the importance of running both electron-impact ionization and NCI when analyzing environmental samples. Electron-impact ionization is more specific for monitoring the molecular ion compared with NCI, which might overestimate the concentration of certain PBDE congeners.
Tetra- and tribromophlorizin have been synthesized under mild brominating conditions. With catalytic debromination in the presence of hydrogen or tritium gas, bromine atoms in the derivatives were completely substituted by hydrogen or tritium. The product was identical to the native phlorizin and was chemically pure. Tritiated phlorizin with extremely high specific radioactivity (45 Ci/mmol) was obtained when hydrogen gas was replaced by tritium gas. While the brominated compounds showed little inhibition of sodium D-glucose co-transport by isolated renal brush-border membranes. [3H]phlorizin had the same binding affinity to the brush-border membranes as native phlorizin and a Ki value of 1.2 microM for the sodium-dependent D-glucose transport. Binding studies performed using a flow-dialysis method resulted in 150 pmol of phlorizin-binding sites per milligram of membrane protein. This radioactive phlorizin can be a useful tool for determining D-glucose-(phlorizin) binding sites at a low phlorizin concentration in membranes, in nonvesicle forms such as collapsed membrane vesicles, and in purified protein fractions.
A case-report of poisoning by ingestion of a sea hare, which is thought to be the first report of human poisoning, is presented. The clinical signs were mainly neurological with tremor, psychomotor over-activity, ataxia and muscle twitching being predominant. It is suggested that organic bromine compounds are responsible for the effects.
Sister-chromatid exchange (SCE) frequencies were determined for mouse and rabbit bone-marrow cells following incorporation of 3 different halogenated analogues of thymidine. For both species the SCE frequency was highest for chlorodeoxyuridine, lowest for iododeoxyuridine and intermediate for bromodeoxyuridine. The study demonstrates that halogenated pyrimidine analogues other than brominated compounds can be used for in vivo SCE analysis and that their effects on baseline SCE frequencies are qualitatively similar to results of previous in vitro studies.
Polybrominated diphenyl ethers (PBDEs) have become an issue of global concern. Recent studies have shown that farmed salmon can accumulate high levels of brominated compounds in their tissues and consequently there is a growing concern on its industrial and public health impacts. Little information is found in the international literature on PBDEs in the biotic compartment of the Southern Hemisphere. This paper reports the levels of several PBDE congeners found in the tissues of farmed fish from five different farming areas of Southern Chile. PBDEs were analyzed by HRGC-MS. More analytical data were obtained by analyzing these same pollutants in fish feed. Our results indicate a general trend of PBDE levels averaging 1.46 ng g(-1) wet weight (wwt). The observed congeneric distribution that resulted was quite similar to data previously reported in the open literature. PBDE profiles were found to be dominated by BDE 47. No correlation was observed between levels found in the tissues and the lipid content in such tissues, although a high correlation with the fish feed data was observed indicating that this could probably be the main PDBE entry source into fish, although other sources cannot be excluded. Even though the samples were obtained from different geographical areas, they presented fairly similar profiles, indicating a potential common source. We concluded that PBDE levels in the farmed Chilean salmon are in the low average range of values published in the open literature.
The development of QSAR models useful for the prediction of fish bioconcentration factor (BCF) for a wide range of different chemical classes is crucial for the assessment and prioritisation of potentially persistent bioaccumulative and toxic substances. In this study we present QSAR models for BCF developed on a wide range of chemical structural classes of environmental and toxicological interest (such as dyes and various chlorinated and brominated compounds). The aim is to provide valid QSAR models, statistically validated for predictivity, for the prediction of BCF in general, but also for problematical chemical classes such as highly hydrophobic chemicals. Several descriptors, calculated by different commercially available software packages, have been employed in order to take into account relevant information provided by physicochemical properties (octanol/water partition coefficient and water solubility) and molecular features (structural and quantum-chemical molecular descriptors). The best descriptor subsets for the models were selected using the Genetic Algorithm-Variable Subset Selection strategy (GA-VSS) and calculations were performed by ordinary least squares regression. Starting from a data set of 640 compounds (logK(ow) range from -2.34 to 12.66), we developed linear QSARs, firstly for a data set of 620 compounds (logK(ow) range from -2.34 to 10.35) and secondly specifically for 87 highly hydrophobic chemicals (logK(ow) range from 6.00 to 10.35). All these models have been statistically validated (both internally by cross-validation and bootstrap and externally, by "a priori" splitting of available data by Kohonen Map-ANN in training and prediction sets) and their structural chemical domain has been verified by the leverage approach.
Some of the polybrominated biphenyls (PBBs) found in the environment are axially chiral, due to hindered rotation about the interannular phenyl-phenyl bond. This applies for PBB congeners having two or more bromine substituents in ortho-position to this bond. In this study analytical methods were developed that allow determining the enantiomer fraction (EF) of axially chiral (atropisomeric) PBBs in environmental samples. A white-tailed sea eagle egg was used as test sample. The egg extract was purified and further fractionated by normal phase (NP) high performance liquid chromatography (HPLC), yielding enriched fractions of axially chiral PBB 132 and PBB 149. Gas chromatographic (GC) enantioseparation of the atropisomers of PBB 149 was achieved on one of nine tested modified cyclodextrin phases. Due to coelution with an unknown brominated compound, conventional GC/ECNI-MS, which is based on the detection of the bromide ion, did not allow for the establishment of the EF. However, by means of GC/EI-MS-MS it was possible to verify an EF of 0.42-0.43, i.e. a significant enantiomeric enrichment of the second eluting atropisomer of PBB 149 in the white-tailed sea eagle egg. This is the first proof of non-racemic proportions of a chiral PBB in environmental samples. Despite the testing of nine different chiral stationary phases, GC enantioseparation of PBB 132 or other atropisomeric PBB congeners failed. For this reason, an enantioselective reversed-phase HPLC method was developed. This method proved to be a powerful tool for the separation of PBB atropisomers. It was found that even a standard of the di-ortho substituted PBB 153 could be partially separated into atropisomers at 0 degrees C but already enantiomerized at 5 degrees C. For establishing the EF of PBB 132 in the bird egg sample a combination of enantioselective HPLC followed by non-chiral gas chromatography was employed. Using enantioselective HPLC, the atropisomers of PBB 132 were quantitatively targeted into two separate fractions at room temperature (20 degrees C). After addition of internal standards for volume adjustment the relative amounts of the atropisomers in the isolated fractions were quantified by using non-chiral GC/EI-MS analysis. A deviation from the racemic mixture of the atropisomers of PBB 132 in the egg extract could not be statistically proven.